Ⅵ CLASSIC PAPERS REVISITED Positive Experimental Demonstration of the Negative Brain "Protective" Effects of Anesthetics following Cardiac Arrest

The cerebral metabolic effects of a massive dose of thiopental (177 mg/kg) were investigated in seven dogs. The systemic circulation was supported with an extracorporeal circuit. At an infusion rate of 2 mg/kg/min, cerebral oxygen consumption (CMR O2 ) decreased progressively until cerebral electrical silence was produced. This occurred after a mean dose of 72 mg/kg, which caused a mean decrease in CMR O2 to 58% of the control value (measured at 1.5% halothane inspired). Thereafter, despite continued at 4 mg/kg/min, CMR O2 did not decrease further. The oxygen-glucose index never changed during the infusion period and, at the termination of the infusion, brain assays for ATP, phosphocreatine, lactate, and pyruvate revealed normal concentrations. It is concluded that there was no alteration in normal cerebral metabolic pathways, that cerebral metabolic effects of thiopental are secondary to functional effects, that thiopental would provide no cerebral protection during hypoxia sufficient to abolish cerebral function, and that thiopental does not uncouple oxidative phosphorylation in vivo. (Key words: Anesthetics, intravenous: thiopental; Brain: metabolism; Metabolism: brain.) WHEN I was informed that this article 1 was selected for inclusion in the Classic Papers Revisited section of ANES-THESIOLOGY I was, of course, pleased. One dictionary definition of "classic" is "of lasting significance." I certainly hope this applies to the work selected. Although not consulted in the selection process, I can only say that I consider this study to be my single most important contribution to the massive literature encompassed by the topic "Pharmacologic Brain Protection." A photograph is available on the ANESTHESIOLOGY Web site at http://www.anesthesiology.org. The stimuli for pursuing this study were twofold. 1) Scientifically, there was at the time of this study in the early 70's a "chicken or egg" question: whether anesthetics primarily altered brain metabolism with resulting functional effects, or alternatively, primarily suppressed function with resulting metabolic effects; and 2) Clinically, barbiturates were being used to "protect" the brain during and after anoxic events (i.e., cardiac arrest) based upon an assumed metabolic suppressive effect that would reduce cerebral oxygen requirements. In a previous canine study 2 we had reported compelling (in our opinion), but indirect, evidence that thiopental (and other anesthetics) appeared to impact on brain function primarily and that cerebral metabolic suppression was entirely secondary. If so, this would negate possible brain "protective" effects in a clinical setting of hypoxia/ anoxia sufficient to abolish brain function (i.e., an isolectric EEG). This study was specifically designed to determine by direct approach the interrelationships between brain functional and metabolic effects. The hypothesis and the approach to test it were conceptually simple and straightforward. We used a canine model for the direct measurement of cerebral blood flow and metabolism, which we had previously described and validated 3 ; we in addition utilized extracorporeal circulation to support and maintain satisfactory systemic hemodynamics. The latter permitted the administration of massive doses of anesthetics (in this study, thiopental) which would otherwise overwhelm normal cardiac function. This in turn made possible the measurement of cerebral metabolic parameters in the presence and absence of cerebral function (as reflected by EEG activity) and as impacted upon by even massive doses of thiopental. The resulting observations relating the EEG reflected functional effects and the cerebral metabolic effects were remarkably consistent in a series of seven individual canine preparations. A constant intravenous infusion of thiopental initially produced the expected progressive decrease in cerebral oxygen consumption (CMR O2 ) while the EEG reflected increasing functional suppression. With the onset of an isoelectric EEG there was a simultaneous plateau effect on CMR O2 . This occurred at widely different total thiopental doses in dogs, but at Additional material related to this article can be found on the Anesthesiology Web site. Go to the following address, click on the Enhancements Index, and then scroll down to find the appropriate article and link