Sugammadex reversal of neuromuscular blockade requires quantitative monitoring
Myron Yaster MD and Debra Faulk MD
During the holiday break I will be reposting the highest viewed PAADs of the previous 6 months. Today’s PAAD first posted on August 14th, 2023 had the highest view rate during the month of August…
Many of you have switched from neostigmine to sugammadex and believe, falsely, that sugammadex is so potent and good at reversal that monitoring the train of four is unnecessary. There are many things to unpack in today’s article and editorial by Bowdle et al.1 and Todd and Kopman2 , respectively, but perhaps the most important take home message is that quantitative monitoring of neuromuscular function is essential even with sugammadex reversal.3 I’ve asked the PAAD’s go to expert on this subject, Dr. Debra Faulk, to assist. Myron Yaster MD
Editorial
Todd, M. & Kopman, A. (2023). Sugammadex Is Not a Silver Bullet: Caveats Regarding Unmonitored Reversal. Anesthesiology, 139 (1), 1-3. PMID: 37279102
Original article
Bowdle TA, Haththotuwegama KJ, Jelacic S, Nguyen ST, Togashi K, Michaelsen KE. A Dose-finding Study of Sugammadex for Reversal of Rocuronium in Cardiac Surgery Patients and Postoperative Monitoring for Recurrent Paralysis. Anesthesiology. 2023 Jul 1;139(1):6-15. PMID: 37027807.
We don’t think anyone practicing anesthesia today would do so without monitoring heart rate, blood pressure, temperature, oxygen saturation, and end-tidal carbon dioxide concentrations. And yet when using neuromuscular blockade, flying blind, that is without quantitative monitoring remains common particularly since the widespread introduction of sugammadex into practice.4 The current IARS Doc Matters Discussion Board that tackled the topic of Quantitative Neuromuscular Monitoring in Clinical Practice garnered responses including, “Over my last few years in the US, I moved away from using neuromuscular monitoring at all… Certainly after the use of sugammadex became more widespread, where the reversal of the blockade can be quite dramatic and leave little doubt as to the number of twitches they have or the percentage of their recovery of neuromuscular function.” and “ My clinical area has trialed quantitative neuromuscular monitors on three occasions…Especially with sugammadex, I no longer have any desire to advocate for quantitative neuromuscular monitors…”. The notion that in the era of sugammadex, monitoring of neuromuscular blockade is unnecessary is common, though it is incorrect. It is actually astonishing not only because of the recent ASA practice guideline3 but also because dosing of sugammadex reversal is based on the presence of degree of neuromuscular blockade obtained by quantitative neuromuscular monitoring (2 mg/kg to be administered if at least two twitches are present in response to a train-of-four stimulus, or 4 mg/kg if there are less than two twitches but a posttetanic count of more than 0). Bowdle et al. wondered if some patients might need less than the recommended sugammadex dose to reverse and some might need more? And what was the risk of recurrent paralysis following reversal (“recurarization”)? They conducted a prospective, adult dose-finding study to find out the answers to these questions and their results demonstrate the importance for the routine use of quantitative neuromuscular monitoring, even if sugammadex is the antagonist of choice in one’s practice.
By definition, reversal or recovery from paralysis was defined as a quantitatively measured train-of-four ratio (TOFr) greater than or equal to 0.9 in which the electrode array was applied to stimulate the ulnar nerve and measure the muscle action potential at either the adductor pollicis or the first dorsal interosseous muscle.3, 5 Titrated doses of sugammadex were administered at the end of surgery. “A 200-mg, 2-ml vial of sugammadex was diluted in a syringe to a total of 20 ml with saline to facilitate the administration of sugammadex in 50-mg (5-ml) boluses. Five minutes after each sugammadex dose of 50 mg, the response to the train-of-four stimulus was determined. Sugammadex dosing was continued until a train-of-four ratio of at least 0.9 was achieved, before patient transport to the intensive care unit (ICU).”1
Ok, what did they find? Of the 126 patients enrolled, 26 had at TOFr > 0.9 and were not given sugammadex. “There was substantial variation in dose requirement between patients. While many patients required less than the recommended dose, some patients required more than the recommended dose. Of the 68 patients starting the sugammadex titration with a train-of-four count of at least 2, whose manufacturer’s recommended dose would be 2 mg/kg, 11 required more than 2 mg/kg to achieve a train-of-four ratio of at least 0.9. Of the 29 patients starting the sugammadex titration with a train-of-four count of 1 or less, whose manufacturer’s recommended dose would be 4 mg/kg, 2 required more than 4 mg/kg to achieve reversal.1 This is especially intriguing considering the slow and incremental dosing of sugammadex that occurred in the Bowdle et al. study. As pointed out in the article, the incremental administration of 50mg every 5 minutes led to an extended time for recovery during which spontaneous recovery is also occurring. Thus, the required doses that are noted may be less than what would actually be required if a single bolus dose were administered. For those study patients who required less than the indicated 2mg/kg or 4mg/kg dose, this could bring their dosing closer to the manufacturer’s dosing recommendations. More importantly, dosing for those who required a greater than recommended amount of sugammadex may be an underestimate. Ultimately, as Todd and Kopman point out “reversal based solely on twitch counts (or, worse, not based on any twitch assessment at all) does not guarantee full reversal.. this constitutes some of the strongest evidence to date for the value of routine quantitative neuromuscular blockade monitoring—and clearly demonstrates the fallacy of believing that sugammadex obviates the need for such monitoring.”2
Further as we’ve discussed before in previous PAADs and are the basis of the current ASA guidelines “subjective or qualitative evaluation of the train-of-four (visual, tactile) cannot exclude a substantial degree of residual paralysis as the human senses are not able to detect fade in the train-of-four ratio at minimal levels of blockade (train-of-four ratios greater than 0.40”3 and are really no better than flipping a coin. While Bowdle et al. found that the mean dose of sugammadex needed to achieve recovery of a TOFR ≥ 0.9 was often less than the recommended manufacturer’s dosing (2mg/kg for TOFC = 2 to TOFR < 0.9 or 4mg/kg for PTC >0 to TOFC = 1), they also found great variability in response, necessitating the use of quantitative monitoring to confirm that effective antagonism has been achieved. Indeed, “in the current time, the only method for verifying full reversal—after any nondepolarizing agent or any reversal agent regardless of dose—is quantitative monitoring.”1, 2, 6
Finally, as discussed in the July 25th 2023 PAAD, sugammadex vial wastage: implications for cost of anesthesia care in children, is substantial. We believe that when using sugammadex in children monitored with quantitative neuromuscular blockade monitoring substantial savings can occur by having your pharmacy reformulate sugammedex into 25 or 50 mg vials or syringes. This will significantly reduce waste and hospital pharmacy costs. Bowdle et al. found that 20% of patients in their study achieved spontaneous recovery to a TOFR ≥ 0.9 and therefore did not require sugammadex antagonsim of their neuromuscular blockade. Without quantitative monitoring and the ability to distinguish minimal residual blockade (TOFR 0.4-<0.9) from adequate recovery (TOFR ≥ 0.9), one might elect to administer a 2mg/kg dose of sugammadex in an abundance of caution. Assuming $110/200mg sugammadex vial (approximate cost at my institution – DF) and a single vial used per patient (median weight of the study population 80kg [73-95]), the potential cost of sugammadex adminstered unecessarily approaches $3000. This may not seem like much until considering the thousands of anesthetics that may be performed in a given institution each year utilizing neuromuscular blockade. In a facility performing 10,000 anesthetics with rocuronium each year, a 20% spontaneous recovery rate equates to $220,000 either spent or saved.
What do you do in your practice? Do you use quantitative monitoring to guide reversal? Can you tell us what obstacles you had to overcome to get these monitors and to have your colleagues use them? Does your pharmacy fractionate doses and repackage to reduce waste? Send your thoughts to Myron who will post in a Friday Reader Response.
References
1. Bowdle TA, Haththotuwegama KJ, Jelacic S, Nguyen ST, Togashi K, Michaelsen KE. A Dose-finding Study of Sugammadex for Reversal of Rocuronium in Cardiac Surgery Patients and Postoperative Monitoring for Recurrent Paralysis. Anesthesiology. Jul 1 2023;139(1):6-15. doi:10.1097/aln.0000000000004578
2. Todd MM, Kopman AF. Sugammadex Is Not a Silver Bullet: Caveats Regarding Unmonitored Reversal. Anesthesiology. Jul 1 2023;139(1):1-3. doi:10.1097/aln.0000000000004587
3. Thilen SR, Weigel WA, Todd MM, et al. 2023 American Society of Anesthesiologists Practice Guidelines for Monitoring and Antagonism of Neuromuscular Blockade: A Report by the American Society of Anesthesiologists Task Force on Neuromuscular Blockade. Anesthesiology. Jan 1 2023;138(1):13-41. doi:10.1097/aln.0000000000004379
4. Faulk DJ, Austin TM, Thomas JJ, Strupp K, Macrae AW, Yaster M. A Survey of the Society for Pediatric Anesthesia on the Use, Monitoring, and Antagonism of Neuromuscular Blockade. Anesthesia and analgesia. Jun 1 2021;132(6):1518-1526. doi:10.1213/ane.0000000000005386
5. Nemes R, Lengyel S, Nagy G, et al. Ipsilateral and Simultaneous Comparison of Responses from Acceleromyography- and Electromyography-based Neuromuscular Monitors. Anesthesiology. Oct 1 2021;135(4):597-611. doi:10.1097/aln.0000000000003896
6. Murphy GS, Brull SJ. Quantitative Neuromuscular Monitoring and Postoperative Outcomes: A Narrative Review. Anesthesiology. Feb 1 2022;136(2):345-361. doi:10.1097/aln.0000000000004044