Isoflurane neuroprotection: a passing fantasy, again?

DATING from the first report that isoflurane produces profound reduction in cerebral metabolic rate at clinically relevant concentrations, it has been postulated that isoflurane can provide perioperative neuroprotection. If so, this would be a major advance over using barbiturates for the same purpose. To achieve similar cerebral metabolic rate reduction with barbiturates, patients are committed to hours of postoperative coma, hardly an ideal circumstance for monitoring neurologic status. Considerable work has been dedicated to examining the neuroprotective properties of isoflurane. In this issue of ANESTHESIOLOGY, Kawaguchi et al. present new information important to the debate regarding isoflurane neuroprotection. What they have shown is that isoflurane indeed provides neuroprotection against a focal ischemic insult. However, at least in the case of their laboratory model, the protection provided is not permanent. Over time, the tissue that was initially protected by isoflurane went on to die, and the final result was no different than that found in rats subjected to the ischemic insult in the absence of isoflurane. A historical perspective is useful in placing this observation in context. Early investigations provided evidence that isoflurane is neuroprotective. Mice subjected to hypoxia survived longer in the presence of isoflurane, and isoflurane-anesthetized dogs exposed to hemorrhagic shock had better preservation of brain adenosine triphosphate concentrations. Rats subjected to hemispheric global ischemia had better ischemic outcomes when given isoflurane anesthesia versus nitrous oxide sedation. In humans undergoing carotid endarterectomy, the critical cerebral blood flow threshold required for electroencephalographic changes indicative of ischemia was substantially lower during isoflurane versus halothane anesthesia. However, none of the aforementioned studies was perfect in experimental design, and methodologic criticism of those investigations was buoyed by other reports that isoflurane offered little benefit to ischemic brain. When baboons were anesthetized with isoflurane, thiopental, or fentanyl–nitrous oxide during transient middle cerebral artery occlusion (MCAO), the isoflurane group had worse outcome than the thiopental group. In fact, it was nearly statistically significant (P 5 0.07) that the isoflurane group had a worse outcome than the fentanyl–nitrous oxide group. In a study of monkeys subjected to MCAO combined with induced hypotension (so as to model cerebral aneurysm surgery), there was no difference in outcome between isofluraneand halothane-anesthetized animals. Because halothane was thought to have no neuroprotective potential, it could be concluded that isoflurane also was devoid of this property. Finally, in rats subjected to severe forebrain ischemia, there was no advantage of isoflurane anesthesia versus nitrous oxide sedation. In addition to dashing hopes that we at last had a safe, convenient modality for intraoperative neuroprotection, these studies were used to make the case that cerebral metabolic rate reduction is an insufficient criterion for predicting neuroprotection by pharmacologic agents. Accordingly, the burden of proof was returned to proponents of isoflurane neuroprotection. Methodologically sound evidence was required to prove this benefit. Although it took several years for that evidence to emerge, research teams eventually took advantage of advances in laboratory models of ischemic brain injury to re-address this issue. One problem constantly inhibiting clear definition of neuroprotection by anesthetics was the necessity to anesthetize both control animals as well as those receiving the anesthetic under investigaThis Editorial View accompanies the following article: Kawaguchi M, Kimbro JR, Drummond JC, Cole DJ, Kelly PJ, Patel PM: Isoflurane delays but does not prevent cerebral infarction in rats subjected to focal ischemia. ANESTHESIOLOGY 2000; 92:1335–42. r