The utility of sugammadex in infants: a shifting clinical paradigm

Sugammadex is a gamma cyclodextrin which selectively encapsulates amino steroidal neuromuscular blockade (NMB) agents such as rocuronium or vecuronium, thereby reversing NMB. It has drastically changed the clinical practice for the reversal of moderate and deep levels of NMB in adults. Sugammadex has been widely studied and is approved for use in adult and pediatric populations aged 2 years and older. However, its use in younger patients has largely been based on case series, retrospective reviews, and small prospective studies. This phase IV randomized clinical trial by Mensah-Osman et al. aims to address this evidence gap by evaluating the pharmacokinetics, safety, and efficacy of sugammadex for the reversal of moderate and deep NMB in pediatric patients from birth to under 2 years of age, thereby providing evidence to support its use in this vulnerable population (summarized in Table 1) (1). Compared to older population, infant physiologic immaturity presents several challenges for anesthetic management due to underdeveloped renal, hepatic, and enzymatic pathways that alter drug pharmacokinetics and pharmacodynamics. At the cellular level, developing neuromuscular junctions exhibit an increased, highly variable sensitivity to neuromuscular blocking agents. These factors present unique clinical challenges during major surgeries, amplifying the risks and benefits of neuromuscular management in this age group (2).

This multicenter trial studied 138 participants less than 2 years of age who underwent a planned surgical or medical procedure requiring moderate or deep NMB with either rocuronium or vecuronium. The trial consisted of parts A and B, each featuring four distinct age cohorts: 6 months to less than 2 years, 3 months to less than 6 months, 28 days to less than 3 months, and birth to 27 days. The inclusion of a heterogeneous range of surgical and medical interventions reflects the broad pediatric populations and enhances the generalizability of the findings. However, it is not clear if the surgical characteristics were comparable between study arms, this could potentially confound postoperative recovery and suitability for extubation.

Part A of the study was an open label pharmacokinetics and safety study. Participants were stratified for age and monitored for up to 12 hours after administration. While the youngest cohorts—neonates up to 27 days and infants aged 28 days to 3 months—exhibited lower clearance and plasma concentrations, the overall data demonstrated consistent, predictable trends in correlation with time to neuromuscular recovery (TTNMR), which the authors defined as achieving any of the following.

• Head lift against resistance for ≥5 seconds;
• Hip flexion against resistance for ≥5 seconds;
• Four twitches without fade (qualitative);
• Train-of-four ratio (TOFR) ≥0.9 (quantitative).

Findings suggest that 2 and 4 mg/kg doses of sugammadex were appropriate for moderate and deep NMB reversal, respectively. There were notably few participants in the birth to 27 days cohort.

Part B was a double blinded randomized controlled trial with a 1:1:1 allocation ratio: moderate NMB reversed with sugammadex 2 mg/kg or neostigmine, deep NMB reversed with sugammadex 4 mg/kg. Most notably, the primary endpoint was changed from time to extubation to TTNMR after study initiation. Furthermore, the protocol was amended to permit deep extubation. The reported rationale of this modification was to align with evolving clinical practices that favor deep extubation along with objective neuromuscular transmission monitoring. The investigators noted that the timing of extubation was influenced by broader clinical variables, including site and provider preferences, surgical complexity, deep versus awake extubation, and operational delays (e.g., transport) independent of neuromuscular reversal agent. Time to extubation was amended as a secondary outcome and was comparable between 2 mg/kg sugammadex group (median time 7.9 minutes) and neostigmine group (median time 10.5 minutes) for reversal of moderate blockade [hazard ratio 1.30; 95% confidence interval (CI): 0.76–2.21; P=0.2107]. This conclusion mirrors standard pediatric anesthesia practices, where the decision to extubate is determined by a global assessment, thus faster TTNMR may not translate into faster time to extubation. Furthermore, this may also reflect a conservative approach to extubation timing, particularly for vulnerable neonates.

TTNMR as the primary outcome in theory minimized the impact of variability in clinical context, thereby increasing the statistical confidence. Ultimately, part A of the study demonstrated a strong correlation between sugammadex dosing (2 and 4 mg/kg) and time to recovery across all age groups, despite a small sample size (N=47) and limited enrollment in the youngest age group (N=2 in the birth to 27 days cohort). The comparison between sugammadex and neostigmine in part B of the trial demonstrated faster reversal of moderate NMB by sugammadex compared to neostigmine (median TTNMR: 1.4 vs. 4.4 min, hazard ratio 2.40, 95% CI: 1.37–4.18; P=0.0002).

Conversely, this amendment introduced considerable limitations to the trial; time to extubation may offer greater clinical utility aimed at preventing residual NMB and its associated respiratory complications. It should also be noted that some of the TTNMR criteria, such as head lift and hip flexion may not be sufficiently sensitive in detecting residual NMB, but the investigator noted that the vast majority of participants (97.8%) were evaluated objectively via acceleromyography (AMG). AMG gauges the physical acceleration of a muscle in response to nerve stimulation, whereas electromyography (EMG) quantifies the electrical activity elicited during muscle fiber contraction. Quantitative assessment of muscle recovery via AMG-based TOFR (≥0.9) is recommended as “clinical gold standard” by the American Society of Anesthesiologists to evaluate residual paralysis (3). However, since AMG is based on the measurement of target muscle acceleration, it is sensitive to motion artifacts. Achieving precise AMG readings necessitates unhindered movement of the target muscle, a requirement that presents substantial challenges in infants due to a scarcity of validated pediatric monitors, small patient size, and limited spatial capacity to assess free movement of the adductor pollicis muscle (4). Furthermore, AMG tends to overestimate the TOFR by 10% to 20%. Normalizing TOFR to baseline value can mitigate this overestimation, but this practice is frequently unfeasible in most clinical environments (5,6). EMG offers a potential solution for the physical restrictions of infant extremities by directly recording individual electrical responses; however, literature on pediatric EMG-based train-of-four (TOF) monitoring is limited. A recent study by Tobias et al. (7) explored the flexor hallucis brevis muscle of the foot as an alternative to the preferred site (the thumb) for AMG monitoring. TOFR ≥0.9 at the foot exhibited a 3-minute delay compared to the hand. While this discrepancy may prolong the time to tracheal extubation in practice, it simultaneously provides a safety margin by ensuring additional time for complete neuromuscular receptor recovery.

For deep NMB—where neostigmine is ineffective—the 1.1-minute TTNMR achieved with 4 mg/kg sugammadex was comparable to the 1.2 minutes observed with 2 mg/kg dose for moderate blockade. Of particular clinical relevance, 98.6% of participants in the deep NMB + 4 mg/kg sugammadex group achieved TTNMR within 4 minutes. These findings highlight the value of sugammadex in surgical scenarios requiring deep NMB without compromising recovery times, and they align with established recommendations across both adult and pediatric literature. For instance, a cohort study by Alonso et al. (8) involving 23 neonates (aged 1–7 days) demonstrated that 4 mg/kg sugammadex facilitated fast reversal of deep rocuronium-induced NMB with minimal adverse events or alterations of vitals, further reaffirming its safe profile.

The safety profile of sugammadex was reassuring based on analysis of both part A and part B. The paucity of adverse events such as hypersensitivity and bradycardia at doses of 2–4 mg/mg may support the safe use of sugammadex in patients under 2 years of age. However, the relatively small sample size (138 participants with only 63 receiving 4 mg/kg) may limit the detection of rare adverse events (e.g., hypersensitivity and bradycardia). Clinically relevant bradycardia, defined as bradycardia necessitating rescue treatment, was comparable across all groups (2% and 0% in sugammadex groups vs. 0% in neostigmine group) and resolved with atropine treatment. Additional larger studies, and post-marketing surveillance are needed to determine safety in this vulnerable population.

The study design focused on short-term NMB examining the immediate postoperative period which may not capture delayed adverse events. In addition, the design excluded preterm neonates (born <36 weeks) and infants with severe renal disease, since sugammadex is excreted entirely (95%) unchanged via the kidneys. Compared to term infants, preterm neonates exhibit a significantly lower glomerular filtration rate (GFR). Although nephrogenesis continues until 34–36 weeks of gestation and GFR doubles within 2 weeks postnatally, full renal maturity is not achieved until approximately 18 months of age (9). The findings of this phase IV trial demonstrate that sugammadex use may be extended to patients under 2 years of age without modification to the established dosing in adults and children above 2 years of age (i.e., 2 and 4 mg/kg for moderate and deep NMB reversal, respectively). Nevertheless, further research should expand to include preterm neonates. This age cohort may benefit the most from sugammadex rapid and reliable NMB reversal, thereby mitigating the risk of critical postoperative complications such as residual paralysis and adverse respiratory events. No cases of re-paralysis were noted in this trial, addressing concerns raised by previous retrospective reports (10) and supporting the reliability of sugammadex in infants, despite theoretical concerns related to immature drug clearance. The investigators attributed previously reported recurrence of NMB to factors such as rocuronium overdose, inadequate neuromuscular monitoring, and inappropriate sugammadex dosing relative to the depth of blockade.

An additional knowledge gap for future research to address is the use of a higher dose of sugammadex for reversal after a rapid sequence dose of rocuronium (1.2 mg/kg) in infants with profound NMB in cannot intubate, cannot ventilate (CICV) situations. Case report by Wołoszczuk-Gębicka et al. (11) reported effective reversal with sugammadex 8 mg/kg in a 10-month-old infant who was in CICV situation after administering 0.1 mg/kg vecuronium. Another case report by Efune et al. (12) described successful reversal of CICV situation utilizing sugammadex 16 mg/kg in a premature (born at 25 weeks) 2-week-old, extremely low birth weight infant undergoing exploratory laparotomy for ileal atresia who received rocuronium 1.2 mg/kg for rapid sequence induction. These dosages require further investigation to confirm safety, efficacy, and potential risks in neonates and infants during emergent situations.

This phase IV trial may provide high-quality evidence supporting the value of sugammadex at 2 and 4 mg/kg doses for reversal of moderate and deep NMB, respectively in pediatric patients younger than 2 years of age. The rapid reversal coupled with reassuring safety profile suggests enhanced recovery following surgery. Further larger studies are warranted to investigate long term safety, to explore applications in preterm infants, and to support its use for emergency profound blockade scenarios.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Pediatrics. The article has undergone external peer review.

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0126/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0126/coif). Z.J. was supported by the Long Island Network for Clinical and Translational Science for work, which is unrelated to the content of this manuscript. The other authors have no conflicts of interest to declare.

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