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

Abstract

Background: The aim of this randomized, double-blind trial was to evaluate the safety and tolerability profile, including cardiac safety, of sugammadex-mediated recovery from neuromuscular block in participants undergoing surgery who met the American Society of Anesthesiologists (ASA) Physical Class 3 or 4 criteria. Specifically, this study assessed the impact of sugammadex on cardiac adverse events (AEs) and other prespecified AEs of clinical interest.

Methods: Participants meeting ASA Class 3 and 4 criteria were stratified by ASA Class and NMBA (rocuronium or vecuronium) then randomized to one of the following: 1) Moderate neuromuscular block, sugammadex 2 mg/kg; 2) Moderate neuromuscular block, neostigmine and glycopyrrolate (neostigmine/glycopyrrolate); 3) Deep neuromuscular block, sugammadex 4 mg/kg; 4) Deep neuromuscular block, sugammadex 16 mg/kg (rocuronium only). Primary endpoints included incidences of treatment-emergent (TE) sinus bradycardia, TE sinus tachycardia and other TE cardiac arrhythmias.

Results: Of 344 participants randomized, 331 received treatment (61% male, BMI 28.5 ± 5.3 kg/m2, age 69 ± 11 years). Incidence of TE sinus bradycardia was significantly lower in the sugammadex 2 mg/kg group vs neostigmine/glycopyrrolate. The incidence of TE sinus tachycardia was significantly lower in the sugammadex 2 and 4 mg/kg groups vs neostigmine/glycopyrrolate. No significant differences in other TE cardiac arrythmias were seen between sugammadex groups and neostigmine/glycopyrrolate. There were no cases of adjudicated anaphylaxis or hypersensitivity reactions in this study.

Conclusions: Compared with neostigmine/glycopyrrolate, incidence of TE sinus bradycardia was significantly lower with sugammadex 2 mg/kg and incidence of TE sinus tachycardia was significantly lower with sugammadex 2 mg/kg and 4 mg/kg. These results support the safety of sugammadex for reversing rocuronium- or vecuronium-induced moderate and deep neuromuscular block in ASA Class 3 or 4 participants.

Trial registration: ClinicalTrials.gov Identifier: NCT03346057 .

Keywords: ASA physical class 3 or 4; Sugammadex: safety.

Conflict of interest statement

W.J.H., Y.M., A.W., J.L., J.F.L., L.L., and M.W. are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD). D.M.B. declares funding research and consulting fees from Merck & Co., Inc., Kenilworth, NJ, USA. M.B. declares grants and personal fees from MSD, Haar, Germany; personal fees from Grünenthal, Aachen, Germany; and personal fees from GE Healthcare, Helsinki, Finland.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Description of (A) study design and (B) randomization scheme a Participants were also stratified by neuromuscular blocking agent, rocuronium or vecuronium
Fig. 2
Fig. 2
Participant disposition flow chart

References

    1. Welliver M, Cheek D. An update on sugammadex sodium. AANA J. 2009;77(3):219–228.
    1. Honing G, Martini CH, Bom A, van Velzen M, Niesters M, Aarts L, Dahan A, Boon M. Safety of sugammadex for reversal of neuromuscular block. Expert Opin Drug Saf. 2019;18(10):883–891. doi: 10.1080/14740338.2019.1649393.
    1. Bom A, Bradley M, Cameron K, Clark JK, Van Egmond J, Feilden H, MacLean EJ, Muir AW, Palin R, Rees DC, et al. A novel concept of reversing neuromuscular block: chemical encapsulation of rocuronium bromide by a cyclodextrin-based synthetic host. Angew Chem Int Ed Engl. 2002;41(2):266–270. doi: 10.1002/1521-3773(20020118)41:2<265::AID-ANIE265>;2-Q.
    1. de Boer HD, van Egmond J, van de Pol F, Bom A, Booij LH. Reversal of profound rocuronium neuromuscular blockade by sugammadex in anesthetized rhesus monkeys. Anesthesiology. 2006;104(4):718–723. doi: 10.1097/00000542-200604000-00016.
    1. Epemolu O, Bom A, Hope F, Mason R. Reversal of neuromuscular blockade and simultaneous increase in plasma rocuronium concentration after the intravenous infusion of the novel reversal agent Org 25969. Anesthesiology. 2003;99(3):632–637. doi: 10.1097/00000542-200309000-00018.
    1. Flockton EA, Mastronardi P, Hunter JM, Gomar C, Mirakhur RK, Aguilera L, Giunta FG, Meistelman C, Prins ME. Reversal of rocuronium-induced neuromuscular block with sugammadex is faster than reversal of cisatracurium-induced block with neostigmine. Br J Anaesth. 2008;100(5):622–630. doi: 10.1093/bja/aen037.
    1. Sacan O, White PF, Tufanogullari B, Klein K. Sugammadex reversal of rocuronium-induced neuromuscular blockade: a comparison with neostigmine-glycopyrrolate and edrophonium-atropine. Anesth Analg. 2007;104(3):569–574. doi: 10.1213/01.ane.0000248224.42707.48.
    1. Blobner M, Eriksson LI, Scholz J, Motsch J, Della Rocca G, Prins ME. Reversal of rocuronium-induced neuromuscular blockade with sugammadex compared with neostigmine during sevoflurane anaesthesia: results of a randomised, controlled trial. Eur J Anaesthesiol. 2010;27(10):874–881. doi: 10.1097/EJA.0b013e32833d56b7.
    1. Jones RK, Caldwell JE, Brull SJ, Soto RG. Reversal of profound rocuronium-induced blockade with sugammadex: a randomized comparison with neostigmine. Anesthesiology. 2008;109(5):816–824. doi: 10.1097/ALN.0b013e31818a3fee.
    1. Wu X, Oerding H, Liu J, Vanacker B, Yao S, Dahl V, Xiong L, Claudius C, Yue Y, Huang Y, et al. Rocuronium blockade reversal with sugammadex vs neostigmine: randomized study in Chinese and Caucasian subjects. BMC Anesthesiol. 2014;14:53. doi: 10.1186/1471-2253-14-53.
    1. Herring WJ, Woo T, Assaid CA, Lupinacci RJ, Lemmens HJ, Blobner M, Khuenl-Brady KS. Sugammadex efficacy for reversal of rocuronium- and vecuronium-induced neuromuscular blockade: a pooled analysis of 26 studies. J Clin Anesth. 2017;41:84–91. doi: 10.1016/j.jclinane.2017.06.006.
    1. Merck Sharp & Dohme Corp . Anesthetic and Analgesic Drug Products Advisory Committee Meeting. Washington DC: US Federal Drug Association; 2015. Sugammadex Advisory Committee Briefing Document. Sugammadex Injection NDA 22225.
    1. de Kam PJ, van Kuijk J, Prohn M, Thomsen T, Peeters P. Effects of sugammadex doses up to 32 mg/kg alone or in combination with rocuronium or vecuronium on QTc prolongation: a thorough QTc study. Clin Drug Investig. 2010;30(9):599–611. doi: 10.2165/11537210-000000000-00000.
    1. de Boer HD, van Egmond J, van de Pol F, Bom A, Booij LH. Sugammadex, a new reversal agent for neuromuscular block induced by rocuronium in the anaesthetized Rhesus monkey. Br J Anaesth. 2006;96(4):473–479. doi: 10.1093/bja/ael013.
    1. Bom A, Hope F, Rutherford S, Thomson K. Preclinical pharmacology of sugammadex. J Crit Care. 2009;24(1):29–35. doi: 10.1016/j.jcrc.2008.10.010.
    1. Hurford WE, Welge JA, Eckman MH. Sugammadex versus neostigmine for routine reversal of rocuronium block in adult patients: a cost analysis. J Clin Anesth. 2020;67:110027. doi: 10.1016/j.jclinane.2020.110027.
    1. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. BRIDION (sugammadex) [package insert]. Highlights of Prescribing Information. U.S. Food & Drug Administration Website. . Revised Dec 2015. Accessed 02 Jun 2021.
    1. Hunter JM, Naguib M. Sugammadex-induced bradycardia and asystole: how great is the risk? Br J Anaesth. 2018;121(1):8–12. doi: 10.1016/j.bja.2018.03.003.
    1. Bhavani SS. Severe bradycardia and asystole after sugammadex. Br J Anaesth. 2018;121(1):95–96. doi: 10.1016/j.bja.2018.02.036.
    1. Dahl V, Pendeville PE, Hollmann MW, Heier T, Abels EA, Blobner M. Safety and efficacy of sugammadex for the reversal of rocuronium-induced neuromuscular blockade in cardiac patients undergoing noncardiac surgery. Eur J Anaesthesiol. 2009;26(10):874–884. doi: 10.1097/EJA.0b013e32832c605b.
    1. US Food and Drug Administration: FDA Adverse Events Reporting System (FAERS) Public Dashboard.; 2020. Accessed 02 Jun 2021.
    1. American Society of Anesthesiologists. ASA Physical Status Classification System. Schaumburg: ASA website. Updated Dec 13, 2020. Accessed 02 Jun 2021
    1. Horrow JC, Li W, Blobner M, Lombard J, Speek M, DeAngelis M, Herring WJ. Actual versus ideal body weight dosing of sugammadex in morbidly obese patients offers faster reversal of rocuronium- or vecuronium-induced deep or moderate neuromusculalr block: a randomized clinical trial. BMC Anesthesiol. 2021;21(1):62. doi: 10.1186/s12871-021-01278-w.
    1. Lee C, Jahr JS, Candiotti KA, Warriner B, Zornow MH, Naguib M. Reversal of profound neuromuscular block by sugammadex administered three minutes after rocuronium: a comparison with spontaneous recovery from succinylcholine. Anesthesiology. 2009;110(5):1020–1025. doi: 10.1097/ALN.0b013e31819dabb0.
    1. Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 1985;4(2):213–226. doi: 10.1002/sim.4780040211.
    1. De Cassai A, Boscolo A, Tonetti T, Ban I, Ori C. Assignment of ASA-physical status relates to anesthesiologists' experience: a survey-based national-study. Korean J Anesthesiol. 2019;72(1):53–59. doi: 10.4097/kja.d.18.00224.

Source: PubMed

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