Upload
taber
View
67
Download
0
Tags:
Embed Size (px)
DESCRIPTION
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 Presentation
Citation preview
Neuroprotection for surgery: Is it possible?
Philip Bickler, MD, PhDDepartment of Anesthesia and Perioperative Care
UCSF
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?
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
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!
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
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?
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
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
~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:
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
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.
• Excitoxicity: The glutamate cascade
• Apoptotic (programmed) cell death
• Free radical generation and injury
• Inflammation
• Chronic processes: impaired neurogenesis?
Ischemic injury transcends energy deficit
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
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).
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
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
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
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?
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)
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)
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
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
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
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)
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:
NMDA receptorsIsoflurane
Ca2+
Ca-Calmodulin
MAPK p42/44 HIF 1 Akt
Endoplasmic reticulum
Transcription factors Apoptosis regulation
(-)
(-)
(+)
Ca2+
(-)
Isoflurane and neuroprotective intracellular signaling
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