BJA Advance Access originally published online on March 8, 2007
British Journal of Anaesthesia 2007 98(5):624-627; doi:10.1093/bja/aem057
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Reversal of rocuronium-induced (1.2 mg kg–1) profound neuromuscular block by accidental high dose of sugammadex (40 mg kg–1)
1 Department of Anaesthesiology, Erasmus University Medical Centre, Rotterdam, The Netherlands
2 Department of Anaesthesiology, Radboud University Medical Centre Nijmegen, Martini Hospital Groningen, The Netherlands
3 Global Clinical Development, NV Organon, Oss, The Netherlands
* Corresponding author: Department of Anaesthesiology, Martini Hospital Groningen, PO Box 30033, 9700 RM, Groningen, The Netherlands. E-mail: hd.de.boer{at}mzh.nl
Accepted for publication January 29, 2007.
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Abstract |
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Sugammadex is the first selective relaxant binding agent and reverses rocuronium-induced neuromuscular block. A case is reported in which a patient accidentally received a high dose of sugammadex (40 mg kg–1) to reverse a rocuronium-induced (1.2 mg kg–1) profound neuromuscular block. A fast and efficient recovery from profound neuromuscular block was achieved and no adverse events or other safety concerns were reported.
Keywords: neuromuscular block, rocuronium; neuromuscular relaxant, sugammadex; reversal agent
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Introduction |
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Sugammadex is the first selective relaxant-binding agent and has been designed to reverse the steroidal neuromuscular blocking drug rocuronium.1 2 Encapsulation of the rocuronium molecule by sugammadex results in a rapid decrease in free rocuronium in the plasma and subsequently at the nicotinic receptor at the motor endplate.1 3 After encapsulation, rocuronium is not available to bind to the nicotinic receptor in the neuromuscular junction.1 This promotes the liberation of acetylcholine receptors, and muscle activity reappears.
The reversal of rocuronium-induced neuromuscular block by sugammadex has been demonstrated in vivo in several species, including humans.1 3–10 Clinical studies published thus far have investigated the effect of sugammadex doses up to 16 mg kg–1 on rocuronium-induced neuromuscular block. These studies have shown fast and efficient reversal without the well-known undesirable cholinergic side-effects associated with the use of cholinesterase inhibitors, such as bradycardia, bronchoconstriction, hypersalivation, abdominal cramps, and nausea and vomiting.1–10 This has been explained by the differential mechanism of action, as cyclodextrin derivatives do not interfere with muscarinic or other receptor systems.
We report a case in which a patient, who was participating in a clinical study and randomized to sugammadex 4 mg kg–1, was unintentionally treated with a sugammadex dose of 40 mg kg–1. The safety and efficacy of sugammadex are discussed.
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Case report |
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A 36-yr-old man (weight 94 kg), without medical history and classified as American Society of Anesthesiologists (ASA) class I, participated in a multicentre, randomized, double-blind, parallel, dose-finding study. The study was approved by the local university ethical committee of the Erasmus University Medical Centre. Written informed consent was obtained from this first patient who participated at this study site, who was scheduled for nasal septum surgery.
Neuromuscular function was monitored using train-of-four (TOF) nerve stimulation and acceleromyography (TOF-Watch® SX, Organon Ireland Ltd, Dublin, Ireland). The primary efficacy variable was defined as the time from the start of the administration of sugammadex (or placebo) to recovery of the TOF-ratio to 0.9. Premedication consisted of oral midazolam 7.5 mg and oral acetaminophen 1000 mg on the morning of surgery. On arrival in the operating room two i.v. lines were inserted, one for anaesthetic administration (including rocuronium and sugammadex) and the other for blood sampling. Non-invasive automatic monitoring of arterial pressure, oxygen saturation, and electrocardiography, just before administration of rocuronium and at 2, 30 min, and 24 h after administration of sugammadex (or placebo), were used for monitoring the patient in the theatre. The vital signs blood pressure and heart rate were recorded at the preoperative visit, just before administration of rocuronium, at 2, 10, 30 min, and 24 h after administration of sugammadex (or placebo). Values within the following ranges were considered to be normal values; heart rate change from baseline 
15 beats min–1, systolic/diastolic blood pressure change from baseline 20 mm Hg. Blood samples were obtained before administration of rocuronium and at 5, 20, 60 min, 4–6 h, and 24 h after the administration of sugammadex (or placebo). Assessment of the blood samples included calculation of the peak plasma concentration of sugammadex and rocuronium, blood chemistry, and haematology analysis, among others haematocrit, blood cell counts, sodium, potassium, creatinine, blood urea nitrogen, ALAT, ASAT, 
-GT, bilirubin total, alkaline phosphatase, and fasting glucose.
Anaesthesia was induced with a bolus dose of propofol 180 mg followed by a continuous infusion of propofol 8–12 mg kg–1 h–1 and sufentanil (total dose 0.75 µg kg–1) to maintain anaesthesia. Until the administration of rocuronium, the patient was ventilated by mask with oxygen 100%. After induction of anaesthesia, procedures for the set-up, calibration, and stabilization of neuromuscular monitoring were followed. The patient then received an i.v. bolus injection of rocuronium 1.2 mg kg–1 (NV Organon, Oss, The Netherlands). This was followed by endotracheal intubation, and the lungs were ventilated with a mixture of oxygen and air in a ratio of 2:3. Five minutes after the bolus injection of rocuronium, the patient unintentionally received a bolus injection of sugammadex 40 mg kg–1 (37.6 ml of a 100 mg ml–1 solution, administered by a blinded resident). Two 20 ml syringes were used to inject the volume of 37.6 ml of the study drug. Just after the administration of sugammadex, the error was discovered. The current subject was randomized to a sugammadex dose of 4 mg kg–1 and should have received 3.76 ml of a 100 mg ml–1 solution. The duration of anaesthesia was 150 min.
The patient's recovery from anaesthesia was uneventful and he was discharged to the post-operative recovery ward to be monitored for signs of possible recurarization for at least 120 min after the administration of sugammadex. After full recovery from anaesthesia, the patient was fully informed of the dosing error. The dosing error was also reported, as a major protocol violation, to the local university ethical committee of the Erasmus University Medical Centre.
A safety assessment was performed by a blinded safety assessor who monitored the patient for adverse events (AEs), including serious AEs (SAEs) during the postoperative visit and the 7-day follow-up period.
No AEs or SAEs were reported for this patient. Peak plasma concentrations of sugammadex and rocuronium were 461 and 9 µg ml–1, respectively. No clinical relevant changes occurred in haematology and biochemistry values after administration of the high dose of sugammadex. No changes in renal or liver function were observed. Also, no clinical relevant changes from baseline were observed in blood pressure, heart rate, or electrocardiography after administration of the high sugammadex dose at all time points. Events possibly indicating drug interactions were not reported. Signs of residual neuromuscular block or recurarization were not observed.
Recovery from neuromuscular relaxation, that is, a TOF ratio of 0.9, was achieved at 1:19 (min:s) after administration of 40 mg kg–1 of sugammadex (Fig. 1).
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Discussion |
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Sugammadex, per-6-(2-carboxyethylthio)-per-6-deoxy-
-cyclodextrin sodium salt, has been designed to selectively bind the steroidal neuromuscular blocking drug rocuronium, forming a stable complex.1 In this particular patient, the administration of a high dose of sugammadex (40 mg kg–1), administered 5 min after a bolus dose of rocuronium 1.2 mg kg–1, resulted in a fast recovery from a profound rocuronium-induced neuromuscular block to a TOF-ratio of 0.9 in 1:19 (min:s). This value is in the same range as the times to recovery found in the current clinical trial after the two highest doses of 12 and 16 mg kg–1, indicating a plateauing of effect at these doses.7 The mean recovery times after 12 and 16 mg kg–1 (n = 7 each) as observed in the current study are 1:23 and 1:55 (min:s), respectively, and similar values after these two doses have also been found in a previous dose–response study during which sugammadex was administered at 3 min after a high dose of rocuronium (1.0 or 1.2 mg kg–1).7 8 Results of studies on shallow neuromuscular block also do show similar recovery times, but as expected much lower doses of sugammedex are needed to achieve them.3 9 10 Thus, the data suggest that, independent of the depth of block, the shortest possible recovery time that can be achieved with sugammadex is 1–3 min, with the necessary dose of sugammadex increasing with increasing depth of neuromuscular block. These recovery times could be explained by the mechanism of action of sugammadex. The Ka of sugammadex–rocuronium complex is high (107 M–1) and in vitro data have shown a 1:1 complex formation.1 As peak plasma concentrations of sugammadex and rocuronium were 461 and 9 µg ml–1, respectively, and the molecular weight of sugammadex is about three times higher than the molecular weight of rocuronium, the rocuronium:sugammadex ratio in plasma could be estimated to be about 1:17.1 3 In these circumstances of excess of sugammadex, the onset time of sugammadex may be limited by the cardiac output or circulation time. The dosing error occurred in the first patient who was enrolled by the site, and was related to confusion over the concentration of the sugammadex solution. The study drug sugammadex was supplied as a solution containing 100 mg ml–1 of the active ingredient. The rocuronium solution contained 10 mg ml–1 of the active ingredient. The nurse anaesthetist who prepared the study drug unjustly assumed that the concentration of sugammadex was equal to the concentration of rocuronium. Thus, a 10-fold lower concentration of sugammadex was assumed, resulting in administration of a 10-fold higher volume. This volume was two- to three-fold the maximum volume to be administered according to study protocol.
Despite administration of a very high dose of sugammadex, no cardiovascular AEs or other AEs were observed in this particular patient. This is in line with a favourable cardiovascular safety profile as reported in previous studies in Rhesus monkeys and humans.1 3–10 On the basis of the mechanism of action of sugammadex, one would expect no direct or indirect action on the components of cholinergic transmission, and therefore it is unlikely that muscarinic side-effects will occur.1
The current report, combined with the results from published studies with sugammadex and information about its mechanism of action, indicates a favourable safety and efficacy profile of sugammadex when compared with currently used reversal agents. No AE or other safety concerns were reported in the current patient after administration of an extremely high dose of 40 mg kg–1. Administration of this dose of sugammadex did not lead to a further reduction in recovery time from neuromuscular block, and fast and efficient recovery is likely to occur with lower doses. Randomized and controlled prospective clinical studies should be conducted in order to determine the optimal dose of sugammadex under various depths of neuromuscular block.
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Footnotes |
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Declaration of interest. This case report was part of a study supported by NV Organon, Oss, The Netherlands. 
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References |
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1 Bom A, Bradley M, Cameron K, et al. A novel concept of reversing neuromuscular block: chemical encapsulation of rocuronium bromide by a cyclodextrin-based synthetic host. Angew Chem Int Ed (2002) 41:266–70.
2 Booij LHDJ, De Boer HD, Van Egmond J. Reversal agents for nondepolarizing neuromuscular blockade: reasons for and development of a new concept. Semin Anesth Perioperative Med Pain (2002) 21:92–8.[CrossRef]
3 Gijsenbergh F, Ramael S, Houwing N, van Iersel T. First human exposure of Org 25969, a novel agent to reverse the action of rocuronium bromide. Anesthesiology (2005) 103:695–703.[CrossRef][Web of Science][Medline]
4 de Boer HD, van Egmond J, van de Pol F, Bom A, Booij LHDJ. Chemical encapsulation of rocuronium by synthetic cyclodextrin derivatives: reversal of neuromuscular block in anaesthetized Rhesus monkeys. Br J Anaesth (2006) 96:201–6.
5 de Boer HD, van Egmond J, van de Pol F, Bom A, Booij LHDJ. Sugammadex, a new reversal agent for neuromuscular block in anaesthetized Rhesus monkeys. Br J Anaesth (2006) 96:473–9.
6 de Boer HD, van Egmond J, van de Pol F, Bom A, Booij LHDJ. Reversal of profound rocuronium neuromuscular blockade by sugammadex in anesthetized Rhesus monkeys. Anesthesiology (2006) 104:718–23.[CrossRef][Web of Science][Medline]
7 de Boer HD, Marcus M, Schouten P, Heeringa M, Driessen JJ. Reversal of rocuronium-induced (1.2 mg kg–1) neuromuscular block by Org 25969: a multi center dose finding and safety study. Anesthesiology (2005) 103:A1117.
8 Rex C, Khuenl–Brady K, Sielenkaemper A, Kjaer CC, Puehringer FK. Reversal of high–dose rocuronium (1.2 mg/kg) with Org 25969. Anesthesiology (2005) 103:A1129.
9 Shields M, Mirakhur RK, Moppett I, Adams J, Hermens Y. Org 25969 (sugammadex), a selective relaxant binding agent for antagonism of prolonged rocuronium-induced neuromuscular block. Br J Anaesth (2006) 96:36–43.
10 Sorgenfrei IF, Norrild K, Larsen PB, et al. Reversal of rocuronium-induced neuromuscular block by the selective relaxant binding agent sugammadex: a dose-finding and safety study. Anesthesiology (2006) 104:667–74.[CrossRef][Web of Science][Medline]
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