Sugammadex for Reversal of Neuromuscular Blockade in Neonates and Infants Less than 2 Years Old: Results from a Phase IV Randomized Clinical Trial

Abstract

Background: Sugammadex is well tolerated and effective for reversing neuromuscular blockade (NMB) in adults and children as young as 2 yr old. There is little information on its use in younger children. The aim of this study was to evaluate the efficacy and tolerability of sugammadex in children under 2 yr of age.

Methods: This was a phase IV, randomized, parallel-group, multicenter clinical trial of sugammadex in participants aged birth to less than 2 yr (NCT03909165). Part A was open label and included pharmacokinetic assessments to determine whether sugammadex dose adjustment for part B was necessary based on age. Part B was double-blind and evaluated doses of 2 and 4 mg/kg sugammadex. Participants were randomized to (1) moderate NMB and reversal with 2 mg/kg sugammadex; (2) moderate NMB and reversal with neostigmine + glycopyrrolate or atropine (hereafter, called neostigmine); or (3) deep NMB and reversal with 4 mg/kg sugammadex. The primary efficacy endpoint was time to neuromuscular recovery (TTNMR). The primary efficacy hypothesis was that 2 mg/kg sugammadex would be superior to neostigmine for the reversal of moderate NMB as measured by TTNMR in part B.

Results: A total of 138 participants aged 1 to 720 days were treated in parts A and B (2 mg/kg sugammadex, n = 44; 4 mg/kg sugammadex, n = 63; and neostigmine, n = 31). Based on pharmacokinetic assessments in part A, no dose adjustments for age were needed. In part B, TTNMR for reversal of moderate NMB was faster with 2 mg/kg sugammadex than neostigmine (median of 1.4 min vs. 4.4 min; hazard ratio, 2.40; 95% CI, 1.37 to 4.18; P = 0.0002). A 4-mg/kg dose of sugammadex achieved rapid TTNMR for reversal of deep NMB with a median of 1.1 min (parts A and B). The percentage of participants with one or more adverse events (parts A and B) was similar for sugammadex and neostigmine. No deaths, drug-related serious adverse events, or hypersensitivity or anaphylaxis events were reported.

Conclusions: In children less than 2 yr old, 2 mg/kg sugammadex reversed moderate NMB faster than neostigmine, and 4 mg/kg sugammadex rapidly reversed deep NMB. Sugammadex doses of 2 and 4 mg/kg were well tolerated.

Graphical abstract

Fig. 1.

Study design. *Four age cohorts were enrolled first into panel 1 and then into panel 2, in a sequential order beginning with the oldest age group: 6 months to less than 2 yr; 3 months to less than 6 months; 28 days to less than 3 months; and birth to 27 days. N, number of planned participants; Neo, neostigmine + (glycopyrrolate or atropine); SGX, sugammadex.

Fig. 2.

Disposition of participants. *Includes one participant with missing volume and dose of drug information who was counted as not treated for the efficacy and safety analyses. This participant was assigned to 2 mg/kg sugammadex and provided pharmacokinetic samples. Inspection of pharmacokinetic data from this participant did not suggest any obvious deviation from other participants receiving this dose, and therefore the participant was counted in the 2-mg/kg group for the purposes of the pharmacokinetic analysis only. “Neostigmine” indicates neostigmine + (glycopyrrolate or atropine).

Fig. 3.

Kaplan–Meier plot of time (in min) to neuromuscular recovery (part B). Time to neuromuscular recovery is censored at the time of last assessment of neuromuscular recovery if neuromuscular recovery is not achieved. NEO, neostigmine + (glycopyrrolate or atropine); SGX 2 mg, 2 mg/kg sugammadex.

Fig. 4.

Kaplan–Meier plot of time (in min) to neuromuscular recovery (parts A and B). Time to neuromuscular recovery is censored at the time of last assessment of neuromuscular recovery if neuromuscular recovery is not achieved. NEO, neostigmine + (glycopyrrolate or atropine); SGX, sugammadex.