Jerry E. Fleischer

Dexmedetomidine, an α2-adrenergic agonist, decreases cerebral blood flow in the isoflurane-anesthetized dog

The purpose of this study was to examine the effects of dexmedetomidine, an α2-adrenergic agonist, on cerebral blood flow and metabolic rate in dogs anesthetized with 0.64% isoflurane. After intubation and institution of mechanical ventilation, arterial, venous, pulmonary artery, and sagittal sinus catheters were inserted. Measurements of cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRo2), mean arterial pressure, cardiac output, and blood gas tensions were made at various levels of isoflurane anesthesia (0.64%, 1.9%, and 2.8%), after the administration of 10 μg/kg of dexmedetomidine (a dose that has been shown to reduce anesthetic requirements in dogs by >90%) and finally after 0.3 mg/kg of the α2-adrenergic antagonist idazoxan. Despite an increase in arterial pressure, dexmedetomidine caused a marked reduction (>45%, P < 0.05) in CBF when compared with all preceding concentrations of isoflurane. The administration of dexmedetomidine had no effect on the CMRo2. The electroencephalogram showed a loss of high-frequency activity in a pattern similar to that seen with 1.90% isoflurane. Administration of dexmedetomidine was associated with a 57% decrease in cardiac output (to 0.89 L/min). Administration of idazoxan (an α2-adrenergic antagonist) resulted in an increase in cardiac output and a reversal of the electroencephalogram effects. This experiment indicates that 10 μg/kg of dexmedetomidine in isoflurane-anesthetized dogs is associated with a profound decrease in CBF and cardiac output in the face of an unaltered CMRo2. Despite the large reduction in the CBF/CMRo2 ratio, there was no evidence of global cerebral ischemia.

MK-801, an Excitatory Amino Acid Antagonist, Does Not Improve Neurologic Outcome Following Cardiac Arrest in Cats

The excitatory amino antagonist MK-801 was administered to cats following resuscitation from cardiac arrest to evaluate its effect on neurologic and neuropathology outcome in a clinically relevant model of complete cerebral ischemia. In 29 cats studied, cardiac arrest (ventricular fibrillation) was maintained for 18 min and resuscitation was successfully performed in 21 cats. Four animals underwent a sham arrest. MK-801 or placebo was administered in a blinded, randomized manner. Beginning at 5 min post resuscitation (PR), MK-801 330 μg/kg over 2 min followed by 73 μg/kg/h for 10 h or the same volume of placebo was administered. Resuscitated animals remained paralyzed and sedated in an intensive care setting for 24–30 h PR. Neurologic examinations were performed at 2, 4, and 7 days PR by observers blinded to the treatment groups. Seventeen cats were entered into data analysis (nine MK-801-treated and eight placebo-treated). MK-801-treated animals had a significantly greater neurologic deficit score (NDS) rank (0 = normal, 100 = brain death) 2 days PR (mean rank 12.1 vs. 5.6; p = 0.008). This difference is most likely due to ongoing sedative actions of MK-801. There were no significant differences in NDS rank at 4 (10.3, MK-801 vs. 7.5, placebo) and 7 (9.6, MK-801 vs. 8.3, placebo) days PR. There were no significant differences in frontal cortex, hippocampus, occipital cortex, or cerebellar neuropathology between groups. Sham-arrested cats had normal neurologic and neuropathologic evaluations. In the circumstance of complete cerebral ischemia as employed in the current study, MK-801 had no beneficial effect upon neurologic or neuropathologic outcome.

The noncompetitive N-methyl-d-aspartate receptor antagonist, MK-801 profoundly reduces volatile anesthetic requirements in rabbits

Rabbits anesthetized with volatile anesthetics were given bolus doses of the n-methyl-D-aspartate (NMDA) receptor antagonist MK-801. Following observation and recording of the hemodynamic and electroencephalographic effects of MK-801, the animals were tested for requirements of volatile anesthetic to prevent movement to a noxious stimulus. It was demonstrated that MK-801 significantly reduced anesthetic requirements in a dose-dependent manner, while also affecting hemodynamics and the electroencephalogram in a manner consistent with the production of a deeper plane of anesthesia.

Nimodipine does not improve neurologic outcome after 14 minutes of cardiac arrest in cats.

We tested the effects of nimodipine upon neurologic outcome in 31 cats subjected to 14 minutes of cardiac arrest followed by resuscitation. With the dose schedule used, nimodipine had no effect upon neurologic outcome or upon the percentage of ischemic neurons in frontal, hippocampal, occipital, or cerebellar brain sections. The electroencephalographic recovery pattern did not correlate with neurologic or pathologic findings.

Effects of ischemia duration on neurological outcome, CA1 histopathology, and nonmatching to sample learning in monkeys.

Background and Purpose: Male cynomolgus monkeys (n=10) were subjected to varying durations of global cerebral ischemia to determine the relation between dose (ischemic duration) and response (outcome). Methods: Each monkey was anesthetized with halothane, and global cerebral ischemia was produced by a neck tourniquet and trimethaphan‐induced hypotension. The animal was subjected to 3 (n=3), 9 (n=3), or 12 (n=4) minutes of ischemia. Neurological examinations were performed daily for 30 days or until the monkey was neurologically normal. Approximately 1 month after ischemia, the animal was evaluated for evidence of neurobehavioral abnormalities with the nonmatching to sample test. When testing was complete, the monkey was killed with an overdose of pentobarbital and the brain perfused with formalin and removed for histopathologic analysis, with particular attention devoted to the hippocampal CA1 region. Results: Monkeys subjected to 3 or 9 minutes of ischemia were neurologically normal (except for a very mild injury in one 9‐minute animal) immediately after ischemia and had normal CA1 histology. Monkeys subjected to 12 minutes of ischemia were grossly abnormal neurologically after ischemia, but two of the four animals made a complete recovery (neurological deficit score of 0) by 30 days. Monkeys subjected to 12 minutes of ischemia had mild damage in the CA1 region, with all other brain regions appearing normal. None of the animals had demonstrable decrements in neurobehavioral function as measured by the nonmatching to sample test. Conclusions: We conclude that neurobehavioral testing after global cerebral ischemia in primates is feasible, but the ischemic time necessary to produce CA1 damage that could potentially be quantified antemortem with the nonmatching to sample test is greater than 12 minutes in cynomolgus monkeys and may produce temporary severe gross neurological abnormalities as well. (Stroke 1992;23:1471‐1478)

Effects of levemopamil on neurologic and histologic outcome after cardiac arrest in cats.

Background and MethodsA study was performed to examine the effects of the calcium-channel blocker levemopamil on neurologic outcome and neuropathology in a clinically relevant model of complete global cerebral ischemia (ventricular fibrillation in cats). Levemopamil was administered to cats starting 5 mins after resuscitation from 14 mins of cardiac arrest. In a “blinded” manner, 46 animals received levemopamil 1 mg/kg over 15 mins followed by 10 μg/kg-min for 16 hrs or vehicle. In a nonblinded manner, eight additional animals were pretreated with levemopamil beginning 45 mins before cardiac arrest. After resuscitation, levemopamil was infused at 10 μg/kg·min for 16 hrs. Animals in all three groups remained sedated, paralyzed, and mechanically ventilated for 24 to 30 hrs after resuscitation. Neurologic examinations were performed at 2, 4, and 7 days after resuscitation. Thirty-five cats were entered into data analysis (16 levemopamil posttreated, 14 vehicle-treated, and 5 levemopamil pretreated). ResultsNeurologic deficit scores and over-all neuropathologic scores did not differ among groups at any interval after resuscitation. However, the occipital cortex and CAl region of the pretreated animals showed less severe damage than was observed in the animals that received levemopamil or vehicle, starting after resuscitation (p < .01). ConclusionsPostarrest administration of levemopamil was not associated with improved neurologic or neuropathologic outcome. However, the data suggest that prearrest administration may result in regionally selective improvement in neuropathology. (Crit Care Med 1992; 20:126)

Failure of nimodipine to improve neurologic outcome after eighteen minutes of cardiac arrest in the cat

The calcium entry blocker nimodipine was administered to cats following resuscitation from 18 min of cardiac arrest to evaluate its effect on neurologic and neuropathologic outcome in a clinically relevant model of complete cerebral ischemia. Cardiac arrest (ventricular fibrillation) was maintained for 18 min and resuscitation was performed by a standardized protocol in 40 cats. Beginning at 5 min post-resuscitation, nimodipine, 10 micrograms/kg over 2 min followed by 1 microgram/kg per min for 10 h, or the same volume of placebo was administered in a randomized, blinded fashion. Neurologic deficits were scored at 2, 4, and 7 days post-resuscitation by observers blinded to the treatment group. Thirty cats were evaluated neurologically at 7 days post-resuscitation and were entered into data analysis (n = 15 per group). Neither neurologic deficit scores nor neuropathologic scores were significantly different between groups. The authors conclude that nimodipine administration in the manner and doses stated does not improve neurologic outcome in cats following resuscitation from cardiac arrest.