John D. Michenfelder

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 interdependency of cerebral functional and metabolic effects following massive doses of thiopental in the dog.

The cerebral metabolic effects of a massive dose of thiopental (177 mg/kg) were investigated in seven dogs. The systemic circulation was supported with an extracorporeal circuit. At an infusion rate of 2 mg/kg/min, cerebral oxygen consumption (CMRO2) decreased progressively until cerebral electrical silence was produced. This occurred after a mean dose of 72 mg/kg, which caused a mean decrease in CMRO to 58 per cent of the control value (measured at 1.5 per cent halothane inspired). Thereafter, despite continued infusion at 4 mg/kg/ min, CMRO2 did not decrease further. The oxygen-glucose index never changed during the infusion period and, at the termination of the infusion, brain assays for ATP, phosphocreatine, lactate, and pyruvate revealed normal concentrations. It is concluded that there was no alteration in normal cerebral metabolic pathways, that cerebral metabolic effects of thiopental are secondary to functional effects, that thiopental would provide no cerebral protection during hypoxia sufficient to abolish cerebral function, and that thiopental does not uncouple oxidative phosphorylation in vivo.

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 Anesthesia and Hypothermia on Canine Cerebral ATP and Lactate during Anoxia Produced by Decapitation

ATP and lactate in the canine brain were determined before and during cerebral anoxia induced by decapitation, both at 30 C during halothane anesthesia (0.8 per cent) and at 37 C during four anesthetic circumstances (nitrous oxide, 70 per cent; halothane, 0.8 per cent; halothane, <0.1 per cent; and halothane, 0.8 per cent, with thiopental, 46 mg/kg). The anesthetic circumstances chosen for study at 37 C provided a wide range of mean values for cerebral oxygen consumption rate (CMRo2) (5.9 to 2.9 ml/100 gm/min). At 37 C the CMRo2. associated with the combination of thiopental and halothane (2.9 ml/100 gm/min) approached that at 30 C (2.8 ml/100 gm/min). At 37 C, postdecapitation rates of ATP depletion and lactate accumulation were not influenced by the anesthetic At 30 C, these rates were approximately 40 per cent less. These findings suggest that anesthesia and hypothermia, although they have potentially similar effects on CMRo2, alter cerebral metabolic rate by dissimilar mechanisms, and cannot be expected to provide similar degrees of cerebral protection in the event of anoxia.

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).

Cerebral protection by thiopental during hypoxia.

The effects of thiopental on rates of cerebral ATP depletion and lactate accumulation in dogs anesthetized with N2O during two different circumstances of impaired oxygen delivery were examined. In ten dogs, five with and five without prior thiopental (13 mg/kg), acute hemorrhagic shock (mean arterial pressure 25–30 mm Hg) was produced and maintained for 9 minutes. The EEG remained active in all these dogs. In the dogs given thiopental, cerebral ATP was sustained at a significantly higher level and cerebral lactate accumulation was significantly less in the initial 5–7 minutes of hypotension. In another ten dogs, five with and five without prior thiopental (15 mg/kg), Fio2 was decreased abruptly to zero and hypoxia, progressing rapidly to anoxia (Pao2 < 5 mm Hg), was maintained for 9 minutes. After 3 minutes, the EEG was flat in all dogs, but activity persisted for a significantly longer period (35 see) in dogs given thiopental. The rates of ATP depletion and lactate accumulation were greater than with hypotension and were not significantly altered by thiopental. It is concluded that in the circumstance of hypoxia with continued cerebral function (active EEG), thiopental does afford some cerebral protection; in the absence of function (flat EEG), no protection is apparent. The authors suggest that anesthetics such as thiopental diminish energy requirements of the brain only by reducing its function and hence can provide cerebral protection only when the extent of hypoxia is insufficient to abolish function.

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.