Proost et al. have several concerns regarding our study. 1First, they mention other work in the field. We might add the work of Stanski et al. , 2who proposed that “k eo[the rate constant for equilibration between plasma and the effect site] will be directly proportional to perfusion of the neuromuscular junction and inversely proportional to the blood–muscle drug partition coefficient.” Proost et al. ’s notion of buffering equates to that for partitioning, i.e. , a larger tissue/plasma partition coefficient equates to a larger buffering. We assume that within a given series of muscle relaxants, the same magnitude of relaxation results from the action of a specific number of relaxant molecules at the effect site. A drug that has a small muscle/plasma partition coefficient (i.e. , is poorly “buffered”) requires a large plasma concentration (necessitating a large dose) to yield a sufficient number of (unbuffered) molecules at the neuromuscular junction. Such a drug would have a fast onset, equivalent to the rapid equilibration observed with a poorly soluble inhaled drug such as nitrous oxide. Studies by Bowman et al. , 3Donati and Meistelman, 4Kopman, 5and from our group 6support this relationship between k eo, onset, and potency.
Second, Proost et al. question whether a large k eoalso explains rapacuronium's rapid offset of neuromuscular effect. A large k eopermits a rapid plasma-effect site equilibration during both onset and offset. Thus, as soon as effect-site concentration peaks, the large k eopermits effect-site concentration to track the rapidly decreasing plasma concentration. As previously explained, k eoalso affects potency, i.e. , the smaller the value for k eo, the larger the dose required to achieve the same peak effect-site concentration. Thus, a smaller k eorequires administration of a larger dose to achieve the same peak effect. In turn, the larger dose produces a slower recovery. These phenomenon are illustrated in figure 1
. An additional factor contributing to rapacuronium's rapid recovery profile is its large plasma clearance. However, differences between drugs in their plasma clearances is not sufficient to explain differences in recovery profile: mivacurium's clearance far exceeds that of rapacuronium. In addition, rocuronium's recovery profile is similar to that of vecuronium despite its smaller clearance.
Proost et al. note our statement that “despite [their] lack of comparative data, Schiere et al. concluded…” When our manuscript was published in January 1999, the only public information regarding the study by Schiere et al. was an abstract 7that included no data regarding the potency of rapacuronium. Although we were aware of Schiere et al. ’s results from unpublished sources, it would have been inappropriate for us to “scoop” them regarding their study that was published 2 months later!8
Finally, Proost et al. challenge our recommendations to study volunteers using a crossover design to determine the relative potency of rapacuronium and its metabolite. One assumption in analyzing data from an unpaired study is that groups differ only in a single factor, in this case, the drug under investigation. Unless subjects are carefully matched, this assumption may be flawed. One means to assure that subjects in different groups are comparable is to study each individual on more than one occasion, i.e. , a crossover design. Proost et al. are concerned that studies in volunteers undergoing anesthesia might not apply to patients undergoing anesthesia and surgery. We contend that anesthetized volunteers differ minimally from healthy patients undergoing minimally invasive surgery. If different surgical procedures affect the pharmacokinetics/pharmacodynamics of a compound, then studies need to be performed in patients undergoing those specific procedures; in turn, Schiere et al. should report what types of procedures their patients underwent.
Kopman disputes our claim that time to 25% twitch recovery after rapacuronium is “only slightly longer than after succinylcholine.” As Kopman notes, data supporting our statement are provided in the same sentence. Rather than debate nuances of language, we note that the onset of rapacuronium is faster than that of presently available nondepolarizing muscle relaxants, and its recovery profile is matched only by mivacurium.