Original Research Reports: Original Clinical Research Report

Sugammadex Versus Neostigmine for Reversal of Residual Neuromuscular Blocks After Surgery: A Retrospective Cohort Analysis of Postoperative Side Effects

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

Author Information

From the Departments of ^*Outcomes Research

^†General Anesthesiology, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio

^‡Department of Anesthesia, China-Japan Union Hospital of Jilin University, Changchun, China

Departments of ^§Pediatric Anesthesiology

^∥Intensive Care and Resuscitation

^¶Cardiothoracic Anesthesia, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio

^#Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio

Published ahead of print January 12, 2022.

Accepted for publication November 5, 2021.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

This report was previously presented at the at the annual meeting of the American Society of Anesthesiologists, San Francisco, California, October 3, 2020.

K. Ruetzler and K. Li contributed equally and share first authorship.

Reprints will not be available from the authors.

Funding: Support was provided solely from institutional and/or departmental sources.

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 [email protected].

Anesthesia & Analgesia 134(5):p 1043-1053, May 2022. | DOI: 10.1213/ANE.0000000000005842

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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.

KEY POINTS

Question: Is sugammadex noninferior to neostigmine on a composite of clinically meaningful side effects?
Findings: The composite incidence was less with neostigmine than with sugammadex, but only by 0.4%.
Meanings: From a clinical perspective, sugammadex and neostigmine are therefore comparably safe.

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.

METHODS

With Cleveland Clinic Foundation Review Board approval and waived consent (identifier 20-062, January 22, 2020, primary investigator Kurt Ruetzler, MD), we conducted a retrospective cohort analysis of patients having surgical procedures with general anesthesia who were given rocuronium or vecuronium at Cleveland Clinic, Main Campus between June 2016 and December 2019. We considered patients who were given either neostigmine or sugammadex for reversal of neuromuscular blockade at the end of surgery. Sugammadex and neostigmine were available in our institution throughout the entire study period. We excluded patients with incomplete intraoperative medication records or time stamps.

We collected demographic information (age, sex, weight, and height), relevant medical history (cardiac, renal, hepatic, and neurological), and perioperative data, including American Society of Anesthesiologists (ASA) physical status score, length of anesthesia, type of surgery, medications administered during and after surgery, vital signs, and diagnosis codes.

Important adverse events potentially associated with administered reversal medication were defined by clinical deterioration during or shortly after reversal medication administration that prompted treatment by the responsible anesthesia clinicians. Our primary outcome was a composite of bradycardia, cardiac arrest anaphylaxis, and bronchospasm occurring between administration of the reversal agent and departure from the operation room. Specifically, anesthesia records were electronically screened for the administration of any medication or intervention specified in Table 1 during this period. Neostigmine is routinely coadministered with intravenous (IV) atropine or IV glycopyrrolate to counteract the muscarinic effects, and we, therefore, only considered any additional dose of either drug after the initial dose was given. Because pediatric patients were included, we did not require any particular dose for drug interventions.

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.

Administration of the second dose of IV glycopyrrolate and IV ephedrine was a priori assumed to be given for bradycardia. Administration of salbutamol was a priori assumed to be given due to bronchospasm. All other cases suspected of having a clinically important adverse event as defined in Table 1 were evaluated by an adjudication committee.

The primary adjudication committee included 4 anesthesiology attendees (S.C., K.M., S.K., and A.T.) and 1 cheif adjudicator (K.R.). Adjudicators were asked to evaluate cases suspected of having clinically meaningful adverse events potentially associated with whichever reversal medication was given. For each suspect case, administrative and medical information was accessible to the adjudicators, but they were blinded to the patient’s diagnosis codes, administered reversal medication, and to other adjudicators’ comments. Each adjudicator was responsible for: (1) understanding and accepting our definitions for clinically meaningful adverse events and the adjudication guidelines; (2) carefully reviewing each suspect case; and (3) documenting the assessment of the diagnosis for suspect cases. Potential diagnosis included bradycardia, cardiac arrest, anaphylaxis, bronchospasm, or unrelated/unknown.

Each suspect case was reviewed by at least 3 adjudicators. The chief adjudicator (K.R.) then reviewed each assessment. Cases with consistent assessments by all assigned adjudicators were considered diagnosed. Cases with inconsistent assessment were individually reviewed by the chief adjudicator (K.R.). A diagnosis was considered established if the assessment of the chief adjudicator matched assessments from at least 2 other adjudicators. When there was greater disagreement, the chief adjudicator had the option of consulting other clinicians if deemed necessary. Finally, the adjudication committee (4 adjudicators and the chief adjudicator) met in person and individually reviewed each unresolved case to reach final consensus decisions.

Statistical Analysis

Our primary goal was to estimate the average treatment effect at the population level and then conduct noninferiority testing at the composite level. Some components of the composite are rare, such as cardiac arrest and anaphylaxis, and might be excluded with a propensity score matching method. We, therefore, used inverse probability of treatment weighting (IPTW) that allowed us to include all observations while simultaneously controlling observed potential confounding variables, such as age and sex. Specifically, we first estimated the probability of receiving sugammadex (ie, the propensity score) for each patient using logistic regression, with sugammadex as the outcome and all of the prespecified potential confounding variables listed in Table 2 as the explanatory variables.

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 Table 1). 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.

We then calculated “stabilized” propensity score weights as follows: the weights for the sugammadex group were calculated as the proportion of patients who received sugammadex divided by the propensity score; the weights for the neostigmine group were calculated as the proportion of patients who received neostigmine divided by 1 – the propensity score.^¹²^,^¹³ To avoid extreme weights unduly influencing results, we truncated at the 1st and 99th weighting percentiles. Successful control for confounding was assessed by comparing the 2 groups on all the potential confounding variables used to construct the propensity score using absolute standardized difference (ASD) after weighting each observation. Any covariable with an ASD >0.10 would be entered into the models to reduce potential confounding.^¹⁴ Histogram plots of estimated propensity scores were used to evaluate overlap (ie, common support) and similar distribution (ie, balance) across the groups.

IPTW was used to adjust for available confounding variables (Table 2) in the comparison of sugammadex and neostigmine patients on outcome variables. Sugammadex would be considered noninferior to neostigmine (or vice versa) if the OR for incurring the collapsed composite outcome was no more than a predefined delta of 1.2.

Noninferiority was assessed using a 1-tailed t test, with the log-transformed noninferiority delta as well as estimated log-OR and its standard error from a generalized estimating equation (GEE) to count within-subject correlation resulting from multiple surgeries per patient. If noninferiority was found in either direction, a superiority test would be performed using a 1-tailed t test. The significant level was 0.025 for noninferiority and superiority tests in each direction.

The GEE model included the inverse propensity score weighting and adjusted for any covariable still imbalanced after the weighting. A sensitivity analysis excluding pediatric and cardiac surgeries was also conducted.

Sample Size Considerations

We planned to use all available surgical cases for the study duration who met the inclusion/exclusion criteria for our study and did not conduct an a priori power analysis to guide sample size estimation. Based on a preliminary query from our database, the incidence of the composite outcome was 3%, among 16,480 cases in the sugammadex group and 73,273 in the neostigmine group. With an upper bound of noninferiority boundary of OR at 1.2, this sample would provide 98% power to show noninferiority at a 1-sided alpha level of 0.025 comparing patients given sugammadex versus neostigmine, assuming the odds were similar in each group. SAS statistical software version 9.4 was used for all analyses.

RESULTS

We identified 89,753 surgeries on 70,690 patients who met inclusion and exclusion criteria, including 16,480 (18%) surgeries during which sugammadex was given at the end of surgery and 73,273 (82%) during which neostigmine was given (Figure 1). Table 1 lists the patients who met screening criteria for adjudication of clinically important adverse effects of reversal agents.

Figure 1.:
Flow diagram. ASA indicates American Society of Anesthesiologists; ICD, International Classification of Diseases.

Patients were given a mean (SD) of 3.9 (2.5) mg kg^–1 sugammadex and a mean of 279 (100) µg kg^–1 neostigmine. The average age was 55 (19) years, and 51% were women. Baseline characteristics and surgical factors, after weighting, were well balanced except type of surgery (ASD = 0.23; Table 2; Figure 2). Consequently, the type of surgery was adjusted for in all of the analyses comparing patients who received sugammadex and neostigmine. The histograms of estimated propensity scores showed a good overlap and similar distribution across 2 groups (Supplemental Digital Content 1, Figure 1, https://links.lww.com/AA/D764). Supplemental Digital Content 2, Table 1, https://links.lww.com/AA/D765, summarized postoperative events by types of surgeries. Supplemental Digital Content 3, Table 2, https://links.lww.com/AA/D766, reported the balance of baseline characteristics and surgical factors after excluding pediatric and cardiac surgeries, and the type of surgery was also imbalanced (ASD = 0.112).

Figure 2.:
Plot of ASD between sugammadex group (N = 16,480) and neostigmine group (N = 73,273) on covariables before and after the inverse propensity score weighting. 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 Table 1). 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 1st and 99th percentiles. ASD is absolute difference in means or proportions divided by the pooled standard deviation. Any covariable with an ASD >0.10 was considered to be imbalanced. ASA indicates American Society of Anesthesiologists; ASD, absolute standardized difference; IPTW, inverse probability of treatment weighting.

During the screening process, a total of 2238 potential episodes of clinically meaningful bradycardia, 180 cases of cardiac arrests, 391 cases with anaphylaxis, and 849 cases with bronchospasm were identified. The adjudicators individually assessed all patients who were given supplemental IV atropine, along with patients who were given epinephrine, methylprednisolone, or diphenhydramine via any route. Patients with documented chest compression, defibrillation, or cardioversion were also evaluated, as were patients in whom a diagnosis of anaphylactic reaction was documented.

A total of 459 cases were individually reviewed by the adjudicators. Assessments of the 3 initial adjudicators were consistent in 416 cases. There were also 41 cases that were reviewed by the chief adjudicator who agreed with the diagnosis of the 2 matching assessments. Just 2 cases required discussion by the adjudication committee, with consensus diagnoses being unanimously assigned. Ultimately, we identified 2004 cases of bradycardia, 14 cases of cardiac arrests, 6 cases of anaphylaxis, and 731 cases of bronchospasm.

The observed incidences of the composite outcome and individual side effects are summarized in Table 3. The incidence of the composite outcome was 3.4% in the sugammadex group and 3.0% in the neostigmine group. The most common individual postoperative side effect was bradycardia (2.4% in the sugammadex group versus 2.2% neostigmine). Noninferiority was not found, with the estimated OR of 1.21 (sugammadex versus neostigmine; 95% CI, 1.09–1.34), noninferiority P = .57; (Table 3; Figure 3). However, we found that neostigmine was superior to sugammadex with an estimated OR of 0.83 (0.74–0.92), 1-side superiority P < .001. The results of the sensitivity analysis are consistent with these findings.

DISCUSSION

All adverse events, including those consequents to reversal medications, span a range of severities from trivial to life-threatening. We a priori restricted our analysis to side effects that required pharmacologic treatment and were thus both noticed by the responsible clinicians and deemed sufficiently severe to treat. Because some medications, including epinephrine, atropine, methylprednisolone, and diphenhydramine, are given for various reasons, we further required 3 independent anesthesiologists to adjudicate each event. Glycopyrrolate, ephedrine, and salbutamol were considered a priori diagnostic for bradycardia and bronchospasm. The events we report are thus all presumably clinically meaningful.

Composite

Using our definitions, the overall incidence of clinically important adverse events was 3.4% in patients given sugammadex and 3.0% in those given neostigmine. The difference of 0.4% is based on the higher incidence of bradycardia (2.4% vs 2.2%) and bronchospasm (0.98% vs 0.78%). Both side effects are transient and easy to treat with appropriate drugs. The number of patients who needed to be given neostigmine rather than sugammadex to avoid an episode of bradycardia was 500 and similarly was 500 for avoiding bronchospasm. The number-needed-to-harm for both complications combined was thus 250 patients. Few clinicians would consider a number-needed-to-harm of 250 patients for minor complications, much less 500 patients, a reasonable basis for selecting one drug or the other. In contrast, cardiac arrest and anaphylaxis are life-threatening. Cardiac arrest (0.01% with neostigmine versus 0.02% with sugammadex) and anaphylaxis (0.02% vs 0.004%) were both rare. There were no impressive differences in the incidence of either side effect with the 2 drugs; although with only 6 cases of anaphylaxis and 14 cases of cardiac arrests, our comparisons are underpowered despite including 89,000 surgical cases.

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 Table 1). 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.

^dP 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.

Figure 3.:
Forest plot for noninferiority testing. There were significantly more side effects with sugammadex than with neostigmine. CI indicates confidence interval.

Our results contradict 2 recent meta-analyses of small randomized trials, both of which reported that sugammadex is associated with significantly fewer adverse events. One reported significantly fewer composite adverse events in patients given sugammadex than neostigmine (RR, 0.60; 95% CI, 0.49–0.74; 28 trials; n = 2298).^⁷ The other reported adverse events in 11% (78 of 684) of patients given sugammadex versus 21% (133 of 630) in those given neostigmine (OR, 0.47; 95% CI, 0.34–0.66; 13 studies; n = 1384).^¹¹ Severe adverse events included anxiety, depression and marked fatigue, acute lung injury, severe hypoxemia, bradycardia, and postoperative abdominal pain and were observed in 0.15% of patients given sugammadex and 1.27% of patients given neostigmine (OR, 0.33; 95% CI, 0.09–1.19; P = .091).^¹¹ Cumulatively, both meta-analyses included <3800 patients spread across 41 studies, with sample sizes ranging from 22 to 1198 adults, and included various clinical settings and patient characteristics. Both meta-analyses are seriously underpowered for serious but rare side effects such as anaphylaxis and cardiac arrest, and by variability and inconsistencies in definitions of the outcomes across trials. It is also unclear how anxiety, depression, and fatigue are mechanistically related to reversal agent selection.

Bradycardia

Among the side effects we evaluated, bradycardia was by far the most common consequence of sugammadex and neostigmine administration, accounting for about two-thirds of the adverse events. The anticholinesterase neostigmine is routinely coadministered with a muscarinic receptor antagonist such as glycopyrrolate or atropine to prevent bradycardia that would otherwise occur with elevated plasma acetylcholine concentrations. This clinical practice usually prevents severe bradycardia and did so in about 98% of our cases. The incidence of clinically meaningful bradycardia was 2.2% in patients given neostigmine, which is consistent with a previously reported incidence of 2.9% in a retrospective analysis of >73,000 cases.^¹⁵

Sugammadex also causes bradycardia, although the mechanism remains unclear.^¹¹ The incidence of bradycardia in patients given sugammadex was 2.4% and, therefore, nearly identical to patients given neostigmine (2.2%). Results of our analysis differ from a recent meta-analysis that reported bradycardia in 50 of 597 patients (8.3%) given neostigmine and 4 of 621 patients (0.6%) given sugammadex (RR, 0.16; 95% CI, 0.07–0.34; 11 studies; n = 1218).^⁷ The difference between the meta-analysis and our results is based on differing definitions of bradycardia. We only considered bradycardia events requiring a pharmaceutical intervention instead of using a defined heart rate threshold. Why previous publications did not report any bradycardia after sugammadex administration remains unclear.

Cardiac Arrest

There are anecdotal reports of cardiac arrests after administration of sugammadex or neostigmine.^¹⁶^,^¹⁷ We identified 14 cardiac arrests, 2 among 16,480 patients given sugammadex (0.01%) versus 12 among 73,273 patients given neostigmine (0.02%), none of whom died during their initial hospitalization. Our analysis extends previous work by suggesting that the odds of cardiac arrest are similar in patients given sugammadex and neostigmine; although with so few events, we have a little power for identifying even substantial differences.

Anaphylaxis

Anaphylaxis is a major clinical concern and is independently associated with morbidity and mortality.^¹⁰ We identified 6 cases of anaphylaxis, 3 of which occurred in patients given sugammadex (0.02%) and 3 of which followed neostigmine (0.004%). None of these 6 cases progressed to cardiac arrest, and none died during their initial hospitalization.

Our results are consistent with a large Japanese multicenter retrospective analysis that included nearly 50,000 surgical patients in which the overall incidence of laboratory-confirmed sugammadex-related anaphylaxis was 0.02% (6 of 29,962 patients).^¹⁸ Interestingly, the investigators did not identify any anaphylaxis attributable to neostigmine (0 of 3157 patients). However, the study was seriously underpowered for neostigmine-related anaphylaxis which occurred only once per 25,000 patients in our cohort.

A postmarketing surveillance study of the US Food and Drug Administration (FDA) reported an incidence of sugammadex-related anaphylaxis of 0.024%.^¹⁹ Another Japanese single-institutional study reported an incidence of 0.039%.^²⁰ The reported incidence of anaphylaxis to sugammadex of 0.02% in our study is, therefore, consistent with these results.

The observed incidence of anaphylaxis in our patients was about 5 times more common with sugammadex (1 of 5000 cases) than with neostigmine (1 of 25,000 cases). However, there were so few anaphylaxis events that our estimates are imprecise, and the relative risk with each remains uncertain. Consequently, anaphylaxis is so rare after sugammadex or neostigmine that is should not be a basis for selecting one drug or the other.

Bronchospasm

Bronchospasm is a known side effect of neostigmine’s antimuscarinic mechanism and is aggravated by excessive respiratory secretions. Bronchospasm is usually temporally limited and easily treated with salbutamol or inhaled epinephrine but can also be the initial sign of an allergic or anaphylactic reaction. The incidence of bronchospasm was comparable with each reversal agent, with an incidence of 0.98% (161 of 16,480) in patients given sugammadex and 0.78% (570 of 73,273) in patients given neostigmine. There are several anecdotal reports of bronchospasm after neostigmine, but none after sugammadex that has been given to many fewer patients.^²¹

Respiratory adverse events following administration of sugammadex and neostigmine were evaluated in a recent meta-analysis that included 6 randomized trials. The overall incidence of respiratory adverse events was 1.4% (5 of 345) in patients given sugammadex and 4.5% (15 of 335) in patients given neostigmine (OR, 0.36; 95% CI, 0.14–0.95; P = .0386).^¹¹ However, none of the underlying studies specifically reported bronchospasm.

Methodological Considerations

A strength of our approach was electronically identifying potential cases, followed by individual review and assessment by an independent adjudication committee. Individual review allowed us to identify the most appropriate clinical diagnosis. For example, epinephrine was given to 140 patients, each of whom was individually evaluated by at least 3 independent adjudicators. Ultimately, the adjudication committee allocated these 140 cases to 13 cardiac arrests, 22 episodes of bronchospasm, 6 of anaphylactic events, and 97 cases of bradycardia, with 2 others being obvious misclassifications.

Retrospective analyses are subject to reporting bias and random errors, such as misclassification due to incorrect data input. To reduce misclassification errors and overreporting, a substantial fraction of the adverse events that were electronically identified was individually reviewed by the adjudication committee. Four hundred fifty-nine potential events, including all potential events of anaphylaxis and cardiac arrests, were individually reviewed and <3% (11 events) were considered due to incorrect data input. Because bronchospasm and bradycardia events were not reviewed, misclassification is more likely for these common outcomes. However, there is a little reason to expect misclassification to differ depending on the reversal agent.

Clinicians might have selectively given one reversal drug or the other. We, therefore, used the IPTW approach based on the known and measured confounder to balance baseline and demographic characteristics. Because we included pediatric and adult patients in our cohort, we did not consider reversal agent doses. However, both are usually given on an mg·kg^–1 basis, and there was a relatively narrow range of doses.

Suspected causative agents of anaphylaxis are often gauged by assessing the time of administration of each drug in relation to symptom onset. This approach does not work well during anesthetic induction because various medications are typically given over short periods of time.^²² However, reversal medications are often the only medication given during emergence from anesthesia. We restricted our analysis to the period between administration of neuromuscular blockade reversal agents and departure from the operating room. While late-onset side effects might initially appear in the postanesthesia care unit (PACU) or surgical ward, such long delays seem unlikely—especially for the more severe side effects.

Analyses of large datasets often yield statistically significant associations that are not clinically meaningful. We, therefore, a priori defined 1.2 as the smallest OR that we considered clinically meaningful in this setting. Using observed event rate of 3% in neostigmine patients with noninferiority bound of OR ≤1.2, the number-needed-to-harm from adjusted OR was 165 (102–383).^²³ A final limitation is that we did not consider minor potential side effects such as nausea and vomiting.

Conclusions

The incidence of severe adverse events—anaphylaxis and cardiac arrest—was so rare that even with >89,000 cases, we had little precision for estimating the incidence, much less power for a valid comparison between neostigmine and sugammadex. In contrast, there were many episodes of bradycardia and bronchospasm, both of which are transient side effects that are easy to treat and not especially serious. Our composite was, therefore, largely driven by bradycardia and bronchospasm, and from a practical perspective was essentially a composite of just these 2 side effects.

Neuromuscular blockade reversal with neostigmine was associated with slightly fewer adverse events than sugammadex (3.0% vs 3.4%). Neostigmine was found to be statistically superior to sugammadex, but the composite was mostly driven by minor, temporary, and relatively unimportant complications like bradycardia and bronchospasm. This difference of just 0.4% corresponds to a number-needed-to-harm of 250 patients (95% CI, 137–769). That is, 250 patients would need to be given neostigmine rather than sugammadex to avoid 1 episode of minor complications like bradycardia or bronchospasm. We, therefore, conclude that sugammadex and neostigmine are comparably safe.

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.