Using Actual Body Weight With Sugammadex Speeds Reversal in Morbidly Obese Patients

Orlando, Fla.—Morbidly obese patients experience significantly faster recovery from rocuronium- or vecuronium-induced neuromuscular blockade when sugammadex (Bridion, Merck) dosing uses actual body weight instead of ideal body weight, a new study has concluded. The additional dosing also did not increase safety concerns, although some clinicians questioned whether it was worth the extra cost.

“The FDA approved sugammadex in December 2015,” said W. Joseph Herring, MD, PhD, the associate vice president of Clinical Neuroscience at Merck & Co., Inc., in Kenilworth, N.J. “As one of our post-approval commitments, we were asked to conduct a trial in morbidly obese patients and compare actual body weight dosing with ideal body weight dosing.

“In this study, we included morbidly obese subjects who would be dosed according to actual body weight and ideal body weight for reversal of moderate and deep block using both sugammadex and neostigmine,” Dr. Herring said. “A key safety end point of interest for us was the potential occurrence of cardiac arrhythmias.”

The multicenter, randomized, double-blind trial (ClinicalTrials.gov Identifier: NCT03346070) comprised ASA physical status III adults with a body mass index of at least 40 kg/m² and actual body weight of at least 100 kg. Patients with pacemakers, neuromuscular disorders or severe renal disease were excluded.

The participants—all of whom were recovering from rocuronium- or vecuronium-induced neuromuscular blockade—were randomly allocated to one of five groups:

• moderate block with 2 mg/kg of sugammadex based on actual body weight;
• moderate block with 2 mg/kg of sugammadex based on ideal body weight;
• moderate block with 5 mg of neostigmine and 1 mg of glycopyrrolate;
• deep block with 4 mg/kg of sugammadex based on actual body weight; and
• deep block with 4 mg/kg of sugammadex based on ideal body weight.

Neuromuscular function was monitored at the adductor pollicis muscle using calibrated acceleromyography with supramaximal train-of-four (TOF) stimulation of the ulnar nerve. Blood pressure and ECG monitoring continued for at least 30 minutes after reversal.

The study’s primary end point was the time to achieve a TOF ratio of at least 0.9, pooled across neuromuscular blocking agent and depth of block.

Potential hypersensitivity adverse events were adjudicated by an external blinded committee. Prespecified events of clinical interest included treatment-emergent bradycardia, tachycardia, other arrhythmias, hypersensitivity and anaphylaxis.

The study was performed at 20 sites in five countries. In total, 188 patients received treatment (72% female; body mass index 47±5.1 kg/m²; age 48±13 years). The most common comorbid condition was hypertension (51% of participants); sleep apnea was present in 29%.

Adverse Events Unaffected

As Dr. Herring reported at the 2019 annual meeting of the American Society of Anesthesiologists (abstract A4019), the median time to recover a TOF ratio of at least 0.9 was 1.8 minutes (95% CI, 1.6-2.1 minutes) for patients who received dosing based on actual body weight, compared with 3.3 minutes (95% CI, 2.6-4.1 minutes) for those who received ideal body weight dosing (Figure 1), pooled across both neuromuscular blocking agent and block depth (P<0.0001).

Figure 1. Recovery time to train-of-four ratio of 0.9 or more using actual and ideal body weights.

“We also found it took only 3.8 minutes for 90% of the patients to recover when dosed by actual body weight versus 7.5 minutes when dosed by ideal body weight,” Dr. Herring said.

“In terms of the incidence of recovery times that took longer than 10 minutes, the percentages were low and the differences not statistically significant between the two groups,” he added. Indeed, recovery times lasting longer than 10 minutes occurred in 5.3% of patients in the actual body weight group and 2.7% those in the ideal body weight group (95% CI, –4.8% to 11.0%). By comparison, this incidence was 84% in the neostigmine group.

“It took more than a half-hour for 50% of neostigmine patients to reach a TOF of 0.9,” Dr. Herring added (Figure 2).

Figure 2. Sugammadex-mediated recovery times to a train-of-four ratio of 0.9 or more, compared with neostigmine and glycopyrrolate.

Perhaps not surprisingly, patients who received 2 mg/kg of sugammadex took one-ninth the time to recover as their counterparts in the neostigmine group (hazard ratio, 0.11; 95% CI, 0.08-0.14). The investigators reported the recurrence of neuromuscular blockade in one patient in the neostigmine group and one in the 2-mg/kg sugammadex ideal body weight group.

“There were very few treatment-emergent adverse events, and not different between treatment groups in terms of statistical significance,” Dr. Herring said. “The hypothesis was that events might be more frequent with actual body weight dosing than with ideal body weight dosing, but that’s not what we observed.”

No patients in the study experienced anaphylaxis. One patient in the 4-mg/kg sugammadex ideal body weight group had adjudicated hypersensitivity, while one receiving neostigmine had clinically relevant tachycardia. A clinically relevant cardiac arrhythmia occurred in one patient in the 2-mg/kg ideal body weight sugammadex group, and one in the 4-mg/kg actual body weight group.

“There were too few events to really say anything definitive comparing the groups, except that the safety was good and there were very few clinically relevant events that occurred,” he said.

The researchers concluded that these findings indicate the superiority of actual body weight dosing for patients undergoing reversal of neuromuscular blockade with sugammadex. “These are pretty definitive results that actual body weight–based dosing is better regardless of depth of block,” Dr. Herring said.

Is the Cost Worth It?

Despite the findings, some of the audience members questioned whether dosing sugammadex based on actual body weight was worth the additional cost.

“Calculating ideal body weight versus actual body weight is very easy, but it’s a huge difference in the amount of drug we’re administering to morbidly obese patients,” said Michel Struys, MD, PhD, the head of the Department of Anesthesiology at University Medical Centre Groningen, in the Netherlands. “Because with your recommendation, we’ll be giving double or triple the dose to some patients. We all know sugammadex is a very expensive drug, and if you increase the dose by that much, that’s an extra handful.”

“In the past, there’s been a number of smaller studies using interval dosing between extremes of ideal and actual body weight–based dosing, with reasonable results,” Dr. Herring replied. “These studies tended to indicate that the closer you get to actual weight, the tighter the distribution of recovery times is.

“So somewhere in that spectrum there could be a sweet spot,” Dr. Herring added. “But we can’t really speak to that, since that wasn’t the intention of this study.” Nevertheless, he noted that sugammadex’s manufacturer recommends dosing morbidly obese patients according to actual body weight, in accordance with product labeling.

—Michael Vlessides

Dr. Herring reported that he is a full-time employee of Merck & Co., which manufactures sugammadex (Bridion). Dr. Struys reported no relevant financial disclosures.