From Henry Rosenberg MD on Newborn Genetic Screening (mentioned in PAAD October 16, 2024: new therapeutic advances in sickle cell disease )
I was fortunate enough to attend the International Conference on Newborn Screening (ICONS) in NYC this week. This was the third annual meeting of the group.
Presentations from around the world discussed the development, benefits, and prospects of genetic screening. The significance of newborn genetic screening for Anesthesiology cannot be underestimated in my opinion. There are hundreds of inherited disorders that will be detected by such screening. Of particular note is not only Malignant Hyperthermia but also early detection of genetic predisposition to such disorders as Sickle Cell Disease, Duchenne Muscular Dystrophy and coagulopathies that have direct impact on choice of agents and decisions about practice patterns. It is , in my opinion, going to revolutionize and improve patient evaluation. At the meeting there were presentations by Patricia Guthrie, daughter of Robert Guthrie who first developed heel stick blood spot procedure for detection of phenyl ketonuria (PKU) and Ed Naylor who worked with Guthrie on expanding newborn screening with the use of Tandem Mass Spectroscopy. Because the cost of genetic sequencing has declined dramatically and the ability to detect disorders that might not present clinically until years after birth, the technique has promise to save Lives and prevent life long disability as it has with PKU and has begun to do with sickle cell disease.. The NIH sponsored program PreEMPT at Harvard has begun the process of evaluating the cost , benefit and harm of newborn genetic testing and MH will be included in their analysis. For those interested, see presentations by Dr. Wendy Chung, Chief of Pediatrics at Boston Children’s Hospital and GeneDX, a commercial genetic testing company among others on a variety of sites such as Linked In. Not being a pediatric anesthesiologist, I can only imagine the changes that will follow newborn genetic screening for the practice immediately and in the future.
From Fancine S Yudkowitz, MD FAAP FASA, Professor of Anesthesiology, Perioperative and Pain Medicine, and Pediatrics, Icahn School of Medicine at Mount Sinai, Medical Director of Children's Anesthesiology (MDCA), Mount Sinai Kravis Children's Hospital on neuromuscular block reversal
A few points:
1. Unfortunately, the use of sugammadex has led practitioners to believe that they can give any amount of muscle relaxant because we now have a "rescue" drug. Despite the advent of sugammadex, appropriate neuromuscular blocking agent dosing should still be used intraoperatively.
2. Be aware that sugammadex is not a miracle drug and that a TOF of >0.9 after sugammadex administration does not guarantee that recurarization won't occur. We had two such cases where appropriate doses of sugammadex were administered based on monitoring TOF and 30-45 minutes later the patient became apneic. Both patients were infants. Since then for infants, we have instituted that the administration of sugammadex must be part of the handoff to the next team caring for the patient. Further, if they go to the PACU they must be observed for at least 1 hour after sugammadex was administered.
In response to Dr. Yukowitz from Sorin Brull MD
The only practice that will guarantee safe extubation with NO (0%) incidence of residual neuromuscular block (and attendant pulmonary complications) is through the routine use of quantitative monitoring to confirm TOF ratio ≥0.9 before extubation, regardless of the reversal protocol (neostigmine, sugammadex, or spontaneous recovery) [1]. This fact has been published repeatedly, and as an added benefit, quantitative monitoring SAVES resources ($ and sugammadex) in both adult [1] and pediatric [2] patients.
Even the use of a protocol that specifies rocuronium dosing, and selective use of sugammadex vs. neostigmine based on qualitative assessment of TOF count and fade (i.e., empiric, “clinical experience”) results in an incidence of residual neuromuscular block of 3% (confidence interval of 1-7%) [3]. Furthermore, rocuronium overdose and unadjusted sugammadex administration due to inadequate neuromuscular monitoring can lead to apparent adequate recovery of neuromuscular function, followed by life-threatening re-paralysis, cyanosis (SpO2=39%) and need for rescue manual ventilation [4].
Those practitioners who continue to disregard the science and insist on their “clinical experience” to guide perioperative neuromuscular block are practicing outside the American Society of Anesthesiologists’ recommendations [5], and are placing their patients at preventable risk while increasing the cost of anesthesia care. It is incumbent upon these practitioners to prove that their clinical experience-based methods are at least as safe (and cheap) as those in which quantitative neuromuscular monitoring is used routinely.
References
1. Thilen SR, Sherpa JR, James AM, Cain KC, Treggiari MM, Bhananker SM. Management of Muscle Relaxation With Rocuronium and Reversal With Neostigmine or Sugammadex Guided by Quantitative Neuromuscular Monitoring. Anesth Analg. 2024 Sep 1;139(3):536-544. doi: 10.1213/ANE.0000000000006511. Epub 2023 May 12. PMID: 37171989
2. Haberkorn S, Twite M, Klockau K, Whitney G, Faulk DJ. Quantitative Monitoring Maximizes Cost-Saving Strategies When Antagonizing Neuromuscular Block With Sugammadex. Cureus. 2024 Sep 3;16(9):e68551. doi: 10.7759/cureus.68551. PMID: 39364519; PMCID: PMC11449403.
3. Thilen SR, Liang T, Kruse TN, Cain KC, Treggiari MM, Bhananker SM. Evaluation of a Protocol for the Management of Maintenance and Reversal of Rocuronium Block Using Neostigmine or Sugammadex. Anesth Analg. 2023 Jun 1;136(6):1143-1153. doi: 10.1213/ANE.0000000000006510. Epub 2023 May 19. PMID: 37205804.
4. Salaün JP, Décary E, Veyckemans F. Recurarisation after sugammadex in children: review of case reports and recommendations. Br J Anaesth. 2024 Feb;132(2):410-414. doi: 10.1016/j.bja.2023.09.028. Epub 2023 Oct 28. PMID: 38170632.
5. Thilen SR, Weigel WA, Todd MM, Dutton RP, Lien CA, Grant SA, Szokol JW, Eriksson LI, Yaster M, Grant MD, Agarkar M, Marbella AM, Blanck JF, Domino KB. 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. 2023 Jan 1;138(1):13-41. doi: 10.1097/ALN.0000000000004379. PMID: 36520073.
From Deb Faulk MD
We thank the reader for their comments and agree that the introduction of sugammadex has produced a false sense of security, leading to practice where inappropriate over-dosing of rocuronium may occur. The belief that sugammadex can rescue us from our ‘normal’ dosing practices and that it is so effective that we also no longer need to monitor patients has been seen (1). Unfortunately, these perceptions are untrue. Residual block can still be seen when using sugammadex, especially in the absence of monitoring (2). Dosing for sugammadex is actually BASED on quantitative monitoring (3), so it should be noted that we are counting on a “miracle drug” that without quantitative monitoring, we are not even using appropriately. I (DF) firmly believe we should be monitoring patients not just at the end of anesthesia, but throughout the course of neuromuscular block administration to help guide our dosing neuromuscular blocking agents as well as our antagonism strategies appropriately.
With respect to the appropriate use of rocuronium in infants, this is a particularly vulnerable population that deserves special mention. The reader mentions observed recurarization in two infants where sugammadex was administered based on TOF monitoring, yet apnea occurred 30-45 minutes later. There are reports of recurarization after sugammadex antagonism in infants, but many lack critical information on timing and dosing of neuromuscular blocking agents, and quantitative monitoring is not utilized (4-6). The question of whether these reports involve recurarization or inadequate antagonism to allow appropriate recovery cannot be answered in these instances. I (DF) applaud the reader for their intentional thought regarding potential recurarization in these patients, but without this information it is hard to understand what might be happening here as well. The idea of watching patients for at least 1 hour after sugammadex administration is also laudable, but could be inadequate.
Studies looking at rocuronium dosing in infants have found this patient population requires smaller doses of rocuronium and that their spontaneous recovery times may be quite prolonged compared to older children. Doses of 0.3mg/kg and 0.45mg/kg were found to give adequate intubating conditions within 1-2 minutes without prolonged block (7,8). “Usual dosing” of 0.6mg/kg for standard or 1.2mg/kg for rapid sequence intubation may therefore be 2-4 times what is needed in infants. In addition, bolus rocuronium dosing by anesthesia teams with a mean dose of 1.5mg/kg in 10 infants was seen to require a median time of 14hours for spontaneous recovery to a TOF ratio of 0.7 (9). Indeed, a recent report of potential recurarization in a 2.6 kg infant following sugammadex administration made no mention of monitoring, quantitative or qualitative, being used (6). They also reported intubation dosing of 1.1mg/kg of rocuronium, followed by repeat dosing of 2mg, 5mg, 2mg and 2mg during a total procedural time of just over 4 hours. While recurarization has high potential over time, I am more suspicious that this child was incompletely recovered and was experiencing residual blockade during their observation period. Had quantitative monitoring been used to ensure adequate recovery had been achieved, the question of how long they should have been monitored to avoid recurarization is unknown, but may exceed an hour.
A critical step to avoid residual weakness or recurarization is to dose neuromuscular blocking agents appropriately, maintaining only the depth of block that is necessary for the surgery in progress. We thank the reader for their comments and highlighting this important point. The need to think critically about rocuronium dosing is important, and even sugammadex may not be able to rescue us, especially if we are not even using it correctly. Quantitative monitoring is a key element in appropriate dosing of neuromuscular blockade, its intraoperative management and antagonism (10). Indeed, regardless of whether sugammadex or neostigmine is administered, only with routine use of quantitative monitoring and confirmation of a TOF ratio ≥0.9 prior to extubation can we ensure our patients will not experience residual neuromuscular blockade.
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 Jun 1;132(6):1518-1526
Kotake Y, Ochiai R, Suzuki T, Ogawa S, Takagi S, Ozaki M, Nakatsuka I, Takeda J. Reversal with sugammadex in the absence of monitoring did not preclude residual neuromuscular block. Anesth Analg. 2013 Aug;117(2):345-51. doi: 10.1213/ANE.0b013e3182999672. Epub 2013 Jun 11. PMID: 23757472.
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.
Carollo DS, White WM. Postoperative recurarization in a pediatric patient after sugammadex reversal of rocuronium-induced neuromuscular blockade: a case report. AA Pract. 2019;13:204-5.
Lorinc AN, Lawson KC, Niconchuk JA, et al. Residual weakness and recurarization after sugammadex administration in pediatric patients: a case series. AA Pract. 2020;14:e01225.
Arends, J., & Tobias, J. D. (2020). Sugammadex and recurarisation in an infant. Ped Anesth Crit Care J, 8, 115-119.
Eikermann M, Hunkemöller I, Peine L, Armbruster W, Stegen B, Hüsing J, Peters J. Optimal rocuronium dose for intubation during inhalation induction with sevoflurane in children. Br J Anaesth. 2002 Aug;89(2):277-81. doi: 10.1093/bja/aef177. PMID: 12378667.
Rapp HJ, Altenmueller CA, Waschke C. Neuromuscular recovery following rocuronium bromide single dose in infants. Paediatr Anaesth. 2004 Apr;14(4):329-35. doi: 10.1046/j.1460-9592.2003.01216.x. PMID: 15078379.
Soffer OD, Kim A, Underwood E, Hansen A, Cornelissen L, Berde C. Neurophysiological Assessment of Prolonged Recovery From Neuromuscular Blockade in the Neonatal Intensive Care Unit. Front Pediatr. 2020 Sep 18;8:580. doi: 10.3389/fped.2020.00580. PMID: 33072662; PMCID: PMC7530642
Thilen SR, Weigel WA, Todd MM, Dutton RP, Lien CA, Grant SA, Szokol JW, Eriksson LI, Yaster M, Grant MD, Agarkar M, Marbella AM, Blanck JF, Domino KB. 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. 2023 Jan 1;138(1):13-41. doi: 10.1097/ALN.0000000000004379. PMID: 36520073.