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