Neuromuscular blockade and reversal with sugammadex in infants: “Recurarization” risk factors
Myron Yaster MD, Debra Faulk MD, and Francis Veyckemans MD
In yesterday’s PAAD, we reviewed the seminal paper by Fisher et al.1 that found the volume of distribution at steady state (Vdss) for water soluble, ionic, non-depolarizing muscle relaxants is much greater in neonates than in other age groups. and the plasma concentration required to produce paralysis is much lower (that is, the newborn is much more sensitive to neuromuscular blockade). The changes in Vdss mirror the changes in increased ECF in neonates which may be as much as 80-90% of body weight. Fisher et al also found that t1/2 beta (elimination half life) was longer in neonates which again is related to the larger Vdss and means that recovery from neuromuscular blockade may be slower in neonates, particularly if multiple doses of NMBA are given. Moreover, the plasma concentration required to produce paralysis is much lower (that is, the newborn is much more sensitive to neuromuscular blockade) due to the immaturity of the neuromuscular junction.
In today’s PAAD, we review an article by Cates et al.2 in which the authors “performed a retrospective analysis to identify the influential factors contributing to the need for sugammadex redose for the reversal of rocuronium.” How sugammadex was dosed and redosed is the underlying question in this article and because these decisions were made without quantitative (and in most cases qualitative) monitoring of neuromuscular blockade is in my view the key finding and flaws of this paper. In 2023, we should no longer accept flying blind3 clinically or in academic papers, and all of us should really make the quantum jump to quantitative monitoring.4, 5 For those of you who wish to learn more about the “how to” of quantitative monitoring check out these Anesthesia Patient Safety Foundation or ASA Education websites. Myron Yaster MD
https://www.apsf.org/apsf-technology-education-initiative/quantitative-neuromuscular-monitoring/
Original article
Cates AC, Freundlich RE, Clifton JC, Lorinc AN. Analysis of the factors contributing to residual weakness after sugammadex administration in pediatric patients under 2 years of age. Paediatr Anaesth. 2023 Oct 4. doi: 10.1111/pan.14773. Epub ahead of print. PMID: 37792601.
Sugammadex is increasingly the primary reversal agent of neuromuscular blockade particularly amongst pediatric anesthesiologists with less than 5 years of practice experience.6 The 2023 ASA guidelines for the use, monitoring and antagonism of neuromuscular blockade actually recommends sugammadex be utilized as the antagonist agent for deep, moderate and shallow levels of blockade (Thilen guidelines).Although approved for use in children > 2 years of age by the U.S. Food and Drug Administration (Voss reference), “recommended dose and usage guidelines of sugammadex in children less than 2 years of age remains unknown.”2
Despite its efficacy, residual weakness or possible recurarization after sugammadex administration in pediatric patients has been reported.7 The authors “performed a retrospective analysis in one center (Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, USA) to identify the influential factors contributing to the need for sugammadex redose for the reversal of rocuronium.”2 “The primary outcome was sugammadex redose, defined as any subsequent administration of sugammadex occurring within 250 min of the initial sugammadex administration. This follow-up period was elected based on the half-life of rocuronium such that roughly 90% of the neuromuscular blocking drug would be eliminated at that time.”2 They found the incidence of sugammadex redosing was 4.2% (123/2923 cases), the median time to re-dose was 7 [4-17]min and the median amount of sugammadex re-dose administered was 2.74 [1.96-3.99]mg/kg. Who was at greatest risk for sugammadex redosing? “Increasing patient age (p< .01) and weight (p< .01) were associated with reduced hazard rate of sugammadex redose”2 In other words: patients less than 3 months of age and 4.7 kg were at greatest risk. Cates et al concluded that there was an association between the hazard of sugammadex dosing with both increasing age and weight.
There are several concerns to bear in mind with regards to this article, most importantly is that the how and why of sugammadex redosing was not disclosed. The authors themselves point out that “neuromuscular blockade monitoring was inconsistent, with only 43.7% of patients (n= 1276) in our study population receiving train of four monitoring (TOF) with a peripheral nerve stimulator. There were 123 cases with a documented redose of sugammadex, and 40.7% (n= 50) of these received intraoperative TOF monitoring.”2 Of the 123 cases with documented redosing of sugammadex, more than half received NO intraoperative TOF assessments. Furthermore, neither the initial dose of sugammadex nor the reason for redosing are provided by the authors. This begs the question of how it was determined that the initial dose of sugammadex was correct, how it was determined that redosing was necessary, and whether the additional dosing resulted in adequate recovery from neuromuscular blockade. Without knowing the depth of blockade prior to sugammadex administration, the amount of sugammadex that was given both initially and at re-dose, and the corresponding recovery curve during this time, it is impossible to understand whether the authors revealed re-curarization or simply inadequate dosing of sugammadex due to lack of monitoring.
Quantitative monitoring is the gold standard for assessment to accurately dose antagonists and confirm adequate recovery. Dosing indications for sugammadex are actually based on quantitative monitoring at the adductor pollicis muscle.8 In pediatric anesthesia, it is common to assess depth of blockade with a peripheral nerve stimulator using facial muscles, both of which are known to overestimate the degree of neuromuscular recovery and therefore contribute to potential under-dosing of antagonist agents. Despite the efficacy of sugammdex, variable responses to sugammadex have been seen where less than recommended doses may be utilized, but more importantly, greater than recommedend doses may be required.9 In this study population where dosing indications are not yet published, the use of quantitative monitors and avoidance of facial muscles for assessments seems especially prudent to appropriately titrate sugammadex to effect. In the absence of quantitative monitors, a peripheral nerve stimulator should be used at a minimum.
Another important point to be emphasized is the contribution of inadvertent over-dosing of neuromuscular blocking agents in producing prolonged weakness in this patient population. As Fisher et al.1 pointed out 40 years ago in their d-tubocurarine paper, and Cates acknowledges in their paper, infants have a larger Vdss and underdeveloped neuromuscular function and clearance functions making the more susceptible to reparalysis. Thus, these results are not surprising. Those in the re-dose group received higher median doses of rocuronium and shorter times from last dose of NMB to initial sugammadex administration. Infants have been shown to have prolonged duration of action compared to children when given 0.6mg/kg rocuronium, a “standard intubating dose” equivalent to two times the ED9510 Recognition of this fact and standardization of neuromuscular blockade monitoring are supported by the authors as important steps for decreasing the incidence of weakness in these patients. I (DF) could not agree more and would argue that one of the first step to appropriate antagonism of neuromuscular blockade is its appropriate dosing to maintain only the depth of block necessary for the surgery at hand. Reflexive dosing and re-dosing of rocuronium at 2-4 times ED95 is unnecessary, though likely not uncommon.
In summary, we think ALL patients receiving neuromuscular blocking agents should be monitored with quantitative monitors and as, Fisher and colleagues revealed 40 years ago, the newborn is particularly vulnerable. Let us know if you are making the switch to these new quantitative monitors and how they are affecting your practice. Myron will post in a Friday Reader response.
References
1. Fisher DM, O'Keeffe C, Stanski DR, Cronnelly R, Miller RD, Gregory GA. Pharmacokinetics and pharmacodynamics of d-tubocurarine in infants, children, and adults. Anesthesiology. 1982 1982;57(3):203-208. Not in File.
2. Cates AC, Freundlich RE, Clifton JC, Lorinc AN. Analysis of the factors contributing to residual weakness after sugammadex administration in pediatric patients under 2 years of age. Paediatric anaesthesia. Oct 4 2023;doi:10.1111/pan.14773
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. 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
5. Fülesdi B, Brull SJ. Quantitative Neuromuscular Monitoring: "Love All, Trust a Few, Do Wrong to None". Anesthesia and analgesia. Jul 1 2022;135(1):35-38. doi:10.1213/ane.0000000000006035
6. 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
7. Lorinc AN, Lawson KC, Niconchuk JA, Modes KB, Moore JD, Brenn BR. Residual Weakness and Recurarization After Sugammadex Administration in Pediatric Patients: A Case Series. A A Pract. May 2020;14(7):e01225. doi:10.1213/xaa.0000000000001225
8. Voss T, Wang A, DeAngelis M, et al. Sugammadex for reversal of neuromuscular blockade in pediatric patients: Results from a phase IV randomized study. Paediatric anaesthesia. Mar 2022;32(3):436-445. doi:10.1111/pan.14370
9. 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
10. Rapp HJ, Altenmueller CA, Waschke C. Neuromuscular recovery following rocuronium bromide single dose in infants. Paediatric anaesthesia. Apr 2004;14(4):329-35. doi:10.1046/j.1460-9592.2003.01216.