neuroprotection for surgery: is it possible?
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Neuroprotection for surgery: Is it possible?. Philip Bickler, MD, PhD Department of Anesthesia and Perioperative Care UCSF. Perioperative CNS dysfunction risk. Cardiopulmonary bypass: 4-6% stroke, 79-88% neuropsych. dys. 1 st week, 30-50% at 6 mo. (McKhann, Ann Thoracic Surg, 1997) - PowerPoint PPT PresentationTRANSCRIPT
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Neuroprotection for surgery: Is it possible?
Philip Bickler, MD, PhDDepartment of Anesthesia and Perioperative Care
UCSF
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Perioperative CNS dysfunction risk
• Cardiopulmonary bypass: 4-6% stroke, 79-88% neuropsych. dys. 1st week, 30-50% at 6 mo. (McKhann, Ann Thoracic Surg, 1997)
• Neurologic surgery: Aneurysm clipping 14% transient or permanent deficits
• Surgery (any type) in the elderly: High incidence of neuropsychiatric dysfunction.
Are special precautions indicated in these populations?
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Goals• Review evidence-based neuroprotection for:
– Cardiac surgery, including incidence of neurologic deficits– Perioperative stroke– Aneurysm surgery (cerebrovascular, aortic)
• Describe unique brain injury processes:– Excitotoxity, free radicals, inflammation, energy failure
and targets for intervention
• Propose an algorithm for neuroprotection:– Understand rationale for neurointensive care in the
perioperative period– Balance risks and uncertain benefits
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Ischemic brain injury: a devastating perioperative complication
• The majority of strokes in the surgical population are ischemic
• Patients with hypertension, atrial fibrillation, diabetes, recent MI are at highest risk
• Modifiable risk factors contribute greatly to perioperative stroke
Change what you can!
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Burst suppression for cardiac surgery?
Roach and McSPI, Anesthesiology, 1999– Propofol burst suppression did not improve neurologic
outcome
Nussmeier, Anesthesiology, 1986. Neuropsychiatric complications after cardiopulmonary bypass: cerebral protection by a barbiturate. 89 Patients, no temperature control, delayed awaking
Zaidan, Anesthesiology, 1991. Effect of thiopental on neurologic outcome following coronary artery bypass grafting. 300 patients, burst suppresion: No difference in outcome
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Is hypothermia/pump best for CABG?
• Cochrane Database Syst. Rev. 2001– No definitive advantage of hypothermia or
normothermia in review of 19 trials• JAMA 2002 287: 1405
– On-pump vs. no-pump CABG: No difference in cognitive deficits at 12 months.
Arrowsmith: Remacemide study in the UK: Stroke 1998Benefit with this glutamate antagonist?
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Beta-blockers and neurologic outcome
• Amory et al 2002 (J Cardiovasc Vasc, Anesth)– Betablockers given perioperatively were
associated with a better neurologic outcome afer cardiac surgery
• 3.9% of bata-blocker patients vs. 8.2% of controls had neurologic complications
• Study was retrospective
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Neuroprotection Trials: A Disappointing History
Stroke Center (www.strokecenter.org/trials-192 acute ischemic stroke trials -50 hemorrhagic stroke trials-250 stroke prevention/recovery trialsFailure of chemical neuroprotection?
Pharma: $$$ directed to R&D, clinical testing
NIH: $$$ for basic science, clinical trials
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~100 trials of chemical neuroprotection in stroke anti-excitotoxicity (calcium, glutamate, sodium channels) anti-free radical growth factors/trophic support energy support
Other strategies anti-embolism hypothermia
Successes: Only for thrombolytics
Summary of stroke trials as of January 2004:
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Iatrogenic embolic: air, plaque, thrombus, etc.
Iatrogenic non-embolic: pH or CO2 management, hyperthermia, hypotension
Embolic from atrial fibrillation, MI, vascular disease
Mechanisms of perioperative brain ischemia
Ischemic: retractor pressure, hypotension/hemorrhage, vasospasm, temporary clipping, elevated ICP
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How does ischemia injure neurons?
• Metabolic rate is unlikely the key to injury– Anesthetics that do little to CMRO2 (halothane) are no
better “protectants” than ones that reduce metabolism substantially (isoflurane).
• Even with suppression of metabolism, neurons run out of energy quickly
• Burst suppression may not equal neuroprotection: An active EEG with a barbiturate is just as protective as burst suppression.
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• Excitoxicity: The glutamate cascade
• Apoptotic (programmed) cell death
• Free radical generation and injury
• Inflammation
• Chronic processes: impaired neurogenesis?
Ischemic injury transcends energy deficit
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depolarization
edema
Ca2+
caspase activation
Na+
H20
NO
glut amat e
Injury toot her cells
alt ered gene expression
Delayed cell Deat h
Acute Cell Death
AMPArecept ors
NMDArecept ors
membrane damage
cyt ochrome C
permeabilit y t ransit ion
f ree radicals
energy failure (ATP loss)
act ivat ion ofprot eases, nucleases
NOS
Na+- gl ut amat eco- t r anspor t er
Main Pathways of Neuron Death in Brain Ischemia
Mit ochondrialenergy product ionf ailu re
O2 / subst rat e lack
Na+
Ion Pump failure
glut amat e
glut amat e
ATP l oss
mi t ochondr i on
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Practical neuroprotection strategies—are there any?
• Treat hypertension, recent MI (sinus rhythm!), atrial fibrillation (anticoagulation), diabetes (glucose <180!), carotid artery stenosis, smoking cessation
• There are no randomized, prospective trials showing that one anesthetic technique is more protective than another
• Neuroprotective strategies may have negative consequences (hypotension, persistent hypothermia, delayed awakening).
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Hypothermia
Mild hypothermia (core temp 33-35 C): markedly protective in animal models.
Preliminary study in human cerebral aneurysm surgery: trend towards protection
Benefits include reduction in glutamate release, preservationof energy balance, reduced apoptosis, reduced inflammation andfree radicals
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Hypothermia is not protective in traumatic brain injury
-Hypothermia did have a beneficial effect in the patients with high ICP
Clifton, et al. NEJM, 2001: -392 patients randomized to 33 oC within 8 h, maintained for 48 h. Trial aborted before 500 patient target.
Why does hypothermia provide robust neuroprotection inlaboratory animals but not in man?
- Hypothermia worsened outcome in the elderly
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Hypothermia benefits comatose survivors of cardiac arrest
NEJM 2002: In 136 patients who were successfully resuscitated after cardiac arrest due to ventricular fibrillation, therapeutic mildhypothermia increased the rate of a favorable neurologic outcome and reduced mortality
-patients were cooled to a bladder temp of 32-34oC for 24 hr -mortality at 6 months was 41% in hypothermia group, 55% in normothermia
Mechanism of benefit not clear, BUT it is clear that that a windowof therapeutic potential exists AFTER the global ischemia.
Should this therapy be used in patients having perioperative arrests?
-Bernard et al. (NEJM 2002): similar benefits in 77 patients with 12 hours of post arrest hypothermia
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IHAST-2 Trial
• Brain Aneurysms: Grade 1 - 3
• Randomized to cooling to 33 C or normothermic
• Side effects of hypothermia monitored
• 1000 patients enrolled
Preliminary analysis: No benefit
What are negative consequences of hypothermia?
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Algorithm for Neuroprotection
Risk for IntraoperativeBrain ischemia?
No Standard Anesthesia CareReduce risk factors(HTN, smoking, recent MI, Afib)
yes
Embolic Risk(CPB, valve replacement)
HypothermiaGlucose controlHct ~32Maintain CPP when warmAlphastat pHArterial filters
neurologic Sx?
noyes
PCO2 30-35
Head positionMaintain CPPGlucose control
PCO2 30-35
MannitolLidocaineHead positionThiopentalCPP controlGlucose control
Aneurysm ClippingIntracranial Vessel BypassTemp. occlusion
RetractorPressure, etc.
Mild hypothermiaMannitolThiopental burst supp.EEG monitoringHct about 32%Treat vasospasmMaintain CPPPCO2 30-35 mmHg
Glucose control
Mild hypothermiaMannitolHct 32Maintain CPPPCO2 30-35 mmHg
Glucose control
Consider Specific Neuroprotection:
High TransientIschemia Risk
Elevated ICP/ persistentfocal ischemia (hematoma,mass)
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Oxygenation, Glucose, fluids, ICP, hemodynamics
• Preserve CPP, considering underlying disease (hypertension, vasospasm, diabetes) Hyperventilation not beneficial (NICU)
• fluid loading, elevated MAP, vasopressors, nimodopine (evidence based)
• optimal hematocrit is 32%
• glucose <180 mg/dl (evidence based)
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Acid-base regulation
• Alphastat pH regulation is associated with improved neurologic outcome in CABG: related to decreased CBF and embolization?
• In pediatrics, embolism is rare: pH-stat regulation may be preferable (achieves greater brain cooling)
• Hypocarbia may cause relative brain ischemia
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Neuromonitoring
• EEG changes indicate severe reductions in CBF (EEG flatline below 17 ml/100g/min)
• Useful when specific neural circuits are threatened (spinal surgery, facial nerve preservation in acoustic neuroma surgery)
• Outcomes studies rare
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Barbiturates and neuroprotection
-40 years of animal studies show benefit in focal and global ischemia; theoretical reason to think thiobarbiturates might be better than others
-Human studies are anecdotal, uncontrolled or flawed
-Nussmeier (1986): cardiac surgery patients, no temperature control -pentothal improved outcome -follow up study (Zaidan, 1991): no benefit.
-Barbiturates have negative effects: hypotension, delayed awakening
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Algorithm for Neuroprotection
Risk for IntraoperativeBrain ischemia?
No Standard Anesthesia CareReduce risk factors(HTN, smoking, recent MI, Afib)
yes
Embolic Risk(CPB, valve replacement)
HypothermiaGlucose controlHct ~32Maintain CPP when warmAlphastat pHArterial filters
neurologic Sx?
noyes
PCO2 30-35
Head positionMaintain CPPGlucose control
PCO2 30-35
MannitolLidocaineHead positionThiopentalCPP controlGlucose control
Aneurysm ClippingIntracranial Vessel BypassTemp. occlusion
RetractorPressure, etc.
Mild hypothermiaMannitolThiopental burst supp.EEG monitoringHct about 32%Treat vasospasmMaintain CPPPCO2 30-35 mmHg
Glucose control
Mild hypothermiaMannitolHct 32Maintain CPPPCO2 30-35 mmHg
Glucose control
Consider Specific Neuroprotection:
High TransientIschemia Risk
Elevated ICP/ persistentfocal ischemia (hematoma,mass)
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Are volatile anesthetics neuroprotective?
• Inhibit glutamate receptors
• Activate GABA receptors
• Preconditions neurons to survive ischemia
• Inhibit the release of glutamate caused by hypoxia and by depolarization
• Facilitates use of hypothermia
• Alters intracellular signaling for a long time after administration
Properties of isoflurane:
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NMDA receptorsIsoflurane
Ca2+
Ca-Calmodulin
MAPK p42/44 HIF 1 Akt
Endoplasmic reticulum
Transcription factors Apoptosis regulation
(-)
(-)
(+)
Ca2+
(-)
Isoflurane and neuroprotective intracellular signaling
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CA1
CA3 dentate
Isoflurane preconditions neurons in the hippocampus to avoid death following ischemia
Hippocampalslice culturesfrom rats
48 hours after simulated ischemia:
Control (no preconditioning) Preconditioned 0.5% isoflurane
DeadNeurons