Goodbye suxamethonium! anaesthesia march 2009
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Goodbye suxamethonium! anaesthesia march 2009 Document Transcript

  • 1. Anaesthesia, 2009, 64 (Suppl. 1), pages 73–81 ..................................................................................................................................................................................................................... Goodbye Suxamethonium! C. Lee Emeritus Professor, Department of Anesthesiology, Harbor-UCLA Medical Center, Torrance, CA, USA Summary No drugs in anaesthesia are more problematic than suxamethonium. Yet, no drugs have survived as suxamethonium does in spite of crisis after crisis, and attempt after attempt at its replacement. For decades, suxamethonium has taught us neuromuscular pharmacology and provided us with an encyclopaedia of side effects, while benefiting millions and millions of our anaesthetised patients. With the arrival of sugammadex, it finally appears that suxamethonium can be retired. Suxamet- honium has done its job and seen its days! The present review is intended to offer a eulogy for suxamethonium. . ...................................................................................................... Correspondence to: Dr Chingmuh Lee E-mail: chinglee@chinglee.net Accepted: 15 December 2008 After decades of effort by many investigators around the patients undergoing intra-abdominal procedures. Sux- world to replace suxamethonium, and years after the amethonium was given both by bolus and by infusion, slogan ‘So Long, Sux!’ was first coined with the clinical with doses of 66–1830 mg given over 35–363 min. introduction of atracurium, it now appears that suxame- After premedication with pentobarbital, atropine or thonium is finally on its way out. It has seen its days. As one scopolamine and morphine, anaesthesia was provided by of many investigators who has spent years searching for a thiopental and nitrous oxide. Lung ventilation was mostly non-depolarising replacement for suxamethonium, this spontaneous. Foldes et al. wrote: ‘Assisted respiration was author proposes for eulogy to suxamethonium. No drug in seldom necessary, and respiratory arrest never developed, anaesthesia is more problematic than suxamethonium and except when produced deliberately’. Readers might find yet no drug has survived crisis after crisis as suxametho- it interesting that in those days tracheal intubation was nium has. Suxamethonium is indeed an amazing drug. rare, oxygen and carbon dioxide monitors were absent, and anaesthesia and surgery were very different from today. The results with suxamethonium were considered Preclinical history of suxamethonium ‘close to ideal’, ‘without unwanted side effects’, ‘with low Suxamethonium had a remarkable history from the very postoperative complication rate’, and ‘much superior’ to beginning. Along with other choline-related compounds, curare preparations. Also in those days, postoperative it was first tested as a cardiovascular agent in 1906. Hunt pulmonary complications were common, but none was and Taveau [1] observed that suxamethonium slowed the attributed to the use of suxamethonium. heart and increased the blood pressure. As the experi- Foldes et al. further stated that: ‘the advantages of ments were done on animals already paralysed with suxamethonium as a muscular relaxant in anesthesiology curare, the neuromuscular effects of suxamethonium far outweighed its disadvantages’ [3, 4]. ‘On the basis of were not noticed until 1949 by Bovet [2] almost half a our experience, suxamethonium is the muscle relaxant of century later. In other words, suxamethonium began with choice, especially in debilitated, dehydrated and aged a side effect. patients, in whom prolonged postoperative respiratory depression with other agents is most common’. ‘It is hoped that the clinical use of suxamethonium will Clinical introduction of suxamethonium stimulate the search for other agents – for example, Suxamethonium was introduced into clinical anaesthesia barbiturates – with ultrashort activity’. Points well made! in Europe in 1951 by Br}ke et al. and in the United u Suxamethonium’s flexibility of use was emphasised. States in 1952 by Foldes et al., then of Pittsburgh [3, 4]. Interestingly, an addendum to the paper on suxame- The Foldes report, a classic, reported 202 consecutive thonium stated: ‘Since this paper was submitted for Ó 2009 The Author Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland 73
  • 2. C. Lee Æ Goodbye suxamethonium! Anaesthesia, 2009, 64 (Suppl. 1), pages 73–81 . .................................................................................................................................................................................................................... publication several cases of prolonged respiratory depres- the first two indications, failure to intubate and failure to sion after the use of suxamethonium have been reported. ventilate the lungs could be disastrous, and a rapid return As pointed out elsewhere, unnecessarily high doses of of muscle power becomes crucial. In the last indication, suxamethonium were used in these cases. It has also been an occasional encounter with an unsuspected difficult shown that the depressant effect of a given dose of airway may make suxamethonium a hero if it allows the suxamethonium on respiration is inversely proportional to patient to regain the capacity to breathe spontaneously the plasma cholinesterase activity of the patients. Accord- before hypoxaemia intervenes. Suxamethonium as a ing to our experience in over 500 cases… no prolonged single dose is also useful for fracture setting, cardioversion, respiratory depression was observed’ [3, 4]. It appears that electroconvulsive therapy and other procedures requiring anaesthetic masters of those days practised titration paralysis of very short duration. In otorhinolaryngological according to a patient’s individual responses and the procedures, complete paralysis may be required for needs of surgery. Without nerve stimulators, they foreign body removal and other brief endoscopic proce- watched the patient’s chest and abdomen, as well as the dures. Here, the need for profound paralysis may last breathing bag and the surgical field. through the case, only to end abruptly, thereby making reversal of a deep non-depolarising block difficult. Further, once suxamethonium is chosen, a brief infusion Current uses of suxamethonium may come in handy if one dose is not sufficient. After its introduction, suxamethonium gained great popularity. In the year 1980–1981, sales of suxametho- Mechanisms of actions of suxamethonium nium in the US peaked at 2233 kg [4]. With increased use, more side effects were observed. Many of these side Foldes et al. [3] recognised and attributed the transient effects were previously unheard of. Some were associated twitching upon injection of suxamethonium to the initial with significant mortality. Each issue, such as malignant stimulating effect of depolarising drugs on skeletal muscle. hyperthermia, atypical plasma cholinesterases and Phase II No myalgia was mentioned. Neuromuscular block by block generated great controversy and stimulated impor- depolarisation of muscle cells is, in a sense, like general tant research. Amazingly, as pointed out by Lee [4, 5], a anaesthesia by depolarisation of cerebral neurons. It is drug capable of generating so many controversies and intuitively a bad idea. Electroconvulsive therapy for major surviving so many crises just would not die. Lee [5] also depression produces a transient unconsciousness and yet noted in 1994 that anything that could go wrong had electro-anaesthesia, which was tried in the former Soviet gone wrong, yet suxamethonium still maintains important Union, has not gained popularity. Fortunately, the neuro- uses in clinical anaesthesia, even today in its sixth decade muscular endplates and muscle cells repolarise themselves of use. It survives on a few advantages – rapid onset, rapid in seconds or minutes to maintain cellular homeostasis. recovery, non-toxic metabolites and economy of use. In Suxamethonium is structurally two acetylcholine mol- its niche, suxamethonium is still the gold standard against ecules joined end-on-end on the acetyl side to make a which other neuromuscular block techniques are com- succinyl di-ester of choline, i.e. succinyldicholine, hence pared. For example, rocuronium is said to provide equally its name succinylcholine elsewhere in the world. Its good intubation conditions and TAAC3 claims faster therapeutic actions and side effects are attributed to its onset and shorter duration of action than suxamethonium acetylcholine moieties. Its metabolites are succinylmo- [6, 7]. At the time of writing, suxamethonium again nocholine and choline. Succinylmonocholine has about serves as the gold standard against which sugammadex one-sixth to one-tenth the potency of suxamethonium. reversal of rocuronium is compared for rapid recovery. Choline exists in the body as a normal metabolite. The indications for suxamethonium appear to have Suxamethonium used to be considered a bis-quaternary stabilised in the last decade or two [5]. Among the few neuromuscular blocking agent, and historically it was remaining indications for suxamethonium, the major one thought that two quaternary -onium heads are required is to facilitate rapid sequence tracheal intubation in the for any compound to be a potent neuromuscular blocker. operating room and in the emergency department, mainly Succinylmonocholine is thought to be weak because it is for fear of pulmonary aspiration of stomach contents monoquaternary. However, the notion that monoqua- during intubation. The other indication is when difficult ternary compounds will not make potent neuromuscular intubation is a concern (without full stomach) but blockers was overturned by the realisation that vecuro- circumstances warrant an attempt at intubating the nium is monoquaternary [8]. trachea facilitated by anaesthesia and paralysis, as an During the onset of neuromuscular block, suxametho- alternative to awake intubation. An equivocal indication nium produces fasciculation, which results from depolar- is to facilitate routine intubation in surgical patients. In isation [3]. To be precise, fasciculation is due to an agonist Ó 2009 The Author 74 Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland
  • 3. Anaesthesia, 2009, 64 (Suppl. 1), pages 73–81 C. Lee Æ Goodbye suxamethonium! . .................................................................................................................................................................................................................... action on the motor nerve terminal, a prejunctional action that propagates retrogradely up the motor axon to trigger the axon into firing the entire motor unit. Activation of individual muscle fibres will only cause fibrillation, not fasciculation. Activation of a motor neuron excites the whole motor unit to cause fasciculation. A small dose of curare-like, non-depolarising neuromuscular blocking drug (NMB) is often used to prevent or decrease the fasciculation, mainly to decrease the increase in gastric pressure during fasciculation. While acting as defasciculant prejunctionally, the defasciculating drug also decreases the potency of suxamethonium postjunctionally. Prejunction- al and postjunctional nicotinic receptors are different in their functions, and depolarising and non-depolarising NMBs interact at both places with different pharmacody- Figure 1 Molecular conformation and mechanism of action of suxamethonium (SDC) and succinylmonocholine. Suxametho- namics [9]. nium exists in bent form, too short to bind both receptive sites of the nicotinic receptor simultaneously. Whereas each ACh- moiety of suxamethonium has its functional groups (N, O) The conformational mechanism of action of configured to conform to a receptive site of the nicotinic suxamethonium receptor, no such conformation is possible for the solo ACh- moiety of succinylmonocholine. In suxamethonium, the ACh- Marshall et al. [10] reported in 1990 that it takes two moieties are balanced by the mutually repelling force of the molecules of suxamethonium, as it takes two molecules of methonium heads, which permits each ACh-moiety to maintain acetylcholine, to open one nicotinic channel. In other a nicotinic configuration. In succinylmonocholine, all O atoms words, each half-molecule of suxamethonium acts like are attracted towards the lone -onium head, preventing the ACh- one acetylcholine, and each molecule of suxamethonium moiety from assuming a nicotinic configuration. Arrows indicate the distance from the center of the N atoms to the van der Waals uses only one of its two half-molecules at a time [10, 11]. extensions (dotted red spheres) of the respective O atoms, which This contradicts the traditional belief that suxamethonium determine whether an ACh-moiety will have nicotinic activity works like decamethonium, with a bisquaternary mech- [11, 12]. Atoms are colour-coded: O, red; N, blue; C, white; anism of action. H, green. (Reproduced from reference [11], with permission). The monoquaternary mechanism of action of suxame- thonium is interesting from the viewpoint of modern receptor theory and molecular conformation–action tion. As a molecule constantly vibrates around each relationship [11]. First, vecuronium proves that mono- rotatable bond to seek the lowest possible total energy, it quaternary muscle relaxants could be better than their preferentially populates the lowest energy conformations. bisquaternary analogues [8]. Then, basic thermodynamic According to organic chemistry, molecular shape deter- calculations show that suxamethonium cannot exist as a mines molecular action. Rigid molecules change shape straight molecule [11]. The negatively charged oxygen with difficulty and tend to concentrate on a few lowest- atoms are strongly attracted to the positively charged energy conformations. A rigid compound therefore tends ammonium heads, and the energy penalty in existing as a to either work very well or not at all, depending on straight molecule is too high. In other words, suxame- whether its most populated conformer fits the target thonium is too short to reach both receptive sites receptive site. If it works, it has high potency and few side simultaneously [11] (Fig. 1). In contrast, decamethonium effects. A flexible compound by contrast tends to assume is a straight molecule, and it reaches both receptive sites numerous conformations liberally, allowing it to fit with its twin methonium heads. several receptors, including receptors mediating side Several questions followed. Firstly, if only one acetyl- effects. Lacking conformational concentration, it tends choline moiety is binding the receptor site, what does the to have low potency. For example, vecuronium is a rigid other moiety contribute to the action of suxamethonium? molecule, and its D-ring acetylcholine moiety fits the Secondly, why is suxamethonium not totally like acetyl- receptive site of the endplate receptor with great choline in pharmacology? Thirdly, if succinylmonocholine precision, giving it potency and specificity. By contrast, has the same acetylcholine moiety in the molecule, why is it suxamethonium has a flexible molecule, allowing it to not as potent a neuromuscular blocker as suxamethonium? work on several cholinergic receptors with numerous side Lee [11] recently proposed a general mechanism of effects. Nevertheless, suxamethonium has sufficient con- action of the NMBs based on their molecular conforma- formational preference for the skeletal muscle endplate Ó 2009 The Author Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland 75
  • 4. C. Lee Æ Goodbye suxamethonium! Anaesthesia, 2009, 64 (Suppl. 1), pages 73–81 . .................................................................................................................................................................................................................... receptor to be a useful neuromuscular rather than atypical homozygote will be paralysed for 40–200 min, of cardiovascular or other cholinergic drug. Because of the which 30–90 min could be complete block, and the interaction among its functional groups – the methonium block will manifest Phase II block characteristics [14]. groups, the carbonyl oxygen atoms and the ester oxygen Blood transfusion or administration of plasma cholin- atoms – the molecule assumes a peculiar bent conforma- esterase concentrates will terminate suxamethonium- tion and the acetylcholine moieties assume a conforma- induced prolonged paralysis in patients unable to tion suitable for nicotinic action but not muscarinic action hydrolyse suxamethonium. In fact, most of the injected [11, 12]. The above explains not only why it takes two suxamethonium (80%) is normally hydrolysed in plasma molecules of suxamethonium to open one receptor before reaching the neuromuscular junction. It has also channel but also why suxamethonium is more nicotinic been shown that 10% the normal dose of suxamethonium than muscarinic. The question then becomes: why does will produce a paralysis of nearly normal duration in succinylmonocholine not work equally well as a NMB? patients with homozygous atypical plasma cholinesterase. The answer is that without balance from the second methonium head, the lone acetylcholine moiety of Side effects of suxamethonium succinylmonocholine conforms poorly to the receptive site, nicotinic or muscarinic [11, 12]. In summary, the Twinning of two acetylcholine molecules to make interaction between the two acetylcholine moieties suxamethonium thinly veils the true nature of suxame- render suxamethonium a monoquaternary neuromuscular thonium. What is surprising is not that suxamethonium has blocking agent, although it is a bisquaternary chemical so many acetylcholine-related side effects, but that compound. suxamethonium is still selective enough to be a NMB. This can be explained by its molecular conformation, as described above [11]. Still, suxamethonium has so many Breakdown of suxamethonium side effects that even their classification can prove contro- Suxamethonium is hydrolysed by plasma cholinesterase. versial. Lee [4, 5] classified these side effects according to Patients with hepatic dysfunction have deficient plasma mechanism of action as: depolarisation of the endplate and cholinesterase, while patients taking the eye drop echo- muscle; agonistic actions at other nicotinic sites; musca- thiophate may have inactivated plasma cholinesterase. rinic effects; abnormal breakdown; idiosyncratic actions; They exhibit prolonged neuromuscular block from drug interactions; changing nature of block after prolonged suxamethonium. Echothiophate inhibition of plasma use. Some of these are highlighted below. cholinesterase is irreversible, and recovery of the enzy- Myalgia after suxamethonium is a common occur- matic action depends on generation of new enzymes. rence. However, the precise incidence, severity and Plasma cholinesterase has several variants [13]. The mechanism of pain are very variable. Lying on the atypical enzymes can be identified by their resistance to operating table alone is often enough to cause aches and fluoride, dibucaine and other laboratory agents [13]. pains. Typical suxamethonium myalgia is deep aching in While the normal enzyme hydrolyses suxamethonium all muscles. The large number of proposed remedies effectively, its ability to hydrolyse butyrylcholine is means that none works well. These include non-steroidal markedly inhibited by dibucaine – by up to 80%, in anti-inflammatory drugs, vitamins, physiotherapy, which case the dibucaine number is said to be 80. By stretching exercises, defasciculation, phenytoin, self-tam- contrast, a homozygous atypical enzyme does not ing (pre-treatment with a small dose of suxamethonium hydrolyse suxamethonium effectively, but its ability to itself) and others [5]. The most susceptible patient is the hydrolyse butyrylcholine may be resistant to dibucaine. If young adult female. it is inhibited by only 20%, the dibucaine number is said Fasciculation, if vigorous, may look cruel to observers. to be 20. A heterozygote will have a dibucaine number of One cannot but link vigorous fasciculation to myalgia, 40–60. Besides dibucaine or fluoride-resistant atypical but an exact causal and quantitative relationship is simply plasma cholinesterases, there are silent genes and other not there. Anaesthetists do not even agree on the variants. Interestingly, hyperactive – as opposed to necessity or benefit of defasciculation. Some use fascic- hypoactive – plasma cholinesterase also exists, although ulation to tell that the neuromuscular block has started to it is rare [5]. work. For patients with full stomach, fasciculation may Following a typical intubation dose of suxamethonium increase gastric pressure and result in regurgitation. For (1 mg.kg)1), a patient with normal plasma cholinesterase rapid sequence intubation, many anaesthetists would will be paralysed for 5–11 min, of which 3–7 min may be defasciculate with a small dose of non-depolarising complete block. A heterozygous enzyme could result in a NMB. In frail, older patients, some fear that a forceful neuromuscular block with a duration of 10–30 min. An fasciculation might fracture a bone. Foldes et al. [3] Ó 2009 The Author 76 Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland
  • 5. Anaesthesia, 2009, 64 (Suppl. 1), pages 73–81 C. Lee Æ Goodbye suxamethonium! . .................................................................................................................................................................................................................... observed that a slower injection of suxamethonium elicits minutes, or even as late as in the recovery room or on the less fasciculation. However, slow injection is not suitable first postoperative day. A fulminant malignant hyperther- for rapid sequence intubation. mia attack often manifests as generalised rigidity, difficult Avian and lower animals respond to suxamethonium lung ventilation, hypermetabolism and high fever of rapid and other depolarising neuromuscular blockers with a onset. In patients with malignant hyperthermia trait or spastic paralysis [15]. A bird paralysed by suxamethonium muscle diseases such as Duchene muscular dystrophy, or decamethonium is a stiff bird. Mammalian extra-ocular suxamethonium may cause cardiac arrhythmia and cardiac muscles respond similarly [16]. Whereas a tetanic con- arrest by direct agonistic action on the heart. traction is a fusion of twitches with transmitted electro- A small increase in plasma potassium, in the order of myographic pulses, suxamethonium-induced contracture 0.1–0.5 mmol.l)1, usually follows suxamethonium is a form of paralysis, with no electrophysiological administration. Most anaesthetists avoid suxamethonium evidence of neuromuscular transmission. in patients with borderline or marked hyperkalaemia, Contracture of the extra-ocular muscles is another such as in those with renal failure. In patients with a major controversial issue. The controversy is not about its burn injury, severe trauma, major nerve injury, paraple- occurrence, but in its consequence in patients with an gia, severe metabolic acidosis and other critical condi- open globe injury. Normally, the contracture increases tions, plasma potassium may increase markedly after intraocular pressure. However, the greatest increase in suxamethonium. Fatal cardiac arrest may ensue even if the intraocular pressure appears to result from light anaesthe- plasma potassium concentration before the administration sia, with its associated relative hypertension in response to of suxamethonium is normal. The danger starts at about tracheal intubation, not from extra-ocular muscle con- 12–24 h after a major burn. In burns and in paraplegia, traction. A far greater increase in intra-ocular pressure the danger of hyperkalaemia will last as long as inflam- would be created by a vigorous cough and straining on the mation and the degeneration and regeneration processes tracheal tube. If the globe is open, the contraction may of the dystrophic muscle cells persist. Defasciculation does expel some eye content. For rapid sequence intubation in not protect patients from hyperkalaemia. the presence of open globe injury, both rocuronium and Suxamethonium is an agonist at the heart and the suxamethonium are acceptable drugs but if suxamethoni- ganglia, including the adrenal glands. By direct or reflex um is selected, it might be advisable to defasciculate. With vagal action, suxamethonium not uncommonly causes either drug, it is wise to induce sufficiently deep anaes- bradycardia or transient (10–30 s) cardiac arrest, especially thesia and paralysis before tracheal intubation. The in children and especially upon the administration of a availability of sugammadex for the rapid reversal of second dose of suxamethonium [18]. Anaesthetists often rocuronium may tip the choice of NMB further away inject atropine before the second dose of suxamethonium from suxamethonium and towards rocuronium [17]. to prevent bradycardia. Children are often given atropine Some patients have spasm of the jaw in response to prophylaxis with or before the first dose of suxametho- suxamethonium. Masseter spasm can be an early sign or a nium. However, more often than not, suxamethonium mild form of malignant hyperthermia. It can become an (especially in a large dose) causes tachycardia and obstacle to tracheal intubation. Studies have shown that to hypertension, which may follow an initial bradycardia. a variable degree – usually minor – all humans respond to suxamethonium with increased jaw tension. While some Phase II block investigators have recommended muscle biopsy for all patients who exhibit marked masseter spasm, most Shortly after Ali introduced the train-of-four (TOF), anaesthetists exercise discretion, depending on their Savarese et al. [14] and Lee independently observed clinical assessment. The mortality and morbidity of marked TOF fade in patients with atypical plasma malignant hyperthermia have been decreased by advances cholinesterase who were given suxamethonium. Lee in recognition and treatment, while a diagnostic muscle [4, 5] subsequently applied TOF stimulation to normal biopsy in itself is quite invasive and the biopsy result does subjects receiving suxamethonium and developed criteria not always offer clear-cut benefit. Avoidance of suxame- that set Phase II block in quantifiable terms (Fig. 2). thonium would be the safest alternative. The recognition of Phase II block predated the TOF by When first recognised, a fulminant case of malignant some time [19–21]. Using isolated rabbit lumbrical hyperthermia carried a mortality of about 80%. Treated muscle under constant exposure to decamethonium in with dantrolene, the mortality today should be < 10%. vitro, Jenden et al. [20] described an initial profound The onset of malignant hyperthermia varies. After block, a transitional partial spontaneous recovery (tachy- suxamethonium, it may ensue immediately. After the phylaxis), and a second profound block of the twitch use of inhalational agents, it can manifest in a few response. In surgical patients treated with a continuous Ó 2009 The Author Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland 77
  • 6. C. Lee Æ Goodbye suxamethonium! Anaesthesia, 2009, 64 (Suppl. 1), pages 73–81 . .................................................................................................................................................................................................................... Phase I minor TOF fade exists. This minor fade, typically labelled as ‘minimal fade’, lacks clinical significance [4, 5, 22–24]. During the short time course of a single dose of suxamethonium 1 mg.kg)1, from which the twitch quickly recovers, the TOF ratio will initially read zero, but soon becomes 0.8, and then 1.0. Obviously, any minor fade will make the TOF ratio initially zero. This is not a mild Phase II block. By definition, linear changes do not make phases. Phase II block is differentiated from Phase I by tachyphylaxis, receptor changes and contrast- ing clinical pictures [4, 5, 18–20]. To make the TOF clinically relevant, the TOF ratio should be measured at a point when the first twitch has recovered to 30–50% of control, ideally to 50% [4, 5, 24]. Figure 2 Diagram of changing characteristics of neuromuscular Simply put, the first twitch is a major independent block in humans observed during continuous infusion of sux- amethonium. In Phase I, the train-of-four fades minimally, and determinant of the TOF ratio with suxamethonium as it is edrophonium will deepen the block. During transition, tachy- with a non-depolarising block. If measured in the phylaxis occurs and the twitches show partial recovery despite standardised manner, the TOF ratio clearly shows two constant infusion of the relaxant. The train-of-four ratio and phases: a Phase I of slight fade and a Phase II of marked effect of edrophonium also exhibit transition. In Phase II, the fade, separated by a transitional phase in which tachy- train-of-four fades markedly, the block becomes increasingly reversible by edrophonium although the reversal is rarely phylaxis can be observed [4, 5]. When the standardised complete, and the block deepens and becomes slow to recover. TOF ratio is very low, such as 0.2–0.3, the block always The curve depicting the twitch height is reminiscent of the manifests marked tetanic fade, facilitated post-tetanic original observation in vitro [20], with similar time course and twitch and slowed recovery. A standardised TOF ratio magnitude. (Reproduced from reference [5] with permission). also predicts reversibility with edrophonium. While a TOF ratio > 0.6 predicts block enhancement, a TOF infusion of suxamethonium – a practice once popular – ratio < 0.4 predicts reversal – the greater the fade, the clinical anaetshetists long observed an initial phase of greater the reversibility [25]. The reversal is seldom block characterised by fasciculation, non-fading tetanus, complete because inhibition of tissue cholinesterase does blurred post-tetanic facilitation and potentiation of the not normalise the desensitised receptors. block by cholinesterase inhibitors [4, 5, 19]. A transitional The mechanism of Phase II block is not completely phase is characterised by tachyphylaxis, necessitating a understood. Desensitisation of the endplate receptors to greater and greater infusion rate to maintain the same acetylcholine, a postjunctional phenomenon, accounts for relaxation. By the time the patient becomes well paralysed the protracted residual paralysis. This also accounts for the again, the block has become slow to recover, and is exquisite sensitivity of patients to curariform drugs, as characterised instead by tetanic fade, marked post-tetanic there exists a diminished number of normal receptors facilitation, variable reversibility by cholinesterase inhib- remaining to block. However, as in a curariform block, itors, and without fasciculation upon injection of addi- the fade (TOF and tetanic) is most likely a prejunctional tional bolus dose of suxamethonium. The patient phenomenon [9]. Blockage of the prejunctional feedback becomes extremely sensitive to even small doses of receptors impairs the mobilisation of the transmitter to curariform drugs. Most troublesome is the slow sponta- the immediately releasable site. During neuromuscular neous recovery that cannot be satisfactorily accelerated by block, a 50% block of the twitch means most muscle reversal. Attempts at reversal of the block often result in fibres are at threshold, 50% responding fully and 50% not just enough muscle power to make lung ventilation at all. A minor decrease in transmitter output in response difficult but not enough to sustain a patent airway and to successive nerve impulses will make a significant adequate spontaneous breathing. Using TOF stimulation, difference in the number of muscle cells responding, Lee [4, 5] described two periods of profound neuromus- thereby causing fade. It is likely that tetanic fade and post- cular block interposed by tachyphylaxis in humans being tetanic facilitation in Phase II are also prejunctional, as given a continuous infusion of suxamethonium, echoing they are in curariform block. the very original observation of Phase II block by Jenden Phase II block has been called different names. As few et al. [20]. users of suxamethonium would doubt the existence of As is usual with suxamethonium, even the start of Phase two different blocks, this author prefers to just call it II block is controversial and confusing, because even in Phase II block to echo the original observation made by Ó 2009 The Author 78 Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland
  • 7. Anaesthesia, 2009, 64 (Suppl. 1), pages 73–81 C. Lee Æ Goodbye suxamethonium! . .................................................................................................................................................................................................................... Jenden et al. [20] in 1954. Other terms include desen- Efforts to replace suxamethonium sitisation block, dual block, and non-depolarising block. The term ‘desensitisation block’ is vague, because in Among the proposed criteria for an ideal NMB are: Phase II the endplate is desensitised to acetylcholine, the efficacy, safety and economy of use. Efficacy implies fast twitch is resistant to suxamethonium but sensitive to its onset, high potency and controllable level of block. Safety residual effect, while the patient is very sensitive to implies a lack of undesirable actions by the drug or its curariform drugs. metabolites, and ease of termination of the block. Self-antagonism is an interesting phenomenon in Phase Economy of use depends on dose requirement, cost of II block. It is intrinsic to the agonistic, anti-curare nature synthesis, supply, storage, shelf life and resupply. While of suxamethonium, and it explains tachyphylaxis [26]. To several NMBs fulfil most of the criteria, none so far – not whit, a fresh bolus of a small quantity of suxamethonium even suxamethonium – is fast and short-acting enough to (0.05–0.1 mg.kg)1) will antagonise its own Phase II be ideal, especially considering the risk of hypoxia in the block, as it does curariform block. The twitch and the case of difficult lung ventilation and tracheal intubation TOF ratio will both increase. A larger dose of suxame- [28]. The ideal NMB was once dubbed ‘non-depolarising thonium (0.2–0.5 mg.kg)1) will first briefly antagonise suxamethonium’ because, so far, it is easier to use a the block before adding to the block. The resultant block 5-min drug for 1-h surgery than to reverse a 1-h drug in then becomes protracted and typical of Phase II (Fig. 3). 5 min. The phenomenon explains the clinical observation in the The ‘non-depolarising suxamethonium’ has been 1960s that upon continuous infusion suxamethonium elusive. Nevertheless, searches have resulted in the becomes ineffective, but upon further use the patient introduction of several good NMBs over the decades. becomes weak for a long time afterwards. Among these, doxacurium, pipecuronium, metocurine The few remaining indications for suxamethonium and pancuronium are long-acting; vecuronium, atracu- include brief infusion for short procedures. As a general rium, and cisatracurium are intermediate ⁄ long-acting; guide, up to 2–4 mg.kg)1 of suxamethonium adminis- rocuronium is intermediate-acting; mivacurium and tered over 30–40 min does not result in much prolonged rapacuronium are short-acting. Under the principle of residual block in patients with normal plasma cholines- survival of the fittest, rocuronium, vecuronium and terase [4, 5, 27]. cisatracurium remain popular today. Because suxame- Figure 3 Self-antagonism and prolonged residual block (dual action) in a typical case of well-established Phase II block after infusion of 7.3 mg.kg)1 of suxamethonium. Marked train-of-four fade was evident. Starting with an existing slow-recovering residual block, an additional bolus dose of suxamethonium 0.05 mg.kg)1, (a) only antagonised its own residual block. A dose of 0.1 mg.kg)1, (b) showed greater self-antagonism. A dose of 0.15 mg.kg)1, (c) first antagonised and then deepened the block. A dose of 0.2 mg.kg)1, (d) nearly increased the train-of-four ratio to 0.8, before it markedly depressed the ratio and the twitch. These doses of suxame- thonium are known to also antagonise a curariform non-depolarising block, to a similar extent. Instead of bolus, infusion of suxamethonium would blur the initial antagonism-potentiation sequence, and initially manifest only as inability to deepen the block, namely tachyphylaxis. The subsequent deepening of the slow-recovering residual block depicts a classic ‘desensitisation block’ implying that the receptors are insensitive to the neurotransmitter acetylcholine [19, 27]. (Reproduced from reference [26], with permission). Ó 2009 The Author Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland 79
  • 8. C. Lee Æ Goodbye suxamethonium! Anaesthesia, 2009, 64 (Suppl. 1), pages 73–81 . .................................................................................................................................................................................................................... thonium survives into its sixth decade by being the Recurrence of block did not occur, and both treatments fastest in onset and shortest in duration of action, and were well tolerated. because rocuronium has matched suxamethonium in The 1.2 mg.kg)1 dose is the largest approved dose of providing good tracheal intubation conditions within rocuronium, and is rarely needed clinically. In practice, 1 min [6], all it still takes to retire suxamethonium is 0.6 mg.kg)1 is more commonly used. Likewise, rapid reversal. 16 mg.kg)1 of sugammadex is the largest dose so far The drug TAAC3 is a bis-tropinyl long-chain di-ester tested in human patients. Many other clinical studies have neuromuscular blocking compound that successfully shown that sugammadex can safely and effectively reverse underwent thorough pre-human tests in various animal all degrees of neuromuscular block produced by rocuro- species and preparations. Pure stereo-isomers were syn- nium and vecuronium in a number of patient popula- thesised. It is the only NMB shorter-acting and with a tions. In this study, sugammadex was injected 3 min after faster onset than suxamethonium, with a benign side rocuronium to mimic a clinical scenario of failed tracheal effect profile, and it is non-cumulative [7]. Unfortunately, intubation after two attempts. Theoretically, sugammadex renal toxicity derailed the pursuit of perfection (personal can be administered at any time as clinically indicated, information). with similar efficacy. In the scenario, the speed and Of the asymmetric fumarate tetrahydroisoquinolinium efficacy of reversal is critical because in apnoea susceptible derivatives, GW280430A [29] and its reformulated patients may begin to desaturate within 3 min even if pre- product, and the new halogenated and un-halogenated oxygenated, and then may worsen rapidly by the second products AV002 and congeners, are promising and still [28]. Without pre-oxygenation, the margin of safety is being pursued. Some are short-acting; some are interme- narrower. diate. Some of these compounds have good pharmaco- logical profiles and are broken down rapidly by cysteine So long, sux! and thanks! abduction. Some new AV compounds are immediately reversible by intravenous administration of cysteine or It now appears that suxamethonium can be replaced even glutathione in animals in a manner comparable to the for its final remaining indications. Thinking inside the reversal of rocuronium by sugammadex. Their reversal box, i.e. the neuromuscular junction with its anatomy, ‘drugs’ are normal amino acids in the body, and therefore physiology, enzymology and pharmacology, decades of safe. research have failed to create a single drug to replace suxamethonium. Thinking outside the box, sugammadex, which is entirely non-neuromuscular, promises not only A new challenge to suxamethonium to revolutionise the reversal of neuromuscular block but In a direct challenge to suxamethonium, Lee et al. [17] also to retire the cholinesterase inhibitors as well as recently compared sugammadex reversal of profound suxamethonium. rocuronium-induced neuromuscular block with sponta- Suxamethonium has created great controversies and neous recovery from suxamethonium. In this randomised, survived countless attacks while benefiting millions and multicentre study of 110 patients from 11 North Amer- millions of patients for decades. It has amply taught us ican medical centres, half the patients received 1 mg.kg)1 neuromuscular pharmacology, given us an encyclopaedia of suxamethonium followed by spontaneous recovery; of side effects, and forced us to learn organic and the other half received rocuronium 1.2 mg.kg)1 followed computer chemistry, amongst other things. Suxametho- by sugammadex 16 mg.kg)1 3 min later. Both groups nium has done its job! underwent intravenous anaesthesia, and their tracheas were intubated 1 min after the start of administration of Conflicts of interest the NMBs. Results showed effective and safe reversal of rocuro- The author has in the past received supports for his nium. Intubating conditions were excellent in both neuromuscular pharmacology research from various groups. Mean times to recovery of the first twitch of sponsors including Organon, USA, Inc., now a part of the TOF (T1) to 10% and to 90% were significantly Schering-Plough Corporation, owner of sugammadex. shorter in the rocuronium–sugammadex group (4.4 min He is coprincipal investigator and co-inventor of the and 6.2 min respectively) compared with the suxame- TAAC3 series of compounds (now de-activated) cited in thonium group (7.1 min and 10.9 min respectively, all the text [7], which was in the past sponsored in part by p < 0.001). If timed from sugammadex administration, Organon. At present, he is principal investigator of a the mean times to recovery were: T1 to 10% = 1.2 min; multi-centre study on sugammadex [17], also sponsored T1 to 90% = 2.9 min; TOF ratio to 0.9 = 2.2 min. by Organon. Ó 2009 The Author 80 Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland
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