Michenfelder, John D.

Cerebral adenosine triphosphate and lactate concentrations were measured in the squirrel monkey ( Saimiri sciureus ) before, during, and at selected times after various periods of middle cerebral artery occlusion. The gradual decrease in ATP to 55, 35, and 20%, of normal and the increase in lactate to 7, 8, and 10 times normal after 2, 3, and 4 hours of occlusion, respectively, were reversible with restoration of flow. Electrocorticograms recorded in acute preparations indicated potential for recovery. The correlation of lactate levels with previous determinations of blood flow in this preparation supports the theory that loss of autoregulation and "luxury perfusion" in cerebral ischemia results from localized metabolic acidosis due to accumulation of lactic acid. In a separate group of monkeys, the ischemic lesions were found to be largely reversible after 2 or 3 hours and irreversible after 4 hours of middle cerebral artery occlusion; the cause of death in the monkeys subjected to 4 hours of occlusion was edema, which progressed even after restoration of flow.

Cerebral blood flow (CBF) was measured during 28 carotid endarterectomies in 25 patients, by injection of 133 Xe into the exposed internal carotid artery (ICA). Twenty-three patients had episodic cerebral or retinal ischemia and five had neurologic deficits before operation. Initial CBF values were variable. Increases of Pa Co Co2 caused CBF to increase in four of six patients, to increase slightly in one, and to decrease in one. In each of 19 procedures, CBF decreased during surgical occlusion of the ICA, 11 times to less than 30 ml/100 g/min, but absence of postoperative worsening indicated that decreased ICA blood flow is not a major risk of the procedure; embolization from the site of operation may be a greater threat to the patient. CBF increased after 14 endarterectomies, perhaps due to failure of autoregulation or to reactive hyperemia. Measurements of jugular PV o o2 and lactate concentration were of little value.

Regional cerebral ischemia was produced by common carotid artery occlusion in gerbils and by middle cerebral artery occlusion in dogs, cats, and squirrel monkeys. Anesthesia was induced with either pentobarbital or halothane and maintained for two to there hours after vessel occlusion. In acute studies, the effect of regional cerebral ischemia on cerebral concentrations of ATP, phosphocreatine, lactate, and pyruvate was determined at the end of this period in gerbils, cats, and squirrel monkeys. In chronic studies, the degree of neurological deficit and size of cerebral infarction were determined 48 hours after a two-hour to three-hour period of vessel occlusion in cats and squirrel monkeys and permanent occlusion in dogs. In gerbils, dogs, and cats, there were no differences in the metabolic, functional, or pathological effects of anesthesia with pentobarbital or halothane. However, in the squirrel monkey, in acute studies the metabolic alterations were significantly less with pentobarbital, and in chronic studies the frequency and magnitude of functional deficits and cerebral infarction were significantly less. We conclude that pentobarbital does provide a degree of protection during regional cerebral ischemia but that such effects are only consistently demonstrable in primates. In nonprimates, we assume that variability in the collateral circulation renders demonstration of significant differences difficult or impossible.

We examined the 21-aminosteroid U74006F, a potent inhibitor of lipid peroxidation, for potential neuroprotective effects in a canine model of complete cerebral ischemia. Two 1.5-mg/kg boluses were administered to six dogs, the first bolus 15 minutes prior to a 12-minute episode of complete cerebral ischemia and the second bolus after 11 minutes of ischemia, 1 minute prior to reperfusion. Using this dosage regimen, plasma U74006F levels of greater than 0.3 microgram/ml were maintained for up to an hour postischemia. An additional six animals received equal volumes of the citrate vehicle solution. At 24 and 48 hours postischemia, the dogs were neurologically evaluated by an observer blinded as to treatment selection. All six U74006F-treated animals had a normal neurologic outcome at 48 hours postischemia, while the citrate vehicle-treated animals all suffered moderate to severe neurologic deficits. The difference in outcome was significant at both 24 and 48 hours (p less than 0.005). Although U74006F is a 21-aminosteroid, it is not reported to possess glucocorticoid activity. This is supported by the present finding that no changes in plasma glucose concentration were observed following administration of the drug. The systemic vitamin E levels of citrate vehicle-treated animals decreased significantly (from 4.10 +/- 0.46 micrograms/ml to 2.95 +/- 0.38 micrograms/ml, p less than 0.05), whereas the vitamin E levels in U74006F-treated animals did not decrease significantly. These results suggest that U74006F may be of benefit in improving neurologic outcome when administered prior to an episode of complete cerebral ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Previous studies have shown that occlusion of the middle cerebral artery (MCA) of the squirrel monkey results in a consistent large infarct; that in the initial two hours after occlusion of the MCA, blood flow in the central area of ischemia continues at a reduced rate (20% to 50% of normal); and that restoration of normal flow within three hours results in a survival rate of 65% without infarction. In this study, cerebral adenosine triphosphate (ATP), lactate, and pyruvate concentrations were measured at various time intervals after occlusion of the MCA. ATP decreased slowly during a three-hour period to 30% of normal, and lactate, after an initial rapid accumulation, increased slowly to about eight times normal. This compares to the effects of circulatory arrest which, in the dog, results in a reduction of the ATP level to 25% of normal within four minutes and a reciprocal increase in the lactate level. Because the effects of total cerebral anoxia are potentially reversible prior to four minutes, and, therefore, at an ATP concentration above 25% of normal, the slow rate of ATP depletion observed in the ischemic monkey brain supports the view that a significant period exists after occlusion of a major intracranial vessel wherein the ischemic effects are potentially reversible. Using the methods of this study, future investigations should permit a meaningful evaluation of the relative merits of those measures recommended for the treatment of acute cerebral ischemia.

The goal of this study was to determine the temperature coefficient (Q 10 ) for canine CMRO 2 at temperatures below 14°C. Eight dogs were anesthetized with halothane for surgical preparation. The animals were placed on total cardiopulmonary bypass and CBF was measured by direct sagittal sinus outflow. Duplicate measurements were taken at 37, 13, and 7°C. The EEG became isoelectric at a temperature of 12.0 ± 0.8°C. The Q 10 between 13 and 7°C was 2.19 ± 0.59. With rewarming to 37°C, cerebral metabolic variables returned to control levels. Brain biopsies taken at the end of the study yielded normal values for brain energy stores. We conclude that the Q 10 for CMRO 2 at temperatures between 7 and 37°C can be profoundly affected by the state of cerebral function as reflected by the EEG. In the absence of EEG activity, an expected Q 10 value of 2.2 reflects only the direct effect of temperature on the rates of biologic reactions.

Nimodipine, a calcium entry blocker, was administered in increasing doses of 0.1–3.0 μg kg −1 min −1 to six dogs after they had recovered consciousness from a surgical preparation that was conducted under general anesthesia and while they were under the influence of total spinal anesthesia. CBF was measured with a sagittal sinus outflow technique and CMRO 2 was calculated as the product of CBF and the arteriovenous O 2 difference. Nimodipine did not influence either CBF or CMRO 2 . There was a decrease in the cortical pyruvate level at the end of the study, but no significant change in phosphocreatine, ATP, lactate, or energy charge when compared with six control dogs. It has previously been reported that nimodipine increases the CBF in global ischemia with a potentially beneficial effect on the neurological outcome. With no effect on normal CBF or metabolism, this suggests that nimodipine may be useful in a variety of ischemic situations without fear of either a steal phenomenon or untoward effects on intracranial pressure.

Ten minutes of complete ischemia was produced in 11 dogs by temporary ligation of the aorta. Immediately before the ischemic episode, the dogs received nimodipine, a new calcium entry blocker, 10 μg kg −1 , i.v., followed by an infusion of 1 μg kg −1 min −1 for 2 h. Post-ischemic cerebral blood flow and metabolism were measured for 120 min in six dogs. Neurologic recovery was evaluated 48 h post-ischemia in five dogs. The results were compared to previously determined controls. Nimodipine nearly doubled cerebral blood flow in the delayed post-ischemic hypoperfusion period, compared to untreated dogs (approximately 45% versus 25% of pre-ischemic control values), but had no significant effect on metabolism. Nimodipine also improved neurologic recovery. Four of five treated dogs were normal and one was moderately damaged, whereas six of seven controls were either severely damaged or dead. This suggests that the delayed hypoperfusion state occurring after complete cerebral ischemia probably does contribute to the ultimate neurologic damage, and that nimodipine offers a potential protective effect.

A small number of animal studies have suggested that during the delayed postischemic hypoperfusion state, CO 2 reactivity of the cerebral vasculature is lost whereas autoregulation is retained. These findings, however, are inconsistent with the bulk of experimental evidence which demonstrates that CO 2 reactivity is more robust and may be retained in pathologic circumstances which abolish autoregulation. These opposing viewpoints were therefore further evaluated in 18 dogs in which complete global ischemia was induced by cerebrospinal fluid (CSF) compression for periods of 12 ( n = 12) and 18 ( n = 6) min. Following 45 min of reperfusion and with onset of the delayed postischemic hypoperfusion state, autoregulation and CO 2 reactivity were evaluated using a continuous measurement of CBF (by sagittal sinus outflow). CO 2 reactivity was tested over a P a co 2 range of 20 to 60 mm Hg; autoregulation was tested over a blood pressure range of 60 to 140 mm Hg. Results demonstrated that after both 12 and 18 min of complete global ischemia, autoregulation and CO 2 reactivity of the cerebral vasculature were both present, but attenuated. In the case of CO 2 reactivity, the slope of the CBF response was decreased approximately 75%. In the case of autoregulation, the response in some dogs was incomplete as compared with their preischemic response.

Following complete global cerebral ischemia and reperfusion, a brief period of reactive hyperemia is followed by a prolonged period of low flow commonly referred to as the delayed postischemic hypoperfusion state. It is generally assumed that this low-flow state may be injurious because of inadequate substrate delivery, thus implying that flow is no longer coupled to metabolic needs. This relationship of CBF to CMRO 2 was examined in six anesthetized dogs that were subjected to 12 min of complete ischemia induced either by CSF compression or aortic occlusion. Following reperfusion and onset of the low-flow state, which stabilized at 45 min postischemia, control normothermic (37°C) measurements of CBF and CMRO 2 were determined. Thereafter, femoral arterial blood was circulated through a heat exchanger (42.5°C), and brain temperature was increased to 40°C and measurements were repeated. The brain was then cooled back to 37°C for a final set of normothermic measurements. Thereafter, brain biopsies were taken to determine the energy state of the brain. CMRO 2 changed ∼6%/°C. CBF paralleled the change in CMRO 2 . Accordingly, the ratio of CBF to CMRO 2 remained constant throughout at a value of 8 to 9, demonstrating maintained coupling. The brain energy state was normal at the end of the study. The authors conclude that postischemic CBF is modulated by the brain's metabolic needs.