Effects of sugammadex on activated partial thromboplastin time and prothrombin time in healthy subjects.

OBJECTIVES: To assess the impact of sugammadex on activated partial thromboplastin time (APTT) and international normalized ratio for prothrombin time (PT(INR)) in healthy subjects and characterize the concentration-dependency of sugammadex effects on APTT and prothrombin time (PT) in normal human plasma in vitro. METHODS: Eight healthy subjects (18 - 45 years of age) were administered intravenous doses of 4 mg/kg sugammadex, 16 mg/kg sugammadex, or placebo in a randomized, placebo-controlled, three period cross-over trial. The primary endpoint was area under the curve from 2 to 60 minutes post-dose (AUC2-60min) for APTT and PT(INR). In vitro, the effects of sugammadex on APTT and PT were assessed in pooled normal human citrate plasma. RESULTS: In subjects dosed with 4 and 16 mg/kg sugammadex, geometric mean ratios (treated vs. placebo) for AUC2-60min were 1.085 (95% confidence interval, 0.888 - 1.325) and 1.019 (0.868 - 1.195), respectively, for APTT, and 1.047 (0.904 - 1.213) and 1.096 (0.953 - 1.261), respectively, for PT(INR). At individual timepoints, mean APTT and PT(INR) increased by up to 22% after 16 mg/kg sugammadex compared with placebo. All such increases occurred within 30 minutes post-dose. Sugammadex was generally well tolerated. In the in vitro experiments, addition of sugammadex to plasma resulted in limited, concentration dependent increases in both APTT and PT. At 200 µg/mL (the mean maximum concentration reached therapeutically), the relative increases were 29% and 19%, respectively. CONCLUSIONS: Administration of sugammadex is associated with a dose-related, limited and transient prolongation of APTT and PT(INR) that is unlikely to be of clinical relevance.

Deep Neuromuscular Blockade Improves Laparoscopic Surgical Conditions: A Randomized, Controlled Study.

INTRODUCTION: Sustained deep neuromuscular blockade (NMB) during laparoscopic surgery may facilitate optimal surgical conditions. This exploratory study assessed whether deep NMB improves surgical conditions and, in doing so, allows use of lower insufflation pressures during laparoscopic cholecystectomy. We further assessed whether use of low insufflation pressure improves patient pain scores after surgery. METHODS: This randomized, controlled, blinded study (NCT01728584) compared use of deep (1-2 post-tetanic-counts) or moderate (train-of-four ratio 10%) NMB, and lower (8 mmHg) or higher (12 mmHg; 'standard') insufflation pressure in a 2 × 2 factorial design. Primary endpoint was surgeon's overall satisfaction with surgical conditions, rated at end of surgery using an 11-point numerical scale. Post-operative pain scores were also evaluated. Data were analyzed using analysis of covariance. RESULTS: Of 127 randomized patients, 120 had evaluable data for the primary endpoint. Surgeon's score of overall satisfaction with surgical conditions was significantly higher with deep versus moderate NMB indicated by a least-square mean difference of 1.1 points (95% confidence interval 0.1-2.0; P = 0.026). Furthermore, strong evidence of an effect was observed for standard versus low pressure: least-square mean difference of 3.0 points (95% confidence interval 2.1-4.0; P < 0.001). No significant difference was observed in average pain scores within 24 h post-surgery for low versus standard pressure [0.17 (95% confidence interval -0.67 to +0.33); P = 0.494]. CONCLUSIONS: Although associated with significantly improved surgical conditions, deep NMB alone was insufficient to promote use of low insufflation pressure during laparoscopic cholecystectomy. Furthermore, low insufflation pressure did not result in reduced pain, compared with standard pressure. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01728584. FUNDING: Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Effect of sugammadex on QT/QTc interval prolongation when combined with QTc-prolonging sevoflurane or propofol anaesthesia.

BACKGROUND: We evaluated the potential for QT/corrected QT (QTc) interval prolongation after sugammadex given with propofol or sevoflurane anaesthesia. METHODS: This was a two-factorial, randomized, parallel-group study in 132 healthy subjects. Anaesthesia was maintained with sevoflurane or propofol. At ~20 min following sevoflurane/propofol initiation, sugammadex 4 mg/kg or placebo was administered. Neuromuscular blocking agents were not administered. Electrocardiograms were recorded regularly. The primary variable was the time-matched mean difference in the Fridericia-corrected QT interval (QTcF) change from baseline for sugammadex versus placebo when combined with propofol or sevoflurane. No relevant QTcF prolongation was concluded if the upper one-sided 95 % confidence interval (CI) was below the 10 ms margin of regulatory non-inferiority, up to 30 min post-study drug. Blood samples were taken for pharmacokinetic analysis. An exploratory analysis evaluated potential QT/QTc effects of neostigmine 50 µg/kg/glycopyrrolate 10 µg/kg in combination with propofol. RESULTS: The estimated mean QTcF differences between sugammadex and placebo ranged from -2.4 to 0.6 ms when combined with either anaesthetic. The largest upper one-sided 95 % CI for the mean QTcF difference between sugammadex and placebo was 2 ms, occurring 2 min post-dosing. Propofol and sevoflurane resulted in mean QTcF increases exceeding 10 and 30 ms, respectively. On top of these prolongations, the effect of sugammadex was negligible at all timepoints. The mean peak sugammadex concentration was 66.5 µg/mL, with exposure similar in the sevoflurane/propofol groups. The mean QTcF changes from baseline following neostigmine/glycopyrrolate in 10 healthy subjects ranged between -1.4 and 3.6 ms. CONCLUSION: Sugammadex 4 mg/kg does not cause clinically relevant QTc interval prolongation versus placebo when combined with propofol or sevoflurane.

Flucloxacillin and diclofenac do not cause recurrence of neuromuscular blockade after reversal with sugammadex.

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.