James H. Milde

Nimodipine Improves Cerebral Blood Flow and Neurologic Recovery after Complete Cerebral Ischemia in the Dog

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.

The relationship among canine brain temperature, metabolism, and function during hypothermia.

Cerebral protection by hypothermia is commonly attributed to cerebral metabolic suppression. However, at temperatures below 28 degrees C, the relationship of temperature to cerebral metabolic rate of oxygen consumption (CMRO2) has not been well characterized. Accordingly, the relationship between brain temperature and CMRO2 was determined in eight dogs during cooling from 37 to 14 degrees C while the EEG was continuously monitored. Cardiopulmonary bypass was initiated and control measurements were made at 37 degrees C during anesthesia with nitrous oxide 50-60% inspired and morphine sulfate 2 mg.kg-1 intravenously (iv). Upon cooling to 27 degrees C, the nitrous oxide was discontinued and the morphine was antagonized with naloxone 2 mg iv. Measurements were repeated at 27, 22, 18, and 14 degrees C and in four dogs again at 37 degrees C after nitrous oxide 50-60% had been reestablished at 27 degrees C along with administration of morphine sulfate 2 mg.kg-1. For each temperature interval, the temperature coefficient (Q10) for CMRO2 was calculated (Q10 = CMRO2 at x degrees C divided by CMRO2 at [x - 10] degrees C). Between 37 and 27 degrees C the Q10 was 2.23, but between 27 and 14 degrees C the mean Q10 was doubled to 4.53. With rewarming to 37 degrees C, CBF and CMRO2 returned to control levels, and brain biopsies revealed a normal brain energy state. During cooling, the EEG developed burst suppression at or below 22 degrees C. With further cooling, the periods of suppression increased; however, burst activity continued in seven of eight dogs even at 14 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Nimodipine Improves Outcome when Given after Complete Cerebral Ischemia in Primates

Twenty-seven pigtailed monkeys (Macaca nemestrina) were subjected to 17 min of complete cerebral ischemia followed by 96 h of intensive care treatment. Fourteen of the monkeys were assigned randomly to the treatment group and received nimodipine 10 μg·kg−1 5 min postischemia followed by 1 μg·kg−1·min−1 for 10 h. Six monkeys (three treated) failed to meet preestablished protocol criteria and were excluded. The remaining treated and untreated monkeys were well matched for age, sex, and other physiologic variables. Neurologic outcome at 96 h postischemia was significantly better in the nimodipine-treated monkeys than in the controls. Eight of the 11 treated animals had an apparent normal level of consciousness; four of these had no detectable neurologic deficits and a fifth had only a slight motor apraxia. Only two of the 10 untreated animals had an apparent normal level of consciousness, and all had major neurologic deficits. Histopathologic examination showed variable ischemic neuronal change and infarction to involve gray matter in distal arterial perfusion zones. Significant white matter changes were not observed. A histopathologic scoring system yielded a significantly better mean score for the treated group than for the untreated group, and there was significant correlation between neurologic function and histopathologic findings. The authors conclude that nimodipine improves the neurologic outcome when given after an episode of complete cerebral ischemia in primates, and they recommend controlled clinical trials in patients resuscitated after cardiac arrest.

The effects of dextrose infusion and head position on neurologic outcome after complete cerebral ischemia in primates: examination of a model.

The hypothesis that iv dextrose infusion prior to--and head position during--cerebral ischemia would influence the severity and pattern of neurologic injury was tested in primates. Fifteen pigtail monkeys weighing 3.3 +/- 0.2 kg (mean +/- SE) were subjected to 17 min complete cerebral ischemia followed by 24 h intensive care treatment and neurologic assessment for an additional 72 h. Monkeys were given 50 ml iv infusions of either dextrose 5% in 0.45% saline solution (n = 8) or lactated Ringers solution (n = 7) during the preparatory period. This volume corresponds to approximately 1 1/70 kg individual. These same monkeys were placed in either the lateral (n = 3), prone (n = 5), or supine (n = 7) position during the ischemic period. Two monkeys failed to meet preestablished protocol criteria and were excluded from data analysis. Blood glucose immediately preischemia in the dextrose-treated group (181 +/- 19 mg X dl-1) was not significantly greater than in the group given lactated Ringers solution (140 +/- 6 mg X dl-1; P = 0.07). Dextrose infusion resulted in significantly greater cerebral injury at 96 h postischemia when comparing both neurologic (P less than 0.05) and histopathology (P less than 0.05) scores. Specifically, dextrose administration resulted in the greatest injury to the insular cortex, thalamus, Purkinje cells, and substantia nigra. Although blood glucose was less than 250 mg X dl-1 in all monkeys at the time of complete cerebral ischemia, there was a high correlation between blood glucose rank and neurologic function rank (rs = 0.76; P less than 0.005). The authors were unable to note any effect of head position on the distribution of histopathologic lesions. Prior to removing the brain for histopathologic studies, four monkeys were given repeat infusions of 50 ml dextrose 5% in 0.45% saline solution over 11 +/- 1 min. These infusions produced increases in blood glucose from 56.7 +/- 7.6 to 244 +/- 24.9 mg X dl-1 (P less than 0.01) and increases in brain glucose from 1.64 +/- 0.22 to 5.11 +/- 0.48 mumol X g-1 (P less than 0.01).

The cerebral metabolic effects of isoflurane at and above concentrations that suppress cortical electrical activity.

The effects of 1.4–6.0% end-expired isoflurane on cerebral metabolism and hemodynamics were examined in dogs. A dose-related decrease in cerebral oxygen consumption (CMRo2) occurred until there was suppression of cortical electrical activity as reflected by the onset of an isoelectric electroencephalogram. This occurred at an end-expired concentration of 3% isoflurane when the mean CMRo2, was 2.02 ml · 100 g-1 · min-1. Thereafter, increasing concentrations of isoflurane to 6% had no further effect on the CMRo2. Brain biopsies taken at the end of the study revealed normal concentrations of ATP and phosphocreatine and a normal energy charge. Despite a normal cerebral energy state, there was a mild, dose-related, cerebral lactic acidosis (up to 2.84 μmol/g) that accompanied a mild systemic acidosis. It is concluded that the cerebral metabolic changes produced by isoflurane are secondary to an effect on cortical electrical activity, that abolition of this activity can be produced in dogs by a clinically relevant concentration of isoflurane (3%) without marked systemic hemodynamic effects, and that concentrations of isoflurane necessary to abolish cortical activity have no direct toxic effect on cerebral metabolic pathways.

Cerebral Blood Flow and Neurologic Outcome When Nimodipine Is Given After Complete Cerebral Ischemia in the Dog

Ten minutes of complete cerebral ischemia was produced in 26 dogs by temporary ligation of the aorta and the venae cavae. Twenty dogs received nimodipine, a calcium entry blocker, 10 μg kg−1 i. v. 2 min after the ischemic period, followed by 1 μg kg−1 min−1 for 2–3 h. Six dogs received only the solvent used for nimodipine. Fourteen dogs received nimodipine for 3 h and were subsequently evaluated neurologically up to 48 h postischemia. In the 12 other dogs, CBF and metabolism were followed for 2 h postischemia while either nimodipine or the solvent only was infused. The results were compared to previously published results for untreated dogs and dogs given nimodipine before the ischemic event. Nimodipine had the same effect on postischemic CBF whether started before or after the ischemic event, nearly doubling the flow when compared with untreated controls, whereas the solvent alone caused only a slight increase in CBF over control. By contrast, nimodipine initiated in the preischemic period significantly improved the neurologic outcome, but when initiated in the post-ischemic period the results were equivocal, such that the outcome was not significantly different from either the untreated group or the group in which nimodipine was initiated preischemia. Metabolic measurements did not give any indication of a specific effect of nimodipine, nor could the metabolic results be used as an indicator of neurologic outcome. The results are consistent with a beneficial effect of nimodipine following complete cerebral ischemia; however, evaluation of neurologic functional effects will require a more sensitive model.

Hypothermia and barbiturates: individual and combined effects on canine cerebral oxygen consumption.

Following establishment of total spinal anesthesia, the cerebral metabolic effects of progressive hypothermia (37, 28, 18, and 14° C) were studied initially in six awake dogs. The EEG became iso-electric at temperatures below 18° C. At 14° C, CMROl was reduced to 7% of control. Thereafter, 40 mg/kg thiopental, iv, was given and the dogs were rewarmed while an isoelectric EEG was maintained by a continuous thiopental infusion. The CMROl was then compared at the different temperatures with and without thiopental. The CMRO, was unaffected by the barbiturate at 14 and 18° C. At 28 and 37° C the CMRO, was significantly reduced by the barbiturate (at 37° C to 55% of the 37° C value without thiopental). The change in CMROl with temperature in the absence of EEG activity (due to barbiturates) closely approximated an Arrhenius curve (relating log CMRO, to the reciprocal of absolute temperature). In the presence of EEG activity (no barbiturates) such a simple relationship was less apparent. The results support the following conclusions: barbiturates only affect CMRO, in the presence of neuronal electrical activity; the combined effect of hypothermia and barbiturates on CMROl cannot be expressed as a simple additive relationship; and in the presence of electrical activity, the relationship between temperature and CMRO, cannot be denned by any simple mathematical function.

The Detrimental Effects of Prolonged Hypothermia and Rewarming in the Dog

The authors had previously observed a deleterious cerebrovascular effect of prolonged hypothermia in primates and cats. In this study they examined the systemic as well as cerebral hemodynamic and metabolic effects of 24 hours of hypothermia in the dog. With decreases in temperature to 29 C, cardiac output (&OV0422;) and whole-body oxygen consumption (VO2) initially decreased 52 and 42 per cent, respectively. Thereafter, despite a stable temperature, both &OV0422; and VO2 continued to decrease, and at 24 hours values were 7 and 28 per cent of control, respectively. Cerebral blood flow (CBF) and cerebral oxygen consumption responded similarly. At 24 hours inhomogeneous perfusion of both brain and skeletal muscle was observed. With rewarming, cardiovascular collapse with severe tissue hypoxia and acidosis developed; CBF became grossly inadequate, resulting in depletion of brain energy stores.

Influence of Anesthetics on Metabolic, Functional and Pathological Responses to Regional Cerebral Ischemia

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.

Cerebral Functional, Metabolic, and Hemodynamic Effects of Etomidate in Dogs

The effects of a continuous infusion of etomidate on cerebral function, metabolism, and hemodynamics and on the systemic circulation were examined in six dogs. The infusion rate of etomidate was progressively increased at 20-min intervals from 0.02 to 0.4 mg · kg−1 · min−1 for 2 h. Cerebral oxygen consumption (CMRO2) decreased until there was cessation of neuronal function as reflected by the onset of an isoelectric EEG. This occurred during an infusion of 0.3 mg · kg−1 · min−1 etomidate when the animals had received a total of 10.7 mg · kg−1 over 91 min. At this time the CMRO2 was 2.6 ml · min−1 · 100 g−1, 48% of control. Thereafter, despite continued administration of etomidate to a total dose of 21.4 mg · kg−1 CMRO2 did not decrease further. Cerebral blood flow (CBF) decreased in association with a marked increase in cerebrovascular resistance but was independent of changes in CMRO2 CBF decreased precipitously from 145 ± 23 to 72 ± 6 ml · min−1 · 100 g−1 during the lowest infusion rate of 0.02 mg · kg−1 · min−1 etomidate and stabilized at 34–36 ml · min−1 · 100 g−1 during an infusion rate of 0.1 mg · kg−1 · min−1 · CBF remained at this level despite the continued administration of etomidate and a further decrease in CMRO2 · Etomidate produced physiologically minor but statistically significant changes in the systemic hemodynamic variables. Assays of cerebral metabolites taken at the end of the infusion revealed a normal energy state and a very mild but significant increase in cerebral lactate to 1.49 μmol · g−1. We conclude that etomidate is a potent, direct cerebral vasoconstrictor that appears to be independent of its effect on CMRO2 and that the cerebral metabolic effects of etomidate are secondary to its effect on neuronal function, with little if any direct or toxic effects on metabolic pathways.