Patient Safety Revisited: Reliability Is Paramount

“Better be despised for too anxious apprehensions than ruined by too confident a security.” Reflections on the revolution in France, (1790) —Edmund Burke. An analogy between the new reversal drug, sugammadex, and one of the oldest muscle relaxants must be made in order to emphasize a few important patient safety points: succinylcholine has been considered the “gold standard” muscle relaxant in clinical settings in which rapid airway control is deemed medically necessary.1 For over 50 yr, succinylcholine has been used preferentially in “rapid sequence induction” settings, despite the very long list of known potential side effects (postoperative myalgia, triggering of malignant hyperthermia, hyperkalemia, increase in intracranial/intraocular pressure, etc). Also, because of multiple and sometimes fatal side effects, a search for the “ideal muscle relaxant” has been ongoing for over 50 yr.2 Despite the progress in medicine and pharmacology, however, to date, a succinylcholine replacement is still illusory. There are several reasons why succinylcholine is still today considered the drug of choice for rapid control of the airway: 1) it can be (and usually is) administered in large doses (1–2 mg/kg) without significant cardiovascular side effects, except in the pediatric population, where it may induce bradycardia; 2) because of the large dose administered and its unique mode of action (depolarizing block), the mean onset of complete neuromuscular block is the fastest of any muscle relaxant, usually 1 min or less; 3) in patients with normal pseudocholinesterase function, the mean duration of action of succinylcholine is relatively short, 7–13 min3; and 4) most important from a clinical (and patient safety) standpoint, onset of paralysis with succinylcholine is reliable, as evidenced by a narrow standard deviation (19–22 s).4 What does succinylcholine, however, have to do with a study of a new reversal drug? When placed in a patient safety perspective, the analogy becomes clear. In this issue of the journal, White et al.5 from four other institutions report on the speed of reversal from rocuronium block induced by the novel encapsulating reversal drug, sugammadex. In this multicenter, open-label, prospective, observational, clinical investigation, the authors tried to mimic standard clinical practice and tested the hypothesis that presence of a twitch response to peripheral neuromuscular stimulation (as opposed to absence of twitch response) improves the speed and reliability of reversal by sugammadex. At prima facie, the hypothesis is, self-evident and the results, expected: for many decades, clinicians have known that some minimal degree of neuromuscular recovery is needed for reversal by the traditional anticholinesterases. Sugammadex, however, has been reported in the last few years to rapidly and completely reverse neuromuscular block induced by aminosteroids (rocuronium in particular). Studies have shown that reversal with sugammadex (4 mg/kg dose) is as fast as 2–3 min, and in doses of 16 mg/kg, sugammadex can even rapidly reverse the block from a large dose of rocuronium (1.2 mg/kg) within 3 min of administration, as a rescue from the dreaded “cannot ventilate/cannot intubate” scenario.6 Clearly, the introduction of such an “ideal reversal drug” would hold great promise clinically, especially since most of the studies performed to date in preparation for the Food and Drug Administration (FDA) application for approval have shown sugammadex to have few, if any, cardiovascular side effects. Despite the plethora of efficacy and safety studies, however, we must temper the exuberance with which we embrace new pharmacologic agents or technology. And this is precisely the lesson that White et al.’s study teaches us. One way to look at their data is to declare “sugammadex, 4 mg/kg IV, given in the presence of ≥1 (vs 0) twitch responses in a train-of-four (TOF) was associated with a faster recovery to a TOF ratio of 0.9 (104 ± 73 vs 173 ± 162 s).”5 However, a critical analysis of the data might ask why reversal with sugammadex still required as long as 8.5 min in some patients who had proven, minimal twitch recovery (≥1 twitch). Even more important for patient safety, the time of recovery to TOF of 0.9 was as long as 22.3 min in some patients with no twitch response, despite the administration of sugammadex doses that are in the middle of the range of those intended for the FDA approval application (2–16 mg/kg). Such outliers are similar to those reported previously: large doses of sugammadex (16 mg/kg) administered 15 min after rocuronium 1.2 mg/kg resulted in maximum reversal times of 16.6 min in 1 of the 5 patients.6 In this context, the comparison between succinylcholine and sugammadex becomes clear: succinylcholine, our “gold standard” has a rapid onset and narrow variability (standard deviation of 22 s and range of 40–120 s).4 However, the mean recovery time after a dose of 1 mg/kg is 10.2 min, but its range of recovery times is wide, 4.1–15.4 min.3 For any drug, then, it is critical for the clinician to note the variability (range) of responses to drugs, not just the mean data. From the patients’ safety perspective, the outliers are equally important when making clinical decisions, and this is the lesson we must learn from White et al.’s study.5 Will future studies elucidate the dose-response requirements for sugammadex to become the “ideal reversal drug”? Or will high doses of sugammadex (needed to increase reliability and decrease outliers) prove to increase the potential for pulmonary or allergic reactions that prompted the FDA to issue a “nonapprovable” letter this past August?* As clinicians, we all hope for rapid approval of this promising, novel and effective drug; as patient advocates, however, we know that more answers are needed to prove its reliability and learn to use it appropriately.