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COMMENTARY
Ahead of print publication  

Cardiovascular adverse effects of sugammadex


 Department of Anaesthesiology, Max Smart Super Specialty Hospital, Saket, Delhi, India

Date of Submission21-Mar-2020
Date of Acceptance23-Mar-2020
Date of Web Publication29-Sep-2020

Correspondence Address:
Mukul Chandra Kapoor,
6 Dayanand Vihar, Delhi - 110 092
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/joacp.JOACP_132_20



How to cite this URL:
Kapoor MC. Cardiovascular adverse effects of sugammadex. J Anaesthesiol Clin Pharmacol [Epub ahead of print] [cited 2020 Oct 21]. Available from: https://www.joacp.org/preprintarticle.asp?id=296192



Sugammadex is a synthetic γ-cyclodextrin, designed to selectively bind amino-steroid neuromuscular (NM) blockers (rocuronium and vecuronium). It reverses NM blockade by encapsulating rocuronium, thereby preventing the NM blocker from binding to acetylcholine receptors on the motor endplate.[1] Sugammadex has a hydrophobic cavity, which traps the NM blocker, and has a hydrophilic polar body. The water-soluble guest-host complex formed remains stable until it is eliminated from the body, as it has a high binding rate and a low dissociation rate. Its use is associated with a fast and predictable reversal of any degree of the block, and it reduces the risk of postoperative residual NM blockade. However, cost and regulatory constraints have hindered the widespread use of sugammadex.

Sugammadex has no effect on the NM junction or any receptor system in the body. Its use eliminates the need for anticholinergic drugs, which have undesirable adverse effects. Clinical studies have reported mild adverse effects of sugammadex, and these are limited in duration.

The reported cardiovascular adverse effects of sugammadex include QTc prolongation, atrioventricular block, hypotension, atrial fibrillation, and even asystole.[2],[3],[4],[5],[6] The company package insert notes a 1% incidence of bradycardia with its use, and a recent meta-analysis reported an incidence of 2%.[7] Most cases of bradycardia respond to the administration of anticholinergics, but in some cases, the administration of adrenaline is required to reverse the bradycardia. As sugammadex lacks muscarinic effects and bradycardia may not respond to atropine, some authors suggest the primary use of low-dose adrenaline to treat bradycardia, instead of anticholinergics.[8],[9]

Trent Sims et al. report a high incidence of bradycardia (7%) after sugammadex administration.[10] The higher incidence, compared to the earlier studies, can be attributed to higher heart rate criteria used by them. The authors also suggest that the bradycardia may be dose-related, with those receiving higher initial doses more likely to experience it. A similar high incidence of 8% has been reported in children, with an increased incidence of bradycardia in the presence of a comorbid cardiac condition. However, other studies did not find an association between dose and incidence of bradycardia.[11] The cardiovascular effects might be associated with the amount of free sugammadex plasma molecules.[9]

In 2008, sugammadex use for NM blockade reversal was approved in Europe. However, the United States Food and Drug Administration (FDA) granted its approval only at the end of 2015, due to safety concerns such as the risk of anaphylaxis and bradycardia.[12] Recent case reports have elucidated more serious cardiovascular adverse effects, which include hypotension, third-degree atrioventricular block, and persistent bradycardia.[4],[5],[6],[13],[14] Cardiac arrest after sugammadex administration has been reported, which were triggered by coronary vasospasm in patients.[15],[16] One cardiac arrest victim had normal coronaries[16] while the other had nonobstructive coronary lesions.[15]

Multiple reports of adverse effects warrant further studies to examine its safety. The significant incidence of bradycardia and cardiac arrest after sugammadex highlights the need for extreme vigilance in patients, especially those with slow recovery times.[12],[17] No definitive mechanism for the cause of bradycardia has yet been postulated. Although the occurrence of serious cardiac adverse effects after sugammadex administration is well recognized, no pharmacologic or physiologic mechanism has been proven nor postulated.[11]



 
  References Top

1.
Naguib M, Brull SJ. Sugammadex: A novel selective relaxant binding agent. Expert Rev Clin Pharmacol 2009;2:37-53.  Back to cited text no. 1
    
2.
Cammu G, De Kam PJ, Demeyer I, Decoopman M, Peeters PA, Smeets JM, et al. Safety and tolerability of single intravenous doses of sugammadex administered simultaneously with rocuronium or vecuronium in healthy volunteers. Br J Anaesth 2008;100:373-9.  Back to cited text no. 2
    
3.
De Boer HD, Driessen JJ, Marcus MA, Kerkkamp H, Heeringa M, Klimek M. Reversal of rocuronium-induced (1.2 mg/kg) profound neuromuscular block by sugammadex: A multi center, dose-finding and safety study. Anesthesiology 2007;107:239-44.  Back to cited text no. 3
    
4.
Osaka Y, Shimada N, Satou M, Masuda T, Ando T, Kozono Y, et al. A case of atrioventricular block (Wenckebach type) induced by sugammadex. J Anesth 2012;26:627-8.  Back to cited text no. 4
    
5.
Kokki M, Ali M, Turunen M, Kokki H. Suspected unexpected adverse effect of sugammadex: Hypotension. Eur J Clin Pharmacol 2012;68:899-900.  Back to cited text no. 5
    
6.
Bhavani SS. Severe bradycardia and asystole after sugammadex. Br J Anesth 2018:121:95-6.  Back to cited text no. 6
    
7.
Carron M, Zarantonello F, Tellaroli P, Ori C. Efficacy and safety of sugammadex compared to neostigmine for reversal of neuromuscular blockade: A meta-analysis of randomized controlled trials. J Clin Anesth 2016;35:1-12.  Back to cited text no. 7
    
8.
Booij LH, Van Egmond J, Driessen JJ, de Boer HD.In vivo animal studies with sugammadex. Anaesthesia 2009;64(suppl 1):38-44.  Back to cited text no. 8
    
9.
Sanoja IA, Toth KS. Profound bradycardia and cardiac arrest after sugammadex administration in a previously healthy patient. A&A Practice 2019;12:22-4.  Back to cited text no. 9
    
10.
Sims T, Hansen JK, Peterson J, Hakim M, Roth C, Tobias JD, et al. Heart rate changes following the administration of sugammadex in adults. J Anaesthesiol Clin Pharmacol 2020. Doi: 10.4103/joacp. JOACP_346_19.  Back to cited text no. 10
    
11.
Alsuhebani M, Sims T, Hansen JK, Hakim M, Walia H, Miller R, et al. Heart rate changes following the administration of sugammadex in children: A prospective, observational study (Published online ahead of print, 2020 Jan 24). J Anesth 2020;34:238-42.  Back to cited text no. 11
    
12.
US Food and Drug Administration. Novel Drug Approvals for 2015. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022225lbl.pdf. [Last accessed on 2020 Mar 17].  Back to cited text no. 12
    
13.
Saito I, Osaka Y, Shimada M. Transient third-degree AV block following sugammadex. J Anesth 2015;29:641.  Back to cited text no. 13
    
14.
Bilgi M, Demirhan A, Akkaya A, Tekelioglu UY, Kocoglu H. Sugammadex associated persistent bradycardia. Int J Med Sci Public Health. 2014;3:372-4.  Back to cited text no. 14
    
15.
Ko MJ, Kim YH, Kang E, Lee BC, Lee S, Jung JW. Cardiac arrest after sugammadex administration in a patient with variant angina: A case report. Korean J Anesthesiol 2016;69:514-7.  Back to cited text no. 15
    
16.
Hoshino K, Kato R, Nagasawa S, Kozu M, Morimoto Y. [A case of repetitive cardiac arrest due to coronary vasospasm after sugammadex administration]. Masui. 2015;64:622-7.  Back to cited text no. 16
    
17.
Choi YJ, Park JW, Kim SH, Jung KT. Sugammadex associated profound bradycardia and sustained hypotension in patient with the slow recovery of neuromuscular blockade - A case report. Anesth Pain Med 2019;14:299-304.  Back to cited text no. 17
    




 

 
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