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Neuroprotection for surgery: Is it possible?

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)

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Neuroprotection for surgery: Is it possible?

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  1. Neuroprotection for surgery: Is it possible? Philip Bickler, MD, PhD Department of Anesthesia and Perioperative Care UCSF

  2. 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?

  3. 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

  4. 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!

  5. 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

  6. 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?

  7. 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

  8. 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

  9. 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

  10. Mechanisms of perioperative brain ischemia Embolic from atrial fibrillation, MI, vascular disease Ischemic: retractor pressure, hypotension/hemorrhage, vasospasm, temporary clipping, elevated ICP Iatrogenic embolic: air, plaque, thrombus, etc. Iatrogenic non-embolic: pH or CO2 management, hyperthermia, hypotension

  11. 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.

  12. Ischemic injury transcends energy deficit • Excitoxicity: The glutamate cascade • Apoptotic (programmed) cell death • Free radical generation and injury • Inflammation • Chronic processes: impaired neurogenesis?

  13. 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).

  14. 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

  15. 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?

  16. 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?

  17. 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?

  18. 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)

  19. 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

  20. 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

  21. 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

  22. Are volatile anesthetics neuroprotective? Properties of isoflurane: • 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

  23. Isoflurane NMDA receptors (-) (-) Ca2+ Ca2+ Ca-Calmodulin Endoplasmic reticulum (+) Akt MAPK p42/44 HIF 1a (-) Transcription factors Apoptosis regulation Isoflurane and neuroprotective intracellular signaling

  24. 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

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