Rocuronium-Induced Muscle Relaxation Is Possible
Schering-Plough Corp., (NYSE: SGP) today announced that a study published in the November 2008 issue of the medical journal, Anesthesiology (Vol. 109, No. 5)(1) demonstrated that sugammadex produced a significantly more rapid recovery from profound rocuronium-induced muscle relaxation than the conventional reversal agent neostigmine. Importantly, this is the first comparative study to demonstrate that rapid reversal of profound rocuronium-induced muscle relaxation is possible. In the study, the median time to recovery was 2.7 minutes in the sugammadex group versus 49.0 minutes in the neostigmine group.
Sugammadex is a novel selective relaxant binding agent that works in an entirely new and unique way to encapsulate the muscle relaxant molecule and render it inactive. Sugammadex is approved and marketed in the European Union as BRIDION.
"This study demonstrates that sugammadex is the first agent to permit rapid reversal of a profound level of rocuronium-induced neuromuscular blockade," said lead author R. Kevin Jones, M.D., attending anesthesiologist, Saddleback Memorial Medical Center, Laguna Hills, Calif. "This finding with sugammadex will likely have important clinical implications for how muscle relaxation is managed, providing anesthesiologists with greater control in maintaining the level of blockade necessary during surgery, while allowing for rapid recovery once surgery is completed."
The study, known as the Signal trial, was a Phase III, multicenter, randomized, parallel-group, safety-assessor blinded study that compared the efficacy and safety of sugammadex versus neostigmine/glycopyrrolate in the reversal of profound rocuronium-induced neuromuscular blockade. Traditionally, reversal of nondepolarizing neuromuscular blocking agents (NMBAs) such as rocuronium or vecuronium has been achieved by using acetylcholinesterase inhibitors, such as neostigmine. However, these older agents cannot rapidly reverse profound neuromuscular blockade.
Neuromuscular blockade plays several critical roles in general anesthesia. Anesthesiologists use muscle relaxation to improve surgical conditions and to facilitate intubation and mechanical ventilation. Reversal agents reverse the effects of muscle relaxants, enabling patients to regain normal muscle function sooner and breathe on their own again.
Studies have shown that in clinical practice, patients are often extubated before complete recovery has occurred, leaving the patients at risk of associated postoperative complications such as airway obstruction or pulmonary complications. Residual neuromuscular blockade, which is an important cause of NMBA-associated morbidity in surgical patients, was not reported in any patient in this study.
"These results demonstrate the efficacy of sugammadex in rapidly reversing profound rocuronium-induced neuromuscular blockade, an option that is not possible with conventional reversal agents," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "This study shows that sugammadex offers advantages over neostigmine and may help improve anesthesia management in the millions of surgeries where muscle relaxation agents are used."
In the Signal study, sugammadex or neostigmine was administered at reappearance of 1-2 post-tetanic counts (profound neuromuscular blockade). The primary efficacy endpoint of the study was time from sugammadex or neostigmine/glycopyrrolate administration to return of the train-of-four (TOF) ratio to 0.9. Profound neuromuscular blockade reversal with sugammadex 4 mg/kg was about 17 times faster than with neostigmine 70 mcg/kg (geometric mean times were 2.9 minutes versus 50.4 minutes, respectively [P<0.0001], while median times were 2.7 minutes versus 49.0 minutes). In the study, 97 percent of sugammadex-treated patients recovered to a TOF ratio of 0.9 within five minutes of administration. In contrast, 73 percent of neostigmine-treated patients did not recover until 30-60 minutes, and a large proportion (23 percent) did not recover to a TOF ratio of 0.9 until more than 60 minutes after neostigmine administration.
The study enrolled surgical patients, aged 18 years or older with American Society of Anesthesiology physical status I-IV. Seventy-four patients were randomized to receive sugammadex (4.0 mg/kg) or neostigmine (70 mcg/kg) plus glycopyrrolate (14 mcg/kg) and completed the study. 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.
In the study, sugammadex was well tolerated in the 37 patients who received the treatment, and its safety profile overall was comparable with that of neostigmine. Safety data from the study showed that the most frequently reported adverse events (AEs) for patients in both groups included procedural pain, nausea and incision-site complications. Serious adverse events (SAEs) were reported for two patients in the sugammadex group (postoperative infection and postoperative ileus) and three patients in the neostigmine group (nausea/pain/dyspnea, gastric perforation/procedural complication and postoperative ileus). No SAE was considered study drug-related. Only one patient (neostigmine group) discontinued from the study because of two SAEs (gastric perforation/procedural complication) and subsequently recovered. No cases of hypersensitivity were reported in the study.