Abstract and Introduction
Background: Sugammadex and neostigmine given to reverse residual neuromuscular blockade can cause side effects including bradycardia, anaphylaxis, bronchospasm, and even cardiac arrest. We tested the hypothesis that sugammadex is noninferior to neostigmine on a composite of clinically meaningful side effects, or vice versa.
Methods: We analyzed medical records of patients who had general, cardiothoracic, or pediatric surgery and were given neostigmine or sugammadex from June 2016 to December 2019. Our primary outcome was a collapsed composite of bradycardia, anaphylaxis, bronchospasm, and cardiac arrest occurring between administration of the reversal agent and departure from the operation room. We a priori restricted our analysis to side effects requiring pharmacologic treatment that were therefore presumably clinically meaningful. Sugammadex would be considered noninferior to neostigmine (or vice versa) if the odds ratio for composite of side effects did not exceed 1.2.
Results: Among 89,753 surgeries in 70,690 patients, 16,480 (18%) were given sugammadex and 73,273 (82%) were given neostigmine. The incidence of composite outcome was 3.4% in patients given sugammadex and 3.0% in patients given neostigmine. The most common individual side effect was bradycardia (2.4% in the sugammadex group versus 2.2% neostigmine). Noninferiority was not found, with an estimated odds ratio of 1.21 (sugammadex versus neostigmine; 95% confidence interval [CI], 1.09–1.34; noninferiority P = .57), and neostigmine was superior to sugammadex with an estimated odds ratio of 0.83 (0.74–0.92), 1-side superiority P < .001.
Conclusions: The composite incidence was less with neostigmine than with sugammadex, but only by 0.4% (a negligible clinical effect). Since 250 patients would need to be given neostigmine rather than sugammadex to avoid 1 episode of a minor complication such as bradycardia or bronchospasm, we conclude that sugammadex and neostigmine are comparably safe.
Neuromuscular blocking agents are widely used to facilitate endotracheal intubation, ease mechanical ventilation, and optimize surgical conditions. Most surgical patients are, therefore, given nondepolarizing neuromuscular blocking agents. Residual neuromuscular blockade at the end of surgery is common, occurring in up to 60% of patients who are not reversed, and is associated with postoperative morbidity and mortality.[3–6] It is, therefore, routine to pharmacologically antagonize or reverse neuromuscular blocking agents before extubation, usually by giving neostigmine or sugammadex.
Neostigmine is a commonly used acetylcholinesterase inhibitor, which competitively antagonizes residual neuromuscular blockade by preventing metabolism of acetylcholine. Because the competitive mechanism is limited, neostigmine only reliably reverses mild-to-moderate neuromuscular blocks. Sugammadex, in contrast, reverses neuromuscular blocks by encapsulating and binding rocuronium, and vecuronium molecules. The mechanism is effective, and sugammadex provides complete and rapid reversal even from deep neuromuscular blockade.
Although routinely used, drugs that reverse neuromuscular blocks provoke various side effects, including bradycardia (1%–5%), hypotension (4%–13%), anaphylaxis (0.3%–0.4%), bronchospasm (0.1%–1.5%), nausea (23%–26%), vomiting (11%–13%), and even cardiac arrest.[9,10] The incidence of side effects presumably depends on the reversal agent used, but it remains unclear which medication is safest. For example, a recent Cochrane meta-analysis including 2298 patients reported significantly fewer composite adverse events in patients given sugammadex than in those randomized to neostigmine (risk ratio [RR], 0.60; 95% confidence interval [CI], 0.49–0.74). The incidence of adverse events was 28% in neostigmine patients versus 16% in those given sugammadex. However, the incidence of serious events was similar in each group. Another meta-analysis included 1384 patients and reported that sugammadex caused significantly fewer adverse events (odds ratio [OR], 0.47; 95% CI, 0.34–0.66).
Overall, the risk of side effects apparently caused by neostigmine and sugammadex is inconsistently reported and often based on relatively small sample sizes. Serious side effects, which are fortunately rare, are especially poorly characterized. We, therefore, evaluated the association between reversal of neuromuscular blocks with sugammadex or neostigmine and a composite of clinically important adverse events in a large surgical cohort. Specifically, we tested the primary hypothesis that reversal using sugammadex is noninferior to neostigmine (or vice versa) on a composite of clinically important side effects consisting of bradycardia, bronchospasm, anaphylaxis, and cardiac arrest in patients having general, cardiothoracic, or pediatric surgery.
Anesth Analg. 2022;134(5):1043-1053. © 2022 International Anesthesia Research Society