BACKGROUND Traditionally, reversal of nondepolarizing neuromuscular blocking agents was achieved using acetylcholinesterase inhibitors, but these are unable to adequately reverse profound blockade. Sugammadex is a novel reversal agent, reversing the effects of rocuronium by encapsulation. This study assessed the efficacy and safety of sugammadex versus neostigmine for reversal of profound rocuronium-induced neuromuscular blockade. METHODS This phase III, randomized study enrolled surgical patients, aged 18 yr or older with American Society of Anesthesiologists physical status I-IV. Patients were randomized to receive sugammadex (4.0 mg/kg) or neostigmine (70 microg/kg) plus glycopyrrolate (14 microg/kg). Anesthetized patients received an intubating dose of rocuronium (0.6 mg/kg), with maintenance doses (0.15 mg/kg) as required. Neuromuscular monitoring was performed by acceleromyography. Sugammadex or neostigmine was administered at reappearance of 1-2 posttetanic counts (profound neuromuscular blockade). The primary efficacy parameter was the time from sugammadex or neostigmine-glycopyrrolate administration to return of the train-of-four ratio to 0.9. RESULTS In the intent-to-treat population (n = 37 in each group), geometric mean time to recovery to a train-of-four ratio of 0.9 with sugammadex was 2.9 min versus 50.4 min with neostigmine-glycopyrrolate (P < 0.0001) (median, 2.7 min vs. 49.0 min). Most sugammadex patients (97%) recovered to a train-of-four ratio of 0.9 within 5 min after administration. In contrast, most neostigmine patients (73%) recovered between 30 and 60 min after administration, with 23% requiring more than 60 min to recover to a train-of-four ratio of 0.9. CONCLUSIONS Recovery from profound rocuronium-induced neuromuscular blockade was significantly faster with sugammadex versus with neostigmine, suggesting that sugammadex has a unique ability to rapidly reverse profound rocuronium neuromuscular blockade.

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Reversal of profound rocuronium-induced blockade with sugammadex: a randomized comparison with neostigmine.

Sugammadex is a revolutionary investigational reversal drug currently undergoing Phase III testing whose introduction into clinical practice may change the face of clinical neuromuscular pharmacology. A modified -cyclodextrin, sugammadex exerts its effect by forming very tight water-soluble complexes at a 1:1 ratio with steroidal neuromuscular blocking drugs (rocuronium vecuronium pancuronium). During rocuronium-induced neuromuscular blockade, the IV administration of sugammadex creates a concentration gradient favoring the movement of rocuronium molecules from the neuromuscular junction back into the plasma, which results in a fast recovery of neuromuscular function. Sugammadex is biologically inactive, does not bind to plasma proteins, and appears to be safe and well tolerated. Additionally, it has no effect on acetylcholinesterase or any receptor system in the body. The compound’s efficacy as an antagonist does not appear to rely on renal excretion of the cyclodextrin-relaxant complex. Human and animal studies have demonstrated that sugammadex can reverse very deep neuromuscular blockade induced by rocuronium without muscle weakness. Its future clinical use should decrease the incidence of postoperative muscle weakness, and thus contribute to increased patient safety. Sugammadex will also facilitate the use of rocuronium for rapid sequence induction of anesthesia by providing a faster onset-offset profile than that seen with 1.0 mg/kg succinylcholine. Furthermore, no additional anticholinesterase or anticholinergic drugs would be needed for antagonism of residual neuromuscular blockade, which would mean the end of the cardiovascular and other side effects of these compounds. The clinical use of sugammadex promises to eliminate many of the shortcomings in our current practice with regard to the antagonism of rocuronium and possibly other steroidal neuromuscular blockers. (Anesth Analg 2007;104:575‐81)

http://www.sarasotaanesthesia.com/pdf/Sugammadex3.pdf

Sugammadex: Another Milestone in Clinical Neuromuscular Pharmacology

BACKGROUND: Rocuronium in intubation doses provides similar intubation conditions as succinylcholine, but has a longer duration of action This study compared time to sugammadex reversal of profound rocuronium-induced neuromuscular block with time to spontaneous recovery from succinylcholine METHODS: One hundred and fifteen adult American Society of Anesthesiologists Class I-II surgical patients were randomized to this multicenter, safety-assessor-blinded, parallel group, active-controlled, Phase IIIa trial Anesthesia was induced and maintained with propofol and an opioid Neuromuscular transmission was blocked and tracheal intubation facilitated with 12 mg/kg rocuronium or 1 mg/kg succinylcholine Sugammadex (16 mg/kg) was administered 3 min after rocuronium administration Neuromuscular function was monitored by acceleromyography The primary efficacy endpoint was the time from the start of relaxant administration to recovery of the first train-of-four twitch (T(1)) to 10% RESULTS: One hundred and ten patients received study treatment Mean times to recovery of (T(1)) to 10% and (T(1)) to 90% were significantly faster in the rocuronium-sugammadex group (44 and 62 min, respectively), as compared with the succinylcholine group (71 and 109 min, respectively; all P < 0001) Timed from sugammadex administration, the mean time to recovery of (T(1)) to 10%, (T(1)) to 90%, and the train-of-four (T(4)/T(1)) ratio to 09 was 12, 29, and 22 min, respectively Reoccurrence of the block was not observed There were no serious adverse events related to study treatments CONCLUSION: Reversal of profound high-dose rocuronium-induced neuromuscular block (12 mg/kg) with 16 mg/kg sugammadex was significantly faster than spontaneous recovery from 1 mg/kg succinylcholine

Reversal of profound neuromuscular block by sugammadex administered three minutes after rocuronium: a comparison with spontaneous recovery from succinylcholine.

Background: Sugammadex reverses the neuromuscular blocking effects of rocuronium by chemical encapsulation. The efficacy, safety, and pharmacokinetics of sugammadex for reversal of profound rocuronium-induced neuromuscular blockade were evaluated. Methods: Ninety-eight male adult patients were randomly assigned to receive sugammadex (1, 2, 4, 6, or 8 mg/kg) or placebo at 3, 5, or 15 min after 0.6 mg/kg rocuronium. Patients were anesthetized with propofol and fentanyl. The primary endpoint of the study was the time to achieve a recovery of train-of-four ratio to 0.9. Neuromuscular blockade was measured using acceleromyography. Concentrations of rocuronium and sugammadex were determined in venous blood and urine samples. A population pharmacokinetic model using NONMEM (GloboMax LLC, Hanover, MD) was applied. Results: The mean time to recovery of the train-of-four ratio to 0.9 after dosing at 3, 5, and 15 min decreased from 52.1, 51.7, and 35.6 min, respectively, after administration of placebo to 1.8, 1.5, and 1.4 min, respectively, after 8 mg/kg sugammadex. Sugammadex was safe and well tolerated. However, 20.4% of patients showed signs of inadequate anesthesia after its administration. The median cumulative excretion of rocuronium in the urine over 24 h was 26% in the placebo group and increased to 58-74% after 4-8 mg/kg sugammadex. The mean plasma clearances of sugammadex and rocuronium were 0.084 and 0.26 l/min, respectively. Conclusions: In male subjects, sugammadex safely reversed profound neuromuscular blockade induced by 0.6 mg/kg rocuronium in a dose-dependent manner. Sugammadex enhanced the renal excretion of rocuronium, and its clearance is approximately one third that of rocuronium.

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Early reversal of profound rocuronium-induced neuromuscular blockade by sugammadex in a randomized multicenter study - Efficacy, safety, and pharmacokinetics

Background and objective Sugammadex, a modified gamma-cyclodextrin, is a selective relaxant-binding agent designed to reverse the effects of the steroidal neuromuscular blocking agents rocuronium or vecuronium. This study compared the efficacy of sugammadex and neostigmine for reversal of neuromuscular blockade induced by rocuronium for facilitating elective surgery. Methods This randomised, multicentre, parallel-group trial included 98 adult patients. Patients received intravenous propofol for induction followed by sevoflurane maintenance anaesthesia. Neuromuscular blockade was monitored using acceleromyography and a train-of-four (TOF) mode of stimulation. Patients were randomly allocated to receive sugammadex 2.0 mg kg(-1) or neostigmine 50 microg kg (-1) (with glycopyrrolate 10 microg kg(-1)) at reappearance of the second response of the TOF (mean 16% twitch height of first response) after the last dose of rocuronium. Safety was evaluated by assessing adverse events, laboratory variables and vital signs. Results Time to recovery of the TOF ratio of 0.9 after sugammadex compared with neostigmine was significantly shorter (P Conclusion Sugammadex achieved significantly faster recovery of neuromuscular function after rocuronium to a TOF ratio of 0.9 compared with neostigmine (Clinicaltrials.gov identifier: NCT00451217).

Reversal of rocuronium-induced neuromuscular blockade with sugammadex compared with neostigmine during sevoflurane anaesthesia: results of a randomised, controlled trial

Background:Sugammadex (Org 25969) forms a complex with steroidal neuromuscular blocking agents, thereby reversing neuromuscular block. This study investigated the dose–response relation, safety, and pharmacokinetics of sugammadex to reverse rocuronium-induced block.Methods:Twenty-seven male surgical

Martine E. Prins

Papers

Reversal of rocuronium-induced neuromuscular block by the selective relaxant binding agent sugammadex: a dose-finding and safety study.