The role of neuromuscular blockers as adjuvants of general anaesthesia has been associated with controversy since their introduction in the 1940s. About this time, Beecher and Todd1 surveyed almost 600 000 anaesthetics and their report of 1954 suggested that the use of curare increased the risk of mortality by a factor of 6. This was the first article to relate increased risk of complications and death with the use of neuromuscular blocking drugs.
Many studies were to follow including reports on residual curarisation or residual neuromuscular blockade (RNMB) with an incidence varying from 3.5% to more than 80%.2–4 The source of this wide variation lies in a number of factors that include the type of drug (intermediate versus long-acting), the type of monitor used for blockade assessment (acceleromyography, mechanomyography, electromyography), the definition of residual blockade [Train-of-four (TOF) <0.7 versus <0.9], perioperative management (doses of neuromuscular drugs, type and moment of reversal) and the moment of evaluation [immediately after extubation or on arrival at the postanaesthesia care unit (PACU)]. In a study of eight hospitals in Portugal published in 2013, we reported a global incidence of 26% of TOF less than 0.9 on arrival in the PACU.5 Naguib et al. 6 in a meta-analysis of 24 trials published in 2007 concluded that the incidence of RNMB was significantly reduced with the use of intermediate neuromuscular blocking drugs compared with longer acting drugs. This study also concluded that the use of a neuromuscular monitor was not associated with a reduction in the incidence of RNMB. Baillard et al. 2 compared the incidence of RNBM during four different time periods (1995, 2000, 2002 and 2009) and found a reduction from 60% in 1995 to 3% in 2004. They found that absence of neuromuscular monitoring more than doubled the risk of RNMB and related the reduction in RNMB to the increased use of quantitative neuromuscular monitors and reversal of neuromuscular blockade.
Naguib et al. 7 surveyed the management of neuromuscular blockade by U.S. and European anaesthesiologists, and found that although there was a wide variation among hospitals and countries, neither neuromuscular monitoring nor pharmacological neuromuscular reversal were routine practices. But the most surprising finding from this study was that more than 50% of the responders believed that the incidence of RNMB was less than 1%, something clearly contradicted by the evidence. This widespread belief that RNMB is not a real problem is probably the most important reason for the failure to monitor neuromuscular function. Another reason might be the feeling that although, in the immediate postoperative period patients might have a small degree of paralysis, this would not be associated with an increased risk of complications. Again, this belief is not supported by the evidence, as there are several studies showing the adverse effects of RNMB in volunteers, relating it to signs and symptoms of muscle weakness,8 pharyngeal dysfunction with increased risk of aspiration and impaired inspiratory flow with a risk of upper airway obstruction.9–11 RNMB has also been associated with critical respiratory events and complications, and delayed discharge from the PACU.12–14 Recently, Armendáriz -Buil et al. 15 showed that diabetic patients, independent of glycaemic control, had increased recovery times after rocuronium and therefore increased risk of RNMB. Grosse-Sundrup et al. 16 published a propensity score matched cohort study with nearly 18 600 patients who were given neuromuscular blocking drugs. Their conclusion was that the use of intermediate neuromuscular blocking agents was associated with an increased risk of pulmonary complications and that reversal of blockade at the end of surgery with neostigmine could even increase this risk. Sasaki et al. 17 came to a similar conclusion that neostigmine, especially when given in high doses and not guided by neuromuscular monitoring, was associated with an increased incidence of respiratory complications.
When sugammadex, the first selective binding reversal agent for aminosteroidal neuromuscular blockers, was launched in Europe in 2008, changes in the way that neuromuscular blockade was managed might have been anticipated. Clinical studies proved that sugammadex was effective, rapid and well tolerated as a reversal agent of neuromuscular blockade provided by rocuronium or vecuronium, independently of the depth of blockade provided the correct doses were administered. The recommended sugammadex dose varies depending on the depth of neuromuscular blockade, ranging from 2 mg kg−1 for a moderate block (at least two TOF responses) to 4 mg kg−1 for a deep block (one to two posttetanic count responses) and 16 mg kg−1 for immediate reversal after rocuronium administration. Taking into account these dose recommendations, it was reasonable to expect a decrease in the incidence of RNMB and associated complications. A recently published study by Ledowski et al. 18 retrospectively investigated postoperative outcome after the use of muscle relaxants and found a reduction in pulmonary complications in older and sicker patients [American Society of Anesthesiologists’ physical status 3 and 4 (ASA)] after reversal with sugammadex compared with reversal with neostigmine or no reversal. Unfortunately, this study did not evaluate residual blockade after extubation and so it is not possible to associate this finding with a possible reduction in residual paralysis.
Apart from this potential advantage, sugammadex has been successfully used as a reversal agent in clinical situations wherein anticholinesterase inhibitors were either contraindicated or when their use was a cause of concern. Sugammadex has also been successfully used in a broad range of neuromuscular disorders wherein use of muscle relaxants was described as problematic, and it has also been used as a treatment of anaphylactic shock associated with aminosteroidal neuromuscular blockers. All these facts make sugammadex a fundamental part of modern management of neuromuscular blockade, but as with many new drugs, it is anticipated that wider use in real and noncontrolled situations will reveal new concerns and problems.
With sugammadex, there is still a real risk of recurarisation and residual blockade if insufficient doses are used. Eleveld et al. 19 first described this when a dose of 0.5 mg kg−1 was used instead of 4 mg kg−1 to antagonise deep neuromuscular blockade. Drobnik et al. 20 reported three cases of RNMB and four cases of recurarisation in 30 patients given 1 mg kg−1 of sugammadex when only one posttetanic response was present. But there was neither incomplete reversal nor recurarisation in 60 patients given the appropriate dose of 4 mg kg−1.20
It is common knowledge that muscle relaxants have a wide variation in inter and intra-individual response. This was clearly demonstrated by Debaene et al. 21 in a study published in 2003 that showed a huge variation in individual responses to a single dose of intermediate-acting muscle relaxants. In order to calculate the dose of sugammadex needed to safely and effectively antagonise a given block, we need to measure the block by means of a neuromuscular monitor, preferably a quantitative monitor. We should recognise that sugammadex in common with other neuro-muscular blockers is also subject to the same variation in individual response. Ortiz-Gomes et al. 22 reported a case of apparent resistance to sugammadex and failure to antagonise neuromuscular blockade despite a total dose of 1120 mg. Kotake et al. 23, in an observational study, questioned the ability of sugammadex to eliminate RNMB without the use of neuromuscular monitoring. The study was performed in two parts: one with neostigmine reversal and the other with sugammadex reversal, with the timing of reversal and extubation guided by clinical criteria. The authors concluded that sugammadex decreased the incidence of RNMB when compared with neostigmine (4.3 versus 23.9% for TOF<0.9), but the risk of RNMB with sugammadex remained between 1.7 and 9.4% when no neuromuscular monitor was used.
Some reports of accidental recurarisation after sugammadex have been published.24–26 Predisposing factors include the administration of large doses of rocuronium with either repeated doses or continuous infusion, the presence of comorbidities such as obesity, diabetes, sleep apnoea and renal failure, associated hypothermia (accidental or induced), poor neuromuscular monitoring or no monitoring at all, together with inadequate doses of sugammadex. The ability to antagonise deeper levels of neuromuscular blockade makes the continuous infusion of muscle relaxants to maintain a stable neuromuscular blockade more appealing. There are few data about the use of sugammadex to antagonise neuromuscular blockade after prolonged infusions of rocuronium. Until relevant information is available, infusions of rocuronium should be used with care. Specifically, to reduce the risk of unnecessary accumulation and overdosing, infusions should not be initiated before spontaneous recovery from an initial bolus has occurred and infusion rates should be guided by target neuromuscular blockade and not based on body weight and mean recommended doses.
In a recently published letter, El-Orbany et al. 27 suggested that RNMB should become a ‘never event’. The expectation that sugammadex could make an important contribution towards that goal needs the confirmation of large-scale studies that hopefully will be undertaken in the near future.
Acknowledgements relating to this article
Assistance with the editorial: none.
Financial support and sponsorship: none.
Conflicts of interest: SE has received lectures and consultant fees from MSD.
Comment from the editor: this article was checked and accepted by the editors, but was not sent for external peer-review.
1. Beecher HK, Todd DP. A study of the deaths associated with anesthesia and surgery: based on a study of 599, 548 anesthesias in ten institutions 1948–1952, inclusive. Ann Surg
2. Baillard C, Clec’h C, Catineau J, et al. Postoperative residual neuromuscular block: a survey of management. Br J Anaesth
3. Murphy GS, Szokol JW, Franklin M, et al. Postanesthesia care unit recovery times and neuromuscular blocking drugs: a prospective study of orthopedic surgical patients randomized to receive pancuronium or rocuronium. Anesth Analg
4. Murphy GS, Szokol JW, Marymont JH, et al. Residual paralysis at the time of tracheal extubation. Anesth Analg
5. Esteves S, Martins M, Barros F, et al. Incidence of postoperative residual neuromuscular blockade in the postanaesthesia care unit: an observational multicentre study in Portugal. Eur J Anaesthesiol
6. Naguib M, Kopman AF, Ensor JE. Neuromuscular monitoring and postoperative residual curarization: a meta-analysis. Br J Anaesth
7. Naguib M, Kopman AF, Lien CA, et al. A survey of current management of neuromuscular block in the United States and Europe. Anesth Analg
8. Kopman AF, Yee PS, Neuman GG. Relationship of the train-of-four fade ratio to clinical signs and symptoms of residual paralysis in awake volunteers. Anesthesiology
9. Sundman E, Witt H, Olsson R, et al. The incidence and mechanisms of pharyngeal and upper esophageal dysfunction in partially paralyzed humans: pharyngeal videoradiography and simultaneous manometry after atracurium. Anesthesiology
10. Hårdemark Cedborg AI, Sundman E, Bodén K, et al. Pharyngeal function and breathing pattern during partial neuromuscular block in the elderly: effects on airway protection. Anesthesiology
11. Eikermann M, Groeben H, Husing J, Peters J. Accelerometry of adductor pollicis muscle predicts recovery of respiratory function from neuromuscular blockade. Anesthesiology
12. Murphy GS, Szokol JW, Marymont JH, et al. Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesth Analg
13. Norton M, Xara D, Parente D, et al. Residual neuromuscular block as a risk factor for critical respiratory events in the post anesthesia care unit. Rev Esp Anestesiol Reanim
14. Butterly A, Bittner EA, George E, et al. Postoperative residual curarization from intermediate-acting neuromuscular blocking agents delays recovery room discharge. Br J Anaesth
15. Armendáriz-Buil I, Lobato-Solares F, Aguilera-Celorrio L, et al. Residual neuromuscular block in type II diabetes mellitus after rocuronium. A prospective observational study. Eur J Anaesthesiol
16. Grosse-Sundrup M, Henneman J, Sandberg W, et al. Intermediate acting nondepolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: prospective propensity score matched cohort study. BMJ
17. Sasaki N, Meyer J, Malviya S, et al. Effects of neostigmine reversal of nondepolarizing neuromuscular blocking agents on postoperative respiratory outcomes: a prospective study. Anesthesiology
18. Ledowski T, Falke L, Johnston F, et al. Retrospective investigation of postoperative outcome after reversal of residual neuromuscular blockade. Sugammadex, neostigmine or no reversal. Eur J Anaesthesiol
19. Eleveld DJ, Kuizenga K, Proost JH, Wierda JM. A temporary decrease in twitch response during reversal of rocuronium-induced muscle relaxation with small dose of sugammadex. Anesth Analg
20. Drobnik L, Sparr HJ, Thorn S-E, et al. A randomized simultaneous comparison of acceleromyography with a peripheral nerve stimulator for assessing reversal of rocuronium-induced neuromuscular blockade with sugammadex. Eur J Anesthesiol
21. Debaene B, Plaud B, Dilly MP, Donati F. Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology
22. Ortiz-Gómez JR, Palacio-Abizanda FJ, Fornet-Ruiz I. Failure of sugammadex to reverse rocuronium-induced neuromuscular blockade: a case report. Eur J Anaesthesiol
23. Kotake Y, Ochiai R, Suzuki T, et al. Reversal with sugammadex in the absence of monitoring did not preclude residual neuromuscular block. Anesth Analg
24. Le Corre F, Nejmeddine S, Fatahine C, et al. Recurarization after sugammadex reversal in an obese patient. Can J Anesth
25. Murata T, Kubodera T, Ohbayashi M, et al. Recurarization after sugammadex following a prolonged rocuronium infusion for induced hypothermia. Can J Anesth
26. Bellod A, March X, Hernandez C, Villalonga A. Delayed recurarisation after sugammadex reversal. Eur J Anaesthesiol
27. El-Orbany M, Ali H, Baraka A, Salem M. Residual neuromuscular block should, and can, be a ‘never event’. Anesth Analg