NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
Cell Injury, Cell Death & Adaptations
Understand important terminology related to pathophysiology.
• Etiology: Origin or cause of a disease
• Pathogenesis: The sequence of cellular or tissue events in response to the etiologic agent, from the
initial stimulus to the expression of the disease
• Morphology: Structural alterations in cells and tissues of the body that characterize the disease or are
diagnostic of the etiologic process
• Clinical significance: Functional consequences of the morphologic changes
Know the principal targets of cell injury.
• Cell injury occurs when cells are stressed beyond their ability to adapt
• Oxygen deprivation is the most frequent cause of cell injury
• Targets of Cell Injury:
o Mitochondria
o Calcium Homeostasis
o Cellular Membranes
o DNA
• Increased cytosolic Ca activates phospholipases, proteases, endonucleases, and ATPases
Understand the different mechanisms by which cells adapt to stress & know clinical examples of these
adaptations.
• Cellular Adaptations are reversible changes that occur secondary to physiologic stress and pathologic
stimuli in order to preserve cell function.
o Hypertrophy: An increase in the size of cells and subsequent increase in organ size.
§ Physiologic Adaptation: Uterine enlargement during pregnancy.
§ Pathologic Adaptation: Left ventricular hypertrophy often seen w/ aortic stenosis
o Hyperplasia: Increase in the number of cells resulting from an increase in cellular division.
o Metaplasia: Transformation from one differentiated cell type to another – somehow this is
reversible. (normal cells of one type are replaced by normal cells of another type that can
better withstand stress)
o Atrophy: A decrease in size and function of cells.
o Dysplasia: abnormal mutation of cells; irregularly shaped and disorganized cells
o Neoplasia: continued cellular replication without normal regulatory influences
Cell Injury
• Reversible: Functional and morphologic changes reversible with stimulus removal, but otherwise
accumulates in necrosis.
o Cardiac myocytes, when injured, are transiently non-contractile – which still has a clinical
impact. Creatine Kinase is a serum marker used to detect cardiac necrosis
• Irreversible:
o Inability to reverse mitochondrial dysfunction
o Profound disturbance in cell membrane function
o Loss of DNA and chromatin (the material chromosomes are composed of) integrity
• Process:
o ATP is depleted and ATP synthesis is reduced
§ Intracellular Na+ concentration increases d/t loss of ATP-dependent Na/K pump activity,
resulting in cell swelling
o Dilation of Endoplasmic Reticulum reduces protein synthesis
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
o Rise of cytosolic Ca2+ d/t increased influx activates enzymes that injure cellular components of
catabolize membranes (all the -ase’s)
§ Enzymes ending in “-ase” indicate that they break down the substance listed as the
prefix. For example, phospholipases are enzymes that break down phospholipids into
fatty acids and other lipophilic substances.
o Mitochondria: Leakage of Cytochrome C signals death by Apoptosis.
• Causes of Cellular injury
o Hypoxia and ischemia
o Toxins
o Infectious agents
o Immunologic reactions
o Genetic abnormalities
o Physical agents
o Aging
Be able to differentiate morphologic alterations in necrosis and apoptosis.
Apoptosis
Necrosis
Programmed
Accidental
Pathological
• Physiological: When cells are no longer
needed
• Pathological: When cell is a threat to the
organism (DNA damage, atrophy)
Regulated through internal and external
Unregulated
pathways
Condensation: Membranes remain intact
Cytolysis: Membranes are disrupted
Cellular content shrinkage and release in
Enzymatic digestion and possible cellular content
apoptotic bodies
leakage
No inflammation
Inflammation
Energy required
Energy not required
Discrete DNA fragmentation
Randomized DNA fragmentation
•
•
Autophagy: A third pathway of cell deal, in which lysosomes within the cell digest its own components
– it’s a survival mechanism. May eventually lead to Apoptosis.
Caspase: Activated by either the intrinsic or extrinsic apoptotic pathways, resulting in the breakdown
of the cytoskeleton and creation of the apoptotic body.
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
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Apoptosis in human disease
o Excessive cell death (apoptosis) – heart disease, Alzheimer’s Parkinson’s, diabetes
o Defective cell death (lack of apoptosis leading to proliferation) – carcinoma, leukemia,
lymphomas
Understand the role of reactive oxygen species (ROS) in cell injury and the reactions in which they cause
injury. Know the different types of NOS and their role in the human body.
• Free Radicals: Chemical species with a single unpaired electron in the outer orbit – they’re unstable
and readily react with other molecules
o Accumulate through either increased production or decreased effectiveness of Scavenging
Systems
§ Produced by Neutrophils, Macrophages, Endothelia Cells and…other cells
o Functions: React with lipids, proteins and nucleic acids to stabilize their electronic field:
§ Lipid Peroxidation: Reacting with lipids with plasma and membranes (alters membrane
integrity)
•
Protein Oxidation: Reacting with amino acid chains and enzymes (causes degradation)
DNA Damage: Reacting with nuclear and mitochondrial DNA (prevents adequate repair
of genetic code)
o Two Types: Reactive Oxygen Intermediates and Reactive Nitrogen Intermediates (I think she’s
using “Reactive Oxygen Intermediates” and “Reactive Oxygen Species” interchangeably)
Reactive Oxygen Species (ROS): Free radical intermediates between O2 and H2O
o Superoxide (O2•)
§
§
•
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
o Hydrogen Peroxide (H2O2)
o Hydroxyl Radical (•OH) – Most damaging
o Peroxynitrite (ONOO•)
• Nitric Oxide Intermediates (NOS or Nitric Oxide Synthase): Unstable, free radical precursors to Nitric
Oxide
o Roles:
§ Vascular smooth muscle relaxation (vasodilation)
§ Antagonizes platelet activation
§ Decreases Leukocyte (WBC) recruitment
§ Microbicidal agent
o Types:
§ Endothelial (eNOS): Physiological
§ Neuronal (nNOS): Physiological
§ Inducible (iNOS):
• The “problem” NOS, induced by inflammatory cytokines (IL-1,TNF-a, INF-g) and
present in Macrophages and Endothelial Cells and is responsible for production
of NO in inflammatory reactions.
• Also critical for wound healing – produces a toxic environment for invading
organisms
§ eNOS and nNOS are physiological
• Examples of free radicals and tissue injury
o If •OH is near the cell wall when it is produced, it will interact with the lipid or protein
component of the cell wall and alter the integrity of the cell membrane
o If •OH is produced within the nucleus it will alter DNA structure and prevent adequate repair of
the genetic code
Know the function of antioxidants.
• Antioxidants: Physiologic substances that protect the body against damage from chemical reactions
caused by free radicals.
• Function:
o Bind to and catabolize (break down) free radicals
o Block the formation of free radicals
o Scavenge free radicals – transport proteins bind to free radical’s ion, taking them away from
molecules that they’re likely to combine with
o Repair the damage cause by free radicals to cell structure
• Oxidative Stress: When the balance between free radicals and antioxidants is broken in favor of free
radicals.
o Caused by a reduction in the antioxidant defense system or an increased in free radical
production
o Oxidative stress (caused by excess free radicals) occurs d/t 1. Increased production of ROS or
2. Ineffective scavenging systems
§ A reduction in antioxidant defense (scavenging) system or an increase in free radicals
can lead to oxidative stress
§ Free radicals are continually produced in our body. However, they are controlled by
antioxidants and when the balance between free radicals and antioxidants is broken in
the favor of free radicals it is called Oxidative stress
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
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Types of Antioxidants
o Naturally occurring
§ Superoxide dismutase (SOD)
§ Glutathione Peroxidase (GSH)
§ Catalase
§ Vitamin E, A, C and Beta-Carotene
§ CoQ10
§ Binding of agents that catalyze ROS formation to storage and transport proteins
o Synthetic Antioxidants
§ Dopamine
§ Propofol
§ Other pharmacological agents
Know the different types of NOS (Nitric Oxide Species) and their role in the human body.
•
Nitric oxide is a free radical, which makes it very reactive and unstable.
o There are 3 different types of NOS
§ Endothelial (eNOS)
§ Neuronal (nNOS)
§ Inducible (iNOS)
o eNOS and nNOS are physiological
• iNOS is the “problem” NOS
o Present in macrophages and endothelial cells
o Induced by inflammatory cytokines (IL-1, TNF-a, INF-g)
o Responsible for production of NO in inflammatory reactions
o Although it is the problematic NOS, it is also critical for wound healing. Produces an
environment toxic to invading organisms.
• Role of NOS (eNOS, nNOS, and iNOS)
o Vascular smooth muscle relaxation à (vasodilation)
o Antagonizes platelet activation
o Decreases leukocyte recruitment
o Microbicidal agent
Know how different anesthetic agents affect the generation of oxygen free radicals.
• Neurotoxic effects have been demonstrated during synaptogenesis, the rapid formation of synapses
that occurs in early childhood.
o Associated with NMDA antagonists (Ketamine, NO) and GABA agonists (Barbiturates,
Etomidate, Benzos)
o Infants to early childhood are at highest risk for neurotoxic effects
• Propofol: Antioxidant properties protect lung, heart, hepatic and vascular endothelial tissues (also a
GABA agonist)
• Volatile Gases:
o Desflurane releases more free radicals than Sevoflurane
o Isoflurane has pro-apoptotic effects, inducing the generation of amyloid-beta protein, a
hallmark of Alzheimer’s
o Some effect in decreasing ischemia/reperfusion injury
• Beta Blockers: Prevent myocardial ischemia/reperfusion-related apoptosis by inhibiting caspases (part
of the apoptotic cascade)
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
o Caspase activation – in either pathway (intrinsic or extrinsic) leads to nuclear fragmentation,
breakdown of the cytoskeleton, and ultimately formation of apoptotic bodies
Notes on Bennett’s Article (Section 1 reading)
•
Current information about the process of apoptosis
o Apoptosis, programmed cell death, happens in 50-70 billion human cells / day to maintain the
balance between mitosis to continually balance cell production with cell death
o Physiologic apoptosis: embryologic development, the hormonal mechanisms which control
menstruation, lactation, and menopause, the maintenance of the digestive tract, death of white
blood cells that have been used
o Apoptosis is a form of programmed cell suicide which allows for the orderly removal of
unwanted, improperly functioning, or injured cells, in balance with the production of new cells
by mitosis
o Apoptic cycle is an energy-dependent process in which a genetically controlled sequence of
events regulated by complex and numerous biochemical cell signaling signals result in the
condensation and fragmentation of individual cell into small vesicles that contain cellular
components that will be phagocytized by macrophages and neighboring cells and recycled –
cells are effected individually
o Necrosis is a nonenergy dependent (passive) cell death process that is pathological and occurs
as a result of insult from harmful events such as hypoxia, toxicity, or infection. Cell death is
marked by the presence of inflammation and swelling causing membrane rupture and
resulting in damage to adjacent cells
o High ATP = apoptosis : Low ATP = necrosis nature or severity of an insult that precipitates cell
death may result in depletion of ATP or reduced ATP synthesis thus favoring necrosis\
o Apoptosis: molecular signal received by cell à cell is identified for death à cell shrinks and
separates away from neighboring cells à nucleus is condensed and fragmented, and DNA is
divided into small pieces à cell matrix is consumed by caspases à cytoplasm and organelles
condense à cell breaks apart into membrane-bound particles referred to as apoptotic bodies
à apoptotic bodies are recognized and ingested by macrophages or other neighboring cells
o 4 phases:
§ 1. Signaling – a variety of stimuli can trigger apoptotic pathways. Including:
glucocorticoids, toxins, nitric oxide, nutrient deprivation, viral infection, hypoxia, ligand
(molecule) receptor activation (“death receptors” = Tumor Necrosis Factor (TNF)/TRADD
and Fas receptors/FADD), ionizing irradiation, or attack by cytotoxic lymphocytes.
§ 2. Control and regulation – the cell will either commit to apoptosis or mechanisms are
activated the interrupt the cascade of events to abort apoptosis. Regulators at this stage
include Bcl-2 (life or death switch – elevated levels are associated with cancer) and p53
(suppresses cell proliferation, found in cancer that is resistant to treatment). If allowed
to proceed the signaling phase activates a series of the caspase family of proteases
(from procaspases – inactive caspase) leading to protein cleavage and morphologic
changes in the apoptotic cell. Caspase facilitates apoptosis by increasing permeability of
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
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the mitochondrial membrane releasing mitochondrial proteins into the cytosol to being
inhibitors of apoptosis proteins (EAPs) and allow cell death to proceed
§ 3. Execution – cell undergoes organized degradation of its matrix and organelles by the
proteolytic caspases. Caspases activate cytoplasmic DNase (CAD) to enter the nucleus
and breakdown DNA to condense the chromatin. Then blebbing and formation of
vesicles containing compacted cell structures occurs.
§ 4. Removal of the dead cells – apoptotic bodies present engulfment ligands on their
surfaces which are recognized by scavenger receptor sites in phagocytic cells.
Engulfment ligands may consist of lipid, sugar, protein markers.
o 2 pathways
§ Extrinsic: activated with cell surface proteins TNF or Fas are activated to form the death
domain molecules TRADD and FADD to activate caspase. Plays an important role in
tissue homeostasis, especially lymphocytes.
§ Intrinsic: regulated at the mitochondrial level and is sensitive to both extracellular
stimuli and internal insults such as DNA damage. Initiated by alterations in
mitochondrial membrane potential and increased permeability of the membrane
resulting in leakage of cytochrome c. cytochrome c binds with apoptosis activating
factor (Apaf-1) to activate caspase.
§ Others: Granzyme B may also initiate proapoptotic gene Bcl-2 leading to cell destruction
Role of apoptosis in comorbid diseases
o Disrupted PCD pathways have been implicated in nearly all diseases
o Comorbid diseases that have a pathological basis of apoptosis include: ischemic heard disease,
cardiomyopathy, asthma, emphysema, cancer, diabetes mellitus, neurogenerative diseases,
and sepsis
o Caspase deficiencies or Fas mutations are at increased risk of autoimmune or
immunodeficiency disorders related to defective apoptosis of lymphocytes
o Diseases involving aberrant apoptotic mechanisms can either be due to excessive apoptosis or
insufficient apoptosis.
o Diseases of proliferative apoptosis:
o Cardiac disease:
§ Ischemia of coronary heart disease triggers apoptosis of cardiomyocytes and is a
contributing factor in the evolution of myocardial infarction
§ Ischemia follow by reperfusion is a potent stimulus of cardiac cell death (apoptosis),
which persists even after perfusion is reestablished
§ Production of free radicals and depletion of growth factor and energy sources
§ Apoptotic cardiac insults may precipitate heart failure via gradual loss of myocytes and
thinning of ventricle (ventricular remodeling)
o Respiratory disorders
§ Excessive apoptosis in respiratory infections, bronchial asthma, smoking-induced
obstructive-pulmonary disease (COPD), acute lung injury, hyperoxic lung injury, cystic
fibrosis, and interstitial pulmonary fibrosis.
§ Sphingolipids affect apoptosis in lung tissue and may be proapoptopic
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
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o Neurodegenerative problems
§ Alzheimer disease, Parkinson disease, Huntington disease, and amyotrophic lateral
sclerosis (ALS)
o Immunologic diseases
§ Progression of HIV to AIDS due to depletion (apoptosis) of CD4+ T-helper lymphocytes
o Diabetes
§ Accelerated rates of apoptosis results in destruction of B-cells in the pancrease may
contribute to the development of type 2 diabetes mellitus
§ Apoptosis is the primary mechanism for accelerated pancreatic B-cell death in type 2
diabetes
§ B-cell failure in type 1 is likely related to autoimmune-mediated apoptosis but in type 2
increased apoptosis stimulated by chronic hyperlipidemia and hyperglycemia
o Others: hemorrhage, stroke, sepsis, osteoarthritis, allograft rejection, and inflammation
o Diseases of insufficient apoptosis
o Cancer
§ Gene p53 may be expressed abnormally favoring tumor growth with resistance to
treatment
o Autoimmune disorders
o Viral infections in which apoptosis is inhibited in order to preserve the host cell for viral
replication
§ Papillomavirus and adenovirus inhibit p53 to defer apoptosis
§ Epstein-Barr intergeres with Bcl-2 gene resulting in cancers such as Hodgkin lymphoma
and posttransplant lymphona
Implications of the effects of anesthesia drugs on normal apoptotic mechanisms that need to be
evaluated as potential sources of risk / benefit for surgical patients
o Growing research implicates that some anesthetic drugs produce reactive oxygen species (ROS)
a type of free radical which are associated with increased levels of apoptosis
o Studies have indicated that anesthetic drugs alter the normal apoptotic mechanisms in the
synaptogenesis period of developing neural tissues of rat models, raising concerns over the
potential effects of these drugs on very young pediatric surgical patients
§ Synaptogenesis is the “growth spurt” of brain synapses in humans this is from 6th month
of gestation until several years of age
§ Anesthetic drugs simulate apoptosis in neural tissues and inhibit synaptogenesis and can
impair synaptic function, possibly altering neurologic development
o The 2 principal receptors involved in apoptotic neurodegeneration in the developing brain are
N-methy-D-asparate (NMDA) and y-aminobutyric acid (GABA) receptors
§ NMDA antagonists: ketamine and nitrous oxide
§ GABA receptor potentiation: all inhalation agents, IV barbiturates, propofol,
etomindate, and benxodiasepines
o Neuroapoptrotic effects are time and dose dependent with greater levels of damage occurring
at higher doses and over increasing lengths of exposure
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
•
•
•
o Risks to the older adult: induction of the generation and aggregation on amyloid-B protein in
the brain that is hallmarks of Alzheimer’s disease
o Laboratory and clinical studies have demonstrated that most anesthetic agents are capable of
activating the mechanisms that lead to premature cell death
o Cardioprotective drugs include caspase inhibitors, antioxidants, angiotensin receptor
antagonists, and beta-adrenergic receptor antagonists to control the impact of surgical and
anesthesia stress in patients with known or suspected ischemic heard disease
§ Beta blockers work to prevent myocardial ischemia and reperfusion-related apoptosis
by inhibiting caspases and stress-activated protein kinases by antioxidant mechanisms
o Isoflurane has proapoptotic effects and has been reported to induct the generation and
aggregation of amyloid-Beta protein in the brain
§ Amyloid B-protein production and accumulation are major pathological hallmarks of
Alzheimer’s disease
§ Given this relationship isoflurane-induced apoptosis and subsequent transient increase
in production of amyloid-beta protein in the geriatric patient is a concern for
anesthetists
Reactive Oxygen species
o Physiologic importance in their use by macrophages to disable harmful bacteria by
phagocytoses, the cause cellular and organ damage when produced endogenously in excess,
accumulated from exogenous sources (smoking, pollution) or in the presence of insufficient
antioxidant defenses
o Oxidative stress exists when the body’s antioxidant resources are overwhelmed by reactive
oxygen species (ROS)
o Injury from oxidative stress results in the lipid peroxidation of cell membranes, often causing
cell injury and death related to a wide range of acute and chronic conditions
o Inhalation agents have been shown to increase ROS in human tissues, predisposing the patient
to oxidative stress and increased apoptosis
§ Profound and transient reduction in blood lymphocytes in the immediate post
operative period resulting in immunosuppression rendering the patient susceptible to
infection and sepsis
Local anesthetics (Lidocaine) induce apoptosis via the mitochondrial pathway.
o Higher concentrations of lidocaine were responsible for cell death by necrosis, this is offered as
a possible explanation for lidocaine neurotoxicity
o Myotoxic damage related to continuous peripheral nerve blocks with bupivacaine as both
apoptotic and necrotic cell death were identified in muscle cells after exposure to bupivacaine
Volatile anesthetics may protect the myocardium against ischemia-reperfusion injury
o Mediated through a reduction of ROS in heart tissue by inhalation agenesthesia during
periods of induced ischemia
o Protect myocardial cells from apoptosis death-signaling effects of norepinephrine
Isoflurane reduce neuronal cell death in cortical cells that were subjected to hypoxic conditions raiding
interest in the potential benefits of volatile agents for patients with hypoxic brain injury
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
•
Propofol is structurally similar to pheno-baed free radical scavengers such as butylated hydroxytoluene
(BHT) and alpha-tocopheral (vitamin E)
o well documented antioxidant properties for reducing injury due to oxidative stress in lungs,
heart, hepatic, and vascular endothelial tissues and erythrocytes
o cellular and nuclear protective effect for cardiac and lung cells as well as other tissues
current research favors the use of either intravenous propofol or volatile agents depending on their
known effects on ROS and apoptosis
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
Inflammation & Repair
Know the steps of the inflammatory response.
• Inflammation is part of the body’s innage defense system
o Generalized to any intruder/damage
o Faster than the immune response
o Pre-requisite to the process of repair
• Initiating events
o Cellular injury
o Microbes
o Other foreign substances
• The 5 R’s
o Recognition of the injurious agent
§ Presence of injury sense by resident cells: macrophages, dendritic cells and mast cells
o Recruit of leukocytes (WBC’s)
§ Resident cells and plasma proteins secrete cytokines and inflammatory mediators that
promote the efflux of plasma while recruiting and activating leukocytes to the site of
injury (enhances ability to destroy & remove offending agent)
o Removal of the agent
§ If it’s not removed quickly, chronic inflammation results
o Regulation of response
§ Cytokines and other inflammatory mediators secreted by resident cells and plasma
proteins also serve to regulate the response
o Resolution/Repair
§ If the injurious agent can’t be eliminated quickly, chronic inflammation may result
• 5 Cardinal Signs of Inflammation:
o Redness
o Heat: Due to increased blood flow from vasodilation
o Edema: Due to extravasation of fluid from increase capillary permeability
o Pain: Pain receptors stimulated by kinins
o Loss of function: From all of that pain and swelling
Be able to differentiate the unique features of acute vs chronic inflammation.
Acute
Chronic
Onset
Fast (Mins – Hours)
Days
Response (primary cellular Neutrophils
Monocytes, Macrophages and
infiltrate)
Lymphocytes
Tissue Injury
Mild and self limited
Severe and progressive
Signs
Prominent local and systemic Subtle, fewer local and
signs
systemic signs
Know the mechanisms of leukocyte recruitment and migration through blood vessels.
o Progression of vascular response to inflammation
I. Transient vasoconstriction
II. Vasodilation:
• Induced by chemical mediators
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
Results in increased local hydrostatic pressure and the exudation of protein plasma,
causing edema
III. Increased permeability
• Induced by chemical mediators
• Contraction of endothelial cells results in the formation on endothelial junctions
which allow for the exudation of plasma proteins and fluid into the interstitium,
causing edema
IV. Increased blood viscosity and stasis
o Leukocytes (WBC’s) Involved:
§ Macrophages:
• Predominant tissue phagocytes, already located at the site of injury
• Monocytes arrives in 24 – 48 hours and mature into Macrophages
• Considered the garbage disposers
• Survive and divide in acidic environments
§ Neutrophils (most-abundant)
• Predominant blood phagocyte, they arrive within 1 – 24 hrs
§ Eosinophils: Degranulates the outer membrane of worms/parasites
o Leukocyte Recruitment
I. Cytokines activate Endothelial cells à which express Selectins à
II. Margination: Leukocytes accumulate along vessels and roll along the endothelial surface by
attaching to and detaching from Selectins
to find a point of penetration into the
inflammatory site.
• Selectins: Adhesion molecules
expressed on Leukocytes and
Endothelium which allow
Leukocytes to attach for
margination; Activated by Cytokines
o E-Selectin: On Endothelium
o P-Selectin: On Platelets and
Endothelium
o L-Selectin: On Leukocytes
o Selectins are up-regulated with the stimulation of cytokines and additional
mediators
III. Adhesion: Leukocytes activated by
Chemokines (chemoattractant Cytokines)
convert low affinity Integrins to high affinity
Integrins that bind to endothelial cell
integrins for a firm attachment
• Integrins: Integrin binding between
leukocytes and endothelial cells
results in cytoskeletal changes within
the leukocyte that mediate firm
attachment; must be activated by
Chemokines
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
IV. Transmigration: Migration of Leukocytes
through the vessel wall after adhering to
the endothelial surface; mediated by
PECAM
• Leukocytes are driven by the
chemical gradient created by
extravascular Chemokines
• Leukocytes bind to PECAM
(platelet endothelial cell adhesion
molecules) to pass through the
Endothelium then secrete
Collagenases to facilitate passing
through the Vascular Membrane
V. Chemotaxis: Once in the extravascular space, Leukocytes are attracted to chemo-tactic
stimuli formed by inflammatory mediators
• Leukocytes use their pseudopods for locomotion
VI. Phagocytosis:
1. Recognition:
o Recognition of pathogens
coated in Opsonins (usually
antibodies or complement
component C3b)
o Recognition of component of
the pathogen with Phagocyte
surface receptors
o Recognition of chemical
mediators (chemokines,
cytokines) secreted by other
immune cells
2. Engulfment: The membrane of the
Phagocyte engulfs the pathogen
o After leukocytes have been
recruited to the site of infection, they must be activated to perform their
functions (phagocytosis and intracellular killing)
3. Murder & Degradation:
o Oxygen-Dependent: Release of oxidizing agents which kill the pathogen
i. Superoxide (O2*)
ii. Hydrogen Peroxide (H2O2)
iii. Hydroxyl Ions (OH-)
o Oxygen-Independent: Release of Lysosomal contents that digests the
microbe
i. Release of Lysosomal enzymes into extracellular space can amplify
inflammation and damage surrounding tissue
§ Important!! During the process, lysosomal enzymes and other materials may be
released into the extracellular space to:
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
o Amplify the inflammatory response
o Cause endothelial injury and damage to surrounding tissue
Know the role of mediators in inflammatory reactions. Understand the production of arachidonic metabolites
and their role in inflammation.
o Pre-formed Mediators of Inflammation
§ Histamine
• Released by Basophils, Mast Cells and Platelets
• Involved in immediate inflammatory response
• Causes Vasodilation, increases Vascular Permeability and activates Endothelium
§ Serotonin
• Released by Platelets
• Causes Vasoconstriction and increased Vascular Permeability
o Cell-Derived Mediators of Inflammation (all “Newly Synthesized”)
§ Arachidonic Acid (AA) Metabolites
• Injured cells (Leukocytes, Mast cells, Endothelia cells, Platelets) release
Phospholipids which are converted to Arachidonic Acid – metabolized by two
pathways.
o Cyclooxygenase Pathway Metabolites (COX)
§ Mechanism: COX 1 and COX 2 enzymes act on AA to produce three
metabolites
• Prostaglandin: Vasodilator; Involved in pain and fever
response
• Prostacyclin: Vasodilator; Inhibits platelets aggregation
• Thromboxane: Vasoconstrictor; Promotes platelet aggregation
§ Inhibited by ASA, NSAIDs and COX 2 inhibitors
o Lipoxygenase Pathway Derivatives Metabolites (LOX)
§ Mechanism: Lipoxygenase enzymes act on AA to produce two
metabolites
• Leukotrienes: Vasoconstriction, Bronchoconstriction,
Increased vascular permeability, Promote neutrophil
recruitment
• Lipoxin: Vasodilation, Inhibit neutrophil recruitment
• Steroids inhibit both Cyclooxygenase and Lipoxygenase pathways
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
Platelet Activating Factor
• Released from all Leukocytes and
Endothelial Cells
• Platelet Aggregation, Vasodilation,
Bronchoconstriction, Increases
Leukocyte adhesion to
endothelium
§ Cytokines: Protein molecules that transmit
messages between cells, they’re produced
by and act on many different types of cells
• Types: Interleukins, TNF’s,
Interferons, Colony
stimulating factors
• Functions:
o Stimulates growth,
differentiation and
function of Leukocytes
and Immune cells
o Involved in systemic
inflammatory
response
o Activity can result in
hypotension
• Major Cytokines:
o IL-1, IL-6, TNFa: Induce systemic and acute
phase response
§
o Chemokines: Chemotactic for Leukocytes
§ Nitric Oxide
§ Oxygen-Derives Free Radicals
§ Neuropeptides (Substance P)
o Plasma-Derived Interrelated Systems of Inflammation
§ Complement System
• Activation: All of them result in cleavage of C3, the
critical step in the production of complement products.
o Classic Pathway: Activated by antigen-antibody complexes at C1
o Lectin Pathway: Plasma lectin (a serum protein) binds to carbohydrates on
the surface of microbes and activates C1
o Alternative Pathway: Activated by microbial cell surface products, plasmin
and lysosomes released by neutrophils at C3
• Component of the activated Complement System
o C3a: Anaphylatoxin, activates mast cells and basophils to stimulate histamine
release
o C3b: Opsonins for neutrophils and macrophages, they stimulate phagocytosis
o C4a: Anaphylatoxin, activates mast cells and basophils to stimulate histamine
release
§
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
o C5: Activates the lipoxygenase pathway of AA metabolites
o C5a: Anaphylatoxin, activates mast cells and basophils to stimulate histamine
release
o C6 – C9: Form Membrane Attack Complexes, which rupture plasma
membranes of pathogens
•
o C1a not an anaphylatoxin
§ Kinin System
• Triggered when Hageman Factor XII is activated to Factor XIIa
o Reactivates Hageman Factor XII, amplifying the stimulus
o Activates the Fibrinolytic cascade which produces Plasmin, activating the
Complement System
§ Streptokinase, urokinase-like plasminogen factor, Factor XII, and t-PA
contribute to the generation of plasmin, Fibrin does not
o Results in the release of Bradykinin
§ Vasodilates
§ Increases vascular permeability
§ Results in contraction of extravascular smooth muscle
§ Acts with Prostaglandins to produce pain
§ Clotting System
• Factor XII activated into Factor XIIa when it comes in contact with Collagen, part of
the Intrinsic Clotting Pathway
• Factor XIIa activates Fibrinolytic Cascade to produce Plasmin (Fibrinolytic system is
also activated in order to limit clotting)
• Plasmin activates the Complement System at C3
Know the physiologic effects that result from histamine activation of H receptors
• Vasodilation and increased
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
Neoplasia
Be able to differentiate disorders of cellular growth.
• Reversible disorders of cellular growth and differentiation
o Metaplasia: normal cells of one type are replaced by normal cells of another type that are
better able to withstand stress
o Dysplasia: an abnormality in maturation of cells w/in a tissue or irregularly shaped and
disorganized cells
o Neoplasia: “new growth”; continued replication w/o the regulatory influences that control
normal cell growth
• Irreversible proliferation of disorders cells
o Benign:
§ Structure: well-differentiated (near normal)
§ Function: normal to hyperfunctional
§ Growth: mass remains localized and typically encapsulated. May press against other
structures
§ Naming: the suffix “-oma” is applied to the primary tissue named
o Malignant:
§ Structure: range from well-differentiated to undifferentiated (anaplasia), pleomorphic
(vary in size & shape from neighboring cells)
§ Function: hyper-, hypo-, or abnormal function
§ Growth: higher rate of replication, don’t respond to normal controls, evades immune
system
§ Loss of cell-to-cell adhesionà allowing metastasis
§ Invasive: infiltrate & destroy surrounding tissue by enhancing proteolytic enzymes.
Poorly demarcated from surrounding tissues.
§ Metastatic: tumor implants that are discontinuous w/primary tumor. 30% of cancer pts
present with metastasis
§ Vascular in-growth: neo-vascular growth promotes metastasis
§ Drug resistant
§ Naming based on embryologic origins:
• Ectodermal or endodermal tissue of origin = carcinoma
o “front-line” tissues of the body (GI, skin, respiratory tract, lung colon,
breast, prostate) and are exposed to the outside environment / are in
contact with the microbiome
o Have structures, polarity, and adhesive functions for “border control”
o Exception is the nervous system
o Most common type of cancer
• Mesodermal origin = sarcoma
o Predominantly connective tissues
o More common in children due to rapid proliferation and remodeling of
muscle, cartilage, and bone
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
o Malignancies of blood technically arise from mesenchyme but are
generally grouped together under the entity of hematologic neoplasms
because of their highly specialized nature
• Fundamental differences in the expression of certain proteins, especially
intermediate filaments such as keratins and vimentin will identify the lineage of
origin
Neoplasia classification
Understand the molecular basis of carcinogenesis.
o Neoplasia is a result of stepwise alterations in cellular function. Phenotypic alterations produce
morphologic changes that are readily evident by microscopy and may predate tumor development by
many years
o Malignancy Etiology:
§ Carcinogens:
• With the passing of time and with stochastic occurrence of errors in DNA replication
accelerated by exposure to environmental carcinogens, cells in various tissues of the body
acquire mutations in their genomes
• Environmental Chemicals: produce free radicals causing tissue injury. Dose-dependent
• Radiation
• Viruses: insertional mutagenesis- viral genes are incorporated into the host’s genome at
specific sites & cause cell transformation. During some viral infections, the hosts’ immune
system can become compromised, allowing neoplastic cells to emerge which would
otherwise be rejected
o Viruses can introduce oncogenes (without having to mutate the host gene)
§ Examples:
• Papillomavirus (HPV) à cervical carcinoma, anal carcinoma
• Epstein Barr herpesvirus à nasopharyngeal carcinoma, Burkitt
lymphoma, immunoblastic lymphoma, Hodgkin disease
• Human T cell virus à t cell leukemia
• Hormones
§ Host Factors:
• Host factor involved in etiology of malignancy: immune system function
o Abnormal function of Host stromal cells including connective tissue cells,
hematopoietic, and bone marrow compartment cells, immune system cells and
adipose tissue cells is fundamentally involved in the continued tumor progression
• Inherited predisposition: inheritance of a single mutant gene
o Tumor Suppressor genes: genes that confer an advantage to tumor cells through
a loss-of-function alteration
§ Much more common; can be inactivated through a variety of types of
mutations that result in the loss of the protein product of the gene
• Nonsense
• Frame-shift
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
• Deletion
§ Both alleles must be inactivated; but inactivation of only one allele can
cause a reduction of gene expression, and it sometimes is enough to allow
the tumor to grow
§ Include proteins involved in
• DNA damage control
• Cell cycle control
• Programmed cell death
• Cell adhesion
o Proto-oncogenes: confer an advantage to tumor cells through a gain-of-function
event
§ Oncogene: an activated proto-oncogene
§ Can be activated by
• Mutation
• Gene amplification
• Overexpression
• Chromosomal translocation
§ Only one allele is mutated
§ Include proteins involved in
• Extracellular growth factor signaling pathway from the membrane
receptors to the membrane intermediates to the proteins mediating
the cytoplasmic signaling cascades
o Epidermal Growth factor receptor (EGFR) binds a number
of extracellular ligands and cooperates with HER2 to signal
proliferative and apoptotic pathways
§ Overactivity of one/both of these can lead to
unregulated control of growth and apoptotic signaling
o RAS – a membrane bound signaling switch that functions
immediately downstream of membrane receptors at a key
branch of cytoplasmic signaling; mutational activation causes
overactive cytoplasmic signaling and deregulation of
proliferative and apoptotic pathways
o RAF – a serine-threonine kinase that functions
downstream of RAS; mutation activation is similar to that of
RAS
Familial predisposition: familial clustering of cases but role of inheritance unclear
o High penetrance genes: confer a very high risk of disease when inherited, and
families carrying these alleles are noticeable by their high incidences of cancers
associated with these genes
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
o Rare
example
where
heterozygotes of an oncogene are at increased risk: RET oncogene in the multiple
endocrine neoplasia type II. Individuals that are heterozygous for the RET oncogene
on chromosome 10 are at increased risk of developing two rare neural crest tumors
§ Pheochromocytoma and medullary carcinoma of the thyroid together
with parathyroid tumors
• Other: age, gender, immune system function
o Number of mutations in various tissues increases with age
§ Morphologic abnormalities – changes in cell behavior and function are a result of molecular
abnormalities involving cell signaling due to defects in the genome
• Hypertrophy – enlargement of the cell reflecting too much protein and membrane
synthesis
• Hyperplasia – crowding due to too much cell division
• Dysplasia – reflects a reversion to a more immature cell without a committed identity
• Metaplasia – reflects abnormal cell reprogramming to appear and function like a cell of
a different type
§ Proliferative abnormalities are the primary forces underlying the progressive nature of many
forms of neoplasia that ultimately lead to uncontrolled growth, invasion, and metastasis which are
the hallmarks of cancer
§ Clonal evolution repeated cycles of clonal and sub clonal selection may eventually lead to a
cellular clone with a growth pattern that defies the normal tissue architecture and appears as an
outgrowth or new growth called a neoplasm
§ Neoplasia is this process of new growth – proliferative phenotype passes mutated genes to
more cells, which is a self-perpetuating process, cells that have acquired a growth advantage
owning to DNA mutation may repopulate the tissue over time
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
§ Genetic field defect – a microscopically normal-appearing tissue that bears a high proportion of
cells with genetic mutations and is considered a high risk for future development of cancer
§ Genetic changes associated with cancer involve the nucleic acid sequence of the cellular
genome with or without additional epigenetic phenomena involving chemical modifications of the
DNA/protein complex
• Transcriptome the sum of all the RNS transcripts in the cancer
§ Era of Big Data is reconciling the mass data emerging from the analyses of human cancers
Understand potential adverse effects of cancer treatment and associated anesthesia considerations.
• CV:
o Doxorubicin: cardiotoxic & myelosuppression
§ Consider pre-op echo to eval for LV dysfunction- monitor EKG for QT prolongation.
Invasive monitoring?
§ The cardial depressant effects of anesthesia can unmask cardiac dysfunction
o Bevacizumab – increased risk of bleeding and postoperative wound complications
• Pulmonary:
o Bleomycin: pulmonary HTN & pulmonary toxicity (fibrosis)
§ Consider pre-op PFTs, ABG or chest radiograph
§ Bleomycin-associated pulmonary injury may be exacerbated by high O2
concentrationsà deliver lowest FiO2 that provides adequate oxygenation
§ Carefully titrate fluid replacement because of increased risk of developing interstitial
pulmonary edema
o Nitrous oxide may augment the toxicity of methotrexate, so it is best to be avoided
• Neurologic:
o Cisplatin: potential for elevated ICP; peripheral neuropathy
§ Evaluate sensory deficits pre-operatively; careful positioning and padding
o Alkylating agents (cyclophosphamide) cause drug-induced pseudocholinesterase deficiency and
could experience a prolonged response to succinylcholine
• Airway:
o Radiation to head/neck- difficult airway, tracheal compression
o Complete a thorough airway assessment in pre-op, review radiographs to determine presence
of tracheal deviation
o Does your assessment indicate a difficult airway? Is fiberoptic intubation necessary (asleep or
awake?)
o Intubation in presence of oral mucositis may cause bleeding
o Cancers of the head, neck, and anterior mediastinum may exhibit airway compromise
o Radiation patients may have airway abnormalities that are difficult to detect on physical exam
• Endocrine:
o Chronic steroid therapy results in adrenal suppression, require a stress dose of steroids
o Patients receiving more than 20mg of prednisone (or the equivalent) per day for more than 3
weeks are considered most at risk –
§ Recovery of the hypothealamic0pituitary-adrenal axis may take up to a year
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
•
o Administer 100 mg hydrocortisone w/induction, followed by 100 mg IV Q8h for first 24 hrs
post-op.
Systemic effects of cancer
o Paraneoplastic syndromes: when the tumor affects distant targets
o
Analgesia:
o Many cancer pts take opioids for pain control r/t their underlying diagnosis. Narcotic dosing for
perioperative analgesia may require adjustment to account for drug tolerance
o Neuraxial anesthesia: may be contraindicated due to presence of coagulopathies
o PNB: baseline neuropathies r/t chemotherapeutic agents must be well-documented!
o IV opioids then to blunt natural killer (NK) cells activity, producing an immunosuppressive effect
that supports proliferation of tumor cells
o
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
Know functions of the most commonly mutated proteins and genes.
o RAS is the most commonly mutated oncogene in human tumors. Approximately 30% of all human tumors
contain RAS gene.
§ Function: TAS flips back and forth between and excited signal-transmitting state and a quiescent
state. Activated RAS stimulates downstream regulators of proliferation by several interconnected
pathways that converge on the nucleus and alter the expression of genes that regulate growth,
such as MYC.
o The p53-enconding tumor suppressor gene, TP53 is the most commonly mutated gene in human cancer.
The TP53 protein is a transcription factor that thwarts neoplastic transformation by three interlocking
mechanisms: activation of temporary cell cycle arrest, induction of permanent cell cycle arrest, or
triggered of programmed cell death.
§ In summary, TP53 is activated by stresses such as DNA damage and assists in DNA repair by causing
G1 arrest and inducing the expression of DNA repair genes.
§ Confirming the importance of TP53 in controlling carcinogenesis, more than 70% of human cancers
have a defect in this gene, and the remaining malignant neoplasm often have defects in genes
upstream or downstream of TP53.
Be familiar with the anesthetic management of HIPEC.
• Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC)
• Cytoreductive surgery with HIPEC has emerged as an effective treatment for patients with various GI,
peritoneal, and ovarian cancers with metastasis to the lining of the abdomen and peritoneal cavity
o Cytoreductive Surgery
§ Lengthy exploratory laparotomy involving peritoneal stripping and tumor resection
(potential for significant blood loss)
o HIPEC
§ Following cytoreduction, abdominal and pelvic cavities are flooded with high-dose,
heated chemotherapy (42°C) for approximately 90 minutes
§ Heated chemotherapy increases the drug’s therapeutic effect by increasing cytotoxicity
of malignant cells
§ Increases malignant cell permeability, impairing DNA repair and triggering protein
denaturization
• HIPEC implications
o Preoperative
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
§ Thorough evaluation including baseline lab values
§ Type & crossmatch with blood available
§ Thoracic epidural placement if not otherwise contraindicated
§ Should focus on conditions that may become exacerbated by large fluid fhists that occur
o Intraoperative
§ GETA
§ Standard induction with complete paralysis throughout the procedure
§ Two large bore peripheral IVs & arterial line for hemodynamic monitoring and
frequent blood draws
§ Hotline
• NS or Plasmalyte
• No Hetastarch d/t increased risk of coagulopathy
§ Esophageal temperature probe is essential for accurate temperature monitoring
§ Cytoreductive portion
• Typical “open belly” considerations – anticipate large fluid shifts and administer
replacement fluids accordingly, potential for significant blood loss
• Turn off any warmers (bair hugger, hotline, etc) after tumor debulking, and
prepare for cooling during HIPEC (ice packs to groin and under arms, and
underbody cooling blanket) goal temp 35 *C prior to introduction of
hyperthermic
• Focus (primary goal) on increasing circulating volume during this phase to
counteract the increase in venous capacitance that will occur during the
chemotherapeutic phase
o Large amounts of crystalloid administration may result in coagulopathy
due to dilution of platelets and coagulation factors
• Blood loss can be considerable during this phase
• Alterations in respiratory gas exchange due to decreased O2 delivery to the
microcirculation that has been destroyed by the tumor and debulking
• Patients may have decreased FRC s/t increased abdominal girths that may result
from tumors or ascites putting them at risk for aspiration and rapid desaturation
§ HIPEC portion
• Cisplatin commonly used – closely monitor urine output & increase fluids or
administer lasix to maintain appropriate output
• ABGs will be consistent with metabolic acidosis – treat accordingly
• Major hemodynamic changes resulting in hyperdynamic circulatory state due to
thermal stress that is induced
• Extremes of body temperature increase the metabolic rate leading to a steady
increase in heart rate, cardiac output, and end-tidal CO2 with an overall
decrease in SVR. Due to the decrease in SVR HR will further rise to compensate
• Peripheral vasculature dilates in response to heat stress resulting in heat loss
from the core to the outside environment
• Core temperature goal of 38 C during this phase
• Goal to maintain UO 100 ml of during every 15 min – furosemide and mannitol
can be given in small doses to maintain urine output goal
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
Major fluid shifts, blood loss, electrolyte changes, disturbances in hemodynamics,
coagulation, and respiratory gas exchange are common
o Postoperative
§ Transport patient directly to ICU intubated
§ Typically extubated by morning of POD 1 as long as patient remains hemodynamically
stable
Normal and Abnormal Cell Growth
o Normal Cell Growth:
§ All have proto-oncogenes: cellular genes that promote normal growth & differentiation
§ Types of proto-oncogenes:
• Growth Factors
• Membrane proteins such as receptor proteins
• Cytoplasmic proteins involved in signal transduction
• DNA binding nuclear proteins that can modulate the expression of specific growth
factors, growth factor receptors, signal transducers, nuclear proteins, and tumor
suppressor proteins
• DNA repair genes are NOT proto-oncogenes
§ All have tumor suppressor genes that constrain growth
• Negative growth signals produced by tumor suppressor gene proteins block specific
phases of the cell cycle, block cell-to-cell communications, stop differentiation, and
stimulate cell death
o P53 gene is most common
§ All have DNA repair genes:
• Normal cells sustain DNA damage. DNA damage is either repaired or cell is
destroyed
§ All have genes that regulate apoptosis: some are classifies as tumor suppressor genes.
o Abnormal Cell Growth:
§ In cancer, there is a genetic alteration/mutation or amplification of genetic material that
causes malfunction of the aforementioned genes
• Point mutation, chromosomal translocation, etc.
§ Cancer:
• Mutation of proto-oncogenes result in oncogenes
o Oncogene: cancer gene that makes the cell divide in an uncontrolled manner
o Oncogenes are classified by their proto-oncogene
o Mutations of proto-oncogenes that encode growth factors
§ Acquired GF self-sufficiency and/or over expression of GF.
§ Ex> over expression of fibroblast GF (proto-oncogene) is a/w
melanoma.
o Mutations that encode GF receptors
§ Acquire mutant receptors that deliver continuous mitogenic signals to
the cell
§ Over expression of normal GF receptors
§
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
•
•
o Mutations that mimic the function of normal cytoplasmic signal-transducing
proteins
§ Those located in the inner plasma membrane & transmit to the
nucleus
• The RAS protein is most common
• The mutated form activates a signal that eventually tells the
cell to grow/divide but the signal CANNOT be deactivated
§ Non-receptor associated tyrosin kinase that act in the growth
promoting pathway and pathways that control cell growth CANNOT
be deactivated
o Mutations affecting genes that encode nuclear transcription factors (in
nucleus)
§ Mutated transcription factors bind to DNA that activate transcription
(tell cell to divide)
o Mutations that dysregulate the activity of cyclins & cyclin-dependent
kinasesà Favor cell proliferation
Alteration/inactivation of tumor suppressor genes
o Allows for continuous cell transformationà favors growth/proliferation as
well as malignant potential
o P53 is most commonly mutated gene
§ Functions:
• Cell quiescence (temporary cell cycle arrest)
• Stimulate DNA repair pathways
• Cell senescence (permanent cell cycle arrest)
• Triggers apoptosis
o Alteration/inactivation of tumor suppressor genes coupled w/ activation of
oncogenes allows for:
§ Further anaplastic changes (cells don’t have time to repair DNA
damage)
§ Promotes growth of undifferentiated cells
§ Tumor grows to point that center becomes hypoxicà natural
selection of more aggressive tumor cells resistant to hypoxia
Defects in DNA repair genes
o Promotes cell division of defective cells
o Neoplastic cells emerge
Alteration in genes that regulate apoptosis
o Allows for cell proliferation
o Ex. Bcl-2 is a large family of pro-apoptotic and anti-apoptotic proteins located
in mitochondrial membranes
§ Inhibition of pro-apoptotic proteins allows cell proliferation
§ Over-expression of the anti-apoptotic proteins suppresses apoptosis
and allows cell proliferation
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
Cancer Pain
o Acute pain – pathologic fractures, tumor invasion (especially of bone), surgery, radiation treatment,
chemotherapy
o Nociceptive pain – includes somatic and visceral pain and refers to pain caused by peripheral
stimulation of nociceptors in somatic or visceral structures
§ Somatic pain – tumor involvement in somatic structures such as bones or skeletal muscle –
described as “aching, stabbing, or throbbing”
§ Visceral pain – lesion in a hollow or solid viscus – described as “diffuse, gnawing, or crampy”
if hollow viscus or “achy and sharp” if a solid viscus
§ Nociceptive pain is responsive to both opioid and non-opioid medications
o Neuropathic pain – involves peripheral or central afferent neural pathways – described as “burning
or lancinating”
§ pain responds poorly to opioids – anticonvulsants may be used for chronic neuropathic pain
o drug therapy of cancer management progression:
§ mild – moderate pain: NSADs + acetaminophen
§ moderate pain: addition of codeine or one of its analogs
§ severe pain: addition of more potent opioids such as morphine (starting with oral route
then moving to alternative routes such as IV and transdermal)
§ patients with depressive symptoms: tricyclic antidepressants (may have analgesic
properties by potentiating affects of opioids)
§ corticosteroids can decrease pain perception and have a sparing effect on opioid
requirements, improve mood, increase appetite, and lead to weight gain
§ multimodal analgesia with local anesthetics and adjunctive agents such as gabapentin and
ketamine may be effective after surgery
o neuraxial analgesia
§ an effective way to control pain in patients undergong surgery and may be employed for
treatment of cancer pain
§ not used in patients with local infection, bacteremia, and systemic infection because of
increased risk of epidural abscess
• in the setting of intractable cancer pain there may be a risk-benefit analysis
regarding risk of infection vs end of life comfort
§ morphine is administer intrathecally or epidurally for management of pain from weeks to
long term tunneled catheters
§ patients are considered for neuraxial opioid administration when systemic opioid
administration has failed or because of intolerable side effects
o neurolytic procedures destroy both sensory component of nerve fibers while also destroying motor
and autonomic nerve fibers
§ cordotomy – interruption of the spinothalamic tract in spinal cord for unilateral pain
involving lower extremity, thorax, or upper extremity
§ dorsal rhizotomy – interruption of sensory nerve roots and is used when pain is localized to
a specific dermatomal level
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
Pathophysiology of Obesity
Pathophysiology of obesity :
•
•
•
•
Obesity is a function of a person’s weight
being disproportionally greater than their
height
On a basic level, an energy imbalance
between the caloric intake and caloric
expenditure – in which caloric intake
exceeds calories consumed in basal
metabolic demand, work, or exercise – leads to overweight and ultimately obesity
o Most energy expenditures is determined by basal metabolic rate and occurs within the lean
tissue
o Regular exercise over time increases BMR while caloric restriction decreases BMR
Positive caloric balance is stored in the body as fat in adipocytes. This fat is primarily in the form of
triglycerides
Lipoprotein lipase is responsible for storage of triglycerides and is more active in abdominal region
which is why android fat distribution is more common
Know how to classify BMI.
•
BMI=Weight (Kg)/Height (m)2
o Weight Kg=Weight lbs2.2
o Height m=Height in × 2.54100
•
See table (BMI >30 is considered obese)
•
BMI is only one measure of obesity, some patients with high BMI are in good health.
•
BMI does not take into correlate well with the distribution of fat (android or “apple” vs gynecoid or
“pear”)
o Methods used to estimate body fat distribution include: measurements of skin fold, waist
circumference, waist-to-hip circumference ratios, or radiographic studies such as CT, MRI
•
BMI does not account for the amount of pre-existing muscle mass often seen in some athletes or even
weightlifters
•
For patients with a BMI of 25-35.9 waist circumference should be used in addition to BMI to identify
risk factors (increased risk factors for males with waist >40 in and females >35 in)
o Waist-to-hip >1.0 men or 0.8 women strong predictor of ischemic heart disease, stroke,
diabetes mellites, and death independent of the total amount of body fat
Know comorbidities commonly associated with obesity, especially those for which it is an independent risk
factor.
•
•
Obesity leads to severe metabolic derangements mainly because of disturbances in insulin regulation.
Comorbidities (Bold are independent risk factors):
o Cardiovascular Disease (CVD): HTN, CAD, CVA, dyslipidemia, Heart Failure
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
o
o
o
o
o
o
o
•
•
•
•
§ Obesity is an independent risk factor for CAD (and probz all the CVD diseases)
Neuro: Cerebrovascular accident (stroke)
GI: gallbladder disease
Respiratory: OSA, Respiratory Problems
Cancer: Endometrial, Breast, Prostate, Colon
Metabolic & Miscellaneous: DM2, Gallbladder Disease, Osteoarthritis
Osteoarthritis, back pain, increased risk for depression and cancer as well as social
discrimination
Obese women have menstrual irregularities, subfertility, stress incontinence, and hirsutism,
complications with pregnancy, and increased risk of depression
o
Fat Distribution:
o Visceral (truncal) fat a risk factor for cardiovascular disease, DM2, and frequently correlates
with the development of insulin resistance
§ Adipocytes of visceral fat tissue are more lipolytically active than subcutaneous
adipocytes and contribute more to plasma free fatty acid (FFA) level
o Distribution of fat is a better predictor of health risk than weight alone; gynecoid
(gluteofemoral) fat distribution predicts better risk than android (abdominal) distribution
o Subcutaneous adipose tissue (SAT) is divided into superficial subcutaneous adipose tissue
(sSAT) and deep subcutaneous adipose tissue (dSAT) by the layer of fascia superficialis.
§ dSAT is strongly linked to insulin resistance
§ Leg/hip subcutaneous fat protective against CVD, DM2
Children with obesity have a significantly greater chance of developing associated medical problems
such as diabetes, hypertension, and heart disease at a much younger age
Overweight and obesity are linked to more deaths worldwide than underweight
Cellular distrubances:
o At the cellular level fatty infiltration of the pancreas leads to decreased secretion of insulin
while at the same time, engorgement of adipocytes promotes insulin resistance.
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
o Engorged adipocytes area capable of secreting cytokines: IL-1, IL-6, and tumor necrosis factor
(TNF-a) which worsen glucose intolerance by decreasing secretion of adiponectin an insulin
stabilizer
o Leptin also secreted by adipocytes modulates secretion of neuropeptides that regulate energy
expenditure and food intake (induces satiety when present in high concentrations)
§ Accelerates inflammatory changes by activating monocytes and decreasing capacity of
neutrophils to activate and migrate
o Ghrelin acts in opposition of Leptin and increase appetite and affects the gastric vagal afferents
making them less sensitive to distention and thus facilitating over eating
o all of these substances eventually stimulate the liver to produce increased levels of very lowdensity lipoproteins and apolipoprotein B causing the pancreas to secrete more insulin and
more pancreatic peptides resulting in diffuse intracellular inflammatory changes.
Understand the effects of obesity on breathing and why OSA occurs in these patients.
•
•
•
•
OSA: Cessation of airflow of more than 10 seconds characterized by frequent episodes of apnea or
hypopnea
OSA is an independent risk factor for the development of hypertension, cardiovascular morbidity and
mortality, and sudden death.
Anatomy:
o Increased neck circumference increases soft tissue mass surrounding the pharynx.
§ Regional obesity near the upper pharyngeal airway has a stronger correlation to OSA
than severity of BMI
o Decreased lung volume causes pharyngeal wall collapse through decreased longitudinal
tracheal traction. (The Pharynx is a “flimsy tube” that isn’t pulled as taught by the diaphragm
when lung volumes are lower). Decreased lung volume due to an increase in visceral fat volume
§ Waist circumference may even be a better predictor for OSA than neck circumference or
BMI
o Extra weight around the chest wall also causes decreased lung compliance, resulting a
restrictive breathing pattern: rapid, shallow breathing patterns in obese patients which
ultimately increases the work of breathing
o Increased work of breathing leads to an increased energy requirement to move the chest wall
causing an increased O2 consumption and increased CO2 produced
§ Up to 70% increase in energy expenditure for breathing
o Small airway closure occurs (ie closing volume becomes greater than FRC) resulting in V/Q
mismatch, right-to-left intrapulmonary shunting, and arterial hypoxemia
§ General anesthesia accentuates these changes
Pathophysiology:
o Sleep reduces upper airway tone, resulting in upper airway obstruction and snoring in obese
patients
o Upper airway obstruction results in hypoxemia and hypercarbia, stimulating the autonomic
nervous system
o ANS stimulation arouses the patient, allowing them to breathe but contributing to daytime
somnolence
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
o
Anesthesia Implications:
o OSA is an independent risk factor for difficult mask ventilation
o General anesthesia further decreases the FRC in an obese patient (~50%) compared with a
nonobese patient (~20%) leading to a decrease tolerance of apnea
o Pre-Oxygenation helps prolong the apnea period, although arterial hypoxia is still quite
common during DL
§ Ramp them, increasing lung volume and FRC, decreases pharyngeal closing pressure by
improving pharyngeal anatomic disparity and improves alignment of O, L, P axes
§ Pre-oxygenation with 100% O2 and a tight-fitting CPAP mask to increase apnea
tolerance time and oxygenation
§ Addition of continuous positive airway pressure (CPAP) helps improve FRC at the
expense of cardiac output and O2 delivery
o Airway maneuvers such as mandible advancement, neck extension, and mouth opening (triple
airway maneuver) in addition to use of oral airway often aid in oxygenation and prevention of
airway obstruction
o Use of short-acting neuromuscular blockade allows the patient to return to spontaneous
respiration more quickly should the patient have a difficult airways
o Awake intubation should be considered when any element of the triple airway maneuver is
disturbed in obese patients with severe OSA
o “STOP-BANG” screening for OSA: Snoring, Tiredness, Observed apnea, high blood Pressure, high
BMI, advanced Age, large Neck circumference, male Gender
§ High risk is yes to 3+ items
Be familiar with Pickwickian Syndrome.
•
•
•
•
•
Obesity Hypoventilation Syndrome (OHS) (Pickwickian Syndrome) progresses from OSA and has the
following criteria:
o BMI > 30
o Chronic hypercapnia (PaCO2 > 45 mmHg)
o Sleep disordered breathing
Pathophysiology: Central respiratory centers become desensitized to hypercapnia, resulting in
nocturnal apnea and reliance on hypoxic drive for ventilation
OSA causes hypoventilation, leading to hypoxia and hypercapnia, with metabolic alkalosis to atrial
hypoxemia.
Symptoms:
o Polycythemia: RBC’s increase to compensate for chronic hypoxia
o Pulmonary HTN: Effect of chronic hypoxic pulmonary vasoconstriction
o Right Heart Failure: Reduces function from pumping against increased PVR
o Metabolic Alkalosis: Nocturnal metabolic alkalosis to compensate for respiratory acidosis –
returns to homeostasis during the day.
o Daytime Hypersomnolence (patients present with this)
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
Anesthesia Implications:
o Patients more sensitive to respiratory depression from opioids and hypnotics.
o Consider arterial line to trend ABG’s.
Know the effects of obesity on the cardiovascular system.
•
•
•
•
•
•
Hypertension: Highly vascular adipose tissue results in hypervolemia from excess extravascular fluid
volume, increasing cardiac output and blood pressure.
o cardiac output to increase 0.1L/min for each kg of excess weight related to adipose tissue
o
Biventricular Heart Failure: Systemic hypertension leads to LVH and ultimately CHF and RVH.
o LVH results in poor exercise tolerance as contractility can’t increase.
§ LVH and stiffened LV can’t contract better so cardiac output can only increase by
increasing heart rate without a corresponding increase in stroke volume or ejection
fraction
o RVH results from LV CHF and Pulm HTN from chronic arterial hypoxemia or increased
pulmonary blood flow volume
Atrial Fibrillation: Acid-base disturbances, volume overload and CAD result in arrhythmias.
Ischemic Heart Disease: Obesity is an independent risk factor for CAD.
o
Cardiac surgery patients with obesity are at an increased risk of increased length of assisted
ventilation, longer hospital stay, and increased risk of renal dysfunction
Anesthesia evaluation should focus on age, gender, cardiac and respiratory fitness, electrolyte
imbalances, and heart failure as predictors of morbidity and mortality
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
Obese patients risk of premature death is doubled and the risk of death resulting from cardiovascular
disease in increased fivefold in the obese population
Know the GI and metabolic effects of obesity.
•
•
•
•
Fat issue is an active endocrine organ, and is the largest endocrine organ in the body
o Fat produces many inflammatory mediators including adiponectin which appears to play a
significant role in insulin resistance.
o Adiponectin has an inverse relationship with obesity with levels decreasing as obesity increases
and negatively with glucose, insulin, triglycerides, and increasing BMI
Gastroesophageal reflux disease (GERD):
o Obese patients without symptoms of GERD have a resistance gradient between the stomach
and the gastroesophageal junction similar to non-obese patient (contrary to popular belief)
o Increased gastric volume leads to faster gastric emptying to compensate
o Risk of aspiration at induction is likely overestimated by most clinicians
Diabetes
o Obesity is an independent risk factor.
o Anesthesia Implication: Stress response of surgery may trigger hyperglycemia, necessitating
insulin.
o All obese patients should have a random glucose test preoperatively and if indicated, a glucose
tolerance test
Metabolic Syndrome or “Insulin Resistance Syndrome” (≠DM) or “syndrome X”
o Fat produces adiponectin, an inflammatory mediator which produces insulin resistance,
resulting in hyperinsulinemia.
§ Hyperinsulinemia of insulin resistance is associated with a range of apparently
unconnected disturbances that include: hyperglycemia, hypercholesterolemia,
hypertriglyceridemia, hypertension, hyper-viscosity (increased hematocrit),
hypercoagulability, and hyperuricemia
o Through a number of mechanisms, hyperinsulinemia results in macrovascular damage.
o Result from the maladaptation to overnutrition of genes selected to survive on undernutrition
o Weight gain and insulin resistance are the primary causes of metabolic syndrome as well as
upper abdominal fat
o Presence of at least 3 of the following signs is indicative of disorder: large waist circumference,
high triglyceride levels, low levels of high-density lipoprotein (HDL) cholesterol, glucose
intolerance, and hypertension
§
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
•
Thromboembolic Events: Obese patients are at an increased risk for DVT and PE.
o Compounded effects of polycythemia, increased intraabdominal pressure, increased fibrinogen
levels associated with chronic inflammatory state, and immobilization leading to venostasis
Nutrition disorders:
o
o
Be familiar with the anesthesia implications of obesity, particularly with airway management.
•
Respiratory effects of obesity
o Decreased Lung Volumes: Chest and abdominal adipose tissue impede normal diaphragmatic
motion when supine.
§ Decrease in FRC, ERV and TLC – RV & CC remains the same.
§ GA decreases FRC more in obese patients than non-obese patients.
• Regional anesthesia preferred in severely obese patients
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
•
o Restrictive Ventilatory Defect: Extra weight reduces lung compliance, resulting in rapid, shallow
breathing.
§ O2 consumption and CO2 production increased to compensate for increased WOB.
Ventilation is more difficult in the obese patient; OSA, BMI, and large neck circumference also can
make intubation challenging. A consistent approach with head elevation and preoxygenation can
increase apnea time significantly.
Importance of Denitrogenation
o FRC is lower in obesity, so they have less oxygen reserve
o VO2 (Oxygen Consumption) is greater in obesity due to increased WOB and metabolic need of
adipose tissue
o
Airway management
o Ventilator settings can be challenging, potentially with increasing CO2, decreasing oxygen
saturation (SaO2) and intolerable peak pressure in the airway
o Starting settings: PEEP 8-10 cm H20, TV 10-12 ml/kg of IDEAL BODY WEIGHT, and RR 12-14 /
min and I:E ratio may also need to be adjusted
o Reestablishing saturation after induction via recruitment maneuver (applying CPAP) 30 cm H20
for 30 seconds or 40 cm H2O for 40 s
o Volatile agents should be chosen based on solubility; desflurane was shown to be better than
isoflurane, propofol, or sevoflurane
• Emergence
o A semi-upright or lateral position is recommended for obese OSA patients at the end of surgery
for better oxygenation and pharyngeal airway maintenance
o In OSA patients with pharyngeal obstruction CPAP with O2 is also frequently necessary and
helps decrease the period for atelectasis and improves oxygenation status
• Local or regional anesthesia should be the primary anesthetic choice for obese patients undergoing
surgery, with general anesthesia used only when necessary
Know when to use TBW versus LBW for anesthetic medication dosing
•
•
•
•
Water soluble drugs doses based off of LBW; Vd is larger due to increased plasma volume
Fat soluble drugs doses off of TBW; Vd is much greater due to larger fat mass
General rule: Dose drugs based off of LBW, except maintenance Propofol, SCh, Precedex, Neostigmine
and Sugammadex, which are TBW
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
•
•
•
•
•
•
•
•
•
•
•
Obese patients have an increased amount of both fat and lean body weight compared with nonobese
patients
Increases in cardiac output and total blood volume, and changes in regional blood flow also affect the
peak plasma concentration, clearance, and elimination half-life of many anesthetic agents
The volume of distribution in obese individuals may be influenced by a variety of factors, including
increased blood volume and cardiac output, decreased total body water (fat contains less water than
other tissues) altered protein binding of drugs, and the lipid solubility of the drug being administered
Total blood volume is likely to be increased, which would tend to decrease the plasma concentration
achieved following an IV injection. However, fat has relatively low blood flow, so an increased dose of
drug calculated based on total body weight could result in excessive plasma concentration
both cardiac output and plasma volume are increased, and initially higher dose of drug may be
required for loading to attain peak plasma concentration. The most clinically useful approach is to
calculate the initial dose of drug to be injected into an obese patient based on lean body weigh rather
than total body weight
Lean body weight (LBW): the difference between TBW and fat mass and represents the highly vascular
portion of the body and is significantly correlated to cardiac output
o More highly correlated with cardiac output and drug clearance and should be used for initial
dosing
o LBW = men = 1.10x weight (kg) – 128( weight2 (kg)/ height2 (m)
o LBW = women = 1.07 x weight (kg) – 148 ( weight2 (kg)/ height2 (m)
Ideal body weight (IBW): the optimal weight associated with maximum life expectancy for a given
height. TBW >20% of IBW is defined as being obese. Fails to account for changes in body composition
associated with obesity
o IBW (men) = 50 + 2.3( height (in) – 60)
o IBW (women) = 45.5 + 2.3(height (in) – 60)
Hepain should be based on total body weight
Maintence of anesthesia is best managed with drugs with minimal potential for accumulation in
adipose tissue
Propofol, benzodiazepines, atracurium, cistracurium, and narcotics such as fentanyl are highly
lipophilic and accumulate in the fatty tissue when administered by infusion over a long period
o Remifentanil is the exception due to its rapid metabolism by plasma esterase, therefor has little
potential for accumulation in fat tissue, and is therefor favored over other narcotics
Hydrophilic substances such as muscle relaxants should be based on lean body weight because of their
peak plasma concentrations are independent of their volume of distribution, which is greatly increased
in obese patients
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
•
•
•
•
Patients with clinically severe obesity have a larger absolute succinylcholine requirement than normal
weight patients therefor to achieve neuromuscular blockade dosing should be based on total body
weight
Sugammadex may be a better agent than neostigmine for reverse and should. Be given based on lean
body weight
Fluid replacement should be based on lean body weight
Opioids should be based on lean body weight
Pharmacology for inhalation agents:
o Isoflurane is more lipophilic than sevoflurane of desflurane so is used less frequently in obese
patients
o Sevoflurane and desflurane have been advocated for use in obese patients because they are
least lipophilic and least soluble theoretically limiting their distribution to adipose tissue
§ Emergence with sevoflurane and desflurane is faster than that of isoflurane
o Volatile agents may be useful because of their bronchodilator properties and decrease hypoxic
pulmonary vasoconstriction
o Nitrous oxide should be avoided because of the need to keep a high fraction of inspired oxygen
concentration (FiO2) and its ability to distend the bowel and may worsen pulmonary
vasoconstriction
o
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
Hematopoietic & Lymphoid Disorders
Be able to differentiate anemia by both the pathophysiologic and morphologic classifications.
•
Normal physiology of RBC:
o Disc-shaped cells that are the oxygen carrying component of the blood
o Lack a nuclei at maturity (presence of one suggests a disease state)
o bi-concave shape results in flexibility in small capillaries
o hemoglobin is the more important substance in the erythrocyte
§ Hemoglobin A – two alpha subunits and two beta subunits
•
•
4 total alpha genes exist in each cell, because each cell has 2 chromosome 16’s.
2 alpha x 2 = 4 total alpha and 1 beta x 2 = 2 total beta
•
•
In the adult most Hb is made up of 2 alpha globin and 2 beta globin (HbA) chains
with minor components of HbF and HbA2
§ Heme: the actual oxygen-binding portion
• Located on each alpha and beta subunit (4 total)
• Each heme carries 1 O2 molecule via iron binding site (4 total O2)
o Half life ~120 days before being removed by the spleen into
§ Heme – further degraded into bilirubin that complexes with albumin in the blood
§ Globin – degraded into amino acids
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
Iron – carried in the blood as transferrin (iron +apo=transferrin protein = transferrin)
• Total iron binding capacity (TIBC) = measure of the blood’s capacity to bind Fe
• Fe is stored in the liver bound with protein as ferrin or in skeletal muscle with
myoglobin
• Overload is deposited to the liver and spleen
Erythrocytosis an elevated hemoglobin level
o Increase erythropoietin d/t living at altitude or tumors (especially renal tumors) can make
erythropoietin
o Polycythemia is an abnormality within the bone marrow itself
Anemia: abnormally low hemoglobin concentration the blood
o Adult female <12 g/dL : Adult male <13 g/dL
o Reduction in one of more of the major RBC entities: hemoglobin (Hb) concentration, Hct, and
RBC count
o Most important adverse effect of anemia is the reduction in arterial oxygen concentration and
the potential for decreased tissue oxygen delivery
§ Initial compensation is an increase in cardiac output this occurs via enhanced
sympathetic nervous system activity and decrease in blood viscosity that accompanies
anemia
§ A rightward shift of the oxyhemoglobin dissociation curve which facilitates the release
of oxygen from Hb to tissues followed bt redistribution of blood flow to the
myocardium, lungs, and brain
• Muscle and skin blood flow decrease resulting in pallor
• Blood flow to the kidneys decrease which stimulates erythropoietin to produce
more RBCs
• Fatigue and low exercise tolerance indicate the inability of cardiac output to
increase further to maintain adequate tissue oxygenation
Morphologic classifications are based on red cell shape and size
o Normal erythrocytes are uniform size and shape
o Mean corpuscular volume (MCV) near 90 fL (estimated volume in a single cell)
§ microcytic = Decreased MCV (small cells)
• attributed to abnormalities in hemoglobin production
o alterations in the number or type of hemoglobin molecules per cell
• common causes: iron deficiency, thalassemia’s
§ macrocytic = increased MCV (large cells)
• reflect either abnormal nuclear maturation or higher fraction of young, large red
cells
• common causes: folic acid deficiency, Vitamin B deficiency, Liver Disease, alcohol,
hypothyroidism, drugs (sulfonamides, zidovudine, antineoplastic agents),
myelodysplastic syndromes
• megaloblastic anemia – nuclei of maturing RBC is too large and young for
amount of HgB in the cytoplasm and is often result of vitamin deficiencies or
drugs interfering with DNA synthesis
§ normocytic = normal MCV (normal size)
• result from decreased RBC precursors in marrow, low levels or erythropoietin, or
chronic inflammatory diseases
§
•
•
•
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
§
§
•
common causes: aplastic anemia, anemia of chronic disease, chronic kidney
disease, hemolytic anemia, spherocytosis
• autoimmune inhibition is referred to as pure red cell aplasia
• can also result from decreased life span of cells that are produced
o autoimmune hemolytic anemias – antibodies or complement bind to red
cells and cause their destruction
o sickle cell anemia – abnormal hemoglobin polymerizes and obliterates
the usual resilience of the red cell
o hereditary spherocytosis or elliptocytosis defects in the erythrocyte
membrane affect their ability to squeeze through capillary membranes
poikilocytosis nonuniformity of cell shapes
anisocytosis nonuniformity of cell sizes
§
Pathophysiological classifications
o Acute or chronic blood loss
§ Iron deficiency anemia
§ Acute blood loss:
• Depends on the rate and amount of blood loss
• Shifting fluid from interstitial space results in hemodilution and a ↓ in
hematocrit
• Decreased oxygen to the tissues stimulates an increase in erythropoietin and
erythropoiesis
• Increased reticulocyte count (~7 days after blood loss)
§ Chronic blood loss
• Iron deficiency anemia results from depletion of iron reserves
• Iron is an essential component of hemoglobin synthesis and erythropoiesis
o Hemolytic anemia (Increased destruction)
§ Lower tissue oxygenation triggers renal erythropoietin release to stimulate growth of
erythroid elements and release of reticulocytes from the bone marrow
• Erythroid hyperplasia and reticulocytes are hallmarks of disease
§ Intravascular hemolysis
• A destruction in hematocrit by greater than 1% in 24 hours can only be
attributed to acute blood loss or intravascular hemolysis
• Lysis of cells in the circulation
• Mechanical injury (valves, thrombi), biochemical injury (complement fixation to
RBC), exogenous toxic factors (clostridial toxins)
§ Extravascular hemolysis
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
Increase in red cell destruction in the spleen and lever to due decrease red cell
deformity (reticuloendothelial system)
• sickle cell anemia, thalassemia, G6PDH deficiency
o Decreased RBC production
§ Aplastic anemia, anemia of chronic disease, anemia of chronic kidney disease,
myelodysplastic anemia
• my
o Most important adverse effect is a reduction of arterial oxygen concentration resulting in
decreased tissue oxygen delivery
Type of anemia
Iron deficiency
Morphologic
classification
Microcytic
Pathologic
classification
Acute or chronic blood
loss or intravascular
hemolysis
Depletion of iron
stores caused by
chronic blood loss
Sickle cell anemia
(sickle S hemoglobin)
normocytic
Extravascular hemolysis
of hemolytic anemia
Hereditary single
amino acid substation
in B-globin gene of HgB
molecule
Caused by substitution
of valine for glutamic
acid in the B-globin
subunit
Pathogenesis
Clinical manifestations
Most common form of anemia
Chronic blood loss, low dietary iron intake
(vegetarian), malabsorption (Celiac, h.
pylori, gastrectomy, gastric bypass),
intravascular hemolysis
Fatigue, weakness, SOB, pallor, ↑ HR to
↑ CO, benign cardiac murmurs, glossitis,
achlorhydria (absence of stomach acid),
pica, developmental delays in children,
low ferritin is diagnostic (<41)
Lack of iron lead to production of RBCs
with too little Hb
Treatment: ferrous iron salts
administered PO to replenish iron stores
and find and stop bleeding
Genetic mutation transforming hemoglobin
A (HgA into hemoglobin S (HgS)
Valine reside replaces glutamate at 6th
amino acid position in b-globin. HbS (sickle
hemoglobin) in a deoxygenated state
results in a conformational change that
exposes a hydrophobic region of the
molecule and distorts the red cell
(elongated, crescentic, or sickled in shape)
Initially reversible with reoxygenation
In states of severe deoxygenation the
hydrophobic regions aggregate causing
irreversible distortion of the erythrocyte
membrane, oxidative damage to the
membrane, impaired deformability, and
shorted life span (influx of calcium, loss of
potassium and water, damages membrane
skeleton)
Heterozygous or sickle cell trait – 40% is
HbS and remaineder is HbA
Homozygous or sick cell disease – all HgS
(asymptomatic until ~6 mo when shift
from HgF to HcS is complete)
-presents as end-organ damage
involving the bone marrow, spleen,
kidneys, CNS
Two major pathologic consequences:
Chronic moderately severe hemolytic
anemia produced by red cell membrane
damage and vascular obstructions
causing ischemic tissue damage and
pain crisis
Life span of cells is 20 days
Severity of hemolysis correlates to the
fraction of irreversibly sickled cells
where (vaso-occlusion does not)
Clinical manifestations: hand-foot
syndrome (most common presenting
syndrome in young children),
unremitting course punctuated by crisis,
acute chest syndrome, stroke,
proliferative retinopathy, aplastic crisis
(sudden decrease in RBC production),
sequestration crisis (RBC pool in the
spleen leading to splenomegaly and
chronic hemolysis and decreased
circulating blood volume), vasoocclusive crisis (sickled RBC clump at
small vessels causing tissue hypoxia,
pain, and infarction at bones, liver,
lungs, brain, spleen, and can lead to
rhabdomyolysis)
- kidney can demonstrate painless
hematuria and loss of concentrating
ability as an early feature then progress
to chronic renal failure in the 3rd or 4th
decade of life
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
-pulmonary : lung damage results from
chronic, persistent inflammation. Acute
chest syndrome a pneumonia like
complication is characterized by the
presence of new pulmonary infiltrate
involiving at least one entire lung
sefment plus at least one of the
following: chest pain, fever, tachypnea,
wheezing, or cough
Neurologic complications: stroke,
susually a result of arterial disease
rather than sickling,
Initiating events causing HgS to sickle
(avoid these)
- decrease in paO2
- decrease in pH
- dehydration
- cold, stress, exertion, and infection
Anesthesia considerations:
Preoperative Hct goal of 30%, risk of
complications are independent of the
anesthesia technique, increased
complications with tourniquets
Thalassemia
Microcytic
Extravascular hemolysis
of hemolytic anemia
inherited disorders
caused by mutations in
genes that decrease
the synthesis of alpha
or beta globin
An inherited defect in
globin chain synthesis
A-thalassemia is a result of deletions
involving one or more alpha-globin genes.
Severity of the disease is proportional to
the number of alpha-globin genes lose. All
4 alpha globin is lethal in utero. Loss of 3
alpha-globin cause relative excess of betaglobin or gamma-globin chains to for HbH
and Hb Bart which causes less membrane
damage than alpha-globin changes in Beta
thalassemia
Beta-Thalassemia has 2 subcategories:
B-thalassemia major – no beta globin
chains are produced
B-thalassemia minor/trait – reduced Bglobin synthesis. Can be asymptomatic or
mildly symptomatic. Mainly point
mutations cause defects in transcription,
splicing, or translation of Beta globin
mRNA. Defective synthesis of B-globin can
lead to anemia. Inadequate HbA formation
-> small, poorly hemoglobinized red cells
Sickle cell disease is associated with
perioperative complications whereas
sickle cell trait is not
B-thal and a-thal trait / heterozygous
(thalassemia minor)= asymptomatic /
little accumulation of the unaffected
globin.
B-thal major
Affected children exhibit growth
retardation, severe anemia requiring
regular blood transfusions, iron overload
leads to cardiac dysfunction,
Patients exhibit 3 defects that markedly
depress their O2 carrying capacity: 1)
ineffective erythropoiesis 2) hemolytic
anemia, 3) hypochromia with
microcytosis
Maximum erythropoietin release and
marrow erythroblasts respond by
increasing their unbalanced globin
synthesis and accumulating unpaired
globin chains aggregate and cause
membrane damage to RBCs
If damaged cells with altered
morphology escape into circulation
there is accelerated clearance
(hemolytic anemia) and reduced oxygen
carrying capacity resulting from the
lower Hb content
Ssx: bone marrow hyperplasia, frontal
bossing, maxillary overgrowth, ocerall
stunted growth, osteoporosis, and extramedullary hematopoiesis
(hepatomegaly) and hemolytic anemia
may produce splenomegaly with dypnea
and orthopenia which over time results
in congestive heart failure and
intellectural diability
treatment = stem-cell transplant
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
G6PDH deficiency
Normocytic
Extravascular hemolysis
of hemolytic anemia
Mutation of G6PDH
gene on X
chromosome
Genetic defect causes G6PDH deficiency
(enzyme required for glutathione (GSH)
production. Lack of GSH production causes
RBCs to be subjected to oxidative stress
(GSH is an antioxidant), older cells are most
vulnerable, infections or drugs can
increase oxidative stress and precipitate
RBC damage. The damaged RBCs are
destroyed in the spleen.
hemolysis is the result of the inability of a
G6PD-deficient RBC to protect itself from
oxidative damage
Common medications incriminatedantimalarials, sulfonamides, nitrofurantoin,
ASA, vit K derivatives
Classes:
I: <10% G6PD activity
II: 10% G6PD activity
III: 10-60% G6PD activity
And IV and V have increased G6PD activity
(no hemolysis)
Aplastic anemia
Normocytic
Decreased RBC
production
Multipotent myeloid
stem cells are
suppressed causing
bone marrow failure
and pancytopenia
Extrinsic – immune mediated suppression
of marrow progenitors (autoimmune
related attack by T-cells on bone marrow
stem cells)
Intrinsic – abnormality of stem cells
(drugs/chemicals/radiation damages stem
cells and inhibits stem cell proliferation and
differentiation)
Congenital aplastic anemia (Fanconi
anemia) is an autosomal recessive disorder
that progresses to acute leukemia –
associated with bone marrow failure,
physical defects, chromosomal
abnormalities, and predisposition to cancer
Acquired aplastic anemia is due to bone
marrow toxicity typically from drugs.
Anemia due to bone marrow damage is a
predictable side effect of chemotherapy
and high-energy radiation
B-thal intermedia
Anemia, regular blood transfusions are
not required, iron overload is rarely seen
- have symptoms that attribute to both
anemia and hepatosplenomegaly,
cardiomegaly, and skeletal changes
secondary to bone marrow expnansion
Clinical manifestations: dependent on
the amount of enzyme present
- hemolysis develops 2-3 days after drug
exposure or stress, hemoglobinemia,
hemoglobinuria
- Half life of erythrocytes with G6PD
deficiency is 60 days
Anesthetic considerations:
Avoidance of events that can precipitate
new or aggravate preexisting hemolysis:
infection, certain metabolic conditions
such as diabetic ketoacidosis, certain
drugs, and ingestion of fava beans
function of severity and acuity of
anemia. Invitro studies support
avoidance of medications that further
depress G6PDH = iso, sevo, reglan,
penicillin, methylene blue, vit K
and avoidance of drugs that increase
oxidative stress.
Propofol, fentanyl, and ketamine are
safe
Patients with methemoglobinemia and
G6PDH deficiency can have life
threatening effects of methylene blue.
Drugs that can induce
methemoglobinemia (lidocaine,
prilocaine, silver nitrate) should also be
avoided. Hyperthermia, acidosis,
hyperglycemia, and infection can
further precipitate hemolysis
Slowly progressive anemia, weakness,
pallor, dyspnea, thrombocytopenia
(petechiae and ecchymoses),
pancytopenia, absence of splenomegaly,
bone marrow is hypocellular
Transfusion may be necessary
preoperatively, severity of neutropenia
will affect the need for and choice of
antibiotic coverage. The use of
granulocyte colony stimulating factor
preoperatively my increase neutrophil
counts
Aplastic anemia severe, and irreversible
and has been associated with several drugs
(chloramphenicol)
Immunosuppression of stem cell growth
has been associated with viral hepatitis,
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
Anemia of chronic
disease
Normocytic
Decreased RBC
production
eptein-barr virus infection, HIV infection,
and rubella.
Most common form of anemia in
hospitalized patients
Thought to be from: trapping of iron in
macrophages (resulting in lower level of
circulating iron available for
hematopoiesis), a decrease in
erythropoietin concentrations resulting in a
decrease in bone marrow red cell
production, and a shorted RBC lifespan due
to increased macrophage activity
High levels of plasma hepcidin form
cytokines that block the transfer of iron to
erythroid precursors via downregulation of
ferroportin in macrophages
Chronic inflammation blunts erythropoietin
synthesis by the kidney lowering red blood
cell production by the bone marrow
Anemia of chronic
kidney disease
Myelodysplastic anemia
Pernicious Anemia
(folate and vitamin B12
deficiency anemia)
Normocytic
Macrocytic
Macrocytic
Decreased RBC
production d/t
decreaed
erythropoietin
production
Decreased RBC
production
Abnormal nuclear
maturation as a result
of clonal proliferation
in the bone marrow
producing preleukemic
states
Autoimmune attack on
gastric parietal cells
that produce intrinsic
factor
Chronic atrophic
gastritis (marked loss of
parietal cells,
infiltration of
lymphocytes and
plasma cells, leading to
megaloblastic changes
in mucosal cells)
Results from decreased erythropoietin
production (patients benefit from
erythropoiesis stimulating drugs)
Extensive infiltration of the marrow by
tumors or lesions (most common with
metastatic breast, lung, or prostate cancer)
Decreased serum iron levels, increased
iron storage and serum ferritin, normal
transferrin saturation, (IDA has low
transferrin saturation), low
erythropoietin levels
Markers of active inflammation may be
present such as elevated sedimentation
rate and C-reactive protein level
Treatment is cure of the underlying
disease and management with
administration of iron and
erythropoiesis0stimulating drugs (iron
alone should never be given to paitents
with ACD due to malignancy and
infection, since iron can worsen the
underlying diseases)
Avoid erythropoiesis stimulating drugs in
patients with cancer and during
treatment
Target Hgb 10-12 g/dL
Concurrent iron deficiency anemia
should also be investigated and treated
appropriately
-anemia
-thrombocytopenia
-leukoerythroblasts
-mild leukocytosis
Treatment is aimed at the underlying
cause
Development of autoantibodies that
- attack parietal cell membrane proteins
(H+ - K+ ATPase) leading to gastric atrophy
and loss of gastric acid
-intrinsic factor (IF) leading to loss of IF
- inflammatory response to immune
process
-block binding of vitamin B12 to intrinsic
factor
Vitamin B 12 and folic acid are important
cofactors in synthesis of DNA and myelin
metabolism
Lack of B-12 or folic acid leads to impaired
DNA synthesis and marrow precursors
appear much larger than normal and are
unable to complete cell division the RBC
cannot mature making them macrocytic
Vitamin B 12 deficiency causes a
methionine deficiency causing
demyelination and neurologic deficit
(numbness, tingling, etc)
-Non-specific signs (pallor, fatigue,
dyspnea)
-Mild jaundice
-Beefy, red, tongue
-Spinal cord disease (symmetric
numbness and tingling, burning of feet
or hands, unsteady gait and loss of
position sense) - peripheral neuropathy
due to degeneration of the lateral and
posterior columns of the spinal cord
resulting in symmetrical paresthesia’s
with loss of proprioceptive and vibratory
sensations, especially in the lower
extremities)
Increased risk of gastric carcinoma
Supportive diagnostic findings:
- low serum B12 levels
- normal or elevated folate levels
- moderate to severe macrocytic anemia
-leukopenia
-a dramatic reticulocyte response to
parental administration of B12 (but
neurologic manifestations often fail to
resolve)
-presence of serum antibodies
Sustained exposure to nitrous oxide can
produce an impairment of vitamin B12
activity
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
spherocytosis
Normocytic
Meroblastic anemia
Hemolytic anemia
Macrocytic
Normocytic
Liver Disease, alcohol,
hypothyroidism, drugs
(sulfonamides,
zidovudine,
antineoplastic agents),
Polycythemia
erythrocytosis
Macrocytic
Normocytic
Can be seen with alcoholic individuals
because of alcohol’s interference with
folate metabolism
Osmotic fragility and shortened
circulation half life
Can be clinically silent
May have very mild hemolytic anemia or
more deVere
Inherited autosomal
dominant pattern
Deficiency in membrane skeletal proteins
Hemolysis most often
caused by
hemoglobinopathies
and immune disorders
Premature lysis or accelerated destruction
of mature erythrocytes in circulation.
Hallmark to hemolytic anemias is
erythroid hyperplasia and reticulocytes
(>2%)
Increased reticulocytes, unconjugated
hyperbilirubinemia, increased LDH
levels, decreaed serum levels of
haptoglobin
Elevated hemoglobin
concentration
Relative: dehydration results in decreased
plasma volume and an increase in the HCT
/ Hgb concentration
Hct > 55-60% increases in whole blood
viscosity exponentially,
>60% can be life threatening
Absolute: increase in RBC mass
-primary – gene mutation can cause
autonomous proliferation of erythroid
progenitors
- secondary – increased erythropoietin
levels from hypoxia (altitude)
Be able to identify anesthesia considerations for the anemic patient.
•
•
•
•
Compensatory mechanisms:
o Increased erythropoietin
o Increased hematopoiesis
o Redistribution of blood from skin/renal to heart/brain
o Cardiac = ↑HR to ↑ CO
o Fatigue, weakness, dyspnea
o Tissue hypoxia – generally apparent with 40% blood volume
Preoperative evaluation
o CBC with differential
Minimize culprits that would further reduce oxygen delivery to the tissue
o Left-shift in the oxyhemoglobin dissociation curve
§ Left-shift = less O2 released to the tissues
§ Drug-induced decrease in cardiac output
§ Respiratory alkalosis from iatrogenic hyperventilation
§ Decreased body temperature
o CV depression
§ Anesthetic drugs and hypothermia can induce
§ May cause decreased tissue oxygen requirements
o Decrease in tissue oxygen delivery may be difficult to predict with anesthesia because of the
blunting of the sympathetic nervous system and cardiovascular response (increased cardiac
output) associated with acute normovolemic anemia
Consider efforts to minimize surgical blood loss
o Normovolemic hemodilution and intraoperative blood salvage
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
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•
Volatile anesthetics may be less soluble due to reduction in the lipid-rich RBCs
o Uptake of volatile inhalation anesthetics may be increased; however, the compensatory
increase in CO will make unlikely clinically detectable differences
Blood transfusion trigger
o Based on lost circulating blood volume, Hb level, ongoing surgical bleeding, and risk of end
organ damage
Be able to identify anesthesia considerations for the patient with sickle cell disease.
•
•
•
•
•
•
•
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Initiating events causing HgS to sickle (avoid these)
o decrease in paO2
o decrease in pH
o dehydration
o cold, stress, exertion, and infection
Anesthesia considerations:
o Preoperative Hct goal of 30%
o risk of complications are independent of the anesthesia technique
o increased complications with tourniquets
Sickle cell disease is associated with perioperative complications whereas sickle cell trait is not
Risk factors for complications include: advanced age, frequent and severe episodes of sickling,
evidence of end organ damage (low baseline oxygen saturation, elevated creatinine level, cardiac
dysfunction, history of stroke), and concurrent infection
Consider risks intrinsic to type of surgery
o Orthopedic procedures, hip surgery, and hip replacement in particular are associated with high
risk of complications including excessive blood loss and sickling
Goals of preoperative management
o Aggressive transfusion shows no benefit
o Pre-operative anemia corrected to target a Hct of 30% (all Hb types) with HbS levels below 5%
desirable for cardiac surgery
Goals:
o Avoiding dehydration, acidosis, and hypothermia do help reduce risk of perioperative sickling
events
o Use of occlusive orthopedic tourniquets is not contraindicated but has been shown to increase
complications
o Postoperative pain requires aggressive, typically multimodal, pain management (tolerance to
opioids)
o Regional anesthesia is not contraindicated and may offer an advantageous pain control
Acute chest syndrome may develop 2-3 days post operatively and requires treatment of hypoxemia,
pain, hypovolemia, anemia, likely infection, and possible venous thrombosis
Be familiar with anesthesia considerations for the patient with Hemophilia A and B.
•
•
Hemophilia A
Etiology
o Factor VIII deficiency
o X-linked recessive hereditary disorder
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
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•
•
•
•
•
Pathophysiology
o Inversion or deletion of a major portion of the X chromosome
o Missense mutation resulting in <1% factor VIII activity
o Clinical severity correlates with factor activity level
o Point mutation or minor deletion à milder disease
Clinical manifestations
o Levels <1% : Frequent spontaneous bleeding episodes in joints, muscles, and vital organs
o 1-5% activity level: Reduced symptoms in everyday life but at risk of hemorrhage for
surgery/trauma
o 6-30% activity: Often undiagnosed until adulthood
§ Risk for excessive bleeding during major surgical procedures
Anesthesia considerations
o Labs
§ Prolonged PTT
§ PT is normal
o Normalizing factor VIII
§ DDAVP 30-90 mins prior to surgery (Increases factor VIII 3-5x)
§ Factor VIII concentrate
• Consider antibody development with prior exposure
• Half-life is 12 hours in adults; children ~ 6 hours
§ FFP & cryoprecipitate?
• Know which clotting factors are present in FFP/Cryo.
Hemophilia B
Congenital factor IX deficiency
Clinical spectrum synonymous with hemophilia A
o Petechiae more commonly associated with hemophilia B
Anesthesia considerations
o Labs
§ Prolonged PTT
§ Normal PT
o Prophylaxis for minor surgery
§ Recombinant factor IX
§ Factor IX-prothrombin complex concentrate
• Caution: this contains active clotting factors à risk of thromboembolic events
§ Factor IX half life: 18-24 hours
• Repeat infusion of half the original dose q12-24 hours
Know the differences among platelet disorders (platelet function vs platelet count issue).
•
Disorders affecting platelet function
o Von Willebrand Disorder
§ Etiology – autosomal dominant disorder
• Most common inherited coagulation defect
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
Pathogenesis
• Subendothelial von Willebrand Factor (vWF) acts as a bridge between platelets
and subendothelial collagen à platelet adhesion
o vWF is manufactured by, and released from, endothelial injury
• Circulating vWF carries and stabilizes factor VIII
• In vWD, vWF is reduced or defective à decrease in factor VIII
• Defective platelet adhesion to subendothelial collagen
§ Types
• 1: quantitative defect in plasma vWF
• 2: qualitative defect in plasma vWF
• 3: absence of circulating vWF antigen and low levels of vwF activity and factor
VIII
§ Clinical manifestations
• Spontaneous, prolonged and excessive bleeding
o Prolonged bleeding time with normal platelet count
o Possible prolonged PTT secondary to decrease factor VIII levels
§ Anesthesia considerations
• Desmopressin à stimulates the release of vWF from endothelial cells
o 0.3 mcg/kg IV infusion for 10-20 minutes
o Short-lived effect
o Development of tachyphylaxis
• Cryoprecipitate
• Test your knowledge: Connect desmopressin with the types of vWD. Would this
therapy be effective for all types of vWD?
o Acquired abnormalities of platelet function
§ Causes
• Myeloproliferative disease
• Dysproteinemia
• Uremia
• Liver disease
• Inhibition by medications
Platelet (count) disorders
o Thrombocytosis
§ Too many platelets
• Occurs in recovery from iron deficiency anemia, secondary to inflammatory
response and myeloproliferative disorders
• Essential thrombocythemia (unknown etiology)
o Thrombocytopenia
§ A count less than 150,000 platelets/mL
§ Etiology
• Decreased production of platelets
o Diseases involving bone marrow
o Thrombopoietin production by liver is impaired (cirrhosis)
o Vitamin B12 and folate deficiencies
• Increased platelet destruction
§
•
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
o Immunologically mediated
o Hypersplenism
o Platelet consumption from ongoing clotting
o Mechanical injury
• Infection/radiation/chemotherapy
• Anesthesia considerations
o Minor surgery : Platelet count 20,000-30,000/mm3 may be adequate
o Major surgery 50,000/mm3
o Neurosurgical, eye and neuraxial procedures ~100,000/mm3
o How much should each unit of platelets increase their value?
o Heparin- induced thrombocytopenia
§ Type 1 (nonimmune HIT)
• Modest decrement in platelet count often observed during the first day of
treatment with full-dose unfractionated heparin
o Heparin passively binds to platelets shortening the life-span
• Transient and clinically insignificant
§ Type 2 (immune-mediated HIT)
• Early onset HIT vs delayed-onset HIT
o Early onset develops within 3 months after exposure to heparin; Delayed
onset appears after heparin is discontinued.
• Diagnosis 4 T’s system
o Thrombocytopenia
o Timing of platelet reduction
o Presence of thrombosis
o Presence of other causes of thrombocytopenia
• Epidemiology
o Occurs in 17% of persons receiving heparin and 8% of those treated with
LMWH
o The incidence of type II HIT varies with the type and dose of heparin and
the duration of therapy.
• Pathogenesis
o Heparin binds to circulating platelet factor 4 (PF4) à hapten
o Antibodies form to heparin-platelet factor 4 complex à bind to platelet
receptors à induce platelet activation and aggregation
o Further increase in heparin-platelet factor 4 complex à procoagulant
state
o Complex also binds to endothelial cells à stimulating thrombin
production à ↑ clearance of platelets by the spleen (thrombocytopenia)
and venous/arterial thrombus formation à potential for end organ
damage
• Clinical manifestations
o Low platelet count
o Ecchymoses
o Petechiae
o Epistaxis
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
o Prolonged bleeding time when platelet counts fall below 90,000
o Normal PT and PTT
o Paradoxical clotting à thrombosis
• Anesthesia considerations
o Prophylactic platelet transfusion avoided in HIT type 2 à increases the
risk of thrombosis
o Stop offending drug
o Consider corticosteroids
o CABG – may need bivalirudin
Be able to differentiate lymphoid and myeloid neoplasms.
•
•
Leukopenia
o Types
§ Neutropenia/agranulocytosis
• ↓ number of circulating granulocytes
§ Lymphopenia
• Associated with rare congenital immunodeficiency diseases (Ex: HIV), treatment
with high-dose corticosteroids
o Pathogenesis
§ Decrease in neutrophil production
• Caused by marrow hypoplasia (aplastic anemia or chemotherapy medications)
• Extensive replacement of bone marrow by a tumor
§ Increase in granulocyte destruction
• Medication induced
• Infection results in increased utilization
• Sequestration and destruction in the spleen
o Clinical manifestations
§ Initial symptoms: Malaise, chills, fever
§ Oral cavity lesions
§ Gingiva
§ Floor of the mouth
§ Buccal mucosa
§ Pharynx
Leukocytosis
o Reactive leukocytosis
§ An increase in the number of WBC in the blood in response to an inflammatory state
§ Causes of leukocytosis
• (Kumar - table 12.6- There is no need to memorize this table. The takeaway message is
that leukocytosis is realtively nonspecific and is classified according to the cell series
affected.)
o Infectious mononucleosis
§ An acute, self-limiting disease caused by Epstein-Barr virus (EBV)
§ Usually seen in adolescents and young adults
§ Pathogenesis
• Infection begins in the oropharyngeal epithelial cells à spreads to underlying
lymphoid tissue (tonsils and adenoids) à infected B cells
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
•
•
Ø Infection can lead to viral replication and release of virions
Ø Persists in latent form
§ Once activated the cells proliferate and produce anti-sheep red
cell antibodies (diagnostic test)
• Cytotoxic CD8+ T cells control proliferation of EBV-Positive B cells
§ Clinical manifestations
• Fever, sore throat, generalized lymphadenitis
• Lymphocytosis of activated CD8+ T cells
• Hepatic dysfunction
§ Diagnosis
• The presence of atypical lymphocytes in peripheral blood
• Positive Monospot test
• Rising titer of antibodies specific for EBV antigens
Ø Impaired T-cell immunity
Neoplastic Proliferation of WBCs
lymphomas and leukemias
o Lymphomas
§ Tumors that involve lymph tissue
o Leukemias
§ Tumors involving bone marrow
o General characteristics
§ Uncontrolled proliferation and accumulation of a single progenitor cell
§ Decreased proliferation, production and function of normal hematopoietic cells
• Within bone marrow, gradual stem cell suppression
o Acute lymphomas and leukemias
§ Undifferentiated or immature cells
• Usually, a blast cell from myeloid or lymphoid lines
• Cells are not functional
§ Cell differentiation is blocked
§ Onset of disease is abrupt and rapid – poor prognosis
o Chronic lymphomas and leukemias
§ Cells differentiated, more mature, somewhat functional but do not function normally
§ Slow onset and long duration
leukemias
o General clinical manifestations
§ ↑ WBC (15-150,000/mm3) from count of malignant cells
§ Neutropenia
• Stem cell suppression
• Prone to infections
• Fever and tachycardia
§ Anemia
• Stem cell suppression
• Also secondary to TNF-α and other cytokines which ↓ RBC production
§ Thrombocytopenia
• Stem cell suppression
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
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• Bleeding
§ Bone pain from pressure in marrow
§ Splenomegaly, hepatomegaly, lymphadenopathy
§ Symptoms - fatigue, fever, night sweats and weight loss
lymphoid neoplasms
o Resemble some normal stage of lymphocyte differentiation
o Diagnosis is based on what cells comprise the tumor not where it resides
o General clinical manifestations
§ Splenomegaly, hepatomegaly, lymphadenopathy
§ Obstructed lymph drainage leads to edema
o Constitutional symptoms
§ Fatigue, fever, night sweats, weight loss
§ From increased number of metabolically active cells and release of cytokines (IL-1 and
TNF-α)
o Susceptibility to infection and immune disorders
§ Breakdown of tolerance to self antigen
§ Lymphocytes are dysfunctional
o Lymphoid neoplasms
§ Hodgkin Lymphomas
§ Non-Hodgkin Lymphomas
§ Multiple Myeloma
§ Lymphocytic/lymphoblastic Leukemia
Hodgkin Lymphoma
o 10% of all lymphomas
o Peak incidence
§ 15-34 years of age
Ø 80 years of age
o Etiology
§ EBV infection
§ Immunosuppressed state (status post transplant or HIV)
o A neoplasm arising from germinal center B cells (B-cell zones within lymph nodes)
o Diagnosis: lymph node biopsy
o Pathogenesis
§ Integration of EBV genome is identical in RS cells
§ Mutant B cell growth arises in a single node and spreads characteristically to
anatomically contiguous nodes
§ Initial lymph node involvement typically is above the level of the diaphragm
o Clinical manifestations
§ Predictable, painless locations of lymphadenopathy
• Neck and anterior mediastinum
§ Pruritus, night sweats, and unexplained weight loss
§ Moderately severe anemia
§ Neuropathy, spinal cord compression secondary to tumor growth
§ Presence of Reed-Sternberg (RS) giant cells
§ Bone marrow and CNS involvement is rare
o 20-year survival rate is 90%
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
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Non-hodgkin lymphoma
o Tumors composed of neoplastic lymphoid cells (non-RS cells) that spread throughout the body
including the bone marrow
o Epidemiology
§ Usually found in persons older than 50 years of age
§ Incidence is 6-8%, men > women
o Etiology
§ HIV/AIDS, EBV, immunosuppression, hepatitis C, occupational exposure to herbicides
and chemicals
o Subtypes origin
§ B-cell, T-cell, NK-cell origin
o Pathogenesis
§ Genetic mutation during development or differentiation
§ Diagnosis and classification require tests to determine lineage and maturity
§ Tissue site and manifestation of disease are dependent on what cell gene was
transformed
o Clinical manifestations
§ Adenopathy and pancytopenia
§ Widely disseminated at the time of diagnosis
§ Treatment and prognosis is dependent on cell type
§
Multiple myeloma (Plasma Cell myeloma)
o Poorly controlled growth of a single clone of plasma B cells that produce a monoclonal
immunoglobulin called the M protein
o Epidemiology
§ Median age at diagnosis 69 years old
§ ↑ In people of African origin
o Pathogenesis
§ Myeloma plasma cells accumulate in bone marrow
• Adhesion molecules that are attracted to bone marrow
• IL-6 (from fibroblasts and macrophages) à neoplastic plasma cells to proliferate
§ Myeloma plasma cells produce
• Excessive numbers of single type of immunoglobulin (M protein)
Ø Usually IgG (60%) or IgA (20-25%)
Ø Results in decreased production of normal immunoglobulins
• Defective light chain (κ or λ) only immunoglobulin (15-20%)
Ø Small thus are excreted in the urine as Bence-Jones proteins
Ø Toxic to renal tubular structures
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
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Osteoclast-activating factors à proliferation and activation of osteoclasts à
bone destruction and re-absorption
Ø Myeloma cells replace normal marrow
o Clinical manifestations
§ Bone reabsorption leads to
• Bone pain or fractures
• Impaired ventilation
• Hypercalcemia
Ø Hypercalcemia symptoms - nausea, fatigue, confusion, and polyuria
§ Anemia, thrombocytopenia, neutropenia
§ Renal failure from Bence-Jones proteinuria
§ Recurrent bacterial infections
§ Spinal cord compression due to extramedullary plasmacytomas
• 10% of patients
• Urgent decompressive laminectomy
Lymphocytic/lymphoblastic leukemia
o Leukemia is a result of the uncontrolled production of leukocytes in response to cancerous
mutations of lymphogenous or myelogenous cells
§ Cells begin to invade bone marrow à bone marrow failure
o Lymphocytic leukemia begins in the lymph nodes
o Myeloid leukemias begin in the bone marrow
o Classifications
§ Cell types
• Myeloid
• Lymphoid
§ State of maturity of leukemia cells
• Immature (-blastic)
• Well-differentiated (-cytic)
§ Time course
• Acute: immature cells, rapid course in untreated patients
• Chronic: initially well-differentiated cells and relatively indolent course
o Acute lymphoblastic leukemia (ALL)
§ Epidemiology
• Primary seen in children, adolescents and young adults; Most common cancer in
children
• 3x more common in Caucasians then African Americans
• Hispanics have the highest incidence of any ethnic group
§ Pathogenesis
• Pre-B or pre-T cell neoplasms
Ø 85% are immature B or pre-B neoplasms
§ express ALL antigen
Ø Less commonly are from pre-T cells
• Chromosomal aberrations that lead to dysregulation and abnormal function of
transcription factors required for B or T-cell differentiation
• Pre-B cell involvement
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
•
Ø Overproduction and continuous multiplication of undifferentiated Blymphoblasts within the bone marrow
Ø Ejected into the blood where they accumulate
Ø Infiltrate liver, spleen, and lymph nodes
• If a pre-T cell has already migrated to the thymus, overproduction and
continuous multiplication of undifferentiated T-lymphoblasts within the thymus
§ Clinical manifestations
• Aggressive disease – present within weeks of symptoms
• Bone marrow depression – pancytopenia
Ø Fatigue, infection, bleeding
• Bone pain due to infiltration
• Lymphadenopathy, splenomegaly, hepatomegaly
• CNS symptoms as a result of meningeal spread
Ø Headache, vomiting, nerve palsies
• Bone marrow: high number of lymphoid blast cells
o Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma
§ Etiology
• Genetic mutation
• No link to radiation, chemicals, or viruses
§ Epidemiology
• Most common leukemia in adults; median age at diagnosis is 71
• Men > women
§ Pathogenesis
• Neoplasm of mature B-cells
• Unable to differentiate into plasma cells to produce immunoglobulins
• 15% of patients develop auto-antibodies against RBCs and platelets
• Progressive accumulation of lymphocytosis and lymphocytic infiltrates in the
bone marrow
§ Clinical manifestations
• Slow progression with nonspecific symptoms
• Hypogammaglobulinemia à ↑ susceptibility to bacterial infections
Ø Due to suppression of normal B cell function
• Lymph node enlargement
Ø Obstruction of the ureters
• Less commonly
Ø Autoimmune hemolytic anemia and hypersplenism
§ Corticosteroids may be useful
§ May require a splenectomy
Ø Thrombocytopenia
M y e l o i d n e o p l a s m s : Acute Myelogenous Leukemia (AML) & Chronic Myelogenous Leukemia
(CML)
o Myeloid neoplasms
§ Share a common hematopoietic stem cell origin
o Acute myelogenous leukemia (AML)
§ Etiology
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NURA 809: Advanced Pathophysiology Module 1 Objectives 2022
• Toxins, exposure to radiation and chemotherapy
• Chromosomal mutations
• Myelodysplastic syndrome
§ Epidemiology
• Adults; median age 67 years old
§ Pathogenesis
• Abnormal proliferation of myeloid stem cells or myeloid precursor cells that
produce granulocytes, monocytes, erythrocytes and platelets
• Arrested cellular differentiation
• These cells are blocked at an early stage of myeloid cell development leading to
the accumulation of blasts (immature myeloid cells) in the marrow à replace the
normal blood elements.
§ Clinical manifestations
• Diverse and nonspecific symptoms
• 1/3 of patients present with a serious life-threatening infections (pseudomonas)
• DOE common due to anemia
• Fatigue, bleeding gums, epistaxis, pallor or headache
§ Diagnosis
• Bone marrow smear à greater than 20% early myeloid cells
o Chronic myelogenous leukemia (CML)
§ Etiology
• Philadelphia chromosome
Ø Distinguishing feature is the presence of a chimeric BCR-ABL gene derived
from portions of BCR gene on chromosome 22 and ABL gene on
chromosome 9
§ Epidemiology
• Adults between 25-60 years of age; Peak incidence 4-5th decade of life
§ Pathogenesis
§ Neoplasm involving immature granulocytes
• BRC-ABL gene does not inhibit differentiation à relatively normal blood cells,
particularly granulocytes and platelets
§ Clinical manifestations:
• Three stages: Prolonged dormant phase (asymptomatic) à accelerated phase
à blast crisis
• Splenomegaly
• Hyperuricemia and hypocalcemia
• Hyperleukocytosis (>100,000 cells/mm3) > abnormal granulocytes
• Vascular occlusion secondary to high leukocyte count
• ↑ hematopoiesis – extramedullary hematopoiesis
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