Transcript No Slide Title

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, 7988% 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 1998
Benefit 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 trials
Failure of chemical neuroprotection?
Pharma: $$$ directed to R&D, clinical testing
NIH: $$$ for basic science, clinical trials
Summary of stroke trials as of January 2004:
~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
Mechanisms of perioperative brain ischemia
Embolic from atrial fibrillation, MI, vascular disease
Iatrogenic embolic: air, plaque, thrombus, etc.
Iatrogenic non-embolic: pH or CO2 management,
hyperthermia, hypotension
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.
Ischemic injury transcends energy
deficit
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Excitoxicity: The glutamate cascade
Apoptotic (programmed) cell death
Free radical generation and injury
Inflammation
Chronic processes: impaired neurogenesis?
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.
Benefits include reduction in glutamate release, preservation
of energy balance, reduced apoptosis, reduced inflammation and
free radicals
Preliminary study in human cerebral
aneurysm surgery: trend towards protection
Hypothermia is not protective
in traumatic brain injury
Clifton, et al. NEJM, 2001: -392 patients randomized to
33 oC within 8 h, maintained for 48 h. Trial aborted before 500
patient target.
-Hypothermia did have a beneficial effect in the patients
with high ICP
- Hypothermia worsened outcome in the elderly
Why does hypothermia provide robust neuroprotection in
laboratory animals but not in man?
Hypothermia benefits comatose
survivors of cardiac arrest
NEJM 2002: In 136 patients who were successfully resuscitated
after cardiac arrest due to ventricular fibrillation, therapeutic mild
hypothermia 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
-Bernard et al. (NEJM 2002): similar benefits in 77 patients with
12 hours of post arrest hypothermia
Mechanism of benefit not clear, BUT it is clear that that a window
of therapeutic potential exists AFTER the global ischemia.
Should this therapy be used in patients having perioperative arrests?
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?
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
Are volatile anesthetics neuroprotective?
Properties of isoflurane:
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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
Isoflurane and neuroprotective intracellular signaling
Isoflurane
NMDA receptors
(-)
(-)
Ca2+
Ca-Calmodulin
Ca2+
Endoplasmic reticulum
(+)
MAPK p42/44
HIF 1a
Akt
(-)
Transcription factors
Apoptosis regulation
Isoflurane preconditions neurons in the hippocampus
to avoid death following ischemia
CA1
Hippocampal
slice cultures
from rats
CA3
dentate
48 hours after simulated ischemia:
Dead
Neurons
Control (no preconditioning)
Preconditioned 0.5% isoflurane