Abstract
Background: Sugammadex, a modified γ-cyclodextrin, facilitates rapid reversal of rocuronium- and vecuronium-induced neuromuscular blockade (NMB). Cyclodextrins are known for their ability to form inclusion complexes with various drugs. Theoretically, molecules with a high affinity for sugammadex could interact and displace sugammadex from the sugammadex-rocuronium or sugammadex-vecuronium complex, potentially resulting in the recurrence of NMB due to recirculation of free rocuronium or vecuronium.
Objective: This study aimed to evaluate whether the administration of high doses of flucloxacillin or diclofenac can result in recurrence of NMB through displacement of sugammadex from its complex with rocuronium or vecuronium, following successful reversal of NMB by a suboptimal dose of sugammadex 2 mg/kg. Flucloxacillin has previously been identified using a modelling approach as a drug with displacement potential, while diclofenac was assessed due to its common intravenous use in the peri-operative and post-surgery setting.
Methods: This was a randomized, open-label, parallel, single-centre study conducted at SGS Life Services-CPU, Antwerp, Belgium. Twenty-four healthy, propofol-anaesthetized, adult volunteers were randomized to either rocuronium 0.6 mg/kg or vecuronium 0.1 mg/kg, followed by a suboptimal dose of sugammadex 2 mg/kg 15 minutes after induction of NMB. Five minutes after successful sugammadex reversal, subjects received either diclofenac 75 mg (15-minute infusion) or flucloxacillin 2 g (5-minute infusion) according to randomization. The suboptimal dose of sugammadex and relatively high doses of diclofenac and flucloxacillin were applied to create favourable conditions for the potential displacement of sugammadex from the sugammadex-rocuronium or sugammadex-vecuronium complex, and thus possible recurrence of NMB due to recirculation of free rocuronium or vecuronium. Possible recurrence of NMB was assessed by neuromuscular monitoring, performed with acceleromyography, and was continued until ∼90 minutes after the start of diclofenac or flucloxacillin administration. Recurrence of NMB was concluded if three consecutive train-of-four (TOF) ratios were <0.8.
Results: Following successful reversal with a suboptimal dose of sugammadex 2 mg/kg administered 15 minutes after NMB induction, subsequent administration of diclofenac or flucloxacillin did not result in recurrence of NMB in any subject based on measurement of TOF ratios during anaesthesia and neuromuscular function tests upon awakening. There were no adverse events considered to be related to sugammadex.
Conclusion: Administration of flucloxacillin or diclofenac does not result in recurrence of NMB through displacement of sugammadex from the sugammadex-rocuronium or sugammadex-vecuronium complex.
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Acknowledgements
The authors are responsible for the work described in this paper. All authors were involved in at least one of the following: conception, design, acquisition, analysis, statistical analysis or interpretation of the data, as well as drafting the manuscript and/or revising the manuscript for important intellectual content. All authors provided final approval of the version to be published.
Medical writing and editorial assistance was provided by Neil Venn, PhD, of Prime Medica Ltd (Knutsford, Cheshire, UK), during the preparation of this manuscript. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Sources of financial support: MSD, Oss, the Netherlands provided financial support for the conduct of the study.
Disclosures: Pieter-Jan de Kam (Whitehouse Station, NJ, USA) and Michiel van den Heuvel and Peter Grobara (both Oss, the Netherlands) are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA, who may potentially own stock and/or hold stock options in the Company; Pierre Peeters and Alex Zwiers are former employees of Merck Sharp & Dohme Corp. Jean-Luc Jadoul, Erik de Clerck and Steven Ramael received financial support from Merck Sharp & Dohme Corp. for the study conduct. Steven Ramael is an employee of SGS Life Science Services, the Clinical Research Organization to whom the study was outsourced. Jean-Luc Jadoul and Erik de Clerck are both anaesthesiologists at the ZNA Stuivenberg-Sint Erasmus Hospitals, working as co-investigators subcontracted by SGS Life Science Services to provide necessary anaesthetic care.
Meetings at which the work has been presented: Annual Meeting of the American Society of Anesthesiologists, October 17–21, 2009, New Orleans, LA.
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de Kam, PJ., van den Heuvel, M.W., Grobara, P. et al. Flucloxacillin and Diclofenac do not Cause Recurrence of Neuromuscular Blockade after Reversal with Sugammadex. Clin Drug Investig 32, 203–212 (2012). https://doi.org/10.2165/11598980-000000000-00000
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DOI: https://doi.org/10.2165/11598980-000000000-00000