Summary:The metabolic effects of graded whole body hypothermia on complete global cerebral ischemia and recirculation was investigated in the cat. Hypothermia was induced to one of three levels prior to ischemia; T = 26.8° ± OSC (n = 4), T = 32.1° ± 0.2°C (n = 5), and T = 34.6° ± 0.3°C (n = 6), and maintained constant throughout 16 min of ischemia and 1.5-2 h of recircula tion. Intracellular cerebral pH and relative concentrations of high-energy phosphate metabolites were continuously monitored, using in vivo 31p nuclear magnetic resonance (NMR) spectroscopy. Except for the first 4 min of isch emia, no significant differences were detected in the re sponse of adenylate intensities and intracellular pH to ischemia and recirculation between the hypothermic groups. The three hypothermic groups were then pooledThe effect of whole body hypothermia on cere bral metabolism has a long history (Field et aI., 1944). The possible beneficial effects of hypother mia on cerebral pathophysiological conditions have also been explored (see Siesj6, 1978). Whole body hypothermia, when applied judiciously, can curtail metabolic changes and lessen cerebral edema and neuropathologic damage associated with hypoxia (Carlsson et aI., 1976;Rosomoff 1959), and head injury (Shapiro et aI., 1974 141into one group, and the data compared to previously pub lished data from a normothermic group, T = 38.4° ± 0.6°C (n = 14), and a hyperthermic group, T = 40.6° ± 0.2°C (n = 9), subjected to the identical ischemic and NMR measurement protocols. The hypothermic animals exhibited a statistically significant reduction of cerebral intracellular acidosis, both during ischemia and recircu lation, as well as a more rapid return of adenylate inten sities during recirculation, compared to the normothermic or hyperthermic groups. The data thus suggest that mild hypothermia has an ameliorative affect on brain energy metabolism and intracellular pH under conditions of com plete global cerebral ischemia and recirculation. Key Words: 31p NMR spectroscopy-Cerebral ischemia Hypothermia-Body temperature, and cerebral ischemia. emia, including circulatory arrest, with recircula tion (Marshal et aI., 1956; Kramer et aI., 1968; Ber ing, 1974; Perna et aI., 1973; Wolin et aI., 1973;Hickey, 1985) and without recirculation (Stocker et aI., 1986); the isolated perfused brain (Norwood et aI., 1979); and focal cerebral ischemia (Simeone et aI., 1979;Rosomoff, 1957). These studies, which were performed at temperatures below 30°C, sug gest that hypothermia results in a reduction in the rate of degradation of brain energy metabolism dur ing the onset of hypothermic ischemia as well as a reduced level of brain tissue acidosis compared with normothermic ischemia. However, the clinical application of hypothermia is limited by adverse ef fects associated with level as well as the duration of hypothermia (Popovic, 1960;Michenfelder and Milde, 1977;Bjork and Hultquist, 1960; Brunberg et aI., 1974; Connolly et aI., 1962; Olesen et aI., 1971).

We investigated the effect of mild whole-body hyperthermia before and after 16 minutes of global cerebral ischemia on metabolic recovery during recirculation in cats using in vivo phosphorus-31 nuclear magnetic resonance spectroscopy. Hyperthermia (temperature 40.6±0.2° C) was induced >1 hour before ischemia and was maintained during 1.5-2 hours of recirculation in nine cats; four cats were subjected to hyperthermia without cerebral ischemia, six to hyperthermia during recirculation (after return of intracellular pH to preischemic values), and 14 to normothermic ischemia and recirculation. Our data indicate that preischemic hyperthermia results in an intracellular cerebral pH during recirculation significantly lower than that in normothermic cats. In hyperthermic cats /3-ATP and phosphocreatine (PCr) concentrations and the ratio of PCr to inorganic phosphate failed to return to preischemic levels during recirculation in contrast to normothermic cats. Hyperthermia without ischemia and hyperthermia during recirculation had no significant effect on intracellular pH. Thus, preischemic hyperthermia has a detrimental effect on metabolic recovery after transient global cerebral ischemia. (Stroke 1988;19:1521-1525) F ever or subfebrility in stroke patients causes deterioration of neurologic function by mechanisms as yet unknown. 1 In normal brain, body temperature increases of 1-2° C over a period of hours in response to infection or even ambient thermal conditions have no significant detrimental effects on cerebral metabolism.2 The effects of similar hyperthermia (temperature of <41° C) on cerebral high-energy phosphate metabolism and intracellular pH has not been addressed under conditions of cerebral ischemia. Accordingly, we used in vivo phosphorus-31 nuclear magnetic resonance ( 3I P-NMR) spectroscopy to measure relative concentrations of high-energy phosphate metabolites and intracellular pH before, during, and after transient global cerebral ischemia in cats subsequent to mild wholebody hyperthermia. Our data suggest that preischemic mild hyperthermia prolongs ischemic brain Received February 16, 1988; accepted June 1, 1988. acidosis and has a detrimental effect on metabolic recovery from transient global cerebral ischemia. Materials and MethodsWe used 38 conditioned cats weighing 2.2-3.6 kg. Surgical preparation and induction of transient (16 minutes) global cerebral ischemia using a combination of systemic arterial hypotension and inflation of a cervical cuff were identical to those previously reported. 3Each cat was placed on a water blanket. A water bath recirculator-heater (Model E-12, Haake, Berlin, FRG) connected to a feedback-regulated temperature controller (YSI model 73-A, Yellow Springs Instrument Company, Yellow Springs, Ohio) was used to regulate the cat's temperature. Temperature probes were placed rectally and in the abdominal wall. Over 1-1.5 hours the rectal temperature of cats made hyperthermic rose to between 40° and 41° C. Temperature gradients between rectal and subcutaneous temperatures w...

In 27 cats treated to vary arterial serum glucose concentrations, we measured cerebral highenergy phosphate metabolite concentration and intracellular pH using in vivo phosphorus-31 nuclear magnetic resonance spectroscopy during transient global cerebral ischemia and reperfusion. Hypoglycemia was induced with 4 units/kg i.v. insulin in six cats before ischemia; hyperglycemia was induced with 1.5 g/kg i.v. glucose in six cats before and in six cats during ischemia. Nine untreated cats subjected to ischemia without manipulation of blood glucose concentration served as controls. During ischemia, intracellular pH fell to similar levels in the control and both hyperglycemic groups. During reperfusion, the hyperglycemic before ischemia group initially exhibited a severe further decline in intracellular pH (p<0.003); this further decline was not observed in the control or the hyperglycemic during ischemia groups. Intracellular acidosis was attenuated both during ischemia and early after reperfusion in the hypoglycemic before ischemia group. In all groups, cerebral high-energy phosphate metabolite concentrations were depleted during ischemia and then recovered to the same degree during reperfusion. Our data suggest that brain glucose stores before ischemia determine the severity and time course of intracellular acidosis during ischemia and reperfusion. (Stroke 1988;19:1383-1387) T he influence of systemic blood glucose concentration on the neurologic outcome of stroke has been repeatedly documented in experimental animals and patients.1 -8 Experiments have suggested that this effect is mediated by brain acidosis. 8 -12 Efforts to control blood glucose concentration could have promise in the clinical management of stroke, but the precise conditions under which this might be accomplished remain uncertain. For example, if preexisting high blood and tissue glucose concentrations dictate an unfavorable outcome, control of hyperglycemia after stroke onset will be ineffective. However, if control of blood glucose concentration is worthwhile, should levels be controlled to the normal range and will subnormal (even hypoglycemic) levels produce added benefit? We have begun to address these questions by observing energy metabolism and pH in an animal model of global ischemia using noninvasive in vivo phosphorus-31 nuclear magnetic resonance spectroscopy ( 31 P NMR), a technique that has potential for the dynamic monitoring of stroke patients who might be candidates for manipulation of systemic glucose concentrations. Materials and MethodsWe studied 27 female cats weighing 2.2-3.4 kg. The cats were fasted for 24 hours, with water given ad libitum. Anesthesia induced with 4% halothane in O 2 was followed by tracheotomy, intravenous injection of 0.02 mg atropine and 0.08 mg/kg pancuronium bromide, and mechanical ventilation with <1% halothane/33% O 2 /66% N 2 O + CO 2 . Ventilation gases were adjusted to maintain blood gases within the physiologic range. Rectal temperature was monitored and maintained at 38° C. Both femoral arteri...

We investigated the effects of multiple episodes of cerebral ischemia on intracellular brain pH using in vivo phosphorus-31 nuclear magnetic resonance spectroscopy. Four cats were subjected to two 16-minute episodes of complete global cerebral ischemia 6 hours apart; the second episode occurred under hyperthermic conditions (mean +/- SD body temperature 40.8 +/- 0.4 degrees C). Intracellular pH in these four cats was compared with that in nine cats subjected to a single 16-minute episode of complete global cerebral ischemia under hyperthermic conditions (mean +/- SD body temperature 40.6 +/- 0.2 degrees C). Intracellular pH during hyperthermic recirculation was significantly (p less than 0.03) greater in cats subjected to a previous ischemic event than that in cats subjected to only a single hyperthermic ischemic event. We speculate that the induction of heat shock proteins by an initial ischemic event may protect brain tissue from further ischemic insult.