Incomplete Cerebral Ischemia Research Articles

Effect of the 21-aminosteroid tirilazad on cerebral pH and somatosensory evoked potentials after incomplete ischemia.

Postischemic evoked potential recovery correlates with acidosis during ischemia and early reperfusion. Acidosis promotes lipid peroxidation in vitro. We tested the hypothesis that the 21-aminosteroid tirilazad mesylate (U74006F), an inhibitor of lipid peroxidation in vitro, ameliorates somatosensory evoked potential recovery and acidosis during reperfusion after severe incomplete cerebral ischemia. Cerebral perfusion pressure was reduced to 11 +/- 1 mm Hg (+/- SEM) for 30 minutes by cerebral ventricular fluid infusion in anesthetized dogs. Cerebral intracellular pH and high-energy phosphates were measured by magnetic resonance spectroscopy. Dogs were randomized to receive vehicle (citrate buffer; n = 8) or tirilazad (1 mg/kg; n = 8) before ischemia in a blinded study. Cerebral blood flow was reduced to 6 +/- 1 mL/min per 100 g during ischemia, resulting in nearly complete loss of high-energy phosphates and an intracellular pH of 6.0-6.1 in both groups. Initial postischemic hyperemia was similar between groups but lasted longer in the vehicle group. Tirilazad accelerated mean recovery time of intracellular pH from 31 +/- 5 to 15 +/- 3 minutes and of inorganic phosphate from 13 +/- 2 to 6 +/- 1 minutes. Recovery of somatosensory evoked potential amplitude was greater with tirilazad (49 +/- 3%) than vehicle (33 +/- 6%). Fractional cortical water content was less with tirilazad (0.819 +/- 0.003) than vehicle (0.831 +/- 0.002). Tirilazad attenuates cerebral edema and improves somatosensory evoked potential recovery after incomplete ischemia associated with severe acidosis. Accelerated pH and inorganic phosphate recovery indicates that this antioxidant acts during the early minutes of reperfusion.

Brain α2-Adrenergic Receptor Binding During Incomplete Cerebral Ischemia in the Rat

alpha 2-Adrenergic agonists decrease sympathetic activity and improve outcome from brain ischemia. We evaluated whether changes in alpha 2-adrenergic receptor binding activity may be important in the sympathetic depressant and cerebral protective effects of halothane (1.1% inspired) or isoflurane (1.4% inspired) compared to fentanyl/nitrous oxide (N2O) anesthesia. Brain alpha 2-adrenergic receptor binding was measured using [3H]-clonidine in each of four treatment conditions: 1, unanesthetized; 2, anesthetized (fentanyl/N2O, halothane, or isoflurane): 3, anesthetized with ischemia; 4, after 4 h recovery from ischemia. Ischemia was produced by right carotid artery ligation combined with hemorrhagic hypotension to 30 mm Hg for 30 min. Both halothane and isoflurane decreased alpha 2-adrenergic receptor density 20% compared to unanesthetized values (P < 0.01). This decrease was attenuated in ischemic tissue. There were no consistent changes in receptor affinity. These results suggest that inhaled anesthetics decrease the number of alpha 2-adrenergic receptors. This decrease appears to be unrelated to plasma catecholamine concentrations but may be influenced by the degree of ischemia.

MDA, oxypurines, and nucleosides relate to reperfusion in short-term incomplete cerebral ischemia in the rat

Short-term incomplete cerebral ischemia (5 min) was induced in the rat by the bilateral clamping of the common carotid arteries. Reperfusion was obtained by removing carotid clamping and was carried out for the following 10 min. Animals were sacrificed either at the end of ischemia or reperfusion. Controls were represented by a group of sham-operated rats. Peripheral venous blood samples were withdrawn from the femoral vein from rats subjected to cerebral reperfusion 5 min before ischemia, at the end of ischemia, and 10 min after reperfusion. Neutralized perchloric acid extracts of brain tissue were analyzed by a highly sensitive high-performance liquid chromatography (HPLC) method for the direct determination of malondialdehyde, oxypurines, nucleosides, nicotinic coenzymes, and high-energy phosphates. In addition, plasma concentrations of malondialdehyde, hypoxanthine, xanthine, inosine, uric acid, and adenosine were determined by the same HPLC technique. Incomplete cerebral ischemia induced the appearance of a significant amount (8.05 nmol/g w.w.; SD = 2.82) of cerebral malondialdehyde (which was undetectable in control animals) and a decrease of ascorbic acid. A further 6.6-fold increase of malondialdehyde (53.30 nmol/g w.w.; SD = 17.77) and a 18.5% decrease of ascorbic acid occurred after 10 min of reperfusion. Plasma malondialdehyde, which was present in minimal amount before ischemia (0.050 μmol/L; SD = 0.015), significantly increased after 5 min of ischemia (0.277 μmol/L; SD = 0.056) and was strikingly augmented after 10 min of reperfusion (0.682μmol/L; SD = 0.094). A similar trend was observed for xanthine, uric acid, inosine, and adenosine, while hypoxanthine reached its maximal concentration after 5 min of incomplete ischemia, being significantly decreased after reperfusion. From the data obtained, it can be concluded that tissue concentrations of malondialdehyde and ascorbic acid, and plasma levels of malondialdehyde, oxypurines, and nucleosides, reflect both the oxygen radical-mediated tissue injury and the deppresion of energy metabolism, thus representing early biochemical markers of short-term incomplete brain ischemia and reperfusion in the rat. In particular, these results suggest the possibility of using the variation of malondialdehyde, oxypurines, and nucleosides in peripheral blood as a potential biochemical indicator of reperfusion damage occurring to postischemic tissues.

Ketamine decreases plasma catecholamines and improves outcome from incomplete cerebral ischemia in rats.

Central neuroexcitatory receptors (N-methyl-D-aspartate [NMDA], non-NMDA) may affect outcome from cerebral ischemia by altering sympathetic nervous system activity. We tested whether ketamine, an NMDA antagonist, and NBQX, a non-NMDA antagonist, improve outcome from incomplete cerebral ischemia in the rat and whether a change in outcome is related to changes in plasma catecholamines. There were five treatment groups: group 1 (control, n = 10) received a fentanyl infusion at a rate of 25 microgram.kg-1.h-1 and ventilation with 70% N2O in O2. Group 2 (n = 10) received the same anesthetic treatment and were given an intraperitoneal injection of 30 mg/kg NBQX 15 min prior to ischemia. Group 3 (n = 10) received a ketamine infusion of 1.0 mg.kg-1.min-1 and ventilation with room air. Group 4 (n = 10) received a ketamine infusion of 1.5 mg.kg-1.min-1. Group 5 received a ketamine infusion of 1 mg.kg-1.min-1 plus a 6 ml/kg intraperitoneal injection of 40% glucose solution 15 min before the start of ischemia. Ischemia was produced by right common carotid ligation combined with hemorrhagic hypotension to 35 mmHg for 30 min. Blood gases, pH, and skull temperature were controlled during ischemia. Plasma glucose increased during ischemia in all groups but was lower in ketamine-anesthetized rats (groups 3 and 4). Glucose-loaded ketamine-anesthetized rats (group 5) had plasma glucose concentrations similar to the control group. Plasma epinephrine and norepinephrine concentrations were significantly less in ketamine-anesthetized rats (groups 3, 4, and 5) during ischemia compared to controls (P less than 0.05). Neurologic outcome was significantly better (P less than 0.05) in all ketamine-treated rats (groups 3, 4, and 5) compared to the control group, regardless of plasma glucose concentration during ischemia. NBQX did not improve neurologic outcome. These results suggest that ketamine improves neurologic outcome from incomplete cerebral ischemia by a mechanism related to a decrease in plasma catecholamine activity.

Felbamate reduces hypoxic-ischemic brain damage in vivo

The neuroprotective effects of felbamate were tested in a model of incomplete cerebral ischemia and hypoxia in 7-day-old rat pups. Felbamate pretreatment (300 mg/kg) reduced the surface of infarcted cortex following bilateral carotid ligation, by 42–49% compared to saline and dimethylsulfoxide (DMSO) controls, respectively. The number of necrotic neurons in the d dentate gyrus was reduced by 77% over both DMSO controls and saline controls. These results suggest that felbamate deserves further evaluation for its therapeutic potential in hypoxia-ischemia.

The Effects of Propofol on Brain Electrical Activity, Neurologic Outcome, and Neuronal Damage Following Incomplete Ischemia in Rats

This study compares the effects of propofol and fentanyl/N2O on spontaneous brain electrical activity, neurologic outcome, and neuronal damage due to incomplete cerebral ischemia in rats. Thirty Sprague-Dawley rats were assigned to one of three groups: group 1 (n = 10) received 70% N2O in O2 plus fentanyl (bolus 10 micrograms.kg-1, infusion 25 micrograms.kg-1.h-1); group 2 (n = 10) received 70% N2 in O2 and propofol (infusion 0.8-1.2 mg.kg-1.min-1) adjusted to maintain EEG burst suppression during ischemia; group 3 (n = 10) was anesthetized with propofol and received 6 ml.kg-1 10% glucose intraperitoneally 15 min before the start of ischemia. Incomplete cerebral ischemia was produced by right common carotid artery occlusion combined with hemorrhagic hypotension (35 mmHg) for 30 min. Arterial blood gases, pH, and rectal temperature were kept constant in all groups. Plasma glucose was lower during ischemia in propofol-anesthetized rats compared to that in fentanyl/N2O- (P = 0.009) and glucose-loaded propofol-treated rats (P = 0.008). Neurologic outcome and brain tissue injury were significantly better in propofol-anesthetized compared to fentanyl/N2O-anesthetized rats (P less than 0.05). Elevated plasma glucose in propofol-treated rats resulted in similar neurologic outcome and histopathologic injury as seen in propofol-anesthetized rats given no glucose. Recovery of EEG theta-alpha activity after ischemia was inversely correlated to neurologic deficit (fentanyl/N2O: r = -0.71; propofol: r = -0.83; P less than 0.01). These results show that propofol improves neurologic outcome and decreases neuronal damage from incomplete cerebral ischemia when compared to fentanyl/N2O. This effect is not dependent on plasma glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in striatal dopamine neurohistochemistry and biochemistry after incomplete transient cerebral ischemia in the rat

To evaluate the development of striatal ischemic cell damage in relation to alterations in dopamine (DA) transmission, one year old male Wistar rats underwent a 15 min incomplete cerebral ischemia (ICI) induced by occlusion of the common carotid arteries and by hypovolemic hypotension. The animals were divided into the following experimental groups: sham operated rats, rats with ICI without reperfusion, and rats with ICI followed by 60 min, 24 h, 72 h and 144 h of recirculation. The ischemia induced striatal lesions were investigated in serial coronal brain sections, stained with cresylviolet or immunostained for dopamine and cAMP regulated phosphoprotein (DARPP-32), for tyrosine hydroxylase (TH) and for glial fibrillary acidic protein (GFAP) immunoreactivities (IR). Measurements of striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels were made on analogous experimental groups using HPLC methods. Signs of degeneration in small to medium sized neurons were already seen after 60 min of postischemic reperfusion together with slight decreases of DARPP-32 IR and increases of GFAP IR. The damage continued to increase up to 144 h, and after 24 h of recirculation there were clearly defined areas of reduced DARPP-32 IR, overlapping with increased TH IR and increased GFAP IR. The levels of DA, DOPAC and HVA increased sharply after 60 min (151%, 462% and 201%, respectively) remained high after 24 h and normalized after 72 h of recirculation. The DA metabolism was high after 60 min and had already normalized after 24 h of recirculation. The increased DA metabolism in striatal nerve terminals in response to ischemic injury may reflect an early degenerative change in the DA terminals. The long-lasting increase in TH IR may to some extent represent an adaptive change in response to the disappearance of DA receptor-containing nerve cells. Based on the present findings it is possible that an increased D1 transmission in neostriatum immediately following the ischemic injury may contribute to striatal nerve cell degeneration in which an enhancement of NMDA receptor transduction may be implicated.

Bicarbonate conservation during incomplete cerebral ischemia with superimposed hypercapnia

We superimposed extreme hypercapnia (arterial Pco2 400-450 mmHg) immediately before and during incomplete cerebral ischemia to distinguish the role of intracellular pH (pHi) and bicarbonate [( HCO3-]i) in postischemic metabolic and electrophysiological recovery. Incomplete global ischemia was produced in seven anesthetized dogs by 30 min of intracranial hypertension followed by 4 h of reperfusion. ATP, phosphocreatine (PCr), and pHi were measured with 31P magnetic resonance spectroscopy, and [HCO3-]i was calculated from the Henderson-Hasselbalch equation using the measured pHi and sagittal sinus Pco2. Cerebral blood flow was reduced to 7 +/- 1 ml.min-1.100 g-1 (+/- SE) during ischemia with extreme hypercapnia, and pHi decreased to 5.72 +/- 0.09. During normocapnic reperfusion, pHi rapidly returned to near baseline values by 14 min. [HCO3-]i fell from 12.1 +/- 0.9 to 6.0 +/- 1.2 mM by the midpoint of ischemia and recovered by 30 min of reperfusion. ATP, PCr, and O2 consumption also recovered rapidly and completely. Somatosensory-evoked potentials (SEP) recovered to 43 +/- 10% of control amplitude. These results are in marked contrast to the poor metabolic and SEP recovery previously observed in hyperglycemic dogs in which pHi decreased to the same range as with hypercapnic ischemia, but in which [HCO3-]i was much lower (1.1 +/- 0.5 mM). Therefore, [HCO3-]i depletion during hyperglycemic ischemia may be a more important factor in recovery than end-ischemic pHi per se. We speculate that higher [HCO3-]i may improve glial cell buffering capacity or decrease iron availability for hydroxyl radical production.

Dexmedetomidine Improves Neurologic Outcome from Incomplete Ischemia in the Rat Reversal by the α2-Adrenergic Antagonist Atipamezole

Dexmedetomidine is an alpha 2-adrenergic agonist that decreases central sympathetic activity and reduces the anesthetic requirement for halothane. We evaluated the effect of dexmedetomidine on neurologic and histopathologic outcome from incomplete cerebral ischemia in the rat. Anesthesia was maintained with a 25-micrograms.kg-1.h-1 fentanyl infusion combined with 70% nitrous oxide. Incomplete ischemia was produced by unilateral carotid artery ligation combined with hemorrhagic hypotension to 35 mmHg for 30 min. Arterial blood gas tensions, pH, and head temperature were maintained at normal levels during the experiment. Four ischemic groups were tested: group 1 (n = 15) received an intraperitoneal (ip) saline injection (control); group 2 (n = 10) received an ip injection of 10 micrograms/kg dexmedetomidine 30 min before ischemia; group 3 (n = 10) received 100 micrograms/kg dexmedetomidine; and group 4 (n = 10) received 100 micrograms/kg dexmedetomidine plus 1 mg/kg atipamezole (an alpha 2-adrenergic antagonist). Neurologic outcome was evaluated for 3 days using a graded deficit score. Histopathology was evaluated in coronal section in caudate and hippocampal tissue segments. Dexmedetomidine (10 and 100 micrograms/kg) significantly decreased plasma catecholamines and improved neurologic and histopathologic outcome in a dose-dependent manner compared to control rats (P less than 0.05). Atipamezole abolished the decrease in catecholamines and the improvement in outcome seen with dexmedetomidine, confirming that these effects were mediated by alpha 2-adrenergic receptors. It is concluded that alpha 2-adrenoreceptor stimulation decreases sympathetic activity and decreases ischemic injury in a model of incomplete cerebral ischemia.

Captopril improves neurologic outcome from incomplete cerebral ischemia in rats.

We investigated the effects of the angiotensin-converting enzyme inhibitor captopril on neurologic outcome in a rat model of incomplete cerebral ischemia. Twenty male Sprague-Dawley rats were anesthetized with 70% nitrous oxide in oxygen and fentanyl (10 micrograms x kg-1 i.v. bolus, 25 micrograms x kg-1 x hr-1 i.v. continuous infusion). Animals in group 1 (n = 10) received no angiotensin-converting enzyme inhibitor while animals in group 2 (n = 10) were given 10 mg x kg-1 i.v. captopril 30 minutes prior to the ischemic period. Ischemia was produced by unilateral carotid artery ligation and hemorrhagic hypotension to 35 mm Hg for 30 minutes. Body temperature, arterial blood gases, and arterial pH were maintained constant. Neurologic outcome was evaluated every 24 hours for 3 days using a graded deficit score (0, normal; 18, stroke-related death). On the third day after ischemia, captopril significantly improved neurologic outcome (median deficit score = 4) compared with controls (median deficit score = 18) (p less than 0.05). These results suggest that reduced angiotensin II levels or increased tissue kinin concentrations may decrease ischemic brain injury.

Effect of Blood Glucose Level in Acute Cerebral Ischemia in Spontaneously Hypertensive Rats — Survival and Brain Pathology

The present study was designed to examine the effect of blood glucose level on survival and pathologic changes of the cortical neuronal cells during and after three-hour incomplete cerebral ischemia, which was induced by bilateral carotid artery ligation in spontaneously hypertensive rats (SHRs). Blood glucose levels were varied by intraperitoneal infusion of 50% glucose (hyperglycemia) or insulin with hypertonic saline (hypoglycemia) or hypertonic saline (normoglycemia). None of the hyperglycemic or normoglycemic animals died during three-hour ischemia, whereas 45% of hypoglycemic animals died (p greater than 0.001). The survival rate for twenty-four hours after recirculation was in the following ascending order: hypoglycemia, normoglycemia, and hyperglycemia. Neither hypoglycemia nor hyperglycemia (38-392 mg/dL) in nonischemic animals developed any morphologic changes in the cerebral cortex. However, both the ischemic and recirculated brains showed various degrees of histologic changes such as shrinkage of the neuronal cells with cytoplasmic vacuoles, perineuronal edema, and swelling of neuropils. Such ischemic damage of the brain was more marked in hypoglycemic animals than in hyperglycemic or normoglycemic ones during ischemia, as well as one hour after recirculation. The results suggest that cerebral ischemia and its outcome become more deleterious in hypoglycemic than in normoglycemic and hyperglycemic states. On the other hand, hyperglycemia is not necessarily a disadvantage in acute cerebral ischemia with or without reperfusion in this model.

Intracarotid saline infusion improves outcome from incomplete ischemia in rats.

Previous studies suggest that rheological changes associated with ischemia may produce postischemic hypoperfusion. We tested whether intracarotid or intravenous infusions of saline improve neurological outcome from incomplete cerebral ischemia in rats. Rats were anesthetized with 1.4% isoflurane in air, and ischemia was produced by unilateral carotid artery ligation combined with hemorrhagic hypotension to 30 mm Hg for 30 minutes. Intracarotid (n = 10) or intravenous (n = 10) saline infusion (0.3 ml/min) decreased hematocrit 20% compared with control rats (n = 10). Neurological outcome was significantly improved in rats infused with intracarotid (p less than 0.05) but not intravenous saline during ischemia without a change in brain temperature. Cerebral blood flow, measured in a separate study using laser Doppler flowmetry (n = 5), decreased 70% (p less than 0.01) during carotid ligation and hypotension but was not changed by intracarotid saline infusion (p greater than 0.30). These results show that perfusion of ischemic brain with saline improves outcome by factors not related to changes in hematocrit, brain temperature, or intraischemic tissue blood flow.

The 21-Aminosteroid U74006F Does Not Markedly Improve Outcome from Incomplete Ischemia in the Rat

The 21-aminosteroid U74006F reportedly decreases neuronal injury following head injury or complete cerebral ischemia. We evaluated the ability of U74006F to improve outcome following incomplete cerebral ischemia in the rat. Ischemia was induced by right carotid occlusion combined with 30 min of hemorrhagic hypotension to 30 or 35 mm Hg. Animals in groups 1 and 2 were maintained on 1.4% isoflurane in room air and rats in groups 3 and 4 were ventilated with 70% nitrous oxide (N2O) and 30% oxygen. Rectal temperature was kept at 37C and PaCO2 and pH were maintained constant during ischemia. Group 1 (n = 10) and group 3 (n = 10) received a vehicle treatment. Group 2 (n = 10) and group 4 (n = 10) received 3 mg/kg of U74006F before ischemia and a 3-h infusion of 3 mg/kg/h of the drug after ischemia. Neurologic outcome was measured for 3 days and histopathology was evaluated at the end of the study. U74006F did not significantly improve neurologic outcome or histopathology during either isoflurane or N2O compared to the vehicle-treated groups. These results suggest that U74006F does not substantially inhibit ischemic damage produced in this model of incomplete cerebral ischemia.

Reduction of cellular damage induced by cerebral ischemia in rats

A model of incomplete cerebral ischemia involving bilateral ligation of the common carotid arteries in rats, was used to examine the potential of a Chinese herbal preparation and of nifedipine to reduce cell damage following cerebral ischemia. The herbal preparation contained ginsengosides and extracts of Panax notoginseng, Ligusticum chuanxiong Hort., Carthamus tinctorius L. and Salvia militorrhiza Bge. Histological evidence of cell damage and the formation of peroxidation products were both reduced in rats pretreated with the herbal preparation or with nifedipine. It has been suggested that the free radical reaction is involved in tissue damage, particularly in the pathological neurocyte injury of cerebral ischemia. The results show that in this model of incomplete cerebral ischemia, the degree of lipid peroxidation can be lowered by the pretreatment with Chinese herbs containing ginsengosides or with nifedipine. These drugs maybe beneficial in the treatment of cerebral ischemia in humans.

Lidocaine Accelerates Recovery of Brain Electrical Activity After 3 Minutes of Complete Ischemia in the Rabbit

We recently reported that the continuous infusion of a low dose of lidocaine accelerated the recovery of the electroencephalogram and somatosensory evoked potentials after 20 min of incomplete cerebral ischemia in a single carotid artery preparation in the rabbit. In contrast, the recovery of the electroencephalogram and the auditory evoked potentials was minor on a comparable animal preparation subjected to 5 min of almost complete global ischemia. In the present study, we tested the hypothesis that the facilitatory effect of lidocaine on neuroelectrical recovery is of importance only during a certain combination of duration and severity of an ischemic episode. Similar to the previous studies, the rabbits had one carotid and both vertebral arteries permanently occluded and the other carotid artery reversibly clamped during the ischemic test. In the halothane-anesthetized animals, we monitored mean arterial pressure, carotid stump pressure, cerebral blood flow, auditory evoked potentials, and the electroencephalogram, before and for 90 min after 3 min of complete ischemia. The amplitude of the P1 wave (latency of 10 ms) of the auditory evoked potentials recovered more rapidly than on the previous 5 min preparation and returned towards the control amplitude more completely (p <0.05) in the lidocaine group. More importantly, the amplitude of the P2 wave (latency of 25 ms) recovered only 11% in the control group and 55% (p <0.05) in the lidocaine-infused animals. Comparable effects were observed in the early recovery of electroencephalographic activity during reperfusion. The present findings support the hypothesis that lidocaine may facilitate the recovery of the electroencephalogram and the evoked potentials only when an ischemic episode is below a certain combined level of duration and severity. The accelerating effect of lidocaine on postischemic neuroelectrical recovery was observed using a low dose of the drug, and it was not associated with changes in hemodynamic or cerebrovascular parameters or of blood composition. The latter suggests that the reported action may be related to some specific property of the local anesthetic action of lidocaine, such as blockade of axonal Na channels.

Postischemic treatment with hypothermia improves outcome from incomplete cerebral ischemia in rats.

It is known that hypothermia can improve outcome when induced during ischemia. We evaluated whether hypothermia can decrease ischemic injury if it is induced after incomplete ischemia. Rats were anesthetized with 1.4% inspired isoflurane, and ischemia was produced by right carotid ligation combined with hemorrhagic hypotension to 30 mm Hg for 30 min. Hypothermia (31 degrees C) was induced or normothermia (37 degrees C) was maintained for 1 h after completion of the ischemic challenge. Isoflurane anesthesia was maintained during this period. Five of 15 normothermic rats and 3 of 15 hypothermic rats died of stroke after ischemia. For all rats tested, hypothermic-treated animals had a significantly better neurologic outcome than normothermic rats (p less than 0.05). Histopathology showed a correlation of r = 0.67 (p less than 0.05) with neurologic outcome, and neuronal damage was significantly worse in normothermic compared with hypothermic rats (p less than 0.05). These results show that postischemic hypothermia will decrease neuronal injury and improve neurologic outcome associated with incomplete ischemia.

Dependence of cerebral energy phosphate and evoked potential recovery on end-ischemic pH

We determined whether the rate of metabolic recovery and electrophysiological deficit after incomplete cerebral ischemia is related to intracellular pH (pHi) achieved at the end of ischemia in a dose-dependent manner. End-ischemic pHi was varied by employing two ischemic durations, 12 and 30 min, and by setting preischemic plasma glucose to approximately 80 or 400 mg/dl. Incomplete global ischemia was produced in anesthetized dogs by transient intracranial hypertension followed by 4 h of reperfusion, and pHi, ATP, and phosphocreatine (PCr) were measured with 31P magnetic resonance spectroscopy. Cerebral blood flow was reduced to approximately 6 ml.min-1.100 g-1 during ischemia. End-ischemic pHi was greater than 5.7 in all animals from various treatment groups except for four of seven dogs treated with 30-min hyperglycemic ischemia. When end-ischemic pHi remained greater than 5.7, there was nearly complete recovery of ATP, PCr, pHi, intracellular bicarbonate concentration [( HCO3-]i), and O2 consumption. Partial recovery of somatosensory-evoked potentials (SEP) occurred in most of these animals. In the 30-min hyperglycemic animals in which pHi fell below 5.5, ATP, PCr, and O2 consumption recovered by only one-half over 60 min of reperfusion and then declined to near-zero levels without SEP recovery. In addition, pHi remained less than 6.0, and [HCO3-]i remained less than 2 mM throughout reperfusion. We conclude that there is an apparent in vivo pHi threshold of approximately 5.5-5.7 during incomplete cerebral ischemia that is associated with an inability to significantly restore pHi and [HCO3-]i and with secondary deterioration of high-energy phosphate levels.

Effect of fentanyl on the electrophysiological recovery following incomplete global cerebral ischemia

The effects of two commonly used doses of the opioid fentanyl (50 and 100 μg/kg) on the electrophysiological outcome following global cerebral ischemia were studied in rats. The somatosensory evoked responses (SSER) and EEG activity were utilized to assess neurophysiological outcome. Prior to ischemia, there was no difference in the latency of the cortical peak of the SSER between groups. During the ischemic period, SSER and EEG activity were abolished in both groups. During the reperfusion period, however, the cortical peak of the SSER returned within 30 min in the animals anesthetized with 50 μg/kg of fentanyl, whereas in the animals anesthetized with 100 μg/kg fentanyl the cortical peak did not return by 60 min. This suggests that the animals anesthetized with a high dose of fentanyl are more susceptible to ischemic damage and that a high dose of fentanyl may exacerbate neurological damage following an ischemic insult to the brain.

A comparison of the area of histochemical dysfunction after focal cerebral ischaemia during anaesthesia with isoflurane and halothane in the rat

The investigations that have thus far evaluated the cerebral protective properties of isoflurane have provided conflicting results. Protection would be most likely to occur in the circumstances of incomplete cerebral ischaemia in which there is a penumbral zone of marginal perfusion. The present investigation sought to evaluate further the protective properties of isoflurane in that circumstance. Middle cerebral artery occlusion (MCAO) was performed in Sprague-Dawley rats anaesthetized with 1.2 MAC concentrations of either halothane or isoflurane. At the end of four hours of MCAO, the brains were removed, sectioned and incubated in the histochemical stain 2-3-triphenyltetrazolium (TTC). An image analysis system was used to measure the area of reduced or absent TTC staining in four coronal planes spanning the distribution of the middle cerebral artery. There was no difference between halothane and isoflurane anaesthetized animals with respect to the area of brain with evidence of histochemical dysfunction. It is concluded that isoflurane is not protective (relative to the status of halothane anaesthetized control animals) when administered at 1.2 MAC concentration during four hours of focal (incomplete) cerebral ischaemia in the rat.

Hypothermia Versus Ethanol

We examined neurologic outcome after incomplete cerebral ischemia in rats treated with hypothermia versus ethanol, two techniques that decrease brain metabolism. All animals, including control rats, received a baseline midazolam anesthetic. Ischemia was produced by right carotid artery occlusion combined with hemorrhagic hypotension to a mean arterial pressure of 30 mm Hg for 30 min. Neurologic outcome was evaluated for 3 days after ischemia using a 5-point scale. In separate studies, cerebral blood flow (CBF) was measured using radioactive microspheres, and cortical oxygen consumption (CMRO2) was calculated from the blood flow data and the arteriovenous oxygen difference. Hypothermia to 31 degrees C decreased CBF 50% and CMRO2 52% compared with control rats, and significantly improved outcome. Although ethanol decreased CBF 35% and CMRO2 22%, it did not improve outcome from stroke compared with control rats. These results suggest that hypothermia protects the brain from ischemia and that ethanol does not, despite a decrease in CMRO2.