Author: Joseph F. Answine, MD, FASA
Sugammadex (Bridion, Merck) has proven to be superior to acetylcholinesterase inhibitors for the reversal of neuromuscular blockade with a steroidal nondepolarizing neuromuscular blocking agent (NMBA); and, after high-dose rocuronium (1.2 mg/kg), it has been found superior to succinylcholine for return of neuromuscular function after rapid sequence induction. However, even though it has been available since December 2015 in the United States, it is not yet the primary reversal agent. Initially, this was likely due to unfamiliarity with the molecule, but now it is secondary to economics—the cost of standard-dose sugammadex is more than neostigmine/glycopyrrolate or succinylcholine.
If lower dose sugammadex would be effective, patients would benefit from the superiority of its reversal of NMBAs and the decrease in economic disadvantage from its utilization.
There are three dosing regimens in the sugammadex package insert: 2 mg/kg if two twitches are present using quantitative train-of-four (TOF) monitoring, 4 mg/kg if no twitches are present and a post-tetanic count of 1 to 2, and a 16-mg/kg rescue for immediate reversal of a block obtained after receiving 1.2 mg/kg of rocuronium. These doses were chosen because dose-finding studies demonstrated that they provide the fastest and most reliable onsets of action.1 The problem that exists for clinicians is the reversal as noted by the TOF is a continuum. What if you have one, three or four twitches with a fade? Can you effectively utilize alternative dosing, especially that which is lower than the recommended doses?
Rocuronium, vecuronium and sugammadex have similar elimination half-lives in healthy individuals (normal renal and hepatic function). Based on the known molecular weights of rocuronium and sugammadex (609 and 2,178 g/mol, respectively), 2.2 mg/kg of sugammadex should provide enough molecules to completely reverse 0.6 mg/kg of rocuronium immediately after injection of the NMBA; one molecule of sugammadex binds with a very high affinity to one molecule of rocuronium, followed by renal excretion of the complex. For vecuronium, with a molecular weight of 637 g/mol and being six times more potent than rocuronium, the sugammadex dose required would be even lower. Furthermore, we need to remember that the majority of the nicotinic cholinergic receptors must be blocked by an antagonist before clinical weakness occurs, and flaccidity doesn’t occur until 99% of the receptors are occupied.
The removal of the NMBA occurs rapidly by encapsulation with sugammadex in the central compartment. The speed of reversal is determined by the circulation time (usually slower in elderly patients); the rapidity of the binding of the NMBA, therefore creating the gradient between compartments; the affinity of the NMBA for the nicotinic acetylcholine receptor at the neuromuscular junction; and the speed at which the NMBA moves from the receptor site back into the central compartment. The dose of sugammadex should only affect the speed of reversal if enough molecules are present to bind all the NMBA molecules present, and not the completeness of the reversal.
Based on the mechanism of action of sugammadex reversal, unless other factors are involved, such as neuromuscular abnormalities or the administration of medications potentiating muscle weakness, recurization should not occur. Rocuronium and sugammadex are tightly bound into a very stable complex with a rate of dissociation of about one in 25 million complexes. The cases of recurization that occurred in the clinical trials were based on movement of the TOF from a ratio greater than 0.9 to just under—and not associated with patient morbidity. Furthermore, suspected recurization in everyday practice is difficult to identify since quantitative monitoring is rarely used; therefore, assumed cases are likely due to initial incomplete reversal.
The dosing regimens for sugammadex described in the package insert were determined by increasing the dose at a given level of reversal until consistently no further significant reduction in reversal time occurred. For example, in the phase 2 clinical trials , at two twitches, 1 mg/kg of sugammadex demonstrated a median time to complete reversal (TOF ≥0.9) of 1.7 to 3.3 minutes, 2 mg/kg demonstrated a median time of 1.2 to 1.8 minutes, 3 mg/kg demonstrated a median time of 1.2 to 1.5 minutes, and 4 mg/kg demonstrated a median time of 1.1 to 1.6 minutes. In the comparative study with neostigmine, the median time to reversal with the acetylcholinesterase inhibitor was 21.5 minutes. Therefore, the 2-mg/kg dose was chosen; however, the 1-mg/kg dose was effective within a few minutes. When you look at no twitches and a post-tetanic count of 1 to 2, 1 mg/kg of sugammadex demonstrated a median time to complete reversal of 4.7 to 7.4 minutes, 2 mg/kg demonstrated a median time of 2.5 to 4.1 minutes, 4 mg/kg demonstrated a median time of 1.2 to 2.3 minutes, and 8 mg/kg demonstrated a median time of 1.0 to 1.3 minutes.2 The 4-mg/kg dose was chosen, but again, 1 and 2 mg/kg sugammadex were effective and still much faster than neostigmine reversal.
As for vecuronium, at two twitches, 1 mg/kg of sugammadex demonstrated a median time to complete reversal of 2.3 to 4.5 minutes, 2 mg/kg demonstrated a median time of 2.3 to 2.9 minutes, and 4 mg/kg demonstrated a median time of 1.4 to 2.5 minutes. In the comparative study with neostigmine, the median time to reversal with the acetylcholinesterase inhibitor was 29 minutes. At no twitches and a post-tetanic count of 1 to 2, 1 mg/kg of sugammadex demonstrated a median time to complete reversal of 8.9 to 15.7 minutes, 2 mg/kg demonstrated a median time of 2.8 minutes in all studies, 4 mg/kg demonstrated a median time of 1.9 to 2.3 minutes, and 8 mg/kg demonstrated a median time of 1.4 to 1.6 minutes.2
The third dose described is for rescue after administering 1.2 mg/kg of rocuronium in a “cannot intubate, cannot mask ventilate” situation. With sugammadex, 2 mg/kg demonstrated a median time to complete reversal of 55.3 to 63.3 minutes, 4 mg/kg demonstrated a median time of 11.3 to 12.3 minutes, 8 mg/kg demonstrated a median time of 2.5 to 3.6 minutes, and 16 mg/kg demonstrated a median time of 1.3 minutes in all studies. The time for placebo was 124.3 to 126.1 minutes.2 Based on the relative molecular weights, 1.2 mg/kg of rocuronium is equivalent to 4.3 mg/kg of sugammadex; therefore, reversal after doses less than 4 mg/kg likely involves a significant amount of metabolism of the rocuronium molecule by its usual pathway through the liver. This was evident when looking at the reversal times achieved after receiving the 2-mg/kg dose.
We know from numerous studies that one-third or more of patients reversed with neostigmine are still partially paralyzed (TOF <0.9) on arrival to the PACU. A study in the British Journal of Anaesthesia from 2015 demonstrated a residual paralysis rate in the PACU of none of 74 patients in the sugammadex group and 33 of 76 patients (43.4%) in the usual care (neostigmine) group.3This strengthens the argument for the completeness of reversal and extremely low to zero risk for clinical recurization with sugammadex.
Another study from 2013 looked at dosing sugammadex using ideal versus actual body weight in morbidly obese patients. Rocuronium was dosed at 0.6 mg/kg using ideal body weight, with a dose of one-fourth of the intubating dose at return of the second twitch for maintenance. The durations of intubation and number of maintenance doses of rocuronium were similar in both groups. A TOF value of 0.9 was reached in 151±44 seconds in the ideal body weight group and 121±55 seconds in the actual body weight group. There was no residual neuromuscular blockade in either group.4 The conclusion was that dosing based on ideal body weight in this high-risk patient population was effective and safe.
In a report in Anesthesiology from 2010, the dose of sugammadex required to reverse a TOF of 0.5 (shallow blockade) was studied. This is a level of paralysis that could lead to significant clinical abnormalities yet would be easily missed using qualitative TOF monitoring. A dose of 0.22 mg/kg led to complete reversal in an average time of 2 minutes and within 5 minutes in 95% of the patients.5
The dose-finding studies demonstrated that reducing the sugammadex dose slows the onset and increases variability, but not to the extent that we see with the acetylcholinesterase inhibitors. Based on the mechanism of action of sugammadex, the very low risk for residual neuromuscular blockade with lower doses, and the data that show doses below that recommended by the package insert are effective and safe, the utilization of lower dose sugammadex appears reasonable and appropriate and should decrease the economic burden with its use.
Dr. Answine is a clinical associate professor in the Department of Anesthesiology and Perioperative Medicine at Penn State College of Medicine, in Hershey, Pa. He is also a partner at Riverside Anesthesia Associates, and a staff anesthesiologist at UPMC Pinnacle, in Harrisburg, Pa. Dr. Answine is a member of the advisory board for sugammadex at Merck.
Editor’s note: The views expressed in this article belong to the author and do not necessarily reflect those of the publication.
- Bridion (sugammadex) [package insert]. Kenilworth, NJ: Merck & Co.; 2015.
- Data on file. Sugammadex phase 2 trials. Organon.
- Brueckmann B, Sasaki N, Grobara P, et al. Effects of sugammadex on incidence of postoperative residual neuromuscular blockade: a randomized, controlled study. Br J Anaesth. 2015;115(5):743-751.
- Sanfilippo M, Alessandri F, Abdelgawwad A, et al. Sugammadex and ideal body weight in bariatric surgery. Anesthesiol Res Pract. 2013;2013:389782.
- Schaller SJ, Fink H, Ulm K, et al. Sugammadex and neostigmine dose-finding study for reversal of shallow residual neuromuscular block. Anesthesiology. 2010;113(5):1054-1060.