Focal Cerebral Ischemia: Pathophysiologic Mechanisms and Rationale for Future Avenues of Treatment

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1 Subject Review Focal Cerebral Ischemia: Pathophysiologic Mechanisms and Rationale for Future Avenues of Treatment FREDRIC B. MEYER, M.D., Resident in Neurologic Surgery*; THORALF M. SUNDT, Jr., M.D., Department of Neurologic Surgery; TAKEHIKO YANAGIHARA, M.D., Department of Neurology; ROBERT E. ANDERSON, B.S., Department of Neurologic Surgery Although approximately 500,000 patients suffer from a stroke each year in the United States, treatment of these patients to date has consisted primarily of prevention, supportive measures, and rehabilitation. The modification of experimental cerebral infarction by new pharmacologic agents, along with encouraging results from the restoration of blood flow to areas of focal ischemia in both laboratory and clinical trials, suggests that a more aggressive approach might be considered in selected patients with acute stroke. Despite new insights into the pathophysiologic mechanisms of cerebral infarction, the treatment of focal cerebral ischemia is usually limited to aggressive anticoagulation and supportive measures. This conservative approach may reflect both the lack of proven beneficial therapeutic measures and the question of applicability of experimental models to actual clinical situations. 1 In light of recent evidence in support of the efficacy of certain agents and the role of revascularization, the conventional treatment of focal cerebral ischemia should be critically reevaluated. In this article, we review the cause and pathophysiologic mechanisms of focal cerebral ischemia and consider the applicability of medical and surgical treatment modalities currently under laboratory investigation. FOCAL VERSUS GLOBAL ISCHEMIA Focal cerebral ischemia is a clinical entity distinct from global cerebral ischemia as observed, for *Mayo Graduate School of Medicine, Rochester, Minnesota. Address reprint requests to Dr. T. M. Sundt, Jr., Department of Neurologic Surgery, Mayo Clinic, Rochester, MN example, in patients who have experienced cardiac arrest. The notable differences are that (1) patients with global ischemia have no collateral flow, and irreversible neuronal damage commences within 4 to 8 minutes under normothermic conditions; 2 " 5 (2) in focal ischemia, the trickle of flow from the collateral circulation leads to a more complex biochemical situation including the delivery of glucose under anaerobic conditions, which causes a profound acidosis; and (3) this potential for collateral flow in focal ischemia may facilitate possible reversal of neuronal damage after extended periods of ischemia. Therefore, the pathophysiologic features and treatment of global ischemia differ from those of focal ischemia and will not be considered further in this review. PATHOPHYSIOLOGIC MECHANISMS The pathophysiologic characteristics of focal cerebral ischemia can be analyzed in terms of thresholds of cerebral ischemia, metabolic derangements, and microcirculatory changes. Thresholds of Cerebral Ischemia. In 1948, Kety and Schmidt 6 first measured a normal cerebral blood flow (CBF) in humans of approximately 53 ml/100 g per min. Some 25 years later, two Mayo Clin Proc 62:35-55,

2 36 FOCAL CEREBRAL ISCHEMIA Mayo Clin Proc, January 1987, Vol 62 separate teams of investigators in Denmark and at the Mayo Clinic found, in patients undergoing carotid endarterectomy, that the threshold for brain electrical failure (attenuation in electroencephalograms) approximated 15 to 18 ml/100 g per min. 7,8 Thereafter, in laboratory studies Branston and associates 9 showed that the somatosensory evoked potentials were suppressed when CBF was less than 15 ml/100 g per min. Thus, a threshold of electrical failure was quantitated at 15 to 18 ml/100 g per min, a range that has proved to be relatively constant in numerous animal models anesthetized with various agents. 10,11 In addition, a threshold of ionic failure was substantiated at approximately 10 ml/100 g per min. At this level of flow, investigators noted alterations in extracellular potassium and intracellular calcium, liberation of free fatty acids, disturbances in the water content of the brain, rapid depletion of adenosine triphosphate (ATP), and a profound intracellular acidosis 12 " 18 (Fig. 1). This threshold of ionic failure is presumed to be a CBF at which irreversible neuronal damage rapidly occurs. Although the tolerance of neuronal tissue for these low flows is unknown, a few studies suggest that after 3 to 4 hours, neuronal death is inevitable. 10,18 " 21 Between these two thresholds of electrical and ionic failure exists a small range of flow at which, despite functional loss, membrane homeostasis and structural integrity are maintained. This circumscribed range of CBF has been conceptualized in the term "ischemic penumbra" 12,22 " 24 and explains why the potential for recovery exists in patients with acute focal ischemia if sufficient collateral flow is present to satisfy basic energy requirements. Some evidence suggests, however, that this "ischemic penumbra" is a dynamic state that will deteriorate over time (Fig. I). 18,25 Therefore, after acute occlusion of a vessel, the clinical outcome will reflect both the severity and the duration of reduced flow. Metabolic Derangements. The metabolic aberrations that occur at a CBF of approximately 10 ml/100 g per min are multifactorial and reflect both the rapid depletion of ATP and the accumulation of lactic acid due to the absence of oxidative phosphorylation (Fig. 2). 26 One of the pathways that precipitate irreversible damage is currently thought to be an increase in intracellular calcium. 27 " 31 Failure of ATP-dependent Na + -K + transport, and the resultant increased extracellular K +, will depolarize the neuronal membrane. This situation results in opening of voltage-sensitive calcium channels and an increase in intracellular free calcium (Fig. 3). 17 This influx of calcium is enhanced by failure of the ATP-dependent Na + -Ca + antiport system, failure of the ATPdependent sequestration of Ca + by the endoplasmic reticulum, and electrophoretic accumulation of calcium by mitochondria, which will uncouple oxidative phosphorylation This uncountered increase in intracellular calcium is thought to activate phospholipase A and C, which will attack membrane phospholipids with the production of free fatty acids. 29,30 This loss of membrane phospholipids will increase the permeability of neuronal and mitochondrial membranes, which will further alter calcium homeostasis with additional detrimental effects on oxidative phosphorylation. The accumulated free fatty acids, especially arachidonic acid, may be oxidized along the cyclooxygenase and lipoxygenase pathways in incomplete ischemia. The end result would be the accumulation of prostaglandins, leukotrienes, and possibly free radicals. 29,30,35,36 Thromboxane A2 is a potent vasoconstrictor, leukotrienes alter membrane permeability and cause vasoconstriction, and free radicals, if present, would attack membranes Therefore, inhibition of voltage-sensitive calcium channels by calcium antagonists might attenuate the foregoing cascade of events. The importance of intracellular acidosis during focal ischemia must also be emphasized. As seen in Figure 1, 10 minutes after occlusion of the middle cerebral artery in the rabbit, intracellular brain ph declines to 6.64 in comparison with the preocclusion value of This finding is a direct reflection of the fourfold increase in lactic acid that occurs during the first minutes of severe ischemia (Fig. 2). 26 Intracellular brain ph then decreases to 6.08 during the next 4 hours, a reflection of the accumulation of both lactic acid and free fatty acids. 26,38 This intracellular acidosis has the following detrimental effects: denaturing of proteins with loss of enzymatic function, increasing glial edema that compromises potential collateral flow, suppressing regeneration of the reduced form of nicotinamide-adenine dinucleotide, and possibly increasing production of free radicals. 39 " 42 In focal ischemia, the continued delivery of glucose under anaerobic conditions will increase production of lactic acid.

3 Mayo Clin Proc, January 1987, Vol 62 FOCAL CEREBRAL ISCHEMIA 37 Microcirculatory Changes. The initial circulatory changes noted after vessel occlusion are a darkening of the venous blood and then a decrease in the velocity of flow through veins and venules. Aggregation of blood elements (sludging or particulate flow) results from a reduction in the shearing forces that tend to keep cells dispersed. 43,44 Consequently, blood viscosity and resistance to flow increase. Measurements of the caliber of arteries and arterioles reveal an immediate slight increase. At a variable time after occlusion, cortical pallor develops, the earliest indication of severe ischemia (Fig. 4). When this pallor extends to an area underlying an artery or arteriole, a spasm occurs in that vessel. 45 The mechanism of this ischemia-induced secondary vasospasm is un- Brain intraceilular PH r Moderate ischemia ^. Severe ischemia Control imca I Occluded v 1 -~'---H Tissue perfusion (cc/100g/ min) !. " + "',!. NZZ^ --H 60 _ PaC \ Time (min) Fig. 1. Measurements of intraceilular brain ph and tissue perfusion (cortical blood flow [CBF]) in regions of both severe and moderate ischemia after occlusion of middle cerebral artery (MCA) in the rabbit. Before occlusion, CBF was 51.8 ± 4.6 ml/100 g per min and intraceilular brain ph was 7.01 ± Note normal response of CBF to hypercapnia and hypocapnia before occlusion. In severely ischemic regions (solid line), immediate postocclusion CBF was 12.7 ± 2.3 ml/100 g per min, and brain ph decreased to 6.64 ± 0.06 within 10 minutes (P<0.001). Serial evaluation showed progressive decline in both ph and CBF. Four hours after occlusion, brain ph was 6.08 ± 0.15 and CBF was 5.2 ± 1.5. Histologie analysis with use of light microscopy disclosed ischemic damage in 100% of neurons in this region. In moderately ischemic regions (broken line), although postocclusion flow was 20.0 ± 2.0 ml/100 g per min, brain ph was stable at 6.92 ± Electroencephalographic tracings changed concomitantly (not shown). Therefore, these sites are analogous to "ischemic penumbras." During the next 4 hours, brain ph progressively declined. Four hours after occlusion, CBF was 14.5 ± 3.6 ml/100 g per min (i><0.01) and brain ph was 6.74 ± 0.09 (P<0.001). Histologie evidence of neuronal damage was found in 60 to 70% of neurons examined. Separate animals with sham craniectomy but without occlusion of MCA (dotted line) served as controls for assessing stability of preparation. (Modified from Meyer and associates. 18 By permission of Raven Press.)

4 38 FOCAL CEREBRAL ISCHEMIA Mayo Clin Proc, January 1987, Vol 62 clear, but the cause has been postulated to be either an increase in extracellular K +, which would lead to vascular smooth muscle contraction, or an influx of Ca + into smooth muscle cells. An increase in membrane permeability to Ca + could result from opening of K + depolarized calcium channels, interaction of surface receptors with an extracellular messenger such as serotonin or norepinephrine, or activation of 3',5'-guanosine monophosphate. 46 With restoration of flow to a region of ischemia, the aforementioned chain of events is reversed. The venous blood becomes bright red, particulate flow in the venules is no longer observed, the cortex recolorizes, and, finally, the major vessels resume their normal caliber. Often a true hyperemia develops, with dilatation of conducting vessels in the cortex that were not noted in the normal state. This hyperemia is probably a function of vasomotor paralysis, partially a result of excessive lactic acidosis. During this paralysis, cortical perfusion is directly related to blood pressure. 47 In addition to the intravascular obstruction described (sludging), microcirculatory changes occur the "no-reflow phenomenon," as first described by Ames and colleagues 2 in a model of global ischemia. They postulated that ischemic endothelial damage resulted in impaired vascular filling because of capillary obstruction, after which neurons were then damaged. Electron Occlude + 60 Minutes Release Fig. 2. Measurements of concentrations of cerebral adenosine triphosphate (A TP) and lactate before, during, and after occlusion of middle cerebral artery in monkeys. Preocclusion ATP was 2.00 ±0.11 jumol/g and lactate was /umol/g. After vessel occlusion, ATP declined progressively to 25% of control values at 3 hours. Lactate increased rapidly during first 30 minutes to about 4 times control values. Thereafter, lactate levels increased slowly to about 7 times control values after 2 hours. Despite acute electroencephalographic changes, residual collateral flow was sufficient to support limited metabolism for several hours. Therefore, this finding was early evidence of reversible neuronal damage later conceptualized as "ischemic penumbra." (Data from Michenfelder and Sundt. 26 )

5 Mayo Clin Proc, January 1987, Vol 62 FOCAL CEREBRAL ISCHEMIA 39 % Ischemia 30 min -//- 15 ' ' Re-circulation Period (Min) Ischemia 180 min Fig. 3. Demonstration of transient increase of sodium (closed circles) and calcium (closed triangles) contents (jug/g dry tissue) and decrease of potassium (open circles) content after occlusion of right common carotid artery for 30 minutes and subsequent recirculation in the gerbil. Those alterations became sustained after occlusion for 180 minutes and subsequent recirculation. Water content (%) is shown with cross marks, whereas magnesium content is shown with open triangles. Results are expressed as percentage of the value of right cerebral hemisphere as compared with left cerebral hemisphere based on four experiments (mean ± SEM) for each time interval. P values (*** = <0.01; ** = 0.01<P<0.05; * = 0.05<P<0.1) are based on Student t test by comparison with percentage values (right versus left) from normal gerbils. (Modified from Yanagihara and McCall. 31 By permission of Pergamon Journals, Ltd.) microscopic demonstration of "endothelial blebs" supported this concept. 48 Crowell and Olsson 49 extended this "no-reflow" concept to focal cerebral ischemia by demonstrating impaired vascular filling after transient occlusion of the middle cerebral artery. In the "no-reflow phenomenon," ischemic endothelial damage was postulated to precede neuronal injury. Alternatively, research by Little and colleagues 44 demonstrated that, during focal ischemia, neuronal alterations precede impaired vascular filling and that, at least initially, microvascular obstruction is not the primary determinant of irreversible neuronal damage. Ischemic Edema. One of the primary acute reactions of the brain parenchyma to injury is swelling. Ischemic edema has been divided into an early cytotoxic (intracellular),and a late vasogenic (extracellular) phase. Cytotoxic edema initially involves perivascular glial cells, a finding that suggests that it is secondary to alterations in permeability rather than to the lack of energy substrate. 20,50 Lactic acidosis seems to have a critical role in glial edema. 39 The major detrimental effect of this edema is the impingement on potential collateral flow (Fig. 5). Accordingly, Iannotti and colleagues 51 demonstrated an increase in local tissue pressure in core regions of ischemia commencing within 10 minutes after occlusion of the middle cerebral artery. Corresponding to this increase in tissue pressure was a progressive decline in local CBF. These events occurred early, before the eventual rise in intracranial pressure, and were considered to be a result of local cytotoxic edema. Vasogenic edema occurs hours to days after vessel occlusion and is secondary to irreversible ischemic endothelial damage. The end result is breakdown of the blood-brain barrier and extravasation of plasma into the extracellular compartment. 52,53 Subsequently, the intracranial pressure increases, the extent depending on the volume of the infarct. In turn, secondary effects such as tentorial herniation may occur. Immunohistochemical Alterations. For determination of the reversibility of cerebral ischemia, morphologic assessment of ischemic damage is important. Morphologic damage soon after the onset of ischemia, however, has not been well elucidated because of relative insensitivity of conventional histologic methods. Recent investigations at our institution have demonstrated that the immunohistochemical technique for identifying neuron-enriched or neuron-specific proteins is very sensitive for detection of ischemic and postischemic damage. 54,55 For example, in the gerbil, ischemic lesions of the hippocampus can be identified within 4 minutes after occlusion of a posterior communicating artery (Fig. 6). Approximately 3 minutes later, these ischemic lesions become irreversible. In contrast, a period of 10 minutes of ischemia was necessary before lesions could be detected in the thalamus. 56 These immunohistochemical techniques can be combined with other investigative methods. For example, a recent study that used immunohistochemical and quantitative autoradiographic procedures 57 demonstrated regional differences in tissue vulnerability to CBF of 10 ml/100 g per min or less. Furthermore, immunohistochemically identified vulnerable sites have been analyzed with transmission electron microscopy and immunoelectron micros-

6 40 FOCAL CEREBRAL ISCHEMIA Mayo Clin Proc, January 1987, Vol 62 Fig. 4. Effect of occlusion of middle cerebral artery (MCA) in the monkey. A, Cortex before occlusion of MCA, showing normal caliber of major conducting vessel (large arrow) and location of cortical vein (small arrow). B, Cortex shortly after occlusion of MCA. Diffuse pallor has not yet developed. C, Cortex 1 hour after occlusion. Major artery identified in A is now constricted and cortical pallor is diffuse. Particulate flow is present in adjacent vein (arrowhead). D, Two hours after occlusion, constricted artery has now partially dilated (arrowhead). Note anastomotic artery that was barely visible in A (small arrow). E, Cortex 5 minutes after release of occluding clip. Artery is now more fully dilated, and particulate flow is no longer present in vein. F, Thirty minutes after restoration of flow, brain has recolorized. Conducting vessel is fully dilated (large arrow), and anastomotic artery noted in D has decreased in size (small arrow). (Modified from Sundt and Waltz. 45 By permission of The American Heart Association, Inc.) Dendritic terminals seem to be most vulnerable, and ischemic damage subsequently extends proximally toward neuronal cell bodies. Both variations in tissue vulnerability and the sensitivity of dendrites to ischemia may reflect an increased number of calcium channels at these locations. copy. 58,59 RATIONALE FOR PHARMACOLOGIC THERAPY Herein we will discuss the treatment options that either are of historical interest or seem to be most promising for attenuating neuronal injury during focal ischemia. Certain agents that alleviate damage in global ischemia are of minimal benefit in focal ischemia for example, hypothermia and platelet antagonists. Conversely, some therapeutic measures (such as barbiturates) may attenuate damage in focal but not in global ischemia. Therefore, this review is highly selective and reflects our opinions in regard to specific regimens and their actions in focal ischemia only. Those agents that are most familiar to us because of our own investigations are emphasized; in addition, several other review articles are recom-

7 Mayo Clin Proc, January 1987, Vol 62 FOCAL CEREBRAL ISCHEMIA 41 sm&ä <*,«Fig. 5. Sections of cortex (75 μτη) after infusion of carbon into internal carotid artery, demonstrating effects of glial edema. A, Control nonischemic cortex. B, Pale area of cortex after 3 hours of ischemia. Although penetrating arterioles (arrowheads) are well filled, many capillaries are narrowed and some fail to fill. C, After 6 hours of ischemia, capillary filling is severely impaired. Capillaries appear to be obstructed at their origin from arterioles (arrowhead). (Scale [lower right] = 200 μια.) (From Little and associates. 44 ) mended to provide alternative perspectives on this subject. 60 ' 61 Systemic Supportive Measures. Increasing collateral flow by inducing hypertension and optimal cardiac output may be beneficial. 62 Results of experimental studies, however, have been controversial, some investigators finding evidence of adverse effects secondary to increasing cerebral edema In one laboratory study, measurement of vessel micropressure after occlusion of the middle cerebral artery in cats demonstrated only a slight increase in pressure after induction of hypertension. 66 This finding probably is attributable to the resistance created by secondary vasoconstriction in core regions of ischemia. The fear of increasing the possibility of cerebral edema and hemorrhagic infarction makes clinicians wary of artificially elevating the blood pressure. Alternatively, hypotension will substantially decrease CBF, and neurons with marginal flow may be injured. 62 Although the pathophysiologic mechanism is different, induced hypertension and optimization of cardiac output for ischemia caused by subarachnoid hemorrhage have been proved to be efficacious. 67 Therefore, maintaining an adequate or mildly elevated systolic pressure by hydration with colloids is a reasonable approach in patients with focal cerebral ischemia. Hyperglycemia has been shown to increase lactic acid concentrations in focal ischemia, a result that has deleterious effects on metabolism and survival. 34,39,68-72 During focal ischemia, the residual CBF will continue to supply substrate for anaerobic metabolism. Recent work from our laboratory has confirmed that hyperglycemia worsens intracellular acidosis in primates subjected to occlusion of the middle cerebral artery (Fig. 7). 73 One clinical study has shown a less favorable outcome in patients with ischemic stroke who had hyperglycemia. 74 This result suggests that patients with acute stroke may benefit from hydration with intravenous solutions devoid of glucose. Hemodilution. Early research in our laboratory and elsewhere was focused on agents that would increase microcirculatory flow by decreasing blood viscosity. Analysis of the reports of these studies yields contradictory data. Sundt and colleagues 75,76 demonstrated that although infusion of agents like dextran, saline, and albumin improved cortical blood flow, the morphologic features of the infarction were unaltered in primates, perhaps because of the associated diminution in oxygen-carrying capacity. 77 Alternatively, other investigators have described the opposite results. Wood and colleagues 78 " 80 applied hyper-

8 42 FOCAL CEREBRAL ISCHEMIA Mayo Clin Proc, January 1987, Vol 62 volemic hemodilution to the clinical setting after demonstrating a reduction in blood viscosity and shearing forces and a resultant improvement in CBF in experimental occlusion of the middle cerebral artery. They infused either 5% albumin or dextran 40 to nine patients with acute ischemia. The hematocrit was reduced from 41% to 32%, and central venous pressure was increased from 3.6 to 11.7 mm H2O. Eight patients had objective neurologic improvement 15 minutes to 24 hours after the commencement of therapy. Although six patients had computed tomographic evidence of ischemic damage, the exact mechanism of ischemia was unknown in eight. Therefore, some of these patients may have had transient ischemic attacks. A recent prospective randomized study in Sweden 81 supported the beneficial effects of hypervolemic hemodilution in ischemic stroke; an acute reduction was noted in the hematocrit after venesection and infusion of dextran 40. In that report, 85% of 52 treated patients and 64% of the control patients had improvement in neurologic function within 10 days after the event. Although at 3- month follow-up the mortality rates were similar, the functional outcome was thought to be considerably better in the treated group. One difficulty with this study was the lack of angiographic identification of the pathophysiologic mechanism of ischemia; however, these positive results have prompted a multicenter randomized trial Brain ph 6.70 \ Ϊ- Tissue perfusion % Δ MCA occluded Saline infusion Glucose D5W infusion Serum glucose mg/dl -V/ Time (min) Fig. 6. Photomicrographs, demonstrating disappearance of immunohistochemical reaction for tubulin and creatine kinase BB-isoenzyme from subiculum CA 1 region of right hippocampus after occlusion of right common carotid artery in the gerbil for 10 minutes. In comparison with corresponding areas on nonoccluded side (A and C), note loss of reaction from apical dendrites and pyramidal cell bodies with reaction for tubulin (B) and loss of reaction from apical dendrites with reaction for creatine kinase BB-isoenzyme (D). (Magnification x400.) (From Yanagihara and associates. 54 By permission of the American Association of Neuropathologists, Inc.) Fig. 7. Measurements of intracellular brain ph and percentage change in tissue perfusion in six monkeys infused with saline (solid line) and six infused with 5% dextrose in water (D5W) (dashed line). Preocclusion brain ph and tissue perfusion were similar in the two groups. After occlusion of middle cerebral artery (MCA), infusion of glucose caused a significant decrease in brain ph: intracellular brain ph was in control animals and 6.27 ± 0.02 in glucose-infused animals (P<0.005). The percentage decline in tissue perfusion at 3 hours (23% in control and 15% in infused animals) was significant (P<0.05). Presumably, worsening of intracellular acidosis caused glial edema and compromise of collateral circulation, t = time of death. (From Marsh and associates. 73 By permission of the American Association of Neurological Surgeons.)

9 Mayo Clin Proc, January 1987, Vol 62 FOCAL CEREBRAL ISCHEMIA 43 Caution must still be exercised in evaluating this mode of treatment. 83 For example, in a recently published abstract the effects of isovolemic hemodilution in three patients with acute stroke were analyzed by positron-emission tomographic measurements of CBF and oxygen metabolism. This procedure identified "viable tissue at risk" surrounding the regions of evolving infarcts. These areas of reduced blood flow but normal oxygen metabolism would perhaps correspond to ischemic penumbras. Although CBF improved with hemodilution, oxygen metabolism did not increase, and the clinical status remained relatively unchanged. These same regions, however, did not deteriorate into infarcts. 84 Wood and Kee 85 currently advocate hypervolemic hemodilution. Specifically, they recommend a reduction in hematocrit to 33% of baseline values and maintenance of central venous pressure between 8 and 12 cm H2O or a pulmonary capillary wedge pressure of less than 20 mm Hg. Several researchers have attempted to decrease blood viscosity by increasing erythrocyte deformability, 86 reducing fibrinogen, 87,88 or inhibiting platelet aggregation. 89 The efficacy of these approaches remains unproved. Mannitol and perfluorocarbons, which also decrease blood viscosity, will be discussed separately. Anticoagulation. Anticoagulants such as heparin have no proven benefit in the treatment of acute stroke. These agents were initially recommended as a means of reducing blood viscosity by decreasing particulate flow. Sundt and Waltz, 76 however, found no ameliorating effects with use of anticoagulants in focal cerebral ischemia. In specific clinical situations, anticoagulants may be prescribed to prevent further embolization or propagation of thrombi. Approximately 15 reports have described the use of urokinase or streptokinase in the treatment of acute vertebrobasilar or carotid occlusion. 90 " 95 Although some results are impressive, the risk of hemorrhagic infarction associated with this therapy is undefined. An important fact to note, however, is that the incidence of intracerebral hemorrhage in patients with noncerebrovascular occlusions treated with these medications is approximately 3%. 96 ' 97 In contrast, a recent report suggested that tissue plasminogen activator may lyse experimental cerebral emboli without increasing the risk of hemorrhagic infarction. 98 Despite the substantial improvement in neurologic outcome of treated animals, however, no difference in size or distribution of histologic infarction was noted between treated and control groups. Corticosteroids. Although a few reports have described positive effects, 99,100 the overwhelming consensus is that corticosteroids are of no benefit in attenuating either cytotoxic or vasogenic ischemic edema. 101 " 103 Clinical trials have confirmed these negative laboratory findings. 104 Interestingly, a recent report suggested an improved outcome after reperfusion if animals were pretreated by adrenalectomy. 105 Barbiturates. Barbiturates in a dose of 20 to 70 mg/kg, given either before or after the induction of focal ischemia, have proved beneficial in several experimental protocols. 106 " 113 Michenfelder and associates 114 " 117 initially proposed that barbiturate protection was selective. They postulated that cerebral metabolism could be divided into a basal metabolic component that consisted of the metabolism necessary to maintain membrane integrity and a second component of activated metabolism responsible for functional activity. They suggested that barbiturates selectively decreased the activated component of metabolism and thereby enabled a larger share of the energy charge of the cell to be available for basic cell function. Other proposed mechanisms include scavenging of free radicals, 118,119 preventing production of free fatty acids, 120 attenuating cerebral edema, 109 and improving the microcirculation. 121 Despite these encouraging results, the use of barbiturates in acute stroke remains equivocal because of problems with respiratory depression and alterations in mental status. 122,123 Selman and associates 124 extensively investigated the effects of barbiturates in focal ischemia, in terms of timing of treatment and duration of ischemia. Their work indicated that barbiturates must be given within 1 hour after occlusion to achieve a beneficial effect. Furthermore, if flow is not restored, barbiturates may exert an adverse effect Currently at our institution, thiopental in a dose of 3 to 5 mg/kg is administered in a controlled anesthetic setting before vessel occlusion during intracranial revascularization procedures. Calcium Antagonists. Calcium antagonists that preferentially act on the central nervous system are a promising alternative for use in cerebral ischemia. 125 On the basis of the pathophysiologic mechanisms previously discussed,

10 44 FOCAL CEREBRAL ISCHEMIA Mayo Clin Proc, January 1987, Vol 62 they could act by either preventing calcium flux into the ischemic neuron or antagonizing calciummediated ischemic vasoconstriction. In vitro they dilate cerebral vessels preconstricted with a variety of agents including K +, serotonin, norepinephrine, serum, and prostaglandin F 2 ; 126 they attenuate the postischemic hypoperfusion state after both focal and global ischemia; and they increase CBF in nonischemic models. 125,130 Nimodipine also preserves the energy state during ischemia and after reperfusion. 131 Results of the few studies of the effects of calcium antagonists in focal ischemia, however, are contradictory Recently, we evaluated the effects of nimodipine on intracellular brain ph, cortical blood flow, and electroencephalography in experimental focal ischemia. 135 Nimodipine, at a constant intravenous infusion of 0.5 //g/kg per min given after occlusion of the middle cerebral artery, improved both the metabolic and the electrical function of neurons (Fig. 8). For example, the preocclusion intracellular brain ph was 7.01 ± Four hours after occlusion, brain ph in control animals was 6.08 ± 0.15 in comparison with nimodipine-treated animals with a brain ph of 6.91 ± 0.06 (P<0.001). The electroencephalograms also showed improvement in 70% of treated animals as compared with the controls, none of which had improvement (P<0.01). Concomitant with the improvement in intracellular brain ph was a 90 to 130% increase in cortical blood flow. For example, baseline CBF was 51.8 ± 4.6 ml/100 g per min. In the control animals, CBF was 12.7 ± 2.3 ml/100 g per min 1 hour after occlusion and 5.2 ± 1.5 ml/100 g per min at 4 hours. In the nimodipine-treated animals, the postocclusion 1-hour and 4-hour flows were 24.2 ± 3.3 and 18.8 ± 3.0 ml/100 g per min, respectively (P<0.001). Therefore, nimodipine elevated CBF above the threshold of ionic failure, and the improvements in intracellular brain ph and electroencephalographic tracings could be explained independent of any direct effects on neuronal metabolism. Inspection of the cerebral cortex revealed reversal of ischemia-induced vasoconstriction. Additional studies from our laboratory have shown diminution of infarct size as assessed by immunohistochemistry after occlusion of the middle cerebral artery. 136 Tissue perfusion ml/ 100 g/ min Gelmers 137 reported the action of calcium antagonists in humans who had acute focal ischemia. Five patients received 15 /ug/kg and five received 30 /ig/kg of nimodipine as an intracarotid infu- Intracellular brain ph 6.4 Nimodipine TX Control, occlusion Control, no occlusion J L HH Time (min) Fig. 8. Graph of mean values for tissue perfusion and intracellular brain ph in 10 severely ischemic control sites (solid line) and 10 severely ischemic nimodipine-treated sites (broken line) in rabbits. In each rabbit, two measurements of blood flow and brain ph were performed at a PaCU2 of 40 torr after a normal PaCOi response curve before occlusion of middle cerebral artery (MCA). When data from all 20 animals were pooled, preocclusion cortical blood flow was 51.8 ± 4.6 ml/100 g per min and intracellular brain ph was 7.01 ± Initial postocclusion blood flow was 12.7 ± 2.3 ml/100 g per min in control animals and 10.5 ±1.3 ml/100 g per min in nimodipinetreated animals. Initial postocclusion brain ph was 6.64 ± 0.06 in control animals and 6.57 ± 0.03 in nimodipine-treated animals. During subsequent 4 hours, control rabbits had a progressive decline in both blood flow and brain ph. With nimodipine treatment (TX), blood flow increased to 24.2 ± 3.3 ml/100 g per min in the first hour (P<0.001). Improvement in blood flow in treated versus control rabbits was significant at each hourly interval (P<0.001). Nimodipine treatment also improved intracellular brain ph at each interval; it was 6.91 ± 0.06 at the fourth hour (i><0.001). Three additional animals without occlusion of MCA (dotted line) underwent measurement of brain ph and blood flow for 4 hours for assessment of stability of preparation. (Modified from Meyer and associates. 135 By permission of the American Association of Neurological Surgeons.) sion. Inhalation 133 Xe studies demonstrated a dose-dependent increase in CBF. In three patients, a reverse steal phenomenon was suggested by a relative increase in CBF to the region of focal ischemia as compared with the ipsilateral hemisphere. Perfluorocarbons. Peerless and colleagues 138,139 provided evidence that perfluorocarbons, low-viscosity oxygen-carrying agents, improve both the microcirculation and the delivery

11 Mayo Clin Proc, January 1987, Vol 62 FOCAL CEREBRAL ISCHEMIA 45 of oxygen to ischemic tissue. They demonstrated that an intravenous infusion of 20% Fluosol-DA retarded the evolution of histologic infarction in cats. One laboratory showed that isolated rat brains perfused with a fluorocarbon emulsion maintained metabolic and electrical activity for up to 7 hours. 140 In one study in which 20% Fluosol- DA was administered to patients with ischemic deficits due to subarachnoid hemorrhage, 12 ofthe 20 patients had a dramatic improvement in their neurologic function. 141 Currently, use of this therapeutic modality is limited because of the requirement of a high concentration of inspired oxygen for saturation of perfluorocarbons and the question of toxicity. Results of the limited research with this agent, however, have been promising and merit further investigation. Mannitol. Little and O'Shaughnessy demonstrated that mannitol in a dose of 1.2 g/kg attenuates ischemic neuronal damage when divided into doses given immediately before and then after occlusion of the middle cerebral artery. Peerless and colleagues 138 confirmed the beneficial effects of 1.2 g/kg of mannitol when administered after occlusion of the middle cerebral artery in cats. Certain neurosurgical groups advocate the intraoperative use of mannitol before vessel occlusion. 145,146 Its proposed actions include reduction in cytotoxic edema, improvement in microcirculatory flow, and free radical scavenging. 147,148 Recently, we assessed intracellular brain ph, CBF, and electroencephalography in a model identical to that used to evaluate calcium antagonists, except mannitol (1 g/kg) was given after occlusion of the middle cerebral artery. 149 Our preliminary results only partially support the findings of the aforementioned investigators. Mannitol stabilized cortical blood flow and intracellular brain ph in the ischemic penumbra but not in the core regions of ischemia. Naloxone. Several highly publicized reports have attested to the beneficial effects of naloxone in the treatment of cerebral ischemia. 150,151 Review of the literature, however, shows contradictory results in gerbils, cats, monkeys, and humans If this drug is beneficial, its mechanism of action may be vasodilatation of the cerebral vasculature, 158 as opposed to competitive inhibition of opiate receptors in the central nervous system. 151 In our laboratory, naloxone given after occlusion ofthe middle cerebral artery in cats did not influence CBF, infarct size, electroencephalographic recovery, or neurologic outcome. 152 Therefore, in our opinion, further laboratory investigation is needed before this drug can be endorsed. Propranolol. Some experimental evidence indicates that brain tissue concentrations of norepinephrine and dopamine increase during cerebral ischemia. 159,160 The highest density of /3-adrenergic receptors in the brain is found in the corpus striatum and the cerebral cortex on the neuronal and glial membranes. Excessive stimulation of these receptors could theoretically increase glucose metabolism under anaerobic conditions and thereby worsen intracellular acidosis. Propranolol reduces cerebral glucose metabolism and oxygen consumption in the nonischemic state. 161 Little and associates 162 " 164 evaluated the effects of propranolol when given before and after temporary focal cerebral ischemia in cats subjected to occlusion of the middle cerebral artery. They demonstrated a reduction in infarct size and cerebral edema along with an improved neurologic outcome. This beneficial effect might well be due to suppression of production of lactic acid. Because the safety and the pharmacokinetics of propranolol are well known, early clinical trials might be warranted. Experience in patients with subacute cerebral infarction has suggested that propranolol improves metabolic function and cerebral autoregulation. 165,166 Free Radical Scavengers. Free radicals, highly reactive compounds with a single electron in the outer orbit, are present in the electron transport chain of mitochondria. Oxygen normally terminates the reactions of a free radical by its reduction to water. Some investigators have postulated that, during ischemia, free radicals produced by a cyclooxygenase and lipoxygenase pathway react pathologically with membrane lipids. 36,37,167 " 171 Because this pathway requires the presence of oxygen, production of free radicals is maximal during reflow. 170 During ischemia without reflow, free radicals from the electron transport chain may be dislocated because ofthe lack of oxygen-accepting electrons at the cytochrome oxidase step. Flamm and co-workers 171 investigated this lastmentioned mechanism by demonstrating a reduction in the naturally occurring antioxidant ascorbic acid after occlusion of the middle cerebral artery in cats. Because direct quantification of free radicals is difficult, this result was offered as

12 46 FOCAL CEREBRAL ISCHEMIA Mayo Clin Proc, January 1987, Vol 62 indirect evidence of their formation in ischemia without reflow. In recent work from our laboratory, Superoxide dismutase, a known free radical scavenger, was shown to stabilize intracellular brain ph and cortical blood flow during occlusion of the middle cerebral artery (Fig. 9). 172 As previously mentioned, investigators have proposed that barbiturates and mannitol function as free radical scavengers. 118,148 or-tocopherol may also inhibit lipid peroxidation in the brain. 173 Although agents such as Superoxide dismutase, CBF ml/ 100 g/ min Intracellular brain ph i-^v + + f - V- H ^ + H SOD I Control, occlusion J I L // Time (min) Fig. 9. Graph of mean values for cortical blood flow (CBF) and intracellular brain ph in 10 severely ischemic control sites (solid line) and 10 severely ischemic Superoxide dismutase (SOfl)-treated sites (broken line) in experimental studies in animals. In each animal, two measurements of blood flow and brain ph were performed at a PaCOi of 40 torr after a normal PaC02 response curve before occlusion of middle cerebral artery (MCA). When data from all 20 animals were pooled, preocclusion CBF was 52.4 ± 4.3 ml/100 g per min and intracellular brain ph was 7.02 ± Initial postocclusion blood flow was 12.7 ± 2.3 ml/100 g per min in control animals and 13.5 ± 1.0 ml/100 g per min in SOD-treated animals. Initial postocclusion brain ph was 6.64 ± 0.06 in control animals and 6.61 ± 0.02 in treated animals. An intravenous (IV) bolus of 15,000 units of SOD stabilized intracellular brain ph. Four hours after occlusion, brain ph was 6.08 ± 0.15 in control animals and 6.62 ± 0.05 in SOD-treated animals (P<0.001). Free radicals are theorized to attack cell membranes and liberate free fatty acids, a situation that worsens intracellular acidosis. SOD could attenuate this catalytic pathway. Alternatively, stabilization of brain ph might have been due to improvement in CBF: 4-hour postocclusion CBF was 5.3 ±1.5 ml/100 g per min in control animals as compared with 13.9 ± 2.3 ml/100 g per min in SOD-treated animals. This relationship would suggest that free radicals contribute to deterioration of blood flow after vessel occlusion. catalase, and vitamin C have beneficial effects during reperfusion in organs such as the heart, 174 their use in focal cerebral ischemia is speculative. 175 Pro8tanoids. Although some prostaglandins are thought to contribute to the pathophysiologic changes of cerebral ischemia and infarction, prostacyclin has a vasodilating effect and may be useful for treatment of acute cerebral ischemia. Although negative results have been reported, 176 a cytoprotective action for ischemic neurons in global ischemia 177 and possible protection of the blood-brain barrier in focal ischemia 178 have been observed. Recovery of CBF during reperfusion has also been demonstrated with use of eicosapentaenoic acid, a precursor of prostacyclin. 179 In a clinical trial, substantial neurologic improvement has been reported after intravenous administration of prostacyclin. 180 Although further evaluation of the usefulness of prostacyclin and its derivatives is warranted, a short biologic half-life, a potential for systemic hypotension, and the possibility of an intracerebral steal phenomenon may prevent wide practical use. Antagonists for Excitatory Amino Acid Transmitters. Recently, L-glutamic acid and iv-methyl-d-aspartate have been identified as putative excitatory amino acid neurotransmitters. Although the available information about topographic distribution of postsynaptic receptors for these putative neurotransmitters is still insufficient, they are believed to be abundant in the hippocampus and cerebral cortex. 181 Prevention of seizures, 182 ischemic damage, 183 and hypoglycemic damage 184 by 2-amino-7-phosphonoheptanoic acid, an antagonist for iv-methyl-daspartate, suggests that putative excitatory amino acid neurotransmitters may play an important role in various pathophysiologic conditions of the central nervous system. Whether this preventive effect universally applies to cerebral ischemia or whether such an antagonist can prevent or minimize neuronal damage in human cerebrovascular disease is uncertain at the present time. RATIONALE FOR SURGICAL INTERVENTION Causes of Ischemic Stroke. Acute focal cerebrovascular lesions are usually caused by thrombosis or embolism. 185 In the extracranial carotid

13 Mayo Clin Proc, January 1987, Vol 62 FOCAL CEREBRAL ISCHEMIA 47 system, acute stroke is often due to thrombosis of a preexisting atherosclerotic lesion. 186 Intracranially, the major conducting vessels may be subjected to either embolic occlusion or, less commonly, thrombosis associated with underlying atherosclerosis. 186,187 The penetrating arterioles are usually involved in hypertensive arteriolar sclerosis. 188 In the vertebrobasilar system, stroke is often due to thrombosis of a preexisting atherosclerotic lesion in a large intracranial vessel or to arteriolar sclerosis of a small conducting vessel or penetrating arteriole. 189,190 In the subsequent discussion of treatment regimens, only major vessel occlusion was considered. Lacunar infarcts, which constitute up to 20% of cerebral infarctions, 191 are not included. Because they are due to occlusion of functional end-arteries, such as the lenticulostriate or penetrating arterioles, potential surgical intervention is limited. The major vessels most likely to be involved with acute occlusion are the cervical internal carotid artery or middle cerebral artery. Only rarely does a carotid occlusion undergo spontaneous lysis or recanalization. 192 An acute occlusion of the middle cerebral artery will often recanalize during a 1- to 2-week period. 193 " 196 The rate and amount of collateral development after vessel occlusion, however, are unknown and may be influenced by many factors. Emergency Surgical Revascularization. Therapy for acute stroke should provide neuronal protection after vessel occlusion by decreasing neuronal energy requirements (administering barbiturates) and by increasing collateral flow (administering nimodipine or mannitol). Ultimately, reestablishment of CBF will be necessary because the aforementioned therapeutic measures are temporizing and of limited duration. Flow may be reestablished through lysis of a clot or through the natural development of collateral vessels. As noted, spontaneous recanalization may occur during a period of 1 to 2 weeks, and the rate of development of collateral vessels is unknown. At this time, the efficacy of clot lysis by urokinase, streptokinase, or tissue plasminogen activator is unknown. Therefore, in selected patients, aggressive treatment of focal ischemia may include possible revascularization procedures, with medical treatment as an adjunct to stabilize jeopardized neurons before restoration of flow. Some experimental studies have indicated that emergency revascularization procedures may retard ischemic damage after vessel occlusion. 197 " 201 Recently, we reported on two separate series of patients who underwent either an emergency carotid endarterectomy or embolectomy of the middle cerebral artery because of acute occlusion. 202,203 At the time of occlusion, all these patients had profound neurologic deficits, including hemiparesis, aphasia, altered sensorium, and conjugate deviation of the eyes. Of the 34 patients treated by an emergency endarterectomy, 9 (26%) had no neurologic deficits during follow-up; 4 (12%) had a good recovery with minimal deficits; 10 (29%) had a fair outcome with moderate hemiparesis or aphasia that was less than the preoperative deficit; 4 (12%) had a poor result with appreciable deficits and dependent living; and 7 (21%) died. The natural history of patients with acute carotid occlusion who have profound neurologic deficits at the time of initial examination is difficult to determine because of deficiencies in various epidemiologic studies. Analysis of the available data suggests that 2 to 12% of patients will have a good recovery, 40 to 69% will have profound deficits, and 16 to 55% will die of the ictus. 204 " 208 Therefore, in our surgical series, 13 patients (38%) did remarkably well without increasing the expected mortality rate. In the second series of 20 patients treated with an emergency embolectomy of the middle cerebral artery, 2 (10%) had normal findings on neurologic examination during follow-up; 5 (25%) had a good recovery with minimal deficits; 7 (35%) had a fair outcome with deficits that were less than those preoperatively; 4 (20%) had a poor outcome; and 2 (10%) died. Therefore, seven patients (35%) had a result that was better than their preoperative status. The natural history of patients with acute occlusion of the middle cerebral artery and severe neurologic deficits is also difficult to determine, but approximately 10 to 20% will have a good or fair recovery, 18 to 38% will have profound deficits, and 10 to 50% will die. 194 " 196,209 " 212 Therefore, in our small series, an emergency embolectomy yielded an outcome better than that predicted with no treatment. These two nonrandomized retrospective studies demonstrated that in each situation an emergency revascularization procedure seemed to have salvaged approximately a third of the patients without increasing the overall mortality rate. They also emphasized the concept of thresholds of

14 48 FOCAL CEREBRAL ISCHEMIA Mayo Clin Proc, January 1987, Vol 62 cerebral ischemia. Because all these patients had profound neurologic deficits at the time of occlusion, CBF was at least below the threshold of electrical failure. A subset of patients, however, had collateral flow probably sufficient to retain CBF above the threshold of ionic failure. The most important prognostic factor was angiographic opacification of intracranial vessels qualitative but not quantitative assessment of collateral flow. 213 The worst prognosis was in patients with simultaneous occlusions of the carotid and middle cerebral arteries. That circumstance would limit the likelihood of leptomeningeal collateral flow and also isolate the lenticulostriate arteries. The time between vessel occlusion and restoration of flow was not an important prognostic factor, evidence that collateral flow can maintain neurons within a penumbral state for a period during which diagnostic studies can be performed. Experimentally, however, this penumbral state may slowly deteriorate. 18 ' These surgical series were noncontrolled retrospective reports. Although the results were encouraging, no definite statements can be made at present. Thus, the optimal treatment for progressive stroke due to acute vessel occlusion might combine both medical and surgical options. On the basis of our investigations, we would advocate the use of nimodipine, mannitol, and hydration without glucose to stabilize jeopardized neurons during the neurologic and radiologic workup. Barbiturates would have to be given within 1 hour after the onset ofischemia. The decision to operate would necessitate angiographic documentation of vessel occlusion, evaluation of collateral flow, and overall assessment of the patient's clinical status. If an aggressive management protocol is developed, an important issue would be the maximal time permissible between the onset of ischemic symptoms and the commencement of therapy. The two primary factors in resolving this issue are assessing the risks of hemorrhagic infarction and determining the point of irreversible neuronal damage. Depending on the experimental model used, investigators have found evidence that restoration of flow after 4 to 6 hours leads to an increased risk of hemorrhagic infarction. 20 ' 22 ' 45,215,216 Our two series of emergency revascularization procedures, however, did not exhibit this association between duration of vessel occlusion and hemorrhagic infarction. Many of our operations performed after 6 hours were not associated with this complication. In addition, although neuronal death is an expression of both the duration and the severity of reduced flow, the level of reduced flow is more critical. Realistically, the sequence of medical and radiologic evaluation followed by surgical restoration of CBF would encompass a minimum of 4 to 6 hours. This span of time does not include the interval between onset of ictus and arrival of the patient at a medical facility. Because of the multiplicity of factors in neuronal susceptibility to ischemia further altered by medical intervention, establishing a time limit to enact any protocol is arbitrary. A practical guideline, however, might be less than 2 hours. With the aid of adjunctive medical therapy, reversibly damaged neurons could survive for an extended period, if some collateral blood flow was present to support basal metabolism after vessel occlusion. Available information from animal experimentation indicates that these patients might require special postoperative management. At the time of reperfusion, a sudden change in the physiologic condition may occur in many subcellular elements. For example, in cerebral ischemia caused by occlusion of a common carotid artery in the gerbil, improvements in both the energy state and lactic acidosis occurred within 1 hour after reestablishment of cerebral circulation. 217 Transient increases in water, 31 sodium, 31,218 and calcium 31 content were observed after 30 minutes of ischemia followed by reperfusion; continuous increases in sodium and calcium content also occurred 31 if the ischemic period was extended to 3 hours before recirculation. Although transport of 2-deoxy-Dglucose in the nerve endings and radioligand binding at the postsynaptic receptor sites were tolerant of the effects of ischemia and reperfusion, 219 disaggregation of polyribosomes 220,221 and impairment of protein synthesis occurred in the neuronal cytoplasm. Moreover, impairment of RNA synthesis 221 and alteration of the nuclear hormone receptor sites 222 occurred within the nucleus immediately after reperfusion. If the ischemic period was short (30 minutes), these alterations were transient; however, no recovery ensued if the ischemic period was extended to 3 hours before reperfusion. Additionally, ischemia followed by reperfusion was associated with a transient accumulation of prostaglandins 223 and free fatty acids 35 and an increase in lipid peroxidation. 35 Even though the aforementioned biochemi-

15 Mayo Clin Proc, January 1987, Vol 62 FOCAL CEREBRAL ISCHEMIA 49 cal abnormalities were transient if the ischemic period before reperfusion was short, postischemic extension of tissue damage ensued in the subsequent few hours, as has been shown by immunohistochemical studies. 55 Therefore, it is important to implement measures to prevent postoperative cerebral edema, influx of ions, tissue acidosis, and peroxidation. Prevention of seizures may also reduce energy requirements and tissue acidosis. 224 " 227 Other Stroke Syndromes. Although we have reviewed primarily the pathophysiologic mechanisms and treatment of acute focal cerebral ischemia, some patients suffer from progressive stroke, slow stroke, or generalized cerebral ischemia. The patients in these three subgroups have prolonged focal or widespread hypoperfusion in one or both cerebral hemispheres. The cause is usually severe stenosis or occlusion of extracranial or intracranial vessels. In progressive stroke, a neurologic deficit evolves progressively or stepwise during a period of hours or days. Although a similar symptom complex can occur after occlusion of small intracranial arteries such as the lenticulostriate arteries, cerebral angiography often discloses severe stenosis or occlusion of the internal carotid or middle cerebral artery in these patients. In slow stroke, a neurologic deficit evolves during a period of weeks, and the history often suggests the presence of a space-occupying lesion. 228 The third subgroup of patients can best be described as having a chronic hypoperfusion state or chronic cerebral ischemia in which sustained neurologic signs and symptoms may be present. 228 Episodic symptoms such as limb weakness, involuntary movement, 229 or dimming of vision may occur, often in association with standing or walking. Although this condition may not change for several weeks or months, it may eventually shift to progressive ischemia or stroke. Measurements of CBF in this group of patients reveal a reduction in regional blood flow, 230 and electroencephalography may show intermittent or persistent focal slow-wave activity. 228 We expect preservation of the regional oxygen extraction fraction 231,232 if these patients are subjected to positron-emission tomography. At our institution, many of these patients have been treated with an extracranial-intracranial bypass procedure. 233 After such a procedure (that is, superficial temporal artery-middle cerebral artery bypass or saphenous vein interposition graft), neurologic function is often rapidly recovered, particularly if the patient had a unilateral carotid occlusion preoperatively It should be noted that the recent cooperative EC/IC Bypass Study Group 234 failed to show reduction in the risk of subsequent stroke in patients who had undergone an extracranial-intracranial arterial bypass procedure for stenosis or occlusion in the carotid system. This study, however, did not analyze the subset of patients under discussion here. On the contrary, review of our institution's results 235 suggests that this group of patients with progressive or sustained cerebral ischemia may still benefit from a revascularization procedure, especially if functional benefit is taken into consideration. 236 SUMMARY The recent improved understanding of the pathophysiologic mechanisms of acute focal cerebral ischemia has prompted the development of therapeutic modalities that experimentally attenuate ischemic neuronal damage. Two clinical series of emergency revascularization procedures suggest that severe neurologic deficits from major vessel occlusion are reversible if collateral flow is sufficient to retard neuronal death. Medical efforts to improve collateral flow and decrease neuronal energy requirements may lengthen the time during which jeopardized neurons can exist within a penumbral state and may thereby maximize the salvaging effects of an emergency operation. Thus, physicians should realize that neuronal damage is reversible under certain conditions and that intervention (medical, surgical, or a combination) may be a better alternative than supportive measures alone. ACKNOWLEDGMENT We thank Lisa A. Fabian, Bernita J. Bruns, and Kathleen K. Janssen for assistance in the preparation of the original manuscript. REFERENCES 1. Hossmann K-A: Treatment of experimental cerebral ischemia. Cereb Blood Flow Metab 2: , Ames A III, Wright RL, Kowada M, Thurston JM, Majno G: Cerebral ischemia. II. The no-reflow phenomenon. Am J Pathol 52: , Nemoto EM, Hossmann K-A, Cooper HK: Post-ischemic hypermetabolism in cat brain. Stroke 12: ,1981

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Pathol Biol 30: , Rehncrona S, Mela L, Siesjö BK: Recovery of brain mitochondrial function in the rat after complete and incomplete cerebral ischemia. Stroke 10: , Yoshida S, Inoh S, Asano T, Sano K, Kubota M, Shimazaki H, Ueta N: Effect of transient ischemia on free fatty acids and phospholipids in the gerbil brain: lipid peroxidation as a possible cause of postischemic injury. J Neurosurg 53: , Demopoulos HB, Flamm ES, Pietronigro DD, Seligman ML: The free radical pathology and the microcirculation in the major central nervous system disorders. Acta Physiol Scand [Suppl] 492:91-119, Wolfe LS: Eicosanoids: prostaglandins, thromboxanes, leukotrienes, and other derivatives of carbon-20 unsaturated fatty acids. J Neurochem 38:1-14, Kuwashima J, Nakamura K, Fujitani B, Kadokawa T, Yoshida K, Shimizu M: Relationship between cerebral energy failure and free fatty acid accumulation following prolonged brain ischemia. 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17 Mayo Clin Proc, January 1987, Vol 62 FOCAL CEREBRAL ISCHEMIA Knisely MH, Bloch EH, Eliot TS, Warner L: Sludged blood. Science 106: , Little JR, Kerr FWL, Sundt TM Jr: Microcirculatory obstruction in focal cerebral ischemia: relationship to neuronal alterations. Mayo Clin Proc 50: , Sundt TM Jr, Waltz AG: Cerebral ischemia and reactive hyperemia: studies of cortical blood flow and microcirculation before, during, and after temporary occlusion of middle cerebral artery of squirrel monkeys. Circ Res 28: , Sundt TM Jr, Davis DH: Reactions of cerebrovascular smooth muscle to blood and ischemia: primary versus secondary vasospasm. In Cerebral Arterial Spasm. Edited by RH Wilkins. Baltimore, Williams & Wilkins, 1980, pp Waltz AG: Red venous blood: occurrence and significance in ischemic and nonischemic cerebral cortex. J Neurosurg 31: , Fischer EG, Ames A III, Hedley-Whyte ET, O'Gorman S: Reassessment of cerebral capillary changes in acute global ischemia and their relationship to the "no-reflow phenomenon." Stroke 8:36-39, Crowell RM, Olsson Y: Impaired microvascular filling after focal cerebral ischemia in monkeys. J Neurosurg 36: , Little JR, Sundt TM Jr, Kerr FWL: Neuronal alterations in developing cortical infarction: an experimental study in monkeys. J Neurosurg 40: , Iannotti F, Hoff JT, Schielke GP: Brain tissue pressure in focal cerebral ischemia. J Neurosurg 62:83-89, Olsson Y, Crowell RM, Klatzo I: The blood-brain barrier to protein tracers in focal cerebral ischemia and infarction caused by occlusion of the middle cerebral artery. Acta Neuropathol (Berl) 18:89-102, Plum F, Posner JB, Alvord EC Jr: Edema and necrosis in experimental cerebral infarction. Arch Neurol 9: , Yanagihara T, Yoshimine T, Morimoto K, Yamamoto K, Homburger HA: Immunohistochemical investigation of cerebral ischemia in gerbils. J Neuropathol Exp Neurol 44: , Yoshimine T, Morimoto K, Brengman JM, Homburger HA, Mogami H, Yanagihara T: Immunohistochemical investigation of cerebral ischemia during recirculation. J Neurosurg 63: , Yamamoto K, Yoshimine T, Homburger HA, Yanagihara T: Immunohistochemical investigation of regional cerebral ischemia in the gerbil: occlusion of the posterior communicating artery. Brain Res 371: , Matsumoto M, Hatakeyama T, Yanagihara T: Combination of cerebral blood flow measurement and immunohistochemical technique in cerebral ischemia (abstract). Stroke 17:137, Yamamoto K, Yanagihara T: Immunoelectronmicroscopic investigation of cerebral ischemia in gerbils (abstract). J Neuropathol Exp Neurol 44:337, Yamamoto K, Morimoto K, Yanagihara T: Cerebral ischemia in the gerbil: transmission electronmicroscopic and immunoelectronmicroscopic investigation. Brain Res 384:1-10, Selman WR, Spetzler RF: Therapeutics for focal cerebral ischemia. Neurosurgery 6: , Diaz FG, Ausman JI: Experimental cerebral ischemia. Neurosurgery 6: , Davis DH, Sundt TM Jr: Relationship of cerebral blood flow to cardiac output, mean arterial pressure, blood volume, and alpha and beta blockade in cats. J Neurosurg 52: , Hope DT, Branston NM, Symon L: Restoration of neurological function with induced hypertension in acute experimental cerebral ischaemia. Acta Neurol Scand [Suppl] 64: , Michenfelder JD, Milde JH: Failure of prolonged hypocapnia, hypothermia, or hypertension to favorably alter acute stroke in primates. Stroke 8:87-91, Fenske A, Kohl J, Regli F, Reulen HJ: The effect of arterial hypertension on focal ischemic edema: an experimental study. J Neurol 219: , Matsuoka Y, Hossmann KA: The effect of induced hypertension on pial artery micropressure after middle cerebral artery occlusion in cats. J Cereb Blood Flow Metab 1 (Suppl 1): , Sundt TM Jr, Onofrio BM, Merideth J: Treatment of cerebral vasospasm from subarachnoid hemorrhage with isoproterenol and lidocaine hydrochloride. J Neurosurg 38: , Ginsberg MD, Welsh FA, Budd WW: Deleterious effect of glucose pretreatment on recovery from diffuse cerebral ischemia in the cat. I. Local cerebral blood flow and glucose utilization. Stroke 11: , Welsh FA, Ginsberg MD, Rieder W, Budd WW: Deleterious effect of glucose pretreatment on recovery from diffuse cerebral ischemia in the cat. II. Regional metabolite levels. Stroke 11: , Myers RE: Lactic acid accumulation as cause of brain edema and cerebral necrosis resulting from oxygen deprivation. In Advances in Perinatal Neurology. Vol 1. Edited by R Korobkin, C Guilleminault. Jamaica, New York, Spectrum Publications, 1979, pp Siemkowicz E, Hansen AJ: Clinical restitution following cerebral ischemia in hypo-, normo- and hyperglycemic rats. Acta Neurol Scand 58:1-8, Plum F: What causes infarction in ischemic brain? The Robert Wartenberg Lecture. Neurology (NY) 33: , Marsh WR, Anderson RE, Sundt TM Jr: Effect of hyperglycemia on brain ph levels in areas of focal incomplete cerebral ischemia in monkeys. J Neurosurg 65: , Pulsinelli WA, Levy DE, Sigsbee B, Scherer P, Plum F: Increased damage after ischemic stroke in patients with hyperglycemia with or without established diabetes mellitus. Am J Med 74: , Sundt TM Jr, Waltz AG, Sayre GP: Experimental cerebral infarction: modification by treatment with hemodiluting, hemoconcentrating, and dehydrating agents. J Neurosurg 26:46-56, Sundt TM Jr, Waltz AG: Hemodilution and anticoagulation: effects on the microvasculature and microcirculation of the cerebral cortex after arterial occlusion. Neurology (Minneap) 17: , Hossmann KA, van den Kerckhoff W, Matsuoka Y: Treatment of cerebral ischemia by hemodilution. Bibl Haematol 47:77-85, Wood JH: Hypervolemic hemodilution: rheologic therapy for acute cerebral ischemia. Contemp Neurosurg 4:1-6, Wood JH, Snyder LL, Simeone FA: Failure of intravascular volume expansion without hemodilution to elevate cortical blood flow in region of experimental focal ischemia. J Neurosurg 56:80-91, Wood JH, Fleischer AS: Observations during hypervolemic hemodilution of patients with acute focal cerebral ischemia. JAMA 248: , Strand T, Asplund K, Eriksson S, Hägg E, Lithner F, Wester P-O: A randomized controlled trial of hemodilution therapy in acute ischemic stroke. Stroke 15: , 1984

18 52 FOCAL CEREBRAL ISCHEMIA Mayo Clin Proc, January 1987, Vol Scandinavian Stroke Study Group: Multicenter trial of hemodilution in ischemic stroke background and study protocol. Stroke 16: , Marshall J: The viscosity factor in cerebral ischaemia. J Cereb Blood Flow Metab 2 (Suppl l):47-49, Babikian VL, Ackerman RH, Correia JA, Alpert NM, Feinberg WM, Heros RC, Taveras JM: Effects of hemodilution on intravascular and cerebral physiology in acute stroke disease (abstract). Neurology 36 (Suppl 1):140, Wood JH, Kee DB Jr: Hemorheology of the cerebral circulation in stroke. Stroke 16: , Steen PA, Michenfelder JD: Pentoxifylline does not protect mice against hypoxia. Acta Anaesthesiol Scand 25: , Grotta J, Ostrow P, Fraifeld E, Hartman D, Gary H: Fibrinogen, blood viscosity, and cerebral ischemia. Stroke 16: , Hossmann V, Heiss W-D, Bewermeyer H, Wiedemann G: Controlled trial of ancrod in ischemic stroke. 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Neuroradiology 26: , Marbet GA, Eichlisberger R, Duckert F, Ritz R, da Silva MA, Biland L, Widmer LK, Schmitt HE: Side effects of thrombolytic treatment with porcine plasmin and low dose streptokinase. Thromb Haemost 48: , Aldrich MS, Sherman SA, Greenberg HS: Cerebrovascular complications of streptokinase infusion. JAMA 253: , Zivin JA, Fisher M, DeGirolami U, Hemenway CC, Stashak JA: Tissue plasminogen activator reduces neurological damage after cerebral embolism. Science 230: , Anderson DC, Cranford RE: Corticosteroids in ischemic stroke. Stroke 10:68-71, Fenske A, Fischer M, Regli F, Hase U: The response of focal ischemic cerebral edema to dexamethasone. J Neurol 220: , Donley RF, Sundt TM Jr: The effect of dexamethasone on the edema of focal cerebral ischemia. Stroke 4: , Plum F, Alvord EC Jr, Posner JB: Effect of steroids on experimental cerebral infarction. Arch Neurol 9: , Siegel BA, Studer RK, Potchen EJ: Steroid therapy of brain edema: ineffectiveness in experimental cerebral microembolism. Arch Neurol 27: , Patten BM, Mendell J, Bruun B, Curtin W, Carter S: Double-blind study of the effects of dexamethasone on acute stroke. Neurology (Minneap) 22: , Sapolsky RM, Pulsinelli WA: Glucocorticoids potentiate ischemic injury to neurons: therapeutic implications. Science 229: , Smith AL, Hoff JT, Nielsen SL, Larson CP: Barbiturate protection in acute focal cerebral ischemia. Stroke 5:1-7, Moseley JI, Laurent JP, Molinari GF: Barbiturate attenuation of the clinical course and pathologic lesions in a primate stroke model. Neurology (Minneap) 25: , Levy DE, Brierley JB: Delayed pentobarbital administration limits ischemic brain damage in gerbils. Ann Neurol 5:59-64, Simeone FA, Frazer G, Lawner P: Ischemic brain edema: comparative effects of barbiturates and hypothermia. 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Anesthesiology 41: , Michenfelder JD, Milde JH: Influence of anesthetics on metabolic, functional and pathological responses to regional cerebral ischemia. Stroke 6: , Steen PA, Michenfelder JD: Mechanisms of barbiturate protection (editorial). Anesthesiology 53: , Demopoulos HB, Flamm ES, Seligman ML, Jorgensen E, Ransohoff J: Antioxidant effects of barbiturates in model membranes undergoing free radical damage. Acta Neurol Scand [Suppl] 64: , Smith DS, Rehncrona S, Siesjö BK: Inhibitory effects of different barbiturates on lipid peroxidation in brain tissue in vitro: comparison with the effects of promethazine and chlorpromazine. Anesthesiology 53: , Shiu GK, Nemoto EM: Barbiturate attenuation of brain free fatty acid liberation during global ischemia. J Neurochem 37: , Black KL, Weidler DJ, Randall OS: Improved cerebral microcirculation in focal cerebral ischemia after treatment with pentobarbital (abstract). 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19 Mayo Clin Proc, January 1987, Vol 62 FOCAL CEREBRAL ISCHEMIA Weir B: Calcium antagonists, cerebral ischemia and vasospasm. Can J Neurol Sei 11: , Allen GS, Banghart SB: Cerebral arterial spasm. Part 9. In vitro effects of nifedipine on serotonin-, phenylephrine-, and potassium-induced contractions of canine basilar and femoral arteries. Neurosurgery 4:37-42, Mohamed AA, Gotoh O, Graham DI, Osborne KA, McCulloch J, Mendelow AD, Teasdale GM, Harper AM: Effect of pretreatment with the calcium antagonist nimodipine on local cerebral blood flow and histopathology after middle cerebral artery occlusion. Ann Neurol 18: , Steen PA, Newberg LA, Milde JH, Michenfelder JD: Nimodipine improves cerebral blood flow and neurologic recovery after complete cerebral ischemia in the dog. J Cereb Blood Flow Metäb 3:38-43, Steen PA, Newberg LA, Milde JH, Michenfelder JD: Cerebral blood flow and neurologic outcome when nimodipine is given after complete cerebral ischemia in the dog. J Cereb Blood Flow Metab 4:82-87, Harper AM, Craigen L, Kazda S: Effect of the calcium antagonist, nimodipine, on cerebral blood flow and metabolism in the primate. J Cereb Blood Flow Metab 1: , Heffez DS, Passonneau JV: Effect of nimodipine on cerebral metabolism during ischemia and recirculation in the mongolian gerbil. J Cereb Blood Flow Metab 5: , Harris RJ, Branston NM, Symon L, Bayhan M, Watson A: The effects of a calcium antagonist, nimodipine, upon physiological responses of the cerebral vasculature and its possible influence upon focal cerebral ischaemia. Stroke 13: , Roy MW, Dempsey RJ, Meyer KL, Donaldson DL, Tibbs PA, Young AB: Effects of verapamil and diltiazem on acute stroke in cats. J Neurosurg 63: , Smith M-L, Kägström E, Rosen I, Siesjö BK: Effect of the calcium antagonist nimodipine on the delayed hypoperfusion following incomplete ischemia in the rat. J Cereb Blood Flow Metab 3: , Meyer FB, Anderson RE, Yaksh TL, Sundt TM Jr: Effect of nimodipine on intracellular brain ph, cortical blood flow, and EEG in experimental focal cerebral ischemia. J Neurosurg 64: , Maciunas R, Anderson RE, Sundt TM Jr, Yanagihara T: Effects of nimodipine on cerebral blood flow and stroke severity in middle cerebral artery occlusion in the rabbit (submitted for publication) 137. Gelmers HJ: Effect of nimodipine (Bay e 9736) on postischaemic cerebrovascular reactivity, as revealed by measuring regional cerebral blood flow (rcbf). Acta Neurochir (Wien) 63: , Peerless SJ, Ishikawa R, Hunter IG, Peerless MJ: Protective effect of Fluosol-DA in acute cerebral ischemia. Stroke 12: , Sutherland GR, Farrar JK, Peerless SJ: The effect of Fluosol-DA on oxygen availability in focal cerebral ischemia. Stroke 15: , Dirks B, Krieglstein J, Lind HH, Rieger H, Schütz H: Fluorocarbon perfusion medium applied to the isolated rat brain. J Pharmacol Methods 4:95-108, HandaH: Effectof Fluosol-DA on cerebral circulation in humans. In Oxygen Carrying Colloidal Blood Substitutes. Edited by R Frey, H Beisbarth, K Stosseck. Munich, W. Zuckschwendt Verlag, 1982, pp Little JR: Modification of acute focal ischemia by treatment with mannitol. Stroke 9:4-9, Little JR, O'Shaughnessy D: Treatment of acute focal ischemia with continuous CSF drainage and mannitol. Stroke 10: , Little JR: Treatment of acute focal cerebral ischemia with intermittent, low dose mannitol. Neurosurgery 5: , Yoshimoto T, Sakamoto T, Watanabe T, Tanaka S, Suzuki J: Experimental cerebral infarction. Part 3. Protective effect of mannitol in thalamic infarction in dogs. Stroke 9: , Yoshimoto T, Suzuki J: Intracranial definitive aneurysm surgery under normothermia and normotension utilizing temporary occlusion of major cerebral arteries and preoperative mannitol administration. 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20 54 FOCAL CEREBRAL ISCHEMIA Mayo Clin Proc, January 1987, Vol Meyer JS, Okamoto S, Sari A, Koto A, Itoh Y, Ericsson AD: Effects of beta-adrenergic blockade on cerebral autoregulation and chemical vasomotor control in patients with stroke. Stroke 5: , Meyer JS, Okamoto S, Shimazu K, Koto A, Ohuchi T, Sari A, Ericsson AD: Cerebral metabolic changes during treatment of subacute cerebral infarction by alpha and beta adrenergic blockade with phenoxybenzamine and propranolol. Stroke 5: , Demopoulos HB: Control of free radicals in biologic systems. Fed Proc 32: , Flamm ES, Demopoulos HB, Seligman ML, Tomasula JJ, DeCrescito V, Ransohoff J: Ethanol potentiation of central nervous system trauma. J Neurosurg 46: , Misra HP, Fridovich I: The univalent reduction of oxygen by reduced flavins and quinones. J Biol Chem 247: , Watson BD, Busto R, Goldberg WJ, Santiso M, Yoshida S, Ginsberg MD: Lipid peroxidation in vivo induced by reversible global ischemia in rat brain. 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