Anesthesia & Analgesia | 2021
Chasing Shadows, Catching Smoke, and Estimating Anaphylaxis to Sugammadex.
Abstract
Although the incidence of rare adverse events is difficult to measure, clinicians yearn for accurate information to better guide patient care and inform patients of potential risks. When new drugs or devices are introduced, clinician-scientists are keen to characterize the incidence of adverse events. This is an important component of the drug or device regulatory approval process. Even though the Food and Drug Administration requires a rigorous multistep process for new drug development in the United States, the process cannot evaluate all possible rare adverse events before release for widespread use. To do this would require large sample sizes and be cost prohibitive. This is why “Phase IV” or postmarketing assessment of safety is necessary and may even be required for ongoing approval. A clear picture of a new drug’s safety emerges only after months if not years of clinical use. This process has been enabled in the Information Age by the advent of large collections of granular patient data, and the tools to query them. In this month’s issue of Anesthesia & Analgesia, Burbridge1 describes the incidence of anaphylaxis to sugammadex in a single-center cohort of nearly 20 thousand patients, captured from the institution’s electronic medical record. He reports an incidence of 1 in 9910. This is in stark contrast to previously reported rates. For example, the sugammadex package insert reports a rate of 1 in 300 as described by Min et al.2 In a prior retrospective large cohort study, Miyazaki et al3 reported a rate of 1 in 2500. Which of these widely different numbers should we believe? Although estimates from each study were reported in reputable journals with rigorous peer review, at face value, the range in anaphylaxis rates is too large to be of clinical use in estimating the rate of an adverse event. As is common in clinical research, the reason lies in the methodology of the individual studies: in this case, how the diagnosis of anaphylaxis was established. To better understand how investigators arrived at these very different rates, a brief review of each study’s design reveals significant differences and limitations in the methods used. For the data presented in the sugammadex package insert, Min et al2 utilized a prospective placebocontrolled volunteer study. Their design used 3 groups of volunteers. One group (n = 151 volunteers) received sugammadex 4 mg/kg (a dose used to reverse deep neuromuscular blockade). A second group (n = 148 volunteers) received sugammadex 16 mg/kg (a dose used to reverse profound neuromuscular blockade). A third group received a placebo. Only 1 subject, in the 16 mg/kg group, exhibited signs of anaphylaxis according to the Sampson criteria developed by the National Institute of Allergy and Infectious Diseases.4 To estimate a rate of anaphylaxis, the authors summed up the total number of volunteers that received either dose of sugammadex to generate the rate of 1 in 299 or 0.3%. Positive features of this experimental design include that (1) it was prospective and enrolled healthy volunteers; (2) doses were more than what is routinely used for reversal of neuromuscular blockade; (3) each volunteer received repeated doses of sugammadex to explore the influence of prior exposure as a source of sensitization; and (4) the authors used published criteria to perform a rigorous assessment of the timing of anaphylaxis onset, skin and mucosal Chasing Shadows, Catching Smoke, and Estimating Anaphylaxis to Sugammadex