Sugammadex provides fast dose-dependent reversal of neuromuscular blockade (NMB) by rocuronium. However, delayed recovery has been reported.1 We would like to report a case of failure of sugammadex to reverse rocuronium NMB.
A 60-year-old man, weight 115 kg, height 175 cm, American Society of Anesthesiologists’ (ASA) physical status 2 (arterial hypertension) was anaesthetised for laparoscopic resection of the sigmoid colon. He received midazolam and target-controlled infusions of propofol and remifentanil. NMB monitoring was performed using train-of-four (TOF) nerve stimulation with acceleromyography (TOF-Watch SX, Bluestar Enterprises, Omaha, Nebraska, USA) at the adductor pollicis muscle following internationally accepted rules2 and calibrated before the administration of succinylcholine 100 mg (risk of difficult intubation or ventilation). The trachea was intubated within 2 min (single twitch height = 0%). Seven minutes after administration of suxamethonium, recovery was observed (movements and acceleromyographic evidence) and a 2× ED95 bolus dose of rocuronium (70 mg) was administered. Central body temperature was measured and maintained using standard techniques of heat conservation. A continuous infusion of rocuronium 1 to 4 μg kg−1 min−1 (total 83 mg) was used to maintain a posttetanic count of zero to one responses. The patient also received cefotaxime, metronidazole, dexamethasone, ondansetron, pantoprazole and morphine.
At the end of the 6 h operation (and 27 min after the rocuronium infusion was stopped) with one TOF response (T1 height amplitude 4%), he was given intravenous sugammadex 4 mg kg−1 (460 mg), but 5.5 min later, NMB was unchanged. Further doses of sugammadex were administered: 4 mg kg−1 at 5.5 min; and 200 mg at 11.5 min, both without clinical and acceleromyographic effect, with a total dose of 1120 mg (9.74 mg kg−1). To exclude malfunction of the TOF-Watch, a different peripheral nerve stimulator was used at the facial nerve, with the same visual result as in the adductor pollicis: one weak response to TOF stimulation. Neostigmine 1 mg was then injected 26.5 min after the first dose of sugammadex, and 1.5 mg 3 min later. The patient started breathing spontaneously, but was still curarised (four responses to TOF with T1 of 8 to 9% in the adductor pollicis muscle, four weak responses to TOF stimulation at the facial nerve, low inspiratory volumes, carbon dioxide retention, sweating and so on), so he was transferred intubated to the postanaesthesia care unit and extubated there without incident 3 h later.
There are several possible explanations for our observation, relating to the drug, the monitoring or the patient. There was evidence of recovery from succinylcholine, so an abnormal effect of the drug or impaired plasma cholinesterase activity was rejected. An administration error was excluded after checking medication vials used and faulty medications were also dismissed because drugs are kept in accordance with the manufacturer's recommendations and subsequent doses of the same batch of sugammadex and rocuronium were used without problems.
An NMB monitor malfunction was rejected because the TOF-Watch SX performed normally before and after this case, the patient remained in the same position with his hand properly secured during surgery and its data were consistent with the second NMB monitor and the clinical signs.
Hypothermia was excluded and there were no ionic or pH alterations or diseases that could explain these findings; renal function was normal, and the patient was neither a smoker nor drinker and had no hepatic or neuromuscular diseases.
Drug interactions were also considered. Sugammadex has been specifically designed to form high-affinity complexes with rocuronium, but might also form complexes with other molecules. Interactions could be due to capture or displacement reactions.3 In a capturing reaction, when the affinity of sugammadex for a certain molecule is sufficiently high, sugammadex may encapsulate it and reduce the effect of the remaining drug. In a displacement reaction, after successful NMB reversal, administration of another molecule with high-affinity for sugammadex may displace a fraction of the encapsulated rocuronium from its complex with sugammadex, potentially resulting in recurrence of NMB. The drugs identified with potential interactions with sugammadex include toremifene, flucloxacillin, fusidic acid and the oral contraceptive pill. There is no previous evidence of an interaction between sugammadex and the anaesthetic drugs used in this case, nor with the patient's regular medication (valsartan and hydrochlorothiazide). Other possibilities such as an endogenous molecule in the patient, or even immunological resistance to cyclodextrins, might be considered; of note, cyclodextrins are normal molecules in our daily diet (4 g per day). Overall, this hypothesis seems unlikely unless a very potent displacement reaction occurs, because with the high doses of sugammadex used, at least a minimal recovery response should have been seen. The reversal of rocuronium by sugammadex is very selective and both molecules bind in a 1 : 1 molar ratio, so one molecule of sugammadex (molecular weight of 2.178 kDa) antagonises one molecule of rocuronium (610 kDa); thus, theoretically, 3.57 mg of sugammadex is required to bind 1 mg of rocuronium.4 This patient received 1160 mg of sugammadex and 153 mg of rocuronium (2 : 1 molar ratio), which should have been a sufficient dose to cause a substantial reversal despite drug interactions unless a displacement reaction was potent enough to cause almost immediate recurarisation.
Finally, and this is the explanation that the authors believe to be probable, this patient may be what is described in statistical terms as ‘an extreme outlier’. Usually, when we use a drug in the clinical scenario, the drug has been studied previously in a large number of patients, and the doses recommended are the most common for almost everybody.5 A small number of patients, however, have either a left-shift of the dose–response curve (more sensitivity to the drug) or a right-shift (relative resistance to the drug). We suggest that this case report represents an extreme outlier with a marked rightward shift of the dose–response curve.
Sugammadex has been described as the ideal reversal drug.1 Nevertheless, delayed recovery has been described previously;6,7 in these cases, the time to recovery of TOF ratio to 0.9 after treatment with sugammadex 4 mg kg−1 took 24.6 and 22.3 min respectively, compared with a mean of 173 s in other patients. The present case report shows not just delay but failure to reverse rocuronium 45 min after the first dose of sugammadex was administered. These data suggest that excessive NMB depth should not be considered a well tolerated practice in all circumstances, because there are some patients (though very rare) in whom fast reversal with sugammadex may not be achievable.
Acknowledgements relating to this article
Assistance with the letter: we would like to thank the patient for his kindness in giving written informed consent for publication.
Conflict of interests: none.
Financial support and sponsorship: none.
1. Brull SJ. Patient safety revisited: reliability is paramount. Anesth Analg
2. 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
3. Mirakhur RK. Sugammadex in clinical practice. Anaesthesia
2009; 64 (Suppl 1):45–54.
4. Donati F. Sugammadex: an opportunity for more thinking or more cookbook medicine? Can J Anesth
5. Puhringer FK, Rex C, Sielenkamper AW, et al. Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points: an international, multicenter, randomized, dose-finding, safety assessor-blinded, phase II trial. Anesthesiology
6. Sparr HJ, Vermeyen KM, Beaufort AM, et al. Early reversal of profound rocuronium-induced neuromuscular blockade by sugammadex in a randomized multicenter study: efficacy, safety, and pharmacokinetics. Anesthesiology
7. White PF, Tufanogullari B, Sacan O, et al. The effect of residual neuromuscular blockade on the speed of reversal with sugammadex. Anesth Analg