Cerebral circulation and metabolism in the acute stage of subarachnoid hemorrhage

OBJECT: The mechanism of reduction of cerebral circulation and metabolism in patients in the acute stage of aneurysmal subarachnoid hemorrhage (SAH) has not yet been fully clarified. The goal of this study was to elucidate this mechanism further. METHODS: The authors estimated cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), O2 extraction fraction (OEF), and cerebral blood volume (CBV) preoperatively in eight patients with aneurysmal SAH (one man and seven women, mean age 63.5 years) within 40 hours of onset by using positron emission tomography (PET). The patients' CBF, CMRO2, and CBF/CBV were significantly lower than those in normal control volunteers. However, OEF and CBV did not differ significantly from those in control volunteers. The significant decrease in CBF/CBV, which indicates reduced cerebral perfusion pressure, was believed to be caused by impaired cerebral circulation due to elevated intracranial pressure (ICP) after rupture of the aneurysm. In two of the eight patients, uncoupling between CBF and CMRO2 was shown, strongly suggesting the presence of cerebral ischemia. CONCLUSIONS: The initial reduction in CBF due to elevated ICP, followed by reduction in CMRO, at the time of aneurysm rupture may play a role in the disturbance of CBF and cerebral metabolism in the acute stage of aneurysmal SAH.     

Hemodynamic and metabolic effects of cerebral revascularization

Pre- and postoperative positron emission tomography (PET) was performed in six patients undergoing extracranial to intracranial bypass procedures for the treatment of symptomatic extracranial carotid occlusion. The six patients were all men, aged 52 to 68 years. Their symptoms included transient ischemic attacks (five cases), amaurosis fugax (two cases), and completed stroke with good recovery (one case). Positron emission tomography was performed within 4 weeks prior to surgery and between 3 to 6 months postoperatively, using oxygen-15-labeled CO, O2, and CO2 and fluorine-18-labeled fluorodeoxyglucose. Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rates for oxygen and glucose (CMRO2 and CMRGlu), and the oxygen extraction fraction (OEF) were measured in both hemispheres. Preoperatively, compared to five elderly control subjects, patients had increased CBV, a decreased CBF/CBV ratio, and decreased CMRO2, indicating reduced cerebral perfusion pressure and depressed oxygen metabolism. The CBF was decreased in only one patient who had bilateral carotid occlusions; the OEF, CMRGlu, and CMRO2/CMRGlu and CMRGlu/CBF ratios were not significantly different from control measurements. All bypasses were patent and all patients were asymptomatic following surgery. Postoperative PET revealed decreased CBV and an increased CBF/CBV ratio, indicating improved hemodynamic function and oxygen hypometabolism. This was associated with increased CMRO2 in two patients in whom the postoperative OEF was also increased. The CMRGlu and CMRGlu/CBF ratio were increased in five patients. Changes in CBF and the CMRO2/CMRGlu ratio were variable. One patient with preoperative progressive mental deterioration, documented by serial neuropsychological testing and decreasing CBF and CMRO2, had improved postoperative CBF and CMRO2 concomitant with improved neuropsychological functioning. It is concluded that symptomatic carotid occlusion is associated with altered hemodynamic function and oxygen hypometabolism. Cerebral revascularization results in decreased CBV, indicating improved hemodynamic reserve, but does not consistently improve oxygen metabolism.     

The effect of glycerol on regional cerebral blood flow, blood volume and oxygen metabolism

Using positron emission tomography with 15O-labelled CO2 O2 and CO gases, the effects of glycerol on regional cerebral blood flow (CBF), blood volume (CBV) and oxygen metabolism (CMRO2) were investigated in 6 patients with meningioma accompanying peritumoral brain edema. The same study was done in 5 normal volunteers. The changes of blood gases, hematocrit and hemoglobin were also examined. After a drip infusion of glycerol, the regional CBF increased not only in the peritumoral cortex and white matter but also in the intact cortex and white matter on the contralateral side. The increase of CBF was extensive and substantially there were no regional differences. In contrast, the changes of CMRO2 were not significant. This was derived from the increase in oxygen extraction fraction throughout extensive areas including the peritumoral area. There were no changes in CBV. Hematocrit and hemoglobin decreased to a small degree. In the normal volunteers, the same findings were noted. Thus, glycerol increases the functional reserve for cerebral oxygen metabolism, not only in the peritumoral regions but also in the intact regions. The effects of glycerol on hemodynamics and metabolism were discussed with reference to some differences from mannitol.     

Cerebral blood flow and vasodilatory capacity in anemia secondary to chronic renal failure

BACKGROUND: Our previous study reported that cerebral oxygen extraction fraction (OEF) increased in hemodialysis patients with anemia. The increased OEF suggests that the cerebral vasodilatory capacity might be impaired in these patients. To clarify this issue, we measured the CO2 response in patients with anemia secondary to chronic renal failure (CRF) using positron emission tomography (PET). METHODS: Ten anemic patients with CRF (6 females and 4 males) and 6 age-matched normal controls were studied. The underlying diseases of CRF were glomerulonephritis in 8 patients, systemic lupus erythematosus (SLE) in one patient, and hypertension in one patient; in this cohort, 5 patients were on hemodialysis treatment and the remaining 5 patients were in a pre-hemodialysis state. The cerebral blood flow (CBF) was measured by the O-15 H2O bolus injection method with each patient in a resting state and during 5% CO2 inhalation. The CO2 response was estimated as the percentage change of CBF per 1 mm Hg change of PaCO2. RESULTS: The CO2 response was significantly attenuated in anemic patients with CRF in comparison to the normal controls, and it inversely correlated with the severity of anemia. There was no significant difference in the CO2 response between the hemodialysis and pre-hemodialysis patients. The CO2 response significantly correlated with CBF and the cerebral metabolic rate for oxygen (CMRO2) at rest, however, it did not correlate with OEF and cerebral blood volume (CBV). CONCLUSIONS: The present study revealed the existence of a reduced cerebral vasodilatory capacity in anemic patients with CRF, suggesting that chronic hypoxic brain damage might play a role in the impaired cerebrovascular response to CO2.     

Regional effects of craniotomy on cerebral circulation and metabolism: PET study on the un-ruptured aneurysmal surgery

Regional effects of craniotomy on cerebral circulation and metabolism, such as regional cerebral blood flow (rCBF), regional cerebral oxygen consumption (rCMRO2), regional oxygen extraction fraction (rOEF), and regional cerebral blood volume (rCBV) were examined by a PET (positron emission tomography) study concerning surgery that was performed on unruptured aneurysm patients. Eight patients with intracranial un-ruptured aneurysms were studied pre- and post-operatively by the 15O labelled-gas steady-state method, using HEADTOME-III. All patients underwent aneurysmal surgery performed by the transsylvian approach. There was a significant increase in the mean OEF values taken from the whole-brains of 8 patients, but there was not a significant change in CBF, CMRO2 or CBV. The increase in OEF was caused by decrease of O2 content, which was caused by post-operative decrease in the Hb value. So, this OEF increase was not the direct effect of craniotomy. In 2 patients, the rCBF and rCMRO2, in the fronto-temporal region (where craniotomy was performed) increased post-operatively. This regional effect suggests transient reactive hyperemia following compressive ischemia during the operative procedure, and metabolic demands for recovery of brain function. In 2 other patients, who had relatively low rCBFs during the pre-operative study, rCBF and rCMRO2 in the bi-frontal region had decreased more at the post-operative study. This change appears to have been caused by removal of cerebrospinal fluid and depression of the frontal lobe. From this study, it becomes evident that the regional effect of craniotomy on cerebral circulation and metabolism is not so great, when adequate microsurgical techniques are used.     

Negative BOLD with large increases in neuronal activity

Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is widely used in neuroscience to study brain activity. However, BOLD fMRI does not measure neuronal activity directly but depends on cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate of oxygen (CMRO(2)) consumption. Using fMRI, CBV, CBF, neuronal recordings, and CMRO(2) modeling, we investigated how the signals are related during seizures in rats. We found that increases in hemodynamic, neuronal, and metabolic activity were associated with positive BOLD signals in the cortex, but with negative BOLD signals in hippocampus. Our data show that negative BOLD signals do not necessarily imply decreased neuronal activity or CBF, but can result from increased neuronal activity, depending on the interplay between hemodynamics and metabolism. Caution should be used in interpreting fMRI signals because the relationship between neuronal activity and BOLD signals may depend on brain region and state and can be different during normal and pathological conditions.     

Brain oxygen extraction fraction as an indicator for shunting operation in normal pressure hydrocephalus]

It is still difficult for neurosurgeons to determine which patients with suspected idiopathic normal pressure hydrocephalus (NPH) should undergo shunting. We need to find a more accurate indicator to predict the effect of shunting. We introduced a new preoperative examination of brain oxygen extraction fraction (OEF) and examined whether preoperative OEF value is effective for prediction of the surgical results. Global brain OEF was calculated from oxygen contents of arterial blood (AO2) and jugular venous blood (VjO2) selectively sampled from the right jugular bulb using the Seldinger method: OEF = (AO2-VjO2)/AO2. Since June 1996 we have treated 9 patients suspected of idiopathic and 10 patients suspected of secondary NPH. OEF in non-NPH patients with dilated ventricle (n = 10) and in infarct patients (n = 85) were 0.33 +/- 0.02 and 0.38 +/- 0.06, respectively. In contrast, OEF increased both in idiopathic NPH (0.42 +/- 0.04) and secondary NPH (0.45 +/- 0.02), and the NPH patients with the higher preoperative OEF values showed the better symptomatic recovery. The present study suggests that brain function may be reversible when OEF can be increased and that OEF can be a useful indicator for predicting the effect of a shunting operation in NPH.     

Effect on cerebral blood flow of midazolam during modified neurolept-anesthesia]

Midazolam (0.2 mg.kg-1) was administered to ten patients undergoing neurosurgical operation and its influence on CBF was studied under modified NLA. Simultaneously, the plasma concentration of midazolam was measured. Heart rate and mean arterial blood pressure showed no significant changes after injection in comparison with the control. Cerebral blood flow (CBF) decreased for about 15-20% after 5 minutes, 10 minutes and 15 minutes in comparison with the control. However, 30 minutes later, CBF showed a trend to return to the control. This change in CBF is related to the changes of cerebro-vascular resistance. We applied cerebral oxygen extraction fraction (OEF) to evaluate cerebral metabolism. OEF was constant, showing no significant changes. It is concluded that cerebral oxygen consumption (CMRO2) has decreased together with the decrease in CBF. The plasma concentration of midazolam was 250-300 ng.ml-1 or greater after 5 minutes, 10 minutes and 15 minutes. We think that the sedative dose of midazolam can also sufficiently reduce CBF and CMRO2. The results suggest that midazolam is a safe and effective agent to use for anesthesia and provides adequate sedation for patients with intracranial hypertension.     

Regional cerebrovascular and metabolic effects of hyperventilation after severe traumatic brain injury.

OBJECT: Recently, concern has been raised that hyperventilation following severe traumatic brain injury (TBI) could lead to cerebral ischemia. In acute ischemic stroke, in which the baseline metabolic rate is normal, reduction in cerebral blood flow (CBF) below a threshold of 18 to 20 ml/100 g/min is associated with energy failure. In severe TBI, however, the metabolic rate of cerebral oxygen (CMRO2) is low. The authors previously reported that moderate hyperventilation lowered global hemispheric CBF to 25 ml/100 g/min but did not alter CMRO2. In the present study they sought to determine if hyperventilation lowers CBF below the ischemic threshold of 18 to 20 ml/100 g/ min in any brain region and if those reductions cause energy failure (defined as a fall in CMRO2). METHODS: Two groups of patients were studied. The moderate hyperventilation group (nine patients) underwent hyperventilation to PaCO2 of 30 +/- 2 mm Hg early after TBI, regardless of intracranial pressure (ICP). The severe hyperventilation group (four patients) underwent hyperventilation to PaCO2 of 25 +/- 2 mm Hg 1 to 5 days postinjury while ICP was elevated (20-30 mm Hg). The ICP, mean arterial blood pressure, and jugular venous O2 content were monitored, and cerebral perfusion pressure was maintained at 70 mm Hg or higher by using vasopressors when needed. All data are given as the mean +/- standard deviation unless specified otherwise. The moderate hyperventilation group was studied 11.2 +/- 1.6 hours (range 8-14 hours) postinjury, the admission Glasgow Coma Scale (GCS) score was 5.6 +/- 1.8, the mean age was 27 +/- 9 years, and eight of the nine patients were men. In the severe hyperventilation group, the admission GCS score was 4.3 +/- 1.5, the mean age was 31 +/- 6 years, and all patients were men. Positron emission tomography measurements of regional CBF, cerebral blood volume, CMRO2, and oxygen extraction fraction (OEF) were obtained before and during hyperventilation. In all 13 patients an automated search routine was used to identify 2.1-cm spherical nonoverlapping regions with CBF values below thresholds of 20, 15, and 10 ml/ 100 g/min during hyperventilation, and the change in CMRO2 in those regions was determined. In the regions in which CBF was less than 20 ml/100 g/min during hyperventilation, it fell from 26 +/- 6.2 to 13.7 +/- 1 ml/ 100 g/min (p < 0.0001), OEF rose from 0.31 to 0.59 (p < 0.0001), and CMRO2 was unchanged (1.12 +/- 0.29 compared with 1.14 +/- 0.03 ml/100 g/min; p = 0.8). In the regions in which CBF was less than 15 ml/100 g/min during hyperventilation, it fell from 23.3 +/- 6.6 to 11.1 +/- 1.2 ml/100 g/min (p < 0.0001), OEF rose from 0.31 to 0.63 (p < 0.0001), and CMRO2 was unchanged (0.98 +/- 0.19 compared with 0.97 +/- 0.23 ml/100 g/min; p = 0.92). In the regions in which CBF was less than 10 ml/100 g/min during hyperventilation, it fell from 18.2 +/- 4.5 to 8.1 +/- 0 ml/100 g/min (p < 0.0001), OEF rose from 0.3 to 0.71 (p < 0.0001), and CMRO2 was unchanged (0.78 +/- 0.26 compared with 0.84 +/- 0.32 ml/100 g/min; p = 0.64). CONCLUSIONS: After severe TBI, brief hyperventilation produced large reductions in CBF but not energy failure, even in regions in which CBF fell below the threshold for energy failure defined in acute ischemia. Oxygen metabolism was preserved due to the low baseline metabolic rate and compensatory increases in OEF; thus, these reductions in CBF are unlikely to cause further brain injury.     

Effect of labetalol on cerebral blood flow, oxygen metabolism and autoregulation in healthy humans

We have studied the effects of labetalol on cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO2) in eight healthy volunteers. CBF was measured by single photon emission computerized tomography before and during infusion of labetalol. CMRO2 was calculated as CBF x cerebral arteriovenous oxygen content difference (CaO2-CvO2). CBF autoregulation was tested during infusion of labetalol by changing arterial pressure and estimating relative changes in global CBF from changes in (CaO2-CvO2). CBF before and during infusion of labetalol was 67 and 65 ml/100 g min-1, respectively (P > 0.05). CMRO2 was 2.9 and 2.8 ml/100 g min-1, respectively (P > 0.05). CBF autoregulation was preserved in all subjects. The lower limit of CBF autoregulation was 88 mm Hg (94% of baseline mean arterial pressure). We conclude that labetalol did not influence global or regional CBF, or CMRO2, and CBF autoregulation was preserved.      

Effect of graded hyperventilation on cerebral metabolism in a cisterna magna blood injection model of subarachnoid hemorrhage in rats

In subarachnoid hemorrhage (SAH) with cerebrovascular instability, hyperventilation may induce a risk of inducing or aggravating cerebral ischemia. We measured cerebral blood flow (CBF) and cerebral metabolic rates of oxygen (CMRO2), glucose (CMRglc), and lactate (CMRlac) at different PaCO2 levels after experimental SAH in rats (injection of 0.07 mL of autologous blood into the cisterna magna). Four groups of Sprague-Dawley male rats were studied at predetermined PaCO2 levels: group A: normocapnia (5.01-5.66 kPa [38.0-42.0 mm Hg]); group B: slight hyperventilation (4.34-5.00 kPa [32.5-37.5 mm Hg]); group C: moderate hyperventilation (3.67-4.33 kPa [27.5-32.4 mm Hg]); group D: profound hyperventilation (3.00-3.66 kPa [22.5-27.4 mm Hg]). Each of the four groups included eight rats with SAH and eight sham-operated controls. CBF was determined by the intracarotid Xe method; CMRo2, CMRglc, and CMRlac were obtained by cerebral arteriovenous differences. In both SAH rats and controls, hyperventilation decreased CBF in proportion to the decrement in PaCO2 without affecting either CMRO2, CMRglc, or CMRlac. In groups C and D, CBF decreased by 20%-35%, but CMRs were maintained by a compensatory increase in oxygen extraction fraction (OEF). The results show that even profound hyperventilation in this model of SAH is associated with an adequate increase in OEF so that CMRs of oxygen, glucose, and lactate remain similar to levels observed in normocapnic conditions.     

Cerebral circulation and metabolism in adults' Moyamoya disease-PET study

Summary Regional cerebral blood flow (rCBF), oxygen extraction fraction (rOEF), cerebral metabolic rate for oxygen (rCMRO₂) and cerebral blood volume (rCBV) in nine cases of moyamoya disease in adults were studied with positron emission CT (PET) scan, using¹⁵O steady-state methods. Three cases showed ischaemic symptoms and the other six cases showed haemorrhagic symptoms. PET scan was performed during the chronic stage. Control data were obtained from eight normal volunteers. Regional cerebral blood flow and other physiological parameters in cerebral gray matter, white matter and basal ganglia were compared with normal controls.All nine cases of Moyamoya disease showed decreased rCBF, though not significant, in cerebral gray matter, white matter and basal ganglia. Reduction of rCBF was significant in the cerebral cortex of six haemorrhagic cases. This significant decrease was considered to be due to diaschisis and also brain atrophy caused by the cerebral haemorrhage. There was a significant increase in rCBV in white matter of the both ischaemic and haemorrhagic cases. The calculated value of CBF/CBV is considered to be an index of perfusion pressure. This value was significantly decreased in all three regions, though rOEF was not significantly increased in moyamoya disease. Hence the cerebral circulation in adults with moyamoya disease appears to be characterized by a mild decrease in perfusion pressure and prolonged circulated time.     

S-Ketamine Anesthesia Increases Cerebral Blood Flow in Excess of the Metabolic Needs in Humans

Background: Animal studies have demonstrated neuroprotective properties of S-ketamine, but its effects on cerebral blood flow (CBF), metabolic rate of oxygen (CMRO2), and glucose metabolic rate (GMR) have not been comprehensively studied in humans.

Methods: Positron emission tomography was used to quantify CBF and CMRO2 in eight healthy male volunteers awake and during S-ketamine infusion targeted to subanesthetic (150 ng/ml) and anesthetic (1,500-2,000 ng/ml) concentrations. In addition, subjects' GMRs were assessed awake and during anesthesia. Whole brain estimates for cerebral blood volume were obtained using kinetic modeling.

Results: The mean +/- SD serum S-ketamine concentration was 159 +/- 21 ng/ml at the subanesthetic and 1,959 +/- 442 ng/ml at the anesthetic levels. The total S-ketamine dose was 10.4 mg/kg. S-ketamine increased heart rate (maximally by 43.5%) and mean blood pressure (maximally by 27.0%) in a concentration-dependent manner (P = 0.001 for both). Subanesthetic S-ketamine increased whole brain CBF by 13.7% (P = 0.035). The greatest regional CBF increase was detected in the anterior cingulate (31.6%; P = 0.010). No changes were detected in CMRO2. Anesthetic S-ketamine increased whole brain CBF by 36.4% (P = 0.006) but had no effect on whole brain CMRO2 or GMR. Regionally, CBF was increased in nearly all brain structures studied (greatest increase in the insula 86.5%; P < 0.001), whereas CMRO2 increased only in the frontal cortex (by 15.7%; P = 0.007) and GMR increased only in the thalamus (by 11.7%; P = 0.010). Cerebral blood volume was increased by 51.9% (P = 0.011) during anesthesia.     

S-ketamine anesthesia increases cerebral blood flow in excess of the metabolic needs in humans

BACKGROUND: Animal studies have demonstrated neuroprotective properties of S-ketamine, but its effects on cerebral blood flow (CBF), metabolic rate of oxygen (CMRO2), and glucose metabolic rate (GMR) have not been comprehensively studied in humans. METHODS: Positron emission tomography was used to quantify CBF and CMRO2 in eight healthy male volunteers awake and during S-ketamine infusion targeted to subanesthetic (150 ng/ml) and anesthetic (1,500-2,000 ng/ml) concentrations. In addition, subjects' GMRs were assessed awake and during anesthesia. Whole brain estimates for cerebral blood volume were obtained using kinetic modeling. RESULTS: The mean +/- SD serum S-ketamine concentration was 159 +/- 21 ng/ml at the subanesthetic and 1,959 +/- 442 ng/ml at the anesthetic levels. The total S-ketamine dose was 10.4 mg/kg. S-ketamine increased heart rate (maximally by 43.5%) and mean blood pressure (maximally by 27.0%) in a concentration-dependent manner (P = 0.001 for both). Subanesthetic S-ketamine increased whole brain CBF by 13.7% (P = 0.035). The greatest regional CBF increase was detected in the anterior cingulate (31.6%; P = 0.010). No changes were detected in CMRO2. Anesthetic S-ketamine increased whole brain CBF by 36.4% (P = 0.006) but had no effect on whole brain CMRO2 or GMR. Regionally, CBF was increased in nearly all brain structures studied (greatest increase in the insula 86.5%; P < 0.001), whereas CMRO2 increased only in the frontal cortex (by 15.7%; P = 0.007) and GMR increased only in the thalamus (by 11.7%; P = 0.010). Cerebral blood volume was increased by 51.9% (P = 0.011) during anesthesia. CONCLUSIONS: S-ketamine-induced CBF increases exceeded the minor changes in CMRO2 and GMR during anesthesia.     

Sequential changes in cerebral blood flow and metabolism in patients with subarachnoid haemorrhage

Summary Haemodynamic and metabolic sequences were investigated in nine patients having subarachnoid haemorrhage (SAH) up to 3 months following aneurysmal rupture, using positron emission tomography (PET). In the pre-spasm stage (2–4 days after SAH) cerebral blood flow (CBF, ml/100 ml/min) was 45±11, the cerebral metabolic rate of oxygen (CMRO₂, ml/100 ml/min) was 2.68±0.50, and cerebral blood volume (CBV, ml/100 ml) was 5.5±1.2. CBF within the normal range and a relatively low CMRO₂, indicated relative hyperaemia. This was possibly due to the direct toxic effect of SAH on the brain metabolism. CBV was considerably elevated. The spasm stage (6–15 days after SAH) showed CBF values of 39±7, CMRO₂ values of 2.42±0.50, and CBV values of 5.4±1.7. CBF decreased significantly (p<0.05 vs pre-spasm stage), and CMRO₂ also tended to decrease, while they were coupling. It is likely that this may have been induced by vasospasm. Thereafter, the PET parameters normalized gradually. During all the stages studied, significant laterality of the PET parameters was not observed. This may be because SAH and vasospasm provide diffuse pathophysiological conditions for the entire brain and cerebral arteries.     

Effects of phenobarbital on cerebral blood flow and metabolism in young and aged rats

The cerebrovascular and cerebral metabolic changes produced by intraperitoneal injection of phenobarbital (50, 150, and 250 mg/kg) were studied in young adult (6-month) and senescent (28-month) Wistar rats. Cerebral blood flow (CBF) was measured using radioactive microspheres and cerebral oxygen consumption (CMRO2) was obtained by multiplying cortex CBF by the arterial-sagittal sinus oxygen content difference. Control values for blood pressure, blood gas tensions, CBF, and CMRO2 were similar in the young and aged animals during 70% N2O/30% O2. Intraperitoneal phenobarbital produced dose-dependent decreases in CBF with no significant difference between young and aged rats at each phenobarbital dose. At the highest phenobarbital dose (250 mg/kg) CBF was reduced by 49% in the young rats and 52% in the aged rats (P greater than 0.10). CMRO2 was also depressed in a dose-dependent fashion in both young and aged animals with each phenobarbital dose. However, the decrease produced by the highest phenobarbital dose was significantly greater in the aged rats (55%) than the young rats (43%, P less than 0.05), even though the EEG was isoelectric in both groups. The difference in CMRO2 between young versus aged rats at a time when the EEG is isoelectric suggests that high-dose phenobarbital may depress nonelectrical cerebral metabolic processes more in aged rats.     

Cerebral vascular and metabolic effects of fentanyl and midazolam in young and aged rats

Cerebral blood flow (CBF) and cerebral oxygen consumption (CMRO2) were measured, and electroencephalogram (EEG) was recorded in young (6-month-old) and aged (28-month-old) rats during ventilation with 70% N2O/30% O2 and following fentanyl or midazolam administration. Cerebral blood flow (CBF) was measured with radioactive microspheres, and cerebral oxygen consumption (CMRO2) was calculated from the arterial-sagittal sinus oxygen content difference and CBF measurements. Fentanyl at the highest dose used (200 micrograms/kg and 400 micrograms.kg-1.h-1) depressed the EEG and decreased CBF 49% and CMRO2 39% in young rats, whereas in old rats, this fentanyl dose decreased CBF 37% and CMRO2 34%, both significantly less than in young rats (P less than 0.05). Midazolam at the highest dose used (5.75 mg/kg) also depressed EEG in both age groups, and decreased CBF 51% and CMRO2 38% in young rats. This depression was significantly less than the 62% decrease in CBF and 59% decrease in CMRO2 produced by midazolam in old rats (P less than 0.05). These results indicate that aging attenuates the cerebrovascular and cerebral metabolic depression produced by fentanyl, but potentiates the same effects produced by midazolam. The enhanced cerebral metabolic depression produced by midazolam in the aged is similar to that seen with phenobarbital, and suggests a similar action of these drugs at the central GABA-benzodiazepine-barbiturate receptor complex.     

Cerebral blood flow, vasoreactivity, and oxygen consumption during barbiturate therapy in severe traumatic brain lesions

Mean hemispheric cerebral blood flow (CBF) and intracranial pressure (ICP) were measured in 19 severely head-injured patients treated with barbiturate coma. The CBF was calculated from the clearance of tracer substance monitored by extracranial scintillation detectors after intravenous administration of xenon-133. In 11 of the patients cerebral arteriovenous oxygen differences were measured simultaneously. In all patients the effects of pronounced hyperventilation were recorded prior to initiation of barbiturate treatment. A normal CBF response to hyperventilation (delta CBF/delta PaCO2 greater than or equal to 1) was obtained in eight patients. In these patients induction of barbiturate coma was accompanied by physiological decreases in CBF and in the calculated cerebral metabolic rate of oxygen (CMRO2); they also exhibited a rapid and lasting decrease in ICP. A decreased or an abolished CO2 reactivity was recorded (delta CBF/delta PaCO2 less than 1) in 11 patients. In 10 of these 11 patients the physiological decreases in CBF and CMRO2 were not obtained during barbiturate treatment and the decrease in ICP was transitory. This study demonstrates a correlation between cerebral vasoreactivity, physiological effects of barbiturate therapy, and clinical outcome.     

CBF and CMRo2 during craniotomy for small supratentorial cerebral tumours in enflurane anaesthesia. A dose-response study

In 14 patients with supratentorial cerebral tumours with midline shift less than or equal to 10 mm, cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) were measured twice on the contralateral side of the craniotomy, using a modification of the Kety & Schmidt method. For induction of anaesthesia, thiopental, fentanyl and pancuronium were used. The anaesthesia was maintained with enflurane 1% in nitrous oxide 67%. Moderate hypocapnia to a level averaging 4.3 kPa was achieved. The patients were divided into two groups. In Group 1 (n = 7), 1% enflurane was used throughout the anaesthesia, and CBF and CMRO2 measured about 70 min after induction averaged 30.1 ml 100 g-1 min-1 and 1.98 ml O2 100 g-1 min-1, respectively. During the second CBF study 1 h later, CBF and CMRO2 were unchanged (P greater than 0.05). In Group 2 (n = 7), the inspiratory enflurane concentration was increased from 1 to 2% after the first CBF measurement. In this group a significant decrease in CMRO2 was observed, while CBF was unchanged. In six patients EEG was recorded simultaneously with the CBF measurements. In patients subjected to increasing enflurane concentration (Group 2), a suppression in the EEG activity was observed without spike waves. It is concluded that enflurane induces a dose-related decrease in CMRO2 and suppression in the EEG activity, whereas CBF was unchanged.     

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.