1. Anaesthesia, 2009, 64 (Suppl. 1), pages 73–81
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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.
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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
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2. C. Lee Æ Goodbye suxamethonium! Anaesthesia, 2009, 64 (Suppl. 1), pages 73–81
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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!
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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
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4. C. Lee Æ Goodbye suxamethonium! Anaesthesia, 2009, 64 (Suppl. 1), pages 73–81
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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!
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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
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6. C. Lee Æ Goodbye suxamethonium! Anaesthesia, 2009, 64 (Suppl. 1), pages 73–81
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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

9. Anaesthesia, 2009, 64 (Suppl. 1), pages 73–81 C. Lee Æ Goodbye suxamethonium!
. ....................................................................................................................................................................................................................
15 Bowman WC, Rand MJ. Striated Muscle and Neuromuscular
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Journal compilation Ó 2009 The Association of Anaesthetists of Great Britain and Ireland 81