Anesthetic Neuroprotection? It's Complicated.

Abstract

Anesthesiology, V 126 • No 4 579 April 2017 A NESTHETICS possess num erous pharmacologic properties that could increase tolerance of brain to an ischemic insult. Despite investigation for over half a century,1 and robust demonstration of such benefit in laboratory animals,2 there is no solid evidence that anesthetic neuroprotection is present in humans.3 The article by Archer et al.4 in this issue of A nesthesiology provides considerable insight into this apparent paradox. It once seemed so straight forward. The brain consumes adenosine triphosphate at an incredible rate and holds little stores of this critical metabolite. Hence, continuous delivery of oxygen and glucose is essential to maintain adenosine triphosphate synthesis, neural function, and cellular integrity. Most anesthetics can markedly suppress metabolic rate. Thus, the duration the brain can survive in low-flow or no-flow states should be increased substantially. Neuroprotection investigation was focused on the perioperative environment for several decades. Anesthesiologists and surgeons were at the forefront of therapeutic stroke research. In the late 1980s, problems arose for the metabolic suppression hypothesis. Nonanesthetic drugs that had little or no effect on metabolic rate were found highly neuroprotective in the laboratory. Evidence rapidly grew in support of protective benefits from mild hypothermia, which again induced little change in metabolic rate. It was becoming clear that other neuroprotective mechanisms were important. And later, it became evident that exposure of brain to a mild stressor stimulus, either before (preconditioning) or after (postconditioning) a severe ischemic insult, set in play a biomolecular cascade that improved ischemic outcome. It is now known that anesthetics can also serve as effective conditioning stimuli, again independent of effects on metabolic rate during the ischemic insult. At the same time, a series of failures in detecting anesthetic neuroprotection in clinical trials accumulated, dashing almost all hope for such intervention. This caused a pivot of investigation away from neuroprotection in the perioperative environment toward development of nonanesthetic drugs relevant to the large number of patients who sustain out-of-hospital stroke. While the above logic sequence seems reasonable, is it all correct? The fact remains that after trials of scores of drugs in human stroke, other than tissue plasminogen activator, there is no pharmacologic intervention proven efficacious for any form of stroke in humans. This body of failure has led to serious questions regarding the pathway from bench to bedside for stroke drugs. Most such criticism has focused on the preclinical side of efficacy analysis. While major flaws in clinical trial designs must also be considered, lessons from the preclinical stroke research community are highly relevant to the study of anesthetics in the perioperative environment. Our method of translating from bench to operating table should also be reconsidered. This is where the study of Archer et al.4 becomes important. Using a robust search strategy, 80 laboratory investigations were identified that employed the intraluminal filament middle cerebral artery occlusion model5 to investigate anesthetic neuroprotection in rodents. Although this focal ischemia model has been criticized for nearinstantaneous flow restoration compared to gradual restoration of flow occurring with endogenous or pharmacologic thrombolysis,6 the model may be particularly relevant to anesthetic neuroprotection. Rapid flow restoration occurs with numerous perioperative events (e.g., temporary arterial occlusion during cerebral aneurysm or carotid surgery). Further, the model is widely employed allowing this search strategy to capture a large body of research. The model has been the workhorse for study of nonanesthetic neuroprotective drugs. Hence, parallels from that body of literature can be also drawn. The results of the Archer et al.4 analysis were surprising. Anesthetic Neuroprotection? It’s Complicated