Elsevier

Brain Research

Volume 1076, Issue 1, 3 March 2006, Pages 216-224
Brain Research

Research Report
Isoflurane exerts neuroprotective actions at or near the time of severe traumatic brain injury

https://doi.org/10.1016/j.brainres.2005.12.106Get rights and content

Abstract

Isoflurane improves outcome vs. fentanyl anesthesia, in experimental traumatic brain injury (TBI). We assessed the temporal profile of isoflurane neuroprotection and tested whether isoflurane confers benefit at the time of TBI. Adult, male rats were randomized to isoflurane (1%) or fentanyl (10 mcg/kg iv bolus then 50 mcg/kg/h) for 30 min pre-TBI. Anesthesia was discontinued, rats recovered to tail pinch, and TBI was delivered by controlled cortical impact. Immediately post-TBI, rats were randomized to 1 h of isoflurane, fentanyl, or no additional anesthesia, creating 6 anesthetic groups (isoflurane:isoflurane, isoflurane:fentanyl, isoflurane:none, fentanyl:isoflurane, fentanyl:fentanyl, fentanyl:none). Beam balance, beam walking, and Morris water maze (MWM) performances were assessed over post-trauma d1-20. Contusion volume and hippocampal survival were assessed on d21. Rats receiving isoflurane pre- and post-TBI exhibited better beam walking and MWM performances than rats treated with fentanyl pre- and any treatment post-TBI. All rats pretreated with isoflurane had better CA3 neuronal survival than rats receiving fentanyl pre- and post-TBI. In rats pretreated with fentanyl, post-traumatic isoflurane failed to affect function but improved CA3 neuronal survival vs. rats given fentanyl pre- and post-TBI. Post-traumatic isoflurane did not alter histopathological outcomes in rats pretreated with isoflurane. Rats receiving fentanyl pre- and post-TBI had the worst CA1 neuronal survival of all groups. Our data support isoflurane neuroprotection, even when used at the lowest feasible level before TBI (i.e., when discontinued with recovery to tail pinch immediately before injury). Investigators using isoflurane must consider its beneficial effects in the design and interpretation of experimental TBI research.

Introduction

Isoflurane, one of the most commonly used anesthetics in experimental traumatic brain injury (TBI), confers beneficial effects on functional outcomes compared to fentanyl anesthesia in experimental TBI (Statler et al., 2000, Statler et al., 2001, Statler et al., 2003, Statler et al., 2006). Specifically, in a direct comparison study, in which treatment with either isoflurane or the narcotic fentanyl was initiated before and continued 4 h after TBI, isoflurane-treated rats had better post-traumatic functional outcomes and less hippocampal neuronal death (Statler et al., 2000). A follow-up comprehensive comparison study of isoflurane and six clinically relevant agents (diazepam, fentanyl, ketamine, morphine, pentobarbital, and propofol) corroborated this finding, with isoflurane-treated rats demonstrating the quickest functional recovery and the best hippocampal neuronal survival after TBI (Statler et al., 2006). In order to mimic clinical TBI, in which victims are not anesthetized at the time of injury, as close as humanely possible, all experimental groups in the comprehensive comparison study had been treated with isoflurane prior to injury. TBI was delivered immediately upon return of tail pinch response, and the study drug was then administered immediately after TBI. Interestingly, rats receiving no sustained additional post-traumatic anesthesia (i.e., rats only pretreated with isoflurane) had similar outcomes to those administered additional post-traumatic isoflurane, suggesting that residual effects of pretreatment with isoflurane conferred benefit at the time of TBI (Statler et al., 2006). Further, the beneficial effects of isoflurane vs. fentanyl in our comprehensive comparison study (Statler et al., 2006) did not appear as marked as in our prior study, in which rats were injured while fully anesthetized with either isoflurane or fentanyl (Statler et al., 2000).

Based on these observations, we speculated that putative neuroprotective effects of isoflurane anesthesia might be confounding results in experimental TBI, even when isoflurane is stopped immediately prior to TBI. The current study was designed to assess the temporal profile of the protective effects of isoflurane. We hypothesized that pretreatment with isoflurane exerts beneficial effects at the time of TBI. Further, we suspected that administration of additional post-traumatic isoflurane provides minimal added benefit. To test our hypotheses, we have systematically compared functional and histopathological outcomes in experimental TBI in adult, male Sprague–Dawley rats treated with either isoflurane or fentanyl for 30 min before TBI, followed by post-traumatic administration of 1 h of isoflurane, fentanyl, or no additional anesthesia. Our study design thus includes 6 pre:post-TBI anesthetic groups (isoflurane:isoflurane, isoflurane:fentanyl, isoflurane:none, fentanyl:isoflurane, fentanyl:fentanyl, and fentanyl:none). Given the ubiquitous use of isoflurane in experimental TBI, our results will have direct implications for the design and interpretation of future investigations in experimental TBI.

Section snippets

Results

In all groups, rectal and brain temperatures were controlled at 37 ± 0.5 °C, PaCO2 was maintained between 35 and 45 mm Hg, PaO2 was greater than 100 mm Hg, and hematocrit values remained within normal limits. Serum glucose values ranged between 140 and 250 mg/dl and did not differ between groups. MAP was higher in rats during treatment with fentanyl vs. isoflurane (P < 0.05, Fig. 1), but remained within the autoregulatory range for the adult rat in all groups (Hernandez et al., 1978, Hoffman et

Discussion

Motor and cognitive outcomes after TBI were minimally affected by the post-traumatic treatment and largely determined by anesthetic administration immediately prior to TBI. Rats pretreated with fentanyl, followed by any post-traumatic treatment, had worse beam walking and MWM performances than rats treated with isoflurane pre- and post-TBI. Importantly, post-traumatic administration of isoflurane failed to improve functional or cognitive outcome in rats administered fentanyl before TBI.

Experimental procedures

Adult, male (300–440 g), Sprague–Dawley rats were used in all experiments. The rats were allowed free access to food and water before and after surgery. The University of Pittsburgh Animal Care and Use Committee approved all studies. All surgical procedures were performed using aseptic technique.

Rats were anesthetized with 4% isoflurane (Isoflo, Abbott Laboratories, North Chicago, IL) via nose cone and then endotracheally intubated with a 14-guage angiocatheter and mechanically ventilated.

Acknowledgments

We thank the U.S. Army (DMAD 17-91-7009), the National Institutes of Health (NS30318 and T32-HD40686), and the Laerdal Foundation for Acute Medicine for generous support of this project. We also thank Marci Provins for assistance with preparation of the manuscript.

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