The effect of etomidate pretreatment on cerebral high energy metabolites, lactate, and glucose during severe hypoxia in the rat.

Etomidate was compared with thiopental with respect to preventing loss of brain high energy metabolites and accumulation of lactate during 20 min of hypoxemia (Pa2 of 16-19 mmHg) in rats with unilateral carotid artery ligation. Male Sprague-Dawley rats, anesthetized with halothane and nitrous oxide (N2O) in oxygen were randomly assigned to one of six groups. A normoxic control group which received 70% N2O in oxygen, a hypoxia group received no iv drug treatment (hypoxia-N2O), and four iv drug treatment groups (N2O was replaced by 70% nitrogen at the start of drug administration). The iv drug groups were treated as follows: hypoxia-etomidate low dose (1 mg.kg-1 iv followed by an infusion at 0.35 mg.kg-1.min-1); hypoxia-etomidate high dose (1 mg.kg-1 then 1.3 mg.kg-1.min-1); hypoxia-thiopental low dose (15 mg.kg-1, then 1.5 mg.kg-1.min-1); and hypoxia-thiopental high dose (15 mg.kg-1, then 5 mg.kg-1.min-1). After hypoxia or a corresponding period in the normoxic group, the brains were frozen in situ for later biochemical analysis. Blood was obtained prior to and at the end of hypoxia and analyzed for glucose. Brain metabolite concentrations on the side ipsilateral to the ligated carotid artery in the normoxia-N2O group were adenosine triphosphate (ATP), 2.76 +/- 0.1, phosphocreatione (PCr) 3.88 +/- 0.12, lactate 2.34 +/- 0.16, and glucose 3.56 +/- 0.28 (mumole.g-1 wet weight, mean +/- SE). There was no significant decrease in ATP in any of the hypoxia groups. PCr decreased by 45% (compared to normoxia-N2O) in the hypoxia-N2O group.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of fentanyl upon cerebral high-energy metabolites, lactate, and glucose during severe hypoxia in the rat.

The effects of intravenous administration of high-dose fentanyl (100 micrograms.kg-1, loading dose followed by an infusion of 200 micrograms.kg-1.h-1) were compared with those of a barbiturate (pentobarbital sodium 25 mg.kg-1, intraperitoneal) or hypothermia (rectal temperature 32 degrees C) on changes in cerebral cortical tissue levels of adenosine triphosphate (ATP), phosphocreatine (PCr), lactate, and glucose in severely hypoxemic rats (PaO2 13-23 mmHg for 20 min) with unilateral (left side) carotid ligation (10-12 animals in each group). Ligation of the carotid artery alone produced no change in brain high-energy metabolites, lactate, or glucose. The control values on the ligated side (nitrous oxide, 70%, + normoxia group) for cortical ATP, PCr, lactate, and glucose were 2.86 +/- 0.09 (mumol.g-1 wet weight, mean +/- 1 SE), 3.83 +/- 0.11, 1.68 +/- 0.21, and 3.29 +/- 0.47, respectively. Hypoxia (nitrous oxide, 70%, + hypoxia group) produced a significant (P less than 0.05) decrease in ATP (1.83 +/- 0.37) and PCr (1.93 +/- 0.48) and an increase in lactate (15.8 +/- 1.77) compared with the normoxic group, whereas brain glucose was not significantly changed (1.97 +/- 0.65). Fentanyl (fentanyl + hypoxia group) did not prevent the deleterious effects of hypoxia on cortical high energy metabolites (ATP, 2.0 +/- 0.27; PCr, 2.24 +/- 0.3) or lactate (19.33 +/- 3.16); however, fentanyl caused no alteration in high-energy cerebral metabolite concentrations in normoxic rats, nor did fentanyl produce a significant difference in brain tissue glucose or lactate.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of sufentanil on cerebral metabolism and circulation in the rat.

The authors examined the effects of large intravenous doses of sufentanil (5-160 micrograms/kg) on cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) in rats. CBF and CMRO2 were measured by a modified Kety-Schmidt technique using 133Xenon washout. Progressive decreases in CBF and CMRO2 occurred in animals receiving sufentanil. The maximum decrease was 53% and 40% for CBF and CMRO2 respectively, at a dose of 80 micrograms/kg. The values for CBF and CMRO2 in this group were 105 +/- 10 ml X 100 g-1 X min-1 (mean +/- SEM) and 6.5 +/- 0.5 ml X 100 g-1 X min-1, respectively, compared with 226 +/- 28 ml X 100 g-1 X min-1 and 10.9 +/- 1 ml X 100 g-1 X min-1 in the control group, which received N2O 70% in oxygen. Larger doses of sufentanil did not cause further significant changes in CBF and CMRO2. Sharp waves appeared on the electroencephalogram (EEG) of all the animals following sufentanil injection, and some animals had EEG changes develop consistent with seizure activity. This seizure-like activity appeared to consist of a single episode of short duration in the groups receiving 5, 10, and 20 micrograms/kg sufentanil. The incidence and frequency of seizure activity increased in the groups receiving higher doses of sufentanil, although the duration of seizures was still short. The results of this study indicate that sufentanil causes a significant decrease in CBF and CMRO2 similar to that previously reported for fentanyl, and high doses of sufentanil may cause frequent seizure-like patterns appearing on EEG.

Effects of fentanyl on local cerebral blood flow in the rat.

Fentanyl reduces the cortical cerebral blood flow and metabolic rate for oxygen in rats, though seizure activity occurs in some animals at high doses. However, the effects of fentanyl on blood flow and metabolism in subcortical structures have not been clearly delineated. The present study examines the effects of intravenous fentanyl (100 or 400 micrograms . kg-1) on local cerebral blood flow (1-CBF) in paralyzed, mechanically ventilated rats. Rats ventilated with 70% N2O in 30% O2 served as controls. Local CBF was measured using 14C-iodoantipyrine and autoradiography. Blood pressure, PaO2, PaCO2, pH, and temperature were comparable in all groups. The EEG showed slow wave activity in most animals given 100 micrograms . kg-1 fentanyl while seizure activity occurred in all animals given 400 micrograms . kg-1 fentanyl. With 100 micrograms . kg-1 fentanyl, CBF tended to be depressed in all cortical and subcortical areas, except the peri-aqueductal gray; and with 400 micrograms . kg-1 fentanyl, 1-CBF tended to be elevated (compared to 100 micrograms . kg-1 fentanyl) in most areas of the brain. The limbic system structures, however, were most affected by 400 micrograms . kg-1 fentanyl with statistically significant increases (compared to the 100 micrograms . kg-1 group) in 1-CBF of 86% and 67% respectively in the amygdala and septal nucleus. These results confirm that moderately high doses of fentanyl which cause slow wave activity on the EEG also depress 1-CBF in rats; moreover, doses of fentanyl that produce seizure activity produce increases in 1-CBF in most cerebral structures with greatest effects on limbic system 1-CBF.

Comparison between high-dose sufentanil-oxygen and high-dose fentanyl-oxygen for neuroanaesthesia.

The cardiovascular responses to anaesthesia, neurosurgery and the postoperative administration of naloxone were studied in 20 patients. Ten patients were anaesthetized with sufentanil 20 micrograms kg-1 and 10 with fentanyl 100 micrograms kg-1, and oxygen. At 30-min intervals, sufentanil 50 micrograms or fentanyl 250 micrograms was given to maintain anaesthesia. Mean arterial pressure and heart rate did not increase following intubation, incision of the scalp or infusion of naloxone. Because of inadequate anaesthesia, thiopentone was administered at the end of surgery to one patient who had received sufentanil and seven patients who received fentanyl. Apart from one patient in each group the tracheal tubes were removed within 1 h of the start of the administration of naloxone. Recall of tracheal intubation or surgery was not reported by any patient. High-dose sufentanil-oxygen anaesthesia, like high-dose fentanyl-oxygen anaesthesia, was satisfactory for use in neurosurgery. However, high-dose narcotic anaesthesia, followed by the postoperative administration of naloxone, requires that skilled nursing care be available for many hours after surgery.

Effects of sufentanil on regional cerebral glucose utilization in rats.

Sufentanil, a narcotic five to ten times more potent than fentanyl, reduces cortical cerebral blood flow and oxygen consumption in rats, with seizure activity occurring in some animals. However, the effects of sufentanil on blood flow and metabolism in subcortical structures have not been defined clearly. The present study examines the effects of intravenous sufentanil (40 or 160 micrograms/kg) on regional cerebral glucose utilization (r-CMRgl) in paralyzed, mechanically ventilated rats using 2-deoxy-D-[14C]glucose and autoradiography. Regional cerebral glucose utilization was decreased in all cortical areas examined in rats receiving either dose of sufentanil; the larger dose of sufentanil (160 micrograms/kg) decreased r-CMRgl in cortical structures 20-45% below control values. Two subcortical structures, the caudate nucleus and the ventral thalamic nucleus, manifested a 39-54% decrease in r-CMRgl at each dose of sufentanil. Limbic system structures responded differently. Sufentanil 40 micrograms/kg produced focal areas of markedly increased r-CMRgl in the amygdala of two of six rats; sufentanil 160 micrograms/kg produced marked increases in r-CMRgl in focal areas of hippocampus (four of eight rats) and amygdala (seven of eight rats). EEG activation suggestive of seizure activity was evident in the two low-dose sufentanil and six of the seven high-dose sufentanil rats that had focally increased r-CMRgl in the amygdala. Sufentanil causes a selective increase in r-CMRgl in subcortical limbic nuclei, particularly the amygdala, in the rat. EEG patterns of seizure activity may reflect subcortical, rather than cortical activation.

High dose fentanyl-oxygen anesthesia for intracranial mycotic aneurysm surgery: a clinical report.

The resection of a mycotic aneurysm in a patient with concurrent cardiac valvular disease was carried out successfully using high dose fentanyl-oxygen anesthesia followed by immediate postoperative naloxone reversal. The technique and benefits of this type of anesthesia in neurosurgical procedures are discussed.

The effects of high-dose fentanyl on cerebral circulation and metabolism in rats.

There is considerable controversy with respect to the effects of narcotics on the cerebral blood flow (CBF) and the cerebral metabolic rate for oxygen (CMRo2). The present study examined the effects of high doses of intravenous fentanyl (25-400 micrograms/kg) on the CBF and CMRo2 in rats. Cerebral cortical blood flow and metabolism were measured using the 133Xenon modification of the Kety-Schmidt technique. Fentanyl produced a dose-related decrease in both the CBF and the CMRo2. CBF and CMRo2 were maximally depressed by 50 and 35%, respectively, in rats given fentanyl 100 micrograms/kg compared with nitrous oxide-oxygen ventilated controls. The values for CBF and CMRo2 were 168 +/- 15 ml . 100 g-1 . min-1 and 10.3 +/- 0.7 ml . 100 g-1 . min-1, respectively in the nitrous oxide controls compared with 85 +/- 3 ml . 100 g-1 . min-1 and 7.1 +/- 0.1 ml . 100 g-1 . min-1 in animals receiving fentanyl 100 micrograms/kg. Higher doses of fentanyl did not further decrease either CBF or CMRo2 (108 +/- 12 ml . 100 g-1 . min-1 and 7.0 +/- 0.4 ml . 100 g-1 . min-1, respectively for fentanyl 400 micrograms/kg); however, seizures activity was noticed in about 25% of the rats receiving either 200 or 400 micrograms/kg fentanyl. The seizures seemed to be related to the narcotic in that they could be abolished by injections of naloxone. The seizure activity appeared to increase the CMRo2 relative to animals who received the same dose of fentanyl but did not have seizures. The CBF was not affected. The results confirm that narcotics in high enough doses may depress the CBF and CMRo2.

Reduction of the cerebral protective effect of hypothermia by oligemic hypotension during hypoxia in the rat.

The effect of arterial hypotension on cerebral cortical tissue levels of adenosine triphosphate (ATP), phosphocreatine (PGr), lactate, and reduced nicotinamide adenine dinucleotide (NADH) was studied in male Wistar rats with unilateral carotid ligation exposed to arterial by hypoxia (PaO2 25 torr) for 20 min. while the body temperature was maintained at 32 degrees C and 27 degrees C. Brain metabolite levels were normal in normotensive hypothermic animals exposed to hypoxia, but reduction in arterial pressure to 75 torr caused a significant (p less than 0.05) decrease in ATP and PCr values and a significant increase in lactate and NADH levels. These changes were comparable to those of normothermic normotensive, hypoxic animals. Furthermore, there was no significant differences in the brain metabolite levels between the two hypotensive hypoxic groups. These results indicate that arterial hypotension severely alters the cerebral protective effect of hypothermia against injury caused by hypoxia, and that further reduction in body temperature (from 32 degrees C to 27 degrees C) will not prevent the harmful effect of hypoxia upon the brain in hypotensive rats.

Cerebral protective effect of low-grade hypothermia.

Male Wistar rats with unilateral carotid ligation were exposed to arterial hypoxia (PaO2 20-23 torr for 20 min) while body temperature was controlled at 37 degrees C, 36 degrees C, or 34 degrees C. Brain cortical concentrations of ATP, phosphocreatine (PCr) and lactate were measured microfluorometrically. Normothermic hypoxic rats had severe metabolic changes with low brain ATP and extremely high brain lactate. When rectal temperature was controlled at 36 degrees C during hypoxia, brain ATP was not different from that observed in normothermic, normoxic rats, and brain lactate was significantly lower than during normothermic hypoxia. At 34 degrees C, brain lactate was even less, but still three times higher than that observed in normothermic normoxic rats. PCr was significantly higher following hypoxia at 34 degrees C than at 37 degrees C. In part, this latter finding may reflect preservation of intracellular pH at 34 degrees C. A decrease of body temperature of 1-3 degrees C can minimize or prevent brain energy failure during hypoxia as well as decrease the magnitude of brain tissue acidosis. Thus, in experiments examining "cerebral protective effects" of therapies during brain hypoxia-ischemia, stringent control of body temperature is necessary. Furthermore, a possible clinical benefit resulting from modest reduction in body temperature in patients with marginal cerebral oxygenation is suggested.

Effect of high vs. low arterial blood oxygen content on cerebral energy metabolite levels during hypoxia with normothermia and hypothermia in the rat.

The effects of different levels of arterial blood oxygen content (CaO2) on brain tissue adenosine triphosphate (ATP), phosphocreatine (PCr), lactate, and reduced nicotinamide adenine dinucleotide (NADH) were studied during cerebral hypoxia in normothermic and hypothermic male Wistar rats with unilateral carotid ligation. Animals were exposed to hypoxia (PaO2 19--26 torr) for 25 min, and brain tissue metabolite values measured microfluorometrically were compared with those of normothermic normoxic controls. CaO2 was 4.0 +/- 0.2 ml/dl (mean +/- SEM) at PaO2 26 torr in normothermic animals. CaO2 was increased to 8.2 +/- 0.3 ml/dl at PaO2 26 torr by means of bicarbonate infusion producing a leftward shift of the oxyhemoglobin-dissociation curve in one normothermic hypoxic group. In all normothermic hypoxic groups ATP and PCr decreased and lactate and NADH increased significantly compared with control values. There was no significant difference in brain tissue metabolite values among these groups despite an increase in CaO2 by twofold in one group. Hypothermia (32 C) resulted in CaO2 8.4 +/- 0.2 ml/dl at PaO2 26 torr. This was decreased to 4.0 +/- 0.2 ml/dl by decreasing PaO2 to 19 torr in another group at the same temperature. ATP and PCr were well preserved in both groups despite the difference in CaO2s. Although the lactate and NADH levels were increased in the hypothermic group with CaO2 4.0 +/- 0.2 ml/dl, they were significantly lower than those values in normothermic hypoxic groups. These results indicate that the increase in CaO2 produced by hypothermia is not a major determinant in hypothermic protection during cerebral hypoxia.

Additive effects of hypothermia and phenobarbitol upon cerebral oxygen consumption in the rat.

The quantitative effects of a combination of hypothermia and phenobarbital on cerebral oxygen uptake (CMRo2) was studied in rats, curarized and artificially ventilated with 70% nitrous oxide in oxygen. Cerebral blood flow (CBF) was measured with a modification of the KETY & SCHMIDT (1948) technique, using 133xenon as a tracer. Arteriovenous difference in oxygen content over the brain was measured and CMRo2 was calculated. Four groups were studied. Group 1 was a control group. The three experimental groups were injected with phenobarbital intraperitoneally: Group 2 with 50 mg/kg body weight; Group 3 with 150 mg/kg; and Group 4 with 50 mg/kg of phenobarbital, and, in addition, body temperature was lowered to 32 degrees C in this group. CMRo2 in groups 2, 3 and 4 was reduced by 22, 37 and 43%, respectively, compared to Group 1. The changes in CBF were of the same magnitude. In a previous study we have found that CMRo2 decreases by 5% per 1 degree C decrease in body temperature. The value for CMRo2 in Group 4 is close to the value obtained if the effect of 50 mg/kg body weight of phenobarbital on CMRo2 is added to the effect of a temperature reduction of 5 degrees C. It is concluded that the effects of barbiturates and hypothermia on CMRo2 are additive.

Cerebral energy levels during trimethaphan-induced hypotension in the rat: effects of light versus deep halothane anesthesia.

Hypotension may be expected to produce less perturbation of metabolism in the brain when cerebral metabolic rate is lowered by deep anesthesia. Male Wistar rats having unilateral carotidartery ligation were exposed to mean arterial pressure (MAP) of 40 torr for 22 min by an intravenous infusion of trimethaphan during anesthesia with halothane, 0.6 or 2 per cent, in oxygen. Cortical tissue metabolite levels on the side of the ligated carotid artery were more abnormal in rats receiving halothane, 0.6 per cent, than in those receiving halothane, 2 per cent. Values at halothane, 0.6 per cent, were adenosine triphosphate (ATP), 1.71 +/- 0.05 (+/-SEM) mumol/g, phosphocreatine (PCr) 1.97 +/- 0.07 mumol/g. and lactate 16.5 +/- 5.1 mumol/g; corresponding values at halothane, 2 per cent, were ATP 2.27 +/- 0.02, PCr 4.02 +/- 0.23, and lactate 4.75 +/- 0.9 mumol/g. ATP and PCr values were significiantly lower (P less than 0.05) and the lactate value was significantly higher with halothane, 0.6 per cent, than with halothane 2 per cent. Cerebral oxygen consumption decreased 47 per cent in rats anesthetized with halothane, 2 per cent. Preservation of cortical metabolite levels in deeply anesthetized animals suggests a protective effect of cerebral metabolic depression.

Cerebral energy metabolite levels and survival following exposure to low inspired oxygen concentration.

To determine the relationship between brain energy metabolites and neurologic status after ischemia-hypoxia, we measured cortical tissue levels of adenosine triphosphate (ATP), phosphocreatine, and lactate. Rats with permanent unilateral carotid occlusion were exposed to 5, 10, and 15 min of hypoxic atmosphere (FIO2 0.048) and, to examine metabolic restitution, 60 min after recovery in rats exposed to the same hypoxic mixture for 15 min. At 5 and 10 min of hypoxia, there were significant reductions in phosphocreatinine and elevations in tissue lactate, but only after 15 min of hypoxia, did ATP levels significantly decrease. By 60 min after recovery, phosphocreatinine values returned to the normal range, ATP values to 15% less than normal, and tissue lactate toward normal. In parallel survival studies, neurological status was examined following hypoxic exposure (PaO2 18 to 19 torr) for 5 an 10 min. Evidence for neurological injury in the form of posthypoxic seizures occurred at a point in time preceding significant changes in brain tissue ATP level. Since injury occurs prior to ATP reduction, changes in brain tissue ATP level may not be an appropirate endpoint for determining brain tissue injury in hypoxia.

The effect of halothane anaesthesia upon cerebral oxygen consumption in the rat.

The influence of halothane (0.6 and 2%) upon cerebral (cortical) blood flow (CBF) and cerebral metabolic rate for oxygen (CMRo2) was studied in artificially ventilated rats, using a modified technique of Kety & Schmidt (1948). The values obtained in halothane anaesthesia were compared to those recorded in nitrous oxide anaesthesia, or to those measured in unanesthetized animals given an analgesic drug (fentanyl citrate). Although it could be confirmed that halothane induces vasodilatation in the brain, there were relatively small differences in CBF between the groups. The results demonstrate that, in the rat, halothane depresses CMRo2 in a dose-dependent way. With 0.6% halothane, CMRo2 was reduced by 20-30% and, with 2% halothane, CMRo2 was reduced by about 50%. Thus, in the rat the effect of 2% halothane upon metabolic rate is comparable to that observed in barbiturate anaesthesia.