We are very grateful for the impassioned reading of our article1  by Drs. Kopman and Naguib as their contributions to the field of neuromuscular blockade research are outstanding. We understand their concern that our nuanced conclusion may be misinterpreted in the clinical world, especially one without better neuromuscular blockade reversal alternatives. We specifically performed our study to provide current and meaningful data to identify and/or reinforce best practices for the application of neostigmine in clinical settings where neuromuscular blockade reversal alternatives are unavailable. Our article is a hypothesis-driven study, and we draw our conclusions based on our data. We appreciate their perspective on our article and the opportunity to elaborate on our conclusion and address their question on our control for surgical complexity.

We agree with Drs. Kopman and Naguib that our study did not control for anatomical site of surgery, but we did control for “high-risk surgery” by using a method based on the previously published data.2  In addition, we addressed the concern of surgical procedure–related confounding with a follow-up study. In the June 2015 edition of Anesthesiology, our laboratory published a retrospective analysis of nearly 50,000 patients who received intermediate-acting nondepolarizing neuromuscular-blocking agents.3  This large sample size study controlled for both surgical body region and procedure relative value units. We identified a neostigmine dose-dependent increase in the risk of respiratory complications that is eliminated when neostigmine administration is guided by neuromuscular transmission monitoring.

The observed efficacy of neostigmine as a neuromuscular blockade reversal agent in clinical effectiveness studies, where clinicians independently administer and monitor its application, is different than in efficacy studies where clinicians follow strict protocols. Our article reinforces the phenomenon we have previously identified: Clinicians in everyday practice who routinely administer neostigmine reversal without neuromuscular transmission monitoring may be more likely to harm their patients than help.4,5  Drs. Kopman and Naguib noted this paradox in an earlier publication, “Routine reversal of residual neuromuscular block is less common in parts of Europe than in the US, yet Europeans are less likely to have witnessed postoperative residual paralysis.”6  This observation supports the argument that the clinical use of neostigmine as a reversal agent varies and that this variation in practice may explain the variance in the incidence of residual neuromuscular blockade and postoperative respiratory complications.

The sixteenth-century physician Paracelsus concluded, “All substances are poisons. The right dose differentiates a poison and a remedy.” Our data support the intraoperative monitoring of neuromuscular transmission, particularly before tracheal extubation. Intraoperative neuromuscular function should be evaluated by observing the mechanical response to peripheral nerve stimulation whenever a nondepolarizing relaxant is administered; clinical signs (e.g., head lift, hand grip, respiratory effort) are not adequate indicators of depth of neuromuscular blockade. Our data also support the dosing of neostigmine based on train-of-four monitoring.7 

The clinical take-home message is that the titration of neostigmine must be done carefully and under monitored conditions. We do not seek to have anything in both ways; we seek to have neostigmine administered in the safest way possible.

Dr. Eikermann, M.D., Ph.D., has filed a patent application for a new drug to reverse the effects of neuromuscular- blocking agents. In addition, he receives funding for investigator- initiated research from Merck, Whitehouse Station, New Jersey, and Massimo, Irvine, California. The other authors declare no competing interests.

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