Correspondence  |   June 2016
In Reply
Author Notes
  • Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (M.E.).
  • (Accepted for publication February 23, 2016.)
    (Accepted for publication February 23, 2016.)×
Article Information
Correspondence   |   June 2016
In Reply
Anesthesiology 6 2016, Vol.124, 1417-1418. doi:
Anesthesiology 6 2016, Vol.124, 1417-1418. doi:
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 (Emax) 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 Emax, 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 Emax 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.
Supported by Merck & Co., Inc., Kenilworth, New Jersey (to Dr. Eikermann).
Competing Interests
Dr. Eikermann holds equity shares of Calabash Bioscience, Inc. (College Park, Maryland), which is developing calabadion 2 for biomedical applications. The other author declares no competing interests.
Friederike Haerter, M.D., Matthias Eikermann, M.D., Ph.D. Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (M.E.).
Haerter, F, Simons, JC, Foerster, U, Moreno Duarte, I, Diaz-Gil, D, Ganapati, S, Eikermann-Haerter, K, Ayata, C, Zhang, B, Blobner, M, Isaacs, L, Eikermann, M Comparative effectiveness of calabadion and sugammadex to reverse non-depolarizing neuromuscular-blocking agents.. Anesthesiology. (2015). 123 1337–49 [Article] [PubMed]
Hoffmann, U, Grosse-Sundrup, M, Eikermann-Haerter, K, Zaremba, S, Ayata, C, Zhang, B, Ma, D, Isaacs, L, Eikermann, M Calabadion: A new agent to reverse the effects of benzylisoquinoline and steroidal neuromuscular-blocking agents.. Anesthesiology. (2013). 119 317–25 [Article] [PubMed]
Diaz-Gil, D, Mueller, N, Moreno-Duarte, I, Lin, H, Ayata, C, Cusin, C, Cotten, JF, Eikermann, M Etomidate and ketamine: Residual motor and adrenal dysfunction that persist beyond recovery from loss of righting reflex in rats.. Pharmaceuticals (Basel). (2014). 8 21–37 [Article] [PubMed]
Grosse-Sundrup, M, Henneman, JP, Sandberg, WS, Bateman, BT, Uribe, JV, Nguyen, NT, Ehrenfeld, JM, Martinez, EA, Kurth, T, Eikermann, M Intermediate acting non-depolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: Prospective propensity score matched cohort study.. BMJ. (2012). 345 e6329 [Article] [PubMed]
Ladha, K, Vidal Melo, MF, McLean, DJ, Wanderer, JP, Grabitz, SD, Kurth, T, Eikermann, M Intraoperative protective mechanical ventilation and risk of postoperative respiratory complications: Hospital based registry study.. BMJ. (2015). 351 h3646 [Article] [PubMed]
Holford, NH, Sheiner, LB Understanding the dose-effect relationship: Clinical application of pharmacokinetic-pharmacodynamic models.. Clin Pharmacokinet. (1981). 6 429–53 [Article] [PubMed]
Katzung, BG, Trevor, AJ, Masters, SB Pharmacodynamics, Katzung and Trevor’s Pharmacology, 13th edition. (2015). New York, McGraw-Hill 65–7
Agency for Healthcare Research and Quality: What is comparative effectiveness research.. Available at: Accessed February 19, 2015