Assessing and Managing Sedation
in the Intensive Care and the
Perioperative Settings
SEDATION Curriculum
Learning Objectives
• Manage adult patients who need sedation and
analgesia while receiving ventilator support according
to current standards and guidelines
• Use validated scales for sedation, pain, agitation, and
delirium in the management of these critically ill
patients
• Assess recent clinical findings in sedation and
analgesia management and incorporate them into the
management of patients in the acute care,
procedural, and surgical sedation settings
Desirable Properties for Sedatives
in Neurological Surgery
•
•
•
•
Preservation of intracranial hemodynamics
Hemodynamic stability
Noninterference with neurophysiologic monitoring
Cooperative sedation (for functional
neurosurgery)
• Controllability (rapid onset and offset of effect)
• Neuroprotection
• Antinociception
Potential Drawbacks of Sedative
and Analgesic Therapy
•
•
•
•
Oversedation
Impede assessment of neurologic function
Increase risk for delirium
Numerous agent-specific adverse events
Kollef MH, et al. Chest. 1998;114:541-548.
Pandharipande PP, et al. Anesthesiology. 2006;104:21-26.
Sedation in Volunteers
Regional and Global CBF
• 9 volunteers were infused with a 1 mcg/kg IV
loading dose of dexmedetomidine, followed by
an infusion of 0.2 mcg/kg/h and 0.6 mcg/kg/h
• Measured hemodynamics and CBF (via PET
scan)
Prielipp RC, et al. Anesth Analg. 2002;95:1052-1059.
Cerebral Blood Flow
Baseline
Low Infusion
High Infusion
30 min posttermination
• Dexmedetomidine
infusion at 2 doses
• Both low and high doses
– Reduced global CBF by
one third
– Decreased mean
systemic BP, HR, and CO
15% to 20%
– Increased PaCO2 no
more than 5 mm Hg
Note: Color intensity correlates with CBF
Prielipp RC, et al. Anesth Analg. 2002;95:1052-1059.
• CBF reduced during
infusion
• Decreased CBF
persisted at least 30
minutes
Effects of Treatment on
Hemodynamic Variables
Baseline
DEX load
(20 min)
LOW
DEX
HIGH
DEX
DEX off
(30 min)
9
9
9
9
5
CO (L/min)
7.3
6.1*
6.3*
5.9*
6.0*
MAP (mm Hg)
92
91
79*
81*
77*
HR (bpm)
73
60*
65
62*
62*
7.39
NA
7.35*
7.35*
7.36*
PaCO2 (mm Hg)
37
NA
42*
42*
39
PaO2 (mm Hg)
96
NA
98
96
98
[DEX] (pg/mL)
0.0
NA
466*
628*
380*
Global CBF
(mL · 100 g−1 · min−1)
90.5
NA
63.9*
60.6*
63.4*
Variable
n
pH
* P < 0.05, compared with baseline
Prielipp RC, et al. Anesth Analg. 2002;95:1052-1059.
Effect of Sedative on Global CBF
Global
CBF
Treatment
CBF
CBF
P value
(mL · 100 g−1 · min−1)
(95% CI)
(vs baseline)
Baseline
91
(72–114)
DEX-LOW
64
(51–81)
0.0002
DEX-HIGH
61
(48–76)
0.0006
DEX-OFF
63
(49–83)
0.0120
Prielipp RC, et al. Anesth Analg. 2002;95:1052-1059.
Cerebral Blood Flow Velocity, Cerebral Metabolic
Rate, and Carbon Dioxide Response
in Normal Humans
• Hypothesis: dexmedetomidine would reduce the
CBF/CMR ratio
• Middle cerebral artery velocity was recorded
continuously in 6 volunteers
• CBFV and CMR were measured at 6 intervals
before, during, and after DEX administration
Drummond JC, et al. Anesthesiology. 2008;108:225-232.
CBFV and CMRe
Drummond JC, et al. Anesthesiology. 2008;108:225-232.
Sedation Did Not Decrease
CBFV/CMR Ratio
• The expected decrease in CBFV was offset by
an unanticipated decrease in CMR, leaving
CBFV/CMR unchanged
• Significant reduction in the slope of the
PaCO2–CBFV relation during dex
administration
• Conclusion: dex should be further evaluated in
patients with neurologic injury
Drummond JC, et al. Anesthesiology. 2008;108:225-232.
Brain Oxygenation Maintained in
Neurovascular Surgery Patients
Small Case Series
• N = 5 patients
• General anesthesia
• Sufentanil
• Sevoflurane
• N2O
• Dex at time = 0
*P < 0.04 from
baseline
Drummond JC, et al. J Neurosurg Anesthesiol. 2010;22(4):336-341.
Intracranial Surgery
Need for Sedation and
Analgesia in Neurosurgical Patients
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•
•
•
•
Prevent pain and anxiety
Decrease oxygen consumption
Decrease the stress response
Patient-ventilator synchrony
Avoid adverse neurocognitive sequelae
– Depression, PTSD
Rotondi AJ, et al. Crit Care Med. 2002;30:746-752.
Weinert C. Curr Opin in Crit Care. 2005;11:376-380.
Kress JP, et al. Am J Respir Crit Care Med. 1996;153:1012-1018.
Double-Blind Randomized Controlled Trial:
Intracranial Tumor Surgery
• 54 patients scheduled for elective surgery of
supratentorial brain tumor were randomized
– Placebo
– Dex, target plasma conc = 0.2 ng/mL
– Dex, target plasma conc = 0.4 ng/mL
• Dex groups received fentanyl 2 mcg/kg at
induction and before the start of the operation;
placebo group received 4 mcg/kg
• Anesthesia maintained with NO2 in O2 and
isoflurane
Tanskanen PE, et al. Br J Anaesth. 2006;97(5):658-665.
Hemodynamics
Maximum increases from baseline
**P
< 0.01, DEX-0.4 vs DEX-0.2 and placebo
##P < 0.01, DEX-0.2 and DEX-0.4 vs placebo
Tanskanen PE, et al. Br J Anaesth. 2006;97(5):658-665.
Hemodynamics
Intraoperative cardiovascular variability
Dex increased median percentage of time points with SD and HR
within 20% of comparison values
Tanskanen PE, et al. Br J Anaesth. 2006;97(5):658-665.
Randomized Controlled Trial of Sedation
in IC Tumor Surgery
• Dex infusion decreased hemodynamic responses to noxious
stimuli and attenuated the emergence from anesthesia
– Decreased the immediate hemodynamic response
– Decreased the time to removal of the tracheal tube
• However, the need to treat hypertension or tachycardia was
similar in all groups
• No difference between the groups in the occurrence of
bradycardia or hypotension
• At 2 hours after extubation, there was no difference in the
Hudes class or subjective sedation score between the groups
Tanskanen PE, et al. Br J Anaesth. 2006;97(5):658-665.
Hemodynamics During Craniotomy
• Double-blind, placebo-controlled study in patients
undergoing intracranial surgery
• Comparison of patients receiving either sevofluraneopioid-placebo anesthesia (n = 28) or sevofluraneopioid-dexmedetomidine anesthesia (n = 28)
• Data collected:
– Hemodynamic variables – systolic blood pressure (SBP)
and heart rate (HR)
– Administration of sevoflurane, opioids, and/or
antihypertensive agents intraoperatively
– Time spent in PACU and administration of opioids and/or
antihypertensive agents postoperatively
Bekker A, et al. Anesth Analg. 2008;107:1340-1347.
Hemodynamics During Craniotomy
No increase of hypotensive episodes or bradycardia
Placebo (n = 28)
Dexmedetomidine (n = 28)
Median (IQR)
Median (IQR)
> 130 mmHg
35 (10-101)
9 (1-49)‡
< 90 mmHg
27 (8-58)
48 (10-96)
> 90 bpm
12 (0-59)
8 (0-26)
< 50 bpm
0 (0-2)
0 (0-4)
Mean (SD)
Mean (SD)
SBP (mmHg)
106.5 (9.9)
102.2 (9.4)
HR (bpm)
74.6 (13.0)
67.9 (1.7)‡
AUCSBP (mmHg×min/hr)
AUCHR (beats×min/hr)
Intraoperative Average
‡P
< 0.05
Bekker A, et al. Anesth Analg. 2008;107:1340-1347.
Hemodynamics During Craniotomy
Placebo (n = 28)
Dexmedetomidine (n = 28)
1.16 (0.38)
1.00 (0.37)
Fentanyl, μg/kg
2.6 (1.9)
1.9 (1.0)
Remifentanil, μg/kg
27 (13)
19(11)*
Any BP med, n (%)
24 (86%)
12 (43%)†
PACU duration (min)
130 (27)
91 (17)‡
Times SBP > 130 mmHg
2.5 (2.0)
1.25 (1.55)*
Any analgesic, n (%)
18 (64%)
15 (54%)
Any BP med, n (%)
14 (50%)
10 (36%)
Intraoperative Drugs
Sevoflurane, mean (%ET)
Postoperative Measures
*P
< 0.05 compared with placebo
†P = 0.0008 compared with placebo
‡P < 0.0001 compared with placebo
Bekker A, et al. Anesth Analg. 2008;107:1340-1347.
NeurolCU
Managing Traumatic Brain Injury
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•
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•
•
•
Monitor ICP
Diagnosis
Urgent surgery when indicated
Blood pressure management
Hyperosmolar therapy (mannitol, hypertonic saline)
Sedation/analgesia
Nutrition
DVT prophylaxis
Prevention of seizure
Saiki RL. Crit Care Nurs Clin North Am. 2009;21:549-559.
Sedation/Analgesia for
Traumatic Brain Injury
Goal: reduce ICP by decreasing pain, agitation
Agent
Advantages
Considerations
Propofol
• Short acting
• Reduces cerebral
metabolism, O2
consumption
• Improves ICP after 3d
• Propofol infusion syndrome
Barbiturates
• Reduce ICP
• Neuroprotection
• Interfere with neuro exam
• Hypotension, reduced CBF
• OCs not improved with severe TBI
Saiki RL. Crit Care Nurs Clin North Am. 2009;21:549-559.
Traumatic Brain Injury with Reduced PbtO2
Medical Interventions
Bohman LE, et al. Neurocrit Care. 2011;14:361-369.
Traumatic Brain Injury with Reduced PbtO2
Response Rate/
Overall Patient Response Rate
Effectiveness of Interventions
Benefit of PbtO2 not proven
Bohman LE, et al. Neurocrit Care. 2011;14:361-369.
Monitoring ICP After TBI
• Retrospective analysis
• 246 TBI patients
• Classify ICP profiles by
time to peak
• Correlate with
outcomes
Bremmer R, et al. Neurocrit Care. 2010;12:362-368.
1-2 d peak
3-5 d peak
>5 d peak
Monitoring ICP After TBI
Bremmer R, et al. Neurocrit Care. 2010;12:362-368.
Awake Craniotomy
Functional Neurosurgery
Awake Craniotomy Procedures
Bilotta F, et al. Curr Opin Anaesthesiol. 2009;22(5):560-565.
Characteristics of Cooperative Sedation
• Patients easily transition from sleep to wakefulness
and task performance when aroused
• Patients can resume rest when not stimulated
• Most useful during procedures in which
communication with the patient must be maintained,
facilitates patient participation in therapeutic
maneuvers
• Reduces risk of drug-induced complications
Bekker A, et al. Neurosurgery. 2005;57(1 Suppl):1-10.
Current Sedatives for
Awake Craniotomy
Bonhomme V, et al. Eur J Anaesthesiol. 2009;26(11):906-912.
Asleep-Awake-Asleep Overview
Anesthesia
Surgical Preparation
Cooperative Sedation
Eloquent Area Mapping
Surgery
Anesthesia
Surgical Closure
Sedation During Awake Craniotomy
Is Dex Compatible With Neurocognitive Testing?
Patient Number
Indication
Dex Load, μg/kg
Bekker 2001
Bustillo 2002
Lotto 2003
Ard 2003
Ard 2005
1
5
11
2
17
Neoplasm
AVM
Tumor, epilepsy,
aneurysm
Pediatric epilepsy
Tumor, epilepsy
1
0 or 1
1
0.5
0.81
3.4
1.6
0.2–0.7
0.6
2.8
1
Mean Dex Dose, μg/kg
Dex Infusion, μg/kg.h
0.4, 0.2, 0.1
Mean MDZ, mg
Mean Fentanyl, μg
Other Anesthesia
Cognitive Test
Test successful?
100
160
Prop, N2O, sevo
(flumazenil)
Language
1/1
0.5, 0.2, 0.1
0.1–0.4
1.7 (in 6 pts)
100
191 (in 16 pts)
Prop
Prop, N2O, sevo
Prop, N2O, sevo
Wada
Language
Language
Language
0/5
10/11
2/2
17/17
Bekker AY, et al. Anesth Analg. 2001;92(5):1251-1253.
Bustillo MA, et al. J Neurosurg Anesthesiol. 2002;14(3):209-212.
Lotto M, et al. Anesthesiology. 2003; 99: A356.
Ard J, et al. J Neurosurg Anesthesiol. 2003;15(3):263-266.
Ard JL, et al. Surg Neurol. 2005;63(2):114-116.
AVM = arteriovenous malformation
Prop = propofol
Sevo = sevoflurane
Implanting DBS for PD
• Sedation is demanding
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–
–
–
Recordings of movement-related neurons
Preservation of PD symptoms for DBS localization
Patient cooperation
Halo restricts movement, respiratory depression problematic
• GABAergic sedatives (MDZ, propofol) not useful
– Ameliorate tremor and rigidity (precludes mapping & testing)
– Impair consciousness
– May cause respiratory depression
Rozet I, et al. Anesth Analg. 2006;103(5):1224-1228.
Implanting DBS for PD
• Retrospective study with dexmedetomidine
– Control (no sedative)
n = 8 patients
– Dex (0.1-0.3 mcg/kg.h, more to goal [OAA/S = 4])
n = 11 patients
• Results
– MER unimpaired by dex
– Surgical time shorter with dex (4 vs 6 h, P = 0.05)
– Less intraoperative use of antihypertensives (100% vs 54%, P = 0.048)
– Dex preserved clinical signs of PD
• Tremor
• Rigidity
• Bradykinesia
• Study limitations
– Small
– Observational
– Only perioperative outcomes presented
Rozet I, et al. Anesth Analg. 2006;103(5):1224-1228.
Implanting DBS (2)
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•
•
•
Retrospective analysis of 258 procedures (250 patients)
Patients with motor disorders, 68% PD
Propofol most common sedative, 91%
Propofol used almost exclusively in the first 30 to 45 minutes to
facilitate head-frame placement
Khatib R, et al. J Neurosurg Anesthesiol. 2008;20:36-40.
Conscious Sedation
for Glioma Resection?
• Retrospective cohort-matched study
• Initial and final surgery with propofol/sevoflurane
• Dex with prn midazolam during resection
Peruzzi P, et al. J Neurosurg. 2011;114(3):633-639.
Monitoring EEG in Patients with
Temporal Lobe Epilepsy
Oda Y, et al. Anesth Analg. 2007;105(5):1272-1277.
Talke P, et al. J Neurosurg Anesth. 2007;19(3):195-199.
Spinal Surgery/AFOI
Drugs for Fiberoptic Intubation
Agent
Class
Example
Advantages
Considerations
GABA
agonist
Benzodiazepine
Midazolam
• Quick onset
• Injection not painful
• Short duration
• Not analgesic
• Airway reflexes persist
GABA
agonist
Benzodiazepine
Propofol
• Quick onset
• Respiratory depression
• Unconsciousness
• Decreased bp, cardiac
output
• Increased HR
Opioid
Fentanyl
Remifentanil
• Analgesic
• Cough suppressive
• Respiratory depression
a2 Agonist
Dexmedetomidine
• Pt easily arousable
• Anxiolytic
• Analgesic
• No respir. depression
• Transient hypertension
• Hypotension
• Bradycardia
Summary courtesy of Pratik Pandharipande, MD.
Propofol vs Combined Sedation
in Flexible Bronchoscopy
• Randomized non-inferiority trial
• 200 diverse patients received propofol or
midazolam/hydrocodone
• 1o endpoints
– Mean lowest SaO2
– Readiness for discharge at 1h
• Result
– No difference in mean lowest SaO2
– Propofol group had
 Higher readiness for discharge score (P = 0.035)
 Less tachycardia
 Higher cough scores
• Conclusion: Propofol is a viable alternative to
midazolam/hydrocodone for FB
Stolz D, et al. Eur Respir J. 2009;34:1024-1030.
Dexmedetomidine Increases Comfort in AFOI
Double-blinded randomized trial
Midazolam +/- dexmedetomidine
Awake fiberoptic intubation (AFOI)
Patient comfort rated by 2 observers
Total Comfort Score (max = 35)
•
•
•
•
n = 24
n = 31
Preoxygenation
Introduction
of scope
Bergese SD, et al. J Clin Anesth. 2010;22(1):35-40.
Introduction of ET tube
Sedation for AFOI
Study Design 1
• Phase 3 multicenter study comparing Dex with placebo
(Pbo) in the sedation of nonintubated patients with
anticipated difficult-to-intubate airways who were
undergoing AFOI
• Patients randomized
– Dex 1 μg/kg loading dose (10 min) and 0.7 μg/kg/hr maintenance
infusion
– Pbo in normal saline
• After topical anesthesia (lidocaine) and a Ramsay
Sedation Scale (RSS) score ≥ 2 was achieved, nasal or
oral intubation using a flexible fiberoptic bronchoscope
was performed
Bergese SD, et al. Am J Ther. 2010;17(6):586-595.
Sedation for AFOI
Study Design 2
• MDZ was administered as required as rescue medication
for patients with a RSS score = 1 until target RSS score ≥
2
• Primary endpoint: percentage of patients requiring rescue
MDZ to achieve and/or maintain a target sedation level
(RSS score ≥ 2)
Bergese SD, et al. Am J Ther. 2010;17(6):586-595.
Sedation for AFOI
Results
• Significantly fewer patients in the Dex group required
rescue MDZ to achieve and/or maintain sedation
compared with the Pbo group
– 47.3% vs 86.0%, P < 0.001
• The total mean supplemental MDZ dose required was
significantly lower in Dex-treated patients than in Pbotreated patients
– 1.07 mg vs 2.85 mg, P < 0.001
• Blood pressure was the most often reported AE
– 27% of the Dex group had hypotension
– 28% of the placebo group had hypertension
Bergese SD, et al. Am J Ther. 2010;17(6):586-595.
Sedation for AFOI
MDZ Use
100
90
14%
53%
Patients (%)
80
86%
70
Did Not Require MDZ
60
Required MDZ
50
40
47%*
30
20
10
0
Mean MDZ
Dose
1.07 mg
% patients
receiving MDZ
and mean dose
both P < 0.001
Dexmedetomidine
(n = 55)
Bergese SD, et al. Am J Ther. 2010;17(6):586-595.
Mean MDZ
Dose
2.85 mg
Placebo
(n = 50)
Sedation for AFOI
Conclusions
• Compared to placebo, Dex reduced MDZ
requirement in patients with high-risk airways
undergoing AFOI
– Fewer Dex patients received MDZ
– Dex patients requiring MDZ received a lower mean
dose
• Dex is a viable choice for sedation of patients
requiring AFOI
Bergese SD, et al. Am J Ther. 2010;17(6):586-595.
SSEP Amplitude and MEP Voltage
SSEPs: posterior tibial nerve (P37)
median nerve (N20)
Bala E, et al. Anesthesiology. 2008;109(3):417-425.
MEPs: dorsal interossei
abductor hallucis longus
Median Nerve SSEPs Tracings
Case Report
Baseline
Left
Instrumentation/propofol
Closure/dex
Baseline
Right
Instrumentation/propofol
Closure/dex
Bloom M, et al. J Neurosurg Anesth. 2002;13(4):320-322.
Does Sedation Attenuate tceMEP?
•
•
•
•
Subjects
Procedure
Anesthesia/analgesia
Primary endpoint
44 patients with idiopathic scoliosis
Posterior spine fusion surgery
N2O, sevoflurane, fentanyl, MDZ, remifentanil
Amplitude of transcranial electric motorevoked potential (tceMEP)
• Treatment Groups
Mahmoud M, et al. Anesthesiology. 2010;112(6):1364-1373.
Does Sedation Attenuate tceMEP?
• 14/40 Dex subjects experienced reduction of tceMEP amplitude
(≥ 3/4 muscles affected)
– Mean time to recovery (≥ 70% of baseline) = 68 min
• Dex main effect significant in FDI and TA (P = 0.015 and 0.012)
• Propofol main effect not significant
Percent Change from Baseline in tceMEP Amplitude
Mahmoud M, et al. Anesthesiology. 2010;112(6):1364-1373.
Does Sedation Attenuate tceMEP?
• Attenuation of tceMEP varied with Dex dose
–
High and intermediate group 11/23 (48%)
–
Low group 2/17 (12%)
P < 0.025
• Increasing the target level of propofol from 2.5 to 5 μg/ml without
increasing the level of Dex had no significant effect on the amplitude of
the tceMEPs
• Propofol–Dex interaction was not significant
• Study limited by early termination, only loading phase analyzed
Conclusions
• Dex can be used as an adjunct to remifentanil-propofol total IV
anesthesia when tceMEP and SSEP monitoring is required
• Target plasma concentrations of 0.4 ng/ml Dex and 2.5 μg/ml propofol
seem to have minimal effect on tceMEP amplitude
Mahmoud M, et al. Anesthesiology. 2010;112(6):1364-1373.
Neurosurgery Summary
• Neurosurgery presents special challenges for
sedation
– Preserve cerebral hemodynamic stability
– Maintain patient consciousness for some procedures
• Oversedation presents risks
– Delirium
– Increased ICU LOS
– Lack of patient interaction during procedure
• Emerging combinations of anesthetic and sedative
compounds have attractive properties for addressing
these unique requirements