Alan A. Artru

Cerebral metabolic, vascular and protective effects of midazolam maleate. Comparison to diazepam

The effects of midazolam maleate and diazepam on cerebral metabolism and circulation were examined for each drug in six dogs maintained on N2O 70 per cent and halothane < 0.1 per cent. Midazolam maleate at 0.2 mg/kg and diazepam at 0.3 mg/kg (the ED 100 per cent for induction of anesthesia for each

Cerebral protective, metabolic, and vascular effects of phenytoin.

In mice breathing 5 percent oxygen, pretreatment with the optimal dose of 200 mg/kg of phenytoin increased survival time 123 percent This increase was somewhat less than that observed with certain barbiturates using the same model but significantly greater than that obsened with diazepam which is more effective than phenytoin in suppressing hypoxemlc convulsions in this model. In dogs maintained at an expired halotfaane concentration of either 0.87 percent or < 0.1 percent, phenytoin tended to decrease cerebral blood flow and had no effect on the cerebral metabolic rate for oxygen at 3 different doses. Assuming a similar effect in mice, the cerebral protection during hypoxemia observed with phenytoin cannot be explained by a reduction in metabolic rate, an increase in oxygen delivery, or by an anticonvulsant effect per se. In additional dog studies, pretreatment with phenytoin decreased the rate of potassium accumulation in cisteraal cerebrospinai fluid following 20 minutes of anoxia. We speculate that pbenytoin protection may be linked to this effect.

Influence of hypothermia or hyperthermia alone or in combination with pentobarbital or phenytoin on survival time in hypoxic mice

The effect of temperature, either alone or in combination with pentobarbital or phenytoin, on survival time in the hypoxic (FIO2 = 0.05) mouse was examined. With hypothermia alone only a mild level (35 C) was needed to increase survival time significantly (63%). Between 29 and 40 C, hypothermia alone increased hypoxic survival time and hyperthermia decreased it. When mild hypothermia was combined with moderate doses of pentobarbital or phenytoin, survival time was generally further increased, whereas at lower temperatures or increased drug doses the effect on survival time of combined treatments was unpredictable. In addition, the magnitude of the effect of hypothermia was quite different following injection of pentobarbital and following injection of phenytoin. A practical corollary of these results is that to obtain reproducible results with this model, the temperature of the mice should not vary more than ± 0.2 to 0.3 C.

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.

Effects of Hypercarbia on Canine Cerebral Metabolism and Blood Flow with Simultaneous Direct and Indirect Measurement of Blood Flow

While it is generally agreed that cerebral blood flow (CBF) increases during hypercarbia, measurements of cerebral metabolic rate (CMRO2) during hypercarbia have yielded divergent results. Accordingly, the authors reexamined the changes in CMRO2 during normocarbia and hypercarbia to 80 and 100 torr employing a canine model designed to minimize potential measurement errors introduced by hypercarbia. Repetitive measurements of arterial–cerebral venous blood oxygen content differences C(a-v)O2 were made, and CBF was measured simultaneously by both a direct (sagittal sinus blood flow collection) and an indirect (133Xe washout) technique. CMRO2, derived from the direct CBF measurements and C(a-v)O2, was unchanged at PaO2, 80 torr and was significantly decreased (by 10 per cent) at PaCO2 100 torr. Comparison of the two techniques for determining CBF showed good agreement between the direct method and fast compartment analysis of the 133Xe washout.

Canine Cerebral Metabolism and Blood Flow during Hypoxemia and Normoxic Recovery from Hypoxemia

There are conflicting reports regarding the effects of hypoxemia on the cerebral metabolic rate for oxygen (CMRO2). Accordingly, we examined the changes in CMRO2 during normoxia, progressive hypoxia (PaO2 of 37, 27, and 23 mm Hg), and normoxic recovery from hypoxia, Measurements were made in dogs anesthetized with nitrous oxide (60–70%) and halothane (<0.1%) in oxygen. Arterial-cerebral venous blood oxygen content differences and cerebral blood flow (CBF) were measured simultaneously, the latter by a technique (collection of sagittal sinus outflow) previously validated for conditions of near-maximal CBF, The duration of each of the three hypoxic exposures was approximately 10 min. CMRO2 was significantly decreased (14%) only when the arterial blood oxygen tension was reduced to 23 mm Hg. CBF increased progressively to a maximum of 153% of control. Posthypoxemic brain biopsy values for cerebral metabolites obtained 40 min after normoxemia had been restored were normal. These results, in conjunction with an unchanged CMRO2 at 40 min normoxic recovery, suggest that no gross irreversible brain cell damage occurred. We conclude that with progressive hypoxemia. CMRO2 remains stable until oxygen demand exceeds oxygen delivery, resulting there after in a progressive reduction in CMRO2.

A re-examination of physostigmine-induced cerebral protection in the hypoxic mouse. A critical assessment of the model.

Using the hypoxic (FiO2 = 0.05) mouse model as originally described, the survival time following pretreatment with physostigmlne was examined. Tbe maximum Increase in arrival time was 87% following a physostigmine dose of 0.4 mg/kg. This increase was considerably less than that previously reported for this drug in a hypoxic mouse study wherein the standard method for exposing mice to hypoxia was altered. We speculate that this alteration in methodology resulted in small variations in FiO2 sufficient to account for the differences between these studies.

Cyclocreatine Phosphate, an Analogue of Creatine Phosphate, Does not Improve Hypoxic Tolerance in Mice

Abstract: Dietary cyclocreatine has been reported to increase brain highenergy stores in mice and to prolong the generation and utilization of these stores following decapitation. A possible cerebral protective action after 50 days of dietary cyclocreatine 0.5% and 1.0% was therefore examined in mice. Cyclocreatine 0.5% did not increase survival time during hypoxia (5% 02). Cyclocreatine 1.O% in the absence of hypoxia caused significant mortality and decreased weight in survivors despite prophylactic antibiotic treatment. Dietary cyclocreatine offers no cerebral protection against hypoxia in mice.

Cerebral Metabolism during Porcine Malignant Hyperthermia

The cerebral response during halothane–succinylcholine anesthesia was examined in six malignant hyperthermia (MH)-susceptible and two normal swine. Cerebral and systemic values were determined for 50 min at 10-min intervals. These values were also determined in a susceptible animal given pentobarbital prior to and during halothane–succinylcholine anesthesia, and two susceptible animals in which MH was triggered by external warming. After the 50-min values had been obtained, biopsy specimens were taken from the brains of five animals. During MH induced by either drugs or warming, the cerebral metabolic rate for oxygen was similar to that determined prior to induction of MH and to that determined for the normal swine. While cerebral blood flow immediately increased in the six animals with drug-induced MH following the introduction of halothane, no such increase occurred either in the pentobarbital-treated animal or in the animals wherein MH was induced by external warming. In brain biopsy specimens from the susceptible animals, increases in lactate and lactate/pyruvate and a decrease in phosphocreatine were consistent with changes in systemic variables such as temperature and acid–base indices. When the influences of systemic and other variables are considered, the cerebral metabolic data suggest that the primary process(es) that generates MH does not occur in brain tissue, and that MH itself does not cause gross irreversible brain-cell damage or cerebral metabolic failure.