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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, 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 • • • • • 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: • • • • 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