In Reply:
We thank Dr. Cross for his insightful comments concerning our recent article.1Dr. Cross makes several excellent points in regard to the nonlinear dose-response curves and the validity of partial minimum alveolar concentration (MAC) values.
In 1963, Merkel and Eger2originated the term MAC, describing it as an “index of comparison” for different anesthetic agents. They defined 1 MAC as the end-tidal concentration of anesthetic that prevents movement in 50% of animals in response to a supramaximal painful stimulus.2Subsequently, the use of MAC, to represent “a unifying concept of inhaled anesthetic potency” has grown to incorporate other clinical endpoints, such as MAC awake, MAC intubation, and MAC-BAR (blunt autonomic reflexes).3,4
The idea of partial MAC values has become part of the clinical jargon, and it is—more or less—an accurate reflection of partial potency because the slopes of the relationships for sevoflurane and isoflurane are quite similar. Moreover, it is common practice for patients as well as animals to use MAC multiples to compare the effects of various inhalational anesthetics on a wide variety of physiologic endpoints—for example, brain acetylcholine level,5cerebral blood flow,6vasoconstriction,7cardiac function,8and hemodynamics.9In fact, many reviewers insist on the use of MAC multiples.
As Dr. Cross suggests, in terms of equal points on two separate dose-response curves for our study, a more precise comparison would have been 1 MAC isoflurane versus 1 MAC sevoflurane. Unfortunately, neonatal mice do not tolerate prolonged exposure to isoflurane at 1 MAC without developing confounding physiologic derangements.10Thus, we used a lower concentration, that, by design, is commonly used clinically. This clinical applicability was an essential goal of our study, to compare the neurotoxicity of two agents at concentrations used clinically. We certainly agree with Dr. Cross that a more thorough method of comparing anesthetic neurotoxic potency would involve constructing full dose–response curves for apoptosis (or other endpoints) for each agent. Nevertheless, our results speak to common clinical practice as the immediate goal. We recognize that further work is necessary to establish the comparative mechanistic basis for these findings.
*University of Pennsylvania, Philadelphia, Pennsylvania. weih@uphs.upenn.edu
