A. McAllister

Sevoflurane and halothane reduce focal ischemic brain damage in the rat : possible influence on thermoregulation

BackgroundThere has been little systematic examination concerning the comparative effects of the anesthetized versus the awake state on outcome from cerebral ischemia. This experiment evaluated infart volume and neurologic function in rats subjected to temporary focal ishemia while anesthetized with either sevoflurane or halothane. Outcome in these animals was compared to that observed in rats maintained unanesthetized during a similar ischemic insult. MethodsAll rats were anesthetized with halothane and surgically prepared for filament occlusion of the middle cerebral artery. After preparation, one group (Halothane) remained anesthetized with approximately 1.4 MAC halothane. In another group (Sevoflurane), halothane was discontinued and substituted with sevoflurane, which was administered until electroencephalographic burst suppression was evident (approximately 1.4 MAC). The final group (A wake) was allowed to awaken immediately after the onset of ischemia. Middle cerebral artery occlusion persisted for 90 min all groups. The middle cerebral artery filament then was removed, and a 96-h survival interval was allowed. Neurologic function and infarct volume were determined. Recent evidence indicates that transient mild hyperthermia occurs in awake rats undergoing filament occlusion of the middle cerebral artery. To examine the potential role of mild hyperthermia in this experiment, a second experiment was performed in which rats anesthetized with halothane underwent 90-min focal ischemia, with pericranial temperatures held at either 38.0° C or 39.2° C. ResultsIntraischemic mean arterial pressure was 20–25 mmHg lower in the two anesthetized groups compared with awake animals. Despite this finding, cortical infarct volumes (mean ± SD; Halothane, 17 ± 32 mm3; Sevoflurane, 36 ± 57 mm3; Awake, 115 ± 104 mm3) and subcortical infarct volumes (mean ±:SD; Halothane, 39 ± 57 mm3; Sevoflurane, 50 ± 29 mm3; Awake, 88 ± 46 mm3) were reduced in both groups of anesthetized rats. This reduction correlated with improved neurologic function. The rats in whom the pericranial temperature was maintained at 39.2° C had a larger total infarct volume (218 ± 81 mm3) and increased neurologic deficits when compared to those in whom the pericranial temperature was maintained at 38.0° C (total infarct volume, 75 ± 77 mm3). ConclusionsBoth halothane and sevoflurane substantially reduced damage in this focal ischemia model when compared to outcome resulting from the same insult induced in awake rats. The reduction in intraischemic mean arterial pressure caused by the anesthetics did not seem contributory to out-come. Brain temperature differences among the groups were not defined. Because small differences in pericranial temperature were shown to have major effects on outcome, further work is required to determine if differences in brain temperature explain the observed protective effects of these anesthetics.

Comparison of Remifentanil and Fentanyl in Patients Undergoing Craniotomy for Supratentorial Space-occupying Lesions

BackgroundRemifentanil hydrochloride is an ultra-short-acting, esterase-metabolized micro-opioid receptor agonist. This study compared the use of remifentanil or fentanyl during elective supratentorial craniotomy for space-occupying lesions.MethodsSixty-three adults gave written informed consent for

In vivo models of cerebral ischemia : effects of parenterally administered NMDA receptor glycine site antagonists

Both in vitro and in vivo experiments have implicated extracellular glycine in the pathogenesis of ischemic brain damage. Recently, halogenated derivatives of quinoxaline-2,3-dione have been synthesized that possess bioavailability when parenterally administered and minimal psychotomimetic properties. Such compounds have allowed investigation into the efficacy of glycine receptor antagonism as a strategy for protection against cerebral ischemic insults. Rats underwent either 90 min of middle cerebral artery filament occlusion or 10 min of forebrain ischemia with recovery while receiving intraperitoneal injections of either a glycine receptor antagonist (ACEA-1021, ACEA-1031, or ACEA-1011) or vehicle (dimethyl sulfoxide). Both ACEA-1021 and ACEA-1031 reduced cerebral infarct volumes and were associated with a reduced incidence of hemiparesis resulting from MCA occlusion. ACEA-1011, administered in a smaller dose had no effect. In the forebrain ischemia model, glycine receptor antagonism had no effect on delayed neuronal necrosis in the hippocampal CA1 sector, neocortex, or caudoputamen. We conclude that pharmacologic antagonism of glycine at the strychnine-insensitive glycine receptor presents a neuroprotective profile similar to that previously observed for antagonists of glutamate at the N-methyl-d-aspartate complex with a potential for fewer side effects.

Insulin-induced normoglycemia improves ischemic outcome in hyperglycemic rats.

Background and Purpose: Hyperglycemia is known to aggravate ischemic brain damage. This study sought to determine if preischemic insulin-induced normoglycemia would improve outcome in hyperglycemic rats. Methods: Normal rats and rats with 5-7 days of streptozotocin-induced diabetes were studied. Normal rats served as either fasted normoglycemic controls or dextrose-infused (hyperglycemic) controls. In the acutely diabetic rats either no insulin was given or insulin was given at 30 or 90 minutes before ischemia so as to induce preischemic normoglycemia. All rats underwent 10 minutes of forebrain ischemia. After 5 days of recovery, motor function and histological outcome were assessed. Results: Untreated diabetic rats and dextrose-infused control rats had greater hippocampal CA1 damage than normoglycemic control rats. In contrast, insulin-treated diabetic rats had less hippocampal CA1 damage than either untreated diabetic rats or dextrose-infused control rats. Injury in the two insulin-treated groups was not significantly different from that in the normoglycemic control group (all three groups had plasma glucose values of 120-150 mg/dl immediately prior to ischemia). Despite similar plasma glucose values (300-400 mg/dl), fewer postischemic seizures (0% versus 67%) were observed in the untreated diabetic group than in the dextrose-infused control group (p<0.001). Conclusions: Hyperglycemia caused by either dextrose infusion or streptozotocin-induced diabetes resulted in exacerbated ischemic brain damage. Insulin therapy to rapidly induce preischemic normoglycemia improved outcome from forebrain ischemia in the acutely diabetic rats. Glucose-infused hyperglycemic rats frequently exhibited postischemic generalized seizures while acutely diabetic rats did not. The latter results implicate some adaptive/protective mechanism associated with acute streptozotocin-induced diabetes that results in a decreased sensitivity to hyperglycemia-augmented ischemic brain damage.

Temporal Thresholds for Hyperglycemia-Augmented Ischemic Brain Damage in Rats

BACKGROUND AND PURPOSE Although acute hyperglycemia is known to increase global ischemic brain damage, the duration of ischemia necessary to elicit such an effect is unknown. Accordingly, an experiment was performed to determine the duration of forebrain ischemia at which hyperglycemia becomes a factor in histological and behavioral outcome in rats. METHODS Fasted rats were anesthetized and prepared for forebrain ischemia. Before ischemia, rats received either intravenous saline (plasma glucose, 112 +/- 18 mg/dL) or glucose (plasma glucose, 343 +/- 50 mg/dL). After 4, 8, 12, or 15 minutes of ischemia (n = 12), recovery was allowed. Rats surviving 7 days underwent evaluation of motor function and then histological analysis of damage in the caudate putamen, hippocampal CA1, and substantia nigra pars reticulata. RESULTS After 4 minutes of ischemia, damage was present in all structures. Only in the caudate putamen was hyperglycemia associated with worsened damage, but this did not result in seizures or death. After 8 minutes of ischemia, seizures occurred in 33% of hyperglycemic rats, and a hyperglycemic effect on damage in the CA1 and substantia nigra pars reticulata was observed. No seizures or mortality occurred in normoglycemic rats regardless of duration of ischemia. Longer durations of ischemia resulted in an increased incidence of seizures and mortality in hyperglycemic rats only. Among surviving rats, motor function was worsened in hyperglycemic rats after 12 minutes of ischemia. CONCLUSIONS Hyperglycemia-augmented brain damage is evident after global ischemic insults as brief as 4 minutes and becomes critical to survival after 8 minutes of ischemia.

Nitrous oxide does not alter infarct volume in rats undergoing reversible middle cerebral artery occlusion

This experiment was designed to determine if nitrous oxide alters neurologic and pathologic outcome from temporary focal cerebral ischemia in spontaneously hypertensive rats deeply anesthetized with a barbiturate. Two groups of rats were given intravenous methohexital such that a stable EEG pattern of burst suppression was achieved. In one group of rats (n = 11), the lungs were mechanically ventilated with 70% N2O/30% O2, and in the other group (n = 10), ventilation was done with 70% nitrogen/30% O2. The middle cerebral artery was then occluded for 2 h, during which time mean arterial pressure, blood gases, hematocrit, plasma glucose, and head temperature were held constant between groups. The total doses of methohexital administered were similar in both groups as were the plasma methohexital concentrations immediately prior to onset of ischemia. After reperfusion of the middle cerebral artery, the animals were allowed to awaken. Neurologic evaluations were performed prior to ischemia and at 24 and 96 h postischemia. Cerebral infarct volume was measured at 96 h postischemia using triphenyl tetrazolium chloride staining and computer imaging techniques. There were no neurologic differences between the N2O and nitrogen groups at any experimental interval although both groups exhibited deficits at both 24 and 96 h postischemia relative to preischemic values. The two groups also had nearly identical cerebral infarct volumes (N2O = 231 +/- 97 mm3; nitrogen = 226 +/- 75 mm3; mean +/- SD).(ABSTRACT TRUNCATED AT 250 WORDS)

Secondary hypotensive insults in a rat forebrain ischemia model

Previous studies have shown that the recently injured brain has an increased sensitivity to subsequent brief episodes of severe ischemia. This investigation was designed to assess whether less severe secondary insults, which alone would be incapable of producing injury, exacerbate brain damage resulting from a primary episode of global ischemia. Rats were subjected to either 10 min of 2-vessel forebrain ischemia (primary insult alone), 20 min of hypotension (mean arterial pressure, MAP = either 40 or 25 mmHg) without vessel occlusion (secondary insult alone), or 10 min ischemia followed 1 h later by the hypotensive challenge (primary + secondary insult). Seven days later, the animals were neurologically evaluated and the brains then prepared for histologic analysis. Neither magnitude of secondary insult alone was found to produce injury. In contrast, the primary insult alone caused moderate damage in the hippocampus, caudoputamen and neocortex. With the exception of increased neuronal necrosis in the hippocampal CA1 sector in rats receiving the primary + secondary insult (MAP = 25 mmHg), no worsening of outcome could be attributed to the secondary insults. These results indicate that the recovering brain may not be as sensitive to hypoperfusion as has previously been suggested.

Comparison of Remifentanil and Fentanyl in Patients Undergoing Craniotomy for Supratentorial Space-Occupying Lesions

Background Remifentanil hydrochloride is an ultra‐short‐acting, esterase‐metabolized micro‐opioid receptor agonist. This study compared the use of remifentanil or fentanyl during elective supratentorial craniotomy for space‐occupying lesions. Methods Sixty‐three adults gave written informed consent for this prospective, randomized, double‐blind, multiple‐center trial. Anesthesia was induced with thiopental, pancuronium, nitrous oxide/oxygen, and fentanyl (n = 32; 2 micro gram [center dot] kg [center dot] sup ‐1 min sup ‐1) or remifentanil (n = 31; 1 micro [center dot] kg sup ‐1 [center dot] min sup ‐1). After tracheal intubation, infusion rates were reduced to 0.03 micro gram [center dot] kg sup ‐1 [center dot] min sup ‐1 (fentanyl) or 0.2 micro gram [center dot] kg sup ‐1 [center dot] min sup ‐1 (remifentanil) and then adjusted to maintain anesthesia and stable hemodynamics. Isoflurane was given only after specified infusion rate increases had occurred. At the time of the first burr hole, intracranial pressure was measured in a subset of patients. At bone flap replacement either saline (fentanyl group) or remifentanil ([nearly equal] 0.2 micro gram [center dot] kg sup ‐1 [center dot] min sup ‐1) were infused until dressing completion. Hemodynamics and time to recovery were monitored for 60 min. Analgesic requirements and nausea and vomiting were observed for 24 h. Neurological examinations were performed before operation and on postoperative days 1 and 7. Results Induction hemodynamics were similar. Systolic blood pressure was greater in the patients receiving fentanyl after tracheal intubation (fentanyl = 127 +/‐ 18 mmHg; remifentanil = 113 +/‐ 18 mmHg; P = 0.004). Intracranial pressure (fentanyl = 14 +/‐ 13 mmHg; remifentanil = 13 +/‐ 10 mmHg) and cerebral perfusion pressure (fentanyl = 76 +/‐ 19 mmHg; remifentanil = 78 +/‐ 14 mmHg) were similar. Isoflurane use was greater in the patients who received fentanyl. Median time to tracheal extubation was similar (fentanyl = 4 min: range = ‐1 to 40 min; remifentanil = 5 min: range = 1 to 15 min). Seven patients receiving fentanyl and none receiving remifentanil required naloxone. Postoperative systolic blood pressure was greater (fentanyl = 134 +/‐ 16 mmHg; remifentanil = 147 +/‐ 15 mmHg; P = 0.001) and analgesics were required earlier in patients receiving remifentanil. Incidences of nausea and vomiting were similar. Conclusion Remifentanil appears to be a reasonable alternative to fentanyl during elective supratentorial craniotomy.