Essential Neuroanesthesia

https://t.me/Anesthesia_Books ESSENTIALS OF NEUROANESTHESIA This page intentionally left blank ESSENTIALS OF NEUROANESTHESIA Edited by HEMANSHU PRABHAKAR Department of Neuroanaesthesiology and Critical Care All India Institute of Medical Sciences New Delhi, India Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1800, San Diego, CA 92101-4495, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2017 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. 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To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-805299-0 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals Publisher: Mara Conner Acquisition Editor: Melanie Tucker Editorial Project Manager: Kristi Anderson Production Project Manager: Edward Taylor Designer: Maria Ines Cruz Typeset by TNQ Books and Journals Dedicated to my parents—Avinash and Kanti Prabhakar The best gifts they stored for me—Kavita and Hemant, who in turn gifted me Sunil and Deepali To those who mean the world to me—Pallavi, Anavi, and Amyra To Aishwarya, Avi, and Anav This page intentionally left blank Contents II List of Contributors xvii Foreword xix Preface xxi Acknowledgments xxiii Introduction and Brief History of Neuroanesthesia W. S. Jellish xxv NEUROPHYSIOLOGY 4. Neurophysiology M. SETHURAMAN Intracranial Pressure Introduction Normal Intracranial Pressure Cerebral Compliance Importance of Intracranial Pressure Summary Cerebral Blood Flow Introduction Vascular Anatomy Summary Brain Metabolism Introduction Normal Cerebral Metabolism Summary Cerebrospinal Fluid Introduction Ventricular System Summary The Spinal Cord Introduction Anatomy Organization of the Spinal Cord Summary References I NEUROANATOMY 1. Neuroanatomy D. GUPTA Introduction Embryological Differentiation of Different Parts of Brain Anatomy of Brain Vascular Supply of the Brain The Meninges and Cerebrospinal Fluid Acknowledgment References 3 4 4 30 33 39 40 2. Neuroembryology G.P. SINGH Formation of Zygote Formation of Blastocyst Formation of Embryonic or Germ Disc Formation of Definitive Notochord Development of Nervous System References 41 41 42 44 45 50 5. Brain Protection in Neurosurgery H. EL BEHEIRY Introduction Nonpharmacological Strategies Mild Hypothermia Blood Pressure Control Induced Arterial Hypertension Normoglycemia Target Hemoglobin Concentration Pharmacological Strategies Nonanesthetic Agents Anesthetic Agents Conclusion References 3. Blood–Brain Barrier A.K. KHANNA AND E. FARAG Introduction Permeability at the Blood–Brain Barrier Cellular and Molecular Effects of Anesthetics on the Blood–Brain Barrier Clinical and Experimental Implications of Anesthetics on the Blood–Brain Barrier Conclusion References 62 62 62 62 63 68 68 68 68 74 74 74 74 79 79 79 79 83 83 83 84 84 89 89 51 51 52 54 56 56 vii 91 91 92 93 94 94 95 96 97 97 98 98 viii CONTENTS III Cerebral Microdialysis Conclusion References NEUROPHARMACOLOGY 158 159 159 9. Multimodal Monitoring 6. Neuropharmacology A. DEFRESNE AND V. BONHOMME P. GANJOO AND I. KAPOOR Anesthetic Drugs and Sedatives Intravenous Anesthetic Agents Inhalational Anesthetic Agents Neuromuscular Blocking Agents Local Anesthetic Agents Miscellaneous Drugs Future Directions in Neuropharmacology Conclusion References 104 104 111 115 116 116 116 116 118 7. Anesthetic Agents: Neurotoxics or Neuroprotectives? Introduction Temperature Oxygen Transport, Hemodynamics, and Brain Metabolism Intracranial Pressure Monitoring Electroencephalography and Depth of Anesthesia Monitoring Miscellaneous Integration of Information and DecisionHelping Systems Clinical Pearls References 161 162 162 171 173 174 175 176 176 J. FIORDA-DIAZ, N. STOICEA AND S.D. BERGESE Introduction Pharmacological Considerations Anesthesia Practice: Clinical Outcomes Anesthesia and Fragile Brain Conclusion Abbreviations References 123 124 126 127 127 128 128 IV NEUROMONITORING 8. Neuromonitoring V.J. RAMESH AND M. RADHAKRISHNAN Introduction Cerebral Blood Flow Transcranial Sonography Thermal Diffusion Flowmetry Laser Doppler Flowmetry Intra-Arterial 133Xenon CT Perfusion Xenon Enhanced CT Positron Emission Tomography Single Photon Emission Computed Tomography Magnetic Resonance Imaging Intracranial Pressure Electroencephalogram Evoked Potential Monitoring Motor Evoked Potentials Depth of Anesthesia Cerebral Oxygenation Monitoring Jugular Venous Oximetry Regional Cerebral Oximetry Brain Tissue Oxygen Monitoring 134 134 139 139 139 139 139 139 140 140 140 140 143 145 149 150 152 152 154 156 V POSITIONS IN NEUROSURGERY 10. Positioning in Neurosurgery G. SINGH Introduction Historical Background Principles of Positioning The Conduct of Positioning Surgical Approach for Craniotomies Positioning for Craniotomy Positions Used for Craniotomies Surgical Approach for Procedures of the Spine Patient Positioning For Spinal Procedures Conclusion Abbreviations References 184 184 184 185 186 187 189 195 195 203 203 204 VI PREANESTHETIC EVALUATION 11. Preanesthetic Evaluation of Neurosurgical Patients R. MARIAPPAN Introduction Preoperative Evaluation of Patient-Related Risk Factors Preoperative Evaluation of Specific Neurosurgical Conditions References 209 210 217 225 CONTENTS VII 16. Anesthesia for Epilepsy Surgery N. GUPTA NEUROSURGERY 12. Supratentorial Lesions H. BHAGAT AND S. MAHAJAN Introduction Classification Pathophysiology and Clinical Correlations Clinical Features Neuroimaging Intraoperative Considerations: The Team Approach Anesthetic Management Intraoperative Management Emergence From Anesthesia Postoperative Management Awake Craniotomy Conclusions Acknowledgment References 231 232 233 235 235 236 236 238 240 241 242 245 245 245 13. Emergence From Anesthesia Introduction Surgical Management of Epilepsy Types of Surgical Treatment Presurgical Evaluation Anesthesia for Epilepsy Surgery Effect of Anesthetic Agents in Patients With Epilepsy Antiepileptic Drug Interactions Preanesthetic Evaluation and Preparation Anesthetic Management of Preoperative Procedures Anesthesia for Intracranial Electrode Insertion Anesthetic Management of Resection of Seizure Focus Awake Craniotomy Resection of Epileptogenic Focus Under General Anesthesia Neurostimulation for Drug-Resistant Epilepsy Anesthetic Management of the Patient With Epilepsy for Incidental Surgery Abbreviations References 247 248 248 250 251 252 252 Introduction Epidemiology Classification Cause Pathophysiology Diagnosis Management Treatment Conclusions References 14. Anesthesia for Posterior Fossa Surgery 18. Aneurysmal Subarachnoid Hemorrhage C. MAHAJAN 255 255 256 256 264 271 272 272 273 15. Transesophageal Echocardiography A. LELE AND V. KRISHNAMOORTHY Introduction Basics of Transesophageal Echocardiography Summary References 300 301 302 303 304 17. Refractory Status Epilepticus K. SANDHU AND N. GUPTA Introduction Anatomy Clinical Presentation Perioperative Management of Patients for Posterior Fossa Surgery Venous Air Embolism Postoperative Management Complications Abbreviations References 285 286 286 287 288 288 290 291 292 294 295 295 M. PANEBIANCO AND A. MARSON M. ECHEVERRÍA, J. FIORDA-DIAZ, N. STOICEA AND S.D. BERGESE Introduction Neurophysiological Response During Emergence in Neurosurgical Patients Specific Perioperative Considerations Delayed Emergence and Arousal Complications Conclusion References ix 277 277 283 283 History Introduction Clinical Presentation and Diagnosis Grading of Subarachnoid Hemorrhage Initial Management Concerns in Neurocritical Care Unit Timing of Surgery Clipping or Coiling Evaluation of a Patient With Subarachnoid Hemorrhage for Anesthesia Anesthetic Management Temporary Clipping and Brain Protection Strategy Intraoperative Aneurysm Rupture Giant Aneurysms and Circulatory Arrest Endovascular Management for Aneurysm Ablation Postoperative Management of Patients Conclusion References 309 309 310 310 311 311 311 312 313 314 316 316 317 319 321 327 327 328 328 330 330 331 331 333 333 333 x CONTENTS 19. Circulatory Arrest Rapid Ventricular Pacing–Assisted Cerebral Blood Flow Arrest References D.E. TRAUL Introduction Deep Hypothermic Circulatory Arrest Anesthesia Management Complications Adenosine-Induced Circulatory Arrest Anesthesia Considerations Complications Summary References 339 339 340 341 341 342 342 342 343 20. Cerebrovascular Disease M. ABRAHAM AND M. MARDA Intracerebral Hemorrhage Incidence and Risk Factors Imaging Clinical Presentation Management of Intracerebral Hemorrhage Arteriovenous Malformations Cause and Incidence Natural History Pathophysiologic Effects and Clinical Presentation Grading of Arteriovenous Malformations Imaging Cerebral Hemodynamics in Arteriovenous Malformation Management Surgical Resection of Arteriovenous Malformation Anesthetic Considerations for Resection of Arteriovenous Malformation Postoperative Management Anesthetic Considerations for Arteriovenous Malformation Embolization Complications During Arteriovenous Malformation Embolization Pediatric Arteriovenous Malformations Pregnancy and Arteriovenous Malformations Vein of Galen Aneurysmal Malformations Dural Arteriovenous Fistula Clinical Presentation Management Carotid Endarterectomy Preoperative Evaluation Management of Carotid Artery Disease Monitoring Intraoperative Management Postoperative Complications and Outcomes Coronary Angioplasty and Stenting Moyamoya Disease Management of Moyamoya Disease References 346 346 346 346 348 352 352 353 353 353 354 354 354 355 355 356 356 357 357 358 358 360 360 360 360 362 362 362 363 363 363 363 364 364 21. Flow Arrest in Cerebrovascular Surgery M.L. JAMES, M.-A. BABI AND S.A. KHAN Deep Hypothermic Circulatory Arrest Adenosine-Assisted Cerebral Blood Flow Arrest 367 370 372 373 22. Neuroendocrine Lesions P.K. BITHAL Hypothalamic-Pituitary–Adrenal Axis Evaluation Neuroendocrine Response Related to Anesthesia and Surgery Pituitary Gland Adenomas Physiology of Pituitary Gland Endocrine Diseases Nonfunctioning Tumors Intraoperative Considerations Advantages of Endoscopic Endonasal Approach Relative Contraindications to Transsphenoidal Approach Intraoperative Issues Disorder of Water and Electrolytes References 376 377 377 379 380 382 383 384 384 384 387 389 23. Pituitary Apoplexy S.S. THOTA Clinical Features Management References 395 395 397 24. Spinal Surgery M.S. TANDON AND D. SAIGAL Introduction Spine Types of Spine Surgeries Surgical Approaches to the Spine Common Spine Disorders Imaging in Spine Lesions Positioning for Spine Surgeries Neurophysiological Intraoperative Monitoring During Spine Surgeries Preanesthetic Assessment and Optimization Anesthesia Management Postoperative Management Special Considerations Conclusion References 400 400 401 403 403 417 417 418 420 423 430 431 437 437 25. Postoperative Visual Loss K.M. KLA AND L.A. LEE Introduction Central Retinal Artery Occlusion Ischemic Optic Neuropathy Cortical Blindness Recent Advances Conclusion References 441 441 442 442 443 445 445 xi CONTENTS 26. Neuroendoscopy S. MONINGI AND D.K. KULKARNI Introduction Anesthetic Goals and Management Anesthetic Management of Specific Neuroendoscopic Procedures Advances in Neuroendoscopy Conclusion Clinical Pearls References 447 450 453 466 467 467 468 N. FÀBREGAS AND L. SALVADOR 513 514 515 516 516 517 517 F. RABAI AND R. RAMANI 471 471 472 473 475 477 477 28. Anesthesia for Functional Neurosurgery S.K. DUBE Introduction Procedure Anesthetic Consideration Anesthetic Techniques Complications Anesthesia in Patients With Deep Brain Stimulator In Situ Conclusion References 510 31. Magnetic Resonance Imaging: Anesthetic Implications 27. Pressure Inside the Neuroendoscope Introduction Indications and Procedures How Do Neurosurgeons Perform an Intraventricular Endoscopic Procedure? Anesthetic Procedure: What to Take Into Account? Perioperative Complications Conclusion References Anesthetic Management of Endovascular Coiling Anesthetic Management of Endovascular Embolization of Arteriovenous Malformation, Arteriovenous Fistula, and Vein of Galen Malformation Anesthesia for Stroke Interventions Issues Related to Radiation During Neurointervention Anesthesia for Stereotactic Radiosurgery Pregnancy and Neuroradiology Clinical Pearls References 479 479 481 484 485 486 486 486 29. Awake Craniotomy P.H. MANNINEN AND T. Y. YEOH Introduction: The Road From X-Ray to Magnetic Resonance Imaging Principles of Nuclear Magnetic Resonance and Magnetic Resonance Imaging Various Types of Signals Recorded Hazards Related to Magnetic Resonance Imaging Magnetic Resonance Imaging Safety: General Considerations Magnetic Resonance Imaging Safety: Management of Cardiac Implantable Electronic Devices and Other Implantable Devices Anesthesia for Magnetic Resonance Imaging Research Applications/Emerging Clinical Applications of Magnetic Resonance Imaging References 519 521 522 524 526 527 530 531 532 IX NEUROTRAUMA 32. Neurotrauma Introduction Patient Selection Awake Craniotomy for Tumor Surgery Awake Craniotomy for Epilepsy Conclusion References 489 490 490 496 499 499 VIII NEURORADIOLOGY 30. Anesthesia for Neuroradiology K. SRIGANESH AND B. VINAY Introduction Issues Relating to Anesthesia Care in Neuroradiology Anesthesia for Computed Tomographic Study Anesthesia for Magnetic Resonance Imaging Study Anesthesia for Diagnostic Angiography 505 506 506 506 510 D. PADMAJA, A. LUTHRA AND R. MITRA Traumatic Brain Injury Introduction Definition Epidemiology Classification of Traumatic Brain Injury Physiologic Response to Brain Injury Neuroimaging Severity of Traumatic Brain Injury Management of Traumatic Brain Injury Outcome Emerging Treatment Modalities Conclusion Spine and Spinal Cord Trauma Introduction Epidemiology Classification of Spinal Injury Pathophysiology of Spinal Cord Trauma Systemic Complications of Spinal Cord Injuries 536 536 536 536 537 543 545 549 549 559 559 560 560 560 560 561 563 565 xii CONTENTS Management of Spine and Spinal Cord Injury Emerging Treatment Modalities References 567 578 582 33. Biomarkers in Traumatic Brain Injury J. ŽUREK Introduction Conclusion References 587 590 590 X NEUROINTENSIVE CARE 34. Neurological Critical Care G.S. UMAMAHESWARA RAO AND S. BANSAL Introduction History of Neurocritical Care Design of a Neurocritical Care Unit Clinical Conditions Requiring Admission to Neurocritical Care Unit Justification for Neurological Critical Care Units Pathophysiological Issues in Neurological Critical Care Management of Patients in a Neurological Intensive Care Unit Management of General Systemic Physiology Specific Therapeutic Issues in Individual Clinical Conditions Advanced Neuromonitoring Outcomes of Neurological Intensive Care Unit End-of-Life Issues in Neurological Critical Care Clinical Pearls References 595 596 596 596 596 597 598 598 603 603 606 606 608 608 Intraoperative Management Postoperative Considerations Management of Specific Conditions Conclusion References 37. Fluid and Blood Transfusion in Pediatric Neurosurgery S. RAJAN AND S. RAO Introduction Fluid and Electrolyte Choices Type of Fluids for Perioperative Administration in Pediatric Patients Fluid Management in Pediatric Neurosurgery Osmotherapy Fluid and Electrolyte Disturbances in Pediatric Neurosurgery Blood Transfusion Blood Components Special Situations Epilepsy Surgery Scoliosis Conclusion References Introduction Implications of Surgical Stress and Anesthesia on the Elderly Neurosurgical Concerns Unique to the Elderly Conclusion References Introduction Definitions, Epidemiology, and Pathophysiology Risk Factors Prevention Screening Tools Treatment Outcome References 653 653 654 658 658 661 661 663 664 664 665 666 666 40. Pregnancy XI V. SINGHAL SPECIAL CONSIDERATIONS 36. Pediatric Neuroanesthesia G.P. RATH Overview Pediatric Neurophysiology General Principles of Pediatric Neuroanesthesia 647 647 648 649 649 649 650 650 39. Postoperative Cognitive Dysfunction 35. Antibiotics: Prophylactic and Therapeutics 616 620 623 645 645 646 38. Geriatric Neuroanesthesia S. ERB, L.A. STEINER AND C. OETLIKER 613 613 643 644 S. TRIPATHY A. BOROZDINA, L. PORCELLA AND F. BILOTTA Introduction Principles of Antimicrobial Therapy in Neurosurgery Treatment of Central Nervous System Infections in the Neurosurgical Patient Antimicrobial Prophylaxis in Neurosurgery References 631 633 633 641 641 629 629 630 Requirement of Neurosurgery During Pregnancy Physiological Alterations During Pregnancy Effect of Anesthetic Agents on Fetal Outcome Uteroplacental Drug Transfer and Neonatal Depression Timing and Method of Delivery Anesthetic Considerations During Pregnancy Induction: Rapid Sequence Versus Slow Neuroinduction Combined Cesarean Delivery and Neurosurgery 670 671 673 674 675 675 676 678 CONTENTS Intracranial Pressure and Regional Anesthesia Postoperative Management Anesthesia for Interventional Neurosurgical Procedures References 678 678 679 679 41. Cerebral Venous Thrombosis E.E. SHARPE AND J.J. PASTERNAK Definition Venous Anatomy Incidence of Cerebral Venous Thrombosis Risk Factors Pathophysiology Clinical Manifestations Diagnostic Evaluation Treatment Anesthetic Management Prognosis Conclusion References 681 681 681 683 684 685 687 688 689 690 690 690 42. Neurosurgical Anesthesia in Patients With Coexisting Cardiac Disease S. SRIVASTAVA AND A. KANNAUJIA Introduction Preoperative Evaluation Risk Stratification Perioperative Monitoring Ischemic Heart Disease Valvular Heart Disease Tumors of the Heart Congenital Heart Disease Hypertension Conclusion References 693 694 694 695 695 697 699 700 700 701 701 43. Intraoperative Cardiopulmonary Resuscitation R. GORJI AND M. SIDANI Introduction Incidence, Morbidity, and Mortality Survival From Intraoperative Cardiac Arrest Predictors Cause of Intraoperative Cardiac Arrest Cardiopulmonary Resuscitation Quality Cardiac Arrest and Cardiopulmonary Resuscitation in Neurosurgical Patients Prognosis Conclusion References 703 703 704 704 705 706 706 709 709 710 44. Coexisting Diabetes Mellitus in Neurosurgical Patients N.B. PANDA, S. SAHU AND A. SWAIN Introduction Incidence of Diabetes Mellitus Glycemic Indices 714 714 714 Modes of Glucose Measurement Pathophysiology of Diabetes Mellitus Cerebral Glucose Metabolism Hyperglycemia and the Brain Hyperglycemic Neuropathy Diabetic Dysautonomia Hypoglycemia and the Brain Evidence of Glycemic Control in Important Neurosurgical Subsets Traumatic Brain Injury Subarachnoid Hemorrhage Cerebrovascular Accidents Tumor Surgery Spine Surgery Blood Sugar Management in Perioperative Period and Neurocritical Care Intraoperative Management Anesthetic Management Postoperative Glycemic Management Blood Sugar Control in Emergency Neurosurgical Patient Blood Sugar Control in Intensive Care Setup Nutrition Conclusions Coexisting Hypertension in Neurosurgical Patients Introduction Physiology of Cerebral Circulation Pathophysiology of Arterial Hypertension Hypertension in Patients With Traumatic Brain Injury Perioperative Management Preoperative Evaluation Antihypertensive Drugs Intraoperative Management Monitoring Induction of Anesthesia Maintenance of Anesthesia Recovery From Anesthesia Postoperative Care Neurocritical Care Conclusion References xiii 714 715 715 715 716 716 716 717 717 717 717 718 718 718 719 719 719 720 720 720 720 721 721 721 722 723 724 724 725 725 725 725 726 726 726 727 727 727 45. Neuromuscular Disorders P.U. BIDKAR AND M.V.S. SATYA PRAKASH Introduction Myasthenia Gravis Myasthenic Crisis Lambert–Eaton Myasthenic Syndrome Guillain–Barré Syndrome Periodic Paralysis Myotonias Muscular Dystrophies Motor Neuron Diseases Multiple Sclerosis Parkinson’s Disease Alzheimer’s Disease Huntington’s Disease References 734 735 743 747 748 753 755 758 759 760 761 763 764 765 xiv CONTENTS 46. Neuromuscular Electrical Stimulation in Critically Ill Patients Conclusion Clinical Pearls References N. LATRONICO, N. FAGONI AND M. GOBBO Introduction Neuromuscular Electrical Stimulation: Basic Concepts and Practical Considerations Neuromuscular Electrical Stimulation in the Intensive Care Unit Contraindications and Adverse Effects Recommendations for the Use of Neuromuscular Electrical Stimulation in the Intensive Care Unit References 771 772 775 776 777 780 Crystalloid Fluids Colloid Fluids Which Fluid to Choose? Conclusions References 827 829 830 831 832 XIII PAIN MANAGEMENT K. JANGRA, V.K. GROVER AND H. BHAGAT 784 788 791 793 794 797 800 48 Anesthesia for Electroconvulsive Therapy U. GRUNDMANN Background Technique of Electroconvulsive Therapy Contraindications Preprocedure Management Anesthesia for Electroconvulsive Therapy Side Effects Special Conditions Conclusion References 50. Crystalloid and Colloid Fluids R.G. HAHN 47. Neurological Patients for Nonneurosurgeries Neurodegenerative Diseases Demyelinating Disease Neuromuscular Disease: Myasthenia Gravis Epilepsy Intracranial Tumors Traumatic Brain Injury References 824 825 825 805 805 806 806 806 809 809 810 810 XII FLUIDS AND ELECTROLYTE MANAGEMENT 51. Pain Management Z. ALI, S. SINGH, N. HASSAN AND I. NAQASH Postcraniotomy Pain Introduction Incidence Anatomical and Physiological Basis of Pain Following Craniotomy Pain-Sensitive Structures of Cranium Pathogenesis of Postcraniotomy Pain Factors Affecting Postcraniotomy Pain Classification and Assessment of Postcraniotomy Pain Preemption of Pain Treatment of Acute Pain Postcraniotomy Pain Management in the Pediatric Population Conclusion Acute Pain Management After Spinal Surgery Pathophysiology Treatment Modalities for Acute Postoperative Spinal Pain Conclusion References 836 836 836 836 838 838 838 839 840 840 843 843 843 844 844 848 849 XIV 49. Fluids and Electrolyte Management BRAIN DEATH AND ETHICAL ISSUES J.N. MONTEIRO Introduction Anatomy and Physiology Pathophysiology Definitions Choice of Fluids Hypertonic Fluids Isotonic Fluids Colloids Hypotonic Fluids Fluid Management Commonly Encountered Fluid Abnormalities 815 815 817 817 818 818 820 820 821 822 823 52. Brain Death and Ethical Issues in Neuroanesthesia Practice M. RADHAKRISHNAN AND S. LALWANI Part A: Brain Death Introduction Criteria for Diagnosing Death Need for Brain Death Diagnosis Rules Regulating Diagnosis of Brain Death Criteria for Certifying Brain Stem Death Pitfalls/Controversies 856 856 856 856 856 857 859 xv CONTENTS Conclusion Appendix I Part B: Ethical Issues in Neuroanesthesia Practice Introduction Ethical Issues in Clinical Care Ethical Issues Related to Research Ethical Issues Related to Team Work Ethical Issues Related to Training Ethical Issues Related to Innovative Neurosurgery Conclusion References 861 861 863 863 863 867 868 868 869 869 869 53. Organ Donation M.J. SOUTER Introduction Conclusion References 871 876 876 901 902 903 57. Stem Cell Therapy S. SHARMA AND R. AGGARWAL Hypothesis of Stem Cell Research Stem Cell Historical Background Types of Stem Cells Sources of Stem Cells Mesenchymal Stem Cells Stem Cells in Neurological Diseases Mode of Action of Stem Cell Therapy Ethical Issues Recent Advances References 907 907 908 908 908 909 909 910 910 911 911 58. Pharmacogenomics XV Y.N. MARTIN AND W.T. NICHOLSON EVIDENCE-BASED PRACTICE 54. Evidence-Based Practice of Neuroanesthesia I. KAPOOR AND H. PRABHAKAR Introduction Evidence-Based Practice and Neuroanesthesia Evidence and the Brain Trauma Foundation Guidelines Unresolved Issues in the Practice of Neuroanesthesia Conclusion Clinical Pearls References Brain Monitoring New Assays for Creutzfeldt–Jakob Disease References 881 883 887 887 887 889 889 55. Translational Research M. IDA AND M. KAWAGUCHI Introduction Basic Genetic Principles Basic Pharmacologic Principles Anesthesia Contribution to the History of Pharmacogenomics Pharmacogenomics: Current Application to Clinical Anesthesia Conclusion References 913 914 914 915 916 921 922 XVII STERILIZATION TECHNIQUES 59. Sterilization and Disinfection Introduction Definition In Neuroanesthesia Why Not Lead to Clinical To Be a Successful Translation Conclusion References 891 891 893 893 894 894 894 XVI RECENT ADVANCES 56. Recent Advances in Neuroanesthesiology T.L. WELCH AND J.J. PASTERNAK Introduction Endovascular Treatment of Stroke and Perioperative Stroke Indications for Deep Brain Stimulation Anesthetic Neurotoxicity Pre- and Postconditioning 897 897 898 899 900 S. MOHAPATRA Background Recommendation of Preferred Methods for Various Medical Devices Recommendation for the Cleaning and Decontamination of Environmental Surfaces Recommendation for Blood Spill on the Surface Cleaning and Disinfection of Medical Instruments Cleaning and Reprocessing of Patient Care Equipment Reprocessing of Respiratory Apparatus and Endoscopes Reprocessing of Endoscopes Specific Issues Special Precaution for Inactivation of Creutzfeldt–Jakob Disease Health Care–Associated Infections Infections in Operating Rooms and Intensive Care Units Conclusion References 930 931 931 932 933 933 935 936 938 939 940 940 943 943 xvi CONTENTS 60. Universal Precautions in the Intensive Care Unit A.YU LUBNIN AND K.A. POPUGAEV Introduction Prophylactics of Health Care–Associated Infections in the Intensive Care Unit Early Diagnosis of Pathogens and Infection Complications in the Intensive Care Unit Rational Antibiotic Therapy Systemic Approach Conclusion References 945 946 947 947 948 948 948 XVIII PALLIATIVE CARE 61. Palliative Care to Neurological and Neurosurgical Patients S. BHATNAGAR AND S.J. BHARTI Introduction References 953 961 62. Quality of Life and Health-Related Issues L. VENKATRAGHAVAN AND S. BHARADWAJ Introduction Quality of Life and Health-Related Quality of Life Utility of Health-Related Quality of Life Tools for Measuring Health-Related Quality of Life Uses of Measuring Health-Related Quality of Life Health-Related Quality of Life in Relation to Neurosurgical/Neurological Conditions Conclusion References 963 963 964 964 965 965 970 970 XIX BIOSTATISTICS 63. Biostatistics M. KALAIVANI, S. AMUDHAN, A.D. UPADHYAY AND V.K. KAMAL Introduction to Biostatistics Definition of Statistics Biostatistics and Its Applications 976 976 976 Uses of Statistical Methods in Medical Sciences Some Basic Statistical Concepts Population and Sample Scale of Measurements Constant Variables Parameter and Statistic Ratio, Proportion, and Rate Statistical Inference Estimation Hypothesis Testing Steps in Hypothesis Testing or Testing the Statistical Significance Defining the Null and Alternative Hypotheses Calculating the Test Statistic Obtaining, Using, and Interpreting the p-Value Errors in Hypothesis Testing The Possible Mistakes We Can Make Other Important Concepts That Are Essential in Statistical Inference Parametric and Nonparametric Statistical Methods Basic Principles of Statistics Probability Distributions Study Design Sample Size Data Collection and Preparing Data for Analysis Analysis and Presentation of Data Summarizing Data Comparing Groups: Continuous Data Comparing Groups: Categorical Data Comparing Groups: Time to Event Data Relation Between Two Continuous Variables Multivariable Analysis Conclusion References Index 976 976 977 977 977 977 978 978 979 979 979 979 980 980 980 980 980 981 981 981 982 982 985 987 989 989 989 991 991 992 994 995 995 997 List of Contributors M. Abraham Max Hospital Panchsheel, New Delhi, India R. Aggarwal All India Institute of Medical Sciences, New Delhi, India D. Gupta Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India N. Gupta Indraprastha Apollo Hospital, New Delhi, India Z. Ali SKIMS, Srinagar, India R.G. Hahn Södertälje Hospital, Södertälje, Sweden S. Amudhan NIMHANS, Bengaluru, India N. Hassan Government Gousia Hospital, Srinagar, India M.-A. Babi Duke University, Durham, NC, United States M. Ida Nara Medical University, Kashihara, Japan S. Bansal National Institute of Mental Health and NeuroSciences (NIMHANS), Bangalore, India M.L. James Duke University, Durham, NC, United States S.D. Bergese Ohio State University, Columbus, OH, United States H. Bhagat Postgraduate Institute of Medical Education and Research, Chandigarh, India S. Bharadwaj NIMHANS, Bangalore, India S.J. Bharti AIIMS, New Delhi, India K. Jangra Postgraduate Institute of Medical Education and Research, Chandigarh, India M. Kalaivani AIIMS, New Delhi, India V.K. Kamal AIIMS, New Delhi, India A. Kannaujia Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India S. Bhatnagar AIIMS, New Delhi, India I. Kapoor All India Institute of Medical Sciences, New Delhi, India P.U. Bidkar JIPMER, Puducherry, India M. Kawaguchi Nara Medical University, Kashihara, Japan F. Bilotta Sapienza University of Rome, Rome, Italy A.K. Khanna Cleveland Clinic Foundation, Cleveland, OH, United States P.K. Bithal AIIMS, New Delhi, India V. Bonhomme CHR Citadelle, Liege, Belgium A. Borozdina I.M. Sechenov First Moscow Medical University, Moscow, Russia A. Defresne CHR Citadelle, Liege, Belgium S.K. Dube All India Institute of Medical Sciences, New Delhi, India M. Echeverría Centro Médico Docente Paraíso, Maracaibo, Venezuela H. El Beheiry University of Toronto, Toronto, ON, Canada; Trillium Health Partners, Toronto, ON, Canada S. Erb University Hospital Basel, Basel, Switzerland N. Fàbregas Hospital Clinic Universitari, Barcelona, Spain N. Fagoni University of Brescia, Brescia, Italy E. Farag Cleveland Clinic Foundation, Cleveland, OH, United States S.A. Khan Duke-NUS Medical School, Singapore, Singapore K.M. Kla Vanderbilt University Medical Center, Nashville, TN, United States V. Krishnamoorthy University of Washington, Seattle, WA, United States D.K. Kulkarni Nizam’s Institute of Medical Sciences, Hyderabad, India S. Lalwani All India Institute of Medical Sciences, New Delhi, India N. Latronico University of Brescia, Brescia, Italy L.A. Lee Kadlec Regional Medical Center, Richland, WA, United States A. Lele University of Washington, Seattle, WA, United States J. Fiorda-Diaz Ohio State University, Columbus, OH, United States A.Yu Lubnin Neurocritical Care of Burdenko Research Neurosurgical Institute, Ministry of Health, Moscow, Russia P. Ganjoo GB Pant Hospital, New Delhi, India A. Luthra PGIMER, Chandigarh, India M. Gobbo University of Brescia, Brescia, Italy C. Mahajan AIIMS, New Delhi, India R. Gorji Upstate Medical University, Syracuse, NY, United States S. Mahajan Postgraduate Institute of Medical Education and Research, Chandigarh, India V.K. Grover Postgraduate Institute of Medical Education and Research, Chandigarh, India P.H. Manninen Toronto Western Hospital, Toronto, ON, Canada U. Grundmann Saarland University Medical Center, Homburg/Saar, Germany M. Marda Max Hospital Panchsheel, New Delhi, India R. Mariappan Christian Medical College, Vellore, India xvii xviii LIST OF CONTRIBUTORS A. Marson University of Liverpool, Liverpool, United Kingdom K. Sandhu Max Superspeciality Hospital, New Delhi, India Y.N. Martin Mayo Clinic, Rochester, MN, United States M. Sethuraman Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India R. Mitra Care Hospital, Bhubhaneswar, India S. Mohapatra AIIMS, New Delhi, India S. Moningi Nizam’s Institute of Medical Sciences, Hyderabad, India J.N. Monteiro P.D. Hinduja Hospital and Medical Research Centre, Mumbai, India M.V.S. Satya Prakash JIPMER, Puducherry, India S. Sharma All India Institute of Medical Sciences, New Delhi, India E.E. Sharpe Mayo Clinic College of Medicine, Rochester, MN, United States I. Naqash SKIMS, Srinagar, India M. Sidani Upstate Medical University, Syracuse, NY, United States W.T. Nicholson Mayo Clinic, Rochester, MN, United States V. Singhal Medanta (The Medicity), Gurgaon, India C. Oetliker University Hospital Basel, Basel, Switzerland G. Singh Christian Medical College, Vellore, India D. Padmaja Nizam’s Institute of Medical Sciences, Hyderabad, India G.P. Singh AIIMS, New Delhi, India N.B. Panda Post Graduate Institute of Medical Education and Research, Chandigarh, India M.J. Souter University of Washington, Seattle, WA, United States M. Panebianco University of Liverpool, Liverpool, United Kingdom K. Sriganesh NIMHANS, Bangalore, India J.J. Pasternak Mayo Clinic College of Medicine, Rochester, MN, United States S. Singh SKIMS, Srinagar, India S. Srivastava Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India L.A. Steiner University Hospital Basel, Basel, Switzerland K.A. Popugaev Federal Medical-Biological Agency, Ministry of Health, Moscow, Russia N. Stoicea Ohio State University, Columbus, OH, United States L. Porcella Spedali Civili University Hospital, Brescia, Italy A. Swain Tata Main Hospital, Jamshedpur, India H. Prabhakar All India Institute of Medical Sciences, New Delhi, India M.S. Tandon University of Delhi, New Delhi, India F. Rabai University of Florida, Gainesville, FL, United States M. Radhakrishnan National Institute of Mental Health and NeuroSciences, Bengaluru, India S. Rajan Cleveland Clinic, Cleveland, OH, United States R. Ramani University of Florida, Gainesville, FL, United States V.J. Ramesh National Institute of Mental Health and NeuroSciences, Bengaluru, India S. Rao Yale New Haven Hospital, New Haven, CT, United States G.P. Rath All India Institute of Medical Sciences (AIIMS), New Delhi, India S. Sahu Tata Main Hospital, Jamshedpur, India D. Saigal University of Delhi, New Delhi, India L. Salvador Consorcio Hospital General Universitario de Valencia, Valencia, Spain S.S. Thota Upstate Medical University, State University of New York, Syracuse, NY, United States D.E. Traul Cleveland Clinic, Cleveland, OH, United States S. Tripathy All India Institute of Medical Sciences Bhubaneswar, Bhubaneswar, India G.S. Umamaheswara Rao National Institute of Mental Health and NeuroSciences (NIMHANS), Bangalore, India A.D. Upadhyay AIIMS, New Delhi, India L. Venkatraghavan University of Toronto, Toronto, ON, Canada B. Vinay Gulf Medical University, Ajman, United Arab Emirates T.L. Welch Mayo Clinic College of Medicine, Rochester, MN, United States T.Y. Yeoh Toronto Western Hospital, Toronto, ON, Canada J. Žurek University Hospital Brno, Brno, Czech Republic Foreword There has been substantial flux in the field of neuroanesthesia over the past two decades. This followed what could be viewed as a relatively quiescent and narrowly focused period in neuroanesthesia. During the latter period much of the focus was on the roles of hypotension in aneurysm surgery, hyperventilation for head injury, anesthetics as cerebral protectants, and endless debates about intravenous versus inhaled anesthetics. More recently the purview of neuroanesthesia broadened substantially partly reflecting the huge expansion in the way patients with neurological diseases are managed. Patients are cared for not only in the traditional operating theater and intensive care unit but also in more complex ways inside and outside the operating theater. Examples include endovascular treatment of aneurysms, magnetic resonance imaging (MRI)- and computed tomography (CT)-guided surgery, minimally invasive approaches such as deep brain stimulation (DBS), the growth in neurological monitoring from the awake patient to complex electrophysiology, and the ever increasingly aggressive spine reconstructions. The neuroanesthesiologist of today is not only a traveler going to different parts of the hospital but needs to be an expert in patient management in all the newer scenarios. Furthermore, this expansion of the repertoire requires greater refinement in our intimate knowledge of how drugs and techniques may enhance or adversely affect the nuanced neurosurgical outcomes. Given the above changes in practice, the novice and experienced neuroanesthesia practitioners now, more than ever, need an authoritative text not just full of “book knowledge” but written by those who on a daily basis meld the academic with the practical. To his credit, Hemanshu Prabhakar has brought together an accomplished group of international experts to contribute to this excellent volume. Their writing is authoritative and up to date while being practical and easy to understand. There is no doubt that this book is a very useful contribution to the modern practice of neuroanesthesia. Adrian W. Gelb Distinguished Professor Department of Anesthesia and Perioperative Care University of California San Francisco xix This page intentionally left blank Preface Neuroanesthesia is growing fast as a superspecialty as more and more research is being conducted to improve the practice. The focus is now not restricted to the bench but has also extended to the bedside. There is a need to have a volume that provides a comprehensive view of various topics and issues related to neuroanesthesia. This book provides easy understanding of anesthesia related to neurological sciences. This book will be useful for any medical practitioner associated with neurosurgical and allied branches such as neurology and neuroradiology. This book also caters to the needs of all those anesthetists who practice neuroanesthesia but do not have a formal training in it. It will provide a quick and easy access to understand neuroanesthesia. This book will provide an insight into all possible aspects of anesthetic management of neurosurgical and neurologic patients. This book has been written mainly for the residents and students appearing for examination and anesthetists practicing neuroanesthesia. This book includes the basic sciences such as anatomy, physiology, and pharmacology related to brain and spinal cord. This book also provides an understanding of related issues such as palliative care, evidence-based practice of neuroanesthesia, sterilization techniques, and ethical issues. This book covers all topics related to neuroanesthesia and provides complete knowledge about brain and spinal cord. The book includes chapters related to allied specialties such as critical care, neurology, and neuroradiology. This book also contains a section on biostatistics, which would be extremely useful to residents and trainees who have to submit dissertation or thesis during their course. This book contains pieces of information that have been brought together, which may have otherwise been available in different books. I am grateful to all my authors across the globe, from as many as 14 different countries. The knowledge and information shared by the authors through different chapters is the representation of the global practice of neuroanesthesia and not limited to geographical boundaries. I sincerely hope this endeavor will improve our knowledge in the management of neurologically compromised patients and bring about an improved patient care. Hemanshu Prabhakar xxi This page intentionally left blank Acknowledgments I wish to acknowledge the support of the administration of the All India Institute of Medical Sciences (AIIMS), New Delhi, in allowing me to conduct this academic task. Words are not enough to express my gratitude for the constant support and encouragement from Prof. P.K. Bithal (Former Head of Neuroanesthesiology and Critical Care, AIIMS, New Delhi). I thank the faculty and staff of the department of Neuroanesthesiology and Critical Care, for their support. Special thanks are due to the production team at Elsevier. xxiii This page intentionally left blank Introduction and Brief History of Neuroanesthesia W.S. Jellish Loyola University Medical Center, Maywood, IL, United States Neuroanesthesia has evolved as a subspecialty of anesthesiology and has continued to evolve in association with further surgical advancements such as minimally invasive techniques and three-dimensional imaging using neuronavigation. Neuroradiology has also advanced with invasive neurovascular procedures, once done in the operating rooms, now performed in the neurointerventional radiology suite with the support of the anesthesiologists. Early neuroanesthesia was performed as a method to support the practice of trephination. It was uncertain whether brain surgery had been performed during this trephination or if it was part of a religious or social ritual (Fig. 1). Some were obviously related to injury, but the presence of multiple defects in the absence of other apparent injuries in both young and old suggested a possible therapeutic purpose. A popular aspect was that these openings were used to alleviate pain or allow the escape of evil spirits and humors or to drain pus or reduce inflammation. No matter what the reason for the trephination, skulls with these types of defects have been found all over the world. There are several documented examples, which point out that these skull defects were produced as part of a neurosurgical procedure. The Edwin Smith Papyrus is one of the earliest written records of surgical practice (Fig. 2). The text may well represent the first neurosurgical practitioner’s manual as it describes 48 cases that consist of 15 head injuries, 12 facial wounds and fractures, and 7 vertebral injuries. Several other written works produced around 400 BC have been linked to Hippocrates. One of the texts on injuries of the head describes trephination for skull fractures, epilepsy, blindness, and headaches. The practitioner was advised to avoid suture lines and the temporal areas because of fear of damaging the anatomy that would lead to contralateral convulsions.1 It was also noted that the inner table should be preserved to protect the dura and this bone fragment would later be extracted by suppuration. Despite the advanced neurosurgical and neuroanatomical knowledge for the times in Greece and Rome, use and understanding of neuroanesthesia did not appear to be much different from those of fellow practitioners elsewhere in the world. In the prehistoric period, anesthesia was probably done by chewing or locally applying a mixture of coca and yucca.2 Daturas had also been used with its anesthetic effect thought to be produced by its contents of scopolamine, hyoscyamine, and atropine. In early cultures, wine making was highly developed. In Egypt the soporific effects of alcohol had been well documented in hieroglyphic writings. It is considered likely that some analgesia and amnesic effects were derived from this source. Sometimes just compression of the carotid artery was used to induce unconsciousness.3 Progress in neurosurgery slowed considerable during the Middle Ages. The Roman Catholic Church became very influential in medical care and monasteries were the centers for science and knowledge. With the edict of AD 1163 entitled, “Ecclesia abhoret a sanguine,” there were restrictions placed on the use of human bodies for anatomical studies, and progress in the field of surgery was almost halted. At the beginning of the 10th century, Rhazes compiled the Liber Continens, a collection of all literature belonging to the Arab world including medicine, philosophy, religion, mathematics, and astronomy. Among the several important observations he made with this work, one was particularly remarkable. He wrote that the pressure on the brain, rather than the presence of the skull fracture itself, was more important in determining the outcome after head injury.4 It was not until later in the 10th century with the establishment of a medical school in Salerno, Italy, that this and other medical principles were brought forward to revive European medicine. Few references were made on the use of anesthesia, perhaps because pain was mentioned so many times in religious teachings and was felt to be a noble state that served God’s purpose. When anesthesia was attempted, opium, hyoscyamine, and sometimes wine were used as agents to alleviate pain.5 On occasion Cannabis indica and henbane were used, along with a sponge containing opium, marberry, water hemlock, and ivy which was boiled and then applied to the patient’s nose during the surgery.6 It was thought that wine was added to the sponge during boiling to enhance its sedative power. The physicians of Myddavi, herbalist from Wales, further advised that to improve xxv xxvi INTRODUCTION AND BRIEF HISTORY OF NEUROANESTHESIA FIGURE 1 The trephined skulls discovered in paracus, Peru (≈500 BC), and obsidian blades. The surgical holes are covered with roles of cotton dressing (A). The trepanation had been performed using obsidian blade (B). FIGURE 2 The Edwin Smith Papyrus. The terms of brain, as original term “iesh,” pointed by an arrow (and depicted below) can be seen. From James Henry Breasted. The Edwin Smith Surgical Papyrus. Chicago: University Chicago Press; 1930 (reproduced from Eric R Kandel, James H Schwartz, Thomas M Jessell, editors Principles of Neural Science. 4th ed. New York: McGraw-Hill; 2000). anesthetic efficiency, when you prepare to operate on a patient, direct them to avoid sleep as long as possible then let some of the potion be poured into the nostril of the patient who will fall asleep without fail.7 The first account of inducing anesthesia and reversing sedation was attempted by two Hindu brothers who performed a craniotomy in AD 927 to remove an unidentified tumor from the brain of the King of Dhar. They induced anesthesia with a drug called samohine and reversed the anesthetic effects by pouring an onion compounded with vinegar into the subject’s mouth.7 Numerous other concoctions both oral and topical were administered to patients for better outcomes. Some combined puppies boiled in an oil of lilies and earthworms and prepared in turpentine of Venice.2 Other mixtures used were rose oil, egg yolk, and turpentine, which were either heated in cold weather or cooled in warm weather to maintain temperature. This was done to produce optimal wound healing. The major improvements and overall advancement in anesthesia for neurosurgery occurred in the latter half of the 18th century. The discovery of carbon dioxide, hydrogen, and nitrogen along with experiments by Priestly and others using several gases including oxygen and nitrous oxide created interest in the use of these agents to support patients who were sedated or anesthetized for procedures.8 However, the reluctance of surgeons to perform cranial operations slowed the implementation of anesthesia for neurosurgery. Nevertheless, the accumulation of knowledge of functional neuroanatomy, establishment of concepts of asepsis, and the discovery of general anesthesia all moved the process of neurosurgery accompanied by anesthesia forward. William Macewen was the first neurosurgeon to excise a brain tumor under endotracheal intubation. He was the first to show the necessity of controlling the airway and ventilation during craniotomy. At the beginning of the 20th century there was a great deal of controversy as to what was the best inhalational anesthetic, chloroform, or either. Victor Horsley performed a series of experiments in animals in 1883–85 and concluded that, although ether was the safer drug, it was not to be recommended in favor of chloroform because it produced a rise in blood pressure and an INTRODUCTION AND BRIEF HISTORY OF NEUROANESTHESIA xxvii FIGURE 3 The Vernon Harcourt vaporizer arranged with a cylinder of compressed oxygen. increase in blood viscosity with a potential for hemorrhage.9 He also noted a propensity for postoperative vomiting and concluded it should not be used for neurosurgery. Also, since morphine constricted blood flow, he suggested that a combination of morphine and chloroform be used. He subsequently abandoned morphine use because of its recognized depressant effect on respiration.9 Death related to the administration of chloroform was not uncommon, and several commissions were set up to study the effects of the drug. In 1901, The British Medical Association appointed a special chloroform committee to study its use. It was known that approximately 2% chloroform vapor in air was sufficient to induce anesthesia with much less required for maintenance. Some believed that the concentration should be strictly controlled with a vaporizer, while others thought it could be administered strictly by sprinkling onto a cloth. Horsley was of the opinion that the concentration should be controlled and used a vaporizer designed by Vernon Harcourt, which delivered chloroform at a 2% maximum (Fig. 3). In patients undergoing craniotomy, Horsley felt that chloroform administration should be reduced to 0.5% once the bone flap was removed.10 Determination of concentration was particularly important in patients with raised intracranial pressure (ICP) since higher concentrations in these patients could be fatal. Horsley also contributed to neuroscience and neurosurgery by his support and defense of surgery done on animals for scientific research and to advance clinical knowledge. His work and testimony against the Anti-Vivisection Society helped to defend the use of animal models to advance neurosurgery.11 Around the same time, the use of local anesthesia began to gain prominence. Cocaine had been formally discovered in 1860 and was introduced in surgery in 1884. Procaine was first synthesized in 1905 and immediately became commonplace among surgical anesthesia. Most neurosurgeons used local anesthetics selectively. However, in 1913 deMartel popularized its use, and it became common practice for use in all craniotomies. By 1917, Harvey Cushing, considered the founder of neurosurgery, recommended the use of local anesthesia for all neurosurgical cases.7 Besides being one of the leading neurosurgeons of the early 20th century, Cushing introduced numerous new methods of anesthesiology. His first contracts in providing anesthesia were not entirely successful. He had several notable patient deaths while providing ether for procedural anesthesia. In all instances, he was told the deaths occurred due to the patient’s condition, but he remained unconvinced that adverse reactions to anesthesia were due only to the condition of the patients. At the coaxing of Dr. F. B. Harrington, Cushing and fellow student Amory Codman tried to determine who gave the best anesthetics. To make the decision objective, they documented their anesthesia in the form of “ether charts” (Fig. 4).12 Their most important parameters measured were the pulse rate, xxviii INTRODUCTION AND BRIEF HISTORY OF NEUROANESTHESIA FIGURE 4 An example of the ether charts made by Cushing. breathing, and temperature of the patients. According to Cushing, “a perfect anesthetic was supposed to be one in which the patient was sufficiently conscious to respond when left in the ward with the nurse and did not subsequently vomit.” The use of these either charts was a major step toward improvement in what had been a casual administration of a very dangerous drug. In 1900, Cushing began an extended tour of Europe, and while in Bern, he recognized the association between raised ICP and systemic arterial hypertension.13 While in Padua, Italy, at the Ospidale di St. Matteo, he learned the use of Riva-Rocci’s method of blood pressure measurement (Fig. 5). After returning to Baltimore, he adopted this method of blood pressure measurement into clinical practice. He gave a lecture in 1903 titled, “Considerations of Blood Pressure,” only to have a committee of the Harvard Medical School state that, “the skilled finger was of much greater value clinically for determination of the state of circulation than any pneumatic instrument, and the work should be put aside, as of no significance.” Even though blood pressure monitoring was not supported by thought leaders at that time, Cushing still supported the recording of blood pressure during surgery. He also attached great importance to continuous auscultation of the heart and lungs, a technique he learned from his anesthesiologist, Dr. S. Griffith Davis.14 The precordial auscultation device used a transmitter of the phonendoscope secured by adhesive strips over the precordium and was connected with a long tube to the anesthesiologist’s ear. The receiver was held in place by a device similar to a telephone operator’s headgear.15 Cushing remained skeptical about general anesthesia for neurosurgery. Mortality was still high and many of the anesthetics were performed by students. He began to experiment on work started by Halsted with block anesthesia using circumferential cocaine infiltration.16 He popularized the use of several local anesthetic techniques and coined the term “regional anesthesia.” From his first work dealing with regional anesthesia, it was noted that the purpose of administering it was to avoid side effects in patients with full stomachs and to ensure better cardiovascular stability in elderly patients. INTRODUCTION AND BRIEF HISTORY OF NEUROANESTHESIA xxix FIGURE 5 Dr. Harvey Cushing’s sketch of Riva-Rocci’s blood pressure device. Dr. Fedor Krause, the founder of German neurosurgery, was exposed to combination morphine–chloroform anesthesia but was not convinced of its worth for neurosurgery. He felt that controlled hypotension produced by higher concentrations of chloroform alone were beneficial to reduce bleeding.17 He also noted that sudden death could occur in patients with intracranial tumors who stopped breathing. He used the Roth-Drager oxygen–chloroform apparatus which allowed high concentrations of oxygen to be administered. He also noted the brain was insensitive to pain, and only very light planes of anesthesia were needed to perform these surgeries.18 He concluded a good neurosurgical outcome required a rapid aseptic technique, minimal blood loss, normothermia, and general narcosis. During the early 20th century, new delivery systems for anesthesia were being developed. The Junker bottle used a hand bellows to blow air through a vaporizer and the Ombrédanne ether inhaler could be used in the prone position (Fig. 6). Airway management became less supportive and passive and more active with endotracheal intubation and insufflation of air to maintain oxygenation without ventilation. By 1930, endotracheal anesthesia was recommended for neurosurgery. Inhalational anesthetics such as trichloroethylene with nitrous oxide were developed as a neuroanesthetic technique,18 while other physicians such as Hershenson used low concentrations of closed circuit cyclopropane and reported this method in 1942.19 Volwiler and Tabern developed thiopental in 1930 and was introduced into clinical practice 4 years later.20 Halothane was synthesized in 1956 and introduced into practice that same year.21 Though popular, its propensity to increase ICP and brain size made it a concern to anesthesiologists and neurosurgeons alike. In 1932, most fluids were given rectally along with a wide variety of anesthetic techniques including ether-based anesthesia, rectal ether in oil, ethylene, and nitrous oxide. Certain large centers began to publish their outcomes for neurosurgical procedures and many included a description of the anesthetic techniques used. The Montreal Neurologic Institute showed that of 1000 cases, 700 were performed under general anesthesia and 300 with local anesthetics.22 The major concerns were still airway management and fluid replacement. A wide variety of agents were used. However, by 1949 and the early 1950s, pentothal was the induction agent of choice for oral intubation. Throat packing and the use of a nonrebreathing valve to prevent the buildup of carbon dioxide was also common. After World War II, great advances in neuroanesthetic techniques were brought on by the development of new anesthetic agents and advanced knowledge of neurophysiology and pharmacology. Lundy in 1942 noted that in the presence of hypoventilation it was difficult to reduce ICP unless the patient was artificially ventilated.23 The effects of hypoventilation on intracranial and systemic dynamics were further elucidated by Keaty and Schmidt (Fig. 7). They also described methods to measure cerebral blood flow using inhaled N2O.24 Another group used the injection of intraarterial krypton to measure blood flow in the brain and speed of washout.25 The measurement of ICP had been discovered by Cannon in 1901 but continuous ICP measurement was not described until 1960.26 The link between CO2, O2 tension and cerebral blood flow was also developed at this time. Dr. Thomas Langfitt further xxx INTRODUCTION AND BRIEF HISTORY OF NEUROANESTHESIA FIGURE 6 (A) Ombrédanne inhaler. (B) Ombrédanne inhaler in use. 5 Arterial N2O Conc Vol% 4 3 A-V Venous 2 1 1 2 3 4 5 6 Time (minutes) 7 8 9 10 FIGURE 7 Kety–Schmidt method of arterial and venous nitrous oxide concentration for calculating cerebral blood flow. INTRODUCTION AND BRIEF HISTORY OF NEUROANESTHESIA xxxi defined intracranial dynamics based on previous work and developed the pressure volume curves along with the concept of intracranial compliance.27 Three major anesthesia groups contributed to the development of the specialty, the Glascow Group, Pennsylvania Group, and the Mayo Clinic Group. All the three centers were considered think tanks in the development of neuroanesthetic principles and techniques to help improve intracranial surgery. Most of the principles for neuroanesthesia have been developed over the last 70 years. The term, “neuroanesthesia” was coined by John Michenfelder from the Mayo Clinic.28 In the 1960s, researchers at the University of Pennsylvania studied the cerebral effects of nitrous oxide, cyclopropane, halothane, enflurane, hypotension, and hyperventilation.29–31 These studies formed many of the basics for neuroanesthesia principles today. At the same time, researchers at the University of Glascow studied anesthetic effects on intracranial dynamics. This group was one of the first to confirm that anesthetic agents did indeed exert a measurable effect on cerebral blood flow and metabolism in patients with intracranial mass lesions.32,33 It was some of these studies that were used to justify the abandonment of the use of halothane because of its vasodilating properties, especially in patients with mass lesions in the brain. At the Mayo Clinic the only emphasis of research by Michenfelder was of providing cerebral protection, especially with hypothermia during neurovascular procedures. These same three centers continued to expand their influence in neuroanesthesia, and at the University of Pennsylvania the role of the neuroanesthesiologist was expanded to the intensive care unit. In the 1980s, research continued on glucose control and again on the effects of modest hypothermia. A wide range of drugs emerged as possible cerebral protective agents. A much clearer understanding of pathways involved in cell damage was also achieved. Research on brain trauma and survival also became important because of the effects of war on traumatic brain injury. Despite much of this research, the morbidity and mortality from subarachnoid hemorrhage, stroke, trauma, and neoplastic lesions have remained largely unchanged in the past several decades. Nevertheless, neuroanesthesia practice has appreciably changed over the past few decades. Hyperventilation has long been known to reduce ICP. At the beginning of the 1990s it was widely held that this had therapeutic value for intracranial procedures. However, with the use of oximetric pulmonary artery catheters, investigators have been able to do retrograde cannulation of the jugular vein up to the bulb to examine venous Hb saturation in response to therapeutic hyperventilation in head trauma patients. In some patients, this hyperventilation resulted in increased hypoxia that has resulted in abandonment of hyperventilation unless surgical conditions dictate. However, other recent studies have demonstrated that hyperventilation, especially for supratentorial brain tumors, was associated with reduced ICP and a 45% reduction in brain bulk, once again demonstrating its worth, especially with supratentorial surgery.34 The early 1990s also demonstrated a surge of new anesthetic techniques and drugs. Both desflurane and sevoflurane were introduced and were found to have cerebral metabolic properties similar to isoflurane. However, some questions still remain regarding desflurane causing an insidious increase in ICP. There are also questions concerning the metabolism of sevoflurane and possible renal toxicity, especially with the effect of anticonvulsants on hepatic function. Since both drugs have been accepted and widely used as neuroanesthetics, these concerns do not seem to hold major importance. Remifentanil was also introduced in the 1990s and was found to be essentially identical to other opioids with respect to µ-opioid agonist-mediated events. It does have a much more rapid and predictable emergence compared to other opioid-based techniques. However, the drug produces hypertension and tachycardia with increased sympathetic activity during emergence which could be especially problematic with large tumor resections where hemodynamic stability during emergence to prevent bleeding is imperative. The administration of proper IV fluids and correct fluid replacement therapy was better developed in the 1990s. There was a widespread acceptance that glucose-containing solutions were not essential in patients undergoing neurosurgical procedures. Perioperative glycemic control is one of the important topics that have been investigated in the 1980s and 1990s. Hyperglycemia in ischemic conditions has been proven to be detrimental, and strict control of plasma glucose has been shown to produce better outcomes in critically ill patients. Many studies have demonstrated that plasma glucose levels are well maintained at close to normal ranges with nonglucose-containing solutions, while patients who received glucose had high plasma levels which fluctuated dramatically during their care. Therefore, routine use of glucose-containing solutions should be avoided during neurosurgery. The use of crystalloid solutions has also been altered by studies from the last 20 years. In the 1980s it remained a standard practice to dehydrate patients with intracranial pathology under the assumption that brain volume would be decreased. This was often performed at the expense of stable hemodynamics and cerebral perfusion pressure. However, extensive studies have demonstrated that fluid restriction for neurosurgical procedures may be detrimental. In addition, many large trials evaluating colloid versus crystalloid solutions, especially with trauma-related injury, showed that saline resuscitation may be of greater benefit than treatment with albumin. In fact, studies demonstrated xxxii INTRODUCTION AND BRIEF HISTORY OF NEUROANESTHESIA a detrimental effect of albumin treatment, especially with the relative risk of death within 24 months.35 This has led to a recommendation that colloids not be used for resuscitation in patients with brain injury. The early 1990s also provided consistent evidence that small changes in brain temperature could have a major impact on outcome from ischemic or traumatic brain injury.36 These changes did not require overt cooling or the use of extracorporeal perfusions but were well within the range of routine manipulation by anesthesiologists. The practice of the use of mild hypothermia increased, but there were other warnings about inadvertent hypothermia from other patient populations, which caused concerns. In the late 1990s, a multinational consortium of investigators was formed to examine the risks and benefits of mild hypothermia in patients undergoing aneurysm clipping and was inconclusive as to the benefit of hypothermia on survival and outcome after a neurologic event producing ischemia. Based on clinical data, mild hypothermia may still have beneficial effects in patients with good grade subarachnoid hemorrhage (SAH).37 The latest American Heart Association and American Stroke Association guidelines for the management of aneurysmal SAH recommend induced hypothermia as a reasonable option in selected cases.38 At the clinical level, no progress has been made in pharmacologic neuroprotection. Despite successful experimental studies, by far no anesthetic technique has been convincingly shown to provide profound neuroprotection in humans. Barbiturates remain the gold standard, although clinical evidence of efficacy from this class of compounds is suspected on methodologic grounds. In a post hoc analysis of IHAST (intraoperative hypothermia for aneurysm surgery trial) data administration of thiopentanil or etomidate was not found to have a demonstrable effect on postoperative neurological outcomes in patients undergoing temporary clipping.39 Use of etomidate has waned as a neuroprotective agent as a result of absence of clinical evidence of benefit in both clinical and laboratory studies. Some of the most exciting and important clinical advances in neuroanesthesia have been in the area of monitoring, both in the operating room and neurointensive care units. With the advancement of near-infrared spectroscopy (NIRS) and transcranial Doppler, the detection of cerebral ischemia, especially under general anesthesia, has improved tremendously. Multimodal intraoperative monitoring of spinal cord sensory and motor function during surgical correction of adult spinal deformity is feasible and provides useful neurophysiological data with an overall sensitivity of 100% and specificity of 84.3%.40 In the neurointensive care unit, insertion of microdialysis and multiparameter biochemical probes into traumatized human brains has confirmed findings. Cytokine production and proapoptotic markers have been detected during oxidative stress, and these markers have recovered during enhanced perfusion. Ischemic events have been associated with tissue acidosis, and spontaneous depolarizations have been observed. Use of these monitors in the operating room has occurred. What remains to be totally defined is what values constitute thresholds for interventions. These thresholds have been characterized mostly for NIRS monitoring, and much of this has revolutionized the treatment of patients with the possibility of cerebral hypoperfusion. The development of neuroanesthesia has paralleled advances in neurosurgery. As techniques and procedures have become advanced, so have the techniques and protocols to anesthetize and monitor neurologic function. The overall goal is to provide a good surgical outcome and better quality of life. Procedures will become less invasive with more functional neurosurgery requiring a cooperative patient. This makes the anesthetic management for these procedures even more complex. It is also likely that there will be greater integration of neurosurgery and neuroradiology, with greater emphasis on maintaining cerebral vascular function without the effects of inhalational anesthetics and opioids. Neurosurgery is ever evolving; the practice of anesthesiology for these procedures will also have to evolve to accommodate the demands of the surgeon and improve patient outcomes. Neuroanesthesia practice will shadow neurosurgical breakthroughs. These changes will accelerate over the next 10 years as scientific advances, and the understanding of the diseases we treat enhance the capacity of the anesthesiologist to develop techniques to provide an ideal surgical environment with rapid awakening to assess neurologic function. References 1. Hippocrates on injuries of the head [Adams F, Trans.]. London: The Genuine Works of Hippocrates, in 2 vols.; 1849. 2. Frost EAM. A history of neuroanesthesia. In: Eger E, Saidman LJ, Westhope RN, editors. The wondrous story of anesthesia. New York: Springer; 2014. p. 871–85. 3. Gunther RT. Dioscorides Pedanius. The greek herbal of dioscorides. Oxford: Oxford University Press; 1934. 4. Cooper A. Lectures on the principles and practice of surgery. London: Westley; 1829. 5. Raper HR. Man against pain: the epic of anesthesia. New York: Prentice-Hall; 1945. p. 8. 6. Robinson V. Victory over pain: a history of anesthesia. New York: Henry Schumann; 1945. p. 29. 7. Walker AE. A history of neurological surgery. New York: Hafner; 1967. 8. Priestley J. Experiments and observations on different kinds of air. London: Thomas Pearson; 1790. 9. Horsley V. On the technique of operations on the central nervous system. BMJ 1906;2:411–23. 10. Horsley V. On the technique of operations on the central nervous system. Address in Surgery. Toronto Lancet 1906;2:484. INTRODUCTION AND BRIEF HISTORY OF NEUROANESTHESIA xxxiii 11. Lyons JB. Citizen surgeon. London: Peter Downay; 1966. 12. Beecher HK. The first anesthesia records (Codman Cushing). Surg Gynecol Obstet 1940;71:689. 13. Cushing HW. Concerning a definitive regulatory mechanism of the vasomotor center which controls blood pressure during cerebral compression. Bull Johns Hopkins Hosp 1901;12:290. 14. Cushing HW. Some principles of cerebral surgery. JAMA 1909;52:184. 15. Shephard DA. Harvey Cushing and anesthesia. Can Anaesth Soc J 1965;12:431–2. 16. Halsted WS. Surgical papers. Baltimore: Johns Hopkins Press; 1924. p. 167. 17. Krause F. [Haubold H, Thorek M, Trans.]. Surgery of the brain and spinal cord based on personal experiences, vol. 1. New York: Rebman & Co.; 1912. p. 137. 18. Jackson DE. A study of analgesia and anesthesia with special reference to such substances as trichloroethylene and vinesthene together with apparatus for their administration. Anesth Analg (Curr Res) 1934;13:198. 19. Hershenson BB. Some observations on anesthesia for neurosurgery. NY State J Med 1942;42:2111. 20. Lundy JS. Intravenous anesthesia: preliminary report of the use of two new thiobarbiturates. Mayo Clin Proc 1935;10:536. 21. Johnstone M. The human cardiovascular response to flurothane anaesthesia. Br J Anesth 1956;28:392. 22. Stephen CR, Pasquet A. Anesthesia for neurosurgical procedures. Analysis of 1000 cases. Anesth Analg 1949;28:77. 23. Lundy JS. Clinical anesthesia. Philadelphia: WB Saunders; 1942. p. 3. 24. Kety SS, Schmidt CF. Determination of cerebral blood flow in man by the use of nitrous oxide in low concentrations. Am J Physiol 1945;143:53. 25. Lassen NA, Ingvar DH. The blood flow of the cerebral cortex determined by radioactive krypton. Experientia 1961;17:42. 26. Lundberg N. Continuous recording and control of ventricular fluid pressure in neurosurgical practice. Acta Psychiatr Neurol Scand 1960;36 (Suppl. 149). 27. Langfitt TW. Increased intracranial pressure. Clin Neurosurg 1969;16:438. 28. Michenfelder JD, Gronert VA, Rehder K. Neuroanesthesia. Anesthesiology 1969;30:65–100. 29. Alexander SC, Wollman H, Cohen PJ, Chase PE, Behar M. Cerebral vascular responses to PaCO2 during halothane anesthesia in man. J Appl Physiol 1964;19:561. 30. Smith AL, Wollman J. Cerebral blood flow and metabolism: Effects of anesthetic drugs and techniques. Anesthesiology 1972;36:378. 31. Pierce Jr EC, Lambertsen CJ, Deutsch S, Chase PE, Linde HW, Dripps RD, et al. Cerebral circulation and metabolism during thiopental anesthesia and hyperventilation in man. J Clin Invest 1962;41:1664. 32. Okuda Y, McDowall DG, Ali MM, Lane JR. Changes in CO2 responsiveness and in autoregulation of the cerebral circulation during and after halothane induced hypotension. J Neurol Neurosurg Psychiatry 1972;39:221. 33. Harper AM, Bell RA. The effect of metabolic acidosis and alkalosis on the blood flow through the cerebral cortex. J Neurol Neurosurg Psychiatry 1963;26:341. 34. Gelb AW, Craen RA, Rao GS, Reddy KR, Megvesi J, Mohanty B, et al. Does hyperventilation improve operating condition during supratentorial craniotomy? A multicenter randomized crossover trial. Anesth Analg 2008;106:585–94. 35. SAFE Study Investigators, Australian and New Zealand Intensive Care Society Clinical Trials Group, Australian Red Cross Blood Service, George Institute for International Health, Myburgh J, Cooper DJ, Finfer S, Bellomo R, Norton R, Bishop N, et al. Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med 2007;357:874–84. 36. Clifton GL, Valadka A, Zygun D, Coffey CS, Drever P, Fourwinds S, et al. Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomized trial. Lancet Neurol 2011;10:131–9. 37. Li LR, You C, Chaudhary B. Intraoperative mild hypothermia for postoperative neurological deficits in intracranial aneurysm patients. Cochrane Database Syst Rev 2012;2:CD008–445. 38. Connolly Jr ES, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association. Stroke 2012;43:1711–37. 39. Hindman BJ, Bayman EO, Pfisterer WK, Torner JC, Todd MM. IHAST Investigators. No association between intraoperative hypothermia of supplemental protective drug and neurologic outcomes in patients undergoing temporary clipping during cerebral aneurysm surgery: findings from the intraoperative hypothermia for aneurysm surgery trial. Anesthesiology 2010;112(1):86–101. 40. Quraishi NA, Lewis SJ, Kelleher MO, Sarjeant R, Rampersaud UR, Fehlings MG. Intraoperative multimodality monitoring in adult spinal deformity: analysis of a prospective series of one hundred two cases with independent evaluation. Spine (Phil PA 1976) 2009;34:1504–12. This page intentionally left blank S E C T I O N I NEUROANATOMY This page intentionally left blank C H A P T E R 1 Neuroanatomy D. Gupta Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India O U T L I N E Introduction 3 Embryological Differentiation of Different Parts of Brain 4 Anatomy of Brain Cerebrum Frontal Lobe Temporal Lobes Parietal Lobe Functional Areas (of Cerebral Cortex) Premotor Area Sensory Areas Visual Area Acoustic (Auditory) Area Association Areas Diencephalon The Thalamus Hypothalamus Epithalamus Habenular Nucleus Afferent Fibers Efferent Fibers Nucleus Subthalamicus Zona Incerta Basal Ganglia 4 4 6 6 7 8 10 10 11 11 11 11 11 13 15 15 16 16 16 16 16 Internal Capsule White Matter Corpus Callosum Ventricular System Lateral Ventricles Third Ventricle Fourth Ventricle Limbic System Midbrain (Mesencephalon) Pons Medulla Reticular Formation Cerebellum 17 18 19 19 20 21 22 22 23 25 26 29 29 Vascular Supply of the Brain Arterial System Cerebral Venous System 30 30 32 The Meninges and Cerebrospinal Fluid The Meninges Dura Mater The Spinal Cord Ascending Tracts of Spinal Cord (Sensory Tracts) 33 33 33 34 36 Acknowledgment 39 References 40 INTRODUCTION Why should a well-established neuroanesthetist study clinical neuroanatomy? This question, albeit a vexing one, is very pertinent in the present day scenario. The answer is evident. A tower of knowledge built on broad and diverse information helps one to prepare for all the eventualities that one may encounter. Anatomy is the basis of every procedure that we perform. An anesthetist who embarks on a new journey into the anatomical Essentials of Neuroanesthesia http://dx.doi.org/10.1016/B978-0-12-805299-0.00001-4 3 © 2017 Elsevier Inc. All rights reserved. 4 1. NEUROANATOMY basis of his or her clinical practice has adapted well to a vista that emphasizes fundamental sciences as the basis of all medical education. It helps the person improve his or her procedural skills. Finally, it helps him or her to be better equipped to deal with a changing and unpredictable world where knowledge empowers and also acts as a haven of safety. About 100 billion neurons and 10–50 trillion neuroglias make up the brain, which has a mass of about 1300– 1500 g in adult. On average each neuron forms 1000 synapses with other neurons1. The total number of synapses, about 1000 trillion, is larger than the number of stars in the galaxy. The central nervous system (CNS) included the brain and the spinal cord and is composed of (1) cerebral hemisphere, (2) diencephalon, (3) basal ganglion, (4) midbrain, (5) pons, (6) medulla, (7) cerebellum, and (8) spinal cord. This chapter will provide information of these parts individually, that is integrated, informative, and relevant to educational need of the neuroanesthesiologists. EMBRYOLOGICAL DIFFERENTIATION OF DIFFERENT PARTS OF BRAIN Knowledge of the embryological development of the brain is necessary to understand the terminology used for the principal part of the adult brain. The development of the brain is dealt with details in the following chapter. ANATOMY OF BRAIN Cerebrum The cerebrum consists of two cerebral hemispheres that are partially connected with each other by corpus callosum. Each hemisphere contains a cavity called the lateral ventricle. The cerebrum is arbitrarily divided into five lobes: frontal, parietal, temporal, occipital, and insula.2 On the lateral surface three sulci (central, lateral or Sylvian, and parietooccipital sulci) and two imaginary lines divide the cerebrum into four lobes (Fig. 1.1). The first imaginary line (lateral parietotemporal line) is drawn from parietooccipital sulcus to preoccipital notch and second (temporooccipital line) backward continuation of posterior ramus of lateral sulcus before it turns upward to meet first line. The central sulcus and posterior ramus of Sylvian fissure (SF) separate frontal lobe from parietal lobe and temporal lobe. Posteriorly parietooccipital sulcus and lateral parietotemporal line separate occipital lobe from parietal lobe and temporal lobe. Temporal and parietal lobes are separate by posterior ramus of SF and temporo-occipital line (Fig. 1.1). The cerebral cortex is the outermost sheet of neural tissue of the cerebrum whereas white matter lies in the center. Cerebral cortex is folded into sulci and gyri, which actually increases the surface area of cortex. Sulci include the central lateral and parietooccipital. The central sulcus begins by cutting the superomedial border of the hemisphere a little behind the midpoint between the frontal and parietal lobe. It runs on the superolateral surface obliquely downward and forward for about 8–10 cm and ends a slight above the posterior ramus of lateral sulcus. It separates precentral gyrus (motor area) from postcentral gyrus (sensory area) (Figs. 1.2 and 1.3). It was originally called the fissure of Rolando or the Rolandic fissure. FIGURE 1.1 Schematic diagram of lateral aspect of left cerebral hemisphere. Line 1. Lateral parietotemporal line; Line 2. Temporooccipital line. I. NEUROANATOMY ANATOMY OF BRAIN 5 FIGURE 1.2 Brain anatomy. Superior view. 1. Longitudinal fissure of cerebrum. 2. Frontal pole. 3. Superior margin of cerebrum. 4. Superior frontal sulcus. 5. Inferior frontal sulcus. 6. Precentral sulcus. 7. Central sulcus. 8. Postcentral sulcus. 9. Intraparietal sulcus. 10. Parietooccipital sulcus. 11. Transverse occipital sulcus. 12. Occipital pole. 13. Superior parietal lobule. 14. Inferior parietal lobule. 15. Paracentral lobule. 16. Postcentral gyrus. 17. Precentral gyrus. 18. Inferior frontal gyrus. 19. Middle frontal gyrus. 20. Superior frontal gyrus. FIGURE 1.3 Brain anatomy. Lateral view of right hemisphere. 1. Central sulcus. 2. Precentral sulcus. 3. Precentral gyrus. 4. Superior frontal gyrus. 5. Superior frontal sulci. 6. Middle frontal gyrus. 7. Middle frontal sulcus. 8. Frontal pole. 9. Orbital gyri. 10. Olfactory bulb. 11. Olfactory tract. 12. Anterior ramus of lateral sulcus (Sylvian fissure (SF)). 13. Frontal operculum. 14. Ascending ramus lateral sulcus (SF). 15. Frontoparietal operculum. 16. Posterior ramus lateral sulcus (SF). 17. Superior temporal gyrus. 18. Middle temporal gyrus. 19. Superior temporal sulcus. 20. Inferior temporal sulcus. 21. Inferior temporal gyrus. 22. Pons. 23. Pyramid (medulla oblongata). 24. Olive. 25. Flocculus. 26. Cerebellar hemisphere. 27. Preoccipital notch. 28. Occipital pole. 29. Postcentral gyrus. 30. Supramarginal gyrus. 31. Angular gyrus. 32. Transverse occipital sulcus. 33. Inferior parietal lobule. 34. Intraparietal sulcus. 35. Superior parietal lobule. 36. Postcentral sulcus. I. NEUROANATOMY 6 1. NEUROANATOMY The lateral sulcus or Sylvian fissure (SF) is one of the earliest-developing sulci of the human brain. It first appears around the 14th gestational week.3 It is the deepest and most prominent of the cortical sulci. The lateral sulcus (SF) separates frontal and parietal lobes from temporal lobe. It begins on the superomedial margin. The SF starts on basal and extends to the lateral surface of the brain. It has both a superficial part and a deep part. Superficial part has a stem and three rami (Figs. 1.2 and 1.3). The anterior portion of the deep part (Sylvian cistern) is called the sphenoidal compartment and the posterior part is called the operculoinsular compartment. SF is an important corridor in neurosurgery as it connects the surface of anterior part of brain to its depth with all the neural and vascular components along the way. The structures within the reach through the Transylvian approach include middle cerebral artery; optic nerves; internal carotid artery; and its branched lamina terminalis, insula, basal ganglia, and interpeduncular fossa. Parietooccipital sulcus begins on the medial surface of hemisphere nearly 5 cm in front of the occipital pole (Fig. 1.4). The upper end of the sulcus reaches the superomedial border to meet the calcarine sulcus, and a small part of it is seen on the superolateral surface. Frontal Lobe The frontal lobe is an area in the brain of mammals, located at the front of each cerebral hemisphere and positioned anterior to (in front of) the parietal lobe and superior and anterior to the temporal lobes. A prefrontal sulcus runs downward and forward parallel to the central sulcus. The area between it and central sulcus is the precentral gyrus. Two sulcus run horizontally anterior to precentral gyrus, i.e., superior and inferior frontal sulcus and divide the region into superior, middle, and inferior frontal gyri (Fig. 1.3). The frontal lobe contains most of the dopamine-sensitive neurons in the cerebral cortex associated with reward, attention, short-term memory tasks, planning, and motivation. Temporal Lobes Temporal lobes are bounded by SF superiorly and temporo-occipital and lateral parietotemporal line posteriorly (Fig. 1.3). The temporal lobe has two sulci, superior and inferior, that run parallel to the posterior ramus of the lateral sulcus and divide superiolateral surface into superior, middle, and inferior temporal gyri (Fig. 1.3). The temporal lobes are involved in the retention of visual memories, processing sensory input, comprehending language, storing new memories, emotion, and deriving meaning.4 FIGURE 1.4 Brain surface anatomy, view of medial surface of right hemisphere. 1. Frontal pole of frontal lobe. 2. Medial frontal gyrus. 3. Cingulate sulcus. 4. Sulcus of corpus callosum. 5. Cingulate gyrus. 6. Paracentral lobule. 7. Precuneus. 8. Subparietal sulcus. 9. Parietooccipital sulcus. 10. Cuneus. 11. Calcarine fissure. 12. Occipital pole of occipital lobe. 13–16. Corpus callosum (cut surface). (Parts of Corpus callosum 13. Splenium. 14. Trunk. 15. Genu. 16. Rostrum.). 17. Lamina terminalis. 18. Anterior commissure. 19. Septum pellucidum. 20. Fornix. 21. Tela choroidea of the third ventricle. 22. Choroid plexus of the third ventricle. 23. Transverse cerebral fissure. 24. Thalamus. 25. Interthalamic adhesion. 26. Interventricle foramen of Monro. 27. Hypothalamus. 28. Suprapineal recess and pineal body. 29. Vermis of cerebellum. 30. Cerebral hemisphere. 31. Choroid plexus of the fourth ventricle. 32. Medulla oblongata. 33. Pons. 34. Fourth ventricle. 35. Tectal lamina and mesencephalic aqueduct of Sylvius. 36. Mammillary body. 37. Oculomotor nerve. 38. Infundibular recess. 39. Temporal lobe of lateral occipitotemporal gyrus. 40. Rhinal fissure. 41. Hypophysis with adenohypophysis (anterior lobe) and neurohypophysis (posterior lobe) of pituitary gland. 42. Optic chiasma. 43. Optic nerve. 44. Olfactory bulb and tract. I. NEUROANATOMY ANATOMY OF BRAIN 7 Parietal Lobe The parietal lobe is positioned superior to the occipital lobe and posterior to the frontal lobe. The parietal lobe is bounded anteriorly by central sulcus, inferiorly by SF and temporo-occipital line, medially by interhemispheric fissure, and posteriorly by parietotemporal line. The two main sulci are postcentral sulcus, which run downward and forward parallel to central sulcus, and intraparietal sulci, which are directed posteriorly and inferiorly toward occipital pole. Thus divide the parietal lobe into postcentral gyrus, superior parietal lobule, and inferior parietal lobule (Fig. 1.3). The upturn posterior end of the posterior ramus of lateral sulcus or SF extends into inferior parietal lobule, also superior and inferior temporal sulci turn upward to enter into this lobule and constitute supramarginal, angular gyri, and arcus temporo-occipitalis (Fig. 1.3). The parietal lobe integrates sensory information from different modalities, particularly determining spatial sense and navigation. For example, it comprises somatosensory cortex and the dorsal stream of the visual system. This enables regions of the parietal cortex to map objects perceived visually into body coordinate positions. Several portions of the parietal lobe are important in language processing. Just posterior to the central sulcus lies the postcentral gyrus. This area of the cortex is responsible for somatosensation.5 The occipital lobule occupies space behind the lateral parietotemporal line. It has a number of short lobules divided by short sulci. A horizontal sulci, lateral to occipital sulcus divides the lobe into superior and inferior occipital gyri (Fig. 1.3). A vertical strip anterior to curved lunate sulcus is the gyrus descendens. The transverse occipital sulcus is located in the uppermost part of the occipital lobe. A strip superiolateral to this sulcus is arcus parietooccipitalis. The occipital lobe is the visual processing center of the brain containing most of the anatomical region of the visual cortex.6 Insula is a portion of the cerebral cortex folded deep within the lateral sulcus. This area grows less than its surrounding areas during development and thus lies deep and not seen from surface view (Fig. 1.5). The surrounding cortical areas are called opercula such as frontal opercula, frontoparietal opercula, and temporal opercula. The insula are believed to be involved in consciousness and play a role in diverse functions usually associated to emotion or the regulation of the body’s homeostasis. These functions include perception, self-awareness, cognitive functioning, and interpersonal experience. Two hemispheres are attached with each other by corpus callosum. On the medial surface above the corpus callosum there are many sulci and gyri (Fig. 1.4). The most prominent sulcus is the cingulate sulcus, which follows the curve course parallel of corpus callosum. The area between the cingulate sulcus and corpus callosum is the gyrus cinguli. Above the cingulate sulcus, large anterior part is medial frontal gyrus and posteriorly paracentral lobule (Fig. 1.4). Behind the paracentral lobule, two major sulci, parietooccipital sulcus and calcarine sulcus, cut the area into a triangular area called the cuneus. Between parietooccipital sulcus and paracentral lobule, a quadrangular area is called precuneus, which is anteriorly separated from gyrus cinguli by suprasplenial sulcus. FIGURE 1.5 Coronal section through the brain. 1. Longitudinal fissure of the cerebrum. 2. Cingulate sulcus. 3. Cingulate gyrus. 4. Corpus callosum. 5. Sulcus of corpus callosum. 6. Caudate nucleus. 7. Claustrum. 8. Putamen. 9. Lateral sulcus (Sylvian fissure). 10. Globus pallidus. 11. Thalamus. 12. Subthalamic nucleus. 13. Mammillary body. 14. Amygdala. 15. Optic tract. 16. Third ventricle and choroid plexus. 17. Body of fornix. 18. Lateral ventricle and choroid plexus. 19. Cortex of insula. 6, 8, and 10. Corpus striatum. 8 and 10. Lentiform nucleus. I. NEUROANATOMY 8 1. NEUROANATOMY The majority of the space of cerebral hemisphere deep to the cortex is full of the white matter. There are some important structures that are embedded within the white matter. On coronal section the corpus callosum is seen as a strip connecting both the hemispheres (Fig. 1.5). Third ventricle is situated in midline just below corpus callosum. Thalamus and hypothalamus, which are derived from diencephalon, lie adjacent to lateral wall of the third ventricle. Caudate nucleus is situated above and lateral to thalamus. Another gray matter mass lentiform nucleus lies more lateral and just deep to insula. There is a strip of gray matter between insula and lentiform nucleus called claustrum (Fig. 1.5). The caudate nucleus, lentiform nucleus, claustrum along with some other gray matter nucleus are (derived from telencephalon) collectively mentioned as basal nuclei or basal ganglia. There is a white matter, an internal capsule that lies between thalamus and lentiform nucleus (Fig. 1.5). The white matter that radiates from the upper part of internal capsule to the cortex is called corona radiate. Functional Areas (of Cerebral Cortex) Korbinian Brodmann was a German neurologist who studied the brain in the early part of the 20th century.7 Brodmann originally defined and numbered (from 1 to 52) different areas of cerebral cortex based on cytoarchitecture or how the cells were functionally organized (Box 1.1). Brodmann areas have been discussed, debated, refined, and renamed exhaustively for nearly a century and remain the most widely used and frequently cited cytoarchitectural organization of the human cortex.8 On the basis of function, regions of the cerebral cortex are divided into three functional categories of areas (Fig. 1.6). (1) Primary sensory areas, which receive signals from the sensory nerves and tracts by way of relay nuclei in the thalamus. Primary sensory areas include the somatosensory cortex in the parietal lobe, visual area of the occipital lobe, and the auditory area in parts of the temporal lobe and insular cortex. (2) Primary BOX 1.1 I M P O R TA N T B R O D M A N N A R E A S Frontal lobe contains areas that Brodmann identified as involved in cognitive functioning and in speech and language (Fig. 1.8). t Area 4 corresponds to the precentral gyrus or primary motor area. t Area 6 is the premotor or supplemental motor area. t Area 8 is anterior of the premotor cortex. It facilitates eye movements and is involved in visual reflexes as well as pupil dilation and constriction. t Areas 9, 10, and 11 are anterior to area 8. They are involved in cognitive processes such as reasoning and judgment which may be collectively called biological intelligence. t Area 44 is Broca’s area. Parietal lobe plays a role in somatosensory processes (Fig. 1.8). t Areas 3, 2, and 1 are located on the primary sensory strip, with area 3 being superior to the other two. These are somastosthetic areas, meaning that they are the primary sensory areas for touch and kinesthesia. t Areas 5, 7, and 40 are found posterior to the primary sensory strip and correspond to the presensory to sensory association areas. t Area 39 is the angular gyrus. Temporal lobe: Areas that are involved in the processing of auditory information and semantics as well as the appreciation of smell (Fig. 1.8). t Area 41 is the primary auditory area. t Area 42 is immediately inferior to area 41 and also involved in the detection and recognition of speech. The processing done in this area of the cortex provides a more detailed analysis than that done in area 41. t Areas 21 and 22 are the auditory association areas. Both areas are divided into two parts; one half of each area lies on either side of area 42. t Area 37 is found on the posterior–inferior part of the temporal lobe. Occipital lobe contains areas that process visual stimuli (Fig. 1.8). t Area 17 is the primary visual area. t Areas 18 and 19 are the secondary visual areas. I. NEUROANATOMY ANATOMY OF BRAIN 9 motor cortex, which sends axons down to motor neurons in the brain stem and spinal cord and finally innervate voluntary skeletal muscles; (3) remaining parts of the cortex, which are called the association areas. These areas receive input from the sensory areas and lower parts of the brain which integrate sensory information with emotional states, memories, learning, and rational thought processes that we call perception, thought, and decision-making. Motor areas—The motor area is classically located in precentral gyrus on the superiolateral surface of the hemisphere and in anterior part of paracentral lobule. It is shaped like a pair of headphones stretching from ear to ear (Fig. 1.6). Specific area within the motor cortex controls voluntary muscle activity on the opposite part of body. The body is represented on the motor strip in an upside–down fashion (Fig. 1.7). The lower parts of the body, such as the FIGURE 1.6 Traditional concept of functional areas on the superolateral aspect of the cerebral hemisphere (left sided). FIGURE 1.7 The motor homunculus in primary motor cortex. Coronal section anterior view of the left hemisphere. I. NEUROANATOMY 10 1. NEUROANATOMY feet and the legs, receive motor movement commands from the superior part of the precentral gyrus (motor strip). Parts of the face, on the other hand are innervated by the inferior part of the motor strip. The motor strip extends down some distance into the longitudinal cerebral fissure. The portion inside this fissure is its medial aspect. The part on the lateral surface of the hemisphere is called its lateral aspect. The medial cortex controls the movements of the body from the hips on down while the lateral aspect sends commands to the upper body including the larynx, face, hands, shoulders, and trunk (Fig. 1.7). The medial and lateral aspects of the motor strip have different blood supplies. Blood comes to the medial area from the anterior cerebral artery while the lateral cortex is supplied by the middle cerebral artery. Premotor Area There is supplementary motor area on and above the superior part of cingulate sulcus on the medial aspect hemisphere that reaches to the premotor cortex (Brodmann areas 6 and 8) on the lateral surface of brain. The cortical area in inferior frontal gyrus corresponds to motor speech area or speech area of Broca (Brodmann areas 44 and 45) and frontal eye area (Fig. 1.8). Lesion into the motor speech area of Broca results in aphasia even the muscles concerned are intact. In 95% of right-handers do have left-hemisphere dominance for language functions, only around 19% of left-handers have right-hemisphere language dominance, with another 20% or so processing language functions in both hemispheres.9 Sensory Areas From the specific nuclei of the thalamus, neurons are projected into two somatosensory areas of the cortex: somatosensory area I in postcentral gyrus and somatosensory area II in the wall of the SF (Fig. 1.6). The arrangement of the thalamic fibers in somatosensory area I is such that the part of the body is represented in order along the postcentral gyrus, with leg on the top and head at the foot of the gyrus. The area of the cortex that receives sensation from a part FIGURE 1.8 Brodmann areas in the neocortex. A number of important Brodmann areas have been marked out in the figure. I. NEUROANATOMY ANATOMY OF BRAIN 11 of the body is not proportional to the size of that part rather the complexity of sensation received from it, as cortical areas for the sensation from the trunk and back are small whereas, hand and part of mouth concerned in speech are very large. Visual Area The primary visual receiving area (visual cortex, Brodmann area 17) is located primarily in occipital lobe on the sides of the calcarine fissure (Fig. 1.6). This area also extends into the cuneus and into the lingual gyrus. The visual area is continuous, above and below, with area 18 and beyond this 19. These areas often described as psychovisual areas are responsible mainly for interpretation of visual impulses reaching visual area (Fig. 1.6). Acoustic (Auditory) Area The primary auditory cortex (Brodmann area 41) is in the superior portion of temporal lobe. It is located in the part of temporal gyrus which forms the inferior wall of the posterior ramus of the lateral sulcus (Fig. 1.6). The auditory associated areas adjacent to the primary auditory receiving areas are widespread and extend into insula. Association Areas Specific areas of the cerebral cortex integrate sensory information with emotional states, memories, learning, and rational thought processes. Primary motor cortex (precentral gyrus of frontal lobe) is located just anterior to the central sulcus in the frontal lobe of the cerebral cortex, of the gray matter motor neurons, which initiates impulses routed through the medulla and spinal cord. It represents the conscious voluntary commands to the prime movers of skeletal muscle groups for specific actions; it is highly organized with specific regions representing each part of the body. Primary sensory cortex (postcentral gyrus of parietal lobe) is located just posterior to the central sulcus in the parietal lobe of the cerebral cortex, of the somatic sensory neurons and receives impulses from the thalamus, medulla, and spinal cord. It responds with the first conscious perceptions/awareness of cutaneous sensations arriving from stimulated receptors in the skin and subcutaneous tissues; it is highly organized with specific regions representing each part of the body. Frontal eye field—a specific motor area within the frontal cortex which controls the voluntary scanning movements of the eyes, such as tracking a bird in flight, by sending impulses to the extrinsic muscles of the eyes. Diencephalon The diencephalon is midline structure and embedded in the cerebrum. The third ventricle is considered as the cavity of diencephalon. Diencephalon is bounded anteriorly from the plane through the optic chiasm and anterior commissure; caudally from plane through the posterior commissure and the caudal edge of the mammillary bodies; medially from wall of the third ventricle, stria medullaris thalami, and mass intermedia; laterally from the internal capsule, tail of caudate nucleus, and stria terminalis; and dorsally by the fornix and floor of the lateral ventricles (Figs. 1.4 and 1.5). Diencephalon consists of the following parts: 1. 2. 3. 4. Thalamus Hypothalamus Subthalamus Epithalamus The Thalamus It is a large, egg-shaped (ovoid), 4 × 1.5-cm nuclear mass. It makes up about 80% of the mass of the diencephalon. It consists mainly of gray matter, but its superior and lateral surfaces are covered by thin layers of white matter termed the stratum zonale and the external medullary lamina, respectively. The gray matter is incompletely divided into anterior, medial, and ventrolateral nuclei by a Y-shaped lamina of white matter called the internal medullary lamina. It has two ends (anterior and posterior) and four surfaces (superior, inferior, medial, and lateral) (Fig. 1.9). I. NEUROANATOMY 12 1. NEUROANATOMY FIGURE 1.9 Schematic representation of thalamic nuclei and their projections. CM, centromedial; LD, lateral dorsal; LGB, lateral geniculate body; LP, lateral posterior; MD, mediodorsal; MGB, medial geniculate body; VA, ventroanterior; VL, ventrolateral; VPI, ventroposterior inferior; VPL, ventroposterior lateral; VPM, ventroposterior medial; VPMpc, ventroposterior medial part mammillothalamic. It extends anteriorly to the interventricular foramen; superiorly to the transverse cerebral fissure (between corpus callosum and fornix); inferiorly to the hypothalamic sulcus; and posteriorly it overlaps the midbrain (pulvinar). Anterior end of thalamus is smaller than posterior end and lies behind interventricular foramen which connects the lateral ventricle and the third ventricle. Posterior end is large and expanded, called as pulvinar (Fig. 1.9). It is projected backwards and laterally over superior colliculus of midbrain. There are two small swellings on inferior surface of pulvinar called the medial and lateral geniculate bodies. Superior surface is not clearly demarcated from lateral surface. Stria medullaris thalami marks the junction between the superior and medial surfaces. It is separated from the ventricular surface of caudate nucleus by the stria terminalis and thalamostriate vein. It is divided into two areas by an impression produced by the lateral margin of fornix. The lateral area is covered by ependyma and forms part of the floor of the body of lateral ventricle (Fig. 1.5). The median area is covered by the tela choroidea I. NEUROANATOMY ANATOMY OF BRAIN 13 of the third ventricle (double fold of pia matter) (Fig. 1.4). Inferior surface lies upon the subthalamic tegmental region [i.e., hypothalamus, subthalamus, and midbrain (from before backwards)]. Medial surface forms part of lateral wall of the third ventricle separated from corresponding surface of opposite thalamus by a narrow interval. The two thalami are connected by a short band called the interthalamic adhesion (Fig. 1.4). Lateral surface separated from lentiform nucleus by posterior limb of internal capsule. Many fibers stream out of this surface and enter internal capsule en route for cerebral cortex and form the thalamic radiation. Functions of Thalamus 1. Relay station a. Most somatic sensory pathways except olfaction b. Few motor pathways (e.g., cerebellar) 2. Integrating center For impulses from many sources (e.g., somatic sensory; visual; visceral; some motor, e.g., cerebellar, corpus striatum) 3. Maintenance and regulation of state of: Consciousness, alertness, attention (through influence upon cerebral cortex) 4. Emotional connotations (Which accompany most sensory experiences?) 5. Crude sensations (For example, pain which may reach consciousness at this level even when all connections between thalamus and cortex are destroyed.) Thalamus is not simply a relay station where information is passed onto the neocortex but thalamus acts as receptionist for information to the cerebral cortex, preventing or enhancing the passage of specific information depending on behavioral state of the individual. Though it has more than 50 nuclei, however, classically they are divided into four groups depending on their position in relation to the internal medullar lamina. Anterior group is connected from mammillary bodies and subiculum of the hippocampal formation and closely associated with the limbic system (Fig. 1.9). This connection is concerned with emotional tone and mechanism of recent memory. Stimulation or ablation of mammillothalamic tract causes alteration in autonomic control and loss of recent memory. The medial group receives input from basal ganglion, amygdala, and midbrain and its major output is to the frontal cortex (Fig. 1.9). It provides mechanisms for the integration of certain somatovisceral impulses projecting to prefrontal cortex. It mediates impulses of an affective nature which contributes to the formation of personality. Stimulation, disease, or surgical ablation of medial nuclei results in changes in (1) motivational drive, (2) ability to solve problems, (3) consciousness level, (4) general personality, (5) subjective feeling status (affective tone), (6) pain perception (indifference to pain), (7) emotional content. The ventral anterior and anterior lateral nuclei transmit information basal ganglia and cerebellum to the motor cortex (Fig. 1.9). These make important contribution to initiation of movements, control of muscle tone, regulation of cortical reflexes. The posterior group includes medial and lateral geniculate nucleus, lateral posterior nuclei, and pulvinar (Fig. 1.9). Lateral geniculate nucleus receives information from the retina and conveys to the primary visual cortex; medial geniculate nucleus is a component of the auditory system. The nonspecific projecting nuclei are located either in the midline or within the internal medullary lamina. The largest intralaminar nuclei, centromedial nucleus, is projected to amygdala, hippocampus, and basal ganglia. Hypothalamus Hypothalamus is a part of the diencephalon which forms lateral wall and floor of the third ventricle. Laterally it is in contact with internal capsule and ventral thalamus; posteriorly it merges with ventral thalamus and tegmentum of the midbrain; anteriorly it extends up to lamina terminalis; and inferiorly it is related with structures in the floor of the third ventricle (tuber cinereum, infundibulum, and mammillary bodies). Hypothalamus receives afferent from retina, frontal lobe, hippocampus, corpus striatum, and reticular formation of brain stem. It has efferent to supraopticohypophyseal tract from optic nuclei to the posterior pituitary, pars tuberalis, and pars intermedius. Thus posterior pituitary is brought under the retinal control. It also has efferent to mammillothalamic tract and mammillotegmental tract. The Hypothalamus is also subdivided anterior-posteriorly into three regions (Box 1.2). I. NEUROANATOMY 14 1. NEUROANATOMY BOX 1.2 HYPOTHALAMIC NUCLEI (FIG. 1.10) Zone 1. Preoptic 2. Supraoptic (anterior) 3. Infundibulo- tubular (middle) 4. Mammillary (caudal) Nuclei Preoptic nuclei 1. 2. 3. Supraoptic nuclei Paraventricular nuclei Suprachiasmatic nuclei 1. 2. 3. Dorsomedial nuclei Ventromedial nuclei Arcuate nuclei (infundibular) 1. 2. 3. Posterior nuclei Mammillary nuclei Mammilloinfundibular nuclei FIGURE 1.10 Nuclei in the right hypothalamus: midsagittal section of the right hemisphere viewed from the medial side. I. NEUROANATOMY ANATOMY OF BRAIN 15 Functions of Hypothalamus 1. Endocrine control: i. Release factors Anterior pituitary ii. Release inhibiting factors 2. Neurosecrtion: i. Vasopressin (supraoptic nucleus) Posterior pituitary ii. Oxytocin (paraventricular nucleus) 3. Autonomic control: Higher center for control of lower autonomic centers in brainstem & spinal cord i. Anterior region Influence parasypathetic activity ii. Preoptic region iii. Posterior region Influence sympathetic activity iv. Lateral region 4. Temperature regulation a. Anterior region controls dissipation of heat b. Posterior region controls conservation of heat 5. Food intake regulation a. Lateral region (hunger center) initiates eating and increases food intake b. Medial region (satiety center) inhibits eating and reduces food intake 6. Water intake and balance Lateral region (thirst center) increases water intake. Vasopressin effects on distal convoluted tubules and collecting tubules of kidney. 7. Emotion and behavior Hypothalamus, limbic system and prefrontal cortex interconnect intensively and responsible for emotional state and behavior however, hypothalamus generates behaviors involved in rage, aggression and escape. 8. Circadian rhythms (daily rhythm of a biological function) Circadian rhythms include body temperature, adrenocortical activity, sleep, and wakefulness (anterior region). Suprachiasmatic nucleus (afferent from retina) plays a role in control of circadian rhythms (variation in intensity of light is transmitted by this nucleus to many hypothalamic nuclei). Epithalamus Epithalamus is composed of the following: 1. Pineal body 2. Habenula 3. Posterior and habenular commissures It is the most dorsal, smallest, and oldest part of diencephalon. Epithalamus is functionally and anatomically linked to the limbic system. It is implicated in the following functions: 1. Autonomic functions (e.g., respiratory, cardiovascular, etc.) 2. Endocrine functions (e.g., thyroid functions) 3. Reproductive functions (e.g., mating behavior) Habenular Nucleus The habenular nuclei are situated in relation to a triangular depression in the wall of the third ventricle called habenular trigone. It is the center for integration of olfactory, visceral, and somatic afferent pathways (correlation of olfactory and somatic afferent impulses). Ablation of these nuclei produces changes in metabolism, endocrine regulation, and thermoregulation. I. NEUROANATOMY 16 1. NEUROANATOMY Most of the fibers travel through the stria medullaris thalami. Afferent Fibers 1. 2. 3. 4. 5. 6. 7. Amygdaloid complex (via stria terminalis) Hippocampal formation (via fornix) Olfactory tubercle Preoptic and septal areas (via stria medullaris thalami) Anterior perforated substance Various hypothalamic nuclei Globus pallidus Efferent Fibers 1. Interpeduncular nuclei (via fasciculus retroflexus) 2. Medial nucleus of thalamus 3. Tectum and reticular formation of midbrain The stria medullaris thalami, habenula, and fasciculus retroflexes form segments of visceral efferent pathways which carry impulses to parts of brain stem and spinal cord (e.g., Tectotegmentospinal tracts and dorsal longitudinal fasciculus), which connect with autonomic preganglionic centers. Nucleus Subthalamicus It lies medial to internal capsule and is continuous with substantia nigra. Important site for integration of a number of motor control centers especially through its connections with the corpus striatum and midbrain tegmentum. Lesion of one subthalamic nuclei results in a condition called hemiballismus (subthalamic dyskinesia). It receives afferent fibers from globus pallidus, motor cortex (precentral), and pedunculopontine nucleus. It has efferent fibers to globus pallidus, contralateral globus pallidus, substantia nigra, and opposite subthalamic nucleus. Zona Incerta This is a thin strip of gray matter that lies between thalamic and lenticular fasciculi. It is continuous with thalamic reticular nuclei. Functionally associated with the zona incerta are the nuclei of prerubral field and entopeduncular nuclei. It receives signals from precentral motor cortex and sends impulses to midbrain reticular formation. Basal Ganglia The basal ganglia (or basal nuclei) are a group of nuclei (mostly of telencephalic origin) in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus, and other brain areas. The four main components of the basal ganglion are (1) the striatum (caudate nucleus, putamen, and nucleus accumbens), (2) the globus pallidus, (3) the substantia nigra, and (4) the subthalamic nucleus (Fig. 1.5). The basal ganglia play a major role in voluntary motor movement, although they do not have direct input or output with spinal cord. The largest component, the striatum, receives input from many brain areas but sends output only to other components of the basal ganglia. Inputs to striatum are from entire cerebral cortex (glutamatergic fibers), intralaminar nuclei of the thalamus, pars compacta (dopaminergic fibers), raphe nuclei of reticular formation (noradrenergic fibers), and locus coeruleus (serotonergic fibers). The pallidum gets input from the striatum and sends inhibitory output to a number of motor-related areas. The substantia nigra receives striatal input of the neurotransmitter dopamine, which plays an important role in basal ganglia function. The subthalamic nucleus receives input mainly from the striatum and cerebral cortex, and projects to the globus pallidus. Each of these areas has a complex internal anatomical and neurochemical organization. The disturbance of basal ganglia causes a number of movement disorders including Parkinson’s disease, which involves degeneration of the dopamine-producing cells in the substantia nigra pars compacta, and Huntington’s I. NEUROANATOMY ANATOMY OF BRAIN 17 disease, which primarily involves damage to the striatum.10 The lesion in basal ganglia causes hypertonicity (lead pipe type), loss of automatic associated movement, and involuntary movement. Internal Capsule A massive layer (8–10 mm thick) of white matter situated between the caudate nucleus and thalamus (medial) from the more laterally situated lentiform nucleus (globus pallidus and putamen) (Fig. 1.5). In axial (horizontal) section it appears in the form of a V opening out laterally. It is a narrow gate through which fibers are densely crowded and consequently a small pinpoint lesion causes widespread neurological deficit. It consists of five parts: an anterior limb, genu, posterior limb, retrolentiform (or retrolenticular) limb, and sublentiform (or sublenticular) limb (Fig. 1.11A). Internal capsule consists of two types of fiber populations: fibers ascending from the thalamus to the cerebral cortex that comprises of anterior thalamic radiation, among others, the visual, auditory, and somatic sensory radiations, and fibers descending from the cerebral cortex to the thalamus, subthalamic region, midbrain, hindbrain, and spinal cord (Fig. 1.11B). 1. Anterior limb lies between head of caudate nucleus and lentiform nucleus. It contains descending tract: frontopontine fibers and ascending tract: anterior thalamic radiation. 2. Genu is a bend of internal capsule and lies close to ventricular surface immediately lateral to the foramen of Monro. It contains descending tract: corticonuclear fiber and ascending tract: anterior fiber of thalamic radiation. 3. Posterior limb lies between thalamus and lentiform nucleus and contains descending tracts: corticospinal tract, frontopontine, corticorubral fibers and ascending tract: fibers of the superior thalamic radiation. 4. Retrolenticular part lies behind the lentiform nucleus and contains descending tracts: parietopontine, occipitopontine, occipitocollicular, occipitotectal fibers and ascending tract: optic radiation. 5. Sublenticular part lies below lenticular nucleus and contains descending tracts: temporopontine, parietopontine and ascending tract: acoustic radiation from medial geniculate body to superior temporal and transverse temporal gyri. As these ascending and descending fibers are densely passed through a narrow space in internal capsule, a lesion in the internal capsule causes widespread paralysis on the opposite half of the body, which may also involve lower part of the face and tongue. The lesions in internal capsule result from thrombosis or rupture of the arteries supplying it (Box 1.3). FIGURE 1.11A Schematic representation of the horizontal view showing the three parts of the internal capsule: anterior limb, genu, and posterior limb. I. NEUROANATOMY 18 1. NEUROANATOMY FIGURE 1.11B Schematic representation of the horizontal view showing the ascending pathways and descending tracts passing through the internal capsule. BOX 1.3 B L O O D S U P P LY O F I N T E R N A L C A P S U L E Anterior limb Upper part is supplied by lenticulostriate branches of middle cerebral artery, and lower part is supplied by recurrent branch (Heubner artery) of anterior cerebral artery. Genu Upper part is supplied by lenticulostriate branches of middle cerebral artery, and lower part is supplied by recurrent branch (Heubner artery) of anterior cerebral artery. Posterior limb Upper part is supplied by lenticulostriate branches of middle cerebral artery, and lower part is supplied by anterior choroidal artery (branch of internal carotid artery). White Matter The white matter is mainly myelinated nerve fibers, occupy deeper part of cerebrum, and connect various parts of the cortex to one another and also to other part of the CNS. These may be classified as association fibers, projection fibers, and commissural fibers (Fig. 1.12). Association fibers: These are the fibers connecting different cortical areas of the same side to one another. Short association fibers connect adjacent gyri. Long association fibers connect distant part of the cerebral cortex in the same side (Fig. 1.12). 1. Uncinate fasciculus: temporal pole to motor speech area and orbital cortex 2. Cingulum fasciculus: cingulum gyrus to parahippocampal gyrus I. NEUROANATOMY ANATOMY OF BRAIN 19 FIGURE 1.12 Schematic diagram showing the short and long association fibers of the cerebrum. Fasc., fasciculus. 3. Superior longitudinal fasciculus: frontal to occipital and temporal lobes 4. Inferior longitudinal fasciculus: temporal to occipital lobe Projection fibers: These are the fibers which connect the cerebral cortex to other parts of the CNS such as brain stem and spinal cord in both directions, e.g., corticospinal and corticopontine fibers. Commissural fibers: These fibers connect corresponding areas of the two hemispheres. The commissural fibers include the following: 1. 2. 3. 4. 5. 6. 7. Corpus callosum Anterior commissure Posterior commissure Hippocampal commissure Habenular commissure Hypothalamic commissure Cerebellar commissure Corpus Callosum The corpus callosum is the largest commissure, which connects two hemispheres. The corpus callosum has two anterior parts, rostrum and genu, a central part, trunk, and posterior part, splenium (Fig. 1.4). Corpus callosum is closely related to lateral ventricle. The fibers of the genu run forward into the frontal lobes and make the forklike structure called the forceps minor. This forms the anterior wall of frontal horn of lateral ventricle. The rostrum is located below and forms the floor of the frontal horn. The genu and trunk form roof of both of the frontal horns and body of lateral ventricles. Fibers of the trunk run laterally and intersect the fiber of corona radiate. As some fibers of trunk and splenium run laterally they form a flattened band called the tapetum. The tapetum is closely related to posterior and inferior horn of the lateral ventricle. Tapetum separates the fibers of the optic radiation from temporal horn and the atrium. Large fibers of splenium run backward into occipital lobe to form forceps major. Ventricular System The ventricles of the brain are a communicating network of cavities filled with cerebrospinal fluid (CSF) and located within the brain parenchyma. The ventricular system is composed of two lateral ventricles, one third ventricle, the cerebral aqueduct, and the fourth ventricle (Fig. 1.13). It is continuous with the central canal of the spinal cord. The ventricle lining consists of a specialized epithelial membrane called ependymal layer. The choroid plexuses located in the ventricles produce CSF, which fills the ventricles and subarachnoid space, following a cycle of constant production and reabsorption. CSF flows from the lateral ventricles via the foramina of Monro into the third ventricle, and then it reaches into the fourth ventricle through the cerebral aqueduct in the brain stem (Fig. 1.13). From there it passes into the central I. NEUROANATOMY 20 1. NEUROANATOMY FIGURE 1.13 Human ventricular system (left lateral view). canal of the spinal cord or into the cisterns of the subarachnoid space via three small foramina: the central foramen of Magendie and the two lateral foramina of Luschka. The fluid then flows around the superior sagittal sinus to be reabsorbed via the arachnoid villi into the venous system. CSF within the spinal cord flows down to the lumbar cistern at the end of the cord around the cauda equine and bath whole of the spinal cord. Lateral Ventricles Lateral ventricles are two c-shaped cavities one on each side of cerebral hemisphere. It consists of a central part called body and three extensions: anterior (frontal horn), posterior (occipital horn), and inferior (temporal horn). Each lateral ventricle communicates with the third ventricle with a common interventricular foramen or foramen of Monro (Fig. 1.13). Central part of the lateral ventricle extended anteroposteriorly from interventricular foramen to splenium of corpus callosum. Their boundaries are roof: trunk of corpus callosum, floor: superior surface of the thalamus medially and body of caudate nucleus laterally and in between these two stria terminalis and thalamostrial vein, medial surface: septum pallucidum and body of fornix. There is space between fornix and upper surface of the thalamus called choroid fissure. The frontal horn is located in front of interventricular foramen or foramina of Monro. It is triangular in shape with boundaries anterior part of trunk of corpus callosum as roof, head of caudate nucleus as head, septum pellucidum as medial wall. The occipital horn of the lateral ventricle extends backward into occipital lobe with its roof and lateral wall formed by tapetum, optic radiation, and inferior longitudinal fasciculus; and bulb of posterior horn (floor and medial wall) is raised by forcep major and calceravis. I. NEUROANATOMY ANATOMY OF BRAIN 21 FIGURE 1.14 Detailed system limbic structure and connections. The temporal horn or inferior horn projecting form the posterior end of central part run downward and forward into temporal lobe and reach the uncus. In cross section it is a narrow cavity with boundaries: roof and lateral wall formed by tapetum, tail of caudate lobe, stria terminalis and amygdaloid body and floor by hippocampus. Third Ventricle This is a narrow funnel-shaped cavity of the diencephalon which lies between the thalamus (Fig. 1.5). It communicates anteriosuperiorly on each side with lateral ventricles by foramen of Monro or interventricular foramen. Posteriorly, it communicates with the fourth ventricle through aqueduct of Sylvius (Fig. 1.13). It is bounded by an anterior wall, a posterior wall, roof, floor, and two lateral walls. The lateral wall is formed superiorly by thalamus and below by hypothalamus. Hypothalamus is separated from thalamus by hypothalamic sulcus, a groove that extends from foramen of Monro anteriorly to aqueduct posteriorly. The interventricular foramen of Monro is seen on lateral wall just behind the column of fornix. The anterior wall is formed by lamina terminalis. Lamina terminalis is a thin layer of gray matter in the telencephalon that extends backward from the corpus callosum above the optic chiasma and forms the median portion of the rostral wall of the third ventricle of the cerebrum (Fig. 1.4). Posterior wall is formed by pineal body and posterior commissure. The roof is extended from foramen of Monro anteriorly to suprapineal recess posteriorly. The roof is formed by ependyma that stretches across the two thalami. The floor extends from optic chiasma anteriorly to the orifice of aqueduct of Sylvius posteriorly. It is formed by optic and infundibular recess, tuber cinereum, mammillary bodies, and posterior perforated substance of tegmentum of midbrain. The cavity of the third ventricle shows number of prolongations or recesses, e.g., infundibular recess, optic recess, pineal recess, and supraspinal recess. Endoscopic third ventriculostomy is a surgical procedure in which an opening is created in the floor of the third ventricle using an endoscope placed within the ventricular system through a burr hole. This allows the CSF to flow directly to the basal cisterns, thereby shortcutting any obstruction. It is used as an alternative to a cerebral shunt to treat certain forms of obstructive hydrocephalus, such as aqueductal stenosis. I. NEUROANATOMY 22 1. NEUROANATOMY Fourth Ventricle The fourth ventricle is a cavity of hindbrain connected to the third ventricle by a narrow cerebral aqueduct. The fourth ventricle is a diamond-shaped cavity located dorsal to the pons and upper medulla oblongata and anterior to the cerebellum (Fig. 1.13). Fourth ventricle connected to the third ventricle above and central canal below. Through medial aperture, foramen of Magendie, it communicates with subarachnoid space. Laterally on either side it communicated with subarachnoid space through foramen of Luschka. The superior cerebellar peduncles and the anterior and posterior medullary vela form the roof of the fourth ventricle. The apex or fastigium is the extension of the ventricle up into the cerebellum. The floor of the fourth ventricle is named the rhomboid fossa. The lateral recess is an extension of the ventricle on the dorsal inferior cerebellar peduncle. Inferiorly, it extends into the central canal of medulla. The fourth ventricle communicates with the subarachnoid space through the lateral foramen of Luschka, located near the flocculus of the cerebellum, and through the median foramen of Magendie, located in the roof of the ventricle. Most of the CSF outflow passes through the medial foramen. The cerebral aqueduct contains no choroid plexus. The tela choroidea of the fourth ventricle, which is supplied by branches of the posterior inferior cerebellar arteries, is located in the posterior medullary velum.11,12 The lateral wall of fourth ventricle on the upper side is formed by superior cerebellar peduncle and lower part is formed by inferior cerebellar peduncle and gracile and cuneate tubercle. The roof is tent in shape and projected into cerebellum (Fig. 1.13). Roof is formed superiorly by superior cerebellar peduncle and superior medullary velum and inferiorly by membrane consisting of ependymal and double layer of pia meter which constitute tela choroidea of the fourth ventricle. Floor of the fourth ventricle is rhomboid in shape and thus called as rhomboid fossa. Upper triangular part is formed by pons and lower triangular part by medulla. Intermediate part prolonged laterally to form the lateral recess. The floor of the fourth ventricle is divided into two symmetrical halves. Each half contains facial colliculus, hypoglossal triangle, sulcus limitans, vestibular area, stria medullaris, and vagal triangle. The vital centers are situated in vagal triangle and injury during surgery into the fourth ventricle to these areas can be fatal. Limbic System The limbic system (or paleomammalian brain) is a complex set of brain structures that involves with learning, memory, and emotion. It is affected in many neuropsychiatric diseases including schizophrenia, Alzheimer disease, and some forms of epilepsy. It is a collection of structures from the telencephalon, diencephalon, and mesencephalon.13 The limbic system includes the olfactory bulbs, hippocampus, amygdala, anterior thalamic nuclei, fornix, and column of fornix, mammillary body, septum pellucidum, habenular commissure, cingulate gyrus, parahippocampal gyrus, limbic cortex, limbic midbrain areas, and pons (Fig. 1.14). The limbic lobe is a ring of cortex on the medial aspect of the cerebral hemisphere (Fig. 1.14). This ring of cortex consists of the cingulate gyrus, parahippocampal gyrus, and septal cortex. These cortical areas are connected via the cingulum (Fig. 1.12). The cortical areas within the limbic lobe, together with certain adjacent deep structures, are known as the limbic system. The areas that are usually included within the limbic system include the following: 1. 2. 3. 4. 5. 6. Limbic lobe Hippocampal formation and fornix Amygdala Septal area Mammillary bodies (or in some accounts, the entire hypothalamus) Anterior nuclei of the thalamus The fornix connects the hippocampus to the mammillary bodies, which in turn is connected to the anterior nuclei of the thalamus by mammillothalamic tract. The anterior nuclei of thalamus are projected to the cingulate cortex. From the cingulate cortex, these are connected to the hippocampus, completing a complex closed circuit. This circuit was originally described by Papez and later named as Papez circuit. The complexity of the behavioral responses presumably explains the complexity of the limbic system. Connections with sensory, motor, and autonomic systems are required. The presence of these connections may give rise to misleading results when different parts of the limbic system are stimulated electrically in an attempt to discern their I. NEUROANATOMY ANATOMY OF BRAIN 23 functions. For example, stimulation of most components of the limbic system produces autonomic effects such as changes in blood pressure and respiration. Similarly, movement can be obtained from stimulation at many points. This does not mean that the limbic system is primarily involved with autonomic control and movement, but, rather, that it has connections with the hypothalamus and motor areas of the brain for integrating the output of these systems in whatever ways are necessary for the production of visceral or emotional behavioral patterns. This also explains why emotions and visceral sensations have a strong effect on the learning process. It is therefore not too surprising that the part of the brain that appears to control our emotions and regulate visceral functions also plays a central role in learning and memory. Midbrain (Mesencephalon) The midbrain or mesencephalon (from the Greek mesos—middle, and enkephalos—brain14) is a portion of the CNS that connects hindbrain with forebrain and associated with vision, hearing, motor control, sleep/wake, arousal (alertness), and temperature regulation.15 Midbrain passes through the tentorial notch and is related to each side to parahippocampal gyri, optic tract, trocheal nerve, and posterior cerebral artery and geniculate bodies (Figs. 1.15–1.17). Interpeduncular structures are anterior to it whereas great cerebral vein, pineal body, splenium of corpus callosum, and pulvinar are posterior to it (Figs. 1.4 and 1.17). The part that lies posterior to cerebral aqueduct is called the tectum. It consists of superior and inferior colliculi of the two sides (Fig. 1.18). The part anterior to cerebral aqueduct is made up of the right and left halves called cerebral peduncles. Each peduncle consists of three parts: (from anterior to posterior side) crus cerebri (or basal peduncle), the substantia nigra, and tegmentum (Fig. 1.18). The crus cerebri consists of vertically running a large mass of fibers. These fibers descend from the cerebral cortex, some reach to the pons while other extents FIGURE 1.15 Lateral view of the brain stem. 1. Medial geniculate body. 2. Lateral geniculate body. 3. Optic tract. 4. Dorsal part (mesencephalic tegmentum). 5. Ventral part (Crus cerebri). 6. Mammillary body. 7. Infundibulum. 8. Hypophysis. 9. Trigeminal nerve. 10. Pons. 11. Abducens nerve. 12. Olive. 13. Pyramids (medulla oblongata). 14. Hypoglossal nerve. 15. Ventrolateral sulcus. 16. Ventral root of first cervical nerve. 17. Spinal root of accessory nerve. 18. Dorsal root of first cervical nerve (retracted). 19. Dorsolateral sulcus (medulla oblongata). 20. Cranial root of accessory and vagus nerve. 21. Tenia of the fourth ventricle. 22. Glossopharyngeal and vagus nerve. 23. Middle cerebellar peduncle. 24. Facial nerve with nervous intermedius and vestibulocochlear nerve. 25. Inferior cerebellar peduncle. 26. Superior cerebellar peduncle. 27. Trochlear nerve. 28. Inferior colliculus and brachium of inferior colliculus. 29. Superior colliculus. 30. Pulvinar. I. NEUROANATOMY 24 1. NEUROANATOMY FIGURE 1.16 Dorsal view of brain stem. (Neocortex and cerebellum has been removed.) 1. Caudate nucleus. 2. Lamina affixa. 3. Terminal stria and superior thalmostriate vein in terminal sulcus. 4. Tenia choroidea. 5. Pulvinar (thalamus). 6. Habenular trigone. 7. Pineal body. 8–11. Mesencephalon. 8. Brachium of superior colliculus. 12. Brachium of inferior colliculus. 9. 10. Tectum. 9. Superior colliculus. 10. Inferior colliculus. 11. Superior medullary velum. 13. Trochlear nerve. 14. Superior cerebellar peduncle. 15. Median eminences. 16. Facial colliculus. 17. Middle cerebellar peduncle. 18. Inferior cerebellar peduncle. 19. Stria medullaris (fourth ventricle) and lateral recess of the fourth ventricle. 20. Tenia of the fourth ventricle. 21. Trigone of hypoglossal nerve. 22. Trigone of vagus nerve (ala cinerea). 23. Obex. 24. Dorsal intermediate sulcus. 25. Dorsolateral sulcus. 26. Dorsal median sulcus. 27. Lateral funiculus. 28. Fasciculus gracilis. 29. Fasciculus cuneatus. 30. Tuberculum gracile. 31. Tuberculum cuneatum. 32. Vestibular area. 33. Median sulcus. 34. Sulcus limitans. 35. Cerebral peduncle. 36. Lateral geniculate body. 37. Medial geniculate body. to the spinal cord. The two crura are separated by a notch on anterior aspect of midbrain. The substantia nigra consists of pigmented gray matter and therefore appears dark. The tegmentums of the two sides are continuous across the midline and contain important mass of gray matter and fiber bundle. The red nucleus is the largest of the nuclei of midbrain and lies in upper half of midbrain (Fig. 1.18). The tegmentum also contains the reticular formation which is continuous below with that of the pons and medulla. The medial lemniscus is a fiber bundle of tegmentums that lie behind the substantia nigra and lateral to red nucleus. In the lower part of tegmentum, the fibers of superior cerebellar peduncles decussate before ending into red nucleus. Trochlear nucleus lies in ventral part of midbrain; its fibers run dorsally and decussate before emerging from dorsal surface brain stem (Figs. 1.15–1.17). Mesencephalic nucleus of trigeminal nerve lies in the lateral part of gray matter and receives proprioceptive impulses from the muscles of mastication, face, facial muscles, ocular muscle and from teeth (Fig. 1.18). Superior colliculus receives afferents from retina (visual), spinal cord (tactile), inferior colliculus (auditory), and occipital cortex (modulating pathway). Efferent goes to retina, spinal cord, brain stem nuclei, and tegmentum. Inferior colliculus receives afferent impulses from lateral lemniscus and efferent to medial geniculate body. It controls auditory reflex and helps in localizing the source of sound. Red nucleus lies in anterior part of tegmentum dorsomedial to substantia nigra (Fig. 1.20). It receives afferent from superior cerebellar peduncle, globus pallidus, subthalamic nucleus, and cerebral cortex. It supplies efferent to spinal cord as rubrospinal tract, reticular formation, thalamus, subthalamic nucleus, and olivary nucleus. It has inhibitory influence over muscle tone. Oculomotor nucleus of two sides closes together, forms a single complex. The Edinger–Westphal nucleus (supplies the sphincter pupillae and ciliaris muscles) forms part of oculomotor complex. I. NEUROANATOMY ANATOMY OF BRAIN 25 FIGURE 1.17 Ventral view of brain stem comprising of midbrain, pons, and medulla oblongata. 1. Corpus callosum in depths of anterior interhemispheric or longitudinal cerebral fissure. 2. Olfactory bulb. 3. Olfactory tract. 4. Medial olfactory stria. 5. Lateral olfactory stria. 6. Olfactory trigone. 7. Anterior perforated substance. 8. Diagonal band of Broca. 9. Optic tract. 10. Cut surface of left temporal lobe. 11. Infundibulum with hypophyseal stalk. 12. Mammillary body. 13. Interpeduncular fossa with interpeduncular perforated substance. 14. Ventral part of cerebral peduncle. 15. Pons. 16. Basilar sulcus. 17. Pyramid (medulla oblongata). 18. Middle cerebellar peduncle. 19. Olive. 20. Ventrolateral sulcus. 21. Ventral root of first cervical nerve. 22. Ventral median sulcus. 23. Decussation of pyramids. 24. Hypoglossal nerve. 25. Spinal root of accessory nerve. 26. Accessory nerve and cranial root. 27. Glossopharyngeal and vagus nerve. 28. Facial nerve with nervous intermedius and vestibulocochlear nerve. 29. Abducens nerve. 30. Motor and sensory root of trigeminal nerve. 31. Trochlear nerve. 32. Oculomotor nerve. 33. Optic chiasm. Pons Pons is the forepart of the hindbrain situated in front of the cerebellum. Pons is continuous behind and below with the medulla oblongata. Pons is separated from medulla in front by a furrow in which the abducent, facial, and acoustic nerves appear (Figs. 1.15 and 1.17). Trigeminal nerves emerge at the junction of pons and middle cerebellar peduncle. Anterior surface of pons is convex and has a sulcus in midline called basilar sulcus which is occupied by basilar artery (Fig. 1.17). Superior surface of pons is related to superior cerebellar artery and lower surface is related to anterior inferior cerebellar artery. Posterior surface of pons is hidden by cerebellum and bounded laterally by superior cerebellar peduncle (Fig. 1.17). On either side of the lower part of the pons there is a region called cerebellopontine angle. The facial, vestibulocochlear, glossopharyngeal nerves; nervous intermedius; and labyrinthine arteries lie in this region (Fig. 1.19). On transverse section, pons can be divided into two parts: ventral part and dorsal part (Fig. 1.20). Ventral part of pons contains (1) the pontine nuclei, (2) vertically running corticopontine and corticospinal fibers, and (3) transversely running arising from pontine nuclei and projecting to opposite half of cerebellum through middle cerebellar peduncle. The bulk of ventral part is due to pontine nuclei and their connection (corticopontocerebellar) (Fig. 1.20). Dorsal part (tegmentum) of pons is occupied mainly by reticular formation. The dorsal part is bounded laterally by the inferior cerebellar peduncle in the lower part of the pons and by the superior cerebellar peduncle in the upper part (Fig. 1.20). Structures present at the level of upper pons are medial longitudinal fasciculus, cerebellar peduncle, locus ceruleus, parabrachial nucleus, and pediculopontine nucleus (Fig. 1.20). Structures present at the level of middle cerebellar peduncle are medial lemniscus, lateral lemniscus, trapezoid body, and trigeminal nucleus (sensory and motor). Structures present at the level of facial nucleus are cranial nerve (CN) VI nucleus (abducens nerve), CN VII nucleus (facial nerve), and CN VIII (vestibular nuclei) (Figs. 1.15 and 1.17). I. NEUROANATOMY 26 1. NEUROANATOMY FIGURE 1.18 Transverse section through the midbrain at the level of superior colliculi. FIGURE 1.19 Schematic representation of left cerebellopontine angle (CP angle) as in a suboccipital approach showing various nerves and PICA. CN, cranial nerve; PICA, posterior inferior cerebellar artery. Medulla Medulla is the lowest part of the brain stem and with other part of hindbrain occupies infratentorial space of the skull. It is the direct and expanded upward continuation of spinal cord and includes important fiber tracts (Fig. 1.4). The medulla oblongata extends from the lower margin of the pons to a plane passing transversely below the pyramidal decussation and above the first pair of cervical nerves. This plane corresponds with the foramen magnum, i.e., I. NEUROANATOMY ANATOMY OF BRAIN 27 FIGURE 1.20 Transverse section through the mid-pons. upper border of the atlas behind and the middle of the odontoid process of the axis in front. Anteriorly it is related with clivus and meninges; posteriorly, to the vallecula of the cerebellum. Its caudal part is like the spinal cord, while its cranial half is split open to form lower part of the floor of the fourth ventricle. Thus medulla is often thought of as being in two parts: open and closed. An open part or superior part where the dorsal surface of the medulla is formed by the fourth ventricle (Fig. 1.21) whereas a closed part or inferior part where the central canal lies within the medulla. The bulbopontine sulcus separates oblongata and pons ventrally; the sixth, seventh, and eighth CNs arise from the bulbopontine sulcus (Figs. 1.15 and 1.17). Two median fissures (anterior and posterior) divide medulla into two symmetrical halves (Fig. 1.21). Anterior median fissure is crossed by pyramidal decussation. Each half of medulla is marked by two longitudinal sulci, anterolateral sulci between pyramids and olive, and posterolateral between olive and inferior cerebellar peduncle. Thus these two sulci divide each half of medulla into three regions: anterior, lateral, and posterior region. Anterolateral sulcus lies in line with ventral root of spinal nerves and the 12th CN emerges from it (Fig. 1.21). Posterolateral sulcus lies in line with dorsal root of spinal nerve and gives attachment to the 11th, 10th, and 9th CNs. The region (anterior region) between the anterior median sulcus and the anterolateral sulcus is occupied by an elevation on either side known as the pyramid (Fig. 1.21). This elevation is caused by corticospinal tract. In the lower part of the medulla some of these fibers cross each other thus obliterating the anterior median fissure. This is known as the decussation of the pyramids. Some other fibers that originate from the anterior median fissure above the decussation of the pyramids and run laterally across the surface of the pons are known as the external arcuate fibers. The region (lateral region) between the anterolateral and posterolateral sulci in the upper part of the medulla is marked by a swelling known as the olivary body. It is caused by a large mass of gray matter known as the inferior olivary nucleus (Fig. 1.21). The posterior part (posterior region) of the medulla between the posterior median sulcus and the posterolateral sulcus contains tracts that enter it from the posterior funiculus of the spinal cord. These are the fasciculus gracilis, lying medially next to the midline, and the fasciculus cuneatus, lying laterally (Fig. 1.21). These fasciculi end in rounded elevations known as the gracile and the cuneate tubercles. They are caused by masses of gray matter known as the nucleus gracilis and the nucleus cuneatus. Just above the tubercles, the posterior aspect of the medulla is occupied by a triangular fossa, which forms the lower part of the floor of the fourth ventricle (Fig. 1.21). The fossa is bounded on either side by the inferior cerebellar peduncle, which connects the medulla to the cerebellum. The lower part of the medulla, immediately lateral to the fasciculus cuneatus, is marked by another longitudinal elevation known as tuberculum cinereum. It is caused by an underlying collection of gray matter known as the spinal nucleus of the trigeminal nerve (Fig. 1.21). The gray matter of this nucleus is covered by a layer of nerve fibers that I. NEUROANATOMY 28 1. NEUROANATOMY FIGURE 1.21 Transverse section of the medulla oblongata (lower portion). TABLE 1.1 Medulla Oblongata at Different Levels Level Cavity Nuclei Motor Tract Sensory Tract Junction of pons and Fourth ventricle medulla Lateral vestibular nucleus, cochlear nucleus Pyramids Medial longitudinal fasciculus, tectospinal tract, medial lemniscus, lateral spinothalamic tract, anterior spinothalamic tract, spinal tract of the fifth cranial nerve Olives, inferior cerebellar peduncles Fourth ventricle Inferior olivary nucleus, Pyramids spinal nucleus of 5th nerve, nucleus of the 8th–11th nerves, nucleus ambiguous, nucleus solitarius Medial longitudinal fasciculus, tectospinal tract, medial lemniscus, lateral spinothalamic tract, anterior spinothalamic tract, spinal tract of the fifth cranial nerve Decussation of medial lemniscus Central canal Nucleus gracilis and cuneatus, spinal nucleus of the fifth nerve, accessory nucleus, hypoglossal nucleus Pyramids Decussation of medial lemniscus, fasciculus gracilis, and cuneatus, spinal tract of the fifth nerve, posterior and lateral spinothalamic tract, anterior spinocerebellar tract Decussation of pyramids Central canal Nucleus gracilis and cuneatus, spinal nucleus of the fifth nerve, accessory nucleus Decussation of Spinal tract of the fifth nerve, posterior corticospinal tracts and lateral spinothalamic tract, anterior spinocerebellar tract form the spinal tract of the trigeminal nerve. The base of the medulla is defined by the commissural fibers; crossing over from the ipsilateral side in the spinal cord to the contralateral side in the brain stem. Below this lies the spinal cord. The medulla oblongata controls autonomic functions and relays nerve signals between the brain and spinal cord. It is also responsible for controlling several major autonomic functions of the body such as respiration via dorsal respiratory nucleus and ventral respiratory nucleus, vital reflex arcs, vomiting, swallowing, reflexes, etc. (Table 1.1). I. NEUROANATOMY ANATOMY OF BRAIN 29 Lateral medullary syndrome, or “Wallenberg’s syndrome.” The most commonly affected artery is the vertebral artery, followed by the posterior inferior cerebellar artery (PICA), superior middle and inferior medullary arteries.20 The spinothalamic tract is damaged, resulting in loss of pain and temperature sensation to the opposite side of the body. There is sensory deficit affecting the trunk and extremities on the opposite side of the infarction and sensory deficits affecting the face and CNs on the same side. The damage to the cerebellum or the inferior cerebellar peduncle can cause ataxia. Other clinical symptoms and findings are swallowing difficulties (dysphagia) slurred speech, facial pain, vertigo, nystagmus, Horner syndrome, diplopia, and possibly palatal myoclonus. Medial medullary syndrome. It results from occlusion of the vertebral artery or of a branch of the vertebral or lower basilar artery.21 This results in the infarction of medial part of the medulla oblongata. The infarction leads to infarction of the ipsilateral medullary pyramid, the ipsilateral medial lemniscus, and hypoglossal nerve fibers that pass through the medulla. It results into contralateral hemiparesis sparing the face, hemisensory loss of the posterior column type (contralateral), and deviation of the tongue. Reticular Formation In addition to the distinct nuclei, much of the brain stem consists of small bunches of neuronal cell bodies (gray matter) interspersed among small bundle of myelinated axons (white matter). The broad region where gray matter and white matter form a network-like arrangement is known as reticular formation. Reticular formation network extends from the upper part of spinal cord, throughout the brain stem and into the lower part of the diencephalon. Reticular formation have both ascending (sensory) and descending (motor) fibers. Part of the reticular formation called the reticular activating system consists of sensory axons that project to sensory cortex. The reticular activating system helps in maintaining consciousness and activates awakening from sleep.21 The reticular formation descending tracts help in regulating posture and muscle tone.22, 23 Cerebellum The term cerebellum literally means “little brain.” It is located dorsal to the brain stem and is connected to the brain stem by three pairs of cerebellar peduncles. The cerebellum consists of primarily of white matter surrounded by a thin layer of gray matter (cerebellar cortex) and four pairs of deep nuclei. Cerebellum has three surfaces: tentorial, suboccipital, and petrosal. Superior surface or tentorial surface is convex and related superiorly to tentorium cerebelli, the suboccipital surface is in relation to squamous pat of occipital bone, and petrosal surface is related anteriorly to petrous part of the temporal bone. The fourth ventricle is intimately in relation with the cerebellum. The fourth ventricle is a tent-shaped midline structure surrounded by vermian of cerebellum. Morphologically cerebellum consists of three parts: a part lying in midline called vermis and of two large lateral cerebellar hemispheres. Cerebellum (both vermis and hemisphere) is divided by fissure and sulci, into lobules. Thus, parts of cerebellar hemisphere represent lateral extension of vermis (except the lingual which has no extension). The connections of the cerebellum are grouped into three cerebellar peduncles which are named according to their position. (1) Inferior cerebellar peduncle connects the cerebellum with the medulla, contains afferent and efferent axons; (2) middle cerebellar peduncle connects cerebellum with the pons, contains only afferent axons from pontine nuclei; and (3) superior cerebellar peduncle connects cerebellum with the midbrain, it is predominantly efferent axons. Gray matter of cerebellar cortex consists of four pairs of nuclei and all the output come from them. These are (1) nucleus dentatus (of neocerebellum), (2) nucleus globosus, (3) nucleus emboliformis (of paleocerebellum), and (4) nucleus fastigi (of archicerebellum). From the functional viewpoint, the cerebellum represents three distinct regions: one is the vermis and the other two regions are located in intermediate and lateral parts of the cerebellar hemisphere. The functional cerebellum can be divided into three regions. The smallest region, the flocculonodular lobe (Fig. 1.22) is the oldest part in evolutionary terms (archicerebellum) and participates mainly in balance and spatial orientation; its primary connections are with the vestibular nuclei, although it also receives visual and other sensory input. Damage to it causes disturbances of balance and gait.16 The medial zone of the anterior and posterior lobes (Fig. 1.22) constitutes the spinocerebellum, also known as paleocerebellum. It receives proprioception input from the dorsal columns of the spinal cord (including the spinocerebellar tract) and from the trigeminal nerve, as well as from visual and auditory systems. It sends fibers to deep cerebellar nuclei that, in turn, project to both the cerebral cortex and the brain stem, thus providing modulation of descending motor systems thus control tone, posture, and crude movements.16 I. NEUROANATOMY 30 1. NEUROANATOMY FIGURE 1.22 Schematic representation of the major anatomic subdivisions of the cerebellum. The lateral zone (Fig. 1.22), which in humans is by far the largest part, constitutes the cerebrocerebellum, also known as neocerebellum. It receives input exclusively from the cerebral cortex (especially the parietal lobe) via the pontine nuclei (forming corticopontocerebellar pathways) and project mainly to the motor areas of the premotor cortex and primary motor area of the cerebral cortex and to the red nucleus.16 It is involved in planning and mental rehearsal of complex motor actions, conscious assessment of movement error17 in evaluating sensory information for action,16 and in a number of purely cognitive functions.18,19 VASCULAR SUPPLY OF THE BRAIN Arterial System Brain is supplied by branches of two main pairs of arteries, i.e., internal carotid arteries and vertebral arteries. The left carotid artery is branch of the aortic arch whereas; the right is branching from the brachiocephalic trunk. The common carotid artery branches into the internal and external carotid arteries at the level of cervical vertebra 3–4. The internal carotid artery enters the cranial cavity at the base of the skull through the carotid canal, then forms the S shape siphon and passes through the sinus cavernous. The internal carotid artery ends as a bifurcation into anterior and middle cerebral arteries. Ophthalmic artery is the first branch of the internal carotid artery (Fig. 1.23). In addition, two small branches of internal carotid artery are anterior choroidal artery and recurrent branch of anterior cerebral artery also called as artery of Heubner. The anterior choroidal artery which arises directly forms the internal carotid artery, runs backward in relation to optic tract, and enters the inferior horn of the lateral ventricle through choroid fissure (Fig. 1.23). Artery of Heubner runs backward and laterally to enter the anterior perforated substances. Thrombosis of artery of Heubner results in contralateral paralysis of the face and upper extremity. Large branches of the internal carotid artery are anterior cerebral artery, middle cerebral artery, posterior communicating artery. The two vertebral arteries in their extravertebral course (after arising from subclavial artery) are in close relation to the cervical vertebrae. The vertebral arteries run in the transverse foramen of the cervical vertebrae C6 and above. Vertebral arteries ascend on the anterolateral aspect of medulla and unit at the lower border of pons to form basilar artery. Basilar artery is then divided into two posterior cerebral arteries at the upper end of the pons (Fig. 1.23). They are connected to the carotid field by joining a posterior communicating artery. The internal carotid artery and vertibrobasilar system are connected by the posterior communicating arteries. The anterior communicating artery connects both anterior cerebral arteries. As a result of these anastomoses an arterial ring, the circulus arteriosus (or circle of Willis), is formed in relation to the base of the brain, and through this circle it is possible to compensate the obliteration of any mentioned artery (Fig. 1.23). The anterior, middle, and posterior cerebral arteries give rise to two sets of branches: cortical and central. The cortical branches divide on the surface of the cerebral hemisphere and supply the cortex. The central (or perforating) branches pass deep into the substance of the cerebral hemisphere to supply white matter and masses of gray matter. I. NEUROANATOMY VASCULAR SUPPLY OF THE BRAIN 31 FIGURE 1.23 Circle of Willis (viewed from below the brain). a., artery; A-comm a., anterior communicating artery; ACAs, anterior cerebral arteries; AICA, anterior inferior cerebellar artery; Cr., cranial nerve; ICA, internal carotid artery; MCA, middle cerebral artery; n., nerve; P-comm a., posterior communicating artery; PCA, posterior cerebral artery; PICA, posterior inferior cerebellar artery. The central branches are end arteries. The amount of blood supply is more in the gray matter than the white matter; this is related to the intensity of the metabolic rate. Arterial supply to important structure of brain. Middle cerebral artery supplies greater part of superiolateral surface of the cerebral cortex. A band 0.5–1 inch wide extended from frontal pole to the parietooccipital sulcus is supplied by anterior cerebral artery. The area of occipital lobe is supplied by the posterior cerebral artery. The inferior temporal gyrus is also supplied by the posterior cerebral artery (Fig. 1.24). Medial surface of the cerebral cortex is mainly supplied by anterior cerebral artery except occipital lobe which is supplied by posterior cerebral artery (Fig. 1.24). Orbital surface on the lateral part is supplied by middle cerebral artery and medial part by the anterior cerebral artery. Tentorial surface is supplied by the posterior cerebral artery. The temporal pole is supplied by middle cerebral artery (Fig. 1.24). Thrombosis of the anterior cerebral artery causes paralysis of the muscles of the leg and foot of the opposite side, loss of the sensation from the leg and foot of the opposite side, and personality changes. Thrombosis of the middle cerebral artery causes hemiplegia and loss of the sensation of the opposite side of the body mainly face and arm, homonymous hemianopia of opposite side, and aphasia (by involvement of the Broca’s and Wernickes’s area) specially in left side thrombosis in right-handed person. Thrombosis of the posterior cerebral artery causes visual disturbance mainly homonymous hemianopia of the opposite side. Choroid plexuses of the lateral and the third ventricles are formed by anterior choroidal (branch of internal carotid) and posterior choroidal artery (branch of posterior cerebral artery). The choroid plexus of the fourth ventricle is formed by a branch from the posterior inferior cerebellar artery. Internal capsule is supplied by central branches of middle cerebral artery, the lenticulostriate branches, anterior cerebral artery, the Huebner recurrent branch, posterior communicating artery, and anterior choroidal artery. Thalamus is supplied mainly by perforating branches of the posterior cerebral artery (posteromedial) and partly anteromedial central branches (Fig. 1.24). I. NEUROANATOMY 32 1. NEUROANATOMY FIGURE 1.24 Vascular supply of cerebral hemispheres. AChA, anterior choroidal artery; MCA, middle cerebral artery; P-comm a., posterior communicating artery; RAH, recurrent artery of Heubner. Hypothalamus is supplied by central branches of anterior medial group and posterior medial group arising from posterior cerebral and posterior communicating arteries. Corpus striatum (caudate and putamen) is mainly supplied by anterolateral central branches of the middle cerebral artery and partly by the anteromedial central branches from the anterior and anterior communicating artery. The main supply of the globus pallidus is from the anterior choroidal artery. Medulla is supplied by the various branches of vertebral artery including anterior and posterior spinal artery, posterior inferior cerebellar artery, and small direct branches. Pons is supplied by the branches from the basilar artery (paramedian branches and short and long circumferential branches) (Fig. 1.23).Midbrain is supplied by branches from basilar artery (posterior cerebral, superior cerebellar arteries, and direct branch from basilar artery). Cerebellum is supplied by superior cerebellar, anterior inferior cerebellar of basilar artery, and posterior cerebellar branches of vertebral artery. Cerebral Venous System Venous system of the brain can be divided into a superficial system and a deep system. The superficial system comprises of cortical veins and sagittal sinuses (Fig. 1.25). These drain superficial surfaces of both cerebral hemispheres. The superficial cerebral veins can be divided into three groups.24 A mediodorsal group draining into superior sagittal sinus and the straight sinus; a lateroventral group draining into the lateral sinus; and an anterior group draining into the cavernous sinus. The veins of the posterior fossa may again be divided into three groups: (1) superior group draining into the galenic system, (2) anterior group draining into petrosal sinus, and (3) posterior group draining into the torcular. The superior sagittal sinus drains major part of the cerebral hemispheres (Fig. 1.25). The cavernous sinuses drain blood from the orbits, the inferior parts of the frontal and parietal lobe, and the superior and inferior petrosal sinuses. Blood from them flow into the internal jugular veins. The inferior sagittal sinus runs in the free edge of falx cerebri and unites with the vein of Galen to form the straight sinus. Straight sinus runs backward in the center of the tentorium cerebelli at the attachment of the falx cerebri, emptying into the torcular Herophili at the internal occipital protuberance (Fig. 1.25). The lateral sinuses extend from torcular Herophili to jugular bulbs and consist of a transverse and sigmoid portion. They receive blood from the cerebellum, the brain stem, and posterior parts of the hemisphere. The deep cerebral veins are more important than superficial veins from the angiographic point of view.25 The deep system comprises of lateral sinus, straight sinus, and sigmoid sinus along with draining deeper cortical veins. I. NEUROANATOMY THE MENINGES AND CEREBROSPINAL FLUID 33 FIGURE 1.25 Dural sinus tributaries from the cerebral veins (right lateral view). Venous blood collected deep within the brain drains to the dural sinuses through superficial and deep cerebral vein. The red arrows in the diagram show the principal directions of venous blood flow in the major sinuses. Three veins (choroid vein, septal vein, and thalamostriate vein) unite just behind the interventricular foramen of Monro to form the internal cerebral vein. The internal cerebral veins of each side run posteriorly in the roof of the third ventricle and unite beneath the splenium of the corpus callosum to form the great cerebral vein. The great cerebral vein of Galen is a short (1–2 cm long), thick vein that passes posterosuperiorly behind the splenium of corpus callosum in the quadrigeminal cistern. It receives the basal veins and the posterior fossa veins and drains to the anterior end of the straight sinus where this unites with the inferior sagittal sinus (Fig. 1.25). Both these venous systems mostly drain into internal jugular veins (Fig. 1.25). The cerebral veins and sinuses neither have valves nor tunica muscularis. Because they lack valves, blood flow is possible in different directions. The cortical veins are linked by numerous anastomosis, allowing the development of a collateral circulation and probably explaining the good prognosis of some cerebral venous thrombosis. Lack of tunica muscularis permits veins to remain dilated and prone for venous air embolism during intracranial surgery. The dural sinuses especially the superior sagittal sinus contains most of the arachnoid villi and granulations, in which absorption of CSF takes place. So dural sinus thrombosis blocks villi and leads to intracranial hypertension and papilledema. THE MENINGES AND CEREBROSPINAL FLUID The Meninges The meninges consists of (from outside to inside) dura mater, arachnoid mater, and pia mater. Dura Mater It consists of two layers over the brain, named periosteal and meningeal or investing. The two layers are fused to each other all over, except where the cranial venous sinuses are enclosed between them. The outer periosteal layer: The outer periosteal layer is the periosteum of the inner surface of the skull. It is continuous with the pericranium through the suture and foramina. It is firmly adhered over base, less over the vault except at the suture, where it is attached with pericranium by suture membrane. It ends at foramen magnum. It provides sheath for CNs. Owing to its firm fixation to the base of the skull, it usually is torn in the skull base fracture. Since it forms the wall of basal venous sinuses, a fracture of skull base is often associated with bleeding from ear, nose, or pharynx. I. NEUROANATOMY 34 1. NEUROANATOMY Meningeal layer: This lies close to the brain. It forms four folds by projecting inward to form the folds and thus compartmentalized the cranial cavity into many freely communicating compartments which lodge different parts of brain. The large midline fold separates the two hemispheres and is called the falx. A smaller fold separates the cerebral hemispheres from the cerebellum and is known as the tentorium cerebelli. Where the edges of the falx and tentorium meet the skull, the dura mater encloses large venous sinuses that are responsible for draining venous blood from the brain.26 Falx cerebri: This is a sickle shaped reduplication which intervenes between medial surfaces of two cerebral hemispheres. It contains three venous sinuses: (1) the superior sagittal along its upper border; (2) the inferior sagittal along its lower free border; (3) the straight sinus along its line of attachment to the tentorium cerebelli. Tentorium cerebelli: This is a semilunar reduplication of the dura mater that separates cerebellum from occipital lobes of cerebrum. It therefore forms the roof of posterior fossa of cranium. Its outer convex border is attached to the lips of the transverse sinuses on the occipital bone, mastoid angle of parietal bone, and the superior border of petrous part of temporal bone; and end by attaching posterior clinoid process. It is attached anteriorly to the anterior clinoid process. This border bound to an oval space which is occupied by midbrain. The transverse sinuses lie between the two layers of the tentorium along its posterior border. Superior petrosal sinus lies along its anterior border. Falx cerebelli: It is a small sickle-shaped fold intervening posteriorly between the two halves of cerebellum. Its base is attached to the posterior part of inferior surface of the tentorium cerebelli. Anterior margin is concave and free whereas posterior margin is convex and contains the occipital sinus. Diaphragm sella: It is a fold of dura mater which forms the roof of the pituitary fossa. It has a central opening for emergence of stalk of the pituitary. It encloses intercavernous sinuses. The Spinal Cord The spinal cord is a long cylindrical lower part of CNS confined within the vertebral canal. Spinal cord extends from the level of foramen magnum to end (by conus medullaris) at the first lumbar. So, the rest of lumbar, sacral, and coccygeal part of vertebral canal are free from spinal cord, i.e., the spinal cord is shorter than vertebral canal. The spinal cord itself has thick cervical region (origin of brachial plexus), thin thoracic, and thick lumbosacral (origin of lumbosacral plexus). The lowest part of the spinal cord is conical called conus medullaris. Spinal cord below become fibrous and is called filum terminalis. The spinal cord is developed from the caudal cylindrical part of the neural tube. During intrauterine life, the cord fills the whole length of the vertebral canal. At birth, lower end of the cord is found at the level of the third lumbar vertebrae (L3). In adulthood, the lower end of spinal cord recedes to the first lumbar vertebral (L1). Its adult length is about 45 cm in males and 42 cm in females. Spinal cord is divided into two halves by an anterior median fissure and a posterior median sulcus (Fig. 1.26). The two anterolateral sulci and two posterolateral sulci further divide each halve. Inside the spinal cord, there is a FIGURE 1.26 Spinal cord pathways. I. NEUROANATOMY 35 THE MENINGES AND CEREBROSPINAL FLUID central canal which contains fluid called CFS. The canal is surrounded by gray matter in the form of H-shaped horns. So in each halves the gray matter has larger ventral mass (anterior or ventral) gray column or thin elongated posterior (dorsal) gray column (Fig. 1.26). In some part of the spinal cord a small lateral projection of gray matter is seen. Therefore, there are six horns present in the spinal cord: two dorsal horns, two lateral horns, and two ventral horns (Table 1.2). The gray matter of both halves is connected in the midline by a band of gray matter called gray commissure which is traversed by central canal. Spinal cord gives attachment to series of the spinal nerves on each side. Each spinal nerve is formed by two roots: ventral and dorsal root. Just proximal to the junction of two nerve roots, the dorsal root is marked by a swelling called the dorsal nerve root ganglion or spinal ganglion. There are 31 pairs of spinal nerve (8 cervical, 12 thoracic, 5 lumbar, 5 sacral, 1 coccygeal). As a result of upward migration of cord the roots of the spinal nerve have to follow an oblique downward course to reach appropriate intervertebral foramen. The oblique course and length of the roots is most marked in the lower nerves, and many of these roots occupy the vertebral canal below the level of spinal cord. These roots collectively constitute cauda equine. The spinal cord is also surrounded by the meninges (dura mater, arachnoid mater, and pia mater) in the same way as brain. The dura mater is a thick membrane whereas pia and arachnoid maters are thin. The space between pia mater and arachnoid mater is called as subarachnoid space, which is filled by CSF. The gray matter can also be divided into layers of axon termination, based on cytological criteria. This was first done by the Swedish neuroanatomist Bror Rexed (1914–2002), who divided the gray matter in to laminae I–X. This laminar architecture is especially well defined in the posterior (dorsal) horn, where primary sensory axon makes synapses in specific layers. In the spinal cord, nerve cells are arranged into 10 laminae, which have different properties (Fig. 1.27). Some nuclei (columns of cell bodies) are present throughout the spinal cord gray matter, other nuclei have more restricted segmental distributions (Table 1.3). 1. 2. 3. 4. 5. Lamina I—at the tip of dorsal horns Lamina II until VI—along dorsal horns Lamina VII and VIII—at ventral horns Lamina IX—at anterior part of ventral horns Lamina X—around central canal TABLE 1.2 Horns of the Spinal Cord 2 Dorsal Horns (Sensory Horns) 2 Ventral Horns (Motor Horns) 2 Lateral Horns (Autonomic Horns) Position in spinal cord Along the whole segment of spinal cord Along the whole segment of spinal cord Thoracic segment and lumbosacral segments Functions Sensory functions Motor functions Autonomic functions Nuclei Receive exteroceptive and proprioceptive. The nuclei are: 1. Substantia gelatinosa of Rolandi 2. Main sensory nucleus 3. Nucleus dorsalis of Clarke Supply skeletal muscle. The nuclei are: 1. Anteromedial nucleus 2. Anterolateral nucleus 3. Posteromedial nucleus 4. Posterolateral nucleus 5. Central nucleus Supply visceral structures. The nuclei are: 1. Intermediomedial nucleus 2. Intermediolateral nucleus FIGURE 1.27 Synaptic layers in the gray matter. (A) Cervical cord. (B) Thoracic cord. (C) Lumbar cord. Motor neurons are shown in red and sensory neurons in blue. I. NEUROANATOMY 36 1. NEUROANATOMY In spite of highly organized and complexed structure, spinal nuclei play in the 3 most important basic functions of individual: motor, sensory and autonomic control (Table 1.4). Whole of the gray matter is surrounded by white matter. On each side, there are three columns separated by sensory and motor horns. These are (1) dorsal column, (2) ventral column, and (3) lateral column. Through these columns, there are nerve bundles called tracts running, which are classified into two groups: ascending and descending tracts (Table 1.5). Ascending Tracts of Spinal Cord (Sensory Tracts) Type of Ascending Tracts (Fig. 1.26) 1. Gracile and cuneate (posterior white column) 2. Spinothalamic Lateral and ventral 3. Spinocerebellar Posterior and ventral Pathway of the Ascending Tract Each sensory pathway, from body to the brain is made up of three principal neurons. The cell body of the first neuron is situated in the sensory ganglion of the spinal nerve and extends in the CNS to varying level for different sensibilities. The second neuron crosses to the opposite side and forms fiber bundles known as lemnisci that ascend up to the thalamus. The third-order neuron extends from the thalamus to the sensory cortex, in the form of radiation (Box 1.4). TABLE 1.3 Sensory and Motor Nuclei of Spinal Cord Nuclei Site Functions Substantia gelatinosa of Rolandi At tip of sensory horn of all segments For pain and temperature sensation t G ive first-order neuron of lateral spinothalamic tract. Main sensory nucleus (nucleus proprius) At middle of sensory nucleus in all segments Receive crude and pressure sensation t P rojects first-order neuron of ventral spinothalamic tract Nucleus dorsalis (Clark’s column) At base of sensory horns of all thoracic segment and upper 3 lumbar Receive proprioceptive sensations from collateral branch of gracile tract. t S tarts dorsal spinothalamic tract of same side t S tarts ventral spinothalamic tract of same and opposite side Lateral nucleus (autonomic) At lateral horn of all thoracic segment and upper 3 lumbar, and appear again at sacral 2–4. Autonomic (parasympathetic and sympathetic) Ventromedial motor nucleus At middle part of motor horns in all segment. Effect axial musculature Dorsal-medial motor nucleus At thoracic and upper 3 lumbar Supply axial muscle Ventrolateral and dorsolateral nuclei Along lateral plane of motor horns in cervical and lumbosacral on. Supply axial muscle Central motor In cervical and lumbosacral motor Supply axial muscle TABLE 1.4 Functions of Spinal Cord Sensory t R eceives superficial general sensations from skin and mucous membrane from all of the body except face and other body organs t S uperficial external sensations is called exteroceptive sensations t P roprioceptive sensations receive deep types of sensation from tendons and muscles Motor t M otor nuclei convey efferent fibers that pass through spinal nerves to control all muscles of body except muscles of head and neck Autonomic t S ympathetic nuclei are found at thoracolumbar region of spinal cord which control arrector pili muscle, vasomotor, and dilates the pupil t T hey may join spinal or cranial nerves or may pass directly t P arasympathetic nuclei are located at sacral segments of spinal cord and control sphincters. t T hey give pelvic splanchnic nerve which carries parasympathetic outflow to derivatives of the hind gut I. NEUROANATOMY 37 THE MENINGES AND CEREBROSPINAL FLUID TABLE 1.5 Descending Tracts Tract Origin Site and Course End Lateral corticospinal tract Cortex (premotor and sensory) Posterior limb of internal capsule, middle 2/3 of crus cerebri, pyramid in medulla, decussation at medulla Anterior gray column cells Fine-skilled motor activity, (interneurons and lower modulation of sensory motor neurons) function Anterior corticospinal tract Cortex (premotor and sensory) Posterior limb of Internal capsule, middle 2/3 of crus cerebri, pyramid in medulla, decussation at spinal level they innervate Anterior gray column cells Gross and postural motor (interneurons and lower motor neurons) Corticonuclear Cortex (premotor and sensory) Genu of internal capsule, Cranial nerve nuclei middle 2/3 of crus cerebri, decussation at brainstem Fine-skilled motor activity, modulation of sensory function Rubrospinal tract Red nucleus in midbrain Descends into lateral column of spinal cord just ventral corticospinal tract Facilitator to flexors of opposite limbs Tectospinal tract Superior colliculus nuclei Descends and crosses to Cervical anterior horn cells Visuospinal reflex to move locate on surface of ventral of opposite side eyes and neck toward column. It relays on stimulus reflexly anterior horn nuclei Olivospinal tract Inferior alivary nucleus in medulla Descends without crossing Cervical anterior horn cells Equilibrium and of same side proprioceptive Medial vestibular spinal tract Medial, lateral, and inferior Into medial column vestibular nuclei of same side along anterior median fissure (sulcomarginal) Anterior horn cells of cervical and thoracic regions of same side Equilibrium Lateral vestibular spinal tract Lateral vestibular nucleus in pons Anterior horn cells of all segments of spinal cord of same side Equilibrium Descending on same side on surface of ventral column of all spinal segments Anterior horn motor nuclei of opposite side Function Lateral reticulospinal tract Reticular formation nuclei in medulla of opposite side Lateral column just medial Anterior horn cells of to lateral corticospinal opposite side and lateral tract and in all segments of horn cells (autonomic) spinal cord Facilitatory to extensor muscles through its connection with extrapyramidal center (corpus striatum) and also has pressor and depressor effects on respiration and circulation through its connection with hypothalamus Medial reticulospinal Reticular formation nuclei of pons of same side Descends on same side along ventral white column Anterior horn cells all over the cord of same side and also lateral horn of same side Facilitatory to extensor muscles through its connection with extrapyramidal center (corpus striatum) and also has pressor and depressor effects on respiration and circulation through its connection with hypothalamus (same side like lateral reticulospinal tract) Medial longitudinal fasciculus Vestibular nucleus Anterior column Cervical and midthoracic Coordination of head and anterior column (extending eye movements to upper point of brainstem) I. NEUROANATOMY 38 1. NEUROANATOMY BOX 1.4 O R G A N I Z A T I O N O F A S C E N D I N G P A T H W AY S First-order neuron: dorsal root ganglion (spinal ganglion) Second-order neuron: spinal cord Third-order neuron: posterolateral ventral nucleus of the thalamus Termination: cerebral cortex “postcentral gyrus” FIGURE 1.28 Schematic diagram of spinal cord arterial supply. Function of Ascending Tract 1. Gracile and cuneate tracts: Discriminative touch, vibratory sense, and conscious muscle joint sense (sense of position) 2. Lateral spinothalamic tract: Pain—Temperature 3. Anterior spinothalamic tract: Crude touch—pressure 4. Spinotectal tract: Provides afferent information for spinovisual reflexes and brings movements of the eyes and head toward the source of the stimulation. 5. Spinoolivary tract: Carries unconscious proprioceptive and exteroceptive sensation. 6. Spinocerebellar tract (dorsal and ventral): Carries unconscious proprioceptive sensation. 7. Lissuar’s gelatinosa tract: Links the spinal segments. Both the anterior and posterior spinal arteries are reinforced by the anastomotic arteries entering along the nerve roots. These anastomotic arteries are the special importance at the level of T1 and T11 vertebrae and called the arteries of Adamkiewicz which correspond to the enlarged spinal cord (Fig. 1.28) (Table 1.6). I. NEUROANATOMY THE MENINGES AND CEREBROSPINAL FLUID 39 TABLE 1.6 Arterial Supply of the Spinal Cord (Figs. 1.28 and 1.29) Arteries Origin and Site Course and Supply Single anterior spinal artery From each vertebral artery They unite forming single anterior spinal artery. t S upply anterior column and anterior horn Two posterior spinal arteries From each vertebral artery They did not unite. t P osterior arteries supply posterior column and posterior horn. t T he anterior artery shares in formation of arterial corona (supply lateral column) Lateral spinal arteries From vertebral artery, ascending and deep cervical, and descending aorta at interventricular foramina Each run along the spinal nerve trunk to divide into anterior and posterior radicular arteries. t T hese arteries anastomos with arterial corona to supply lateral column. FIGURE 1.29 Diagrammatic representation of blood supply of spinal cord at single level. Veins Around the Surface of Spinal Cord These six channels are freely connected with each other to encircle the spinal cord by what is called “Vena Corona.” It drains interior of the cord. Then venous blood goes to epidural venous plexus. Obstruction of venous return causes edema of spinal cord with subsequent paralysis. Venous return of the spinal cord is through: 1. 2. 3. 4. 5. One anterior median vein One posterior median vein Two anterior lateral veins Two posterior lateral veins Vena corona Acknowledgment I am thankful to Mr. Anil Kumar, a senior artist from SGPGIMS, Lucknow, for drawing all diagrams given in this chapter. I. NEUROANATOMY 40 1. NEUROANATOMY References 1. Tortora G, Derrickson B, Principle of Anatomy and Physiology: organization, support and movement, and Control system of Human body. 13th ed. Asia: John Wiley and Sons; 2009. 2. Ono M, Kubik S, Aberbathey CD. Atlas of the cerebral sulci. Stuttgart: Georg TheimeVerlag; 1990. 3. Chi JG, Dooling EC, Gilles FH. Gyral development of the human brain. Ann Neurol January 1977;1(1):86–93. 4. Kosslyn S. Cognitive psychology: mind and brain. New Jersey: Prentice Hall; 2007. p. 21. 194–9, 349. 5. http://www.ruf.rice.edu/∼lngbrain/cglidden/parietal.html. 6. SparkNotes: brain anatomy: parietal and occipital lobes. Archived from the original on 2007-12-31. 7. Loukas M, Pennell C, Groat C, Tubbs RS, Cohen-Gadol AA. Korbinian Brodmann (1868–1918) and his contributions to mapping the cerebral cortex. Neurosurgery January 2011;68(1):6–11. discussion 11. 8. Garey LJ. Brodmann’s localisation in the cerebral cortex. New York: Springer; 2006. 9. Taylor I, Taylor MM, Psycholinguistics: Learning and using Language, Lincolnshire: Anybook Ltd; 1990, 362. 10. Stocco A, Lebiere C, Anderson JR. Conditional routing of information to the cortex: a model of the basal ganglia’s role in cognitive coordination. Psychol Rev April 2010;117(2):541–74. 11. FitzGerald MJT, Folan-Curran J. 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Sci Am December 1997;277(6):72. 20. Barkar AB. Cerebrovascular disease. IX. The medullary blood supply and the lateral medullary syndrome. Neurology October 1961;11:852–61. 21. Gan R, Noronha A. The medullary vascular syndromes revisited. J Neurol March 1995;242(4):195–202. 22. Olson DM, Graffagnino C. Consciousness, coma, and caring for the brain-injured patient. AACN Clin Issues October–December 2005;16(4):441–55. 23. Skinner RD, Homma Y, Garcia-Rill E. Arousal mechanisms related to posture and locomotion: 2. Ascending modulation. Prog Brain Res 2004;143:291–8. Review. 24. Einhaupl KM, Masuhr F. Cerebral venous and sinus thrombosis – an update. Eur J Neurol 1994;1:109–26. 25. Dora F, Zileli T. Common variations of the lateral and occipital sinuses at the confluence sinuum. Neuroradiology 1980;20:23–7. 26. Sinnatamby CS, Last RJ. Last’s anatomy: regional and applied. 11th ed. Churchill Livingston; 2006. I. NEUROANATOMY C H A P T E R 2 Neuroembryology G.P. Singh AIIMS, New Delhi, India O U T L I N E Formation of Zygote 41 Formation of Blastocyst 41 Formation of Embryonic or Germ Disc 42 Formation of Definitive Notochord 44 Development of Nervous System Development of Brain 45 46 Prosencephalon Mesencephalon Rhombencephalon 46 47 47 Development of Spinal Cord Development of Peripheral Nervous System Spinal Nerve Autonomic Nervous System References 48 49 49 49 50 Embryology is a branch of science that is related to the formation, growth, and development of embryo. It deals with the prenatal stage of development beginning from formation of gametes, fertilization, formation of zygote, development of embryo and fetus to the birth of a new individual.1,2 Two basic processes involved during conversion of a single-celled zygote to a complex, multicellular organism are growth and differentiation. Growth occurs by increase in cell number (cell division and multiplication) or cell size. On the other hand, cell differentiation is a complicated process in which the cell acquires special characteristics to perform specific functions. These lead to the formation of various tissues and organs assigned to perform specific functions.2 FORMATION OF ZYGOTE The germ cells or gametes (sperm and ovum) are specialized haploid cells (with 23 unpaired chromosomes in human). Fertilization results in union of the gametes (i.e., fusion of sperm with ovum, Fig. 2.1) to form an undifferentiated, mononucleated, diploid cell (with 23 pairs or 46 chromosomes) called zygote. The fertilization usually takes place in the ampulla or lateral third of fallopian tube. After fertilization, the fertilized egg travels down the fallopian tube to reach the uterus.2,3 FORMATION OF BLASTOCYST The single-celled zygote (Fig. 2.2) divides repeatedly by mitotic division thereby retaining the same number of chromosomes (i.e., 46 chromosomes) in each of the two daughter cells. The cells so formed are called blastomeres, and the process of division is called cleavage (Fig. 2.2). Thus a single-celled zygote results in the formation of a mass of cell called morula (16- to 32-celled stage). The inner cells of the morula called the inner cell mass gives rise to embryo proper, and the outer layer of cells called the outer cell mass forms the covering of embryo and contributes to formation of placenta. As the cells of Essentials of Neuroanesthesia http://dx.doi.org/10.1016/B978-0-12-805299-0.00002-6 41 © 2017 Elsevier Inc. All rights reserved. 42 2. NEUROEMBRYOLOGY FIGURE 2.1 Fertilization of an ovum by sperm. FIGURE 2.2 A single-celled zygote results in formation of morula (16- to 32-cell stage) and blastocele by the process of multiple cell division called cleavage. morula continue to divide, fluid from uterine cavity enters the intercellular spaces between the inner and outer cell mass. Later the intercellular spaces fuse to form a single cavity called blastocele, and this stage of embryo is called blastocyst.2 The cells of the inner cell mass are pushed to one side of blastocyst and this side of blastocyst is known as the embryonic pole. The cells of the inner cell mass are called embryoblast cells. The cells of outer cell mass flatten and form the wall of blastocyst and are called trophoblast cells (Fig. 2.2). The trophoblast cells covering the embryonic pole have the property to invade the epithelial cells of uterine mucosa and thus get attached to uterus. After fertilization in the fallopian tube, as the fertilized egg (zygote) divides repeatedly to form morula, it travels down the fallopian tube to reach the uterine cavity. The morula reaches the uterine cavity on the third to fourth day of fertilization. On day 5, blastocyst is formed, which adheres to uterine mucosa on the sixth day of fertilization and gets implanted in the uterus. FORMATION OF EMBRYONIC OR GERM DISC During the second week of development, the cells of the inner cell mass (embryoblasts) differentiate and organize into two epithelial layers—the inner layer of cuboidal cells or hypoblast on the ventral surface that faces the blastocyst cavity and the outer layer of columnar cells or epiblast on the dorsal surface. These layers together form the bilaminar germ disc or embryonic disc (Fig. 2.3).2,4,5 The trophoblasts start forming the placenta. Fluid begins to collect between the cells of outer layer (epiblast cells) and the trophoblasts and forms a fluid-filled cavity known as amniotic cavity. The epiblast cells proliferate and migrate to line the roof of amniotic cavity. These cells are called amniogenic cells. Similarly, the hypoblast cells facing the blastocyst cavity proliferate and migrate to line the blastocyst cavity to form the yolk sac (Fig. 2.3).5 I. NEUROANATOMY FORMATION OF EMBRYONIC OR GERM DISC 43 FIGURE 2.3 Formation of bilaminar germ disc. FIGURE 2.4 Germ disc or embryonic disc as seen from dorsal aspect after opening the amniotic cavity. (A) Appearance of primitive streak and primitive node. (B) Growth of embryonic disc due to migration of cells from primitive streak. Formation of prechordal plate and notochordal process. FIGURE 2.5 Formation of trilaminar germ disc. During the third week of embryonic development, bilaminar germ disc is converted to trilaminar germ disc with the formation of the three primary germ layers—ectoderm, mesoderm, and endoderm.4,5 This process is called gastrulation, which begins with the appearance of primitive streak (characterized by narrow median groove with slight raised margins) on the outer surface (epiblast) of the embryonic disc. At the cranial end of this streak there is a primitive node (Hensen’s node), the center of which presents a depression called primitive pit (Fig. 2.4A). The cells of the epiblast migrate toward the primitive streak, get detached from the epiblast layer, and come to lie underneath it (Fig. 2.5). This is called invagination. Some of these invaginated cells displace the hypoblast cells from the endoderm I. NEUROANATOMY 44 2. NEUROEMBRYOLOGY FIGURE 2.6 Formation of definitive notochord. (A) Sagittal section of the embryonic disc showing the notochordal process (hollow) between the ectoderm and endoderm layers. The base of this process fuses with endoderm cells and then both disappear thus forming a communication between the amniotic cavities and the yolk sac called the neurenteric canal. (B) Cross-section through the embryonic disc which shows roof of opened notochordal process forming the notochordal plate. (C) Notochordal plate detaches from the endoderm to form the solid cord-like structure called definitive notochord (lying in the intraembryonic mesoderm). while others migrate to occupy the space between the epiblast and hypoblast (endoderm) cell layers to form the third germ layer—the intraembryonic or secondary mesoderm.2,5 The remaining cells of epiblast forms the ectoderm. The three germ layers thus formed give rise to all the tissues and organs in the embryo. FORMATION OF DEFINITIVE NOTOCHORD At the cephalic end of the germ or embryonic disc, some of the endodermal cells thicken to form an oval plate called the prechordal plate (Fig. 2.4B).2,4 The prechordal plate decides the cephalic end of the embryo. The intraembryonic mesoderm extends between the ectoderm and endoderm over the entire embryonic disc except at two sites—one in the region of prechordal plate and the other caudal to primitive streak. At these sites, the endoderm is closely adherent to overlying ectoderm without mesoderm in between forming two bilayered membranes—the buccopharyngeal membrane (cranially) and the cloacal membrane (caudally) (Fig. 2.4). Buccopharyngeal membrane is the site for future oral opening and cloacal membrane for anal opening.4 The embryonic disc grows more at the cephalic end than the caudal end because of continuous migration of cells from primitive streak and primitive node in the cephalic direction. This causes the rounded embryonic disc to become elongated with broad cephalic and narrow caudal end (Fig. 2.4B).4 The primitive streak regresses after the third week and finally disappears. The primitive pit surrounded by cord of cells extends in cephalic direction from primitive node to the prechordal plate in midline and lies between the ectodermal and endodermal layers. This canalized cellular cord is called notochordal process (Fig. 2.4B). This process cannot extend beyond the prechordal plate as the endoderm and ectoderm are firmly adherent to each other here.2 The cells in the floor of the notochord canal fuse with the endoderm cells beneath it (which forms roof of yolk sac) and subsequently both group of cells disappears in craniocaudal direction. Thus, the yolk sac communicates with amniotic cavity through primitive pit. This temporary communication between the two cavities is called neurenteric canal, which later gets closed (Fig. 2.6A). The notochord process now forms a notochordal plate along the roof of the yolk sac (Fig. 2.6B). Later this plate folds along its long axis and separates from the roof of yolk sac, which is now lined by endoderm. This chord of cells is known as definitive notochord (Fig. 2.6C).5,6 I. NEUROANATOMY DEVELOPMENT OF NERVOUS SYSTEM 45 FIGURE 2.7 Stages in the formation of neural tube and neural crest cells. Formation of (A) neural plate (B,C) neural fold, neural groove and neural crest cells and (D) neural tube with neural canal. FIGURE 2.8 Differentiation of neural tube into different layers and formation of alar and basal plates. DEVELOPMENT OF NERVOUS SYSTEM The nervous system develops from the ectodermal cell layer. During the fourth week, the individual differentiation of the three germ layers and formation of the folds of embryo occur. The ectoderm cell overlying the notochord thickens to form neural plate (Fig. 2.7A). The cells of neural plate are called neuroectodermal cells, which later give rise to nervous system.5,7,8 The lateral margins of the neural plate become raised to form the neural folds forming a longitudinal groove in between known as neural groove (Fig. 2.7B). The margins of the neural fold are lined by special neuroectodermal cells called the neural crest cells (Fig. 2.7B,C). Gradually, the neural folds come close to each other and fuse dorsally to form a hollow tune known as neural tube (Fig. 2.7D). The fusion begins at the future cervical region and then proceeds both in cranial and caudal direction. The process of conversion of neural plate into the neural tube is known as neurulation. The neural tube initially has the openings at the cephalic and caudal ends known as anterior and posterior neuropores, respectively. These openings get closed by the end of 4 weeks, thus giving rise to a completely closed, hollow neural tube from which the central nervous system (brain and spinal cord) develops. Later, the dorsal surface of the neural tube gets detached from the surface ectoderm, and the neural tube comes to lie underneath the surface ectoderm (Fig. 2.7D). The neural crest cells dissociate from the neural tube (Fig. 2.7D) and migrate to form melanocytes in skin and hair, dorsal root ganglion (DRG), sympathetic ganglion, enteric neurons, cells of adrenal medulla, and Schwann cells. The cranial part of the neural tube enlarges and gives rise to the brain while the narrow caudal part forms the spinal cord. The cavity of the neural tube, known as neural canal, gives rise to the ventricles of the brain and the central canal of spinal cord. The peripheral nervous system (PNS) I. NEUROANATOMY 46 2. NEUROEMBRYOLOGY FIGURE 2.9 Development of central nervous system (brain and spinal cord) from the neural tube. (A) Anterior part enlarges to form the three primary vesicles of brain while the narrow posterior part forms the spinal cord. (B) Primary and secondary vesicles of the brain develop into various parts of brain. The cavity of the neural tube gives rise to ventricles of brain and central canal of spinal cord. AS, aqueduct of Sylvius; FV, fourth ventricle; LV, lateral ventricle; TV, third ventricle. (which includes spinal, cranial and autonomic nerves, and their ganglia) is derived partly from the neural tube and partly from the neural crest cells.5 As the growth occurs, the lateral walls of the neural tube thicken by proliferation of the cells lining the tube called neuroepithelial cells. However, the roof and floor of neural tube remain thin. These neuroepithelial cells differentiate into two types of cell—the neuroblasts that form the neurons and gliablasts that forms the glial cells (astrocytes and oligodendrocytes). The neuroblasts form a layer around the neuroepithelium called the mantle layer that forms the gray matter of brain and spinal cord. The axons of these neuroblasts form the marginal layer outside the mantle layer that forms the white matter. The neuroepithelial cells layer around the neural canal form the ependymal or germinal layer (Fig. 2.8). The thickened lateral wall of neural tube gets divided into an alar plate dorsally and a basal plate ventrally by a longitudinal groove called sulcus limitans (Fig. 2.8).5 Development of Brain The cephalic portion of the neural tube enlarges to form three successive dilatation (separated by two circular constrictions) known as primary brain vesicles (Fig. 2.9). These are prosencephalon or forebrain vesicle, mesencephalon or midbrain vesicle, and rhombencephalon or hindbrain vesicle, which later form the forebrain, midbrain, and hindbrain, respectively. Two evaginations appear one on each side of forebrain vesicle (prosencephalon) and divide it into an anterior part called telencephalon (which includes the two evaginations and the area intervening between them) and a posterior part called diencephalon. The hindbrain (rhombencephalon) vesicle is also subdivided into an anterior part called metencephalon and a posterior part called myelencephalon. The cavities of the telencephalon, diencephalon, mesencephalon, and rhombencephalon form the lateral ventricles, third ventricle, aqueduct of Sylvius, and the fourth ventricle, respectively (Fig. 2.9).2–7 All these cavities are connected with each other and caudally with the cavity of the spinal cord. Each lateral ventricle is connected to the third ventricle through the interventricular foramen of Monro. The third ventricle in turn is connected to the fourth ventricle through aqueduct of Sylvius. The fourth ventricle communicates caudally with the central canal of spinal cord and subarachnoid space around the brain through foramen of Luschka and Magendie. This forms a continuous channel for the flow of cerebrospinal fluid (CSF). Prosencephalon It includes telencephalon and diencephalon and forms the forebrain. Telencephalon It gives rise to the two cerebral hemispheres and corpus striatum. The telencephalon consists of two lateral outbulgings or evaginations (telencephalic vesicles), which form the right and left cerebral hemispheres and (a median portion between the two evaginations) lamina terminalis. As the telencephalic vesicles increase in size, they completely I. NEUROANATOMY DEVELOPMENT OF NERVOUS SYSTEM 47 cover the lateral aspect of diencephalon and eventually fuse with it. With further expansion of telencephalic vesicles (in upward, forward, and backward direction), the two vesicles forming cerebral hemisphere come to lie in opposition to each other. Due to the growth of the telencephalic vesicles in the anteroposterior direction, the frontal and occipital lobes are formed taking the cavity along with it (forming anterior and posterior horn of lateral ventricle). The upward expansion forms the parietal lobe. The posterior part of the telencephalic vesicle also grows downward and forward forming the temporal lobe into which extends the inferior horn of the lateral ventricle. Thus the lateral ventricle now becomes C-shaped. Due to enlargement of telencephalon, the medial surfaces of the two cerebral hemispheres lie opposite to each other with a groove in between. The floor of this groove is formed by the roof of the third ventricle (diencephalon). Just above the floor of this groove, the medial wall of each hemisphere invaginates into the lateral ventricle forming the choroid fissure. A fold of piamater extends into this fissure and forms the telachoroidea in which lies bundle of capillaries forming choroid plexus. Immediately above the choroid fissure, the wall of each cerebral hemisphere thickens to form hippocampus, which bulges into the lateral ventricle on each side.5 Corpus striatum develops from the wall of the telencephalon. The floor of the developing hemispheres thickens to form corpus striatum that bulges into the floor of the lateral ventricles. The growth of the temporal lobe carries the caudal part of the corpus striatum along with it into the roof of inferior horn of the lateral ventricle. Thus, the corpus striatum becomes a C-shaped structure. As the axons of developing neurons grow to make connections between the cerebral hemisphere and other areas of brain and spinal cord, they pass through the corpus striatum and divide it into dorsomedial part (caudate nucleus) and ventrolateral part (lentiform nucleus). The developing axon collectively forms the fiber bundle known as internal capsule. The caudate nucleus is C-shaped and consists of head, body, and tail. The head and body lie in the floor of the lateral ventricle and the tail in the roof of the inferior horn of lateral ventricle. The tail ends in an enlargement known as amygdaloid body. The lentiform nucleus is later divided into putamen and globus pallidus. The cerebral cortex overlying the corpus striatum grows at a relatively slower rate, so that it gets completely buried by the adjoining lobes. This area is called as insula, with the overlying lobes forming the operculum.5 A groove appears on the under surface of the telencephalic vesicles in the anteromedial part, which evaginates rostrally. It outgrows as a solid structure forming the olfactory tract and dilates at the distal end to form the olfactory bulb. The area where the olfactory tract is attached to the under surface of brain is known as the piriform area.2 The growth of the surface of cerebral hemisphere (i.e., cerebral cortex) is more than the hemisphere as a whole. Thus, the cortex is thrown into folds which form the sulci and gyri on the surface. The axons of the cortical neurons grow toward the other areas of the same cortex (association fibers) or opposite cortex (commissural fibers) or to other regions of brain such as brain stem or spinal cord (projection fibers). Axons also connect basal ganglia, hypothalamus, and thalamus to each other and to the cerebral cortex. Also there are axons projecting from the spinal cord and brain stem to thalamus and cerebral cortex. All these constitute the white matter of the cerebral hemisphere. The corpus callosum is the largest bundle of commissural fibers connecting the two cerebral hemispheres.5–8 Diencephalon It gives rise to thalamus, hypothalamus, epithalamus, optic cup, and stalk and pars nervosa of pituitary gland. The cavity of diencephalon forms the third ventricle of brain. Diencephalon gets hidden from the surface due to growth of telencephalic vesicles which covers it completely. The roof of diencephalon is a thin plate formed by single layer of ependymal cells. The posterior of the roof plate thickens in midline to form the pineal gland or epiphysis. Above the roof lies the mesoderm into which the capillary vessels grow. This plexus of capillaries together with single layer of ependymal cells of the diencephalon forms the choroid plexus which projects from the roof into the third ventricle. The alar plate forms the lateral wall of diencephalon. Two grooves (epithalamic and hypothalamic sulci) appear and divide the lateral wall (alar plate) into three regions. Region above the epithalamus sulcus forms the epithalamus, region dorsal to hypothalamic sulcus (between the epi- and hypothalamic sulcui) forms the thalamus, and region ventral to the hypothalamic sulcus forms the hypothalamus. On ventral surface of hypothalamus, a group of cells form a midline structure called mammillary body on each side.2–5 Mesencephalon It gives rise to midbrain and its cavity forms the aqueduct of Sylvius. Midbrain mainly contains axons (fiber tracts) connecting the forebrain to the hindbrain or spinal cord and some group of cell bodies called nuclei. The basal and alar plates of mesencephalon give rise to important nuclei. The basal plate gives rise to nucleus of oculomotor, trochlear nerves, and the Edinger–Westphal nucleus while the alar plate gives rise to superior and inferior colliculus, red nucleus, and substantia nigra. The marginal layer of basal plate expands to form the crus cerebri.2,4 Rhombencephalon It gives rise to hindbrain and consists of two parts—metencephalon cranially and myelencephalon caudally. The cavity of rhombencephalon forms the fourth ventricle. I. NEUROANATOMY 48 2. NEUROEMBRYOLOGY Metencephalon It forms the pons and cerebellum. Pons develops from ventral part of metencephalon. The lateral wall of metencephalon becomes everted so that the alar plate comes to lie on the dorsolateral aspect of basal plate and the roof of the metencephalon becomes wide and thin. These plates give rise to various nuclei in the region of pons. From the basal plate develops the abducent nerve nucleus, motor nuclei of trigeminal and facial nerves, and the superior salivatory nucleus of facial nerve while the alar plate gives rise to cranial part of dorsal nucleus of vagus, pontine part of nucleus tractus solitaries, pontine part of sensory nucleus of trigeminal nerve, and nuclei of vestibulocochlear nerve. The nuclei of basal and alar plates are arranged on the dorsal aspect of pons and together they form the tegmentum of pons. Some neurons from alar plate migrate ventrally and form pontine nuclei. Marginal layer of basal plate expands through which fibers connecting the cerebral cortex and cerebellum to medulla and spinal cord cross. Hence the name pons, meaning bridge. The cerebellum develops from alar plates of metencephalon. The margins of the alar plates that attach to the roof of metencephalon bend medially to form the rhombic lip bilaterally.2–6 The rhombic lips are wide apart in the caudally but are close to each other cranially. The cells of rhombic lip proliferate to form the cerebellar plates. These cerebellar plates grow to form the cerebellum. The median portion forms the vermis, and the lateral portion forms the cerebellar hemispheres. As further growth occurs, numerous fissures appear on its surface and divide it into lobes and folia. Axon (white fibers) connecting the cerebellum to the cerebral cortex, pons, and medulla or spinal cord form the superior, middle, and inferior cerebellar peduncles, respectively.5 Myelencephalon Myelencephalon gives rise to medulla oblongata. Medulla oblongata has a closed lower part with a central canal and an open upper part forming the caudal area of the fourth ventricle. Like pons, the lateral wall is everted so that the alar plate comes to lie dorsolateral to basal plate and the roof is stretched. The cells of the basal and alar plates give rise to various nuclei. The basal plate forms the hypoglossal nucleus, nucleus ambiguous (which contributes fibers to glossopharyngeal, vagus, and accessory nerves), dorsal nucleus of vagus nerve, and inferior salivatory nucleus of glossopharyngeal nerve. The alar plate contributes to dorsal nucleus of vagus, nucleus of tractus solitarius, spinal nucleus of trigeminal nerve, cochlear and vestibular nuclei.2 The roof plate of myelencephalon is thin, which is formed by single layer of ependymal cells. Over it lies the piamater derived from vascular mesenchyme. The pia along with ependymal cells forms the telachoroidea into which tuft of capillaries grow. This plexus of capillaries is called choroid plexus that bulges from roof of the fourth ventricle and produces CSF. At three areas the roof the fourth ventricle bulges and finally ruptures forming the foramen of Magendie in the middle and foramen of Luschka on each side.2 Development of Spinal Cord The caudal part of the neural tube develops into the spinal cord (Fig. 2.9). The thickened lateral wall of neural tube gets divided into an alar plate dorsally and a basal plate ventrally by a longitudinal groove called sulcus limitans (Fig. 2.10A). The basal plate forms the motor area of spinal cord containing the motor horn cells ventrally. The alar plate forms the sensory area of the spinal cord containing sensory horn cells dorsally. Another group of neurons appear in the thoracolumbar region of the spinal cord (T1-L3) between the ventral and dorsal horn cells. These form the intermediate horn and are concerned with sympathetic nervous system. The enlargement of the basal plate on either side forms a furrow ventrally in the midline called the anterior or ventral median fissure.5 FIGURE 2.10 Development of spinal cord from the lower part of the neural tube. (A) The neural tube is divided into alar and basal plates by sulcus limitans. (B) The alar plate forms the dorsal or sensory horn while the basal plate forms the ventral or motor horn of the spinal cord. I. NEUROANATOMY DEVELOPMENT OF NERVOUS SYSTEM 49 FIGURE 2.11 Transverse section of spinal cord. Each spinal nerve is attached to the spinal cord through the dorsal (sensory) root and ventral (motor) root. Both the spinal nerve roots join to form the trunk of spinal nerve which then divide into dorsal and ventral primary rami. Initially, the spinal cord extends throughout the length of developing vertebral column. However, the vertebral column grows faster in length than the spinal cord, so that the spinal cord ends at the level of the third lumbar vertebrae at birth and at lower border of the first or upper border of the second lumbar vertebrae in adults.5 Below this level the nerve roots of spinal nerve extends toward the corresponding intervertebral foramina as a bundle of nerve roots known as cauda equina. Development of Peripheral Nervous System The PNS consists of the spinal and cranial nerves and the autonomic (sympathetic and parasympathetic) nervous system. Spinal Nerve Each spinal nerve is connected to the spinal cord by the dorsal (sensory) and ventral (motor) nerve roots (Fig. 2.11). The axons of the basal plate neurons (motor neurons) pass through the marginal layer and form the ventral or motor root of spinal nerve. The dorsal or sensory root of spinal nerve is formed by the axon of neurons located in DRG of each spinal nerve. The DRG is formed by the neural crest cells. The cells in the DRG give two processes. The central process migrates toward the spinal cord and reaches the spinal cord along the dorsal root of spinal nerve. The peripheral process moves peripherally and joins the fibers of the ventral root to form the nerve trunk of spinal nerve which then divides into the dorsal and ventral primary rami and supplies the skin, joints. and muscles of a specific region of the body (Fig. 2.11). The peripheral process of DGR neurons thus reaches the sensory receptors in the distribution of spinal nerve. These neurons carry sensory impulse from periphery to spinal cord.5,6 The fibers that form the peripheral nerves and constitute the PNS, are covered by a sheath around them called neurilemma. This sheath is formed by the Schwann cells which are derivatives of neural crest cells. The Schwann cells form the myelin sheath around the axons in the peripheral nerves.2,4 The axons of DRG, which reach the spinal cord through the dorsal root either synapse with neurons of alar plate or ascend without synapsing through the marginal layer. The axons of the alar plate neurons also ascend through the marginal layer. The axons (ascending in the marginal layer) form the ascending tracts. The descending tracts are formed by the axons of neurons in the brain, which descends in the marginal layer. These axons synapse with the neurons of ventral basal plate and carry motor impulse from the brain. Due to formation of dorsal and ventral horns by the mental layer (gray matter), the marginal layer (white matter) gets organized into the anterior, lateral, and posterior columns having the fibers of ascending and descending spinal tracts.5 Autonomic Nervous System Sympathetic Nervous System It consists of a pair of sympathetic trunks which are elongated chains of sympathetic nerve fibers running along each side of vertebral column with number of sympathetic ganglia along its length.9 The cells of sympathetic ganglia arise from the neural crest cells. The neural crest cells migrate to lie posterior to aorta (to form sympathetic ganglia) or in front of aorta (to form preaortic ganglia such as celiac ganglia). The axon from the intermediate horn of spinal cord migrates toward the sympathetic ganglia by passing through the ventral root of spinal nerve to reach the sympathetic ganglia via white rami communicantes. These are known as preganglionic fibers and are myelinated. These axons either I. NEUROANATOMY 50 2. NEUROEMBRYOLOGY FIGURE 2.12 Arrangement of pre- and postganglionic sympathetic nerve fibers. make connections with the neurons in the same sympathetic ganglia or travel up or down through the sympathetic chain without synapsing to other sympathetic ganglia and synapse there. The axons of the neurons in the sympathetic ganglion pass back through gray rami communicantes to reach the spinal nerves (Fig. 2.12). These are the nonmyelinated postganglionic sympathetic fibers which supply blood vessels, hairs, sweat glands of skin through spinal nerves. A few preganglionic sympathetic fibers may leave the sympathetic trunk, without synapsing, via the visceral branches of sympathetic trunk such as cardiac, pulmonary, or splanchnic nerves to reach the autonomic nerve plexuses and synapse in these plexuses. The postganglionic fibers supply the various visceral organs such as heart, lungs, intestine, etc. (Fig. 2.10).5,9,10 Parasympathetic Nervous System The parasympathetic fibers emerge from the brain and sacral segment of spinal cord along with the cranial and sacral spinal nerves (craniosacral outflow). The parasympathetic neurons are located in the brain stem associated with the nuclei of origin of cranial nerves III, VII, IX, and X.9,10 The axons of these neurons pass through the corresponding cranial nerves to synapse in the peripheral parasympathetic ganglia. These axons constitute the preganglionic parasympathetic fibers. The postganglionic fibers from these ganglions are short, nonmyelinated and supply various glands, eye, thoracic, and abdominal viscera. In the sacral region, the parasympathetic neurons are located in the gray matter of the second, third, and fourth sacral segment of spinal cord. The preganglionic parasympathetic fibers (myelinated) emerge through the ventral root of corresponding sacral spinal nerves and reach the pelvic autonomic plexuses passing through the pelvic splanchnic nerves and synapse here. The postganglionic (nonmyelinated) fibers innervate the pelvic viscera and part of large intestine.11 References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Balinsky BI, Fabian BC, editors. An introduction to embryology. 5th ed. Philadelphia: WB Saunders Co.; 1981. Dutta AK, editor. Essentials of human embryology. 3rd ed. Calcutta: Current Books International; 1995. Austin CR, Short RV, editors. Reproduction in mammals. 2nd ed. Cambridge: Cambridge University Press; 1984. Singh I, editor. Human embryology. 10th ed. New Delhi: Jaypee Brothers Medical Publishers Ltd; 2014. Kumar R, editor. Human embryology. 1st ed. New Delhi: Top Publishing Company; 2011. Carlson BM, editor. Human embryology and developmental biology. Philadelphia (PA): Elsevier Saunders; 2013. Schoenwolf GC, Bleyl SB, Brauer PR, Francis-West, editors PH. Larsen’s human embryology. 5th ed. Philadelphia (PA): Elsevier Saunders; 2015. Sadler TW, editor. Langman’s medical embryology. 12th ed. Philadelphia: Lippincott Williams and Wilkins; 2012. Snell RS, editor. Clinical anatomy for medical students. 5th ed. Boston: Little Brown and Company (inc.); 1995. Young PA, Young PH, Tolbert DL, editors. Basic clinical neurosciences. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 2008. Singh, editor I. Textbook of anatomy. 5th ed. New Delhi: Jaypee Brothers Medical Publishers; 2011. I. NEUROANATOMY C H A P T E R 3 Blood–Brain Barrier A.K. Khanna, E. Farag Cleveland Clinic Foundation, Cleveland, OH, United States O U T L I N E Introduction 51 Permeability at the Blood–Brain Barrier 51 Anesthetic Neuroprotection in Perioperative Neurological Injury 54 Antiinflammatory Effects of General Anesthetics in the Treatment of Refractory Status Epilepticus 55 Antiinflammatory Considerations in Barbiturate Induced Coma for Traumatic Brain Injury 55 Cellular and Molecular Effects of Anesthetics on the Blood–Brain Barrier 52 Anesthesia and Nitric Oxide Signaling 52 Anesthesia Effects on Tight Junctions 52 Anesthesia Effects on Endothelial Cells 53 Anesthesia and Neuroinflammation 53 Clinical and Experimental Implications of Anesthetics on the Blood–Brain Barrier Conclusion 56 References 56 54 INTRODUCTION The blood–brain barrier (BBB) maintains the brain parenchyma and blood components in separate compartments. In addition, by allowing glucose transport it helps fuel neuronal function. Maintenance of the integrity of this closed compartment comprises a dynamic combination of vascular, cellular, molecular, and ionic factors.1 Structurally, this barrier is composed of endothelial cells supported mainly by astrocytes and pericytes. BBB endothelial cells also have a transport function that acts to maintain a constant parenchymal milieu. Endothelial cells transport amino acids, participate to ionic homeostasis, and allow a controlled exchange of solute and water. Importantly, a variety of traumatic and nontraumatic inflammatory insults to the BBB may lead to a loss of the closed compartment and consequences of such. The anesthesiologist must be aware that interventions such as cardiopulmonary bypass,2,3 cerebral arteriography,4 and osmotic BBB opening5 have all been linked to impairment of cerebral homeostasis in patients. We will focus our text to the effects of anesthetics on the BBB and clinical implications of the same. PERMEABILITY AT THE BLOOD–BRAIN BARRIER Structurally, the brain microvasculature is lined with endothelial cells that are secured together by tight junctions (TJs). These TJs provide a means to regulate movement of substances into and out of the brain. The lipid bilayer of these endothelial cells allows movement and determines permeability across the BBB. Substances do not cross through the alternative paracellular route.6 Essentials of Neuroanesthesia http://dx.doi.org/10.1016/B978-0-12-805299-0.00003-8 51 © 2017 Elsevier Inc. All rights reserved. 52 3. BLOOD–BRAIN BARRIER Translated into clinical practice, this unique structure means that the BBB does not allow a majority of CNS drugs to enter the brain parenchyma.7 Interestingly anesthetics are an important exception in that they freely exert CNS effects, and it has been proven that the lipophilicity of these agents drives them to cross the BBB. The log octanol/water partition coefficient has a significant role in predicting how and if compounds will cross the BBB. Typically this coefficient is determined using an aqueous substance (water) and a hydrophobic substance (octanol). Compounds with a high log (P) favor hydrophobic compartments and will cross a lipid bilayer while compounds with a low log (P) will tend to stay in hydrophilic compartments (e.g., serum) and will not cross the BBB.8 As a general rule, compounds with a log (P) > 0 will cross the BBB rapidly with the major limiting factor being supply of the drug. On the other hand, compounds with a log (P) < −1 are limited in their ability to cross the BBB.9 Importantly, log (P) is a velocity, and therefore a higher value is necessary for a clinically relevant effect. It is indeed in actuality a pharmacokinetic property that allows anesthetic agents to move from blood to brain. Also, compounds with similar log (P)s can have differing ability to cross the BBB.9 To cross the BBB efficiently, a number of conditions must be met: (1) Larger compounds (greater than 400 Da) require some additional transport mechanism to cross the BBB. These are too large to pass through TJs or directly across the lipid bilayer. (2) Many drugs have changes in ionization states that affect the ability of a drug to cross the BBB. (3) Hyperthermia enhances while hypothermia impedes BBB permeability. (4) Highly regulated mechanisms of transport by BBB endothelial cells. This type of facilitated transport is dependent on membrane receptors and is the major mechanism of transport regulation across the BBB (most notably glucose).10 CELLULAR AND MOLECULAR EFFECTS OF ANESTHETICS ON THE BLOOD–BRAIN BARRIER Anesthetic agents may interact in several different ways with the BBB. This is because the same anesthetic agent establishes a different relationship with the target, signaling pathway, and pathology involved. Both direct and indirect effects of anesthetic agents on the molecular components of BBB integrity may affect these signaling pathways. At the cellular level several changes may be important such as tight and adherens junctions, vasodilation, endothelial cell survival, and neuroinflammation.11–15 Therefore, anesthetic action at the BBB depends upon the extent to which the agent modulates these pathways of signal transmission and in addition the systemic cerebral milieu in which it is administered. Anesthesia and Nitric Oxide Signaling Anesthetics have a varied effect on nitric oxide (NO) signaling pathways. NO is a signaling molecule and potent vasodilator that has been effective in ischemic preconditioning and, at low levels, shown to induce neuroprotection mediated by the BBB. NO has important downstream effects such as vascular regulation, mediation of neuroinflammation, and regulation of endothelial cell survival.15–17 Volatile anesthetics result in potent cerebral vasodilation that in turn can induce endothelial stretching, increasing the gap between neighboring endothelial cells, and hence BBB permeability.12,13 These agents act in part via modulation of NO signaling (via nitric oxide synthase iNOS) and regulation of ATP-sensitive K+ channels in vascular smooth muscle cells.11 Let us look at isoflurane as a specific example. Isoflurane can induce nitric oxide synthase (iNOS)-dependent cerebral vasodilation and also neuroprotection via NO downstream effects. But as both the agents, on the flip side, NO and isoflurane are known to stimulate prostanoid production, this may potentially result in increased inflammation.15 Some other studies have also noted the proapoptotic effects of NO donors in vitro that lead to disruption of the cerebral endothelial cell monolayer and increased leukocyte adhesion in the presence of NO.16 Some of these effects may be attenuated by propofol administration.17 Volatile anesthetics are important regulators of cardiovascular output, vascular tone, and cerebral blood flow. This may be a mechanism of BBB perturbation (via endothelial stretching) and a potential experimental confounder when assessing other molecular mechanisms influencing permeability.18 Anesthesia Effects on Tight Junctions Animal models have shown isoflurane results in an increased edema in comparison to other anesthetics such as sevoflurane or pentobarbital.12,19–21 While vasodilation-induced cell starching and separation may play a role, I. NEUROANATOMY CELLULAR AND MOLECULAR EFFECTS OF ANESTHETICS ON THE BLOOD–BRAIN BARRIER 53 other mechanisms are important in determining the direct effects on TJs.12 TJs are redistributed following ischemia, inflammation, and TBI.22–24 Sevoflurane compared to isoflurane, may alter the balance between TJ proteins that are modulated by anesthetics specifically by greater induction of zonula occludens-1 (ZO-1) as compared to occludin.13,25,26 This coincides with a reduction in cerebral edema in sevoflurane-treated animals. The other important TJ protein, occludin, is regulated in part by glutamate signaling, which is altered by certain anesthetics. Glutamatergic signaling alters the phosphorylation of certain occludin residues, resulting in its redistribution and a consequent increase in BBB permeability. The clinically important implication for this mechanism is the reversal of this increased permeability via NMDA antagonists including the commonly used ketamine.25,27 An increase in circulating amino acids levels results in elevated plasma and cerebrospinal fluid (CSF) glutamate. This presents another possible mechanism by which anesthetic administration may modulate BBB TJs via glutamatergic signaling.28,29 As a direct effect, isoflurane downregulates the expression of occludin in human brain vascular endothelial cell cultures in a hypoxia inducible factor-1α (HIF-1α)–dependent manner.30 In addition to its role in occludin expression, HIF-1α acts in biphasic manner with BB integrity to both protect against and exacerbate damaging pathways of cerebral ischemia and consequently plays a significant role in mediating cerebral water content.31–33 Propofol and isoflurane have both been implicated in modulation of this signaling pathway, which regulates expression of vascular endothelial growth factor, aquaporin-1, aquaporin-4, and matrix metalloprotease expression, among many others.32 Importantly, for the traumatized brain, HIF-1α has a biphasic expression, with a trough at 24 h postreperfusion that corresponds to a decrease in BBB permeability.31 While the protective effects of early HIF-1α inhibition with respect to increased BBB integrity have been confirmed by several studies, biological reality is likely to be far more complex.26,31,33 The reader is referred to the bibliography to find more reading of the HIF pathways, which is beyond the scope of inclusion in this text. Anesthesia Effects on Endothelial Cells Endothelial cell survival, structure, and expression of adherens or TJ proteins represent another set of pathways by which anesthetics, particularly isoflurane and propofol, alter the integrity of the BBB.17,34,35 In addition to its aforementioned roles, isoflurane posttreatment upregulates the activity of sphingosine kinase 1 (SphK1), which catalyzes production of sphingosine 1 phosphate (S1P). One such downstream signaling receptor of S1P is S1P1, signaling of which has been shown to decrease BBB permeability by inducing changes in expression of junction proteins such as VE-cadherins and altering cytoskeletal structure that decreases space between neighboring endothelial cells via GTPases Rho/Rac.36–38 Endothelial cell proliferation and migration is mediated via another such S1P receptor, S1P3. Furthermore, S1P3 alters calcium signaling and induces vasoconstriction in vascular smooth muscle, while S1P1 activation upregulates endothelial nitric oxide synthase activity, resulting in vasodilation.39,40 Isoflurane activates the antiapoptotic Akt pathway, increasing endothelial cell survival and improving cerebral edema via SphK1.14,35 The long-term protective effects of isoflurane postconditioning appear to depend upon the model of cerebral injury (e.g., hemorrhagic versus ischemic stroke), outcomes measured, and anesthetic protocol.14,35,41 This reemphasizes that clinical context remains of paramount importance in that the effects of anesthetics such as isoflurane in different experimental neurological pathologies are different, where the mechanism of early brain injury may be similar, but the sequelae distinct.42 Anesthesia and Neuroinflammation Neuroinflammation plays a significant role in the damage that follows a cerebral insult by mediating acute increases in permeability leading to delayed cell death.41 The role of inflammation via NFκB, IL-1β, TNF-α, and other reactive oxygen species in oxidative stress, endothelial dysfunction, and apoptosis has been described in many studies with potential clinical implications including cerebral edema, neuronal death, and short- and long-term cognitive impairment.35,43–45 Significantly, anesthesia has mostly antiinflammatory or rather minimal proinflammatory effects in healthy animals.46,47 Pretreatment or postconditioning with isoflurane reduces expression of the proinflammatory cytokines NFκB, IL-1β, and IL-6, while ketamine consistently demonstrates similar antiinflammatory properties, decreasing expression of NFκB, COX-2, iNOS, TNF-α, IL-1β, and other important inflammatory signaling molecules.41,43,48 Propofol exhibits similar antiinflammatory effects in endothelial cells in vitro through inhibition of NFκB, iNOS, and IL-1β.17 Extending beyond endothelial cells, astrocytes (an integral part of the BBB) exposed to midazolam and corticosterone challenge produced pregnenolone and progesterone, both of which are cytoprotective.49,50 Clinical effects of delayed cognitive dysfunction that are not immediately evident during acute-phase reactions may be secondary to the role of neuroinflammation acting in conjunction with delayed apoptotic signaling.14,46 This also I. NEUROANATOMY 54 3. BLOOD–BRAIN BARRIER may translate into timed administration of specific anesthetics that may protect the BBB and thus reduce cerebral edema and neuronal death in common inflammatory states such as infection, malignancies, etc.41,46 Accumulating evidence of the effect of surgery on neuroinflammation and neurodegeneration suggests a potentially important role in anesthetic selection for vulnerable populations such as children, the elderly, and those with preexisting neurologic conditions such as Alzheimer disease.46,51 Induction of neuroinflammation by anesthetics is of particular concern in pediatric populations due to the documented inhibitory effect of proinflammatory cytokines on long-term potentiation.46 Indeed, consistent administration of sevoflurane or isoflurane to young mice results in cognitive impairment, although the causal mechanisms have yet to be fully elucidated.51,52 In young mice, sevoflurane administration upregulates the production inflammatory cytokines IL-6 and TNF-α, possibly as a downstream result of NFκB induction.52 Moderate induction of neuroinflammation by sevoflurane may have a particularly significant effect during periods of neurodevelopment due to the documented inhibitory effect of proinflammatory cytokines on long-term potentiation. This would support the clinical findings that repeated exposures to anesthesia during childhood can raise the risk for cognitive impairment as well as experimental results identifying neurodegeneration in neonatal rats exposed to isoflurane.12,53 In light of the evidence in favor of an antiinflammatory role of volatile anesthetics under pathologic conditions, it is unclear whether this is related to an age-dependent difference or to experimental variability in models (e.g., TBI vs healthy animals) or dosage protocol. The much talked about general anesthesia compared to spinal anesthesia (GAS trial) will examine outcomes at 2 and 5 years of age after exposure of the infant brain to volatile anesthesia. This will help establish whether general anesthesia in infancy has any effect on neurodevelopmental outcome. Outcomes at 2 years of age were accessed using the Bayley Scales of Infant and Toddler Development III during this multicenter, randomized controlled trial. These outcomes that have since been published found no evidence that just less than 1 h of sevoflurane anesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anesthesia.54 In summary, anesthetic agents differentially regulate several pathways directly and indirectly involved in BBB integrity including TJ formation, endothelial cell survival, vasodilation, reactive oxygen species production and signaling, and neuroinflammation. The varied effects of volatile anesthetics on inflammation and permeability underscore the potential role of variability in administration protocols and the presence and type of underlying neuropathology. These are important factors to account for in interpreting the above highlighted data by the bedside clinician. It is safe to conclude at this moment of time that the bulk of available data suggest a possible role for anesthetic agents in pre- or postconditioning of the BBB, though some other studies have also identified potentially detrimental effects including increased BBB permeability and neuroinflammation. CLINICAL AND EXPERIMENTAL IMPLICATIONS OF ANESTHETICS ON THE BLOOD–BRAIN BARRIER The proceeding text has shown us that the interpretation of clinical and animal research to the operating room, and intensive care units is guarded to say the least. The clinician would specifically like to know if anesthetic neuroprotection exists in common clinical scenarios. The following section highlights some such common clinical scenarios, such as perioperative neurological injury in cardiac surgery, the use of general anesthetics to treat refractory status epilepticus (SE), and high-dose barbiturate therapy to treat refractory intracranial hypertension. Anesthetic Neuroprotection in Perioperative Neurological Injury Perioperative neurological injury is one of the most serious adverse complications of general anesthesia. Manifestations are on a diverse spectrum ranging from dense coma and brain death to the relatively subtle (though importantly very disabling) postoperative cognitive dysfunction (POCD).55 Thus, perioperative brain damage is a major concern after cardiac surgery and is one such surgical insult where both cerebral ischemia and the POCD have a significantly higher incidence compared to noncardiac surgery.56–58 While the etiology of perioperative neurological injury is incompletely understood, it is believed that in addition to ischemia due to hypoperfusion and cerebral microembolization, followed by reperfusion injury, cardiac surgery induces a systemic inflammatory response that may act in concert to disrupt the BBB and cause cerebral edema and inflammation, thereby leading to neurocognitive dysfunction.59,60 This is supported by animal models demonstrating that cardiopulmonary bypass leads to opening of the BBB.61,62 Importantly, more recent studies have also corroborated these results in patients undergoing cardiac surgery. Reinsfelt et al. I. NEUROANATOMY CLINICAL AND EXPERIMENTAL IMPLICATIONS OF ANESTHETICS ON THE BLOOD–BRAIN BARRIER 55 demonstrated a pronounced cerebral inflammatory response in patients following “on-pump” surgical aortic valve replacement. Their results show increased levels of proinflammatory cytokines in CSF as well as BBB disruption and glial cell injury as assessed using biomarkers of BBB dysfunction and astrocytic damage in CSF.63 Further, using MRI-DTI and FLAIR, others found subclinical BBB disruption in both on- and off-pump cardiac surgery patients.64 Nussmeier et al. conducted a randomized, clinical trial in patients undergoing cardiac surgery with normothermic cardiopulmonary bypass, in which they compared the infusion of thiopental with fentanyl in control subjects.65 They concluded that thiopental offers neuroprotection in patients undergoing cardiopulmonary bypass. However, in a previous randomized trial in patients undergoing coronary artery bypass grafting comparing thiopental to placebo, Zaidan et al. reported that, contrary to the Nussmeier et al. results, there was no significant difference in either the incidence of neurological deficits or rate of recovery among the two groups.66 It was concluded that thiopental does not offer neuroprotection in patients undergoing coronary artery surgery. While many now regard thiopental as “an agent of the past,” this example highlights the difficulty in ascertaining a clear outcome signal in these types of studies. The heterogeneity of the population and the methods used are the biggest problems when comparing these and other studies. Similarly a review of numerous other clinical trials investigating the neuroprotective properties of other anesthetics has led to ambiguous conclusions.67 As a result, the neuroprotective statuses of both lidocaine58,68–71 and ketamine72,73 are currently still controversial. Propofol does not appear to have significant neuroprotective properties in patients undergoing cardiac surgery.74,75 It is important to note that the follow-up period for a number of these studies was quite short (5–10 days postsurgery), which may have contributed to the significant findings. Thus, the question of whether any anesthetic neuroprotection is observed for a long term still remains. One randomized trial investigating the influence of propofol versus desflurane on the long-term incidence of POCD in patients undergoing coronary artery bypass surgery found that although desflurane was associated with decreased incidences of POCD early in recovery (4–7 days postsurgery), there was no significant difference in incidence between the two groups at 3 months postsurgery.93 This result is in agreement with others who also looked at long-term follow-up and found no evidence for neuroprotection on POCD incidence.69–71,74 Antiinflammatory Effects of General Anesthetics in the Treatment of Refractory Status Epilepticus SE refers to the state in which a patient has continuous or rapidly repeating seizures most commonly generalized tonic–clonic. To treat SE, benzodiazepines are used as first-line therapy (first 30 min) and intravenous antiepileptic drugs, such as phenytoin, are used as second-line therapy (30–120 min).76 If SE does not respond to either first- or second-line therapy, it is considered refractory SE and requires the application of general anesthetics. While the neuronal molecular mechanisms by which general anesthetics work as antiepileptic drugs are widely accepted—propofol and thiopental are γ-aminobutyric acid (GABA) receptor agonists and ketamine is an NMDA receptor antagonist—these anesthetic drugs also have important immunomodulatory effects that partially overlap with those of corticosteroids.9 Thiopental, propofol, and ketamine exert potent antiinflammatory effects that are mediated through inhibition of the activation of NFκB, a transcription factor essential for the expression of proinflammatory cytokines, in the experimental setting.77–82 Studies in patients have also corroborated the antiinflammatory effects of ketamine.82 Sevoflurane lacks the antiinflammatory effects of general anesthetics and thus may actually have an epileptogenic effect.77,80 BBB breach has been shown to decrease seizure threshold and promote seizure development in both animals and humans.83,84 While general anesthetics have direct antiepileptic neuronal effects, they may be more effective in treating refractory SE because of their antiinflammatory properties that prevent BBB disruption and promote the repair of the cerebrovasculature.23,78,79,81,85,86 Antiinflammatory Considerations in Barbiturate Induced Coma for Traumatic Brain Injury Increased intracranial pressure (ICP) or intracranial hypertension occurs commonly in 25–40% of patients with severe traumatic brain injury usually as a consequence of both vasogenic and cytotoxic edema.87–89 Vasogenic edema is secondary to BBB disruption and results in the extravasation of proteins and fluid from the cerebrovasculature into the extracellular space. On the other hand, cytotoxic edema—the accumulation of intracellular fluid—is believed to occur as a result of loss of the cell’s ability to regulate ionic gradients. The Monroe–Kellie doctrine determines that due to the rigidity of the skull, cerebral edema causes a significant increase in ICP and cerebral ischemia once the I. NEUROANATOMY 56 3. BLOOD–BRAIN BARRIER compensatory mechanisms are overwhelmed. However, despite aggressive management strategies, refractory intracranial hypertension may persist in approximately 10–15% of patients with severe TBI.90,91 High-dose barbiturates are recognized as an effective therapy for controlling refractory intracranial hypertension.92 One randomized, multicenter trial found that inducing barbiturate coma in such patients resulted in double the chance of achieving ICP control.93 High-dose barbiturates, when used in hemodynamically stable patients (to account for the effects on mean arterial pressure), are believed to lower ICP through the suppression of cerebral metabolism, which reduces cerebral blood volume and ICP due to the coupling of cerebral blood flow to regional metabolic demands.94 Thiopental exerts potent antiinflammatory effects through the inhibition of NFκB activation.79,85 Importantly, it has been demonstrated that it is the thio-group of thiopental that is of functional importance for this inhibitory effect, as the oxibarbiturate analogs of thiobarbiturates (such as pentobarbital vs thiopental) fail to inhibit NFκB in equimolar amounts.78 Considering that vasogenic edema is secondary to BBB disruption, thiopental may thus help to decrease cerebral edema by promoting the repair of the BBB through its antiinflammatory effects—although it is important to note that it is actually cytotoxic edema that is believed to be the more insidious of the two types of edema involved in intracranial hypertension.22 CONCLUSION Anesthetics influence the BBB via a multitude of different mechanisms and roles. While some anesthetics appear to have a negative effect on BBB permeability, others can provide protection to the BBB and decrease inflammation. Molecular mechanisms of anesthetic influences on the BBB tailoring anesthesia to specific needs and personalization of anesthetics to individual patients undergoing a specific procedure are all areas of future research. The bulk of evidence points to a neuroprotective and antiinflammatory effect of anesthetics on the brain. There is a limitation in comparing studies with a lack of standardization of experimental practices. Once standardization is achieved, the true nature and impact of anesthesia on the BBB and inflammation may be revealed. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. Janigro D. Are you in or out? Leukocyte, ion, and neurotransmitter permeability across the epileptic blood–brain barrier. Epilepsia 2012;53:26–34. Scott DAEL, Silbert BS. 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Greig NH, Yu Q-S, Utsuki T, et al. Optimizing drugs for brain action. Blood—Brain Barrier 2001:281–309. Goldstein GW, Betz AL. The blood–brain barrier. Sci Am 1986;255:74–83. Matta BF, Heath KJ, Tipping K, Summors AC. Direct cerebral vasodilatory effects of sevoflurane and isoflurane. Anesthesiology 1999;91:677. Tétrault S, Chever O, Sik A, Amzica F. Opening of the blood–brain barrier during isoflurane anaesthesia. Eur J Neurosci 2008;28:1330–41. Thal SC, Luh C, Schaible E-V, et al. volatile anesthetics influence blood–brain barrier integrity by modulation of tight junction protein expression in traumatic brain injury. PLoS One 2012;7:e50752. Altay O, Hasegawa Y, Sherchan P, et al. Isoflurane delays the development of early brain injury after subarachnoid hemorrhage through sphingosine-related pathway activation in mice. Crit Care Med 2012;40:1908–13. Zhao P, Zuo Z. Isoflurane preconditioning induces neuroprotection that is inducible nitric oxide synthase-dependent in neonatal rats. Anesthesiology 2004;101:695–703. Lehmberg J, Waldner M, Baethmann A, Uhl E. Inflammatory response to nitrous oxide in the central nervous system. Brain Res 2008;1246:88–95. Chen R-M, Tai Y-T, Chen T-G, et al. Propofol protects against nitrosative stress-induced apoptotic insults to cerebrovascular endothelial cells via an intrinsic mitochondrial mechanism. Surgery 2013;154:58–68. Sakabe T, Matsumoto M. Effects of anesthetic agents and other drugs on cerebral blood flow, metabolism, and intracranial pressure. In: Cottrell and Young’s neuroanesthesia. Elsevier BV; 2010. p. 78–94. Ritz M-F, Schmidt P, Mendelowitsch A. Effects of isoflurane on glutamate and taurine releases, brain swelling and injury during transient ischemia and reperfusion. Int J Neurosci 2006;116:191–202. Hu Q, Ma Q, Zhan Y, et al. Isoflurane enhanced hemorrhagic transformation by impairing antioxidant enzymes in hyperglycemic rats with middle cerebral artery occlusion. Stroke 2011;42:1750–6. Stover JF, Kempski OS. Anesthesia increases circulating glutamate in neurosurgical patients. Acta Neurochir 2005;147:847–53. Unterberg AW, Stover J, Kress B, Kiening KL. Edema and brain trauma. Neuroscience 2004;129:1019–27. Sandoval KE, Witt KA. Blood–brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis 2008;32:200–19. Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood–brain barrier. Nat Med 2013;19:1584–96. András IE, Deli MA, Veszelka S, Hayashi K, Hennig B, Toborek M. The NMDA and AMPA/KA receptors are involved in glutamate-induced alterations of occludin expression and phosphorylation in brain endothelial cells. J Cereb Blood Flow Metab 2007;27:1431–43. I. NEUROANATOMY REFERENCES 57 26. Colgan OC, Collins NT, Ferguson G, et al. Influence of basolateral condition on the regulation of brain microvascular endothelial tight junction properties and barrier function. Brain Res 2008;1193:84–92. 27. Miller RD, Monsul NT, Vender JR, Lehmann JC. 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Effects of anesthesia on lipopolysaccharide-induced changes in serum cytokines. J Trauma Inj Infect Crit Care 2008;65:170–4. 49. Guo W-Z, Miao Y-L, An L-N, et al. Midazolam provides cytoprotective effect during corticosterone-induced damages in rat astrocytes by stimulating steroidogenesis. Neurosci Lett 2013;547:53–8. 50. Abbott NJ. Astrocyte-endothelial interactions and blood–brain barrier permeability. J Anat 2002;200:629–38. 51. Liu Y, Gao M, Ma L, Zhang L, Pan N. Sevoflurane alters the expression of receptors and enzymes involved in Aβ clearance in rats. Acta Anaesthesiol Scand 2013;57:903–10. 52. Hirschy JC, Thorpe JJ, Cortese AF. Meckel’s stones. Radiology 1976;119:19–20. 53. Shen X, Dong Y, Xu Z, et al. Selective anesthesia-induced neuroinflammation in developing mouse brain and cognitive impairment. Anesthesiology 2013;118:502–15. 54. Davidson AJ, Disma N, de Graaff JC, et al. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet 2016;387:239–50. 55. Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: summary article. J Am Coll Cardiol 2004;44:1146–54. 56. Selim M. Perioperative stroke. N Engl J Med 2007;356:706–13. 57. Coburn M, Fahlenkamp A, Zoremba N, Schaelte G. Postoperative kognitive dysfunktion. Der Anaesthesist 2010;59:177–85. 58. Newman MF, Mathew JP, Grocott HP, et al. Central nervous system injury associated with cardiac surgery. The Lancet 2006;368:694–703. 59. Rinder C. Cellular inflammatory response and clinical outcome in cardiac surgery. Curr Opin Anaesthesiol 2006;19:65–8. 60. Grocott HP. Cognitive dysfunction after cardiac surgery: revisiting etiology. Semin Cardiothorac Vasc Anesth 2005;9:123–9. 61. Okamura T, Ishibashi N, Kumar TS, et al. Hypothermic circulatory arrest increases permeability of the blood–brain barrier in watershed areas. Ann Thorac Surg 2010;90:2001–8. 62. Cavaglia M, Seshadri SG, Marchand JE, Ochocki CL, Mee RBB, Bokesch PM. Increased transcription factor expression and permeability of the blood–brain barrier associated with cardiopulmonary bypass in lambs. Ann Thorac Surg 2004;78:1418–25. 63. Reinsfelt B, Ricksten S-E, Zetterberg H, Blennow K, Fredén-Lindqvist J, Westerlind A. Cerebrospinal fluid markers of brain injury, inflammation, and blood–brain barrier dysfunction in cardiac surgery. Ann Thorac Surg 2012;94:549–55. 64. Merino JG, Latour LL, Tso A, et al. Blood–brain barrier disruption after cardiac surgery. Am J Neuroradiol 2012;34:518–23. 65. Nussmeler NA, Arlund C, Slogoff S. Neuropsychiatric complications after cardiopulmonary bypass. Anesthesiology 1986;64:165–70. 66. Zaidan JR, Klochany A, Martin WM, Ziegler JS, Harless DM, Andrews RB. Effect of thiopental on neurologic outcome following coronary artery bypass grafting. Anesthesiology 1991;74:406–11. 67. Bilotta F, Gelb AW, Stazi E, Titi L, Paoloni FP, Rosa G. Pharmacological perioperative brain neuroprotection: a qualitative review of randomized clinical trials. Br J Anaesth 2013;110:i113–20. 68. Wang D, Wu X, Li J, Xiao F, Liu X, Meng M. The effect of lidocaine on early postoperative cognitive dysfunction after coronary artery bypass surgery. Anesth Analg 2002;95:1134–41. 69. Mitchell SJ, Merry AF, Frampton C, et al. Cerebral protection by lidocaine during cardiac operations: a follow-up study. Ann Thorac Surg 2009;87:820–5. 70. Mitchell SJ, Pellett O, Gorman DF. Cerebral protection by lidocaine during cardiac operations. Ann Thorac Surg 1999;67:1117–24. 71. Mathew JP, Mackensen GB, Phillips-Bute B, et al. Randomized, double-blinded, placebo controlled study of neuroprotection with lidocaine in cardiac surgery. Stroke 2009;40:880–7. 72. Nagels W, Demeyere R, Van Hemelrijck J, Vandenbussche E, Gijbels K, Vandermeersch E. Evaluation of the neuroprotective effects of S(+)-ketamine during openheart surgery. Anesth Analg 2004:1595–603. I. NEUROANATOMY 58 3. BLOOD–BRAIN BARRIER 73. Hudetz JA, Iqbal Z, Gandhi SD, et al. Ketamine attenuates post-operative cognitive dysfunction after cardiac surgery. Acta Anaesth Scand 2009;53:864–72. 74. Roach GW, Newman MF, Murkin JM, et al. Ineffectiveness of burst suppression therapy in mitigating perioperative cerebrovascular dysfunction. Anesthesiology 1999;90:1255–64. 75. Kanbak M, Saricaoglu F, Avci A, Ocal T, Koray Z, Aypar U. Propofol offers no advantage over isoflurane anesthesia for cerebral protection during cardiopulmonary bypass: a preliminary study of S-100ß protein levels. Can J Anesth/J Can Anesth 2004;51:712–7. 76. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. 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Does intraoperative ketamine attenuate inflammatory reactivity following surgery? A systematic review and meta-analysis. Anesth Analg 2012;115:934–43. 83. van Vliet EA, Aronica E, Gorter JA. Role of blood–brain barrier in temporal lobe epilepsy and pharmacoresistance. Neuroscience 2014;277:455–73. 84. Seiffert E, Dreier JP, Ivens S, et al. Lasting blood–brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J Neurosci 2004;24:7829–36. 85. Ichiyama T, Nishikawa M, Lipton JM, Matsubara T, Takashi H, Furukawa S. Thiopental inhibits NF-κB activation in human glioma cells and experimental brain inflammation. Brain Res 2001;911:56–61. 86. Welters ID, Hafer G, Menzebach A, et al. Ketamine inhibits transcription factors activator protein 1 and nuclear factor-κB, interleukin-8 production, as well as CD11b and CD16 expression: studies in human leukocytes and leukocytic cell lines. Anesth Analg 2010;110:934–41. 87. 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Guidelines for the management of severe traumatic brain injury. XI. Anesthetics, analgesics, and sedatives. J Neurotrauma 2007;24(Suppl. 1):S71–6. 93. Eisenberg HM, Frankowski RF, Contant CF, Marshall LF, Walker MD. High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosurg 1988;69:15–23. 94. Roberts I, Sydenham E. Barbiturates for acute traumatic brain injury. Cochrane Database Syst Rev 2012;12:CD000033. I. NEUROANATOMY S E C T I O N I I NEUROPHYSIOLOGY This page intentionally left blank C H A P T E R 4 Neurophysiology M. Sethuraman Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India O U T L I N E Intracranial Pressure 62 Introduction 62 Normal Intracranial Pressure 62 Cerebral Compliance 62 Importance of Intracranial Pressure Intracranial Waves Intracranial Wave Analysis Factors Influencing the Intracranial Pressure Waveform Pathological Intracranial Pressure Waves Intracranial Pressure–Derived Indices Pressure–Volume Compensatory Curve Cerebrovascular Pressure Reactivity Intracranial Pressure Monitoring Methods 63 64 64 Summary 68 Cerebral Blood Flow Effects of Temperature and Anesthetic Agents Measurement of Cerebral Blood Flow 73 73 Summary 74 Brain Metabolism 74 Introduction 74 68 Normal Cerebral Metabolism Brain Energy is Utilized for the Following Process Brain Metabolism in Presence of Oxygen Cerebral Metabolism in Hypoxic State Cerebral Metabolism in Hypoglycaemic States Control of Cerebral Metabolism Metabolic Coupling Metabolic Uncoupling Cerebral Metabolism in Pathological States Apoptosis Monitoring of Cerebral Metabolism Cerebral Microdialysis 74 74 75 75 75 76 76 77 77 78 78 78 Introduction 68 Summary 79 Vascular Anatomy Arterial System Venous System Control of Venous Circulation Regulation of Cerebral Blood Flow Cerebral Autoregulation Mechanisms of Autoregulation Myogenic Control Neurogenic Control Flow Metabolism Coupling Factors Affecting Cerebral Blood Flow Partial Pressure of Arterial CO2 Effects of Partial Pressure of Arterial Oxygen Effects of Hematocrit Effects of Age and Gender 68 68 69 70 70 70 71 71 71 72 72 72 72 73 73 Cerebrospinal Fluid 79 Introduction 79 Ventricular System Formation of Cerebrospinal Fluid Cerebrospinal Fluid Circulation Cerebrospinal Fluid Absorption Cerebrospinal Fluid Volume and Composition Regulation of Cerebrospinal Fluid Dynamics Effects of Anesthetic Agents Effects of Pathologies on Cerebrospinal Fluid Dynamics Imaging of Cerebrospinal Fluid Pathways CT Scan Magnetic Resonance Imaging 79 79 80 81 81 82 82 82 83 83 83 Summary 83 Essentials of Neuroanesthesia http://dx.doi.org/10.1016/B978-0-12-805299-0.00004-X 64 66 66 66 67 68 61 © 2017 Elsevier Inc. All rights reserved. 62 4. NEUROPHYSIOLOGY The Spinal Cord 83 Introduction 83 Anatomy 84 Organization of the Spinal Cord White Matter of Spinal Cord Intrinsic Pathways Ascending Pathways Descending Pathways Spinal Cord Interneurons Glial Cells of Spinal Cord Blood Supply 84 84 84 84 84 86 86 86 Intrinsic Supply Extrinsic Blood Supply Venous System of Spinal Cord Pathophysiology Autoregulation and CO2 Reactivity of the Spinal Cord Functions of the Spinal Cord Sensory Function Motor Function Autonomic Function 87 87 88 88 88 88 89 89 89 Summary 89 References 89 INTRACRANIAL PRESSURE INTRODUCTION Brain is enclosed in the skull which is ought to be a protective layer. However, the rigid skull can be damaging the brain in case of pathological lesion. The relationship between the skull contents was initially proposed by Alexander Munro in 1783 and his colleague George Kellie. A modified Munro–Kellie doctrine was proposed by George Burrows in 1846 by including the cerebrospinal fluid (CSF) component along with brain and blood.1 The current doctrine was introduced by Harvey Cushing who states that in an intact skull, the volume of brain, blood and CSF remains constant. Any increase in the volume of one compartment needs to be compensated by the reduction in either one or both of the other compartments.2 In normal circumstances the intracranial pressure (ICP) is kept in its normal range, maintaining the relationship between the CSF, blood, and brain tissue constant. Any increase in the ICP can lead to reduced cerebral perfusion and can be harmful. This chapter describes the normal ICP, factors affecting the ICP, and overview of the monitoring of ICP. NORMAL INTRACRANIAL PRESSURE The ICP is derived from the circulating intracranial blood and CSF (ICPtotal = ICPvascular + ICPCSF). The vascular component is difficult to quantify due to variation in cerebral blood volume, the autoregulation. The circulatory CSF component may be expressed using Davson’s equation; ICP = (resistance to CSF outflow) × (CSF formation) + (pressure in sagittal sinus).3 The normal values of ICP in different age groups in horizontal position are 10–15 mmHg for adults and 3–7 mmHg for children. The ICP is lower in newborn (1.5–6 mmHg) due to the opened cranial sutures and fontanels. In the vertical position it is negative with a mean of around −10 mmHg, but not exceeding −15 mmHg. ICP is considered to be high if the value exceeds 20 mmHg and needs to be treated.4 When the ICP exceeds 60 mmHg, cerebral perfusion ceases and there will be irreversible brain damage and death. CEREBRAL COMPLIANCE Since the intracranial volume is inversely proportional to the pressure, a curve can be plotted for change in pressure for a change in volume.5 This measures the intracranial compliance (Fig. 4.1). The first part of the curve is characterized by a very limited increase in pressure with increase in volume because compensatory reserve is large enough to accommodate the extra volume. With further increasing volume, the compensatory reserve is eventually exceeded, causing a rapid increase in pressure. The normal intracranial compliance is II. NEUROPHYSIOLOGY 63 IMPORTANCE OF INTRACRANIAL PRESSURE FIGURE 4.1 Pressure–volume relationship of intracranial pressure. TABLE 4.1 Stages of Increase in Intracranial Pressure (ICP) With Clinical Symptoms6 Stage Changes in ICP Clinical Symptoms 1 Increase in tumor volume, compensatory reduction in cerebrospinal fluid and blood volume, no raise in ICP Usually asymptomatic 2 Compensatory mechanisms exhausted, gradual rise in ICP with increase in volume Drowsiness, headache 3 Rapid rise in ICP, falling cerebral perfusion pressure Deterioration of consciousness, raised blood pressure, bradycardia 4 Cerebral vasomotor paralysis, ICP equals mean arterial blood pressure, cerebral perfusion ceases Coma, dilated fixed pupils, and death 60–80 mL in young adults and 100–140 mL in older people due to cerebral atrophy. Depending on the compliance the increase in ICP produces various clinical symptoms. Theoder Koher described four stages of raised ICP6 (Table 4.1). IMPORTANCE OF INTRACRANIAL PRESSURE ICP can be raised due to various pathological processes such as brain tumor, trauma, hemorrhage, ischemia producing a stroke or cerebral edema. The raised ICP has two important consequences: 1. The cerebral perfusion pressure (CPP) is denoted by CPP = MAP−ICP, where MAP is the mean arterial pressure and ICP is the intracranial pressure. When the ICP increases, the CPP decreases. In addition, there can be vasomotor paralysis caused by the raised ICP and the intracranial pathological process. Both these factors result in the reduction of CPP causing ischemia and damage to the neurons. 2. The skull is divided into various partial compartments by the folds of dura mater (right and left hemispheres, supratentorial and infratentorial compartments). This leads to compartmentalization of the pressure in case of any pathology. The increase in pressure in one of the compartments pushes the surrounding brain to the other compartments below the dural folds causing herniation of brain. The various herniation syndromes are given in Table 4.2 (Fig. 4.2).7 II. NEUROPHYSIOLOGY 64 4. NEUROPHYSIOLOGY TABLE 4.2 Various Features of Brain Herniation Syndromes Herniation Structures Involved Clinical Feature Subfalcine herniation Cingulate gyrus is pushed below the falx Dilation of contralateral ventricle With collapse of ipsilateral ventricle Uncal herniation Medial temporal lobe structures are displaced against tentorial edge Unilateral pupillary dilation with contralateral hemiplegia Central herniation Downward displacement of brain stem and diencephalon Cheyne Stokes respiration, bilateral pinpoint pupils, rapidly progressing to death Tonsillar herniation Cerebellar tonsils are pushed downward through foramen magnum Hydrocephalus, coma, hemodynamic disturbances, and respiratory arrest Transcalvarial Brain is pushed against a defect in the skull Effects depend on the brain area involved FIGURE 4.2 Diagrammatic representation of various brain herniation syndromes. Intracranial Waves Monitoring of ICP is important as a guide to diagnosis as well as therapeutic interventions. No universally accepted guidelines exist for ICP monitoring, and the indications vary considerably between hospitals and physicians. Some of the indications of ICP monitoring include severe head injury, intracerebral hemorrhage, acute stroke, metabolic encephalopathy, etc. Intracranial Wave Analysis Intracranial waveform analysis provides wealth of information regarding the ICP and compliance. It is important to understand the waveform morphology and its changes in different conditions. The pulsations of the CSF are predominant because of transmission of the arterial pulsations. Jugular venous pulsations and respiration also affect the waveform. However, in pathological raise it is mainly the arterial waveform that influences the ICP waves. Under normotension, normocarbia, and normal PO2, the ICP waveform shows two distinct patterns. A slow, large sinusoidal wave and a rapid, small peak wave (Fig. 4.3). The slow sinusoidal pattern corresponds to the phase of respiration (Fig. 4.3A and B). The rapid waves correspond to arterial pulse. The rapid wave has an initial peak, followed by dicrotic peak, and few other peaks after the dicrotic peak. These are referred to P1 (percussion wave corresponds to choroid plexus pulsations), P2 (dicrotic wave), and P3 (tidal wave–venous pulsations) waves. In normal persons, P1 amplitude will be higher than P2; however, in patients with raised ICP, P2 will have more amplitude than P1 (Fig. 4.4). Factors Influencing the Intracranial Pressure Waveform Various systemic factors can influence the ICP waveforms.8 It is important to understand the effects of these factors while interpreting the waveforms. II. NEUROPHYSIOLOGY IMPORTANCE OF INTRACRANIAL PRESSURE 65 FIGURE 4.3 Relationship between intracranial pressure (ICP) waveform (A) with arterial tracing and central venous tracing and changes in ICP with respiration (B). ABP, arterial blood pressure; CVP, central venous pressure. FIGURE 4.4 Normal intracranial pressure (ICP) waveform (A) as well as in poor brain compliance (B). 1. Blood pressure: The effects of the changes in blood pressure (BP) depend on the cerebral autoregulation and intracranial compliance. A transient fall in BP causes reduced cerebral blood flow (CBF), fall in CSF production and ICP. However, if the fall is severe or sustained, there will be cerebral vasodilation, brain ischemia, cerebral edema, and rise in ICP. A transient high BP does not affect the ICP within autoregulation. If the BP increases beyond autoregulation, then the CBF will be pressure passive and the ICP will increase (Fig. 4.3A). The morphology of the ICP wave changes and the amplitude increases with the shape like arterial pulse waveform. 2. Central venous pressure (CVP): Elevated CVP causes increase in ICP (Fig. 4.3B). The morphology shows more prominent “a” wave peaks. 3. Respiration: During inspiration there is fall in intrathoracic pressure, CVP and is reflected by fall in ICP and vice versa in expiration. In addition, the ICP waveform shows sinusoidal pattern corresponding to respiration (Fig. 4.3B). 4. ICP: In case of increase in ICP two distinct changes occur in ICP waveform. The waveform assumes the shape of arterial waves and the venous pulsation disappear. The amplitude of the ICP wave increases. In addition, there will be increase in P2 amplitude compared to P1 wave, and later there will be rounding off without distinct II. NEUROPHYSIOLOGY 66 4. NEUROPHYSIOLOGY waves. This is called blunting of waves. P1/P2 ratio of more than 0.8 along with an ICP value of more than 10 has been associated with poor compliance of the intracranial compartment. However, there are differences of opinion regarding the predictive value of P1/P2 ratio regarding reduced compliance. 5. Partial pressure of O2 (PaO2): In the presence of hypoxia, there was cerebral hyperemia and moderate increase in ICP. The amplitude of the CSF wave increases and the venous pulsations disappear. 6. Partial pressure of CO2 (PaCO2): The effects of hypercarbia on the ICP waveform is similar to the pattern seen in increased BP. There will be increased CBF, ICP and the amplitude of the wave increases. Pathological Intracranial Pressure Waves The ICP waveform shows three different patterns during increase in ICP. They are of clinical significance. 1. A waves: These are also called plateau waves. A wave comprises a steep rise in ICP from near normal values to 50 mmHg or more, persisting for 5–20 min and then falling sharply. These waves are always pathological and indicate greatly reduced compliance. They are frequently accompanied by neurological deterioration. As the baseline ICP increases the magnitude of A wave also increases. A wave is seen when there are sudden painful stimuli such as endotracheal suctioning to the patient. A waves are associated with severe fall in CPP and needs to be avoided in the ICU care (Fig. 4.5). 2. B waves: These are rhythmic oscillations that occur every 1–2 min. ICP rises in a crescendo manner to levels 20–30 mmHg higher than baseline and then falls abruptly. These waves were originally always associated with Cheyne–Stokes respiration. However, they also occur in ventilated patients and are probably related to changes in cerebrovascular tone and cerebral blood volume. B waves are also indicative of failing intracranial compensation. 3. C waves: These oscillations occur with a frequency of 4–8 per minute and are of smaller amplitude than B waves. They are synchronous with spontaneous Traub–Hering–Meyer type variations in BP and are probably of limited pathological significance. Intracranial Pressure–Derived Indices There are two indices which are derived from ICP monitoring: (1) pressure–volume compensatory curve and (2) cerebrovascular pressure reactivity. Pressure–Volume Compensatory Curve The pressure–volume compensatory curve measures the degree of compensation that can be achieved due to change in intracranial volume.9,10 This measures the relationship between the amplitude (A) of the ICP wave and absolute ICP (P). When the ICP increases the amplitude of the wave also increases; however, the degree of increase in amplitude depends on the intracranial compliance (Fig. 4.6). The curve to the left of the line indicates good compliance, and the change of amplitude to pressure will be nonlinear whereas to the right on the line there is linear increase in both amplitude and pressure. The index called RAP [correlation coefficient (R) between AMP amplitude (A) and mean pressure (P); which is the index of compensatory reserve] can be derived by calculating the linear correlation between consecutive, time averaged data points of AMP and ICP (usually 40 of such samples are used) acquired over a reasonably long period FIGURE 4.5 The Lundberg waves of intracranial pressure (ICP). II. NEUROPHYSIOLOGY IMPORTANCE OF INTRACRANIAL PRESSURE 67 FIGURE 4.6 The relation between the changes in the amplitude of intracranial pressure (ICP) waves and ICP values. FIGURE 4.7 The positive PRx (top panel) and negative PRx (bottom panel) along with the curve of compensatory stages. ICP, intracranial pressure; ABP, arterial blood pressure; PRx, pressure reactivity index. to average over respiratory and pulse waves (usually 6–10 s periods). This index indicates the degree of correlation between AMP and mean ICP over short periods of time usually 4 min. Interpretation: If RAP = 0, there is a good intracranial reserve; if RAP = 1, then the compliance is reduced; if RAP <0, the compliance is in steeper part of the curve and autoregulation is lost, the amplitude decreases. Cerebrovascular Pressure Reactivity The cerebrovascular reactivity is measured using pressure reactivity index (PRx).11 It measures the relationship between the slow changes in the arterial BP and ICP. It indirectly measures the autoregulatory state. When the cerebrovascular reactivity is intact, changes in BP cause inverse change in cerebral blood volume and ICP. When the autoregulation is lost, then II. NEUROPHYSIOLOGY 68 4. NEUROPHYSIOLOGY the increase in BP increases the CBF with a corresponding increase in ICP. PRx is determined by calculating the correlation coefficient between 40 consecutive, time averaged data points of ICP and arterial blood pressure (Fig. 4.7). Interpretation: When PRx is negative (−1), it indicates good cerebrovascular reserve (Stage 1). When PRx = 0, the patient is in compensatory part of the ICP curve (Stages 2 and 3). When PRx is positive (+1), it implies poor reserve (Stage 4). Intracranial Pressure Monitoring Methods ICP can be monitored invasively or noninvasively.12 Invasive methods are more common in use due to their reliability and continuous monitoring. Intraventricular catheter is the gold standard method, whereas fiber optic catheters are more advanced techniques of monitoring. The details of different methods of ICP monitoring will be beyond the scope of this chapter. SUMMARY ICP is a key component of the measurement of the intracranial volume/compliance. Many pathological conditions present with features of raised ICP. The symptoms and signs depend on the level of compensation and the duration of the change. Long-standing and slow-growing lesions may produce mild symptoms, whereas severe and acute lesions will rapidly progress to various herniation syndromes and death. Hence it is important to understand the pathophysiology of the disease process and its effect on the ICP so that methods to monitor and treatment plan can be made accordingly. CEREBRAL BLOOD FLOW INTRODUCTION The brain is 2% of body weight. However, it receives 15–20% of cardiac output, utilizes 20% of the oxygen, and 25% of the glucose used by the whole body at rest. The high blood flow is due to high metabolic demand and lack of substrate storage in brain. This high metabolic function is devoted to synaptic activity (50%), maintenance of ionic gradient (25%), and biosynthesis of cellular material and proteins (25%). Hence precise control of CBF is essential for survival.18 Hence understanding of various factors affecting the CBF becomes important to prevent its fall. Alterations in CBF can be either etiology or contributing factor in many brain pathological conditions.19 In addition, various drugs and anesthetic agents alter the CBF differently. This chapter reviews the normal blood supply of the brain, factors governing the blood supply, and the effect of various pathological process and drugs. VASCULAR ANATOMY Arterial System Brain is supplied by two internal carotid arteries (anterior circulation) and two vertebral arteries that join to form basilar artery (posterior circulation). The arteries form anastomoses called circle of Willis (CW). The CW is the pyramidal shaped anastomoses in the interpeduncular cistern formed between anterior and posterior circulation as well as between arteries of two cerebral hemispheres (Fig. 4.8). The anastomosis was thought to prevent ischemia if blood supply of any of the major vessels is compromised. However, a recent view on the existence of the CW is it reduces the pressure within the arterial system. Pressure gradient exists because pulse wave and blood flow arrive into the skull through different cerebral arteries asynchronously, due to arterial tree asymmetry. Therefore CW and its communicating arteries protect cerebral artery and blood–brain barrier from hemodynamic stress. The CW is formed by anterior cerebral arteries on either side, anterior communicating artery, internal carotid artery bifurcation, posterior communicating artery, posterior cerebral artery (PCA) on either side. The PCA is a part of posterior circulation. Rest of the arteries mentioned above belongs to the anterior circulation. II. NEUROPHYSIOLOGY 69 VASCULAR ANATOMY Anterior Cerebral Artery Anterior Communicating Artery ICA Bifurcation Middle Cerebral Artery Posterior Cerebral Artery Posterior Communicating Artery Basilar Artery Vertebral Artery Extracranial Internal Carotid Artery (ICA) FIGURE 4.8 The arterial supply of the brain along with circle of Willis. Venous System The cranial veins are classified into three different systems: 1. Superficial—draining the scalp, muscles, and tendons. 2. Intermediate—draining the bone, diploe, and dura mater and consists of emissary veins, diploid veins, meningeal veins, and venous sinuses. 3. Deep system—veins draining the brain. Normally the flow scalp veins drain mostly to extracranial venous system and partly through emissary veins to dural venous sinus. In case of raised intracranial pressure, there will be retrograde flow from intracranial to extracranial venous system resulting in dilation of scalp veins and emissary veins. The diploid and scalp veins serve as collateral between superior sagittal sinuses to extracranial veins. The veins of the brain form the superficial and deep venous system. The superficial veins include cortical vein, and they drain to the superior sagittal and transverse sinus. The veins of the medial and inferior cortical surface drain to vein of Galen. There are anastomotic channels between superficial and deep venous systems, which include occipital vein, posterior Calloway vein, and basal vein of Rosenthal. The deep venous system consists of internal cerebral vein, thalamo striate veins, and vein of Galen. The deep venous system drains of inferior sagittal II. NEUROPHYSIOLOGY 70 4. NEUROPHYSIOLOGY FIGURE 4.9 The description of flow metabolism coupling. CBF, cerebral blood flow. sinus to form straight sinus. The veins of the infratentorial compartment form a network which drains to straight sinus or transverse sinus. Control of Venous Circulation The transmural pressure across the intracranial veins is very low, and as the ICP increases the pressure in the cortical veins also increases. There is a cuff system at the junction of the venules where it drains to venous sinuses. The venous sinus pressure remains lower as a result of cuffing of the venules. Animal experiments have found that among the myogenic, metabolic, and neurogenic control, the venous flow is influenced by the sympathetic system especially alpha 1 adrenergic mechanism. During resting conditions 70–80% of the cerebral blood volume is located in the venous system, and it is controlled by cervical sympathetic system. When the ICP increases, the activation of sympathetic system results in veno constriction and drives the blood away thereby offsetting the effects of raised ICP. There is little evidence of metabolic and myogenic control of the venous system. In the presence of hypercapnia, the pial venules dilate in response to increased arterial flow produced by arterial dilation. However, as the PaCO2 raises further, the increased sympathetic activity causes pial–veno constriction and tries to offset the increased ICP. Acute arterial hypertension causes areas of cortical venous dilation due to increase in the blood flow. The venous transmural pressure may be higher than ICP and can lead to perivenular disruption of blood–brain barrier. Regulation of Cerebral Blood Flow The normal CBF is 50–55 mL/100 g/min.18 The distribution of CBF is not uniform. The gray matter receives approximately 80 mL/100 g/min, whereas white matter receives 20 mL/100 g/min (4:1). Blood flow of less than 20 mL/100 g/min is considered to be critical below which irreversible cellular death can occur. The CBF is affected by many factors (Fig. 4.9). Among them partial pressure of arterial carbon dioxide (PCO2), the MAP, cerebral metabolism, and the autonomic nervous system are the principal regulators of CBF.19 They do not act independently. There is usually an integration of various factors, which precisely determine the CBF. Cerebral Autoregulation Experiments have proved the CBF remains constant despite variation in many local and systemic factors that affect the blood flow. This ability to maintain a constant CBF with wide variation in CPP is called as cerebral autoregulation (Fig. 4.10). Beyond the limits of the autoregulation, the CBF depends on the MAP. However, the limits of autoregulation have been questioned.20 This questioning is because of the fact that the autoregulation measurement assumes a II. NEUROPHYSIOLOGY VASCULAR ANATOMY 71 FIGURE 4.10 The normal cerebral autoregulation. linear relationship between the CBF and the BP. However, other factors such as baroreceptor reflex, PaCO2 levels can also affect the validity of the data. In an analysis of transcranial doppler (TCD), MRI, positron emission tomography (PET), etc. based on 41 studies, the authors have found that the cerebrovasculature does have autoregulatory capacity, but its efficacy is not perfect and is dependent on the severity and direction of change in perfusion pressure.21 Recent data have found that cerebral autoregulation derived from pressure–flow recordings needs to consider not only absolute BP as an input to the cerebral circulation, but also whether BP is accelerating or decelerating and rising or falling.22 It was found that the compliance of the cerebral vessels also is a major factor in the autoregulation. The brain vessels respond well to rapidly rising BP than a rapidly falling BP.23 There are two types of autoregulation described: static and dynamic. “Static” autoregulation refers to a steadystate relationship between MAP and CBF. It is usually assessed using TCD either by changes in the CBF or by changes in MAP by administering phenylephrine. “Dynamic” refers to the cerebral pressure–flow relationship during transient changes in MAP. It is usually measured by transient hyperemic response test. However, many studies have found that the difference between the two is little.21 Recent methods for assessing the continuous autoregulation include transfer function analysis based on the principle that higher frequency BP fluctuations are more linearly transferred to the cerebral circulation than lower frequency fluctuations. Mechanisms of Autoregulation The principle mechanism by which the cerebral vessels respond to change in the MAP is by changing the cerebral vascular resistance (CVR). The initial thought was that the pial arterioles were primarily responsible for CVR; however, it was found that the large intracranial arteries are responsible for changing CVR in response to changes in MAP.23 The postulated mechanism of autoregulation includes neurogenic, myogenic, and local factors. Myogenic Control The myogenic theory described by Bayliss in 1902 proposes that autoregulation is caused by the stretching of the smooth muscle cells of the vessel wall leading to vasoconstriction.24 The mechanism behind it is by the calciummediated pathway in the vascular muscle since it is inhibited by the Ca+2 channel inhibitors. There is an opening of voltage-gated Ca+2 channel following the stretch leading to entry of calcium and vasoconstriction.25 A calciumindependent mediated theory is also proposed for myogenic action called calcium sensitization, which occurs in the absence of calcium entry. Neurogenic Control A large body of data has been published on the role of autonomic nervous system in the control of CBF. The cerebral blood vessels, perivasculature innervations, and astrocyte foot process have been identified as a single unit called “neurovascular unit.” The neurogenic theory suggests that two distinct mechanisms exist in the neural control of CBF. The extrinsic mechanisms are mediated by the superior cervical ganglion (sympathetic), sphenopalatine ganglion (vagus–parasympathetic), and trigeminal ganglion that innervate the cerebral blood vessels from neck to II. NEUROPHYSIOLOGY 72 4. NEUROPHYSIOLOGY Virchow Robin spaces. The sympathetic stimulation leads to the cerebral vasoconstriction up to the upper limit of CA. The parasympathetic activity has not been fully elucidated. In addition, stimulation of trigeminal nerve leads calcitonin gene-related peptide (CGRP)–mediated vasodilation.26 The intrinsic mechanism is caused after the vessels leave the Virchow Robin spaces. The nerves originate from the distal regions of the brain as well as local interneurons which connect to the astrocyte foot process rather than the blood vessels. These nerves control constriction or dilation of the vessels depending on the stimuli. The exact mechanism is not understood. GABA-mediated vasodilation occurs in the interneurons. Flow Metabolism Coupling Even though the brain is only 2% of body weight, it consumes 20% of energy of the whole body. Another unique feature of the brain energy consumption is the regional differences in the synaptic activity. Much of the energy expenditure is used maintaining the ion homeostasis. Sherrington in the 19th century proposed that the brain possesses an intrinsic ability to maintain its local blood flow depending on its need which is otherwise its activity.27 This intrinsic ability is called “flow metabolism coupling” (Fig. 4.9). Brain is unique in that different function is represented in specific areas. Initiation of a particular function such as motor movements, speech, etc. results in increase in the blood flow in that area subserving the function. This is the principle used in functional MRI using blood-oxygen-level dependent contrast imaging signals. The increase in blood flow was thought to be due to initiation of action potentials.28 However, studies have shown that increased synaptic transmission during activity leads to increase product of metabolism either adenosine or changes in ions like K+ and H+ ions. Potassium ions released during synaptic transmission have been shown to act via K+-dependent ATP channels in the vascular smooth muscle causing vasodilation. Hydrogen ions also produce vasodilation, but the exact mechanism is not known. It is probably thought to be similar to CO2induced vasodilation or via nitric oxide pathways.29 Among the metabolites, adenosine appears to be a potent vasodilator. Extracellular levels of adenosine were found to increase with neuronal activity, and topical application of adenosine to cerebral microcirculation causes vasodilation.30 Factors Affecting Cerebral Blood Flow Partial Pressure of Arterial CO2 Changes in the PaCO2 affect the CBF as cerebral circulation is very sensitive to the levels of PaCO2. Studies have shown an approximate 3–6% increase and/or 1–3% decrease in flow per mmHg in PaCO2 above and below eucapnoeic PaCO2, respectively.31 All the vessels of cerebral circulation such as large arteries of the neck, intracranial vessels, pial arterioles are sensitive to changes in PaCO2. The CO2 reactivity of the microvasculature in gray matter is greater than that of white matter because of relatively less vascularization of white matter. The mechanism by which PaCO2 acts is not known. It is thought to exert action by directly acting on the smooth muscle of the blood vessels or by changes in local tissue pH. The actions of PaCO2 occur regardless of blood pH. An increase in PaCO2 causes cerebral vasodilation and hypocapnia causes vasoconstriction.32 The lower limit of CA has been found to shift upwards in acute hypercapnia. The lower limit of CA of 50–60 mmHg under normocapnia (PaCO2 = 30–50 mmHg) was shifted to 80–100 mmHg when hypercapnia (PaCO2 = 70–95 mmHg) was instituted.33 The upper limit in hypercapnia was found to be limited leading to a situation in which the CA limits were shorter in hypercapnia conditions.33 In severe hypercapnia, the blood flow is pressure dependent. It is also found that PaCO2 of more than 55 mmHg abolishes CA (Fig. 4.11). During hypocapnia, there is vasoconstriction of cerebral blood vessels. The effect on CA is well established than hypercapnia. Hypocapnia has been found to decrease the plateau of CA curve; the change in the lower limit was not significant compared to normocapnia; however, data on the upper limit has not been elucidated.32 Effects of Partial Pressure of Arterial Oxygen The changes in PaO2 under normoxic conditions are less pronounced compared to PaCO2. However, when the PaO2 is below 50 mmHg, there is cerebral vasodilation. The effects of the changes in PaO2 depend on the PaCO2 levels. Studies have shown that hypercapnia increases and hypocapnia decreases cerebrovascular sensitivity to hypoxia.34 The mechanism by which hypoxia acts is thought to be by (1) products of metabolism in the ECF, (2) stimulus from local neurovascular coupling, or (3) adenosine. Isocapnic hypoxia below 50 mmHg produces cerebral vasodilation. However, in clinical situations, when there is low CBF, there is excessive ventilatory drive to wash out the PaCO2 leading to vasoconstriction. This hypocapnia opposes the hypoxia-induced vasodilation and the net results in minimal change or further reduction in CBF.35 Compared to II. NEUROPHYSIOLOGY VASCULAR ANATOMY 73 FIGURE 4.11 The effect of partial pressure of CO2 (PaCO2) (hypocapnia and hypercapnia) on the autoregulatory curve. acute hypoxia, effects of chronic hypoxia on CBF are complex. The data are obtained from high altitude climbing. Initially (3–5 days), there is an increase in CBF of approximately 20% after which it tends to fall. After 2 weeks the CBF returns to normal level, which is thought to be due to adaptation of hypoxia by increase in hematocrit, and mild.36 Effects of Hematocrit Level of hemoglobin (Hb) or hematocrit (Hct) is one of the factors affecting the CBF. Since oxygen content is a major factor in the delivery of oxygen changes, the level of Hct can impact the oxygen delivery and cerebral metabolism. The optimum level of Hct is a matter of big debate. Higher Hct >44 has been shown to increase the blood viscosity and reduce CBF.37 Hct <28 has been shown to increase the CBF.38 The mechanism of increase in CBF is thought to be due to vasodilation induced by either low viscosity or low oxygen content. It has been found in a recent experiment that combination of low Hct and hypercapnia is detrimental as the autoregulation is abolished.39 In such cases, occurrence of hypotension in patients with low Hct can lead to severe ischemia. Various studies have shown that low Hct of less than 25 or Hb <7 g% has been associated with poor outcome.40 Effects of Age and Gender Age has been found to be an important factor in the CBF. Studies have shown that there is a decrease in the mean FV in TCD as the age advances. The mean FV was found to decrease from 74 cm/s at 20–39 years to 58 cm/s in persons older than 60 years.41 In addition to the peak systolic flow, diastolic flow also decreases, and the pulsatality index and resistance index increase as age advances.41 Moreover the difference in FV gets exaggerated in patients with SAH. Females upto 60 years have been found to have higher FV compared to males after which the differences are abolished.41 Effects of Temperature and Anesthetic Agents Hypothermia causes reduction in the CBF, and maximum reduction is seen at 18°C whereas the suppression of metabolism has been found to continue below 18°C. Temperatures below 18°C are associated with loss of autoregulation and vulnerable to ischemia.42 Hyperthermia during exercise has been shown to reduce global CBF without reduction in cerebral metabolism. Hence hyperthermia is detrimental to brain.43 The anesthetic agents have variable effects on the CBF depending on the type (intravenous vs. inhalational) and concentration used and has been described elsewhere. Measurement of Cerebral Blood Flow Since CBF and cerebral oxygenation are major determinants of brain function, it is essential that a technique be available to monitor in various situations. CBF measurement has been advocated in traumatic brain injury, stroke, deep circulatory arrest, cardiopulmonary bypass, etc. Such techniques need to be simple, accurate, capable of measuring both global as well as regional CBF, noninvasive, and cost effective. Various techniques are available to measure the CBF.44 Unfortunately, the accurate estimation of CBF is done by invasive methods and requires complex II. NEUROPHYSIOLOGY 74 4. NEUROPHYSIOLOGY equipment, more expensive, and cannot be used bedside. Currently CT- and MRI-based techniques such as PET, SPECT scan are widely used for clinical use compared to radiolabeled techniques. Methods which are noninvasive, such as TCD, optical, or laser systems, do not measure the CBF directly, but only the FV which is a surrogate marker of CBF. Moreover, the values are affected by various local and systemic factors to be used for clinical/research purpose. SUMMARY CBF is one of the major determinants of brain function, and various factors can affect the autoregulation, metabolism, and function. Both elevated as well as reduced blood flow can be detrimental to the brain function. It is affected by both intrinsic as well as extrinsic factors. The measurement of CBF is a challenging process due to limited availability of bedside techniques. It is important to understand the changes in CBF in different pathological conditions so that optimum CBF can be ensured. BRAIN METABOLISM INTRODUCTION Brain is one of the organs in the body with high blood flow as well as metabolism. In addition to basic needs for cellular energy, large amount of energy is needed to maintain the neurological function especially ion homeostasis. Brain utilizes glucose as a main substrate for energy production.45 Alternate sources of energy include ketone bodies in case of starvation and lactate in case of high physical activity.46 The cerebral metabolism can be altered in various physiological as well as pathological states. It is important to understand the normal cerebral metabolism, its monitoring, and various factors that alter the metabolism. In this overview, we will discuss the normal metabolism of the brain and how it is altered in pathological conditions. NORMAL CEREBRAL METABOLISM Unlike other organs of the body, brain is totally dependent on the glucose for its energy.45 No other substances have been found as energy source under normal conditions. The understanding of the cerebral metabolism comes from the measurements of arteriovenous differences of glucose, oxygen, CO2. The normal, conscious human brain consumes oxygen at a rate of 156 µmol/100 g tissue/min. CO2 production is the same, leading to a respiratory quotient of 1.0, which shows that the carbohydrate is the ultimate substrate for oxidative metabolism. For complete oxidation of glucose, the theoretical ratio of O2:glucose utilization is 6.0; but the measured ratio in brain is 5.5. The actual glucose utilization measured is 31 µmol/100 g/min, which indicates that glucose consumption is not only sufficient to account for total O2 consumption but is in excess by 5 µmol/100 g/min. The excess amount of glucose is thought to be utilized for synthesis of chemical constituents.47 Brain Energy is Utilized for the Following Process 1. In the resting state, there are more Na+ ion outside the cell and more K+ ion inside the cell. There is a tendency for the ions to move down the electrochemical gradient. In the resting state, there is leakage of K+ ion outside the cell and Na+ inside the cells. The inside of the cell is kept at an electronegativity of −70 mV by means of the ion transporters. If there were no ion transporters there will be depolarization to 0 mV, and there will be cell death. During the period of activity, there is opening of the Na+ and Ca+2 ion channels which leads to rapid depolarization of the cell membrane and generation of the action potentials. After the spread of the action potential, the cell should come back to its hyper polarization state. This is possible only by moving the Na+ and Ca+2 ions against concentration gradient to ECF. The ion transporters and cotransporters pump out these ions to bring the cell back to its resting state. This is an energy-dependent process. Effective functioning of the ion transporters and cotransporters require large amount of energy.48 2. Various cellular organelles such as vesicles, mitochondria, endoplasmic reticulum are involved in the catabolism and synthesis of various proteins, enzymes, neurotransmitters that require energy. 3. Many of the neurotransmitters are synthesized in the cell body of the neuron and need to be transported to the axons for release, which require energy. II. NEUROPHYSIOLOGY NORMAL CEREBRAL METABOLISM 75 FIGURE 4.12 The normal metabolic pathway of glucose utilization by the brain. Brain Metabolism in Presence of Oxygen Glucose from the blood is transported via carrier-mediated mechanism via Glut 1 transporter to the brain ECF. From the brain ECF it is transported into the neuronal cells via Glut 3 cotransporter. Inside the cell the glucose is converted to glucose 6 phosphate, which is utilized in one of the three pathways (Fig. 4.12): 1. It enters the glycolytic pathway which is the most common destination of the glucose. 2. It enters pentose phosphate pathway. 3. It enters the glycogenesis in astrocytes. In the presence of oxygen, glucose enters the glycolytic pathway and the end product is generation of pyruvate molecules as well as two molecules of ATP. The pyruvate enters the TCA cycle in which additional 34 molecules of ATP are generated. Cerebral Metabolism in Hypoxic State If there is lack of oxygen the pyruvate enters anaerobic glycolysis and lactate and H+ ion is produced. During this process two ATP is released compared to 34 ATP in oxidative glycolysis. The resultant H+ ions cause a cellular acidosis and block the enzymatic process and ion transport. Therefore the end result of oxygen deprivation is intracellular acidosis and cell death. It should be borne in mind in case of severe ischemia that supply of both oxygen as well as glucose is limited resulting in accelerated cell death. Cerebral Metabolism in Hypoglycaemic States In case of hypoglycemia, the brain tries to utilize alternate source of energy. During periods of low glucose levels, the body tries to produce glucose from alternate sources such as stored glycogen from liver, amino acids, and fat. Once these stores are exhausted a state of ketosis occurs, where the blood levels of ketone bodies especially beta II. NEUROPHYSIOLOGY 76 4. NEUROPHYSIOLOGY hydroxy butyrate and acetoacetate increase. Normal brain does not utilize these ketone bodies due to the presence of glucose. However, in states of ketosis, the ketones enter the neurons from blood via cotransport mechanisms. The brain has enzymes to utilize the ketone bodies, and acetyl CoA is formed. Acetyl CoA enters the citric acid cycle and produces ATPs. Although it produces ATPs, it is an inefficient way of metabolism for the brain. If the hypoglycemia resolves, the metabolism of brain shifts back to normal. Additional source of energy for the brain in hypoglycemic states is derived from lactate. Normal blood lactate levels are 0.5–1 mmol/dL. Under normal conditions lactate is exported from the brain to blood. The brain utilizes lactate less than 10% as energy source. In case of low energy supply as in hypoglycemia, lactate enters the neurons of the brain via astrocyte, and the lactate can be up to 60% as substrate for oxidative phosphorylation. The entry of lactate is called astrocyte-to-neuron lactate shuttle.48 Control of Cerebral Metabolism Metabolic Coupling One of the most important features of the cerebral metabolism is the flow-metabolism coupling and the neuron-glia metabolic coupling.49 Neuronal activity is both spatial and temporal in nature. Whenever there is increased activity of specific neuronal population, there is increase in regional blood flow, increased uptake of oxygen and glucose. This is called flow-metabolism coupling. The mechanism by which the metabolism is coupled with activity is described by the neuron-glia coupling (Fig. 4.13). Major proportion of brain energy is needed to maintain the ion balance and neurotransmitter uptake. Synaptic potentials, rather than action potentials, appear to represent by far the main energetic cost related to maintenance of excitability. Excitatory synapses largely dominate in the gray matter, glutamatergic ones alone represent at least 80% of cortical synapses suggesting that excitatory neurotransmission accounts for most of the energy requirements at the cortical level. There is a close relationship between brain activity, glutamatergic neurotransmission, energy requirements, and glucose utilization. Glutamate is the major neurotransmitter of the brain which is released from the presynaptic terminals to synaptic cleft. The glutamate is stored in vesicles and present in high concentration in the cytoplasm of neurons. The glutamate inside the cell is nontoxic to neurons. However, once they are released in synaptic cleft, it can potentiate the excitatory pathway and cause Ca+2 influx which can damage the neurons. Hence it needs to be removed from synaptic cleft. Once released, the neurons are incapable of glutamate uptake. The released glutamate is taken up by the astrocytes and converted to glutamine. The glutamine is released into brain ECF and taken up by neurons, which will convert it to glutamate for future release. This process is called glutamate–glutamine cycle and anaplerotic pathway. The astrocytes are the only structures which can generate glutamate from glucose because of the presence of enzyme pyruvate carboxylase. This process is an energy-dependent process. Another important role in the neuron-glia coupling is the lactate shuttle50 (Fig. 4.14). FIGURE 4.13 The neuron-glial coupling in the energy metabolism. II. NEUROPHYSIOLOGY NORMAL CEREBRAL METABOLISM 77 As already mentioned, the intracellular glucose can be utilized by three pathways in neurons. However, the neurons lack capacity for formation of fructose-2,6-biphosphate, which is a key product in the glycolytic pathway. Hence the glycolytic pathway is slow inside the neurons, and majority of glucose is diverted via the “pentose phosphate pathway” which is important in forming NADPH from NADP. NADPH is a potent antioxidant that protects the neurons from overexpression of oxygen and apoptosis. Hence for energy source the neurons rely on the astrocytes. Astrocytes produce lactate from the glycolytic pathway, and the lactate is taken by the neurons. The lactate is utilized in the citric acid cycle to produce 30–34 ATPs. Thus the energy of the neurons is spent efficiently by slowing a glycolytic process which yields only two ATPs as well as reducing the oxygen utility. Metabolic Uncoupling During physical activity increased amount of lactate is produced from the muscle that raises the serum lactate levels. Coupled with increased physical activity there is increased metabolism in the brain. The sympathetic stimulation associated with exercise increases the CBF, CMRO2, and cerebral glucose uptake. It was found that there is a metabolic uncoupling in these states, i.e., uptake of carbohydrates is more than the CMRO2. Cerebral metabolic uncoupling is a consequence of increased lactate availability leading both to passive lactate influx and increased cerebral dependence on lactate as fuel. The uptake of lactate depends on the cerebral metabolic activity and is independent of sympathetic stimulation. The lactate is used as a substitute for glucose by the brain. Cerebral Metabolism in Pathological States When the CBF reduces to critically low levels, there is reduction in substrates such as glucose and oxygen delivery to the neurons. The cells will switch over from aerobic to anerobic metabolism. This leads to reduction in the number of ATPs produced in anerobic (2) compared to that in aerobic (32) metabolism. The energy required for the ionic homeostasis is not matched with the supply. The uptake of glutamate released from the presynaptic neurons is inhibited, and the glutamate accumulates in the synaptic vesicles. The glutamate causes stimulation of the postsynaptic neurons via the AMPA and NMDA receptor leading to persistent depolarization. The Ca+2 and Na+ channels opening for longer duration cause massive influx of calcium and sodium into the cell. Moreover, the lower energy prevents the membrane-bound ion exchangers to function adequately. The high cytoplasmic calcium level is thought to trigger a number of events that lead to the ischemic damage. These include increasing the activity of proteases and phospholipases. These enzymes convert membrane lipid molecules to products of arachnoid acid metabolism. FIGURE 4.14 The astrocyte–neuron lactate shuttle. II. NEUROPHYSIOLOGY 78 4. NEUROPHYSIOLOGY In addition there is release of oxygen-free radicals. All these events lead to cell death and disruption of blood–brain barrier, edema formation. Later stages lead to infiltration of the ischemic area by the macrophages causing necrosis. Apoptosis The process of necrosis described above is a severe form of neuronal damage. There are other forms of cell injury in which the neurons die, but do not disintegrate. There is no inflammation and immune activation. This process is called apoptosis. In apoptosis there is expression of genes such as c-Jun and c-Fos. These genes express the formation of new proteins that can be either apoptotic or antiapoptotic. The final fate of the neurons to survive or to die depends on which of the protein action dominates. Monitoring of Cerebral Metabolism Normal cerebral metabolism is affected in various pathological conditions that can result in deficiency in substrate supply such as glucose or oxygen which in turn depend on the CBF. This can result in anaerobic metabolism and if severe, results in cell death. It is therefore important to monitor the cerebral metabolism. The monitoring modalities include global as well as regional techniques. Global metabolism is usually assessed using jugular venous oximetry whereas regional metabolism can be assessed noninvasively by near-infrared spectroscopy (NIRS) and invasively cerebral microdialysis. Jugular Venous Oximetry Jugular venous oximetry is a measure of global oxygen utilization of the brain.51 The basic principle lies on the fact that the blood draining the jugular vein is from both the hemispheres (70% ipsilateral, 30% from contralateral side), there is a dominance usually on the right side; blood sampled from the jugular bulb is predominantly drained from brain whereas anything below can be contaminated from an extracranial source. When there is increased demand of oxygen, brain extracts more oxygen resulting in reduced jugular venous oximetry. Normal values for jugular venous oxygen saturation (SjVO2) are 55–75%. If the value falls less than 55%, it shows increased oxygen extraction due to imbalance in supply–demand ratio. However a value of more than 75% can be due to either excess blood supply or decreased demand as in a metabolically suppressed state such as hypothermia, barbiturate coma. A SjVO2 of less than 50% has been associated with cerebral anaerobic metabolism, <40% with electroencephalogram slowing, <30% with unconsciousness or low Glasgow coma scale score. In addition to the SjvO2 values, the information obtained from jugular venous oximetry helps in deriving other values of cerebral circulation such as cerebral metabolic demand for oxygen (CMRO2), arteriovenous oxygen difference (AjvDO2) = CMRO2/CBF. Near-Infrared Spectroscopy NIRS provides a real-time continuous measurement of regional cerebral blood oxygenation and indirect blood flow. NIRS uses the principle of reflectance spectrophotometry.52 NIRS has been used to measure rSO2 in a variety of clinical conditions. In patients with SAH it is used during clipping of aneurysm, early detection of vasospasm. It is also used for managing head-injured patients, carotid endarterectomy, cardiac surgery during cardiopulmonary bypass. There are limitations of NIRS use. The absorption by extra skull tissues, presence of hematomas, other pigments such as melanin, bilirubin can give false values. The skull thickness as well as hemoglobin concentration also interferes with the accuracy of monitoring. Cerebral Microdialysis The concept of cerebral microdialysis originated in 1960 for assessment of brain ECF composition, especially amino acids. Progression in science has led to development of commercially available cerebral microdialysis catheter and dialyzate analyzer.53 Cerebral microdialysis is used to monitor brain ischemia. 1. Head injury: Microdialysis has been found to be useful in assessing the patients, as a guide for lower limit of autoregulation and optimization of CPP, adjusting the hyperventilation, guiding the surgical planning. 2. Subarachnoid hemorrhage: Microdialysis is useful in early detection of vasospasm and delayed ischemia neurological damage and guiding the triple H therapy. 3. Other potential benefits for cerebral microdialysis includes drug and substrate delivery. This application is in research and yet to be utilized to its potential. II. NEUROPHYSIOLOGY VENTRICULAR SYSTEM 79 Positron Emission Tomography Positron emission tomography is useful in assessing the cerebral metabolism for glucose, CMRO2, and CBF. The neurometabolic and flow metabolic coupling form the basis of the PET scan. The PET/CT or PET/MRI can be used; many of them prefer the later investigation. The glucose utilization can be assessed using 18F-fluoro-2-deoxyglucose. The tracer is injected into the vein and after approximately 30 min the scan is performed. PET scan for glucose metabolism is useful in epilepsy and degenerative conditions such as Parkinsonism, Alzheimer disease, etc. SUMMARY The cerebral metabolism is unique that it is continuously dependent of the substrate supply from the brain. Advances in technology have helped us to understand the basic process of cerebral metabolism. At present many of these monitors are limited to research tools. However, there are limited studies on the ways to improve the metabolism in ICU as well as OT setting and how the therapeutic interventions improve the outcome in these patients. CEREBROSPINAL FLUID INTRODUCTION The CSF is the fluid covering the brain and spinal cord. The main function of the CSF initially was thought to reduce the buoyancy of the brain. However, evidence shows it has many other important functions, especially the regulation of neuronal function.13 The CSF composition and secretion is altered in various disease processes. Hence it is important to understand the physiology of CSF which will be elaborated in this chapter. VENTRICULAR SYSTEM The interior of the brain contains cavities filled with CSF. The lateral ventricle is present one in each cerebral hemisphere and a median cavity, the third ventricle between the hemispheres. The fourth ventricle is located dorsal to pons and medulla. The ventricles communicate with each other through various foramen as well as to central canal of spinal cord and subarachnoid spaces. The cavity of ventricle is covered with ependymal cells. Formation of Cerebrospinal Fluid CSF is formed by several regions of the central nervous system (CNS). The choroid plexus of the ventricles forms the main bulk (two-thirds) of the CSF. The remaining is formed from extrachoroidal sources. Choroidal secretion: Microscopically the choroid plexus consists of layer of capillary endothelium, matrix, and the lining epithelium (Fig. 4.15). The choroid plexuses have granular villous protrusions into the ventricular lumen, the epithelial surface of which is continuous with the ependyma. Each villus is composed of a single layer of epithelial cells overlying a core of connective tissue and blood capillaries. The capillaries in the choroid plexus, unlike those in the majority of the cerebral circulation, are fenestrated and hence provide little resistance to the movement of small molecules, ions, and water. They comprise a tuft of fenestrated capillaries. A barrier is formed by the junctional complexes between the epithelial cells, which restrict the passage of molecules and ions freely into the CSF. Choroidal cells are epithelial cells which have microvilli at their apical pole and are interconnected by tight junctions with a variable distribution according to the site on the ventricular wall. The choroid plexus epithelial cells form the “blood–CSF barrier.” CSF formation occurs in two stages: passive filtration of fluid across choroidal capillary endothelium along the pressure gradient into the choroidal interstitium, followed by a regulated active secretion across a singlelayered epithelium from the interstitium into ventricles.14 The solute movement from blood to CSF occurs by diffusion, facilitated transport, and active transport. A blood flow of about 4 mL/min/g is converted to a CSF formation of approximately 0.4 mL/min/g. CSF formation begins as plasma is filtered across permeable choroidal capillaries. Net filtration is proportional to the hydrostatic pressure gradient between blood and choroid II. NEUROPHYSIOLOGY 80 4. NEUROPHYSIOLOGY FIGURE 4.15 The structure of the choroid plexus. interstitial fluid. Hence a lower BP as well as increased interstitial pressure as occurs in raised ICP reduces the formation of CSF. The choroid plexus epithelium is polarized both structurally and functionally. Actively formed CSF stems from coordinated secretion of solutes across the thin epithelial interface between the inner choroidal plasma and outer ventricular fluid. Although bidirectional transport of ions and water can occur, CSF formation is mainly by the passage of the Na+, K+, HCO3− from interstitium to ventricles. Ions and water are taken up by facilitating mechanisms at the basolateral membrane, convected through cytoplasm, and then released or actively secreted by the epithelium into the ventricles on the apical side (Fig. 4.16). Cytoplasmic carbonic anhydrase catalyzes the formation of H + and HCO3− ions from water and CO2. The carrier proteins of basolateral membranes of choroidal cells exchange H+ and HCO3− ions for Na+ and Cl− ions. ATPdependent ion pumps of the apical membrane expel Na+, Cl−, HCO3−, and K+ ions toward the ventricular lumen. Water transport is facilitated by aquaporins I of the apical membrane, and it follows the osmotic gradients generated by these pumps. The NaK2Cl cotransporter of the apical membrane generates ion transport in both directions and participates in regulation of CSF secretion and composition.14 Extrachoroidal secretion: Extrachoroidal secretion of CSF is derived from the brain extracellular fluid (ECF), cerebral capillaries across blood–brain barrier and ependymal cells. Under normal conditions, this pathway appears to be less significant source of CSF formation. Cerebrospinal Fluid Circulation The CSF flows from the lateral to the third ventricle via the cerebral aqueduct and the fourth ventricle to subarachnoid space in cisterna magna and subarachnoid spaces. The flow of CSF across the ventricles is pulsatile, unidirectional, and is caused by the transmission of the arterial pulsations. Ventricular CSF also flows by another route to the basal and midbrain cisterns, i.e., into subarachnoid extensions of the velum interpositum (from dorsal third ventricle) and superior medullary velum (rostral fourth ventricle). Thereafter fluid is convected to the subarachnoid spaces of the spinal cord and brain convexities. As CSF flows through the ventriculosubarachnoid system, there are diffusional and bulk flow exchanges between CSF and brain depending upon region-specific gradients for concentration and hydrostatic pressure that promote widespread distribution of CSF-borne materials. From the subarachnoid II. NEUROPHYSIOLOGY VENTRICULAR SYSTEM 81 FIGURE 4.16 The secretion of various substances into the cerebrospinal fluid. spaces the CSF moves cranially over the surface of the brain to the superior sagittal sinus from where it is absorbed and caudally to the spinal subarachnoid spaces. Cerebrospinal Fluid Absorption In humans, major portion of CSF is absorbed through the arachnoid villi into superior sagittal sinus especially in its posterior part. The arachnoid villi are projections of the arachnoid matter through defects in the dura of the sinus at the embryonic life. The arachnoid villi consist of thin layer of endothelium. The pressure gradient between subarachnoid spaces and the venous sinus necessary to ensure CSF drainage is between 3 and 5 mmHg.15 Each arachnoid villus was thought to have a one-way (CSF outward) valve-like mechanism that opened in response to a positive hydrostatic pressure gradient between CSF and dural venous blood. This belief has been questioned with recent research showing that bulk of CSF flow is absorbed through olfactory and optic nerve sheath, via cribriform plate to nasal mucosa and cervical lymph in animals.14 The absorption via arachnoid villi occurs only in case of raised CSF pressure. However, evidence is lacking in humans to this type of absorption. Spinal arachnoid villi in contact with the epidural venous plexus represent a pathway of CSF absorption especially during effort. In man, arachnoid villi in lumbosacral nerve roots increase CSF absorption in the upright position in response to gravity, and the absorbed CSF then enters the lymphatic system.15 Cerebrospinal Fluid Volume and Composition The CSF volume is estimated to be about 150 mL in adults. It is distributed between 125 mL in cranial and spinal subarachnoid spaces and 25 mL in the ventricles. CSF secretion in adults varies between 400 and 600 mL/day or 0.3– 0.6 mL/min/g. CSF is renewed four to five times per 24 h in young adults. In old age the CSF volumes are more due to atrophy of the brain and there is low turnover of CSF. The composition of CSF is different than plasma in which it has less potassium, calcium, glucose, and proteins, whereas it contains more chloride and magnesium compared to plasma (Table 4.3). II. NEUROPHYSIOLOGY 82 4. NEUROPHYSIOLOGY TABLE 4.3 Composition of the Cerebrospinal Fluid (CSF) Compared to Plasma Component Plasma CSF Na+ (mmol/dL) 140 141 K+ (mmol/dL) 4.6 2.9 Cl− (mmol/dL) 101 124 Ca+2 5 2.5 1.7 2.4 23 21 Glucose (mg/dL) 90 54 Proteins (mg/dL) 700 4.3 Osmolarity 305 298 pH 7.4 7.3 PaCO2 (mmHg) 41 51 (mmol/dL) Mg+2 (mmol/dL) HCO3− (mmol/dL) Regulation of Cerebrospinal Fluid Dynamics CSF production, circulation, and absorption can be affected by pathological process or by administration of the drugs. The choroid plexus receives cholinergic, adrenergic autonomic innervation. The sympathetic stimulation reduces CSF secretion whereas the cholinergic stimulation causes increased CSF secretion. In addition to autonomic innervation, choroid plexus has seretonergic and peptigergic systems. Monoamines and neuropeptide factors have also been shown to play a role. Dopamine, serotonin, melatonin, atrial natriuretic peptide (ANP), and arginine vasopressin receptors are present on the surface of choroidal epithelium. Alteration in the ANP and vasopressin receptors has been thought to be involved in the pathophysiology of hydrocephalus and dementia of Alzheimer type. Drugs such as loop diuretics and carbonic anhydrase inhibitors act on the transporter mechanisms and reduce the CSF secretion. In patients with raised ICP, especially hydrocephalus, the pressure gradient between the plasma and CSF is reduced leading to reduced secretion of CSF as well as diversion of CSF from intracranial to spinal compartments. Effects of Anesthetic Agents Anesthetic agents have variable effects on the CSF rate of formation (Vf) as well as resistance to absorption (Ra). Among the intravenous agents ketamine, in the anesthetic doses, increases Ra, but has no effect on Vf. Other intravenous anesthetic agents such as thiopentone, etomidate, and propofol tend to decrease both Vf and Ra, especially in higher dose range. Inhalational agents have different effects compared to intravenous agents. Nitrous oxide has no effect on Vf and Ra. Isoflurane has variable effects on Vf and Ra depending on the concentration. At higher doses it decreases Ra. In other situations they have either no effect on Vf and Ra or decrease Vf. Sevoflurane reduces Vf and increases Ra. Halothane decreases Vf and increases Ra. Desflurane has variable effects depending on PaCO2 and ICP levels. Under normocapnia, desflurane increases CSF pressure whereas in hypocapnia it decreases CSF pressure. Midazolam appears to have variable effects on the CSF dynamic depending on the dose. Low-dose fentanyl has no effect on Vf and it decreases Ra, whereas high-dose fentanyl reduced Vf. Sufentanil was found to have no effect on Vf, but reduced Ra. Effects of Pathologies on Cerebrospinal Fluid Dynamics 1. Head injury: Patients with head injury may have high ICP; however, the Vf has not changed in head-injured patients, whereas the Ra was increased contributing to additional cause of raised ICP in 20% of patients. II. NEUROPHYSIOLOGY INTRODUCTION 83 2. Intracranial tumors: The intracranial mass lesion can compress the CSF spaces and shift the CSF to spinal from intracranial compartment. Depending on the speed with which the ICP increases the effects on CSF dynamics are affected. Since CSF rate of formation depends on CBF, acute increase in ICP can compromise CBF and can reduce CSF production whereas Ra is increased. A slow growing mass lesion has limited effects on Vf, whereas it can increase Ra. 3. Bacterial meningitis: In bacterial meningitis there is increased Ra which is a major factor in the increase in ICP seen in meningitis. 4. Pseudotumor cerebri: There are multiple mechanisms for raised ICP in this condition. An increase in Vf, Ra, CBV, and CBF all have been thought to be responsible. Prednisolone treatment has been found to reduce Ra. 5. Subarachnoid hemorrhage (SAH): Patients with SAH can present with hydrocephalus. Various studies have shown that the presence of blood in the subarachnoid space increases Ra leading to raised ICP.16 Imaging of Cerebrospinal Fluid Pathways Various pathological lesions can affect the CSF pathways. The earliest one used was cisternal puncture and injecting air or contrast agents and using X-rays to assess the ventricular size and pathology. This is no more in vogue. Currently the CT scans and magnetic resonance imaging (MRI) are used for assessing the CSF pathways. CT Scan CT scan of the brain is the initial imaging of choice for identifying the ventricle. The normal CSF spaces will appear dark in the CT films. The size of the different ventricles, the cisterns can be seen well with CT. Lesions such as dilated ventricles, slit ventricles, tumors, etc., can be readily delineated in CT imaging. Contrast enhanced CT will help in visualizing the choroid plexus and its pathology. Magnetic Resonance Imaging In addition to the size and pathology of the ventricles, MRI will help in identifying site of obstruction of CSF pathways, tumors in the ventricles as well as surrounding the pathways, CSF flow dynamics using phase contrast MRI. In T1-weighted images, CSF will appear darker and in T2-weighted images CSF will appear as bright structures. The phase contrast MRI generates signal contrast between flowing and stationary nuclei by sensitizing the phase of transverse magnetization to the velocity of motion.17 Axial and sagittal images are obtained for CSF flow analysis. The gray scale intensity of each pixel is directly related to the velocity of CSF. Caudal flow of CSF is conventionally represented as shades of white on phase images, whereas cranial flow is by shades of black. Phase contrast MRI is used to differentiate communicating and noncommunicating hydrocephalus. In addition, it helps in identifying patients with normal pressure hydrocephalus who will benefit from shunt surgery. Patients with CSF flow velocity (FV) of more than 18 mL/min have been shown to benefit from shunt surgery. Phase contrast MRI is also useful in assessing the function of ventriculoperitoneal shunts. SUMMARY The CSF is an important component of the skull having multitude of functions ranging from protecting the brain, supplying nutrients, maintaining the cerebral homeostasis, and removal of waste materials. The CSF dynamics is a complex process which is affected by various physiological, pathological mechanisms as well as by the drugs including anesthetic agents. The CSF pathway is also a mechanism for the spread of some brain metastasis as well as infections. The major disorder affecting the CSF dynamics is the hydrocephalus which is also a commonest clinical situation in practice. Advanced flow sequences based on MRI technique help us to study the CSF dynamics in various pathological states. THE SPINAL CORD INTRODUCTION The spinal cord is a neural structure that connects the brain to the peripheral nerve system. The major function of the spinal cord is to transmit action potentials between the brain and the peripheral structures via the peripheral nerves. The spinal cord is enclosed in the vertebral column with intervening intervertebral discs. Similar to the brain II. NEUROPHYSIOLOGY 84 4. NEUROPHYSIOLOGY there are three protective meningeal coverings. Since the spinal cord is enclosed in a closed space like brain, it is vulnerable for injury due to various diseases. This chapter enumerated the basic anatomy, physiology, and various pathophysiological aspects of the spinal cord. ANATOMY The spinal cord is a part of CNS which extends from the lower end of medulla oblongata to the caudal equina which are the tuft of spinal nerves. In adults the spinal cord ends at L1-2 vertebra and in children at L2-3 vertebra. The difference is due to the rapid growth of the vertebral column compared to the spinal cord. The spinal cord is divided into four segments, from cranial to caudal as cervical, thoracic, lumbar, and sacral. There are two enlargements, cervical and lumbar. There are 31 bilateral spinal nerves that consist of cervical (8), thoracic (12), lumbar (5), sacral (5), and coccyx (1) nerves. ORGANIZATION OF THE SPINAL CORD The spinal cord is made up of central gray matter that consists of cell bodies of neurons and the outer white matter that consists of fiber tracts. The spinal cord is divided incompletely into two symmetrical hemispheres by the anterior median fissure which is much deeper than the posterior median fissure with the intervening undivided central gray matter. On either side of the spinal cord, the anterior lateral and posterior lateral fissures are present which represent the area where the ventral and dorsal rootlets (later roots) emerge from the cord to form the spinal nerves. Each spinal nerve has two roots, a dorsal and ventral. The dorsal root emerges from the dorsal gray horn, dorsolateral funiculus and enters a dorsal root ganglion located in the intervertebral foramen. Outside the foramen it joins the ventral root that emerges from the ventral gray horn and ventrolateral funiculus to form the spinal nerve. The spinal nerves in the cervical and lumbar areas form plexus from where peripheral nerve emerges. The white matter circumferentially surrounds the gray matter. The gray matter has three horns namely, the ventral, intermediate, and dorsal horn. The white matter is conventionally divided into the dorsal, dorsolateral, lateral, ventral, and ventrolateral funiculi. The spinal cord consists of neurons and nonneuronal cells. The neurons of the gray matter have specific laminar architectural pattern which was described by Rexed54 and Scheibel and Scheibel.55 White Matter of Spinal Cord White matter of the spinal cord has various interconnecting fibers. The connections of spinal cord can be classified as intrinsic pathways, ascending pathways, and descending pathways (Fig. 4.17). Intrinsic Pathways Intrinsic pathways establish connections between spinal interneurons and various ascending and descending fibers and also between different segments of the spinal cord. They may be important for proprioception and reflex pathways. Examples of intrinsic pathways include Lissauer’s tract, comma tract, septomarginal tract, cornucommissural tract, etc. Ascending Pathways Table 4.4A shows various ascending pathways in the spinal cord. The ascending pathways consist of axons of the dorsal root ganglion that enters the spinal cord via dorsal root. Descending Pathways Table 4.4B shows various descending pathways. The major descending pathway of the spinal cord is the corticospinal tract that originates in the motor cortex. Majority of the fibers cross in the medulla and descends as lateral corticospinal tract. Few uncrossed fibers descend as ventral corticospinal tract and cross at the level of spinal cord. II. NEUROPHYSIOLOGY 85 ORGANIZATION OF THE SPINAL CORD ASCENDING TRACTS DESCENDING TRACTS Fasciculus Gracilis septomarginal Comma Fasciculus Cuneatus Dorsal spinocerebellar Lateral corticospinal Rubrospinal Lateral Spinothalamic Olivospinal Ventral spinocerebellar Ventral Spinothalamic Lateral reticulospinal Vestibulospinal Spinotectal Medial reticulospinal Tectospinal Ventral corticospinal Spino olivary FIGURE 4.17 The various ascending and descending pathways of spinal cord. TABLE 4.4 The Important Ascending and Descending Pathways for Spinal Cord A. Ascending Pathways Funiculus Tracts Destination Function Posterior Fasciculus gracilis Ventral posterolateral nucleus of thalamus Touch, proprioception from lower limbs, lumbar, sacral, coccygeal, and lower thoracic t F asciculus cuneatus Ventral posterolateral nucleus of thalamus Touch, proprioception from upper limbs, upper thorax, neck Posterior spinocerebellar Anterior spinocerebellar Cerebellum Unconscious proprioception (posture control) Lateral spinothalamic Ventral posterolateral nucleus of thalamus Pain and temperature t S pinotectal Superior colliculus Connection between eye and body parts t S pinoreticular Reticular formation of medulla and pons Lateral t D orsolateral (Lissauer’s tract) Continued II. NEUROPHYSIOLOGY 86 4. NEUROPHYSIOLOGY TABLE 4.4 The Important Ascending and Descending Pathways for Spinal Cord—Cont'd A. Ascending Pathways Funiculus Tracts Destination Function Anterior Anterior spinothalamic Ventral posterolateral nucleus of thalamus Crude touch Spino olivary Superior olivary nucleus t S pinotectal Superior colliculus t S pinoreticular Reticular formation of medulla and pons Connection between eye and body parts B. Descending Pathways Funiculus Tracts Origin Posterior Fasciculus interfascicularis (semilunar tract/comma tract of Schultz) To cervical and thoracic cord Located between fasciculus gracilis and cuneatus Function Septomarginal tract Lateral Anterior Lateral corticospinal Motor area Muscle innervation Rubrospinal Red nucleus Facilitates flexors, inhibitory to extensors Lateral reticulospinal Reticular system from medulla Facilitates flexors, breathing control Olivospinal Inferior olivary nucleus to cervical cord Control of neck in equilibrium Descending autonomic bres Hypothalamus Anterior corticospinal Motor area Muscle innervation Lateral vestibulospinal Lateral vestibular nucleus Equilibrium Medial vestibulospinal Medial vestibular nucleus Equilibrium Tectospinal Superior colliculus Connection between eye and body parts Medial reticulospinal Reticular system from medulla Facilitates extensors, posture control Spinal Cord Interneurons Spinal interneurons are distributed widely and they are responsible for the fine control of the spinal cord function. They receive sensory inputs from various areas (both peripheral and central), and the final output depends on the type of inputs by which the functions are modified. The interneurons express various neurotransmitters such as glycine. Glial Cells of Spinal Cord In addition to the neurons, glial cells are also present in the spinal cord. The cell types are similar to those in brain: astrocyte, oligodendrocyte, ependyma, and microglia. Microglia are derived from monocytes whereas the other glial cells are derived from neuroectodermal cells. Astrocytes during development helps in migration of neurons, whereas in mature stage they contribute to the structural support of other cells. Astrocyte foot process contributes to the formation of blood spinal cord barrier formation. Oligodendrocytes produce myelin which cover the multiple axons within CNS, whereas Schwann cells contribute myelin to peripheral nerves. They are the targets in diseases that cause demyelination. Microglia are immune cells of the spinal cord. They are dendritic antigen-presenting cells expressing major histocompatibility extraspinal antigens. Blood Supply The blood supply of the spinal cord is unique in that it receives blood supply from multiple extraspinal arteries. Despite these abundant interconnections, the spinal cord is vulnerable to ischemia due to the variability of the blood supply. The blood supply can be classified as intrinsic system and extrinsic system. II. NEUROPHYSIOLOGY 87 ORGANIZATION OF THE SPINAL CORD Posterior Spinal Artery Dorsal Nerve roots Ventral Nerve Roots Spinal Nerve Central artery Radiculo medullary Artery Anterior Spinal Artery Artery of Ademkiewicz FIGURE 4.18 The diagrammatic representation of spinal cord blood supply. Intrinsic Supply The intrinsic system of blood supply to the spinal cord is by single anterior spinal artery (ASA) and two posterior spinal arteries (PSAs), which are located on the surface of the cord and the pial anastomotic system (Fig. 4.18). The intrinsic system has been classified to be a central and a peripheral system based on the supply.56 The central system predominantly supplies two-thirds of the spinal cord and is derived from the ASA. The blood flow is centrifugal. The central system supplies the anterior gray matter, anterior portion of the posterior gray matter and posterior white columns, inner half of the anterior and lateral white columns, and base of the posterior white columns. In the peripheral system, the blood flows centripetally from the PSAs and pial arterial plexus. This system supplies the outer portion of the anterior and lateral white columns and the posterior portion of the posterior gray matter and posterior white columns.56 The ASA arises from the branches of the vertebral arteries that are intracranially proximal to basilar artery. The diameter of the ASA is larger in the cervical region, and it decreases as it descends down the cord. At the lower end of the sacral or coccygeal region, branches from the ASA loop caudally around the conus medullaris and join each limb of the PSA forming anastomoses. The ASA receives segmental arteries along the length of the cord. The PSA arises from the vertebral or posterior inferior cerebellar arteries, winds around the brain stem, and descends on the dorsomedial surface of the spinal cord. The PSA ends at the conus medullaris by forming anastomosis with the terminal branches of the ASA. Throughout the surface of the spinal cord the branches of the ASA and PSA form a pial arterial plexus. Most of the branches from the pial arterial plexus penetrate the dorsal midline of the spinal cord. All of the penetrating branches run directly inward, perpendicular to the surface of the spinal cord. These branches mostly supply the outer portions of the spinal cord, including the greater part of the posterior horns up to the substantia gelatinosa. The central arteries, which are the branches of the ASA, supply the central portion of the spinal cord. The central arteries feed the central area of the spinal cord, which consists of the white matter bordering the central sulcus, the gray matter of anterior horn, and the deep gray matter of posterior horn.57 Extrinsic Blood Supply The extrinsic supply refers to the blood supply of the spinal cord which feeds the ASA and PSA. The radicular arteries which are usually 31 pairs are the main arteries that feed the ASA and PSA. Radicular arteries supply blood to the dura mater, nerve roots that they accompany, dorsal spinal ganglia, and ASA and PSA.57 The radicular arteries arise from anterior cervical arteries, thoracic aorta, and lumbar arteries. The artery of Ademkiewicz is the largest of II. NEUROPHYSIOLOGY 88 4. NEUROPHYSIOLOGY the radicular artery. It usually joins the ASA. In 75% people, this artery travels with the T9–12 roots. In 10% it follows roots L-1 or L-2, and in 15% it has a high origin at posterior roots T5–8. Ligation of artery of Ademkiewicz in animals results in paraplegia indicating that this is the major source of blood to lower parts of spinal cord.57 Despite abundant blood supply, watershed regions are common in spinal cord especially between the areas where the radicular arteries join the ASA. The blood flow at the watershed area is both upward and downward making the spinal cord vulnerable to ischemia. The mid thoracic area where the distance between radicular arteries is the greatest has the maximum watershed effect. Venous System of Spinal Cord The veins of the spinal cord have extrinsic and intrinsic veins. The intrinsic veins (sulcal and radial veins) drain the substance of the cord to the extrinsic system. The extrinsic system consists of anterior spinal vein which accompanies the ASA till the filum terminale and continues as filum terminale vein, the greatest spinal vein which traverses in the posterior median sulcus along with two posterolateral veins on either sides. The spinal veins drain into the anterior and posterior radiculomedullary veins, which in turn drain into the paravertebral and intervertebral plexuses. Finally, the venous plexuses drain into the segmental veins, draining into the ascending lumbar veins, azygos system, and pelvic venous plexuses. Pathophysiology Various disease processes such as tumors, atherosclerosis, trauma, vascular malformations, aortic surgeries, etc. can affect the vascular supply and can cause cord ischemia. It is important to recognize the specific pattern of vascular involvement. Two types of infarct can occur: 1. Anterior spinal artery syndrome: It is caused by reduced supply of the ASA. The clinical manifestations include, bilateral loss of motor function and pain/temperature sensation, with relative sparing of proprioception and vibratory senses below the level of the lesion. Autonomic disturbance also can occur. 2. Posterior spinal artery syndrome: It is caused by reduced blood supply in the territory of posterior spinal artery. It is characterized by sensory symptoms such as loss of proprioception and vibratory senses below the level of the injury and total anesthesia at the level of the injury. Motor weakness is usually mild. 3. Other infarcts include incomplete infarcts, central cord infarct (bilateral spinothalamic lesion with sparing of motor and posterior columns), transverse medullary infarct (paraplegia or tetraplegia with loss of sensations). Autoregulation and CO2 Reactivity of the Spinal Cord Autoregulation of the spinal cord blood flow is similar to that seen in the brain. The studies on the autoregulation are derived from animal experiments. Spinal cord receives 40–60% of the CBF (50–55 mL/100 g/min). The tissue oxygen levels are the same (35–39 mmHg).58 The blood flow was found to be constant over a MAP of 40–100 mmHg in animal studies.59 Hitchon et al. have found wide variation in the blood flow between gray matter and white matter (approximate ratio of 5:1) and also differences in the blood flow between cervical and the lumbar levels.60 There was a drop in spinal cord blood flow below MAP of 50 mmHg in their study. In another animal study, an MAP of >135 mmHg was associated with increased blood flow and risk of disruption of the blood spinal cord barrier and edema and neuronal damage.61 The mechanism of the spinal cord autoregulation has not been fully understood. Experimental evidence suggests that blockade of dorsal sympathetic ganglion distal to the medulla has been found to abolish the autoregulation. The sensors for the autoregulation have been thought to be in the glomeruli of the capillaries in and around anterior and posterior horns in the spinal cord. The CO2 reactivity of the spinal cord also appears to be similar to brain with vasodilation in response to hypercapnia and vice versa.62 The spinal cord blood flow was found to be constant between 10 and 50 mmHg of CO2.62 Beyond 50 mmHg there was an increase in the spinal cord blood flow. Functions of the Spinal Cord The spinal cord is a complex structure that plays a major role in three important functions. They are sensory control, motor, and autonomic functions. The spinal cord is not a simple relay system of the signals to and fro between brain and the organ system via peripheral nerves as thought to be. In spinal cord there is a complicated network II. NEUROPHYSIOLOGY REFERENCES 89 of neurons that normally operates in conjunction with the rest of the CNS to allow perfect control of sensory, autonomic, and motor functions. Sensory Function Different sensations arising from various areas are transmitted via the peripheral nerves which are the axons whose cell body is located in the dorsal root ganglion. The dorsal root ganglion represents the first-order neurons that project into the spinal cord. Table 4.4 shows the various spinal processing of different sensory modalities. Motor Function The spinal cord is involved in two major motor activities by itself without the concurrent activity of the brain. 1. Monosynaptic stretch reflex: Stimuli originating from the muscle spindles cause contraction of the muscle in which the stimuli originated via 1A afferent fibers. 2. Patterned movements: The spinal cord can generate patterned responses that involve movement of several joints. Examples of reflex of this type are the flexor or withdrawal reflex in response to various sensory stimuli, and in particular in response to pain. Autonomic Function Spinal cord function is important for the autonomic control of the viscera such as bladder, GI tract, and sexual function. The sympathetic and parasympathetic neurons are located in the spinal cord. The preganglionic neurons of the sympathetic system are localized in the thoracic and lumbar part of the spinal cord, while neurons that control the parasympathetic ganglia originate in the sacral region. Spinal cord damage can result in dysfunction of the autonomic functions such as bladder dysfunction, defecation, and sexual dysfunction. SUMMARY The spinal cord is a part of CNS connecting between the brain and the peripheral nervous system and subserving the integration of various functions. The spinal cord is vulnerable to various injuries and can lead to long-lasting morbidity. It is important to know the anatomy and physiology to aid in the monitoring, management of patients with spinal cord problems. Newer therapies such as stem cell implantation, immunomodulatory therapy, neuroplasticity, electrostimulation are emerging in the management of these patients. References 1. Burrows G. On disorders of the cerebral circulation and on the connection between affections of the brain and diseases of the heart. London: Longman, Brown, Green and Longman; 1846. p. 55–6. 2. Cushing H. The third circulation in studies in intracranial physiology and surgery. London (UK): Oxford University Press; 1926. 3. Malm J, Kristrensen B, Karlsson T, Fagerlund M, Elfverson J, Ekstead J. 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Contribution of arterial Windkessel in low-frequency cerebral hemodynamics during transient changes in blood pressure. J Appl Physiol 2011;110:917–25. 23. Heistad DD, Marcus ML, Abboud FM. Role of large arteries in regulation of cerebral blood flow in dogs. J Clin Invest 1978;62:761–8. 24. Bayliss WM. On the local reactions of the arterial wall to changes of internal pressure. J Physiol 1902;28:220–31. 25. Gokina NI, Park KM, McElroy-Yaggy K, Osol G. Effects of Rho kinase inhibition on cerebral artery myogenic tone and reactivity. J Appl Physiol 2005;98:1940–8. 26. Cauli B, Tong XK, Rancillac A, et al. Cortical GABA interneurons in neurovascular coupling: relays for subcortical vasoactive pathways. J Neurosci 2004;24:8940–9. 27. Roy CS, Sherrington CS. On the regulation of the blood-supply of the brain. J Physiol 1890;11:85–158. 28. Nielsen AN, Lauritzen M. Coupling and uncoupling of activity-dependent increases of neuronal activity and blood flow in rat somatosensory cortex. J Physiol 2001;533:773–85. 29. Iadecola C. Does nitric oxide mediate the increases in cerebral blood flow elicited by hypercapnia? Proc Natl Acad Sci U.S.A. 1992;89:3913–6. 30. Hoehn K, White TD. Role of excitatory amino acid receptors in K+- and glutamate-evoked release of endogenous adenosine from rat cortical slices. J Neurochem 1990;54:256–65. 31. Battisti-Charbonney A, Fisher J, Duffin J. The cerebrovascular response to carbon dioxide in humans. J Physiol 2011;589:3039–48. 32. Meng L, Gelb AW. Regulation of cerebral autoregulation by carbon Dioxide. Anesthesiology 2015;122:196–205. 33. Häggendal E, Johansson B. Effects of arterial carbon dioxide tension and oxygen saturation on cerebral blood flow autoregulation in dogs. Acta Physiol Scand Suppl 1965;258:27–53. 34. Ogoh S, Sato K, Nakahara H, Okazaki K, Subudhi AW, Miyamoto T. Effect of acute hypoxia on blood flow in vertebral and internal carotid arteries. Exp Physiol 2013;98:692–8. 35. Mardimae A, Balaban DY, Machina MA, Battisti-Charbonney A, Han JS, Katznelson R, Minkovich LL, Fedorko L, Murphy PM, Wasowicz M, Naughton F, Meineri M, Fisher JA, Duffin J. The interaction of carbon dioxide and hypoxia in the control of cerebral blood flow. Pflugers Arch 2012;464:345–51. 36. Ogoh S, Ainslie PN. Regulation of cerebral blood flow in mammals during chronic hypoxia: a matter of balance. Exp Physiol 2009;95:251–62. 37. Massik J, Tang YL, Hudak ML, Koehler RC, Traystman RJ, Jones Jr MD. Effect of hematocrit on cerebral blood flow with induced polycythemia. J Appl Physiol 1987;62:1090–6. 38. Crystal GJ, Salem MR. Myocardial and systemic hemodynamics during isovolemic hemodilution alone and combined with nitroprusside induced controlled hypotension. Anesth Analg 1991;72:227–37. 39. Crystal GJ, Czinn EA, Salem MR. The mechanism of increased blood flow in the brain and spinal cord during hemodilution. Anesth Analg 2014;118:637–43. 40. Le Roux P. Haemoglobin management in acute brain injury. Curr Opin Crit Care 2013;19:83–91. 41. Krejza J, Mariak Z. Effect of age on cerebral blood flow velocity in patients after aneurysmal subarachnoid hemorrhage. Stroke 2002;33:640–2. 42. Ehrlich MP, McCullough JN, Zhang N, Weisz DJ, Juvonen T, Bodian CA, Griepp RB. Effect of hypothermia on cerebral blood flow and metabolism in the pig. Ann Thorac Surg 2002;73:191–7. 43. Nybo L, Møller K, Volianitis S, Nielsen B, Secher NH. Effects of hyperthermia on cerebral blood flow and metabolism during prolonged exercise in humans. J Appl Physiol 1985;93:58–64. 44. Sethuraman M. Cerebral blood flow monitoring. J Neuroanaesthesiol Crit Care 2015;2:204–14. 45. Magistretti PJ, Pellerin L. Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. Phil Trans R Soc Lond B 1999;354:1155–63. 46. Larrabee MG. Lactate metabolism and its effects on glucose metabolism in an excised neural tissue. 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Br J Anaesth 2006;97:18–25. 54. Rexed B. A cytoarchitectonic atlas of the spinal cord in the cat. J Comp Neurol 1954;100:297–379. 55. Scheibel ME, Scheibel AB. Spinal motor neurons, interneurons and Renshaw cells. A Golgi study. Arch Ital Biol 1966b;104:328–53. 56. Tveten L. Spinal cord vascularity. III. The spinal cord arteries in man. Acta Radiol Diagn (Stockh) 1976;17:257–73. 57. Lazorthes G, Gouaze A, Zadeh JO, Santini JJ, Lazorthes Y, Burdin P. Arterial vascularization of the spinal cord: recent studies of anastomotic substitution pathways. J Neurosurg 1971;35:253–62. 58. Ducker TB, Perot Jr PL. Spinal cord oxygen and blood flow in trauma. Surg Forum 1971;22:413–5. 59. Lobosky JM, Hitchon PW, Torner JC, Yamada T. Spinal cord autoregulation in the sheep. Curr Surg 1984;41:264–7. 60. Hitchon PW, Lobosky JM, Yamada T, Johnson G, Girton RA. Effect of hemorrhagic shock upon spinal cord blood flow and evoked potentials. Neurosurgery 1987;21:849–57. 61. Kobrine AI, Doyle TF, Martins AN. Local spinal cord blood flow in experimental traumatic myelopathy. J Neurosurg 1975;42:144–9. 62. Kobrine AI, Doyle TF, Martins AN. Auto regulation of spinal cord blood flow. Clin Neurosurg 1975;22:573–81. II. NEUROPHYSIOLOGY C H A P T E R 5 Brain Protection in Neurosurgery H. El Beheiry1,2 1University of Toronto, Toronto, ON, Canada; 2Trillium Health Partners, Toronto, ON, Canada O U T L I N E Introduction 91 Target Hemoglobin Concentration 95 Nonpharmacological Strategies 91 Pharmacological Strategies 96 Mild Hypothermia 92 Nonanesthetic Agents 97 Blood Pressure Control 93 Anesthetic Agents 97 Induced Arterial Hypertension 94 Conclusion 98 Normoglycemia 94 References 98 INTRODUCTION Neuroprotection describes strategies to protect neuronal elements against damage and impairment of neurologic function. One of the essentials of neuroanesthesia practice is to provide the patient with neuroprotective measures. It is hoped that these measures will reduce poor neurologic outcomes, i.e., motor and sensory deficits and cognitive dysfunction resulting from inevitable surgical brain injury during neurosurgical procedures. The most common forms of brain injury during neurosurgical procedures are (1) brain retraction, (2) incising and removing brain tissue, and (3) temporary vascular occlusion.1 For instance, eliminating pathological brain tissue and brain retraction will inevitably lead to injury of normal brain structures. Moreover, clamping of a carotid artery during carotid endarterectomy or temporary clipping of intracerebral arteries can simulate unilateral global ischemia or acute ischemic stroke, respectively (Table 5.1). Neuroprotective strategies can be classified into nonpharmacological and pharmacological (Table 5.2). Some of these strategies are based on laboratory evidence and are either target specific or with indeterminate targets.2,3 Other neuroprotective approaches are “empiric” meaning that they are guided by experience not precepts or theory. NONPHARMACOLOGICAL STRATEGIES Nonpharmacological strategies signify the manipulation of homeostatic processes in a manner that will have neuroprotective effects (Table 5.2). Essentials of Neuroanesthesia http://dx.doi.org/10.1016/B978-0-12-805299-0.00005-1 91 © 2017 Elsevier Inc. All rights reserved. 92 5. BRAIN PROTECTION IN NEUROSURGERY TABLE 5.1 Surgical Brain Injury During Neurosurgical Procedures Forms of Surgical Brain Injury Effects Surgical brain incisions Neuronal death, brain edema, disruption BBBa Application of thermal and ultrasonic energy Neuronal death, disruption BBB Retraction of brain tissue with brain retractors Decreased CBFb, rebound brain edema Temporary or permanent vascular occlusion Cessation of CBF or decreased CBF Local surgical bleeding and brain contusion Brain edema, disruption BBB Major air embolism or surgical bleeding Global brain hypoperfusion aBBB bCBF indicates blood–brain barrier. indicates cerebral blood flow. TABLE 5.2 Strategies for Neuroprotection During Neurosurgical Procedures Nonpharmacological Strategies Pharmacological Strategies Anesthesia related Agents with specific site of action Hypothermia Antiexcitotoxicity Normoglycemia Ca2+ channel blockers Maintenance of adequate CBFa (Normotension, induced hypertension) Antioxidants Target hemoglobin concentration Antiinflammatory Respiratory gases manipulation (PaO2 optimization, PaCO2 control) Antiapoptosis Osmotherapy Agents with nonspecific site of action Surgery related Cell membrane stabilizers Decrease brain tissue injury (Micro- and image-guided neurosurgery) Erythropoietin CSFb drainage Antithrombotics and thrombolytics Limit ischemic time Anesthetics Embolic load reduction Inert gases aCBF bCSF indicates cerebral blood flow. indicates cerebrospinal fluid. MILD HYPOTHERMIA Hypothermia has been commonly classified into three levels: mild from 32 to 35°C, moderate from 32 to 28°C, and deep under 28°C. Deep hypothermia associated with circulatory arrest was previously used during clipping of giant complex intracerebral aneurysms without favorable but detrimental outcomes.4,5 Such disappointing experience has steered the evolution of mild hypothermia as a neuroprotective strategy based on encouraging results shown in many laboratory investigations.6,7 The mechanisms of the presumed hypothermic neuroprotection are multifaceted and include changes in various cellular processes including its ability to decrease the cerebral metabolic rate by about 10% for every degree Celsius.8–10 Hypothermia maintains the integrity of the blood–brain barrier after ischemic insults and constricts cerebral blood vessels and thus reduces brain edema and cerebral blood volume and decreases intracranial pressure (ICP). Additionally, it inhibits excitotoxicity by decreasing glutamate release resulting in decrease of cellular depolarization and inhibition of deleterious calcium influx through voltage- and receptor-operated calcium channels. Also, hypothermia depresses the delayed responses to brain injury, namely reactive oxygen species production and mitochondrial dysfunction that II. NEUROPHYSIOLOGY BLOOD PRESSURE CONTROL 93 triggers neuronal tissue inflammation and programmed cell death (apoptosis), respectively. Finally, hypothermia can ameliorate secondary neuronal damage by downregulating certain gene-induced proteomic responses leading to cell damage and upregulating a small subset of cold-shock proteins that depress apoptosis and promote cell proliferation. Despite the various neuroprotective mechanisms of mild hypothermia reported in the laboratory, its clinical efficacy is still indefinable. A recent carefully conducted metaanalysis11 showed that among patients undergoing craniotomy for various neurosurgical indications including aneurysm clipping,12,13 traumatic brain injury,14 and ischemic stroke15 there was no evidence that intraoperative or postoperative hypothermia significantly reduces or increases mortality or significantly alters the risk of severe neurologic disability. Application of mild hypothermia did not alter the risk for postoperative complications, i.e., intracranial hemorrhage, ischemic stroke, congestive cardiac failure, or myocardial infarction. There was some weak evidence that postoperative hypothermia may increase the risk of infective complications. Such lack of efficacy and relative safety of mild hypothermia has been in agreement with other systematic reviews.16,17 It should be noted that mild hypothermia might be beneficial in the case of comatose survivors of out-of-hospital cardiac arrest18,19 and peripartum asphyxia-induced brain injury.20,21 To date, there is no convincing clinical evidence to establish the value of mild hypothermia as a neuroprotective strategy during neurosurgery. Anesthesiologists who opt to use mild hypothermia for their patients because of its favorable safety profile and efficacy in nonneurosurgical situations of global brain ischemia should consider the following precautions: core temperature should be monitored at two sites to avoid inadvertent excessive cooling, target temperature has to be reached before opening the dura, rewarming should start after brain tissue handling has ended, rewarming should continue in the postoperative period until core temperature normalizes, and active cooling equipment should be calibrated and tested before use. BLOOD PRESSURE CONTROL During neurosurgical procedures, regional and global cerebral blood flow (CBF) is compromised mainly due to brain retraction and surgical bleeding, respectively (Table 5.2). Regional CBF was shown to decrease during brain retraction in swine animal models by about 50% of baseline during normoventilation or hyperventilation.22 Global CBF decrements are not uncommon during neurosurgery and can lead to surgical brain injury and unfavorable outcomes.23–25 CBF is autoregulated, i.e., sustained within a normal range (50–60 mL per 100 g brain tissue per minute) provided that the mean arterial pressure (MAP) is between 60 and 150 mmHg and the ICP is about 10 mmHg. CBF is correlated to the cerebral perfusion pressure (CPP) and CPP = MAP-ICP (normal CPP is 70–90 mmHg). During neurosurgery, the autoregulatory mechanisms for CBF maintenance are not optimal and the extent of its dysfunction is unknown. In fact, the relationship between CBF and CPP may become linear due to loss of vessel reactivity that is responsible for autoregulation. Therefore, decrements in MAP should be avoided and kept above 80 mmHg to maintain CPP near 70 mmHg during neurosurgery. Recent reports provide important indirect evidence of the deleterious effects of intraoperative regional and global brain hypoperfusion. In patients with severe traumatic brain injury, who had neurosurgical intervention in the form of decompressive craniotomies, the autoregulatory curves were determined.26 Data from these patients revealed constant brain perfusion over a wide CPP range (50–90 mmHg) and a 100% incidence of ischemia when CPPs fell below the lower limit of autoregulation. As CPPs increased there was a corresponding decrease in the incidence of ischemia, potentially mediated through an associated force-dependent dilation of the cerebral vessels. In another population of patients who undergo endovascular treatment of acute ischemic stroke, a relatively consistent conclusion from studies is that general anesthesia appears to be associated with higher mortality and morbidity compared with monitored anesthesia care.27,28 This has been attributed to the hypotensive actions of general anesthesia resulting from anesthetic agents and positive pressure ventilation, and such depressive cardiovascular effects will lead to decrements in brain perfusion. Additionally, data from the International Stroke Trial suggest that for every 10 mmHg below asystolic blood pressure of 150 mmHg early death increased by about 18%.29 Finally, acute reductions in MAP in patients with intracerebral hemorrhage caused diminishing cerebral tissue diffusion on MRI and were associated with cerebral ischemia, disability, and mortality.30 In conclusion, during neurosurgical procedures moderate and severe intraoperative hypotension should be avoided and MAP should be maintained close to the patient’s baseline pressure. Elevation of MAP could be achieved by using a combination of measures including volume resuscitation, decreasing anesthetic levels and vasopressors, i.e., alpha agonists and ephedrine. II. NEUROPHYSIOLOGY 94 5. BRAIN PROTECTION IN NEUROSURGERY INDUCED ARTERIAL HYPERTENSION Induced (or permissive) hypertension is a technique that can achieve stable and adequate collateral CPP during neurosurgical procedures associated with localized ischemic compromise of brain tissue. Such technique uses vasopressors to raise the arterial blood pressure by 20–40% to recruit cerebral collateral networks including the leptomeningeal circulation particularly in patients who have incomplete circle of Willis.31 Hence, induced hypertension will be potentially beneficial to reduce the incidence of perioperative cerebral ischemic events during: (1) interventional neuroradiology procedures, (2) temporary clipping or clamping during cerebral aneurysmal surgery or carotid endarterectomy, respectively, (3) extracranial to intracranial bypass surgery, (4) surgery in patients with cerebral vasospasm and (5) surgery in patients with conditions leading to significant cerebral autoregulation dysfunction, e.g., intracranial pathology with mass effect, severe systemic hypertensive disease and traumatic brain injury.32 Several reports allude to the potential benefits of induced hypertension. Actually, increased middle cerebral artery mean blood flow velocity by intentional hypertension during dissection of the carotid artery in carotid endarterectomy prevented the postoperative development of new cerebral ischemic lesions as detected by diffusion weighted MRI imaging.33 In another recent study, reactionary approach to malperfusion, i.e., selective shunting or elevation of blood pressure was compared to a preemptive routine protocol for induced hypertension during carotid clamping to maintain adequate collateral CBF during carotid endarterectomy. The risk of temporary neurologic malperfusion was 18.1% in the groups where a reactionary approach to malperfusion was addressed by shunt, or the elevation of blood pressure, as compared with 0.86% of patients with pretreated collateral CPP with a standard induced hypertension protocol.34 Additionally, the safety of induced hypertension has been described in several reports. For example, induced hypertension did not cause rupture in small, intact, unprotected intracranial aneurysms in subarachnoid hemorrhage patients.35 Similarly, there were no reported events of myocardial infarction, congestive heart failure, intracranial hemorrhage, or hyperperfusion syndrome.33–35 Phenylephrine (50–200 µg IV boluses) and ephedrine (5–10 mg IV boluses) are the primary vasoconstrictors used to raise blood pressure during induced hypertension. Phenylephrine is a pure α1-adrenergic receptor agonist and causes reflex bradycardia. It does not have chronotropic or inotropic effect. It has an immediate onset of action and a short half-life of approximately 5 min that makes it suitable for use as a variable rate infusion. If severe bradycardia occurs, anticholinergic agents can be administered to antagonize the baroreceptor-mediated vagotonic effect of phenylephrine. Ephedrine is a sympathomimetic amine. It indirectly stimulates the adrenergic receptor system by increasing the activity of norepinephrine at the postsynaptic α and β receptors thus causing vasoconstriction and week chronotropic and inotropic effects. Other sympathomimetic agents have been used to induce hypertension particularly in the ICU, e.g., dopamine, dobutamine, and vasopressin. NORMOGLYCEMIA Perioperative hyperglycemia may occur in diabetic as well as nondiabetic patients. In nondiabetic patients, perioperative hyperglycemia exists in two forms: stress hyperglycemia and glucose variability.36 The latter is a measure of the magnitude of glucose excursions over time and can occur in diabetic patients. Perioperative hyperglycemia results from neuroendocrine responses activated by surgery or trauma that includes an increase in the stress hormones such as catecholamines, cortisol, and glucagon providing conditions for tissue recuperation. Nonetheless, the intensification of such homeostatic response mechanisms can trigger organ damage of its own accord.37 In fact, the evidence consistently suggests that perioperative hyperglycemia leads to unfavorable neurologic and nonneurologic outcomes after various neurosurgical procedures. A recent study showed that after surgical intervention in diabetics with cervical spondylosis myelopathy, perioperative glucose levels were linearly associated with impaired improvement in Nurick score that is based on the extent of walking disability.38 In carotid endarterectomy, patients with operative day glucose more than 11.1 mmol/L (200 mg/dL) were 2.8-, 4.3-, and 3.3-fold more likely to experience perioperative stroke or transient ischemic attack, myocardial infarction, or death, respectively.39 Additionally, patients with elevated fasting blood sugar 6.1 mmol/L (>110 mg/dL) undergoing carotid artery stenting are at a greater risk for worse major acute events, namely stroke, myocardial infarction, and death in both the short and long term.39 The Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) concluded that blood glucose levels more than 7.2 and 8.4 mmol/L (130 and 150 mg/dL) at the time of clipping of a ruptured cerebral aneurysm are associated with long-term changes in cognition and gross neurologic dysfunction, respectively.40 In the pediatric population, patients who developed postoperative complications exhibited higher mean blood glucose levels on II. NEUROPHYSIOLOGY TARGET HEMOGLOBIN CONCENTRATION 95 TABLE 5.3 Suggested Intraoperative Therapy for Hyperglycemia in Neurosurgical Patients Intraoperative Blood Sugar Control [Target: 7.8–10.0 mmol/L (140–180 mg/dL)] 1. Patients who are undergoing elective neurosurgery do not use insulin and whose blood glucose is controlled (normal finger-stick readings and A1C values) in the outpatient setting do not require an insulin drip and can be managed with subcutaneous (SC) supplemental insulin therapy guided by the following sliding scale: Glucose value Insulin dose mmol/L mg/dL IU ≤8.3 ≤ 150 — 8.4–11.1 151–200 5 11.2–13.9 201–250 10 13.9–16.7 251–300 15 16.7–19.4 301–350 20 2. Patients who are undergoing urgent surgery or using insulin to control their blood sugar or having uncontrolled diabetics: Prepare insulin drip: 100 IU of regular insulin in 100 mL normal saline (1 IU/mL) Start an empiric infusion 0.02 IU/kg/h 2–3 h prior to the surgery Measure blood sugar after 1 h and adjust the infusion according to a sliding scale In the operating room, continue insulin infusion Measure blood sugar every hour Adjust the insulin infusion according to the following sliding scale: Glucose value Insulin infusion rate mmol/L mg/dL IU/h 8.3–9.4 150–169 2 9.4–11.0 170–199 3 11.1–13.8 200–249 4 13.9–16.6 250–299 6 16.7–22.1 300–399 8 22.2 + 400 + 10 If hypoglycemia is detected (blood sugar < 60 mg/dL or <3.3 mmol/L): Administer hypertonic dextrose (50%) according to the following formula: (100 − glycemia or 7.8 mmol/L) × 0.3 = dextrose 50% in mL IV bolus Check blood glucose every 30 min If glucose < 60 mg/dL (3.3 mmol/L), repeat the IV bolus step as necessary “This approach will prevent over correction of hypoglycemia” In the PACU, the insulin infusion is continued as mentioned above with hourly measurement of blood sugar Then patient is transferred to a step-down or intensive care unit where the infusion will be transitioned to SC insulin or oral hypoglycemic medications according to the intensivist discretion admission to the intensive care unit 9 mmol/L (162.0 mg/dL) and mean peak blood glucose levels on postoperative day one 9.6 mmol/L (171.9 mg/dL).41 Because the brain tissue is vulnerable at the extremes of blood sugar values, a consensus pertaining to the blood sugar target is still controversial in neurosurgical patients. However, to date most evidence cannot support intensive insulin therapy with tight glucose control in the neurosurgical population during the perioperative period.42–44 Tight glucose control has been shown to cause much higher incidence of severe hypoglycemic episodes, stroke, myocardial infarction, and death as well as brain energy crisis that correlates with increased mortality.45,46 Consequently, a consensus statement by the American Association of Clinical Endocrinologists and the American Diabetes Association47 has recommended that treatment should be initiated at a threshold of >10.0 mmol/L (>180 mg/dL), preferably with IV insulin therapy, and maintain the glucose level between 7.8 and 10.0 mmol/L (140 and 180 mg/dL). The consensus also conveyed that (1) greater benefit may be obtained at the lower end of this range, (2) glucose concentrations <6.0 mmol/L (110 mg/dL) are not recommended, and (3) the suggested glucose targets should be flexible and individualized to the patient and the clinical situations relating to the speed of achieving normoglycemia and the insulin regimen used. Several insulin regimens have been proposed. A modified guideline is suggested in Table 5.3. TARGET HEMOGLOBIN CONCENTRATION Anemia causes activation of compensatory physiologic cardiovascular and cellular mechanisms to optimize tissue oxygen delivery. These include (1) increased cardiac output, (2) preferential blood flow to the brain, and (3) induction of neuronal nitric oxide synthase that is necessary for the function of hypoxia inducible factor-1α II. NEUROPHYSIOLOGY 96 5. BRAIN PROTECTION IN NEUROSURGERY to stimulate the cellular responses to anemia to maintain adequate tissue oxygenation. Such cellular responses to anemia are enhancement of angiogenesis, promotion of erythropoiesis, increase in cellular glucose, and prompting of glycolytic anaerobic metabolism.48 Despite the activation of these potent responses, tissue oxygen tension in the brain decreases in proportion to the hemoglobin level when these mechanisms become overwhelmed and fail. A previous report showed that packed red blood cell transfusion in subarachnoid hemorrhage patients with initial hemoglobin of 8 g/dL resulted in brain tissue oxygen (PbtO2) improvement and a positive and independent association between hemoglobin concentration and PbtO2 as verified by univariate and multivariate analyses.49 While there is an abundance of experimental studies showing the harmful effects of anemia on the brain, the causation link has yet to be established in neurosurgical patients. Nonetheless, a large retrospective cohort study including about 8000 elective neurosurgical patients provided evidence that anemia is an independent risk factor for increased postoperative mortality and neurologic morbidity in the form of stroke or coma. In addition, a specific level of anemia corresponding to hemoglobin below 11 g/dL was shown to be associated with increased morbidity.50 In other large retrospective studies, hemoglobin concentration <11 g/dL was an independent risk factor for symptomatic postoperative cerebral vasospasm in spontaneous subarachnoid hemorrhage patients. Furthermore, a hemoglobin concentration of <11 g/dL during the hospital stay was associated with unfavorable outcomes including increased mortality, and brain infarction.51,52 Although anemia is associated with poor neurologic outcome, especially in the presence of cerebral ischemia, there is a lack of level I evidence by which transfusion thresholds can be suggested. Furthermore, packed red cell transfusion was not always associated with improved outcome, e.g., in traumatic brain injury and acute ischemic stroke.53 Hence, based on the evidence currently available, it may be prudent to recommend more higher transfusion thresholds for patients undergoing neurosurgical procedures: preoperative and intraoperative hemoglobin levels in neurosurgical patients can be maintained at a minimum of 12 and 9 g/dL, respectively.53–55 PHARMACOLOGICAL STRATEGIES Pharmacological strategies comprise the use of pharmaceutical agents to oppose or block a pathologic process in the brain injury cascade of events leading to cell death by necrosis or apoptosis (Figs. 5.1 and 5.2). Energy Failure Depolarization Glutamate Release & Excitotoxicity Opening Ca Channels Increased [Ca2+]i Enzyme Induction Formation of O2 free radicals Membrane Damage Inflammation Necrosis Mitochondrial damage DNA damage Apoptosis FIGURE 5.1 A flow diagram shows the cascade that is activated after an ischemic insult to the brain. The pathways within the cascade lead to cell death by necrosis or apoptosis. The immediate response to brain injury is represented by the necrosis pathway and the delayed responses are represented by the inflammatory and the apoptotic pathways. II. NEUROPHYSIOLOGY ANESTHETIC AGENTS 97 FIGURE 5.2 The integration of injury mechanisms excitotoxicity, inflammation, and apoptosis that lead to cell death are shown in a temporal representation. Excitotoxicity causes neuronal depolarization, excessive presynaptic glutamate release, increased intraneuronal calcium and increased production of free radicals. Inflammatory mechanisms lead to increased secretion of injurious interleukins and adhesion molecules. Apoptosis is initiated by activation of cellular destructive enzymes, endonucleases, and caspases. NONANESTHETIC AGENTS Countless pharmaceutical compounds targeting the cascade of neuronal death were successful when tested in the laboratory to achieve neuroprotection. However, phase II and phase III single and multicenter clinical trials of many of those strategies failed to show any neurological benefit in the case of brain injury resulting from cardiac and vascular surgery, stroke, head trauma, intracerebral hemorrhage, or subarachnoid hemorrhage56–59 (Table 5.4). In cardiac surgery the use of magnesium and atorvastatin in single-center trials showed potential neuroprotective effects, but the small number of studies, methodological inconsistencies, and weakness of the evidence do not allow any firm conclusions.56 To date, there are no randomized controlled studies that determined the efficacies of pharmacologic agents as neuroportectants in neurosurgical patients undergoing intracranial procedures. Thus, the hope is to develop a “blanket neuroprotection” against surgical brain injury.60 This concept depends on the fact that failures of many neuroprotective agents may have resulted from their administration outside the narrow therapeutic window which is usually when the majority of the patients arrive at the hospital. In elective neurosurgery, the timing of surgical brain injury is known and the neuroprotective agents can be administered before, during, and after the neurosurgical intervention to prevent inevitable brain injuries associated with routine neurosurgical procedures. A therapeutic regimen “blanket neuroprotection” can be designed using apparently neuroprotective agents. This concept has not been studied in patients and has to be initially validated in animal models of surgical brain injury.60 ANESTHETIC AGENTS Many laboratory studies have shown neuroprotective effects of various volatile and intravenous anesthetics. However, recent reviews of the topic have shown conflicting evidence pertaining to their clinical neuroprotective effects. Anesthetics may have temporary cerebrodynamic benefits in decreasing cerebral metabolism, ICP, and brain volume but their role in improving neurologic mortality or morbidity is still elusive.56,61–63 In the IHAST study, anesthetic agents did not impact the odds of favorable neurologic function in patients undergoing clipping of ruptured cerebral aneurysms who had temporary arterial clamping during the procedure.64 Such uncertainty about the neuroprotective effects of anesthetic agents has been shown in another large multicenter trial, the GALA trial for comparing the use of general anesthesia versus local anesthesia for carotid endarterectomy.65 The incidence of stroke at postoperative day 30 was similar in patients having general or local anesthesia. Anesthetic preconditioning is a phenomenon of transient organ exposure to anesthetic clinical concentrations that triggers endogenous cellular neuroprotective processes. Similarly, anesthetic postconditioning describes the neuroprotection induced by introducing short episodes of anesthetic exposure during the early phase of reperfusion after a prolonged episode of ischemia. The molecular processes stimulated during these cellular events include activation of II. NEUROPHYSIOLOGY 98 5. BRAIN PROTECTION IN NEUROSURGERY TABLE 5.4 Examples of Completed Multicenter Randomized Controlled Trials for Neuroprotection as Determined by Improvement in Neurologic Function. Pharmaceutical Agents with Diverse Molecular Targets were Tested Drug Clinical Setting Target and Action Result Gavestinel (GAIN trial) Acute ischemic stroke NMDA receptor antagonist Failed Mg2+ Acute ischemic stroke NMDA receptor antagonist Failed Flunatrizine (FIST trial) Acute ischemic stroke Ca2+ channel blocker Failed Nimodipine (VENUS trial) Acute ischemic stroke Ca2+ channel blocker Failed Clomethiazole (CLASS trial) Acute ischemic stroke GABAA receptor agonist Failed Citalopram (TALOS trial) Acute ischemic stroke Selective serotonin reuptake inhibitor Failed Repinotan (mRECT trial) Acute ischemic stroke Serotonin receptor agonist Failed NXY-059 (SAINT I and II trials) Acute ischemic stroke Antioxidant Failed Trilazad (RANTASS trial) Subarachnoid hemorrhage Antioxidant Failed Progesterone (ProTECT III & SyNAPSE trials) Traumatic brain injury Antioxidant and antiinflammatory Failed Citicoline trial Traumatic brain injury Nonspecific (cell membrane stabilizer) Failed Erythropoietin (EPO stroke trial) Acute ischemic stroke Nonspecific (hemopoietic agent) Failed Erythropoietin (TENPEAKS trial) Coronary artery bypass Nonspecific (hemopoietic agent) Failed (IMAGES and FAST-MAG trials) sarcolemmal and mitochondrial ATP-potassium dependent channels, stimulation of adenosine receptors and the initiation of cellular signaling cascades. This will prevent acute and delayed neuronal death by necrosis and apoptosis, respectively.66 There are no clinical data that convincingly support the occurrence of anesthetic pre- or postconditioning in the clinical setting despite the numerous laboratory reports showing their benefit. Xenon recently reemerged as an anesthetic agent, and its neuroprotective properties have been shown in the laboratory. The presumed mechanism is competitive inhibition of the NMDA receptor. Consequently, xenon suppresses the increase in intraneuronal calcium concentration thus preventing cell death67 (Fig. 5.1). Clinical trials are underway to elicit the neuroprotection efficacy of xenon in several clinical situations including cardiopulmonary bypass, neonatal asphyxia, and cardiac arrest. To date, none of these trials have been completed. Nonetheless, small clinical studies did not show any benefit in using xenon to decrease the incidence of neurologic morbidity.68 CONCLUSION There is no convincing evidence that pharmaceutical agents including anesthetics can protect the brain during vulnerable clinical situation including neurosurgical procedures. Hence, the anesthesiologist is compelled to use nonpharmacological approaches that may be based on physiologic and pharmacologic empiric evidence to protect the brain during surgery. Accordingly, CPP should be maintained by controlling the systemic mean arterial pressure above 80 mmHg. Additionally, induced hypertension should be used in certain neurosurgical situations in which there is arterial vessel occlusion or a deleterious change in the cerebral autoregulation mechanism. Blood glucose levels should be kept within a liberal normal range (7.8–10 mmol/L; 140–180 mg/L) and intensive insulin therapy protocols avoided. Adequate hemoglobin levels preoperatively (≥120 g/dL) and intraoperatively (≥90 g/dL) will ensure optimum oxygen delivery to the brain. To date there is no conclusive evidence that mild hypothermia (32–35°C) has neuroprotective benefit. However, because of its relative safety, the anesthesiologist who would like to extrapolate its beneficial effects from asphyxiated neonates and cardiac arrest patients may use it cautiously. References 1. Jadhav V, Solaroglu I, Obenaus A, Zhang JH. Neuroprotection against surgically induced brain injury. Surg Neurol 2007;67:15–20. 2. Badenes R, Gruenbaum SE, Bilotta F. Cerebral protection during neurosurgery and stroke. Curr Opin Anaesthesiol 2015;28(5):532–6. 3. Turner RC, Dodson SC, Rosen CL, Huber JD. The science of cerebral ischemia and the quest for neuroprotection: navigating past failure to future success. J Neurosurg 2013;118(5):1072–85. 4. Drake CG, Barr HW, Coles JC, Gergely NF. 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Curr Opin Anaesthesiol 2015;28(4):424–30. 67. Banks P, Franks NP, Dickinson R. Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor mediates xenon neuroprotection against hypoxia-ischemia. Anesthesiology 2010;112:614–22. 68. Maze M. Preclinical neuroprotective actions of xenon and possible implications for human therapeutics: a narrative review. Can J Anaesth 2016;63(2):212–26. II. NEUROPHYSIOLOGY S E C T I O N I I I NEUROPHARMACOLOGY This page intentionally left blank C H A P T E R 6 Neuropharmacology P. Ganjoo1, I. Kapoor2 1GB Pant Hospital, New Delhi, India; 2All India Institute of Medical Sciences, New Delhi, India O U T L I N E Anesthetic Drugs and Sedatives 104 Intravenous Anesthetic Agents Barbiturates Cerebral Effects of Barbiturates Other Effects of Barbiturates Current Status Recent Research Propofol Cerebral Effects of Propofol Other Effects of Propofol Current Status Recent Research Etomidate Cerebral Effects of Etomidate Other Effects of Etomidate Current Status Recent Research Ketamine Cerebral Effects of Ketamine Other Effects of Ketamine Current Status Recent Research Benzodiazepines Cerebral Effects of Benzodiazepines Other Effects of Benzodiazepines Current Status Recent Research Opioids Cerebral Effects of Opioids Other Effects of Opioids 104 105 105 105 107 107 107 107 107 107 107 108 108 108 108 108 108 109 109 109 109 109 110 110 110 110 110 110 111 Essentials of Neuroanesthesia http://dx.doi.org/10.1016/B978-0-12-805299-0.00006-3 Current Status Recent Research 111 111 Dexmedetomidine Recent Research 111 111 Inhalational Anesthetic Agents Desflurane Cerebral Effects of Desflurane Other Effects of Desflurane Current Status Recent Research Sevoflurane Cerebral Effects of Sevoflurane Other Effects of Sevoflurane Current Status Recent Research Isoflurane Cerebral Effects of Isoflurane Other Effects of Isoflurane Current Status Recent Research Nitrous Oxide Cerebral Effects of N2O Other Effects of N2O Current Status Recent Research Xenon Cerebral Effects of Xenon Other Effects of Xenon Current Status 103 111 111 112 112 112 113 113 113 113 113 113 113 114 114 114 114 114 114 114 115 115 115 115 115 115 © 2017 Elsevier Inc. All rights reserved. 104 6. NEUROPHARMACOLOGY Neuromuscular Blocking Agents Depolarizing Neuromuscular Blocking Agents Nondepolarizing Neuromuscular Blocking Agents 115 115 116 Local Anesthetic Agents 116 Miscellaneous Drugs 116 Future Directions in Neuropharmacology 116 Conclusion 116 References 118 With the advent of newer neurosurgeries like minimally invasive procedures, endovascular neurosurgeries and complex revascularization operations, increased use of sophisticated intraoperative neurological monitors, and significant advances in neurocritical care, the scope of neuroanesthesia has also expanded tremendously. This has necessitated a quest for more capable, more rapidly titratable, and safer drugs for anesthesia and sedation. Drugs used in neuroanesthesia should be able to provide optimal brain conditions for surgery and also help maintain adequate brain tissue perfusion to meet increased regional metabolic demands. The ability to not only rapidly achieve deeper intraoperative anesthesia levels but also allow quick postoperative recovery of consciousness, good analgesic effects, no epileptogenic effects, minimal interference with neuromonitoring modalities, no adverse effects on other body organs, and capability of preserving systemic and cerebral hemodynamic stability are some of the desirable attributes in a neuroanesthetic drug. The beneficial cerebral effects of these drugs would be maintenance of cerebral autoregulation, vasoreactivity to carbon dioxide (CO2) and coupling of cerebral blood flow (CBF) and cerebral metabolic rate (CMR), and prevention of increases in intracranial pressures (ICPs) and cerebral blood volume (CBV). The correct choice of drugs and their doses for anesthesia and sedation is thus vital in preventing further worsening of the intracranial pathology or introduction of a new cerebral insult. This necessitates a better understanding of the cerebral effects and other important issues related to the commonly used anesthetics and sedatives, and is the main scope of this chapter. Discussion on other drugs and adjuvants used in neurosurgical practice can be found elsewhere in this book. ANESTHETIC DRUGS AND SEDATIVES Anesthetic drugs cause their cerebral effects by producing metabolic and functional changes in the central nervous system (CNS). Broadly, intravenous agents tend to reduce both CBF and CMR in a parallel manner and maintain their coupling, while inhalational agents decrease the CMR and increase the CBF and appear not to maintain coupling. However, anesthesia-related CBF–CMR coupling may vary under different brain conditions as the effects of anesthetics on CBF is influenced by both a direct effect on the cerebral vascular tone (vasoconstriction or vasodilatation) and indirect changes in the CMR. Furthermore, this dual mechanism of action makes it difficult to predict whether anesthetics can cause an “intracerebral steal” or the beneficial “reverse intracerebral steal” phenomenon in the pathological brain in which CO2 reactivity and autoregulation may be lost. Anesthetics also produce changes in the ICP by changing the CBF and thereby the CBV, and by their influence on cerebrospinal fluid (CSF) dynamics, i.e., the rate of production and reabsorption of CSF. The cerebral effects of anesthetics are also governed by their systemic effects, primarily on the blood pressure, arterial CO2, and body temperature. A promising attribute of anesthetic drugs that has been identified lately is that some of them have the potential for neuroprotective effects and may even be able to reduce neuronal damage from ischemic insults. These effects are attributed to their ability to reduce neuronal activity and metabolic rates. Lidocaine, thiopental, and sevoflurane have shown to be protective against ischemia in animal studies, particularly when given at the beginning of an ischemic insult due to their proposed “preconditioning effect.” However, the clinical utility of anesthetics in preventing and ameliorating ischemic damage needs further investigation. The neuroprotective effects of various anesthetic drugs are discussed in a separate chapter. Recent suggestions that anesthetic drugs can cause neurotoxicity and postoperative cognitive dysfunction (POCD) is an area of great concern for the anesthetists. Detailed discussion on this important subject can be found elsewhere in this book. INTRAVENOUS ANESTHETIC AGENTS Intravenous anesthetic agents are small hydrophobic compounds that when injected, enter the highly perfused and lipophilic tissues in the brain and spinal cord where they produce anesthesia in a single circulation time. Termination of anesthesia with these drugs does not reflect metabolism but their redistribution out of the CNS into the blood and III. NEUROPHARMACOLOGY 105 INTRAVENOUS ANESTHETIC AGENTS then into the lesser perfused tissues like muscles and viscera. Drug redistribution can cause accumulation and slower recovery from its effects. Barbiturates Barbiturates are CNS depressant drugs commonly used in neurological practice for providing mild sedation to total anesthesia, and also as anticonvulsants, hypnotics, anxiolytics and analgesics. While sodium thiopental (thiobarbiturates), thiamylal (thiobarbiturates), and methohexital (oxybarbiturates) are used for induction of anesthesia, amobarbital is mainly used for performing “the Wada test,” also known as the “intracarotidsodium amobarbital procedure” used for testing cerebral language and memory representation of the cerebral hemispheres. Barbiturates are derivatives of barbituric acid (2,4,6-trioxohexahydropyrimidine) (Fig. 6.1)1 and act primarily as γ-aminobutyric acid (GABA) receptor agonists (http://en.wikipedia.org/wiki/Barbiturate).2 They also act on the glutamate, adenosine, and nicotinic acetylcholine receptors. The clinically recommended dosages and pharmacokinetics of barbiturates are summarized in Table 6.1.3–6 Cerebral Effects of Barbiturates (Table 6.2) Barbiturates produce cerebral function depression and cause a dose-dependent decrease in cerebral metabolic rate for oxygen consumption (CMRO2) and CBF till the electroencephalograph (EEG) becomes isoelectric.7 The induction dose of thiopental causes a 25–30% decrease in CMRO2 with a maximum 55% decrease occurring at 2–5 times that dose.8 They cause a reduction in ICP9 due to decreases in CBF and CBV, and also maintain cerebral autoregulation and CO2 reactivity. In low doses, thiopental sodium causes no change in the rate of CSF formation, and either no change or an increase in the resistance to reabsorption of CSF, but in higher doses, it causes decrease in CSF formation rate with either no change or a decrease in the resistance to resorption resulting in a raised ICP. As autoregulation is similar in both brain and spinal cord,10 high-dose barbiturate therapy causes a significant decrease in spinal cord blood flow (SCBF) suggestive of a protective effect of barbiturates on spinal cord injury,11 although spinal cord metabolism seems to be less sensitive to depression by barbiturates.12 Other Effects of Barbiturates Barbiturates cross the blood–brain barrier (BBB) very rapidly. Methohexital has been shown to reduce the seizure threshold,13 and hence seizure activity may be a concern on emergence from barbiturate anesthesia. Cognitive impairment on chronic use of barbiturates is well known; both propofol and barbiturates were shown to cause severe cognitive side effects, but the result was confounded by the differences in age distribution in the two study groups.14 Curcumin, a substance in turmeric, is being considered as a safe and effective adjuvant to barbiturates in preventing cognitive impairment due to its antioxidant, antiinflammatory, and neuroprotective properties.15 Recent literature has demonstrated that drugs that antagonize N-methyl-d-aspartate (NMDA) receptors and agonize GABA receptors produce widespread neurodegeneration in the developing brain.16 Fredriksson et al. observed a reduction in cognitive function in rodents, after a combination of thiopental or propofol and ketamine at postnatal day 10 and at 8–10 weeks of age.17 Significant systemic effects of barbiturates include hypotension and respiratory depression. FIGURE 6.1 Barbituric acid. TABLE 6.1 Physical Properties of Intravenous Anesthetic Agents Anesthetic Agents Thiopentone Sodium Propofol Etomidate Ketamine Induction dose (mg/kg) 3–5 2.0–2.5 0.2–0.4 0.5–1.5 Induction duration (mins) 5–8 4–8 4–8 10–15 t1/2 (h) 12.1 1.8 2.9–5.3 3 Clearance (mL/kg/min) 3.4 23–50 18–25 19.1 Protein binding(%) 85 95–99 76 12 t1/2, half-life. III. NEUROPHARMACOLOGY III. NEUROPHARMACOLOGY ↑↑ ↑↑ ↓↓ ↑/− ↓/− ↓/− − − ↓/− ↑ ↓↓ ↓↓ ↑↑ ↓/− ↑/−/↓ ↑/−/↓ ↑/−/↓ − − ↑/− ↓ Propofol Etomidate Ketamine Midazolam Fentanyl Sufentanil Remifentanil Vecuronium Rocuronium Succinylcholine Dexmedetomidine ↓↓ ↑/− − − ↓/−/↑ ↓/−/↑ ↓/−/↑ ↓ ↑↑ ↓↓ ↓↓ ↓↓↓ ↑ ↑ ↑ ↑ ↓ CBF ↓↓ ↑/− − − ↓/− ↓/− ↓/− ↓ ↑ ↓↓ ↓↓ ↓↓↓ ↑ ↓↓ ↓↓ ↓↓ ↓↓ CMRO2 − − − − − − −/↓ −/↓ − −/↓ − −/↓ − − ↑ ↓/−/↑ ? Resistance to Resorption − − − − − ↑/−/↓ ↑/−/↓ −/↑ ↑ −/↓ − ↑/−/↓ − −/↑ ↓ − ? CSF Formation CSF Dynamics + / / / + + + + + + + + + + + + + BBB Yes No No No Yes Yes Yes No Yes Yes No No Yes No Yes No No Epileptogenic BBB, blood–brain barrier; CBF, cerebral blood flow; CMRO2, cerebral metabolic rate of oxygen consumption; CPP, cerebral perfusion pressure; CSF, cerebrospinal fluid; ICP, intracranial pressure; ↑, increase; ↓, decrease; −, no effect; +, cross; /, does not cross; ?, unknown. − ↑↑ ↓↓ ↓/− ↑/−− Desflurane Thiopentone sodium ↓/− ↑/− Sevoflurane ↓↓ ↓/− ↑/− Isoflurane ↑↑ ↓/− ↓ Xenon Nitrous oxide CPP ICP Anesthetic Agents/Muscle Relaxants TABLE 6.2 Cerebral Effects of Anesthetic Agents and Muscle Relaxants 106 6. NEUROPHARMACOLOGY INTRAVENOUS ANESTHETIC AGENTS 107 FIGURE 6.2 2,6-Diisopropylphenol. Current Status Due to its ICP-reducing and possibly neuroprotective effects, barbiturates continue to be used widely in neurosurgical anesthesia, especially in patients with raised ICP. However, barbiturates may require vasopressor support to maintain cerebral perfusion pressure (CPP) and may cause delayed recovery due to accumulated effects. Recent Research At present, there is no evidence to prove that the administration of barbiturates in patients with acute severe head injury improves the overall outcome.18 A systematic review in 2012 has also found inefficient evidence in favor of its effectiveness as an anxiolytic drug.19 Propofol The chemical formulation of propofol is 2,6-diisopropylphenol (Fig. 6.2). It is used for induction and maintenance of general anesthesia as well as for sedation. Propofol is also known as “milk of amnesia,” because of its milklike appearance.20 The presently available preparation of propofol is 1% (10 mg/mL), which contains 2.25% of glycerol as a tonicity-stabilizing agent, 10% soybean oil, and 1.2% purified egg phospholipid as an emulsifier, with sodium hydroxide to adjust the pH. The mechanism of action of propofol is either though activation of GABA receptors21,22 or blocking action on sodium channels.23,24 A 2004 research also suggests that the endocannabinoid system may also contribute significantly to the anesthetic action of propofol.25 The recommended clinical dosage and pharmacokinetics of propofol is summarized in Table 6.1.26–28 Cerebral Effects of Propofol (Table 6.2) Propofol causes decreases in CMRO2 and CBF similar to barbiturates,26 the reduction in CMRO2 being less than decreases in CBF. It also causes decreases in ICP by decreasing the CBF; the ICP is lowered while maintaining the CPP, unlike with barbiturates and inhalational anesthetic agents like sevoflurane and isoflurane.29 In clinical dosages, it does not affect cerebral autoregulation.30 The CO2 vasoreactivity is preserved, and hence, hyperventilation will decrease the ICP under propofol anesthesia. Propofol has no effect on the production and resorption of CSF.31 The SCBF autoregulation is maintained with low- and high-dose propofol infusion.32 It induces depression of metabolic activity in spinal cord gray matter also.33 Propofol may also have direct cerebral vasoconstrictive activity. Other Effects of Propofol Propofol as a highly lipophilic drug crosses BBB and placenta and distributes into the breast milk too. The anticonvulsant effect of propofol is not clear as some data suggest a proconvulsant effect when used with other drugs.34 A measurable postoperative memory impairment has been observed in patients who have received 1–2 h of anesthesia with propofol and remifentanil.35 No differences in the incidence of POCD has been demonstrated in patients anesthetized with xenon, propofol, desflurane, or sevoflurane.36–39 Propofol anesthesia for prolonged period (5 h) can cause death of neurons and oligodendrocytes in both the fetal and neonatal brain.40 Hence prolonged infusion in small children is best avoided as it can cause acidosis, heart failure, and even death. Current Status It is useful anesthetic for neurosurgery due to favorable cerebral effects, rapid onset and recovery, and minimal interference with neurophysiological monitoring. Cerebral vasoconstriction makes it a suitable drug for vascular neurosurgeries.41 It is useful in patients with intracranial hypertension, but caution is required as it can decrease CPP due to associated hypotension. Recent Research Propofol is widely used in pediatric and adult populations its safety in neonates has not been defined and at present, there is no evidence supporting its use in neonates.42 Both thiopental sodium and propofol are used for the treatment of refractory status epilepticus, but there is no clear evidence supporting the efficacy of either of the two drugs in terms of clinical outcome.43 III. NEUROPHARMACOLOGY 108 6. NEUROPHARMACOLOGY Etomidate Etomidate is a short-acting anesthetic agent used for induction of general anesthesia and for sedation.44 The chemical formulation of etomidate is ethyl 3-[(1R)-1-phenylethyl] imidazo 5-carboxylate (Fig. 6.3). Etomidate has limited suppression of ventilation and lack of histamine release and protects from myocardial and cerebral ischemia.45 The “etomidate speech and memory test” is used to determine speech lateralization in patients prior to performing lobectomies to remove epileptogenic centers in the brain. The drug acts primarily on GABA receptors46 and is highly protein bound. It is metabolized by hepatic and plasma esterases to inactive products.47,48 The pharmacological characteristics of etomidate are described in Table 6.1.49–51 Cerebral Effects of Etomidate (Table 6.2) Etomidate reduces CMRO2 and CBF in a parallel manner to produce an isoelectric EEG.52 The maximal fall in CMRO2 is achieved after a fall in CBF, and this effect is possibly due to a direct effect causing cerebral vasoconstriction.53 It also causes a dose-dependent fall in ICP following reduction in CBF. In pediatric patients with severe traumatic brain injury, singledose etomidate administration results in significant reductions in ICP and improvement in CPP.54 The reactivity to CO2 is maintained well under etomidate anesthesia. Its effect on cerebral autoregulation has not been evaluated. Etomidate in low dose causes no change in the rate of CSF formation and resistance to CSF resorption. However, in higher doses etomidate causes reduction in rate of CSF formation with either decrease or no change in resistance to CSF resorption.55 Other Effects of Etomidate It is a hydrophobic drug and crosses BBB very rapidly like barbiturates; the CNS effect lasts only for few minutes. Etomidate has been used to protect against cerebral ischemia in high risk patients, however no human trials are available to support the evidence. Also its role in seizure control has not been proven.34 Etomidate can cause POCD in elderly patients.56 Prolonged infusion of etomidate can cause propylene glycol toxicity that can clinically present as hyperosmolality with an increased osmolal gap, hemolysis, hemoglobinuria, and metabolic acidosis.57 It can cause adrenocortical suppression and involuntary muscle activity. Current Status Lack of cardiovascular side effects makes etomidate a useful neuroanesthetic. It can also be used safely for neurophysiological monitoring as it maintains both somatosensory evoked potential (EP) and motor EP threshold.58,59 It should be avoided or used cautiously in patients with seizure history. Recent Research Etomidate provides more stable hemodynamic parameters as compared to propofol. It can be used safely without serious cortisol suppression lasting more than 24 h.60 In comparison with ketamine for rapid sequence induction, etomidate does not provide superior intubating conditions and more favorable hemodynamic response to laryngoscopy and tracheal intubation.61 Ketamine Ketamine is a phencyclidine derivative, and its chemical formulation is arylcyclohexylamine (Fig. 6.4). It produces a state called “dissociated anesthesia,” which is characterized by the presence of dissociation between thalamocortical and limbic system.62 It also provides intense analgesia as well as amnesia. Because of the possibility of increased airway secretions and emergence delirium, it is advised to give an antisialagogue (glycopyrrolate) and midazolam as premedication in patients receiving ketamine. Ketamine mainly binds to NMDA receptors. It acts on other receptors O O N N FIGURE 6.3 Ethyl 3-[(1R)-1-phenylethyl] imidazo 5-carboxylate. III. NEUROPHARMACOLOGY INTRAVENOUS ANESTHETIC AGENTS 109 FIGURE 6.4 Arylcyclohexylamine. FIGURE 6.5 C9H8N2. like opioid receptors, GABA receptors, muscarinic receptors, voltage-sensitive sodium channels, and calcium channels.63 The pharmacological characteristics of ketamine are described in Table 6.1. Cerebral Effects of Ketamine (Table 6.2) Unlike other intravenous anesthetic agents, ketamine increases the CBF and CMRO2. At subanesthetic doses, ketamine acts as a potent cerebral vasodilator and increases the CBF by 60% in normal situations.64 In patients with brain tumor and aneurysmal resection, 1 mg/kg ketamine administration does not cause increase in middle cerebral artery velocity.65 It was believed earlier that an induction dose of ketamine significantly increases the ICP and hence was considered contraindicated in patients with a raised ICP. However, some studies have found its use safe when accompanied with hyperventilation.66,67 Cerebral autoregulation and CO2 reactivity are well maintained with ketamine. It increases the rate of CSF formation but either decreases or causes no change in resistance to CSF resorption. Ketamine has protective effects on the spinal cord. It prevents loss of antioxidant activity in spinal cord tissue in cord injury cases.68 Other Effects of Ketamine Ketamine is highly lipid soluble and rapidly crosses the BBB producing quick onset of action and rapid recovery from anesthesia. Ketamine would be unlikely to have proconvulsant action; however, myoclonic and seizure like activities may occur in normal patients.34 It is known to cause emergence delirium, which occurs more frequently within an hour and is less frequent in children.69 Ketamine increases the amplitude of somatosensory EPs but decreases the auditory and visual evoked response in humans.70 Current Status It is not the first choice in neuroanesthesia, and is avoided in patients with raised ICP or decreased intracranial compliance. Recent Research According to Schreiberova et al., sedation by dexmedetomidine–ketamine–midazolam combination is a safe and suitable method for endovascular neurointerventions. It provides hemodynamic stability without respiratory depression.71 Benzodiazepines The chemical formula of benzodiazepine is C9H8N2 (Fig. 6.5). Benzodiazepines exert their CNS effects by escalating the effect of GABA neurotransmitter leading to hypnosis, sedation, anxiolysis, anticonvulsant effect, and anterograde amnesia.72 Side effects of this central action includes dizziness, sedation, weakness, loss of orientation, headache, irritability, aggression, sleep disturbances, and confusions. III. NEUROPHARMACOLOGY 110 6. NEUROPHARMACOLOGY Cerebral Effects of Benzodiazepines (Table 6.2) Benzodiazepines (midazolam, diazepam, lorazepam) cause decrease in CBF and CMRO2 in all doses. Midazolam also produces dose-related changes in regional CBF.73 These agents may produce EEG slowing but cannot completely eliminate EEG activity. They cause little or no increase in ICP but do not blunt the reflex increase in ICP during direct laryngoscopy.74 The benzodiazepine antagonist (flumazenil) can increase the ICP when used in large doses to reverse midazolam action. CBF autoregulation and CO2 reactivity are well preserved with benzodiazepines.75 At low doses, benzodiazepines cause no change in the rate of CSF formation, but at higher doses, they decrease CSF formation; the resistance to resorption is either increased or there is no change. Other Effects of Benzodiazepines Low doses of midazolam are shown to preserve SCBF but higher doses can cause a decrease.76 Benzodiazepines cross the BBB. They also have potent anticonvulsant effects. Prolonged benzodiazepine infusions can cause encephalopathy.77 Seizures can be precipitated by the administration of large doses of benzodiazapine antagonist flumazenil. POCD can also be induced by benzodiazapines.78 The metabolism of benzodiazepine in neonates is very slow, and its effect can persist up to 2 weeks after birth if consumed during pregnancy resulting in the “floppy infant syndrome” characterized by hypotonia, CNS depression, and failure to suck.79 Current Status They are used as supplemental drugs in neuroanaesthesia. Use of flumazenil to reverse benzodiazepine-induced sedation must be done cautiously in patients with impaired intracranial compliance. Recent Research Although benzodiazepines are used to treat muscle spasms due to their muscle relaxant effects, there is no current evidence to support their efficacy for treatment of muscle spasm, especially in patients suffering from rheumatoid arthritis.80 Midazolam is commonly used as infusion to sedate children or neonates in the intensive care unit (ICU), but again, at present there is insufficient data to promote this use of midazolam and further research is required to evaluate the effectiveness of midazolam in neonates.81 Opioids All opioids have variable effects on cerebral circulation and metabolism, which is attributed to the other anesthetics used in combination. With a vasodilating drug, opioids produce cerebral vasoconstriction, and with drug having vasoconstriction properties, it produces vasodilation in cerebral circulation. In animal studies it has been found that fentanyl and sufentanil along with a volatile anesthetic agent CBF and CMRO2.82 However, sufentanil with no volatile agent in background produces an increase in CBF.83 There are some reports that show that both fentanyl and sufentanil increase ICP in patients with severe head injury.84,85 According to Werner et al., under well-controlled mean arterial blood pressure (MABP), sufentanil had significant effects on ICP in patients with head-injury, whereas with a low MABP it produced only transient increases in ICP.86 In one study there was no difference in ICP-elevating effect of fentanyl in patients with impaired and preserved autoregulation.87 Alfentanil and remifentanil produce little effect on ICP and CBF and middle cerebral artery velocity.88–90 These two drugs are considered ideal for neuroanesthesia and have shown satisfactory results in neurosurgical patients.91,92 Cerebral Effects of Opioids (Table 6.2) Opioids have minimal effects on CBF and CMRO2 in low doses, while in higher doses, there is a progressive reduction in both CBF and CMRO2. Like benzodiazepines, opioids also cause slowing of EEG activity but cannot eliminate it. Opioids directly produce either minimal reduction or no change in the ICP but can markedly raise the ICP secondary to respiratory depression causing hypercapnia. Large doses of opioids can cause hypotension and decrease the CPP and hence, should be used cautiously in neurosurgical patients. The opioid antagonist (naloxone) has minimal effects on CBF and ICP if given in titrated doses, but large doses of naloxone can cause intracranial hemorrhage and arrhythmias. Cerebral autoregulation and CO2 reactivity are well preserved with all opioids. In low doses, they cause no change in rate of CSF formation and decrease the resistance to resorption of CSF. Fentanyl, at higher doses, decreases CSF formation with either an increase or no change in resistance to resorption, while alfentanil at higher doses causes no change in CSF formation and resistance to resorption. High doses of sufentanil cause no change in CSF formation and either no change or increase in resistance to resorption. III. NEUROPHARMACOLOGY INHALATIONAL ANESTHETIC AGENTS 111 Other Effects of Opioids All opioids cross the BBB. High doses of narcotics have been shown to produce seizures in laboratory animals but rarely in humans. Normeperidine, a metabolite of meperidine, is a known convulsant. Opioids and associated disturbances of calcium, sodium, and glucose homeostasis can cause POCD.93 Severe neonatal CNS depression is reported after maternal consumption of opioids.94 They have minimal effects on the somatosensory EPs. Current Status As clinical doses of most opioids produce minimal effects on cerebral circulation and metabolism, these are used widely in neurosurgical patients in combination with other anesthetics. However, caution is required when using them in patients with raised or unstable ICP. Recent Research No significant difference in extubation time was observed between patients receiving remifentanil and sufentanil by target control infusion during elective intracranial surgery.95 In comparison to continuous remifentanil infusion, a single dose of dexmedetomidine (0.5 µg/kg) provided smooth emergence with hemodynamic stability in patients undergoing cerebral aneurysm clipping.96 Dexmedetomidine Dexmedetomidine is an agonist of α2-adrenergic receptors in certain parts of the brain and acts as an anxiolytic, sedative, and analgesic. It provides sedation without causing risk of respiratory depression and is often used in the ICU for providing light to moderate sedation to critically ill patients. Its use is associated with less delirium. Data on the cerebral effects of dexmedetomidine are limited. It decreases the CBF, CMRO2, and ICP97,98 and can impair cerebral autoregulation, but it does not abolish CO2 reactivity.99 Dexmedetomidine has an important role during awake craniotomy surgeries. Along with scalp block, dexmedetomidine provides an effective and safe anesthetic approach in these surgeries.100 Dexmedetomidine during general anesthesia may effectively inhibit or reduce perioperative stress responses in children with brain tumors.101 Both in vitro and in vivo studies have shown neuroprotective effects of dexmedetomidine102; however, the mechanism of neuroprotection is not yet clear. It does not cause any significant alteration in sensory or motor EPs. Recent Research A 2015 randomized controlled trial reports better controlled postoperative arterial pressures and superior analgesia with the use of dexmedetomidine during craniotomy.103 When used as an adjunct to total intravenous anesthesia, dexmedetomidine does not seem to alter EPs and therefore can be safely used during surgeries requiring neurophysiological monitoring.104 Infusion of low-dose ketamine and dexmedetomidine both provide good postoperative analgesia with minimal side effects. Both of the tested analgesic regimes can be used safely and effectively for postoperative pain relief in patients after spine surgery.105 INHALATIONAL ANESTHETIC AGENTS The commonly used inhaled anesthetic agents in clinical practice are nitrous oxide and volatile liquids like desflurane, sevoflurane, and isoflurane.106 Halothane and enflurane are used less frequently.107 The inhalational anesthetic agents have very narrow margin of safety, and each of them have a distinctive side effect. An ideal inhaled anesthetic agent will produce rapid induction and rapid recovery from anesthesia. At higher concentrations, ICP may increase due to increase in CBF secondary to loss of cerebral autoregulation. This may get limited by reduction in CPP due to decrease in mean arterial pressure due to systemic vasodilation (Fig. 6.6). The physical properties of various inhaled anesthetic agents are described in Table 6.3. Cost is an important factor in adopting these agents. Xenon, an inert gas with anesthetic property, is hardly used because of its high cost.108 Desflurane Desflurane (1,2,2,2-tetrafluoroethyl difluoromethyl ether) is a highly fluorinated inhalational anesthetic agent (Fig. 6.7). Desflurane is a highly pungent inhalational agent with low potency. Because of its odor, desflurane can cause III. NEUROPHARMACOLOGY 112 6. NEUROPHARMACOLOGY 1.5 MAC Cerebral blood flow (ml/100 gm/min) 1 MAC 0.5 MAC Unanesthetized 0 50 150 Cerebral perfusion pressure (mm Hg) FIGURE 6.6 Cerebral autoregulatory response attenuation by inhaled anesthetic agents. Cerebral blood flow relates to cerebral perfusion pressure at >1.5 minimal alveolar concentration. TABLE 6.3 Physical Properties of Inhalational Anesthetic Agents Xenon Desflurane Sevoflurane Isoflurane Nitrous Oxide Odor Odorless Pungent Sweet Pungent Sweet Minimum alveolar concentration 71 6.6 1.8 1.2 104 Molecular weight 131.29 168 200 184 44 Blood–gas partition coefficient 0.115 0.42 0.69 1.46 0.46 Soda lime stability Yes Yes No Yes Yes FIGURE 6.7 1,2,2,2-Tetrafluoroethyl difluoromethyl ether. airway irritation leading to its infrequent use to induce anesthesia. Another drawback of desflurane anesthesia is its high cost. The precise mechanisms of action by which volatile anesthetic agent produce unconsciousness has not been clearly defined. These agents bind to membrane proteins and alter its function109 and potentiate the activity of the inhibitory neurotransmitter GABA. The pharmacological characteristics of desflurane are described in Table 6.3. Cerebral Effects of Desflurane (Table 6.2) Desflurane causes increase in CBF resulting in increase in ICP in patients with decreased intracranial compliance with normal end tidal carbon dioxide and blood pressure. At 1 minimal alveolar concentration (MAC), desflurane reduces CMRO2 by half and CBF by 22%.110 Desflurane impairs the cerebral autoregulation. The cerebrovascular reactivity to carbon dioxide is well maintained at desflurane concentrations between 0.5 and 1.5 MAC. Desflurane causes no change in resistance to CSF resorption and it either increases or has no effects on CSF formation. Desflurane (7%) in patients with midline shift causes increase in CSF pressure despite hypocapnia.111 Other Effects of Desflurane The neuroprotective effect of desflurane is almost similar to that of isoflurane; however, because desflurane causes increase in ICP to a greater extent than isoflurane or sevoflurane, it is used cautiously in patients with low intracranial compliance. Desflurane crosses the BBB but does not have epileptogenic property. Current Status Desflurane provides rapid onset and recovery of anesthesia and facilitates early neurological evaluation, hence is useful for shorter neuroprocedures and not suitable in unstable ICP situations. III. NEUROPHARMACOLOGY INHALATIONAL ANESTHETIC AGENTS 113 Recent Research According to a 2014 clinical trial, desflurane has greater hypnotic effect and produces low bispectral index than sevoflurane during general anesthesia.112 In patients who were undergoing elective supratentorial craniotomy, both sevoflurane and desflurane had similar intraoperative brain conditions, hemodynamics, and postoperative recovery profile.113 Sevoflurane The chemical formula of sevoflurane is fluoromethyl 2,2,2-trifluoro-1-[trifluoromethyl]ethyl ether (Fig. 6.8). Sevoflurane is one of the most widely used volatile anesthetic agents. It is commonly used in children because of sweet odor and rapid induction and recovery of anesthesia. It acts on many receptors, causing activation of GABA receptors and glycine receptors and inhibition of NMDA receptors, nicotinic acetylcholine (nACh) receptors and 5-hydroxytryptamine 3 receptors.114,115 The pharmacological characteristics of sevoflurane are described in Table 6.3. Cerebral Effects of Sevoflurane (Table 6.2) Sevoflurane causes increase in CBF, ICP, and decrease in CMRO2. The rise in ICP is less than isoflurane and desflurane and can be blocked by hyperventilation. It maintains cerebral autoregulation and the CO2 reactivity is well preserved. Sevoflurane decreases the rate of CSF formation and increases the resistance to CSF resorption. It is observed that in patients undergoing pituitary surgery through the transsphenoidal approach show minimal increase in lumbar CSF pressure comparable to desflurane and isoflurane.116 Other Effects of Sevoflurane There is evidence that sevoflurane can also induce in vitro preconditioning due to alteration of biochemical pathways before an ischemic insult.117 Due to the supposed neuroprotective effects of sevoflurane in animal experiments, it may be prudent to choose sevoflurane for anesthesia, although its clinical benefits are yet unestablished. Some investigators have reported epileptogenic activity with sevoflurane anesthesia mostly during the induction phase.118 It is biodegradable and can produce toxic metabolites, which can cause renal toxicity, although toxicity is not yet reported in humans. Current Status Used widely for neuroanesthesia in small children. Less preferred than propofol in patients requiring tight control of ICP. Prolonged use of sevoflurane should be avoided, especially in low-flow circuits and in patients with prior renal disease. Recent Research According to the Cochrane systemic review, high initial concentration sevoflurane technique offers rapid induction of anesthesia but can cause apnea.119 Cerebral cortical oxygenation measured by near-infrared spectroscopy is better preserved with sevoflurane than with propofol.120 Isoflurane Isoflurane is a halogenated volatile agent, 2-chloro-2-(difluoromethoxy)-1,1,1-trifluoro-ethane (Fig. 6.9). Its pungent odor can irritate the airway leading to laryngospasm, and so it is not considered for induction of anesthesia in pediatric patients. Isoflurane binds to GABA and glycine receptors and enhances the activity of glycine receptors FIGURE 6.8 Fluoromethyl 2,2,2-trifluoro-1-[trifluoromethyl]ethyl ether. FIGURE 6.9 2-Chloro-2-(difluoromethoxy)-1,1,1-trifluoroethane. III. NEUROPHARMACOLOGY 114 6. NEUROPHARMACOLOGY resulting in decreased motor function. It also has inhibitory action on NMDA receptors and potassium channels. The pharmacological characteristics of isoflurane are described in Table 6.3. Cerebral Effects of Isoflurane (Table 6.2) Isoflurane causes cerebral vasodilation leading to increase in CBF and ICP and markedly reduces the CMRO2. However, at MAC values below 1, isoflurane produces no changes in CBF.121 Increases in ICP are mild and can be reduced satisfactorily by hyperventilation.122 Cerebral autoregulation is well maintained at low (0.5%) and high concentrations, with moderate hypocapnia.123 At low or high concentrations, isoflurane causes no change in rate of CSF formation and there is no change (increase or decrease) in resistance to resorption of CSF. Isoflurane produces an increase in SCBF and an attenuation of autoregulation at 1 and 2 MAC. The changes seen at 2 MAC are greater for the spinal cord than for the cortex. Other Effects of Isoflurane There is evidence that isoflurane improves recovery from cerebral ischemia by preconditioning of neurons in male mice.124 Isoflurane crosses the BBB but does not produce epileptogenic activity. Current Status Although the cerebral protective effects of isoflurane (mainly due to pronounced decreases in cerebral metabolism) are not proven clinically, it may be a useful anesthetic for neurosurgeries where the threat of cerebral ischemia is large like carotid endarterectomy. Propofol is preferred over isoflurane in patients with raised ICP. Recent Research A 2015 systematic review supports the use of isoflurane in treatment of status epilepticus to produce burst suppression.125 It can also be used to sedate the patients with stroke and trauma in the neuro-ICU. Isoflurane decreases the occurrence of cortical spreading depolarization, which is a major mechanism of delayed brain injury in stroke and brain trauma.126 Nitrous Oxide Nitrous oxide (N2O) is also known as laughing gas because of its euphoric effect. Its chemical formula is “dinitrogen monoxide” (Fig. 6.10). Due to its poor blood solubility, alveolar and brain concentrations are achieved very rapidly (Table 6.3). It also has analgesic and anesthetic effects. Its mechanism of action includes partial blockade of NMDA receptors, nAch receptors, GABA receptors, and histamine (5-HT3) receptors and partial potentiation of GABA and glycine receptors (http://en.wikipedia.org/wiki/Nitrous_oxide).127,128 The pharmacological characteristics of N2O are described in Table 6.3. Cerebral Effects of N2O (Table 6.2) N2O is no longer considered an inert gas as it has significant cerebral effects. When administered alone or with minimal background inhalational anesthesia it causes increases in CBF. However, when administered with certain intravenous anesthetics, its effects on CBF may be reduced. The CBF is higher with 1 MAC combination of 0.5 MAC volatile agent and 0.5 MAC N2O, compared to 1 MAC of volatile agent alone. N2O may increase or produce no change in CMRO2. N2O may cause increased ICP in patients with mass lesions. This increase in ICP can be reduced by intravenous drugs like barbiturates or propofol. N2O can impair cerebral autoregulation but preserves CO2 reactivity and has no effect on the rate of CSF formation and resistance to CSF resorption. N2O increases the spinal cord’s utilization of glucose similar to the effect in the brain (approximately 25%). Both neurotoxic and neuroprotective properties have been demonstrated with N2O use. Other Effects of N2O N2O diffuses rapidly into closed air-filled spaces and expands. In case of venous air embolism, N2O can increase the size of the air bubble and worsen the consequences of air embolism. N2O crosses the BBB and can produce epileptogenic activity. FIGURE 6.10 Di nitrogen monoxide. III. NEUROPHARMACOLOGY NEUROMUSCULAR BLOCKING AGENTS 115 Current Status Use of N2O in neuroanesthesia has generated a lot of debate. Due to its ICP-raising effects and potential to enlarge air spaces, and a higher incidence of nausea and vomiting associated with its use, N2O has been discontinued in neurosurgical practice at many centers. Recent Research There is very little evidence that N2O as an inhalation agent is also effective. Furthermore, well-designed randomized controlled trials to evaluate this effect of N2O are needed.129 Avoiding N2O during craniotomies in neurosurgical patients will not affect the overall outcome.130 Xenon Xenon is a colorless, dense, and odorless gas. Currently, its use as a general anesthetic agent is limited because of its high cost and scarcity. However, it proposes many advantageous properties for its use in neuroanesthesia. It has been shown to have neuroprotective properties through its antagonist action on NMDA receptors, has exceptional cardiovascular stability, and has a rapid induction and rapid recovery from anesthesia due to its low blood gas coefficient. Cerebral Effects of Xenon (Table 6.2) Xenon decreases CBF leading to decreases in ICP and CMRO2 more than the CBF.131,132Cerebrovascular autoregulation and CO2 reactivity are well maintained with xenon at 1 MAC concentration.133 Its effect on rate of CSF production and resistance to resorption is unknown. Other Effects of Xenon Xenon crosses the BBB and does not induce seizures. Subanesthetic levels of xenon may have an anticonvulsant effect. Inhaled xenon may be a valuable new therapy in neonatal asphyxial seizures.134 It does not cause POCD or delirium in elderly patients.135 Current Status Due to its low blood/gas partition coefficient, xenon allows rapid anesthetic recovery and may be useful in neuroanesthesia. Its potential for causing cerebral neuroprotection is also attractive. However, the unclear clinical benefits and high cost preclude widespread use of xenon in neurosurgical practice. NEUROMUSCULAR BLOCKING AGENTS The depolarizing agents mimic the action of acetylcholine, while the nondepolarizing drugs interfere with the action of acetylcholine. These drugs do not cross the BBB and hence do not cause any CNS side effects. Depolarizing Neuromuscular Blocking Agents Succinylcholine (SCh) produces a very rapid paralysis and recovery from muscle relaxation, and makes it a muscle relaxant of choice for rapid sequence induction in emergency situations.136 It can release potassium ions from the cells resulting in increase in serum potassium levels by 0.5 mEq/L, and hence should be used cautiously in small children and posttrauma patients with electrolyte imbalance. The cerebral effects of SCh (Table 6.2) mainly include increases in ICP from muscle fasciculations, increased EEG activity, and increases in CBF.137 The rise in ICP can be blunted by prior administration of nondepolarizing neuromuscular blocking agents.138 Cerebral autoregulation and CO2 reactivity is preserved, and it causes no change in CSF dynamics. SCh does not cross the BBB and does not induce seizures. A recent study has found magnesium to be effective in preventing SCh-induced fasciculations.139 Succinylcholine should be used cautiously with propranolol, a nonselective β-blocker that also affects the intracellular redistribution of potassium resulting in hyperkalemia.140 Use of SCh has declined in neuroanesthesia except in emergency situations and in patients with anticipated difficult intubation. III. NEUROPHARMACOLOGY 116 6. NEUROPHARMACOLOGY Nondepolarizing Neuromuscular Blocking Agents Nondepolarizing muscle relaxants combine with nAch receptors at postsynaptic junction and antagonize the action of acetylcholine.141,142 They have minimal or no effects on CBF, CMRO2, and ICP. However, large doses of pancuronium can cause rapid increases in blood pressure that could adversely affect the ICP. Release of histamine with high doses of atracurium can cause increases in ICP. Cerebral autoregulation and CO2 reactivity is well preserved with nondepolarizing muscle relaxants. These drugs do not alter the CSF dynamics. There is no change in rate of CSF formation or resistance to resorption. They are also unable to cross the BBB and do not induce seizurelike activity, although laudanosine, a metabolite of atracurium, can cause seizures but is produced in low levels only. Cis-atracurium produces less laudanosine and histamine than atracurium. Rocuronium is also a preferred drug for rapid sequence induction due to its rapid onset of action. Spine surgery under general anesthesia without muscle relaxants provides adequate working conditions, earlier eye opening, earlier tracheal extubation, and higher levels of consciousness on emergence.143 LOCAL ANESTHETIC AGENTS Lidocaine is considered as the standard local anesthetic agent. It acts mainly through blockade of sodium ion channel.144 Local anesthetics produce a dose-related fall in CBF and CMRO2. Lidocaine in large doses cause 30% decrease in CMRO2 in dogs. These drugs also decrease the ICP following fall in CBF. Lignocaine 1.5 mg/kg given intravenously is useful in preventing ICP fluctuations during endotracheal intubation, suctioning, and skin incision. Cerebral autoregulation and CO2 reactivity is maintained with local anesthetics, and the rate of CSF formation is reduced. Lidocaine causes sedation at low concentrations, while it may result in seizures at higher doses. Although neuroprotective properties have been demonstrated with lidocaine, it has not been seen in severe ischemic conditions. A clinical trial reported long-term improvement in neuropsychological condition with lidocaine infusion during cardiac surgery,145 but examination of its role in cerebral ischemia needs further investigation. Present evidence does not support the use of local anesthetic sympathetic blockade for complex regional pain syndrome as it is not found effective in reducing pain.146 There is also no supportive evidence available to prove the role of local anesthetics in treating meralgia paraesthetica.147 MISCELLANEOUS DRUGS Description of pharmacology of various other drugs used in the practice of neuroanesthesia is beyond the scope of this chapter and is incorporated in different chapters focusing on their clinical use. However, the cerebrovascular effects of the commonly used vasoactive drugs are tabulated here (Table 6.4). FUTURE DIRECTIONS IN NEUROPHARMACOLOGY There is a need for measurement of continuous blood levels of intravenous anesthetics. Although online monitoring of propofol levels has been tried, its common use is not supported by enough evidence.148 Future pharmacologic work also needs to be directed toward development of methods for achieving faster, reliable emergence after neuroanesthesia, pharmacologic therapies specific for patients with spinal cord injury, and development of anesthesia robots that would assist in administering anesthetic drugs based on the effects of drugs like hypnosis, analgesia, neuromuscular blockade, etc.149 CONCLUSION The main emphasis in neuroanesthesia in patients undergoing neurosurgery and those with cerebrovascular disease is to attenuate further brain tissue damage, prevent new damage, and provide a good surgical field to the neurosurgeon. An accurate pharmacologic manipulation is necessary to help achieve a good neurologic outcome and patient safety in patients with brain injury. III. NEUROPHARMACOLOGY III. NEUROPHARMACOLOGY + ? + + ++ + 0 + − ? ? ? 0 0/− Nimodipine Nicardipine Milrinone Dobutamine Dopamine Epinephrine Norepinephrine Ephedrine Phenylephrine Vasopressin Nitroglycerine Sodium nitroprusside Labetalol Esmolol ? ? ? ? + + ? + + ? +/0/− ? ? + CPP ? ? + + ? ? ? 0 0 + ? ? ? − ICP ? ? ? − ? ? 0 0 0 ? 0 ? – + Cerebral Autoregulation 0 0 ? ? ? ? 0 ? ? ? 0 0 − − CO2 Reactivity CBF, cerebral blood flow; CPP, cerebral perfusion pressure; ICP, intracranial pressure; + = increase or improve; − = decrease; 0 = no effect, ? = not known. CBF Drugs TABLE 6.4 Cerebral Effects of Miscellaneous Drugs −/0 −/0 −/0 −/0 +/0 +/− + ++ +++ +/− ++ 0 0 0 Cerebral Oxygen Delivery 0 − — — +++ ++ + +++ +++ + − – – — Vasomotor Tone CONCLUSION 117 118 6. NEUROPHARMACOLOGY References 1. Garrett ER, Bojarski JT, Yakatan GJ. 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Prielipp RC, Wall MH, Tobin JR, Groban L, Cannon MA, Fahey FH, Gage HD, Stump DA, James RL, Bennett J, Butterworth J. Dexmedetomidineinduced sedation in volunteers decreases regional and global cerebral blood flow. Anesth Analg 2002;95:1052–9. 99. Ogawa Y, Iwasaki K, Aoki K, et al. Dexmedatomidine weakens dynamic cerebral autoregulation as assessed by transfer function analysis and the thigh cuff method. Anesthesiology 2008;109:642–50. 100. Garavaglia MM, Das S, Cusimano MD, Crescini C, Mazer CD, Hare GM, Rigamonti A. Anesthetic approach to high-risk patients and prolonged awake craniotomy using dexmedetomidine and scalp block. J Neurosurg Anesthesiol 2014;26:226–33. 101. Wu L, Lv H, Luo W, Jin S, Hang Y. Effects of dexmedetomidine on cellular immunity of perioperative period in children with brain neoplasms. Int J Clin Exp Med 2015;8:2748–53. 102. Ma D, Hossain M, Rajakumaraswamy N, Arshad M, Sanders RD, Franks NP, Maze M. Dexmedetomidine produces its neuroprotective effect via the alpha 2A-adrenoceptor subtype. Eur J Pharmacol 2004;502:87–97. 103. Rajan S, Hutcherson MT, Sessler DI, Kurz A, Yang D, Ghobrial M, Liu J, Avitsian R. The effects of dexmedetomidine and remifentanil on hemodynamic stability and analgesic requirement after craniotomy: a randomized controlled trial. J Neurosurg Anesthesiol 2016;28:282–90. 104. Rozet I, Metzner J, Brown M, Treggiari MM, Slimp JC, Kinney G, Sharma D, Lee LA, Vavilala MS. Dexmedetomidine does not affect evoked potentials during spine surgery. Anesth Analg 2015;121:492–501. 105. Garg N, Panda NB, Gandhi KA, Bhagat H, Batra YK, Grover VK, Chhabra R. Comparison of small dose ketamine and dexmedetomidine infusion for postoperative analgesia in spinesurgery-a prospective randomized double-blind placebo controlled study. J Neurosurg Anesthesiol 2016;28:27–31. 106. Smith I, Nathanson M, White PF. Sevoflurane-a long awaited volatile anesthetic. Br J Anaesth 1996;76:435–45. III. NEUROPHARMACOLOGY REFERENCES 121 107. Eger II EI. New inhaled anesthetics. Anesthesiology 1994;80:906–22. 108. Goto t, Nakata Y, Morita S. Will xenon be a stranger or a friend? The cost, benefit, and future of xenon anesthesia. Anesthesiology 2003;98:1–2. 109. Koblin DD. Mechanisms of action. In: Miller RD, editor. Anesthesia. 4th ed New York: Churchill Livingston, Inc.; 1994. p. 67–99. 110. Mielck F, Stephan H, Buhre W, et al. Effects of 1 MAC desflurane on cerebral metabolism, blood flow and carbon dioxide reactivity in humans. Br J Anaesth 1998;81:155–60. 111. Muzzi DA, Losasso TJ, Dietz NM, et al. The effect of desflurane and isoflurane on cerebrospinal fluid pressure in humans with supratentorial mass lesions. Anesthesiology 1992;76:720–4. 112. Kim JK. Relationship of bispectral index to minimum alveolar concentration during isoflurane, sevoflurane or desflurane anaesthesia. J Int Med Res 2014;42:130–7. 113. Dube SK, Pandia MP, Chaturvedi A, Bithal P, Dash HH. Comparison of intraoperative brain condition, hemodynamics and postoperative recovery between desflurane and sevoflurane in patients undergoing supratentorial craniotomy. Saudi J Anaesth 2015;9:167–73. 114. Brosnan, Robert J, Thiesen R. Increased NMDA receptor inhibition at an increased Sevoflurane MAC. BMC Anesthesiol 2012;12:9. 115. Suzuki T, Koyama H, Sugimoto M, Uchida I, Mashimo T. The diverse actions of volatile and gaseous anesthetics on human-cloned 5-hydroxytryptamine3 receptors expressed in Xenopus oocytes. Anesthesiology 2002;96:699–704. 116. Talke p, Caldwell J, Dodsont B, et al. Desflurane and isoflurane increase lumbar cerebrospinal fluid pressure in normocapnic patients undergoing transsphenoidal hypophysectomy. Anesthesiology 1996;85:999–1004. 117. Wang J, Lei B, Popp S, Meng F, Cottrell JE, Kass IS. Sevoflurane immediate preconditioning alters hypoxic membrane potential changes in rat hippocampal slices and improves recovery of CA1 pyramidal cells after hypoxia and global cerebral ischemia. Neuroscience 2007;145:1097–107. 118. Constant I, Seeman R, Murat I. Sevoflurane and epileptiform EEG changes. Paediatr Anaesth 2005;15:266–74. 119. Boonmak P, Boonmak S, Pattanittum P. High initial concentration versus low initial concentration sevoflurane for inhalational induction of anaesthesia (review). Cochrane Syst Rev 2012;9:CD006837. 120. Valencia L, Rodríguez-Pérez A, Kühlmorgen B, Santana RY. Does sevoflurane preserve regional cerebral oxygen saturation measured by near-infrared spectroscopy better than propofol? Ann Fr Anesth Reanim 2014;33:59–65. 121. Schlunzen L, Cold GE, Rasmussen M, et al. Effects of dose dependent levels of isoflurane on cerebral blood flow in healthy subjects studied using positron emission tomography. Acta Anaesthesiol Scand 2006;50:306–12. 122. McPherson RW, Briar JE, traystman RJ. Cerebraovascular responsiveness to carbon dioxide in dogs 1ith 1.4% and 2.8% isoflurane. Anesthesiology 1989;70:843–50. 123. McCulloch TJ, Boesel TW, Lam AM. The effect of hypocapnia on the autoregulation of CBF during administration of isoflurane. Anesth Analg 2005;100:1463–7. 124. Kitano H, Young JM, Cheng J, Wang L, Hurn PD, Murphy SJ. Gender-specific response to isoflurane preconditioning in focal cerebral ischemia. J Cereb Blood Flow Metab 2007;27:1377–86. 125. Zeiler FA, Zeiler KJ, Teitelbaum J, Gillman LM, West M. Modern inhalational anesthetics for refractory status epilepticus. Can J Neurol Sci 2015;42:106–15. 126. Takagaki M, Feuerstein D, Kumagai T, Gramer M, Yoshimine T, Graf R. Isoflurane suppresses cortical spreading depolarizations compared to propofol–implications for sedation of neurocritical care patients. Exp Neurol 2014;252:12–7. 127. Yamakura T, Harris RA. Effects of gaseous anaesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol. Anesthesiology 2000;93:1095–101. 128. Mennerick S, Jevtovic-Todorovic V, Todorovic SM, Shen W, Olney JW, Zorumski CF. Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures. J Neurosci 1998;18:9716–26. 129. Lourenço-Matharu L, Ashley PF, Furness S. Sedation of children undergoing dental treatment (review). Cochrane Syst Rev 2012;(3):CD003877. 130. Singh GP, Prabhakar H, Bithal PK, Dash HH. A comparative evaluation of nitrous oxide-isoflurane vs isoflurane anesthesia in patients undergoing craniotomy for supratentorial tumors: a preliminary study. Neurol India 2011;201(59):18–24. 131. Laitio RM, Kaisti KK, Låangsjö JW, Aalto S, Salmi E, Maksimow A, Aantaa R, Oikonen V, Sipilä H, Parkkola R, Scheinin H. Effects of xenon anesthesia on cerebral blood flow in humans: a positron emission tomography study. Anesthesiology 2007;106:1128–33. 132. Rex S, Meyer PT, Baumert JH, Rossaint R, Fries M, Büll U, Schaefer WM. Positron emission tomography study of regional cerebral blood flow and flow-metabolism coupling during general anaesthesia with xenon in humans. Br J Anaesth 2008;100:667–75. 133. Schmidt M, Marx T, Papp Jambor C, et al. Effect of xenon on cerebral autoregulation in pigs. Anesthesia 2002;57:960–6. 134. Azzopardi D, Robertson NJ, Kapetanakis A, Griffiths J, Rennie JM, Mathieson SR, Edwards AD. Anticonvulsant effect of xenon on neonatal asphyxial seizures. Arch Dis Child Fetal Neonatal Ed 2013;98:437–9. 135. Sanfilippo M, Wefki Abdelgawwad Shousha AA, Paparazzo A. Emergence in elderly patient undergoing general anesthesia with xenon. Case Rep Anesthesiol 2013;2013:736–90. 136. Griffith HR, Johnson GE. The use of curare in general anesthesia. Anesthesiology 1942;3:418–20. 137. Lanier WL, Iaizzo PA, Milde JH. Cerebral blood flow and afferent muscle activity following IV succinylcholine in dogs. Anesthesiology Rev 1987;14:60–6. 138. Minton MD, Grosslight K, Stirt JA, et al. Increase in intracranial pressure from succinylcholine: prevention by prior nondepolarizing blockade. Anesthesiology 1986;65:165–9. 139. Ahsan B, Rahimi E, Moradi A, Rashadmanesh N. The effects of magnesium sulphate on succinylcholine-induced fasciculation during induction of general anaesthesia. J Pak Med Assoc 2014;6:1151–3. 140. Ganigara A, Ravishankar C, Ramavakoda C, Nishtala M. Fatal hyperkalemia following succinylcholine administration in a child on oral propranolol. Drug Metabol Personal Ther 2015;30:69–71. 141. Bowman WC. Neuromuscular block. Br J Pharmacol 2006;147:277–86. 142. Waud BE, Waud DR. The relation between tetanic fade and receptor occlusion in the presence of competitive neuromuscular block. Anesthesiology 1971;35:456–64. III. NEUROPHARMACOLOGY 122 6. NEUROPHARMACOLOGY 143. Li Y-L, Liu Y-L, Xu C-M, Lv X-H, Wan Z-H. The effects of neuromuscular blockade on operating conditions during general anesthesia for spinal surgery. J Neurosurg Anesthesiol 2014;26:45–9. 144. Butterworth JF, Strichartz GR. Molecular mechanisms of local anesthetics: a review. Anesthesiology 1990;72:722–34. 145. Mitchell SJ, Pellett O, Gorman DF. Cerebral protection by lidocaine during cardiac operations. Ann Thorac Surg 1999;67:1117–24. 146. Stanton TR, Wand BM, Carr DB, Birklein F, Wasner GL, O’Connell NE. Local anaesthetic sympathetic blockade for complex regional pain syndrome (review). Cochrane Database Syst Rev 2013;8:CD004598. 147. Khalil N, Nicotra A, Rakowicz W. Treatment for meralgia paraesthetica. Cochrane Database Syst Rev 2012;12:CD004159. 148. Takita A, Masui K, Kazama T. Online monitoring of end-tidal propofol concentration in anesthetized patients. Anesthesiology 2007;106:659–64. 149. Rossignol S, Scwab M, Schwartz M, Fehlings MG. Spinal cord injury: time to move? J Neurosci 2007;27:11782–92. III. NEUROPHARMACOLOGY C H A P T E R 7 Anesthetic Agents: Neurotoxics or Neuroprotectives? J. Fiorda-Diaz, N. Stoicea, S.D. Bergese Ohio State University, Columbus, OH, United States O U T L I N E Introduction 123 Anesthesia Practice: Clinical Outcomes 126 Pharmacological Considerations Neurotoxicity of Anesthetic Drugs Inhaled Anesthetics Intravenous Anesthetics Neuroprotection of Anesthetic Drugs Inhaled Anesthetics Intravenous Anesthetics 124 124 124 124 125 125 126 Anesthesia and Fragile Brain 127 Conclusion 127 Abbreviations 128 References 128 INTRODUCTION The National Health Statistics Report published in 2010 estimated that around 45 million inpatient surgical procedures are carried out annually in the United States with an increasing rate among older population (≥65 years old).1 Newborns’ data was excluded from this survey although around 1.5 million interventions per year have been reported.2 Therefore, a considerable number of patients are annually being exposed to potential perioperative complications. Central nervous system (CNS) functioning is affected during anesthesia. Neurons in eloquent areas are commonly targeted by local and general anesthetic drugs, interfering with their physiologic mechanisms and autoregulation.3,4 An extensive body of evidence assessed the neuroprotective and neurotoxic effects of anesthetics. Different individual factors should be considered to assess the actual risk of developing perioperative neurological complications. Cerebral metabolic rate is decreased as a result of anesthetic drugs use. However, correlation between cerebral blood flow (CBF) and oxygen consumption is usually conserved. Disruption of the cerebral autoregulation involves several variables related to anesthesia (exposition to anesthetics, depth of anesthesia, high plasmatic concentration of anesthetics), surgery (cardiovascular or neurologic surgery), or patient demographics and medical history (aging, comorbidities, etc.). Molecular mechanisms involving anesthetic-induced neurotoxicity were extensively studied in animal models.5 Nevertheless, because of the natural limitations imposed by the clinical research it is difficult to conclude whether these processes similarly occur within human physiopathological conditions.6–9 Studies published in more than five decades have reported on neuroprotective effects of anesthetics. Decreased CBF, intracranial pressure (ICP), and Essentials of Neuroanesthesia http://dx.doi.org/10.1016/B978-0-12-805299-0.00007-5 123 © 2017 Elsevier Inc. All rights reserved. 124 7. ANESTHETIC AGENTS: NEUROTOXIC OR NEUROPROTECTIVE? rate of oxygen consumption were the first neuroprotective mechanisms described for both volatile and intravenous anesthetics.10,11 Paradoxically, anesthetics’ neuroprotective mechanisms are linked to mitochondria, the same organelle in which anesthetics’ neurotoxic effects are carried out. PHARMACOLOGICAL CONSIDERATIONS Neurotoxicity of Anesthetic Drugs In general, the molecular effect of anesthetics is studied in different species including nonhuman primates. Relevant findings explaining potential neurotoxic effects in fragile brain models have been reported.12,13 A pioneer study published by Ikonomidou et al. in 1999 associated anesthesia with neurotoxicity.14 Glutamate is one of the major neurotransmitter with an important role during developing brain stages. Therefore, N-methyl-daspartate (NMDA) antagonists (+MK801, ketamine, phencyclidine, and carboxypiperazin-4-yl-propyl-1-phosphonic acid) are able to trigger dose- and time-dependent proapoptotic responses leading to cellular degeneration in rats. Similar consequences may be responsible for neurological impairments observed in children whose mothers were exposed to comparable substances during pregnancy.14 Inhaled Anesthetics Retinal cells have shown neurodegeneration and apoptosis after isoflurane exposure in rats. Cheng et al. studied two groups of 7-day-old rats comparing mitochondrial responses in retinal cells. One of the groups was exposed for 1 h to air (control group), and the second group was exposed for 1 h to isoflurane 2% inhalation (interventional group) in 8–12 L of fresh gas flow mixture.15 Caspase 3 activation is the final stage after intrinsic and extrinsic apoptotic cascade initiation. Isoflurane is capable of acting on caspase 3 and initializing final apoptotic cascade throughout several mechanisms such as inactivation of proteins with antiapoptotic activity (BCL-xL and BCL-2), increase of the mitochondrial membrane permeability, and activation of caspases 8 and 9.15,16 Retinal cells seem to be a good starting point to assess the potentially deleterious effects of some anesthetics on the CNS as they may be directly observed using noninvasive techniques.15 Additionally, the effect of inhaled anesthetics in the progression of neurodegenerative disorders in humans is supported by studies done in animal models experiencing an increase in proinflammatory cytokines levels, such as tumor necrosis factor-α (TNF-α), after isoflurane exposure.17 Wang et al. reported that sevoflurane administration for a 6-h period in 7-day-old rats causes a significant impairment in astrocytes functioning. An important reduction in GLAST (glutamate-aspartate transporter) and JAK/STAT (Janus kinase/signal transducer and activator of transcription) activity was noticed after sevoflurane administration and considered to be associated with impaired astrocytic proliferation.18 Neuronal cells exposure to sevoflurane triggered endoplasmic reticulum dysfunction and dysregulation of intracellular Ca2+ homeostasis.19 Schallner et al. studied the effects of sevoflurane, isoflurane, and desflurane in neuronal cells after induced hypoxia. Activation of a protein linked to cellular stress response (NF-κB) with concomitant inactivation of p75NTR, was seen under isoflurane exposure but not after the use of sevoflurane or desflurane. In other words, isoflurane is associated with the progression of neuronal death under hypoxic conditions. This mechanism was not associated with sevoflurane or desflurane during in vitro and in vivo studies, promoting the use of these agents in patients with a history of stroke and cardiovascular interventions.20 Intravenous Anesthetics Komuro and Rakic also studied the role of the NMDA receptor and its blockade during neurological cells development. A significant disruption in cell migration was noticed using NMDA receptor antagonists (MK-801 and D-AP5), but not γ-aminobutyric acid (GABA) receptors antagonists. Cellular migration is a major stage necessary for CNS formation and functionality. These findings may explain how ketamine triggers some neurotoxic mechanisms associated with its use.21 Upregulation of NMDA receptor with a consequent increase in receptor expression and activity is a well-described neuronal mechanism occurring after its exposure to several antagonists. Ketamine is responsible for an overstimulation of NMDA receptors through their natural ligand (glutamate), explaining other mechanisms related to subsequent activation of the proapoptotic cascade with a greater influx of sodium, calcium, and chloride into the cytosol.22 Anesthesia-related neurodegeneration in rats is characterized by an accelerated rate of cellular genesis commonly found during developmental phases. However, with respect to clinical studies several variables might interfere.12,23 III. NEUROPHARMACOLOGY PHARMACOLOGICAL CONSIDERATIONS 125 Therefore, it is important to differentiate and identify important factors involving basic research (drug-related information such as dose and length of exposure, vitals monitoring, oxygenation, and others) and general anesthesia in children undergoing surgery.23 This “controlled setting” characterizing clinical research may explain some of the remaining controversies between research findings in animal models and clinical outcomes in humans. Slikker et al. compared the response of rhesus monkeys to anesthetic doses of ketamine with a control group, monitoring hemodynamics, and other physiological variables (oxygen saturation, capnography, noninvasive blood pressure, and temperature).12 Even under “physiological conditions,” caspase 3 expression in cortical neurons was found to be significantly increased in ketamine group, indicating stimulation of the apoptotic cascade.12 Comparable in vitro results were published by Bai et al. who found that ketamine induced caspase 3 activation and increased reactive oxygen species (ROS) in human stem cells.24 However, cell death and degeneration also depend on some other factors such as age, dose, and duration of exposure. Even during a single exposure to ketamine, anesthetic concentrations achieved in critical periods of brain cell development may be responsible for longterm cognitive impairment.25 Propofol is a well-known anesthetic drug used in pediatrics either for sedation or general anesthesia. Similar to ketamine, in vitro animal model studies using different propofol concentrations, comparable with in vivo plasmatic values reached during general anesthesia, reported unfavorable reactions of immature neuronal tissue. In fact, increased influx of calcium and chloride, mediated by GABAA receptor activation, may stimulate proapoptotic pathways leading to programmed cell death in immature neuronal cells.26,27 A comparable mechanism for neuronal degeneration and apoptosis in animal models has also been described with benzodiazepines use.28 Diazepam used at 10 mg/kg was associated with neuronal cell damage in rats during early stages of brain development. These proapoptotic reactions were not triggered when diazepam was antagonized by flumazenil administration.29 Additionally, cortical neurons and the caudate/putamen nuclei seem to be the most affected after midazolam use, a short-acting benzodiazepine, with greater apoptotic effects obtained during concomitant ketamine administration.28 The combination of these two anesthetic drugs is common in pediatric anesthesia. Opioids have also been associated with neurotoxicity and brain cell dysfunction. Fentanyl, remifentanil, sufentanil, and other µ-agonists have been associated with brain cells damage with consequent seizure activity in animal models.30,31 Neuroprotection of Anesthetic Drugs The neuroprotective effects of intravenous and inhaled anesthetics consist of preserving cerebral autoregulation and normal ICP, avoiding seizure activities, and providing at the same time an adequate anesthetic and analgesic level during surgery. In general, these effects are dose dependent. Hence, administration of more than 1.0 minimal alveolar concentration (MAC) of most inhaled anesthetics is associated with cerebral vasodilation with a subsequent increase in CBF.32 Coupling between CBF and neurological cells metabolism is a well-described physiologic and protective mechanism. Brain pathologies and pharmacological effects of some drugs may result in cerebral coupling disruption.33 Inhaled Anesthetics There is no consensus regarding the preference of inhaled anesthetic use during neurosurgery, although particular effects have been described for all of them. Sevoflurane has shown the ability to maintain cerebral coupling in a better way than isoflurane at anesthetic doses without significantly increasing ICP.34 Reduction in CBF as a result of reduced metabolism (coupling mechanism) has been reported with low doses of sevoflurane, isoflurane, and halothane.35 However, specific reactions may occur simultaneously within anterior and posterior cerebral circulation depending on the type of inhaled anesthetic used.36 Neurological cell impairment has been described as a result of the activation of NMDA receptors. Partial inhibition of these receptors during inhalational anesthesia is linked to the neuroprotective effect conferred by isoflurane, sevoflurane, and desflurane. In vitro, isoflurane is responsible for a greater percentage of NMDA receptor inhibition when compared to other halogenated anesthetics, in preference to sevoflurane and desflurane.37 Moreover, studies conducted in animal models and using inhalational anesthesia with sevoflurane and isoflurane reported enhanced mitochondrial activity by decreasing the activation of crucial proapoptotic mechanisms and preconditioning to cerebral ischemia.38–40 III. NEUROPHARMACOLOGY 126 7. ANESTHETIC AGENTS: NEUROTOXIC OR NEUROPROTECTIVE? Intravenous Anesthetics Systemic pathophysiological responses including exacerbation of sympathomimetic reactions and generation of ROS are triggered by the ischemia/reperfusion phenomenon in neurological cells. ROS generated during hypoxic stages will cause peroxidation of cells’ membranes during reperfusion. Malondialdehyde (MDA) is one of the metabolic markers used to quantify the intensity of these events. Propofol seems to have a significant neuroprotective role by preventing peroxidation of the membranes, its antioxidant effect being described in ischemic animal models.41 Propofol administration is responsible for regulation of proapoptotic and antiapoptotic genes, decreased caspase 3 activity, and regulation of other proteins such as p53 involved in programmed death of cells.42 Ischemic insult in neurological cells is associated with downregulation of GABA receptors. In vitro studies have shown that stimulation of GABA receptors may be linked to cellular death. However, diazepam exerts a positive allosteric effect on GABA receptors enhancing the affinity for its ligand, and providing a neuroprotective effect in vivo by attenuating cells death.43,44 This attenuation has been explained as a result of increased local blood flow in the penumbra areas or decreased nitric oxide (NO) synthesis.44 Dexmedetomidine, a well-known α2 agonist, has the ability to mitigate sympathomimetic effects by mediating the norepinephrine and dopaminergic effects on hippocampal cells avoiding neuronal cell death after sustainable ischemia.45,46 Moreover, inflammatory markers, ROS, and their consequent deleterious effects during ischemiareperfusion phenomena have been found to be reduced in hippocampal and dentate gyrus cells after dexmedetomidine administration.47 Eser et al. reported the effects of dexmedetomidine on ischemia/reperfusion animal models by describing significant differences in levels of TNF-α, NO, MDA, and apoptotic neuronal cells with concomitant increased activity in superoxide dismutase and catalase.47 Moreover, an increased activation of antiapoptotic pathways involving the modulation of Bcl-2 proteins activity has also been reported in ischemia/reperfusion models after dexmedetomidine exposure.48 Li et al. reported an increase of 217% in caspase 3 activity in fetal rats whose mothers were exposed to propofol during pregnancy.49 This proapoptotic response was significantly attenuated when dexmedetomidine was used and explained by a decrease of microglial stimulation.49 ANESTHESIA PRACTICE: CLINICAL OUTCOMES During the past decades, a considerable body of scientific evidence supports the association between general anesthesia and behavioral changes within the first year of life in infants undergoing surgeries. Most of these associations were described in retrospective studies. Levy (1945) named these outcomes “emotional sequelaes” and linked the behavioral changes to surgery and anesthesia. Levy observed that children exposed to surgery and anesthesia within the first months of life were characterized by learning impairments, poor social skills, behavioral changes, and common habits such as nail biting, masturbation, hair pulling, enuresis, and soiling. Surprisingly, he found that 50% of children who underwent surgery (usually tonsillectomy) at the age of 3 years or earlier had one or more emotional sequelaes.50 However, several anesthetic drugs have been created since then and several research trials have been developed to determine these correlations. Even though human anesthetic neurotoxicity cannot be assessed by reproducing studies from animal models, different clinical outcomes such as postoperative cognitive dysfunction (POCD), delirium, and impaired learning abilities in children are identified as consequences of neurological cell dysfunction after anesthesia exposure. Zhang et al. carried out a pilot study to analyze the cognitive changes after general anesthesia with different hypnotics. The authors randomized 45 subjects undergoing lower extremity or abdominal surgery to three groups. One group received spinal anesthesia and isoflurane general anesthesia, the second group received spinal anesthesia and desflurane general anesthesia, and the third group received spinal anesthesia (control). Although with considerable limitations, this study showed a significant increased incidence of POCD in the isoflurane group (27%) when compared with control group (0%), and desflurane (0%).51 Therefore, stimulation of proapoptotic pathways observed in animal models after isoflurane exposure may be comparable with neurological outcomes such as cognitive dysfunction reported in patients who underwent general anesthesia with isoflurane. However, decreased dynamic cerebral autoregulation has been noticed at 0.5 MAC for both isoflurane and desflurane, with absence of autoregulation at 1.5 MAC.52 Evaluation of the cognitive function in children who underwent general anesthesia in critical stages of brain development has been a major concern during the past decades among physicians. To avoid the limitations entailed by studies with retrospective design, a multidisciplinary group has initiated a longitudinal multicenter study to evaluate the cognitive outcomes in children who received general anesthesia before the age of 3 years. The PANDA (Pediatric III. NEUROPHARMACOLOGY CONCLUSION 127 Anesthesia and Neurodevelopment Assessment) study will compare the cognitive functionality and neuropsychological characteristics between siblings where one of them was exposed to general anesthesia due to inguinal hernia repair. A pilot study published by the PANDA group showed the feasibility of developing an ambidirectional project, collecting previous data from parents, electronic medical (anesthesia) records, and by performing neuropsychological examinations in children at different stages of the life.53 The Mayo Anesthesia Safety in Kids study is also expected to offer valuable data by enrolling patients who were exposed to general anesthesia before they were 3 years old. They planned to assess neurocognitive status in children between ages of 8–12 and 15–19 years and exposed to multiple, single or no anesthesia through an extensive battery of tests performed one time during a period 2012–16.54 Flick et al. reported no difference in learning ability between patients who had a unique general anesthesia episode before the age of 2 years and those who did not receive anesthesia. Nevertheless, receiving general anesthesia two or more times was identified as a risk factor for learning disabilities. Additionally, individualized education programs were more commonly used for patients who received anesthesia two or more times.55 On the other hand, the GAS study assessed the neurological development in 2-year-old children who underwent inguinal hernia repair by receiving either general anesthesia with sevoflurane, or regional anesthesia within the first 60 postmenstrual weeks (gestational + chronological age). Quality data was collected from more than 500 children showing that general anesthesia with sevoflurane lasting less than 1 h was not associated with developmental neurological impairment.56 Decreased CBF and brain metabolism has been described during propofol anesthesia in patients undergoing cardiopulmonary bypass.57,58 Although these encouraging results have been considered as neuroprotective effects in animal models, current clinical data do not show conclusive results.59,60 Randomized clinical trials using propofol during coronary artery bypass grafting and brain aneurysm clipping surgery found no significant differences in POCD incidence or neurological outcomes.61,62 ANESTHESIA AND FRAGILE BRAIN POCD, delirium, and dementia are commonly diagnosed among elderly patients who underwent cardiac and noncardiac major surgery. Age, nutritional state, and preoperative cognitive impairment are the main risk factors for the aforementioned postoperative complications.63,64 Perioperative management of hemodynamic parameters such as oxygen saturation and mean arterial pressure (MAP) may not play a significant role in the onset of postoperative cognitive impairment as it was thought. The International Study of Post-Operative Cognitive Dysfunction analyzed the data collected from 1218 elderly patients (more than 60 years old) who underwent major noncardiac surgical procedures. Patients with low Mini–Mental State Examination scores (≤23) and those with neurological comorbidities were excluded during screening. Continuous monitoring of oxygen saturation was performed along with periodic monitoring of the blood pressure. POCD was diagnosed in 266 patients (25.8% vs. 3.4% in control group) in the first postoperative week. After 3 months, POCD was diagnosed in 94 patients (9.9% vs. 2.8% in control group). Finally, authors could not find a significant correlation between low oxygen saturation or MAP and POCD incidence.65 Certainly, apoptosis is linked to the onset and progression of many neurological diseases. Apoptotic mechanisms along with an increase of β-amyloid protein play an essential role in the development of the Alzheimer disease. In addition to the proapoptotic effects, isoflurane has been linked to an increase in β-amyloid protein synthesis by modulating enzymatic reactions.66,67 This positive enzymatic modulation is dose dependent, being attenuated at lower doses and explained by a potential protective cellular mechanism.68 CONCLUSION Human research describing potential mechanisms of neurodegeneration is limited. Studies conducted in animal models are difficult to reproduce in the clinical setting. Neuroprotective and neurotoxic effects of anesthetics are currently under exhaustive investigation, especially for extreme age populations (children and older patients). Surgery and anesthesia trigger several molecular responses reflected in patient clinical outcomes. Most of the studies concluded that neurotoxic effects are usually found at higher doses, neuroprotective effects commonly being achieved under regular plasmatic concentration. Currently, plenty of anesthetic drugs with different mechanisms of action are available. Taking advantage of synergic effects of hypnotic and opioid medication should be considered based on patient comorbidities. III. NEUROPHARMACOLOGY 128 7. ANESTHETIC AGENTS: NEUROTOXIC OR NEUROPROTECTIVE? Data collected from ongoing clinical trials will contribute to the general effort of establishing guidelines for anesthesia management during early stages of human neurological development. Whether or not these trials will find a direct association between anesthesia, neurotoxicity, and impaired neurological development in children, they will definitely bring new valuable information for parents and physicians. Inflammation-induced reactions, cellular dysfunction, and apoptosis studied in vivo and in vitro after anesthesia exposure are strongly related to persistent cognitive dysfunction diagnosed in older patients. In addition, patients’ comorbidities and current psychosocial status may impact postoperative neurological outcomes. Although new anesthetic drugs with less associated neurotoxic effects seem to be an attractive option, future research encourages various techniques of brain preconditioning to improve patient preoperative cognitive status. However, an important role is played by translational research through its ability to create bridging designs by applying animal model concepts to clinical trial protocols. ABBREVIATIONS BCL-xL and BCL-2 B-cell lymphoma-extra large and B-cell lymphoma 2 CPP Carboxypiperazin-4-yl-propyl-1-phosphonic acid D-AP5 d-2-Amino-5-phosphono-pentanoic acid MK-801 (+)-5-Methyl-10,11-dihydro-5H-dibenzo{a,d}cyclohepten-5,10-imine hydrogen maleate NF-κB Nuclear factor-kappa light chain enhancer of activated B cells p75NTR p75 Neutrophin receptor PCP Phencyclidine References 1. Hall MJ, DeFrances CJ, Williams SN, Golosinskiy A, Schwartzman A. National hospital discharge survey: 2007 summary. Natl Health Stat Rep 2007;(29):1–20, 24. 2. Anand KJ, Soriano SG. Anesthetic agents and the immature brain: are these toxic or therapeutic? J Am Soc Anesthesiol 2004;101(2):527–30. 3. Pittson S, Himmel AM, MacIver MB. Multiple synaptic and membrane sites of anesthetic action in the CA1 region of rat hippocampal slices. BMC Neurosci 2004;5(1):52. 4. Franceschini MA, Radhakrishnan H, Thakur K, et al. The effect of different anesthetics on neurovascular coupling. Neuroimage 2010;51(4):1367–77. 5. Stratmann G. Neurotoxicity of anesthetic drugs in the developing brain. Anesth Analg 2011;113(5):1170–9. 6. Thomas J, Crosby G, Drummond JC, Todd M. Anesthetic neurotoxicity: a difficult dragon to slay. Anesth Analg 2011;113(5):969–71. 7. McGowan Jr FX, Davis PJ. Anesthetic-related neurotoxicity in the developing infant: of mice, rats, monkeys and, possibly, humans. Anesth Analg 2008;106(6):1599–602. 8. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Anesth Analg 2007;104(3):509–20. 9. Armstrong R, Xu F, Arora A, Rasic N, Syed NI. General anesthetics and cytotoxicity: possible implications for brain health. Drug Chem Toxicol 2016:1–9. 10. Smith AL, Hoff JT, Nielsen SL, Larson CP. Barbiturate protection in acute focal cerebral ischemia. Stroke 1974;5(1):1–7. 11. Yatsu F, Diamond I, Graziano C, Lindquist P. Experimental brain ischemia: protection from irreversible damage with a rapid-acting barbiturate (methohexital). Stroke 1972;3(6):726–32. 12. Slikker W, Zou X, Hotchkiss CE, et al. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci 2007;98(1):145–58. 13. Durieux ME. Anesthetic neurotoxicity: it’s not just for children anymore. Anesth Analg 2010;110(2):291–2. 14. Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999;283(5398):70–4. 15. Cheng Y, He L, Prasad V, Wang S, Levy RJ. Anesthesia-induced neuronal apoptosis in the developing retina: a window of opportunity. Anesth Analg 2015;121(5):1325–35. 16. Wang H, Dong Y, Zhang J, et al. Isoflurane induces endoplasmic reticulum stress and caspase activation through ryanodine receptors. Br J Anaesth 2014:aeu053. 17. Wu X, Lu Y, Dong Y, et al. The inhalation anesthetic isoflurane increases levels of proinflammatory TNF-α, IL-6, and IL-1β. Neurobiol Aging 2012;33(7):1364–78. 18. Wang W, Lu R, Feng D-y, Zhang H. Sevoflurane inhibits glutamate-aspartate transporter and glial fibrillary acidic protein expression in hippocampal astrocytes of neonatal rats through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Anesth Analg 2016;123(1):93–102. 19. Komita M, Jin H, Aoe T. The effect of endoplasmic reticulum stress on neurotoxicity caused by inhaled anesthetics. Anesth Analg 2013;117(5):1197–204. 20. Schallner N, Ulbrich F, Engelstaedter H, et al. Isoflurane but not sevoflurane or desflurane aggravates injury to neurons in vitro and in vivo via p75NTR-NF-ĸB activation. Anesth Analg 2014;119(6):1429–41. 21. Komuro H, Rakic P. Modulation of neuronal migration by NMDA receptors. Science 1993;260(5104):95–7. 22. Wang C, Sadovova N, Hotchkiss C, et al. Blockade of N-methyl-d-aspartate receptors by ketamine produces loss of postnatal day 3 monkey frontal cortical neurons in culture. Toxicol Sci 2006;91(1):192–201. 23. Loepke AW, McGowan Jr FX, Soriano SG. CON: the toxic effects of anesthetics in the developing brain: the clinical perspective. Anesth Analg 2008;106(6):1664–9. 24. Bai X, Yan Y, Canfield S, et al. Ketamine enhances human neural stem cell proliferation and induces neuronal apoptosis via reactive oxygen species-mediated mitochondrial pathway. Anesth Analg 2013;116(4):869. 25. Paule M, Li M, Allen R, et al. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol 2011;33(2):220–30. 26. Kahraman S, Zup SL, McCarthy MM, Fiskum G. GABAergic mechanism of propofol toxicity in immature neurons. J Neurosurg Anesthesiol 2008;20(4):233. 27. Sinner B, Becke K, Engelhard K. General anaesthetics and the developing brain: an overview. Anaesthesia 2014;69(9):1009–22. 28. Young C, Jevtovic-Todorovic V, Qin YQ, et al. Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Br J Pharmacol 2005;146(2):189–97. 29. Bittigau P, Sifringer M, Genz K, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci USA 2002;99(23):15089–94. 30. Kofke WA, Garman RH, Stiller RL, Rose ME, Garman R. Opioid neurotoxicity: fentanyl dose-response effects in rats. Anesth Analg 1996;83(6):1298–306. 31. Kofke WA, Attaallah AF, Kuwabara H, et al. The neuropathologic effects in rats and neurometabolic effects in humans of large-dose remifentanil. Anesth Analg 2002;94(5):1229–36. III. NEUROPHARMACOLOGY REFERENCES 129 32. Conti A, Iacopino D, Fodale V, Micalizzi S, Penna O, Santamaria L. Cerebral haemodynamic changes during propofol–remifentanil or sevoflurane anaesthesia: transcranial Doppler study under bispectral index monitoring. Br J Anaesth 2006;97(3):333–9. 33. Hansen TD, Warner DS, Todd MM, Vust LJ. The role of cerebral metabolism in determining the local cerebral blood flow effects of volatile anesthetics: evidence for persistent flow-metabolism coupling. J Cereb Blood Flow Metab 1989;9(3):323–8. 34. Matta BF, Heath KJ, Tipping K, Summors AC. Direct cerebral vasodilatory effects of sevoflurane and isoflurane. J Am Soc Anesthesiol 1999;91(3):677. 35. Engelhard K, Werner C. Inhalational or intravenous anesthetics for craniotomies? Pro inhalational. Curr Opin Anesthesiol 2006;19(5):504–8. 36. Rozet I, Vavilala MS, Lindley AM, Visco E, Treggiari M, Lam AM. Cerebral autoregulation and CO2 reactivity in anterior and posterior cerebral circulation during sevoflurane anesthesia. Anesth Analg 2006;102(2):560–4. 37. Solt K, Eger EI, Raines DE. Differential modulation of human N-methyl-d-aspartate receptors by structurally diverse general anesthetics. Anesth Analg 2006;102(5):1407–11. 38. Ye R, Yang Q, Kong X, et al. Sevoflurane preconditioning improves mitochondrial function and long-term neurologic sequelae after transient cerebral ischemia: role of mitochondrial permeability transition. Crit Care Med 2012;40(9):2685–93. 39. Zhang H-p, Sun Y-y, Chen X-m, et al. The neuroprotective effects of isoflurane preconditioning in a murine transient global cerebral ischemia–reperfusion model: the role of the notch signaling pathway. Neuromol Med 2014;16(1):191–204. 40. Wang H, Shi H, Yu Q, Chen J, Zhang F, Gao Y. Sevoflurane preconditioning confers neuroprotection via anti-apoptosis effects. Brain Edema XVI: Springer 2016:55–61. 41. Ergün R, Akdemir G, Șen S, Tașçı A, Ergüngör F. Neuroprotective effects of propofol following global cerebral ischemia in rats. Neurosurg Rev 2002;25(1–2):95–8. 42. Fan W, Zhu X, Wu L, et al. Propofol: An anesthetic possessing neuroprotective effects. Eur Rev Med Pharmacol Sci 2015;19:1520–9. 43. Sarnowska A, Beręsewicz M, Zabłocka B, Domańska-Janik K. Diazepam neuroprotection in excitotoxic and oxidative stress involves a mitochondrial mechanism additional to the GABA A R and hypothermic effects. Neurochem Int 2009;55(1):164–73. 44. Aerden L, Kessels F, Rutten B, Lodder J, Steinbusch H. Diazepam reduces brain lesion size in a photothrombotic model of focal ischemia in rats. Neuroscience Lett 2004;367(1):76–8. 45. Kuhmonen J, Pokorny J, Miettinen R, Haapalinna A, Jolkkonen J, Sivenius J. Neuroprotective effects of dexmedetomidine in the gerbil hippocampus after transient global ischemia. J Am Soc Anesthesiol 1997;87(2):371–7. 46. Farag E, Argalious M, Sessler DI, Kurz A, Ebrahim ZY, Schubert A. Use of α2-agonists in neuroanesthesia: an overview. Ochsner J 2011;11(1):57–69. 47. Eser O, Fidan H, Sahin O, et al. The influence of dexmedetomidine on ischemic rat hippocampus. Brain Res 2008;1218:250–6. 48. Engelhard K, Werner C, Eberspächer E, et al. The effect of the α2-agonist dexmedetomidine and the N-methyl-d-aspartate antagonist S (+)-ketamine on the expression of apoptosis-regulating proteins after incomplete cerebral ischemia and reperfusion in rats. Anesth Analg 2003;96(2):524–31. 49. Li J, Xiong M, Nadavaluru PR, et al. Dexmedetomidine attenuates neurotoxicity induced by prenatal propofol exposure. J Neurosurg Anesthesiol 2016;28(1):51–64. 50. Levy DM. Psychic trauma of operations in children: and a note on combat neurosis. Am J Dis Child 1945;69(1):7–25. 51. Zhang B, Tian M, Zhen Y, et al. The effects of isoflurane and desflurane on cognitive function in humans. Anesth Analg 2012;114(2):410. 52. Strebel S, Lam A, Matta B, Mayberg TS, Aaslid R, Newell DW. Dynamic and static cerebral autoregulation during isoflurane, desflurane, and propofol anesthesia. J Am Soc Anesthesiol 1995;83(1):66–76. 53. Sun LS, Li G, DiMaggio CJ, et al. Feasibility and pilot study of the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) project. J Neurosurg Anesthesiol 2012;24(4):382. 54. Gleich SJ, Flick R, Hu D, et al. Neurodevelopment of children exposed to anesthesia: design of the Mayo Anesthesia Safety in Kids (MASK) study. Contemp Clin Trials 2015;41:45–54. 55. Flick RP, Katusic SK, Colligan RC, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics 2011;128(5):e1053–61. 56. Davidson AJ, Disma N, de Graaff JC, et al. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet 2016;387(10015):239–50. 57. Newman MF, Murkin JM, Roach G, et al. Cerebral physiologic effects of burst suppression doses of propofol during nonpulsatile cardiopulmonary bypass. Anesth Analg 1995;81(3):452–7. 58. Souter M, Andrews P, Alston R. Propofol does not ameliorate cerebral venous oxyhemoglobin desaturation during hypothermic cardiopulmonary bypass. Anesth Analg 1998;86(5):926–31. 59. Zwerus R, Absalom A. Update on anesthetic neuroprotection. Curr Opin Anesthesiol 2015;28(4):424–30. 60. Bilotta F, Stazi E, Zlotnik A, Gruenbaum SE, Rosa G. Neuroprotective effects of intravenous anesthetics: a new critical perspective. Curr Pharm Des 2014;20(34):5469. 61. Mahajan C, Chouhan RS, Rath GP, et al. Effect of intraoperative brain protection with propofol on postoperative cognition in patients undergoing temporary clipping during intracranial aneurysm surgery. Neurol India 2014;62(3):262. 62. Kanbak M, Saricaoglu F, Avci A, Ocal T, Koray Z, Aypar U. Propofol offers no advantage over isoflurane anesthesia for cerebral protection during cardiopulmonary bypass: a preliminary study of S-100ß protein levels. Can J Anesth 2004;51(7):712–7. 63. Chen CCH, Saczynski J, Inouye SK. The modified Hospital Elder Life Program: adapting a complex intervention for feasibility and scalability in a surgical setting. J Gerontol Nurs 2014;40(5):16–22. 64. Bergese S. Fragile brains,,The Brain of the Elderlyʼ. J Neuroanaesth Crit Care 2016;3(4):41. 65. Moller J, Cluitmans P, Rasmussen L, et al. Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study. Lancet 1998;351(9106):857–61. 66. Wei H. The role of calcium dysregulation in anesthetic-mediated neurotoxicity. Anesth Analg 2011;113(5):972. 67. Wei H, Xie Z. Anesthesia, calcium homeostasis and Alzheimer’s disease. Curr Alzheimer Res 2009;6(1):30. 68. Pan C, Xu Z, Dong Y, et al. The potential dual effects of anesthetic isoflurane on hypoxia-induced caspase-3 activation and increases in β-site amyloid precursor protein-cleaving enzyme levels. Anesth Analg 2011;113(1):145. III. NEUROPHARMACOLOGY This page intentionally left blank S E C T I O N I V NEUROMONITORING This page intentionally left blank C H A P T E R 8 Neuromonitoring V.J. Ramesh, M. Radhakrishnan National Institute of Mental Health and NeuroSciences, Bengaluru, India O U T L I N E Introduction 134 Cerebral Blood Flow Transcranial Doppler Assumptions Technique Pulsatility Index Uses of Transcranial Doppler Limitations of Transcranial Doppler 134 134 135 135 135 135 138 Transcranial Sonography 139 Thermal Diffusion Flowmetry 139 Laser Doppler Flowmetry 139 Intra-Arterial 133Xenon 139 CT Perfusion 139 Xenon Enhanced CT 139 Positron Emission Tomography 140 Single Photon Emission Computed Tomography 140 Magnetic Resonance Imaging 140 Intracranial Pressure Technology Values Pathophysiology Waveform Analysis Pressure–Volume Relationship Pressure Reactivity Index Indications for Intracranial Pressure Monitoring 140 140 141 141 141 142 142 142 Electroencephalogram Recording Normal EEG Analysis 143 143 144 144 Essentials of Neuroanesthesia http://dx.doi.org/10.1016/B978-0-12-805299-0.00008-7 Electrocorticogram Uses of Electroencephalogram 145 145 Evoked Potential Monitoring Somatosensory Evoked Potentials Variables Affecting Somatosensory Evoked Potentials Recording Uses Limitations Brain Stem Auditory Evoked Potential Stimulus Characteristics Normal Waveforms Factors Affecting Brain Stem Auditory Evoked Potentials Uses Visual Evoked Potential Stimulus Characteristics Normal Waveform Variables Affecting Visual Evoked Potential 145 145 Motor Evoked Potentials Changes Considered Significant Uses Complications Contraindications Limitations 149 150 150 150 150 150 Depth of Anesthesia Bispectral Index Uses Limitations of Bispectral Index Monitoring Spectral Entropy Uses of Entropy 150 150 151 151 151 151 Cerebral Oxygenation Monitoring 152 Jugular Venous Oximetry Technology 152 153 133 146 147 147 147 147 148 148 148 149 149 149 149 © 2017 Elsevier Inc. All rights reserved. 134 8. NEUROMONITORING Normal Values Indications Limitations Complications Contraindications 153 153 154 154 154 Regional Cerebral Oximetry Equipment Normative Values (Based on INVOS Device) Factors Influencing rSO2 Values Indications Limitations 154 155 156 156 156 156 Brain Tissue Oxygen Monitoring Technology Probe Placement PbtO2 Values 156 156 157 157 O2 Reactivity Index Uses Limitations Complications 157 157 157 158 Cerebral Microdialysis Probe Placement Uses Limitations 158 158 158 158 Conclusion 159 References 159 INTRODUCTION It is important to monitor continuously the organ that we want to see perform correctly at all the times. Brain is a very complex organ to monitor, and in fact we can call the brain as an organ of organs. There are many structures that have to be monitored separately and continuously, if we have to ensure the correct functioning of all those structures. However, with so many independent structures, it is impossible to monitor all of them continuously. Thus, the neuromonitoring is always a challenging task and the information gained may not always transform into clinical utility. However, with so many modalities available, and in combination, we are able to gain some insight into the pathophysiology of the brain. We are now able to use the neuromonitoring in clinically managing the patients. CEREBRAL BLOOD FLOW Transcranial Doppler TCD is the most commonly used technique to measure the cerebral blood flow (CBF). The TCD uses a principle of Doppler sound waves where the waves reflected from a moving object are at a higher frequency than the origin frequency (Fig. 8.1). Similarly, reflected waves from the object moving away will be at a FIGURE 8.1 Doppler principle. IV. NEUROMONITORING CEREBRAL BLOOD FLOW 135 lower frequency than the origin frequency. The ultrasound waves were used to measure the CBF velocity at basal arteries. The RBCs in the vessels act as a moving object toward the probe or away from the probe. Assumptions 1. TCD is measuring the blood flow velocity (FV) in the vessel and not the actual flow. However, we presume the FV is equivalent to flow. 2. The diameter of the vessel remains constant. This is debatable but few studies have shown that vessel diameter indeed remains constant in many conditions.2 3. The angle of insonation has to remain constant for comparing the measurements. Technique The technique commonly used is 2 MHz probe as the waves have to penetrate through the bone. Higher the frequency, lower is the capability to penetrate the bone. Most commonly used site is transpterional, where the bone thickness is the least. It is just above the zygus, about 1–2 cm anterior to tragus. Keeping the probe perpendicular to the skin and directed slightly anterior will frequently encounter the middle cerebral artery (MCA). The MCA is identified with flow toward the probe at a depth of 50–65 mm and with characteristic flow sound (Fig. 8.2). From that point, with slight manipulation, it is possible to trace back to internal carotid artery (ICA) bifurcation: anterior cerebral artery (ACA) and posterior cerebral artery. Transorbital (carotid artery) and suboccipital (basilar and vertebral arteries) approaches are also used in some situations (Table 8.1). Pulsatility Index Pulsatility refers to peak systolic to lowest diastolic FV. With constant cerebral perfusion pressure (CPP), any change in pulsatility reflects the change in the cerebrovascular resistance (CVR), i.e., higher the CVR, higher is the pulsatility index (PI). The normal PI is 0.5–1.0, which is a dimensionless number. 0) &6SYS å &6DIA &6MEAN Uses of Transcranial Doppler 1. Subarachnoid hemorrhage (SAH): Commonly used to diagnose the vasospasm to quantify the degree of vasospasm and its response to treatment. Any FV more than 120 cm/s with PI of more than 1.5 is considered indicative of vasospasm (Table 8.2 & Fig. 8.3). Many centers use TCD regularly to monitor SAH patients. FIGURE 8.2 Transcranial Doppler recording from middle cerebral artery (A) and anterior cerebral artery (B). IV. NEUROMONITORING 136 8. NEUROMONITORING TABLE 8.1 Normal Transcranial Doppler Parameters in Different Vessels Artery FV (cm/s) Depth of Insonation (mm) Direction of Flow Effect of Ipsilateral Carotid Compression Middle cerebral artery 40–60 45–60 Toward Decreases Anterior cerebral artery 40–50 60–75 Away Decreases Posterior cerebral artery 30–45 60–75 Toward No change Carotid art (orbital) 35–50 60–80 Toward Decreases Basilar 35–50 60–80 Away No change Vertebral 30–45 80–110 Away No change TABLE 8.2 Transcranial Doppler Classification of the Severity of Vasospasm Severity of Vasospasm MFV Value (cm/s) MCA/ICA Ratio Normal <85 <3 Mild <120 <3 Moderate 120–150 3–5.9 Severe 151–200 >6 Critical >200 >6 ICA, anterior cerebral artery; MCA, middle cerebral artery. From Kassab MY, Majid A, Farooq MU, Azhary H, Hershey LA, Bednarczyk EM, Graybeal DF, Johnson MD. Transcranial Doppler: an introduction for primary care physicians. J Am Board Fam Med 2007;20:65–71. FIGURE 8.3 Middle cerebral artery in cerebral vasospasm with increased pulsatility index of 1.83 and peak FV of 92 cm/s. 2. Carotid endarterectomy (CEA): TCD is used to identify many things: a. Ischemia: During cross clamping, FV decrease <40% of baseline is considered as ischemia. Simultaneous monitoring of electroencephalogram (EEG) will help in better delineation of ischemia. Generally, surgeon considers placement of shunt if the FV < 40%. There is a study further classified the decrease as mild (16–40% of baseline value) and ≤15% as severe.3 b. Emboli: Detection of emboli is easy with TCD. Surgeon can modify their technique to decrease emboli. Detection of emboli will also help in the prediction of postoperative cognitive deficits.4 IV. NEUROMONITORING CEREBRAL BLOOD FLOW 137 c. Identification of the shunt malfunction. d. Hyperemia: Postoperatively patient may develop sudden hyperemia due to vasoparalysis in the ischemic area. This can lead to cerebral edema and hemorrhage. TCD can identify the patients early and thus, preventive measures can be instituted. e. Postoperative ischemia: Carotid occlusion at operative site is a lethal complication. TCD can help in identifying these patients before total occlusion by identifying decrease in the FV. 3. Head Injury: It is useful in identifying cerebral vasospasm. Cerebral vasospasm develops in 20–30% of patients with head injury. TCD is used to measure intracranial pressure (ICP) and CPP noninvasively.5 It is also used to assess the presence or absence of autoregulation and carbon dioxide reactivity. It is also used to diagnose the brain death where typical oscillatory flow is seen with intact skull (Fig. 8.4). 4. Other uses: a. Cardiac surgery: TCD is used to detect emboli during cardiac surgery and also to measure the CBF during cardiopulmonary bypass. b. Hepatic encephalopathy: TCD is used to assess the ICP and CPP noninvasively because of bleeding risks with invasive monitoring. c. Eclampsia: TCD is used to assess the ICP and CPP noninvasively. d. TCD is used in noninvasive assessment of CBF in diverse conditions.6,7 TCD is also used in: 1. Testing of pressure autoregulation: With intact autoregulation, any changes to the arterial pressure does not affect any change in CBF (measured by FV with TCD). Both the static and dynamic autoregulation can be tested using TCD.8 a. Dynamic tests: i. Dynamic autoregulation: Sudden hypotension is induced by deflation of a large thigh cuff [at least 20 mm Hg drop in mean arterial pressure (MAP)]. The FV also drops immediately, but recovers within few seconds. With continuous TCD monitoring this drop and recovery are mapped. This map will be compared with standardized graphs and the degree of autoregulation would be said [autoregulatory index (ARI)]. Normally the return of autoregulation is complete within 5 s, i.e., dynamic rate of autoregulation (dRoR) is 20%/s. This measurement has to be done within 10 s of deflation of thigh cuff to avoid confusion due to carbon dioxide (CO2) changes. ii. Transient hyperemic response test: This is the most commonly used test due to ease of testing. The baseline FV is recorded and the carotid artery is compressed for 5–8 s and released. With the compression the FV would decrease and after the release, FV would increase due to cerebral vascular dilation in response to ischemia. This increase would return back to baseline within 5 s with intact autoregulation. If the autoregulation is impaired, there would be no hyperemia as there would be no cerebral vasodilation in response to ischemia (Fig. 8.5). The success of the test depends on the adequate compression of the carotid artery. b. Static tests: The MAP is raised by 20 mm Hg by vasopressor (phenylephrine) infusion. The change in the FV would be minimal if the autoregulation is intact. The FV would increase if the autoregulation is impaired. FIGURE 8.4 Transcranial Doppler in brain death. Only little flow is seen entering the middle and anterior cerebral arteries (near carotid bifurcation) with each beat during systole. IV. NEUROMONITORING 138 8. NEUROMONITORING FIGURE 8.5 Transient hyperemic response test in a patient with normal autoregulation. 3TATIC RATE OF REGULATION (S2O2) ° % #62E -!0 where CVRe = MAP/FV; sRoR of “1” indicates perfect autoregulation and “0” indicates an absence of autoregulation. 2. Cerebrovascular CO2 reactivity: With every mm Hg change in CO2, there will be 3–4% change in the CBF in the same direction until limitation/saturation develops, i.e., within a range of 20–80 mm Hg CO2 levels. TCD FV can be used instead of CBF measurements in assessing the change in CBF to change on CO2 levels. It is considered that the diameter of basal arteries remains constant with the changes in CO2 levels. It is also assumed that only the distal vessel diameter is altered with CO2.2 Therefore TCD is used to assess the CBF changes to CO2 levels, i.e., percentage of change in the FV to percentage of change in CO2 levels. T is commonly used in head-injured patients to assess the CO2 reactivity9 and to prognosticate these patients. 3. Noninvasive assessment of ICP: One of the important uses of TCD is noninvasive assessment of ICP and CPP. Many techniques of assessment have been described but still they have not achieved the perfection to be used in clinical management of patients. The estimated CPP by TCD is calculated using the formula #00E -!0 ° &6D&6M MM(G It is calculated both the sides and averaged. Authors were able to achieve <15 mm Hg error in 92% (<10 mm Hg error in 89%) of measurements.5 Initially, Aaslid et al.10 described #00E &6M ° !& (A1—amplitude of fundamental frequency component of arterial pressure, F1—amplitude of fundamental frequency component of FV.) Fundamental frequency is calculated by fast Fourier transformation of the waveform. Other techniques are based on the following: 1. Increased pulsatility11 2. Decreased diastolic FV12 3. Decreased ratio of diastolic to mean FV13 Limitations of Transcranial Doppler 1. It is a blind procedure. The accuracy depends on the individual doing it. 2. In 5–10% of patients, insonation is not possible because of thick bone. 3. Difficult to detect the distal branches. IV. NEUROMONITORING XENON ENHANCED CT 139 TRANSCRANIAL SONOGRAPHY Recently transcranial B-mode ultrasound is used to monitor brain parenchyma. Repeated measurements of ventricular size, midline shift, intracerebral hemorrhage size, optical nerve sheath diameter to monitor raised ICP is possible. The technology is used in the early diagnosis of Parkinson disease, other movement disorders, sleep disorders, treatment of stroke, etc. Even though at present the utility is very limited, the technology holds great promise to future.14–16 THERMAL DIFFUSION FLOWMETRY The principle is that two sensors are placed nearby and one sensor is heated and the temperature is measured by the other sensor. The temperature difference between the sensors is inversely proportional to the thermal conductivity of the brain tissue between the sensors. There are many types of sensors and many techniques of heating and measuring the temperature difference. The assumption is thermal conductivity is constant in all the individuals. The probe is about 1 mm thickness, which is placed deep into the brain tissue in the arterial territory of interest. It gives the absolute values of CBF and almost instantaneous (1–2 s) and continuous measurement. Operative lights, irrigation of surgical fields, febrile patients can cause problems in measuring. However, thermal diffusion flowmetry is slowly getting popular and many feel that there is a greater role for this modality in monitoring the CBF in neurological patients.17 LASER DOPPLER FLOWMETRY Laser Doppler flowmetry (LDF) measures the CBF noninvasively (with open skull), semi quantitatively, but continuously over the cortical surface. It detects the Doppler shift of laser light reflected from the RBCs in a small volume of cortical tissue. It can be used to scan a large surface of cortical tissue. It has been used intraoperatively to detect both ischemia and hyperemia.18,19 INTRA-ARTERIAL 133XENON Kety–Schmidt technique using the Fick principle perfected the measurement of CBF. The method quantifies the difference between cerebral washin and washout of freely diffusible inert gas (N2O) by serial measurements of arterial and jugular bulb blood concentrations of the tracer. Now it is well known that the N2O is not an inert gas, thus 133Xe is used. The tracer is injected into carotid artery and washout is recorded by multiple external scintillation counters. The rate at which the tracer is washed out is proportional to CBF. With appropriate mathematical equations, gray and white matter blood flow calculation is possible. Carotid puncture is not possible every time and thus, noninvasive techniques have been developed, i.e., inhalational 133Xe and intravenous 133Xe. These noninvasive techniques also provide reproducible results with a reasonable spatial resolution.20 CT PERFUSION The iodinated contrast is injected and simultaneously images are acquired using a helical CT multislice scanner in a cine mode which allows for the measurement of CBF and cerebral blood volume (CBV). This technique is relatively fast and can be done in most of the CT scanners. Clinically this method can be used to measure the perfusion of the brain in many clinical scenarios, e.g., perfusion of the brain in severe traumatic brain injury (TBI) and hypoperfused areas in the SAH patients.21 XENON ENHANCED CT The technique involves inhalation of nonradioactive xenon and simultaneous acquisition of CT images. Similar to intra-arterial xenon technique with modified Kety–Schmidt equation, CBF is calculated. IV. NEUROMONITORING 140 8. NEUROMONITORING POSITRON EMISSION TOMOGRAPHY Both CBF and metabolism can be measured with positron emission tomography (PET) scan. Regional CBF, regional CBV, regional oxygen extraction fraction (rOEF), and regional cerebral metabolic rate of oxygen (rCMRO2) from the whole brain can be obtained. Kety–Schmidt technique is used to measure CBF. Resolution is about 4–6 mm. However, it is not useful in emergency settings and used mainly in the research settings because of high cost. SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY Single photon emission computed tomography is similar to 133Xe technique described earlier but is reconstructed in three dimensions with a rotating camera. Whole brain is covered and takes about 10–15 min for the study. Absolute values are difficult to obtain. It has slightly less resolution but much cheaper than the PET scan. MAGNETIC RESONANCE IMAGING Many magnetic resonance imaging (MRI) techniques measuring CBF have been developed. The most successful approaches are dynamic tracking of a bolus of a paramagnetic contrast agent (dynamic susceptibility contrast) or on arterial spin labeling. Whole brain is covered and anatomical localization is possible. Good resolution is possible but absolute values are difficult to obtain. INTRACRANIAL PRESSURE It is defined as the pressure within cranial cavity relative to the atmospheric pressure. Technology ICP can be measured by either invasive or noninvasive techniques. 1. Invasive a. Fluid-filled external pressure transducer: This is similar to arterial pressure and central venous pressure monitoring. A catheter is inserted in to the lateral ventricle and is connected to the transducer (Wheatstone bridge) through fluid-filled tubing. b. Miniature strain gauge transducer (Codman): In this, the sensor is placed in the tip of the catheter. Changes in pressures cause change in resistance of the circuit within the sensor and is interpreted as a waveform. Zeroing has to be done preinsertion and once placed cannot be rezeroed in vivo. Hence, zero drifting can occur over a period of days and results in false ICP values. c. Fiberoptic (Camino): The sensor at the catheter tip uses a light source. Pressure changes cause change in the light reflection and this is quantified as pressure change. Zeroing has to be done preinsertion and once placed cannot be rezeroed in vivo. d. Spielberg ICP system: In this system, a fluid-filled catheter has an air balloon pouch at the tip of the catheter. A fluctuation in balloon pressure is interpreted as ICP change. 2. Noninvasive: a. Tympanic membrane displacement. b. TCD: Various formulae have been described to estimate CPP noninvasively (see the detailed discussion earlier). c. Optic nerve sheath diameter: Measurement is taken 3 mm behind the globe. It is qualitative. Diameter >6 mm is highly indicative of raised ICP. IV. NEUROMONITORING 141 INTRACRANIAL PRESSURE As ICP measures the pressure inside the cranial cavity, the catheter can be placed in the epidural/subdural/ intraparenchymal or ventricular space (Table 8.3). Ventricular measurement is considered as gold standard. Epidural (Richmond, Gaeltec) and subdural sites are less commonly used. For intraparenchymal monitoring (Codman, Camino), a burr hole is placed separately or as a part of triple bolt system into the nondominant frontal region. The tip is usually placed in to the white matter. Values Normal: 5–15 mm Hg (healthy adults, supine); 3–7 mm Hg (children); 1–5 mm Hg (infants). Cutoff values for treating ICP depends on the intracranial pathology. For head injury, treatment is initiated when the ICP exceeds 20–25 mm Hg. Pathophysiology High ICP is an indicator of brain injury and also results in secondary brain injury by reducing CBF (Fig. 8.6). Waveform Analysis ICP is made up of three components: arterial vascular component, cerebrospinal fluid (CSF) circulatory component, and cerebral venous outflow component.22 Normal waves have three peaks: percussion (P1), tidal (P2), and dicrotic (P3) (Fig. 8.7). During reduced compliance, the P2 merges with P1 or exceeds P1. TABLE 8.3 Different Sites of Intracranial Pressure Measurement Site of Catheter Placement Advantages Disadvantages Intraventricular t S imple, cost-effective t D ifficult placement in slitlike ventricles t Z ero calibration possible t I nfection t T herapeutic—cerebrospinal fluid t H emorrhage—along catheter pathline, withdrawal, antibiotic instillation, studying intraventricular pressure volume index curves Intraparenchymal t E asier to place t Z ero drifting t A ccurate measurement t E xpensive t L ess complications including infections and t T herapeutic options not possible hemorrhage FIGURE 8.6 High intracranial pressure (ICP) and the unfavorable consequences. CBF, cerebral blood flow; CPP, cerebral perfusion pressure. IV. NEUROMONITORING 142 8. NEUROMONITORING FIGURE 8.7 Intracranial pressure waveforms. Three types of waveforms (Lundberg) has been reported: t A waves (plateau waves): In patients with reduced intracranial compliance, systemic hypotension results in cerebral vasodilation leading to increase in CBV and hence ICP. The ICP values reach up to 40 mm Hg and stays there for 5–15 min. When the duration of plateau waves exceeds >30 min, there are high chances for cerebral ischemia. Due to intact autoregulation, blood pressure rises that reverses the phenomenon. This condition should always be treated to prevent cerebral ischemia and herniation syndromes. t B waves: The frequency is around 0.5–2/min with amplitudes going up to 20–30 mm Hg. These waves indicate vasomotor center instability due to low CPP or at the lower end of cerebral autoregulation. t C waves: Frequency is around 4–8/min with amplitudes around 20 mm Hg. This wave has been documented in healthy individuals. Pressure–Volume Relationship Pressure and volume relationship within the intracranial compartment is nonlinear. Intracranial compliance is defined as the changes in volume for a given change in pressure. The inverse of compliance is called elastance and the relationship is nonlinear. The slope of this relationship in the logarithmic scale is linear and is described in terms of pressure–volume index (PVI). PVI is the volume required to change the ICP by 10-fold (PVI = ∆V/log 10 Po/pm). Normal value is around 20–25 mL. This is calculated by withdrawal of around 2 mL of CSF and noting the pressure change. This procedure is repeated multiple times with aspirating and injecting saline into the catheter, and the pressure changes noted. Reduced compliance occurs even before the ICP values go high. On the other hand, high PVI values can be seen in patients with normal CPP but defective cerebral autoregulation. Caution should be exercised when interpreting PVI inpatients whose CPP is below the autoregulatory threshold. Pressure Reactivity Index Pressure reactivity index (PRx) describes the changes in smooth muscle tone of the arterial walls in relation to the changes in transmural pressure. It is calculated as a linear correlation coefficient between averaged ICP and arterial blood pressure over a 3–5 min period. Negative PRx index indicates good pressure reactivity index. The index helps in identifying patients who might benefit from targeted CPP therapy as increasing CPP will reduce ICP only in patients with intact vasomotor reactivity. CPP at which PRx is lowest is the optimal CPP. Indications for Intracranial Pressure Monitoring t Severe head injury with abnormal CT head scan t Severe head injury with normal head CT with any of the two—age >40 years, systolic blood pressure <90 mm Hg, and abnormal motor posturing IV. NEUROMONITORING ELECTROENCEPHALOGRAM 143 t Systemic diseases causing raised ICP, e.g., Rye’s syndrome, hepatic failure t In patients with head injury where clinical neurological examination is not possible for prolonged periods of time (e.g., patients undergoing general surgery) t In intracerebral and SAH t Malignant cerebral infarction t Hydrocephalus, meningitis ELECTROENCEPHALOGRAM The EEG is a recording of spontaneous electrical activity of the cerebral cortex and is recorded from the surface of scalp. EEG is a continuous, noninvasive indicator of cerebral function, even when the patient’s consciousness is not adequate. It is a summation of excitatory (EPSP) and inhibitory (IPSP) postsynaptic potentials produced from the pyramidal cells of the cerebral cortex. Recording EEG is recorded from the cup electrodes or needle electrodes from the scalp. Meticulous cleaning of the area is important to remove the oil and dead cells from the surface. Thus the electrical resistance (impedance) is decreased and signal conduction is increased. A pair of electrodes is called as a montage. The montage can be bipolar or referential. In the bipolar montage both the electrodes are active (i.e., electrodes lie on the underlying cerebral cortex and are capable of recording the electrical activity of the cortex), and the voltage difference between the two electrodes is recorded. In referential montage only one electrode is active and the other one is common referential electrode which is commonly on the mastoid, ear lobe, or the shoulder. The focal lesions/changes are better picked up by the bipolar and diffuse changes are better picked up by referential (unipolar) montages. Intraoperative monitoring is more commonly done with bipolar montage. The 10–20 system of electrode placement is commonly employed. It is 10% or 20% of the nasion–inion line or preauricular line or hemi-circumference line. The midline electrodes are designated as “z” and the right-sided electrodes as even numbers and left-sided electrodes as odd numbers. There are frontal prominence, frontal, central, parietal, and occipital electrodes. Artifacts are common during EEG recording. Many filters are used to decrease these artifacts. However, most of the filters are frequency filters which will filter low-frequency and high-frequency waveforms. Artifacts within clinically useful range of frequency are difficult to eliminate [electromyogram (EMG), blinking, motion, cautery, etc.] (Fig. 8.8). FIGURE 8.8 Electrode placement for electroencephalogram (EEG) recording in 10–20 system (A) and morphology of EEG waveforms (B). IV. NEUROMONITORING 144 8. NEUROMONITORING Normal EEG It is a plot of voltage versus time of 1–35 Hz frequency. Based on the frequency, the waveforms are classified into different bands. Normally higher is the frequency, lower is the amplitude (Table 8.4). Analysis The raw EEG is looked for frequency, amplitude, sleep spindles, spikes, spike and wave pattern, burst suppression, etc. and changes occurring in them. As the waveform is different in each individual and also from time to time in the same individual, the analysis requires training and dedicated person to look for any changes happening intraoperatively. Therefore, the automated analysis has come into vogue, and the anesthesiologists prefer them. Synchronized EEG activity with higher amplitude is seen during sleep or general anesthesia. However, deep anesthesia produces burst suppression. Awakening produces desyncronization with higher frequency and lower amplitude. Normally, higher the complexity of the function, higher will be the frequency and lower will be the amplitude with lesser synchronization. Initial step in automated analysis is breaking the EEG waveform into small segments called as “epoch.” The epoch length varies from 2 to 16 s. Each epoch is scanned for the presence of artifacts and any epoch with artifact is rejected. Commonest analysis is power spectrum analysis. The waveform is transformed into frequency components by fast Fourier analysis. The amplitude at each frequency is noted and the power is calculated (amplitude2). The power is displayed as a compressed spectral array (CSA) or density spectral array (DSA). The CSA is obtained by creating a histogram of power at each frequency. By smoothening of the histogram a nice line of the power versus frequency in the epoch is obtained. By stacking up these power lines we can see the changes happening over a long duration and thus create a z axis (time). The same can be displayed in a two-dimensional form as DSA, i.e., the time as x axis, frequency as y axis, and the power as density. In the same analysis we can measure median frequency, spectral edge frequency. Also various ratios can be calculated, e.g., beta ratio, alpha/delta ratio (ADR, 8–13 Hz/1–4 Hz), mean amplitude, total power (TP, 0–23 Hz), burst suppression percent, etc. with specific utility.23,24 Further advanced analysis includes coherence/bispectral analysis. This analysis measures the phasic relationship between two or more frequencies in a single channel or two channels25 (Fig. 8.9). TABLE 8.4 Electroencephalogram Classification and Characteristics Waves Frequency (Hz) Normal Amplitude (µV) Characteristics Beta (β) >13 20 With mental activity, mainly frontal Alpha (α) 8–12.5 40–100 Adults with eyes closed, mainly seen in the occipital Theta (θ) 4–7.5 >50 Sedation/anesthesia/sleep Delta (δ) 0.5–3.5 >50 Sedation/anesthesia/sleep/ischemia FIGURE 8.9 Intraoperative electroencephalogram (EEG) monitoring showing various measured parameters (A) and compressed spectral array (B). IV. NEUROMONITORING EVOKED POTENTIAL MONITORING 145 FIGURE 8.10 Electrocorticogram: strip electrode with four electrodes placed on the gyrus adjacent to the lesion on the brain surface. Electrocorticogram Recording of the spontaneous electrical activity of the brain from the cortical surface or depth of the brain is called electrocorticogram. The waveforms are better localized and better delineated with electrocorticogram. It is recorded intraoperatively to delineate the seizure focus and area of surgical resection. Sometimes a grid electrode is placed on the cortical surface by the surgery, and electrocorticogram is recorded postoperatively to locate the seizure focus (Fig. 8.10). Uses of Electroencephalogram EEG is a reflection of cortical neuronal function. It can be used wherever the cortical neuronal function has to be monitored continuously. EEG is used with the intension of picking up cerebral ischemia before the cellular structure is damaged and to identify the seizures. The EEG shows abnormal changes at CBF of less than 20 mL/100 g/min much before the level at which cellular integrity is threatened (12 mL/100 g/min).26 CEA: Used to detect cerebral ischemia during cross clamping. SAH: Used to detect cerebral ischemia during temporary occlusion of the vessel during dissection of the aneurysm. The quantitative EEG has also been used for early prediction of delayed cerebral ischemia.27 Cerebral protection: In surgeries where severe metabolic suppression is required for cerebral protection, EEG is used to titrate the drugs. Intensive care unit: EEG is used to titrate sedation, detect subclinical seizures, monitor the adequacy of metabolic suppression. EEG can also be used to assess the degree of anoxic damage and to prognosticate the ICU patients.28,29 EVOKED POTENTIAL MONITORING Evoked potentials are recordings of electrical activity of specific neuronal pathways in response to external stimulus. The recordings involve either the sensory pathway or motor pathway. When neural tissues are stimulated, the electrical activity ascends along specific neuronal pathway. Based on stimulation site and recording location, characteristic waveform of the traveling impulses can be recorded. t Sensory evoked potentials t Somatosensory evoked potentials (SSEP) t Brain stem auditory evoked potentials (BAEP) t Visual evoked potentials (VEP) t Motor evoked potentials Somatosensory Evoked Potentials Following peripheral stimulation, electrical activity travels along the posterior column (proprioception, mechanoception) and spinothalamic pathways (nociception, thermal). The pathways are supplied by the posterior spinal artery. At the level of brain stem, it is supplied by the vertebral arteries and perforators of the basilar artery. At the level of sensory cortex, vascular supply is from ACA (lower limb) and MCA (upper limb, face and trunk). The IV. NEUROMONITORING 146 8. NEUROMONITORING electrical activity is recorded, along the sensory pathways via the dorsal column in the spinal cord and the scalp overlying the sensory cortex. The stimulation site should be below the area at risk of ischemia from surgery and the recording site should be above, so that the neuronal pathway should travel through the area at risk from surgery30 (Table 8.5). Variables Affecting Somatosensory Evoked Potentials Recording Anesthetic agents: As anesthetics act predominantly on the synapses and to some extent on the axonal conduction, cortical potentials are more affected than the subcortical potentials. Volatile: Halogenated compounds produce dose-dependent increase in latency and decrease in amplitude. This effect is pronounced with the addition of nitrous oxide. Nitrous oxide per se can delay latency and depress amplitude of SSEP. Intravenous: At low doses, barbiturates and propofol cause minimal changes in SSEP. At higher doses, their cause delayed latency and suppressed amplitude. Etomidate and ketamine augment amplitude of SSEP. Opioids when given as a bolus cause depression, while low-dose continuous infusion causes minimal changes. Alpha agonists are compatible with intraoperative SSEP recordings. Benzodiazepines have minimal depressant effects. Neuromuscular blocking agents directly do not affect SSEP. Temperature: Mild hypothermia produces increased latency of cortical SSEP. With profound hypothermia, cortical potentials disappear followed by increased latency and reduced amplitude of subcortical potentials, finally leading to disappearance of potentials. Hemodynamics: Perfusion of the neuronal pathways can affect the SSEP recordings. Ischemia can result in prolonged latency and reduced amplitude. Severe anemia can affect cortical latency and amplitude. Increased ICP can reduce amplitude and prolong latency of cortical SSEP. Ventilation: Severe hypoxemia results in changes in amplitude of cortical SSEP. Hypercapnia has no effect on SSEP. Though hypocapnia augments amplitude and reduce latency of SSEP in awake volunteers, these effects are not seen in anesthetized patients. Changes are considered significant in the following conditions: t latency: prolongation by ≥10% t amplitude: decrease by ≥50% Values are lower if the initial waveforms are of low signal quality (Fig. 8.11). TABLE 8.5 Somatosensory Evoked Potential Monitoring Parameters Nerves stimulated Upper limb: median, ulnar Lower limb: posterior tibial Stimulus specifications Square wave pulses Intensity: 20–35 mA (for lower limb up to 50 mA) Duration: 200–300 ms Rate: 2–7 Hz Average: 250–500 stimulus Filters: 2 Hz–3 KHz Recording areas (Upper limb stimulation): Erb’s point, C5, C2, C3’/4′ (Lower limb stimulation): T12, C5, C2, Cpz Electrodes Stimulating: skin/subdermal needles Recording: skin, subdermal needles Normal waveforms (neural generators) Upper limb: N9: Erb’s point N13: dorsal column (cervical spine region) N18—thalamus N20, P22: cortex origin Central conduction time (N13–N20): 5–8 ms IV. NEUROMONITORING Lower limb: Lumbar potentials: depending on level of recording N30: dorsal column N37: cortex origin EVOKED POTENTIAL MONITORING 147 FIGURE 8.11 Somatosensory evoked potential following right median nerve stimulation. Uses t For spinal procedures: intramedullary tumors, scoliosis surgery, spine stabilization t For cerebral vascular surgeries where the specific pathways are affected by ischemia: t Intracranial aneurysm (median/ulnar nerve for MCA territory; posterior tibial nerve for ACA territory) t CEA t In tumor surgeries: to locate the junction of sensory and motor cortex (phase reversal) t To identify patient position related nerve injury (ulnar, median) Limitations t Does not monitor spinal cord supplied by the anterior spinal artery. A normal intraoperative SSEP does not rule out occurrence of postoperative paraplegia. t Artifacts by OT table, cautery machine, convection warmer, anesthesia machine, drill, CUSA, etc. can pose problems in SSEP recording. Brain Stem Auditory Evoked Potential BAEP is the recording of the activities of the neural generators involved in the auditory pathways following stimulation of the cochlear nerve. The first 10 ms recordings represent the activities up to the brain stem and are termed early latency; up to 80 ms represent cortical activities and are termed middle latency; beyond 80 ms, waveforms represent the cortical association areas and are termed late latency potentials. Following stimulation of the ear, cochlea gets activated. The electrical impulses travel along the vestibulocochlear nerve to the brain stem, midbrain and reach the primary auditory cortex. Auditory stimuli have bilateral representation in the cortex. Stimulus Characteristics Filter: 30 Hz–3 KHz Amplitude: 0.3–3 microV Stimulus averaging: around 2000 Frequency: 10–40 Hz Intensity: click, square wave electrical pulse, 100–110 dBpeSPL (decibel peak equivalent sound pressure level) IV. NEUROMONITORING 148 8. NEUROMONITORING Normal Waveforms (Fig. 8.12) Waves I–VII: early latency BAEP Interpeak latency: I–III: 2.1 ms III–V: 1.9 ms Changes considered significant: V waveform: latency prolongation >0.5 ms; 50% decrease in amplitude; prolonged interpeak latency III–V (Table 8.6). Factors Affecting Brain Stem Auditory Evoked Potentials Early latency BAEP are resistant to the anesthetic effects. Use of drill during surgeries can interfere with the auditory stimuli and waveforms get distorted. Damage to the cochlear vessel (or vasospasm) will abolish all the waveforms and will not be helpful in brain stem monitoring. Mid latency potential are very sensitive to the anesthetic agents and are used as a depth of anesthesia monitor. Uses t Surgeries at the cerebellopontine angle t Brain stem procedures t Posterior circulation vascular surgeries FIGURE 8.12 Early latency brain stem auditory evoked potential (BAEP) response depicting five waveforms (A) and middle latency BAEP response (B). TABLE 8.6 Generators of Brain Stem Auditory Evoked Potential Waveforms Waves Latency (ms) Origin I 1.7 Cochlear nerve II 2.8 Cochlear nucleus III 3.9 Superior olivary complex IV 5.1 Lateral lemniscus V 5.7 Inferior colliculus VI Medial geniculate body, auditory cortex VII Cortex Middle latency No, Po, Na, Pa, Nb, N1 Pa <12 ms, Nb < 44.5 ms (indicate awareness during anesthesia) Late latency P2, N2 IV. NEUROMONITORING 149 MOTOR EVOKED POTENTIALS (A) (B) Nasion Nasion FPZ FPZ Ground A1 CZ Ground A2 A1 CZ O1 A2 O2 Inion FIGURE 8.13 Electrode placement for recording brain stem auditory evoked potential response (A) and visual evoked potential response (B). t Surgeries in the posterior fossa t Microvascular decompression of the lower cranial nerves. Visual Evoked Potential VEP records the electrical activity from neural generators along the visual pathway. Following light stimuli, retinal receptors get activated. The electrical activity travels along the optic nerve, optic chiasm, optic tracts, lateral geniculate body and reach visual projection areas in the occipital cortex (Fig. 8.13). Stimulus Characteristics Light source: white or red LED-loaded goggles; 500–2000 lumens Stimulus rate: 1–2.5 Hz (for steady state responses: 8–30 Hz) Filter: 5–100 Hz Signal averaging: 50–200 Recording electrodes: Oz–Fz; Oz–A1; Oz–A2; Ground Cz Normal Waveform t Triphasic waveform response t P40 (lateral geniculate body) t N70 (striatum) t P100 (areas 17–19 of visual cortex in occipital lobe) Variables Affecting Visual Evoked Potential Halogenated compounds depress VEP to a greater extent. Low-dose opioids, benzodiazepines, and low-dose propofol infusion do not affect VEP responses. Opioids cause pupillary constriction resulting in reduced light transmission into the retina, and this can reduce VEP response. It is better to use mydriatics at the beginning of surgery. Reduced core temperature results in prolonged latency of VEP (20% at 35°C). MOTOR EVOKED POTENTIALS Following stimulation (electrical or magnetic) of the motor cortex, electrical impulses travel along the cortical spinal tract, descend at the level of brain stem, travel down to the anterior funiculi of the spinal cord, and result in muscle activity (Table 8.7). IV. NEUROMONITORING 150 8. NEUROMONITORING TABLE 8.7 Stimulus Characteristics for Motor Evoked Potential Myogenic D Waves Intensity 200–1000 V 100–500 V Amplitude 24–2000 microV 1–30 mmicroV Filter 10–5 KHz 10–2 KHz Duration 0.05–1 ms (usually 0.2–0.5 ms) Rate Trains of 4–8 with interstimulus latency 2–4 ms Stimulus site C1–C2 or C3–C4 Recording site Muscle: abductor hallucis, gastrocnemius, abductor pollicis, tibialis anterior Spinal cord (epidural/subdural) Changes Considered Significant The dictum is that unchanged stimulus parameters should produce similar responses in a particular group of muscles (provided there is no change in anesthetic depth and no use of muscle relaxants). So, changes are considered significant when there is: t an increased requirement of stimulus strength (>50 V) to produce the same initial response t increased number of stimuli to achieve the same initial response t decrease in amplitude by more than 80%. Uses t t t t For spinal procedures as a supplement to SSEP, e.g., scoliosis correction surgery, intramedullary tumors Spinal decompression procedures Intracranial tumors where motor cortex is involved To map motor cortex when tumor is situated close to the motor cortex (stimulus strength required is minimal when cortex is directly stimulated: 2–10 mA). Complications t Tongue injury t Bone fractures including mandible t Patient fall from OT table Contraindications t Patients with implantable deep brain stimulator, clips t Recent craniotomy (relative)—possibility of stimulating needle penetrating brain through skull defect t Cardiac pacemaker (arrhythmias) Limitations t Not sensitive to individual root injury t Highly sensitive to anesthetic agents DEPTH OF ANESTHESIA Bispectral Index Most commonly used and extensively studied monitor to assess depth of anesthesia. BIS examines the relationship/synchronization among the waves. The monitor utilizes various subparameters in time domain, frequency domain, and bispectral domain.25 IV. NEUROMONITORING 151 DEPTH OF ANESTHESIA &REQUENCY DOMAIN "ETA RATIO ,OG "ISPECTRAL $OMAIN 3YNCH &AST 3LOW (P å (Z) (P å (Z) (3UM OF ALL BISPECTRUM PEAKS (. å (Z)) (3UM OF BISPECTRUM IN THE AREA ( å (Z)) Time domain: Burst suppression ratio and QUAZI—both are burst suppression calculated by different algorithm. All the above parameters are fitted in an equation with different weightings to obtain a dimensionless number called BIS. Also, the given weighting to a parameter is altered according to the patient’s consciousness level. The values range from 100 (awake) to 0 (isoelectric EEG). As the patient is sedated the BIS value drops to <90 and the values of 60 to 40 are considered adequate hypnosis component of general anesthesia. A value of less than 40 is considered as deeply anesthetized (Fig. 8.14). Uses The BIS monitoring was developed to assess the depth of hypnosis during general anesthesia and to prevent the awareness under anesthesia. Later, it was used to assess adequacy of sedation in various clinical situations, to assess and to monitor the depth of coma. BIS is used to detect cerebral ischemia and in the diagnosis of brain death. The indications for BIS monitoring during diagnostic and therapeutic procedures are ever increasing. Limitations of Bispectral Index Monitoring In general, all the factors that affect the EEG can cause inaccuracy in the BIS measurement even though the technological advances are decreasing the inaccuracies. Ketamine: May increase BIS due to EEG activation. Nitrous oxide: Seen to decrease the BIS values when used with other general anesthetic agents. But when used as a sole agent it does not decrease the BIS values. Opioids: They decrease the BIS values to some extent but not to levels suggestive of general anesthesia.31 Serious medical conditions: Cardiac arrest, hypovolemia, hypotension, cerebral ischemia/hypoperfusion, hypoglycemia, hypothermia have shown very low BIS values presumably due to decreased metabolism. Neurological disorders: Disorders having EEG changes and metabolic suppression would show abnormal BIS values, e.g., severe brain injury, postictal state, dementia, cerebral palsy, etc. Patients who have received electroconvulsive therapy have shown low BIS values even much later than postictal phase.32 Different anesthetic agents may have different BIS values: It has been shown that decrease in BIS values with halothane is much less in comparison with isoflurane. There is a mild difference between isoflurane and propofol also.31,33 Technical: It is important to remember that the value displayed is not real time. There is a 10–15 s delay. EMG activity of the frontalis muscle and electrocautery can produce artifacts. Spectral Entropy This mode of assessing depth of anesthesia was introduced by the Datex company. Entropy means randomness. The principle in measuring entropy is that as the depth of anesthesia increases the randomness in the EEG comes down and rhythmic oscillations and predictability increases. The EEG and EMG are recorded from the sensor attached to forehead. It calculates two parameters: state entropy (SE) and response entropy (RE). SE is calculated from the 0.8 to 32 Hz frequency and RE is calculated from 0.8 to 47 Hz. SE is a more stable number and ranges from 0 to 91 (isoelectric EEG to awake state). For the calculation of RE, the EMG activity is also taken into calculation. Thus, in entropy assessment, the EMG signal is not discarded. The RE ranges from 0 to 100 and for anesthesia, the recommended range for both is 40–60. The RE is always equal to or higher than the SE. Uses of Entropy The entropies are similar to BIS monitoring, although few studies suggest that response to pain is better detected by entropy (RE) as the EMG signal is included into the analysis. Other depth of anaesthesia monitors are: IV. NEUROMONITORING 152 8. NEUROMONITORING FIGURE 8.14 Bispectral index (BIS) monitor. BIS value, electroencephalogram, signal quality index, electromyogram, burst suppression ratio, (SR) and trend graph are seen. Narcotrend Patient state analyzer Index of consciousness Auditory evoked potential index (ARx index) CEREBRAL OXYGENATION MONITORING Brain is highly dependent on oxygen as its fuel. The purpose of monitoring is to identify ischemia at an early (reversible) stage, so that interventions can be planned. When the oxygen supply is less than consumption, initially oxygen extraction increases (resulting in fall in venous oxygen level) and when the supply falls below the critical level, ischemia sets in. Monitors of cerebral oxygenation include jugular venous oximetry, cerebral oximetry, and brain tissue oxygen. JUGULAR VENOUS OXIMETRY Jugular venous oximetry (SjvO2) measures the oxygen saturation of the venous blood at jugular bulb. SjvO2 represents the global oxygen extraction of the cerebral tissues. Oxygen delivery to the cerebral tissues is dependent on CBF and arterial oxygen content. CBF is dependent on MAP, CVR, and cerebral autoregulation. Arterial oxygen content is dependent on hemoglobin, saturation, arterial partial pressure of oxygen. Cerebral oxygen consumption (CMRO2) is calculated as a product of CBF and arteriovenous oxygen difference (A-VO2). CMRO2 = CBF × A-VO2 A-VO2 = Hb × 1.39 (SaO2 − SjvO2) + 0.003 × (PaO2 − PjvO2) Considering Hb to be a constant, dissolved oxygen to be negligent (except in hypothermia), and SaO2 equivalent to 1, the equation can be rewritten as A-VO2 α 1 − SjvO2 CMRO2/CBF α 1 − SjvO2 The above equation shows that SjvO2 is inversely proportional to CMRO2 and A-VO2 and has direct relationship with CBF. In healthy situations, when there is increased demand (CMRO2), CBF increases by autoregulatory IV. NEUROMONITORING JUGULAR VENOUS OXIMETRY 153 mechanisms thereby keeping arteriovenous oxygen difference (oxygen extraction) a constant. In brain injury, there is defective autoregulation and CBF does not compensate demand resulting in increased oxygen extraction leading to decreased SjvO2. Thus, reduced SjvO2 indicates imbalance in supply–demand ratio irrespective of the cause. On the other hand, high SjvO2 indicates reduced consumption either because of infarct or hyperemia. Technology The dominant jugular vein is cannulated retrograde and catheter tip is placed at the jugular bulb. Correct position is confirmed by X-ray of the skull. In lateral X-ray skull view, catheter tip should lie cranial to C1–C2 interspace. In AP X-ray skull view, catheter tip should lie cranial to the line joining the two mastoid processes and caudal to the lower margin of the orbit. The dominant side of the jugular vein is identified by the size of the jugular foramen in CT head and ICP response to jugular vein compression. If the catheter tip lies within 2.5 cm of the jugular bulb, the chances for extracerebral contamination is minimal.34 A standard central venous catheter can be placed and blood can be sampled intermittently or dedicated fiberoptic catheters can be placed, which give continuous measurements. Normal Values A-V O2: 2.2–3.3 µmol/mL (5–7.5 vol%) SjvO2: 60–75% Right to left side difference ranges from 5% to 15% (Tables 8.8 and 8.9). Indications t Head injury patients to identify secondary neuronal injury. t SAH patients, to differentiate vasospasm from hyperemia (TCD shows high velocity in both conditions). t To titrate hyperventilation therapy (2 tier therapy to manage intracranial hypertension). TABLE 8.8 Classification of SjvO2 Values. Value (in %) Conditions >90 Brain death, severe hypothermia, arteriovenous malformations (AVM) 75–90 Hyperemia, AVM 60–75 Normal 50–60 Increased O2 extraction 45–50 Mild–moderate cerebral ischemia <45 Severe ischemia, anaerobic metabolism associated with EEG changes TABLE 8.9 Factors Affecting SjvO2 Values Low SjvO2 (<50%) High SjvO2 (>75%) t D ecreased O2 supply: Decreased cerebrospinal fluid (low cerebral perfusion pressure, high intracranial pressure) Low cardiac output Anemia Hyperventilation Low PaO2, low FIO2 t I ncreased demand Hyperthermia Seizures t I ncreased supply Arteriovenous malformations Cerebral hyperemia Hypercapnia Bohr effect (pH > 7.6, oxygen dissociation curve shift to left prevents dissociation of O2) Cerebral infarction Brain death t R educed demand Hypothermia IV. NEUROMONITORING 154 8. NEUROMONITORING Limitations t It is a global indicator of oxygen imbalance and focal ischemic changes can be readily missed out. t The amount of venous drainage into each jugular vein is unknown. The amount of contralateral contamination can result in abnormal values. t Low values indicate only oxygen imbalance status, not the cause for the imbalance. Other systemic monitors are required to identify possible causes. Complications t Injury to brachial plexus and carotid artery during catheter insertion. t Infection t Jugular vein thrombosis (possibly raised ICP) Contraindications t Bleeding diathesis t Cervical spine injuries REGIONAL CEREBRAL OXIMETRY Cerebral oximetry noninvasively and continuously measures the regional cerebral tissue oxygen saturation (rSO2) by near-infrared (NIR) spectroscopic technique. NIR light has the ability to penetrate tissue including bone. Oxygen binding to the hemoglobin affects the absorption spectrum. By measuring light absorption at two or more wavelengths, it is possible to measure the concentration of oxy and deoxyhemoglobin. The peak absorption for reduced hemoglobin is around 740 nm, for oxy hemoglobin it is around 850–1000 nm and at 810 nm, the absorption spectrum of oxy and deoxyhemoglobin are similar (isosbestic point). The principle behind the NIR technology is based on the Lambert Beer equation. This equation calculates the absolute concentration of the chromophore provided the sampling volume and the path length of the light source are known. In biological tissues such as the skull, light (photons) has the tendency to scatter resulting in increased and variable path length and some photons do not reach the detector. To overcome this, different types of reflectance spectroscopic techniques are employed.36 Differential spectroscopy: In this technique, path length and the amount of scattered light are assumed to be constant. The monitor is useful as a trend monitor starting from an arbitrary baseline value. Currently available commercial monitors do not employ this technique. Spatially resolved spectroscopy (Invos, Equanox): The light (from diodes) reflecting from the extracranial and intracranial tissues is differentiated by using two detectors. The depth of penetration and reflection of photons are dependent on the distance between the light emitter and the detector. The detector (silicone photodiode/ photomultiplier tube) closer to the diode (shallow) receives photons from extracranial tissues, and the detector which is farther (deeper) receives signals from the intracranial tissues (Figs. 8.15 and 8.16). Frequency-resolved spectroscopy (Oxiplex): Light intensity with known radio frequency is used as the source. This technique measures the absolute chromophore concentration. Multiple wavelength technology facilitates measurements of other chromophores such as cytochrome a–a3 and with dyes, such as indocyanine green, facilitates CBV measurements. For a given cortical tissue, cerebral vascular bed is made of 70–85% venous and capillary and the remaining arterial. The measurement made by the cerebral oximetry predominantly reflects the concentration/saturation of hemoglobin in the venous and capillary bed. Cerebral oximetry provides a continuous, bedside, noninvasive measurement for focal oxygenation status of the brain tissues. Any intervention to improve oxygen delivery can be assessed by the corresponding changes in the rSO2 values. The sensor is usually placed over the forehead on either side of the midline few centimeters above the eye brow to avoid contamination by the sagittal sinus and the frontal sinus. It is better to have a look at the X-ray skull and CT head to have knowledge on the extent of the frontal sinus before placing the sensors. The sensors must be protected IV. NEUROMONITORING REGIONAL CEREBRAL OXIMETRY 155 from external light source to prevent contamination. Perspiration can result in displacement of the sensors. Cerebral oximeters are generally resistant to motion artifacts and cautery. The pressure on the forehead by the sensors might cause damage to the skin. Equipment 1. 2. 3. 4. 5. 6. 7. 8. Invos 5100 (Somenetics corporation) (735- and 810 nm-light source) CAS Medical Fore sight (Branford, CT) CerOx (OrNim Inc. LosGatos, CA) EquanoX 7600 Nonin Inc. (Plymouth, MN) NIRO 300 (Hamamastsu Photonics, Japan) Oxymon (Ortinis, the Netherlands) OxiplexTS (ISS, IL) TRS-20 (Hamamatsu, Japan) FIGURE 8.15 Equanox cerebral oximetry monitor (Nonin Inc.) and Equanox sensor. It contains two LED light sources on either end of the sensor. There are two detectors: 2 and 4 cm away from the light source on either side. FIGURE 8.16 Diagram representing light pathway into brain tissue. IV. NEUROMONITORING 156 8. NEUROMONITORING Normative Values (Based on INVOS Device) Normative values differ between different equipments. The values given below are from the INVOS device. Adult: 71 ± 6% Children: 71 ± 7% Neonate: 76 ± 8% Normative values are generally greater than jugular venous saturation. The values are independent for hematocrit values greater than 30%. The value is age dependent. Right to left differences is generally less than 10% in majority of the patients. Values less than 40–50% or fall >20–25% of the baseline values are generally considered as cutoff for development of cerebral ischemia.36 Factors Influencing rSO2 Values Blood pressure Systemic oxygenation Hemoglobin Arterial PO2, PCO2, pH Temperature Anesthesia Seizure Indications t t t t t Surgeries such as CEA, cardiac surgeries Neuroradiology suite during balloon occlusion testing of ICA ICU, to titrate blood pressure in patients with shock Detect cerebral vasospasm following SAH During surgery in elderly patients under general anesthesia. Maintaining normal rSO2 values reduces the incidence of perioperative strokes and cognitive dysfunction Limitations t Presence of abnormal hemoglobins and bilirubin can give erroneous rSO2 values. t Presence of extracranial collection of CSF or blood can give inaccurate results (e.g., extradural hematoma). At the same time the abnormal values on one side can give a clue to the presence of abnormal collection and facilitate surgical decision. t Placement over the infarcted brain tissue (frontal cortex) can give falsely high values. t In patients who have undergone surgeries such as decompressive craniectomy, the light is excessively reflected and the values are unreliable. t rSO2 measurement (regional) is restricted to the focal prefrontal cortex and infarct on other areas can be easily missed. BRAIN TISSUE OXYGEN MONITORING This technique measures (focal) oxygen tension at the brain’s interstitial space. It represents the oxygen available for mitochondrial oxidative phosphorylation. Brain tissue oxygen monitoring (PbtO2) is determined by the CBF and the difference in cerebral arterial and venous oxygen tension. Technology PbtO2 is measured by two different techniques: 1. Modified Clark electrode (e.g., Licox, Neurovent-P) 2. Optical fluorescence (e.g., Neurotrend, Codman, Oxylab) In Clark electrode, a membrane surrounds an electrolyte layer and two electrodes made of noble metal. Oxygen diffuses in to the membrane, electrochemically gets reduced, and causes a voltage difference which is proportional to IV. NEUROMONITORING BRAIN TISSUE OXYGEN MONITORING 157 the oxygen tension. This process is temperature dependent, and brain temperature must be simultaneously measured for PbtO2 calibration. Brain area monitored by Licox probe is around 14–18 mm2 while with that of Neurovent-P is around 24 mm2. Hence, values by different probes cannot be compared. Clark-type electrodes are precalibrated and following insertion requires at least an hour for stabilization before actual measurements take place. In optical fluorescence technology, optode sensors are coated with colored markers that emit color when comes in contact with oxygen. The intensity of color depends upon the oxygen tension and is picked up by fluorescent sensors. However, this probe requires calibration with the known oxygen concentration prior to its insertion. Probe Placement PbtO2 probes are fine catheters, approximately 0.5–0.8 mm in diameter, placed in to the white matter close (roughly 3.5 cm below the dura) to the injured brain, preferably in the penumbral region. In diffuse injury, the probe is usually placed in the nondominant frontal subcortical white matter. The position of the probe must be confirmed with the CT head. If brain temperature is not monitored, the probe must be calibrated with body temperature at regular intervals. PbtO2 Values PbtO2 is a focal measurement. In diffuse injury, values correlate with global monitors such as jugular venous oximetry. Values depend on probe location and oxygen diffusion from capillaries. Brain hypoxia is not only dependent on the values but also on the duration of low values. Values are listed as follows: Normal 20–35 mm Hg Compromised 20 mm Hg Brain hypoxia <15 mm Hg O2 Reactivity Index It is the ability of the brain to maintain a constant PbtO2 in spite of varying CPP. Impaired reactivity predicts worse outcomes in TBI and in SAH (Table 8.10). Uses Cerebral hypoxia has been detected [using cerebral microdialysis (CMD), PbtO2] in spite of normal ICP and CPP. PbtO2 monitoring is useful to titrate individualized therapy such as osmotherapy, hyperventilation, CPP, patient positioning, and deciding on timing of decompressive craniectomy. It is useful in identifying delayed cerebral ischemia in SAH before ICP rise or clinical deterioration. PbtO2 monitoring is also useful to determine transfusion trigger, and blood product administration can be rationalized. As secondary neuronal injury is caused by multiple mechanisms, multimodal monitoring is required to pick up the changes, and PbtO2 monitoring is a useful component to this multimodality. Limitations PbtO2 is a focal measure of oxygen tension. In conditions such as severe head injury, there will be greater regional differences in blood flow and metabolism. TABLE 8.10 Factors Affecting PbtO2 Values Systemic Factors Local Factors Mean arterial pressure, intracranial pressure Capillaries—number, length, diameter, flow pattern, perfusion rate PaO2 and PaCO2 Oxygen consumption—neurons and glial cells Hemoglobin, oxygen dissociation, viscosity Oxygen diffusion gradients pH, temperature IV. NEUROMONITORING 158 8. NEUROMONITORING Complications t Infection t Hemorrhage during probe placement t Probe malfunction, displacement CEREBRAL MICRODIALYSIS This monitoring modality measures the brain’s metabolic substrate, both aerobic and anaerobic, in the interstitial tissue space. The probe consists of a coaxial double lumen tube (outer diameter 0.6 mm) covered by a dialysis membrane in the distal 10 mm. The tube is continuously infused with an artificial CSF with known concentrations using a microinjector pump at a rate 0.3 µl/min. Depending on the concentration gradients and the pore size of membrane, metabolic substrates diffuse through the dialysis membrane into the probe and are collected in to a sampling bottle. The sample is then analyzed (hourly) for substrates using photometric enzyme-kinetic analyzer or by high-performance liquid chromatography. Currently three cutoff values (in KD) for membrane pore size are available. 20 and 100 KD are commercially available for human use, and 10 KD is available for animal research purpose. 20 KD is used for assessing metabolic substrates such as glucose, lactate, pyruvate, glycerol, and glutamate. 100 KD is used for assessing cytokines, interleukins, neurotrophic factors and neuronal biomarkers such as s-beta-100 protein. 10 KD is used for assessing neurotransmitters such as acetylcholine and norepinephrine. Metabolic substrate measurements done by CMD are not absolute. It depends on various factors such as pore size, rate of diffusion, and flow rate. Hence, the measurement is called as relative recovery. For a CMD probe of 10-mm membrane length, 20 KD cutoff, and with a flow rate of 0.3 micro L/min, the relative recovery rate is around is 70%. In ischemia, there is accumulation of lactate and increase in lactate/pyruvate ratio (>25, significant). Also the glucose level falls to <0.8 mmol/L (critical). Glutamate increase during ischemia indicates excitotoxicity. Glycerol is a component of cell membrane and its accumulation indicates cell death.37 Probe Placement CMD probe can be placed separately or as a component of triple bolt system. The probe is placed into the white matter. Site depends on the lesion and the etiology. For diffuse injury, the probe is placed into the nondominant frontal subcortical white matter and the values are representative of global changes. The probe can also be placed in the pericontusional area (in TBI) or in the vasospastic territory (in SAH), and the values are representative of focal changes in the penumbra. The CMD measures the metabolic substrates in the surrounding 1-cm brain area. Uses t CMD helps in monitoring metabolic substrates to pick up neuronal ischemia at a reversible stage, e.g., in severe head injury. t In SAH, metabolic changes occur much before clinical manifestations of vasospasm and provide a window of opportunity to treat this condition. t CMD allows for glucose management in the ICU. Limitations t t t t Localized measurement Expensive Intermittent Comparison between different studies using different threshold values is difficult to interpret as recovery rates differ IV. NEUROMONITORING REFERENCES 159 CONCLUSION Any one modality of monitoring is very unlikely to give complete picture of the cerebral functioning. At best it can give complete information on one aspect of the cerebral functioning. Therefore, it is essential to have multimodal monitoring and obtain as much information as possible and assimilate that information to come to some decision. The neuromonitoring depends on the area of the brain at risk during the surgery and needs to decide how best to monitor that part using various combination of modalities. References 1. Kassab MY, Majid A, Farooq MU, Azhary H, Hershey LA, Bednarczyk EM, Graybeal DF, Johnson MD. Transcranial Doppler: an introduction for primary care physicians. J Am Board Fam Med 2007;20:65–71. 2. Huber P, Handa J. Effect of contrast material, hypercapnia, hyperventilation, hypertonic glucose and papaverine on the diameter of the cerebral arteries. Angiographic determination in man. Invest Radiol 1967;2:17–32. 3. Halsey Jr JH. Risks and benefits of shunting in carotid endarterectomy. The International Transcranial Doppler Collaborators. Stroke 1992;23:1583–7. 4. Jansen C, Ramos LM, van Heesewijk JP, Moll FL, van Gijn J, Ackerstaff RG. Impact of microembolism and hemodynamic changes in the brain during carotid endarterectomy. Stroke 1994;25:992–7. 5. Schmidt EA, Czosnyka M, Gooskens I, Piechnik SK, Matta BF, Whitfield PC, Pickard JD. Preliminary experience of the estimation of cerebral perfusion pressure using transcranial Doppler ultrasonography. J Neurol Neurosurg Psychiatry 2001;70:198–204. 6. Salgado AS, Zângaro RA, Parreira RB, Kerppers II. The effects of transcranial LED therapy (TCLT) on cerebral blood flow in the elderly women. Lasers Med Sci 2015;30(1):339–46. 7. Alpaidze M, Beridze M. Reversible cerebral vasoconstriction syndrome and migraine: sonography study. Georgian Med News March 2014;228:28–36. 8. Tiecks FP, Lam AM, Aaslid R, Newell DW. Comparison of static and dynamic cerebral autoregulation measurements. Stroke 1995;26:1014–9. 9. Puppo C, Fariña G, López FL, Caragna E, Biestro A. Cerebral CO2 reactivity in severe head injury. A transcranial Doppler study. Acta Neurochir Suppl 2008;102:171–5. 10. Aaslid R, Lundar T, Lindegaard KF, Nornes H. Estimation of cerebral perfusion pressure from arterial blood pressure and transcranial recordings. In: Miller J, Teasdale G, Rowan J, Galbraith SL, Mendelow A, editors. Intracranial pressure VI. Berlin: Springer; 1986. p. 226–9. 11. Chan KH, Miller JD, Dearden NM, Andrews PJ, Midgley S. The effect of changes in cerebral perfusion pressure upon middle cerebral artery blood flow velocity and jugular bulb venous oxygen saturation after severe brain injury. J Neurosurg 1992;77:55–61. 12. Nagai H, Moritake K, Takaya M. Correlation between transcranial Doppler ultrasonography and regional cerebral blood flow in experimental intracranial hypertension. Stroke 1997;28:603–7. 13. Czosnyka M, Matta BF, Smielewski P, Kirkpatrick PJ, Pickard JD. Cerebral perfusion pressure in head-injured patients: a noninvasive assessment using transcranial Doppler ultrasonography. J Neurosurg 1998;88:802–8. 14. Soltani A, Singhal R, Obtera M, Roy RA, Clark WM, Hansmann DR. Potentiating intra-arterial sonothrombolysis for acute ischemic stroke by the addition of the ultrasound contrast agents (Optison™ & SonoVue(®)). J Thromb Thrombolysis 2011;31:71–84. 15. Harrer JU, Eyding J, Ritter M, Schminke U, Schulte-Altedorneburg G, Köhrmann M, Nedelmann M, Schlachetzki F. The potential of neurosonography in neurological emergency and intensive care medicine: basic principles, vascular stroke diagnostics, and monitoring of strokespecific therapy – Part 1. Ultraschall Med 2012;33:218–32. 16. Harrer JU, Eyding J, Ritter M, Schminke U, Schulte-Altedorneburg G, Köhrmann M, Nedelmann M, Schlachetzki F. The potential of neurosonography in neurological emergency and intensive care medicine: monitoring of increased intracranial pressure, brain death diagnostics, and cerebral autoregulation – Part 2. Ultraschall Med 2012;33:320–31. 17. Vajkoczy P, Roth H, Horn P, Lucke T, Thomé C, Hubner U, Martin GT, Zappletal C, Klar E, Schilling L, Schmiedek P. Continuous monitoring of regional cerebral blood flow: experimental and clinical validation of a novel thermal diffusion microprobe. J Neurosurg 2000;93:265–74. 18. Nakase H, Kaido T, Okuno S, Hoshida T, Sakaki T. Novel intraoperative cerebral blood flow monitoring by laser-Doppler scanner. Neurol Med Chir (Tokyo) 2002;42:1–4. 19. Kawamata T, Kawashima A, Yamaguchi K, Hori T, Okada Y. Usefulness of intraoperative laser Doppler flowmetry and thermography to predict a risk of postoperative hyperperfusion after superficial temporal artery-middle cerebral artery bypass for moyamoya disease. Neurosurg Rev 2011;34:355–62. 20. Young WL, Prohovnik I, Schroeder T, Correll JW. OstapkovichN.Intraoperative 133Xe cerebral blood flow measurements by intravenous versus intracarotid methods. Anesthesiology 1990;73:637–43. 21. Wintermark M, Sesay M, Barbier E, Borbély K, Dillon WP, Eastwood JD, Glenn TC, Grandin CB, Pedraza S, Soustiel JF, Nariai T, Zaharchuk G, Caillé JM, Dousset V, Yonas H. Comparative overview of brain perfusion imaging techniques. Stroke 2005;36:e83–99. 22. Zweifel C, Hutchinson P, Czosnyka M. Intracranial pressure monitoring. In: Matta BF, Menon DK, Smith M, editors. Core topics in neuroanaesthesia and neurointensive care. Cambridge University Press; 2011. p. 45–62. 23. Leon-Carrion J, Martin-Rodriguez JF, Damas-Lopez J, Barroso y Martin JM, Dominguez-Morales MR. Delta-alpha ratio correlates with level of recovery after neurorehabilitation in patients with acquired brain injury. Clin Neurophysiol 2009;120:1039–45. 24. Foreman B, Claassen J. Quantitative EEG for the detection of brain ischemia. Crit Care 2012;16:216. 25. Rampil IJ. A primer for EEG signal processing in anesthesia. Anesthesiology 1998;89:980–1002. 26. Sundt Jr TM, Sharbrough FW, Piepgras DG, Kearns TP, Messick Jr JM, O’Fallon WM. Correlation of cerebral blood flow and electroencephalographic changes during carotid endarterectomy: with results of surgery and hemodynamics of cerebral ischemia. Mayo Clin Proc 1981;56:533–43. IV. NEUROMONITORING 160 8. NEUROMONITORING 27. Gollwitzer S, Groemer T, Rampp S, et al. Early prediction of delayed cerebral ischemia in subarachnoid hemorrhage based on quantitative EEG: A prospective study in adults. Clin Neurophysiol 2015;126(8):1514–23. 28. Guerit JM. Neurophysiological testing in neurocritical care. Curr Opin Crit Care 2010;16:98–104. 29. Sivaraju A, Gilmore EJ, Wira CR, et al. Prognostication of post-cardiac arrest coma: early clinical and electroencephalographic predictors of outcome. Intensive Care Med 2015;41:1264–72. 30. Zouridakis G, Papanicolaou AC, editors. A concise guide to intraoperative monitoring. New York: CRC Press; 2001. 31. Glass PS, Bloom M, Kearse L, Rosow C, Sebel P, Manberg P. Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology 1997;86:836–47. 32. Thimmiah R, Thirthalli J, Ramesh VJ, et al. Effect of a course of Electroconvulsive therapy on interictal bispectral index values. JECT 2012;28:20–3. 33. Umamaheswara Rao GS, Ali Z, Ramamoorthy M, Patil J. Equi-MAC concentrations of halothane and isoflurane do not produce similar bispectral index values. J Neurosurg Anesthesiol 2007;19:93–6. 34. Sarrafzadeh AS, Kienin KL, Unterberg AW. Neuromonitoring: brain oxygenation and microdialysis. Curr Neurol Neurosci Rep 2003;3:517–23. 35. Deleted in review. 36. Ghosh A, Elwell C, Smith M. Cerebral near-infrared spectroscopy: A work in progress. Anesth Analg 2012;115:1373–83. 37. Rey JR, Guerrero JJE, Sanchez MAM, Cabezas FM. Cerebral microdialysis in the current clinical setting. Med Intensiva 2012;36:213–9. IV. NEUROMONITORING C H A P T E R 9 Multimodal Monitoring A. Defresne, V. Bonhomme CHR Citadelle, Liege, Belgium O U T L I N E Introduction 161 Intracranial Pressure Monitoring Temperature 162 Electroencephalography and Depth of Anesthesia Monitoring Electroencephalography, Electrocorticography, and Evoked Potentials for Monitoring Nervous System Integrity Hypnotic Component of Anesthesia Monitoring Nociception Monitoring Oxygen Transport, Hemodynamics, and Brain Metabolism Arterial Blood Pressure Cardiac Output Intravascular Volume Status Hemoglobin Concentration Jugular Venous Oxygen Saturation Near Infrared Spectroscopy Intraoperative Indications of Near Infrared Spectroscopy Limitations of Near Infrared Spectroscopy Transcranial Doppler Ultrasonography Ultrasound Basic Physics Practical Applications 162 162 163 164 164 166 166 166 168 168 169 169 171 173 173 173 174 Miscellaneous 174 Integration of Information and Decision-Helping Systems 175 Clinical Pearls Inaccessible Forehead for Electroencephalographic Monitoring 176 References 176 176 INTRODUCTION The intraoperative anesthetic management of neurosurgical patients, particularly in case of intracranial neurosurgery, necessitates close attention to maintaining perfect homeostasis, to avoid secondary lesions to eventually suffering neural tissues.1 This involves rapid and smooth anesthetic depth transitions, adequate hypnotic and antinociceptive depth, hemodynamic stability, minimal interference with cerebral circulation, control of intracranial pressure (ICP) and cerebral perfusion pressure (CPP), temperature, hematosis, and, ideally, neuroprotection.2 Specific situations also require avoidance of a too marked interference with recordings that aim at assessing nervous system integrity. In addition to classical anesthesia monitoring, including electrocardiography, pulse oximetry, noninvasive blood pressure, and respiratory gas concentration, flow and pressure monitoring, several dedicated monitors may be of utility in achieving these specific goals of neuroanesthesia and eventually help improving patient outcome. They will be reviewed in this chapter, with emphasis on their basic principles, their routine use, the additive value of multimodality, and their demonstrated clinical benefits. Essentials of Neuroanesthesia http://dx.doi.org/10.1016/B978-0-12-805299-0.00009-9 161 © 2017 Elsevier Inc. All rights reserved. 162 9. MULTIMODAL MONITORING TEMPERATURE Temperature control during neuroanesthetic procedures is mandatory. Hyperthermia is known to worsen computed tomography–evidenced lesions and the clinical status of brain-injured patients,3 and hypothermia is associated with undesirable side effects including alterations of pharmacokinetics and pharmacodynamics of anesthetic agents, shivering, discomfort upon recovery, sympathetic nervous system activation, increase of myocardial workload, arrhythmias, coagulation disorders, facilitated wound infection, delayed healing, and immune deficit.4 Active warming and tight temperature control lower the occurrence of hypothermia-related adverse events.5 Hence, maintenance of normothermia is the rule for most neurosurgical procedures and is a requirement for a good quality early recovery after intracranial neurosurgery and adequate subsequent neurological follow-up.6 Apart from its deleterious effects, hypothermia has been advocated as a potential intraoperative neuroprotective measure in specific neurosurgical procedures but has never proved to be beneficial in terms of outcome,7,8 except for deep hypothermia during the rarely occurring surgical treatment of giant aneurism involving prolonged circulatory arrest.9 Temperature can be reliably measured using either thermistors or thermocouples. Thermistors are composed of a semiconductor, whose impedance increases with temperature. Thermocouples contain two metals, and the electric potential difference between them changes with temperature. Other devices are based on infrared emission and measure temperature in the external auditory canal, or they contain a liquid crystal sensor that can be applied on the skin,4 but they are less frequently used in the operating room. Temperatures of interest during neurosurgical procedures are mainly core and brain temperatures, which are not necessarily identical. Routinely monitored sites generally allow obtaining only estimates of those temperatures. Tympanic temperature is probably the closest to brain temperature, but the risk of tympanic lesion by the probe is not negligible. Gold standard assessment of core temperature is the central blood temperature measured at the level of a pulmonary artery catheter. However, those catheters are rarely necessary for hemodynamic control during anesthesia for neurosurgery. Reliable alternatives for measuring core temperature are esophageal, bladder, and rectal temperatures. Temperature monitoring and active control for all intracranial procedures and procedures that last for more than 1 h sound reasonable. OXYGEN TRANSPORT, HEMODYNAMICS, AND BRAIN METABOLISM To fulfill metabolism requirements, adequate oxygen delivery to all parts of the central nervous system must be constantly insured. This requires effective hematosis in the lungs, high enough blood hemoglobin concentration, and adequate cardiac output. Aside from global systemic transport, oxygen delivery to the brain also depends on global and regional cerebral hemodynamics, which is under the dependency of physiological regulating systems, and may be impeded by pathological processes, iatrogenic interventions, or by medications. Raised ICP and decreased CPP, vasospasms, or hypocarbia are examples of such. Several monitoring devices, either invasive or noninvasive, may be used to control for the adequacy of all intervening elements. Arterial Blood Pressure Intermittent noninvasive blood pressure monitoring is standard during all anesthetic procedures and is considered to be enough control for most moderately invasive spine surgeries. A beat-to-beat control of blood pressure is necessary when managing fragile patients or during potentially bleeding surgeries, as well as during all intracranial procedures. Indeed, such a tight control and invasive monitoring allows maintaining adequate cerebral perfusion10 and limiting the risk of bleeding, either during the course of the procedure or upon recovery.6 Invasive arterial blood pressure monitoring may also be of help when assessing the intravascular volume status and for drawing arterial blood samples and performing gas analysis. The entire set for invasive blood pressure monitoring includes an arterial cannula, a continuous irrigation system through infusion of saline under pressure, a pressure transducer that transforms the mechanical signal into an electrical one, and a monitor with a display screen. Zeroing is required at starting of use, with the transducer placed at the horizontal level of the heart. Site for arterial cannula insertion may vary, the most frequent being the radial artery at the wrist. Ulnar, pedal, and femoral arteries can also be used. Humeral artery should be avoided because its distal territory cannot be supplied by collateral vascularization. Strict sterile conditions must be respected during insertion, and echo guiding may be of help for difficult cases11 (Fig. 9.1). IV. NEUROMONITORING OXYGEN TRANSPORT, HEMODYNAMICS, AND BRAIN METABOLISM 163 FIGURE 9.1 Example of an echo-guided arterial cannula insertion. Localization of the radial artery is made easy using echography and color Doppler, allowing visualization of flux pulsatility and direction (1). After puncture of the artery, the insertion of the metallic guide can be followed online (2) and the adequate positioning of the catheter into the artery can be checked thereafter (3). Continuous beat-to-beat measurement of blood pressure is also possible noninvasively, using volume clamp or arterial tonometry methods.12 The volume clamp derives blood pressure according to pressure variations in a finger cuff, so as to keep finger artery volume constant. Arterial tonometry uses fingertip plethysmography and pulse volume amplitude. Some authors have evaluated the use of such systems during neurosurgical procedures, in patients where arterial blood sampling is not expected to be necessary. The idea was to avoid the well-known complications of an arterial cannula, including vessel or nerve trauma, pseudo-aneurysm formation, bleeding due to unnoticed disconnection, local hematoma, infection, arterial thrombosis, distal embolism, and ischemia.13 Although some studies have reported acceptable bias as compared to invasive intra-arterial measurement,14 a recent meta-analysis has warned about out of acceptable range inaccuracy and imprecision.12 Blood pressure management during a neurosurgical procedure must take account of patient comorbidities, risk of bleeding, and brain perfusion. Large hemodynamic variations frequently occur during induction of and recovery from general anesthesia, and practitioners should seek after stability as much as possible. However, perfusion pressure is not the only determinant of cerebral blood flow. In addition to CPP, autonomic regulation, metabolism coupling, and cerebrovascular reactivity to CO2 and O2, acute or chronic changes in global cardiac output play a role. Cerebral blood flow autoregulation should be regarded as a dynamic integrated process, displacing the lower limit, upper limit, and plateau height of the autoregulatory perfusion pressure curve as a function of circumstances. Hence, combining blood pressure monitoring with estimates of cardiac output and cerebral circulation seems to be sound and might reveal efficient at ameliorating patient outcome in the future.10 The respiratory variation of the blood pressure curve also offers simple means for assessing the intravascular volume status. This point is developed later in the chapter. Cardiac Output Assessment of cardiac output during intracranial neurosurgery has recently been advocated as a potential interesting monitoring to help optimizing cerebral hemodynamics.10 However, systematic cardiac output monitoring in a neurosurgical context is not the rule, except for very specific and rare procedures such as giant aneurysm clipping under circulatory arrest and in patients with severe cardiovascular comorbidities. IV. NEUROMONITORING 164 9. MULTIMODAL MONITORING Gold standard methods of cardiac output measurement are the classical thermodilution techniques through a pulmonary artery catheter and transthoracic or transesophageal echocardiography. For neurosurgical procedures, and in otherwise healthy patients, transesophageal echocardiography is mainly used during surgery in the sitting position15 in case of patent oval foramen to detect eventual paradoxical air embolism.16 Transesophageal Doppler of the aorta can also estimate the stroke volume from the aortic velocity waveform and is sometimes considered as a reference measure of cardiac output.17 Its accuracy highly depends on probe placement and on any modification of the aortic diameter such as in case of intra-aortic balloon or coarctation. Several noninvasive devices are also proposed with variable performance, accuracy, and precision.18 Electrical thoracic bioimpedance relies on the assumption that thoracic impedance changes parallel to those of stroke volume. The limitations of the technique include electrode positioning, electrical interference, abnormal fluid inside the thorax, changes in peripheral vascular resistance, age, gender, arrhythmias, and movement. Thoracic bioreactance is a variant, which takes account of thoracic voltage phase shift and has almost the same limitations, except that it can still provide an estimate of cardiac output in case of cardiac arrhythmia because it averages values over several seconds. Cardiac output may also be derived from the arterial pressure contour, obtained either directly or from the noninvasive methods described above, and using variable algorithms.17 All these techniques are highly dependent on arterial pressure waveform signal quality, and therefore on eventual finger edema, intense vasoconstriction, sensor position, and movement. Some of them necessitate calibration and others not.19 The clinical utility and reliability of cardiac output measurement in neuroanesthesia have been relatively poorly studied. Thoracic bioimpedance has been demonstrated to reliably mirror the hemodynamic changes associated with crucial events during neurosurgical procedures such as induction, scalp infiltration, changes in anesthetic depth,20 or mannitol administration.21 Stroke volume monitoring is also sometimes used to guide fluid administration during intracranial neurosurgery.22 Up to now, scientific evidence does not support equivalence between invasive and noninvasive methods of hemodynamic monitoring and the lasts cannot replace the formers when close monitoring is needed, such as during surgery in the sitting position.15 Intravascular Volume Status Substantial fluid shifts can occur during neurosurgical procedures, either as a consequence of blood loss or following the administration of medications aiming at improving brain relaxation, such as mannitol or furosemide. Hence, controlling for the intravascular volume status is essential. Several methods are available of which some are simple and easy to implement. Indeed, central venous pressure and pulmonary capillary wedge pressure are no longer considered as gold standards,23 at least in patients under positive pressure ventilation. The invasive arterial pressure waveform allows measuring the delta pulse pressure (DPP) or the delta-down (DD) intermittently (Fig. 9.2). To do so, the patient must be in cardiac sinus rhythm and under mechanical ventilation. The tidal volume should be set at least at 8 mL/kg, and the frequency rate reduced to values as low as 4 per min to mimic respiratory pauses. DPP corresponds to the difference between the maximal and minimal pulse pressure during one breathing cycle, divided by the mean of those two pulse pressures,24 while DD is the difference between the systolic arterial pressure at the end of a 5-s respiratory pause, immediately before lung inflation, and its minimal value during the course of one respiratory cycle.25 Values of DPP higher than 13%, and values of DD higher than 5 mmHg are indicative of an increased probability of preload cardiac output dependency and a positive hemodynamic response to fluid loading. Both indices have been demonstrated to be accurate in the context of intracranial neurosurgery.26 Their main disadvantages are their intermittent nature and susceptibility to confounding factors, including nonsinus cardiac rhythm, ventilation volume and pressure, vasopressor administration, abdominal pressure, and cardiac failure.27 Dynamic parameters may have additive value, insofar as they offer a continuous assessment of the intravascular volume. They are based on systolic pressure or stroke volume variability as assessed by pulse contour analysis of an arterial or plethysmographic waveform. Using such technology, several commercially available devices provide indexes of susceptibility to fluid loading.23,28 Closed-loop systems of fluid administration have even been proposed.29 Accumulating evidence suggests that goal-directed fluid administration is beneficial for enhanced recovery after specific types of surgeries,30,31 but this question has still not been fully addressed for neurosurgical procedures. Hemoglobin Concentration The main oxygen transporter in the blood is hemoglobin. During potentially bleeding neurosurgical procedures and in patients with preexisting anemia, it is necessary to have prompt access to rapid, accurate, and reliable hemoglobin IV. NEUROMONITORING OXYGEN TRANSPORT, HEMODYNAMICS, AND BRAIN METABOLISM 165 FIGURE 9.2 Illustration of delta-down (DD) and delta pulse pressure (DPP) calculation. For this measurement, respiratory rate should be set at 4 per min or lower to mimic a respiratory pause. The patient should be in cardiac sinus rhythm, and the respiratory tidal volume should be 8 mL/kg or higher. DPP corresponds to the difference between maximum and minimum pulse pressure over a respiratory cycle, divided by their mean. DD is the difference between maximum and minimum systolic blood pressure over a respiratory cycle. TABLE 9.1 Characteristics of Point-of-Care Hemoglobin Concentration Measuring Devices Commercial Devices Technology Blood Sample Needed Comparison With Automated Laboratory Measurements MD (LA) Hemocue Reagent-based photometry Yes 0.08 (−1.3–1.4)32 Diaspect Nonreagent-based photometry Yes −0.18 (−2.05–1.68)165 i-Stat Conductivity Yes 0.05 (−1.16–1.25)166 CO-Oxi Multiple wavelength co-oximetry No −0.03 (−3.0–2.9)32 OrSense Occlusion spectroscopy No −0.66 (−3.39–2.09)165 Haemospect Transcutaneous reflection spectroscopy No −0.22 (−2.64–2.21)167 An example for each type of technology is presented. Mean difference (MD), 95% limits of agreement (LA) in g/dL compared to automated laboratory measurements are indicated, as well as the source from which those data were driven. CO-Oxi, Pulse CO-Oximetry (Masimo Corp., Irvine, CA, USA); Diaspect, Diaspect Hemoglobinometry (Diaspect Medical GmbH, Germany); Haemospect, Haemospect™ (MBR Optical Systems, Herdecke, Germany); Hemocue, Hemocue (HemoCue, Angelholm, Sweden); i-Stat, i-Stat (Abbott Laboratories, Abbott Park, IL, USA); OrSense, OrSense™ (Ness Ziona, Israel). concentration measuring devices. Aside from automated laboratory hemoglobin measurement systems, which may be too time demanding particularly in the context of an emergency, several point-of-care devices are proposed.32 Blood sample–requiring systems at the bedside use reagent-based33 or nonreagent-based34 absorption photometry at multiple wavelengths or conductivity.35 Other noninvasive, and hence non–blood sample–requiring devices involve multiple wavelength co-oximetry,36 occlusion spectroscopy,37 or transcutaneous reflection spectroscopy38 technologies. Several studies have been performed to compare the results obtained with those devices and those obtained using automated laboratory systems or between them (Table 9.1), not necessarily in the context of neurosurgery. Although bias as compared to laboratory values is generally small, the limits of agreement may be large with a significant amount of outliers. In addition, discrepancies may vary according to real hemoglobin level39 and several confounding factors. Pulse co-oximetry may be confounded by ambient light, bilirubin, hemoglobin variants, intravascular dyes, motion, sensor positioning, temperature, venous congestion, edema, high tissue lipid content, and hypovolemia.40 Although having been demonstrated to be indicative of hemoglobin level during complex spine surgery,41 pulse co-oximetry remains less accurate than conventional laboratory measurements.42 Accuracy may improve when calibrating with a baseline laboratory testing at the beginning of the procedure, particularly in children undergoing neurosurgery.39 Those noninvasive monitors provide more timely information, but should be considered as trend monitors rather than absolute indicators of transfusion need. IV. NEUROMONITORING 166 9. MULTIMODAL MONITORING Jugular Venous Oxygen Saturation Near infrared spectroscopy (NIRS) combined with transcranial Doppler ultrasonography (TCDU) and jugular venous oxygen saturation (SjvO2) monitoring are means for appreciating brain hemodynamics and oxygen delivery. SjvO2 monitoring requires the retrograde placement of a catheter into a jugular vein, up to the jugular bulb, to monitor the mixed cerebral venous blood and above the C1/C2 level to limit contamination by the facial venous blood.43 Side for placement should preferably be the dominant side of the brain or the side with the most prominent pathology, if any. Oxygen saturation may be measured in regularly drawn blood samples or using a fiber-optic catheter and light absorption in the red/infrared wavelength range. Although generally quite easily placed, the catheter may be the source of rare complications, including hematoma, infection, thrombosis, raised ICP, or incidental wrong vessel puncture.44 SjvO2 reflects the balance between oxygen delivery to the brain and cerebral metabolic consumption of oxygen. Normal values range between 50% and 75%. Decreases in SjvO2 can be seen in case of systemic or local oxygen supply deficiency, including hypoxia, low blood pressure, decreased CPP, embolism, or vasospasm (Table 9.2), and in case of increased oxygen consumption including hyperthermia and seizure. Causes of SjvO2 values above normal range can be classified into those related to a decrease in cerebral metabolism, restricted oxygen diffusion or extraction, shunting, increased oxygen supply, or a combination of these. For example, a global decrease in cerebral metabolism can be observed during hypothermia. Infarction or inflammation causes restriction in oxygen diffusion and extraction, as well as microvascular shunting. Increased oxygen supply is observed during hyperoxia, and hypercarbia can be responsible for substantial shunting. Interpretation of SjvO2 values may be uneasy in some instances. It is a global measure and it may miss eventually occurring focal brain ischemia.45 When brain tissue death is massive, SjvO2 can be high as a consequence of shunting. Classical causes of wrong SjvO2 values are displacement of the catheter, thrombus around its tip, and contamination by facial venous blood. Anesthesia may also have an influence on SjvO2 values. Transient desaturations have been reported under propofol anesthesia, more frequently in normothermic than in hypothermic patients,46 while SjvO2 increases have been observed under sevoflurane anesthesia.47 This is due to the different properties of those agents on cerebral vasculature, propofol being vasoconstrictive, and sevoflurane vasodilating. Side of recording may also be important, insofar as cerebral venous drainage usually predominate on one side through the dominant jugular bulb.48 SjvO2 has mostly been used to guide therapy in the intensive care unit for traumatic brain injury and subarachnoid hemorrhage patients. However, its intraoperative use during intracranial neurosurgery allows commonly detecting desaturation episodes,48 and its combination with TCDU49 may impact on clinical decision-making to optimize cerebral physiology. Large randomized clinical trials investigating the impact of intraoperative SjvO2 monitoring on patient outcome are lacking. Near Infrared Spectroscopy NIRS consists in measuring near infrared light absorption by the superficial part of brain tissues. Light is emitted through the skin and the skull, entering the brain tissue to a depth of approximately 1–2 cm. Absorption at different wavelengths allows estimating the mixed capillary–venous regional cerebral oxygen saturation (rScO2).50 rScO2 depends on the balance between local metabolism and oxygen delivery, which in turn depends on regional cerebral blood flow and blood oxygen content. If metabolism is constant, rScO2 can be regarded as a surrogate measure of regional cerebral blood flow changes. The system necessitates the use of a noninvasive scalp probe and allows continuous monitoring of rScO2 over a restricted area of approximately 1 cm2. Normal rScO2 values at atmospheric oxygen levels range from 62% ± 6% in cardiac surgery patients51 to 71% ± 6% in healthy young men.52 Low preoperative baseline rScO2 values are predictive of increased 30-day morbidity and mortality.50,51 There is no consensus in the literature on the rScO2 threshold value indicating significant desaturation, but a decline of more than 20% as compared to baseline is generally accepted as a predictor of cerebral ischemia. It is also generally agreed that both depth and duration of desaturation are important.50,53 A less extreme threshold of 10% should probably prompt therapeutic intervention to raise rScO2.54 Intraoperative Indications of Near Infrared Spectroscopy At the extremes of age, in the very young and in the elderly over 60 years, the brain is at risk of injury during surgery and anesthesia.55 In addition to the sensitivity of their brain to the effects of anesthetic agents, aged patients are prone to experience postoperative cognitive decline and develop delirium or stroke. Evidence accumulates demonstrating IV. NEUROMONITORING t S pO2 t B GA t I CP monitor t T CDU Hypoxia ↓ CPP t C O monitoring Low CO Embolism Thrombosis Cause t I mprove hemodynamics t T ransfuse t E EG monitoring t L ighten t D HOA monitoring anesthesia if appropriate Deep sedation IV. NEUROMONITORING Hypercarbia Cause Correction t R espiratory CO2 t O ptimize ventilation monitoring t B lood gas analysis Diagnosis t I dentify cause t T reat cause t E ventual reperfusion strategies if not too late Shunting t I maging t E EG monitoring Inflammation t I maging Infarction Correction Hyperoxia Cause Inflammation Infarction Cause t C alcium antagonist Seizure t A ngiography and endovascular reperfusion strategies t I ncrease CPP Restricted Oxygen Diffusion Diagnosis Cause t A ntiepileptic medications t C ooling Correction Correction t B GA Diagnosis t O ptimize ventilation and FiO2 Correction Increase in Oxygen Supply Same as restricted oxygen diffusion Diagnosis Restricted Oxygen Extraction t E EG monitoring t T emperature monitoring Diagnosis Increased Cerebral Oxygen Consumption t I dentify cause Hyperthermia t S ystemic or endovascular reperfusion strategies Correction High SjvO2 ( > 75%) t E EG t T CDU t E EG Diagnosis Local Oxygen Supply Deficiency ABP, arterial blood pressure; BGA, blood gas analysis; CO, cardiac output; CPP, cerebral perfusion pressure; EEG, electroencephalography; FiO2, inspired oxygen fraction; ICP, intracranial pressure; SjvO2, jugular venous oxygen saturation; SpO2, peripheral saturation in oxygen; TCDU, transcranial Doppler ultrasonography. Same as restricted oxygen diffusion Infarction Inflammation Correction Diagnosis Cause Microvascular Shunting t W arming t T emperature monitoring Hypothermia Correction Diagnosis Cause Cause t L ower ICP Vasospasm t I mprove hemodynamics t O ptimize ventilation t ↑ FiO2 Correction Decrease in Cerebral Metabolism t H emoglobin measurement Anemia t ↑ ICP t ↓ ABP Diagnosis Cause Systemic Oxygen Supply Deficiency Low SjvO2 (<50%) TABLE 9.2 Causes of Abnormal Jugular Venous Oxygen Saturation Values and Proposed Diagnosis Help, and Corrective Measures OXYGEN TRANSPORT, HEMODYNAMICS, AND BRAIN METABOLISM 167 168 9. MULTIMODAL MONITORING that cerebral oxygen deprivation episodes lead to adverse clinical outcomes including cognitive decline, major organ dysfunction, and prolonged hospital length of stay, both in cardiac and noncardiac surgery patients.54,56 The intraoperative use of NIRS was initially described for aortic arch surgeries and carotid endarterectomies. Despite an increasingly large use of rScO2 monitoring during cardiac surgery, Zheng et al. were not able, in their systematic review, to strongly link cerebral desaturations, and interventions to improve it, with the incidence of postoperative neurological complications.57 Indeed, most of NIRS observational studies in aortic arch surgery patients have small sample sizes, and a very low incidence of strokes, rendering the assessment of the relationship between cerebral desaturation and neurological outcome uneasy. Some case reports, as well as observational studies, have shown the usefulness of NIRS to warn about cannula malposition and failure of cardiopulmonary bypass.58–60 During carotid endarterectomy, the most efficient approach to cure reduced rScO2 is the insertion of a shunt. NIRS has a sensitivity of approximately 75% and a specificity of 98% at correctly indicating the need for shunting.61,62 After clamp release, an increase in rScO2 of more than 20% predicts the occurrence of a cerebral hyper-perfusion syndrome.63,64 Regarding nonvascular surgical procedures, a review performed by Nielsen identified surgeries where a decrease in rScO2 is reported. These surgeries include procedures in the Fowler position, which are characteristic of shoulder and laparoscopic surgeries, for example. Hip surgery and single lung ventilation thoracic surgery are also at risk of decrease in rScO2. The link between repeated occurrences of cerebral desaturation and worse postoperative outcome is, however, not straightforward. A pronounced intraoperative cerebral desaturation does not necessarily lead to postoperative cognitive decline after shoulder surgery in the beach chair position. In addition, an association between cerebral desaturation and outcome parameters such as postoperative wound infection, kidney failure, and myocardial infarction remains to be established.54 Current evidence points toward worse outcome, including postoperative cognitive decline, kidney dysfunction, and prolonged hospital length of stay in cardiac surgery patients having experienced severe cerebral desaturation, as well as in patients having been submitted to certain types of other noncardiac surgeries. Even if more studies are needed to demonstrate a clear association, the overall risk to benefit ratio goes in favor of the intraoperative utility of NIRS, all the more since it is noninvasive, continuous, and has a moderate cost. Limitations of Near Infrared Spectroscopy Several confounding factors may impede the adequate interpretation of rScO2 values. A contamination by blood originating from the external carotid artery territory may occur, and the extent to which this contamination may skew NIRS accuracy varies from a device to another. External carotid contamination may be as high as 20%.50,56 An influence of anatomic variability in skull shape, for example enlarged frontal sinus, or uncommon cerebral venous drainage through superior sagittal veins must be considered.54 When vasopressors such as noradrenaline are administered to maintain arterial pressure, up to one-third of changes in rScO2 can be accounted for by changes in skin blood flow. Ephedrine, by increasing mean arterial pressure without affecting cardiac output, does not change rScO2, while pure α1-adrenergic agonists such as phenylephrine do. In that case, the decrease in rScO2 is secondary to a drop in cardiac output. It may therefore be advised to check for an adequate intravascular volume status before interpreting changes in rScO2 following the administration of a vasopressor.54,56 In patients with a liver disease, high bilirubin plasma concentrations alter NIRS measurements through the competitive absorption of light by this pigment.54,56 Another limiting factor is the limited frontal brain area where NIRS can measure oxygenation. Embolism or ischemia occurring in distant areas can therefore be undetected53. Finally, commercial cerebral oximetry devices assume a fixed value of either 70:30 or 75:25 for the venous to arterial blood volume ratio. Relative changes in the volume of one compartment or the other will change the overall cerebral hemoglobin saturation, without any real change in the saturation of each individual compartment.53 Transcranial Doppler Ultrasonography In 1982, Aaslid was the first to describe the use of transcranial Doppler for measuring cerebral blood flow velocity.65 Ultrasound brain exploration has long been limited to Doppler exploration, but technological advances now allow grossly imaging the main brain structures using echography. Through the visual recognition of the insonated vessel, it has considerably facilitated Doppler use and has added morphological elements that can be useful to diagnosis. TCDU is the only noninvasive and cost-effective bedside tool that provides real-time information on cerebral hemodynamics. It has no contraindications, and its technical limitations can often be overcome by the intravenous administration of a sonography contrast agent.66 In adults, insonation usually occurs through the four commonly defined acoustic windows, including the temporal, orbital, suboccipital, and submandibular window. These windows are characterized by a thinner bone layer, permitting ultrasound penetration. IV. NEUROMONITORING OXYGEN TRANSPORT, HEMODYNAMICS, AND BRAIN METABOLISM 169 Ultrasound Basic Physics Echography necessitates an ultrasound transducer, which acts both as a transmitter and a receiver. Reflection of ultrasound waves occurs at the interface between different tissue types, and depends on the resistance to ultrasound breakthrough, or acoustic impedance. When ultrasounds are reflected, and thus sent back to the transducer, the piezoelectric crystals convert the mechanical energy of the returning echoes into an electrical current, which is processed by the ultrasound machine to produce a two-dimensional gray scale image. During their travel into the tissues, ultrasound waves are attenuated.67 Attenuation depends on three factors, namely the attenuation coefficient of the tissue, the traveled distance, and the ultrasound frequency. Insofar as bones are substantially impervious to ultrasounds, and that attenuation increases with ultrasound frequency, a low-frequency transducer in the order of 2 MHz is necessary for transcranial ultrasonography. The flow within vascular structures can be studied using color flow Doppler. Red blood cells moving toward the transducer return waves at a higher frequency than the emitted signal. The corresponding image of flow is displayed in red on the device. Contrarily, when those cells are moving away from the transducer, the returned waves have a lower frequency and are displayed in blue.68 Color flow Doppler helps identifying arteries through the integration of information coming from the anatomical view, as well as direction and pulsatility of flow. Pulse wave Doppler is based on the Doppler principle described by Christian Doppler in 1843. Exactly like in color flow Doppler, the reflected ultrasound wave has a higher or a lower frequency than the emitted one. This is termed as a positive or negative shift in frequency, respectively. The velocity of red blood cells as measured by a pulse wave Doppler depends on the cosine of the angle of insonation (Fig. 9.3). As a consequence, when the angle of insonation is 0°, the measured velocity equals the true velocity. When the angle is 90°, the measured velocity is 0, irrespective of the actual velocity.67–69 Practical Applications In the operating room and during neurosurgery, TCDU can be used to seek for hyperemia, vasospasm, microembolic signals, vasomotor reactivity (VMR), and to estimate ICP. These indications are also common in the neurointensive care unit. Other common indications of TCDU are the identification of sickle cell disease children at the highest risk of first-ever stroke,70 and those in need of blood transfusion.71 TCDU is also very sensitive and specific to detect right-to-left shunt and to quantify the functional repercussions of such a shunt. The last indication of TCDU is the diagnosis of a cerebral circulatory arrest.69,72 This paragraph will be limited to the indications that are of potential utility in the operating room. Vasospasm and Hyperemia Vasospasm is a suddenly occurring and rapidly evolving pathology. TCDU is therefore a key tool for its identification and diagnosis, as well as for daily monitoring, appreciation of severity, and circumscription of incriminated territory. A change in mean flow velocity (MFV) often precedes an eventual neurological deficit. Detecting those changes in velocity authorizes to adapt the treatment precociously, and prevent complications.73 The threshold for deciding on an increased MFV varies according to the studied artery (Table 9.3).74 More than an absolute number, the magnitude of a change in mean velocity is also important. An increase of more than 50 cm/s in 24 h is predictive of the occurrence of a vasospasm-related ischemic lesion. In the middle cerebral artery, when the MFV remains between 120 and 200 cm/s, the sensitivity for diagnosing a vasospasm is weak (67%).75 In that case, only arteriography may provide certainty. Another useful parameter for diagnosing vasospasm in the middle FIGURE 9.3 Illustration of the importance of the insonation angle in pulse wave Doppler. IV. NEUROMONITORING 170 9. MULTIMODAL MONITORING TABLE 9.3 Proposed Criteria for Diagnosing Vasospasm on Most Frequently Studied Cerebral Arteries Concerned Artery MCA MFV Lindegaard’s ratio for the MCA Moderate vasospasm >120 and <200 cm/s Severe vasospasm >200 cm/s Hyperemia: <3 Moderate vasospasm: 3–6 Severe vasospasm: >6 ACA MFV Discreet vasospasm >80 cm/s Significant vasospasm >130 cm/s PCA MFV Discreet vasospasm >90 cm/s Significant vasospasm >110 cm/s Vertebral artery MFV Vasospasm >80 cm/s Basilar artery MFV Vasospasm >95 cm/s ACA, anterior cerebral artery; Lindegaard’s ratio, ratio between the mean flow velocity in the MCA and the mean flow velocity in the submandibular internal carotid artery; MCA, middle cerebral artery; MFV, mean flow velocity; PCA, posterior cerebral artery. cerebral artery is the Lindegaard’s ratio. It corresponds to the ratio between the MFV in the middle cerebral artery and the MFV in the submandibular internal carotid artery. The Lindegaard’s ratio may also help differentiating hyperemia from vasospasm, which have completely opposite treatments.72,76 Microembolic Signals or High Intensity Transient Signals During carotid surgery, monitoring an intracranial artery distal to the steno-occlusive site allows detecting spontaneous embolic signals and quantifying the embolic potential of the atherosclerotic plaque. According to the International Cerebral Hemodynamics Society, those signals are characterized by a high intensity, that is more than 10 dB higher than blood flow, a random occurrence during the cardiac cycle, a unidirectional nature, a short duration (10–100 ms), and an audible component (explosive signal) (Fig. 9.4). This kind of surveillance is useful not only during carotid surgery, but also during aortic, cardiac, or even orthopedic surgery. It helps identifying the critical phase of surgery, when the risk of embolism is important. Detecting such a high risk should prompt corrective measures at the level of the equipment (e.g., extracorporeal circulation) or the surgical technique.72 Vasomotor Reactivity VMR represents the ability of cerebral vessels to maintain a near constant blood flow in response to a vasomotor stimulus. TCDU allows a real-time observation of vasomotor changes in response to various stimuli. Concerned stimuli can be hemodynamic stimuli such as a rapid leg cuff deflation or a Valsalva maneuver or the transient hyperemia response to medications such as acetazolamide, breath-holding, and CO2 inhalation.77 CO2 is the strongest vasodilation stimulus to the cerebral circulation. Several factors may influence VMR, including gender and level of estrogenic impregnation, as well as chronic cardiovascular pathologies such as chronic high blood pressure and diabetes. In those two last cases, VMR is reduced. A simple method for measuring VMR has been described by Markus et al. It consists in calculating the breathholding index (BHI) as follows: -&6END å -&6BASELINE -&6BASELINE ° SECONDS OF BREATH HOLDINGS where the middle cerebral artery MFV is measured during an at least 30 s breath-holding. MFVbaseline corresponds to the MFV before breath-holding and MVFend to the MFV 4 s after restarting breathing. When BHI is lower than 0.69, VMR is impaired. In patients with asymptomatic carotid stenosis, BHI can be used to identify those at a higher risk of stroke.78 IV. NEUROMONITORING INTRACRANIAL PRESSURE MONITORING 171 FIGURE 9.4 Illustration of microembolic signals or high intensity transient signals as evidenced by transcranial Doppler ultrasonography. Estimation of Intracranial Pressure To avoid invasiveness of direct ICP monitoring, TCDU can serve as a noninvasive alternative. This bedside tool may be used to study the hemodynamic changes induced by an increase in ICP. There exists a qualitative relationship between the progressive increase in ICP and the occurrence of abnormal TCDU waveform, while assuming a constant arterial CO2 content and a constant degree of distal vasoconstriction. The most sensitive parameters to detect an increase in ICP, and hence a decrease in CPP, are the diastolic velocity (Vd) and the pulsatility index (PI) measured at the level of the middle cerebral artery. Vd reflects the distal resistance to flow and decreases proportionally to CPP. Contrarily, PI is inversely proportional to a decrease in CPP. A PI higher than 1.4 and a Vd lower than 20 cm/s are indicative of severity.77,79 PI is not dependent on the angle of insonation cosine (Cos α), as indicated in its calculation formula: #OSȗ (6S å 6D) 6S å 6D , where Vs = systolic velocity, Vd = diastolic velocity, and Vm = mean velocity. For that #OSȗ6M 6M reason, PI is the most important variable to take account of when analyzing the Doppler signal. A low flow velocity with a normal PI means an open insonation angle. These values should not be considered as pathological and should motivate new measurements with a different insonation angle. Of note, PI is dependent on arterial CO2 partial pressure.74 TCDU and direct measures of ICP are not interchangeable. In this indication, TCDU should rather be considered a guide to identify critical patients, to orient therapeutic options while waiting for the insertion of an invasive monitoring device, and to unravel intraoperative doubts when not having a real ICP number.80 The information derived from TCDU should always be integrated with several other available data, including mean arterial pressure, arterial CO2 partial pressure, peripheral saturation in oxygen, hemoglobin concentration, and the clinical status of the patient. Other TCDU limitations are the operator skills, depth and angle of insonation accuracy, impermeable insonation window, and eventual arterial stenosis or microangiopathy.81 Some of these limitations may be overcome by targeting the ophthalmic artery through the eye, using extracranial and intracranial segments of it as pressure sensors. In that case, no patient-specific calibration is necessary.82 0) INTRACRANIAL PRESSURE MONITORING Contrarily to neurointensive care, direct ICP and CPP monitoring is not often available intraoperatively during intracranial neurosurgical procedures. The reasons are that patients often come to surgery without any implanted monitoring device and intracranial neurosurgery involves skull and dura opening, hence compromising any pressure measurement. As a consequence, ICP monitoring will only be useful during the beginning of the procedure, before skull opening, in patients already holding a probe. Otherwise, estimations of ICP can be obtained through indirect means such as TCDU or those that are described hereafter. IV. NEUROMONITORING 172 9. MULTIMODAL MONITORING Classical invasive methods of ICP monitoring include intraventricular or lumbar catheters connected to a pressure transducer, as well as intraparenchymal transducers.81 Subdural and epidural systems are less accurate (Fig. 9.5). Several annoyances may impede the adequate use of those invasive devices, including infection, hemorrhage, malfunction, obstruction, wrong positioning, or impossibility of insertion.83 There exist several noninvasive indirect methods of ICP estimation (Fig. 9.5), but none of them are frankly validated for routine clinical use.84 Before any intracranial surgical procedure, it is recommended to have a look at cerebral imagery. Signs of elevated ICP on the computerized tomography or magnetic resonance imaging (MRI) include a midline shift, ventricles and cisterns of reduced size, reduced sulci size, and presence of a mass of any origin. However, normal imagery does not exclude elevated ICP.81 Some have proposed an MRI-based measurement of ICP, through the estimation of ICP/volume changes over cardiac cycles, but with doubtful reliability.85,86 Aside from TCDU (see Section 3.7.3.4.), ultrasounds, and, more precisely, ocular echography may serve to estimate ICP. This technique consists in measuring the optic nerve sheath diameter that correlates with ICP.87–89 Others have proposed the use of optical coherence tomography, a noninvasive infrared light–based method, to detect changes in optical nerve head shape according to ICP.90 Chen et al. have used the electroencephalogram power spectrum analysis to derive ICP, but the technique still needs to be validated.91 Audiological methods of ICP estimation study the tympanic membrane displacement in response to sound. This displacement varies as a function of ICP, necessitates a patent stapedial reflex, and no middle ear dysfunction.92 Another method consists in recording phase-shift changes in evoked otoacoustic emissions in response to sounds of low frequencies but interindividual variability is high.93 A novel method uses transcranial acoustic signals and head-generated sounds with rather good accuracy.94 Mean ICP is usually considered normal when ranging between 5 and 15 mmHg. Continuous ICP monitoring provides more information than a simple static number, showing variations of the ICP value as a function of the cardiac cycle (frequency of 40–160 per min), the respiratory cycle (8–20 per min), or the vasogenic regulation of cerebral blood volume (0.3–3 per min).95 Current concepts now advocate the individualized adjustment of ICP and CPP rather than a fixed threshold, to take account of the underlying pathophysiology and external influencing factors such as sedation, anesthesia, or cardiac output. For example, it is recommended to individually estimate the range of CPP where cerebral blood flow autoregulation persists. This can be done through the calculation of the correlation coefficient between the mean arterial pressure and ICP. When this correlation coefficient is negative, it means that autoregulation is preserved. The automatic calculation of the mean arterial pressure/ICP correlation coefficient is possible through the use of dedicated software.96 Ideally, the individualized approach should be completed by the use of monitors of brain oxygenation and metabolism, such as brain tissue partial pressure of oxygen monitoring or microdialysis.97 FIGURE 9.5 Summary of the different types of direct (red) and indirect (blue) means for estimating intracranial pressure. CT, computerized X-ray tomography; EEG, electroencephalography; MRI, magnetic resonance imaging; TCDU, transcranial Doppler ultrasonography. IV. NEUROMONITORING ELECTROENCEPHALOGRAPHY AND DEPTH OF ANESTHESIA MONITORING 173 ELECTROENCEPHALOGRAPHY AND DEPTH OF ANESTHESIA MONITORING Recording of central nervous system electrical activity constitutes the most direct insights into function exploration. Clinical applications of electrophysiological recordings are numerous, ranging, for example, from the identification of epileptogenic sources to in-depth recordings for the implantation of deep brain stimulation electrodes, to the assessment of spinal cord integrity during scoliosis repair surgery, and to the monitoring of the depth of the hypnotic component of anesthesia. The most frequently encountered modalities of electroencephalography (EEG) are described in the following paragraphs. Electroencephalography, Electrocorticography, and Evoked Potentials for Monitoring Nervous System Integrity The intraoperative use of multiple channel EEG, with electrodes placed on the scalp, is seldom practiced during intracranial neurosurgery. The main reason is a conflicting territory with the surgical field. EEG may, however, be of utility during several types of procedures to detect the occurrence of seizure activity or focal ischemia. During carotid surgery, its interpretation may be limited by the user expertise, the anesthetic regimen, the temperature, and the hemodynamic stability.98 In addition, electrodes may not cover all territories at risk of ischemia.99 Processed EEG and the analysis of parameters such as total power, power spectrum, spectral edge frequency, or bispectral index is generally not of supplementary help.98,100–103 Changes may occur in varying directions, the most alarming tracing being a flat EEG.104 In that respect, neurological testing in the wake patient remains the most reliable. In epilepsy surgery, electrocorticography is the reference method for identifying seizure foci. It consists in recording surface electrical activity through electrodes directly placed on the cortical surface. Most of hypnotic agents, including propofol, barbiturates, halogenated vapors, and benzodiazepines, dose-dependently affect interictal epileptiform activities, therefore impeding the identification of foci.105 Ketamine and etomidate have a nonspecific facilitating effect on those activities, while opioids and dexmedetomidine have minimal effects. As a consequence, the preferred anesthetic technique for managing those patients will be a wake technique or sedation with dexmedetomidine and/or opioids. Should general anesthesia be preferred, doses of hypnotic agents will be set at their minimum during mapping, with the inherent risk of intraoperative awareness. Somatosensory evoked potentials are mainly used to monitor the sensory dorsal column–medial lemniscus pathway integrity during scoliosis repair.106 They necessitate repeated and regular peripheral skin stimulations distal to the surgical site. The cortical and subcortical signals evoked by the stimulations are recorded through scalp electrodes, and then averaged. A 50% decrease in amplitude or a 10% increase in latency as compared to baseline is considered alarming. A persistent decrease in the amplitude of somatosensory-evoked potentials can also be observed during an intraoperative cerebral ischemia.107 Transcranial stimulation–evoked motor potentials are equally of utility during scoliosis repair, to monitor the motor system integrity,106 as is spontaneous or triggered electromyography for the integrity of nerve roots. Of note, evoked potentials are sensitive to the action of anesthetic agents, and particularly of halogenated vapors and nitrous oxide. Again, propofol and benzodiazepines have fewer effects, while ketamine rather increases responses. Opioids and dexmedetomidine remain best choice in that respect. Muscle relaxants impede recording of motor-evoked potentials and electromyography.106 Hypnotic Component of Anesthesia Monitoring During the 1990s, considerable effort has been made to develop EEG-derived dimensionless indices of the depth of the hypnotic component of anesthesia to appreciate the degree to which consciousness is altered. The general principle governing the calculation of those indices is first the extraction of EEG parameters that are known to be dose-dependently influenced by hypnotic anesthetic agents and second their treatment through a mathematical algorithm whose output is generally a number between 0 and 100.108 At least seven of those EEG-derived indices are currently commercially available, the most famous being the Bispectral Index. Despite initial expectancies regarding their ability to prevent unexpected intraoperative awareness with recall, they are relatively poor performant in that respect.109 The main reasons of this lack of efficacy are first the low incidence of awareness with recall, rendering the demonstration of a preventive effect difficult. Second, EEG-derived index parameters may be affected by several confounding factors, including electrical artifacts, interindividual variability, site of recording, delay for value display, eventual hypothermia or hypoglycemia, cortical atrophy, age, seizures, carotid clamping, cerebral ischemia, and interactions with other medications. Third, the parameters entering the calculation algorithm were arbitrarily chosen and may not adequately reflect the presence or the absence of consciousness and/or connectedness to the IV. NEUROMONITORING 174 9. MULTIMODAL MONITORING environment.108,110 At present, EEG-derived indices are proven to prevent awareness with recall when guiding total intravenous anesthesia, at least in patients at risk of such an event, but they are not superior to a low concentration alarm during inhaled anesthesia.109 Nevertheless, they help individually adjusting hypnotic agent administration, avoiding episodes of overdose,111 and predicting the moment of recovery.112 Their use in the context of intracranial neurosurgery may not always be possible, because of surgical site inaccessibility to the adhesive scalp electrodes, but acceptable alternatives exist (see the Clinical Pearls later).113–116 Recent advances in the understanding of the mechanisms of consciousness and its alteration by anesthetic agents now offer the perspective of improving depth of the hypnotic component of anesthesia monitoring. It appears that mental content is sustained by the activity of brain networks, which are composed of circumscribed brain regions that communicate with each other.117 The functioning of these higher-order cognitive networks is differentially, specifically, and dose-dependently altered by hypnotic anesthetic agents. For example, integrate frontoparietal communication seems necessary for having conscious thoughts, with or without connectedness to the environment.118,119 New EEG-derived parameters are now proposed to specifically monitor this frontoparietal communication.120,121 Nociception Monitoring Several parameters are now proposed to intraoperatively assess the balance between the intensity of noxious stimulation and antinociception provided by anesthesia, but they are not necessarily derived from the EEG.108 Insofar as noxious stimulation processing involves complex pathways and multiple brain regions, in addition to connections with the autonomic and motor nervous systems, and as the conscious aspect of painful stimulation is lost during anesthesia, no direct witness mirroring all elements of this processing exists. Aside from the indicators that are derived from pharmacodynamic modeling,122,123 the proposed parameters can be classified into three categories according to the response to stimulation they are markers of: the autonomic nervous system response,124 the motor response or the brain responses in the form of evoked potentials,125,126 processed EEG parameters,127–130 or the EEG and electromyogram variability.131 Examples of such parameters for the autonomic nervous system are the pupil diameter,132 the heart rate variability,133 the pulse amplitude,134 the skin conductance,135 the skin vasomotor reflex,136,137 or a combination of them.138 Devices for the monitoring of the motor response are based on spinal reflexes.139,140 To date, clinical utility has been demonstrated for only a few of those monitors, in terms of prediction of movement in response to stimulation,141 better intraoperative adjustment of opioid administration,142 improved hemodynamic stability,142 and prediction of the intensity of pain felt upon recovery.143–145 For most of them, clinical validation is still in progress. Again, confounding factors may impede the interpretation of recorded data. Autonomic nervous system–derived parameters may be influenced by cardiovascular medications146 and cardiac pacing,147 regional anesthesia,148 the intravascular volume status,149,150 the temperature, dysrhythmia, and the ventilation mode. Factors influencing the EEG are the same as those described for the depth of hypnosis monitoring, and muscle relaxants are the main confounders of the motor response to stimulation. MISCELLANEOUS Other monitoring devices are part of the anesthesiologist’s armamentarium, but may be of lower utility or provide less readily available information in the context of a neurosurgical procedure in the operating room, as compared to the intensive care unit. For example, muscle relaxation for the management of neurosurgical procedures usually occurs at induction of anesthesia, to facilitate tracheal intubation, but is seldom necessary thereafter. The main reason is that the ability to observe a motor response to various kinds of stimulations is often necessary.151 As a consequence, muscle relaxation monitoring is often omitted, except for situations where doubt on muscle relaxation exists, for endovascular embolization procedures, where total immobility and profound neuromuscular blockade is necessary, or for procedures of less than 2 h, where residual muscle relaxation is possible upon recovery.152 Microdialysis has been introduced into clinical practice in 1992 by Persson.153 This technology uses a flexible catheter, whose tip contains a semipermeable membrane. The catheter is infused with a dialysate and is inserted into the white matter. After equilibration between the dialysate and the brain, the concentration of lactate, pyruvate, glutamate, glycerol, and glucose can be measured. The use of a 100-kDa molecular weight membrane, instead of the traditional 20-kDa membrane, permits the study of larger molecules, including cytokines, concomitantly to the smaller ones. Hourly sampling appears adequate to detect metabolic changes, although more frequent sampling is possible.154,155 Insofar as microdialysis is a focal technique, brain chemistry should be interpreted according to IV. NEUROMONITORING INTEGRATION OF INFORMATION AND DECISION-HELPING SYSTEMS 175 the position of the catheter within the brain. Brain injury is frequently heterogeneous, and the catheter position relative to the injury location is important. Cerebral microdialysis provides information on the underlying cerebral metabolism and oxygen delivery. In this respect, measuring glucose, lactate, and the lactate/pyruvate ratio is now considered more useful than measuring glutamate and glycerol.156 Microdialysis is primarily a research tool, and it has been mainly used to acquire knowledge on some diseases pathophysiology such as traumatic brain injury or subarachnoid hemorrhage. It has evolved into a complementary clinical tool for the management of patients on an individual intention-to-treat basis, mainly in the intensive care unit, but its utility in the operating room has not been evaluated yet. The invasive measurement of oxygen partial pressure into brain parenchyma (PbtO2) allows a continuous and real-time evaluation of the brain tissue oxygenation balance. PbtO2 values identify brain tissue at risk of secondary injury. It can serve to optimize hemodynamics, and transfusion thresholds, and it can be a trigger for a systemic evaluation. The Brain Trauma Foundation recommends the use of a brain oxygenation monitoring whenever strategies of hyperventilation are employed in traumatic brain-injured patients,157 and more recent guidelines from the Neurocritical Care Society advocate to placement of such a monitoring in any patients at risk of cerebral ischemia.158 The PbtO2 probe is a Clark electrode and is placed within the white matter. It looks at a small volume of brain tissue. Similarly to microdialysis, PbtO2 probe location relative to brain injury is important and should be taken into account when interpreting PbtO2 data. Brain oxygenation relies on adequate oxygen supply by the blood and on adequate oxygen diffusion to the tissue. Hence, PbtO2 monitoring provides information on adequate oxygen delivery when targeting optimal CPP and can identify brain hypoxia that is not related to inadequate perfusion when the CPP target is attained.159 Normal PbtO2 values range between 20 and 35 mmHg.160,161 Sustained PbtO2 values lower than 15 mmHg lead to cerebral ischemia and poor neurological outcome. The most recent guidelines suggest a threshold of 20 mmHg for setting up treatment.158 PbtO2 is a complex variable because it is sensitive to the inspired oxygen fraction, the arterial oxygen partial pressure, and the cerebral blood flow, which in turn depends on CPP and CO2 partial pressure. It can also be modified during the hypermetabolic states such as fever, shivering, or seizures.162,163 PbtO2 must always be interpreted according to several clinical and physiologic factors. INTEGRATION OF INFORMATION AND DECISION-HELPING SYSTEMS In face of devices multiplicity and huge afflux of information coming from the monitoring station (Fig. 9.6), there might sometimes be difficulties of information integration by the practitioner, particularly in emergency situations or in the context of fatigue. Although no existing machine surpass the human brain in its capacity of integration, dedicated software may help identifying converging changes in physiological variables to end up with propositions of a diagnosis. The best therapeutic option can then be chosen by the practitioner according to his/her own experience and sagacity. Such softwares are currently being developed and show promising abilities,164 but they still need to be improved. FIGURE 9.6 Photograph illustrating the multiplicity of monitors and screens displaying the information to the anesthesiologist during an anesthetic procedure. IV. NEUROMONITORING 176 9. MULTIMODAL MONITORING FIGURE 9.7 Alternative position for the adhesive depth of the hypnotic component of anesthesia monitoring (here a spectral entropy electrode) as proposed by Nelson et al.113 CLINICAL PEARLS Inaccessible Forehead for Electroencephalographic Monitoring During intracranial neurosurgical procedures, the forehead is frequently not accessible to the placement of EEG electrodes, and this may be a problem to obtain recordings for several purposes, including depth of anesthesia monitoring. The main reasons are that the surgical field may be frontal or one of the pins of the head holder is placed there. Some authors have proposed alternative positions for the commercially available adhesive electrodes and have compared the numbers obtained from that position with numbers obtained classically. They report reasonable concordance and acceptable bias and limits of agreement. Hence, these alternatives may be a solution, keeping in mind that they do not offer exactly the same as when those devices are used according to the manufacturer recommendations. Alternative positions can be on the upper part of the face (Fig. 9.7),113 on the lower part of the face following a curved line joining the lateral temporal cheek and the tip of the chin,114 more posterior, with one electrode on the lateral temporal cheek and the others posterior to the ear,115 or even totally occipital.116 References 1. Hans P, Bonhomme V. Why we still use intravenous drugs as the basic regimen for neurosurgical anaesthesia. Curr Opin Anaesthesiol 2006;19:498–503. 2. El Beheiry H. Protecting the brain during neurosurgical procedures: strategies that can work. Curr Opin Anaesthesiol 2012;25:548–55. 3. Algarra NN, Lele AV, Prathep S, et al. Intraoperative secondary insults during orthopedic surgery in traumatic brain injury. J Neurosurg Anesthesiol 2016. epub ahead of print. 4. Kurz A. 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Glover CD, Carling NP. Neuromonitoring for scoliosis surgery. Anesthesiol Clin 2014;32:101–14. 107. Manninen PH, Tan TK, Sarjeant RM. Somatosensory evoked potential monitoring during carotid endarterectomy in patients with a stroke. Anesth Analg 2001;93:39–44. 108. Marchant N, Sanders R, Sleigh J, et al. How electroencephalography serves the anesthesiologist. Clin EEG Neurosci 2014;45:22–32. 109. Avidan MS, Mashour GA. Prevention of intraoperative awareness with explicit recall: making sense of the evidence. Anesthesiology 2013;118:449–56. 110. Sanders RD, Tononi G, Laureys S, Sleigh JW. Unresponsiveness not equal unconsciousness. Anesthesiology 2012;116:946–59. 111. Klopman MA, Sebel PS. Cost-effectiveness of bispectral index monitoring. Curr Opin Anaesthesiol 2011;24:177–81. 112. White PF. Use of cerebral monitoring during anaesthesia: effect on recovery profile. Best Pract Res Clin Anaesthesiol 2006;20:181–9. 113. Nelson P, Nelson JA, Chen AJ, Kofke WA. An alternative position for the BIS-Vista montage in frontal approach neurosurgical cases. J Neurosurg Anesthesiol 2013;25:135–42. 114. Lee SY, Kim YS, Lim BG, Kim H, Kong MH, Lee IO. Comparison of bispectral index scores from the standard frontal sensor position with those from an alternative mandibular position. Korean J Anesthesiol 2014;66:267–73. 115. Akavipat P, Hungsawanich N, Jansin R. Alternative placement of bispectral index electrode for monitoring depth of anesthesia during neurosurgery. Acta Med Okayama 2014;68:151–5. 116. Shiraishi T, Uchino H, Sagara T, Ishii N. A comparison of frontal and occipital bispectral index values obtained during neurosurgical procedures. Anesth Analg 2004;98:1773–5. 117. Bonhomme VL, Boveroux P, Brichant JF, Laureys S, Boly M. Neural correlates of consciousness during general anesthesia using functional magnetic resonance imaging (fMRI). Arch Ital Biol 2012;150:155–63. 118. Lee U, Kim S, Noh GJ, Choi BM, Hwang E, Mashour GA. The directionality and functional organization of frontoparietal connectivity during consciousness and anesthesia in humans. Conscious Cogn 2009;18:1069–78. 119. Hudetz AG. Feedback suppression in anesthesia. Is it reversible? Conscious Cogn 2009;18:1079–81. 120. Jordan D, Stockmanns G, Kochs EF, Pilge S, Schneider G. Electroencephalographic order pattern analysis for the separation of consciousness and unconsciousness: an analysis of approximate entropy, permutation entropy, recurrence rate, and phase coupling of order recurrence plots. Anesthesiology 2008;109:1014–22. 121. Ku SW, Lee U, Noh GJ, Jun IG, Mashour GA. Preferential inhibition of frontal-to-parietal feedback connectivity is a neurophysiologic correlate of general anesthesia in surgical patients. PLoS One 2011;6:e25155. 122. Luginbuhl M, Schumacher PM, Vuilleumier P, et al. Noxious stimulation response index: a novel anesthetic state index based on hypnotic-opioid interaction. Anesthesiology 2010;112:872–80. 123. von Dincklage F, Correll C, Schneider MH, Rehberg B, Baars JH. Utility of nociceptive flexion reflex threshold, bispectral index, composite variability index and noxious stimulation response index as measures for nociception during general anaesthesia. Anaesthesia 2012;67:899–905. 124. De Jonckheere J, Bonhomme V, Jeanne M, et al. Physiological signal processing for individualized anti-nociception management during general anesthesia: a review. Yearb Med Inform 2015;10:95–101. 125. Kochs E, Treede RD, Schulte am EJ, Bromm B. Modulation of pain-related somatosensory evoked potentials by general anesthesia. Anesth Analg 1990;71:225–30. 126. Bonhomme V, Llabres V, Dewandre PY, Brichant JF, Hans P. Combined use of bispectral index and A-Line autoregressive index to assess anti-nociceptive component of balanced anaesthesia during lumbar arthrodesis. Br J Anaesth 2006;96:353–60. 127. Liley DT, Sinclair NC, Lipping T, Heyse B, Vereecke HE, Struys MM. Propofol and remifentanil differentially modulate frontal electroencephalographic activity. Anesthesiology 2010;113:292–304. 128. MacKay EC, Sleigh JW, Voss LJ, Barnard JP. Episodic waveforms in the electroencephalogram during general anaesthesia: a study of patterns of response to noxious stimuli. Anaesth Intensive Care 2010;38:102–12. 129. Jensen EW, Valencia JF, Lopez A, et al. Monitoring hypnotic effect and nociception with two EEG-derived indices, qCON and qNOX, during general anaesthesia. Acta Anaesthesiol Scand 2014;58:933–41. 130. Melia U, Vallverdu M, Borrat X, et al. Prediction of nociceptive responses during sedation by linear and non-linear measures of EEG signals in high frequencies. PLoS One 2015;10:e0123464. 131. Mathews DM, Clark L, Johansen J, Matute E, Seshagiri CV. Increases in electroencephalogram and electromyogram variability are associated with an increased incidence of intraoperative somatic response. Anesth Analg 2012;114:759–70. 132. Barvais L, Engelman E, Eba JM, Coussaert E, Cantraine F, Kenny GN. Effect site concentrations of remifentanil and pupil response to noxious stimulation. Br J Anaesth 2003;91:347–52. 133. Jeanne M, Clement C, De JJ, Logier R, Tavernier B. Variations of the analgesia nociception index during general anaesthesia for laparoscopic abdominal surgery. J Clin Monit Comput 2012;26:289–94. 134. Bergmann I, Gohner A, Crozier TA, et al. Surgical pleth index-guided remifentanil administration reduces remifentanil and propofol consumption and shortens recovery times in outpatient anaesthesia. Br J Anaesth 2013;110:622–8. 135. Shimoda O, Ikuta Y, Sakamoto M, Terasaki H. Skin vasomotor reflex predicts circulatory responses to laryngoscopy and intubation. Anesthesiology 1998;88:297–304. 136. Gjerstad AC, Storm H, Hagen R, Huiku M, Qvigstad E, Raeder J. Skin conductance or entropy for detection of non-noxious stimulation during different clinical levels of sedation. Acta Anaesthesiol Scand 2007;51:1–7. 137. Gjerstad AC, Storm H, Hagen R, Huiku M, Qvigstad E, Raeder J. Comparison of skin conductance with entropy during intubation, tetanic stimulation and emergence from general anaesthesia. Acta Anaesthesiol Scand 2007;51:8–15. 138. Martini CH, Boon M, Broens SJ, et al. Ability of the nociception level, a multiparameter composite of autonomic signals, to detect noxious stimuli during propofol-remifentanil anesthesia. Anesthesiology 2015;123:524–34. 139. von Dincklage F, Hackbarth M, Mager R, Rehberg B, Baars JH. Monitoring of the responsiveness to noxious stimuli during anaesthesia with propofol and remifentanil by using RIII reflex threshold and bispectral index. Br J Anaesth 2010;104:201–8. 140. Baars JH, Mager R, Dankert K, Hackbarth M, von DF, Rehberg B. Effects of sevoflurane and propofol on the nociceptive withdrawal reflex and on the H reflex. Anesthesiology 2009;111:72–81. 141. Gruenewald M, Herz J, Schoenherr T, Thee C, Steinfath M, Bein B. Measurement of the nociceptive balance by analgesia nociception index and surgical pleth index during sevoflurane-remifentanil anesthesia. Minerva Anestesiol 2015;81:480–9. IV. NEUROMONITORING 180 9. MULTIMODAL MONITORING 142. Chen X, Thee C, Gruenewald M, et al. Comparison of surgical stress index-guided analgesia with standard clinical practice during routine general anesthesia: a pilot study. Anesthesiology 2010;112:1175–83. 143. Boselli E, Bouvet L, Begou G, et al. Prediction of immediate postoperative pain using the analgesia/nociception index: a prospective observational study. Br J Anaesth 2014;112:715–21. 144. Boselli E, Daniela-Ionescu M, Begou G, et al. Prospective observational study of the non-invasive assessment of immediate postoperative pain using the analgesia/nociception index (ANI). Br J Anaesth 2013;111:453–9. 145. Aissou M, Snauwaert A, Dupuis C, Atchabahian A, Aubrun F, Beaussier M. Objective assessment of the immediate postoperative analgesia using pupillary reflex measurement: a prospective and observational study. Anesthesiology 2012;116:1006–12. 146. Ahonen J, Jokela R, Uutela K, Huiku M. Surgical stress index reflects surgical stress in gynaecological laparoscopic day-case surgery. Br J Anaesth 2007;98:456–61. 147. Hocker J, Broch O, Grasner JT, et al. Surgical stress index in response to pacemaker stimulation or atropine. Br J Anaesth 2010;105:150–4. 148. Ilies C, Gruenewald M, Ludwigs J, et al. Evaluation of the surgical stress index during spinal and general anaesthesia. Br J Anaesth 2010;105:533–7. 149. Bonhomme V, Uutela K, Hans G, et al. Comparison of the surgical pleth indexTM with haemodynamic variables to assess nociception-anti-nociception balance during general anaesthesia. Br J Anaesth 2010;106:101–11. 150. Hans P, Verscheure S, Uutela K, Hans G, Bonhomme V. Effect of a fluid challenge on the surgical pleth index during stable propofol-remifentanil anaesthesia. Acta Anaesthesiol Scand 2012;56:787–96. 151. Hans P, Bonhomme V. Muscle relaxants in neurosurgical anaesthesia: a critical appraisal. Eur J Anaesthesiol 2003;20:600–5. 152. Hans P, Welter P, Dewandre PY, Brichant JF, Bonhomme V. Recovery from neuromuscular block after an intubation dose of cisatracurium and rocuronium in lumbar disc surgery. Acta Anaesthesiol Belg 2004;55:129–33. 153. Persson L, Hillered L. Chemical monitoring of neurosurgical intensive care patients using intracerebral microdialysis. J Neurosurg 1992;76:72–80. 154. Skjoth-Rasmussen J, Schulz M, Kristensen SR, Bjerre P. Delayed neurological deficits detected by an ischemic pattern in the extracellular cerebral metabolites in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 2004;100:8–15. 155. Bhatia R, Hashemi P, Razzaq A, et al. Application of rapid-sampling, online microdialysis to the monitoring of brain metabolism during aneurysm surgery. Neurosurgery 2006;58:ONS-20. 156. Hutchinson PJ, Jalloh I, Helmy A, et al. Consensus statement from the 2014 International Microdialysis Forum. Intensive Care Med 2015;41:1517–28. 157. Bratton SL, Chestnut RM, Ghajar J, et al. Guidelines for the management of severe traumatic brain injury. X. Brain oxygen monitoring and thresholds. J Neurotrauma 2007;24(Suppl. 1):S65–70. 158. Le Roux P, Menon DK, Citerio G, et al. The International Multidisciplinary Consensus Conference on multimodality monitoring in neurocritical care: a list of recommendations and additional conclusions: a statement for healthcare professionals from the neurocritical care society and the European society of intensive care medicine. Neurocrit Care 2014;21(Suppl. 2):S282–96. 159. Roh D, Park S. Brain multimodality monitoring: updated perspectives. Curr Neurol Neurosci Rep 2016;16:56. 160. Pennings FA, Schuurman PR, van den Munckhof P, Bouma GJ. Brain tissue oxygen pressure monitoring in awake patients during functional neurosurgery: the assessment of normal values. J Neurotrauma 2008;25:1173–7. 161. Hoffman WE, Charbel FT, Edelman G. Brain tissue oxygen, carbon dioxide, and pH in neurosurgical patients at risk for ischemia. Anesth Analg 1996;82:582–6. 162. Stiefel MF, Udoetuk JD, Spiotta AM, et al. Conventional neurocritical care and cerebral oxygenation after traumatic brain injury. J Neurosurg 2006;105:568–75. 163. Jaeger M, Schuhmann MU, Soehle M, Nagel C, Meixensberger J. Continuous monitoring of cerebrovascular autoregulation after subarachnoid hemorrhage by brain tissue oxygen pressure reactivity and its relation to delayed cerebral infarction. Stroke 2007;38:981–6. 164. Defresne A, Harrison M, Bonhomme V. Clinical pertinence and diagnostic accuracy of an evidence-based monitoring system: custos(c). Eur J Anaesthesiol 2016. epub ahead of print. 165. Singh A, Dubey A, Sonker A, Chaudhary R. Evaluation of various methods of point-of-care testing of haemoglobin concentration in blood donors. Blood Transfus 2015;13:233–9. 166. Maslow A, Bert A, Singh A, Sweeney J. Point-of-Care hemoglobin/hematocrit testing: comparison of methodology and technology. J Cardiothorac Vasc Anesth 2016;30:352–62. 167. Ardin S, Stormer M, Radojska S, Oustianskaia L, Hahn M, Gathof BS. Comparison of three noninvasive methods for hemoglobin screening of blood donors. Transfusion 2015;55:379–87. IV. NEUROMONITORING S E C T I O N V POSITIONS IN NEUROSURGERY This page intentionally left blank C H A P T E R 10 Positioning in Neurosurgery G. Singh Christian Medical College, Vellore, India O U T L I N E Introduction 184 Historical Background 184 Principles of Positioning 184 The Conduct of Positioning 185 Surgical Approach for Craniotomies 186 Positioning for Craniotomy Positioning of the Head Alignment of the Head and Neck Monitoring During Head and Neck Positioning Fixation of the Head for Craniotomy 187 187 187 187 188 Andrew’s Hinder–Binder Frame (OSI, Union City, CA, USA) Wilson Supporting Frame (OSI, Union City, CA, USA) Equipment for Stabilizing the Head Dough Nut–Shaped Foam/Gel Pads Prone Pillows Gardner-Wells Tongs, Traction Systems Pulmonary Compliance in the Prone Position Position-Related Factors Affecting Blood Loss in Spinal Procedures in Prone Position Alignment of the Spine for Procedures of the Spine Positioning of the Head for Procedures of the Spine Hemodynamic Monitoring in the Prone Position Problems Associated With Prone Position Increased Intra-Abdominal Pressure in the Prone Position Nerve Palsies/Neuropraxia Pressure Sores Edema of the Face Venous Air Embolism Endotracheal Tube Displacement Perioperative Vision Loss Ischemic Optic Neuropathy Central Retinal Artery Occlusion (Headrest Syndrome) Cortical Blindness Acute Angle Closure Glaucoma Positions Used for Craniotomies 189 Supine Position or Dorsal Decubitus Position 189 Lateral Position 190 Park Bench Position 190 Semilateral Position (Janetta Position) 191 Prone Position 191 Concorde Position 191 Three-Quarters Prone (Lateral Oblique or Semiprone) 192 Transoral Approach 192 Approach for Transnasal Transsphenoidal Surgery 192 Sitting Position 193 Complications Associated With Sitting Position 194 Contraindications to Sitting Position 194 Surgical Approach for Procedures of the Spine 195 Patient Positioning for Spinal Procedures Equipment Required for Prone Positioning Frames Used for Positioning the Body in Prone Relton and Hall Four Poster Frame (1969, Imperial Surgicals, Quebec, Canada) 195 195 195 Essentials of Neuroanesthesia http://dx.doi.org/10.1016/B978-0-12-805299-0.00010-5 196 196 197 197 197 197 198 198 198 198 199 199 199 199 200 201 201 201 201 201 201 202 202 Conclusion 203 Abbreviations 203 References 204 196 183 © 2017 Elsevier Inc. All rights reserved. 184 10. POSITIONING IN NEUROSURGERY INTRODUCTION Positioning is an important aspect of the perioperative care in a neurosurgical patient. The prolonged duration of neurosurgical procedures and the need for precise localization of pathological lesions demands that the patient is in a physiologically optimal, physically safe and comfortable position which offers the best approach to the neurosurgeon and access to the anesthesiologist. It must also ensure that the neurosurgeon is able to approach the area of interest with ease and minimal injury to the normal brain. Often it is achieved by positions, which are a compromise between a comfortable position for the patient and the surgeon. It is also desirable that the intended position complements the anesthetic and surgical goals such as minimizing intracranial pressure (ICP), reduction of brain retraction, providing a clear and bloodless field, and avoiding venous obstruction. Meticulous positioning is critical in the overall planning and successful outcome of any neurosurgical procedure. Inadequate planning or execution during positioning can have serious consequences. HISTORICAL BACKGROUND Sir Victor Horsley, the pioneer of neurological surgery described the use of a separate headrest for immobilizing the head for positioning during neurosurgical procedures. Although Harvey Cushing the father of neurosurgery did not feel the need for a separate headrest, he emphasized the need for elevating the head so as to decrease the venous pressure and described the use of pillows and loosely filled long sandbags to elevate the head end. Krause the German Neurosurgeon described the need for the head of the table to be able to change its position on its transverse axis in such a way should there be an excessive bleeding, it is possible to elevate the head end. Frazier introduced the use of headrest attached to the operating table for surgeries performed for cerebellar tumors in the prone position. Later, Cushing developed a horse shoe headrest for use in the prone position. In 1916, Dr. Martel, who pioneered in sitting position, introduced the special chair and head fixation holder for surgeries performed in the sitting position.1 Over the past century, a lot of positions have been tried by trial and error. Various adjuncts to positioning have also been tried and many refinements of these further the cause of safety. In 1950, Moore and Edmunds2 described the first prone position frame for use in spinal procedures following which multiple frames have been designed. Frank Mayfield and George Kees developed the Mayfield horseshoe and general purpose headrest to stabilize the head. Subsequently in 1973, the Mayfield Kees (MFK), three pins skull clamp which is the most common and widely used in neurosurgical practice to rigidly fix the patient’s head during craniotomy was introduced. PRINCIPLES OF POSITIONING A precise and scrupulous approach should be undertaken during positioning of the patient for neurosurgical procedures to avoid potential complications. Since neurosurgical procedures often involve positions which have multiple effects on the cardiopulmonary systems, it should be proceeded to in a gradual fashion with vigilant monitoring of the hemodynamic status of the patient. Moreover, the prolonged duration, varying hemodynamic status, mechanical pressure, preexisting weakness, and immobility makes the patient more vulnerable to tissue damage.3 It is also essential to assess patients at risk to see if they will tolerate the intended position. Preoperative radiographs and MRI may be helpful in deciding position of the neck. Although the responsibility of positioning the patient is primarily shared by the neurosurgeon and the attending anesthesiologist, every member of the surgical team plays a vital role. Positioning is usually attended to by the circulating nurse, neurosurgeon, anesthesiologist, theater technologist, and anesthetic assistants. It is initiated soon after induction of anesthesia and placement of adequate venous access and essential monitoring devices. The neurosurgeon decides the approach to the surgical site and position required for the same depending on the location of the tumor and the intended route for its approach. The anesthesiologist ensures adequate depth of anesthesia, hemodynamic stability, adequacy of oxygenation, securing the vascular and invasive accesses during and after positioning. They also ensure that all the detached monitoring cables are reconnected and checked to verify optimal performance. The circulating nurse safeguards the dignity and safety while ensuring comfort of the anesthetized patient. Although, these individual responsibilities may vary with each institution, it is usually the circulating nurse who is responsible for keeping the positioning devices and equipment ready and ensuring adequate personnel are available for the change in position. Each member of the team has a distinctive role, and it is important that there is a close coordination between the different members of the team to avoid potential mishaps during positioning.3 V. POSITIONS IN NEUROSURGERY THE CONDUCT OF POSITIONING 185 THE CONDUCT OF POSITIONING Once all the preparations are made and lines, catheter, monitors are secured, members of the team take their respective positions. IV lines, A-lines, endotracheal tube (ETT), monitoring cables are disconnected creating a blackout state and a period of hypoventilation. It is necessary that the period of blackout state is kept to the minimum and there is at least pulse oximetry ECG and blood pressure monitoring during this period. Patency of external ventricular drains and chest tubes should be maintained. The transfer should be swift, smooth, and coordinated. After achieving the final desired position, adequate access, optimal function of the IV lines, A -lines and monitors are checked and confirmed. Special attention is paid to the hemodynamic stability and respiratory compliance in the newly achieved position. Normal alignment of the head and neck with the body should be maintained. The endotracheal tube migration (either in to the bronchus or outside) should be ruled out and then stabilized to avoid kinking. The cuff pressure needs to be rechecked in the new position as there may be changes and kept within the normal range.4 To ensure optimal safety, a repositioning checklist is ideal.5 Table 10.1 describes a comprehensive repositioning checklist to be performed after achieving the desired position. The anesthesiologist ensures that the eyes are free from direct pressure to minimize ocular damage. Optimal head end elevation is provided to reduce venous pressure. All potential pressure points (sacrum, ischium, trochanter, and heel) are well padded by the placement of viscoelastic (gel) pads so as to redistribute mechanical pressure. Any contact of the patient’s skin with metal surfaces should be avoided to prevent burns related to the use of diathermy. Since there is a rapid fall of temperature following induction of general anesthesia, active efforts should be undertaken to reduce fall in temperature by limiting the exposure of the skin to the minimum and use of temperature-regulating blankets or forced air warming devices. Warm and humidified inspired gas and fluids should be used combined with temperature monitoring. Since many of the neurosurgical patients have weakness related to immobility and use of anticoagulants is not preferred except under special circumstances, it is important to prevent thromboembolic complications. Thromboembolic deterrent stockings and sequential compression devices are applied in patients undergoing prolonged procedures. The operating table is an important accessory. The position and stability of the operating table should be checked by the operating nurse before the patient is placed on the table. Optimal functioning of the remote control should be confirmed since this is a vital adjunct for subsequent changes in position.6 It is important to ensure that no body part extends beyond the edge of the OR table or positioning devices. The OR table safety strap must not be secured in such a manner that it is not too tightly placed across the patient in order to avoid pressure. It must be possible to comfortably insert two fingers under the mid-section of the safety strap to ensure that it is safely applied. The final position of the patient should be acceptable to the surgeon and anesthesiologist, providing easy access to operating microscope, navigation systems, and radiological imaging. TABLE 10.1 Repositioning Checklist A Airway ETT—Connected and incorrect position Confirmation of capnography trace Auscultation of both axilla B Breathing Check PAP, VTE (compliance) Ventilation C Circulation Heart rate, blood pressure, ECG D Devices All monitoring devices connected and working, SPO2, ETCO2, temperature, BIS, Warmers, NM monitor, intraoperative neuromonitoring devices E Extremity and eyes Pulses are checked, eyes taped and free of pressure F Flows Oxygen concentration optimized and anesthetic gas levels are checked G Gel pads Padding of pressure points H Head Head end elevation. Ensure two fingerbreadths between chin and mentum Alignment of head and neck checked I Intravenous access IV lines checked and extensions obtained Infusions restarted J Joints Appropriately positioned BIS, bispectral index; ETCO2, end tidal carbon dioxide; ETT, endotracheal tube; IV, intravenous; NM, neuromuscular; PAP, pulmonary arterial pressure; SPO2, peripheral saturation in oxygen; VTE, venous thromboembolism. V. POSITIONS IN NEUROSURGERY 186 10. POSITIONING IN NEUROSURGERY SURGICAL APPROACH FOR CRANIOTOMIES There are about six standard craniotomies described. t t t t t t Pterional craniotomy (frontotemporal) Temporal and subtemporal craniotomy Anterior parasagittal and subfrontal approach Posterior parasagittal craniotomy Midline suboccipital craniotomy Lateral suboccipital approach Table 10.2 describes the standard surgical approach for craniotomies, their variants, and the various options of body positions for each approach. TABLE 10.2 Surgical Approach for Craniotomies Type of Craniotomy Location of Lesion Body Position Pterional Lesions in anterior and Supine middle cranial fossa, anterior circulation aneurysms Head Position Variants Flexion, 45° of head rotation toward contralateral shoulder, shoulder roll under ipsilateral shoulder Cranio–orbito–zygomatic approach Fronto temporal craniotomy Subfrontal approach Temporal and subtemporal Petrous apex pathology, basilar top aneurysms, middle cranial fossa lesions Supine Flexion, 90° rotation, roll under ipsilateral shoulder Lateral Lateral flexion of neck, dependent ear toward ipsilateral shoulder (gravity facilitates retraction of temporal lobe) DACAs Third and lateral ventricular tumors Intraventricular diseases Interhemispheric approach Supine Neutral midline with degrees of flexion depending upon the surgical target Lateral decubitus Head tilted up Anterior cranial fossa Supine Neutral with extension until the brow is at the superior point (to facilitate frontal lobe retraction) Supine oblique More flexion than that required for anterior sagittal Prone/Lateral Neck flexion so that tumor is at highest point of operating field (nose pointing down) Fourth ventricular tumors, midline cerebellar, pineal lesions, posterior third ventricular tumors Prone/Concorde Neck flexion not exceeding two fingerbreadths head lifted upwards Sitting (supracerebellar infratentorial approach) Neck flexion back elevated elevation of thighs flexion of knees Lateral suboccipital Cerebellopontine angle tumors lateral cerebellar tumors Concorde/prone/lateral park bench sitting Varying degrees of neck flexion Transsphenoidal approach Pituitary, suprasellar lesions Supine with head on Head rotated with flexion until horseshoe headrest, body the bridge of the nose is 45° from close to right side horizontal axis Anterior parasagittal Subfrontal Posterior parasagittal Midline suboccipital DACA, distal artery aneurysm; PICA, posterior inferior cerebellar artery. V. POSITIONS IN NEUROSURGERY Park bench position Lateral transcondylar approach for lesions of the anterior foramen magnum, aneurysm of PICA POSITIONING FOR CRANIOTOMY 187 POSITIONING FOR CRANIOTOMY Positioning of the Head Ideal position of the head is one which provides optimal surgical approach to the target area with minimal trespass of the normal brain. It is based on two principles. t The imaginary trajectory from the highest point of the skull surface to the area of interest in the brain should be the shortest distance. t The exposed surface of the skull and an imaginary perimeter of the skull should be parallel to the floor.7 Alignment of the Head and Neck Rotation of the Head While extreme care is taken that the surgical target is reached, it is important to remember that the neck is in line with the head and the body. The head can be safely turned between zero and 45° laterally to the right and left from the body’s sagittal access. If more than 45 degrees of head rotation is required, the ipsilateral shoulder is raised on a pillow or roll to maintain the axis.1 Though trivial complications such as cervical strain may frequently occur with extreme rotation of the head, occasionally it may have extremely deleterious effects on the vascular structures of the neck. It decreases the blood flow in the ipsilateral vertebral arteries as they traverse the narrow foramina in the transverse process along the cervical spine. It also impairs venous return from the internal jugular veins leading to increased ICP, brain swelling, thereby increasing the bleeding. Although there is conflicting evidence regarding the side that develops compromised blood flow, when the head is placed in rotation, it is evident from a recent metaanalysis that the flow is more often reduced on the contralateral side of rotation and more in the intracranial part as compared to the cervical part.8 Mechanical compression of the extracranial vertebral artery during neck rotation has also been described.9 Patients with associated risk factors such as cervical spondylosis, vertigo, atherosclerosis, osteoarthritis, elderly, etc. are more likely to have compromised vertebral blood flow with lateral rotation of the neck. Preoperatively, identifying the patients with signs of possible vertebrobasilar insufficiency (VBI) such as vertigo will better enable the neurosurgeons and anesthesiologists to optimally position the neck. In such individuals, evaluation of VBI with a transcranial Doppler USG will be beneficial.10 Flexion and Extension of the Head Hyperflexion of the head also leads to a decrease in blood flow in both the vertebral and carotid arteries which may possibly lead to brain stem and cervical spine ischemia. It also reduces the anteroposterior size of the hypopharynx causing ischemia of the base of tongue leading to pharyngeal and tongue edema. This phenomenon may be accentuated by the placement of the other devices in the oropharynx such as the transesophageal echocardiography (TEE) probe, oral airway. Hence it is recommended that at least the neck flexion should not be less than two to three fingerbreadths of thyromental distance.11 Extension of the head may cause dislodgement of ETT. External pressure on the neck due to tight tapes for endotracheal tube fixation, securement of oral airway, neck collar also impair venous drainage resulting in poor surgical conditions. Any obvious neck vein distension is a sign of inadequate head and neck positioning which will contribute to raised ICP. Elevation of the Head The head is often positioned above the heart to facilitate venous return. In supine patients, 10° reverse Trendelenberg produces a significant decrease in ICP while the cerebral perfusion pressure (CPP) is unchanged.12 This occurs 1 min after the position change and remains stable. This is true in the prone position as well.13 As per Munroe–Kelly doctrine, the decrease in ICP due to the reverse Trendelenberg position is due to the displacement of the cerebrospinal fluid (CSF) into the spinal segment.14 In patients positioned prone, increases in the intra-abdominal pressure often contribute to the rise in ICP and hence elevating the head end is vital to reduce the ICP. Monitoring During Head and Neck Positioning Although in practice no additional routine monitoring is utilized during head and neck positioning, in vulnerable patients, ICP monitoring may be helpful aiming at a target of 20 mmHg. Jugular bulb pressure and jugular venous saturation are surrogates to ICP monitoring. It can be easily monitored using a retrograde jugular catheter. Simultaneous measurement of the central venous pressure (CVP) and jugular venous pressure (JVP) with the V. POSITIONS IN NEUROSURGERY 188 10. POSITIONING IN NEUROSURGERY appropriate reference points (CVP at right atrium and JVP at the level of tragus) should show no change in pressures as compared to the baseline with optimal positioning. Partial obstruction of venous outflow should be considered should there be an increase in JVP, and prompt repositioning of the head should be undertaken.15 Fixation of the Head for Craniotomy Fixation of the head after deciding on the final position of the head is a crucial step in positioning the neurosurgical procedure. The head may be positioned on a variety of fixation devices depending upon the surgery. The common devices used are MFK head clamp, Sugita head frame assembly, horseshoe headrest. Mayfield Kees Skull Fixation Device (Ohio Medical Instrument Co., Cincinnati, OH) The Mayfield head holder (Fig. 10.1A) consists of a clamp with three sterile pins. It is inserted into the skull in a band-like area just above the orbits and the pinna. Special care is taken to avoid the frontal sinus and the temporal bone. It should be positioned such that it does not interfere with the cranial incision but facilitates the attachment of the halo self-retaining retractor. When the clamps are squeezed together, the gears slide until the pins are seated in the skull. The knob housing the tension spring and gauze is tightened. Each ring exerts a pressure of 20 lb. In the adults, up to 80 lb of pressure is allowable whereas in the pediatric population, 30–40 lb is the preferable limit. It is then clamped on to the head frame assembly which is attached to the table (Fig. 10.1B). The manufacturer recommends the use of specially designed pediatric pins for children less than 10 years of age but it is preferable to avoid using MFK in children less than 3 years.6 Problems associated with the use of Mayfield Kees t t t t t t t t t t Pressure necrosis Perforation/Fracture of skull Injury to middle meningeal artery leading to hematoma or arteriovenous fistula Extradural hematoma remote from pin site Scalp and eye laceration due to slippage of the head holder Bleeding from the pin site Air embolism Malposition, poor fixation Pin site infection Cervical spine injuries due to inadvertent patient movement Sugita Multipurpose Head Frame Sugita multipurpose head frame devised by Dr. Sugita uses four head pins to position the patient’s head (Fig. 10.1C). It is ideal for procedures where maximum support is necessary. It allows for a full 360° rotation and adjustment of the angle of patient’s head during surgery if required. It consists of a robust head frame assembly and a head holder. The head holder consists of four pins. The head frame assembly consists of a basal frame which is mounted on to the head holder (Fig. 10.1D). The self-retaining retractors are attached to the base frames using thumb screws which are spaced at 35° angles. At each end of the basal frame, there are two holes to support the hand rest and instrument receptacles. The angle and height of the hand rest are all adjustable to suit individual requirements. The semicircular bar mounted on the basal frame is used to attach the scalp hooks or the self-retaining retractors. There is an additional provision of a quarter frame such that it provides enough space to facilitate lateral suboccipital approach. FIGURE 10.1 (A) Mayfield Kees three-pin head holder, (B) Mayfield Kees with head frame assembly, (C) Sugita four-pin head holder, (D) Sugita pins with head frame assembly. V. POSITIONS IN NEUROSURGERY 189 POSITIONS USED FOR CRANIOTOMIES Horse Shoe Head Rest It is a horseshoe-shaped headrest with both vertical and lateral adjustments which provide flexibility in patient positioning both in supine and prone position. It also has gel pads which make it comfortable for use. The pulley rod attachment for skeletal traction makes it an attractive option for cervical spine procedures. Precaution must be taken so as to avoid pressure on the face in the prone positions which may lead to necrosis of the forehead, injury to the eye. Scalp alopecia is a known complication in patients positioned supine on horseshoe headrest for prolonged duration.1 POSITIONS USED FOR CRANIOTOMIES Supine Position or Dorsal Decubitus Position It is the most commonly used position in neurosurgery. It does not require any special equipment for positioning and is often easily achievable because the patient is able to move into the bed by themselves thereby allowing most of the positioning to be completed before the induction of anesthesia. It is safe since it does not require disconnection of the ETT and other monitoring devices. In this position, the stroke volume (SV), cardiac output (CO), and venous return are optimal, and there is minimal decrease of the mean arterial blood pressure. The functional residual capacity (FRC) and total lung capacity (TLC) are decreased due to atelectasis of the dependent lung zones causing ventilation–perfusion (V/Q) mismatch. Manikandan et al.16 have shown that the PaCO2 levels, 30 minutes after induction of anesthesia and positioning in the supine position, were elevated due to increased alveolar dead space. The CPP is maintained but the CSF drainage may be impaired. The head should be positioned above the level of the heart to promote venous drainage and to reduce cerebral edema. The head may be rotated up to 45° relative to the body but if more rotation is needed, a roll or pillow should be placed under the contralateral shoulder. This also causes mild displacement of the abdominal viscera downwards, improving the ventilation. After the final positioning of the head either in the flexion or extension position, it is important to rule out endobronchial migration of the endotracheal tube. It is preferable to fix the ETT on the side opposite to the surgery to avoid accidental disconnections. Certain procedures such as the transoral approach to the odontoid requires tube placement at the center of lips. A bar across the table enables access to the tubes and allows for observation of the face after draping. Direct pressure on the globe is avoided by the placement of an attachment placed over the patients face to prevent the drapes falling over the eyes. It is important to avoid skin to metal contact. The head is positioned above the heart to facilitate venous return. The arm should be positioned so as to minimize the pressure on the ulnar groove. Neutral forearm position should be maintained when the arms are tucked inside. There must be adequate padding at the ulnar nerve to avoid ulnar neuropathy. Brachial plexus injury can occur if the arms are abducted more than 90°, where the head of the humerus acts as a fulcrum around which the nerves of the brachial plexus are stretched.17 Prolonged pressure on the peroneal nerve at the fibular head should be minimized by protective padding. Bony contact points at elbow, knee, occiput, sacrum, and heel must be padded.18 The patient is firmly secured to the operating table with safety straps, which are across the patient’s thigh so that the vessels are not occluded. The classical supine position leads to the loss of lateral lumbar lordosis and may cause postoperative back pain. The supine positioning is often slightly modified either into a contoured position (lawn chair position) or reverse Trendelenberg position. The lawn chair or contoured position (Fig. 10.2) is physiologically more favorable for the lumbosacral spine. A 15° angulation and flexion at the trunk, thigh, and knee is provided. The knee is kept flexed by a pillow under it. This position is also associated with improvement of the venous return from the lower extremities with optimal CSF and lymph drainage. The head-up tilt or reverse Trendelenberg position involves 10–15° tilt from the horizontal axis, and it improves the venous drainage from the heart. 15 ° 15 ° FIGURE 10.2 Lawn chair position. V. POSITIONS IN NEUROSURGERY 15 ° 190 10. POSITIONING IN NEUROSURGERY Post positioning, the nurse assesses and documents that the pressure points such as the occiput, scapula, olecranon, elbows, popliteal space, and calcaneum are free of pressure. It is also important that these are rechecked and documented at the end of the procedure. Lateral Position In the lateral position, hemodynamic parameters are minimally changed with mild decrease in SV, CO, and increase in systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR). This leads to modest decreases in systolic blood pressure and mean arterial pressure (MAP) as compared to supine position. With regard to ventilation, there is mild increase in PaO2 as compared to the supine position with a normal value of PaCO2.16 Perfusion is best in the dependent lung zone while the nondependent lung is better ventilated thereby causing a mild V/Q mismatch. However, since the abdominal excursions are free as compared to the supine position, its impact on oxygenation is limited. With extreme neck flexion, there is a possibility of decreased jugular venous flow (JVF), jugular venous resistance (JVR), and ICP. A chest or axillary roll is placed under the thorax below the axilla to prevent axillary compression. When the head is on the MFK, the dependent shoulder is brought beyond the cephalad edge of the operating theatre table and the dependent arm is rested on a low padded arm rest which is inserted between the table and head fixation. In these cases, there is no need for an axillary roll. The nondependent arm is usually placed over the trunk on a pillow. It may also be positioned on the airplane arm rest. To monitor the blood flow to the dependent arm, it is prudent to place the saturation probe or arterial line on the dependent arm (Fig. 10.3A and B). The trunk is supported on lateral bolsters and secured by tapes. When the head is not fixed on MFK, it is important to support the patient’s head with a pillow to avoid angulation of the cervical spine. The lower limbs are positioned with pillow between the legs and the dependent extremities are flexed to avoid pressure over the fibula head and the peroneal nerve. Complications anticipated with lateral positioning are brachial plexus injury, vascular compromise to the dependent upper extremity, ear and eye injuries, and injury to the suprascapular nerve of the dependent shoulder. Park Bench Position It is a modification of the lateral position, and it provides better access to the low lying cranial lesions and provides the surgeon with access to the anterior brain stem and foramen magnum as well as cerebellopontine angle tumors. In this position, the trunk is rotated 15° from the lateral position. The upper arm is positioned along the lateral trunk and the upper shoulder is taped toward the table. The dependent shoulder and arm are positioned outside the OR bed and the arm is supported by a sling.3 The lower extremity is slightly flexed and a pillow is placed between the knees. It is important not to tape the shoulder tightly or to drop the neck too much (Fig. 10.4). FIGURE 10.3 (A) Left lateral position, hand on padded arm rest, (B) lateral position, view from behind. FIGURE 10.4 Park bench position. V. POSITIONS IN NEUROSURGERY POSITIONS USED FOR CRANIOTOMIES 191 Semilateral Position (Janetta Position) This position has been named after the neurosurgeon who popularized its use for microvascular decompression of the fifth cranial nerve. It is achieved by semilateral tilting of the table combined with a generous shoulder roll. Extreme head rotation which may cause compression of the contralateral jugular by the chin should be avoided. Head is rotated slightly away from the affected side and flexed to approximately two fingerbreadths from the sternum. The vertex of the head is kept parallel to the floor.19 Prone Position In the prone position, there are significant cardiovascular and respiratory changes. Venous return and SV are significantly reduced due to increased intra-abdominal pressure and pooling of blood at the extremities leading to a decreased CO, decreased left ventricular ejection fraction, and cardiac index (CI). To compensate for the significantly reduced CO, heart rate increases along with increases in SVR and PVR. As compared to the supine position, the FRC and TLC increase and there is improved perfusion. Moreover, there is a decrease in atelectasis due to opening up of the dorsal zone of the lungs, thus minimizing V/Q mismatch and improving oxygenation. Although there is decrease in chest wall compliance due to increase in intra-abdominal pressure, this is usually overcome by positive pressure ventilation. On the whole, the oxygenation improves with prone positioning.16 The cerebral hemodynamics varies with the position of the head. When the head is maintained neutral, the JVF is increased and JVR is decreased. However, if the head is lower than the heart, there is venous congestion leading to increase in ICP.15 For positioning prone, the patient is usually anesthetized on the trolley and then turned prone on to the operating table which is prepared with chest rolls placed longitudinally/transversely. The head is fixed on to the head fixation device such as MFK before turning prone. There are multiple potential problems with the turning of the patient such as disconnection/dislodgement of monitors, IV accesses, ETT, etc. All these may contribute to either delayed recognition of anesthetic incidents such as hypotension, hypoventilation, desaturation, arrhythmias, or cardiac arrest. Extreme vigilance is required during turning the patient, and it is prudent to keep the pulse oximeter and invasive arterial line/ECG monitoring for early recognition of these events. All catheters [urinary, central venous, chest drain, external ventricular drainage (EVD)] should be firmly secured to the body before turning. Once the patient is positioned prone, the patient’s chin must be free from the table/frame. Extreme flexion, rotation, or extension of the neck may impair venous return thereby increasing ICP. Pressure points such as knees, groins should be padded. The breasts should be medially displaced and pressure on the nipples should be avoided. The lower extremity peripheral pulses should be checked to rule out vascular compromise of the femoral vessels. The upper extremities are positioned by the patient’s side with the hands facing the patient. The eyes, nose, ears should be protected and eyelids should be closed. It is important to secure the endotracheal tube firmly to avoid accidental extubation in the prone position. Antisialogogues may be used to decrease secretion which may loosen the fixation of endotracheal tubes. A soft gauze roll is placed as a bite block to prevent inadvertent tongue bite during monitoring of motor-evoked potentials and to securely hold the endotracheal tube in place. Reinforced ETT may also be considered to avoid kinking. The anesthesiologist must be prepared for sudden loss in the airway in the prone position. Reports of laryngeal mask airway (LMA) being secured in the prone position as an emergency alternative to endotracheal intubation have been described.20 Since prone positioning has been associated with significant hemodynamic changes, it is prudent to preload the patient adequately before turning and also be prepared to handle sudden hemodynamic instability in the prone position. Patients who are susceptible to significant hemodynamic compromise such as those with uncontrolled diabetes or hypertension may require vasopressor treatment while proning.21 Backup plans should be made for sudden cardiac arrest in the prone position in patients with significant comorbidities, and the need for the placement of transcutaneous pads in patients with significant cardiovascular risk should be considered before proning. It is also important that the trolley is readily accessible in case of a need to turn supine (Fig. 10.5). Concorde Position It is preferred for the lateral suboccipital approach for the posterior fossa tumors, especially for the occipito transtentorial and supracerebellar infratentoreal approach. The patient is positioned as for a midline suboccipital position. The head is secured in MFK before turning the patient prone. It is then flexed with the thoracolumbar region extended such that the head is elevated above the heart. It is slightly modified to make the craniotomy or craniectomy site more prominent by rotating the patient’s head approximately 45° to the shoulder ipsilateral to the lesion. Reverse Trendelenberg positioning is done to improve the venous return (Fig. 10.6). There is a lower incidence of air embolism22 and less fatigue for the surgeon. Moreover, complicated instrumentation is not needed. The complications are the same as that V. POSITIONS IN NEUROSURGERY 192 10. POSITIONING IN NEUROSURGERY FIGURE 10.5 Prone position, head on Mayfield Kees. FIGURE 10.6 Concorde position. of prone position.23 In the modified concorde position, the patient’s arm at the surgeon’s side hangs down over the head end of the operating table, with elbow flexion supported by an arm holder. This arm-down Concorde position provides good access for the surgeon in muscular- or broad-shouldered, short-necked, or obese patients.24 Three-Quarters Prone (Lateral Oblique or Semiprone) The three-quarter prone positioning is very similar to the lateral position and is used for approaching both the posterior fossa and the parietooccipital region. The head is placed on the MFK and the nondependent arm is placed behind the body in a coma or sleeping position. However, if a suboccipital approach is used, the hand may be taped down toward the foot. The upper shoulder may be pulled away from the head and neck area toward the foot of the bed with a tape. The patient’s trunk is supported by straps, tapes, or braces. The dependent lower extremity is extended with the knee padded to prevent pressure on the peroneal nerve, and the upper lower extremity is flexed at the hip and knee. The advantages are that it is comfortable for the surgeon and decreased risk of venous air embolism (VAE). Transoral Approach Most direct access to pathologies is located on the ventral side of the craniovertebral junction such as foramen magnum, atlas, axis, atlantoaxial instability.25 The transoral approach is achieved by placing the patient in the supine position on the horseshoe headrest or MFK with the head in extension. Oral intubation with an armored ETT is preferred. The arms are placed by the side. The Crockard retractor is placed over the tongue and the counterfoil is placed against the incisor teeth.1 Approach for Transnasal Transsphenoidal Surgery The patient is usually positioned supine with the head on a horseshoe headrest and hands by the side. The head is turned to the patient’s right with the bridge of the nose parallel to the floor. The head is rotated in such a way that the nostrils and nasal cavities are easily accessible for endoscopy. Reverse Trendelenberg position is performed to decrease venous congestion. Incorrect positioning of patients for the transsphenoidal approach makes the surgery V. POSITIONS IN NEUROSURGERY POSITIONS USED FOR CRANIOTOMIES 193 difficult and dangerous, since a small alteration in the planned trajectory may result in disastrous consequences such as injury to the carotid or the brain stem.26 Sitting Position Sitting position offers optimum access to the midline lesions. It also improves cerebral venous decompression lowering ICP, decreases the need for cerebellar retraction, promotes gravity-assisted drainage of blood and CSF thereby enabling a clean surgical field and visualization of bleeding points and unobstructed view of the patient’s face permitting observation of motor responses to cranial nerve stimulation. Although sitting position offers distinct advantages to the surgeon, the extent of removal of tumor, neurological outcomes, and facial nerve preservation have not been shown to be very different as compared to the lateral position in a recent study.27 Instrumented cervical surgeries have also been done in the sitting position.28 In the sitting position, there is significant venous pooling of the lower extremities due to the effect of gravity leading to decrease in CO and hence arterial hypotension. Heart rate and SVR are increased. SV and CI are decreased. PCWP is decreased, and SVR is increased. Increase in FRC and TLC have been observed. However, since perfusion is limited, no major benefit in oxygenation is observed. Ventilation is unimpeded as the diaphragmatic movement is improved, lowering the airway pressures. Since arterial blood pressure reduces by 0.77 mmHg for each centimeter gradient above the heart, decrease in CPP occurs after positioning the patient in sitting position leading to the possible development of cerebral ischemia. The ICP is also reduced in the sitting position. A modified semisitting (lounging) position aiming to create a positive pressure in the transverse and sigmoid sinuses, with lower head and higher legs positioned above the top of the head, decreases the incidence and severity of VAE.29 The patient is initially positioned supine on the operating table and anesthetized. The head is placed in head fixation. The patient is placed in the sitting position by slowly elevating the back of the operating table incrementally over minutes while maintaining hemodynamic stability. It is important to avoid hyperventilation as it may compromise cerebral blood flow.30 As the patient is made to sit, the operating table is flexed, elevating the thighs and the foot of the operating table is dropped, flexing the knees to prevent stretch on the sciatic nerve. A pillow may be placed under the knees. The operating table is tilted backward as the table is flexed. The patient’s neck is kept in neutral or flexed. The arms should be secured across the body or on arm rest to prevent drooping of the shoulder downward compressing on the brachial plexus. The feet should not be allowed to hang off the table and the ankles should be rested to prevent injury to the Achilles tendon.1 The frame of the head holder is properly clamped to the side rails of the back section so that it is possible to lower the head end in the event of a significant air embolism. If improperly attached to the thigh section, it will require that the head be disengaged from the head holder when the head needs to be lowered31 (Fig. 10.7). FIGURE 10.7 Schematic representation of sitting position. V. POSITIONS IN NEUROSURGERY 194 10. POSITIONING IN NEUROSURGERY To avoid injury during neck flexion, it is preferable to monitor somatosensory evoked potential (SSEP) while positioning. It is recommended that the patient be checked preoperatively to determine the degree of neck flexion possible. The hemodynamic changes during positioning may be influenced by patient’s factors such as intravascular volume status, preexisting hypotension, BMI. Positioning the patient with flexion of hips and elevating the knees to the level of the heart help to minimize hypotension. Slow-staged positioning after adequate hydration over a period of 5–10 min with intermittent boluses of vasopressors as required will prevent any abrupt fall in blood pressures. Wrapping up of the lower extremities, placing the patient in G suit also promotes venous return from the lower extremities. Complications Associated With Sitting Position Venous Air Embolism Incidence ranges from 25% to 50% in a precordial Doppler study32 and 76% in a TOE study.33 The negative venous pressure and the exposure of bony venous sinuses to air are responsible for the VAE. Various monitoring modalities have been described with varying sensitivities such as capnography, fractional excretion of nitrogen, transthoracic precordial Doppler, right heart catheter, TOE, and transcutaneous oxygen measurement. VAE reduces CO by causing an air lock and subsequent mechanical overdistention of the right ventricle and obstruction to the pulmonary circulation. Precordial Doppler is the best noninvasive device to monitor VAE and is placed from the third to sixth intercostal space, right sternal border where the highest pitch over the right upper sternal border with intravenous injection of agitated saline. Carbon dioxide field flooding has been used to reduce the hemodynamic effects of VAE.34 Intrajugular balloon catheter is also used to prevent VAE.35 Turgut et al. have shown that the use of paramedian approach leads to increased incidence of VAE as compared to the median approach.27 Usefulness of preoperative contrast ECHO as a screening technique to detect patent foramen ovale (PFO) has been described.36 Paradoxical Air Embolism The gradient between the atria is an important factor in the pathophysiology of VAE. Any condition which increases right atrial pressure relative to left atrial pressure may predispose to paradoxical air embolism (PAE). Application and release of positive end-expiratory pressure increases right atrial pressures thereby promoting right to left shunting and PAE. Patients at risk of PAE such as those with right to left shunts, PFO must be preoperatively identified. Pneumocephalus The incidence of pneumocephalus is almost 100%. Diminution of the brain volume secondary to mannitol administration, hyperventilation, intraoperative drainage of CSF predispose to pneumocephalus. Avoiding intracranial dehydration, hyperventilation during dural closure to facilitate the expansion of brain helps to decrease the incidence of pneumocephalus. High index of suspicion is required to diagnose potentially life-threatening complication, tension pneumocephalus. Confusion, headache, convulsions, neurological deficits in the immediate postoperative period should be evaluated with a prompt CT scan. Rapid evacuation of the tension pneumocephalus results in prompt recovery. Quadriplegia Extreme flexion of the neck stretches the cord at C5 leading to decreased regional cord perfusion, especially during periods of hypotension. SSEP may be used to monitor the adequacy of regional cord perfusion. Nerve Injuries Common peroneal neuropathy often occurs secondary to nerve compression as it courses around the neck of the fibula. Hyperflexion of thigh may lead to stretching of the peroneal division off the sciatic nerve. Recurrent laryngeal nerve injury also may be noticed due to extreme flexion. Other Complications Macroglossia may occur leading to airway obstruction. This is more pronounced in infants where there is an anterior larynx, small tracheal diameter, and large tongue. Injury to the soft palate and posterior pharyngeal wall and tongue has also been described. Sustained neck flexion, prolonged duration, and use of oral airway have been implicated in the pathogenesis of macroglossia. Bite blocks and smaller diameter TEE probes will minimize the incidence of macroglossia. Contraindications to Sitting Position Absolute t t t t PFO Cerebral ischemia when upright and awake Patent ventriculoatrial shunt Right atrial pressure more than left atrial pressure V. POSITIONS IN NEUROSURGERY 195 PATIENT POSITIONING FOR SPINAL PROCEDURES Relative t t t t Extremes of age Uncontrolled hypertension Chronic obstructive pulmonary disease Degenerative disease of the spine Careful patient selection, intraoperative techniques, prompt diagnosis and treatment decrease the incidence of VAE and the risks associated with sitting position. SURGICAL APPROACH FOR PROCEDURES OF THE SPINE PATIENT POSITIONING FOR SPINAL PROCEDURES There are wide varieties of spinal procedures ranging from simple laminectomies to major instrumentation, performed in various positions. Positioning appropriately is an important component of successful postoperative outcome in spinal procedures. The surgeon decides on the optimal surgical approach and the position required. Since procedures of the spine are associated with extensive use of fluoroscopy, radiography, and navigation systems intraoperatively, these should be taken into consideration while positioning. Surgical objectives during any spine procedure are to facilitate exposure, minimize bleeding, prevent injury to vital structures, and have a good functional outcome postoperatively. The anesthesiologist aims at providing optimal ventilation and oxygenation together with hemodynamic stability. In some situations, the associated comorbidities in a patient demand modifications to the commonly used approach. Table 10.3 describes the various approaches for procedures of the spine. Equipment Required for Prone Positioning t Basic operating table with appropriate prone positioning frames t Jackson’s spinal table (Misuho OSI, Union City, CA, USA) Although a basic operating table may be used for most procedures, the modular spine-specific operating tables such as Jackson’s are adjustable offering greater vertical range providing ergonomic advantage to surgeons. The radiolucent carbon fiber frame allows for the use of fluoroscopy, intraoperative CT scanning, and navigation systems which precisely locate the levels and to course the trajectory of pedicle screws. The ability to rotate 360° allows intraoperative repositioning for combined anterior and posterior procedures. The accessories allow customization to suit individual patient and surgical needs. The head may be supported either with foam headrest, rigid fixator or traction, and the legs may be supported in a sling or on a rigid frame.37 Frames Used for Positioning the Body in Prone Various techniques and frames have been designed to position the patient in the prone position so as to have optimal ventilation and oxygenation while facilitating exposure and minimizing the blood loss. TABLE 10.3 Approaches for Surgery of the Spine Approach Procedures Body Position Immobilization of Head Anterior ACDF Cervical corpectomies Anterior lumbar fusion Supine Tapes Gardner-Wells tongs Lateral Thoracic corpectomies Thoracolumbar lesions Anterior lumbar lesions Lateral Jackson’s table Gel headrest Posterior Posterior spine fusions Lumbar and thoracic discectomies, laminectomies Scoliosis correction, CVJ anomalies Prone on chest rolls, Wilson’s frame, Relton and Hall frame, Jackson’s table Prone headrest MFK for cervical laminectomies Transoral Atlanto occipital dislocation Supine Head on horseshoe headrest with hyperextension ACDF, anterior cervical discectomy and fusion; CVJ, craniovertebral junction; MFK, Mayfield Kees. V. POSITIONS IN NEUROSURGERY 196 10. POSITIONING IN NEUROSURGERY Chest rolls are the most effective and inexpensive techniques used for prone surgery. They may be placed either transversely or longitudinally. Relton and Hall Four Poster Frame (1969, Imperial Surgicals, Quebec, Canada) It consists of four padded supports in two “V” shaped pads, which support the lateral parts of the upper chest rostrally and the lateral aspect of the hip caudally in such a manner to allow free abdominal excursion. The supports are angled 45° inwardly and are adjustable (Fig. 10.8). The hyperextension of the vertebral column is limited by lowering the legs. As compared to the use of chest rolls, the use of four poster frame is associated with decreased intra-abdominal pressure, inferior vena cava (IVC) pressure, and preservation of lumbar lordosis.38 Andrew’s Hinder–Binder Frame (OSI, Union City, CA, USA) It has an adjustable tibial support to allow for a varying range of hip flexion and it allows for the use of C-arm. Patients are positioned in a modified knee chest position on the Andrew’s table. It allows C-arm integration for both A/P and lateral intraoperative views.38 Wilson Supporting Frame (OSI, Union City, CA, USA) It consists of two curved full length pads to provide support to the chest and pelvis and adjust laterally to improve ventilation and to relieve pressure from the abdomen. Blood loss and intra-abdominal pressure were lower in patients positioned on wider Wilson frame support.39 More recently, a newer version of this frame, Wilson Plus offers 360° of unobstructed radiolucency, for easily obtainable images by either C-arm or X-ray is available38 (Fig. 10.9). FIGURE 10.8 Relton hall frame. FIGURE 10.9 Wilson’s frame. V. POSITIONS IN NEUROSURGERY PATIENT POSITIONING FOR SPINAL PROCEDURES 197 Equipment for Stabilizing the Head It is important to maintain neutral position of the cervical spine to avoid postoperative cervical myeloradiculopathy. t t t t t Dough nut–shaped foam/gel pads Prone pillows Gardner-Wells tongs MFK Horseshoe headrest Dough Nut–Shaped Foam/Gel Pads This may be utilized to provide head support and to maintain neck in neutral position for patients undergoing procedures in the supine and lateral procedures. Appropriate sizes must be chosen to avoid neck flexion, extension, or hyperextension. Prone Pillows Different prone head positioners are available to position the head for spine procedures in the prone position (Fig. 10.10). They are usually made of polyurethane foam with preformed slits designed such that the eyes and nose are free of pressure, and there is a provision for the exit of the endotracheal tube. Recently a dry flotation device with multiple adjustable rubber-filled bladders is being used (ROHO group, Belle Vue, IL).40 The prone view helmet system (Dupaco, Oceanside, CA) was developed to address visual loss caused by direct pressure. It consists of a rigid helmet to support the head, soft foam inserts to disperse pressure while avoiding pressure on eyes, nose, mouth, and a mirror to reflect the patient’s eyes.41 Geordie et al. have described the use of a prone view helmet system with a modified table platform for open access to the eyes during prone position allowing them to measure intraocular pressure, ocular perfusion pressure, and ocular perfusion (using digital retinal or optic disc imaging).40 Mc Michael, in a study comparing polyurethane foam, prone view, and neoprene rubber pillows, has shown that the prone view positioner was considered the most comfortable for patients.42 The prone view positioner and the ROHO neoprene pillow demonstrated significantly lower face pillow interface pressures as compared to the commonly used polyurethane foam. Gardner-Wells Tongs, Traction Systems This provides two ropes for the traction. The alignment of the spine can be altered during surgery because of the availability of dual vectors for traction. Placement of the upper thoracic pedicle screw causes movement which may result in dislodgement of head from even a rigid skull fixation device. In such cases, it is beneficial to use a properly placed traction system.37 FIGURE 10.10 Prone pillow. V. POSITIONS IN NEUROSURGERY 198 10. POSITIONING IN NEUROSURGERY Pulmonary Compliance in the Prone Position By compressing the abdomen and limiting the chest wall movement, there is a significant compromise of the pulmonary compliance in the prone position. In a study comparing the three commonly used prone positioning devices, longitudinally placed chest rolls, Jackson spinal table, and Wilson’s frame, Sally et al. have shown that patients undergoing procedures in the prone position have an increase in peak airway pressure and decrease in lung compliance when moved from the supine to prone position in both the group with chest rolls and the Wilson’s frame, but not while using the Jackson’s table, suggesting that the pulmonary mechanisms are frame dependent.43 Free movement of the abdomen improves the excursion of the diaphragm, thereby improving the oxygenation and ventilation. It also decreases bleeding due to decrease in the intra-abdominal pressure and improves venous return from the lower extremities.15 Position-Related Factors Affecting Blood Loss in Spinal Procedures in Prone Position There are several plexuses of thin-walled valveless veins that contain blood at low pressure, and the direction of flow of blood is reversible.44 The vertebral veins are connected to those in the chest through the vertebral canal and the ones in the abdomen and pelvis through intercostal, lumbar, and other connecting veins.38 With the obstruction of IVC, blood from the lower part of the body could be diverted into the vertebral venous system. Batson’s plexus consists of the following: 1. Internal venous system, which is continuous from the base of skull to the sacrococcygeal region. It is formed by the anterior internal venous veins (on the posterior surface of the vertebral body), posterior internal venous veins (on the surface of the lamina), and the anastomotic veins between the two. 2. External venous system which consists of the longitudinal traversing veins anterior to the vertebral bodies on the outer aspect of the lamina. 3. Anastomotic or connecting veins which are a group of veins connecting the internal to the external venous system and the systemic and vertebral venous systems. During prone positioning, multiple reasons are responsible for IVC obstruction, and increase in IVC pressure results in diversion of blood into the vertebral veins. Pressure on the anterior abdominal wall due to sandbags, bolsters, or excessive abdominal muscle tension is transmitted to the IVC.45 Even moderate increase in abdominal pressure is known to cause rise in caval pressure. The altered respiratory compliance associated with prone positioning can cause elevated airway pressures which impair venous return to the heart thereby decreasing CO and increasing systemic venous pressure. This often leads to decreased perfusion pressure of the spinal cord as well (SEPP = MAP— spinal venous pressure) leading to potential for increased neurological complications. Hypercarbia with increase in airway pressure during expiration also causes an increase in venous pressure. All these factors contribute to blood loss in the prone position. Optimal positioning is hence essential to minimize the blood loss in this position. Alignment of the Spine for Procedures of the Spine It is important to achieve proper spinal alignment during positioning for the best clinical outcome. When arthrodesis is not performed, the aim in intraoperative positioning is to provide optimal neural decompression without excessive bleeding. But if arthrodesis is planned, positioning must include the placement of spine in anatomic alignment to avoid iatrogenic deformity. Improper alignment of the occipitocervical region can have various complications. In the extremely extended position, fusion of the spine leads to the inability of the patient to see his own body, whereas in the excessive flexion, there is difficulty with swallowing. Rotational malalignment will lead to head tilt. In lumbar arthrodesis, maintaining adequate lumbar lordosis is crucial to prevent flat back syndrome, and hence it is preferable to avoid Wilson’s frame for fusion procedures of the lumbar spine.37 Positioning of the Head for Procedures of the Spine In cases of unstable cervical spine, the head needs to be stabilized with a rigid immobilization device such as Philadelphia collar or cervical traction. Careful and meticulous transfer from the supine to the prone position should be done while maintaining the alignment of the axis of the body and head. In cases of suspected myelopathy, motor evoked potential monitoring should be done before and after positioning to confirm integrity of the V. POSITIONS IN NEUROSURGERY PATIENT POSITIONING FOR SPINAL PROCEDURES 199 neural pathways.46 In the absence of such monitoring, awake proning may also be done.47 Neural integrity may be confirmed by the patient and then anesthetized for the procedure. Recurrent laryngeal nerve palsy has been associated with procedures involving the anterior approach to the lower cervical spines specially from the right side.48 Endotracheal tube–mediated compression of the recurrent laryngeal nerve due to retraction for anterior cervical spine surgery is a significant cause of vocal cord paralysis. Monitoring the endotracheal cuff pressure frequently and keeping it within the normal range during the procedure is recommended. Deflating the endotracheal tube cuff and reinflating just to seal the pressure after the placement of retractors helps to reduce the incidence of temporary recurrent laryngeal nerve palsies.49 In procedures of the lumbar, lower thoracic, and sacral spine, the use of head fixation devices is not required, and head is positioned on a gel or foam headrest. The upper extremities are usually positioned either upwards—superman position for procedures on the lumbar spine or by the side for thoracic cases. Care must be taken that the brachial plexus is not stretched. Hemodynamic Monitoring in the Prone Position Since there is a decrease in venous return leading to decreased CO, it is essential to maintain euvolemic status. CVP monitoring may be used to monitor intravascular volume. Since the CVP values are not accurate, the trends should be monitored rather than absolute values. Dynamic indices of preload assessment such as pulse pressure variation, stroke volume variation, and systolic pressure variation are reliable in the prone positioning. Beat to beat monitoring of the blood pressure with an arterial line enables the anesthesiologist to pick up unanticipated sudden decreases in CO due to VAE, massive bleeding, etc. and allows for frequent blood sampling. High-risk patients should be identified and optimized prior to surgery and adhesive defibrillator pads are placed. The least change in hemodynamic status due to proning has been observed with Jackson’s table and it should be used in high-risk cases. In case of sudden arrest, chest compressions may have to be initiated while in the prone position itself.56 Prolonged hypotension in the prone position may lead to ischemic hepatitis. Maintaining the neck in the neutral nonextended position helps reducing pressure on the neurovascular bundle. Kinking, intimal injury, and thrombosis have been observed to cause carotid and vertebrobasilar dissections in patients with nonneutral neck position. Any foreign body in the internal jugular vein such as cannulas may predispose to thrombosis and stroke. It is preferable to use subclavian catheters since they have been noted to be less thrombogenic.57 Increased age, malignancy, obesity, and recent major surgery predispose to thrombosis and stroke in these patients. Problems Associated With Prone Position Brachial plexus stretch injury is known to occur in the prone position. Extreme degrees of extension or rotation of the head to the contralateral side causes stretching of the nerve roots leading to brachial plexus injury. Excessive pressure on the clavicle can compress the neurovascular bundle against the first rib. Head of humerus can press on the brachial plexus when the arms are hyperabducted (abducted more than 90 degrees) and the shoulder is not sufficiently mobile and relaxed. Increased Intra-Abdominal Pressure in the Prone Position With improper positioning and in obese patients, the intra-abdominal pressure increases with prone positioning which leads to abdominal compartment syndrome and increased bleeding in procedures of the spine. An increase in intra-abdominal pressure of more than 12 mmHg from the supine position is a high risk for developing abdominal compartment syndrome (ACS). Due to tight abdominal closure, patients with previous abdominal surgery are at high risk for developing ACS. Prolonged elevation of intra-abdominal pressures may lead to decreased perfusion pressure predisposing to multiorgan failure. Identifying patients who are at risk to develop high intra-abdominal pressure and to monitoring intra-abdominal pressure in them should be considered. Any decrease in blood pressure, urine output or persistence of abnormal base deficit, increase in PCO2 may point toward multiorgan failure. Prompt abdominal decompression should be done if ACS is suspected.50 Nerve Palsies/Neuropraxia In the prone position, there is an increased risk of injury to the cervical spine and the brachial plexus. Impaired axoplasmic transmissions due to increased intraneural venous pressure, local edema are the pathophysiologic mechanisms leading to nerve palsies and neuropraxias. This may be due to stretch, compression, generalized ischemia, or metabolic causes. Several risk factors have been identified such as male gender, extremely thin individuals, obese, V. POSITIONS IN NEUROSURGERY 200 10. POSITIONING IN NEUROSURGERY TABLE 10.4 Practice Advisory for the Prevention of Perioperative Peripheral Neuropathies SUMMARY OF ADVISORY STATEMENTS I. Preoperative history and physical assessment When judged appropriate, it is helpful to ascertain that patients can comfortably tolerate the anticipated operative position. II. Specific positioning strategies for the upper extremities t A rm abduction in supine patients should be limited to 90°. t P atients who are positioned prone may comfortably tolerate arm abduction greater than 90°. Supine patient with arm on an arm board The upper extremity should be positioned to decrease pressure on the postcondylar groove of the humerus (ulnar groove). Either supination or the neutral forearm positions facilitate this action. Supine patient with arms tucked at side t T he forearm should be in a neutral position. t F lexion of the elbow may increase the risk of ulnar neuropathy, but there is no consensus on an acceptable degree of flexion during the perioperative period. t P rolonged pressure on the radial nerve in the spiral groove of the humerus should be avoided. t E xtension of the elbow beyond the range that is comfortable during the preoperative assessment may stretch the median nerve. t P eriodic perioperative assessments may ensure maintenance of the desired position. III. Specific positioning strategies for the lower extremities t S tretching of the hamstring muscle group—Positions that stretch the hamstring muscle group beyond the range that is comfortable during the preoperative assessment may stretch the sciatic nerve. t L imiting hip flexion—Because the sciatic nerve or its branches cross both the hip and the knee joints, extension and flexion of these joints, respectively, should be considered when determining the degree of hip flexion. t N either extension nor flexion of the hip increases the risk of femoral neuropathy. t P rolonged pressure on the peroneal nerve at the fibular head should be avoided. IV. Protective padding t P added arm boards—Padded arm boards may decrease the risk of upper extremity neuropathy. t C hest rolls—The use of chest rolls in the laterally positioned patient may decrease the risk of upper extremity neuropathy. t P adding at the elbow—Padding at the elbow may decrease the risk of upper extremity neuropathy. t P adding to protect the peroneal (fibular) nerve—The use of specific padding to prevent pressure of a hard surface against the peroneal nerve at the fibular head may decrease the risk of peroneal neuropathy. t C omplications from the use of padding—The inappropriate use of padding (e.g., padding too tight) may increase the risk of perioperative neuropathy. V. Equipment t T he use of properly functioning automated blood pressure cuffs on the arm (i.e., placed above the antecubital fossa) does not change the risk of upper extremity neuropathy. t T he use of shoulder braces in a steep head-down position may increase the risk of perioperative neuropathies. VI. Postoperative assessment t A simple postoperative assessment of extremity nerve function may lead to early recognition of peripheral neuropathies. An updated report by the American Society of Anesthesiologists Task Force on prevention of perioperative peripheral neuropathies. hypotension, diabetes mellitus, hypothermia, anatomic variations, and malnutrition.51,52. Positioning the humerus anterior to the trunk and placement of supportive padding for the arm is beneficial to prevent brachial plexus injury. Palpation of the pectoralis major muscle tendon may be used to monitor tension on the brachial plexus.51,52 Anterior shoulder dislocation is higher in the prone position and may lead to ischemia and compartment syndrome that may cause rhabdomyolysis, raised myoglobin, and the development of limb compartment syndrome. Long-duration procedures, presence of peripheral vascular disease, obesity, increased muscularity predispose to compartment syndrome. Table 10.4 describes the task force recommendations for prevention of neuropathy.53 Pressure Sores In the prone position, extreme pressure is exerted on the chin, forehead, supraorbital, malar eminence, and ears. On an average, pressure on the face is 30 mmHg which is above the capillary perfusion pressure. It may be even up to 50 mmHg.54 Although supportive padded headrests do reduce the pressures, the risk increases with prolonged duration of surgery, head-down position, and excessive use of crystalloids for replacement. The head end improves the venous drainage and reduces the venous congestion. 15 pounds of upward traction at 45° angle produced by Gardner-Wells tong alleviates the pressure on the face.55 Pressure on the chest ranges from mild erythema to skin V. POSITIONS IN NEUROSURGERY PATIENT POSITIONING FOR SPINAL PROCEDURES 201 FIGURE 10.11 (A) Gel pads for positioning, (B) gel sacral pads and axillary rolls, (C) knee pads and heel rests. peeling. Patients with larger breasts are more susceptible to injury. Breast rupture and necrosis are possible in those with implants.52 Hematoma, chondritis, ischemia, and necrosis have been reported in the ear. All pressure points need to be padded with appropriate padding such as gel pads (Fig. 10.11A–C). Edema of the Face Oropharyngeal swelling, macroglossia, and sublingual hematoma have been observed in patients positioned prone. Kinking and stretching of the salivary ducts, blood vessels, and lymphatics when the neck is flexed predispose to salivary gland swellings.58 Temporomandibular joint dislocation during intubation, poor oral hygiene, dehydration, malnutrition, repeated laryngoscopy, use of angiotensin converting enzyme inhibitors are known risk factors for salivary gland swellings. Use of soft bite block to prevent tongue compression is preferred over hard oral airways. It is important to monitor the head and neck positioning in the prone position every hour. Cuff leak should be checked before extubation, and extubation should be postponed if there is no cuff leak or if there is significant facial swelling. Patient should be monitored in the first few hours for postextubation stridor.59 Venous Air Embolism Risk of air entrainment is higher if the venous pressure is low or if the surgical site is positioned above the heart. Central venous catheter should be placed in those at higher risk for VAE. Endotracheal Tube Displacement Patients in prone position are at higher risk for endotracheal tube displacement due to the weight of the breathing circuits. LMA may be used as a rescue airway disease in case of accidental extubation.20 To avoid displacement of the LMA in the prone position, it is essential to maintain higher cuff pressures.60 Perioperative Vision Loss The incidence of perioperative vision loss following procedures of the spine is 0.05–1%.61 Faulty positioning accounts for only a small percentage of postoperative vision loss. Direct pressure on the eye causes trauma resulting in conjunctival edema, hemorrhage, chemosis, and pain. Ischemic Optic Neuropathy Increased intraocular pressure and increased orbital venous pressure leads to decreased perfusion pressure on the optic nerve head. Ischemic optic neuropathy (ION) may be either anterior to the lamina cribrosa or posterior. Posterior ION is more common postoperatively and is more severe than the anterior.62 They are known to occur even with sufficient support to facial padding. Risk factor for ION is longer operative time in the prone position in a patient with anemia, hypotension, and blood transfusion.63. Central Retinal Artery Occlusion (Headrest Syndrome) This may be due to direct or indirect pressure and is characterized by periorbital and scleral edema and a cherry red spot appearance on the fundus. The risk for central retinal artery occlusion (CRAO) is usually due to improper positioning during the surgery.63 Pathogenesis may be due to vasospasm, emboli, compression, or V. POSITIONS IN NEUROSURGERY 202 10. POSITIONING IN NEUROSURGERY hypotension.61 Dislodgement of plaques from the carotid artery may cause CRAO. Direct pressure from the headrest may be higher in patients with exophthalmos or low nasal bridge. Cortical Blindness This is due to infarction of the posterior cerebral artery or significant hypotension. This may recover slowly but not completely. Risk factors for cortical blindness include cardiac arrest, air embolism, significant hypotension, or prolonged hypoxia. Prone positioning and obesity were found to be most commonly associated with development of cortical blindness.63 Acute Angle Closure Glaucoma The prone position shifts the lens iris diaphragm forward and obstructs the flow of aqueous humor. This causes sudden increase in intraocular pressure. In high-risk patients, even short surgical procedures may precipitate acute angle closure glaucoma. Most POVL is ION which has been associated with duration of procedure more than 6 h, blood loss more than 1000 ml, DM, hypertension, smoking, and small cup to disc ratio. ION occurs irrespective of the frame and frequency of eye checks. Short-staged procedures with careful positioning of the head (10–15° head up), avoiding swings of blood pressure, maintaining MAP ≥ 70 mmHg, hematocrit > 25 mmHg are strategies which will reduce the incidence of POVL. Continuous real-time monitoring of the eye has been described by Woodruff et al. as an alternative to frequent monitoring of eye position. Table 10.5 summarizes the task force recommendation for prevention of perioperative vision loss.64 TABLE 10.5 Practice Advisory for Perioperative Visual Loss Associated With Spine Surgery SUMMARY OF ADVISORY STATEMENTS I. Preoperative patient evaluation and preparation Although the consultants and specialty society members agree that there are identifiable preoperative risk factors, at this time the Practice Advisory Task Force does not believe that there are identifiable preoperative patient characteristics that predispose patients to perioperative ION. t F urther, the Task Force believes that there is no evidence that an ophthalmic or neuro-ophthalmic evaluation would be useful in identifying patients at risk for perioperative visual loss. t T he Task Force believes that the risk of perioperative ION may be increased in patients who undergo prolonged procedures, have substantial blood loss, or both. t C onsider informing patients in whom prolonged procedures, substantial blood loss, or both are anticipated that there is a small, unpredictable risk of perioperative visual loss. t B ecause the frequency of visual loss after spine surgery of short duration is very low, the decision to inform patients who are not anticipated to be “high risk” for visual loss should be determined on a case-by-case basis. II. Intraoperative management blood pressure management t S ystemic blood pressure should be monitored continually in high-risk patients. t T he Task Force believes that the use of deliberate hypotensive techniques during spine surgery has not been shown to be associated with the development of perioperative visual loss. Therefore, the use of deliberate hypotension for these patients should be determined on a case-by-case basis. Management of intraoperative fluids t C entral venous pressure monitoring should be considered in high-risk patients. t C olloids should be used along with crystalloids to maintain intravascular volume in patients who have substantial blood loss. Management of anemia t H emoglobin or hematocrit values should be monitored periodically during surgery in high-risk patients who experience substantial blood loss. t T he Task Force believes that there is no documented lower limit of hemoglobin concentration that has been associated with the development of perioperative visual loss. Therefore, the Task Force believes a transfusion threshold that would eliminate the risk of perioperative visual loss related to anemia cannot be established at this time. Use of vasopressors t T he Task Force consensus is that there is insufficient evidence to provide guidance for the use of adrenergic agonists in high-risk patients during spine surgery. Therefore, the decision to use adrenergic agonists should be made on a case-by-case basis. V. POSITIONS IN NEUROSURGERY ABBREVIATIONS 203 TABLE 10.5 Practice Advisory for Perioperative Visual Loss Associated With Spine Surgery—cont’d Patient positioning t T he Task Force believes that there is no pathophysiologic mechanism by which facial edema can cause perioperative ION. t T here is no evidence that ocular compression causes isolated perioperative anterior ION or posterior ION. However, direct pressure on the eye should be avoided to prevent CRAO. t T he high-risk patient should be positioned so that the head is level with or higher than the heart when possible. t T he high-risk patient’s head should be maintained in a neutral forward position (e.g., without significant neck flexion, extension, lateral flexion, or rotation) when possible. III. Staging of surgical procedures t A lthough the use of staged spine surgery procedures in high-risk patients may entail additional costs and patient risks (e.g., infection, thromboembolism, or neurologic injury), it also may decrease these risks and the risk of perioperative visual loss in some patients. Therefore, consideration should be given to the use of staged spine procedures in high-risk patients. IV. Postoperative management t T he consensus of the Task Force is that a high-risk patient’s vision should be assessed when the patient becomes alert (e.g., in the recovery room, intensive care unit, or nursing floor). t I f there is concern regarding potential visual loss, an urgent ophthalmologic consultation should be obtained to determine its cause. t A dditional management may include optimizing hemoglobin or hematocrit values, hemodynamic status, and arterial oxygenation. t T o rule out intracranial causes of visual loss, consider magnetic resonance imaging. t T he Task Force believes that there is no role for antiplatelet agents, steroids, or intraocular pressure-lowering agents in the treatment of perioperative ION. An updated report by the American Society of Anesthesiologists Task Force on perioperative visual loss. CRAO, central retinal artery occlusion; ION, ischemic optic neuropathy. CONCLUSION Surgical procedures of the brain and spine require complex positioning so that the surgical target is easily accessible to the surgeon. It is a delicate balance between the best surgical approach and the physiologically optimal position for the patient. Within physiological limits, positioning should be modified so as to assist the surgical goals such as reduction of bleeding, ICP, minimal brain retraction. Careful attention and meticulous protection should be offered to vulnerable tissues especially during prolonged duration of surgery. Optimal positioning is the key to prevent morbidity and improve surgical outcomes following complex neurosurgical procedures. ABBREVIATIONS A-line Arterial line CI Cardiac index CO Cardiac output CPP Cerebral perfusion pressure CSF Cerebrospinal fluid CVJ Craniovertebral junction ECG Electrocardiogram EDH Extradural hemorrhage ETT Endotracheal tube EVD External ventricular drainage FRC Functional residual capacity ICP Intracranial pressure IV Intravenous JVF Jugular venous flow JVR Jugular venous resistance LVEF Left ventricular ejection fraction MFK Mayfield Kees OT Operating theater PAP Pulmonary arterial pressure PVR Pulmonary vascular resistance SCD Sequential compression device SV Stroke volume SVR Systemic vascular resistance TED Thromboembolic deterrent TLC Total lung capacity V/Q Ventilation–perfusion VTE Venous thromboembolism V. POSITIONS IN NEUROSURGERY 204 10. POSITIONING IN NEUROSURGERY References 1. Richard Winn H. General principles of operative positioning. In: YOUMANS neurological surgery. 5th ed. Philadelphia, PA: Saunders, Elsevier; 2004. p. 595–621. 2. Moore DC, Edmunds LH. 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J Anesth 2008;22(3):312–6. 61. Stambough JL, Dolan D, Werner R, Godfrey E. Ophthalmologic complications associated with prone positioning in spine surgery. J Am Acad Orthop Surg March 2007;15(3):156–65. 62. Lee LA, Newman NJ, Wagner TA, Dettori JR, Dettori NJ. Postoperative ischemic optic neuropathy. Spine April 20, 2010;35(Suppl. 9):S105–16. 63. Li A, Swinney C, Veeravagu A, Bhatti I, Ratliff J. Postoperative visual loss following lumbar spine surgery: a review of risk factors by diagnosis. World Neurosurg December 2015;84(6):2010–21. 64. American Society of Anesthesiologists Task Force on Perioperative Visual Loss. Practice advisory for perioperative visual loss associated with spine surgery: an updated report by the American Society of Anesthesiologists Task Force on perioperative visual loss. Anesthesiology February 2012;116(2):274–85. V. POSITIONS IN NEUROSURGERY This page intentionally left blank S E C T I O N V I PREANESTHETIC EVALUATION This page intentionally left blank C H A P T E R 11 Preanesthetic Evaluation of Neurosurgical Patients R. Mariappan Christian Medical College, Vellore, India O U T L I N E Introduction Preoperative Evaluation of Patients With Diabetes and Hypertension Preoperative Medication Evaluation Comprehensive Neurological Examination for Neuroanesthesiologist 209 Preoperative Evaluation of Patient-Related Risk Factors 210 Preoperative Evaluation of Cardiac Risk in Neurosurgical Patients 210 Risk Assessment Tools for Estimating Cardiac Risk 210 Assessment of Functional Capacity 211 Indication for Cardiac Testing During Preoperative Evaluation 211 Evaluation of Pulmonary Risk in Patients Undergoing Neurosurgical Procedure 211 Preoperative Pulmonary Risk Stratification 212 Indication for Preoperative Pulmonary Testing 212 Preoperative Evaluation of Patients With Obstructive Sleep Apnea 213 Various Screening Tools for the Diagnosis of Obstructive Sleep Apnea 213 Specific Issues to Be Considered During Preoperative Evaluation of Patients With Obstructive Sleep Apnea 213 Preoperative Evaluation of Specific Neurosurgical Conditions Preoperative Evaluation of Patients With Supratentorial and Posterior Fossa Tumor Preoperative Evaluation of Patients for Awake Craniotomy Preoperative Evaluation of Patients With Pituitary Diseases Preoperative Evaluation of Patients With Suprasellar Lesions Preoperative Evaluation of Patients With Epilepsy Preoperative Evaluation of Patients With Subarachnoid Hemorrhage Preoperative Evaluation of Patients With Arteriovenous Malformation References 213 214 214 217 217 219 220 220 222 223 224 225 INTRODUCTION A routine preanesthetic evaluation is a process that includes clinical assessment, risk stratification, and optimization before surgery. The primary aim of the preanesthetic evaluation is to reduce the perioperative morbidity and mortality. This involves many steps, which include: 1. Establishing rapport with the patient and family, explaining the process of surgery, anesthesia, and recovery. 2. Reviewing the past medical, surgical, personal and family history and history of medication allergy and the lists of current medication. Essentials of Neuroanesthesia http://dx.doi.org/10.1016/B978-0-12-805299-0.00011-7 209 © 2017 Elsevier Inc. All rights reserved. 210 11. PREANESTHETIC EVALUATION OF NEUROSURGICAL PATIENTS 3. A through general and clinical examination focusing on cardiopulmonary system and nervous system. 4. Review of investigations and to assess whether further investigations or multidisciplinary care is needed, which would help to improve the patient condition. 5. Risk-stratifying the patient for perioperative morbidity and mortality using clinical and laboratory data for the proposed surgical procedure. 6. Optimization of the patient using the risk reduction strategies. 7. To plan the type of anesthesia after assessing the risk/benefit of each anesthetic technique for that particular procedure. 8. Utilization of best available resources to maximize the safety, to reduce the morbidity and mortality, and to speed up the recovery by providing adequate postoperative pain management. 9. Getting an informed consent after explaining the risk and benefits of anesthesia technique and the need for invasive monitoring, blood transfusion (if applicable), and its associated risks. Preanesthetic evaluations should be performed well ahead of the surgical procedure especially for high-risk patients [American Society of Anesthesiologists (ASA) grades 3 and 4] thereby allowing time for preoperative optimization, which has been shown to reduce the perioperative morbidity and mortality.1,2 Patients with ASA grades 1 and 2 can undergo preoperative evaluation either on the day of surgery or the day before surgery. ASA classification of physical status is a universally accepted grading system to stratify the patient’s preexisting health condition. Although it was not designed for outcome prediction, there has been a good correlation between the grading and perioperative morbidity and mortality.3–5 Most patients undergoing neurosurgical procedures will have an underlying medical comorbidities such as diabetes, hypertension, ischemic heart diseases (IHD), obstructive sleep apnea (OSA), and chronic obstructive pulmonary disease (COPD), or bronchial asthma and seizures. These medical conditions require more intense scrutiny than the pathological process to prevent perioperative morbidity and mortality. Each neurosurgical procedure carries its inherent risk and requires specific preoperative evaluation and optimization. So, during the preoperative evaluation both patient- and procedure-related factors should be kept in mind and optimized accordingly. PREOPERATIVE EVALUATION OF PATIENT-RELATED RISK FACTORS In this section, the preoperative evaluation of patient-related risk factors focusing on cardiac and respiratory conditions, OSA, diabetes, and hypertension are discussed. Preoperative Evaluation of Cardiac Risk in Neurosurgical Patients Most neurosurgical procedures are considered to be intermediate- to high-risk surgeries. Patients with cardiac diseases undergoing neurosurgical procedure can have aggravation of cardiac dysfunction due to the systemic effect of raised intracranial pressure (ICP) (tumor, head injury) or catecholamine surge [in subarachnoid hemorrhage (SAH)] or autonomic dysfunction (Parkinson disease, cervical myelopathy, and brainstem lesion) leading to increased morbidity. Long-standing hypertension and diabetes are common in patients undergoing carotid endarterectomy and spine surgery, and these patients are more prone for IHD. Identification of cardiac risk associated with each neurosurgical procedure provides information to both the patient and the surgeon, which in turn helps them to understand the benefit vs. risk of a procedure. Cardiac interventions even before the surgery in certain high-risk cases decreases the perioperative morbidity and mortality. Risk Assessment Tools for Estimating Cardiac Risk There are various risk assessment tools available to assess the cardiac risk in patient undergoing neurosurgery. These tools use the information obtained from the history, physical examination, electro- and echocardiogram, and type of surgery. The various tools are given below. 1. Revised Cardiac Risk Index (Lee’s) tool6: This is the most commonly used tool and was originally published in 1999; it has been used to assess the risk for >15 years. It uses six factors such as high-risk surgery, history of IHD, congestive heart failure (CHF), cerebrovascular diseases, diabetes or insulin, and presence of high creatinine to estimate the cardiac risk. Using the aforementioned predictors, the estimated risk of cardiac death, nonfatal cardiac arrest, and nonfatal myocardial infarction (MI) following the elective surgical procedure are 0.4% [95% VI. PREANESTHETIC EVALUATION PREOPERATIVE EVALUATION OF PATIENT-RELATED RISK FACTORS 211 confidence interval (CI): 0.1–0.8] if there is no risk factor and 1.0% (95% CI: 0.5–1.4) if there is one risk factor. The risk increases to 2.4% (95% CI: 1.3–3.5) and 5.4% (95% CI: 2.8–7.9) if there are two and three or more risk factors, respectively.7 2. American College of Surgeons-National surgical Quality Improvement Program (ACS-NSQIP) universal surgical risk calculator8: This surgical risk calculator model is a Web-based tool consisting of 20 patient factors such as body mass index (BMI), age, sex, ASA classification, functional status, prior cardiac history, and so on. The calculator then provides a risk of a major adverse cardiac event for the patient. This model had excellent performance for mortality, morbidity, and six additional complications. Limitations of this tool are that it is more cumbersome and its external validity is still questionable. 3. Gupta myocardial infarction/cardiac arrest (MICA)-NSQIP database risk model9: This risk model uses the following five factors to assess the risk of perioperative MI and cardiac arrest. They are (1) type of surgery, (2) dependent functional status, (3) abnormal creatinine, (4) American Society of Anesthesiologists’ class, and (5) increased age. Assessment of Functional Capacity Assessment of patients functional capacity is the next step in cardiac evaluation, expressed in metabolic equivalents (METs). One MET is defined as 3.5 mL of O2 uptake/kg/min in a sitting position, which is a resting oxygen uptake. Duke activity state Index is one of the most frequently used scales to assess the functional status.10 Ability to take care of oneself, such as eating, dressing, or using the toilet is considered 1 MET. Walking up a flight of steps or a hill or walking on level ground at 3–4 mph is considered as 4 METs. Participating in strenuous sports such as swimming, singles tennis, football, basketball, and skiing is equivalent to >10 METs. Ability to do an activity that requires >4 METs indicates good functional activity. Assessing the functional capacity in patients with walking disability such as paraplegia or hemiplegia can be done by using bicycle or arm ergometry stress testing.11 After determining the cardiac risk and functional capacity, one can follow the multistep algorithm provided by the American College of Cardiology (ACC) and American Heart Association (AHA) for determining the need for further preoperative cardiac evaluation before proceeding with surgery. Refer ACC and AHA 2014 guideline for details.12 Indication for Cardiac Testing During Preoperative Evaluation Electrocardiogram (ECG): All patients with cardiac problems such as IHD, arrhythmias, valvular heart diseases (VHD), and peripheral arterial diseases should obtain a baseline ECG to compare the changes that occur during the perioperative period. Patients with neurological problem such as raised ICP or SAH have underlying cardiac dysfunction, they often need baseline ECG. Echocardiography: It is indicated to assess the ventricular function in symptomatic patients (dyspnea or heart failure), patients with VHD, and patients with past history of previously documented cardiac dysfunction with no assessment within 1 year.13 Stress echocardiography: Although there is a correlation between the degree of MI and the prognosis, there is no evidence that prophylactic revascularization at the time of surgery improves outcomes. So, further cardiac evaluation (stress echocardiography or 24-h ambulatory monitoring) is only indicated in patients with known IHD with recent deterioration.14 Evaluation of Pulmonary Risk in Patients Undergoing Neurosurgical Procedure The incidence of perioperative pulmonary complications (POPCs) are high in patients with preexisting lung (obstructive, restrictive) diseases. Perioperative hypoxia and hypercapnia not only affect the cardiorespiratory status but also can aggravate the existing neurological illness. Neurosurgical patients are more prone to pulmonary complications because of low Glasgow Coma Scale (GCS) score (tumor, head injury, seizure, SAH), lower cranial nerve dysfunction in posterior fossa tumors or cranio vertebral junction anomalies causing aspiration pneumonia, or the presence of a high cervical or thoracic spine lesion causing cord compression leading to restrictive lung diseases. POPCs contribute significantly to overall perioperative morbidity and mortality in the neurosurgical population. According to the NSQIP report, POPCs are the costliest of all postoperative medical complications (including cardiac, thromboembolic, and infectious) and resulted in the longest length of hospital stay.15,16 POPC is defined as any pulmonary disease or dysfunction that is clinically significant or adversely affects the clinical course of the patient.17,18 They are (1) atelectasis, (2) infection including bronchitis and pneumonia, (3) prolonged mechanical ventilation (>48 h), (4) respiratory failure, (5) exacerbation of underlying chronic lung disease, and (5) bronchospasm. VI. PREANESTHETIC EVALUATION 212 11. PREANESTHETIC EVALUATION OF NEUROSURGICAL PATIENTS Preoperative Pulmonary Risk Stratification A complete history and physical examination are the most important elements of preoperative pulmonary risk assessment. Based on the available literature, the risk factors for POPC are classified into definite and probable, which are listed in Table 11.1.19,20 There are many risk prediction tools available to stratify the postoperative pulmonary risk21,22; they are (1) ARISCAT (Canet) risk index used for predicting POPC,21 (2) Arozullah index for predicting postoperative pneumonia23 and respiratory failure,24 (3) Gupta calculator for predicting postoperative pneumonia25 and respiratory failure,26 and (4) ASA grading for predicting POPC.5 1. ARISCAT (Canet) risk index: It predicts the overall incidence of postoperative pulmonary complications using the patient’s age, preoperative oxygen saturation, recent respiratory infection, preoperative anemia, type of surgical incision, and duration of surgery. It has a total of 165 points; patients with low scores (<26 points) are considered as low risk and patients with high score (>45 points) are considered as high risk for POPC. According to this risk index the incidence of POPC is 1.6%, 13.3%, and 42.2% for low-, intermediate-, and high-risk classes. It is a very simple tool that calculates the risk manually at the bedside using the readily available clinical information. The limitation of this tool is it that includes even the minor complications such as wheezing treated with bronchodilators, which is not clinically significant. 2. ASA classification: ASA classification has been shown to predict the postoperative pulmonary complication.5 The incidence of POPC for ASA grades 1, 2, 3, and 4 are 1.2%,5.4%, 11.4%, and 10.9%, respectively. Indication for Preoperative Pulmonary Testing 1. Chest X-ray: Recent chest X-ray (within 6 months) is warranted for patients older than 50 years with cardiopulmonary diseases undergoing major surgery.27 2. Pulmonary function test (PFT): Based on a systematic review, the American College of Physicians guideline recommends that PFT should not be used for risk stratification. It should be reserved to determine the clinical cause only in patients with COPD and asthma, in whom clinical evaluation cannot determine the reduction in airflow obstruction, and in patients with unexplained dyspnea or poor exercise tolerance.28 3. Arterial blood gas (ABG) analysis: In patients with severe COPD, PaCO2 >45 mmHg is one of the probable risk factors for POPC. However, routine ABG is not warranted for risk stratification.29 Preoperative risk reduction strategies to reduce POPCs are as follows28: 1. Smoking cessation for more than 8 weeks prior to surgery has been shown to reduce the perioperative morbidity and mortality.30,31 2. Preoperative administration of inhaled bronchodilators and glucocorticoids in patients with COPD and asthma.32,33 3. Treating the exacerbation of asthma and COPD with systemic glucocorticoids (e.g., prednisone 40 mg/day for 5 days) and treating the lower respiratory tract infection with antibiotics and postponing the elective surgery.34 4. Preoperative education regarding lung expansion maneuvers and initiation of chest physiotherapy such as aerobic exercises, breathing exercises, and inspiratory muscle training.35 TABLE 11.1 Risk Factors for POPC Definite Risk Factors Probable Risk Factors Patient related 1. Age >65 years 2. Poor general health status (ASA class >2) 3. Functional dependence 4. Heart failure 5. Chronic obstructive lung disease Procedure related 6. Upper abdominal, open thoracic, head and neck, neurosurgical, and abdominal aortic aneurysm surgery 7. Emergency surgery 8. Anesthesia lasting >3 h, 9. Use of long-acting muscle relaxants 1. General anesthesia (compared to spinal, epidural anesthesia, or other regional anesthetic techniques) 2. Arterial tension of carbon dioxide (PaCO2) >45 mmHg (5.99 kPa) 3. Postoperative nasogastric tube placement 4. Abnormal chest radiograph 5. Cigarette use within the previous 8 weeks 6. Current upper respiratory tract infection Test predictors 10. Albumin level <3 g/dL ASA, American Society of Anesthesiologists; POPC, postoperative pulmonary complication. VI. PREANESTHETIC EVALUATION PREOPERATIVE EVALUATION OF PATIENT-RELATED RISK FACTORS 213 Preoperative Evaluation of Patients With Obstructive Sleep Apnea OSA is a sleep-related breathing disorder characterized by repetitive episodes of apnea or hypopnea due to upper airway obstruction during sleep. It is classified into mild, moderate, and severe according to the Apnea–Hypopnea Index (AHI). AHI of 5–15 per hour is mild OSA, AHI of 15–30 per hour is considered as moderate OSA, and AHI >30 per hour is considered as severe OSA. Over the past two decades, with the parallel increase in obesity, the prevalence of OSA is rapidly increasing.36 Studies have reported that the incidence of OSA is >30% in neurosurgical population. Patients with Cushing disease, acromegaly, intractable epilepsy, and intracranial tumors are more prone to OSA.37–39 Studies and metaanalysis have concluded that the incidence of postoperative desaturation, respiratory failure, postoperative cardiac events, and intensive care unit (ICU) transfers were higher in patients with OSA.40,41 Over half of patients with OSA who present for surgery are undiagnosed42; the complication rates are two- to fourfold higher when compared with those who are optimized preoperatively.43 OSA-related postoperative complications are common because of the following reasons: 1. Administration of perioperative medication (sedatives, opioids, neuromuscular blocking drugs) 2. Worsening of airway edema (endotracheal tube placement, throat pack application, tracheal retraction, headdown positioning, prone position) 3. Discontinuation of continuous positive airway pressure (CPAP) therapy in patients undergoing transsphenoidal surgery 4. Sleep deprivation due to pain, anxiety, and ICU environment can all lead to increased rapid eye movement sleep, which increases the OSA episodes44 5. Presence of OSA-related comorbidities [obesity systemic hypertension, obesity hypoventilation syndrome (OHS), pulmonary hypertension, cardiac arrhythmias, coronary artery disease, and heart failure] Various Screening Tools for the Diagnosis of Obstructive Sleep Apnea 1. STOP-BANG questionnaire45,46: It is a very simple tool to screen, and it is the most frequently used questionnaire in our practice. It requires “Yes” or “No” responses to eight questions about snoring, tiredness, observed apnea, and blood pressure; body mass index>35 kg/m2, age >50 years, neck circumference >40 cm, and male gender. Patients with zero to two positive responses are considered “low risk,” those with three to four are considered “intermediate risk,” and those with five to eight positive responses are considered “high risk for OSA.” Patients with raised serum bicarbonate level (≥28 mmol/L) with a STOP-BANG score of ≥3 are equals to STOP-BANG score of ≥5. These patients are considered to have moderate to severe OSA.47 2. Sleep Apnea Clinical Score—Flemons’ screening tool48: It is four-item questionnaire (habitual snoring, nocturnal gasping/choking, neck circumference, hypertension) with the score ranging from 0 to 100. Values >15 indicate that the patient is at high risk for OSA. 3. Berlin Questionnaire49: This uses items such as snoring, excessive daytime sleepiness, sleepiness while driving, apnea during sleep, hypertension, and BMI to stratify patients as having a high or low risk for OSA. Specific Issues to Be Considered During Preoperative Evaluation of Patients With Obstructive Sleep Apnea While evaluating patients with OSA, the symptoms and signs of OSA; the duration, severity, and presence of OSA-related comorbidities, type of treatment given (CPAP or bilevel positive airway pressure); response to treatment; and the details of current airway pressure setting all, need to be documented. Patients with long-standing OSA are more prone for OHS and pulmonary hypertension.50 Elevated bicarbonate level and hypoxemia are the indicators OHS. Presence of OHS and pulmonary hypertension indicates the need for echocardiography. Patients with severe OSA have to be admitted and optimized at least 1 week prior to surgery. Practice Guidelines for the Perioperative Management of Patients With OSA—an updated report by the American Society of Anesthesiologists Task Force—was published in 2014 based on expert opinion, literature review, and consensus.51 Preoperative Evaluation of Patients With Diabetes and Hypertension Detailed discussion on preoperative evaluation on both these conditions are beyond the scope of this chapter. Specific concerns regarding diabetes and hypertension and their anesthetic implications are given in Tables 11.2 and 11.3. VI. PREANESTHETIC EVALUATION 214 11. PREANESTHETIC EVALUATION OF NEUROSURGICAL PATIENTS TABLE 11.2 Specific Concerns While Evaluating Patients With DM Specific Concerns Details Regarding Specific Points 1. Type and duration of diabetes Patients with type I DM are more prone for perioperative complications. Longer duration of diseases is associated with increased perioperative complications 2. Treatment history Insulin: Type of insulin, dose, frequency, timing. OHA: Type, dose, frequency, complication of drugs (lactic acidosis) 3. Adequacy of glycemic control Trends and ranges of blood glucose level during the immediate preoperative period including HbA1C (reveals 3 months’ control). Incidence of hypoglycemia, and its severity Perioperative administration of dexamethasone can cause aggravation of hyperglycemia 4. Presence of long-term complications Look for signs of neuropathy, retinopathy, nephropathy, peripheral vascular diseases, and IHD—increases the perioperative morbidity and mortality DM, diabetes mellitus; HbA1C, glycosylated hemoglobin; IHD, ischemic heart diseases; OHA, oral hypoglycemic agents. TABLE 11.3 Specific Concerns While Evaluating a Patient With Hypertension Specific Concerns Details Regarding Specific Points 1. Duration of hypertension Long-standing hypertension is associated with LVH and its associated complication (systolic and diastolic dysfunction), which increases the perioperative morbidity 2. Type of antihypertensive β-Blocker/calcium channel blocker/ACE inhibitor/ARB/central sympatholytic drugs Drug effects and its anesthetic implications are discussed in detail in medication evaluation section 3. Adequacy of blood pressure control Blood pressure trends during the perioperative period should be noted especially in the presence of white coat hypertension 4. Presence of long-term complications Look for LVH as well as systolic and diastolic dysfunction. Presence of these complications are associated with increased perioperative morbidity ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; LVH, left ventricular hypertrophy. Preoperative Medication Evaluation Patients undergoing neurosurgical procedures will be on multiple medication, either for their neurological diseases itself (anticonvulsants, antiedema drugs, H2 blockers, or proton pump inhibitors) or for their associated medical comorbidities. Most medications are known to cause interaction with anesthetics. There are large variations in recommendation among the anesthesiologist in regard to continuing/discontinuing certain drugs during the perioperative period. Every physician should balance the risks vs. benefits of continuing/discontinuing the drug during the perioperative period. Commonly used drugs in neurosurgical practice and their anesthetic interactions and the recommendation regarding whether they need to be continued or stopped before surgery are given in Table 11.4. These recommendations are based on expert opinions and their reviews and the theoretical considerations. Comprehensive Neurological Examination for Neuroanesthesiologist If an anesthesia technique (general or regional) can affect an organ system, then that organ system should be evaluated and documented preoperatively by the anesthesiologist. Although most patients’ neurological status is assessed and documented by the neurosurgeon before coming to the preanesthesia clinic, it is better that every neuroanesthesiologist know how to perform a comprehensive neurologic screening examination. While doing a preoperative evaluation of neurosurgical patients, the pulmonary and cardiac examination should be done prior to neurological examination to integrate other physical findings with the presenting neurological abnormality. For VI. PREANESTHETIC EVALUATION 215 PREOPERATIVE EVALUATION OF PATIENT-RELATED RISK FACTORS TABLE 11.4 Showing the Commonly Used Medications in Neurosurgical Practice and the Benefits/Risk of Continuing These Drugs in the Perioperative Settings Drug Strategy to Continue Yes/No Β$Blockers Yes Perioperative Anesthetic Implications Benefits/Anesthetic Drug Interaction Risks Decreases the myocardial ischemia by reducing the oxygen demand Increases the risk of perioperative bradycardia and hypotension Controls and prevents arrhythmias Nonselective β-blockers can interact with epinephrine or ephedrine and cause hypertensive crisis due to unopposed alpha stimulation Perioperative initiation reduces the cardiovascular morbidity but increases the risk of stroke (POISE I trial) in high-risk cardiac patients. Abrupt withdrawal increases the cardiovascular morbidity α-Blocker (clonidine) Calcium channel blocker Yes Yes Improves the perioperative outcome (proven only in a smaller studies) Increases the incidence of hypotension and nonfatal cardiac arrest. (POISE II trial) Abrupt withdrawal can cause rebound hypertension and myocardial ischemia Perioperative initiation is not warranted No interaction with anesthetic drugs Abrupt withdrawal can cause coronary spasm Since it decreases the platelet aggregation, there is a conflicting opinion regarding its bleeding risk ACE inhibitor and angiotensin II receptor blocker Yes/no Decision to continue or discontinue depends on the patient’s condition Increased incidence of perioperative hypotension and the need for inotropes According to ACC/AHA 2014 guidelines— Withdrawal can cause postoperative to continue if the patient is taking for hypertension hypertension or CHF Risk vs. benefits of intraoperative hypotension should be kept in mind Diuretics Yes/no No consensus available regarding discontinuation HMG CoA reductase inhibitors (statins) Yes Reduces the cardiovascular and cerebrovascular morbidity because of its cholesterol-lowering effect, plaque stabilization, antiinflammatory, and decreased thrombogenesis effects Increased incidence of perioperative hypotension and hypokalemia No interaction with anesthetic drug OHAs No No interaction with anesthetic drugs Intraoperative hypoglycemia with sulfonylureas Increased incidence of lactic acidosis with metformin Thiazolidinediones worsen the peripheral edema and fluid retention and HF Sodium–glucose cotransporter 2 inhibitors increase the risk of hypovolemia DPP-IV inhibitors and GLP-1 analogs alter the GI motility and worsen the postoperative state AEDs Yes Continued VI. PREANESTHETIC EVALUATION 216 11. PREANESTHETIC EVALUATION OF NEUROSURGICAL PATIENTS TABLE 11.4 Showing the Commonly Used Medications in Neurosurgical Practice and the Benefits/Risk of Continuing These Drugs in the Perioperative Settings—cont’d Drug Strategy to Continue Yes/No Carbamazepine, phenytoin, Hepatic microsomal isoenzyme (CYP 450) inducer Perioperative Anesthetic Implications Benefits/Anesthetic Drug Interaction Risks Drugs that causes enzyme induction accelerate the metabolism of drugs metabolized by this enzyme system, thereby increasing the requirement of propofol, opioid, and muscle relaxants Oxcarbamazepine, eslicarbazepine: weak enzyme inducer Sodium valproate: enzyme inhibition Drugs that cause enzyme inhibition decrease the metabolism of drugs metabolized by this enzyme system, thereby decreasing the requirement of propofol, opioid, and muscle relaxants Gabapentin, lamotrigine, levetiracetam, tiagabine, vigabatrin: do not affect hepatic enzyme system Aspirin (low dose 75–300 mg) No Neurosurgical operations are closed space surgery and considered to be moderateto high-risk surgeries, aspirin has to be stopped 7 days prior to surgery Platelet P2Y12 receptor blockers Increases the bleeding risk if it is continued. Increased bleeding risk Clopidogrel No Clopidogrel to be stopped 5–7 days prior to surgery Ticlopidine No Ticlopidine had to be discontinued 10 days prior to surgery Dipyridamole No Dipyridamole has to be discontinued 2 days prior to surgery Aggrenox (Aspirin + dipyridamole) No Aggrenox had to be stopped 7–10 days prior to surgery H2 blockers and proton pump inhibitors Yes Decreases the mucosal damage, decreases Cimetidine is the only drug that interferes the gastric secretion, and increases the with many drug metabolism gastric pH thereby decreasing the chance of aspiration pneumonitis TCAs No (Imipramine, amitriptyline, nortriptyline, desipramine, and clomipramine) Abrupt withdrawal causes insomnia, Increases the risk of perioperative nausea, headache, increased salivation, and arrhythmia in combination with volatile sweating and should be avoided anesthetics and sympathomimetics SSRIs No Abrupt discontinuation can lead to dizziness, chills, muscle aches, and anxiety SSRIs increases the bleeding risk so, it has to be tapered and stopped 2–3 weeks earlier. It has to be replaced with another regime of antidepressant to avoid exacerbation of mood disorder No Causes accumulation of biogenic amines in central and autonomic system neurons by causing irreversible inhibition of MAO Concomitant administration of sympathomimetic agents can result in hypertensive crisis (Paroxetine, fluvoxamine, sertraline, fluoxetine) MAO inhibitors With pethidine and tramadol, it can cause serotonin syndrome VI. PREANESTHETIC EVALUATION PREOPERATIVE EVALUATION OF SPECIFIC NEUROSURGICAL CONDITIONS 217 Table 11.4 Showing the Commonly Used Medications in Neurosurgical Practice and the Benefits/Risk of Continuing These Drugs in the Perioperative Settings—cont’d Strategy to Continue Yes/No Drug (Isocarboxazid, pargyline, phenelzine, and tranylcypromine) Perioperative Anesthetic Implications Benefits/Anesthetic Drug Interaction Risks Recovery of MAO function takes 2 weeks after discontinuation of the drug. So, drug should be tapered and stopped 2 weeks before elective surgery Coadministration of pethidine can cause type I serotonin syndrome By inhibiting the hepatic microsomal enzyme system responsible for opioid metabolism, it can cause type II reaction. (sedation, respiratory depression, and cardiovascular collapse) Antipsychotics Yes/no Antipsychotic effectively controls the psychoses in vulnerable patients. Both typical and atypical antipsychotic drugs are associated with an increased risk for sudden death because of QT prolongation and arrhythmogenic effect Should be used cautiously in the perioperative settings. Frequent ECG monitoring is needed especially in the perioperative settings Potentiates the effect of sedatives, anaesthetics, and analgesics ACC, American College of Cardiology; ACE, angiotensin-converting enzyme; AED, antiepileptic drugs; AHA, American Heart Association; CHF, congestive heart failure; DPP-IV, dipeptidyl peptidase IV; ECG, electrocardiogram; GLP-1, glucagon-like peptide 1; GI, gastrointestinal; HMG-CoA, 3-hydroxy-3-methyl-glutarylcoenzyme A; MAO, monoamine oxidase; OHA, oral hypoglycemic agents; SSRIs, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressants. example, raised ICP decreases the pulmonary compliance and causes cardiac conduction abnormality. Similarly, SAH can cause myocardial dysfunction and pulmonary edema due to severe catecholamine surge. The purpose of the neurological examination is: 1. 2. 3. 4. To determine the general location and extent of the neurological lesion. To document the nervous system malfunction so that perioperative comparison is easier. To determine and document the patient’s preoperative physical status and stability. To develop an appropriate anesthesia management plan according to their physical status. Neurological examination can be accomplished within minutes if it is performed in an organized and systematic fashion. Based on the patient’s chief complaint or findings on the screening examination, components of the evaluation are then elaborated upon. For example, a full mental status examination is not necessarily warranted in the patient who is awake, oriented, and conversant, while it must be fully investigated in patients with altered mental status or a history of a change in behavior. Likewise, in a patient with no sensory complaints, determination of the ability to distinguish sharp from dull bilaterally is sufficient, while a patient complaining of vague sensory deficits needs to be tested for extinction on simultaneous sensory stimulation on both the limbs for assessing the sensory level, or for astereognosis (inability to identify an object by palpation). A comprehensive method to perform a quick neurological examination is listed in Table 11.5. PREOPERATIVE EVALUATION OF SPECIFIC NEUROSURGICAL CONDITIONS Preoperative Evaluation of Patients With Supratentorial and Posterior Fossa Tumor Brain tumors are the leading cause of cancer-related death in children and young adults with an estimated prevalence of 222/100,000.52 While evaluating a patient with supra- or infratentorial tumor one should focus on history including the current medication, neurological examination, relevant general and systemic examination, radiological examination, review of laboratory investigation, and the probable diagnosis. The main aim of preoperative evaluation is to find out the extent of impairment in cerebral autoregulation and intracranial compliance. Patients who are at the edge of intracranial compliance have to be recognized and treated VI. PREANESTHETIC EVALUATION 218 11. PREANESTHETIC EVALUATION OF NEUROSURGICAL PATIENTS TABLE 11.5 Methods of Performing a Comprehensive Neurological Examination Systems Performing a Quick Neurological Examination Mental status Appearance, mood, thought processes, cognitive function, and speech can be examined while interacting with the patient Altered mental status can be examined using “AVPU” score (A: Alert; V: response to Verbal stimuli; P: response to Painful stimuli U: Unresponsive) and glasgow coma S score Motor system Observe the patient’s gait, ability to perform toe and heel walk. Pronator drift and hand grasp test on the ulnar side: for checking the upper limb weakness Lower limb drift and ability to perform dorsiflexion and plantarflexion: for checking the lower limb weakness If there is an abnormal test result with motor testing as described earlier, more formal testing of the extremity Motor power testing: using 0–5 point score. Grade 0 being no movement and grade 5 being full range of movements against gravity and resistance Reflex testing: biceps (C5, C6), triceps (C7, C8), and patellar (L2, L3, L4) and tendoachilles reflex (S1, S2) and plantar reflex (Babinski sign for UMN lesion) to be tested. Response is graded 0 (no response) to 4+ (hyperreflexia) Note: UMN lesion: spasticity, hyperreflexia, no atrophy or fasciculation on muscle. LMN lesion: flaccidity, hyporeflexia, atrophy or fasciculation of muscle will be present Sensory system Sensory examination is done by testing the pain and light touch on patient’s hands, feet, and limbs bilaterally. Simultaneous sensory extinction testing helps to identify the subtle central nervous system sensory deficits Posterior column testing is generally reserved for patients with suspected neuropathies or patients who present with sensory symptoms Note: Anterior spinothalamic tract carries temperature, pain, and light touch fibers, while the posterior column carries fibers for crude touch, vibration, two-point discrimination, and proprioception Cranial nerve examination By history taking and by observing the patient, the cranial nerves are examined. Cranial nerves II, III, IV, and VI are critical components of the screening examination and must be carefully assessed in all patients with neurologic complaints Cranial nerve II: testing of visual acuity, field, and ophthalmoscopic examination Cranial nerve III: bilateral pupil size and symmetry. Adduction and vertical gaze is checked Cranial nerve IV: internal depression via the superior oblique Cranial nerve VI: abduction via lateral rectus is tested Cerebellar function (coordination and balance) Balance requires an integration of cerebellar, visual, vestibular, and proprioception input. It is evaluated by the Romberg test Romberg test: The patient is asked to stand with his feet together (proprioceptive input), without support; first with eyes open (visual input) and then with eyes closed. Closing the eyes eliminates vision, but with proprioception and vestibular sense intact, the patient will not sway. If there is a proprioceptive deficit, the patient will keep his balance with the eyes open and lose his balance when the eyes are closed. When this occurs, the Romberg test is positive. This indicates posterior spinal column diseases If the patient sways with the eyes open or closed, this is suggestive of a cerebellar lesion that is not compensated by sensory input from the other systems Vertical nystagmus is always central in origin and it persists even at rest, does not fatigue, and does not change with position. (Nylen–Barany maneuver) appropriately to avoid the permanent neurological deficit. The details of preoperative evaluation in patients undergoing supratentorial and infratentorial tumor surgery are given in Tables 11.6 and 11.7. Each tumor type has its own anesthetic significance, so it is important to know the tumor type, its vascularity, and the position of the patient during the surgery. This will help us to plan the anesthetic technique and the type of vascular access needed during surgery. VI. PREANESTHETIC EVALUATION PREOPERATIVE EVALUATION OF SPECIFIC NEUROSURGICAL CONDITIONS 219 TABLE 11.6 Preoperative Evaluation of Patients With Supratentorial Tumor History Focusing on 1. Symptoms of raised ICP: headache, nausea, vomiting, blurring of vision, somnolence 2. Symptoms of focal neurological deficit: motor, sensory and cranial nerve deficit 3. Seizure: type, frequency, antiepileptic use, duration of treatment, response to medication 4. Steroid use: duration, side effects of steroids (hyperglycemia), long-term steroid use warrants perioperative steroid cover 5. Diuretic use: associated hypovolemia. Intraoperative hypotension is severe; can be detrimental to patients with raised ICP 6. Past history of chemotherapy or radiation: certain chemotherapeutic medications are associated with complications such as cardiomyopathy (doxorubicin) or inhibition of plasma cholinesterase activity (cyclophosphamide) and renal or hepatotoxicity Physical Examination 1. Signs of raised ICP: low GCS, hypertension, bradycardia, and papilledema: indicates low intracranial compliance Pupillary asymmetry, hemiparesis, aphasia, deep shallow breathing: indicates decompensated state 2. Other systemic examination focusing the CVS and RS and renal system and risk stratification (discussed separately) 3. Estimation of volume status: because of associated vomiting, diuretic use, SIADH, DI Radiological Examination Using MRI or CT Brain (1) Location (eloquent or noneloquent); (2) size of the tumor and surrounding edema; (3) presence of contrast enhancement (increased vascularity) and involvement of major blood vessel (high risk for bleeding); (4) signs of raised ICP such as midline shift (>5 mm), presence of ventricular effacement or hydrocephalus, and transtentorial or subfalcine herniation; (5) probable diagnosis: meningioma and high-grade glioma; metastasis: bleeding risk is high Others (1) Type of craniotomy planned (frontal, parietal, temporal); (2) position of the patient (supine, supine oblique, lateral, or prone); (3) the need for neuromonitoring technique such as SSEP, MEP, cortical mapping (tumor arising from eloquent areas); (4) need for lumbar drain in patients with deep-seated tumors to avoid excessive brain retraction CT, computed tomography; CVS, cardiovascular system; DI, diabetes insipidus; GCS, Glasgow Coma Scale; ICP, intracranial pressure; MEP, motor evoked potential; MRI, magnetic resonance imaging; RS, respiratory system; SIADH, syndrome of inappropriate antidiuretic hormone; SSEP, somatosensory evoked potential. TABLE 11.7 Preoperative Evaluation in Patients With Posterior Fossa Lesion Symptoms 1. Headache, nausea, vomiting (raised ICP or direct compression of vagal nucleus or area postrema), papilledema (raised ICP) 2. H/o gait disturbance (cerebellar compression) 3. H/o vertigo (brainstem compression) 4. H/o facial deviation or asymmetry (seventh cranial nerve involvement) 5. H/o hearing loss, tinnitus (eighth cranial nerve involvement) 6. H/o dysphagia, and frequent aspiration (lower cranial nerve IX, X, and XI involvement) 7. H/o hoarseness of voice (10th cranial nerve involvement) Signs 1. Cushing response due to raised ICP as well as brainstem compression. 2. Ataxia, tremor, dysmetria, (cerebellar hemisphere), truncal ataxia, titubation, broad based gait (cerebellar vermis) ipsilateral cranial nerve deficit and opposite sensory and motor deficit, rotatory or vertical nystagmus (brainstem involvement). 3. Signs of cranial nerve dysfunction (facial, auditory, glossopharyngeal, vagus): need for postoperative ventilation. 4. Assessment of volume status: to avoid precipitous drop in BP after induction and positioning. 5. CVS examination: to identify the PFO; PFO is one of the relative contraindication for sitting positioning. Presence of long-standing diabetes, Hypertension with LVH, autonomic dysfunction, cervical canal stenosis, presence of a functioning VP shunt are contraindications for sitting position. 6. Cerebellar hemangioblastoma has strong association with pheochromocytoma and VHL syndrome: This has to be evaluated and treated before surgery. Vestibular schwannoma is associated with neurofibromatosis type II. Radiological Examination of MRI or CT (1) Location; (2) size of the tumor and surrounding edema and degree of brainstem compression; (3) features of raised ICP: severity of hydrocephalus, presence of transtentorial (upward), or Tonsillar herniation; (4) probable diagnosis using the radiological findings Other Considerations 1. Type of craniotomy (approach), position of the patient (lateral, prone, park bench position, and sitting position), need for neuromonitoring technique such as SSEP and MEP, facial and other lower cranial nerve monitoring BP, blood pressure; CT, computed tomography; CVS; ICP, intracranial pressure; LVH, left ventricular hypertrophy; MEP, motor evoked potential; MRI, magnetic resonance; PFO; SSEP, somatosensory evoked potential; VHL; VP. Preoperative Evaluation of Patients for Awake Craniotomy Awake craniotomy is the technique of choice for tumors involving eloquent cortical areas and procedures for epilepsy and movement disorders. It is a safe, well-tolerated procedure; careful patient selection is the key to success. Benefits of awake craniotomy are (1) better preservation of eloquent function in tumor surgery,53,54 VI. PREANESTHETIC EVALUATION 220 11. PREANESTHETIC EVALUATION OF NEUROSURGICAL PATIENTS (2) better localization of seizure foci with complete resection in seizure surgery,55 and (3) reduces the hospitalization time and cost when it is performed routinely for some neurosurgical procedure such as small tumor resection, ventriculostomy, and for functional neurosurgery.56 Presence of alcohol or drug abuse, chronic pain disorders, low tolerance to pain, anxiety, and psychiatric disorders are known to cause sedation failure during the procedure. Presence of difficult airway, OSA, morbid obesity, poor seizure control even with multiple medication, and inability to lie flat (orthopnea) are some of the relative contraindications for awakecraniotomy.57,58 Although there are reports of safe use of awake craniotomy in pediatric patients, case selection should be more rigorous and based on the patients’ maturity and the individual risk–benefit assessment.59 Good preoperative psychological preparation, explaining about the level of cooperation needed, and the realistic description of the entire procedure with expected discomforts at certain time period (during craniotomy and dural opening) will help the patient to tolerate the procedure well. A well-conducted preoperative consultation can alleviate the anxiety and improve their cooperation during awake craniotomy. Preoperative Evaluation of Patients With Pituitary Diseases Pituitary gland is a master endocrine gland which controls the other endocrine glands of the body. Pituitary tumors are classified as either micro or macroadenoma according to the size of the tumor (<10 mm: microadenoma, >10 mm: macroadenoma) or it is classified as functioning or nonfunctioning tumor according to presenting features. Microadenomas are often present with features of hormonal hypersecretion and macroadenomas are nonfunctioning tumors that often present with pressure symptoms such as headache, visual field defect, or features of raised ICP due to obstruction of cerebrospinal fluid flow at the level of third ventricle. Sometime macro adenomas can bleed into the tumor and present with hormonal hyposecretion symptoms, otherwise called pituitary apoplexy. These patients often need supplements of steroid and thyroid hormone. The common presentation of pituitary tumors, their associated problems, and their anesthetic significance and specific investigations are discussed in detail in Table 11.8. Preoperative Evaluation of Patients With Suprasellar Lesions Common suprasellar lesions are craniopharyngioma, diaphragma sella meningioma, epidermoid, optic chiasmal glioma, Rathke cleft cyst. Its clinical presentations depend upon the location of the tumor and the involvement of (compressive symptoms) of neighboring structures. Preoperative investigation: In the presence of endocrine dysfunction, apart from routine laboratory investigation, full endocrine workup needs to be done to know the degree of dysfunction and for optimization. In the presence of diabetes insipidus, serum sodium, serum and urine osmolality, and urine specific gravity all, need to be checked and the patient had to be optimized before surgery. Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain had to be seen to know the size and extent of the tumor such as cavernous sinus invasion and carotid artery encasement. Adequate blood needs to be arranged in the presence of vascular involvement TABLE 11.8 Showing the Common Presentations, the Associated Problems, Its Anesthetic Implications, and the Relevant Investigations of Patients With Pituitary Tumor Pituitary Tumor Associated Problems and Its Anesthetic Implications Investigations GH-secreting pituitary adenoma—acromegaly 1. Excess peripheral soft tissue deposition, nerve entrapment syndrome. Enlargement of jaw, hand, feet—difficult IV cannulation and arterial cannulation, difficult mask ventilation 2. Macrognathia, macroglossia, expansion of upper airway soft tissues, hypertrophy of aryepiglottic fold, recurrent laryngeal nerve injury—Difficult airway OSA: need for postoperative respiratory support 3. Hypertension, eccentric LVH, ischemic heart diseases, arrhythmia, heart block, cardiomyopathy—perioperative MI and heart failure 4. Diabetes: already discussed 5. Kyphoscoliosis and proximal myopathy—postoperative respiratory support Routine investigations: CBC, basic metabolic panel (Na, K, creatinine, AC, PC) ECG, echo, chest X-ray, CT brain, MRI brain, ophthalmic examination Specific investigations VI. PREANESTHETIC EVALUATION 1. GH >5 ng/mL 2. Elevated IGF-1 3. Failure to suppress the GH to <1 ng/mL after administration of 75 g of oral glucose 4. Other endocrine workup—TFT, cortisol, LH, FSH, or testosterone PREOPERATIVE EVALUATION OF SPECIFIC NEUROSURGICAL CONDITIONS 221 TABLE 11.8 Showing the Common Presentations, the Associated Problems, Its Anesthetic Implications, and the Relevant Investigations of Patients With Pituitary Tumor Pituitary Tumor Associated Problems and Its Anesthetic Implications Investigations ACTH-secreting tumour: Cushing diseases Truncal obesity, moon facies, buffalo hump, supraclavicular pad of fat—difficult mask ventilation and intubation Routine investigations: same as mentioned earlier Specific investigations: 1. Elevated serum and urinary cortisol 2. Loss of diurnal variation of cortisol 3. Low-dose dexamethasone suppression test (1 mg administered night before sampling)—ACTH undetectable, adrenal cause; ACTH 10–100 ng/mL, pituitary cause; ACTH >200 ng/mL, ectopic origin 4. High-dose dexamethasone suppression test (2 mg every 6 h for 48 h) suppresses both serum and urinary cortisol 5. Inferior petrosal sinus sampling of ACTH 6. CRH stimulation test: increased ACTH level will be seen in pituitary diseases 7. Other endocrine workup—TFT, GH, LH, FSH, or testosterone Friable skin and thin peripheral veins—difficult IV access, extravasation of IVF Osteoporotic joints, especially vertebral joints, vertebral collapse—cervical spine fracture during laryngoscopy and intubation. Fracture of spine during positioning for lumbar drain Retrobulbar fat deposit—Exophthalmos: corneal abrasion and ulcer, proper eye covering is needed Hypertension, eccentric LVH, ischemic heart diseases, diastolic dysfunction—discussed earlier Diabetes—discussed earlier proximal myopathy, hypernatremia, hypokalemia, alkalosis—muscle weakness TSH-secreting tumor Very rare. Presents with features of hyperthyroidism— tachycardia, hypertension, arrhythmia, loss of weight, increased appetite, diarrhea, heat intolerance, mental changes—need to be euthyroid before surgery, possibility of intraoperative thyrotoxicosis crisis Routine: as mentioned earlier Specific investigations: TFT: TSH, T4, FTC with other endocrine workup Prolactin-secreting tumours—prolactinoma Women: galactorrhea, menstrual dysfunction; men: loss of libido, erectile dysfunction—no anesthetic implications Routine: same as mentioned earlier Specific investigations: Elevated serum prolactin level; >20 ng/ mL is considered elevated; 50–100 ng/mL, microadenoma; >300 ng/mL, macroadenoma; >150 ng/mL, pituitary stalk effect Other endocrine workup LH-, FSH-, and testosteronesecreting tumor Very rare. Menstrual disturbance in woman, increased sperm production in men, and precocious puberty in children Routine: as mentioned earlier Specific: full endocrine workup Hyposecretion syndrome due to sudden bleeding into the pituitary gland (pituitary apoplexy) or compression of normal gland by macroadenoma Hypothyroidism: increased sensitivity, delayed metabolism of anesthetic drugs, delayed emergence from anesthesia, abnormal ventilatory response to hypoxia, hypercapnia, bradycardia, postoperative ventilatory support Same as mentioned earlier Adrenocortical insufficiency, but the rennin-angiotensinaldosterone axis is preserved—perioperative hemodynamic instability. Need for perioperative steroid cover DI: severe dehydration—hemodynamic instability. Hypernatremia and its associated problems Nonfunctioning macroadenoma Headache, visual field defect (bitemporal hemianopia), prolactinemia (due to stalk effect), obstructive hydrocephalus Same as mentioned earlier AC, ante cibum (before meal); ACTH, adrenocorticotrophic hormone; CBC, complete blood count; CRH, corticotropin-releasing hormone; CT, computed tomography; DI, diabetes insipidus; ECG, electrocardiogram; FSH, follicle-stimulating hormone; FTC, fractional thyroxine concentration; GH, growth hormone; IGF, insulinlike growth factor; IV, intravenous; LH, luteinising hormone; LVH, left ventricular hypertrophy; MI, myocardial infarction; MRI, magnetic resonance imaging; OSA, obstructive sleep apnea; PC, post cibum (after meal); TFT, thyroid function test; TSH, thyroid stimulating hormone. VI. PREANESTHETIC EVALUATION 222 11. PREANESTHETIC EVALUATION OF NEUROSURGICAL PATIENTS Preoperative Evaluation of Patients With Epilepsy Epilepsy is a common neurological disorder with a prevalence of 0.5–1% of the population. With the introduction of newer drugs, there has been an improvement in pharmacotherapy for controlling epilepsy with less side effects. About one-third of patients have persistent seizure, which are refractory to medical therapy and need surgery for controlling the epilepsy. Before undergoing epilepsy surgery, all patients undergo extensive presurgical evaluation to identify both the seizure foci and the functional areas of the brain near the seizure foci so that the seizure foci can be excised without causing damage to the eloquent area, which improves the surgical and functional outcomes. Anesthesiologists are involved in both, during the presurgical evaluation and in the anesthetic management of an epilepsy surgery. Apart from routine history and physical examination these patients undergo neuropsychological examination, followed by series of noninvasive and invasive testing (Table 11.9).60,61 These tests are done with or without sedation. Studies have shown that the presence of an anesthesiologist during presurgical evaluation testing will definitely improve the reliability and safety.60,62 After seizure foci localization, definitive surgery will be carried out. Common surgical techniques performed are amygdalohippocampectomy, hemispherectomy, hemispherotomy, corpus callosotomy, and multiple subpial transection and vagus nerve stimulation and deep brain stimulation of hippocampus. During the preoperative evaluation all the details of seizure, which include type of seizure (simple partial or generalized tonic clonic seizure), frequency, presence or absence of aura, the time of occurrence of last episode, the medication history, side effects of medication, need to be documented. Awareness of pharmacological properties of antiepileptic drugs and their potential interaction with anesthetic drugs should be kept in mind63 (see medication TABLE 11.9 Noninvasive and Invasive Tests Performed During the Presurgical Evaluation and the Anesthesiologist’s Role Noninvasive Testing Role in Epilepsy Anesthesiologist Role Video EEG Commonly done noninvasive test for foci localization. Patients are admitted and continuous EEG recording will be done for 2–3 days Not needed CT scan Identifies the gross structural lesion, e.g., tumor, cavernoma If the patient is uncooperative, the procedure will be done under sedation MRI Identifies the structural lesion such as hippocampal sclerosis, focal cortical dysplasia, gliosis, low-grade tumors, and vascular malformation If the patients need GA, anesthesiologist will be involved SPECT 99mTc-labeled Anesthesiologists are involved in pharmacoactivation compounds are injected after the seizure Increased tracer uptake in the seizure foci due to increased CBF. Scan can be taken up to 4 h of tracer injection Activation of focal epileptiform discharges by pharmacological measures is called pharmacoactivation Methohexital, Etomidate, Clonidine are used for this purpose. PET scan The scan will be taken during the interictal period. Neuronal uptake of glucose is measured by injecting 18fluorodeoxygenase tracer. An area of decreased tracer indicates the seizure foci Same as mentioned earlier MEG MEG signals are derived from the intracellular electrical current flowing from sulci and fissures Patient may or may not need sedation Grid, needle, depth, strip electrodes are placed over the cortex GA is administered for placing the electrode through the burr hole or craniotomy. Patients will be monitored for 2–7 days. While removing the electrode pharmacoactivation is done using methohexitol, etomidate, alfentanil, or sedation dose of propofol Invasive Testing EcoG These electrodes are biologically inert, radioopaque, and MRI compatible such as platinum, stainless steel, and silastic material VI. PREANESTHETIC EVALUATION PREOPERATIVE EVALUATION OF SPECIFIC NEUROSURGICAL CONDITIONS 223 TABLE 11.9 Noninvasive and Invasive Tests Performed During the Presurgical Evaluation and the Anesthesiologist’s Role Noninvasive Testing Role in Epilepsy Anesthesiologist Role Neuropsychological testing Memory, language, motor skills, attention, concentration, visual spatial skills, executive abilities, and emotional function are tested Not needed fMRI Used for identifying the eloquent cortex using Not needed the cerebral blood oxygenation level in the brain while assessing the different task. Language fluency, semantsc task: for Brocas area Stress comprehension, story listening: for Wernicke area WADA test (intracarotid amobarbital procedure) Short-acting intravenous anaesthetics are injected into one cerebral hemisphere to anesthetize the particular side and then the language and memory of contralateral hemisphere will be tested using different questionnaire to lateralize the language and memory function Functional Assessment Testing In many centers anesthesiologist often involved for this procedure Traditionally sodium amobarbital was used. Because of nonavailability of this drug various drugs such as methohexitol, pentobarbital, secobarbital, propofol, and etomidate are used to perform a WADA test CBF; CT, computed tomography; ECoG, electrocorticography; EEG, electroencephalography; fMRI, functional MRI; GA, general anesthesia; MEG, magnetoencephalography; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single photon emission computed tomography. evaluation section). Some patients with seizure disorder will have an associated genetic disorder such as tuberous sclerosis (arrhythmia, cardiac tumor, renal and pulmonary dysfunction), Huntington chorea (abnormal response to thiopentone), or von Recklinghausen disease (atlanto axial dislocation, airway compromise), which are associated with many anesthetic implications.62 Preoperative Evaluation of Patients With Subarachnoid Hemorrhage SAH is a devastating clinical event with significant neurological morbidity and mortality (50%). Most SAHs are due to rupture of an intracranial aneurysm (75–80%), About 20–25% are due to rupture of an arteriovenous malformation (AVM) or rupture of a blood vessel due to dural sinus thrombosis, vasculitis, or cerebral arterial dissection. Preoperative evaluation and optimization depends on the cause. The three main predictors of morbidity and mortality after SAH are (1) advanced age, (2) impaired level of consciousness (higher grade, bad prognosis), and (3) volume of blood in the CT imaging (more blood, bad prognosis).64–66 The anesthesiologist is involved at various stages while managing the patients with SAH: initial resuscitation and stabilization, therapeutic management in the ICU, and providing anesthesia for aneurysm clipping or coiling. Preanesthetic evaluation involves the following steps; 1. History and physical examination focusing on neurological examination and grading the SAH using the various grading systems available. Commonly used grading are Hunt and Hess grading, Fisher grading, and World Federation of Neurological Surgeons grading67–69 (details of grading are discussed in respective chapters in detail). 2. Reviewing the intracranial pathology using CT of the brain, CT angiography, CT perfusion scan, and digital subtraction angiography. The location, size, type of the aneurysm and extent of bleed, presence of hydrocephalus, cerebral edema, and midline shift are assessed. 3. Evaluation of systemic functions focusing on the systems that are affected by the SAH (Table 11.10). 4. Reviewing the physiological and biochemical disturbances associated with SAH using the available investigations and optimization of patient’s condition before surgery. 5. Since SAH is common in patients with hypertension, polycystic kidney disease, coarctation of aorta, fibromuscular dysplasia, and chronic smoking, all these factors should be kept in mind during the preoperative evaluation. 6. Communicate with the neurosurgeon regarding the complexity of aneurysm, hemodynamic goals, need for temporary clipping, neurophysiological monitoring (somatosensory evoked potential) and the need for VI. PREANESTHETIC EVALUATION 224 11. PREANESTHETIC EVALUATION OF NEUROSURGICAL PATIENTS TABLE 11.10 Systemic Effects of SAH and Its Anesthetic Implications and the Relevant Investigations System Involved Systemic Effects and Its Anesthetic Implications Investigations Needed CNS Raised ICP, cerebral edema, obstructive hydrocephalus CT brain Anesthetic implication: Raised ICP and its concerns, TIVA may be better compared to inhalational anaesthetics CT angiography, CT perfusion, or DSA to assess the cause Rate and rhythm disturbances in ECG, QTc prolongation, myocardial injury, catecholamine surge induced Takatsubo cardiomyopathy with severe LV dysfunction ECG, echo, cardiac enzymes Anesthetic implication: Perioperative hemodynamic instability, MI, worsening of myocardial function Patients with MI/hemodynamically unstable/ CHF/poor LV function (EF <30%) need preoperative optimization before surgery Pulmonary edema due to cardiac dysfunction Chest X-ray, USG chest—Kerley B line CVS RS Aspiration pneumonia, basal atelectasis in patients with low GCS Anesthetic implication: Perioperative hypoxia and hypercarbia causes secondary neurological injury and increases POPCs Renal Acute renal failure: may be due to hypovolemia or contrast induced BUN, serum creatinine Anesthetic implication: Fluid overload, prolonged drug effect because of decreased renal elimination Vascular Intravascular volume depletion due to supine diuresis, mannitol effect, negative nitrogen balance, iatrogenic blood loss, and decreased erythropoiesis CBC, basic electrolyte panel (sodium, potassium, magnesium, calcium, glucose) Electrolyte disturbances: hyponatremia due to SIADH, CSW. Hypokalemia, hypocalcemia, and hypomagnesaemia Coagulation parameters Anesthetic implications: Severe hemodynamic instability, delayed awakening, cardiac arrhythmia BUN, blood urea nitrogen; CBC, complete blood count; CHF, congestive heart failure; CNS, central nervous system; CSW, cerebral salt wasting; CT, computed tomography; CVS, cardiovascular system; DSA, digital subtraction angiography; ECG, electrocardiogram; EF, ejection fraction; GCS, Glasgow Coma Scale; ICP, intracranial pressure; LV, left ventricular; MI, myocardial infarction; POPCs, perioperative pulmonary complications; RS, respiratory system; SAH, subarachnoid haemorrhage; SIADH, syndrome of inappropriate antidiuretic hormone; TIVA, total intravenous anesthesia; USG, ultrasonography. lumbar drain placement for brain relaxation, as well as indocyanine green injection to see the relationship of an aneurysm to parent vessel and to confirm the complete obliteration after clipping. 7. In case of a complex aneurysm, the anesthesiologist has to be prepared to administer adenosine for producing transient asystole to facilitate clipping. Patients with high-grade SAH often present with vasospasm, obstructive hydrocephalus, impaired autoregulation, and cerebrovascular CO2 reactivity. The incidence of hypovolemia, hyponatremia, arrhythmia, myocardial dysfunctions, and mortality are higher in these patients.70 SAH affects almost every organ system of the body, the systemic effects, its anesthetic implication, and the relevant preoperative investigations are mentioned in Table 11.10. Preoperative Evaluation of Patients With Arteriovenous Malformation AVM is an abnormal (nidus) communication between small arteries and veins without intervening capillaries producing low resistance and high-flow shunt. Cerebral AVM is a congenital malformation involving the cerebral vasculature; although it is congenital, it usually manifests between the second and fourth decades. It commonly presents with signs and symptoms of intracranial bleed, seizure, focal neurological deficits, hydrocephalus, or rarely CHF (in large AVMs). Most AVMs are supratentorial in origin (70–97%); some are located in infratentorial (3–30%) or deeper brain structures (5–18%). Anesthesiologists often deal with these patients either for diagnostic investigation (angiography, MRI) or for therapeutic embolization and/or for excision/ stereotactic radiosurgery. VI. PREANESTHETIC EVALUATION REFERENCES 225 There are various studies looking at several factors for stratifying the surgical risk. Pasqualin et al.71 studied several anatomic and hemodynamic factors such as (1) volume of AVM (>20 mL), (2) presence of deep feeding vessels and deep draining system, (3) shunt flow >120 cm/s and pulsatility index <0.5, using transcranial Doppler, (4) involvement of eloquent area of brain, and (5) history of previous bleed, to stratify the surgical risk. Langer et al.72 had suggested that the presence of hypertension and small-size and deep venous drainage are associated with increased risk of hemorrhage. The Spetzler and Martin grading system73 uses three factors, namely, (1) size, (2) involvement of eloquent area of the brain, and (3) pattern of venous drainage to stratify the risk. It is the most frequently used grading system to stratify the surgical risk. The steps of preoperative evaluation are very similar to aneurysmal SAH: signs and symptoms of presenting features, neurological status, and physical condition of the patient [congestive cardiac failure (CCF), pulmonary edema, renal dysfunction]; history of transient ischemic attack or cerebrovascular accident, which are the relative contraindications for giving controlled hypotension during embolization; history of allergy to protamine (protamine insulin use, fish allergy, vasectomy) and contrast (general atopy/selfish allergy); as well as history of prior anticoagulation or coagulation disorders, which changes the coagulation management during embolization, all should be documented. In female patients of reproductive age group, pregnancy test should be done. Some patients with large AVM can have sacular aneurysms inside the nidus (incidence 3.7–8.7%); this should be ruled out before commencing treatment for AVM. 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Participants in the National Veterans Affairs Surgical Quality Improvement Program. Development and validation of a multifactorial risk index for predicting postoperative pneumonia after major noncardiac surgery. Ann Intern Med November 20, 2001;135(10):847–57. 24. Arozullah AM, Daley J, Henderson WG, Khuri SF. Multifactorial risk index for predicting postoperative respiratory failure in men after major noncardiac surgery. Ann Surg August 2000;232(2):242–53. 25. Gupta H, Gupta PK, Schuller D, Fang X, Miller WJ, Modrykamien A, et al. Development and validation of a risk calculator for predicting postoperative pneumonia. Mayo Clin Proc November 2013;88(11):1241–9. 26. Gupta H, Gupta PK, Fang X, Miller WJ, Cemaj S, Forse RA, et al. Development and validation of a risk calculator predicting postoperative respiratory failure. Chest November 2011;140(5):1207–15. 27. Archer C, Levy AR, McGregor M. Value of routine preoperative chest x-rays: a meta-analysis. Can J Anaesth November 1993;40(11):1022–7. 28. Qaseem A, Snow V, Fitterman N, Hornbake ER, Lawrence VA, Smetana GW, et al. Risk assessment for and strategies to reduce perioperative pulmonary complications for patients undergoing noncardiothoracic surgery: a guideline from the American College of Physicians. Ann Intern Med April 18, 2006;144(8):575–80. 29. Tisi GM. Preoperative evaluation of pulmonary function. Validity, indications, and benefits. Am Rev Respir Dis February 1979;119(2):293–310. 30. Warner DO. Perioperative abstinence from cigarettes: physiologic and clinical consequences. Anesthesiology February 2006;104(2):356–67. 31. Wong J, Lam DP, Abrishami A, Chan MTV, Chung F. Short-term preoperative smoking cessation and postoperative complications: a systematic review and metaanalysis. Can J Anaesth March 2012;59(3):268–79. 32. Woods BD, Sladen RN. Perioperative considerations for the patient with asthma and bronchospasm. Br J Anaesth December 2009;103(Suppl. 1):i57–65. 33. Silvanus M-T, Groeben H, Peters J. Corticosteroids and inhaled salbutamol in patients with reversible airway obstruction markedly decrease the incidence of bronchospasm after tracheal intubation. Anesthesiology May 2004;100(5):1052–7. 34. Lawrence VA, Cornell JE, Smetana GW. American College of Physicians. Strategies to reduce postoperative pulmonary complications after noncardiothoracic surgery: systematic review for the American College of Physicians. Ann Intern Med April 18, 2006;144(8):596–608. 35. Makhabah DN, Martino F, Ambrosino N. Peri-operative physiotherapy. Multidiscip Respir Med January 23, 2013;8(1):4. 36. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol May 1, 2013;177(9):1006–14. 37. Rahimi E, Mariappan R, Tharmaradinam S, Manninen P, Venkatraghavan L. Perioperative management and complications in patients with obstructive sleep apnea undergoing transsphenoidal surgery: our institutional experience. J Anaesthesiol Clin Pharmacol 2014;30(3):351–4. 38. Malow BA, Levy K, Maturen K, Bowes R. Obstructive sleep apnea is common in medically refractory epilepsy patients. Neurology October 10, 2000;55(7):1002–7. 39. Pollak L, Shpirer I, Rabey JM, Klein C, Schiffer J. Polysomnography in patients with intracranial tumors before and after operation. Acta Neurol Scand January 2004;109(1):56–60. 40. Kaw R, Chung F, Pasupuleti V, Mehta J, Gay PC, Hernandez AV. Meta-analysis of the association between obstructive sleep apnoea and postoperative outcome. Br J Anaesth December 2012;109(6):897–906. 41. Lockhart EM, Willingham MD, Abdallah AB, Helsten DL, Bedair BA, Thomas J, et al. Obstructive sleep apnea screening and postoperative mortality in a large surgical cohort. Sleep Med May 2013;14(5):407–15. 42. Singh M, Liao P, Kobah S, Wijeysundera DN, Shapiro C, Chung F. Proportion of surgical patients with undiagnosed obstructive sleep apnoea. Br J Anaesth April 2013;110(4):629–36. 43. Abdelsattar ZM, Hendren S, Wong SL, Campbell DA, Ramachandran SK. The impact of untreated obstructive sleep apnea on cardiopulmonary complications in general and vascular surgery: a cohort study. Sleep August 2015;38(8):1205–10. 44. Persson HE, Svanborg E. Sleep deprivation worsens obstructive sleep apnea. Comparison between diurnal and nocturnal polysomnography. Chest March 1996;109(3):645–50. 45. Chung F, Yegneswaran B, Liao P, Chung SA, Vairavanathan S, Islam S, et al. STOP questionnaire: a tool to screen patients for obstructive sleep apnea. Anesthesiology May 2008;108(5):812–21. 46. Chung F, Subramanyam R, Liao P, Sasaki E, Shapiro C, Sun Y. High STOP-Bang score indicates a high probability of obstructive sleep apnoea. Br J Anaesth May 2012;108(5):768–75. 47. Chung F, Chau E, Yang Y, Liao P, Hall R, Mokhlesi B. Serum bicarbonate level improves specificity of STOP-Bang screening for obstructive sleep apnea. Chest May 2013;143(5):1284–93. 48. Flemons WW, Whitelaw WA, Brant R, Remmers JE. Likelihood ratios for a sleep apnea clinical prediction rule. Am J Respir Crit Care Med November 1994;150(5 Pt 1):1279–85. 49. Netzer NC, Stoohs RA, Netzer CM, Clark K, Strohl KP. Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Intern Med October 5, 1999;131(7):485–91. 50. Chau EHL, Lam D, Wong J, Mokhlesi B, Chung F. Obesity hypoventilation syndrome: a review of epidemiology, pathophysiology, and perioperative considerations. Anesthesiology July 2012;117(1):188–205. 51. Gross JB, Bachenberg KL, Benumof JL, Caplan RA, Connis RT, Coté CJ, et al. Practice guidelines for the perioperative management of patients with obstructive sleep apnea: a report by the American Society of Anesthesiologists Task Force on Perioperative Management of patients with obstructive sleep apnea. Anesthesiology May 2006;104(5):1081–93. quiz 1117–8. 52. Porter KR, McCarthy BJ, Freels S, Kim Y, Davis FG. Prevalence estimates for primary brain tumors in the United States by age, gender, behavior, and histology. Neuro-Oncol June 2010;12(6):520–7. 53. Nguyen HS, Sundaram SV, Mosier KM, Cohen-Gadol AA. A method to map the visual cortex during an awake craniotomy. J Neurosurg April 2011;114(4):922–6. 54. Taylor MD, Bernstein M. Awake craniotomy with brain mapping as the routine surgical approach to treating patients with supratentorial intraaxial tumors: a prospective trial of 200 cases. J Neurosurg January 1999;90(1):35–41. 55. Chui J, Manninen P, Valiante T, Venkatraghavan L. The anesthetic considerations of intraoperative electrocorticography during epilepsy surgery. Anesth Analg August 2013;117(2):479–86. 56. Serletis D, Bernstein M. Prospective study of awake craniotomy used routinely and nonselectively for supratentorial tumors. J Neurosurg July 2007;107(1):1–6. 57. Chui J. Anesthesia for awake craniotomy: an update. Rev Colomb Anestesiol Engl Ed January 1, 2015;43:22–8. 58. Burnand C, Sebastian J. Anaesthesia for awake craniotomy. Contin Educ Anaesth Crit Care Pain June 19, 2013. mkt024. 59. Klimek M, Verbrugge SJC, Roubos S, van der Most E, Vincent AJ, Klein J. Awake craniotomy for glioblastoma in a 9-year-old child. Anaesthesia June 1, 2004;59(6):607–9. 60. Chui J, Venkatraghavan L, Manninen P. Presurgical evaluation of patients with epilepsy: the role of the anesthesiologist. Anesth Analg April 2013;116(4):881–8. 61. Van Paesschen W, Dupont P, Sunaert S, Goffin K, Van Laere K. The use of SPECT and PET in routine clinical practice in epilepsy. Curr Opin Neurol April 2007;20(2):194–202. 62. Bhagat H, Dash HH. Anaesthesiologist’s role in the management of an epileptic patient. Indian J Anaesth 2006;50(1):20–2. 63. Perks A, Cheema S, Mohanraj R. Anaesthesia and epilepsy. Br J Anaesth April 1, 2012;108(4):562–71. VI. PREANESTHETIC EVALUATION REFERENCES 227 64. Ko S-B, Choi HA, Carpenter AM, Helbok R, Schmidt JM, Badjatia N, et al. Quantitative analysis of hemorrhage volume for predicting delayed cerebral ischemia after subarachnoid hemorrhage. Stroke J Cereb Circ March 2011;42(3):669–74. 65. Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL. Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke J Cereb Circ August 2007;38(8):2315–21. 66. de Oliveira Manoel AL, Goffi A, Marotta TR, Schweizer TA, Abrahamson S, Macdonald RL. The critical care management of poor-grade subarachnoid haemorrhage. [Internet] Crit Care 2015. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724088/. 67. Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg January 1968;28(1):14–20. 68. Report of World Federation of Neurological Surgeons Committee on a Universal Subarachnoid Hemorrhage Grading Scale. J Neurosurg June 1988;68(6):985–6. 69. Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery January 1980;6(1):1–9. 70. Pong RP, Lam AM. Anaesthetic management of cerebral aneurysm surgery. In: Cottrell JE, Young WL, editors. Cottrell and Young’s neuroanesthesia. 5th ed. Philadelphia: Elsevier Health Sciences; 2010. 481 pp. 71. Pasqualin A, Barone G, Cioffi F, Rosta L, Scienza R, Da Pian R. The relevance of anatomic and hemodynamic factors to a classification of cerebral arteriovenous malformations. Neurosurgery March 1991;28(3):370–9. 72. Langer DJ, Lasner TM, Hurst RW, Flamm ES, Zager EL, King JT. Hypertension, small size, and deep venous drainage are associated with risk of hemorrhagic presentation of cerebral arteriovenous malformations. Neurosurgery March 1998;42(3):481–6. Discussion 487–9. 73. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg October 1986;65(4):476–83. VI. PREANESTHETIC EVALUATION This page intentionally left blank S E C T I O N V I I NEUROSURGERY This page intentionally left blank C H A P T E R 12 Supratentorial Lesions H. Bhagat, S. Mahajan Postgraduate Institute of Medical Education and Research, Chandigarh, India O U T L I N E Introduction 231 Classification 232 Pathophysiology and Clinical Correlations 233 Clinical Features 235 Neuroimaging 235 Intraoperative Considerations: The Team Approach 236 Anesthetic Management Emergency Management of Patients With Supratentorial Tumors Nonemergent Management of Patients With Supratentorial Tumors 236 Intraoperative Management Monitoring Induction and Maintenance of Anesthesia Hemodynamics Preservation of Systemic Milieu 238 238 238 239 239 236 237 Intraoperative Medications Intraoperative Surgical Field 239 239 Emergence From Anesthesia 240 Postoperative Management Postcraniotomy Pain Postoperative Seizures Postcraniotomy Nausea and Vomiting 241 241 242 242 Awake Craniotomy Indications Techniques for Awake Craniotomy Steps in the Conduct of Awake Craniotomy Postoperative Care Complications 242 243 243 243 244 245 Conclusions 245 Acknowledgment 245 References 245 INTRODUCTION The supratentorial region accounts for major intracranial distribution in the intracranial compartment. The supratentorial region is bound superiorly and laterally by the tense dura mater and skull. The inferior boundary consists of the anterior cranial fossa, middle cranial fossa, posterior cranial fossa, and tentorium cerebelli. The supratentorial region is divided into the right and left halves by the falx cerebri. The contents include the subarachnoid space containing cerebrospinal fluid and major vessels of the two cerebral hemispheres and lateral ventricles. The supratentorial region consists of the part of the brain that lies above the tentorium cerebelli. It consists of two cerebral hemisphere, ventricles and blood vessels. The two cerebral hemispheres are separated by falx cerebri (Fig. 12.1). Each cerebral hemisphere consists of four lobes: frontal, parietal, temporal, and occipital. Individual lobes have specific neurological functions. The supratentorial lesions may be associated with either a compromise or loss of neurological functions depending on the site and size of the lesion. Essentials of Neuroanesthesia http://dx.doi.org/10.1016/B978-0-12-805299-0.00012-9 231 © 2017 Elsevier Inc. All rights reserved. 232 12. SUPRATENTORIAL LESIONS FIGURE 12.1 Sketch of the coronal section of supratentorial compartment. CLASSIFICATION The supratentorial lesions can be broadly classified as follows (Box 12.1). Although supratentorial lesions can occur due to causes related to tumors, trauma, and infections, the present chapter will focus on supratentorial tumors only. BOX 12.1 C L A S S I F I C AT I O N O F S U P R AT E N T O R I A L L E S I O N S Intra-Axial Lesions (Within Brain Parenchyma) 1. Neoplasm a. Primary i. Glioblastoma multiforme ii. Astrocytoma iii. Primary central nervous system lymphoma iv. Ganglioma v. Oligodendroglioma b. Metastasis 2. Infections a. Abscess b. Neurocysticercosis 3. Hemorrhage (intracerebral hemorrhage) Extra-Axial Lesions (External to Brain Parenchyma) 1. Neoplasm a. Meningioma b. Hemangiopericytoma c. Pituitary tumors 2. Hemorrhage a. Subarachnoid hemorrhage b. Subdural hematoma c. Extradural hematoma 3. Arachnoid cysts Intraventricular Lesions 1. Neoplasms a. Ventricular wall and septum pellucidum i. Ependymoma ii. Central neurocytoma b. Choroid plexus i. Choroid plexus papilloma/carcinoma c. Others i. Intraventricular meningioma 2. Colloid cysts 3. Infections a. Hydatid cysts b. Tuberculoma c. Neurocysticercosis VII. NEUROSURGERY 233 PATHOPHYSIOLOGY AND CLINICAL CORRELATIONS PATHOPHYSIOLOGY AND CLINICAL CORRELATIONS INTRACRANIAL PRESSURE (mmHg) The supratentorial region is well protected within the confines of the tough dura mater and skull. The pressure within the right and left sides of the supratentorial compartment is in equilibrium as is the pressure within the supratentorial and infratentorial compartments. The supratentorial compartment follows the Monro–Kellie doctrine that states that the sum total of the volume of the compartment at any point remains constant. This would translate into a realization that the compensation for any expanding mass lesion would be limited and could lead to an increase in intracranial pressure (ICP). During the initial phase of a slow-growing mass lesion there would be compensation in terms of egress of cerebrospinal fluid and reduction of blood volume (phase I, Fig. 12.2). At this point of time surgery can be planned as an elective procedure. As the mass lesion grows further, there comes a point whereby the compensatory mechanisms are exhausted (phase II, Fig. 12.2). With further growth of mass lesion, there is increase in ICP. Discordance in ICP between the two halves in the supratentorial compartment leads to shift of brain parenchyma from one half to the other, which is referred to as subfalcine herniation or midline shift (phase III, Fig. 12.2). A midline shift of more than 5 mm is usually considered to be associated with significant mass effect (Fig. 12.3). At this point of time surgery is 80 70 60 50 40 30 20 10 IV HERNIATION SPATIAL EXHAUSATION III SPATIAL COMPENSATION I II INTRACRANIAL VOLUME FIGURE 12.2 Intracranial pressure–volume curve. FIGURE 12.3 Computed tomograpgic scan showing significant midline shift due to a supratentorial tumor. VII. NEUROSURGERY 234 12. SUPRATENTORIAL LESIONS considered as an urgent procedure. The unabated growth of mass lesion may lead to differential pressure between the supratentorial and infratentorial compartments. The transtentorial pressure gradient may lead to herniation of the medial portion of the temporal lobe into the infratentorial compartment, called “uncal herniation/central herniation” (phase IV, Figs. 12.2 and 12.4). This leads to compression of the ipsilateral third cranial nerve, which clinically manifest as anisocoria. Radiologically this is manifested as obliteration of basal cisterns. This is the time when surgical procedure for decompression of mass lesion is an absolute emergency. The enlarging supratentorial mass in animal studies has been associated with loss of autoregulation in the regions of brain ipsilateral and contralateral to the lesion. However, there is relative preservation of midbrain autoregulation.1 The understanding of the effect of supratentorial tumors with regard to the integrity of blood– brain barrier (BBB) is limited. The integrity of BBB as studied by contrast enhanced scanning will depend on the degree of the malignancy of the supratentorial tumors.2 The effect on the BBB depends on the type and stage of tumor development.3,4 BBB permeability is heterogeneous within the tumor site and depends on the type of tumor and stage of tumor development. Low-grade gliomas usually have preservation of the BBB. It has been found that BBB is intact in the initial steps of tumor development with significant increase in BBB permeability only during the later stages as tumor mass increases. Low-grade gliomas and tumor in early stages are least likely to impact the BBB.5 Nevertheless, even in later stages, BBB is still functional and limiting in terms of solute and drug permeability in and around the tumor.6 The regional blood cerebral flow can be affected ipsilateral as well as contralateral to the supratentorial mass lesion.7 The blood flow to the midbrain is preserved till the point of total decompensation and herniation. Various animals studies have shown that the progressive expansion of a supratentorial epidural space gave rise to a series of pathophysiological reactions.8,9 The vital physiological variables and sequential magnetic resonance (MR) images were recorded simultaneously using intracranial expanding mass. When the expanding mass was increased into 4–5% of the intracranial volume (ICV), there was a progressive slow rise in systemic arterial pressure, along with changes in pulse and respiratory frequency. This volume is known as reaction volume. At a volume of 8–10% of ICV, apnea (referred to as apneic volume) and an isoelectric electroencephalogram were observed. Following apnea the systemic arterial pressure increased as part of the Cushing triad. The changes in vital physiological variables progressed in a rostrocaudal direction. Reaction volume associated with a marked transtentorial pressure gradient and magnetic resonance imaging (MRI) changes were consistent with tentorial herniation. Respiratory arrest (apneic arrest) was associated with occlusion of the cistern magna, consistent with some degree of foramen magnum herniation. Epileptogenesis associated with tumors can be due to changes in peritumoral microenvironment, alterations of synaptic neurotransmitter release and reuptake and the exitotoxic effect of glutamate.10,11 FIGURE 12.4 Transtentorial herniation. VII. NEUROSURGERY NEUROIMAGING 235 CLINICAL FEATURES The clinical features of the patients with supratentorial lesions will depend on the following three factors(S3): (1) site of lesion (localizing signs), (2) size of lesion and mass effect (nonlocalizing signals), and (3) speed/rate of growth of lesion. The clinical manifestations of a supratentorial lesion may be site specific and may produce localizing clinical manifestation. The lesion affecting the motor frontal cortex may be associated with contralateral hemiparesis. The tumors of speech area will result in aphasia. Affection of visual pathway at a particular site will help in localizing features (e.g., bitemporal hemianopia) in case of suprasellar lesion. Presence of a focal seizure can help in precise localization of a tumor. Large tumors and associated mass effect may produce generalize signs and symptoms, which are referred as nonlocalizing clinical manifestations. Raised ICP is a feature of many supratentorial lesions. Raised ICP may manifest as headache and/or nausea and vomiting. Papilledema may be a common accompaniment. There may be elevation of blood pressure with increase or decrease in pulse rate. A slow pulse rate appears to be due to vagal excitation or a response of carotid sinus to acute rise in blood pressure. The rise of blood pressure has been hypothesized to be due to compensatory autoregulatory responses to decreased cerebral blood flow caused by the raised ICP. An expanding mass lesion causes third nerve palsy due to compression by herniating temporal lobe at the edge of the tentorium. Sixth nerve palsy can occur as a consequence of stretching of the abducens nerve due to rostrocaudal displacement of brain stem. Compression of foramen of Monro or third ventricle can result in hydrocephalus. A supratentorial mass lesion may result in cognitive decline. The speed of growth of the lesions determine the nature of onset and progress of the signs and symptoms. Slowgrowing tumors have an insidious onset of presentation and are gradually progressive. Rapidly expanding masses have fast progression. Similarly, a bleed into the tumor may result in an acute presentation. A transtentorial herniation (TTH) is representative of an acute neurological deterioration. An acute neurological deterioration may manifest as sudden loss of consciousness. NEUROIMAGING Neuroimaging is a routine diagnostic procedure in patients with suspected intracranial lesions. This helps in precise localization as well as differentiating the type of lesion. The type of radiological imaging will depend upon the clinical presentation and urgency for evaluation and management. Patients who have slow onset and progression of neurological symptoms are more commonly subjected to MRI, which is more sensitive in the detection and differentiation of intracranial lesions as compared to computed tomographic (CT) scans. Various sequences of MRI can help in delineating the intracranial tumor and the associated mass effect (Fig. 12.5). MR spectroscopy evaluates the chemical spectrum of the mass, and it helps in differentiating tumors from various FIGURE 12.5 Magnetic resonance imaging sequences of brain (T1, T2, and FLAIR, from left to right; showing ill-defined supratentorial mass in insular region with midline shift). VII. NEUROSURGERY 236 12. SUPRATENTORIAL LESIONS mass lesions like abscess. Patients who present with acute neurological deterioration are usually subjected to CT scan as this procedure is faster and can help in emergency management of these groups of patients. Cerebral angiography may define the arterial supply of the tumor and help in planning tumor resection. In case of highly vascular tumor preoperative radiologically guided intravascular embolization helps in reducing the vascularity and intraoperative bleeding. Angiography is also helpful in distinguishing arteriovascular malformations and giant aneurysm, which may present as mass lesions. It is important for the neuroanesthesiologist to have a working knowledge of the imaging scans so as to estimate the mass effect and take appropriate intraoperative steps to optimize the brain conditions. In case of giant tumors it is possible that despite all the physiological, pharmacological, and mechanical methods advocated by the anesthesiologist to reduce the ICP, the brain may still be bulging. It is important to interact with the surgeons prior to the surgery regarding the possibility of refractory brain bulge and the need to drain the CSF if required. Imaging scans can also help to triage patients who may otherwise need an urgent surgery. Positron emission tomographic (PET) scan gives the amount of metabolic activity in the brain, thus differentiating the tumors from inflammatory lesions. PET scans are promising in differentiating between recurrent tumors and treatment-induced changes.12 PET scan can be superior to MRI for follow-up of patients who have been treated surgically or by radiation for brain tumors. INTRAOPERATIVE CONSIDERATIONS: THE TEAM APPROACH The conduct of neurosurgery is a team work, which includes the anesthesiologist, surgeons, operating room technicians, nursing staff, and at time radiographers and neurophysiologists. There should be good understanding and communication among the team members so as to conduct smooth anesthesia, perioperative management, optimal patient positioning, and maximal safe tumor resection. The surgery for intracranial lesions is challenging and can be associated with variable intraoperative patient dynamics. Consequently it is important to be familiar not only with the disease process and presentation but also with the important surgical steps so as to anticipate complications and appropriately manage them. It is important in this regard for the anesthesiologist to interact with the surgeon prior to surgery and discuss various concerns regarding the patient. An understanding of the crucial surgical steps and anticipating blood loss keeps one vigilant and prepared to handle a critical situation. The surgical site should always to be confirmed and should be kept free from interference of monitoring sensors/electrodes like those used for monitoring the depth of anesthesia. Similarly the endotracheal tubes, drug delivery systems, intravenous fluids, various monitoring devices, and anesthesia equipment should be adequately secured and should be placed in such a way that they do not affect the working in the operation theater. It is important to advocate measures to facilitate maximal brain relaxation, which will enable the surgeons to conduct maximal tumor resection. The anesthesiologist should brief the surgeons from time to time the hemodynamic changes during surgical stimulation so as to warn him against damage to vital brain structures. In situations in which intraoperative evoked potential studies are conducted there needs to be good communication between the anesthesiologist, neurophysiologist, and the surgeons. The surgical approaches and craniotomy depend on the tumor location. Most of the surgeries anterior to coronal suture are conducted in supine position. Pterional and frontal approaches are the most common surgical approaches. The lesion behind the coronal suture may require the patient to be positioned in the semsitting or lateral decubitus position. The lesion in the pituitary gland and the sellar and suprasellar regions can be approached through the transsphenoidal route. The nursing staff should ensure adequate sterility and absolute cleanliness of the operating room environment. The operation theater technicians should be well trained, should be alert, and should be ready with all the equipment required for the conduct of anesthesia and surgery. ANESTHETIC MANAGEMENT An anesthesiologist may encounter a patient with supratentorial lesions in three scenarios: (1) emergency medical and surgical management, which poses threat to the life of the patient and needs immediate action, (2) urgent surgery, which does not pose immediate threat to the life of patient but has to be performed within 24–48 h, and (3) elective surgery, which can be taken up at the convenience of the patient and availability of hospital resources. Emergency Management of Patients With Supratentorial Tumors The patients may present with acute neurological deterioration in the emergency room or in the neurosurgical ward following fluid and electrolyte imbalance, bleed in the tumor bed, or have a herniation following a seizure/an VII. NEUROSURGERY ANESTHETIC MANAGEMENT 237 FIGURE 12.6 Schema of management of patient with acute neurological deterioration. CT, computed tomography. expanding mass lesion. The patient may be unconscious with an abnormal breathing pattern, hemodynamic fluctuations, pupillary and localizing signs. An AB-5C protocol would be a good option for the emergency management of patients with acute neurological deterioration. 1. Secure the airway. The patients who suffer acute neurological deterioration and become unresponsive may have an obstructed airway and are also at risk of aspiration. The consequent hypoxemia can lead to aggravation of ongoing neurological insult. It is imperative to secure the airway with an endotracheal tube. The technique to facilitate tracheal incubation is best judged by the onsite anesthesiologists depending on expertise and experience. It is important to emphasize that in the setting of hypoxemia the airway management would take precedence; it would be prudent to avoid further rise in ICP. 2. Breathe the patient. Correction of hypoxemia and hypercapnia as initial temporizing measures would minimize the risk of any impending herniation. 3. Check for circulation. Any hemodynamic instability should be meticulously diagnosed and managed. Acute rise in ICP is associated with systemic catecholamine surge and myocardial dysfunction.13 In the presence of hemodynamic instability, raised central venous pressure (CVP) and electrocardiographic (ECG) changes should arouse a suspicion of myocardial dysfunction. 4. Correct physiological factors (blood sugar, arterial blood gases, and serum electrolytes). 5. Cerebral resuscitation should be initiated if there are signs suggestive of raised ICP. A 20–30 degrees head-up position would help in cerebral venous drainage and reducing ICP. Once the hemodynamic stability is ensured, the use of hyperventilation, cerebral decongestant (mannitol, hypertonic saline), and intravenous anesthetics (thiopentone/propofol) has been shown to be associated with reversal of raised ICP and TTH in significant number of patients with supratentorial lesion with clinically defined TTH (decrease in level of consciousness and pupillary dilation).14 This may help in extending the window for CT scanning and adjunctive treatment. 6. Catheterize the patient as a full bladder can lead to raised ICP. 7. Shift the patient for CT scanning. If a patient has a lesion that needs surgical intervention, then the patient should be taken for emergency surgery. If there is no indication for surgery then the patient should be medically managed in a neuro–intensive care unit (Fig. 12.6). Nonemergent Management of Patients With Supratentorial Tumors Patients with supratentorial pathology can have dynamic intracranial as well as systemic physiology depending on the site, size, and speed of growth of the tumor. The anesthetic management of these patients should be VII. NEUROSURGERY 238 12. SUPRATENTORIAL LESIONS comprehensive, beginning at the preoperative phase and continuing in the postoperative period. The active and keen participation of an anesthesiologist in perioperative management can be an important factor in the critical outcome of neurosurgical patients. An anesthetic evaluation should entail detailed neurosurgical and systemic evaluation of the patient. The anesthesiologist should develop good rapport with the patient and his family members. The concept of conduct of a preanesthetic evaluation should be to have a comprehensive systemic evaluation and the need for optimization of any existing medical illness. Following the assessment of risk we need to plan our perioperative anesthesia technique and discuss it with the patient and/or relatives of the patient. The possible complications as well as the need for invasive monitoring and postoperative mechanical ventilation must be discussed and informed consent must be sought. The need to administer sedative premedication will depend on the surgery, site of lesion, as well as the neurological and systemic illness of the patient. Similarly, the administration of antisialogogues will have to be considered in patients who are operated in prone position. INTRAOPERATIVE MANAGEMENT The goals of anesthetic management are to maintain CPP, avoid secondary systemic insults (maintain the systemic milieu of the body), provide a slack brain, institute neuroprotective strategies, and to facilitate early awakening. A patient who is in the operating room should undergo assessment as regard to the status of hydration. The moistness of the tongue, color of urine, and heart rate can give some idea regarding the hydration. Neurological patients with raised ICP are on diuretics, have high incidence of vomiting, and the concomitant reduced desire to drink orally predisposes them to a dehydrated state. The consequence may be a falsely elevated hematocrit and postinduction hemodynamic instability. It is important to rehydrate them prior to induction of anesthesia. The choice of fluids for resuscitation and maintenance in neurosurgical patients is debatable. Normal saline has the advantage of being mildly hyperosmolar but has the risk of hyperchloremic metabolic acidosis. Ringer lactate is a balanced salt/solution with the disadvantage of being mildly hypoosmolar. It is important to avoid dextrose-containing fluids. A 2014 study has indicated that intraoperative use of half strength (0.45%) normal saline in patients undergoing surgery for craniopharyngioma was associated with better outcome when compared with normal saline or 5% dextrose solution.15 Monitoring Standard American Society of Anesthesiologists’ monitoring guidelines have to be followed in all patients undergoing craniotomy for supratentorial lesions. Besides, these patients should have an invasive arterial pressure monitoring for beat-to-beat monitoring of heart rate and blood pressure. This also allows for obtaining an arterial blood sample for blood gas analysis, electrolyte, and hematocrit estimation. The need for central venous cannulation and CVP monitoring will be dictated by the nature of the lesion, patient position during expected blood loss and hemodynamic perturbations, and the need for postoperative fluid and hemodynamic management. The patient being operated in sitting or semisitting position for occipital lesions should be monitored for venous air embolism using a precordial Doppler or transesophageal echocardiography. Induction and Maintenance of Anesthesia Amnesia, analgesia, and muscle relaxants are the cornerstones of anesthesia management. However, it is important to understand its effect on systemic and cerebral physiology and consequently on the cerebral perfusion. An ideal anesthetic agent could be the one that should maintain systemic hemodynamics, maintain cerebral blood flow (CBF), and cause reduction of cerebral metabolic requirement of oxygen (CMRO2) and ICP. The effect of the various anesthetic agents on hemodynamics, CBF, CMRO2, and ICP is described in the chapter relating to pharmacological effects of anesthetics. The induction of anesthesia in neurosurgical patients is usually a coinduction with intravenous anesthetic agents and opioids. The popular choice for anesthetic induction is propofol and thiopentone sodium. Etomidate has the advantage of providing hemodynamic stability but can result in adrenal suppression. Ketamine is best avoided as it has the potential to cause increase in ICP and postoperative hallucination and delirium. The commonly used muscle relaxants to facilitate intubation are rocuronium and vecuronium. Rocuronium enables faster intubating conditions when compared to vecuronium. Succinylcholine has the potential to cause/increase in ICP and should preferably be avoided. The commonly used opioids for neurosurgical procedures are fentanyl and morphine. The effect of opioids for intraoperative analgesia as well on cerebral physiology appears to be similar. Opioids have minimal effect on cerebral VII. NEUROSURGERY INTRAOPERATIVE MANAGEMENT 239 blood flow, metabolism, and ICP, provided that normocapnia and normotension are maintained. The choice of agent for the maintenance of anesthesia is either propofol or an inhalational agent. A 2015 study comparing propofol, sevoflurane, and desflurane along with nitrous oxide found all the three agents similar and acceptable for the conduct of anesthesia in patients undergoing craniotomy for supratentorial tumors.16 Hemodynamics The brain tissue meets its metabolic need and substance on cerebral perfusion, which depends on mean arterial blood pressure. Consequently, hypotension is an important factor to be avoided at all costs. What should be an optimal mean arterial pressure (MAP) will vary individually depending on the lesion volume, site, and mass effect as well as the status of the autoregulation. The cerebral perfusion pressure is very dynamic depending on the MAP and ICP. Avoidance of intraoperative hypertension is also important as it can increase the cerebral blood volume (CBV) beyond the autoregulation capacity and increased ICP. The two important time points when hypertension occurs are during skull pin insertion of head holders and during periosteum elevation. Increasing the depth of anesthesia along with supplementary agents like intravenous opioids, β-blockers, and lignocaine has shown reduction in the hypertensive response to noxious stimulus. Preservation of Systemic Milieu Paramount importance has to be given to maintaining normal systemic physiology. The perilesional area has compromised perfusion due to mass effect and raised ICP. Hence systemic hypoxemia can lead to impaired neuronal oxygenation and death. Ventilation should be adjusted to maintain normocapnia. Hypercapnia leads to cerebral vasodilation and increase in cerebral blood volume and further rise in ICP. Glycemic control needs to be advocated in the modest range of 110–160 mg/dL as hyperglycemia predisposes to anaerobic metabolism and normal acidosis, which has deleterious effects on the neurological outcome of the patients.17 The hematocrit values have to be optimally balanced, and anemia can jeopardize oxygen delivery and preservation of neurons in the penumbral area around the lesion. Preoperative iron supplementation may be considered to correct preoperative anemia.18 The need for intraoperative blood transfusion should take into account the balance of expected blood loss and allowable blood loss. The transfusion trigger will have to be individualized based on the physiological end points of oxygen delivery and oxygen requirements: base deficit, bicarbonate ions, and pH, as well as clinical end points, i.e., hemodynamics. The intraoperative hematocrit estimation may not be reliable due to either hemoconcentration due to dehydration or hemodilution resulting from overzealous fluid administration. Normothermia should be maintained and hyperthermia has to be corrected as it predisposes to increase in CMRO2. This can be deleterious in the face of raised ICP and reduced neuronal perfusion.19 Intraoperative Medications There are different types of practices with regard to the use of intraoperative medications. The antibiotic prophylaxis is administered following inductions in patients who have not received them preoperatively. Use of diuretics has been the conventional method of reduction of ICP. 20% Mannitol in the dose of 0.25–1 g/kg has been seen to be associated with reduction of ICP. Coadministration of loop diuretics like furosemide have been supported by few studies in being additives in reduction of ICP, although the clinical reduction of ICP has not been convincing to strongly advocate its use.20 Steroids have been used to reduce the perilesional interstitial edema associated with the tumor. It reduces the leakage of fluids through the neocapillaries that form around tumors. They are usually started once the patient has been diagnosed to have a tumor and are continued in the perioperative period. Seizure is a common symptom in patients who have supratentorial lesion. The lesions in and around the cortex have increased seizure potential and are usually on anticonvulsant medications. Phenytoin sodium is commonly used in these patients. Patients who do not tolerate phenytoin receive either phenobarbitone or sodium valproate. Emerging drug for seizure prophylaxis is second-generation antiepileptics (levetiracetam).21 The administration of these medications is popularly remembered in our institution as MAAD (mannitol, antibiotic, antiepileptic, dexamethasone) regime. Intraoperative Surgical Field One of the important goals of anesthetic management is to provide a slack surgical field so as to allow the neurosurgeon to have maximal exposure to the lesion into minimal brain retraction and perilesional neuronal injury. It VII. NEUROSURGERY 240 12. SUPRATENTORIAL LESIONS FIGURE 12.7 Intraoperative brain bulge. is also important to understand the fact that the role of the anesthesiologist in controlling the brain bulge depends on CBF management. The arterial blood flow accounts for 15% of CBV, while venous accounts for 40% of CBV. Management of intraoperative brain bulge should encompass manipulation of cerebral arterial and venous blood flow. The venous outflow can be improved by head-up position. A modest 15–20 degrees head-up position helps in cerebral venous outflow and reduction of ICP. It is also important to avoid extreme head rotation, which may impede cerebral venous outflow resulting in raised ICP. Manipulation of arterial blood flow by various methods like modification of anesthesia technique and hyperventilation should be instituted. Consequently the anesthesiologist can achieve about 55% reduction of CBV and ICP, which may be significant in numbers but actually may not achieve clinical translation when the lesions are large with significant midline shifts and mass effects. In such cases when the craniotomy is achieved, the tense brain follows the pathway of least resistance leading to transcalvarial herniation referred to as “brain bulge” (Fig. 12.7). One of the important causes of intraoperative bulge can be surgical bleeding. In such cases the surgeon needs to control bleeding and evacuate hematoma to achieve sufficient brain relaxation. Suggested stepwise management for intraoperative brain bulge: 1. Head-up position 2. Hyperventilation 3. Repeat a bolus of cerebral decongestants: mannitol 4. Switch it over to intravenous anesthetic agents 5. Ventriculostomy and cerebrospinal fluid drainage EMERGENCE FROM ANESTHESIA Emergence from anesthesia following craniotomy closure is an important aspect that needs to carried out with proper planning and skills. The goals of emergence in neurosurgical patients are twofold: an early awakening and good quality of awakening. An awake patient is the best neurological monitor. Early awakening from anesthesia allows to conduct a neurological examination and detect a postoperative complication like postoperative hematoma. Early reintervention in management of prospective complication will result in better neurological outcome of patients. However, fast-track awakening from anesthesia has its own pitfalls like emergence hypertension, which can lead to postoperative hematoma formation. The anesthesia technique that can lead to early awakening from anesthesia have been addressed from time to time. Use of propofol, sevoflurane, and desflurane along with nitrous oxide did not show any difference in the awakening times,16 although a few studies have demonstrated a benefit in awakening times with use of desflurane and sevoflurane.22 It would be prudent to allow 15 min for awakening following cessation of anesthesia, considered as “early awakening.” Early examination and detection with radiological confirmation will allow to do a reintervention. Most of the commonly used anesthetics have demonstrated acceptable emergence times, and there appears no clinically significant difference with the use of either propofol, sevoflurane, or desflurane.16 One of the important beliefs in neuroanesthesia practice is that use of morphine may be associated with delayed emergence when compared to fentanyl. A study compared the effect of morphine to that of fentanyl in patients VII. NEUROSURGERY POSTOPERATIVE MANAGEMENT 241 undergoing surgery for supratententorial tumors in two different tertiary care centers of India. No difference was noted in the emergence times.23 Fast-track awakening from anesthesia has its own drawbacks. Emergence hypertension is a common phenomenon associated with early awakening, which can predispose to intracranial hematoma formation. Various pharmacological agents like lignocaine, esmolol, nicardipine, etc., have been used to manage emergence hypertension. One clinical trial tried to address the issue of facilitating early emergence along with limiting the consequence hypertension. They conclude that low dose of fentanyl along with nitrous oxide during craniotomy closure was effective in facilitating early emergence along with control of emergence hypertension.24 Coughing during emergence from anesthesia is an unpleasant experience for the patients. It leads to sympathetic stimulation and increase in blood pressure as well as metabolic requirement of the body. It increases the intrathoracic pressure and cerebral venous pressure leading to the disruption of venous hemostasis and intracranial hematoma formation. The effect of intravenous agents as well as inhalational agents appears to be similar on the incidence of coughing during emergence. Use of lignocaine in the pilot balloon of the endotracheal tube has been found to be associated with reduced incidence of emergence coughing.25 Emergence agitation is another undesirable response following neurosurgery. An agitated patient will not allow for an adequate neurological examination. Moreover, it may be difficult to ascertain the cause due to anesthetics or neurosurgical factors. However, the incidence of emergence agitation has been found to be similar with use of propofol, sevoflurane, and desflurane.16 POSTOPERATIVE MANAGEMENT The management of a patient following supratentorial craniotomy should be carried out in a specialized neuro– intensive care unit. These patients require continuous neurological and systematic physiological monitoring. Any neurological deterioration can have systemic manifestation, while a compromise in systemic condition like hypertension, hypoxemia, hyperthermia, and hyperglycemia can adversely affect the neurological outcome of the patients. Constant vigilance with immediate detection of any postoperative complications is the key to good outcome in these groups of patients. Meticulous care has to be taken to maintain fluid and electrolyte balance in the patients along with nutritional supplementation. Patients who are mechanically ventilated in the postoperative period should be adequately sedated so as to allow them to tolerate the endotracheal tube and ventilatory support. The sedative agent used should be easily titrable with fast onset and offset so as to allow for adequate neurological assessment. Seizure prophylaxis, corticosteroids, and cerebral decongestants should be continued in the postoperative period. Postcraniotomy Pain Postcraniotomy pain is an important aspect of postoperative management and needs to be dealt with utmost care. The incidence is around 60%, with the highest incidence observed 12 h after surgery, the majority being moderate in nature and intensity.26 Patients of our institute experience mild pain within 48 h of craniotomy (Figs. 12.8 and 12.9). FIGURE 12.8 Incidence of postcraniotomy pain (PGIMER Chandigarh data, 2009). Figures represent percentage of patients. VII. NEUROSURGERY 242 12. SUPRATENTORIAL LESIONS FIGURE 12.9 Incidence and duration of postcraniotomy pain (PGIMER Chandigarh data, 2009). Figures represent percentage of patients. The management can be pre-emptive or based on symptoms. Scalp block administrated prior to craniotomy has been found to reduce intraoperative analgesic requirement as well as delay the onset of postcraniotomy pain. Use of bupivacaine or ropivacaine has been found to be effective. Paracetamol alone is not effective. Combination of paracetamol with other analgesic medication may be effective. Opioids have been commonly advocated with oral codeine being the most common. Patient-controlled analgesia with fentanyl, remifentanil, and morphine has been found to be useful in ameliorating postcraniotomy pain. It is common belief that use of nonsteroidal antiinflammatory drugs in patients with postcraniotomy can lead to intracranial hematoma formation due to its effect on platelet function. This is yet to be proven. Our personal experience is to use diclofenac 2 mg/kg as intravenous dose during craniotomy closure, which is effective in reducing postoperative pain. Postoperative Seizures The occurrence of seizures following craniotomy has been found to be present in 15–20% patients.27 Postoperative seizure has the potential to increase CMRO2 and CBF leading to raised ICP and neurological deterioration. In case of inability to maintain the airway or an unconscious patient, there will be a need to secure the airway and maintain oxygenation. Single focal seizures can be managed with reassurance. However, generalized tonic-clonic seizure need to be managed with anticonvulsant drug. The cause could be postoperative edema or hematoma or pneumocephalus mass effect. Significant pneumocephalus or hematoma will require evacuation, and presence of edema will need antiedema measures. Beside this proper oxygenation and maintenance of hemodynamics are also important. If the patient is already on antiepileptic drugs, the dose should be increased after repeating loading dose or newer antiepileptic agent is added to the current medications. If it is new-onset seizure, then loading dose of antiepileptics followed by maintenance dose should be started. Antiepileptics that are effective include phenytoin and levetiracetam. Sodium valproate and phenobarbital have not proven beneficial in preventing postoperative seizures. Moreover, these drugs are also associated with significant side effects such as hepatotoxicity and hematological abnormalities.28,29 Postcraniotomy Nausea and Vomiting Postcraniotomy nausea and vomiting (PONV) is one of the most important preventable complication. Its incidence is up to 45–70% without treatment.30 Vomiting and retching cause increase in intra-abdominal intrathoracic pressure, which leads to raised ICP. In addition, it increases chances of pulmonary aspiration and cause fluid electrolyte imbalance. All these factors deteriorate patient neurological status. Antiemetics are the mainstay of prophylaxis against PONV and 5-HT3 antagonists are considered as agent of choice. 5-HT3 antagonists have acceptable side effects such as sedation, no extrapyramidal reactions, and no drug interactions. Dexamethasone routinely administered in neurosurgical patients for reduction of peritumoral edema increases the antiemetic efficacy of 5-HT3 antagonists. AWAKE CRANIOTOMY Awake craniotomy refers to conduct of intracranial tumor surgery under conscious sedation so as to enable clinical neuromonitoring, which allows the neurosurgeon to conduct tumor resection with no or minimal neurological deficit. The conduct of awake craniotomy must ensure the patients’ comfort, which in turn help in seeking VII. NEUROSURGERY AWAKE CRANIOTOMY 243 patient cooperation. Awake craniotomy has been traditionally used from ancient times and is a challenge for the anesthesiologist. With the advent of new monitoring gadgets and availability of short-acting drugs, the conduct of awake craniotomy has become comfortable for the anesthesiologist and a pleasant experience for the patient. Indications 1. Supratentorial tumors close to eloquent areas like motor strips and speech area. 2. Epilepsy surgery. Techniques for Awake Craniotomy There are conventionally three techniques for the conduct of awake craniotomy. Although there are no clear-cut guidelines for preference of each over the other, but the clinical experience and patients clinical profile will help the anesthesiologist in identifying the technique that suits the patient. Awake technique: This particular technique refers to conduct of entire intracranial surgery under conscious sedation and monitoring. The process of conscious sedation is initiated, and scalp block is administered. The skin, periosteal layer of cranium, and the dura matter are infiltrated by local anesthetics as the surgeon conduct surgery. Our experience indicates that this technique is good for patients who have some degree of cognitive impairment due to neurological condition, alcoholism, and drug withdrawal. Similarly, patients with alcoholic liver disease may fair better in this technique as awakening after general anesthesia (GA) may have residual anesthetic effects and patients may not be cooperative. There are few limitation with awake techniques. The patients may perceive pain during periosteal elevation and dural incision despite optimal-level sedation and presumed analgesia. Sleep–awake technique: This technique encompasses the use of GA with a supraglottic airway device (SAD) till the raising of dural flap. Muscle relaxants are preferably avoided. Subsequently, the GA is switched of and SAD removed. The tumor is resected with patients under conscious sedation to enable neurological examination. This technique is comfortable for the patients as the painful part of the procedures like periosteal elevation and dural incision are not perceived by the patient. However, some patients may experience pain during dural and skin closure. This can be limited by increasing the depth of sedation and adequate supplementation of analgesia. Care must be taken to ensure adequate awakening in obese patients and those with history suggestive of obstructive sleep apnea (OSA) before removal of SAD following GA. Sleep–awake–sleep technique: The initial phase is similar as described under sleep–awake technique. Following tumor resection and hemostasis the patients are readministered GA and airway is secured with a SAD. This procedure mitigates any chances of pain during craniotomy closure. The issue that needs to be addressed is resecuring of airway during craniotomy closure. It has to be preoperatively ensured that the patient has adequate mouth opening and there should be adequate access of the airway. Use of proseal laryngeal mask airway, which comes with an inserter, is usually handy in resecuring the airway. Steps in the Conduct of Awake Craniotomy Once the patient has been identified for awake craniotomy, the patient should be counseled extensively by the surgeon and the anesthesiologist. The surgeon should explain the need and advantage of this surgery under awake condition. The anesthesiologist should first develop the support with the patient by introducing himself and having a general discussion. Then the patient should be explained about the various steps in the conduct of awake craniotomy assured from time to time that he will be kept comfortable in the entire procedure. It has to be emphasized to the patients with due care the need to remain calm and cooperative during the procedure. They have to be assured that should any pain discomfort or complication arise, it will be adequately taken care of. The patients should be subsequently explained about the various techniques of conduct craniotomy and the neurological and psychometric testing to be conducted interoperatively. After proper explanation, the patients should be allowed time to understand and have their queries answered. Subsequent visits would boost patient’s confidence, and this is one important factor for the success of awake craniotomy The preanesthetic evaluation should specifically take into consideration airway and mouth opening. History should be sought regarding snoring, seizures, and motion sickness. Preoperative cognitive function assessment has to be done to assess the anesthesia technique to be adopted for awake craniotomy, and the neurological and cognitive function for motor power, speech, and vision has to be explained and rehearsed in the preoperative period. VII. NEUROSURGERY 244 12. SUPRATENTORIAL LESIONS The operation theater has to be specifically prepared for the smooth conduct of awake craniotomy. Special arrangements have to made to allow visualization and access to patients during conduct of surgery (Fig. 12.10). The environment should be calm, and the patient should feeling relaxed (Fig. 12.11). Premedication includes antianxiety and antiemetic measures. Standard monitoring like ECG, peripheral capillary oxygen saturation, blood pressure, and capnography should be done. Invasive arterial blood pressure in the limbs, which may not require extensive neurological examination, may be considered as use of non-invasive blood pressure may be a source of discomfort due to repeated inflation. During conscious sedation, the capnography can be monitored by placing the sampling line near to one of the nostrils of the patient; monitoring of the depth of anesthesia would allow for easy titrability of anesthetics and sedative agents. The intravenous cannula should be placed in the limbs, preferably not in the primary limb to be examined. Patient should be covered with a warming blanket. Scalp block should be given to all patients (Fig. 12.12). Neurological examination should be carried out prior to and time to time during tumor resection. Any alteration in neurological and cognitive function should be promptly informed to the surgeon. The patient has to be emotionally supported and assured about the surgery. Any discomfort has to be promptly attended. Postoperative Care The standard of postoperative care should be the same as is with any patient undergoing neurosurgical procedures. Beside it is important to make a postoperative visit to the patient to understand the experience of the patient and make necessary modifications related to anesthetic management. FIGURE 12.10 Arrangement of operation theater for awake craniotomy. FIGURE 12.11 Canopy for easy accessibility of patient for communication. VII. NEUROSURGERY REFERENCES 245 FIGURE 12.12 Nerves for scalp block. Complications 1. Oversedation can occur, which may result in lack of patient cooperation for conduct of intraoperative neurological examination. Use of bispectral index or entropy monitors may help in titrating the sedative drugs and avoid oversedation. Oversedation can also lead to tongue fall and obstruction of airway especially in patients who are obese and those who have history suggestive of OSA. 2. Undersedation can lead to patients’ anxiety, restlessness, and movements, which can affect the conduct of surgery. A calculated bolus dose and stepping up of infusion of seductive drugs can help in providing comfort to the patients. 3. Pain may be perceived during various stages of awake craniotomy. Reassurance and use of bolus dose of shortacting opioids can help in ameliorating pain during procedure. 4. Nausea and vomiting can occur during the procedure. Antiemetic prophylaxis can be effecting in reducing the incidence of intraoperative nausea and vomiting. 5. Seizures can occur intraoperatively, which can jeopardize the procedure. In our experience seizure prophylaxis has shown to be effective in preventing the intraoperative convulsions. Nevertheless, if seizures occur, the first concern should be to ensure adequate airway and breathing. Simultaneously the surgeon should instill ice cold saline on the brain surface. Intravenous midazolam can help in limiting the seizure episode. If the patient is comfortable and cooperative after the seizure episode, the surgery can proceed under conscious sedation. If not, then the airway will need to be secured and the surgery has to be conducted under GA. 6. Patient discomfort like dry mouth, itching around the face, heaviness of head, etc., has to be adequately addressed. CONCLUSIONS Supratentorial lesions account for the major bulk of case load at neurosurgical centers. The anesthesiologists who are involved in the management of neurosurgical patients should have working knowledge of anatomy and radiology related to supratentorial lesions. The anesthesiologist should develop clinical skills in the assessment of patients with supratentorial lesion and accord them due care with respect to the changes in cerebral and systemic physiology. Active participation of an anesthesiologist in the perioperative management of patients is important in the critical outcome of these groups of patients. Acknowledgment We are thankful to Mr. Munish Kumar, Junior Research Fellow in the Department of Anaesthesia and Intensive Care, for the sketches of Figs 12.1, 12.2, and 12.4. References 1. Smith DR, Jacobson J, Kobrine AI, Rizzoli HV. Regional cerebral blood flow with intracranial mass lesions. Part II: autoregulation in localized mass lesion. Surg Neurol 1977;7:238–40. 2. Butler AR, Passalaqua AM, Berenstein A, Kricheff II . Contrast enhanced CT scan and radionuclide brain scan in supratentorial gliomas. Am J Roentgenol 1979;132:607–11. VII. NEUROSURGERY 246 12. SUPRATENTORIAL LESIONS 3. Wiranowska M, Gonzalvo AA, Saporta S, Gonzalez OR, Prockop LD. Evaluation of blood–brain barrier permeability and the effect of interferon in mouse glioma model. J Neurooncol 1992;14:225–36. 4. Fidler IJ, Yano S, Zhang RD, Fujimaki T, Bucana CD. The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol 2002;3:53–7. 5. Finizio FS. CT and MRI aspects of supratentorial hemispheric tumors of childhood and adolescence. Childs Nerv Syst 1995;11:559–67. 6. On NH, Mitchell R, Savant SD, Bachmeier CJ, Hatch GM, Miller DW. Examination of blood–brain barrier (BBB) integrity in a mouse brain tumor model. J Neurooncol 2013;111:133–43. 7. Smith DR, Jacobson J, Kobrine AI, Rizzoli HV. Regional cerebral blood flow with intra cranial mass lesions. Part I: local alterations in cerebral blood flow. Surg Neurol 1977;7:233–40. 8. Zwetnow NN, Schrader H, Löfgren J. Effects of continuously expanding intracranial lesions on vital physiological parameters. An experimental animal study. Acta Neurochir (Wien) 1986;80:47–56. 9. Thuomas KA, Vlajkovic S, Ganz JC, Nilsson P, Bergström K, Pontén U, et al. Progressive brain compression, changes in vital physiological variables, correlated with brain tissue water content and brain tissue displacement, experimental MR imaging in dogs. Acta Radiol 1993;34:289–95. 10. Liubinas SV, O’Brien TJ, Moffat BM, Drummond KJ, Morokoff AP, Kaye AH. Tumour associated epilepsy and glutamate excitotoxicity in patients with gliomas. J Clin Neurosci 2014;21:899–908. 11. Buckingham SC, Campbell SL, Haas BR, Montana V, Robel S, Ogunrinu T, et al. Glutamate release by primary brain tumors induces epileptic activity. Nat Med 2011;17:1269–74. 12. Chen W. Clinical applications of PET in brain tumors. J Nucl Med 2007;48:1468–81. 13. Kolin A, Norris JW. Myocardial damage from acute cerebral lesions. Stroke 1984;15:990–3. 14. Qureshi AI, Geocadin RG, Suarez JI, Ulatowski JA. Long-term outcome after medical reversal of transtentorial herniation in patients with supratentorial mass lesions. Crit Care Med 2000;28:1556–64. 15. Mukherjee KK, Dutta P, Singh A, Gupta P, Srinivasan A, Bhagat H. Choice of fluid therapy in patients of craniopharyngioma in the perioperative period: a hospital-based preliminary study. Surg Neurol Int 2014;5:105. 16. Bastola P, Bhagat H, Wig J. Comparative evaluation of propofol, sevoflurane and desflurane for neuroanaesthesia: a prospective randomised study in patients undergoing elective supratentorial craniotomy. Indian J Anaesth 2015;59:287–94. 17. Sieber F, Smith DS, Kupferberg J, Crosby L, Uzzell B, Buzby G, et al. Effects of intraoperative glucose on protein catabolism and plasma glucose levels in patients with supratentorial tumors. Anesthesiology 1986;64:453–9. 18. Kozek-Langenecker SA, Afshari A, Albaladejo P, Santullano CAA, De Robertis E. Management of severe perioperative bleeding. Guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol 2013;30:270–382. 19. Dietrich WD. The importance of brain temperature in cerebral injury. J Neurotrauma 1992;9:S475–85. 20. Eccher M, Suarez JI. Cerebral edema and intracranial pressure. Monitoring and intracranial dynamics. In: Suarez JI, editor. Critical care neurology and neurosurgery. Totowa (NJ): Humana Press; 2004. p. 47–100. 21. Gokhale S, Khan SA, Agrawal A, Friedman AH, McDonagh DL. Levetiracetam seizure prophylaxis in craniotomy patients at high risk for postoperative seizures. Asian J Neurosurg 2013;8:169–73. 22. Magni G, Rosa IL, Melillo G, Savio A, Rosa G. A comparison between sevoflurane and desflurane anesthesia in patients undergoing craniotomy for supratentorial intracranial surgery. Anesth Analg August 2009;109:567–71. 23. Bhagat H, bukhal I, bastola P, Bithal PK, Dash HH. A47 does morphine prolong emergence in neurosurgical patients. Eur J Anaesthesiol 2012;29:S-14. 24. Bhagat H, Dash HH, Bithal PK, Chouhan RS, Pandia MP. Planning for early emergence in neurosurgical patients: a randomized prospective trial of low-dose anesthetics. Anesth Analg 2008;107:1348–55. 25. George SE, Singh G, Mathew BS, Fleming D, Korula G. Comparison of the effect of lignocaine instilled through the endotracheal tube and intravenous lignocaine on the extubation response in patients undergoing craniotomy with skull pins: a randomized double blind clinical trial. J Anaesthesiol Clin Pharmacol 2013;29:168–72. 26. De Benedittis G, Lorenzetti A, Spagnoli D, Migliore M, Tiberio F, Villani R. Postoperative pain in neurosurgery: a pilot study in brain surgery. Neurosurgery 1996;38:466–70. 27. Foy PM, Copeland GP, Shaw MD. The incidence of postoperative seizures. Acta Neurochir 1981;55:253–64. 28. Glantz MJ, Cole BF, Friedberg MH, et al. A randomized, blinded, placebo-controlled trial of divalproex sodium prophylaxis in adults with newly diagnosed brain tumors. Neurology 1996;46:985–91. 29. Franceschetti S, Binelli S, Casazza M, et al. Influence of surgery and antiepileptic drugs on seizures symptomatic of cerebral tumours. Acta Neuro Chirurgica 1990;103:47–51. 30. Latz B, Mordhorst C, Kerz T, Schmidt A, Schneider A, Wisser G, et al. Postoperative nausea and vomiting in patients after craniotomy: incidence and risk factors. J Neurosurg 2011;114:491–6. VII. NEUROSURGERY C H A P T E R 13 Emergence From Anesthesia M. Echeverría1, J. Fiorda-Diaz2, N. Stoicea2, S.D. Bergese2 1Centro Médico Docente Paraíso, Maracaibo, Venezuela; 2Ohio State University, Columbus, OH, United States O U T L I N E Introduction 247 Neurophysiological Response During Emergence in Neurosurgical Patients 248 Specific Perioperative Considerations Surgical Site and Lesion Location Anesthetic Techniques Balanced Anesthesia Total Intravenous Anesthesia Anesthetic Technique and Recovery of Cognitive Function Dexmedetomidine 248 248 248 249 249 249 249 Delayed Emergence and Arousal Agitation During Emergence From Anesthesia Delayed Emergence Planned Delayed Emergence Causes of Delayed Emergence 250 250 250 250 251 Complications Intracranial Hemorrhage or Hematoma Hypertension and Cerebral Hyperperfusion Postoperative Nausea and Vomiting 251 251 251 252 Conclusion 252 References 252 INTRODUCTION Multiple historical factors may be related directly or indirectly with the emergence from anesthesia. William Harvey’s statement in Exercitatio anatomica de motu cordis et sanguinis in animalibus (On the Movement of the Heart and Blood in Animals) regarding the blood circulating around the body (1628) took down Galenic dogma (130 BC) about blood circulatory mechanism1 and created the basis of physiological and pharmacological principles. In 1846, William T. Morton performed the first successful administration of anesthesia but little was known about emergence from anesthesia and patients’ reaction after ether administration. Prior to this successful experience, Morton tried couple of times to anesthetize a patient with unexpected reactions: agitation and disorganized speech.2 Cerebral autoregulation and physiological adaptation in the immediate postoperative period are linked to intraoperative efforts to maintain homeostasis. Induced hypocapnia, use of osmotic fluids, and placement of drains are examples of perioperative variables with an important impact in outcomes during the emergence from anesthesia.3 An increasing body of evidence regarding anesthesia management supports different techniques based on physicians and institutions’ preferences such as total intravenous anesthesia (TIVA), balanced anesthesia, local anesthesia, or use of adjuvants and their combinations.4 Postoperative stress response during extubation may entail increased catecholamine response, oxygen consumption (VO2), blood pressure, and heart rate due to laryngeal stimulation, although other mechanisms are described.5 Variations in metabolism, hemodynamic parameters, cerebral blood flow (CBF), and intracranial pressure may be developed as a result of shivering or pain with consequent impairment in patients’ outcomes.5 Essentials of Neuroanesthesia http://dx.doi.org/10.1016/B978-0-12-805299-0.00013-0 247 © 2017 Elsevier Inc. All rights reserved. 248 13. EMERGENCE FROM ANESTHESIA Neurological examination should be carried out in the operating room during emergence to identify a potential neurological deficit or emergence delirium. Some patients undergoing complex procedures involving eloquent areas of the brain may be suitable for a planned delay in emergence from anesthesia, avoiding life-threatening complications such as intracranial hemorrhage (ICH), respiratory impairment, and aspiration due to unprotected airway.6 NEUROPHYSIOLOGICAL RESPONSE DURING EMERGENCE IN NEUROSURGICAL PATIENTS Several physiological changes take place during the emergence from anesthesia including metabolic variations and those affecting brain homeostasis. Even with slightly normal PaCO2 levels, bicarbonate levels in the cerebrospinal fluid (CSF) may decrease significantly.7 Therefore, consequent pH reduction in brain perivascular areas will lead to vasodilation and hyperemia.7 Apparently, these events occur regardless of the anesthetic agent used during maintenance. Bruder et al. reported a significant increment of 60% from baseline in CBF velocity during extubation and within the first hour after neurosurgery, with no relation found between these values and the surgery or anesthesia techniques.8 Increased catecholamine blood levels have been reported after neurological surgery.7,8 However, this condition by itself may interfere with the CBF only in the presence of a defective blood–brain barrier or when autoregulation is compromised.8 Different options are available to treat catecholamine hemodynamic effects such as β-blocker use (e.g., esmolol)9,10 and hypothermia prevention.11 On the other hand, sympathetic activation may play a crucial role on the central nervous system (CNS) responses during emergence from anesthesia. Reuptake inhibition of dopamine and norepinephrine by methylphenidate administration will trigger several mechanisms within the CNS leading to a faster recovery after isoflurane and propofol exposure.12,13 Surgery and anesthesia may also increase the incidence of emesis during the emergence. The “emesis center” includes the area postrema (AP), nucleus tractus solitarius, and the dorsal motor nucleus of the vagus nerve. No less than 17 neurotransmitters exert their action on this center throughout the interaction with several receptors such as dopamine, substance P/neurokinin-1, cannabinoid, histamine, among others.14 The aforementioned responses may be generated during extubation as a result of the autonomic nervous system activation. SPECIFIC PERIOPERATIVE CONSIDERATIONS Diagnosis of potential postoperative complications may be delayed due to a slow return to consciousness making neurological examination difficult to perform after neurosurgery. Postanesthesia arousal is a variable considered when assessing anesthesia quality.15,16 Preoperative neurologic status, location and size of the lesion, and anesthesia technique are some of the variables interfering with the early postoperative recovery of cognition, hemodynamics, and nociception during emergence. Surgical Site and Lesion Location Brain herniation, ischemia, and poor surgical field are the expected consequences of increased intracranial volume. These events have been associated with delayed arousal after intracranial surgery.10 Predictive factors for delayed postsurgical emergence are the following: mass effect of space-occupying lesion (over 30 mm size), cerebral structures shifting from midline >3 mm with perilesional edema, and prolonged retraction pressure needed to expose the surgical field during tumor resection.10 Anesthetic Techniques Definitive criteria for quality of recovery related to the anesthesia technique during neurosurgical procedures have not been established.15 However, a targeted and neurological evaluation is performed at the end of surgery to assess outcomes.17 The Short Orientation Memory Concentration Test (SOMCT) and the Aldrete score are commonly used when comparing the time and quality of recovery of patients undergoing supratentorial craniotomy, either under balanced or TIVA technique.18,19 VII. NEUROSURGERY SPECIFIC PERIOPERATIVE CONSIDERATIONS 249 TIVA based on propofol–remifentanil has shown slightly shorter extubation time, faster return to consciousness, and faster recovery in comparison with balanced anesthesia.17,20 However, most of the studies have demonstrated no statistical significance in quality of recovery among patients either when TIVA or balanced anesthesia was performed.5,18,21–24 The NeuroMorfeo Study was carried out in 411 patients reporting no difference in time after extubation to achieve an Aldrete score ≥9 between both balanced and TIVA groups. Hemodynamics and brain surgical conditions were also similar among groups. Nevertheless, a reduced endocrine response to surgical stress was linked to propofol/ remifentanil combination.24 Balanced Anesthesia Desflurane provides shorter extubation and recovery time than sevoflurane in patients undergoing craniotomy under balanced anesthesia.25,26 Magni et al. compared the effects of sevoflurane (1.5–2%) and desflurane (6–7%) on emergence analyzing the data collected from 120 neurosurgical patients. No significant difference was found regarding the time for emergence (12.2 ± 4.9 min versus 10.8 ± 7.2 min), recorded as the time when eye opening occurred since the inhaled agent administration was suspended. On the other hand, the sevoflurane group needed more time for tracheal extubation in contrast to the desflurane group (18.2 ± 2.3 min versus 11.3 ± 3.9 min). Similarly, the time of recovery (defined in this study as the time that patients’ consciousness allowed them to repeat their name and date of birth) was longer in the sevoflurane group (12.4 ± 7.7 min versus 1.3 ± 3.9 min).25 The characteristic of the surgical field, such as state of the brain tissue and the intracranial pressure (ICP) and postoperative cognitive function are also comparable between both inhaled anesthetics during supratentorial surgeries.27 Cognitive impairment commonly occurs in both groups within the first 15 min after extubation25 or after Aldrete score was ≥9, usually returning to baseline during the next 30 min.26 Moreover, when compared with opioids such as fentanyl, alfentanil, and sufentanil in combination with isoflurane showed no clinical relevance regarding the time for obtaining a satisfactory neurological evaluation after surgery.28 Total Intravenous Anesthesia Despite the advantages of propofol use in neurosurgery such as reduction of cerebral metabolic rate of oxygen and ICP, increase of cerebral perfusion pressure (CPP), and antiemetic effect,17,29–32 adverse events like shivering, high blood pressure, and postoperative nausea and vomiting (PONV) are not uncommon.4 The effects and outcomes of several combinations of opioids and propofol infusions have been compared during neurosurgery with different results. Gerlach et al. compared propofol/remifentanil versus propofol/sufentanil in supratentorial surgeries and reported a reduced time for extubation in the remifentanil group (6.4 min vs. 14.3 min).33 When remifentanil/propofol combination was used, SOMCT and Rancho Los Amigos Scale scores are comparable to baseline sooner than the interval of time reported by sufentanil/propofol group.19 Nevertheless, Djian et al. showed similar results among groups regarding extubation time and reported an increase in costs in the remifentanil group when compared to the sufentanil group.34 On the other hand, remifentanil is characterized by a faster onset in reducing cardiovascular responses during intubation when compared with fentanyl. However, hemodynamic parameters, ICP, and CPP levels are similar during the maintenance of anesthesia with both, remifentanil and fentanyl, whereas naloxone administration after neurosurgery is importantly increased in patients who received fentanyl.35 Moreover, remifentanil/propofol seems to be a common option for transsphenoidal procedures as it may offer a reduced incidence of postoperative coughing during and after extubation by providing an ideal emergence.36 In fact, these studies provide more evidence on the convenience of using opioid drips in neuroanesthesia as discontinuation at an appropriate time will result in a shorter extubation and recovery. Anesthetic Technique and Recovery of Cognitive Function Recovery of cognitive functions after surgery has become one of the major concerns among neuroanesthesiologists and also an important parameter when comparing different anesthetic techniques in neurosurgical patients.37 In fact, a connection between the pathogenesis of neurodegenerative diseases and the development of postoperative cognitive dysfunction has been described.37 Dexmedetomidine Some adjuvants such as the alpha-2 adrenoreceptor agonist dexmedetomidine have been widely used in neuroanesthesia with potential intra- and postoperative advantages. Dexmedetomidine produces dose-dependent sedation, anxiolysis, and analgesia without any concomitant respiratory depression along with decreased anesthetic VII. NEUROSURGERY 250 13. EMERGENCE FROM ANESTHESIA requirements (hypnotics and opioids).38,39 These characteristics make dexmedetomidine a suitable drug for neuroanesthesia.38,39 Smoother arousal and recovery after neurological surgery has been reported with the use of dexmedetomidine as an adjunct during neuroanesthesia. Bekker et al. carried out a prospective, randomized, double-blinded study and concluded that dexmedetomidine use during sevoflurane/remifentanil general anesthesia was associated with less perioperative antihypertensive drugs administration, when compared with placebo (43% vs. 86%).38 Dexmedetomidine is also associated with a reduction in CBV, leading to minimization of intraoperative brain retraction, optimization of oxygen supply/demand relation, and inhibition of hypercapnia-induced cerebral vasodilation.39,40 DELAYED EMERGENCE AND AROUSAL Agitation During Emergence From Anesthesia Agitation during and after emergence is a clinical situation commonly seen in neurosurgical patients (up to 30% of incidence) and usually described within the first hours after intensive care unit admission. The sedation-agitation scale (SAS) and the Richmond Agitation-Sedation Scale are useful clinical assessing tools for both physicians and nurses, to detect a potential postoperative agitation or delirium event.41,42 Around 80% of neurosurgical patients who experienced agitation during the emergence received a score of ≥6 based on SAS classification (very agitated or dangerous agitation).41 Systemic high blood pressure, increased ICP, hemorrhage, and PONV are the most relevant postoperative complications associated with a fast emergence from anesthesia in neurosurgical patients.43 In addition, extremely agitated patients may unintentionally pull out their catheters or even the endotracheal tube.41 Randomized controlled trials have compared the influence of different anesthetics on emergence agitation after intracranial surgery, revealing that the incidence of agitation during the early phase of recovery varied from 2.5% to 13.3%.17,24,44 Chen et al. identified several independent factors associated with emergence agitation after craniotomy under general anesthesia such as patient-related factors (male gender or patients taking antidepressant drugs or benzodiazepines), anesthesia-related factors (anesthesia management, time exposed to anesthesia, and existence of endotracheal tube), and surgery-related factors (frontal approach).41 Surgery and anesthesia time, pain, and anesthesia management have been also reported as relevant predictors for delirium and agitation during emergence in nonneurosurgical patients.45–47 In this patient setting, TIVA using propofol seems to decrease the incidence of agitation during the emergence from anesthesia.45,46,48 In summary, preemptive techniques and pharmacological interventions could be applied to decrease the onset of agitation during the emergence or within the first postoperative hours. Delayed Emergence Early neurological assessments after surgery entail a fast recovery from the moment of emergence from general anesthesia. Nevertheless, rapid emergence is not an adequate option for every patient. Baseline assessed neurological status, surgical concerns and prognosis, hemodynamics, and respiratory support, among other factors, may play an important role on delaying emergence (planned or unexpected).43 Hypothermia or pain may contribute to the postoperative physiologic stress responses to emergence.43,49 Delayed emergence is considered when patients failed to awake being unable to respond to simple verbal commands. The time when a delayed emergence should be diagnosed is 15 min after anesthesia discontinuation, although up to 30 min has also been considered.6,50 Planned Delayed Emergence In patients with compromised clinical conditions, risks of early extubation may outweigh the benefits. Impaired baseline level of consciousness, poor airway control, prolonged (>6 h) or complicated surgery, unstable intraoperative hemodynamics or ventilation difficulties, and increased brain swelling are some of the clinical situations in which planned delayed recovery should be considered.5 Other considerations may include surgery involving eloquent areas of the brain, significant brain ischemia, and posterior fossa lesions.5 Cai et al. reported a 49.8% rate of delayed extubation after intracranial surgery (398 out of 800 patients).51 Although data may be limited, the criteria for delayed extubation have been described in reviews and observational prospective studies.43,51 VII. NEUROSURGERY COMPLICATIONS 251 If a planned emergence delay has been decided, the possibility of a brief awakening to perform a short neurological assessment is a common practice among physicians. Complementary options to an early neurologic evaluation are postoperative computed tomography or ICP monitoring.6 In patients undergoing posterior fossa or infratentorial surgery, the feasibility of postoperative extubation will be determined by (but not limited to) the location of the lesion, the extent of surgery (especially if the brainstem is involved), and brain edema.52,53 PONV is also more frequent in posterior fossa surgery.53 Unprotected airway combined with PONV may result in life-threatening situations such as aspiration of gastric content, increased ICP, among others. Surgical positioning may also interfere with patient outcomes during emergence. Macroglossia and consequent upper airway obstruction is usually related with the sitting and prone position probably due to a regional disruption in venous and lymphatic drainage.54 Some authors suggest that patients undergoing posterior fossa surgery should be extubated at least 1–2 h after they are considered to be fully recovered from anesthesia. However, increased incidence of pneumonia coexisting with other comorbidities, higher incidence of tracheostomy, prolonged hospital admission, and increased costs have been associated with delayed emergence after neurosurgery.51 Causes of Delayed Emergence Scientific evidence incriminates multiple factors in delayed emergence such as perioperative opiate analgesia,50 hypothermia,5 anxiolytics, metabolic or electrolyte disturbances, drug clearance impairment, stroke, pneumocephalus, CSF hypotension, and seizures.10 COMPLICATIONS Even though PONV and hypertension are commonly diagnosed complications in patients recovering in postanesthesia care unit, preventing their onset is one of the main goals in neurosurgical patients due to associated life-threatening consequences.5 The most common signs of deterioration after intracranial surgery are decreased level of consciousness and focal neurologic deficit. Cerebral hemorrhage usually occurs in the first 6 h after surgery, justifying the importance of closed clinical monitoring within the first postoperative hours.5 PONV occurs more frequently after neurosurgical procedures than after general surgical procedures.53 ICH and seizures are also described as complications after neurosurgery.5 Intracranial Hemorrhage or Hematoma Physiological responses to stimulation induced by extubation and recovery are associated with ICH and tissue edema.8 Overall the incidence of ICH after neurosurgery may vary between 0.77% and 3.9% among studies, with a maximum value of 10.8% reported by Fukamachi et al. in the 1980’s.55 A retrospective study conducted by Basali et al. in 11,214 craniotomy surgeries found that 62% of patients with ICH experienced intraoperative hypertension, acute episodes of postoperative hypertension being linked to increased morbidity and mortality by cerebral edema or ICH.56 Hypertension and Cerebral Hyperperfusion Increased blood pressure is an expected postoperative event after brain surgery,9,57 probably due to activation of autoregulatory mechanisms. However, postoperative hypertension has been associated with an increased risk of postoperative cerebral hyperemia.8,56 Autoregulation may be impaired after neurosurgery, especially in retracted areas and its surroundings. Therefore, any postoperative increase in blood pressure will overwhelm autoregulatory responses and compromise cerebral perfusion. Although blood pressure control may be achieved during the emergence from anesthesia and reduce the incidence of postoperative intracranial bleeding, it cannot prevent cerebral hyperperfusion.55,56,58–60 Bruder et al. considered that cerebral hyperemia occurs as a result of cerebral metabolic stress.7 Additionally, CBF reestablished after prolonged hypocapnia may be also considered a contributing factor to cerebral hyperemia in neurosurgical patients.7,8,61 In terms of postoperative hemodynamic changes, when comparing TIVA to inhalational anesthesia, differences in blood pressure and heart rate seem to have no statistical significance.20,21,23 However, Magni et al. concluded that remifentanil is associated with more frequent hypertension than sevoflurane/ fentanyl.18 VII. NEUROSURGERY 252 13. EMERGENCE FROM ANESTHESIA Esmolol, a selective β-adrenergic receptor antagonist, is considered an effective pharmacological option to attenuate hyperdynamic responses occurring during extubation and postextubation stages.62,63 Moreover, blocking the β1adrenergic receptor may reduce cerebral stress responses and hyperperfusion without any relevant change on ICP.27,63 Postoperative Nausea and Vomiting The overall incidence of PONV has been reported with high variability from 38% to 80% in some patient populations.64,65 Fabling et al. found an important incidence of PONV in patients who underwent infratentorial surgery even when prophylactic medication was administered. Therefore, multiple variables not related to anesthesia management must be taken into consideration to achieve a successful control of PONV in neurosurgical patients,65 improving outcomes, and avoiding hemorrhagic complications associated with this complication.32 Intracranial surgery entails a higher risk for PONV when compared to general surgery. In addition to general PONV risk factors such as gender and smoking status, surgical site (higher incidence in infratentorial procedures), and manipulation around the AP have a specific weight in the onset of PONV after neurosurgery.66 Triple therapy for PONV prophylaxis (droperidol, promethazine, and dexamethasone) is widely accepted among physicians. Moreover, other pharmacological options such as aprepitant and fosaprepitant have demonstrated longer effects,67 but supporting clinical literature is limited. CONCLUSION Hemodynamic and pathologic responses to complications occurring during emergence from anesthesia are potentially life threatening in neurosurgical patients, as they will disrupt the physiology of an overwhelmed central nervous system. Certainly, anesthetics and adjuvants play an important role in maintaining perioperative cerebral homeostasis. Cardiovascular, neurologic, and respiratory effects of the anesthetics are dose dependent in the vast majority of the cases. Therefore, a combination of drugs with different mechanisms of action offers synergistic effects by reducing the plasmatic concentrations of every single one, avoiding the onset of adverse events usually linked to higher concentrations. Although no definitive criteria have been established for anesthesia management during neurosurgery, there are general considerations that should be addressed based on current clinical conditions of the patient and expected surgery outcomes. Attenuation of neurological responses to local or systemic stimulation during emergence should be the paramount to the neuroanesthesia management, improving patients’ outcomes and decreasing postoperative complications. References 1. Wright T. William Harvey goes back to the future. Lancet 2013;381(9867):620–1. 2. Haridas RP. “Gentlemen! This is no humbug” Did John Collins Warren, MD, proclaim these words on October 16, 1846, at Massachusetts General Hospital, Boston? J Am Soc Anesthesiol March 1, 2016;124(3):553–560. 3. Yan L-M, Chen H, Yu R-G, et al. Emergence agitation during recovery from intracranial surgery under general anaesthesia: a protocol and statistical analysis plan for a prospective multicentre cohort study. BMJ Open 2015;5(4):e007542. 4. Wong A, O’Regan A, Irwin M. Total intravenous anaesthesia with propofol and remifentanil for elective neurosurgical procedures: an audit of early postoperative complications. Eur J Anaesthesiol 2006;23(7):586–90. 5. 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Factors influencing delayed extubation after infratentorial craniotomy for tumour resection: a prospective cohort study of 800 patients in a Chinese neurosurgical centre. J Int Med Res 2013;41(1):208–17. 52. Artru AA, Cucchiara RF, Messick JM. Cardiorespiratory and cranial-nerve sequelae of surgical procedures involving the posterior fossa. J Am Soc Anesthesiol 1980;52(1):83–5. 53. Jagannathan S, Krovvidi H. Anaesthetic considerations for posterior fossa surgery. Contin Educ Anaesth, Crit Care Pain 2014;14(5):202–6. 54. Lam AM, Vavilala MS. Macroglossia: compartment syndrome of the tongue? J Am Soc Anesthesiol 2000;92(6):1832. 55. Fukamachi A, Koizumi H, Nukui H. Postoperative intracerebral hemorrhages: a survey of computed tomographic findings after 1074 intracranial operations. Surg Neurol 1985;23(6):575–80. 56. Basali A, Mascha EJ, Kalfas I, Schubert A. Relation between perioperative hypertension and intracranial hemorrhage after craniotomy. J Am Soc Anesthesiol 2000;93(1):48–54. 57. Günes Y, Türktan M, Erman T, Özcengiz D. Comparison of dexmedetomidine, remifentanil, and esmolol for the control of hypertension during tracheal extubation and emergence from anesthesia after a craniotomy. Neurosurg Q 2013;23(4):294–8. 58. Felding M, Jakobsen CJ, Gold G, Davidsen B, Jensen K. The effect of metoprolol upon blood pressure, cerebral blood flow and oxygen consumption in patients subjected to craniotomy for cerebral tumours. Acta Anaesthesiol Scand 1994;38(3):271–5. 59. Felding M, Cold G, Jagobsen CJ, Stjernholm P, Voss K. The effect of ketanserin upon postoperative blood pressure, cerebral blood flow and oxygen metabolism in patients subjected to craniotomy for cerebral tumours. Acta Anaesthesiol Scand 1995;39(5):582–5. 60. Dalman J, Beenakkers I, Moll F, Leusink J, Ackerstaff R. Transcranial Doppler monitoring during carotid endarterectomy helps to identify patients at risk of postoperative hyperperfusion. Eur J Vasc Endovasc Surg 1999;18(3):222–7. 61. Albrecht RF, Miletich DJ, Ruttle M. Cerebral effects of extended hyperventilation in unanesthetized goats. Stroke 1987;18(3):649–55. 62. Hosseinzadeh H, Eydi M, Ghaffarlou M, Ghabili K, Golzari S. Esmolol: a unique beta-blocker in maintaining cardiovascular stability following neurosurgical procedures. Adv Pharm Bull 2012;2(2):249–52. 63. Bilotta F, Lam AM, Doronzio A, Cuzzone V, Delfini R, Rosa G. Esmolol blunts postoperative hemodynamic changes after propofol-remifentanil total intravenous fast-track neuroanesthesia for intracranial surgery. J Clin Anesth 2008;20(6):426–30. 64. Gan TJ, Diemunsch P, Habib AS, et al. Consensus guidelines for the management of postoperative nausea and vomiting. Anesth Analg 2014;118(1):85–113. 65. Fabling JM, Gan TJ, El-Moalem HE, Warner DS, Borel CO. A randomized, double-blind comparison of ondansetron versus placebo for prevention of nausea and vomiting after infratentorial craniotomy. J Neurosurg Anesthesiol 2002;14(2):102–7. 66. Latz B, Mordhorst C, Kerz T, et al. Postoperative nausea and vomiting in patients after craniotomy: incidence and risk factors. J Neurosurg 2011;114(2):491–6. 67. Tsutsumi YM, Kakuta N, Soga T, et al. The effects of intravenous fosaprepitant and ondansetron for the prevention of postoperative nausea and vomiting in neurosurgery patients: a prospective, randomized, double-blinded study. BioMed Res Int 2014:2014. VII. NEUROSURGERY C H A P T E R 14 Anesthesia for Posterior Fossa Surgery K. Sandhu1, N. Gupta2 1Max Superspeciality Hospital, New Delhi, India; 2Indraprastha Apollo Hospital, New Delhi, India O U T L I N E Introduction 255 Anatomy 255 Clinical Presentation 256 Perioperative Management of Patients for Posterior Fossa Surgery 256 Preoperative Evaluation 256 Surgical Approach 257 Anesthetic Considerations During Posterior Fossa Craniotomy 257 Premedication 258 Patient Positioning 258 Supine 258 Lateral 258 Park-Bench (Semiprone) 258 Prone 258 Sitting or Semisitting Position 259 Technical Considerations 259 Anesthetic Management Respiratory Management Hemodynamic Management Intraoperative Monitoring 261 261 262 263 Venous Air Embolism Incidence Pathophysiology Clinical Presentation of Venous Air Embolism Monitoring Grading of Venous Air Embolism Paradoxical Air Embolism Management of Venous Air Embolism 264 264 264 265 265 268 268 270 Postoperative Management 271 Complications 272 Abbreviations 272 References 273 INTRODUCTION Posterior fossa surgery poses significant challenges to both the anesthesiologist and surgeons with a wider variety of complications than surgery in the supratentorial compartment. Apart from the general perioperative considerations involving any intracranial lesion, highlights of posterior fossa lesions include unusual surgical positioning and its complications, potential for brain stem injury, lengthy surgical procedures, perioperative cardiovascular and respiratory embarrassment, and acute obstructive hydrocephalus. A thorough understanding of the patient’s history, neurological findings, imaging studies, operative anatomy, as well as all potential adverse events associated with the procedure is thus of paramount importance to minimize complications. ANATOMY Posterior cranial fossa is the largest and deepest cranial fossa. It houses the brain stem (midbrain, pons, and upper medulla), the cerebellum, 3rd to 12th cranial nerve nuclei, the ascending and descending tracts, and the vertebrobasilar vascular system. Essentials of Neuroanesthesia http://dx.doi.org/10.1016/B978-0-12-805299-0.00014-2 255 © 2017 Elsevier Inc. All rights reserved. 256 14. ANESTHESIA FOR POSTERIOR FOSSA SURGERY The presence of structures vital for control of airway, cardiovascular and respiratory systems within the narrow confines of this rigid and compact space makes the surgical anatomy unique and challenging. The presence of any space occupying pathology may lead to mass effect on vital brain stem structures. In addition, the cerebrospinal fluid (CSF) pathway is very narrow through the cerebral aqueduct, and a minor obstruction can cause acute hydrocephalus with significant increase in intracranial pressure (ICP). Presence of multiple large venous sinuses contained within the dural folds of the tentorium further adds to the risk of bleeding and air entrainment during surgery. CLINICAL PRESENTATION Symptomatology of lesions in the posterior cranial fossa differs from supratentorial tumors in terms of presentation and rapid worsening, as seen with acute hydrocephalus. Most posterior fossa tumors present with signs and symptoms of increased ICP including headache, nausea, or vomiting and papilledema. Signs and symptoms typical to the site of the lesion include movement disorders, altered tonicity, and ocular signs such as nystagmus, strabismus, diplopia, and pupillary abnormality. Additionally, there may be cranial nerve dysfunction, bulbar palsy, bradycardia, respiratory embarrassment, and sudden brain stem herniation leading to death. The classic triad of symptoms referable to a mass in the posterior fossa is said to be headache, vomiting, and ataxia. Unlike supratentorial tumors, seizures are rare. From pathological perspective, lesion in the posterior fossa may be neoplastic (most common), developmental, vascular, and traumatic (Table 14.1). PERIOPERATIVE MANAGEMENT OF PATIENTS FOR POSTERIOR FOSSA SURGERY Preoperative Evaluation As a routine, preoperative evaluation should include a thorough history and clinical evaluation of respiratory, cardiovascular, and neurologic systems; airway anatomy and necessary investigations based on patient’s requirements; and institutional protocols. Specific considerations for posterior fossa lesions include evaluation based on surgical approach and the intended patient positioning. The focus of preoperative evaluation should be on the identification as well as optimization of any coexisting medical conditions. Quantification and risk stratification of patients with known coronary artery disease and carotid disease is essential as it poses excessive risks in certain surgical positions. Hypertension resets autoregulatory range and might result in significant perfusion deficits due to hypotension associated with positions such as sitting and prone. A decrease in the level of consciousness and altered respiratory pattern may indicate the presence of elevated ICP. External ventricular drainage or other shunt procedures may be indicated to manage hydrocephalus before surgery or intraoperatively. Raised ICP may be associated with vomiting and inadequate intake resulting in hypovolemic status, which may give rise to significant hemodynamic perturbations on induction of anesthesia and positioning. In addition, presence of diabetes insipidus, administration of diuretics, and use of intravenous (IV) contrast agents to facilitate imaging may contribute to dehydration and electrolyte disturbances. Preoperative administration of IV fluid and optimization of electrolytes should be considered on an individual basis. Cerebellar hemangioblastomas often secrete erythropoietin, resulting in polycythemia, which should be taken into consideration during preoperative evaluation. Preoperative evaluation and documentation of dysphagia, cough, gag, and other cranial nerve dysfunctions; evaluation of cerebellar functions; vision and auditory functions may be needed in specific types of tumor. In patients with bulbar dysfunction, loss of gag and cough reflex increases the risk of aspiration pneumonitis and extubation failure. Hence, possibility of need for postoperative ventilation or tracheostomy and extended intensive care unit (ICU) stay should be explained preoperatively. Patients with atlantoaxial subluxation and lack of neck movement secondary to craniocervical fusion can present challenges during airway management and positioning, especially in sitting and prone position surgery. Hence, a preoperative assessment of cervical spine by dynamic flexion and extension views and Doppler study of neck vessels to look out for carotid insufficiency should be done in all patients where extreme neck flexion is anticipated, especially in the elderly.1,2 VII. NEUROSURGERY 257 PERIOPERATIVE MANAGEMENT OF PATIENTS FOR POSTERIOR FOSSA SURGERY TABLE 14.1 Location and Types of Various Posterior Fossa Pathologies Intraaxial tumors Cerebellum Astrocytoma Hemangioblastoma Metastasis Fourth ventricle and pons Medulloblastoma Ependymoma Choroid plexus papilloma Hemangioblastoma Extraaxial tumors Cerebellopontine angle Vestibular schwanoma Meningioma Epidermoid tumor Glomus jugulare tumor Skull base Metastasis Chordoma Chondrosarcoma Brain stem Glioma Hemangioblastoma Vascular malformations Posterior cerebellar artery aneurysm Vertebral/vertebrobasillar aneurysm Basillar tip aneurysm AV malformations Cerebellar hematoma Cerebellar infarction Cysts Epidermoid cyst Arachnoid cyst Cranial nerve lesion Trigeminal neuralgia (cranial nerve V) Hemifacial spasm (cranial nerve VII) Glossopharyngeal neuralgia (cranial nerve IX) Craniocervical abnormalities Atlanto-occipital instability Congenital Acquired Atlantoaxial instability Congenital Acquired Arnold–Chiari malformation For patients to be operated on in a sitting position, there is not a uniform approach on what special preoperative evaluation is necessary. However, detailed evaluation should be conducted to minimize complications that are preventable if known. If sitting position is planned, it is prudent to rule out a patent foramen ovale (PFO) using a transthoracic echocardiography3–6 and perform PFO closure if present,7 to prevent paradoxical air embolism (PAE) (discussed in detail later). Surgical Approach There are several surgical approaches to the posterior fossa, which include suboccipital (retrosigmoid) approach and midline posterior approach, which can be subtentorial or transtentorial. There are less common ones such as translabyrinthine, subtemporal/middle cranial fossa approaches or combinations of the above. Anesthetic Considerations During Posterior Fossa Craniotomy The surgical complexity of the posterior fossa and the hazards of different patient positioning make the intraoperative management of a patient posted for posterior fossa craniotomy quite challenging and unique. In addition VII. NEUROSURGERY 258 14. ANESTHESIA FOR POSTERIOR FOSSA SURGERY to the basic neuroanesthetic considerations inherent to any neurosurgical procedure, the major intraoperative goals during posterior fossa craniotomy are: 1. to provide optimal patient positioning and surgical access, with minimum possibility of positioning-related hazards to the patient; 2. maintaining adequate depth of anesthesia while avoiding hemodynamic instability; 3. to provide optimum conditions for intraoperative neurophysiological monitoring (IONM); 4. prevention, early identification, and effective management of venous air embolism (VAE); and 5. to allow smooth emergence with early awakening so as to facilitate neurological assessment. Premedication Premedication should include all regular medications, including steroids (dexamethasone). The role of sedative premedication is limited in patients with posterior fossa lesions with their inherent risk of hypoventilation and potential to increase ICP. However, short-acting benzodiazepine given under supervision may be reserved for anxious patients who are neurologically intact.6 Patient Positioning Proper patient positioning during posterior fossa surgery is one of the most important factors for success or failure of the procedure. All positions have advantages and disadvantages, assessed either from the surgical or anesthetic perspective. The greatest challenge for the anesthesiologist is to choose the most appropriate surgical position that provides the best surgical exposure as well as pose minimum positioning related risks to the patient. Great attention should thus be paid to the physical and physiologic consequences of different surgical positions to help prevent serious adverse events and associated complications.8 Depending on the planned surgical approach and the lesion, the most common positions for posterior fossa surgery are supine, lateral, park bench (semiprone), prone, and semisitting. (Discussed in detail elsewhere in the book.) The surgical approach must be individualized for each patient because the risk of postoperative complications may vary greatly with patient’s age, neurological status, and lesion location. Supine Acoustic neuroma and cerebellopontine angle (CPA) tumors may be carried out in the supine position with the head turned to the opposite side and placement of a sandbag under the ipsilateral shoulder to minimize stretching of the brachial plexus. Lateral The lateral position facilitates gravity-assisted drainage of blood and CSF and provides good surgical access for unilateral procedures. Patient instability and brachial plexus injury are potential positioning hazards of this position. Park-Bench (Semiprone) The park-bench position is a modification of lateral position with back elevated and head turned about 30% facing down with maximum possible neck flexion. It provides better access of the posterior fossa, as compared with the lateral position and can be attained quickly. It may be used to gain rapid access to cerebellar hemispheres, for example, need for rapid evacuation of a posterior fossa bleed. It gives lesser hemodynamic perturbations but the surgical orientation of the neck may be lost after draping. Prone The prone position is the oldest and most suited for midline approach during infratentorial craniotomies. Over a period of time, it gained popularity because of much lower incidence of clinically significant VAE when compared with the sitting position (discussed in VAE section). However, a retrospective survey comparing the semisitting and prone positions for posterior fossa surgery in children found more intraoperative and postoperative complications in the prone position, with increased length of intensive care and hospital stay.9 In addition, the amount of blood loss is more than in sitting craniotomies.10 Logistically, it is the most difficult positioning due to challenges associated with VII. NEUROSURGERY PERIOPERATIVE MANAGEMENT OF PATIENTS FOR POSTERIOR FOSSA SURGERY 259 providing adequate oxygenation, ensuring adequate ventilation, maintaining hemodynamics, and securing intravenous lines and the tracheal tube.8 Sitting or Semisitting Position In neurosurgical practice, sitting position remained popular during the 1960s and 1970s for procedures involving the cervicodorsal spine and posterior and lateral cranial fossae. Later, its use declined throughout the neurosurgical community because of its potential severe consequences and associated litigations, with an only absolute indication being the supracerebellar infratentorial surgical approach for pineal gland tumors. Indeed, there has been a great difference between countries in its use since its introduction into clinical practice, being popular mainly in Europe and India and is still a subject of controversy.10–13 At present, however, there is no hard scientific evidence justifying the abandonment of this patient position with the recent literature proving its safety in experienced hands, with appropriate monitoring.4,6 Feigl et al. have demonstrated that under meticulous anesthesia and neurosurgical management, even patients with a PFO can be operated on in the semisitting position with only a very low risk for VAE.4 Henceforth, by keeping a high index of suspicion for possible VAE and managing them promptly to limit their progression, the sitting position is a safe alternative to the prone and lateral positions for posterior fossa and posterior cervical spine surgery. Nonetheless, the potential advantages of the sitting position in emergency cases (reduction of cerebellar swelling) may be annihilated by the additional time spent for positioning. Therefore alternative techniques of positioning (e.g., concorde, semiprone, etc.) should be considered whenever applicable. The extra positioning time to put a patient into the sitting position takes approximately 15–20 min longer and consists of placing the transesophageal echocardiography (TEE) probe and bringing the patient in an upright position. Technical Considerations Sitting or semisitting position offers a number of technical advantages for the neurosurgeon and neuroanesthesiologist compared to other positions, especially for surgeries of large and vascularized tumors in the posterior cranial fossa and CPA1,4,6,10,11,14,15 (Table 14.2). Various studies have shown reduced operating time, less intraoperative venous bleeding with lower transfusion rates, and better preservation of cranial nerve function in the sitting position compared with horizontal positions, despite having a higher incidence of VAE.10,14,16 Sitting position, however, poses unique physiological challenges for the neuroanesthesiologist. Changing from the supine to the sitting position induces a significant decrease of cardiac index, stroke volume index, right atrial TABLE 14.2 Advantages of the Sitting Position1,4,6,10,11,14,15 For the neurosurgeon: 1. Improved surgical exposure 2. Improved anatomical orientation 3. Improved venous drainage from the surgical field 4. Cleaner operating field due to gravitational drainage of the cerebrospinal fluid, blood, or irrigation fluid from the operative field permitting more rapid access to bleeding points 5. Reduced intraoperative blood loss and reduced blood transfusion requirements 6. Reduces need for coagulation allowing a well-defined tumor–brain interface 7. Provides optimum surgical access to midline structures 8. Significant reduction of cerebellar swelling 9. Better surgical teaching due to the nonrotated anatomical situation 10. Shorter surgical time 11. Minimizes the amount of cerebellar retraction needed to gain access to deeper structures during supracerebellar infratentorial approaches to the pineal gland 12. Improved postoperative cranial nerve function compared to other positions 13. Technically easier procedure than is possible in the prone position For the neuroanesthesiologist: 1. Improved access to the tracheal tube, chest wall, and arms 2. Improved ventilation with lower airway pressure 3. Free diaphragmatic movements 4. Provides an unobstructed view of the patient’s face, enabling observation of motor responses to cranial nerve stimulation 5. Decreased intracranial pressure 6. In the event of cardiac arrest, cardiopulmonary resuscitation is easier, with decreased intrathoracic pressure permitting easier ventilation VII. NEUROSURGERY 260 14. ANESTHESIA FOR POSTERIOR FOSSA SURGERY pressure, mean arterial pressure (MAP), mean pulmonary arterial pressure (PAP) and pulmonary wedge pressure, and an increase in pulmonary and systemic vascular resistance.17 Sitting may also affect brain arterial and venous pressure and alter the venous or arterial ratio with different blood distributions.18 Cerebral perfusion pressure (CPP) decreases in the sitting position in nonanesthetized patients and could further decrease under anesthesia because of vasodilation and impaired venous return. This can be further aggravated by jugular venous obstruction caused by unfavorable head and neck position. Sitting position has the potential for serious complications10,19–22 (Table 14.3). The increased risk of VAE, with its most feared sequela of PAE, is by and large the most feared complication20–22 (discussed in detail later). Paying meticulous attention during patient positioning is thus of paramount importance to prevent positioning related complications. Prerequisite for a safe and routine adaption of the sitting position is an interdisciplinary dialogue between neurosurgeons and neuroanesthesiologist considering the relative risk–benefit of sitting position surgery for the individual patient, based on physical status and specific intracranial pathology, absence of contraindications (Table 14.4), anticipation of potential complications; level of comfort, both with the procedure, and with each other and careful perioperative monitoring. Since its introduction, this patient position has been modified for neurosurgery to a modified semisitting or lounging position as it is used today to reduce the risk of an air embolism.1,4,5,24,25 This position aims to achieve a positive venous pressure at the operation site by a combination of adjustments. The upper body and legs are elevated by bending the operating table to a position in which the hip is flexed to a maximum of 90°. A 30° flexion of the knees is maintained to avoid overstretching of the tendons and nerves of the leg. The patient’s head is flexed anteriorly and a two-finger space between the sternal notch and the chin is left to avoid venous outflow obstruction. The inclination of the whole operating table is then changed to a lower head and higher leg position, in which the legs of the patients are as high as the vertex. Arms are supported to avoid traction of the shoulders; and all pressure points including legs, arms, and heels are adequately padded. The patient positioning should be done incrementally to avoid any hemodynamic instability. Positioning of the head should ideally be performed under electrophysiologic neuromonitoring to minimize cervical cord compression. Finally, it must be ensured that the anesthesiologist has adequate access to the patient with minimum possible disturbance to the surgical field. TABLE 14.3 Potential Complications of the Sitting Position10,19–22 1. 2. 3. 4. 5. 6. 7. 8. Increased incidence of venous air embolism and paradoxical air embolism Hemodynamic instability, particularly if intravascular volume is inadequate Increased incidence of pneumocephalus Lingual and laryngeal trauma (including trauma from a TEE probe if used) Quadriplegia due to excessive neck flexion Macroglossia Pressure points sores Compressive peripheral neuropathy TABLE 14.4 Contraindications to the Sitting Position8,22,23 Absolute 1. Patent ventriculoatrial shunt 2. Signs of cerebral ischemia when upright and awake Relative 1. Right to left intracardiac shunt or other pulmonary-systemic shunt 2. Cervical spine instability 3. Severe cervical canal stenosis 4. Hemodynamic instability 5. Anesthesia or surgical team not familiar with the position 6. Extremes of age 7. Severe autonomic neuropathy VII. NEUROSURGERY PERIOPERATIVE MANAGEMENT OF PATIENTS FOR POSTERIOR FOSSA SURGERY 261 Anesthetic Management During anesthetic induction, care should be taken to avoid hypotension, hypoxia, and hypercapnia with attendant cerebral ischemia and brain stem herniation in view of low compliance of the posterior fossa. Considering the choice of anesthetic drugs during posterior fossa craniotomies, total intravenous anesthesia has been reported as the most commonly employed anesthetic maintenance technique in recent studies.26 Anesthesia is usually maintained by using a continuous infusion of propofol (6–8 mg/kg/h) with supplemental administration of opioids (either repetitive boluses of fentanyl or continuous infusion of remifentanil or sufentanil titrated to effect). Few studies report on the use of sevoflurane with a maximum concentration of 1 MAC during anesthetic maintenance.5,6 The use of nitrous oxide (N2O) is the most controversial in posterior fossa interventions, especially in sitting craniotomies.27–38 During supratentorial craniotomy, N2O has potential advantages in terms of stable hemodynamics,28 good surgical conditions,28,29 reduction of awareness with recall, and use in neurologically and cardiovascularly “atrisk” patients.30,31 However, the classic adverse characteristics, such as unfavorable effects on intracranial dynamics, expansion of gas-filled spaces, and postoperative nausea and vomiting (PONV) are often cited as reasons to avoid N2O-based anesthetic regimen during posterior fossa surgery.32,33 Nitrous oxide has been hypothesized to convert a pneumocephalus into a tension pneumocephalus.34 However, there appears to be no difference in the volume of intracranial gas postcraniotomy in patients who have received N2O versus those who have had a nitrous-free anesthetic.35 In fact it may be advantageous to maintain anesthesia with high-inspired concentrations of N2O until dural closure so that the rapid washout of N2O may actually decrease the pneumocephalus when it is discontinued.36 It has been postulated that N2O equilibrates with the intracranial air-containing cavity while the dura is open, such that after dural closure, no further volume expansion and/or significant ICP increase will occur.37 Hence, it is not necessary to discontinue N2O prior to dural closure for reasons of avoiding expansion of intracranial air and increasing ICP. Also of concern during posterior fossa surgery is the risk that N2O, being 34 times more soluble in blood than nitrogen, can dramatically increase the size of venous air emboli. However, Losasso and colleagues38 found no evidence that N2O increased the risk, volume, or clinical consequences of VAE, if its administration is discontinued immediately upon Doppler detection of VAE. Nonetheless, N2O administration in presence of VAE results in its volume augmentation and intensifies the hemodynamic alterations thus allowing for earlier detection and, consequently, prompter treatment of VAE. Although it is not rational then to omit N2O solely on the fear of a VAE or tension pneumocephalus, it is still prudent to avoid it during a repeat craniotomy within 6–8 weeks after dural opening and stop its administration as soon as an air embolus is suspected intraoperatively.33 The emetogenic effect of N2O, although undesirable after a craniotomy, can be controlled with antiemetic prophylaxis.31 Respiratory Management The polyvinyl endotracheal tube (ETT) may kink during posterior fossa surgery from overbending of the softened tube (due to oral temperature) and neck flexion required to improve surgical access.39 Manual straightening of the tube may be helpful to relieve kinking of ETT. In a recent report the placement of Berman intubating airway was found helpful to relieve the kinking of the ETT in a prone patient.40 Nonetheless, most neuroanesthesiologist prefer reinforced ETT to prevent kinking in view of varied patient positioning during posterior fossa craniotomies. A gap of at least two-finger space should always be present between the chin and the chest, and head rotation should be minimized. Patients are mechanically ventilated to maintain either normocapnia5,6,25,41 or mild hypercapnia [to allow for a change in end-tidal carbon dioxide (EtCO2) to be more prominent].1 A higher arterial partial pressure of carbon dioxide (PaCO2) level of about 35 mmHg (slightly greater than during neurosurgery in other positions) may be acceptable in sitting position craniotomy because ICP is usually less in this position. Fraction of inspired oxygen (FiO2) is usually maintained between 0.4 and 1.26 Nonetheless, when administering anesthesia for operations involving risk of intrapulmonary right-to-left transmission, higher levels of FiO2 should be maintained as hyperoxia may prevent or reduce blood flow through arteriovenous pathways bypassing the capillary system when they are exercise induced.41 It, however, remains unknown whether FiO2 or oxygen tension specifically regulates these recruited anastomoses or opens them indirectly. VII. NEUROSURGERY 262 14. ANESTHESIA FOR POSTERIOR FOSSA SURGERY The use of positive end-expiratory pressure (PEEP) during sitting position craniotomies is controversial. PEEP has been proposed to lower the incidence of VAE essentially by increasing the central venous pressure (CVP)42 and has been found safe up to 10 cm H2O in terms of non-alteration of interatrial pressure difference.43 Nonetheless, VAE has been shown to occur during release of PEEP and repositioning after sitting position surgery.44 Earlier studies have documented that PEEP is potentially detrimental during sitting craniotomies as it does not decrease the incidence of VAE, impairs hemodynamic performance, and might predispose patients with a probe PFO to the risk of PAE.45,46 However, current literature gives mixed results in the usage of PEEP with many groups using PEEP from 6 to 10 cm H2O1,25,47 while some avoid it all together.5 It is generally contraindicated in patients with PFO.4 However, Ammirati et al. have established biphasic PEEP (7–10 cm H2O) in patients with proven PFO to increase the intrathoracic pressure.1 Use of spontaneous ventilation for the time period of tumor excision has been advocated by some authors to monitor the structural and functional integrity of vital brain stem structures but is no longer in vogue.48,49 During spontaneous ventilation, changes in the respiratory pattern would provide the surgeon with a warning signal for potential damage of these structures; thus avoiding any iatrogenic injury. However, it is necessary to maintain adequate depth of anesthesia to avoid coughing and patient movement. Hemodynamic Management In addition to the effects of anesthetic agents, patient’s cardiovascular system is exposed to the effects of gravity with venous pooling of blood in lower extremities during sitting position craniotomy. Intraoperative VAE or cranial nerve manipulation further adds to hemodynamic instability, thereby jeopardizing cerebral blood flow (CBF), especially in patients with disturbed autoregulation. Hence, any hemodynamic instability during induction and positioning should be avoided and aggressively managed. Normovolemia must be maintained at all times as dehydration exacerbates the low venous pressure and increases the risk of VAE. To combat positioning related hypotension, prepositioning controlled fluid loading5,25,50 and use of antigravity devices3,5 have been advised. Fluid loading should be done meticulously in patients with reduced cardiovascular reserves (e.g., elderly patients) taking into account their existing intravascular volume status. In the first randomized study focusing on fluid therapy in neurosurgical patients operated on in sitting position with a stroke volume–guided therapy, Lindroos et al. found that 6% hydroxyethyl starch (HES) boluses resulted in 34% smaller infusion volume and less positive fluid balance than crystalloid while significantly increasing cardiac and stroke volume indexes.5 Furthermore, no difference was observed in thromboelastometry coagulation analysis between Ringer’s acetate and HES groups. Authors thus suggested that use of stroke volume–guided HES therapy might be advantageous during sitting craniotomies, especially in patients with decreased brain compliance. Later, similar study was done by the same author group in patients undergoing neurosurgery in prone position utilizing the same protocol of stroke volume–directed administration of HES (130/0.4) and Ringer’s acetate.51 Although, the amount of HES needed for comparable hemodynamics was 24% less, a slight disturbance in coagulation parameters was observed, and hence authors suggested caution while using colloids in neurosurgical patients. Use of intermittent sequential compression device on the lower extremities is another simple and effective method to decrease intraoperative hypotensive episodes and improve cerebral oxygen saturation.52 With hypotension induced by the upright sitting position, both intracranial blood flow velocity53 and cerebral oxygen saturation are reported to decrease.54 Arterial pressure should thus be maintained close to preinduction values, to preserve cerebral perfusion and reduce any risk of cerebral injury or postoperative cognitive dysfunction. Lindroos et al. have suggested maintaining a target MAP of 60 mmHg or higher at the brain level during sitting craniotomies.5 Unfortunately, a single targeted value of MAP may not suffice in all the patients. Moreover, a reported CPP of 60 mmHg may vary from a true head-level value of 43–60 mmHg, depending on reference point, head-of-bed elevation and height of the patient.55 Emphasis should thus be given on use of individualized targeted MAP with the help of bedside autoregulation testing, to continuously adjust the “better MAP” to maintain CBF and brain oxygenation without increasing cerebral blood volume. Ephedrine and phenylephrine are the most frequently used vasopressors to treat intraoperative hypotension during sitting craniotomies. However, when comparing both agents, cerebral oxygenation was found to decrease significantly after phenylephrine bolus treatment and remained unchanged after ephedrine bolus treatment, even though MAP was significantly increased by both agents.56 Phenylephrine infusion has also been associated with cerebral oxygen desaturation, possibly caused by cerebral vasoconstriction, despite preventing hypotension in the upright position.57 Norepinephrine also negatively affects cerebral oxygenation.58 VII. NEUROSURGERY PERIOPERATIVE MANAGEMENT OF PATIENTS FOR POSTERIOR FOSSA SURGERY 263 Intraoperatively, various frequent changes in cardiovascular responses including bradycardia, tachycardia, hypotension, or hypertension and arrhythmia occur during surgical manipulation of the lower pons, upper medulla, floor of the fourth ventricle, and the cranial nerve nuclei.59,60 Hence, drugs that would mask these sentinel cardiovascular responses, including anticholinergic medications and/or long acting beta-adrenergic blockers, should be avoided. The surgeon should be notified immediately, with most of these changes subsiding immediately after the surgical stimulus is withdrawn and pharmacological treatment is generally not required. Transcutaneous pacing should, however, be considered in high-risk patients in view of bradycardia and risk of asystole during the surgery. In a rare cause of bradycardia during posterior fossa surgery, Prabhakar et al. have reported reproducible bradycardia following hydrogen peroxide irrigation at the end of surgery, which resolved following aspiration of the effervescent solution.61 Intraoperative Monitoring During posterior fossa surgeries, patients are susceptible to intraoperative hemodynamic instability, blood loss, cardiac arrhythmias, VAE, and specific positioning related complications. Hence, in addition to “routine” neuroanesthesia monitoring, such as electrocardiography (ECG), pulse oximetry, capnography, temperature, urine output, invasive arterial blood pressure (ABP), arterial blood gases and CVP, additional specific VAE (discussed in detail in VAE section) and neurophysiological monitoring, with minimal interruptions during positioning, is required to increase the safety of the procedure. Invasive arterial monitoring allows continuous ABP monitoring and repeated blood gas analysis. During sitting craniotomies, the arterial line transducer should be located and zeroed at the level of tragus to estimate the CPP correctly.4,5,47,62 Central venous catheter is essential as it is helpful for aspirating air during VAE, in addition to monitoring CVP (discussed in detail in VAE section). Electroencephalography-based monitors can be used to detect cerebral hypoperfusion as well as to determine the depth of anesthesia, especially when spontaneous ventilation is planned during tumor resection. IONM techniques including somatosensory evoked potentials (SSEPs); transcranial electrical motor evoked potentials; brain stem auditory evoked responses (BAERs); and spontaneous electromyography (EMG) offer a great tool for live monitoring of the integrity of central nervous structures. Thus, any dysfunction can be identified early and prompt modification of the surgical technique or operating conditions helps to avoid permanent structural damage.5,25,63 SSEPs help to monitor spinal cord ischemia (related to hypotension in the sitting position) and should be opted during neck positioning whenever feasible to reduce the risk of midcervical flexion myelopathy.2,64 However, the incidence of false positives during SSEP monitoring is very high, particularly for cases of brain stem monitoring.65 The vestibulocochlear nerve (CN VIII) and, to a greater extent, the auditory pathways (as they pass through the brain stem) are especially at risk during CPA, posterior/middle fossa, or brain stem surgery. The CN VIII can be damaged by several mechanisms, from vascular compromise to mechanical injury by stretch, compression, dissection, and heat injury. Additionally, cochlea itself can be significantly damaged during temporal bone drilling, by noise, mechanical destruction, or infarction, and because of rupture, occlusion, or vasospasm of the internal auditory artery. Intraoperative monitoring of CN VIII can be successfully achieved by live recording of the function of one of its parts, using the BAERs, electrocochleography (ECochG), and compound nerve action potentials of the cochlear nerve.66 The BAERs is the most widely used method for hearing preservation as it has high sensitivity and reliability to detect cochlear nerve damage. Latency increase of wave V of 1.0 s and amplitude decrease of 50% are the most widely used criteria to warn the surgeon about potential cranial nerve damage and thus encourage redirection of the operative plan of action.67 However, BAERs are prone to presenting false-positive results and there is a significant time delay of several seconds to minutes to deliver reliable response of wave changes. In this interim, a permanent damage to the cochlear nerve could happen, preventing the surgical team from detecting and avoiding it. In comparison, ECochG and direct stimulation of CN VIII are “near-field” techniques with shorter latency periods and provide immediate feedback on the state of the auditory system. Facial nerve injury is a complication of major concern after posterior fossa surgery due to severe negative impact on patient’s quality of life. Continuous intraoperative facial nerve monitoring helps to minimize accidental damage to the nerve during CPA surgery and skull base tumor surgery. Current standard facial nerve monitoring modalities include direct electrical stimulation, free-running continuous EMG, and facial MEP. However, a lack of standardization in electrode montage and stimulation parameters precludes a definite conclusion regarding the best method of monitoring.68 VII. NEUROSURGERY 264 14. ANESTHESIA FOR POSTERIOR FOSSA SURGERY In addition to the seventh and the eighth nerve monitoring, lower cranial nerves (CN IX–XII) can be monitored similarly by EMG, using needle electrodes within their respective musculature.69 Use of these monitors requires modification of the anesthetic technique to minimize interference with the monitoring (discussed elsewhere in the book). VENOUS AIR EMBOLISM Neurosurgical procedures carry the highest risk of VAE among surgical procedures as the surgical site is always at a higher level relative to the heart creating a negative venous pressure at the surgical wound level, irrespective of the patient position. The risk exists for all kinds of neurosurgical procedures; however, its incidence is higher for procedures requiring the patient to be in a sitting or semisitting position.1,6 The presence of numerous large, noncollapsible venous channels in the surgical field—especially involving cervical procedures and craniotomies that breach the dural sinuses—leads to air entrainment in the venous system. Air entrainment usually occurs through the diploic veins tethered patent by their bony and dural attachment or through open venous sinuses. High degree of vascularity of lesions as in tumors or malformations or compromised vessel (like in trauma) further increases the risk. In a recent study, surgical tumor resection was found to have a higher incidence of VAE opposed to decompressive surgery alone.6 Incidence The reported incidence of VAE varies widely in literature, ranging from 1.6% to 76%.6,7,9,20,23,25,70–73 The variability exists in view of different monitoring modalities used for its detection and different definitions for VAE and its associated hypotension. Nonetheless, most detected VAE are reported not to be clinically relevant. In a recent metaanalysis of neurosurgical procedures performed in the sitting position, Fathi et al. reported an overall incidence of VAE of 39% and 12% for posterior fossa and cervical procedures, respectively.7 In their retrospective review of 600 cases, Ganslandt et al. found an overall incidence of VAE in 19% of all patients, whereas the rate of severe complications associated with VAE, such as a decline of arterial partial pressure of oxygen (PaO2) or a drop of blood pressure, was only 3.3% in all patients.6 However, in only 0.5% of cases, a termination of the surgical procedure became necessary, which were operated on uneventfully afterward. In all other cases, the cause of air embolism could be found and eliminated during surgery. Considering pediatric patients undergoing surgery in sitting position, Harrison and coworkers reported a low incidence of VAE (9.3%) and VAE associated hypotension (in only 2% of 407 operations) without any perioperative morbidity or mortality directly attributed to it.72 The age of the patients ranged from 6 weeks to 17 years with a median age of 5 years. When compared with adults, Bithal et al. have reported an equal incidence of capnometry detected VAE (28% versus 22%) and VAE with consequent hypotension (37% versus 33%) in adults and children undergoing neurosurgery in the sitting position.73 Venous air embolism during neurosurgery is not exclusive to the sitting position and has frequently been reported in the prone and supine positions.10,14,16 Pathophysiology The severity of symptoms resulting from VAE varies according to the amount and rate at which air enters the venous system and the end location of the air bubble. Local factors such as the presence of venous plexus may be equally important. Patients may be asymptomatic or may have complete cardiovascular collapse. In adults, approximately 100 mL of air in the venous system may trigger clinical manifestations. The adult lethal volume has been described as 3–4 mL/kg.19,74 Small built and pediatric patients, however, poorly tolerate similar volumes of air. Furthermore, closer the vein of entrainment is to the right heart, the smaller the required lethal volume. Several pathophysiologic pathways may be elucidated after a substantive volume of air entrainment. The pathway manifested is greatly dependent on the volume of air accumulated within the right ventricle (RV). If entrainment is slow, the heart may be able to withstand large quantities of air despite entrainment over a prolonged period. Continuous entrainment of low volume air will lead to breaking up into microbubbles in turbulent flows. These microbubbles on reaching the pulmonary vasculature, cause increase in pulmonary vascular resistance by pulmonary vasoconstriction and mechanical obstruction. Obstruction of the pulmonary circulation results in an increase in physiological dead space. Thus EtCO2 falls and arterial PaCO2 rises. Lack of treatment at this stage leads to hypoxia. Further, air entrainment into VII. NEUROSURGERY VENOUS AIR EMBOLISM 265 the pulmonary circulation causes gaps between endothelial cells and consequential mediator release, which in turn can lead to platelet or complement activation, thus facilitating pulmonary edema. Intravascular air also induces direct binding of platelets to air bubbles, forming air–platelet conglomerates. The formation of platelet–air–clots affects air reabsorption and thus is likely to contribute to a sustained increase in right ventricular afterload, and prolonged occlusion of pulmonary arterioles or capillaries which might aggravate cardiopulmonary complications of VAE. In addition, the microbubbles formed due to turbulent flow in the circulation precipitate platelet aggregation and the release of platelet activator inhibitors, resulting in platelet dysfunction that contributes to the bleeding diathesis.50 If the embolism is large (approximately 5 mL/kg), a gas air-lock scenario immediately occurs. There may be complete outflow obstruction from the RV. This rapidly leads to right-sided heart failure and immediate cardiovascular collapse. Moderate volume of air goes through to the right atrium (RA), RV, and finally into the pulmonary circulation causing an increase in pulmonary vascular resistance and pulmonary hypertension. This results in elevated right heart pressure and the risk of PAE. Large VAEs also result in an increase in pulmonary shunt. Under certain conditions, air bubbles may pass through lung capillaries and reach the pulmonary veins. However, the transpulmonary passage of air into the systemic circulation is a rare clinical event during VAE as lung is a very good filter. Clinical Presentation of Venous Air Embolism Venous air embolism may produce a broad array of catastrophic cardiovascular, pulmonary, neurological, and coagulation sequela. Elevated right atrial pressure results in decreased venous return, elevated CVP measurements, jugular venous distension followed by hypotension and shock. ECG demonstrates peaking of “P” waves, tachyarrythmias, right heart strain pattern, and new onset ST-T changes. Massive VAE or a large embolus obstructing the outlet of the RV can result in a sudden onset right heart failure and cardiac arrest. The classic finding of a “mill wheel murmur” indicates a near fatal entity. After an episode of VAE, the progressive decrease in lung perfusion leads to an increased physiological dead space, which is reflected by a sudden decrease in EtCO2 and an increase in EtN2. With resolution of VAE, the EtCO2 returns to normal, often with an overshoot due to the raised arterial PaCO2. Other pulmonary signs of VAE include wheeze and/ or crepitations. An arterial blood gas would reveal respiratory acidosis with hypercarbia and hypoxia.25,47 Neurological manifestations include cerebral hypoperfusion as a result of shock and stroke in the event of a PAE. Postoperative mental status changes, presence of focal deficits or seizures should raise the suspicion of cerebral ischemia secondary to cerebral air embolism in at-risk individuals. Coagulation abnormalities are under-recognized complications of VAE. The interaction of Factor VIII with the prostaglandin system and possibly other blood/tissue factors initiate a coagulation derangement.75 VAE is also associated with a significant decrease in platelet count. Nonlethal VAE induces an almost one-third decrease in platelet count, and even grade 1 VAE evokes marked thrombocytopenia.50 There is a relationship between the grade of VAE and the severity of thrombocytopenia, with a greater fall in platelet count associated with a higher grade of VAE. Thus, patients with a major VAE who already have bleeding disorders or preexisting thrombocytopenia may be particularly at risk for perioperative bleeding. Based on these findings, it appears prudent to reassess blood coagulation and platelet count intraoperatively, following VAE. Near-patient tests such as rotational thrombelastometry and impedance aggregometry allows immediate and sophisticated analysis of platelet function and whole blood coagulation.76 Monitoring For VAE detection, it is recommended to use more than one monitoring modality during posterior fossa surgery (especially during sitting position), as no single monitor is completely reliable. In addition, timely anticipation of VAE during critical portions of a procedure is as vital to patient well-being as any detection device. In order of decreasing sensitivity, detection of VAE intraoperatively may be done through TEE, precordial Doppler (PCD), pulmonary artery catheter, EtCO2 by capnography, EtN2 by mass spectrometry, right heart catheterization, and esophageal stethoscope (Table 14.5). Although intracardiac transvenous echocardiography is reportedly superior to TEE, it has not yet become routine.81 Currently, TEE is considered the gold standard monitoring modality to detect VAE as well as PAE.4,25,41 In clinical studies, the incidence of VAE in patients monitored with TEE was significantly higher compared to the patients monitored with PCD (25.6% versus 9.4%).6 However, TEE is too sensitive and not necessarily specific for VAE.25 With use of continuous intraoperative TEE, the risk of false positive increases, which can be VII. NEUROSURGERY VII. NEUROSURGERY Placement of such an invasive device should have other cardiac indication and not risk of VAE alone Pulmonary artery High (0.25 mL/kg) catheter Basic anesthesia monitor used intraoperatively in all cases Probe is placed at the of SVC-RA junction on the chest wall (corresponds with the third or fourth intercostal space just to the right of the sternum) Probe should be placed when the patient is already in the final surgical position Appropriate placement should be verified by injecting a small bolus of saline through the RAC, which should cause detectable changes in sound78 High (0.05 mL/kg) Precordial Doppler Moderate (0.15 mL/kg) The TEE probe is placed with the patient in supine position and is then readjusted so that the probe is in the mid-esophagus for mid-esophageal four-chamber view or mid-esophageal bicaval view visible on the TEE monitor, after the patient is put in the semisitting position (Fig. 14.1) Excessive neck flexion should be avoided A bolus of cold saline solution is injected to test whether it is shown as a reflex pattern on the monitor and to verify that the system is adjusted correctly Highest (0.02 mL/kg)7 Transoesophageal echocardiography End-tidal CO2 Technical Considerations Sensitivity Modality TABLE 14.5 Detection of Vascular Air Embolism19,21,47 Most convenient Semiquantitative VAE detected by capnography is always clinically significant79 Noninvasive Offers continuous objective monitoring Continuous monitoring Objective Semiquantitative The pressure gradient between the left and right atria may help in assessing the risk of PAE Considered standard of care for VAE (along with EtCO2 monitoring) Noninvasive High sensitivity (small emboli can be detected) Detects air before it enters the pulmonary circulation Gold standard for VAE monitoring Most sensitive Objective monitoring of VAE Gives information about the size of the embolus and whether it is ongoing Useful for assisting with optimal positioning of a RAC Also useful for detection of a PFO or other possible pulmonary-systemic shunt before placing the patient in the sitting position Detects PAE that may result in ischemic cerebral complications (observation of air appearing in the left atrium is by far the best way of confirming PAE) Advantages Less sensitive Nonspecific for air Not reliable in the event of systemic hypotension, tachypnea, and patients with chronic obstructive pulmonary disease An acute reduction in EtCO2 may occur as an artifact during partial blockade in the gas sampling line80 Less sensitive Invasive Nonspecific for air Of limited ability to withdraw air because of its fixed distance and small orifice Use is restricted to those patients who have significant comorbidities that may benefit from its use as a monitoring tool for cardiac output or mixed venous saturation Placement done for optimal air aspiration may not allow pulmonary capillary wedge pressure measurement Subjective Nonquantitative Interference by diathermy False negative results in approximately 10% of cases where air does not pass beneath ultrasonic beam False positive in presence of mannitol crystals Continuous embolism is easily missed, as the ear detects changes in sound more readily than an “abnormal” sound Difficult to position the probe accurately in obese patients, patients with chest wall deformity, and during prone and lateral patient positioning Invasive Expensive Requires operator expertise Requires constant vigilance Nonquatitative Can cause laryngeal and oral trauma Rapid intravenous infusion, however, can be confused with VAE, but differentiation is easily done by slowing the infusion Almost too sensitive (detecting virtually any amount of air in the circulation, most leading to no adverse sequela) Despite high sensitivity, PFO cannot be ruled out 100% and it can even fail to detect some VAE incidents77 Disadvantages 266 14. ANESTHESIA FOR POSTERIOR FOSSA SURGERY Low (1.7 mL /kg) Air in the RV produces a loud churning sound called the “mill wheel murmur” Not readily available Not useful if N2O is used as a carrier gas The presence of EtN2 may also indicate air clearance from the pulmonary circulation prematurely Routinely used Noninvasive Useful in confirming VAE in equivocal cases Routinely used during all craniotomies Late changes Associated with signs of cardiovascular collapse Of little clinical use Late changes Late indicator Has therapeutic value during VAE19,20,71 Complications associated with central venous cannulation (depending upon the route of insertion) Most specific monitoring modality EtCO2, end-tidal carbon dioxide; EtN2, end-tidal nitrogen; N2O, nitrous oxide; PaCO2, arterial partial pressure of carbon dioxide; PAE, paradoxical air embolism; PaO2, arterial partial pressure of oxygen; PFO, patent foramen ovale; RA, right atrium; RAC, right atrial catheter; RV, right ventricle; SVC, superior vena cava; TEE, transesophageal echocardiography; VAE, venous air embolism. Esophageal stethoscope ST–T changes are noted first, followed by supraventricular and ventricular tachyarrythmias An increase in arterial PaCO2 and a reduction in arterial PaO2, associated with no change in ventilation, may be due to VAE Low Oxygen saturation Electrocardiogram Low (1.25 mL/kg) Accurate placement of a right atrial catheter tip is quintessential for aspirating air Catheter tip should be readjusted and confirmed after final patient positioning If appropriately positioned, then aspiration of air will confirm VAE The sensitivity compares to or exceeds that of EtCO2 during large-bolus VAE but may be less sensitive during slower entrained volumes Air aspiration via a central vein catheter End-tidal N2 by Moderate (0.5 mL/kg) mass spectrometry VENOUS AIR EMBOLISM VII. NEUROSURGERY 267 268 14. ANESTHESIA FOR POSTERIOR FOSSA SURGERY FIGURE 14.1 Transesophageal echocardiogram showing entrained air emboli (white arrow) in the right atrium. interpreted as the cases found to have a positive TEE and negative air aspiration and/or no instability in vital signs. PCD is the most sensitive noninvasive monitor for VAE and is preferred over TEE in many centers1,3,47 and during emergency cases.6 Capnography is an efficient monitoring technique for detection of all episodes of VAE severe enough to cause hemodynamic disturbances.79 On the basis of EtCO2 monitoring, VAE has been defined variedly in the literature with some authors considering that a VAE episode has occurred when EtCO2 decreases suddenly by more than 3 mmHg6 whereas others use a value of more than 5 mmHg, without a change in minute volume ventilation.21,46,73,79 The right atrial catheter (RAC) can be inserted via the antecubital, the subclavian, or internal jugular veins. Accurate placement of a RAC is quintessential for aspirating air from the circulation should an air embolism occur. The ideal location for multiorifice catheters is 2 cm below the junction of the superior vena cava (SVC) and RA at an inclination of 80° for maximal efficacy (up to 80%) in aspirating air.82 A single-orificed catheter gives a maximum yield of 45–50% aspiration when the tip is positioned 3.0 cm above the SVC and arterial chamber junction.82 Appropriate placement of RAC can be confirmed either by plain chest X-ray, real-time X-ray imaging, intravascular ECG (point of large negative P complex),82 TEE-guided placement83 or by withdrawing the catheter after eliciting right ventricular waveform on pressure transducer. The relationship of the heart to the thoracic contents changes when a patient is changed from the supine to the sitting position, thereby resulting in migration of the catheter tip. Hence, catheter tip should be readjusted and confirmed after final patient positioning. Grading of Venous Air Embolism Literature till date have several comparable scales for VAE grading, which differ in their definition and details, and hence cause confusion when comparing the data in systematic reviews4, 20,25,70,84 (Table 14.6). New scales should be introduced sparingly and preferably after validation for either an outcome or a management decision. Paradoxical Air Embolism PAE occurs when VAE passes into the systemic arterial circulation, for example, through PFO. Air in the systemic circulation can cause catastrophic consequences. Blockage of coronary arteries can cause myocardial infarction of various degrees and that in the cerebral vessels may cause cerebral infarction. The incidence of PFO in the general population seems to be relatively high (about 10–30%).85 Hence, preoperative screening to determine the presence of a right-to-left cardiac shunt should be performed in all patients who are to be operated in a sitting position.4–6 Few centers, however, perform PFO search only after anesthesia induction.1,47 A PFO has been detected in up to 5–33% of the neurosurgical patients while the reported rate of clinical and TEE detected PAE is between 0% and 14%.7 VII. NEUROSURGERY 269 VENOUS AIR EMBOLISM TABLE 14.6 Grading of Venous Air Embolism Traditional According to Volume of Air84 Lobato VAE Grading70 Tübingen VAE Grading4 Girard Scale20 Jadik Scale25 Grade I: PCD changes only Grade 0: No air bubbles visible, no air embolism Grade 1: Positive PCD signal without hemodynamic alterations Minor clinical VAE: Positive TEE accompanied by an EtCO2 decrease >3 mmHg Moderate VAE (10–50 mL): Grade II: PCD changes t I n addition to detection plus a decrease in EtCO2 by PCD and TEE, there is >3 mmHg a fall in EtCO2 and a rise in PAP t U sually accompanied by a sympathetic response, and heart rate and ABP often increase Grade I: Air bubbles visible on TEE Grade 2: Positive PCD signal + increase in systolic PAP >5 mmHg and/ or a decrease of EtCO2 ≥3 mmHg Moderate clinical VAE: Positive TEE with ABP decrease or heart rate increase Large VAE (>50 mL): Grade III: PCD changes and t M ajor changes are a decrease in systolic blood detected on all monitors pressure > l0% of baseline t D ysrhythmia, tachycardia, bradycardia, hypotension, right ventricular failure, and cardiac arrest may occur Grade II: Air bubbles visible on TEE with decrease of EtCO2 ≤3 mmHg Grade 3: ABP decreases >20% or >20% increase in heart rate, plus one positive “grade 2” criterion Severe clinical VAE: Positive TEE and decrease ABP >40% or heart rate increase> 40%; including situations requiring cardiopulmonary resuscitation Grade III: Air bubbles visible on TEE with decrease of EtCO2 >3 mmHg Grade 4: Sudden ABP decrease of at least 40% or a 40% increase in heart rate in the presence of at least one positive “grade 2” criterion Grade IV: Air bubbles visible on TEE with decrease of EtCO2 >3 mm Hg and decrease of MAP ≥20% or increase of heart rate ≥40% (or both) Grade 5: Cardio circulatory collapse in the presence of at least one positive “grade 2” criterion Small VAE (<10 mL): t D etected with PCD or TEE t N o changes in EtCO2, oxygen saturation, or PAP Grade IV: PCD changes and cardiovascular collapse Grade V: VAE causing arrhythmia with hemodynamic instability requiring cardiopulmonary resuscitation ABP, arterial blood pressure; EtCO2, end-tidal carbon dioxide; MAP, mean arterial pressure; PAP, pulmonary arterial pressure; PCD, precordial doppler; TEE, transesophageal echocardiography; VAE, venous air embolism. Paradoxical embolism can occur even in the absence of a PFO, commonly via intrapulmonary transmission of air.41 Flow across a PFO is more typically functional and therefore dependent on relative pressures in the two atria. Right-to-left interatrial shunting may occur only when the pressure in the RA exceeds the pressure in the left atrium (minimum pressure gradient of 5 mmHg), allowing paradoxical embolism of thrombus.86 Usually left atrial pressure is slightly higher than RA pressure, but the opposite may occur transiently during part of the normal respiratory cycle,87 after release of PEEP,44 after about half an hour in upright sitting position86 and during any episode of VAE and hypovolemia.84 However, in a study done in anesthetized neurosurgical patients (positioned both supine and seated prior to operation), Zasslow et al. concluded that levels of PEEP up to 10 cm H2O does not alter the interatrial pressure difference in seated neurosurgical patients, and, therefore, would not predispose these patients to PAE.43 VII. NEUROSURGERY 270 14. ANESTHESIA FOR POSTERIOR FOSSA SURGERY For the detection of right-to-left shunting across a PFO, agitated saline contrast medium is typically injected into a peripheral vein during the strain phase of the valsalva maneuver (or coughing) and the atrial septum is imaged during the release phase of this maneuver. Currently, semi-invasive bubble contrast TEE is accepted as the gold standard to detect right-to-left shunt across a PFO, but the use of sedation makes the performance of the valsalva maneuver more difficult along with incomplete glottis closure. Agitated saline is generated by mixing 9 mL of 0.9% saline with approximately 0.75 mL of the patient’s venous blood and 0.25 mL of air, which is then agitated repeatedly through two 10 mL syringes connected via a 3-way stopcock. The size of the PFO has been categorized (somewhat arbitrarily) according to the amount of agitated venous saline contrast bubble passage at rest or with the valsalva maneuver within the first three to five cardiac cycles: small PFO ≤ 20 bubbles, moderate PFO = 20–50 bubbles, and large PFO ≥50 bubbles.88 Any cause of right-to-left shunt, however, including atrial or ventricular septal defect, sinus venous defect, or intrapulmonary arteriovenous malformation, can lead to a positive bubble study, thus lowering the specificity of this test. Other imaging modalities utilizing contrast such as second-harmonic transthoracic echocardiogram with a valsalva maneuver, transcranial Doppler sonography, cardiac computed tomography (CT), and magnetic resonance imaging have been shown to have similar sensitivity and specificity in detecting a PFO when compared with TEE.88 However, TEE has an added advantage of confidently measuring PFO size and morphologic details, and also assisting in PFO closure device deployment. Many neurosurgeons consider PFO an absolute contraindication for neurosurgery in the semisitting position because of the high risk of PAE.25 However, there is no hard scientific evidence to prove a significantly higher risk for these patients.4,89 Sitting position cannot always be avoided during posterior fossa surgeries, as some neurosurgeons feel uncomfortable with the horizontal position for certain surgical procedures (surgeries of large and vascularized tumors in the posterior cranial fossa) and are prepared to accept the increased risk for PAE.4,10 Feigl et al. have studied the incidence of VAE in a retrospective study of 52 patients who had PFO and underwent a neurosurgical procedure in a semisitting position with meticulous specific monitoring (TEE with intermittent jugular compression to detect any bleeding and evoked potentials).4 In 29 patients, a total of 63 events occurred during which air bubbles appeared in the TEE, and only 1 patient experienced clinically relevant VAE without any clinical consequence. Despite clinical studies proving safety of semisitting position surgery in the presence of PFO, the potential risk of an air embolism remains and should by no means be underestimated. Percutaneous PFO closure using dedicated devices under intracardiac echocardiography guidance involves low risk with a high success rate and should be considered prior to sitting position neurosurgery.7,90 Management of Venous Air Embolism The optimum management of VAE includes prevention and prompt recognition of this event to avoid or minimize the serious complications. Preoperative risk evaluation; intraoperative real-time monitoring; adequate hemostasis; strict adherence to a standardized protocol; and a collaborative approach by neurosurgeons, neuroanesthesiologists, and cardiologists are prerequisites to minimize the risk of VAE and its complications.25 The most important measure to prevent VAE is to avoid injury to the venous system in the first place. Special care has to be taken during the craniectomy, where an opening in the venous system might be difficult to close because of the limited access at that stage of the surgery. Careful preoperative study of the cranial CT scan is mandatory for the neurosurgeon to be aware of and prepared for the quick closure of emissary veins. Burr holes are not made anywhere close to the transverse or sigmoid sinus. Any necessary exposure of the transverse or sigmoid sinus is always performed as the last step to ensure an optimal access in case of an injury to the venous system. Other preventive measures include optimal intravascular volume loading, avoiding drugs that dilate the venous capacitance vessels, use of antigravity devices, and the final positioning of the patient with the toes above the heart. Application of PEEP to increase CVP to prevent air entrainment is controversial (discussed earlier in Anesthetic Management). Once diagnosed, the management of VAE is generally supportive. Treatment requires simultaneous management by both neurosurgeon and neuroanesthesiologist to stop air entrainment and reduce the size of embolism. Immediate measures taken by neuroanesthesiologist include alerting the surgeon, administering 100% oxygen, ceasing N2O administration, IV fluids to increase venous pressure, and aspiration of air from the RAC.19,84 Myocardial perfusion is optimized with IV fluid loading and a vasopressor, if required to augment blood pressure. The neurosurgeon should immediately flood the surgical field with moist cotton strips or a veil of irrigation fluid using a pressurized irrigation system to prevent further air entrainment, and lower the head if possible. Any suspected air entry point is identified and closed. The possible sources of air emboli include the muscles, in the diploe of the bones, and along VII. NEUROSURGERY POSTOPERATIVE MANAGEMENT 271 the venous channels, especially around the draining intracranial sinuses. The open veins are coagulated or plugged with either moist cotton pledget, gelatin foam, or fibrin glue and open diploic channels may be sealed with bone wax. If a RAC is in place, attempts should be made to aspirate air from RA as it is probably the only management strategy with demonstrated clinical efficacy.19 Two large series of patients have found a success rate of 43–52%.20,71 During craniectomies, bilateral compression of the jugular veins has been described to increase the intracranial venous pressure quickly, thereby checking for a potential venous leak and in case of a VAE to prevent air bubbles from reaching the RV via the noncompressed jugular vein.91 In their study in patients with known PFO and operated on semisitting position, Feigl et al. employed frequent bilateral jugular compression for early detection of any bleeding that could imply venous air entrance.4 However, compression of the external jugular vein for anterior scalp procedures is still logical, but the majority of neck and scalp incidences of air embolism occur via the posterior venous complexes.19 In addition, bilateral compression of the jugular veins also increases ICP, decreases CBF, and increases the risk of carotid artery atheromatous plaque rupture because of the simultaneous compression of the carotid artery. Other complications include severe bradycardia because of carotid sinus stimulation and venous engorgement leading to cerebral edema. Hence, it may only be considered (with utmost caution) on an emergent basis situations when high volume and rapid entrainment of air occurs. Some authors recommend immediate lowering of the operative site to below heart level if possible thereby preventing air entry into the pulmonary artery based on the work of Durant et al. (i.e., placing the patient in Trendelenburg and left lateral decubitus position also known as Durant’s maneuver).92,93 This positioning is proposed to allow the entrapped air in the heart to be stabilized within the apex of the ventricle. At present, however, there is little scientific evidence to support special patient positioning as a means to enhance air dispersion. Moving the patient into left lateral decubitus position obscures the surgeon’s view of the operative field and also allows a very grave potential for contamination of the operative field. Moreover, the lateral position would interrupt or delay cardiac massage and vasopressor therapy that are evidence-based interventions. In the event of massive VAE with cardiovascular collapse, immediate initiation of chest compression can result in the breaking down of a large air bubble obstructing the right ventricular outflow tract with return of spontaneous circulation. In patients who survive the initial insult of a left-sided air embolism, hyperbaric oxygen therapy has shown some benefit in reversing neurologic deficits.94 High oxygen tension promotes the absorption of nitrogen from the bubble and the elevated ambient pressure reduces the size of the bubbles in accordance with Boyle’s law. POSTOPERATIVE MANAGEMENT Extubation depends on the preoperative neurological condition of the patient and the intraoperative course. In a neurologically intact patient with an uneventful surgery, smooth emergence and extubation is feasible, with the patient monitored postoperatively in the neurosurgical ICU for signs of neurological deterioration.95 Caution should, however, be taken in patients with poor physical status undergoing vascular surgery and long procedures with potential significant fluid shifts. Patients who have had small intraoperative VAE or PAE can also be extubated at the end of surgery. Patients with symptomatic VAE, who have been managed adequately, tolerate spontaneous ventilation and extubation well. Ganslandt et al. found no difference in the rate of immediate postoperative extubation, postoperative duration of ventilation, length of ICU stay, length of hospital stay, reoperation rate, and in-hospital mortality in patients with and without VAE operated upon in sitting position for different posterior fossa and cervical spine pathologies.6 However, in patients with clinical evidence of PAE, the management decision is more difficult and prolonged ventilation and hyperbaric oxygenation may be required. Delayed emergence after posterior fossa surgery is not uncommon and multifactorial. Tension pneumocephalus, air embolism, and intracranial hemorrhage have been cited as reasons for nonreversal of patients after posterior fossa craniotomies.14,96–98 Patients with preoperative bulbar dysfunction and extensive intraoperative dissection, particularly in the floor of the fourth ventricle and near the brain stem, may precipitate central respiratory dysfunction and hence, may require elective ventilation.95 ICP monitoring should be considered if postoperative ventilation is required because hydrocephalus remains a risk. Postoperative hypertension should be carefully managed to avoid operative site hematoma. Postoperative pain and PONV are important considerations after posterior fossa surgery. Infratentorial procedures are associated with severe postoperative pain (both at rest and with movement), due to extensive muscle damage from resection and reflection of the temporalis and posterior cervical muscles and subsequent spasm.99,100 Patients are also at high risk of PONV because of the proximity of the vomiting center to the surgical site and postoperative use of opioids to control the pain. VII. NEUROSURGERY 272 14. ANESTHESIA FOR POSTERIOR FOSSA SURGERY COMPLICATIONS Posterior cranial fossa surgery can be performed in most patients with acceptable morbidity and mortality. Flexman et al. have reported that infratentorial craniotomy is associated with an increased risk of postoperative respiratory failure and death when compared with supratentorial craniotomy, and death is the most important contributor to the elevated risk experienced by this population.101 Dubey et al. reported an overall complication rate of 31.8% in their 10-year retrospective study of 500 patients who underwent posterior fossa surgery.102 CSF leaks were the most frequently encountered, presenting in 13% patients followed by meningitis (9.2%), wound infection (7%), and cranial nerve palsies (4.8%). Other complications that were observed to develop almost exclusively in patients undergoing cerebellar parenchymal tumor resection included cerebellar edema (5%), hydrocephalus (4.6%), cerebellar hematoma (3%), and cerebellar mutism (1.2%). The overall mortality rate related to surgery was 2.6% occurring in 13 patients. Venous air embolism and its sequelae PAE are the most feared complications during posterior fossa surgery (discussed in detail earlier). Other complications commonly associated with the sitting position include hemodynamic instability (concerning patients especially at extreme ages), pneumocephalus and its complication tension pneumocephalus, peripheral neuropathies, macroglossia, subdural hematoma, central cord syndrome, and quadriplegia.8,14,72,98,103–106 Complications associated with prone positioning in neurosurgery includes hemodynamic instability; poor access to patient’s airway; macroglossia risking post extubation airway obstruction; brachial plexus injuries; axillary, ulnar, and radial neuropathies; retinal ischemia from orbital compression; inferior vena caval compression; pressure sores, VAE; and cervical cord compression with quadriplegia.14,107 Rath et al. compared two groups of patients who were either operated in the sitting position or in the prone position with regard to intra and postoperative complications. While the incidence of VAE was higher in the sitting position (15.2 vs. 1.4%) the incidences of postoperative complications were equal in both groups.14 Depending on the location of the lesions and the surgical approaches, the postoperative cranial nerve dysfunction may involve CN III to XII, which may be temporary or permanent. Lower cranial nerve dysfunction can result in increased risk of reintubation or failure to wean from mechanical ventilation. Hence, patients may require feeding tube placement and a tracheostomy to prevent aspiration pneumonia, until they sufficiently recover function. Supratentorial pneumocephalus is a known complication of posterior fossa neurosurgery with incidence varying from 57% to 73% in horizontal positions to 100% in sitting position.103,104 In recently published studies on sitting craniotomy, pneumocephalus was found to cause transient postoperative lethargy with a 3.7% incidence in one study47 and 31% in the other.25 For tension pneumocephalus, immediate aspiration of air with twist drill burr hole evacuation is required to prevent rapid and irreversible neurological deterioration.97,98 High-flow oxygen is recommended for less severe cases. Macroglossia after neurosurgical procedures in sitting, prone, and lateral positions is presumed to be caused by an extreme neck flexion (often employed to increase surgical access) and a resultant bilateral lingual vein thrombosis, lymphatic obstruction, or arterial compromise.108,109 Macroglossia may occur in conditions without neck flexion due to abnormal brain stem signaling.109 Quadriplegia is a rare but potentially disastrous complication of posterior fossa surgery that can be caused either by prolonged focal pressure on the spinal cord secondary to the acute flexion of the head in the sitting position or by ischemic damage to the spinal cord during episodes of significant hypotension.23 ABBREVIATIONS ABP Arterial blood pressure BAERs Brain stem auditory evoked responses CBF Cerebral blood flow CN VIII Vestibulocochlear nerve CPA Cerebellopontine angle CPP Cerebral perfusion pressure CSF Cerebrospinal fluid CT Computed tomography CVP Central venous pressure ECG Electrocardiography ECochG Electrocochleography EMG Electromyography EtCO2 End-tidal carbon dioxide VII. NEUROSURGERY REFERENCES 273 EtN2 End-tidal nitrogen ETT Endotracheal tube FiO2 Fraction of inspired oxygen HES Hydroxyethyl starch ICP Intracranial pressure ICU Intensive care unit IONM Intraoperative neurophysiological monitoring IV Intravenous MAP Mean arterial pressure MEPs Motor evoked potentials N2O Nitrous oxide PaCO2 Arterial partial pressure of carbon dioxide PAE Paradoxical air embolism PaO2 Arterial partial pressure of oxygen PAP Pulmonary arterial pressure PCD Precordial Doppler PEEP Positive end-expiratory pressure PFO Patent foramen ovale PONV Postoperative nausea and vomiting RA Right atrium RAC Right atrial catheter RV Right ventricle SSEPs Somatosensory evoked potentials SVC Superior vena cava TEE Transesophageal echocardiography VAE Venous air embolism References 1. Ammirati M, Lamki TT, Shaw AB, Forde B, Nakano I, Mani M. A streamlined protocol for the use of the semi-sitting position in neurosurgery: a report on 48 consecutive procedures. 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Deinsberger W, Christophis P, Jödicke A, Heesen M, Böker DK. Somatosensory evoked potential monitoring during positioning of the patient for posterior fossa surgery in the semisitting position. Neurosurgery 1998;43(1):36–40. discussion 40–2. 65. Wiedemayer H, Sandalcioglu IE, Armbruster W, Regel J, Schaefer H, Stolke D. False negative findings in intraoperative SEP neurosurgical cases and review of published monitoring: analysis of 658 consecutive reports. J Neurol Neurosurg Psychiatry 2004;75(2):280–6. 66. Simon MV. Neurophysiologic intraoperative monitoring of the vestibulocochlear nerve. J Clin Neurophysiol 2011;28(6):566–81. 67. Loiselle DL, Nuwer MR. When should we warn the surgeon? Diagnosis based warning criteria for BAEP monitoring. Neurology 2005;65(10):1522–3. 68. Acioly MA, Liebsch M, de Aguiar PH, Tatagiba M. Facial nerve monitoring during cerebellopontine angle and skull base tumor surgery: a systematic review from description to current success on function prediction. 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Macroglossia in a child undergoing posterior fossa surgery in sitting position. Saudi J Anaesth 2012;6(1):85–6. VII. NEUROSURGERY C H A P T E R 15 Transesophageal Echocardiography A. Lele, V. Krishnamoorthy University of Washington, Seattle, WA, United States O U T L I N E Introduction 277 Basics of Transesophageal Echocardiography 277 Common Indications for Utilization of Transesophageal Echocardiography in Neuroanesthesia 278 Screening for Venous Air Embolism During Neurosurgical Procedures 278 Absolute Contraindications 279 Relative Contraindications 279 Steps in Preparation for Placement of Transesophageal Echocardiography Probe Under Anesthesia 279 Screening, Risk Stratification, and Preparation of Patients at High Risk for Vascular Air Embolism Prior to Proposed Neurosurgical Procedures 280 Verification of Multiorifice Catheter Placement for High-Risk Neurosurgical Procedures and Ventriculoatrial Shunts Monitoring Intraoperative Cardiac Function in Patients With Cardiomyopathy 280 281 Complications Associated With Transesophageal Echocardiography 282 Advantages and Disadvantages of Using Transesophageal Echocardiography as an Intraoperative Monitor 282 Summary 283 References 283 INTRODUCTION The ability to visualize the chambers of the heart during neurosurgical procedures provides the anesthesiologist with data regarding cardiac function, valvular abnormalities, and presence or absence of intracardiac shunts; helps to visualize intracardiac extraneous material such as clots and air; and helps facilitate certain bedside hemodynamic and neurosurgical procedures. Via a detailed literature search, this chapter reviews the utilization of transesophageal echocardiography (TEE) in the management of patients during neuroanesthesia. Upon reading the chapter, the reader will be able to understand the common indications, procedural characteristics, and practical applications of this technique. BASICS OF TRANSESOPHAGEAL ECHOCARDIOGRAPHY Unlike surface cardiography, TEE allows real-time visualization of various cardiac chambers. It is facilitated via placement of a TEE probe into the esophagus aimed anteriorly at the cardiac chambers. Due to the proximity to the heart, TEE examination generally provides images with a high degree of spatial resolution. With the probe in place, cardiac walls, valves, interatrial and interventricular septum, pericardial structures, and left and right outflow tract structures can be easily visualized. A traditional complete TEE examination covers such views. Essentials of Neuroanesthesia http://dx.doi.org/10.1016/B978-0-12-805299-0.00015-4 277 © 2017 Elsevier Inc. All rights reserved. 278 15. TRANSESOPHAGEAL ECHOCARDIOGRAPHY Common Indications for Utilization of Transesophageal Echo

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