Physiology of Brain Protection
The brain is very vulnerable to ischemic injury because of its relatively high oxygenconsumption and near total dependence on aero-bic glucose metabolism (above). Interruption of cerebral perfusion, metabolic substrate (glucose), or severe hypoxemia rapidly results in functional impairment; reduced perfusion also impairs clear-ance of potentially toxic metabolites. If normal oxygen tension, blood flow, and glucose supply are not reestablished within 3–8 min under most conditions, ATP stores are depleted, and irrevers-ible neuronal injury begins. When CBF decreases below 10 mL/100 g/min, cell function is deranged, and ion pumps fail to maintain cellular vitality. The ratio of lactate to pyruvate is increased second-ary to anaerobic metabolism. During ischemia, intracellular K + decreases, and intracellular Na + increases. More importantly, intracellular Ca 2+ increases because of failure of ATP-dependent pumps to either extrude the ion extracellularly or into intracellular cisterns, increased intracellular Na+ concentration, and release of the excitatory neurotransmitter glutamate. Glutamate acts at the NMDA receptor, further enhancing Ca2+ entry into the cell, hence the potential benefit of NMDA blockers for neuroprotection.
Sustained increases in intracellular Ca 2+ activate lipases and proteases, which initiate and propagate structural damage to neurons. Increases in free fatty acid concentration and cyclooxygenase and lipoxy-genase activities result in the formation of prosta-glandins and leukotrienes, some of which are potent mediators of cellular injury. Accumulation of toxic metabolites, such as lactic acid, also impairs cellu-lar function and interferes with repair mechanisms. Lastly, reperfusion of ischemic tissues can cause additional tissue damage due to the formation of oxygen-derived free radicals. Likewise, inflamma-tion and edema can promote further neuronal dam-age, leading to cellular apoptosis.
Ischemic brain injury is usually classified as focal (incomplete) or global (complete). Global ischemia includes total circulatory arrest as well as global hypoxia. Cessation of perfusion may be caused by cardiac arrest or deliberate circulatory arrest, whereas global hypoxia may be caused by severe respiratory failure, drowning, and asphyxia (includ-ing anesthetic mishaps). Focal ischemia includes embolic, hemorrhagic, and atherosclerotic strokes, as well as blunt, penetrating, and surgical trauma.
In some instances, interventions aimed at restoring perfusion and oxygenation are possible; these include reestablishing effective circulation, normalizing arterial oxygenation and oxygen-car-rying capacity, or reopening an occluded vessel. With focal ischemia, the brain tissue surrounding a severely damaged area may suffer marked func-tional impairment but still remain viable. Such areas are thought to have very marginal perfusion (<15 mL/100 g/min), but, if further injury can be lim-ited and normal flow is rapidly restored, these areas (the “ischemic penumbra”) may recover completely. When the above interventions are not applicable or available, the emphasis must be on limiting the extent of brain injury.
From a practical point of view, efforts aimed at preventing or limiting neuronal tissue damage are often the same whether the ischemia is focal or global. Clinical goals are usually to optimize CPP, decrease metabolic requirements (basal and electri-cal), and possibly block mediators of cellular injury. Clearly, the most effective strategy is prevention, because once injury has occurred, measures aimed at cerebral protection become less effective.
Hypothermia is an eff ective method for pro-tecting the brain during focal and global isch-emia. Indeed, profound hypothermia is often used for up to 1 hr of total circulatory arrest. Unlike anesthetic agents, hypothermia decreases both basal and elec-trical metabolic requirements throughout the brain; metabolic requirements continue to decrease even after complete electrical silence. Additionally, hypo-thermia reduces free radicals and other mediators of ischemic injury. Induced hypothermia has shown benefit following cardiac arrest and is a routine part of most postarrest protocols for comatose patients.
Barbiturates, etomidate, propofol, and isoflurane can produce complete electrical silence of the brain and eliminate the metabolic cost of electrical activity; unfortunately, these agents have no effect on basal energy requirements. Furthermore, with the excep-tion of barbiturates, their effects are nonuniform, affecting different parts of the brain to variable extents.
Ketamine may also have a protective effect because of its ability to block the actions of gluta-mate at the NMDA) receptor.
No anesthetic agent has consistently been shown to be protective against global ischemia. The ever increasing number of studies highlighting the potential neurotoxicity of anesthetics (especially in infants) also questions the role of volatile anesthetics in neuroprotection.
Nimodipine plays a role in the in the treatment of vasospasm associated with subarachnoid hemor-rhage. Studies are ongoing to discern the roles of various NMDA receptor antagonists, erythropoi-etin, Ca2+ antagonists, and free radical scavengers to mitigate ischemic neuronal injury.
Maintenance of a satisfactory CPP is critical. Thus, arterial blood pressure should be normal or slightly elevated, and increases in venous and ICP should be avoided. Oxygen-carrying capacity should be maintained and normal arterial oxygen tension preserved. Hyperglycemia aggravates neurological injuries following either focal or global ischemia, and blood glucose should be maintained at less than 180 mg/dL. Normocarbia should be maintained, as both hypercarbia and hypocarbia have no benefi-cial effect in the setting of ischemia and could prove detrimental; hypocarbia-induced cerebral vaso-constriction may aggravate the ischemia, whereas hypercarbia may induce a steal phenomenon (with focal ischemia) or worsen intracellular acidosis.
Electrophysiological monitors are used to assess the functional integrity of the CNS. The most com-monly used monitor for neurosurgical procedures is evoked potentials. EEG is much less commonly used. Proper application of these monitoring modalities
is critically dependent on monitoring the specific area at risk and recognizing anesthetic-induced changes.
The effects of anesthetic agents on the EEG are summarized in Table26–2.
EEG monitoring is useful for assessing the adequacy of cerebral perfusion during carotid endarterectomy (CEA), as well as anesthetic depth (most often with processed EEG). EEG changes can be simplistically described as either activation or depression. EEG activation (a shift to predominantly high-frequency and low-voltage activity) is seen with light anesthe-sia and surgical stimulation, whereas EEG depres-sion (a shift to predominantly low-frequency and high-voltage activity) occurs with deep anesthesia or cerebral compromise. Most anesthetics produce an EEG consisting of an initial activation (at sub-anesthetic doses) followed by dose-dependent depression.
Isoflurane can produce an isoelectric EEG at high clinical doses (1–2 MAC). Desflurane and sevoflurane produce a burst suppression pattern at high doses (>1.2 and >1.5 MAC, respectively) but not electrical silence. Nitrous oxide is alsounusual in that it increases both frequency and amplitude (high-amplitude activation).
Benzodiazepines can produce both activation and depression of the EEG. Barbiturates, etomidate, and propofol produce a similar pattern and are the only intravenous agents capable of producing burst sup-pression and electrical silence at high doses. In contrast, opioids characteristically produce only dose-dependent depression of the EEG. Lastly, ket-amine produces an unusual activation consisting of rhythmic high-amplitude theta activity followed by very high-amplitude gamma and low-amplitude beta activities.
Somatosensory evoked potentials test the integrity of the spinal dorsal columns and the sensory cortex and may be useful during resection of spinal tumors, instrumentation of the spine, CEA, and aortic surgery. The adequacy of perfusion of the spinal cord during aortic surgery is probably better assessed with motor evoked potentials (which assess the anterior part of the spinal cord). Brainstem auditory evoked potentials test the integrity of the eighth cranial nerve and the audi-tory pathways above the pons and are used for surgery in the posterior fossa. Visual evoked potentials may be used to monitor the optic nerve and occipital cortex during resections of large pituitary tumors.
Interpretation of evoked potentials is more complicated than that of the EEG. Evoked potentials have poststimulus latencies that are described as short, intermediate, and long. Short-latency evoked potentials arise from the nerve stimulated or the brain stem. Intermediate- and long-latency evoked potentials are primarily of cortical origin. In general, short-latency potentials are least affected by anes-thetic agents, whereas long-latency potentials are affected by even subanesthetic levels of most agents. Visual evoked potentials are most affected by anes-thetics, whereas brain stem auditory evoked poten-tials are least affected.Intravenous agents in clinical doses gener-ally have less marked effects on evoked potentials than do volatile agents, but, in high doses, can also decrease amplitude and increase latencies.
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