INTRODUCTION
Neuromuscular blockade (NMB) facilitates balanced anesthesia and smooth airway management, and can improve the surgical field by suppressing reflex muscle movement [1,2]. Neuromuscular blocking agents (NMBAs) are used perioperatively to induce NMB, reduce accidental movement, and potentially reduce laryngeal injury during airway manipulation. Because adequate muscle strength is required prior to emergence from general anesthesia, pharmacological reversal of NMB is essential to ensure safe recovery of respiratory function.
Acetylcholinesterase (AChE) inhibitors have traditionally been used for NMBA reversal. However, these agents exhibit limited efficacy in treating deep NMB. In addition, AChE inhibitors non-selectively increase acetylcholine levels, enhance parasympathetic tone, and potentially cause bradycardia, hypotension, dry mouth, and bronchoconstriction [3-5]. To address these limitations, sugammadex, a selective aminosteroidal NMBA binding agent, was introduced [3,4].
Sugammadex enables rapid and reliable reversal of rocuronium-induced NMB. In contemporary perioperative care, enhanced recovery after surgery (ERAS) pathways emphasize rapid recovery, minimization of postoperative complications, and improved patient-centered outcomes. In pediatric anesthesia, efficient reversal of NMB and reduction of postoperative nausea and vomiting (PONV) are considered important components aligned with ERAS principles [6]. In the USA, the use of sugammadex in adults was approved by the Food and Drug Administration (FDA) in December 2015, leading to its widespread adoption in clinical practice. As pediatric patients may differ from adults in terms of pharmacokinetics and pharmacodynamics, pediatric approval requires additional evidence. Following multiple studies evaluating efficacy and safety in children, the FDA approved sugammadex for patients aged ≥ 2 years on July 2, 2021 [2,7,8]. Although sugammadex has not yet been approved for use in children < 2 years of age, its off-label use in this population has been reported in several randomized controlled trials (RCTs) and prospective studies, particularly in settings where rapid and reliable reversal of NMB is clinically desirable [4,9,10]. Since approval for children ≥ 2 years, additional studies have reported advantages such as reduced NMB, faster recovery time, and potential utility in scenarios such as difficult airway management [2-4]. The inclusion of studies involving children < 2 years of age in the present review was, thus, intended to comprehensively synthesize the available evidence and to explore the potential efficacy and safety profile of sugammadex in this understudied and vulnerable population, rather than to suggest its clinical use beyond current regulatory approval.
Previous meta-analyses by Won et al. [11] and Lang et al. [8] demonstrated the superior efficacy of sugammadex compared with conventional reversal agents in pediatric patients. However, these analyses primarily focused on children aged ≥ 2 years. The present systematic review aimed to update the available evidence by including more recent RCTs, incorporating broader pediatric age ranges (including < 2 years), and to evaluate the conclusiveness of the findings using trial sequential analysis (TSA).
MATERIALS AND METHODS
Study identification
This systematic review and meta-analysis followed the Cochrane handbook for systematic reviews of interventions [12]. We searched PubMed, EMBASE, the Cochrane Library, Web of Science, Scopus, and KoreaMed from inception to December 31, 2023. ClinicalTrials.gov was searched to identify ongoing or unpublished trials, and EMBASE conference abstracts were also screened. Also, this study is not subject to institutional review board.
The search terms included sugammadex, Org 25969, Bridion, NMB, rocuronium (e.g., Esmerone), and pediatric-related terms (neonate, infant, child, children, adolescent, juvenile, and pediatric). The full search strategy is provided in Supplementary File 1. The reference lists of the included studies were also screened. Any duplicates were removed and all records were assessed for eligibility.
Study selection
This systematic review and meta-analysis was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [12]. Two reviewers (BGL and HSK) independently screened the titles and abstracts. Meta-analyses, retrospective studies, and review articles were excluded. Full texts were assessed to determine final eligibility. Discrepancies were resolved through discussions between the reviewers.
We included RCTs comparing sugammadex with placebo, neostigmine alone, or neostigmine plus an anticholinergic agent in pediatric patients (< 18 years). For efficacy evaluation, studies were required to report either the time to recovery to a train-of-four (TOF) ratio ≥ 0.9 or extubation time. Trials reporting adverse events were included in safety analyses. No restrictions were applied with regard to language or type of surgery.
Data extraction
Outcomes were extracted by one reviewer (HSK) and verified by a second reviewer (BGL). Any disagreements were resolved by a third reviewer (YSK). The variables extracted included patient age, sample size, type of surgery, timing of reversal administration, sugammadex dose, and control intervention.
Primary efficacy outcomes were (1) the time from reversal agent administration to recovery to a TOF ratio ≥ 0.9 and (2) time from reversal agent administration to extubation. Secondary outcomes included overall postanesthetic adverse events, bradycardia, tachycardia, PONV, desaturation, anaphylaxis, and recurarization.
For continuous outcomes, means and standard deviations (SDs) were extracted. When outcomes were reported as medians, the values were converted to means and SDs using established methods [13]. When data were presented graphically, numerical values were extracted using WebPlotDigitizer (Ankit Rohatgi) [14]. For dichotomous outcomes, numbers of participants experiencing each event were extracted.
Risk of bias and certainty of evidence
The risk of bias was assessed using the Cochrane risk-of-bias tool across seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other bias [12]. Each domain was rated as low, high, or unclear. Two reviewers (BGL and HSK) independently assessed the risk of bias, and disagreements were resolved by a third reviewer (YSK).
The certainty of evidence for pooled outcomes was evaluated using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach with the GRADEpro GDT, considering the risk of bias, inconsistency, indirectness, imprecision, and publication bias [15].
Statistical analysis
Continuous outcomes were pooled as mean differences (MDs) with 95% confidence intervals (CIs), using a random-effects model. Dichotomous outcomes were pooled as risk ratios (RRs) with 95% CIs using a random-effects model. Statistical heterogeneity was assessed using the Cochrane Q test and I2 statistics, with I2 > 50% indicating substantial heterogeneity.
MDs were analyzed using the inverse variance method for continuous variables and the Mantel-Haenszel method was used for dichotomous variables. For secondary variables, adverse events could be zero and were excluded from the analysis, regardless of their clinical significance. To reduce exclusion, a value of one was added to dichotomous variables with zero events [12].
Analyses were performed using Review Manager (RevMan version 5.4.1, Cochrane). Publication bias was assessed using funnel plots and Egger’s regression test, where applicable. TSA was conducted to control for random errors (type I and II errors) using Copenhagen Trial Unit software [16].
Subgroup analysis was performed according to sugammadex dose (2 mg/kg vs. 4 mg/kg) and age (< 2 years vs. ≥ 2 years) for efficacy outcomes.
RESULTS
Identification of studies
A total of 1,002 records were identified after removing duplicates. After title screening, 891 records were excluded because of ineligible population and/or study designs. Of the remaining 111 records, abstracts were screened, and ineligible studies were excluded owing to insufficient data or protocol mismatches. Twenty-seven full-text articles were assessed and 21 RCTs met the inclusion criteria (Fig. 1).
Characteristics and demographics of studies
The included RCTs enrolled pediatric patients (< 18 years of age) undergoing general anesthesia across various surgical procedures. Studies reporting age-stratified outcomes within broader pediatric populations were also included. The intervention was sugammadex compared with a placebo, neostigmine alone, or neostigmine plus atropine. The study characteristics are summarized in Table 1 [7,9,10,17,19,20-35].
In total, 1,394 patients were included: 823 received sugammadex (2 or 4 mg/kg) and 574 were allocated to the control group. The ages of the participants ranged from newborns to < 18 years.
For the dose subgroups, 14 studies assessed 2 mg/kg (380 patients in the sugammadex group and 385 in the control group) and eight studies assessed 4 mg/kg (167 and 169 patients, respectively). In the subgroup of patients aged < 2 years, four studies were included (79 patients in each group).
Risk of bias
The risk-of-bias assessments are summarized in Table 2. Random sequence generation was judged to be of low risk in 17 studies (80.9%). Allocation concealment was considered low risk in 13 studies (61.9%), whereas 8 studies did not report sufficient details. The blinding of participants and personnel was found to be of low risk in 11 studies (52.4%), unclear in 9 studies, and high risk in one study. Blinding of the outcome assessors was at low risk in 7 studies (33%). Incomplete outcome data was considered high risk in three studies (14%) and low risk in 16 studies (76%). Selective reporting was low risk in 15 studies (71%), and other biases were low risk in 17 studies (80.9%).
Primary outcomes
Time to TOF ratio ≥ 0.9: Twenty studies (1,089 patients; 554 sugammadex; 535 control) reported this outcome. Despite substantial heterogeneity (I2 = 99%), sugammadex significantly reduced the time to TOF ratio ≥ 0.9 (MD [95% CI], -12.14 [-14.18 to -10.10] min; P < 0.00001) (Fig. 2A). TSA demonstrated that the cumulative Z-curve crossed the boundary for benefit and exceeded the required information size (Fig. 2B).
Dose subgroup analysis: For the 2 mg/kg (14 studies), time to TOF ratio ≥ 0.9 was shorter with sugammadex administration (I2 = 99%; MD [95% CI], -6.03 [-7.85 to -4.21] min; P < 0.00001 (Fig. 3). For 4 mg/kg (eight studies), time to TOF ratio ≥ 0.9 was also shorter (I2 = 99%; MD [95% CI], -30.06 [-37.58 to -22.55] min; P < 0.00001) (Fig. 4). The TSA for both dose subgroups showed that the Z-curve crossed the boundary for benefit and exceeded the required information size.
Using GRADE, the certainty of evidence for time to TOF ratio ≥ 0.9 was rated low for both dose subgroups, primarily due to the substantial inconsistency (high heterogeneity) and suspected publication bias based on funnel plot asymmetry (Fig. 5).
Extubation time: Thirteen studies (816 patients; 406 sugammadex; 410 controls) reported extubation time. The extubation time was significantly shorter with sugammadex (I2 = 99%; MD [95% CI], -14.26 [-17.22 to -11.30] min; P < 0.00001). TSA indicated that the Z-curve crossed the boundary for benefit and exceeded the required information size (Fig. 6). The certainty of the evidence was rated low due to heterogeneity and suspected publication bias.
Age < 2 years subgroup: Four studies (158 patients) were included in this subgroup analysis. Despite the heterogeneity (I2 = 88%), sugammadex reduced the time to TOF ratio ≥ 0.9 compared with control (MD [95% CI], -8.96 [-10.94 to -6.98] min; P < 0.00001) (Fig. 7). TSA was not performed due to the limited number of studies included. The certainty of the evidence was rated as moderate.
Secondary outcomes
The safety outcomes are summarized in Table 3. The incidence of tachycardia (RR [95% CI], 0.16 [0.07 to 0.40]), PONV (RR [95% CI], 0.44, [0.28 to 0.68]), and desaturation (RR [95% CI] = 0.50 [0.25 to 1.00]) were lower with sugammadex (Fig. 8). In contrast, the overall post-anesthetic adverse events (RR [95% CI], 0.83 [0.40 to 1.73]), bradycardia (RR [95% CI], 0.63 [0.26 to 1.51]) and recurarization (RR [95% CI], 1.06 [0.30 to 3.76]) were comparable between groups (Fig. 8).
DISCUSSION
In this updated meta-analysis of 21 RCTs including 1,394 pediatric patients, sugammadex was associated with faster and more complete recovery from NMB than control interventions. This benefit was observed at both 2 and 4 mg/kg doses, and extubation time was shorter with sugammadex, consistent with more rapid neuromuscular recovery. TSA supported the robustness of these efficacy findings, demonstrating that cumulative evidence exceeded the required information size and crossed the monitoring boundary for benefit.
Our findings are consistent with those of previous pediatric meta-analyses reporting the superior efficacy of sugammadex compared with conventional reversal agents. Notably, this review included additional data from children aged < 2 years. In the subgroup analysis of four studies including 158 patients aged < 2 years, sugammadex also significantly shortened time to TOF ratio ≥ 0.9 compared with control, suggesting potential efficacy even in this younger population.
Regarding safety, the incidences of tachycardia, PONV, and desaturation were lower with sugammadex, whereas the overall post-anesthetic adverse events, bradycardia, and recurarization were similar between the groups. Bradycardia related to cholinergic effects is a recognized concern with conventional reversal in pediatric patients. However, bradycardia showed a lower trend with sugammadex, though the difference did not reach statistical significance, suggesting similar hemodynamic stability.
In the context of ERAS, faster and more reliable reversal of NMB may contribute to improved perioperative efficiency and patient-centered outcomes. In particular, PONV is a key outcome of interest in ERAS-oriented perioperative care. Anticholinesterase agents have been suggested as risk factors for PONV, and several studies have reported lower PONV rates with sugammadex than with conventional reversal agents [17]. In the included pediatric trials, atropine was commonly administered in combination with neostigmine; however, PONV occurred less frequently in the sugammadex group. These findings suggest that sugammadex may offer an advantage in pediatric anesthesia settings where ERAS principles are increasingly emphasized, although further studies are needed to confirm its role in structured ERAS protocols [8,18].
The major limitation of this meta-analysis was the substantial heterogeneity in efficacy outcomes. The timing of reversal administration likely contributed to variability: most studies administered reversal at the reappearance of T2, whereas a few administered at different depths of block (Ammar et al. [7], Gaona et al. [19], and Xiaobing et al. [20]). Differences were identified in anesthetic maintenance, patient age ranges, surgical procedures, and the type and dose of control reversal agents may also have contributed. Although subgroup analyses according to sugammadex dose were performed, the heterogeneity remained high; therefore, these subgroup analyses should be interpreted as exploratory rather than explanatory.
In addition, adverse events were relatively rare, limiting statistical power for safety outcomes, particularly in patients aged < 2 years, for whom few trials were available. Further well-designed trials focusing on the safety in younger children are warranted. In addition, although a comprehensive literature search was conducted, limiting the inclusion to RCTs may have introduced the risk of publication bias. Although funnel plot analysis, Egger’s regression test, and TSA were used to assess and mitigate this risk, additional quantitative analyses were limited by the small number of studies in certain outcomes and subgroups; thus, residual publication bias cannot be entirely excluded.
This updated meta-analysis showed that sugammadex provides faster and more effective reversal of rocuronium-induced NMB in pediatric patients than neostigmine or placebo, as reflected by shorter time to recovery to a TOF ratio ≥ 0.9 and shorter extubation time, despite the substantial heterogeneity. The TSA indicated that the evidence for these efficacy outcomes was conclusive. Sugammadex was also associated with lower incidences of PONV, tachycardia, and desaturation, without an increase in the incidence of overall post-anesthetic adverse events, bradycardia, or recurarization. Efficacy was maintained in children aged < 2 years; however, additional studies, particularly those evaluating safety in this age group, are needed to further strengthen this evidence.
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