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 Morton’s first anaesthetic in 1846, there was without doubt a quantum leap in 1942 when Griffith 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 curare’s 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 confirmed that a combination 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 identified 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 sufficiently rapid onset of action and provide sufficiently good intubating conditions to make its use during RSI justifiable [3–5]. 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 ‘can’t intubate – can’t 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 [6–8]. 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 modified 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 patient’s trachea proves difficult 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 suxamethonium’s coffin. It may also have an effect on the popularity of the benzylisoquinoline compounds atracurium, cisatracurium Anaesthesia, 2009, 64 (Suppl. 1), pages iv–v