Anesthetic drugs and sustained neuroprotection in acute cerebral ischemia: can we alter clinical outcomes?

Abstract

Anesthetic drugs have been tested for their neuroprotective characteristics for decades because of their potential either to interrupt or to slow the sequence of injurious biochemical and molecular events that ultimately result in irreversible neuronal death. Unfortunately, clinical trials examining the neuroprotective effects of anesthetic agents have failed to translate the experimental evidence. The purpose of this editorial is to consider the current stage of knowledge regarding anesthetic neuroprotection in the context of identifying future directions for this important field of research. A fundamental issue in establishing the need for perioperative neuroprotection is to identify target populations that will benefit neurologically from specific anesthetic agents. Perioperative cerebral ischemia remains a significant source of morbidity and mortality in cardiac and noncardiac patients alike. For example, the incidence of acute ischemic stroke varies from 0.8 to 8.8% in patients undergoing peripheral vascular, aortic reconstructive, and cardiac surgery. In patients undergoing colorectal surgery, total hip arthroplasty, and head and neck surgery, the incidence of perioperative stroke varies from 0.3 to 4.8%. Acute neurodegeneration may also present as postoperative neurocognitive decline. It is rather surprising, then, that this important pathogenicity has been disregarded as a target of neuroprotective strategies, yet it clearly deserves a neuroprotective approach. A second important issue is the need to establish the differential neuroprotective potential of the various general anesthetic agents. The proposed mechanisms of anesthetic neuroprotection include reduction of cerebral metabolism and intracranial pressure, suppression of seizure activity, and lessening of sympathetic discharge. Additionally, anesthetics inhibit synaptic release of excitatory neurotransmitters; they activate inhibitory c-aminobutyric acid (GABA) and glycine receptors and slow the intracellular Caand Naaccumulation. Additionally, anesthetics reduce the generation of reactive free radical species; they increase ischemic tolerance by preand post-conditioning, and they also inhibit apoptotic pathways. Thus, there is considerable evidence that multiple pathways exist by which anesthetic agents have the potential to exert clinically important benefits. But what is the experimental evidence for (sustained) anesthetic neuroprotection? In numerous studies, anesthetic neuroprotection has been confirmed in rodents subjected to focal or incomplete hemispheric ischemia where isoflurane, sevoflurane, desflurane, and xenon, as well as barbiturates and propofol, decreased infarct size and improved motor and cognitive function when given prior to the ischemic challenge. The reduction in ischemic neuronal injury has been shown to be most prominent in study designs comparing ‘‘anesthesia’’ with awake or sedated states and less pronounced when different anesthetics were compared with each other. Neurologic outcome is reproducible only with brief episodes of cerebral ischemia, while longer durations of low-flow states or permanent focal ischemia are resistant to anesthetic neuroprotection. In line with this evidence, anesthetics have no neuroprotective properties in the setting of global cerebral ischemia and when given after the ischemic insult. It is questionable whether the effects of anesthetics seen in these different ischemia models are permanent. Studies in rats subjected to focal cerebral or incomplete global ischemia have shown that cell death was substantially reduced in the immediate post-ischemic period; however, C. Werner, MD, PhD (&) Department of Anesthesiology, Johannes Gutenberg-Universitat Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany e-mail: wernerc@uni-mainz.de