Use of Neuromuscular Blocking and Antagonism Agents across the Spectrum of Renal Impairment Undergoing Major Inpatient Surgery: A Single-center Retrospective Observational Cohort Study

Cisatracurium has traditionally been utilized in patients with severe renal impairment due to its clearance by Hoffman elimination.1 However, cisatracurium cannot be antagonized by sugammadex, which is specific to rocuronium and vecuronium. Sugammadex, compared to neostigmine, reduces the rate of residual neuromuscular blockade in postanesthesia care unit and may be associated with decreases in postoperative pulmonary complications.2,3 Limited, but evolving data describes the use of sugammadex in those with renal failure.1,4,5 Prescribing guidance advises against use of sugammadex in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] less than 30).6 Patients with renal impairment may be at risk of recurarization after sugammadex administration, given reduction in elimination of rocuronium, potential for redistribution of rocuronium, strong binding of rocuronium-sugammadex complex and interindividual variation in sugammadex dose to antagonize a given level of neuromuscular block.1,7,8To understand if neuromuscular blockade and antagonism practice has changed in patients with renal impairment, we performed a single institution retrospective study in adult patients undergoing major surgery across a continuum of renal function. We hypothesized that over time, the odds of receiving cisatracurium-neostigmine for neuromuscular blockade and antagonism in patients with severe renal impairment would decrease.After institutional review board approval (HUM00186906) and recording an a priori statistical analysis plan, our institutional research database was accessed. Adult patients receiving a general anesthetic with an endotracheal tube, between January 1, 2017, to December 31, 2020, undergoing a procedure lasting less than 2 h and were extubated in the operating room were included. Cases were excluded if they were classified American Society of Anesthesiologists (Schaumburg, Illinois) Physical Status classification 5 or 6, patient weight was less than 40 kg, involved cardiopulmonary bypass or organ transplantation, if the patient arrived to the operating room intubated, if preoperative laboratory renal function tests within 60 days prior to surgery were incomplete or missing, if both sugammadex and neostigmine were administered, if no antagonist was used, or if both cisatracurium and a steroidal neuromuscular blocking agent was used or if cisatracurium and sugammadex were both administered. We excluded cases not receiving a minimum dose of non-depolarizing neuromuscular blocking agent: (rocuronium [less than 10 mg], vecuronium [less than 4 mg], or cisatracurium [less than 4 mg]) or when the dose of antagonist was outside a labeled or accepted range ±10% (sugammadex [1.8 to 4.4 mg/kg] or neostigmine [27 to 77 μg/kg]).Medication administration records assigned patients to a single neuromuscular blockade and antagonism strategy. Population characteristics are presented using absolute standardized differences. Using generalized estimating equations with an exchangeable correlation structure we subsequently modeled a binary primary outcome—use of cisatracurium or neostigmine versus rocuronium or sugammadex. eGFR was computed using the most recent creatinine value available prior to anesthesia care using the into chronic kidney disease (CKD)-Epidemiology Collaboration 2021 formula.9 The primary exposure was eGFR categorized into CKD Grades (following Kidney Disease: Improving Global Outcomes [KDIGO] classification) and year. The model included age, co-morbidity burden (sum of Elixhauser comorbidities), body mass index (World Health Organization classification), American Society of Anesthesiologists Physical Status Classification, anatomical region of surgery and case duration. The same model was used to estimate across time (per year) and across eGFR strata. Due to limited sample size, in response to peer review, the CKD Grade 4 and Grade 5 groups were combined.After inclusion and exclusion criteria, 34,757 cases were included in the analysis (Supplemental Digital Content 1, https://links.lww.com/ALN/D573). Primary blockade and antagonism strategies were: cisatracurium or neostigmine (n = 1,848), rocuronium or neostigmine (n = 5,318), rocuronium or sugammadex (n = 25,527), vecuronium or sugammadex (n = 1,104) and vecuronium or neostigmine (n = 960) (Supplemental Digital Content 2, https://links.lww.com/ALN/D574). Trends in the use of each medication and strategy are presented in Supplemental Digital Content 2 (https://links.lww.com/ALN/D574), Supplemental Digital Content 3 (https://links.lww.com/ALN/D575), and Supplemental Digital Content 4 (https://links.lww.com/ALN/D576). Comparisons are presented in tables 1 and 2. The mean eGFR within cases in the cisatracurium or neostigmine group was 69.5 ml/min in Q1 2017 and 24.2 ml/min in Q4 2020 P ≤ 0.001 (Supplemental Digital Content 5, https://links.lww.com/ALN/D577, and Supplemental Digital Content 6, https://links.lww.com/ALN/D578).In the multivariable models comparing the dichotomized choice between rocuronium/sugammadex (predominant strategy) and cisatracurium or neostigmine (predominant straegy in those with severe renal impairment), the odds of receiving cisatracurium or neostigmine across time and CKD Grade were calculated. Compared to a patient with an CKD Grade 1 (eGFR > 90) in 2017, the odds of receiving cisatracurium or neostigmine for a patient with CKD Grade 1 in 2020 was 0.02 (95% CI: 0.01-0.03), for a patient with CKD Grade 3B in 2017 the odds were 28.7 (95% CI: 19.5-42.1) and 2.31 (95% CI: 1.45-3.69) in 2020, for a patient with CKD Grade 4 and Grade 5 the odds were 265 (95% CI: 133-529) in 2017 and 113 (95% CI: 71.7-176) in 2020 (fig. 1). Within CKD Grades, the odds of receiving cisatracurium or neostigmine in 2020 compared to 2017 were 0.02 for a patient with CKD Grade 1 (P < 0.001), 0.08 for a patient with CKD Grade 3B (P < 0.001) and 0.42 for a patient with CKD Grade 4 or Grade 5 (P = 0.031) (Supplemental Digital Content 7, https://links.lww.com/ALN/D579).The odds ratios of receiving cisatracurium or neostigmine decreased over time across all CKD Grades. At the conclusion of the study period the use of cisatracurium or neostigmine appeared to be reserved for those with severe renal impairment.In 2020, greater than 90% of cases used sugammadex for antagonism of neuromuscular blockade. The relative infrequency of the neostigmine use may limit clinician familiarity with implications for safe utilization and trainee education. Our study did not examine neuromuscular blockade related outcomes such as recurarization, respiratory failure, pneumonia or early reintubation. Our study is limited by the single center nature and population selection emphasizing major surgery. Shortages of rocuronium in Q3 of 2017 may have influenced the baseline and result in a slight overestimate of the observed practice change. As creatinine values may change markedly over time, particularly for those on dialysis or experiencing renal injury (or recovery), a single measurement used for estimation of GFR may result in misclassification of longitudinal renal function.10At our institution, during this study period, sugammadex administration in patients with renal impairment appears to generally follow the FDA labeling guidelines, however this may not reflect contemporary US practice. Future work should seek to examine the impact of institutional and anesthesiologist factors on this changing practice. It is not yet established if neuromuscular blockade and antagonism strategy selection is associated with differential impact on patient outcomes in those with renal impairment.Research reported in this publication was supported by National Heart, Lung, and Blood Institute of the National Institutes of Health (Bethesda, Maryland) under award number K08HL159327 (to Dr. Colquhoun). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Drs. Colquhoun, Kumar, and Kheterpal declare research support, unrelated to presented work from Patient-Centered Outcomes Research Institute (Washington, D.C.) paid to the University of Michigan (Ann Arbor, Michigan). Drs. Colquhoun and Kheterpal declare research support unrelated to present work from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey) paid to the University of Michigan. Dr. Colquhoun reports declare research support unrelated to present work from Chiesi USA, Inc. (Cary, North Carolina) paid to the University of Michigan and honoraria from Medscape, Inc. (New York, New York). Dr. Kumar declares research funding paid to the University of Michigan, unrelated to present work from Hemosonics, LLC (Durham, North Carolina) and Edwards Lifesciences (Irvine, California). The other authors declare no competing interests.Supplemental Digital Content 1: Study Flow Chart, https://links.lww.com/ALN/D573Supplemental Digital Content 2: Figure demonstrating percentage of cases receiving each blockade/antagonism agent strategies per quarter during the study period, https://links.lww.com/ALN/D574Supplemental Digital Content 3: Figure demonstrating percentage of cases receiving each blockade agent per quarter during the study period, https://links.lww.com/ALN/D575Supplemental Digital Content 4: Figure demonstrating percentage of cases receiving each antagonism agent per quarter during the study period, https://links.lww.com/ALN/D576Supplemental Digital Content 5: Figure demonstrating the Mean eGFR in each of 5 categories per quarter across the study period, https://links.lww.com/ALN/D577Supplemental Digital Content 6: Figure demonstrating the Median eGFR with Interquartile Range for Cisatracurium-Neostigmine and Rocuronium-Sugammadex strategies per quarter across the study period, https://links.lww.com/ALN/D578Supplemental Digital Content 7: Table providing the odds of receiving Cisatracurium/Neostigmine vs Rocuronium/Sugammadex in 2017 compared to 2020 by CKD Grade, https://links.lww.com/ALN/D579