In Reply

We recently reported that speed of reversal of rocuronium- and vecuronium-induced neuromuscular block is faster with calabadion compared with Bridion (sugammadex; Merck & Co., Inc., USA) given at an equimolar concentration.1 

The question was raised by Drs. Lim and Landsittel as to whether our study should be better characterized as an efficacy study rather than an effectiveness study. There seems to be a general confusion about the proper use of “efficacy and effectiveness” in the literature. We found 6,195 manuscripts listed in PubMed under “comparative effectiveness” and 2,724 manuscripts listed under “comparative efficacy”—it is hard to find in the examples we checked a clear pattern that distinguishes how researchers use these terms. It is also obvious that some researchers use these terms interchangeably, while others use them very specifically.

Our laboratory conducts preclinical effectiveness studies to develop new drugs.^2,3  We also conduct formal “quantitative effectiveness research” in order to evaluate perioperative treatments in a real-world scenario based on existing perioperative databases.^4,5  Our team uses the terms efficacy, effectiveness, and quantitative effectiveness research intentionally, as described below.

In pharmacology, efficacy (E_max) is defined as the maximum response (traditionally at a well-defined receptor) achievable from an agonist given at maximum tolerated doses.^6,7  In our paper under consideration here, we did not test efficacy. Bridion and calabadion are encapsulating agents that do not interact with a receptor, do not leave the blood vessels to act at the neuromuscular junction, and did not demonstrate so far biologic effects when given in the absence of a neuromuscular blocking agent. We did not administer maximum tolerated doses. Of note, we did not conduct pharmacokinetic/pharmacodynamic analyses required to determine E_max, as we did not intend to study if a further increase in blood concentration would have further increased speed of reversal.

In our study, we rather assessed “effectiveness,” the power to produce a desired effect⁸  between two reversal drugs (sugammadex and calabadion) given at the same molar concentrations in three models, in vitro, ex vivo, and in vivo. We found that calabadion 2 reversed rocuronium- and vecuronium-induced neuromuscular blockade with a 1:1 binding ratio, like sugammadex, but it had a higher in vitro binding affinity and a higher molar potency in vivo. Therefore, we argue that the effectiveness to reverse rocuronium- and vecuronium-induced neuromuscular blockade of calabadion is higher compared with Bridion. To our knowledge, the efficacy of these compounds has not been tested by us or by others in any previously published study , probably because E_max of encapsulating agents cannot be studied rigorously. In addition, knowledge on maximum speed of reversal of neuromuscular blockade by maximum tolerated doses of calabadion and sugammadex adds marginal value to the available literature on preclinical effectiveness of these encapsulating agents.