Hudson et al. BMC Anesthesiology 2014, 14:69 http://www.biomedcentral.com/1471-2253/14/69 RESEARCH ARTICLE Open Access Sugammadex is effective in reversing rocuronium in the presence of antibiotics Mark E Hudson1*, Henk Rietbergen2 and Jacques E Chelly1 Abstract Background: The effectiveness of sugammadex in reversing rocuronium-induced neuromuscular blockade (NMB) in the presence of drugs that may potentiate NMB remains to be fully established. The aim of this post-hoc analysis of data from a Phase III clinical trial (VISTA; NCT00298831) was to investigate the impact of antibiotics on recovery from rocuronium-induced NMB after administration of sugammadex for reversal, and compared the neuromuscular recovery in patients who received antibiotics preoperatively with those who did not. Methods: A Phase III, multicenter, open-label study designed to reflect potential use of sugammadex in clinical practice was conducted at 19 sites. Data obtained from patients who received antibiotics were compared with the cohort of patients who underwent the same protocol without antibiotics. Each subject received rocuronium 0.6 mg/kg for muscle relaxation, after which tracheal intubation was performed; patients were also permitted to receive maintenance doses of rocuronium 0.15 mg/kg to maintain the desired level of NMB throughout the operation, as required.. At least 15 min after the last rocuronium dose, patients received sugammadex 4.0 mg/kg for reversal. Neuromuscular monitoring was continued until a train-of-four (TOF) ratio of ≥0.9 was achieved or the anesthetic was discontinued. Results: The presence of antibiotics prior to the administration of sugammadex did not affect the recovery time from rocuronium-induced NMB when sugammadex 4.0 mg/kg was administered at least 15 min after the last dose of rocuronium. In the presence of antibiotics, the geometric mean (95% CI) time from administration of sugammadex 4.0 mg/kg to recovery of the TOF ratio to ≥0.9 was 1.6 (1.4–1.9) min (range: 0.7–10.5 min), compared with 2.0 (1.8–2.3) min (range: 0.7–22.3 min) for patients who did not receive antibiotics. Conclusions: These findings suggest that prophylactic antibiotic use is unlikely to have a major impact on the recovery time from rocuronium-induced NMB with sugammadex reversal. Trial registration: ClinicalTrials.gov Identifier: NCT00298831. Keywords: Sugammadex, Rocuronium, Neuromuscular blockade, Antibiotics Background [6-11], including several antibiotics [6,9-11]. Further- Sugammadex is a modified γ-cyclodextrin that effectively more, the presence of certain antibiotics may limit the reverses moderate and deep neuromuscular blockade ability of traditional reversal agents such as neostigmine (NMB) induced by the non-depolarizing muscle relax- to reverse NMB [6,12]. In cases where neostigmine is ants rocuronium and vecuronium [1-5]. However, the ef- found to be ineffective, this may be a consequence of the fectiveness of sugammadex in reversing rocuronium in antibiotic potentiating NMB through inhibition of acetyl- the presence of drugs that potentiate NMB remains to choline release from the nerve terminal. A reduced con- be fully established. Certain classes of drugs are known centration of acetylcholine would reduce competition for to potentiate the activity of the neuromuscular blocking the NMBA to bind to the nicotinic acetylcholine receptor , agents (NMBAs) if used in the perioperative setting thereby potentiating the NMB. However, since neo- stigmine works by reducing enzymatic breakdown of * Correspondence: [email protected] acetylcholine in the neuromuscular junction to increase 1Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA, USA the concentration of acetylcholine, thereby shifting the Full list of author information is available at the end of the article © 2014 Hudson et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hudson et al. BMC Anesthesiology 2014, 14:69 Page 2 of 5 http://www.biomedcentral.com/1471-2253/14/69 competition between acetylcholine and the NMBA for the general anesthesia requiring muscle relaxation. Non- binding site in favor of acetylcholine, a reduced availability standardized anesthesia was induced and maintained with of acetylcholine may subsequently limit the effectiveness an intravenous opioid, an anesthetic, and other agent(s) of neostigmine. according to the clinical need of each subject. Anesthesia Since sugammadex works by a different mechanism to practices not specified in the protocol were to be consist- neostigmine, forming 1:1 complexes with rocuronium or ent with the routine practices at the study site. Most pa- vecuronium, encapsulating the NMBA, resulting in its tients (99%) included in the study received propofol and/ inactivation [13], it is not anticipated that antibiotics will or an opioid for induction of anesthesia; the remaining impact on its ability to reverse rocuronium- or vecuronium- patients received either sevoflurane or desflurane. The induced NMB. In the current study, we investigate this most common anesthetics used for the maintenance of further. anesthesia were sevoflurane and desflurane, although some Since in previous studies conducted to assess the safety patients received either propofol or isoflurane. and efficacy of sugammadex, patients who received an- Neuromuscular monitoring was performed continuously tibiotics perioperatively were excluded, a post-hoc ana- at the adductor pollicis muscle with acceleromyography lysis of data from a Phase III clinical trial (study ID: (TOF-Watch® SX; Organon Ireland Ltd, a division of NCT00298831) was performed to assess the effects of Merck and Co., Dublin, Ireland). After calibration of the antibiotic administration on sugammadex properties in TOF-Watch, each subject received rocuronium 0.6 mg/kg reversing NMB produced by rocuronium. In an attempt for muscle relaxation, after which tracheal intubation was to reflect clinical practice in this Phase III study, there performed. Patients were permitted to receive mainten- were no restrictions on anesthetic regimen or procedure, ance doses of rocuronium 0.15 mg/kg upon reappearance with only limited restrictions on concomitant medications. of the second twitch of the train-of-four (TOF) to main- However, medications in a dose and/or at a time point tain NMB throughout the operation as required. At least known to interfere with the action of non-depolarizing 15 min after the last dose of rocuronium, patients received NMBAs, including antibiotics, were listed among the ex- sugammadex 4.0 mg/kg for reversal. Neuromuscular mon- clusion criteria. Despite this, a relatively large number of itoring was continued until a TOF ratio of ≥0.9 was patients received prophylactic antibiotics (per the routine achieved or the anesthetic was discontinued. The primary practice for several study sites) in deviation from the study efficacy variable was the time from the start of sugamma- protocol, thereby allowing comparison with those patients dex administration until recovery of the TOF ratio to ≥0.9. who did not receive antibiotics. Data analysis Methods Recovery times were summarized by geometric mean The Phase III (VISTA) study was a multicenter, open- (95% confidence interval [CI]) times, as these times were label study conducted at 19 sites in the USA between expected to follow a skewed distribution and the geo- October 2005 and May 2006, data from which have been metric mean is robust against data distributed in this published previously [1], and was designed to reflect a way [14]. Data were also summarized as number and potential use of sugammadex in clinical practice. This percentage of patients recovering to a TOF ratio of ≥0.9 study was conducted in accordance with principles of within each minute time interval after sugammadex ad- Good Clinical Practice and was approved by the appro- ministration. An analysis of variance (ANOVA) model priate institutional review boards and regulatory agen- was used to investigate the effect of depth of NMB at the cies (Additional file 1). Written informed consent was time of sugammadex administration (number of twitches obtained from all patients. Antibiotic use was listed to TOF stimulation: 0 or ≥1) and use of antibiotics on under the exclusion criteria, as antibiotics may interfere the (log) time to recovery to a TOF ratio of ≥0.9. This with the action of non-depolarizing NMBAs. In the ANOVA model also included study center. current post-hoc analysis to establish the impact of anti- Safety was assessed by adverse events (AEs, coded by biotic administration on the ability of sugammadex to re- Medical Dictionary for Regulatory Activities version 9.1), verse the muscle relaxant property of rocuronium, data laboratory variables, vital signs, and clinical signs of neuro- obtained from sugammadex-treated patients who received muscular recovery. antibiotics (deviating from the study protocol) were com- pared with the cohort of patients who underwent the Results same protocol without antibiotics. Of the 224 patients enrolled in the original trial, only pa- As previously described [1], inclusion criteria