Cerebral protection

Published on 07/02/2015 by admin

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Last modified 22/04/2025

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Cerebral protection

Robert E. Grady, MD

Cerebral ischemia results when the metabolic demands of cerebral tissue exceed substrate (primarily O2) delivery. Ischemia can be categorized as either global—with interruption of substrate delivery to the entire brain, as occurs in cardiac arrest—or focal—with interruption of substrate delivery to a defined region of the brain, such as is produced by embolic cerebral artery occlusion. Cerebral protection is an attempt to prolong the ischemic tolerance of brain tissue and to reduce or abolish neuronal injury.

The traditional concept of cerebral metabolism is illustrated in Figure 131-1. Cerebral metabolism may be divided into a functional component and a cellular integrity component. The functional component comprises 60% of neuronal O2 use. This component is responsible for generating action potentials and may be assessed by evaluating the electroencephalogram. The cellular integrity component consists of the remaining 40% of O2 utilized for protein synthesis and other activities geared toward maintaining cellular integrity.

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Figure 131-1 Theoretical interaction of temperature, brain function, cerebral metabolic O2 consumption (CMRO2), and calculated Q10 value. Q10 is defined as the ratio of metabolic rates at two temperatures separated by 10°C. In reducing temperature from 37° C to 27° C, function is maintained and both of the energy-consuming processes (i.e., function and integrity) are presumed to be affected equally, with a reduction of CMRO2 of slightly more than 50%, thus generating a Q10 value of about 2.4. With a further 10° C reduction in temperature to 17° C, function is abolished, resulting in a steep decrease in CMRO2 such that the calculated Q10 value is 5.0 or greater. At this point, the total O2 consumed by the brain is reduced to less than 8% of the normothermic value of O2. (Reprinted, with permission, from Michenfelder JD, ed. Anesthesia and the Brain. New York: Churchill Livingstone; 1988:14.)

Anesthetic agents and hypothermia are both capable of reducing the functional component of cerebral metabolism, resulting in, at most, a 60% reduction in O2 use. Hypothermia, however, can further reduce O2 use by also decreasing the cellular integrity component. In this traditional and simplistic O2 supply–metabolic demand paradigm, cerebral protection may be produced by simply altering the balance in favor of supply by increasing cerebral perfusion pressure (CPP) and O2 delivery while depressing cerebral metabolism via anesthetic agents and hypothermia.

New evidence paints a much more complex picture of cerebral ischemia, in which an initial ischemic event may trigger a process of neuronal demise that continues long after the inciting event has resolved (Figure 131-2). Excitotoxicity is a cascade of glutamate-mediated neuronal demise that occurs shortly after the onset of neuronal ischemia. Apoptosis (programmed cell death via proteases) and inflammation are initiated by the ischemic event and continue to contribute to neuronal death for days. In this newer model of cerebral ischemia, it may be possible to limit ischemic damage by invoking cerebral protective therapies before, during, or after an ischemic event (Table 131-1). The currently available evidence in support of the use of cerebral protection is derived from a mixture of human experiments and animal data extrapolated to human subjects.

Table 131-1

Evidence-Based Status of Plausible Interventions to Reduce Perioperative Ischemic Brain Injury

  Efficacy in Experimental Animals Efficacy in Humans Sustained Protection in
Intervention Preischemic Postischemic Preischemic Postischemic Animals Humans
Hypothermia            
Mild ++ ++ ± ++* ++ ++
Moderate −−− −−− −− −− −−−  
Hyperventilation −− −− −− −− −− −−
Normoglycemia ++ −− + + ++ −−
Hyperbaric O2 ++ −− −− ± −− −−
Barbiturates ++ − + + ++ −−
Propofol ++ + − −− −− −
Etomidate −−− −− −− −− −− −−
N2O − −− −− −− −− −−
Isoflurane ++ −− −− −− ++ −−
Sevoflurane   −− −− −− ++ −−
Desflurane ++ −− −− −− −− −−
Lidocaine ++ −− + −− −− −−
Ketamine ++ −− −− −− −− −−
Glucocorticoids −−− −− −− −− −− −−

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++, Supported by evidence from repeated physiologically controlled studies in animals/randomized, prospective, adequately powered clinical trials; +, consistent suggestion by case series/retrospective or prospective trials with small sample sizes or data extrapolated from other paradigms; ±, inconsistent findings in clinical trials; may be dependent on characteristics of insult; −, well-defined absence of benefit; −−, absence of evidence in physiologically controlled studies in animals/randomized, prospective adequately powered clinical trials; −−−, evidence of potential harm.

*Out-of-hospital ventricular fibrillation cardiac arrest.

(Adapted, with permission, from Fukuda S, Warner DS. Cerebral protection. Br J Anaesth. 2007;99:10-17.)

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Figure 131-2 Time course of neuronal death after cerebral ischemia. Excitotoxicity rapidly leads to neuronal necrosis. Inflammation and neuronal apoptosis contribute to ongoing cell death for a period that extends from several days to weeks. (From Patel P. Cerebral ischemia and intraoperative brain protection. In: Gupta AK, Gelb AW, eds. Essentials of Neuroanesthesia and Neurointensive Care. Philadelphia: WB Saunders; 2008:36-48.)

Regulation of physiologic parameters

Temperature

Hypothermia reduces both the functional and cellular integrity components of cerebral metabolism. Deep hypothermia (18°-22° C) has long been known to be highly protective of cerebral tissue, permitting little or no cerebral blood flow (CBF) for extended periods of time (∼1 h) without neurologic sequelae. Studies of adults who have survived out-of-hospital cardiac arrest and of neonates with asphyxia have shown that mild hypothermia (32°-35° C) has beneficial cerebral protective effects; however, studies have failed to demonstrate the efficacy of mild hypothermia in patients with a ruptured cerebral aneurysm. Hyperthermia should be avoided because it will increase cerebral metabolism and worsen ischemic insults.

Anesthetic agents

Barbiturates

Barbiturates have been considered to be the “gold standard” neuroprotective anesthetic agent when they are administered prior to a focal ischemic event. The neuroprotective properties of barbiturates are supported by a single human study in patients undergoing cardiopulmonary bypass, and corroborative evidence in humans is lacking. Researchers initially thought that the mechanism of barbiturate cerebral protection in laboratory animals was a dose-dependent reduction in the cerebral metabolic rate. However, subsequent studies revealed that barbiturate doses resulting in electroencephalographic isoelectricity or burst suppression are equally cerebroprotective, suggesting that additional protective mechanisms are in effect. Unwanted effects of high-dose barbiturates, such as cardiovascular instability and delays in awakening and neurologic assessment, must be taken into consideration when using this class of drug.

Conclusion

Protection of the nervous system from ischemic insult via pharmacologic and physiologic means has been a long-sought-after goal of anesthesiology. The current cerebral protective armamentarium has few proven interventions and many speculative ones. Box 131-1 provides a reasonable framework for addressing an ischemic insult based on the current level of knowledge.

Box 131-1

Considerations When Anticipating or Managing a Perioperative Ischemic Insult

*Increasing concern has arisen that hypoxemia may be adverse in global ischemia.

†Not tested by clinical trials in the perioperative environment but supported by consistent efficacy when used in out-of-hospital ventricular fibrillation cardiac arrest.

‡No evidence of efficacy; preclinical evidence of adverse effect in global ischemia.

(Adapted, with permission, from Fukuda S, Warner DS. Cerebral protection. Br J Anaesth. 2007;99:10-17.)

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