A Randomized Trial Evaluating the Safety Profile of Sugammadex in High Surgical Risk ASA Physical Class 3 or 4 Participants

W. Joseph Herring; Yuki Mukai; Aobo Wang; Jeannine Lutkiewicz; John F. Lombard; Li Lin; Molly Watkins; David M. Broussard; Manfred Blobner

Disclosures

BMC Anesthesiol. 2021;21(259) 

In This Article

Background

Sugammadex (Bridion®, Merck & Co., Inc., Kenilworth, NJ, USA), a modified cyclodextrin, reverses neuromuscular blockade from the neuromuscular blocking agents, rocuronium and vecuronium.[1,2] Sugammadex encapsulates unbound rocuronium or vecuronium providing rapid and predictable reversal, and avoiding anticholinesterase side effects and antimuscarinic drug use.[3–5] Studies confirm the safety and efficacy of sugammadex for reversal of moderate or deep, rocuronium- or vecuronium-induced neuromuscular block;[6–11] however, randomized clinical trial data are limited in higher surgical risk ASA Physical Class 3 (defined as severe disease) or 4 (defined as severe systemic disease that is a constant threat to life) participants.[2,6]

Given the uniqueness of its engineered mechanism of action, sugammadex binds to no known human receptors and has no intrinsic biological activity, consistent with the notion that it is effectively inert. Results of in vitro, preclinical, and dedicated human studies have indicated that sugammadex has no direct effect on heart rate or electrical conduction within the heart.[3,12–16] The sugammadex mechanism of action does not suggest any effect on autonomic tone, cardiac impulse generation or cardiac conduction. In the overall comprehensive evaluation of cardiac safety in the sugammadex development program, bradycardia was infrequently observed.[16–20] Notably, bradycardia was not detected in the population of healthy participants studied who received only sugammadex without neuromuscular blocking agent (NMBA).[12,13] In clinical studies involving surgical patients, the rates of bradycardia observed with sugammadex administration consistently appeared lower than that of comparator neostigmine, a reversal agent for which co-administered countermeasures against bradycardia are typically given.[16]

Nevertheless, available approved clinical reports suggest that in rare cases, neuromuscular block reversal with sugammadex may be associated with marked bradycardia.[2,21] This risk of bradycardia, which is readily detectable in the perioperative setting, typically responds well to usual intervention and is appropriately addressed through existing product labelling.[17] While evidence is lacking to suggest a direct causal effect of sugammadex on heart rate, the clinical pattern of bradycardia does not rule out the possibility of an undefined indirect relationship.

Because ASA Physical Class 3 and 4 surgical patients may, by definition, be at higher risk for safety events including arrhythmias, this study was conducted to evaluate the overall safety profile of sugammadex in this important subpopulation with a focus on the comparative incidence of treatment-emergent (TE) cardiac arrhythmias after sugammadex vs neostigmine/glycopyrrolate administration.[22] The primary safety endpoints included incidences of TE sinus bradycardia, TE sinus tachycardia and other TE cardiac arrhythmias. Events of clinical interest (ECI) included clinically relevant (CR) sinus bradycardia, CR sinus tachycardia, other CR cardiac arrhythmias, drug-induced liver injury, and adjudicated hypersensitivity and anaphylaxis.

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