Reduction In Cerebral Metabolic Rate Research Articles

Baseline Cerebral Metabolic Rate Is a Critical Determinant of the Cerebral Vasodilating Potency of Volatile Anesthetic Agents.

A Comparison of the Direct Cerebral Vasodilating Potencies of Halothane and Isoflurane in the New Zealand White Rabbit. By Drummond JC, Todd MM, Scheller MS, and Shapiro HM. ANESTHESIOLOGY 1986; 65:462-7. Reprinted with permission.Halothane is commonly viewed as a more potent cerebral vasodilator than isoflurane. It was speculated that the lesser vasodilation caused by isoflurane might be the result of the greater reduction in cerebral metabolic rate (CMR) that it causes, and that the relative vasodilating potencies of halothane and isoflurane would be similar if the two agents were administered in a situation that precluded volatile-agent-induced depression of CMR. To test this hypothesis, cerebral blood flow (CBF) and the cerebral metabolic rate for oxygen (CMRO2) were measured in two groups of rabbits before and after the administration of 0.75 MAC halothane or isoflurane. One group received a background anesthetic of morphine and N2O, which resulted in an initial CMRO2 of 3.21 ± 0.17 (SEM) ml · 100 g · min; second group received a background anesthetic of high-dose pentobarbital, which resulted in an initial CMRO2 of 1.76 ± 0.16 ml · 100 g · min. In rabbits receiving a background of morphine sulfate/N2O, halothane resulted in a significantly greater CBF (65 ± 10 ml · 100 g · min) than did isoflurane (40 ± 5 ml · 100 g · min). Both agents caused a reduction in CMRO2, but CMRO2 was significantly less during isoflurane administration. By contrast, with a background of pentobarbital anesthesia, CBF increased by significant and similar amounts with both halothane and isoflurane. With halothane, CBF increased from 22 ± 2 ml · 100 g · min in the control stage to 39 ± 3, and with isoflurane from 24 ± to 38 ± 2 ml · 100 g · min. CMRO2 was not depressed further by either halothane or isoflurane. These results suggest that the relative effects of halothane and isoflurane on CBF are dependent on the CMR present prior to their administration. When the preexistent CMR is not markedly depressed, isoflurane decreases CMR and causes less cerebral vasodilation than does halothane. When initial CMR is depressed, halothane and isoflurane have similar vasodilating potencies.

Genetic interaction is associated with lower metabolic connectivity and memory impairment in clinically mild Alzheimer's disease.

Metabolic connectivity as showed by [18F] fluorodeoxyglucose (FDG) positron emission tomography (FDG-PET) reflects neuronal connectivity. The aim of this study was to investigate the genetic impact on metabolic connectivity in default mode subnetworks and its clinical-pathological relationships in patients with Alzheimer's disease (AD). We separately investigated the modulation of 2 default mode subnetworks, as identified with independent component analysis, by comparing APOE-ε4 carriers to noncarriers with AD. We further analyzed the interaction effects of APOE (APOE-ε4 carriers vs noncarriers) with PICALM (rs3851179-GG vs rs3851179-A-allele carriers) on episodic memory (EM) deficits, reduction in cerebral metabolic rate for glucose (CMRgl) and decreased metabolic connectivity in default mode subnetworks. The metabolic connectivity in the ventral default mode network (vDMN) was positively correlated with EM scores (β =0.441, P < .001). The APOE-ε4 carriers had significantly lower metabolic connectivity in the vDMN than the APOE-ε4 carriers (t(96) = -2.233, P = .028). There was an effect of the APOE-PICALM (rs3851179) interactions on reduced CMRgl in regions of vDMN (P < .001), and on memory deficits (F3,93 =5.568, P = .020). This study identified that PICALM may modulates memory deficits, reduced CMRgl and decreased metabolic connectivity in the vDMN in APOE-ε4 carriers. [18F] FDG-PET-based metabolic connectivity may serve a useful tool to elucidate the neural networks underlying clinical-pathological relationships in AD.

Effect of ephedrine and phenylephrine on brain oxygenation and microcirculation in anaesthetised patients with cerebral tumours: study protocol for a randomised controlled trial

IntroductionDuring brain tumour surgery, vasopressor drugs are commonly administered to increase mean arterial blood pressure with the aim of maintaining sufficient cerebral perfusion pressure. Studies of the commonly used vasopressors...

Dissociation of metabolic and hemodynamic levodopa responses in the 6-hydroxydopamine rat model

Dissociation of vasomotor and metabolic responses to levodopa has been observed in human subjects with Parkinson's disease (PD) studied with PET and in autoradiograms from 6-hydroxydopamine (6-OHDA) rat. In both species, acute levodopa administration was associated with increases in basal ganglia cerebral blood flow (CBF) with concurrent reductions in cerebral metabolic rate (CMR) for glucose in the same brain regions. In this study, we used a novel dual-tracer microPET technique to measure CBF and CMR levodopa responses in the same animal. Rats with unilateral 6-OHDA or sham lesion underwent sequential 15O-water (H215O) and 18F-fluorodeoxyglucose (FDG) microPET to map CBF and CMR following the injection of levodopa or saline. A subset of animals was separately scanned under ketamine/xylazine and isoflurane to compare the effects of these anesthetics. Regardless of anesthetic agent, 6-OHDA animals exhibited significant dissociation of vasomotor (ΔCBF) and metabolic (ΔCMR) responses to levodopa, with stereotyped increases in CBF and reductions in CMR in the basal ganglia ipsilateral to the dopamine lesion. No significant changes were seen in sham-lesioned animals.These data faithfully recapitulate analogous dissociation effects observed previously in human PD subjects scanned sequentially during levodopa infusion. This approach may have utility in the assessment of new drugs targeting the exaggerated regional vasomotor responses seen in human PD and in experimental models of levodopa-induced dyskinesia.

Brain Tissue Oxygenation During Dexmedetomidine Administration in Surgical Patients With Neurovascular Injuries

Investigations in dogs have shown substantial dexmedetomidine (Dex)-induced reductions in cerebral blood flow (CBF) unaccompanied by reductions in cerebral metabolic rate (CMR). If this effect were to occur in humans in areas of injured brain in which CBF is already low, oxygen delivery might be critically impaired. The institutional use of brain PO2 monitoring during neurovascular surgery and the use of Dex as a component of the anesthetic allowed insight into this issue. Data from 5 neurovascular surgery patients, 2 for excision of arteriovenous malformations (AVMs), and 3 for intracranial aneurysm clipping were reviewed retrospectively. All had acute, lesion-related neurologic deficits. During general anesthesia with sufentanil and sevoflurane, with or without N2O, a parenchymal brain tissue PO2 (PbrO2) electrode was placed directly in the territory at risk from the pending neurosurgical intervention. After a stable PbrO2 value was achieved, Dex was administered by bolus (1 μg/kg over 10 min) and infusion (0.5 to 0.7 μg/kg/min). Mean arterial pressure (MAP), heart rate (HR), and PbrO2 were observed continuously for at least 25 minutes. Baseline PbrO2 values were relatively low (≤16 mm Hg) in 4 of the 5 patients, a pattern consistent with antecedent neurologic insult. In the 15 minutes after initiation of Dex administration, the pattern was one of a modest increase in Pbr02 (maximum 11.1%; P=0.0147) occurring roughly in parallel with a modest increase in MAP [maximum 3.5 mm Hg (4.5%); P=0.041]. HR did not change. Clinically significant reduction of PbrO2 did not occur before neurosurgical interventions. These observations provide no support for a direct cerebral vasoconstrictive effect of Dex in humans that is independent of any vasoconstriction that may occur as a consequence of Dex-induced reduction in CMR. At a minimum, any such effect was insufficient to have an adverse effect on oxygen delivery to brain parenchyma.

Early Nonischemic Oxidative Metabolic Dysfunction Leads to Chronic Brain Atrophy in Traumatic Brain Injury

Chronic brain atrophy after traumatic brain injury (TBI) is a well-known phenomenon, the causes of which are unknown. Early nonischemic reduction in oxidative metabolism is regionally associated with chronic brain atrophy after TBI. A total of 32 patients with moderate-to-severe TBI prospectively underwent positron emission tomography (PET) and volumetric magnetic resonance imaging (MRI) within the first week and at 6 months after injury. Regional lobar assessments comprised oxidative metabolism and glucose metabolism. Acute MRI showed a preponderance of hemorrhagic lesions with few irreversible ischemic lesions. Global and regional chronic brain atrophy occurred in all patients by 6 months, with the temporal and frontal lobes exhibiting the most atrophy compared with the occipital lobe. Global and regional reduction in cerebral metabolic rate of oxygen (CMRO(2)), cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of glucose were observed. The extent of metabolic dysfunction was correlated with the total hemorrhage burden on initial MRI (r=0.62, P=0.01). The extent of regional brain atrophy correlated best with CMRO(2) and CBF. Lobar values of OEF were not in the ischemic range and did not correlate with chronic brain atrophy. Chronic brain atrophy is regionally specific and associated with regional reductions in oxidative brain metabolism in the absence of irreversible ischemia.

Commentary on “A roadmap for the prevention of dementia II. Leon Thal Symposium 2008.” Facilitating Alzheimer's disease drug development in the United States

Therapeutic research of Alzheimer’s disease (AD) is on the brink of a major advance. The field is poised to add effective disease-modifying treatments to our current symptomatic agents. The basic scientific understanding of AD pathophysiology has yielded a number of exceedingly promising targets for intervention, with many drugs now in various phases of clinical testing. Whether we reach a breakthrough within 5 or 15 years will be determined by the national will. In addition to financial support (specifically, funding by the National Institutes of Health for AD translational research), several concrete steps will facilitate progress toward bringing the next generation of therapeutics to the market. These steps are related to some important issues specific to the development of disease-modifying AD treatments, as well as some broader clinical research issues. 2. Change the diagnostic criteria for AD A diagnosis of AD should indicate the presence of neurobiological abnormalities that, if unchecked, will eventually lead to dementia. At present, diagnostic criteria require the presence of dementia [1]. But we now have tools that allow the documentation of reduction in cerebral metabolic rate [2], amyloid and tau dysregulation [3], amyloid deposition in the brain [4], and regional brain atrophy [5], many years before the appearance of the functional impairments of dementia. Further, we can measure subtle cognitive decline many years before clinically important impairment occurs [6]. Based on observations regarding the prevalence of brain amyloid deposition and mild cognitive decline in the nondemented elderly, we can estimate that the number of cases of ‘‘neurobiological AD’’ is at least 2–3 times larger than the number of cases of clinical AD according to current criteria. In other words, there are now at least 10–15 million people in the United States with AD pathology, though only about 5 million are demented. Appreciation of the ‘‘true’’ prevalence of AD will encourage a more reasonable allocation of resources. But more importantly, the millions of people with early AD neurobiology represent the proper target population for effective disease-modifying interventions. The recently proposed research criteria for AD serve as an excellent start in the process of adjusting diagnoses based on our growing understanding of the neurobiology of AD [7].

A New Approach to Treating Alzheimer's Disease

It is rational to try to normalize changes that correlate with the severity of the clinical disabilities in Alzheimer's disease (AD) rather than focusing on other of the many abnormalities in end-stage AD brain that relate only theoretically to the clinical manifestations. The neurobiological measure that correlates most closely to the degree of cognitive deterioration is reduction in cerebral metabolic rate. An attempt to treat this abnormality in AD patients is described; it is based, in part, on metabolic control theory. Encouraging results of a preliminary double-blind clinical trial do not allow confident conclusions but do support the need for more intensive examination of this approach to AD treatment.

Differential perfusion during cardiopulmonary bypass: maintaining a cool head during warm heart surgery

Introduction. The choice of perfusion temperature during cardiopulmonary bypass (CPB) remains a contentious issue. The reduction in cerebral metabolic rate and cerebral blood flow (CBF) associated with moderate hypothermia is neuroprotective by reducing the brain embolic load and ischemic lesion size. In contrast, normothermic CPB is associated with improved hemodynamic, respiratory, and hematological outcomes. The optimal temperature management during CPB would appear to be a hypothermic brain with a normothermic body. Differential perfusion of the aorta using a dual-lumen catheter provides independent temperature control of the head and body. The purpose of this study was to establish the ability to maintain independent perfusion and to compare CBF values with those during conventional hypothermic and normothermic CPB.

Anesthetic effects on cerebral metabolic rate predict histologic outcome from near-complete forebrain ischemia in the rat.

Although reduction of cerebral metabolic rate is thought to contribute to anesthetic neuroprotection, histologic evidence to support this concept has not been provided. In this study, histologic outcome was evaluated in rats subjected to different durations of severe forebrain ischemia while anesthetized with volatile anesthetics that have substantially different effects on cerebral metabolic rate. Normothermic rats that underwent fasting were anesthetized with 0.75 minimum alveolar concentration (MAC) isoflurane-60% nitrous oxide (N2O) or 0.75 MAC halothane-60% N2O. Ischemia was induced with use of a combination of bilateral carotid occlusion and controlled hypotension. Rats in the isoflurane group were subjected to 6.5 min or 8.0 min ischemia, whereas the halothane group received 6.5 min ischemia. Histologic damage was assessed 4 days later. With 6.5 min ischemia, mean +/- SD, hippocampal CA1 percent of dead (% dead) neurons was reduced with isoflurane-N2O (45 +/- 18) versus halothane-N2O (60 +/- 23, P = 0. 023). Eight minutes of ischemia increased % dead neurons in the isoflurane-N2O group (60 +/- 17, P = 0.017). There was no difference between the isoflurane 8.0-min and halothane 6.5-min groups (P = 0. 935). A similar pattern was observed in hippocampal CA4 and the neocortex. Striatal damage was not affected by anesthetic or ischemic duration. At 6.5 min ischemia, isoflurane provided improved outcome versus halothane. Previous research has shown that 0.75 MAC isoflurane-N2O increases the time to onset of ischemic depolarization by 1.5 min and reduces cerebral metabolic rate by 42% versus 0.75 MAC halothane-N2O. In the current study, when the duration of ischemia was increased by 1.5 min in the isoflurane-N2O group, histologic outcome became similar to that in halothane-N2O-anesthetized rats. These results provide evidence that cerebral metabolic rate reduction has an advantageous effect on outcome from severe brain ischemia, but also suggest that such benefit is likely to be small.

Anaesthesia for craniotomy

The aim of the neuroanaesthetist is to provide good operating conditions for the surgeon while protecting the brain from any physiological damage; a slack brain, maintenance of cerebral perfusion and reduction of cerebral metabolic rate. This is achieved by continual attention to basic details of technique and the application of methods based on an understanding of physiology, pharmacology and the pathological process. The development of new drugs, both inhalational, sevoflurane, and intravenous, propofol, alfentanil and remifentanil, given by infusion rather than boluses has enabled the anaesthetist to come closer to achieving the ideal. A better appreciation of post-operative pain and the effects of conventional analgesics, morphine and paracetamol will improve patient care. Morphine, which was previously considered to be contraindicated, is safe to use when given appropriately.

Role of adenosine in regulation of brain temperature in fetal sheep

Objective: The purpose of this study was to test adenosine’s possible suppression of heat production by the ovine fetal brain during acute hypoxia. Study Design: Hypoxia was induced by occluding the umbilical cord for 5 minutes in 8 fetal sheep with and without an adenosine receptor blocker, theophylline, and fetal brain and core temperatures were recorded. Results: In 8 untreated fetuses, cord occlusion induced severe but reversible hypoxemia (decrease in carotid arterial P O 2 from 23 ± 1 to 5 ± 1 mm Hg ( P < .01), a 2.3-fold increase in plasma adenosine, and an increase in body core temperature of 0.19°C ± 0.03°C ( P < .01), yet brain temperature remained constant. However, after cord occlusion with prior and continuing administration of theophylline, brain temperature did not increase as hypothesized but rather decreased, suggesting marked reductions in cerebral metabolic rate. This response occurred despite similar degrees of hypoxemia and similar increases in plasma adenosine and body core temperature. Conclusion: We conclude that the temperature of the fetal ovine brain remains constant or decreases during severe reversible hypoxemia by mechanisms other than those dependent on adenosine. (Am J Obstet Gynecol 1999;181:681-7.)

Improving Neurologic Outcome after Cardiac Surgery

Improving Neurologic Outcome after Cardiac Surgery

EEG burst suppression is not necessary for maximum barbiturate protection in transient focal cerebral ischemia in the rat.

Barbiturates have been demonstrated to reduce the cerebral metabolic rate (CMR) in a dose-dependent manner but investigations of a dose-response relationship for their neuroprotective efficacy are scant. It has been suggested that barbiturates possess other mechanism of action that may be critical to their protective effect. If so, it is conceivable that the peak effect of such mechanisms does not parallel the reduction in CMR. Thus, maximal neuroprotection may be achieved with a substantially lower dose of the drug. Thirty Sprague-Dawley rats were subjected to 2 h of middle cerebral artery occlusion while either anesthetized with (1) halothane (control) or (2) intravenous thiopental titrated to cause mild EEG suppression or (3) thiopental titrated to maintain EEG burst suppression. Cortical blood flow was recorded by continuous bilateral laser Doppler flowmetry (LDF). Infarct volume was assessed after 3 h of reperfusion. Low-dose thiopental decreased blood flow to 80% of baseline and high-dose thiopental to 70% of baseline. LDF did not indicate improvement of blood flow by thiopental in the ischemic area. Compared to controls, low-dose thiopental significantly decreased infarct volume by 28% and high-dose thiopental by 29%. The results of this study and a review of literature indicate that barbiturates provide cerebral protection but that the magnitude of this effect has been overestimated. Other mechanisms than CMR reduction seem to contribute to their beneficial effects, and high doses administered to the point of burst suppression may not be required to obtain maximal protection.

Effects of Propofol on Cerebral Blood Flow, Metabolism and Cerebral Autoregulation in the Anesthetized Pig

We studied the effects of propofol on the cerebral circulation and flow/pressure autoregulation in eight anesthetized pigs. Regional cerebral blood flow (rCBF) was measured with a cerebral venous outflow technique. Autoregulation was tested with angiotensin infusions and gradual blocks of the caval vein for hyper- and hypotensive challenges, respectively. Propofol was given in a bolus of 2.5 mg.kg-1 followed by an infusion starting at 12 mg.kg-1.h-1 and gradually reduced to 8 mg.kg-1.h-1. As expected, propofol caused a substantial reduction in cerebral metabolic rate of oxygen, which was accompanied by an increase in cerebrovascular resistance and a decrease in CBF. In the control situation, i.e., during background anesthesia (low-dose isoflurane+nitrous oxide) only, the autoregulation was well preserved, and its lower limit was found at a mean arterial blood pressure (MABP) of 48 mm Hg. Propofol did not affect autoregulation in the group as a whole: the slope of the regression line of regional cerebrovascular resistance (rCVR) versus MABP during blood pressure reduction (caval test) was not significantly changed during propofol when compared to the control, neither was the lower limit of autoregulation (MABP, 54 mm Hg). All pigs but one followed this response pattern. The nonautoregulating pig had a completely pressure-dependent rCBF during propofol anesthesia, despite a perfectly intact auto-regulation in the control situation. It is concluded that propofol in clinical dosage does not affect autoregulation in this pig model, although individual animals may display a different response pattern.

Cerebral Hemodynamic and Metabolic Changes Caused by Brain Retraction after Aneurysmal Subarachnoid Hemorrhage

OBJECTIVE: The cerebral hemodynamic and metabolic effects of aneurysmal subarachnoid hemorrhage are complex. To investigate the impact of surgical retraction, we analyzed positron emission tomography (PET) studies that measured the regional cerebral metabolic rate for oxygen, regional oxygen extraction fraction, and regional cerebral blood flow in four patients before and after right frontotemporal craniotomies for clipping of ruptured anterior circulation aneurysms. METHODS: Preoperative studies were conducted 1 day before surgery and postoperative studies 6 to 17 days after surgery. No patient had hydrocephalus or intracerebral hematoma. At the time of the second PET study, none of the patients had signs of clinical vasospasm. Regional measurements were obtained from the right ventrolateral frontal and anterior temporal regions corresponding to the area of retraction and compared to the same regions in the opposite hemisphere. To establish a quantitative means to differentiate between hemodynamic and metabolic changes related to arterial vasospasm and those caused by brain retraction, we studied a second group of preoperative patients, who had undergone PET during angiographic and clinical vasospasm. RESULTS: There was a 45% reduction in regional cerebral metabolic rate for oxygen(1.87 ± 0.22 to 1.04 ± 0.28 ml 100 g-1 min-1) and 32% reduction in regional oxygen extraction fraction (0.41 ± 0.04 to 0.28 ± 0.03) in the region of retraction but no change in the opposite hemisphere (paired t test; P = 0.042 and 0.003, respectively). There was no change in regional cerebral blood flow in any region. Brain retraction produced a focal area of tissue injury at the site of retractor blade placement, as compared to more diffuse vascular territory changes produced by vasospasm. CONCLUSION: This reduction in the cerebral metabolic rate of oxygen and the oxygen extraction fraction indicates a primary reduction in metabolism and uncoupling of flow and metabolism (luxury perfusion). Similar findings of luxury perfusion have been reported after ischemic stroke and traumatic brain injury. Further studies will be necessary to fully understand the clinical and pathophysiological significance of these observations.

The role of adenosine during the period of delayed cerebral swelling after severe traumatic brain injury in humans.

Cerebrovascular failure with an increase in cerebral blood volume or hyperemia contributes delayed cerebral swelling after severe traumatic brain injury (TBI) in humans. One mediator that could be involved in this process is adenosine, which stimulates a concurrent reduction in cerebral metabolic rate and an increase in cerebral blood flow (CBF). We hypothesized that during the delayed phase after TBI in humans: 1) CSF adenosine concentration is associated with uncoupling of CBF and CMRO2, and 2) adenosine formation is driven by mediator-stimulated cAMP production in injured brain. We serially measured CBF and AVDO2, and CSF adenosine, lactate and cAMP after severe TBI in 13 humans. After 6-18 h, global CBF was increased and AVDO2 was reduced vs all other time periods, defining the uncoupling phase as the period between 18 h and 5 days. CSF adenosine concentration was negatively associated with AVDO2 and strongly associated with death (both p < 0.05), CSF lactate peaked during the initial 18 h, but remained increased for 5 days. CSF cAMP concentration was not increased (vs normal). The association between CSF adenosine concentration and death, and the correlation between uncoupling of CBF and oxidative metabolism and CSF adenosine concentration support our first hypothesis. In contrast, the low levels of cAMP in CSF observed in these patients, but persistently increased CSF lactate, refute our second hypothesis. We speculate that hyperglycolysis or occult ischemic foci are possible sources of ATP breakdown and adenosine formation, and that adenosine is playing a neuroprotective role.

Normothermic versus hypothermic cardiopulmonary bypass: Central nervous system outcomes

The recent advent of “warm heart” surgery has resulted in reexamination of the neuroprotective effects of hypothermia in the setting of cardiopulmonary bypass (CPB). Hypothermia has been shown to confer significant protection in the setting of transient, but not permanent, ischemia. The mechanism of this neuroprotection is unclear at this time. Reduction in cerebral metabolic rate is believed to be less important compared with the effect of hypothermia on the release of excitatory neurotransmitters, catecholamines, or other mediators of cellular injury. It is for this reason that mild hypothermia (33–35°C) is believed to confer significant neuroprotection. Two large randomized trials of warm versus cold heart surgery have been reported. Neither study found a difference in terms of neuropsychologic dysfunction. However, one study identified a threefold increase in strokes in the “warm” patients. The reasons for this difference are not clear; however, there were various differences in technique and patient population that may have been important. There are other reports of large series of patients undergoing normothermic bypass, with no increase in stroke rate over what is reported elsewhere in the literature. To date, the evidence would suggest that neuropsychologic function is not affected by CPB temperature, suggesting that the transient ischemia is not an important mechanism in this injury. Stroke after CPB is usually the result of permanent ischemia, and hypothermia's effect in this setting is minimal. It would seem unlikely that hypothermia offers anything more than modest benefits in the clinical situation where there is no circulatory arrest.

The Relation between Cerebral Metabolic Rate and Ischemic Depolarization

Reductions in cerebral metabolic rate may increase the brain's tolerance of ischemia. However, outcome studies suggest that reductions in cerebral metabolic rate produced by anesthetics and by hypothermia may not be equally efficacious. To examine this question, we measured the effects of hypothermia, pentobarbital, and isoflurane on the cerebral metabolic rate for glucose (CMRG) and on the time to the loss of normal membrane ion gradients (terminal ischemic depolarization) of the cortex during complete global ischemia. As pericranial temperature was varied between 39 and 25 degrees C in normocapnic halothane-anesthetized rats, CMRG (using 14C-deoxyglucose) or the time to depolarization (using a glass microelectrode in the cortex) after a K(+)-induced cardiac arrest was measured. In other studies, CMRG and depolarization times were measured in normothermic animals (37.7 +/- 0.2 degrees C) anesthetized with high-dose pentobarbital or isoflurane (both producing burst suppression on the electroencephalogram) or in halothane-anesthetized animals whose temperatures were reduced to 27.4 +/- 0.3 degrees C. These three states were designed to produce equivalent CMRG values. As temperature was reduced from 39 to 25 degrees C, CMRG decreased from 66 to 21 microM.100 g-1.min-1 (Q10 = 2.30), and depolarization times increased from 76 to 326 s. In similarly anesthetized animals at approximately 27 degrees C, CMRG was 32 +/- 4 microM.100 g-1.min-1 (mean +/- SD), whereas in normothermic pentobarbital- and isoflurane-anesthetized rats, CMRG values were 33 +/- 3 and 37 +/- 4 microM.100 g-1.min-1, respectively (P = 0.072 by one-way analysis of variance). Despite these similar metabolic rates, the times to depolarization were markedly different: for hypothermia it was 253 +/- 29 s, for pentobarbital 109 +/- 24 s, and for isoflurane 130 +/- 28 s (P < 0.0001). The time to terminal depolarization is believed to be a measure of the rate at which energy stores are depleted. In this study there was a strong correlation between hypothermic reductions in CMRG and increases in the time to depolarization. This finding supports the belief that metabolic suppression may offer some cerebral protection. However, equivalent reductions in CMRG produced by hypothermia and by anesthesia were not equivalent in their effects on membrane failure. Whether hypothermia slows energy depletion by some unique mechanism or directly retards depolarization is unknown.

Flumazenil Reversal of Midazolam in Dogs

Large doses of flumazenil, given rapidly (over 5-10 s), are reported to elevate cerebral blood flow (CBF) and intracranial pressure to supranormal values when given to dogs receiving midazolam. This study examined the cerebral effects of giving smaller, graduated doses of flumazenil (0.0025, 0.01, 0.04, and 0.16 mg/kg), slowly (over 60 s), to dogs receiving midazolam and to dogs not receiving midazolam both when cerebrospinal fluid (CSF) pressure was normal and when CSF pressure was elevated (intracranial balloon) to about 30 mm Hg. In dogs with normal CSF pressure that were receiving midazolam, the effects of flumazenil were as follows: (a) low doses of flumazenil caused reversal of the reduction in cerebral metabolic rate for oxygen (CMRO2) and activity of the electroencephalogram produced by midazolam, (b) moderate doses of flumazenil produced a decrease of cerebral vascular resistance, and an increase of CBF and CSF pressure that did not significantly change cerebral perfusion pressure (CPP), and (c) the highest dose of flumazenil increased CBF to supranormal values. All of these flumazenil effects "peaked" at 3-6 min, with values returning to pre-flumazenil levels by 15-30 min. Flumazenil caused no such changes in dogs with elevated CSF pressure that were receiving midazolam or in dogs that were not receiving midazolam. The results are consistent with a specific, doserelated benzodiazepineantagonist action of flumazenil. Lack of flumazenil effect at elevated CSF pressure may reflect reversible changes in cerebral structure, metabolism, or benzodiazepine receptors produced by the intracranial balloon and elevation of CSF pressure. The doses of flumazenil used here to reverse the cerebral effects of midazolam appear unlikely to produce adverse effects because increase of CMRO2 was matched by increase of CBF, the mean increase of CSF pressure was modest (+9 +/- 3 mm Hg, mean +/- SEM), and CPP was unchanged.