Preface

v Although millions of people worldwide are anesthetized every year, we still have no true understanding of why the drugs we use do what they do. This remarkable lack of knowledge limits our ability to design drugs that would minimize or eliminate anesthetic side effects. Indeed, our anesthetic drugs are powerful poisons. The therapeutic index is defined as the lethal dose that kills 50% of the population divided by the effective dose for 50% of the population. For many drugs, the therapeutic index is several hundred or thousand fold; for anesthetics, the therapeutic index is only 3–4. This narrow margin of safety underscores the inherent danger of anesthetics. It is only because of the skill of well-trained anesthesiologists that anesthesia is relatively safe. Nonetheless, whereas serious complications such as death are rare, more bothersome complications (nausea, vomiting) are common, and are terribly distressing for patients. Only by thoroughly understanding how anesthetics exert their effects (good and bad) can we design drugs that will do one thing and one thing only—anesthetize patients, rendering them unconscious, amnestic, and insensible to noxious stimulation. Neural Mechanisms of Anesthesia represents our current understanding of anesthetic mechanisms. Its emphasis is rather different from other books on the subject, which in the past focused primarily on molecular mechanisms. We have chosen to examine anesthetic mechanisms at multiple levels: the molecule, the cell, organ systems, and the whole body (Fig. 1). This broad overview is necessary, we believe, because it is difficult to grasp the impact and importance of an experimental finding in the absence of the context of the whole animal or human. For example, when a researcher reports that isoflurane enhances opening time of a particular channel, what does that mean to a clinician? How does that action result in the clinically relevant actions of anesthetics (such as unconsciousness)? Furthermore, how much effect on opening time is required to get the relevant result? If the researcher reports that isoflurane at one minimum alveolar concentration enhances channel opening time 10%, is that sufficient to achieve a clinical goal? One can see the fundamental flaw in not being able to link these specific experimental findings with clinical observations. If we knew through some independent means that 50% enhancement (exclusive of any other action, an important and probably incorrect caveat) was required to cause unconsciousness, then we could conclude that this effect on opening time is not relevant. Thus, we must synthesize all the experimental findings at multiple levels in order to determine the relevance of each. Claude Bernard, the eminent 19th century scientist, clearly recognized the folly of narrowly viewing experimental findings: ... If we break up a living organism by isolating its different parts, it is only for the sake of ease in analysis and by no means in order to conceive them separately. Indeed when we wish to ascribe to a physiological quality its value and true significance we must always refer it to this whole and draw our final conclusions only in relation to its effects in the whole—CLAUDE BERNARD, 1865 Each researcher clearly examines the problem of anesthetic mechanisms from a different perspective, not unlike the six blind men of Indostan, who “examined” the elephant, each having different ideas about the elephant’s shape. In the end, though, the blind men had incomplete “visions” of the elephant: