Reduction In CMRO2 Research Articles

Increased expression of transforming growth factor-beta after cerebral ischemia in the baboon: an endogenous marker of neuronal stress?

There has been an increasing interest in recent years in the evaluation of the neuronal and glial responses to ischemic insult. Some cytokines, including transforming growth factor-beta (TGF-beta), that are overexpressed after experimental stroke in rodents are thought to be implicated in the neuronal processes that lead to necrosis. Thus, such cytokines could predict tissue fate after stroke in humans, although data are currently sparse for gyrencephalic species. The current study addressed the expression pattern of TGF-beta1 in a nonhuman primate model of middle cerebral artery occlusion. Focal permanent ischemia was induced for 1 or 7 days in 6 baboons and the following investigations were undertaken: cerebral oxygen metabolism (CMRO2) positron emission tomography studies, magnetic resonance imaging, postmortem histology, and reverse transcription-polymerase chain reaction. The aim of the current study was to correlate the expression of TGF-beta1 to the underlying metabolic and histologic state of the threatened cerebral parenchyma. The authors evidenced increased TGF-beta1 mRNA levels (up to 25-fold) in those regions displaying a moderate (20% to 49%) reduction in CMRO2. The current findings suggest that the greatly enhanced expression of TGF-beta1 in the penumbral zones that surround tissue destined to infarction may represent a robust index of potentially salvageable brain. The current investigation, in the nonhuman primate, strengthens the authors' hypothesis, derived from rodent models, that TGF-beta1 may be involved in the physiopathology of human stroke.

Reply to Abdul-Khaliq et al.

I was very interested to read the comments of Dr AbdulKhaliq and associates and to read of the results from their own study. Firstly I would like to try and allay concerns regarding the methodology used in our study. The markers of cerebral injury used were recovery of cerebral blood ow (CBF) and cerebral metabolism (CMRO2). We believe that these are important surrogates of brain injury. The reduction in CMRO2 that follows a period of deep hypothermic circulatory arrest (DHCA) has been regarded by some authors as a marker for neuronal injury for some time now as CMRO2 recovers normally after hypothermic bypass when DHCA is not used. More recently however in a study using electron microscopy we have been able to demonstrate a correlation between the recovery of CMRO2 and of cerebral ultrastructure [1]. In the control group in our study 60 min of DHCA followed by 60 min of rewarming resulted in a signi®cant impairment in the recovery of both CBF and CMRO2. This response to DHCA was attenuated by preoperative methylprednisolone (30 mg/kg) given at 8 and 2 h preoperatively. I believe that the conclusions as given in our paper are fully justi®ed. Regarding the study of Dr Abdul-Khaliq and associates there are a number of different reasons which might explain their results. Firstly although methylprednisolone was given in the same dose (30 mg/kg) as in our study I am not sure of either the route of administration, the number of doses or the timing of the doses. In our own study the timing of the doses was based on evidence that de novo protein synthesis is involved in the cerebroprotective effect of corticosteroids [2]. Secondly the duration of the circulatory arrest period was unfortunately not speci®ed. Finally failure to adequately perfusion ®x the brain prior to histological examination with a solution such as that described by Karnovsky [3] can lead to artefactual areas of damage. The suggestion from the letter is that the brains were not perfusion ®xed and this as another possible reason for the results obtained. Nevertheless I would concur wholeheartedly with Dr Abdul-Khaliq that further studies in this area are warranted prior to routine use in neonates.

Cerebral Response to Hemodilution During Hypothermic Cardiopulmonary Bypass in Adults

We examined the cerebral response to changing hematocrit during hypothermic cardiopulmonary bypass (CPB) in 18 adults. Cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO2), and cerebral oxygen delivery (CDO2) were determined using the nitrous oxide saturation technique. Measurements were obtained before CPB at 36 degrees C, and twice during 27 degrees C CPB: first with a hemoglobin (Hgb) of 6.2 +/- 1.2 g/dL and then with a Hgb of 8.5 +/- 1.2 g/dL. During hypothermia, appropriate reductions in CMRO2 were demonstrated, but hemodilution-associated increases in CBF offset the reduction in CBF seen with hypothermia. At 27 degrees C CPB, as the Hgb concentration was increased from 6.2 to 8.5 g/ dL, CBF decreased. CDO2 and CMRO2 were no different whether the Hgb was 6.2 or 8.5 g/dL. In eight patients in whom the Hgb was less than 6 g/dL, CDO2 remained more than twice CMRO2. This study suggests that cerebral oxygen balance during cardiopulmonary bypass is well maintained at more pronounced levels of hemodilution than are typically practiced, because changes in cerebral blood flow compensate for changes in hemoglobin concentration.

Does Hypothermia Prevent Cerebral Ischaemia during Cardiopulmonary Bypass?

It is believed that moderate hypothermia (25–32°C) during cardiopulmonary bypass provides cerebral protection by reducing the cerebral metabolic rate (CMRO2). Nevertheless episodes of ischaemia do occur and thus it has been suggested that cerebral oxygenation should be monitored by jugular venous oximetry. However, this technique is cumbersome and invasive. Near infrared spectroscopy (NIRS) provides a non-invasive assessment of cerebral oxygenation and this was used together with continuous Jugular venous oximetry in 21 patients undergoing hypothermic cardiopulmonary bypass. During the hypothermic period, jugular venous oximetry indicated reduced oxygen extraction consistent with a reduction in CMRO2 (Increase from 61 ± 2.5% to 74 ± 2.5%). In contrast, near infrared spectroscopy demonstrated increased oxygen extraction (HbO2 − 11.5 ± 1 μM. HHb + 3.2 ± 0.3 μM) and a fall in the cerebral concentration of oxidized cytochrome oxidase (– 1.7 ± 0.3 μM) indicating ischaemia. These results suggest that cerebral ischaemia occurs during hypothermic cardiopulmonary bypass with a spurious rise in jugular venous oxygen saturation, which represents arterio-venous shunting. Thus if hypothermia does facilitate cerebral protection it does not appear to be a direct result of a reduction in CMRO2 and oxygen requirement.

Factores determinantes de la ventana terapéutica en el ictus isquémico agudo: características de los estudios de tomografía por emisión de positrones

To make a brief review of the use of PET in the study of patients with acute ischemic stroke. In the cerebral cortex PET may be used to detect a series of changes which permit the definition of three types of patients with different prognoses. The patients of type 1 (severe fall in cerebral blood flow and CMRO2) have an unfavorable prognosis and do not benefit from fibrinolytic treatment and/or neuroprotection to assist recovery of areas of penumbra. Patients of type 2 (marked drop in cerebral blood flow with moderate reduction of CMRO2) have a doubtful prognosis and are those which, in theory, might benefit from fibronolytic and/or neuroprotector treatment to help recovery of zones of penumbra. The patients of type 3 (focal hyperperfusion with CMRO2 maintained) have a favorable spontaneous prognosis. This technique also shows that the therapeutic window should be individually analyzed in each case. This data is of great interest when planning therapeutic clinical studies.

Effects of temperature on cerebral tissue oxygen tension, carbon dioxide tension, and pH during transient global ischemia in rabbits.

A decrease in brain temperature (Tbrain) causes a decrease in the cerebral metabolic rate for oxygen (CMRO2) and provides potent neuroprotection against ischemic damage. In the present study, the effects of mild to moderate hypothermia on cerebral tissue oxygen tension (PO2 brain), carbon dioxide tension (PCO2 brain), and pH (pHbrain) were monitored during short episodes of global cerebral ischemia. After approval by the Animal Care and Use Committee, 10 New Zealand white rabbits were anesthetized (1% halothane in air) and mechanical ventilation was adjusted to maintain the arterial carbon dioxide tension at 35 mmHg (alpha-stat). A sensor to measure PO2 brain, PCO2 brain, pHbrain, and Tbrain was inserted into the brain through a burr hole in the skull. Tbrain was adjusted to 38 degrees C, 34.4 degrees C, and 29.4 degrees C in a random sequence in each animal. PO2 brain, PCO2brain, and pHbrain (all variables are reported at the actual Tbrain) were recorded every 10 s during a 5-min baseline, 3 min of cerebral ischemia induced by inflation of a neck tourniquet, and 10 min of reperfusion at each level of Tbrain. Analysis of variance and Dunnett's test were used for statistical analysis. Data are presented as means +/- SD. During ischemia, PO2 brain decreased from 56 +/- 3 to 33 +/- 2 mmHg at 38 degrees C, from 58 +/- 3 to 32 +/- 3 mmHg at 34.4 degrees C, and from 51 +/- 2 to 32 +/- 2 mmHg at 29.4 degrees C (p = NS). PCO2 brain increased by 6.7 +/- 2 mmHg at 38 degrees C, by 5.1 +/- 1.4 mmHg at 34.4 degrees C, and by 2.3 +/- 0.8 mmHg at 29.4 degrees C. pHbrain inversely followed the trend of PCO2 brain. The attenuated increase in PCO2 brain during hypothermic ischemia results from the reduced CMRO2. The similar decrease in PO2 brain at all temperature levels indicates that despite the reduction in CMRO2, PO2 brain is no better preserved during brief episodes of hypothermic ischemia than during normothermic ischemia.

Intraventricular Dexmedetomidine Decreases Cerebral Blood Flow During Normoxia and Hypoxia in Dogs

We tested the hypothesis that a centrally administered alpha2-receptor agonist could alter the cerebrovascular response to hypoxia, without evidence of systemic absorption of the drug. Beagle dogs were anesthetized with 1.4% isoflurane and exposed to hypoxic hypoxia (PaO2 approximately 22 mm Hg) before and after ventricular-cisternal perfusion with mock cerebrospinal fluid (CSF group, n = 5) or dexmedetomidine (100 micro g/mL; total dose 300 micro g; DEX group, n = 6). Cerebral perfusion pressure, PaCO2 and arterial oxygen content were controlled and regional cerebral blood flow (CBF; microspheres) and global cerebral metabolic rate for oxygen consumption (CMRO2) were measured. In another group (n = 5), drug distribution under the experimental conditions was assessed by3 H-clonidine administered by ventricular-cisternal perfusion. In the mock CSF group, flow to the cerebral hemispheres increased during hypoxia under baseline conditions and after CSF infusion: 66 +/- 8 to 170 +/- 15 mL [center dot] min-1 [center dot] 100 g-1 (265% +/- 24% of baseline value), 83 +/- 9 to 154 +/- 14 mL [center dot] min-1 [centered dot] 100 g-1 (201% +/- 54% of post-CSF infusion value). DEX decreased normoxic flow in the cerebral hemispheres from 76 +/- 6 to 44 +/- 4 ml [center dot] min (-1) [center dot] 100 g-1 with decreases in other regions of similar magnitude. After DEX, the absolute flow in all regions during hypoxia was 52%-55% of that prior to DEX (P < 0.05). However, because DEX also decreased normoxic CBF, the percent increase in flow during hypoxia was similar before and after DEX. CMRO2 was not affected by hypoxia prior to DEX. However, after DEX, hypoxia caused a marked reduction in cerebral oxygen delivery (5.2 +/- 1.0 vs 13.7 +/- 2.3 ml [center dot] min-1 [center dot] 100 g-1 for the CSF group) and CMRO2 (2.5 +/- 0.6 vs 3.9 +/- 0.6 ml [center dot] min-1 [center dot] 100 g-1). Regional accumulation of intraventricularly administered3 H-clonidine was greatest in periventricular brain structures (e.g., caudate nucleus, dorsal brainstem), and the concentration in the cerebral cortex was approximately 1% of the concentration in the ipsilateral caudate nucleus. We conclude that centrally administered DEX reduces CBF during normoxia and prevents adequate oxygen delivery during hypoxia. The mechanism of DEX-induced CBF reduction is not metabolically mediated, since CMRO2 is maintained at control values during normoxia despite the significant blood flow reduction. We believe that the reduction in CMRO2 during hypoxia in DEX-treated dogs is the result of a reduction of oxygen delivery rather than the underlying mechanism for the observed reduction in CBF during hypoxia. (Anesth Analg 1997;84:139-47)

Intraventricular Dexmedetomidine Decreases Cerebral Blood Flow During Normoxia and Hypoxia in Dogs

We tested the hypothesis that a centrally administered alpha 2-receptor agonist could alter the cerebrovascular response to hypoxia, without evidence of systemic absorption of the drug. Beagle dogs were anesthetized with 1.4% isoflurane and exposed to hypoxic hypoxia (Pao2 approximately 22 mm Hg) before and after ventricular-cisternal perfusion with mock cerebrospinal fluid (CSF group, n = 5) or dexmedetomidine (100 micrograms/mL; total dose 300 micrograms; DEX group, n = 6). Cerebral perfusion pressure, Paco2 and arterial oxygen content were controlled and regional cerebral blood flow (CBF; microspheres) and global cerebral metabolic rate for oxygen consumption (CMRO2) were measured. In another group (n = 5), drug distribution under the experimental conditions was assessed by 3H-clonidine administered by ventricular-cisternal perfusion. In the mock CSF group, flow to the cerebral hemispheres increased during hypoxia under baseline conditions and after CSF infusion: 66 +/- 8 to 170 +/- 15 mL.min-1.100 g-1 (265% +/- 24% of baseline value), 83 +/- 9 to 154 +/- 14 mL.min-1.100 g-1 (201% +/- 54% of post-CSF infusion value). DEX decreased normoxic flow in the cerebral hemispheres from 76 +/- 6 to 44 +/- 4 ml.min-1.100 g-1 with decreases in other regions of similar magnitude. After DEX, the absolute flow in all regions during hypoxia was 52%-55% of that prior to DEX (P < 0.05). However, because DEX also decreased normoxic CBF, the percent increase in flow during hypoxia was similar before and after DEX. CMRO2 was not affected by hypoxia prior to DEX. However, after DEX, hypoxia caused a marked reduction in cerebral oxygen delivery (5.2 +/- 1.0 vs 13.7 +/- 2.3 ml.min-1.100 g-1 for the CSF group) and CMRO2 (2.5 +/- 0.6 vs 3.9 +/- 0.6 ml.min-1.100 g-1). Regional accumulation of intraventricularly administered 3H-clonidine was greatest in periventricular brain structures (e.g., caudate nucleus, dorsal brainstem), and the concentration in the cerebral cortex was approximately 1% of the concentration in the ipsilateral caudate nucleus. We conclude that centrally administered DEX reduces CBF during normoxia and prevents adequate oxygen delivery during hypoxia. The mechanism of DEX-induced CBF reduction is not metabolically mediated, since CMRO2 is maintained at control values during normoxia despite the significant blood flow reduction. We believe that the reduction in CMRO2 during hypoxia in DEX-treated dogs is the result of a reduction of oxygen delivery rather than the underlying mechanism for the observed reduction in CBF during hypoxia.

Basal Q10 for cerebral metabolic rate for oxygen (CMRO2) in rats.

The effect of hypothermia on cerebral metabolic rate for oxygen (CMRO2) is well established and is effectively expressed by the Q10, i.e. the ratio of total CMRO2 (TCMRO2) over a temperature range of 10°C. Reported values for Q10 vary from 2.3 (Michenfelder and Theye, 1968) in dogs to 4.4 in man (Cohen et al, 1964), reflecting the controversy on the “true” value of Q10. Reports over the last decade investigating the metabolic effects of mild and moderate hypothermia on the brain and their protective effects during global and focal ischemia relative to those of barbiturates, have questioned the notion as to whether the predominant mechanism of brain protection by hypothermia or barbiturates is simply attributable to a reduction of CMRO2. We previously reported a Q10 of 2.5 for TCMRO2 in rats but also showed that hypothermia depressed active CMRO2 (ACMRO2) i.e. thiopental suppressible or EEG associated CMRO2 less than basal CMRO2 which is utilized for maintaining cell integrity and viability (Nemoto et al, 1993). On the basis of these results, we hypothesized that Q10 for BCMRO2 differs from that for ACMRO2 and determined the Q10for BCMRO2 in rats

Compartmentation of Whole Brain Blood Flow and Oxygen and Glucose Metabolism in Monkeys

The cerebral metabolic rate of oxygen (CMRO2) has been functionally compartmentalized using the barbiturate thiopental into active CMRO2, associated with electroencephalographic (EEG) activity, and the balance, basal CMRO2, associated with the maintenance of neuronal viability. Previous measurements of these CMRO2 compartments were made in anesthetized animals. Our aim was to determine whether the same proportions for these compartments applied in unanesthetized monkeys. The active: basal distribution of the cerebral metabolic rate of glucose (CMRG) and cerebral flood flow (CBF) were also determined. Three measurements of whole-brain CBF (H2 clearance), CMRO2, and CMRG were made in six unanesthetized rhesus monkeys (Macaca mulatta). Thereafter, thiopental anesthesia was induced and maintained until an isoelectric EEG was obtained. Three additional measurements of CBF, CMRO2, and CMRG were made. Arterial blood pressure, end-tidal CO2, and arterial blood gas were measured with each set of measurements. Thiopental-induced isoelectric EEG resulted in a 47% reduction in CMRO2 from 5.95 +/- 0.54 to 3.10 +/- 0.51 ml/100 g/min (mean +/- SD); a 36% reduction in CBF from 76 +/- 21 to 48 +/- 14 ml/100 g/min; and a 61% reduction in CMRG from 8.09 +/- 2.78 to 3.13 +/- 0.77 mg/100 g/min. The oxygen-glucose index was 0.99 +/- 0.10 for the whole brain, 0.87 +/- 0.15 for the active, and 1.27 +/- 0.25 for the basal compartments. These results indicated an active:basal distribution of approximately 50:50 for CMRO2, 40:60 for CBF, and 60:40 for CMRG. The active:basal CMRO2 distribution corroborates earlier data and shows that relative to CMRO2, the active compartment is underperfused with a lower oxygen-glucose index compared with the basal compartment.

Functional, metabolic, and circulatory changes associated with seizure activity in the postischemic brain.

The present study was undertaken to explore how transient ischemia in rats alters cerebral metabolic capacity and how postischemic metabolism and blood flow are coupled during intense activation. After 6 h of recovery following transient forebrain ischemia 15 min in duration, bicuculline seizures were induced, and brains were frozen in situ after 0.5 or 5 min of seizure discharge. At these times, levels of labile tissue metabolites were measured, whereas the cerebral metabolic rate for oxygen (CMRO2) and cerebral blood flow (CBF) were measured after 5 min of seizure activity. After 6 h of recovery, and before seizures, animals had a 40-50% reduction in CMRO2 and CBF. However, because CMRO2 rose three-fold and CBF fivefold during seizures, CMRO2 and CBF during seizures were similar in control and postischemic rats. Changes in labile metabolites due to the preceding ischemia encompassed an increased phosphocreatine/creatine ratio, as well as raised glucose and glycogen concentrations. Seizures gave rise to minimal metabolic perturbation, essentially comprising reduced glucose and glycogen contents and raised lactate concentrations. It is concluded that although transient ischemia leads to metabolic depression and a fall in CBF, the metabolic capacity of the tissue is retained, and drug-induced seizures lead to a coupled rise in metabolic rate and blood flow.

Effect of 80% Xe on Whole Brain Blood Flow and Metabolism in Awake Monkeys

We previously reported that 33% xenon (Xe) did not activate cerebral blood flow (CBF) and metabolism in monkeys as it appears to do in humans. However, monkeys may be less sensitive to Xe than humans are, which would explain the discrepancy in the results, but no one has studied the effects of higher concentrations of Xe on CBF and metabolism in monkeys. Therefore, we studied the effect of 80% Xe on whole-brain CBF, cerebral metabolic rate for oxygen (CMRO2) and glucose (CMRG) in five awake rhesus monkeys. Platinum microelectrodes and catheters inserted into the torcular Herophili were used to measure H2 clearance CBF, and to withdraw cerebral venous blood for O2 and glucose analysis. Cerebral variables were measured after 15 min exposure to 80% N2/20% O2 followed by 80% Xe/20% O2. Eighty percent Xe compared with 80% N2 increased (p <0.01) CBF by 52.7% from 74 +/- 16 to 113 +/- 25 (mean +/- SD) ml 100 g(-1)/min(-1), CBF/CMRO by 154% from 13 to 33, and decreased (p <0.05) CMRO2 by 39.3% from 6.1 +/- 0.9 to 3.7 +/- 0.8 ml 100 g(-1)/min(-1) and CMRG by 52.4% from 8.4 +/- 2.6 to 4.0 +/- 2.0 mg 100 g(-1)/min(-1). Electroencephalogram frequency decreased from a predominantly alpha to dagger rhythm in three of five monkeys. The 40 and 50% reduction in CMRO2 and CMRG, respectively, by 80% Xe suggests an anesthetic effect at this dose in the rhesus monkey but also activates CBF by 50%.

Cerebral Oxygen Metabolism after Aneurysmal Subarachnoid Hemorrhage

Previous studies of cerebral oxygen metabolism and extraction in patients with subarachnoid hemorrhage (SAH) have yielded conflicting results. We used positron emission tomography (PET) to measure the regional cerebral metabolic rate for oxygen (rCMRO2), oxygen extraction fraction (rOEF), and cerebral blood flow (rCBF) 16 times in 11 patients with aneurysmal SAH. All studies were performed preoperatively; no patient had hydrocephalus or intracerebral hematoma on brain CT. Eight patients with no arteriographic vasospasm who were studied on days 1-4 post-SAH had a significant 25% reduction in global CMRO2 compared to age-matched controls, and no significant change in global OEF, suggesting a primary reduction in CMRO2 caused by SAH. Four patients studied seven times during arteriographic vasospasm had significantly increased rOEF with unchanged CMRO2 in arterial territories affected by arteriographic vasospasm compared to territories without vasospasm, indicative of cerebral ischemia without infarction. No brain regions studied with PET were infarcted on follow-up CT. We conclude that the initial aneurysm rupture produces a primary reduction in CMRO2, and that subsequent vasospasm causes ischemia.

Cerebral O2 metabolism and cerebral blood flow in humans during deep and rapid-eye-movement sleep

It could be expected that the various stages of sleep were reflected in variation of the overall level of cerebral activity and thereby in the magnitude of cerebral metabolic rate of oxygen (CMRO2) and cerebral blood flow (CBF). The elusive nature of sleep imposes major methodological restrictions on examination of this question. We have now measured CBF and CMRO2 in young healthy volunteers using the Kety-Schmidt technique with 133Xe as the inert gas. Measurements were performed during wakefulness, deep sleep (stage 3/4), and rapid-eye-movement (REM) sleep as verified by standard polysomnography. Contrary to the only previous study in humans, which reported an insignificant 3% reduction in CMRO2 during sleep, we found a deep-sleep-associated statistically highly significant 25% decrease in CMRO2, a magnitude of depression according with studies of glucose uptake and reaching levels otherwise associated with light anesthesia. During REM sleep (dream sleep) CMRO2 was practically the same as in the awake state. Changes in CBF paralleled changes in CMRO2 during both deep and REM sleep.

Cerebral blood flow and metabolism following subarachnoid haemorrhage: effect of subarachnoid blood

The amount of effused blood following a subarachnoid haemorrhage (SAH) was estimated in 48 patients by cerebral computerized tomographic scanning. The cerebral oxygen consumption (CMRO2) was calculated as arteriovenous difference for oxygen multiplied by mean cerebral blood flow measured by the 133-Xe inhalation technique. A significant negative correlation was observed between CMRO2 and amount of subarachnoid blood, with additional reduction in CMRO2 in case of ventricular bleeding. Cerebral blood flow on admission, opposed to CMRO2, showed no correlation to amount of blood on CT scan. A correlation was observed for blood flow measured at day 5 and further on, indicating a restored coupling between flow and metabolism. The clinical (Hunt) grade on admission and the outcome correlated to the amount of blood. These observations suggest that the acute reduction in CMRO2 following a SAH is mainly determined by the amount of blood escaping during the aneurysm rupture, and that the cerebral blood flow level a few days after SAH mainly is determined by the initial reduction in oxygen uptake.

Cerebral blood flow and metabolism following subarachnoid haemorrhage: cerebral oxygen uptake and global blood flow during the acute period in patients with SAH

Forty-eight patients with subarachnoid haemorrhage were studied with repeated rCBF and CMRO2 measurements. Cortical rCBF was measured using xenon-inhalation technique. CMRO2 was calculated as AVDO2 x CBF. When first studied the 29 conscious patients showed relative hyperaemia with CBF at 50 ml and reduced CMRO2 at 2.17 ml. In the following week CBF decreased to 41. CMRO2 remained reduced and constant. The 19 unconscious patients showed initially pronounced reduction in CMRO2 to 1.26, followed by gradual increase to 1.73 in 4-5 days. Simultaneously CBF increased from 18 ml to slightly above 30 ml. In the conscious patients the early reduction in CMRO2 and the concomitant luxury perfusion may be explained by global ischaemia because of very high ICP at the time of the haemorrhage. The reduced CBF in the unconscious group could be due to increased ICP, as ventricular drainage increased CBF to levels of relative hyperaemia as demonstrated in one case. As no decrease in CMRO2 was seen during the first 2 weeks, it is suggested that ischaemia at the time of aneurysm rupture is the most important single factor in reduction of global CMRO2.

Streptokinase treatment versus calcium overload blockade in experimental thromboembolic stroke.

Thromboembolic brain ischemia was produced in dogs using an autologous blood clot model. The effect of postembolic treatment with flunarizine and streptokinase on hemispheric cerebral metabolic rate for oxygen (CMRO2), oxygen extraction ratio (OER), and cerebral blood flow (CBF) was studied by positron emission tomography (oxygen-15 technique) 24 hours after the insult. We studied five groups of experimental dogs and compared them with a control group of nonembolized dogs. Group I received no treatment, Group II was treated locally with 500,000 IU streptokinase starting 30 minutes after the insult, Group III received streptokinase locally 30 minutes after the insult and 0.1 mg/kg i.v. flunarizine immediately after the insult and 2 hours later, Group IV received flunarizine as Group III, and Group V was orally pretreated with 0.5 mg/kg/day flunarizine during 2 weeks preceding embolization. Compared with the contralateral hemisphere, in the embolized hemisphere a significant reduction of CMRO2 (-25% to -40%) and CBF in normocapnia (-35%) and hypercapnia (-50%) was observed in Groups I, II, and V. In Groups III and IV, CMRO2, OER, and CBF of the embolized hemisphere were within the normal range during normocapnia and hypercapnia; the extent of the ischemic lesions was markedly less than in the other groups of experimental dogs. We conclude that flunarizine treatment after experimental thromboembolic stroke had a favorable influence on brain tissue. Chronic preventive flunarizine treatment failed to have a beneficial effect.

Regional Cerebral Blood Flow and Oxygen Metabolism in Normal Pressure Hydrocephalus after Subarachnoid Hemorrhage

To clarify the pathophysiology of normal pressure hydrocephalus (NPH) after subarachnoid hemorrhage, the authors measured cerebral blood flow (CBF), cerebral oxygen metabolic rates (CMRO2), the cerebral oxygen extraction fraction (OEF), and cerebral blood volume (CBV) in eight normal volunteers, six SAH patients with NPH, and seven patients without NPH by 15O-labeled gas and positron emission tomography (PET). In the NPH group, PET revealed a decrease in CBF in the lower regions of the cerebral cortex and a diffuse decrease in CMRO2. The decrease in CBF in the lower frontal, temporal, and occipital cortices was significantly greater in the NPH than in the non-NPH group. Reduction of CMRO2 was also more extensive in the NPH group, and both CBF and CMRO2 were more markedly decreased in the lower frontal region. OEF was increased in all areas in both of the patient groups, but the increase was not significant in most areas. CBF, CMRO2 and OEF did not significantly differ between the non-NPH group and the normal volunteers. There was no significant difference in CBV among the three groups. These results indicate that NPH involves impairment of cerebral oxygen metabolism in the lower regions of the cerebral cortex, particularly in the lower frontal region.

Positron emission tomography in minor ischemic stroke using oxygen-15 steady-state technique.

A study with positron emission tomography (PET) was performed on 10 patients with ischemic stroke and mild disability. The patients underwent cerebral angiography, x-ray computed tomography (CT) scan and regional cerebral measurements of CBF, CMRO2, oxygen extraction ratio (OER), and cerebral blood volume (CBV). Only minor arterial involvement was detected by angiography. In all patients, PET images of functional defects were more extensive than the corresponding CT hypodensity, and there were statistically significant reductions in CBF, CMRO2, and CBF/CBV ratio as compared with control subjects. Half of the regions analyzed in the affected hemisphere demonstrated a disruption of the normal coupling between CBF and CMRO2 as reflected by OER values significantly higher or lower than those of the corresponding region of the contralateral hemisphere. The pathophysiological pattern of high OER combined with a reduction in CBF proportionally greater than the reduction in CMRO2 was particularly indicative of regional chronic hemodynamic compromise in these patients.

Barbiturate therapy in acute brain injury

Barbituric acid was first synthesized in 1864, and since that time its derivatives have been in common use for induction of sedation, hypnosis, seizure control, and anesthesia. In recent years barbiturates have been used widely for control of intracranial pressure in a variety of clinical situations, and there has been extensive controversy regarding the effectiveness of barbiturates in protecting against or ameliorating ischemic or anoxic brain damage. Despite numerous studies, there is no clear evidence that these agents protect the brain from such injury. This review addresses some of the known physiologic and metabolic effects of barbiturates, the results of experimental studies using a number of models for focal and global ischemia and anoxia, and clinical reports pertaining to the use of barbiturate coma. Cerebral blood flow is closely coupled with cerebral metabolic rate for oxygen in the awake state; barbiturates reduce both) 3 This effect increases as dose increases; at levels sufficient to produce burst suppression on the EEG, flow can be reduced to as little as one-third normal, and CMRO2 to as low as 45% normal. Barbiturates do not uncouple the effect of CMRO2 on blood flow; in fact, the cerebrovascular effects of barbiturates appear to be the result of reduction in CMRO2 rather than the direct effects on cerebral blood vessels? No further change in these variables occurs if the dose is increased beyond that required to induce an isoelectric EEG, because barbiturates affect only the oxygen consumption required for electrical activity and not that needed for maintenance of cellular integrity? In contrast, lidocaine, a drug that blocks sodium channels and prevents efflux of potassium in ischemic brain, inhibits CMRO2 and cerebral glucose consumption, and continues to exert its effect after the EEG has become fiat. This suggests that lidocaine is a more effective agent in protecting isehemic brain? In clinical situations in which increased intracranial pressure