Effects of isoflurane versus fentanyl-nitrous oxide anesthesia on long-term outcome from severe forebrain ischemia in the rat

BACKGROUND: This study examined long-term outcome from severe forebrain ischemia in the rat, as a function of anesthetic given during the ischemic injury. METHODS: Rats were subjected to 10 min of near-complete forebrain ischemia while anesthetized with either 1.4% isoflurane or 70% nitrous oxide-fentanyl. Neurologic and histologic outcomes were measured at 5 days, 3 weeks, or 3 months after ischemia. RESULTS: At 5 days, isoflurane-anesthetized rats had less damage than did fentanyl-nitrous oxide-anesthetized rats (mean +/- SD, percent alive hippocampal CA1 neurons = 58+/-29 vs. 20+/-16, respectively; P = 0.011). This was accompanied by improved motor function in the isoflurane group (P = 0.002). At 3 weeks, there was no difference between groups for either outcome variable (percent alive CA1 neurons = 35+/-26 and 36+/-28 for isoflurane and fentanyl-nitrous oxide, respectively). Similarly, at 3 months, there was no difference between groups (percent alive CA1 neurons = 56+/-27 and 60+/-27 for isoflurane and fentanyl-nitrous oxide, respectively). Morris water maze performance at 3 months was similar between anesthetic groups and was also similar to sham performance. The percent alive CA1 neurons in the fentanyl-nitrous oxide group increased with duration of recovery (P = 0.004). There were no differences among isoflurane groups over time (5 days vs. 3 weeks, P = 0.26; 5 days vs. 3 months, P = 0.99; 3 week vs. 3 months, P = 0.32). CONCLUSIONS: This study found no change in the percent alive CA1 hippocampal neurons as a function of duration of recovery from severe forebrain ischemia in isoflurane anesthetized rats. In contrast, the percent alive CA1 neurons in fentanyl-nitrous oxide-anesthetized rats tripled over 3 months of recovery. The natural history of long-term responses to forebrain ischemia requires further study before conclusions can be drawn with respect to the permanence of isoflurane neuroprotection.     

Sympathetic ganglionic blockade masks beneficial effect of isoflurane on histologic outcome from near-complete forebrain ischemia in the rat

BACKGROUND: Isoflurane-anesthetized rats have better outcome from global cerebral ischemia than rats anesthetized with fentanyl and nitrous oxide. The authors wanted to determine whether circulating catecholamine concentrations depend on the anesthetic agent and whether sympathetic ganglionic blockade affects anesthetic-mediated differences in outcome from near-complete forebrain ischemia. METHODS: For two different experiments, normothermic Sprague-Dawley rats that had fasted were assigned to one of four groups and subjected to 10 min of 30 mm Hg mean arterial pressure and bilateral carotid occlusion. Rats were anesthetized with 1.4% isoflurane or fentanyl (25 microg x kg(-1) x h(-1)) and 70% nitrous oxide, with or without preischemic trimethaphan (2.5 mg given intravenously). In experiment 1, arterial plasma catecholamine concentrations were measured before, at 2 and 8 min during, and after ischemia (n = 5-8). In experiment 2, animals (n = 15) underwent histologic analysis 5 days after ischemia. RESULTS: In experiment 1, intraischemic increases in plasma norepinephrine and epinephrine levels were 28 and 12 times greater in the fentanyl-nitrous oxide group than in the isoflurane group (P<0.01). Trimethaphan blocked all changes in plasma catecholamine concentrations (P<0.02). In experiment 2, isoflurane reduced the mean +/- SD percentage of dead hippocampal CA1 neurons compared with fentanyl-nitrous oxide (43+/-22% vs. 87+/-10%; P<0.001). Trimethaphan abolished the beneficial effects of isoflurane (91+/-6%; P<0.001). Similar observations were made in the cortex. CONCLUSIONS: Isoflurane attenuated the peripheral sympathetic response to ischemia and improved histologic outcome compared with fentanyl and nitrous oxide. This outcome benefit was reversed by sympathetic ganglionic blockade. The beneficial effects of isoflurane may result from a neuroprotective influence of an intermediate sympathetic response that is abolished by trimethaphan.     

The effect of isoflurane on neuronal necrosis following near-complete forebrain ischemia in the rat

The effect of deep isoflurane anesthesia on ischemically induced neuronal damage was evaluated in the rat. Sixteen mechanically ventilated animals were maintained normocapnic and normothermic while subjected to a near complete forebrain ischemia insult induced with systemic hypotension (MAP = 50 +/- mmHg) and bilateral carotid artery occlusion. Prior to ischemia, eight of the rats received isoflurane by inhalation until the EEG demonstrated a burst suppression pattern; the other eight were untreated controls. After 10 min of ischemia, the carotid clamps were removed, blood pressure was restored, and, in the treated group, isoflurane administration discontinued. Following the ischemic insult, the animals were observed over a 7-day period, at which time they were killed and the brains prepared for histologic study. Severity of damage was assessed by a direct count of irreversibly damaged neurons, which appear bright red when stained with cresyl violet-acid fuchsin. Areas of particular interest were those that characteristically display vulnerability to ischemic damage, i.e., hippocampus, caudate nuclei, and neocortex. The control group revealed severe damage in the hippocampal CA1 sector (70% cells acidophilic) with more variability in the caudate nuclei and neocortex. The treated group showed a similar extent of damage with approximately 74% cells acidophilic in hippocampus (CA1). Clinical appearance was indistinguishable between groups. The authors conclude that pretreatment with isoflurane shows no beneficial effects on delayed neuronal necrosis following near-complete forebrain ischemia.     

Anesthetic effects on cerebral metabolic rate predict histologic outcome from near-complete forebrain ischemia in the rat

BACKGROUND: Although reduction of cerebral metabolic rate is thought to contribute to anesthetic neuroprotection, histologic evidence to support this concept has not been provided. In this study, histologic outcome was evaluated in rats subjected to different durations of severe forebrain ischemia while anesthetized with volatile anesthetics that have substantially different effects on cerebral metabolic rate. METHODS: Normothermic rats that underwent fasting were anesthetized with 0.75 minimum alveolar concentration (MAC) isoflurane-60% nitrous oxide (N2O) or 0.75 MAC halothane-60% N2O. Ischemia was induced with use of a combination of bilateral carotid occlusion and controlled hypotension. Rats in the isoflurane group were subjected to 6.5 min or 8.0 min ischemia, whereas the halothane group received 6.5 min ischemia. Histologic damage was assessed 4 days later. RESULTS: With 6.5 min ischemia, mean +/- SD, hippocampal CA1 percent of dead (% dead) neurons was reduced with isoflurane-N2O (45 +/- 18) versus halothane-N2O (60 +/- 23, P = 0. 023). Eight minutes of ischemia increased % dead neurons in the isoflurane-N2O group (60 +/- 17, P = 0.017). There was no difference between the isoflurane 8.0-min and halothane 6.5-min groups (P = 0. 935). A similar pattern was observed in hippocampal CA4 and the neocortex. Striatal damage was not affected by anesthetic or ischemic duration. CONCLUSIONS: At 6.5 min ischemia, isoflurane provided improved outcome versus halothane. Previous research has shown that 0.75 MAC isoflurane-N2O increases the time to onset of ischemic depolarization by 1.5 min and reduces cerebral metabolic rate by 42% versus 0.75 MAC halothane-N2O. In the current study, when the duration of ischemia was increased by 1.5 min in the isoflurane-N2O group, histologic outcome became similar to that in halothane-N2O-anesthetized rats. These results provide evidence that cerebral metabolic rate reduction has an advantageous effect on outcome from severe brain ischemia, but also suggest that such benefit is likely to be small.     

Periischemic cerebral blood flow (CBF) does not explain beneficial effects of isoflurane on outcome from near-complete forebrain ischemia in rats

BACKGROUND: Isoflurane improves outcome from near-complete forebrain ischemia in rats compared with fentanyl-nitrous oxide (N2O). Sympathetic ganglionic blockade with trimethaphan abolishes this beneficial effect. To evaluate whether anesthesia-related differences in cerebral blood flow (CBF) may explain these findings, this study compared regional CBF before, during, and after near-complete forebrain ischemia in rats anesthetized with either isoflurane (with and without trimethaphan) or fentanyl-nitrous oxide. METHODS: Fasted, normothermic isoflurane anesthetized Sprague-Dawley rats were prepared for near-complete forebrain ischemia (10 min of bilateral carotid occlusion and mean arterial pressure = 30 mmHg). After surgery, rats were anesthetized with either 1.4% isoflurane (with or without 2.5 mg of trimethaphan intravenously at onset of ischemia) or fentanyl-nitrous oxide (25 microgram. kg-1. h-1. 70% N2O-1). Regional CBF was determined (14C-iodoantipyrine autoradiography) before ischemia, 8 min after onset of ischemia, and 30 min after onset of reperfusion. RESULTS: Regional CBF did not differ significantly among groups at any measurement interval. Ischemia caused a marked flow reduction to 5% or less of baseline (P < 0.001) in selectively vulnerable regions, such as the cortex, caudoputamen and hippocampus, whereas flow in the brain stem and cerebellum was preserved. Reperfusion at 30 min was associated with partial restoration of flow to 35-50% of baseline values in ischemic structures. CONCLUSIONS: The results indicate that improved histologic-behavioral outcome provided by isoflurane anesthesia cannot be explained by differential vasodilative effects of the anesthetic states before, during, or after severe forebrain ischemia. This study also shows severe postischemic delayed hypoperfusion that was not affected by choice of anesthetic or the presence of trimethaphan. Mechanisms other than effects on periischemic CBF must be responsible for beneficial effects of isoflurane in this model.     

The effects of anesthetics on stress responses to forebrain ischemia and reperfusion in the rat

Rats exposed to forebrain ischemia have reduced injury when anesthetized with isoflurane versus fentanyl + N(2)O. The protection caused by isoflurane is reversed by trimethaphan. We hypothesized that these anesthetic-dependent effects on ischemic outcome can be associated with altered stress responses to ischemia. Rats were randomized to four treatments: isoflurane; fentanyl + N(2)O; isoflurane + trimethaphan; or isoflurane + metyrapone. Severe forebrain ischemia was then induced for 10 min. Plasma and brain corticosterone, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 were assayed. Plasma corticosterone concentrations were similar in the isoflurane and isoflurane + trimethaphan groups, but greater than in the fentanyl + N(2)O and isoflurane + metyrapone groups. Brain corticosterone was similar among all groups except isoflurane + metyrapone, in which values were markedly reduced. The addition of metyrapone to isoflurane also reduced plasma TNF-alpha; however, values among other groups were similar. There were no differences among groups for brain TNF-alpha. Plasma IL-6 concentrations were below the limit of detection. Brain IL-6 concentrations were increased by ischemia; however, there was no difference among groups. In conclusion, there were no differences between the isoflurane and isoflurane + trimethaphan groups for any of the measured stress markers. Further, there was little difference between the isoflurane and fentanyl + N(2)O groups, except for plasma corticosterone concentration. Accordingly, isoflurane neuroprotection and its reversal by trimethaphan appear to be independent of effects on the stress responses measured in this study. IMPLICATIONS: Differential anesthetic effects on ischemic outcome are independent of effects on adrenergic/noradrenergic responses to ischemia. The absence of a consistent differential effect of anesthetics on either corticosterone or cytokine responses to ischemia serves to further refute the hypothesis that isoflurane neuroprotection can be attributed to dampening of adverse stress responses to ischemic insults.     

A comparison of the cerebral protective effects of isoflurane and mild hypothermia in a model of incomplete forebrain ischemia in the rat.

The present study was undertaken to examine the cerebral protective properties attributed to isoflurane and at the same time to compare its protective effects with those of mild hypothermia (temperature reduction by 3 degrees C). Twenty-one fasted Wistar-Kyoto rats were assigned to one of three groups (n = 7); 1.3 MAC (end-tidal) isoflurane-normothermia (pericranial temperature 38.0 degrees C), 1.3 MAC halothane-normothermia, and 1.3 MAC halothane-hypothermia (pericranial temperature 35.0 degrees C during ischemia). In each animal the trachea was intubated and the lungs were mechanically ventilated. Each animal was subjected to temporary incomplete forebrain ischemia induced by 10 min of bilateral carotid artery occlusion with simultaneous hypotension (mean arterial pressure 35 mmHg) induced by trimetaphan and blood withdrawal. After a 3-day survival period, perfusion-fixation was performed, and two blinded observers assessed histopathologic injury according to a four-point scale (0 = no damage; 1 = less than 10% of neurons damaged; 2 = 10-50% damaged; and 3 = greater than 50% damaged). The assessment was performed at two points in the rostrocaudal axis chosen to permit evaluation of regions with varying levels of ischemic damage. In the rostral sections, in the isoflurane- and halothane-normothermia groups, moderate to severe injury was observed in striatum, cerebral cortex, hippocampus (CA1 and CA3 areas), and reticular nucleus of the thalamus (e.g., the median scores for the CA1 area were 3 in both the halothane-hypothermia and the isoflurane-normothermia groups), and there were no differences between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

The dose-dependent effects of L-carnitine in myocardial protection in normothermic ischemia

L-Carnitine has been shown to improve the post-ischemic recovery of myocardial function and metabolic measurements that are reduced in the course of ischemia and reperfusion of the heart. In this study we used 40 male guinea-pigs in order to determine if the effect of L-carnitine which is used in the protection of the post-ischemic reperfused heart, is dose-dependent or not. All harvested hearts were perfused for 30 min on modified Langendorf apparatus with oxygenized Krebs-Henseleit solution. After this period, in (n = 10), 5 mmol and 10 mmol (group B, n = 10) of L-carnitine were added into a Krebs-Henseleit solution. After 20 min, perfusion was complete and the hearts were then exposed to normothermic ischemia for 20 minutes. Following the ischemia, hearts were reperfused with the same solutions for 30 min. In group C (n = 10), 10 mmol of L-carnitine was added into the solution at the post-ischemic reperfusion step. In the control group, the same procedures were performed without using L-carnitine. Matching was done according to the contractile force of the heart rate and the levels of malondialdehyde and adenosine deaminase. When 10 mmol L-carnitine was added into the perfusion solutions at the pre-ischemic period, the best results were obtained and myocardial damage was much less than the control group. The protective effects of L-carnitine in normothermic ischemia is dose-dependent and it must be given at the pre-ischemic period.     

Low-dose but not high-dose prostaglandin E1 improves the histological outcome of severe forebrain ischemia in rats

Purpose  

Prostaglandin E₁ (PGE₁) has been shown to provide short-term neuroprotection against various types of brain ischemia in a dose-dependent manner in mice. However, these findings were obtained from experiments performed without any control over physiological parameters. We performed an outcome study where physiological parameters were controlled in an attempt to confirm the dose-dependant neuroprotective effects of PGE₁.     

Severe hypotension is not essential for isoflurane neuroprotection against forebrain ischemia in mice

BACKGROUND: Volatile anesthetics provide protection in experimental models of global cerebral ischemia. To date, all models evaluated have included profound systemic arterial hypotension as a component of the ischemic insult. This study was designed to determine if isoflurane protection persists in a global insult devoid of hypotension. METHODS: C57BL/6J mice having a high incidence of posterior communicating artery atresia were anesthetized with isoflurane (1.2%) or fentanyl/N2O and subjected to bilateral carotid artery occlusion for 15 min or 20 min with normotension (80-110 mmHg mean arterial pressure) or for 10 min with hypotension (35 mmHg mean arterial pressure). Three days later, neurologic function and histologic damage were assessed. Other mice underwent measurement of intraischemic cerebral blood flow (4-iodo-N-methyl-[14C]antipyrine autoradiography) or plasma norepinephrine. RESULTS: Isoflurane reduced the percentage of hippocampal CA1 dead neurons (e.g., 10 min bilateral carotid occlusion + hypotension: 43 +/- 18 (isoflurane) vs. 67 +/- 20 (fentanyl/N2O), P = 0.003; 20 min bilateral carotid occlusion + normotension: 49 +/- 27 (isoflurane) vs. 71 +/- 22 (fentanyl/N2O), P = 0.003). Isoflurane also reduced CA3 damage and improved neurologic function under all conditions. Intraischemic forebrain blood flow was similar during bilateral carotid occlusion plus normotension for the two anesthetic states. Plasma norepinephrine values were greater when hypotension was added to the ischemic insult. CONCLUSIONS: Isoflurane resulted in improved neurologic function and reduced histologic damage regardless of the presence or absence of systemic hypotension during the ischemic insult. This indicates that beneficial effects of isoflurane are most likely attributable to direct effects at the neuronal level as opposed to indirect effects resulting from interactions with profound hypotension.     

The dose-dependent effects of fentanyl on rat skeletal muscle microcirculation in vivo

Determining the effects of analgesia on the microcirculation is difficult because the surgery needed to allow in vivo observation often requires anesthesia. In this study, we used the dorsal microcirculatory chamber (DMC) to determine the effects of large (LF) and small (SF) dose IV fentanyl on the microcirculation compared with a conscious control. Male Wistar rats (130 g, n = 5) were implanted with the DMC to enclose a single layer of striated muscle. Animals were allowed 3 wk to recover from surgery and then, over the following 2 wk (1 infusion/wk) using intravital microscopy, the microcirculation was viewed in conscious animals (t = 0-30 min), followed by an induction bolus dose (t = 40-45 min), then a "step-up" maintenance infusion of one of the following, LF (40-90 microg x kg(-1) x h(-1)), SF (10-60 microg x kg(-1) x h(-1)), or saline (5-10 microg x kg(-1) x h(-1)) (t = 45-105 min). Small arterioles (<30 micro m) dilated (23.6% +/- 7.1%) after induction with LF, but constricted (-21.3% +/- 7.1%) with SF (P < 0.05). During maintenance, constriction increased with increasing dose of LF (-21.9% +/- 4.0%) and SF (-16.7% +/- 9.1%) (t = 105 min, P < 0.05). Similar patterns were observed in all arterioles (10-120 microm) and venules (15-250 microm). We conclude that the DMC provides an excellent technique for observing microcirculatory responses to fentanyl, and in rat skeletal muscle in vivo, an i.v. infusion of fentanyl produces significant constriction of arterioles.     

Comparison of the effects of isoflurane and thiopental on neurologic outcome and neuropathology after temporary focal cerebral ischemia in primates

In an attempt to determine whether one anesthetic might be clearly advantageous over another in clinical situations of temporary focal ischemia, isoflurane or thiopental (in concentrations producing equal suppression of cerebral function as measured by the electroencephalogram) were studied for their effects on neurologic outcome and cerebral infarct size in pigtailed monkeys exposed to temporary focal ischemia produced by 5 h of middle cerebral artery occlusion (MCAo). Burst suppression was produced for 15 min before MCAo and maintained throughout the ischemic period by 2.18 +/- 0.11% (mean +/- SE) end-expired isoflurane or 135 +/- 18 mg.kg-1 thiopental. Mean arterial pressure was supported with phenylephrine and maintained at approximately 90 mmHg in both groups throughout the ischemic period. At the end of the ischemic period, the isoflurane or thiopental was discontinued, allowing the animals to awaken. Intensive care was provided as needed. Neurologic function was scored for 8 days at the end of which surviving animals were killed and the brains were fixed in formalin and then examined for infarct size. There was no significant difference in final neurologic outcome between the animals receiving isoflurane and those receiving thiopental as determined by the Mann-Whitney rank sum test. Neurologic deficit scores ranged from normal (one of eight in the group receiving isoflurane and three of nine in the group receiving thiopental) to death resulting from brain injury (three in the isoflurane group and five in the thiopental-treated group). There also was no significant difference in infarct size between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

The protective effects of emulsified isoflurane on myocardial ischemia and reperfusion injury in rats

Purpose

Pretreatment with volatile anesthetics has been demonstrated to exert cardioprotective effects. The purpose of this study was to examine the effect of emulsified isoflurane, a new formulation of isoflurane in lipid emulsion, administered intravenously in an ischemia and reperfusion model of myocardial injury.

Methods

Thirty-two Sprague Dawley rats of both sexes were subjected to 30 min of myocardial ischemia followed by 180 min of reperfusion. Each was assigned to one of four pretreatment groups to receive an isovolumetric intravenous infusion of saline: control group, 30% intralipid group, 8% emulsified isoflurane 2 ml kg^?1 group, and sham group (each group, n = 8). The vehicles were administered at a constant rate for 30 min and then discontinued 30 min before left anterior descending coronary artery occlusion. The cardioprotective effects were examined by determining hemodynamics, infarct size, enzyme activity, and cardiomyocytic apoptosis.

Results

Pretreatment with emulsified isoflurane 2 ml kg^?1 (P = 0.000) significantly reduced infarct size (22.6 ± 2.2%) compared with control (34.8 ± 2.3%) and 30% intralipid (31.1 ± 2.9%). When compared with the control and intralipid groups, emulsified isoflurane increased Bcl-2 expression while decreasing Bax and Caspase-3 expression and enhancing Bcl-2/Bax ratios. The apoptotic index in the emulsified isoflurane treatment group showed a significant reduction compared with that in the control group (P = 0.000) and the intralipid group (P = 0.001). In addition, the serum levels of lactate dehydrogenase and creatine kinase were markedly reduced in the emulsified isoflurane treatment group compared with the control and intralipid groups (lactate dehydrogenase, P = 0.015 vs. control; creatine kinase, P = 0.000 vs. control and intralipid).

Conclusion

These data support a cardioprotective effect of intravenous emulsified isoflurane against myocardial ischemia and reperfusion injury, which are mediated, at least in part, by the inhibition of apoptosis and cell damage.     

The interaction of nitrous oxide and isoflurane with incomplete cerebral ischemia in the rat

In rats with incomplete cerebral ischemia the effects of 70% N2O alone, isoflurane alone (0.5 and 1 MAC), and the combination of N2O + isoflurane on neurologic outcome, neurohistopathology, and EEG were compared. Moderate and severe ischemia were produced by right carotid artery occlusion combined with hemorrhagic hypotension (moderate ischemia, MAP = 30 mmHg, FIO2 = 0.30; severe ischemia, MAP = 25 mmHg, FIO2 = 0.20). Neurologic outcome was evaluated using a graded deficit score from 0 to 5 (0 = normal, 5 = death associated with stroke), and neurohistopathology was evaluated using a 40-point scale from 0 = normal to 40 = total hemisphere infarct at the level of the caudate nucleus in coronal section. Compared with N2O alone, isoflurane (0.5 and 1 MAC) improved neurologic outcome following moderate ischemia (P less than 0.05). Isoflurane also decreased histopathologic damage following moderate ischemia (N2O control = 33 +/- 1 vs. 0.5 MAC isoflurane = 11 +/- 4 and 1 MAC isoflurane = 12 +/- 3, P less than 0.05), whereas only 0.5 MAC isoflurane decreased histopathologic damage following severe ischemia (N2O control = 38 +/- 1 vs. 0.5 MAC isoflurane = 25 +/- 5; P less than 0.05) Adding N2O to 0.5 MAC isoflurane attenuated the neurologic protective effect of isoflurane alone and increased histopathologic damage following both moderate and severe ischemia (moderate = 23 +/- 5, severe = 37 +/- 2; both P greater than 0.05 compared with N2O controls). The effect of adding 70% N2O to isoflurane on cerebral blood flow (CBF) and cerebral oxygen consumption(CMRO2) was also evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term outcome following testicular ischemia in the rat

Male germ cells are quite sensitive to interruption in blood flow. Eight weeks after subjection to 45 minutes of testicular ischemia, the spermatogenic epithelium of the rat remains significantly damaged, though other cell types are well preserved. The authors evaluated the testicular recovery of the rats at 8 and 72 weeks after the 45-minute period of warm ischemia. Twenty-eight rats were studied: 14 underwent 45 minutes of total left testicular ischemia; 14 received no treatment. Four rats from each group were necropsied at 8 weeks to document the ischemic injury. At 72 weeks, the 18 surviving rats were necropsied to evaluate the long-term outcome of the treatment. At 8 weeks, significant left testicular injury was documented. However, at 72 weeks there was no difference in testicular weight or sperm head count between the groups: in all 36 testicles, the repopulation index was 1.00, the epididymal index was 3+, the modified Johnsen index was 14, and the spermatic cord score was 7 (all are maximum obtainable scores). Neither contralateral orchiopathy nor injury to spermatic cord structures was observed. Our work shows that ischemia-induced testicular injury is fully reversible with time in this model.     

Comparison of methohexital and isoflurane on neurologic outcome and histopathology following incomplete ischemia in rats

Using a rat model of incomplete cerebral ischemia the effects of isoflurane (iso) and methohexital (metho) were compared with those of 70% nitrous oxide controls (N2O). Two levels of incomplete cerebral ischemia were produced by right carotid occlusion plus hypotension for 30 min: moderate = 30 mmHg, FIO2 = 0.30; severe = 25 mmHg, FIO2 = 0.20. The iso doses (1 and 2 MAC) and metho doses (0.01 and 0.1 mg.kg-1.min-1) were tested at each ischemic level. These iso and metho doses were selected because without ischemia they produced similar decreases in cerebral oxygen consumption (CMRO2) compared with that produced in N2O controls. In the absence of ischemia, the electroencephalogram (EEG) was suppressed by 0.01 mg.kg-1.min-1 metho and 1 MAC iso and showed burst-suppression with 0.1 mg.kg-1.min-1 metho and 2 MAC iso. The EEG was further depressed by ischemia under all anesthetic conditions. Neurologic outcome was evaluated for 3 days following incomplete cerebral ischemia by using a graded deficit score (0 = normal, 5 = death associated with stroke). Following moderate ischemia all four anesthetic treatments improved outcome compared with N2O controls, but after severe ischemia only 2 MAC iso significantly improved outcome. Neurohistopathology was evaluated on a scale of 0 to 40, 24 h after ischemia. The neurohistopathology score was significantly improved by all four anesthetic treatments compared with N2O following moderate ischemia and was better with 2 MAC iso compared with 0.1 mg.kg-1.min-1 metho after both moderate and severe ischemia. These results show that both iso and metho improve outcome from cerebral ischemia compared with that associated with N2O, but only 2 MAC iso resulted in an improved outcome following severe ischemia. This difference in outcome between the two anesthetics may be related to greater neuronal depression with iso, which may occur with little difference in cerebral metabolic depression.     

An assessment of the cerebral protective effects of etomidate in a model of incomplete forebrain ischemia in the rat.

The cerebral protective effects of etomidate were evaluated in a model of incomplete forebrain ischemia. Fourteen Wistar-Kyoto rats were anesthetized with halothane. After preparation, the rats were alloted to either the control group (halothane anesthesia, n = 7) or the etomidate group (n = 7). In the etomidate group, immediately before and during the period of ischemia, the animals received etomidate in sufficient concentration to achieve electroencephalogram burst suppression (loading dose, 7.5 mg/kg; infusion, 0.3-0.5 mg/kg/min). Both groups were subjected to a 10-minute ischemic insult accomplished by bilateral carotid artery occlusion and simultaneous hypotension (mean arterial pressure, 35 mm Hg). Histological evaluation of the brain was performed after a 4-day recovery period. Injury was evaluated in coronal brain sections in five structures: neocortex, striatum, reticular nucleus of the thalamus, and the CA1 and CA3 areas of the hippocampus. The location of the sections in the rostral-caudal axis was chosen to encompass anterior areas within the core of the ischemic territory as well as more posterior regions within the anticipated "watershed" zone between the occluded anterior and the intact posterior circulations. In the animals that received etomidate, statistically significant (P less than 0.05) reduction in the severity of the ischemic injury was observed in the CA3 area and in the ventral portion of the CA1 area of the hippocampus in the more posterior sections. There was an apparent trend toward protection in other structures in both rostral and caudal sections, but these changes were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Preconditioning with isoflurane produces dose-dependent neuroprotection via activation of adenosine triphosphate-regulated potassium channels after focal cerebral ischemia in rats

In this study, we determined whether repeated brief isoflurane (Iso) anesthesia induces ischemic tolerance to focal cerebral ischemia in a dose-response manner and whether the effect is dependent on adenosine triphosphate-regulated potassium channels. In Experiment 1, 40 rats were randomly assigned to 4 groups: control animals received 100% oxygen 1 h/d for 5 days, whereas the isoflurane (Iso)1, Iso2, and Iso3 groups received 0.75%, 1.5%, or 2.25% Iso in oxygen 1 h/d for 5 days. In Experiment 2, 36 rats were randomly assigned to 4 groups: controls received 100% oxygen 1 h/d for 5 days; animals in the Iso and I+G (Iso+glibenclamide) groups received 2% Iso in oxygen 1 h/d for 5 days, and the I+G group received glibenclamide (GLB) (5 mg/kg intraperitoneally) before each Iso pretreatment. Animals in the GLB group received GLB (5 mg/kg intraperitoneally) once a day for 5 days. Twenty-four hours after the last pretreatment, the right middle cerebral artery was occluded for 120 min. Neurologic deficit scores (NDS) and brain infarct volumes were evaluated at 24 h. The NDS and infarct volumes of Iso2 and Iso3 were less than those of the controls (P < 0.05). The infarct volume in Iso3 was smaller than in Iso2 (P < 0.05). The NDS and infarct volume in the Iso group were less than in the control and I+G groups (P < 0.05). There was no statistical difference among the control, I+G, and GLB groups. The study demonstrated that repeated Iso anesthesia induces ischemic tolerance in rats in a dose-response manner. GLB, an adenosine triphosphate-regulated potassium channel blocker, abolished the tolerance induced by Iso. IMPLICATIONS: Brief isoflurane anesthesia induces ischemic tolerance in the brain. The effect was found to be dose dependent in a rat focal cerebral ischemia model. Ischemic tolerance induced by isoflurane preconditioning is dependent on activation of adenosine triphosphate-regulated potassium channels.     

Different effects of thiopental in severe hypoxia, total ischemia, and low-flow ischemia in rat heart muscle

The effect of thiopental (100 mg X 1(-1] during total ischemia, low-flow ischemia, and severe hypoxia with maintained flow was investigated in the isolated perfused rat heart. During total ischemia the rate of decline of tissue creatine phosphate and adenosine triphosphate was no different in thiopental-treated and untreated hearts. The development of ultrastructural damage during total ischemia, the release of creatine kinase on reperfusion, and the exacerbation of ultrastructural damage after reperfusion were unaffected by thiopental. When thiopental was added to the perfusate during hypoxia and during low-flow ischemia at a normal pH(7.4), creatine kinase release during reoxygenation and during reperfusion was significantly less (P less than 0.005 and P less than 0.05, respectively) than in the untreated groups. After low-flow ischemia at a low pH (6.5), creatine kinase release was no different in thiopental-treated and untreated hearts. Thus, thiopental afforded protection of the myocardium in hypoxia and low-flow ischemia at pH 7.4 but not in total ischemia and low-flow ischemia at pH 6.5. The data are consistent with the hypothesis that during total ischemia and low-flow ischemia at pH 6.5, acidosis favors the entry of thiopental into the cell, causing inhibition of mitochondrial function and reduction of ATP production. During hypoxic perfusion and low-flow ischemia at pH 7.4, when the decrease in pH is less, the cardiodepressant effect of thiopental may offset any deleterious effect of the drug on intracellular organelles such as mitochondria.     

Clonidine decreases plasma catecholamines and improves outcome from incomplete ischemia in the rat

Clonidine decreases central sympathetic activity and anesthetic requirement. We tested whether clonidine improves outcome from incomplete ischemia of the brain in rats. Control rats were anesthetized with 25 micrograms.kg-1.h-1 of intravenous fentanyl and inhalation of 70% nitrous oxide (N2O). Clonidine-treated rats received fentanyl/N2O and 10 micrograms/kg of intravenous clonidine 10 min before ischemia, which was produced by right carotid ligation combined with hemorrhagic hypotension to 35 mm Hg for 30 min. Clonidine increased plasma glucose before ischemia and decreased blood catecholamine concentrations during ischemia compared with the control group. Neurologic outcome was evaluated daily for 3 days after ischemia and histopathology was performed at the end of this period. Clonidine significantly improved neurologic outcome on each of the 3 days after ischemia. Histopathology was severe in the control group but not enough rats survived in this group for statistical analysis. The authors conclude that clonidine decreases sympathetic activity during ischemia and that this is associated with an improvement in outcome from incomplete ischemia.