Petter A. Steen

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.

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.

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.

CEREBRAL METABOLIC AND VASCULAR EFFECTS OF BARBITURATE THERAPY FOLLOWING COMPLETE GLOBAL ISCHEMIA

Complete global cerebral ischemia was induced in dogs by temporary ligation of the ascending aorta for 10min. Prior to the ischemic period, half of the animals were given pentobarbital 30‐38 mg/kg, a maneuver previously reported to prevent or attenuate cerebral damage in this same model. Cerebral blood flow (CBF) and cerebral metabolic rate (CMRO2) were followed from prior to the ischemic period to 6 h post‐ischemia. At varying time intervals following ischemia, brain biopsies were obtained and analyzed for cerebral metabolites to determine the cerebral energy state. Only a few differences were observed between pentobarbital‐treated and untreated animals. Post‐ischemic CMRO2, stabilized at a significantly lower level in treated than in untreated animals. However, CBF was proportionately lower and thus O2 delivery relative to O2 needs in the two groups was comparable. Also in both groups, the CBF and CMRO2 stabilized at levels significantly below pre‐ischemia controls. Cerebral energy stores in both groups were depleted after 10min of ischemia but were restored to near normal within 4min post‐ischemia. Total restoration of the adenine nucleotide pool and ATP were delayed as was the return of brain lactate to normal. A 10min period of post‐ischemic hyperemia was observed in all animals and in the initial 4min post‐ischemia CMRO2 was also increased. The latter is probably accounted for by the O2 needs for restoration of cerebral energy and O2 stores. We conclude that cerebral protection as provided by barbiturates following complete global ischemia cannot be accounted for by any measurable effect on CBF, CMRO2, or the cerebral energy stores during the initial 6 h post‐ischemia.

Superoxide dismutase and catalase failed to improve neurologic outcome after complete cerebral ischemia in the dog.

Superoxide dismutase (SOD) and catalase, natural scavengers of free oxygen radicals, or saline were administered as a continuous systemic infusion to 12 dogs, in a blind randomized fashion, starting 10 mm prior to a 10;min episode of complete cerebral ischemia, and continued thereafter for 60 min. Reversible complete cerebral ischemia was achieved by simultaneously occluding the ascending aorta and venae cavae. There were no significant differences in physiological variables (arterial blood gases, hemoglobin, mean arterial blood pressure, heart rate, and temperature) between the two groups, either pre–ischemia or post–ischemia. There was no significant difference in neurologic outcome when evaluated at 48 h post–ischemia. It has previously been reported that the same dose of SOD and catalase as used in the current study could reduce infarct size by 50% when given systemically before reperfusion following coronary ischemia in dogs. The lack of a measurable effect on neurologic outcome in our cerebral ischemic modelmight be because of the failure of the free oxygen radical scavengers to reach the ischemic cells in sufficient amounts, or because free oxygen radicals do not contribute to brain injury following complete cerebral ischemia.

Barbiturate Protection in Tolerant and Nontolerant Hypoxic Mice

The effects of pentobarbital on survival times of mice exposed to oxygen, 5 per cent, were studied over a large dosage range in normal mice and in mice made tolerant to the effect of barbiturates. Tolerance was induced by pretreatment with phenobarbital, 210 mg/kg, for three days, which increased the median anesthetic dose (AD50) for pentobarbital from 34 to 53 mg/kg. In nontolerant mice there was a dose-related increase in mean survival times for doses between 35 and 60 mg/kg, with a maximum increase to 303 per cent above control. At doses of more than 60 mg/kg survival times progressively decreased toward control. For tolerant mice survival time as a function of pentobarbital dosage was shifted to the right, i.e., protection necessitated higher doses. This shift was not explained by lower brain concentrations of pentobarbital in tolerant animals, but rather parallelled the increased tolerance to the anesthetic effect of the barbiturate. The authors conclude that in this model the protective effect of barbiturate is a function of the anesthetic effect rather than the barbiturate concentration in brain per se. Hypothermia (29 C) resulted in an increase in mean survival time comparable to that in barbiturate-treated animals. This supports the hypothesis that protection is ultimately a function of decreased cerebral metabolism, whether produced by anesthesia or by hypothermia. This model measures only the effect on spontaneous respiration during hypoxia. It is possible that other mechanisms are involved if barbiturates protect in other situations, such as during or after periods of complete ischemia.

γ-Hydroxybutyrate: Cerebral Metabolic, Vascular, and Protective Effects

The cerebral protection afforded by each of several preparations of γ‐hydroxybutyrate (GHB) was examined in the hypoxic (Fio2= 0.05) mouse model. The greatest increase in survival time (85%) occurred after prereatment with 300 mg/kg given as buffered β‐butyrolactone (GBL). Compared with previous studies employing the same hypoxic model, this increase was less than that observed with certain barbiturates and equal to that observed with certain anesthetics. The cerebral and systemic metabolic and vascular effects of each of several preparations of GHB were examined in a canine model. The cerebral metabolic rate for oxygen (CMRo2) tended to increase after GHB 100 mg/kg, then progressively decreased after cumulative doses of 600 mg/kg and 1100 mg/kg. The greatest depression in CMRo2 (48%) occurred with 1100 mg/kg given as unbuffered GBL. With each preparation and at every dose, a reduction in cerebral blood flow (CBF) exceeded the reduction in CMRo2 The major systemic effect was an almost two‐thirds reduction in cardiac output at the largest doses. Assuming no species difference the cerebral protection observed with GHB is probably limited by both the reduction in cardiac output and the unfavorable relationship of cerebral oxygen supply to demand (CBF/CMRo2). Brain biopsies taken after the cumulative dose of GHB 1100 mg/kg showed a trend toward lower phosphocreatine levels and higher lactate and lactate/pyruvate levels than in untreated dogs.

The effects of nimodipine on cerebral blood flow and metabolism.

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 CMRO2 was calculated as the product of CBF and the arteriovenous O2 difference. Nimodipine did not influence either CBF or CMRO2. 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.