Postoperative respiratory complications following neuromuscular blockade: Does the reversal agent matter?
Myron Yaster MD and Debra Faulk MD
The senior author of today’s PAAD, Dr. Joe Tobias, is the chief of the Department of Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, Columbus, Ohio and a former chair (2013-2015) of the American Academy of Pediatrics Section on Anesthesiology and Pain Medicine. Over the course of his remarkable career, he has published 894 peer reviewed articles and counting. This is nothing short of astonishing and I’ve often wondered if he ever sleeps! I just hope there will be some sort of departmental or SPA/AAP celebration when he hits 1,000. Myron Yaster MD
PS: The PAAD will go on a Thanksgiving break and will return November 28th!
Original article
Ralph J Beltran, Christian Mpody, Olubukola O Nafiu, Joseph D Tobias. Association of Sugammadex or Neostigmine With Major Postoperative Pulmonary Complications in Children. Anesth Analg. 2022 Nov 1;135(5):1041-1047. PMID: 35020682
Does the choice of reversal agent (neostigmine or sugammadex) make a difference in postoperative pulmonary complications in children undergoing noncardiac surgery, presumably because of residual blockade? Beltran et al.1 hypothesized that the magnitude of postoperative pulmonary complications would be lower among children who received sugammadex for neuromuscular blockade reversal compared to a matched cohort who received neostigmine. This is a pretty reasonable hypothesis since it is well established in adult studies that the incidence of residual neuromuscular blockade is decreased with the use of sugammadex vs neostigmine and therefore the potential complications of residual blockade, namely respiratory compromise, might also be decreased. As a corollary, it would follow that if you used an antagonist that is more effective and efficient at all levels of blockade (with fewer side effects), you would have a winner! This seems like a no-brainer, but it is perhaps not so clear-cut. Several adult studies have recently shown variable results on this question, finding either improved respiratory outcomes with sugammadex rather than neostigmine antagonism,2-4 or no difference between the two.5-7
What did Beltran et al. find?1 In a propensity score-matched retrospective study using the Pediatric Health Information System (PHIS) dataset spanning the years 2016 and 2020, Beltran et al.1 found that there was no difference between sugammadex and neostigmine in the risk-adjusted incidence of postoperative pulmonary complications, as defined by pneumonia, unplanned tracheal reintubation, and postoperative respiratory failure.
Because of the nature of how this study was done (a retrospective database analysis), we think the conclusions must be carefully considered. While the infrequent nature of pulmonary complications demands thousands of patients to address the question (hence, large retrospective database studies such as this one), they inherently lack the ability to answer key factors in the analysis – namely the dosing, timing of administration and monitoring of patients receiving sugammadex vs neostigmine…and whether they experienced post-operative residual neuromuscular blockade that led to poorer outcomes. Indeed, the POPULAR study5 found no benefit to sugammadex use over neostigmine, and no benefit for monitoring or administration of reversal agents in decreasing the risk of post-operative pulmonary complications. Only 30% of patients in the study had any type of neuromuscular monitoring and less than 20% were monitoring by quantitative means (predominantly acceleromyography-based devices). BUT, post-hoc analysis of subjects receiving quantitative monitoring and utilizing an increased threshold for adequate recovery (a TOF ratio >0.95), found a risk reduction of 3.5% for postoperative pulmonary complications.8 Achieving a TOFR >0.95 was seen to be associated with greater sugammadex dosing suggesting underdosing of sugammadex played a role.8 As Beltran et al.1 acknowledge in their Discussion, they did not have any information on the dosing of the neuromuscular blocking agents nor of the reversal agents. Further and most importantly, they did not know how or if patients had their neuromuscular blockade monitored nor how or when the anesthesia teams decided to reverse neuromuscular blockade.
Why is this important? As discussed in several previous PAADs, (see July 6, 2022 PAAD “I don’t need no stinkin’ quantitative neuromuscular blockade monitor”…you probably do!) how and when you monitor the neuromuscular blockade matters…a lot! Blobner et al. 2 (and our previous PAAD) reviewed this issue in detail. Most pediatric anesthesiologists continue to use qualitative monitors or clinical signs of return of neuromuscular function.9 Neither qualitative neuromuscular monitoring nor clinical tests (head lift, negative inspiratory pressures, etc.) accurately detect residual NMB.10 Further, train of four count, by itself, is not an adequate measure of NMB reversal. A quantitative train of four ratio is required and no patient should be extubated without first verifying that the TOF ratio is >0.9 at the adductor pollicis. Yes, the adductor pollicis and not the orbicularis occuli which is amongst the commonly used sites in pediatric anesthesia. The orbicularis occuli is notoriously inaccurate. Eye muscles recover faster leading to assessments of adequate reversal when residual NMB persists and may be due to direct stimulation of muscle, not nerve.
Without knowing how or when neuromuscular blockade was monitored or how much paralytic and reversal was given, we believe that no conclusions can be made on the superiority or inferiority of one reversal agents over the other. Indeed, if anything this paper further supports the need for universal quantitative monitoring to guide the administration of antagonists (sugammadex or neostigmine) whenever neuromuscular blocking agents are used. We end with a defining statement from this paper that we hope is not lost in the comparison of sugammadex vs neostigmine “…it is imperative to use quantitative measures of the degree of NMB before reversal and the presence of residual NMB as these may be more important in determining the potential for respiratory complications rather than the agent used for reversal of NMB.1”.
References
1. Beltran RJ, Mpody C, Nafiu OO, Tobias JD. Association of Sugammadex or Neostigmine With Major Postoperative Pulmonary Complications in Children. Anesthesia and analgesia. Nov 1 2022;135(5):1041-1047. doi:10.1213/ane.0000000000005872
2. Blobner M, Hollmann MW, Luedi MM, Johnson KB. Pro-Con Debate: Do We Need Quantitative Neuromuscular Monitoring in the Era of Sugammadex? Anesthesia and analgesia. Jul 1 2022;135(1):39-48. doi:10.1213/ane.0000000000005925
3. Ledowski T, Szabó-Maák Z, Loh PS, et al. Reversal of residual neuromuscular block with neostigmine or sugammadex and postoperative pulmonary complications: a prospective, randomised, double-blind trial in high-risk older patients. British journal of anaesthesia. Aug 2021;127(2):316-323. doi:10.1016/j.bja.2021.04.026
4. Krause M, McWilliams SK, Bullard KJ, et al. Neostigmine Versus Sugammadex for Reversal of Neuromuscular Blockade and Effects on Reintubation for Respiratory Failure or Newly Initiated Noninvasive Ventilation: An Interrupted Time Series Design. Anesthesia and analgesia. Jul 2020;131(1):141-151. doi:10.1213/ane.0000000000004505
5. Kirmeier E, Eriksson LI, Lewald H, et al. Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study. Lancet Respir Med. Feb 2019;7(2):129-140. doi:10.1016/s2213-2600(18)30294-7
6. Togioka BM, Yanez D, Aziz MF, Higgins JR, Tekkali P, Treggiari MM. Randomised controlled trial of sugammadex or neostigmine for reversal of neuromuscular block on the incidence of pulmonary complications in older adults undergoing prolonged surgery. British journal of anaesthesia. May 2020;124(5):553-561. doi:10.1016/j.bja.2020.01.016
7. Li G, Freundlich RE, Gupta RK, et al. Postoperative Pulmonary Complications' Association with Sugammadex versus Neostigmine: A Retrospective Registry Analysis. Anesthesiology. Jun 1 2021;134(6):862-873. doi:10.1097/aln.0000000000003735
8. Blobner M, Hunter JM, Meistelman C, et al. Use of a train-of-four ratio of 0.95 versus 0.9 for tracheal extubation: an exploratory analysis of POPULAR data. British journal of anaesthesia. Jan 2020;124(1):63-72. doi:10.1016/j.bja.2019.08.023
9. 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
10. 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