Reducing the Fear of Intraoperative Awareness

THERE are three fundamental goals of anesthesia: unconsciousness, amnesia, and immobility. In years past, most people would have assumed that anesthetics act in the brain to produce all three of these goals. In the past decade, data have emerged indicating that immobility is likely produced by anesthetic action in the spinal cord, prompting a reexamination of “macroscopic” sites of anesthetic action. With regard to amnesia, the hippocampus is certainly involved in declarative memory, and hippocampal lesions can result in profound amnesia. However, the role of other brain areas, such as amygdala and entorhinal cortex, in memory formation is complex and apparently dependent on subtle aspects of the memory task. What is the role, if any, of these structures in anesthetic-induced amnesia? The report by Alkire and Nathan in this issue of ANESTHESIOLOGY provides interesting data supporting the amygdala as a site at which inhaled anesthetics exert an amnestic effect on fear conditioning, one form of memory. The amygdala is strongly implicated in learning under emotionally charged settings such as fear. An inhibitory avoidance paradigm was used by Alkire and Nathan in which rats were placed in a lighted chamber facing a dark tunnel, which they normally prefer to enter. However, entrance into the dark area was negatively reinforced by electrical shock; rats quickly learned to avoid entering the dark tunnel and remained in the nonpreferred but “safe” lighted environment. When retested the next day, the rats continued to avoid entering the dark tunnel; their memory retention latency (i.e., time to enter the dark tunnel) was very long, indicating that they remember being shocked. If a low concentration of sevoflurane was administered during the initial training period, the animals quickly entered the dark tunnel the following day, i.e., sevoflurane prevented avoidance learning. However, after bilateral lesion of the basolateral amygdala, rats exhibited equally long memory retention latencies regardless of whether low-dose sevoflurane was given. These data suggest that, at least for this type of learning, the basolateral amygdala is not the critical site for memory storage and that sevoflurane (and propfol and diazepam) acts in that structure to block this learning. It should be noted that the absence of amnesia in the amygdala-lesioned animals reported by Alkire and Nathan is at odds with the findings of other groups. In any event, the data imply that in the intact animal, sevoflurane activates pathways in the basolateral amygdala that exert an inhibitory effect on avoidance learning at sites outside the lesioned area of the basolateral amygdala. The data of diazepam, propofol, and sevoflurane with respect to inhibitory avoidance are remarkably similar. Figure 2 in Tomaz et al., figure 4 of Alkire et al., and figure 3 of Alkire and Nathan, aside from slight differences in control latency, are virtually superimposable. Because diazepam and propofol act almost exclusively at the -aminobutyric acid receptor type A (GABAA) receptor and sevoflurane also enhances GABAA receptor function, it seems logical to conclude that sevoflurane produces its effect on the amygdala at the GABAA receptor. Ketamine, however, has virtually no action at the GABAA receptor, but it produces amnesia in a dose range equipotent to that of volatile anesthetics. Therefore, it would be folly to assume that, for amnesia, all anesthetics must act at the amygdala and/or via a GABAA receptor effect. Furthermore, the nonimmobilizer 1,2-dichlorohexafluorocyclobutane abolishes fear conditioning, but low-dose isoflurane reverses, not potentiates, this action, underscoring the complex nature of memory and anesthetic-induced amnesia. Clearly, more work is needed to identify the molecular and cellular mechanisms by which memory formation is prevented by inhaled and intravenous anesthetic agents. The data of Alkire and Nathan indicate that the basolateral amygdala is quite sensitive to sevoflurane. The control animals in their study lost memory (or never learned) when the sevoflurane concentration was 0.3%—only 0.15 minimum alveolar concentration (MAC). It is unclear whether other structures associated with memory formation (e.g., hippocampus) are more or less sensitive. Anesthetic effects on fear to context and tone have been extensively studied. Interestingly, fear to context has anesthetic sensitivity comparable to that of inhibitory avoidance, but ablation of fear to tone requires twice as much anesthesia. Nonetheless, the results emphasize the importance of investigating the sites of anesthetic-induced amnesia. It is unknown, however, whether anesthetic action at one single anatomical site in humans prevents all intraoperative memories (implicit This Editorial View accompanies the following article: Alkire MT, Nathan SV: Does the amygdala mediate anesthetic-induced amnesia? Basolateral amygdala lesions block sevoflurane-induced amnesia. ANESTHESIOLOGY 2005; 102:754–60.