Debra J. Faulk MD and Myron Yaster MD
Today’s Pediatric Anesthesia Article of the Day is extremely timely. On July 21, 2021, sugammadex received FDA approval for use in children 2 years of age and older. This decision was based on the data presented in today’s PAAD. Sugammadex was approved for use in adults in 2015 and has been used extensively “off label” in pediatric practice since its introduction.(1) I’ve asked my former colleague and current mentee, Dr. Debra Faulk, to review the article by Voss et al. with me. Deb has been keenly interested in neuromuscular blockade use, reversal, and monitoring and recently published a SPA survey study in Anesthesia and Analgesia.(1). She is currently working on several projects on these topics including the use of quantitative NMB monitoring in pediatrics and she presented a masterful PEDx talk on her preliminary findings at the recent SPA meeting in Tampa. When these lectures become available on the SPA website I’d urge you to watch. Myron Yaster MD
Voss T, Wang A, DeAngelis M, Speek M, Saldien V, Hammer GB, Wrishko R, Herring WJ. Sugammadex for reversal of neuromuscular blockade in pediatric patients: Results from a phase IV randomized study. Paediatr Anaesth. 2022 Mar;32(3):436-445. doi: 10.1111/pan.14370. Epub 2021 Dec 17. PMID: 34878707.
Sugammadex a modified cyclodextrin, acts via encapsulation to reverse neuromuscular blockade (NMB) induced by the commonly used aminosteroidal NMB agents rocuronium or vecuronium.(2,3) It has revolutionized the management of NMB since its introduction and FDA approval in 2015. Today’s PAAD reports phase IV data supporting the safety and efficacy of sugammadex use in children from 2 years to <17 years of age. In this study, pediatric participants recovered from rocuronium- or vecuronium induced moderate neuromuscular blockade significantly faster with sugammadex 2 mg/kg than with neostigmine. Dosing recommendations include 2mg/kg for reversal of moderate (return of the second twitch) and 4mg/kg for reversal of deep (return of 1-2 post-tetanic twitches) levels of blockade. No recommendations are made for reversal of profound (zero post-tetanic twitches, within 3 minutes of rocuronium administration) levels of blockade, which occurs with 16mg/kg in adults.
In this study, the depth of NMB was assessed using quantitative monitoring at the adductor pollicis muscle using calibrated acceleromyography. As discussed in previous PAADs, in our clinical practices, few if any of us do this…indeed, we suck at this! Most of us either don’t monitor the neuromuscular junction at all, or use qualitative monitoring often at the orbicularis oculi forehead muscles giving us information that quite honestly is no better than flipping a coin. Indeed, the RECITE-US study(4) reported 64.7% of adult patients experienced residual neuromuscular blockade at the time of extubation! Did we mention that we suck at this?
The search for a pharmacologic solution to the problem of residual blockade has mainly focused on developing NMBAs with better pharmacokinetic profiles (i.e. rocuronium better than pancuronium better than d-tubocurarine). Shorter acting NMBAs though, still often require reversal. Historically this has been accomplished with anticholinesterases like neostigmine that have a host of side-effects and limitations in their use. Among these limitations are time necessary for full reversal and the inability to effectively reverse deep levels of blockade due to the competitive mechanism of action. Enter sugammadex! In the early 2000’s, the world was introduced to this novel reversal agent that works by binding and encapsulating aminosteroidal non-depolarizing muscle relaxants with few side effects and the ability to reverse even profound levels of blockade quickly.
So a new day is dawning…or is it? Sugammadex has undoubtedly revolutionized our practice with respect to reversal of NMBAs and shown its use can lead to reduction in the incidence of residual blockade in the post-operative period. But, is the unintended consequence of its use an over-reliance on it’s efficacy and reliability causing us to ignore other factors that influence the occurrence of residual neuromuscular blockade? While able to reverse profound levels of blockade, sugammadex can still fail to reverse blockade or prevent re-curarization in the face of over-dosing of NMBA’s. Quantitative monitoring of the depth of blockade is essential to guide appropriate NMBA administration, appropriate dosing of reversal agents, and ensure full recovery has been achieved prior to extubation. Indeed, in our recent survey of the SPA membership,(1) we found that pediatric anesthesiologists who routinely use sugammadex and who are less than 6 years out of training (trained in the era of sugammadex approval) rarely monitor NMB. Are we failing not just our patients, but our trainees as well?
Although not discussed in the article (it was after all sponsored by the manufacturer, Merck & Co, Inc.), sugammadex is considerably more expensive than neostigmine, $223.85 and $186.18 for a 5-mL single-dose vial and 2-mL single-dose vial, respectively. The cost of neostigmine/glycopyrrolate is unlikely to exceed $4/patient. Obviously, this cost analysis does not include longer stays in the OR and PACU until full reversal (TOF> 0.9) occurs. On the other hand, the cost of sugammadex can be significantly reduced with the help of your OR pharmacy if they fractionate and supply smaller unit doses of the drug. When dexmedetomidine was introduced, cost was a limiting factor until the OR pharmacy starting to break down vials to more manageable and economical units (e.g., 4 mcg/mL). Similarly, sugammadex can be unit dosed to minimize cost and waste. Further, quantitative monitoring can assist in determining how much sugammadex needs to be administered or if it needs to be administered at all (if the TOF > 0.9 it isn’t needed)!
In summary, we wish to celebrate and applaud the manufacturer and the researchers involved in the study for their efforts in getting FDA labeling for this drug. We wish more manufacturers would follow their example. Finally, sugammadex is certainly an important addition to our toolbox when it comes to the reversal of NMBA, but we must guard against the trend of doing what is easy and ignoring what is right. Appropriate monitoring (quantitative) of neuromuscular blockade is necessary to guide appropriate intraoperative administration of NMBAs AND to determine the correct dosing of sugammadex for reversal. With these practices, we may actually stand a chance of eliminating residual neuromuscular blockade when using sugammadex as the reversal agent.
Debra J. Faulk MD and Myron Yaster MD
1. 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. Anesth Analg 2021;132:1518-26.
2. Hristovska AM, Duch P, Allingstrup M, Afshari A. Efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults. Cochrane Database Syst Rev 2017;8:Cd012763.
3. Hristovska AM, Duch P, Allingstrup M, Afshari A. The comparative efficacy and safety of sugammadex and neostigmine in reversing neuromuscular blockade in adults. A Cochrane systematic review with meta-analysis and trial sequential analysis. Anaesthesia 2018;73:631-41.
4. Saager L, Maiese EM, Bash LD, Meyer TA, Minkowitz H, Groudine S, Philip BK, Tanaka P, Gan TJ, Rodriguez-Blanco Y, Soto R, Heisel O. Incidence, risk factors, and consequences of residual neuromuscular block in the United States: The prospective, observational, multicenter RECITE-US study. J Clin Anesth 2019;55:33-41.