Failure of Standard‐Dose Sugammadex in an Infant With Trisomy 21: Considerations Including Drug Degradation

A growing body of literature underscores safety and dosing concerns regarding the use of sugammadex for reversal of non-depolarizing neuromuscular blockade in infants and neonates, largely attributable to maturational differences in renal clearance, plasma protein binding, and volume of distribution compared with pediatric patients aged ≥ 2 years, for whom sugammadex is currently FDA-approved [1, 2]. The main safety concerns with sugammadex used in infants include: (1) bradycardia and rare asystole [2-4], (2) hypersensitivity or anaphylaxis [2, 3, 5], (3) risk of recurarization from under dosing reversal or redistribution of unbound drug [3, 5, 6], (4) renal immaturity leading to prolonged elimination [2, 4], and (5) theoretical interactions with other steroidal compounds [4, 5]. Although several case reports and small case series describe recurarization following sugammadex reversal [4, 5, 7], the literature does not adequately address challenging considerations when rocuronium doses are escalated due to concerns for possible drug degradation. A 7-month-old, 8.1 kg female with Trisomy 21, transient abnormal myelopoiesis, and double outlet right ventricle status post complete repair, presented for Hickman catheter placement, bone marrow aspiration, and lumbar puncture with intrathecal cytarabine. Anesthetic induction was achieved with fentanyl 20 μg, propofol 30 mg. Rocuronium 20 mg (2.4 mg kg−1) was administered to facilitate endotracheal intubation, a higher-than-normal dose chosen due to circulating concerns about potential drug degradation of the stocked rocuronium with the goal to ensure adequate immobility throughout the anticipated 90-min procedure. Anesthesia was maintained with a propofol infusion while monitored with standard monitors, including train-of-four (TOF) SunStim Plus peripheral nerve stimulator. A baseline response was not recorded before the administration of rocuronium. No other medication known to alter neuromuscular blocker metabolism (e.g., phenytoin, barbiturates, corticosteroids) had been administered. Spontaneous extremity movement was observed 43 min later while prepping for the line placement, coinciding with the conclusion of the bone marrow biopsy and lumbar puncture. A supplemental dose of rocuronium 10 mg (1.2 mg kg−1) was administered without TOF assessment. Communication from other faculty working that morning indicated that rocuronium appeared to have a shorter duration of action than expected, raising concern that the circulating batch might have been partially degraded. Pharmacy records later confirmed that the rocuronium lot in use was within its expiration date and stored under appropriate conditions; however, no analytical testing (e.g., high-performance liquid chromatography mass spectrometry) was performed to confirm drug integrity. At the conclusion of the procedure, 57 min after the second administration of rocuronium, the patient was assessed and observed to have a TOF count of three out of four twitches at the ulnar nerve for which she received sugammadex 4 mg·kg−1 for reversal. Following administration, spontaneous ventilation resumed with tidal volumes of 5–6 mL·kg−1, and the patient met clinical extubation criteria including adequate respiratory effort and purposeful movement. She was transferred to the post-anesthesia care unit (PACU) breathing room air. Approximately 45 min later, the PACU nurse called for assistance when the patient developed irregular “hiccup-like” movements and declining oxygen saturation (nadir 84%). Manual ventilation via laryngeal mask airway (LMA) was initiated using a Mapleson circuit delivering 100% oxygen. TOF monitoring with the SunStim peripheral nerve stimulator at the ulnar nerve demonstrated four twitches with significant fade (TOF ratio < 0.4), consistent with residual neuromuscular blockade. An additional 12 mg·kg−1 of sugammadex (for a total of 16 mg·kg−1) was administered. Within 1 min, the patient exhibited strong spontaneous ventilation with normal oxygen saturation, recovering thereafter requiring no further intervention. This case highlights the complexities of diagnostic and management challenges associated with recurarization following sugammadex reversal in an infant. Although rocuronium degradation was initially suspected as a contributing factor, alternative mechanisms, particularly insufficient sugammadex relative to circulating and redistributed relaxant must be considered. Rocuronium degradation can occur through hydrolysis of the acetate group or oxidation of the morpholine ring, producing inactive derivatives [8]. These degraded molecules exhibit altered size and charge distribution that may reduce affinity for sugammadex's hydrophobic cavity. However, given that degraded rocuronium possesses little or no neuromuscular blocking activity, it is unlikely that degradation alone explains recurrent paralysis. More plausibly, recurarization may result from (1) incomplete encapsulation of intact rocuronium due to insufficient sugammadex dose [4, 6], or (2) redistribution of unbound relaxant from peripheral to central compartments [4, 6]. The initial rocuronium dose (2.4 mg·kg−1) exceeded typical intubating doses for infants (0.6–1.2 mg·kg−1). While upfront overdosing may be rationalized for a procedure with an expected long duration and need for surgical immobility throughout, upfront overdosing may also increase the amount of rocuronium redistributed to tissue compartments, thereby elevating the risk of postoperative recurarization. Subsequent spontaneous movement suggests that blockade had worn off earlier than expected. At that time, quantitative TOF monitoring was not performed, representing a missed opportunity to accurately assess the depth of neuromuscular blockade, particularly important in infants with Trisomy 21, where baseline hypotonia can make clinical evaluations of weakness and recovery less reliable [9, 10]. Although Down syndrome is well known for upper-airway hypotonia and associated airway management challenges [9, 10], published data do not demonstrate structural or functional abnormalities of the neuromuscular junction. Accordingly, attributing recurarization to receptor level hypersensitivity is less plausible than other contributors such as pharmacokinetic and pharmacodynamic factors, high initial dosing, redistribution of relaxant, and limitations in monitoring. The TOF count of three twitches indicated a moderate level of blockade, for which a 4 mg·kg−1 dose of sugammadex was appropriate. However, this amount did not provide a sufficient molar excess to encapsulate all circulating rocuronium as well as the portion that later redistributed from peripheral compartments. As a result, the patient may have shown transient recovery followed by recurrent weakness once unbound relaxant returned to the central circulation [4, 6, 11]. Although sugammadex typically achieves more rapid and complete reversal than neostigmine, comparisons between these agents are only meaningful when antagonizing a shallow neuromuscular block (TOF count > 0.4, per ASA guidelines) [1, 3, 13]. Neostigmine may be considered in such shallow blocks, particularly when incomplete encapsulation or pharmacokinetic mismatch is suspected [12]. Regardless of the reversal agent used, ASA guidelines continue to emphasize the importance of quantitative TOF monitoring and clinical criteria to confirm full recovery prior to extubation [1-3, 13-15]. The neuromuscular junction possesses a substantial physiologic “margin-of-safety,” such that even when the train-of-four (TOF) ratio has recovered to 0.9, approximately 70%–75% of acetylcholine receptors may still remain occupied by non-depolarizing neuromuscular blocking agents [1]. As Vanlinthout et al. highlight, clinical recovery does not equate to true pharmacologic recovery at the receptor level. Consequently, even a small increase in circulating unbound neuromuscular blocker can overcome this narrow buffer, precipitating clinically significant recurarization despite seemingly reassuring TOF values. In the context of the present case, this margin-of-safety limitation becomes particularly important. The infant received a higher-than-standard initial rocuronium dose, resulting in a larger total body burden of drug and a greater fraction distributing into peripheral compartments. Vanlinthout et al. demonstrate that spontaneous recovery kinetics in infants are highly sensitive to dose-dependent variability and developmental differences in drug disposition. After sugammadex encapsulates plasma rocuronium, any subsequent redistribution of relaxant from peripheral tissues back into the central compartment disproportionately affects infants because their neuromuscular junctions reach functional thresholds with much smaller concentrations of unbound relaxant [1]. In this case, the infant's TOF ratio in the PACU (< 0.4) confirms that the physiologic safety buffer had been exceeded. The larger initial dosing increased peripheral sequestration, and the subsequent redistribution into a circulation containing an insufficient concentration of sugammadex to bind the returning relaxant explains the delayed respiratory deterioration. When combined with the unique pharmacokinetic features of infancy—expanded extracellular fluid volume, immature renal clearance, and developmental variability in neuromuscular junction sensitivity—the margin-of-safety concept underscores why infants are particularly vulnerable to recurarization even after apparently appropriate sugammadex dosing. In this 7-month-old infant with Trisomy 21, apparent recurarization following standard-dose sugammadex was successfully managed with additional dosing. Unsure how much rocuronium remained in peripheral compartments to redistribute, the remaining 12 mg/kg needed to reach the next recommended dose tier of 16 mg/kg was administered. While degraded rocuronium was suspected leading to a higher upfront dosing of rocuronium with induction, the lack of analytical confirmation precludes causal inference. This episode more likely reflects underdosing of sugammadex relative to relaxant load, redistribution, or altered pharmacokinetics associated with infancy. A higher-than-standard rocuronium dose (2.4 mg·kg−1) likely enhanced tissue redistribution in this infant, predisposing to postoperative recurarization despite appropriate reversal based on TOF assessment. In infants, larger doses of rocuronium can increase the risk of recurarization due to pharmacokinetic redistribution. Because infants have a higher extracellular fluid fraction and immature clearance pathways, a greater proportion of the drug distributes into peripheral compartments after high dosing. When reversal is achieved with sugammadex, plasma rocuronium is rapidly encapsulated, but drug stored in peripheral tissues can subsequently diffuse back into the circulation. If the circulating sugammadex concentration is insufficient to bind this returning fraction, free rocuronium may reoccupy neuromuscular receptors, leading to delayed recovery or recurarization. This case underscores the need for vigilant quantitative monitoring, awareness of physiologic variability, and cautious interpretation of incomplete reversal before extubation in infants. Lance Patak was the primary attending anesthesiologist who both proposed and performed the anesthetic, developed the original draft of the manuscript, provided subsequent edits, and helped shape the direction of the final manuscript. Benjamin Trieu assisted in the management of this patient in PACU and helped draft the original manuscript and provided subsequent draft edits. Alex Croes was the primary certified anesthesiologist assistant who performed the anesthetic, helped draft the original manuscript and provided subsequent draft edits. The authors have nothing to report. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.