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Anesth Analg 2000;91:145-151
© 2000 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

The Effects of Anesthetics on Stress Responses to Forebrain Ischemia and Reperfusion in the Rat

Bengt Nellgård, MD, PhD, G. Burkhard Mackensen, MD, Gary Massey, BS, Robert D. Pearlstein, PhD, and David S. Warner, MD

Neuroanesthesia Research Laboratory, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina

Address correspondence and reprint requests to David S. Warner, MD, Department of Anesthesiology, Box 3094, Duke University Medical Center, Durham, NC 27710. Address e-mail to warne002{at}mc.duke.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Rats exposed to forebrain ischemia have reduced injury when anesthetized with isoflurane versus fentanyl + N2O. 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 + N2O; 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 + N2O 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 + N2O 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.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Inhaled anesthetics ameliorate neurologic and histologic damage resulting from either focal or global cerebral ischemia (1–6). The mechanism by which these compounds provide neuroprotection is incompletely understood. Volatile anesthetics reduce cerebral metabolic rate (7), inhibit glutamate excitotoxicity (8), and reduce periinfarct depolarizations (9). In most outcome studies, however, volatile anesthetic neuroprotection has not been demonstrated relative to control animals that were either awake or lightly anesthetized with fentanyl + N2O. Perhaps the stress responses to ischemia were substantial in these studies. The presence of a moderate depth of anesthesia provided by volatile anesthetics might have dampened these stresses.

Stress responses to ischemia have an impact on ischemic outcome although it is controversial whether such effects are beneficial or detrimental. Hoffman et al. (10) demonstrated improved neurologic outcome in rats anesthetized with ketamine versus fentanyl + N2O. Ketamine-treated rats also had reduced plasma norepinephrine/epinephrine concentrations during the ischemic insult. This finding was later extended to both isoflurane and desflurane (11), and it was proposed that anesthetic-mediated neuroprotection can be attributed to reduction of plasma catecholamine concentrations. In contrast, Mackensen et al. (5) examined rats which were anesthetized with 1 minimum alveolar anesthetic concentration of isoflurane or fentanyl + N2O while being subjected to bilateral carotid occlusion plus severe hemorrhagic hypotension. Histologic outcome was also markedly better in the isoflurane group. However, if trimethaphan, the ganglionic blocker, was given to induce hypotension during carotid occlusion, intraischemic increases in plasma catecholamine concentrations were markedly reduced and the neuroprotective effect of isoflurane was abolished.

If plasma catecholamine concentrations are important in defining ischemic outcome, perhaps plasma catecholamines exert direct effects on brain parenchyma. To examine this possibility, Miura et al. (12) performed intracerebral microdialysis simultaneously with measurement of plasma catecholamines in rats anesthetized with fentanyl + N2O or isoflurane. There was no correlation between catecholamine concentrations in brain and plasma as a function of either anesthetic state or periischemic interval. That brain catecholamine concentrations have little direct effect on ischemic outcome was substantiated by Nellgård et al. (13). Rats were subjected to a 95% pharmacologic depletion of brain norepinephrine before severe forebrain ischemia. No effect on histologic outcome was observed when these rats were compared with those having normal brain norepinephrine concentrations.

Alternatively, plasma catecholamine concentrations may alter ischemic outcome by modulating other neuroendocrinologic or inflammatory responses to cerebral ischemia. There is no information on differential effects of anesthetics on either corticosterone or cytokine responses to ischemic insults. Accordingly, we designed a study using an ischemic insult in the rat that has consistently been (4,5) sensitive to differential effects of anesthetics on histologic injury. Plasma and brain cytokine concentrations were assayed and compared as a function of anesthetic state. To provide a frame of reference, additional animals were studied that were administered either trimethaphan or metyrapone, an inhibitor of corticosterone synthesis.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This study was approved by the Duke University Animal Care and Use Committee. Sprague-Dawley rats (8–10 wk of age, Harlan Sprague-Dawley, Indianapolis, IN) were randomly assigned to one of four groups defined on the basis of conditions present during the ischemic insult:

Isoflurane: 1.4% isoflurane in 30% O2/balance N2, n = 12;
Isoflurane + trimethaphan: 1.4% isoflurane in 30% O2/balance N2. Just before onset of forebrain ischemia, 2.5 mg of IV trimethaphan was given, n = 12;
Isoflurane + metyrapone: 1.4% isoflurane in 30% O2/balance N2. Four hours before onset of forebrain ischemia, 150 mg/kg metyrapone in 1 mL saline, was given intraperitoneally, n = 8; or
Fentanyl + N2O: 10 µg/kg fentanyl IV bolus followed by an IV infusion of 25 µg/kg/hr fentanyl and N2O 30% in 70% O2, n = 10.

All rats were acclimated to a standard 12-h day/12-h night cycle. Before the procedure, animals were fasted from food for 12–16 h, but had free access to water. Surgery was begun at 8:00 AM in all rats to control for temporal variations in corticosterone and tumor necrosis factor (TNF)-{alpha} concentrations (14,15). All rats were anesthetized with 4% to 5% isoflurane in oxygen. The trachea was intubated and the lungs were mechanically ventilated. The inspired isoflurane concentration was reduced to 1.5%–2.5% in 40% O2/balance N2. Surgery was performed using an aseptic technique, and all wounds were infiltrated with 1% lidocaine. The tail artery was cannulated for blood pressure measurement and arterial blood sampling. A tail vein was cannulated to allow drug delivery. Via a neck incision, the right jugular vein was cannulated for blood withdrawal. Finally, both common carotid arteries were exposed and encircled with suture, leaving the vagus nerves and cervical sympathetic plexus intact.

After surgery, inspired isoflurane was decreased to 1.4% in all groups except the fentanyl + N2O group in which isoflurane was discontinued and fentanyl + N2O anesthesia was begun, as described previously. A 30-min stabilization interval was then allowed in all groups. Minute ventilation was adjusted to produce normocapnia and mild hyperoxia. Muscle paralysis was provided by a 1 mg IV bolus of succinylcholine before onset of ischemia.

The cortex was continuously monitored by electroencephalogram during the experiment from active subdermal electrodes positioned bilaterally over the parietal cortex. A rectal thermistor was placed and a 22-gauge needle thermistor was percutaneously positioned adjacent to the skull beneath the temporalis muscle. Both temperatures were maintained at 37.5° ± 0.1°C by surface heating or cooling. Heparin 50 IU was given IV.

Near-complete forebrain ischemia was induced by exsanguination (plus trimethaphan in the isoflurane + trimethaphan group) through the jugular venous catheter to produce a mean arterial blood pressure of 30 mm Hg concomitant with bilateral carotid artery occlusion using aneurysm clips. Ten minutes later, ischemia was terminated by reinfusion of the shed blood and removal of the carotid clips. NaHCO3 (0.3 milliequivalent IV) was given to minimize systemic acidosis. Anesthetic states and temperature regulation were continued for an additional 2 h postischemia.

Arterial blood gases and plasma glucose were measured 10 min preischemia and 30 min postischemia. Plasma samples (100–200 µL) were collected in tubes containing sodium metabisulfite and EDTA for corti- costerone, TNF-{alpha}, and interleukin (IL)-6 assays at 10 min preischemia; 8 min intraischemia; and 10 min, 30 min, and 2 h postischemia. After centrifugation, the plasma samples were stored at -70°C for later analysis.

The rats were decapitated 2 h postischemia. The brains were rapidly removed, dissected, weighed, and frozen in 2-methylbutane (-40°C) and then, stored at -70°C for later analysis of TNF-{alpha}, IL-6, and corticosterone concentrations in the hippocampus and neocortex.

To determine normal brain concentrations of TNF-{alpha}, IL-6, and corticosterone, six rats were anesthetized with 5% isoflurane in oxygen. These rats were not subjected to surgery or ischemia. After decapitation, the brains were rapidly removed and frozen for later analysis.

Corticosterone was extracted from brain tissue samples by a modification of the method of Henkin et al. (16). Frozen hippocampal and parietal cortex tissue samples were individually homogenized in ice-cold dichloromethane using a Potter-Elvehjem tissue grinder (10 strokes, 0.15 mm clearance). The tissue homogenate was then centrifuged (1000g x10 min at 4°C) and supernatant removed and washed with 0.1 M sodium hydroxide and then, 0.1 M acetic acid. The dichloromethane phase containing corticosterone was transferred to a glass tube. The solvent was evaporated to dryness under a continuous stream of nitrogen. The extract was dissolved in 95% ethanol and stored at -70°C until analyzed. Corticosterone concentrations in the plasma and tissue extracts were determined by radioimmunoassay (Rat Corticosterone Kit; ICN Biomedicals, Costa Mesa, CA) from a linear least squares method of the standard curve for concomitantly analyzed standards.

Tissue samples were prepared for determination of IL-6 and TNF-{alpha} concentrations by a modification of the method of Saito et al. (17). Samples of hippocampus and cortex were individually homogenized in ice-cold Tris-citrate buffer solution (50 mM, pH 7.4, 5 µL per mg wet weight) using a Branson sonicator with a micro sonicator tip (30W, 10s). The homogenate was centrifuged (1000g x10 min at 4°C) and the supernatant was then, removed and stored at -70°C until analysis. IL-6 and TNF-{alpha} concentrations in the plasma and tissue extracts were analyzed by ELISA, using commercially available kits (Endogen, Woburn, MA). ELISA plates containing samples and concurrently analyzed standards were read on a plate reader. The results were calculated using statistical routines within the plate reader control program.

Parametric data were compared by one-way or two-way (group x time) analysis of variance where appropriate. Post hoc between group comparisons were performed with Fisher’s protected least squares difference test. Because of inhomogeneity of variance, TNF-{alpha} values were log transformed before analysis and are reported as such. Values were expressed as mean ± SEM. Statistical significance was assumed with P < 0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Physiological values were similar among groups except for pre- and postischemic mean arterial blood pressures which were greater in the fentanyl + N2O group (Table 1). Use of fentanyl + N2O anesthesia or addition of metyrapone to isoflurane anesthesia depressed baseline corticosterone values by 40% to 60%, relative to the isoflurane or isoflurane + trimethaphan groups (P < 0.01) (Figure 1). This pattern persisted over the entire periischemic interval. Ischemia and reperfusion had only modest effects on plasma corticosterone concentrations in any group. Parenchymal corticosterone concentrations measured 2 h postischemia in neocortex and hippocampus are shown in Figure 2. In the cortex, animals treated with isoflurane + metyrapone had significantly lower values than the other groups (P < 0.003). There were no differences among the remaining groups. The pattern in the hippocampus was similar.


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  		Table 1. Physiologic Values For the Experimental Groups
 


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  		Figure 1. Plasma corticosterone concentrations (µg/dL) measured pre-, intra-, and postischemia in rats (n = 8–12) treated with: isoflurane; isoflurane + trimethaphan (TMP); isoflurane + metyrapone (M); or fentanyl + N2O. Use of fentanyl + N2O anesthesia or addition of metyrapone to isoflurane anesthesia depressed baseline corticosterone concentrations relative to the isoflurane or isoflurane + TMP groups (P < 0.01). This pattern persisted over the entire periischemic interval. Ischemia and reperfusion had only modest effects on plasma corticosterone concentrations in any group. Values are mean ± SEM.

 


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  		Figure 2. Corticosterone concentrations (ng/gm wet weight) in the cortex and the hippocampus measured 2 h after exposure to 10 min forebrain ischemia in rats (n = 8–12) treated with: isoflurane; isoflurane + trimethaphan (TMP); isoflurane + metyrapone; or fentanyl + N2O. In the cortex, animals treated with isoflurane + metyrapone had significantly lower values than the other groups (P < 0.003). There were no differences among the remaining groups. The pattern in the hippocampus was similar. Values in control rats (n = 6) which underwent neither surgery nor ischemia are provided as reference. Values are mean ± SEM.

 
Plasma TNF-{alpha} concentrations, as a function of periischemic interval, are illustrated in Figure 3. An effect of time was present (P < 0.05) although most inter-interval comparisons were not significant. TNF-{alpha} concentrations in the isoflurane + metyrapone group were less than values in the other three groups preischemia, 8 min after onset of ischemia, and at 10 min postischemia (P < 0.05). There were no differences among the remaining groups at each interval (i.e., there was no differential effect of anesthetic on TNF-{alpha} concentration at any time). By 2 h postischemia, no differences were detected among any groups.



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  		Figure 3. Plasma tumor necrosis factor-{alpha} (TNF-{alpha}) concentrations (pg/mL) measured pre-, intra-, and postischemia in rats (n = 8–12) treated with: isoflurane; isoflurane + trimethaphan (TMP); isoflurane + metyrapone (M); or fentanyl + N2O. Values in the isoflurane + metyrapone group were less than the other three groups preischemia, 8 min after onset of ischemia and at 10 min postischemia (P < 0.05). There were no differences among the remaining groups at each interval. By 2 h postischemia, no differences among any groups were detected. Log transformed values are mean ± SEM.

 
Neocortical and hippocampal TNF-{alpha} concentrations are depicted in Figure 4. Although values numerically increased by 20% to 50% relative to nonischemic control animals, no differences were observed among ischemic treatment groups (P = 0.89 for neocortex; P = 0.98 for hippocampus).



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  		Figure 4. Tumor necrosis factor(TNF)-{alpha} concentrations (ng/gm wet weight) in cortex and hippocampus measured 2 h after exposure to 10 min forebrain ischemia in rats (n = 8–12) treated with: isoflurane; isoflurane + trimethaphan (TMP); isoflurane + metyrapone; or fentanyl + N2O. No differences were observed among groups in either structure. Values in control rats (n = 6) which underwent neither surgery nor ischemia are provided as reference. Values are mean ± SEM.

 
Plasma concentrations of IL-6 were measured in all groups; however, values were so close to the standard zero value that they are not presented. IL-6 concentrations in cortex and hippocampus measured 2 h postischemia are shown in Figure 5. Increases in neocortical IL-6 in ischemic rats were numerically negligible relative to nonischemic control animals, and there was no difference among ischemic groups (P = 0.30). Major numerical increases in hippocampal IL-6 were observed in the ischemic groups relative to control animals; however, there was no difference among ischemic groups (P = 0.72).



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  		Figure 5. Interleukin (IL)-6 concentrations (ng/gm wet weight) in cortex and hippocampus measured 2 h after exposure to 10 min of forebrain ischemia in rats (n = 8–12) treated with: isoflurane; isoflurane + trimethaphan (TMP); isoflurane + metyrapone; or fentanyl + N2O. No differences were observed among groups in either structure. Values in control rats (n = 6) which underwent neither surgery nor ischemia are provided as reference. Values are mean ± SEM.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This experiment failed to provide evidence that differential effects of anesthetics on outcome from severe forebrain ischemia can be attributed to modulation of stress responses induced by the ischemic insult.

Previous studies suggested that some anesthetics reduce ischemic brain injury by attenuating adrenergic responses to the ischemic insult (18,10,5). Recent reports challenged this hypothesis. Anesthetic effects on plasma and brain norepinephrine/epinephrine concentrations could not be correlated with ischemic outcome (19), and near-total depletion of brain norepinephrine, before and during ischemia, did not alter ischemic histologic injury (13).

Our study explored an alternative hypothesis. We proposed that previously observed differences between fentanyl + N2O and isoflurane anesthesia on ischemic outcome might be associated with other aspects of the stress response to ischemia, notably plasma/brain concentrations of corticosterone and the cytokines TNF-{alpha} and IL-6. Stress results in enhanced corticosterone secretion, and anesthetics can influence this process (20–22). Indeed, in our study, plasma corticosterone concentrations were approximately 50% less in the fentanyl + N2O versus isoflurane group throughout the periischemic interval. Despite this, there was no difference between groups for brain corticosterone concentration. This is in contrast to effects of metyrapone, an antagonist of ß-hydroxylase, which potently inhibits the conversion of deoxycorticosterone in the rat adrenal cortex (23). Animals treated with metyrapone had profound depletion of brain corticosterone. Work by others showed a similar periischemic metyrapone-induced reduction of brain corticosterone concentration resulted in substantial amelioration of both focal and global ischemic brain injury (24,25). This suggests that the site affected by corticosterone is in the brain parenchyma. Absence of any differences in brain corticosterone concentrations between the two anesthetic groups, therefore, does not support the hypothesis that anesthetic effects on corticosterone responses are important in defining ischemic outcome.

We also observed no differences in brain or plasma corticosterone concentrations between rats treated with isoflurane alone or isoflurane plus trimethaphan. Previous work has shown that isoflurane results in marked reduction in hippocampal CA1 and neocortical ischemic injury when compared with rats given fentanyl + N2O (4). Co-administration of trimethaphan completely reverses this protection (5). Therefore, it is again difficult to construe any causal relationship between ischemic outcome and effects of anesthetics on changes in corticosterone concentrations resulting from an ischemic challenge.

Over the past decade, the role of cytokines in ischemic brain injury has been intensely scrutinized and activation of cytokines by ischemia has been well established (26,17,27). TNF-{alpha} is a proinflammatory cytokine that enhances permeability of the blood-brain barrier and induces expression of endothelial adhesion molecules leading to further release of inflammatory mediators. TNF-{alpha} production is at least, in part, regulated by the hypothalamic-pituitary-adrenal axis (28). Inhibition of TNF-{alpha} reduces ischemia brain injury (29). IL-6 plays a complex role in both fever and regulation of the hypothalamic-pituitary-adrenal axis; however, IL-6 itself may be regulated by plasma adrenergic factors (30). In both in vivo and in vitro models, however, the administration of IL-6 appears to provide a neuroprotective role (31,32). Because of the potential interactions between both TNF-{alpha} and IL-6 with corticosterone production, we chose to sample these two cytokines in the periischemic interval as a function of anesthetic regimen.

Again, anesthetics had little or no effect on these stress factors. Although metyrapone did reduce plasma TNF-{alpha}, there were no differential effects of anesthetic, metyrapone, or trimethaphan on brain TNF-{alpha} or IL-6. Clark et al. (33) examined the time course of IL-6 expression after focal ischemia in mice. As was the case in our study, IL-6 was undetectable in plasma. IL-6 was detectable in cerebrospinal fluid with peak concentrations occurring at 3 h after recirculation, although brain messenger ribonucleic acid levels did not peak until 24 hours after recirculation. Wang et al. (34) found significant increases in IL-6 at 3 h after focal ischemia in rat brain; however, peak concentrations did not occur until 9 h later. In contrast, Uno et al. (27) studying gerbil forebrain ischemia, found peak brain IL-6 concentrations within 3 h after reperfusion. Because our model was also one of forebrain ischemia, we selected an observation window which would be similar to that of Uno et al. (27). TNF-{alpha} also peaks early after reperfusion from forebrain ischemia. In both gerbil and mouse, peak TNF-{alpha} concentrations have been observed within 1–2 h after recirculation (17,27). Therefore, we feel confident that our 2 hr postischemic observation window was likely to have captured major anesthetic-dependent changes, if present. However, we were limited to a single postischemic brain sampling interval in our experimental design. It remains plausible that differential anesthetic effects on IL-6 or TNF-{alpha} expression could have been found if greater intervals of postischemic reperfusion had been allowed.

In conclusion, we hypothesized that known differential anesthetic effects on outcome from severe forebrain ischemia are associated with effects on either plasma brain corticosterone or cytokine concentrations. Although fentanyl + N2O anesthesia was associated with reduced plasma corticosterone concentrations throughout the periischemic interval, there was no difference between rats anesthetized with fentanyl + N2O versus 1.4% isoflurane for brain corticosterone or cytokine concentrations. Addition of trimethaphan to isoflurane during ischemia produced no effect on plasma or brain corticosterone or cytokine concentrations. We conclude that beneficial effects of isoflurane on ischemic outcome (and its reversal by trimethaphan) are largely independent of any direct effects on stress responses to ischemia. Definition of the mechanistic basis for these differential anesthetic effects on ischemic outcome must be sought elsewhere.


   Acknowledgments
 
Supported, in part, by National Institutes of Health grant RO1 GM39771–13. BN supported by postdoctoral stipends provided by the Laerdal Foundation for Acute Medicine and the Swedish Society of Physicians. GBM supported by a postdoctoral stipend from the German Academic Exchange Service (DAAD).


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication March 29, 2000.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press