Originally published by our sister publication Anesthesiology News

PHILADELPHIA—Sugammadex at a dose of 2 mg/kg is superior to neostigmine in reversing moderate neuromuscular blockade in neonates and infants younger than 2 years of age, a new study has concluded. The trial also found that doses of both 2 and 4 mg/kg were well tolerated in this sometimes fragile patient population.

“Although sugammadex has been shown to be safe and effective in reversing rocuronium- and vecuronium-induced neuromuscular blockade in adults and recently in children 2 years or older, there are very limited data available in children less than 2 years of age,” said W. Joseph Herring, MD, PhD, the associate vice president of clinical neuroscience at Merck. “This randomized trial was designed to compare the tolerability and pharmacokinetics of sugammadex with neostigmine in these patients.”

The multicenter trial comprised 138 ASA physical status class I to III patients less than 2 years old, all of whom underwent a planned nonemergent surgical procedure or clinical procedure requiring moderate or deep neuromuscular blockade with either rocuronium or vecuronium. There were two parts (A and B), with each part including four different age groups: 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.

Part A was open-label and included pharmacokinetic assessments to determine whether dose adjustment was necessary for any of the age groups. Part B was double-blind and evaluated the safety and efficacy of the 2 and 4 mg/kg doses of sugammadex; in that arm, participants were randomized to one of three groups: 1) moderate neuromuscular blockade and reversal with 2 mg/kg of sugammadex (n=29); 2) moderate neuromuscular blockade and reversal with neostigmine plus glycopyrrolate or atropine(n=31); or 3) deep neuromuscular blockade and reversal with 4 mg/kg of sugammadex (n=31).

The trial’s primary efficacy end point was time to neuromuscular recovery for both 2 mg/kg of sugammadex and neostigmine for the reversal of moderate neuromuscular blockade. Time to neuromuscular recovery could be assessed by one of four protocols, which was determined by the clinician investigator at the time: sustained head lift against resistance for at least five seconds; sustained hip flexion against resistance for at least five seconds; four twitches without fade (or, for neonates, comparable to baseline) in response to train-of-four (TOF) stimulation via neuromuscular transmission monitoring; and TOF ratio of 0.9 or greater on objective neuromuscular transmission monitoring. In practice, however, nearly all these assessments used neuromuscular transmission monitoring.

Presenting the study at the 2024 annual meeting of the American Society of Anesthesiologists (abstract A1166), Herring reported that the four age groups in Parts A and B were roughly equal in size, with 38 participants aged 6 months to less than 2 years (27.5%), 37 aged 3 months to less than 6 months (26.8%), 35 aged 28 days to less than 3 months (25.4%) and 28 aged birth to 27 days (20.3%). Pharmacokinetic assessments in Part A revealed that no subsequent dose adjustments were needed.

In Part B of the trial, the median time to neuromuscular recovery after moderate neuromuscular blockade was found to be significantly shorter among children who received 2 mg/kg of sugammadex (1.4 minutes) than their counterparts who received neostigmine (4.4 minutes), yielding a hazard ratio of 2.40 (95% CI, 1.37-4.18; P=0.0002). Moreover, Kaplan-Meier estimates revealed that 79.3% of participants (23/29) in the 2-mg/kg sugammadex group reached neuromuscular recovery within four minutes, compared with 41.9% (13/31) in the neostigmine group. These findings were comparable across the four age groups.

“Although no comparator existed for reversal of deep neuromuscular blockade, we found that the 4-mg/kg dose of sugammadex achieved a rapid time to neuromuscular recovery, with a median time of 1.1 minutes in Parts A and B combined,” Herring said.

Analyses of tolerability found that the percentage of children who experienced at least one adverse event in Parts A and B was comparable in the sugammadex and neostigmine groups. The two most common adverse events were procedural pain and vomiting, with no meaningful differences between intervention groups. While treatment-related bradycardia was similar in the sugammadex and neostigmine groups, relative treatment-related bradycardia (decrease of 20% or more from baseline sustained for =30 seconds) was reported in approximately 3% of sugammadex patients and 19% of neostigmine patients. No deaths or drug-related serious adverse events were reported.

These findings, the researchers said, offer much-needed insights into safe and effective sugammadex dosing in the youngest patients.

“We found that sugammadex 2 mg/kg was superior to neostigmine at reversing moderate neuromuscular block as measured by time to neuromuscular recovery,” Herring said. “Both doses were well tolerated as used in the trial, and the results support the use of sugammadex at the same doses that are recommended in adults and children 2 years and older to reverse moderate and deep neuromuscular blockade.”

For Olubukola O. Nafiu, MD, the vice chair for academic affairs and pediatric anesthesiology at Montefiore Medical Center and Albert Einstein College of Medicine, in New York City, although the study’s findings came as little surprise, they were reassuring.

“In our experience, if a drug works in the preschool child and in older children, it can be expected to perform the same way in younger children, since the physiology is virtually the same,” he said in an interview with Anesthesiology News.

“We’ve been using sugammadex for a very long time in even our youngest pediatric patients and the drug has been safe and effective, without any of the adverse events that have been documented in published case reports, such as bradycardia and allergic reactions,” Nafiu added. “That said, it’s always reassuring to have your experiences confirmed in a randomized trial.”

By Michael Vlessides

Herring reported that he is an employee of Merck. Nafiu reported no relevant financial disclosures.