CHAPTER 345 Intraoperative Cerebral Protection
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.4–8 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).
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.4,9–11 CBF in the penumbra has been determined to be between 10 and 20 mL/100 g per minute.7,12–16 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).19–21 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
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 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+.25–28 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%.31–34 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.36–38 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.40–46 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).49–56
FIGURE 345-3 Simplified overview of pathophysiologic mechanisms in a focally ischemic brain. Energy failure leads to depolarization of neurons. Activation of specific glutamate receptors dramatically increases intracellular levels of Ca2+, Na+, and Cl−, whereas K+ is released into the extracellular space. Diffusion of glutamate (Glu) and K+ in the extracellular space can propagate a series of spreading waves of depolarization (peri-infarct depolarizations). Water shifts to the intracellular space via osmotic gradients, and cells swell (edema). The universal intracellular messenger Ca2+ overactivates numerous enzyme systems (e.g., proteases, lipases, endonucleases). Free radicals, which damage membranes (lipolysis), mitochondria, and DNA, are generated and in turn trigger caspase-mediated cell death (apoptosis). Free radicals also induce the formation of inflammatory mediators, which activate microglia and lead to the invasion of blood-borne inflammatory cells.31
(Used with permission from Barrow Neurological Institute.)
FIGURE 345-4 Calcium handling by cells. Calcium enters the cell through voltage- and agonist-operated channels and through nonspecific channels, such as those opened by reactive oxygen species (ROS), whereas Ca2+ is extruded from the cell by an adenosine triphosphate (ATP)-driven pump or by Ca2+-Na+ exchange. Cytosolic calcium (Ca2+) is sequestered by mitochondria and endoplasmic reticulum (ER) at the expense of respiratory energy or ATP, and it is bound to calcium-binding molecules. Ca2+ is released from the ER in response to agonist activation of receptors coupled to phospholipase C (PLC) and the formation of inositol 1,4,5-triphosphate (IP3) from phosphatidylinositol 4,5-bisphosphate (PIP2). A rise in Ca2+ can cause translocation of protein kinase C (PKC) to membranes where it may be activated by diglycerides (DG) formed during hydrolysis of PIP2. Accumulation of Ca2+ in mitochondria can lead to the activation of a mitochondrial permeability transition (MPT) pore and result in the release of Ca2+ and other molecules with molecular weights of up to 1.5 kD from intramitochondrial compartments.39 ADP, adenosine diphosphate; APCD, 1-aminocyclopentane-1S,3R-dicarboxylic acid; ICDH, isocitrate dehydrogenase; OGDH, oxoglutarate dehydrogenase PDH, pyruvate dehydrogenase; Quis, quisqualate.
(Used with permission from Barrow Neurological Institute.)
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,57–59 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.64–68 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.74–76 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.80–82 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.82,85–90
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.53,91–95 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
Integration of Cellular Injury Mechanisms
Ischemic injury causes dynamic and highly interrelated biochemical changes that have variable outcomes. In the absence of collateral circulation, neuronal tissue undergoes necrosis. When the collateral circulation is able to maintain cellular integrity, these neurons can survive for a finite period but are susceptible to injury leading to various end points, including necrosis, apoptosis, and reperfusion injury (Fig. 345-6).
Cerebroprotective Strategies for Focal 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.107–111 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.107,112–115 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.109,116–128 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.136–138 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 CEA142–144 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.146–149 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.166–170 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
Both mild hypothermia (33°C to 34.5°C) and moderate hypothermia (27.5°C to 30°C) have been associated with decreased infarct size in experimental animals.172–176 Cooling animals beyond 33°C does not appear to provide greater benefit.177 Huh and coworkers demonstrated that both intra-ischemic and postischemic cooling to 32°C in rats with MCA occlusion reduced infarct size by 89% and 88%, respectively.178 Lo and Steinberg found an equivalent benefit of mild and moderate hypothermia as measured by the recovery of evoked potentials and magnetic resonance imaging parameters in rabbits after permanent focal ischemia.179 Karibe and coauthors reported that mild hypothermia was protective when delayed up to 30 minutes after the onset of ischemia but that hypothermia induced 60 minutes after the insult was not beneficial in the rat model.180 Karibe and colleagues also demonstrated an increase in ipsilateral frontal cortex CBF in 12 hypothermic patients versus 12 normothermic patients at day 4.181 Hypothermia ameliorated the focal ischemic injury caused by frontal brain retractor placement.
Conventional cooling has been compared with endovascular cooling. Steinberg and associates found that placement of an endovascular heat exchange catheter in the inferior vena cava via the femoral vein resulted in faster cooling (4.8°C/hr versus 0.9°C/hr with conventional cooling), and 99% of patients reached a target 33°C at the time of clipping as opposed to 20% cooled by conventional means.182
The safety of intraoperative moderate hypothermia has been evaluated. Kimme and coauthors reported on 326 patients who underwent 359 aneurysm-clipping operations.183 No significant difference in circulatory instability, coagulopathy, and infection was evident in comparison to previous studies. Pulmonary complications (ventilator dependency) were thought to be secondary to neurogenic pulmonary edema and could be ameliorated by rapid rewarming and early extubation.
Recently, the Intraoperative Hypothermia After Aneurysm Surgery Trial (IHAST2), an international double-blind trial in which 1001 grade I to III aneurysmal subarachnoid hemorrhage patients were subjected to mild hypothermia (33°C at clip placement) versus normothermia (36.5°C), was conducted. The study demonstrated no improvement with hypothermia, with 66% of hypothermia patients and 63% of normothermia patients reaching a Glasgow Outcome Scale score of 1.184 Hypothermia with circulatory arrest is most often used during aneurysm surgery for giant and complex posterior circulation aneurysms, including those not amenable to endovascular treatment; those with significant intra-aneurysmal thrombus, broad necks, or a projection endangering dissection and preservation of perforators; those adhering to vital structures; and fusiform aneurysms with a distal vessel not suitable for arterial bypass.
Anesthesia (Barbiturates, Etomidate, and Propofol)
Most drugs selected as anesthetics suppress neurotransmission. Such suppression reduces energy requirements, and a reduction in energy requirements should allow tissue to better preserve energy balance during transient interruption of substrate delivery. Because ATP synthesis recovers rapidly after restoration of substrate delivery, anesthetics would be expected to be protective if present during ischemia but not if given after restoration of substrate delivery. The beneficial effect of barbiturates in the treatment of experimental focal cerebral ischemia is well documented.118,185–189 The systemic cardiovascular effects and protracted depression of consciousness after barbiturate administration, as well as the potential need for prolonged postoperative mechanical ventilation, may, however, complicate the use of high-dose barbiturates in clinical situations.
Two groups of investigators have shown that rats anesthetized with barbiturates at doses producing mild EEG suppression have an equivalent reduction in infarct volume as those with barbiturate doses intended to maintain EEG burst suppression.190,191 The use of lower doses in the clinical setting may permit safer administration of barbiturates during cerebrovascular procedures.
Etomidate and propofol, short-acting anesthetics with EEG effects similar to those of barbiturates but without cardiovascular side effects, have been proposed for use in cerebrovascular procedures.128,192,193 Propofol has been shown to reduce intracranial pressure and cerebral swelling while lowering cerebral infusion pressure and CBF to a lesser extent than isoflurane or sevoflurane194 and causes fewer episodes of hypotension during elective intracranial surgery.195 In the past decade, propofol has been shown to be neuroprotective in vivo through its antioxidant protection against peroxynitrite by altering antiapoptotic gene expression and influencing the anti-inflammatory cytokine balance.196
Lavine and coauthors reported a retrospective analysis of 49 patients who underwent surgery for MCA aneurysms.197 Thirty-eight patients received intravenous pentobarbital, etomidate, or propofol, whereas the remaining 11 inhaled isoflurane. Postoperative radiographic evidence of infarction was present in 45.5% of patients receiving the inhaled agent as opposed to 15.8% of those who underwent intravenous anesthesia. Occlusion time was significantly longer in the pentobarbital group: 3.9 ± 2.2 minutes versus 13.6 ± 10.6 minutes in the no-stroke cohort. Although the retrospective, nonrandomized, historical control study design does not allow a definitive statement regarding the benefit of these agents or a comparison of them, it is the best evidence to date demonstrating a protective effect with their use during temporary intracranial vessel occlusion.
Serum Glucose Modulation
Glucose, the fundamental substrate of the central nervous system, is essential for appropriate neuron function, but hyperglycemia in the absence of oxygen results in anaerobic glycolysis and subsequent intracellular lactic acidosis after ischemia, which has been shown to increase ischemic injury by exacerbating damage to neurons and glia in the laboratory and clinical setting.198,199 Hyperglycemia has been shown to negatively influence outcomes in ischemic stroke patients.
Pasternak and colleagues examined post hoc data from 1000 IHAST patients with blood glucose levels higher than 129 mg/mL and found that they had worse neuropsychological outcomes at 3 months than did normoglycemic patients.200 In light of this finding, it is prudent to limit, monitor, and control the amount of glucose delivered in intravenous solutions during cerebrovascular procedures.
Cytoprotective Agents
Within the past few years, a variety of pharmacologic agents have been developed that interfere with biochemical mediators of the ischemic cascade. These compounds have been neuroprotective in experimental stroke models. Drug development has been directed toward pharmaceuticals that will protect patients with acute ischemic stroke. Unfortunately, agents that have survived phase III trials have failed to prove efficacious.201 Additionally, none have been systematically tested in the setting of iatrogenic focal ischemia. It seems intuitive, however, that if a drug proves beneficial when given several hours after the onset of ischemic stroke, the same drug might be protective if given at or just before the onset of focal ischemia during cerebrovascular surgery.
Calcium Channel Blockers
In animal studies of focal cerebral ischemia, a variety of calcium channel antagonists have been associated with reduced infarct volume, decreased peri-infarct edema, improved CBF, and improved neurological outcome.202–213 Nimodipine is a 1,4-dihydropyridine that is more lipophilic than nifedipine and dilates cerebral vessels at lower doses than those required for peripheral vasodilation.214 Nimodipine given within 12 hours of ischemic stroke has been associated with reduced mortality and greater neurological improvement in several studies215–218 but is not beneficial when given from 12 to 48 hours after the ictus.219–222 However, a trial of nimodipine administered within 6 hours of stoke demonstrated no benefit over placebo.223
Glutamate Antagonists
NMDA antagonists have shown beneficial effects in reducing the volume of infarction in a variety of experimental models.224–232 Those with potential clinical efficacy include dextrorphan, dextromethorphan, licostinel, and magnesium.228–235 Perhaps the most promising of these agents for intraoperative use is magnesium. Magnesium has reduced the extent of infarction in several experimental models and has a long history of safe use in humans.236–242 Marinov and coauthors reported that MgSO4 given intra-arterially to rats before temporary MCA occlusion resulted in a 19% to 28% reduction in the volume of infarction, depending on the duration of ischemia.239
Nitric Oxide Synthase Inhibitors
NOS inhibitors and free radical scavengers have provided significant neuroprotection in experimental animals subjected to focal ischemia.243–248 Tirilazad mesylate is a potent inhibitor of lipid peroxidation through suppression of inducible NOS.249 Most studies have shown a significant reduction in infarct volume in focal ischemia models236,250–255; however, human studies for the treatment of ischemic stroke have produced conflicting results.256,257 A multicenter, randomized, placebo-controlled study of tirilazad in patients with acute ischemic stroke was halted prematurely because of lack of benefit.258
Lubeluzole
Lubeluzole, a benzothiazole derivative, is a novel agent that may provide effective therapy for focal ischemia. The drug blocks the postischemic release of glutamate and taurine, blocks Ca2+ and Na+ channels, and inhibits the glutamate-activated NOS pathway.259–264 In focal ischemia models, lubeluzole reduced infarct volume by approximately 25%,265,266 and studies in humans have shown few side effects.267–269 Three randomized, placebo-controlled studies of patients with acute ischemic stroke have reported encouraging results.270–272 Unfortunately, the improvement was in a different outcome measure in each study. Additional clinical trials have failed to show efficacy in the treatment of acute stroke.264
Citicoline
Citicoline (cytidine 5-diphosphocholine) supplies choline and cytidine, both of which are substrates needed for the synthesis of phosphatidylcholine, a key membrane component. Administration of citicoline has been associated with reduced infarct volume in animal models of focal ischemia.273,274 In a multicenter, randomized, placebo-controlled, and blinded study of patients treated within 24 hours of ischemic stroke, citicoline was associated with improved neurologic, cognitive, and functional outcome.275 Most recently, Davalos and coworkers demonstrated in 1652 randomized patients that treatment with 2 g citicoline orally within 24 hours of moderate to severe stroke resulted in a 27.9% recovery rate at 3 months as opposed to 20.2% with placebo.201
Nicardipine
A dihydropyridine antagonist of voltage-sensitive Ca2+ channels, nicardipine has produced inconsistent favorable effects through its vasodilatory action and increase in CBF.276 After MCA occlusion in rats, Kittaka and colleagues demonstrated a direct neuroprotective effect of nicardipine consisting of a reduction in infarct size, improvement in neurological outcome, and a decrease in neuron-specific enolase plasma levels (marker of neuronal injury) without a change in laser Doppler flowmetry (CBF).277
Statins
3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors prevent the first step in cholesterol synthesis. Ischemic injury has been shown to increase central nervous system glutamate release and subsequent excitotoxicity and neuronal cell death through release of calcium and excessive activation of the NMDA receptor. Recently, statins have been demonstrated to provide additional neuroprotection by preventing protected neurons from NMDA-induced neuronal death by 70% through protein rafts.278 In addition, statins have been shown to upregulate the cell survival Bcl-2 gene.279 Lovastatin has also been shown to protect cortical neurons against glutamate-mediated excitotoxicity. Lovastatin increased tumor necrosis factor receptor 2 (TNFR2) expression in cortical neurons. It was previously demonstrated that activation of TNFR2 signaling, which includes phosphorylation of protein kinase B/Akt and activation of nuclear factor κB, protects neurons against ischemic or excitotoxic insults.280
Other Cytoprotective Agents
Other classes of agents have shown promise in laboratory studies of focal ischemia but have undergone limited testing in the clinical setting. Such agents include antibodies designed to prevent leukocyte adhesion, growth factors, caspase inhibitors, DP-b99 (a zinc and calcium chelator), and NXY-059 (free radical scavenger). Antibodies to intercellular adhesion molecule-1 (ICAM-1), CD11/CD18 integrin, and P-selectin have reduced infarct volume in focal models of ischemia.281–283 An uncontrolled study of enlimomab (an anti–ICAM-1 antibody) in patients with ischemic stroke showed minimal side effects284; however, increased mortality and poorer functional outcome were reported in a placebo-controlled trial.285
In experimental models of ischemia, DP-b99 reduced infarct volume and neuron-specific enolase release and increased survival rates.286,287 Unfortunately, a randomized controlled trial by Diener and coworkers failed to demonstrate an improvement in the 90-day National Institutes of Health Stroke Scale (NIHSS) score in 150 stroke patients treated with a 4-day course of DP-b99 versus placebo.288 In addition, NXY-059, a nitrone compound with free radical trapping properties, reduced infarct volume in rats.289,290 In a clinical trial, 1722 patients received NXY-059 versus placebo within 6 hours of stroke (recombinant tissue plasminogen activator was given within 3 hours of ictus). Patients in the NXY-059 group showed an improvement in the modified Rankin score but not in the NIHSS score.291
Surgical Protocol
Before temporary artery occlusion, mild hypertension to approximately 10% above the patient’s baseline mean arterial pressure can be induced with phenylephrine, and an anesthetic regimen consisting of propofol and an inhaled agent is administered for general anesthesia. A loading dose of thiopental (10 mg/kg) can be given, followed by a maintenance infusion titrated to maintain EEG burst suppression (approximately 3 to 5 mg/kg per hour). If possible, occlusion is performed in an intermittent fashion on the basis of time limitations or electrophysiologic evidence of altered function (Fig. 345-7). After permanent clipping, the barbiturate administration is stopped and active rewarming is instituted as soon as blood flow is restored by removal of the temporary clip.
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