As described in Chapter 6, Giles Merkel and I collaborated from 1961 through 1963¹ to define the anesthetic potency of halopropane in dogs. For our measure of potency, we settled on the minimum alveolar concentration (MAC) of halopropane that rendered 50% of the dogs unresponsive to tail clamping or electrical stimulation (they proved to be equivalently unpleasant). A year later, Larry Saidman and I extended the concept to humans (Figure 7.1).² We used reaction to surgical incision as the noxious stimulus, since response to electric current wasn’t particularly interesting in humans and tail clamping wasn’t an option. Our results showed that the addition of morphine premedication slightly decreased MAC for halothane, whereas concurrently administering nitrous oxide caused a dramatic reduction of MAC for halothane.

Larry and I enlisted the assistance of Bernard Brandstater, with whom I had previously collaborated to determine the solubility of methoxyflurane in rubber.³ This was useful because rubber was used in anesthesia circuits, altering anesthetic uptake. Additionally, primitive “anesthesia meters” were based on anesthetics taking the stretch out of rubber bands, with the result appearing on a calibrated scale.

In 1965, Brandstater, Saidman and I published three reports that refined the concept of MAC.⁴,⁵,⁶ The first of these showed that MAC as defined by the use of a supramaximal stimulus was constant from dog to dog (Table 7.1).⁴ We further showed that perturbations that did not unduly stress the central nervous system did not alter MAC. For example, increasing duration of anesthesia did not change MAC. Similarly, modest hypocapnia or hypercapnia did not affect MAC. Neither phenylephrine-induced hypertension, nor mild hypoxia (Pao₂ of 30-60 mm Hg) significantly changed MAC. We found that MAC decreased in certain potentially life-threatening situations. For example, severe hypoxia (Pao₂ <30 mm Hg) decreased MAC 25% to 50%. Hemorrhagic hypotension or marked metabolic acidosis might decrease MAC by 10% to 20%. We also noted that it was the absolute partial pressure that determined anesthetic effect, not the fraction of inspired gas. Therefore, we recommended that MAC, expressed as a percent of inspired gas, should always be calculated to reflect a partial pressure at sea level.

Our next report found that the MAC values of halothane and cyclopropane correlated directly with changes in body temperature.⁵ The correlation of MAC and temperature has clinical implications and also provides insight into possible mechanisms of inhaled anesthetic action. The correlation was steeper with the more potent, more lipid-soluble halothane.

We then reported MAC values for clinically and experimentally available volatile anesthetics: methoxyflurane, halothane, diethyl ether, fluroxene, cyclopropane, xenon, and nitrous oxide in dogs (Figure 7.2).⁶ This report provided the first of several forays into mechanisms of action by noting the correlation of MAC values with lipophilicity of the anesthetic examined, a finding consistent with the “theory” (really an observed correlation) proposed earlier by Meyer⁷ and Overton (Figure 7.3).⁸

The concept of MAC became fundamental to understanding inhaled anesthetic pharmacology. MAC became our primary research tool for describing the essence of anesthesia itself.