Sugammadex Versus Neostigmine for Reversal of Residual Neuromuscular Blocks After Surgery

A Retrospective Cohort Analysis of Postoperative Side Effects

Kurt Ruetzler, MD, FAHA; Kai Li, MD; Surendrasingh Chhabada, MD; Kamal Maheshwari, MD, MPH; Praveen Chahar, MD, FCARCSI; Sandeep Khanna, MD; Marc T. Schmidt; Dongsheng Yang, MS; Alparslan Turan, MD; Daniel I. Sessler, MD

Disclosures

Anesth Analg. 2022;134(5):1043-1053.

Abstract and Introduction

Abstract

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.

Introduction

Neuromuscular blocking agents are widely used to facilitate endotracheal intubation, ease mechanical ventilation, and optimize surgical conditions.^[1] Most surgical patients are, therefore, given nondepolarizing neuromuscular blocking agents.^[2] 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.^[7]

Neostigmine is a commonly used acetylcholinesterase inhibitor, which competitively antagonizes residual neuromuscular blockade by preventing metabolism of acetylcholine.^[6] 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.^[8] 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).^[7] The incidence of adverse events was 28% in neostigmine patients versus 16% in those given sugammadex.^[7] However, the incidence of serious events was similar in each group.^[7] 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).^[11]

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.

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Abstract and Introduction
Methods
Results
Discussion
References
Sidebar

Table 1. Screening Criteria for Adjudication of Clinically Significant Adverse Effects of Reversal Agents
Adverse event	Screening criteria necessitating adjudication^a	Cases found	Cases reviewed	Events after adjudication
Bradycardia^a	Administration of IV atropine	28	Yes	2004
	Administration of IV glycopyrrolate	630	No
	Administration of epinephrine	140	Yes
	Administration of ephedrine	1440	No
Cardiac arrest	Documented chest compressions/defibrillation/cardioversion	40	Yes	14
Cardiac arrest	Administration of IV epinephrine	140	Yes	14
Anaphylaxis	Administration of epinephrine	140	Yes	6
	Administration of methylprednisolone	12	Yes
	Administration of diphenhydramine	238	Yes
	Documented diagnosis of anaphylactic/anaphylactoid reaction	1	Yes
Bronchospasm	Administration of albuterol	709	No	731
Bronchospasm	Administration of epinephrine	140	Yes	731

Abbreviation: IV, intravenous.
^aOnly considered, if neostigmine was coadministered with either glycopyrrolate or atropine, and an additional dosage of any medication was required afterward.

Table 2. Demographic and Baseline Characteristics Before and After the IPTW ^a
Variables	Sugammadex, n = 16,480	Neostigmine, n = 73,273	Unadjusted ASD^b	ASD after IPTW^b
Age (y)	57 ± 19	55 ± 19	0.093	0.015
Sex (female) (%)	50	52	0.031	0.024
Race (White) (%)	81	82	0.045	0.006
ASA status (%)
I	2	3	0.266	0.051
II	14	21
III	63	62
IV	21	13
V	0.11	0.09
Emergency (%)	4.2	3.1	0.058	0.011
Smoking (%)	52	48	0.082	0.013
Medical history (%)
Congestive heart failure	8	6	0.076	0.012
Vascular disease	7	5	0.082	0.008
Pulmonary circulation disease	1	1	0.029	0.009
Peripheral vascular disease	7	5	0.077	0.017
Hypertension	53	48	0.097	0.024
Paralysis	2	2	0.031	0.008
Other neurological disorders	7	6	0.052	0.016
Chronic pulmonary disease	16	11	0.135	0.022
Diabetes	20	18	0.068	0.014
Hypothyroidism	14	13	0.021	0.004
Renal failure	11	10	0.036	0.015
Liver disease	5	4	0.018	0.005
Peptic ulcer disease (bleeding)	1	1	0.008	0.008
AIDS	0	0	0.010	0.002
Lymphoma	1	1	0.007	0.000
Metastatic cancer	8	7	0.041	0.006
Solid tumor without metastasis	13	12	0.042	0.017
Rheumatoid arthritis/collagen vas	4	3	0.028	0.001
Coagulopathy	5	4	0.050	0.018
Obesity	20	19	0.015	0.015
Weight loss	12	10	0.073	0.027
Fluid and electrolyte disorders	16	13	0.062	0.028
Chronic blood loss anemia	1	1	0.001	0.011
Deficiency anemia	9	8	0.021	0.004
Alcohol abuse	1	1	0.014	0.008
Drug abuse	1	1	0.004	0.002
Psychoses	2	2	0.002	0.003
Depression	14	14	0.001	0.007
Duration of surgery (h)	2.3 (1.3–3.8)	3.1 (2.0–4.4)
Type of surgery: top 10 (column %)
Diagnostic bronchoscopy and biopsy of bronchus	8	4	0.772	0.227
Colorectal resection	3	5
Other OR therapeutic procedures on respiratory system	9	3
Laminectomy, excision intervertebral disk	3	4
Other OR lower GI therapeutic procedures	3	4
Conversion of cardiac rhythm	3	4
Other hernia repair	3	3
Hysterectomy, abdominal, and vaginal	2	3
Other OR therapeutic procedures on skin and breast	1	3
Spinal fusion	1	3

Summary statistics (presented as percentage of patients, mean ± SD, or median [Q1–Q3], respectively, for factors, symmetric continuous variables, and skewed continuous variables; duration of surgery was summarized by median [10th, 90th percentiles]).
Abbreviations: AIDS, acquired immune deficiency syndrome; ASA, American Society of Anesthesiologists; ASD, absolute standardized difference; GI, gastrointestinal; IPTW, inverse probability of treatment weighting; OR, odds ratio; SD, standard deviation.
^aIPTW: first, we estimated the probability of receiving sugammadex (ie, the propensity score) for each patient using logistic regression with receiving sugammadex as the outcome using the following prespecified potential confounding variables (listed in ). Then, we calculated the stabilized weights as follows: for the sugammadex group, weight was the proportion of sugammadex patients divided by the propensity score; for the neostigmine group, weight was the proportion of neostigmine patients divided by (1 – propensity score). To be conservative, we also truncated the stabilized weights at the 1st and 99th percentiles.
^bASD: absolute difference in means or proportions divided by the pooled standard deviation after weighting each observation with IPTW. Any covariable with an ASD >0.10 was considered to be imbalanced and would be adjusted for in the analysis.

Table 3. Noninferiority Analysis: Comparison Between Patients Who Received Sugammadex Versus Neostigmine on the Primary Composite Outcome Using IPTW ^a
Primary outcome	Sugammadex (N = 16,480) event (%)	Neostigmine (N = 73,273) event (%)	OR (95% CI)^b	Noninferiority^c P value^d	Superiority P value^d
Collapsed composite	558 (3.4)	2167 (3.0)
Sugammadex versus neostigmine (reference)			1.21 (1.09–1.34)	.57	NA
Neostigmine versus sugammadex (reference)			0.83 (0.74–0.92)	<.001	<.001
Individual components
Bradycardia	401 (2.4)	1603 (2.2)
Cardiac arrest	2 (0.01)	12 (0.02)
Anaphylaxis	3 (0.02)	3 (0.004)
Bronchospasm	161 (0.98)	570 (0.78)
Sensitivity analysis (adult patients with noncardiac surgery, superiority analysis)
	N = 13,065	N = 63,558
Collapsed composite	486 (3.7)	1937 (3.1)
Sugammadex versus neostigmine (reference)			1.28 (1.15–1.44)	.88	NA
Neostigmine versus sugammadex (reference)			0.78 (0.69–0.87)	<.001	<.001
Individual component
Bradycardia	353 (2.7)	1472 (2.3)
Cardiac arrest	2 (0.02)	9 (0.01)
Anaphylaxis	3 (0.02)	2 (0.00)
Bronchospasm	135 (1.03)	470 (0.74)

^aIPTW: First, we estimated the probability of receiving sugammadex (ie, the propensity score) for each patient using logistic regression with receiving sugammadex as the outcome using the following prespecified potential confounding variables (listed in ). Then, we calculated the stabilized weights as follows: for the sugammadex group, weight was the proportion of sugammadex patients divided by the propensity score; for the neostigmine group, weight was the proportion of neostigmine patients divided by (1 – propensity score). We also truncated the stabilized weights at the 1st and 99th percentiles.
^bThe OR of the composite outcome was estimated using a GEE model with IPTW and adjusted for the type of surgery.
^cNoninferiority delta is an OR of 1.2.
^d P value was from 1–1-tailed t test in the given direction.
Abbreviations: CI, confidence interval; GEE, generalized estimating equation; IPTW, inverse probability of treatment weighting; NA, not applicable; OR, odds ratio.

Authors and Disclosures

Kurt Ruetzler, MD, FAHA*†, Kai Li, MD*‡, Surendrasingh Chhabada, MD*§, Kamal Maheshwari, MD, MPH*†, Praveen Chahar, MD, FCARCSI*†||, Sandeep Khanna, MD*†¶, Marc T. Schmidt*, Dongsheng Yang, MS#, Alparslan Turan, MD*† and Daniel I. Sessler, MD*

Departments of *Outcomes Research and †General Anesthesiology, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio; ‡Department of Anesthesia, China-Japan Union Hospital of Jilin University, Changchun, China; and Departments of §Pediatric Anesthesiology, ||Intensive Care and Resuscitation, and ¶Cardiothoracic Anesthesia, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio; and #Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio

Address correspondence to
Kurt Ruetzler, MD, FAHA, Departments of Outcomes Research and General Anesthesiology, Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Ave, P-77, Cleveland, OH 44195. Address e-mail to ruetzlk@ccf.org.

The authors declare no conflicts of interest.

Disclosures
Name: Kurt Ruetzler, MD, FAHA.
Contribution: This author helped with study design, data collection and interpretation, and writing the manuscript, and read and approved the final version of the manuscript.
Name: Kai Li, MD.
Contribution: This author helped with data collection and interpretation and writing the manuscript, and read and approved the final version of the manuscript.
Name: Surendrasingh Chhabada, MD.
Contribution: This author helped with data collection and interpretation and writing the manuscript, and read and approved the final version of the manuscript.Name: Kamal Maheshwari, MD, MPH.
Contribution: This author helped with study design, data collection and interpretation, and writing the manuscript, and read and approved the final version of the manuscript.
Name: Praveen Chahar, MD, FCARCSI.
Contribution: This author helped with data collection and interpretation and writing the manuscript, and read and approved the final version of the manuscript.
Name: Sandeep Khanna, MD.
Contribution: This author helped with data collection and interpretation and writing the manuscript, and read and approved the final version of the manuscript.
Name: Marc T. Schmidt, MD.
Contribution: This author helped with data collection and interpretation and writing the manuscript, and read and approved the final version of the manuscript.
Name: Dongsheng Yang, MS.
Contribution: This author helped with study design; data collection, interpretation, and analysis; and writing the manuscript; and read and approved the final version of the manuscript.
Name: Alparslan Turan, MD.
Contribution: This author helped with study design, data collection and interpretation, and writing the manuscript, and read and approved the final version of the manuscript.
Name: Daniel I. Sessler, MD.
Contribution: This author helped with study design, data collection and data interpretation, and writing the manuscript, and read and approved the final version of the manuscript.
This manuscript was handled by: Ken B. Johnson, MD.