Toward reliable neuromuscular blockade reversal using sugammadex in infants: insights from a phase IV trial

The introduction of sugammadex marked a major milestone in neuromuscular pharmacology, offering the first selective relaxant-binding agent capable of rapidly reversing steroidal neuromuscular blockade without cholinergic side effects (1). Its efficacy and safety have been well demonstrated in adults and in children aged 2 years and older across multiple randomized trials and pooled analyses (2-5). However, despite growing off-label use in infants younger than 2 years, high-quality evidence in this youngest population has been lacking. Previous data were limited to case series, small prospective cohorts, and retrospective reviews, many of which suggested that sugammadex was effective and likely safe but could not provide definitive conclusions (6-9). The multicenter, phase IV randomized clinical trial by Mensah-Osman and colleagues helps to address this critical evidence gap, providing important safety and efficacy data in neonates and infants aged birth to 24 months (10). Although pharmacokinetic information was reported, these data were limited in scope and should be interpreted as supportive rather than definitive.

Infants and young infants are physiologically distinct from older children, although these differences are most pronounced in the early postnatal period and progressively attenuate over the first months of life. Immature renal clearance, increased extracellular fluid volume, and altered protein binding are particularly relevant in neonates and may influence drug distribution and elimination (11). In addition, developmental immaturity of the neuromuscular junction—most evident during the first weeks of life and characterized by variability in synaptic transmission—may contribute to differences in sensitivity to neuromuscular blocking agents and their reversal. Despite ongoing maturation, infants remain particularly vulnerable to the consequences of residual neuromuscular blockade, which can lead to airway obstruction, hypoxia, and postoperative apnea even with mild degrees of residual paralysis (12,13). In addition, the developmental immaturity of upper airway muscle control and diminished responsiveness to hypoxemia make infants substantially less tolerant of even subtle reductions in diaphragmatic or pharyngeal muscle function (14). These age-specific physiological vulnerabilities amplify the clinical relevance of achieving a consistently complete, rapid and predictable reversal of neuromuscular blockade in this population (2,15).

In the study by Mensah-Osman et al., pharmacokinetic information was reported; however, these data were limited in scope and were not derived from detailed population pharmacokinetic modeling. Accordingly, they should be interpreted as supportive rather than definitive, and the primary contribution of the study lies in its safety and efficacy findings.

In the trial population, neuromuscular blockade was administered in the setting of routine surgical and airway management procedures typical for neonates and infants requiring general anesthesia. Moderate blockades were used to facilitate surgical exposure and tracheal intubation, whereas deep blockades were required when complete immobility was deemed necessary by the investigators. Framing the results within these clinical contexts underscores the relevance of rapid and reliable reversal in everyday pediatric anesthetic practice. The randomized portion of the trial yielded clinically relevant data: among infants undergoing moderate neuromuscular blockade with rocuronium or vecuronium, reversal with 2 mg/kg sugammadex occurred in a median of 1.4 minutes, compared with 4.4 minutes with neostigmine (3-5). However, it is important to note that the study protocol defined the timing of neostigmine administration based on a train-of-four (TOF) count >2, whereas contemporary American Society of Anesthesiologists (ASA) and European Society of Anaesthesiology and Intensive Care (ESAIC) recommendations advise administration when the TOF ratio exceeds approximately 0.4. This difference in criteria may influence interpretation of the comparative results. In the sugammadex group, 79.3% of infants receiving sugammadex achieved a TOF ratio ≥0.9 within 4 minutes. Conversely, approximately 20% did not meet this early recovery threshold, emphasizing that even with sugammadex, recovery may not be uniformly immediate. These findings reinforce the need for objective confirmation of adequate neuromuscular recovery prior to extubation. For deep blockade, a setting in which neostigmine is not effective, 4 mg/kg sugammadex provided rapid reversal with a median time of 1.1 minutes and recovery in 96.8% of all children within the first 4 minutes as defined by the study criteria. Importantly, approximately 3–4% did not meet this early recovery threshold, underscoring that even with sugammadex, reversal may not be uniformly immediate in all patients. These recovery profiles suggest that sugammadex is associated with rapid reversal across different depths of neuromuscular blockade under the conditions defined in the study protocol (16). However, interpretation of comparative efficacy should take into account the specific criteria for neostigmine administration and current guideline recommendations (16). The clinical characteristics and monitoring data of those who experienced delayed recovery were not fully detailed, and it remains unclear whether patient-specific factors, variability in monitoring methodology, or pharmacodynamic differences contributed to these findings. In addition, given that quantitative neuromuscular monitoring was not universally applied, the exact degree of recovery achieved in all patients cannot be definitively established. These considerations reinforce that, although sugammadex provides rapid and generally predictable reversal, it does not eliminate the need for objective monitoring and continued vigilance in the peri-extubation period.

This pharmacologic reliability reduces—though does not entirely eliminate—the variability inherent to anticholinesterase agents (17), an issue that may be particularly relevant in infants due to developmental differences in neuromuscular physiology and the variable pharmacodynamic response observed with anticholinesterase agents such as neostigmine (18).

These findings align closely with data from previous pediatric randomized clinical trials in children aged two to seventeen (5) and observational studies in infants younger than 2 years, which have generally reported excellent reversal times and favorable safety profiles (6-9). The present trial adds methodological rigor through randomization, blinding, and pharmacokinetic analysis. However, neuromuscular monitoring was not uniform across study sites, as heterogeneous monitoring approaches were permitted and quantitative monitoring was not universally applied. An important methodological consideration, however, relates to the assessment of neuromuscular recovery. Although the study incorporated neuromuscular monitoring, only a proportion of patients underwent quantitative monitoring capable of objectively confirming a TOF ratio ≥0.9. Furthermore, the quantitative monitoring modality used was acceleromyography (AMG), which is known to require careful calibration and may be influenced by the staircase phenomenon, potentially leading to overestimation of recovery and underestimation of residual neuromuscular blockade. Contemporary consensus statements and expert commentaries emphasize that quantitative monitoring represents the only reliable method for confirming adequate recovery and excluding residual neuromuscular blockade (18-20). Clinical signs or qualitative assessments alone have repeatedly been shown to be insufficiently sensitive for detecting residual weakness, particularly in pediatric populations. As highlighted in recent expert editorial discussions, failure to employ objective monitoring may substantially limit the interpretability of recovery outcomes and safety conclusions. Therefore, while the recovery times reported in this study are encouraging, the absence of universal quantitative monitoring constitutes a meaningful limitation and warrants cautious interpretation of claims regarding complete reversal. Safety findings were similarly reassuring. Across 138 treated participants, there were no cases of hypersensitivity or anaphylaxis, and no drug-related serious adverse events reported. However, the absence of such events in a cohort of this size does not exclude the possibility of rare reactions; the upper bound of the 95% confidence interval for an event with zero occurrences in 138 patients is approximately 2%, underscoring the limited power of the study to detect infrequent adverse events. The incidence of bradycardia was low in both groups and did not differ significantly between sugammadex and neostigmine. Although concerns about “recurarization” in infants have been raised in previous retrospective studies and case reports (21,22), no recurrence of neuromuscular blockade was observed in this trial. Nearly universal use of quantitative neuromuscular monitoring (18,23) likely contributed to appropriate dosing and may have mitigated factors associated with the rare instances of delayed recovery described in earlier literature (21,22). The low incidence of bradycardia observed in this study is consistent with the overall safety profile reported for sugammadex.

One element of the study that warrants discussion is the lack of difference in extubation time between the sugammadex and neostigmine groups. While reversal occurred significantly faster with sugammadex, extubation is multifactorial-particularly in this population. Many infants were scheduled for postoperative neonatal intensive care unit (NICU) admission, and extubation timing in this population is often influenced by multiple clinical considerations, including postoperative disposition and airway management strategies. These factors may attenuate the observable impact of pharmacologic reversal speed on extubation time. However, objective confirmation of adequate neuromuscular recovery remains essential prior to airway removal. Therefore, extubation time alone may not serve as a reliable surrogate endpoint for evaluating reversal agents in this age group.

The results of this randomized controlled trial strongly support the use of sugammadex as the preferred reversal agent for infants under 2 years of age. Its rapidity, predictability, and favorable safety profile offer distinct advantages in a population particularly susceptible to the dangers of residual paralysis.

Nevertheless, there are several points in the study by Mensah-Osman et al. that should not be overlooked. One important concern is the limited power of the phase IV trial to capture rare complications. Although no clinically significant safety signals emerged, the study’s sample size provides insufficient power to exclude infrequent but consequential events. Thus, when sugammadex is administered to infants younger than 2 years, clinicians should be aware of the potential for adverse events, such as hypersensitivity, anaphylaxis, and bradycardia, and careful monitoring is necessary after administration. Additionally, questions remain, including its performance in preterm neonates, infants with renal impairment, or those undergoing prolonged neuromuscular blockade-populations excluded from this study. Future research addressing these groups, as well as comparative analyses evaluating postoperative respiratory outcomes or cost-effectiveness, will be meaningful next steps.

Overall, this study represents a significant advancement in pediatric anesthetic management. By demonstrating both efficacy and safety across the entire infant age spectrum, Mensah-Osman and colleagues provide long-needed clarity for clinicians and reinforce that sugammadex can be used confidently even in the youngest patients to achieve timely and reliable recovery from neuromuscular blockade. Their contribution shifts the evidence landscape and is likely to influence both clinical practice and future regulatory considerations regarding infant-approved indications for sugammadex.

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-2025-1-892/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-892/coif). The authors have no conflicts of interest to declare.

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References

1. Naguib M. Sugammadex: another milestone in clinical neuromuscular pharmacology. Anesth Analg 2007;104:575-81. [Crossref] [PubMed]
2. Plaud B, Meretoja O, Hofmockel R, et al. Reversal of rocuronium-induced neuromuscular blockade with sugammadex in pediatric and adult surgical patients. Anesthesiology 2009;110:284-94. [Crossref] [PubMed]
3. Herring WJ, Woo T, Assaid CA, et al. Sugammadex efficacy for reversal of rocuronium- and vecuronium-induced neuromuscular blockade: A pooled analysis of 26 studies. J Clin Anesth 2017;41:84-91. [Crossref] [PubMed]
4. Hristovska AM, Duch P, Allingstrup M, et al. The comparative efficacy and safety of sugammadex and neostigmine in reversing neuromuscular blockade in adults. A Cochrane systematic review with meta-analysis and trial sequential analysis. Anaesthesia 2018;73:631-41.
5. Voss T, Wang A, DeAngelis M, et al. Sugammadex for reversal of neuromuscular blockade in pediatric patients: Results from a phase IV randomized study. Paediatr Anaesth 2022;32:436-45. [Crossref] [PubMed]
6. Franz AM, Chiem J, Martin LD, et al. Case series of 331 cases of sugammadex compared to neostigmine in patients under 2 years of age. Paediatr Anaesth 2019;29:591-6. [Crossref] [PubMed]
7. Ozmete O, Dardag E, Civi S. Reversal of rocuronium induced neuromuscular block with sugammadex in patients under 2 years of age. A series of 280 cases. Ann Ital Chir 2023;94:612-6.
8. Gaver RS, Brenn BR, Gartley A, et al. Retrospective Analysis of the Safety and Efficacy of Sugammadex Versus Neostigmine for the Reversal of Neuromuscular Blockade in Children. Anesth Analg 2019;129:1124-9. [Crossref] [PubMed]
9. Matsui M, Konishi J, Suzuki T, et al. Reversibility of Rocuronium-Induced Deep Neuromuscular Block with Sugammadex in Infants and Children-A Randomized Study. Biol Pharm Bull 2019;42:1637-40. [Crossref] [PubMed]
10. Mensah-Osman E, Mukai Y, Wang A, et al. Sugammadex for Reversal of Neuromuscular Blockade in Neonates and Infants Less than 2 Years Old: Results from a Phase IV Randomized Clinical Trial. Anesthesiology 2025;143:300-12. [Crossref] [PubMed]
11. Ligi I, Boubred F, Grandvuillemin I, et al. The neonatal kidney: implications for drug metabolism and elimination. Curr Drug Metab 2013;14:174-7.
12. Cammu G. Residual Neuromuscular Blockade and Postoperative Pulmonary Complications: What Does the Recent Evidence Demonstrate? Curr Anesthesiol Rep 2020;10:131-6. [Crossref] [PubMed]
13. Klucka J, Kosinova M, Krikava I, et al. Residual neuromuscular block in paediatric anaesthesia. Br J Anaesth 2019;122:e1-2. [Crossref] [PubMed]
14. Trachsel D, Erb TO, Hammer J, et al. Developmental respiratory physiology. Paediatr Anaesth 2022;32:108-17. [Crossref] [PubMed]
15. Blobner M, Eriksson LI, Scholz J, et al. Reversal of rocuronium-induced neuromuscular blockade with sugammadex compared with neostigmine during sevoflurane anaesthesia: results of a randomised, controlled trial. Eur J Anaesthesiol 2010;27:874-81. [Crossref] [PubMed]
16. Sorgenfrei IF, Norrild K, Larsen PB, et al. Reversal of rocuronium-induced neuromuscular block by the selective relaxant binding agent sugammadex: a dose-finding and safety study. Anesthesiology 2006;104:667-74. [Crossref] [PubMed]
17. Fisher DM. Neuromuscular blocking agents in paediatric anaesthesia. Br J Anaesth 1999;83:58-64. [Crossref] [PubMed]
18. Naguib M, Brull SJ, Kopman AF, et al. Consensus Statement on Perioperative Use of Neuromuscular Monitoring. Anesth Analg 2018;127:71-80. [Crossref] [PubMed]
19. Thilen SR, Weigel WA, Todd MM, et al. 2023 American Society of Anesthesiologists Practice Guidelines for Monitoring and Antagonism of Neuromuscular Blockade: A Report by the American Society of Anesthesiologists Task Force on Neuromuscular Blockade. Anesthesiology 2023;138:13-41. [Crossref] [PubMed]
20. Renew JR, Tobias JD, Brull SJ. The Time to Seriously Reassess the Use and Misuse of Neuromuscular Blockade in Children Is Now. Anesth Analg 2021;132:1514-7. [Crossref] [PubMed]
21. Cates AC, Freundlich RE, Clifton JC, et al. Analysis of the factors contributing to residual weakness after sugammadex administration in pediatric patients under 2 years of age. Paediatr Anaesth 2024;34:28-34. [Crossref] [PubMed]
22. Salaün JP, Décary E, Veyckemans F. Recurarisation after sugammadex in children: review of case reports and recommendations. Br J Anaesth 2024;132:410-4. [Crossref] [PubMed]
23. Fuchs-Buder T, Claudius C, Skovgaard LT, et al. Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision. Acta Anaesthesiol Scand 2007;51:789-808. [Crossref] [PubMed]