Results of this dedicated randomized study in ASA Physical Class 3 or 4 participants demonstrate that treatment with sugammadex compared with neostigmine/glycopyrrolate did not lead to clinically meaningful differences in heart rate or rhythm changes. Overall, TE cardiac events were generally low and less frequent than the incidences observed with the comparator neostigmine/glycopyrrolate. Compared with neostigmine/glycopyrrolate, the incidence of TE sinus bradycardia was significantly lower with sugammadex 2 mg/kg and the incidence of TE sinus tachycardia was significantly lower with sugammadex 2 mg/kg and 4 mg/kg. No significant differences in other cardiac arrythmias (TE or CR) were seen between sugammadex groups and neostigmine/glycopyrrolate.
The overall incidences and type of AEs were generally similar across the intervention groups, including drug-related AEs and SAEs (reported up to 7 days post-treatment). Two deaths occurred among participants who received study medication in this study, 1 each in the sugammadex 4 mg/kg group and 2 mg/kg groups (reporting SAEs of cardiac arrest and cardiac failure, respectively); both SAEs were assessed by the investigator as not related to study medication. The incidences of ECIs were low overall in this study across all interventions. Treatment with sugammadex did not result in any reports of hypersensitivity, anaphylaxis, or liver toxicity (at any timepoint). Further, the overall safety profile was similar when comparing participants by ASA Physical Class (3 vs 4) and NMBA (rocuronium vs vecuronium).
Taken together, these findings demonstrate that the safety profile of sugammadex in ASA Physical Class 3 or 4 patients does not meaningfully differ from the known profile established in the predominantly studied ASA Physical Class 1 or 2 populations.[6–10] Theoretical concerns that ASA Physical Class 3 and 4 participants may be at increased risk for labeled risks associated with sugammadex administration, namely risks for bradycardia or hypersensitivity/anaphylaxis, did not materialize in the current study, supporting the use of sugammadex for reversal of rocuronium- or vecuronium-induced neuromuscular block in this important, medically vulnerable population.
While this study was specifically designed to detect treatment-related differences in the incidences of treatment-emergent (TE) sinus bradycardia, TE sinus tachycardia, and other TE cardiac arrhythmias, a possible limitation of this study is the relative lack of powering for characterization of CR arrhythmias incidences. In this study, all TE arrhythmia events detected were evaluated by the investigator for potential clinical relevance and few TE events were deemed CR, an outcome which may limit further interpretation of the results with regard to risk for CR events. However, consistent with the results of this trial in higher risk ASA Class 3 or 4 participants, CR events associated with sugammadex administration have not been commonly observed in randomized clinical trials,[16–19] but rather in infrequent pharmacovigilance reports,[2,21] suggesting it would be infeasible to design a prospective study specifically for that purpose.
A second potential limitation of the study is the lower sample size allocated to evaluation of the sugammadex 16 mg/kg and neostigmine/glycopyrrolate groups in the overall study population (n = 68, n = 51, respectively), lowering the precision for characterization of CR events in these groups. Of note, however, sugammadex 16 mg/kg is only intended for use in an emergency setting for urgent reversal of rocuronium, where it can be life-saving, a benefit arguably outweighing a potential risk of CR arrhythmia.
Another potential limitation of this study involves the use of the ASA physical status grading system, which is known to have low inter-rater reliability based on the experience level of the anesthesiologist assigning the classification. On average, more experienced anesthesiologists are less accurate in classifying patients compared to less experienced colleagues. While the current study did not control for the potential bias of low inter-rater reliability of the ASA grading system, principal investigators and/or appropriately trained personnel assigned to the study were responsible for evaluating and classifying each patient prior to surgery. Further, the prespecified primary analysis pooled findings across ASA Class 3 and 4 strata thus enabling a general assessment of the relative safety profile of sugammadex vs neostigmine/glycopyrrolate in a broad range of at-risk patients. Nevertheless, caution should be used when drawing conclusions about the relative cardiac safety of sugammadex vs neostigmine/glycopyrrolate between Grade 3 vs Grade 4 patients.
BMC Anesthesiol. 2021;21(259) © 2021 BioMed Central, Ltd.