Reversal of neuromuscular block with sugammadex in five heart transplant pediatric recipients

Abstract

Heart transplantation is a frequent procedure in the treatment of end-stage cardiac dysfunction. Therefore, these patient populations will also be more frequent exposed to other more common surgical procedures after their transplantation. Anesthesiologist should be aware in their assessment of these patients, especially regarding some specific issues related to patients with a history of heart transplantation, like reversal of neuromuscular block. Several reports described that cholinesterase inhibitors drugs, like neostigmine, may produce a dose-dependent life-threatening bradycardia in heart transplant recipients while other publication described the safe use of neostigmine. Reversal of neuromuscular block with sugammadex is another possibility, but limited data exists in literature. We describe five cases in which successful reversal of neuromuscular block was performed with sugammadex in heart transplant pediatric recipients without sequale and discuss the reversal of neuromuscular block in this patient population.

KEYWORDS
Rocuronium; Sugammadex; Cardiac transplantation; Reversal of neuromuscular block

Resumo

O transplante cardíaco é um procedimento frequente no tratamento da disfunção cardíaca em estágio final. Portanto, essa população de pacientes também será exposta com mais frequência a outros procedimentos cirúrgicos mais comuns após o transplante. Em sua avaliação, o anestesiologista deve ter em mente algumas questões específicas relacionadas à história de transplante cardíaco desses pacientes, tais como a reversão do bloqueio neuromuscular. Vários estudos relataram que os inibidores da colinesterase, como a neostigmina, podem produzir uma bradicardia dose-dependente que ameaça a vida em receptores de transplante cardíaco, enquanto um estudo relatou o uso seguro de neostigmina. A reversão do bloqueio neuromuscular com sugamadex é outra possibilidade, mas os dados na literatura são escassos. Descrevemos cinco casos nos quais a reversão bem-sucedida do bloqueio neuromuscular foi realizada com sugamadex em receptores pediátricos de transplante cardíaco sem deixar sequelas e discutimos a reversão do bloqueio neuromuscular nessa população de pacientes.

PALAVRAS-CHAVE
Rocurônio; Sugammadex; Transplante cardíaco; Reversão do bloqueio neuromuscular

Introduction

Heart transplantation is a frequent procedure in the treatment of end-stage cardiac dysfunction. Therefore, these patient populations will also be more frequent exposed to other more common surgical procedures after their transplantation. Anesthesiologist should be aware in their assessment of these patients especially regarding some specific issues related to patients with a history of heart transplantation. One of these issues is the reversal of Neuromuscular Block (NMB).¹ Reversal of NMB to prevent Residual Neuromuscular Block (RNMB) and concomitant pulmonary complications, is a challenge in heart transplant recipients.^1-4 Reversal of NMB can be achieved with either cholinesterase inhibitors (in combination with muscarinic antagonists) or sugammadex. Reversal with cholinesterase inhibitors has not only limitations due to its mechanism of action (ineffective against deeper levels of NMB), but is also associated with undesirable cholinergic side-effects. Although a recent retrospective study showed no severe bradycardia, cardiac arrest or deaths after reversal with cholinesterase inhibitors in heart transplant recipients, several reports described that these drugs may produce a dose-dependent life-threatening bradycardia in heart transplant recipients.^5-9 The use of sugammadex in this patient population consists of only two case reports.^10,11 We describe five cases in which reversal of NMB was performed with sugammadex in heart transplant pediatric recipients and discuss the reversal of NMB in this patient population.

Case report

Case 1

A 14 years-old female patient (47 kg), was diagnosed with cholecystitis for which laparoscopic cholecystectomy under general anesthesia was indicated. The patient had a history of hypertrophic cardiomyopathy since she was 3 month of age. Two months prior to the laparoscopic cholecystectomy she underwent a successful cardiac transplantation. After preoxygenation, anesthesia was induced with sevoflurane and fentanyl 5 µg.kg^-1. This was followed by endotracheal intubation and the lungs were ventilated with oxygen and air (ratio 2:3). Anesthesia was maintained with propofol continuously i.v. and intravenous opioids. Hereafter, Neuromuscular Monitoring (NM Monitoring) was performed using the TOF-Watch^® SX (Schering-Plough Ireland Ltd., Dublin, Ireland) by measuring the effect of stimulation of the ulnar nerve on the activity of the adductor pollicis muscle. After the procedures for the set-up, calibration, and stabilization of NM monitoring, according to the good clinical research practice in pharmacodynamic studies of NMB agents, rocuronium 0.9 mg.kg^-1 was administered.¹² NM monitoring continued until recovery to a TOF-Ratio (TOFR) to 0.9. The data were recorded on a laptop computer using the TOFMON 2.5 monitoring program (NV Organon, Oss, The Netherlands). The primary efficacy variable was defined as the time from the start of the administration of sugammadex, to recovery of the (TOFR) to 0.9. Additional rocuronium doses of 0.3 mg.kg^-1 were administered (total dose 56.4 mg). At the end of the procedure NM monitoring showed a reappearance of T₂, indicating moderate NMB. Reversal of rocuronium-induced NMB was performed with sugammadex 2.0 mg.kg^-1 (94 mg) according to the recommended dose. After 1 minute and 45 seconds the TOFR recovered to 0.90 (Fig. 1-I). No clinical relevant changes from baseline were observed in blood pressure, heart rate or ECG after the sugammadex dose. The trachea was extubated and the patient was fully awake discharged to the PACU. The patient's recovery from anesthesia was uneventful and no signs of RNMB or recurarization were observed. Surgery was uneventful.

Figure 1
(I-V) TOF-Watch SX tracings of the first twitch height (blue vertical lines) and TOF ratio (red dots) and the different time points at which rocuronium and sugammadex were administered.

Case 2

A 9 years-old male patient (26.1 kg) was diagnosed with cholecystitis for which laparoscopic cholecystectomy under general anesthesia was indicated. The patient had a history of hypoplastic ventricular chambers and underwent a successful cardiac transplantation 3 years prior. The patient was planned for surgery under general anesthesia. Anesthesia strategy, NM monitoring and primary end points were identical as in Case 1, except for the initial dose of rocuronium which was in this patient 0.6 mg.kg^-1 and repeat doses of rocuronium 0.3 mg.kg^-1 (total dose 31.3 mg). At the end of the procedure NM monitoring showed 2 Post Tetanic Counts (PTC), indicating deep NMB. Reversal of rocuronium-induced NMB was performed with sugammadex 4.0 mg.kg^-1 (104.4 mg) according to the recommended dose. After 1 minute and 45 seconds the TOFR recovered to 0.90 (Fig. 1-II). No clinical relevant changes from baseline were observed in blood pressure, heart rate or ECG after the sugammadex dose. The trachea was extubated and the patient was fully awake discharged to the PACU. The patient's recovery from anesthesia was uneventful and no signs of RNMB or recurarization were observed. Surgery was uneventful.

Case 3

A 7 years-old male patient 13.1 kg was diagnosed with gastric lymphoma for which stem cells collection was planned under general anesthesia. The patient had a history of hypertrophic cardiomyopathy since he was 1 year-old. Eleven months prior to this procedure he underwent a successful cardiac transplantation.

Anesthesia strategy, NM monitoring and primary end points were identical as in Case 2. Total dose of rocuronium administered was 7.9 mg. At the end of the procedure NM monitoring showed 1 PTC, indicating deep NMB. Reversal of rocuronium-induced NMB was performed with sugammadex 4.0 mg.kg^-1 (52.4 mg) according to the recommended dose. After 7 minutes and 15 seconds the TOFR recovered to 0.90 (Fig. 1-III). No clinical relevant changes from baseline were observed in blood pressure, heart rate and ECG after the sugammadex dose. The trachea was extubated and the patient was fully awake discharged to the PACU. The patient's recovery from anesthesia was uneventful and no signs of residual NMB or recurarization were observed. Surgery was uneventful.

Case 4

A 13 years-old male patient 39.8 kg was diagnosed with cholecystitis for which laparoscopic cholecystectomy under general anesthesia was indicated. The patient had a history of hypertrophic cardiomyopathy and underwent a successful cardiac transplantation 4 years prior. Anesthesia strategy, NM monitoring and primary end points were identical as in Case 2. Total dose of rocuronium administered was 71.6 mg. At the end of the procedure NM monitoring showed 3 PTC, indicating deep NMB. Reversal of rocuronium-induced NMB was performed with sugammadex 4.0 mg.kg^-1 (159.2 mg) according to the recommended dose. After 3 minutes and 45 seconds the TOFR recovered to 0.90 (Fig. 1-IV). No clinical relevant changes from baseline were observed in blood pressure, heart rate or ECG after the sugammadex dose. The trachea was extubated and the patient was fully awake discharged to the PACU. The patient's recovery from anesthesia was uneventful and no signs of residual NMB or recurarization were observed. Surgery was uneventful.

Case 5

A 2.5 years-old female patient, 37 kg, was diagnosed with pneumoperitoneum for which exploratory laparotomy under general anesthesia was indicated. The patient had a history of dilated cardiomyopathy and underwent a successful cardiac transplantation 11 months prior. Anesthesia strategy, neuromuscular monitoring and primary end point were identical as in Case 2. Total dose of rocuronium administered was 20.5 mg. At the end of the procedure NM monitoring showed a reappearance of T₂, indicating moderate NMB. Reversal of rocuronium-induced NMB was performed with sugammadex 2.0 mg.kg^-1 (22.8 mg) according to the recommended dose. After 2 minutes the TOFR recovered to 0.90 (Fig. 1-V). No clinical relevant changes from baseline were observed in blood pressure, heart rate or ECG after the sugammadex dose. The trachea was extubated and the patient was fully awake discharged to the PACU. The patient's recovery from anesthesia was uneventful and no signs of residual NMB or recurarization were observed. Surgery was uneventful.

Discussion

All five pediatric patients (2.5-14 y) showed a mean recovery time to TOFR to 0.9 in 255 s and 112 s for deep NMB and moderate NMB respectively. Reversal times were in line with other patient populations. There was no difference from the baseline regarding heart rate, blood pressure or ECG after the administration of sugammadex. Moreover, no other sequale like hypersensitivity were seen. Reversal of NMB in heart transplanted recipients with sugammadex is reported in one pediatric patient and two adult patients only.^10,11 These patients showed similar recovery times. Reversal of NMB in heart transplant recipients can be achieved by either cholinesterase inhibitors or sugammadex. Reversal with cholinesterase inhibitors is associated with a dose-dependent induced bradycardia and asystole in patients who underwent heart transplantation, both in recent and remote transplanted patients.^6,9,13 However, in a recent retrospective study in 118 anesthetic procedures in heart transplant recipients the safety of reversal of NMB with cholinesterase inhibitors showed no subsequent deaths or cardiac arrest and heart rates were not decreased statistically significant.⁵ Sugammadex unlike cholinesterase inhibitors reverses a rocuronium-induced neuromuscular block rapid and complete and without the well-known undesirable side effects associated with the use of cholinesterase inhibitors.^1,4 This has been explained by the differential mechanism of action because, unlike cholinesterase inhibitors, sugammadex does not interfere with other receptor systems, in particular cholinergic transmission (cholinesterase, nicotinic receptors or muscarinic receptors).¹ Furthermore, the administration of sugammadex, even in high doses, did not influence QTc intervals and blood pressure and was well tolerated in patients with cardiovascular disease.^14-16 Therefore to avoid potential cardiovascular side effects associated with the administration of cholinergic inhibitors in heart transplant recipients, sugammadex might be a good alternative with the prospects of a fast and complete reversal of NMB, no cardiovascular side-effects and the prevention of RNMB.

Ethics

The institutional ethical committee was consulted for approval of publication of the data. As only patients' charts (as individual cases) were retrieved from the hospital archives and no clinical interventions were undertaken, ethical approval was not needed.

References

• ¹
  Miller's Anesthesia, Eight Edition 2015. Anesthesia for cardiac surgical procedures. Chapter 67, pp. 2007-295.
• ²
  Arbous MS, Meursing AEE, van Kleef JW, et al. Impact of anesthesia management characteristics on severe morbidity and mortality. Anesthesiology. 2005;102:257-68.
• ³
  Murphy GS, Szokol JW, Marymont JH, et al. Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesth Analg. 2008;107:130-7.
• ⁴
  Grosse-Sundrup M, Henneman JP, Sandberg WS, et al. Intermediate acting non-depolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: prospective propensity score matched cohort study. BMJ. 2012;345:e6329.
• ⁵
  Barbara DW, Christensen JM, Mauermann WJ, et al. The safety of neuromuscular block reversal in patients with cardiac transplantation. Transplantation. 2016;100:2723-8.
• ⁶
  Bertolizio G, Yuki K, Odegard K, et al. Cardiac arrest and neuromuscular blockade reversal agents in the transplanted heart. J Cardiothorac Anesth. 2013;27:1374-8.
• ⁷
  Beebe DS, Shumway SJ, Maddock R. Sinus arrest after intravenous neostigmine in two heart transplant recipients. Anesth Analg. 1994;78:779-82.
• ⁸
  Bjerke RJ, Mangione MP. Asystole after intravenous neostigmine in a heart transplant recipient. Can J Anaesth. 2001;48:305-7.
• ⁹
  Sawasdiwipachai P, Laussen PC, McGowan FX, et al. Cardiac arrest after neuromuscular blockade reversal in heart transplant infant. Anesthesiology. 2007;107:663-5.
• ¹⁰
  Gomez-Rios MA, Lopez LR. Use of combination of rocuronium and sugammadex in heart transplant recipients. Anaesth Intensive Care. 2012;40:903-4.
• ¹¹
  Tezcan B, Saylan A, Bolukbasi D, et al. Use of sugammadex in a heart transplant recipient: review of the unique physiology of the transplanted heart. J Cardiothorac Anesth. 2016;30:462-5.
• ¹²
  Fuchs-Buder T, Claudius C, Skovgaard LT, et al. Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision. Acta Anaesthesiol Scand. 2007;51:789-808.
• ¹³
  Backman SB, Fox GS, Stein RD, et al. Neostigmine decreases heart rate in heart transplant patients. Can J Anaesth. 1996;43:373-8.
• ¹⁴
  Dahl V, Pendeville PE, Hollmann MW, et al. Safety and efficacy of sugammadex for the reversal of rocuronium-induced neuromuscular blockade in cardiac patients undergoing noncardiac surgery. Eur J Anaesthesiol. 2009;26:874-84.
• ¹⁵
  De Kam PJ, van Kuijk J, Prohn M, et al. Effects of sugammadex doses up to 32 mg/kg alone or in combination with rocuronium or vecuronium on QTc prolongation: a thorough study. Clin Drug Investig. 2010;30:599-611.
• ¹⁶
  De Kam PJ, van Kuijk J, Smeets J, et al. Sugammadex is not associated with QT/QTc prolongation: methodology aspects of an intravenous moxifloxacin-controlled thorough QT study. Int J Clin Pharmacol Ther. 2012;50:595-604.

Publication Dates

• Publication in this collection
  Jul-Aug 2018

History

• Received
  27 Mar 2017
• Accepted
  16 Oct 2017