Dexmedetomidine, a potent alpha 2-agonist, does not affect neuronal damage following severe forebrain ischaemia in the rat.

Central sympathetic activation with increased release of noradrenaline occurs during cerebral ischaemia, but it is not certain how the increased sympathetic activity affects neuronal damage. We have studied the effect of dexmedetomidine, a potent alpha 2-adrenergic receptor agonist that reduces the central release of noradrenaline, on neuronal damage after 10 min of severe forebrain ischaemia in the rat. Ischaemia was achieved by bilateral carotid artery occlusion combined with bleeding to a mean arterial pressure of 50 mmHg. The post-ischaemic neuronal damage was most pronounced in the hippocampal CA1 region (median percentage of necrotic cells 36% (11-69%) and 42% (11-68%) in the dexmedetomidine and vehicle groups, respectively) and in the subiculum. The reticular thalamic nucleus was moderately damaged in all but one rat, while the rest of the thalamus was almost spared. Most rats had mild to moderate damage in cortex and caudoputamen. Dexmedetomidine did not affect the neuronal outcome in this model.

The antioxidant tirilazad does not affect cerebral blood flow or histopathologic changes following severe ischemia in rats.

We studied the effect of tirilazad, an aminosteroid with radical scavenging effect, or its vehicle on cerebral blood flow and neuronal death when given before 15 min of severe global ischemia achieved by hypotensive bilateral carotid clamping in rats. Ischemic blood flows less than 1% of the non-ischemic values were seen in the forebrain regions. Hypoperfusion occurred in all regions 60 min after the insult with flow values 21-58% of those in the non-ischemic group. Tirilazad had no effect on cerebral blood flow in the non-ischemic rats, nor in those decapitated during or after the insult. Five days postischemia neuronal damage had developed in all regions examined, but no significant differences were seen between the tirilazad- and the vehicle-treated rats.

Interpleural or thoracic epidural analgesia for pain after thoracotomy. A double blind study.

The analgetic effect of bupivacaine given epidurally or interpleurally after thoracotomy was investigated in a randomized, double blind, placebo controlled study. 32 patients with both an epidural and an interpleural catheter, were randomized to receive either interpleural or epidural analgesia. The interpleural group was given bupivacaine 5 mg.ml-1 with 5 microgram epinephrine as a 30 ml interpleural bolus, followed by a continuous infusion starting at a rate of 7 ml per hour and epidurally a bolus of 0.9% NaCl followed by a continuous infusion of 0.9% NaCl. The epidural group was given bupivacaine 3.75 mg.ml-1 with 5 microgram epinephrine as a 5 ml epidural bolus, followed by a continuous infusion starting at a rate of 5 ml per hour and interpleurally a bolus of 0.9% NaCl followed by a continuous infusion of 0.9% NaCl. The draining tubes were clamped during the injection of the interpleural bolus and 15 min afterwards. Adequacy of pain relief was evaluated with the Prins-Henry pain scale. Morphine requirement was registered, there was no difference between the groups in pain scores or need for additional morphine.

The severity of postischemic hypoperfusion increases with duration of cerebral ischemia in rats.

Regional cerebral blood flow was studied after a period of hypotensive bilateral carotid occlusion in rats. As other studies have found, we confirm that 15 min of ischemia caused an initial brief hyperemic episode followed by severe hypoperfusion in all areas. With varying duration of ischemia from 5 to 10, 15 and 20 min, the median cerebral blood flow 60 min postischemia was 79%, 46%, 48% and 34% of control, respectively. Thus the degree of postischemic hypoperfusion increased significantly with the duration of ischemia.

Neuronal uptake of plasma proteins after transient cerebral ischemia/hypoxia. Immunohistochemical studies on experimental animals and human brains.

Rapid uptake of plasma proteins into damaged neurons has been demonstrated previously after lesions which cause early breakdown of the blood-brain barrier (BBB). The present study was undertaken to see whether a similar uptake occurred after hypoxic/ischemic episodes in men and experimental animals. Forebrain ischemia was produced in rats by a combination of carotid clamping and hypotension for 15 min, followed by recirculation for 6 h, 24 h, 48 h and 5 d. Paraffin sections from the brains were incubated with antiserum against albumin, and parallel sections were stained with hematoxylin and eosin (H & E). Breakdown of the BBB with extravasation of albumin was seen after 6 h in the lateral reticular nucleus of the thalamus, the dorsolateral striatum, and in restricted areas of the cerebral cortex. Uptake of albumin into damaged neurons was seen in the same structures, and partly before reliable changes were observed in routinely stained sections. With longer survival periods, the staining of the neuropil became stronger and more neurons in the damaged areas were positively labeled. After 48 h and 5 d many neurons in the hippocampal sector CA1 had also taken up plasma proteins. A similar uptake of plasma proteins into damaged neurons was seen in brains from patients with histological evidence of hypoxic injury. Even the small leakage of proteins that occurs after hypoxic/ischemic lesions is thus sufficient to give a definite immunostaining of damaged neurons.

Azepexole, a potent alpha 2-agonist with anaesthetic effects, does not affect cerebral energy consumption in dogs given isoflurane.

The effects of the alpha 2-agonist azepexole on the cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) were studied by a sagittal sinus outflow technique in dogs. Azepexole, 1 mg kg-1 (reported to decrease the anaesthetic requirement for isoflurane by almost 90%), caused no change in CMRO2 when given during 1.4% isoflurane anaesthesia. CBF was reduced by 26%. When the concentration of isoflurane was reduced to 0.2%, CMRO2 increased by 26% as would have been expected for the change in isoflurane concentration alone. Concomitantly CBF increased to a level not significantly different from control. Azepexole might be a useful adjunct to inhalational anaesthetics, and combined with a low dose of isoflurane it should be an excellent background anaesthetic when studying the effect of other drugs on CMRO2 in dogs as the combination seems to have little effect on the CMRO2.

Hypocapnia and cerebral ischaemia in hypotensive newborn piglets.

This study tested the hypothesis that hypocapnia superimposed upon hypotension produces a further reduction in cerebral blood flow velocity (CBFV). In 12 newborn piglets, CBFV was measured continuously by Doppler ultrasound through an artificial fontanelle. Hypotension was induced by removing 30 ml/kg of blood. Increasing the ventilator rate reduced the average arterial carbon dioxide tension from 5.5 to 2.0 kPa. When mean arterial pressure (MAP) was held steady at 45 mm Hg or above, hypocapnia produced a substantial drop in CBFV but, in all the piglets with MAP below 38 mm Hg, hypocapnia failed to change CBFV by 10%. Hypocapnia produced an increase in lactate in sagittal sinus blood but cerebral venous hypoxanthine concentrations were not affected by hypocapnia. Hyperventilation (without haemorrhage) produced a significant drop in MAP, preventable by infusing colloid. Hypocapnia itself does not further reduce CBFV in the hypotensive piglet. However, the pressure effect of hyperventilation may significantly impair the cerebral circulation.

Effect of cerebral ischemia on hypotension-induced increase in plasma vasopressin and hepatic glycogen concentration in the rat.

The effect of cerebral ischemia on the vasopressin response to hemorrhagic hypotension and on the hepatic and muscular glycogen mobilization was studied in rats. The addition of cerebral ischemia to the hemorrhage required withdrawal of significantly more blood to lower mean arterial pressure (MAP) to 50 mmHg but not if combined with ganglionic blockade. The increase in plasma vasopressin concentration during hypotension was not significantly different in rats with and without concurrent cerebral ischemia. Ganglionic blockade blunted the vasopressin response. Thus cerebral ischemia in fact attenuated the vasopressin response to hemorrhage. One hour after the insult, the hormone concentration in rats exposed to combined cerebral ischemia and hemorrhagic hypotension without ganglionic blockade was still above control levels and higher than in all other groups. Concomitantly the hepatic but not the muscular glycogen concentration in these rats was significantly lower than in the other groups.

Effect of dexmedetomidine, a selective and potent alpha 2-agonist, on cerebral blood flow and oxygen consumption during halothane anesthesia in dogs.

The effect of the alpha 2-agonist dexmedetomidine on the cerebral blood flow (CBF) and the metabolic rate for oxygen was studied by a sagittal sinus outflow technique in dogs during halothane anesthesia. Dexmedetomidine was given in a dose (10 micrograms/kg) reported to reduce the anesthetic requirement of halothane by 90%. During 0.9% halothane anesthesia dexmedetomidine caused a significant reduction in CBF without influencing the metabolic rate for oxygen. Reducing the halothane concentration to 0.1% caused no further change in CBF, but increased the metabolic rate for oxygen 19%. The cerebral vasoconstrictive effect, combined with the 90% reduction in MAC for halothane, indicates that dexmedetomidine might be a useful adjunct to inhalation anesthetics during neurosurgery in situations where an increase in CBF should be avoided.

The effects of dizocilpine maleate (MK-801), an antagonist of the N-methyl-D-aspartate receptor, on neurologic recovery and histopathology following complete cerebral ischemia in primates.

The present study was designed to determine if the noncompetitive excitatory amino acid antagonist, dizocilpine maleate, when administered after a 17 min period of complete cerebral ischemia in primates, would improve postischemic neurologic function and hippocampal histopathologic outcome when compared to placebo-treated animals. Ten pigtail monkeys were anesthetized and subjected to complete cerebral ischemia using an established neck tourniquet model. Five minutes postischemia, five monkeys received dizocilpine 300 micrograms/kg i.v. over 5 min, followed by an infusion of 150 micrograms/kg/h for 10 h. This produced plasma levels of the drug in excess of 30 ng/ml for the duration of the infusion. An additional five monkeys were treated with an identical volume of saline placebo. All monkeys received intensive care for the initial 24 to 48 h postischemia. At 96 h postischemia, there was no significant difference in neurologic function between the two groups (p = 0.53, with the placebo group having the numerically better outcome). There also was no significant difference between hippocampal histopathology scores between dizocilpine and placebo-treated monkeys. The authors conclude that dizocilpine is not an efficacious therapy in the treatment of neurologic injury that occurs following complete cerebral ischemia in this primate model.

The effect of the excitatory amino acid receptor antagonist dizocilipine maleate (MK-801) on hemispheric cerebral blood flow and metabolism in dogs: modification by prior complete cerebral ischemia.

The effect of the N-methyl-D-aspartate (NMDA) receptor antagonist dizociplipine maleate (MK-801) on cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO2), intracranial pressure and systemic variables was examined in 6 normal dogs (Group I). In 6 additional dogs (Group II), the effects of a prior 11 min episode of complete cerebral ischemia on the response to dizocilipine was studied. CBF was measured with a sagittal sinus outflow technique and CMRO2 was calculated as the product of CBF and the arterial to sagittal sinus O2 content difference. Dizocilipine was administered as a 150 micrograms/kg i.v. bolus followed by a 75 micrograms.kg-1.h-1 infusion for 90 min. Plasma dizocilipine levels were greater than 25 ng/ml for the duration of the infusion. The CSF levels were approximately half the plasma levels. Five minutes after initiation of dizocilipine treatment, Group I dogs experienced a 63% increase in heart rate (P less than 0.01) and an 8% decrease in the mean arterial blood pressure (P less than 0.05). Over the same time interval. CBF increased by 85% (P less than 0.01) and intracranial pressure nearly doubled (P less than 0.05). In addition, dizocilipine treatment in all Group I animals resulted in EEG quasiperiodic bursts of delta-waves and polyspikes on a background of beta-activity. With the exception of the intracranial pressure, the above changes in systemic and cerebral variables persisted for the duration of the drug infusion. Intracranial pressure was no longer significantly elevated after 80 min of drug infusion. Hemispheric CMRO2 was unchanged by dizocilipine in Group I dogs. There was a decrease in the cortical glucose level at the end of the study, but no significant change in phosphocreatine, ATP, lactate, or energy charge when compared with 6 laboratory normals. An identical dose of dizocilipine administered after an 11 min episode of complete cerebral ischemia resulted in no significant changes in either cerebral or systemic variables. The absence of systemic effects in Group II dogs suggests that dizocilipine administration in normal dogs results in a centrally mediated activation of the peripheral sympathetic nervous system. The uncoupling of CBF and CMRO2 observed following dizocilipine treatment is similar to that reported for two other known NMDA antagonists, ketamine and phencyclidine. If administration of dizocilipine results in improved histopathological and neurological outcome following an episode of complete cerebral ischemia, this improvement is unrelated to changes in postischemic CBF or hemispheric CMRO2.