Intraoperative Cerebral Protection

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CHAPTER 345 Intraoperative Cerebral Protection

Our understanding of the complex mechanisms of cell death from ischemic injury has expanded exponentially and has led to the introduction of various neuroprotective measures to prevent and minimize cellular damage and death during cerebrovascular procedures. Intraoperative events, such as systemic hypotension, vessel occlusion, excessive blood loss, and other factors causing a decrease in cerebral perfusion, can precipitate ischemic changes on a macrocellular and microcellular level. A number of destructive biochemical cascades are activated and cause cellular injury and demise, including nuclear alterations, imbalanced chemical homeostasis, excitotoxicity, reactive free radicals, accumulation of toxic metabolites, membrane instability, and inflammatory responses. These dynamic and integrated events lead to various end points, depending on the duration and extent of the ischemia. An understanding of these pathways is essential for implementing various treatments and prevention strategies to provide neuroprotection during cerebrovascular procedures.

Pathophysiology of Ischemic Injury

Cerebral Blood Flow

In 1948, Kety and Schmidt quantified normal cerebral blood flow (CBF) in “healthy normal men” to be 54 mL/100 g per minute.1 Sundt and others noted that a minimal CBF of 18 mL/100 g per minute is needed to maintain normal electroencephalographic (EEG) parameters during carotid endarterectomy (CEA).2,3 A further decrease in CBF causes neuronal electrical silence and decreased synaptic activity to preserve energy stores. Irreversible cellular damage occurs when CBF is below 10 mL/100 g per minute.48 In response to ischemia, the cerebral vessel autoregulatory mechanism induces vasodilation to increase collateral blood flow and thereby increase oxygen and glucose extraction for preservation of viable neurons (Fig. 345-1).

image

FIGURE 345-1 Cerebral blood flow thresholds for critical functions.

(Adapted from Astrup J, Symon L, Branston NM, et al. Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia. Stroke. 1977;8:51-57.)

Ischemic Penumbra

Laboratory and clinical evidence demonstrates a spectrum of injured neurons when CBF is interrupted as a result of vessel occlusion. In the affected territory, there is a core of irreversibly damaged neurons surrounded by an area of electrically silent but viable neurons known as the ischemic penumbra.4,911 CBF in the penumbra has been determined to be between 10 and 20 mL/100 g per minute.7,1216 These neurons may survive for hours, although the exact duration is unknown. Many factors may reduce the time for survivability of these marginal neurons. Hyperthermia of 1°C to 2°C and serum hyperglycemia have been shown to accelerate cell death.17,18 Restoration of CBF to the penumbra within the “critical hours” may salvage viable neurons and minimize the neurological deficits (Fig. 345-2). Without intervention, the core of the infarcted territory will subsume the penumbra as demonstrated by positron emission tomography (PET) and magnetic resonance imaging (MRI).1921 The temporal and spatial evolution of the infarcted core is highly variable.19,21 Baron demonstrated by PET that the onset of the penumbra occurs as late as 16 hours after infarction.21 Susceptibility to ischemic injury also varies in different areas of the brain, with hippocampal CA1 and striatal neurons being more vulnerable than cortical neurons in ischemic models.22,23

image

FIGURE 345-2 Relationship between time of ischemia and reversibility of neurological deficit. CBF, cerebral blood flow.

(Adapted from Jones TH, Morawetz RB, Crowell RM, et al. Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg. 1981;54:773-782.)

The traditional concept of an infarcted core surrounding by a penumbra may be too simplistic. Many patients who improve with thrombolytic agents do not demonstrate a core surrounded by a larger penumbra on imaging. The core may be surrounded by heterogeneous regions of penumbra, with possibly separate areas of minimal flow or core within the penumbra as a result of variable degrees of collateral circulation.24

Energy Failure

The most immediate biochemical change in neurons affected by ischemia is diversion of the cellular machinery from aerobic to anaerobic metabolism. Insufficient oxygen inhibits the aerobic catabolism of pyruvate and promotes anaerobic glycolysis, thereby leading to accumulation of lactic acid. Diminished CBF limits lactate removal and consequently results in additional accumulation of this by-product. As pH decreases from lactic acidosis, various destructive cascades are activated and lead to cellular death.

The decrease in energy production from anaerobic metabolism (2 adenosine triphosphate [ATP] molecules) versus oxidative phosphorylation (32 ATP molecules) causes failure of the ionic electrochemical gradient established by the sodium-potassium adenosine triphosphatase (Na+,K+-ATPase) pump. Peri-infarct depolarization can be observed in the cortical penumbra with the use of direct current potential. These phenomena are associated with efflux of K+ and influx of Na+ and Ca2+.2528 Biochemical analysis of PO2 and ATP in the penumbra confirms the depletion during depolarization,29,30 thus placing an additional burden on compromised tissue and increasing the size of the ischemic lesion by 30% to 100%.3134 Ionic influx also results in oncosis,35 a condition characterized by swelling of cells and organelles, increased membrane permeability, and nonspecific DNA damage. Swelling of astrocytes causes large amounts of excitatory amino acids (EAAs) to be released through volume-activated anion channels.35 Although the death pathway of astrocytes is unclear, oncosis may contribute to the mechanism.

Altered Calcium Homeostasis and Excitotoxicity

Ischemia causes an increase in the intracellular calcium concentration from depolarization of voltage-gated channels, activation of ligand-gated channels, release of intracytoplasmic stores, and loss of ATP-dependent calcium extrusion pathways. In addition, there is an influx of calcium down an electrochemical gradient (Fig. 345-3).31 The calcium-mediated release of glutamate and EAAs from depolarized neurons plays a major role in ischemic cell death.3638 In the presence of energy failure, depolarization of somatodendritic and presynaptic voltage-dependent calcium channels leads to excessive extracellular glutamate and EAAs (Fig. 345-4).39 When combined with failure of glutamate reuptake, toxic accumulation of extracellular EAAs causes excessive activation of the postsynaptic glutamate receptors N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA). Overactivation of NMDA and AMPA receptors facilitates a massive influx of calcium and sodium ions, respectively.39 Animal models and microdialysis during neurosurgical procedures have shown glutamate and other EAAs to be markedly elevated over baseline levels.4046 Accumulation of ions leads to cellular edema and peri-infarct depolarization.47,48 Such depolarization has been recorded for 6 to 8 hours after an initial ischemic insult.31 The depletion of energy stores needed for restoration of normal depolarization is thought to contribute to enlargement of an infarct. In addition, excessive intracellular calcium directly and indirectly initiates a series of detrimental cytoplasmic and nuclear cascades, including activation of Ca2+-dependent proteases and phospholipases, alterations in plasma membrane permeability, depolarization of mitochondria and release of mitochondrial proapoptotic proteins, production of reactive oxygen species (ROSs) and reactive nitrogen species (RNSs), and activation of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP).4956

Free Radicals

With its high oxygen consumption, the brain is especially susceptible to free radical damage. It also has high levels of iron and ascorbate,5759 which can act as pro-oxidants under pathologic conditions, as well as low levels of antioxidant enzymes such as catalase, glutathione peroxidase, and superoxide dismutase.60 The cellular membranes are rich in polyunsaturated fatty acids, which are vulnerable to radical-induced peroxidation. The acidic environment from lactic acidosis during ischemia promotes dissociation of iron from protein and enhances the conversion of superoxide anion to more reactive radicals.58,61

ROSs and RNSs play significant roles in the pathogenesis and exacerbation of ischemic injury. It has been postulated that low levels of ROSs and RNSs trigger apoptosis and higher levels cause necrosis.62,63 During ischemia, nitric oxide (NO), a vasodilator, is generated by endothelial nitrous oxide synthase (NOS) to increase local CBF.64 Although this may be beneficial locally in the vasculature, a higher concentration of NO is produced by neuronal NOS and inducible NOS from inflammatory cells in the ischemic territory and may play a role in neuronal injury.6468 NO and its derivative peroxynitrite, in addition to oxidizing effects on cellular structures, contribute to the oxidative stress by activating PARP, thus further depleting energy stores.69 PARP catalyzes the transfer of ADP-ribose units from nicotinamide adenine dinucleotide (NAD) to nuclear proteins. For every mole of ADP-ribose transferred, 1 mol of NAD is consumed. Four free energy equivalents of ATP are necessary to regenerate NAD.

Although ROSs are generated during ischemia, reperfusion after ischemia greatly increases ROS generation.57,70,71 Reoxygenation provides an excess supply of substrate for oxidation, thus producing more ROSs and RNSs. This further depletes endogenous antioxidants, including radical scavengers such as tocopherol (vitamin E) and carotene and enzymes such as superoxide dismutase and catalase. ROSs and RNSs are also produced in mitochondria during ischemia and reperfusion and are involved in the release of cytochrome c.58,72 Studies have shown that depletion of glutathione, a reductant, can cause a 100-fold increase in mitochondrial production of ROSs.60,73 Free radicals have been implicated in signaling pathways involving dephosphorylation and translocation of the proapoptotic Bad protein from the cytosol to the mitochondrial membrane.60 By affecting the redox state of neurons and glial cells, free radicals can alter their genetic expression, activate destructive proteins, and inhibit protective enzymes, which ultimately leads to cellular death and breakdown of the blood-brain barrier.

Free Fatty Acids

During ischemia, stimulation of glutamate receptors and an increase in intracellular calcium activate various subtypes of phospholipases, which causes a large amount of fatty acids, particularly arachidonic acid, to be released from the cellular membrane.7476 With free radicals, arachidonic acid is further metabolized by cyclooxygenase/lipoxygenase to produce leukotriene C4, prostaglandin E2, and additional free radicals. These metabolites have been implicated in neuronal demise.77 Recent laboratory evidence suggests that arachidonic acid induces cytosolic and mitochondrial Na+ and Ca2+ overload via nonselective cation conductance, thereby leading to the formation of mitochondrial permeability transition pores, release of cytochrome c, and activation of caspase-3–dependent apoptosis.78

Inflammatory Response

Reperfusion facilitates the arrival of inflammatory cells at the ischemic zone, and postischemic inflammation contributes to ischemic injury in several ways.79 Inflammatory cells can aggravate ischemic injury by compromising blood flow in the microcirculation.8082 These cells also stimulate platelet aggregation and the formation of microthrombi, which further propagates the ischemic injury. After adhesion to the endothelial walls, granulocytes migrate (diapedesis) into the parenchyma and can be seen in peri-ischemic areas within hours of arterial occlusion.83 Inflammatory cells are also responsible for the production of proteolytic enzymes and the generation of free radicals.84 Activation of metalloproteinases and proteases destroys surrounding tissues and the extracellular matrix, independent of the energy status of neurons.24,31 This inflammatory response is enhanced by proinflammatory chemokines such as interleukin-1β (IL-1β), IL-8, and tumor necrosis factor-α (TNF-α) and mediated by upregulation of adhesion molecules, including selectins, integrins (CD11/CD18), and the immunoglobulin supergene family.82,8590

Cell Death

The two processes by which injured neurons die are necrosis and apoptosis, and these processes occur in both the infarcted core and the penumbra.53,9195 When necrosis develops,91 cells swell in the first few hours with the formation of eosinophilic neurons. The cells then shrink and undergo pyknosis (condensation of nuclear chromatin). The number of necrotic neurons increases most markedly during the initial 6 to 12 hours. Phagocytosis of necrotic tissue takes place over a period of days. Pan-necrosis can occur in the infarcted core and give rise to a cystic cavity.25 In the penumbra, infarcted neurons are removed and reactive astrocytes proliferate, thereby creating an incomplete infarct.

Ischemic apoptosis may be triggered by oxidative stress and overactivation of glutamate receptors, although how ischemia triggers the apoptotic mechanism is unclear. The process begins with shrinkage of the nucleus and cytoplasm, followed by condensation of chromatin and nuclear fragmentation. The hallmark of apoptosis is a “laddering” pattern of DNA on gel electrophoresis caused by endonuclease cleavage of DNA into segments of nonrandom length.96,97 Eventually, the cells separate into small, pyknotic bodies that undergo phagocytosis with minimal associated inflammatory response.

Evidence has shown that the Bcl-2 family of proteins plays a significant role in determining whether ischemic neurons resist or succumb to apoptosis.98,99 Proapoptotic Bcl-2 proteins, such as Bad and Bax, are translocated into the mitochondrial membrane, where they induce the formation of pores and release proapoptotic enzymes that lead to the activation of proteases and cell death.100,101 The antiapoptotic proteins Bcl-2 and Bcl-xL may prevent apoptosis by inhibiting the proapoptotic proteins from inducing mitochondrial pore formation (Fig. 345-5).102 Other proteins involved in the mitochondrial pore complex include pancortin-2 and the Wiskott-Aldrich syndrome protein verprolin homologous-1 (WAVE1).103,104 Further evidence in ischemic animal models has demonstrated that pancortin-2 sequesters Bcl-xL in association with WAVE1 to promote the translocation of Bax to mitochondria, which causes release of cytochrome c and apoptosis.103

Other degradative enzymes activated during apoptosis include endonucleases, proteases, and caspases such as IL-1β–converting enzyme. Analysis of the DNA of apoptotic cells shows the laddering of approximately 200 base pairs of DNA fragments, which is specific for apoptosis rather than necrosis. These DNA fragments, indicative of neuronal death through apoptotic mechanisms, have been observed after focal ischemia by many investigators.93,105,106

Cerebroprotective Strategies for Focal Ischemia

Several strategies may be used in an attempt to provide cytoprotection during cerebrovascular procedures. Limiting the duration of ischemia is probably the most intuitive and direct method of reducing ischemic injury. Collateral blood flow can be increased by inducing hypertension. Decreasing the metabolic activity of tissue at risk can be achieved by lowering core temperature and by the use of certain anesthetic agents. A variety of pharmacologic agents have been tested in patients with ischemic stroke. Although not currently in routine use during surgery, it is anticipated that cytoprotective agents with proven efficacy for treating ischemic stroke might be of benefit in temporary intraoperative ischemia.

Limiting the Duration of Ischemia

The use of temporary arterial occlusion for dissection of aneurysms and permanent clipping is now a common standard during aneurysm surgery, but it is crucial to establish a safe occlusion time with emphasis on the anatomic level of occlusion and the vascular territory occluded. The duration of focal ischemia that can be tolerated safely without clinically evident sequelae varies between individuals and vascular territories.107111 The current consensus for temporary vessel occlusion is brief repetitive clipping periods, which provides increased safety and less risk for postoperative neurological deficit than a single episode of occlusion does, but definitive data have yet to confirm this consensus.

Laboratory studies of multiple ischemic events in focal models have demonstrated varying results.107,112115 Sakaki and coworkers examined the response of three 20-minutes episodes of middle cerebral artery (MCA) occlusion in cats versus a single 1-hour period.112 They noted that intermittent occlusion produced less damage than single, longer occlusion did. This report did not specify the length of reperfusion between episodes of ischemia, so it is difficult to assess whether reperfusion injury could occur. Steinberg and colleagues used a rabbit model of multiple intracranial vessel occlusion and demonstrated a 59% decrease in the area of cortical ischemic neuronal damage but no difference in the extent of striatal ischemic damage with intermittent occlusion versus uninterrupted occlusion.115

Goldman and associates studied repetitive MCA occlusion in rats in a protocol designed to simulate intraoperative occlusion techniques.107 The total infarcted areas after 60, 90, and 120 minutes of uninterrupted occlusion were significantly greater than those after identical cumulative ischemic periods but with 5 minutes of reperfusion after each 10-minute ischemic period. In an investigation of normotensive rats undergoing MCA occlusion by Selman and colleagues, biochemical and pathologic evidence demonstrated that a single, prolonged episode of reversible ischemia was more deleterious than multiple occlusions of a similar total duration.113 Statistical differences were seen only when total single occlusion time reached 2 hours. To provide an infarct size that can be statistically evaluated in different treatments, the experimental models used to date have required total occlusion times longer than those generally needed in the clinical setting. The nature of these experimental paradigms and species differences must be kept in mind when attempting to generalize the results and apply them to clinical use.

Most reports on the use of temporary arterial occlusion in humans have been retrospective analyses of case series in which the use or nonuse of temporary occlusion was based on the experience and judgment of the surgeon.109,116128 No randomized, prospective studies have been designed to compare the outcome of cerebrovascular procedures with temporary occlusion and those without local circulatory arrest. In 1961, Pool stated that bilateral anterior cerebral artery occlusion was safe for up to 20 minutes with the protective effects of hypothermia.129 Both Suzuki’s group127 and Ljunggren’s group119 estimated the maximum safe occlusion time of the MCA to be 20 minutes under normothermia. Other authors have recommended maintaining occlusion times at less than 15 minutes when possible,116,123,125,130 although some have reported occlusion lasting longer than 90 minutes without deficit.118

Samson and coworkers reviewed 121 patients from a group of 234 consecutive aneurysm patients.125 One hundred patients who did not experience intraoperative complications were analyzed. These patients underwent elective temporary occlusion under a standard neuroanesthetic regimen, including etomidate-induced burst suppression, normotension, and normothermia. Infarctions were noted in specific arterial territories as follows: basilar, 41%; middle cerebral, 26%; internal carotid, 7%; and anterior communicating, 16%. The authors identified the following factors as significant predictors of postoperative radiographic evidence of infarction: age (≥61 years), poor preoperative grade (Hunt and Hess grades III to IV), protracted duration of temporary occlusion, and the use of incomplete circulatory arrest.125 This series documents that temporary occlusion is not without risk; however, factors other than the duration of temporary occlusion, such as aneurysm configuration and the location of perforators, may be critical in determining this risk.131

In a nonconcurrent, prospective analysis, Ogilvy and colleagues studied the results of 132 consecutive aneurysm clipping procedures performed with temporary vascular occlusion in combination with mild hypothermia (33°C to 34°C), induced hypertension (systolic pressure of 150 mm Hg), and mannitol administration (100 g).126 Multivariate analysis demonstrated that intraoperative rupture and duration of clipping longer than 20 minutes were independently associated with stroke outcome. The average clip application time in patients with radiographic evidence of stroke was approximately 42 minutes as compared with 29 minutes in patients without radiographic evidence of stroke, whereas in patients with a clinically significant stroke, the average time was 50 minutes.126 The overall stroke rate in patients with an occlusion time of less than 20 minutes (1/67, 1.5%) was significantly less than that in patients with occlusion times longer than 20 minutes (12/65, 18.5%).126

Ferch and coauthors reported on 106 aneurysm patients retrospectively analyzed with regard to age, neurological status, aneurysm characteristics, intraoperative rupture, and duration and number of occlusive episodes.132 The overall symptomatic stroke rate attributed to temporary clip placement in this series was 17%. The incidence of stroke was 12% in patients with occlusion times of less than 10 minutes and 35% in patients with occlusion times longer than 10 minutes. In the group of patients who did not suffer stroke, the mean temporary occlusion time was 5.4 ± 5.2 minutes, whereas in those with stroke, it was 7.4 ± 8.1 minutes. In other series, the mean temporary occlusion time of the internal carotid artery without causing a stroke was 7.1 ± 3.8 minutes, and that for the MCA was 5.3 ± 3.9 minutes.132

Juvela and associates prospectively investigated temporary vessel occlusion times in 101 of 156 patients with ischemic lesions seen on computed tomography (CT) 3 months after subarachnoid hemorrhage.133 Thirty-five patients who underwent temporary vessel occlusion and had an ischemic lesion on follow-up CT had a total occlusion time of 8.5 ± 8.2 minutes versus 2.5 ± 2 minutes and a longer single occlusive episode of 6.1 ± 6.2 minutes versus 2.5 ± 2 minutes, with a trend toward significance in patients with a greater number of occlusive episodes lasting 1.78 ± 0.95 minute versus 1.14 ± 0.38 minute.133 Additional occlusion times of 25 to 42 minutes (mean, 33 ± 7 minutes) have been described in superficial temporal artery–MCA bypass patients without permanent neurological deficits.134

As alluded to in earlier studies, temporary clip placement and the duration of occlusion are not the only factors influencing postoperative ischemic injury. Other factors must also be considered, including patient age (>50 years), grade and time of the initial hemorrhage, poor clinical condition (Hunt and Hess grade III to IV), occlusion of perforators, intraoperative rupture, hypertension, the specific vascular territory, multiple aneurysms, and timing of surgery.132,133

Augmentation of Cerebral Blood Flow

Systemic arterial pressure can readily be manipulated in the setting of planned temporary ischemia. Symon and colleagues showed that MCA occlusion in primates results in loss of autoregulation in the ischemic region.135 Elevation of blood pressure should increase cerebral perfusion because of the passive nature of the vessels that have lost autoregulation in the ischemic territory. Other investigators have shown that the decrease in CBF with focal ischemia is less in animals with phenylephrine-induced hypertension than in controls.136138 The beneficial effect of induced hypertension may, however, be limited to relatively brief episodes of ischemia. Smrcka and coworkers reported that hypertension reduced infarct size by 97% in rabbits subjected to 1 hour of arterial occlusion but achieved only a 45% reduction in animals with 2 hours of ischemia.139 In the clinical setting, use of hypertension is limited by the patient’s cardiac tolerance. Close monitoring of cardiac function with limitation of the elevation in blood pressure to approximately 10% above baseline is advisable.

Prevention of Iatrogenic Ischemia (Intraoperative Cerebral Blood Flow Monitoring)

Preoperative measurement of flow rates through cerebral vessels can be achieved with noninvasive studies such as quantitative magnetic resonance angiography (a noninvasive tool also used for bypass surveillance) and xenon-enhanced CT.140 These studies help the surgeon identify patients who have low cerebrovascular reserve and may be at higher risk for iatrogenic ischemia before entering the operating room.

The neurological examination provides a sensitive, qualitative assessment of CBF during cerebrovascular procedures but remains limited to CEA and by patient tolerance of an awake operation.141 Vessel patency after aneurysmal clip placement can be confirmed by a number of modalities, including direct microvascular Doppler (MVD) or transcranial Doppler (TCD) ultrasound, ultrasonic flow probe, intraoperative angiography, EEG studies, electrocorticography, multimodality evoked potential (MEP) and somatosensory evoked potential (SEP) monitoring, brain tissue oxygenation, and more recently, fluorescent angiography with fluorescein sodium or indocyanine green (ICG).

TCD can provide only a relative estimation of CBF based on normal ranges, and results vary according to vessel diameter and operator technique. TCD has been used extensively to monitor MCA CBF during CEA142144 and postoperatively for the detection of vasospasm. MVD is a relatively fast and easy method of establishing vessel patency and aneurysm filling after clipping and can be used in patients undergoing multiple aneurysm clip applications. Use of the probe is limited by vessel depth and confounded by adjacent vascular tributaries. Unfortunately, these techniques do not determine whether flow is sufficient to prevent ischemia.

Direct intraoperative flow measurements can be made with the use of a microvascular ultrasonic flow probe. The device consists of an electronic flow detection unit and a flow-sensing perivascular probe. The probe uses the principle of ultrasonic transit time to assess intravascular flow without close vessel contact.145 The use of intraoperative angiography (IA) remains controversial; some reports recommend IA for complex aneurysms, such as giant aneurysms or those arising from specific locations, including the superior hypophysial, superior cerebellar, and posterior communicating arteries and the internal carotid artery bifurcation.146149 The argument against IA includes increased operative time, poor image quality, exposure of personnel to radiation, and a high cost-benefit ratio. Lopez and coauthors reported on a prospective cohort of 191 patients with various cerebrovascular pathologies in whom 204 angiograms were performed.150 Intraoperative findings were positive in 23% of the patients (residual lesions in 12%, parent or vessel occlusion in 6%, vasospasm in 5%) and resulted in clip repositioning or additional clip placement in 8% of patients. Other studies have found that IA altered surgical treatment in 11% or 12% of cases and was associated with less than a 0.5% morbidity rate.151,152 Whether IA should be performed is ultimately left to the cerebrovascular surgeon’s discretion. Klopfenstein and colleagues prospectively assessed the cerebrovascular surgeon’s accuracy of predicting whether IA was necessary. In this series, 200 patients with 235 aneurysms underwent IA. The results led to changes in surgical treatment in 7% of cases. In 4.4% of these patients, the surgeon thought that IA was unnecessary.153

IA is safe and useful when treating patients with a wide variety of vascular pathologies and may be beneficial in patients for whom surgery has been prospectively deemed unnecessary by the surgeon. However, IA is limited in its evaluation of small perforating vessels, which cause 8% of iatrogenic clip infarcts.154 By no means should IA be a substitute for sound surgical technique and judgment.

EEG, electrocorticographic, SEP, and MEP studies are also used to evaluate CBF. EEG monitoring is commonplace for CEA, but its usefulness is limited with barbiturate use, hypothermia, and global ischemia and in the evaluation of subcortical structures. Intraoperative neurophysiologic SEP monitoring is sensitive in detecting cortical ischemia, but MEP monitoring provides more information on subcortical structures and the motor cortex and pathways.155,156 MEP has been found to be more sensitive than SEP monitoring in detecting insufficient blood flow in the MCA and anterior choroidal artery.157,158 MEP monitoring is limited by the fact that the patient is fixed in a head holder and any movement can be disruptive to the surgeon.

Angiography/fluorescence imaging with ICG, a near-infrared fluorescent tricarbocyanine dye used for several decades by cardiologists, is relatively new in neurosurgical application. An intravenous bolus of 0.2 to 0.5 mg/kg (maximum daily dose, 5 mg/kg) of ICG allows the surgeon to perform real-time evaluation of blood flow within vessels in the operative field. de Oliveira and associates performed a prospective study of 60 patients with 64 aneurysms; ICG angiography demonstrated vessel patency in 62 aneurysms.159 ICG angiography is safe and reliable for evaluation of perforating vessels in the surgical field but is limited in patients with deep-seated aneurysms, blood in the surgical field, complete occlusion, and clip obstruction. It is currently undergoing active evaluation in many neurovascular centers.

Complex and giant aneurysms of the skull base and distal vessels present a unique challenge. These lesions may not lend themselves to open surgical clipping or endovascular coil embolization. Even in light of recent advances in endovascular therapy (i.e., stent-assisted coiling), parent vessel ligation and aneurysm trapping, in addition to bypass, may be the only alternative. Surgical success with selective bypass begins with adequate preoperative planning and implementation in appropriate patients. Flow-assisted surgery allows direct intraoperative flow measurement and may help ensure success of the bypass.160 This measurement can be quantified as a cerebral flow index (CFI): CFI = bypass flow/cut flow. With a CFI of 0.5 as a threshold value, the bypass patency rate was 92% in patients with CFIs greater than 0.5 versus 50% in patients with a CFI of less than 0.5.145,160,161

Reduction of Metabolic Activity

Hypothermia

Hypothermia has been shown to reduce neurological morbidity after cardiac arrest162,163 and neonatal hypoxic encephalopathy.164,165 Intraoperative mild hypothermia can be used during aneurysm surgery to reduce the ischemic injury induced by temporary vessel occlusion and brain retraction. Hypothermia ameliorates the primary and secondary mechanisms of ischemic injury, including metabolism, release of glutamate, generation of NO by NOS, and myeloperoxidase activity, in animal models of focal ischemia.166170 Han and coworkers demonstrated that a decrease in NO produced a 40% reduction in infarct size, a 50% reduction in cells immunoreactive for inducible NOS and peroxynitrite—one of the most dangerous free radicals generated from NO—and the production of superoxide dismutase, thereby resulting in a reduction in the generation of oxygen free radicals.171

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