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Editorial
Management of neuromuscular block: time for a change? Although the progress of the art and science of anaesthesia can be viewed as a gradual process since Mortons rst anaesthetic in 1846, there was without doubt a quantum leap in 1942 when Grifth and Johnson introduced curare into clinical practice [1]. Neuromuscular blocking drugs (NMBs) have been in routine use since then but the search for the ideal NMB is almost as old as the story of NMBs itself, for curare had a slow onset, a long duration and a number of undesirable side effects. Progress in the management of neuromuscular blockade has inevitably been intermittent rather than continuous, as the development of this important aspect of anaesthetic practice is dependent on the introduction of new drugs. With each new drug, the management of neuromuscular blockade takes a step forwards, sideways, and occasionally even back a little. This supplement aims to outline the state of the art as it stands today and to ask whether the introduction of sugammadex, the latest drug in the story of neuromuscular pharmacology, will drive the art and science forwards, sideways or back is it really time for a change? Competitors to curares position as the non-depolarising NMB of choice were slow to come, and even by the early 1980s, it was not at all clear that drugs such as gallamine, alcuronium and pancuronium were superior to curare for the majority of patients. The true leap forward in the late 20th century was the introduction of drugs that worked a little more rapidly and were of intermediate duration: vecuronium and atracurium. In addition, vecuronium offered the anaesthetist excellent cardiovascular stability and an absence of histamine release while atracurium offered nonorgan-dependent metabolism and elimination. Although the introduction of cisatracurium conrmed that a combiiv

nation of cardiovascular stability and non-organ metabolism dependence was possible, none of these three drugs offered a rapid onset. The depolarising NMB suxamethonium was introduced into clinical use in the 1950s and, in spite of its well-recognised, manifest and occasionally life-threatening side effects and complications, is still in use today because of its rapid onset and thereby clinical usefulness for rapid sequence induction (RSI) of general anaesthesia. The search for a non-depolarising equivalent of suxamethonium has been a long and not always fruitful one. Mivacurium was introduced in the 1990s, and while its short duration of action was useful, its slow and variable onset was far from ideal. Rapacuronium had a rapid onset but its clinical lifetime in the US was barely more than a year; it fell victim to safety concerns and was withdrawn. Bowman identied the inverse relationship between potency and the speed of onset of NMBs in the 1980s [2]. This realisation led in part to the creation and introduction of rocuronium, the most rapidly acting non-depolarising NMB in clinical use and a true challenger to suxamethonium in this respect: when used in appropriate doses it can have a sufciently rapid onset of action and provide sufciently good intubating conditions to make its use during RSI justiable [35]. However, its main drawback, and that which perhaps prevents its widespread use for RSI, is its relatively long duration of action. This makes its use unappealing for short surgical procedures, while the spectre of the cant intubate cant ventilate scenario combined with its duration of action haunts its use even for longer procedures. There have until very recently been no quantum leaps forward in the antagonism of neuromuscular blockade. Neostigmine has been the one if not the only reversal agent for non-depolarising NMBs in everyday use. It is a drug that we know well but is not one that can

be described as ideal. It cannot reverse profound blockade, it has a relatively slow onset of action, has unwanted muscarinic side effects and does not always guarantee absence of postoperative residual block [68]. It carries with it a risk of depolarising block and it has recently been shown in animal studies that it can impair upper airway dilator muscle activity and impair breathing [9, 10]. Although reversal has arguably been a quiet backwater of neuromuscular pharmacology in recent years, it has now seen the biggest advance for some time: the development and introduction of sugammadex. This modied c-cyclodextrin reverses neuromuscular block in an entirely novel way: by chelation (encapsulation) of the molecules of NMB, thereby preventing them from acting at the nicotinic receptor. This agent reverses the action of rocuronium effectively and adequately from any degree of blockade after standard intubating or even large intubating doses of rocuronium, and irrespective of the anaesthetic technique used provided an appropriate dose of sugammadex is given. Not only can sugammadex reverse rocuronium effectively, it can do it quickly as well. An appropriate dose of the drug will reverse even deep rocuronium blockade within 3 min. This raises the possibility that rocuronium might be used in place of suxamethonium if rapid muscle relaxation is required, knowing that the block can be readily reversed if the patients trachea proves difcult to intubate or their lungs hard to ventilate. This supplement contains information on the development and clinical evaluation of sugammadex, asks what it may offer anaesthetists and questions whether its introduction will lead to change in practice relating to the use of NMBs. There is also a discussion of whether the appearance of sugammadex will represent the last nail in suxamethoniums cofn. It may also have an effect on the popularity of the benzylisoquinoline compounds atracurium, cisatracurium

2009 The Authors Journal compilation 2009 The Association of Anaesthetists of Great Britain and Ireland

Anaesthesia, 2009, 64 (Suppl. 1), pages ivv Editorial . ....................................................................................................................................................................................................................

and mivacurium in that it has no reversal effects on the neuromuscular blockade produced by these drugs. Sugammadex has been shown to be safe in clinical trials and free from any signicant cardiovascular effects. It does not interfere with acetylcholine metabolism and there should therefore be no effect on the cardiovascular system or smooth muscles and no increase in secretions. There is no requirement to add an anticholinergic drug when giving sugammadex, thereby avoiding any possible side effects due to anticholinergic drugs. However, there has been one report of a hypersensitivity reaction after approximately 2000 administrations, and the US Food and Drug Administration (FDA) has withheld approval for its clinical use for this reason [11]. Whether it proves ultimately to be a safe drug or not will only be known after its widespread use by clinicians outside of the connes of clinical trials. The introduction of sugammadex is not the only recent development examined in this supplement. Changes in our understanding of the physiology of neuromuscular transmission are highlighted in the article by Martyn et al. [12], which provides explanations for the occurrence of fade during a non-depolarising block and the production of some of the side effects associated with suxamethonium. Perhaps surprisingly, the monitoring of neuromuscular block is still regarded by the majority of anaesthetists as an optional extra. This is in spite of the fact that studies have shown that the use of even intermediate duration NMBs can be associated with a signicant incidence of residual block with potential consequences in terms of pulmonary complications, episodes of oxygen desaturation and airway obstruction in the postoperative period [1316]. It is logical that the monitoring of neuromuscular block, particularly using a quantitative method, and thereby ensuring adequate recovery at the end of surgery, should prevent residual block and the complications associated with it. This area is well covered in the article on neuromuscular monitoring in this supplement and will no doubt leave readers sharing our surprise that so many anaesthetists fail to monitor the action of NMBs.

Sixty-seven years after Grifths clinical breakthrough, neuromuscular blockade and its clinical pharmacology remain a fascinating area of interest and the virtual preserve of the anaesthetic community. We hope that readers will enjoy this snapshot of the state of the neuromuscular art and science and will share our hope that the development of new neuromuscular blocking and reversal drugs will continue to improve patient safety and outcome.

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Conicts of interest RKM is a Scientic Advisor to Schering Plough who have provided unrestricted research grants, nancial support for clinical studies with NMBs and sugammadex, and honoraria for lectures on NMBs and sugammadex. WHG has no conicts to declare. References
1 Griffith HR, Johnson GE. The use of curare in general anesthesia. Anesthesiology 1942; 3: 41820. 2 Bowman WC, Rodger IW, Houston J, Marshall RJ, McIndewar I. Structureaction relationship among some desacetoxy analogues of pancuronium and vecuronium in the anesthetized cat. Anesthesiology 1988; 69: 5762. 3 Magorian T, Flannery KB, Miller RD. Comparison of rocuronium, succinylcholine, and vecuronium for rapidsequence induction of anesthesia in adult patients. Anesthesiology 1993; 79: 9138. 4 Bartkowski RR, Witkowski TA, Azad S, Lessin J, Marr A. Rocuronium onset of action: a comparison with atracurium and vecuronium. Anesthesia & Analgesia 1993; 77: 5748. 5 McCourt KC, Salmela L, Mirakhur RK, et al. Comparison of rocuronium and suxamethonium for use during rapid sequence induction of anaesthesia. Anaesthesia 1998; 53: 86771. 6 Magorian TT, Lynam DP, Caldwell J, Miller RD. Can early administration of neostigmine, in single or divided doses, alter the course of neuromuscular recovery from a vecuroniuminduced neuromuscular blockade? Anesthesiology 1990; 73: 4104. 7 Mirakhur RK, McCarthy GJ. Basic pharmacology of reversal agents.

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Anaesthesiology Clinics of North America 1993; 11: 23750. Hayes AH, Mirakhur RK, Breslin DS, Reid JE, McCourt KC. Postoperative residual block after intermediate-acting neuromuscular blocking drugs. Anaesthesia 2001; 56: 3128. Payne JP, Hughes R, Al Azawi S. Neuromuscular blockade by neostigmine in anaesthetized man. British Journal of Anaesthesia 1980; 52: 6976. Eikermann M, Zaremba S, Malhotra A, Jordan AS, Rosow C, Chamberlin NL. Neostigmine but not sugammadex impairs upper airway dilator muscle activity and breathing. British Journal of Anaesthesia 2008; 101: 3449. http://groups.google.com/group/anesthesiologyig/web/fda-delays-release-of-sugammadex. Martyn JA, Fagerlund MJ, Eriksson LI. Basic principles of neuromuscular transmission. Anaesthesia 2009; 64 (in press). Baillard C, Gehan G, Reboul-Marty J, Larmignat P, Samama CM, Cupa M. Residual curarization in the recovery room after vecuronium. British Journal of Anaesthesia 2000; 84: 3945. 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 2003; 98: 10428. Berg H, Roed J, Viby-Mogensen J, et al. Residual neuromuscular block is a risk factor for postoperative pulmonary complications. A prospective, randomised, and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium. Acta Anaesthesiologica Scandinavia 1997; 41: 1095103. Murphy GS, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender JS. Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesthesia & Analgesia 2008; 107: 1307.

R. K. Mirakhur1 and W. Harrop-Grifths2 1 Professor Department of Anaesthetics and ICM, Queens University, Belfast, UK 2 Consultant Anaesthetist, Department of Anaesthesia, Imperial College Healthcare NHS Trust, London, UK

2009 The Authors Journal compilation 2009 The Association of Anaesthetists of Great Britain and Ireland