In Reply:--We appreciate the interest of Savarese et al. in our publications about antagonism of mivacurium-induced paralysis. [1,2]We agree that antagonism of neuromuscular blockade is a complex process that involves both the pharmacokinetics and the inherent "reversibility" of the muscle relaxant. For most nondepolarizing muscle relaxants, administration of either edrophonium or neostigmine presumably does not alter the pharmacokinetics of the muscle relaxant; we demonstrated this for vecuronium. [1,2]The observation by Cook et al.* that "edrophonium …[has] no effect on the in vitro metabolism of mivacurium" led to the assumption that mivacurium's elimination would not be affected in vivo by edrophonium. [3]However, our recent studies in patients demonstrate that both edrophonium and neostigmine alter mivacurium's elimination, [1,2]thereby indicating the greater complexity of antagonism of mivacurium. In that mivacurium is eliminated by cholinesterase, we are surprised that so little data regarding the in vivo effects of cholinesterase inhibitors were available before mivacurium's release to the clinical community.

Savarese et al. question the direct clinical applicability of our studies. Studies are sometimes designed to isolate the contribution of single variables (e.g., intrinsic "reversibility" of the muscle relaxant) while maintaining constant concentrations of the anesthetic, muscle relaxant, and end-tidal PCO2. We have acknowledged this "limitation" of our studies. A common approach to examine antagonism of muscle relaxants is to give an antagonist during recovery from a single bolus dose of a muscle relaxant. Such a design might closely resemble some clinical practice. However, it does not replicate those anesthetics during which a muscle relaxant is given repeatedly or by infusion and cumulative effects of the muscle relaxant (even mivacurium)[4]might hinder recovery. To be clinically relevant, studies should examine antagonism under a variety of adverse conditions, including prolonged administration, profound paralysis, organ dysfunction, and hypothermia.

Savarese et al. claim that antagonism of block > 90% is probably inappropriate. Although this may be true theoretically, antagonism of profound block is probably common practice, as shown by the existence of several studies in which antagonism of profound paralysis was examined. In the absence of the sophisticated monitoring tools available to researchers, clinicians are probably unable to distinguish between twitch depression < 90% and > 90%. In support of this, clinicians consistently underestimate residual paralysis during recovery [5]; however, similar studies to assess profound paralysis are lacking.

Are we "way out on a limb" speculating about other routes of elimination of mivacurium? If so, we are in good company--Savarese et al. [6]speculated that their results regarding mivacurium's duration of action "may suggest additional routes of metabolism and/or elimination." Finally, Savarese et al. suggest that appropriate antagonism of mivacurium requires stopping mivacurium administration and waiting for the presence of two twitches in a train-of-four. We eagerly await studies of this regimen.

Dennis M. Fisher, M.D., Professor of Anesthesia, and Pediatrics.

Janos Szenohradszky, M.D., Assistant Professor of Anesthesia University of California, San Francisco, San Francisco, California 94143–0648.

Paul S. Hart, M.B., London, England.

*Cook DR, Chakravorti S, Brandom BW, Stiller RL: Effects of neostigmine, edrophonium and succinylcholine on the in vitro metabolism of mivacurium: Clinical correlates (abstract). ANESTHESIOLOGY 1992; 77:A948.

Hart PS, Wright PMC, Brown R, Lau M, Sharma M, Miller RD, Gruenke L, Fisher DM: Edrophonium increases mivacurium concentrations during constant mivacurium infusion, and large doses minimally antagonize paralysis. ANESTHESIOLOGY 1995; 82:912-8.
Szenohradszky J, Lau M, Brown R, Sharma ML, Fisher DM: The effect of neostigmine on twitch tension and muscle relaxant concentration during infusion of mivacurium or vecuronium. ANESTHESIOLOGY 1995; 83:83-7.
Savarese JJ: Reversal and monitoring of neuromuscular blockade: Changing attitudes. 1994 Review Course Lectures, 68th Congress of the International Anesthesia Research Society, 1994, pp 100-6.
Shanks CA, Fragen RJ, Pemberton D, Katz JA, Risner ME: Mivacurium-induced neuromuscular blockade following single bolus doses and with continuous infusion during either balanced or enflurane anesthesia. ANESTHESIOLOGY 1989; 71:362-6.
Brull SJ, Silverman DG: Visual and tactile assessment of neuromuscular fade. Anesth Analg 1993; 77:352-25.
Savarese JJ, Ali HH, Basta SJ, Embree PB, Scott RPF, Sunder N, Weakly JN, Wastila WB, El-Sayad HA: The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U), a short-acting nondepolarizing ester neuromuscular blocking drug. ANESTHESIOLOGY 1988; 68:723-32.