V O L U M E T H I R T Y - S E V E N
NEW DEVELOPMENTS THAT
MAY CHANGE YOUR PRACTICE
DAVID KOPMAN, M.D.
ASSISTANT PROFESSOR OF ANESTHESIOLOGY
WEILL CORNELL MEDICAL CENTER
NEW YORK, NEW YORK
CYNTHIA A. LIEN, M.D.
PROFESSOR OF ANESTHESIOLOGY
WEILL CORNELL MEDICAL CENTER
NEW YORK, NEW YORK
EDITOR: MEG A. ROSENBLATT, M.D.
ASSOCIATE EDITORS: JOHN F. BUTTERWORTH IV, M.D.
JEFFREY B. GROSS, M.D.
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Physiology and Pharmacology of
Neuromuscular Transmission: New
Developments That May Change Your Practice
David Kopman, M.D.
Assistant Professor of Anesthesiology
Weill Cornell Medical Center
New York, New York
Cynthia A. Lien, M.D.
Professor of Anesthesiology
Weill Cornell Medical Center
New York, New York
In the more than 60 years since d-tubocurarine was introduced into the clinical
practice of anesthesia, great strides have been made in our understanding of the
pharmacology of neuromuscular blocking agents (NMBAs). The neuromuscular
junction and neuromuscular transmission allow translation of a neuronal electrical
impulse into a motor action potential and subsequent muscular contraction. An
appreciation for the complexity of the system is essential because it helps one both
understand the mechanism by which neuromuscular blocking drugs exert their
pharmacologic effect and rationally deliver, monitor, and reverse these agents.
The Neuromuscular Junction: Prejunctional Components
Motor neurons travel from the ventral horn of the spinal cord to the
neuromuscular junction. The axon is responsible for transmitting the action
potential to the muscle from the spinal cord. The necessary enzymes and other
proteins needed by the nerve ending to synthesize, store, and release acetylcholine
are synthesized in the cell body and transported through the axon to the nerve
As each nerve approaches a muscle, it branches many times to allow for the
formation of junctions with multiple muscle ﬁbers. Immediately before the terminal
axon approaches the muscle to become the prejunctional component of the motor
nerve terminal, it loses its myelin sheath. The nerve terminal contains the synaptic
vesicles in which acetylcholine is stored. When an action potential reaches the nerve
terminal, vesicles fuse with the terminal membrane, releasing acetylcholine into the
Both nicotinic and muscarinic receptors are found presynaptically on the motor
nerve terminal. These prejunctional receptors seem to modulate the release of
acetylcholine into the neuromuscular junction and have been variously assigned
both excitatory and inhibitory roles.1,2 Prejunctional nicotinic receptors are
activated by acetylcholine and function in a positive feedback control system that
maintains availability of acetylcholine when demand for it is high. They are involved
Copyright Ó2009 American Society of Anesthesiologists, Inc. 107
108 KOPMAN AND LIEN
in the mobilization of acetylcholine, but not in the process of acetylcholine release.
Blockade of these receptors by nondepolarizing neuromuscular blockers may
underlie the fade phenomenon seen with tetanic and train-of-four stimulation.
The presynaptic nicotinic receptor is structurally distinct from the postsynaptic
acetylcholine receptor (AchR). Although it, like the postsynaptic receptor, is
composed of ﬁve subunits, it contains only a and b subunits (a3, b2). Synergism
between nondepolarizing NMBAs of different structures has been attributed, in part,
to their different effects on the presynaptic nicotinic receptors.
The Neuromuscular Junction: Postjunctional Components
At the motor end plate, the myocyte forms a recess into which the motor nerve
terminal ﬁts. This recess is characterized by multiple secondary junctional clefts. The
distance between the motor nerve unit and the shoulder of the junctional cleft is
60 nm and it is across this distance that acetylcholine must travel to reach the
receptors of the motor end plate. Most of the released acetylcholine (approximately
80%) never reaches the AchR because it is hydrolyzed by acetylcholinesterase at the
neuromuscular junction. Nicotinic AchRs are found throughout the muscle
membrane but are concentrated at the tops of the secondary junctional clefts.
Mature AchRs are composed of ﬁve subunits: two a, one b, one d, and one e.3 The
a subunits contain the major portion of the AchR binding site. There are two binding
sites on each AchR, one at the a--d and one at the a--e subunit interface.4 Recent
evidence indicates that each of these binding sites has different afﬁnities for the
NMBAs and that the a-d binding site is the more dominant one in determining
receptor afﬁnity for pancuronium, vecuronium, and cisatracurium.5 The ﬁve
subunits that comprise the AchR are arranged in a cylinder that spans the membrane
of the motor end plate. The receptors have a central pore for ion movement into and
out of the muscle ﬁber.
Neuromuscular Transmission: Prejunctional Events
Synchronized release of acetylcholine from presynaptic vesicles in an amount
sufﬁcient to generate a muscle action potential occurs when a neural action potential
reaches the nerve terminal. The rapid release of acetylcholine when an impulse
arrives at the motor nerve terminal necessitates that only those vesicles close to the
membrane of the nerve terminal can participate in the process of exocytosis.
Repetitive nerve stimulation results in trains of electrical impulses. These cause
vesicles to move toward the motor nerve terminal for subsequent release allowing for
the posttetanic potentiation observed during neuromuscular block. The increased
release of acetylcholine allows for a transient increase in apparent muscle strength as
the concentration of available acetylcholine increases relative to the concentration of
Botulinum toxin interferes with the fusion of the vesicle to the cell membrane and
prevents release of acetylcholine. When injected into the muscle groups, it causes
weakness and, ultimately, increased expression of AchRs.6
PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTS 109
Neuromuscular Transmission: Postjunctional Events
When released, acetylcholine diffuses across the junctional cleft to the motor end
plate where it binds to the a subunits of the AchR. When both a subunits are
occupied simultaneously by agonists, the channel of the receptor opens allowing the
inﬂux of calcium and sodium and subsequently the efﬂux of potassium as the ions
move down their concentration gradients. After a nerve impulse, thousands of AchRs
are activated and an end plate potential is generated. With the inﬂux of sodium that
accompanies the activation of the AchRs, the membrane potential of the muscle cell,
which is approximately À80 mV in the rested state, increases to þ 40 mV. When an
adequate number of end plate potentials accumulate, adjacent voltage-gated sodium
channels in the muscle membrane are opened and a muscle action potential, which
activates muscle contraction, is started.
Neuromuscular Transmission and Neuromuscular
The depolarizing NMBA succinylcholine binds to the AchR and mimics the effects
of acetylcholine. Therefore, whether one succinylcholine molecule and one
acetylcholine molecule or either two acetylcholine or two succinylcholine molecules
are bound to a single AchR, the channel will open, allowing for the inﬂux of sodium.
In contrast to acetylcholine, however, succinylcholine is not a substrate for
acetylcholinesterase; therefore, it is not rapidly metabolized in the junctional cleft.
To be broken down, it must move into the plasma where it is metabolized by
butyrylcholinesterase. As long as it remains in the junctional cleft, it remains
available to repeatedly bind to and activate the AchR.
Nondepolarizing NMBAs exert their effect by occupying one or both of the
binding sites on AchRs. With acetylcholine effectively excluded from receptor
binding sites by a NMBA, receptors cannot be activated and their ion channels
remain closed. By preventing ion ﬂux through the AchR, no end plate potentials are
generated on the muscle ﬁber and, consequently, muscle action potentials and
subsequent muscle contraction are prevented.
Recovery from Nondepolarizing Neuromuscular
The competitive block generated by nondepolarizing NMBAs is terminated by an
increase in acetylcholine concentration relative to NMBA concentration in the
neuromuscular junction. This can occur by either or both of two mechanisms. As
the plasma concentrations of the agents decrease, the agents migrate from the
neuromuscular junction back into the plasma, where they are either metabolized
such as cisatracurium and mivacurium or from which they are eliminated such as
vecuronium, rocuronium, and the long-acting agents. Alternatively, the inhibition of
acetylcholinesterase by the administration of an anticholinesterase agent such as
neostigmine allows acetylcholine released into the neuromuscular junction to
remain available to bind to the AchR and thus initiate muscle contraction.
110 KOPMAN AND LIEN
What Constitutes Adequate Clinical Recovery
from Nondepolarizing Neuromuscular Block?
In the early 1970s, Ali et al.7--9 ﬁrst described what has subsequently become the
standard technique for evaluating recovery after the administration of nondepolariz-
ing neuromuscular blocking drugs, the train-of-four ratio. This technique uses four
supramaximal stimuli delivered in quick succession (2 Hz) to the ulnar nerve to
induce four responses in the adductor pollicis brevis muscle. The ratio of the
amplitude of the fourth evoked response as compared with the ﬁrst is deﬁned as
the train-of-four fade ratio (TOFR) (Fig. 1). Ali et al.10 published a follow-up study
correlating TOFR with impairment in the mechanical ventilatory function in
eight healthy conscious volunteers who were given small incremental doses of
tubocurarine. They found that when the TOFR had returned to a value of 0.70, the
vital capacity and peak expiratory ﬂow rate had returned to 90% of control, and
negative inspiratory force was back to 80% of control. They concluded that recovery
to this degree represented adequate return of mechanical respiratory reserve. It
should be noted, however, that it was not until the TOFR was 0.90 that negative
inspiratory force recovered to 90% of control. The authors also reported that all eight
volunteers reported experiencing lightheadedness, diplopia, masseter muscle
weakness, and facial tingling, and one reported difﬁculty in swallowing, after
recovery to a TOFR of greater than 0.7.
In a third study from the same group, the effects of nondepolarizing NMBAs were
allowed to spontaneously resolve, whereas neuromuscular and respiratory functions
were evaluated using both clinical criteria (hand grasp, head lift, tongue protrusion,
sustained eye-opening) and evoked responses (TOFR).11 The investigators observed
that clinical criteria for extubation, including vital capacity of at least 10 to 15 ml/kg,
inspiratory force of at least À25 cm H2O, PaCO2 between 35 and 45 mmHg, and a
respiratory rate of less than 25 per minute, correlated well with TOFR of greater than
FIG. 1. The degree of twitch response at the adductor pollicis after train-of-four (TOF)
stimulation of the ulnar nerve. The depicted TOF fade ratio is 0.64.
PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTS 111
0.70. These three studies essentially established a TOFR of greater than or equal to
0.70 as the threshold for adequate recovery from nondepolarizing neuromuscular
blocking drugs for the next two decades.
Eriksson et al.12 demonstrated that partial vecuronium-induced neuromuscular
blockade (a TOFR of 0.70) reduces the respiratory response to hypoxia, an effect
likely mediated by the blockade of nicotinic receptors located on the carotid body. In
1997, Kopman et al.13 correlated clinical signs and symptoms of motor weakness
with TOFR in 10 healthy awake subjects administered mivacurium by intravenous
infusion. Subjects were asked to carry out a series of tasks, including 5-second head
and leg lifts, biting a wooden tongue depressor between their upper and lower
incisors such that the investigator could not pull it out of their mouths, and having
their grip strength measured. At a TOFR of 0.70, 8 of 10 subjects could perform a
5-second head lift. However, at this level of block, several subjects could not sip
water from a straw, because they could not make a tight seal with their lips. In
addition, more than half of the subjects were unable to retain a wooden tongue
depressor between their incisor teeth. Grip strength was decreased on average by
more than 40% at a TOFR of 0.70, and even at a TOFR of 0.90, measurable effects
were noted in most individuals. All subjects reported visual disturbances, including
diplopia, at TOFR of 0.9. Seven subjects reported feeling that their vision was still
abnormal a full 45 to 90 minutes after the TOFR returned to 1.0. None of the subjects
felt ‘‘street-ready’’ at a TOFR of 0.7, which corroborated the author’s conclusion that
they all had signiﬁcant clinical signs of residual neuromuscular blocking at that time.
Eriksson et al.14 used simultaneous videomanometry and mechanomyography to
assess the functional status of the pharynx in partially paralyzed awake human
subjects. Under ﬂuoroscopic guidance, a catheter with four pressure transducers
was inserted into 14 subjects such that the most distal transducer was located in the
cervical esophagus, whereas the most proximal one was at the base of the tongue.
Subjects were then asked to swallow small boluses of iodine contrast while
manometric and radiographic data were recorded. All subjects were then administered
vecuronium by intravenous infusion and swallow studies were repeated when the
TOFRs recorded at the adductor pollicis muscle were 0.60, 0.70, 0.80, and 0.90. All
volunteers had episodes of misdirected swallowing and aspiration of contrast material
into the larynx, although not into the trachea, at TOFR values of 0.60 to 0.80.
Signiﬁcantly, none of the episodes of aspiration were accompanied by coughing or a
subjective sense of discomfort. No episodes of aspiration were noted when the TOFR
recovered to a value greater than or equal to 0.9.
Although Ali et al.10 showed that a TOFR of 0.70 correlates with adequate
recovery of mechanical ventilatory parameters in most patients, the more recent data
discussed previously indicate that this is not the whole story. At TOFR of 0.70, signs
and symptoms of signiﬁcant residual paralysis are common. On the basis of available
evidence, a return to a TOFR of 0.7 can no longer be considered optimal or even
adequate neuromuscular recovery. The modern standard of recovery is now
considered to be at TOFR of greater than or equal to 0.90.
Residual Curarization in the Recovery Room
Viby-Mogensen et al.15 published a report documenting an alarming incidence of
residual neuromuscular blockade after the administration of NMBAs (tubocurarine,
112 KOPMAN AND LIEN
pancuronium, and gallamine) in patients arriving in the recovery rooms of three
Danish hospitals. Of the 72 patients in the study, 12% had TOFRs of less than 0.40,
20% had TOFRs of less than 0.60, and 40% had TOFRs of less than 0.70 on arrival in
the postanesthesia care unit. Although this study is nearly 30 years old and the long-
acting NMBAs given to patients in this study have been largely replaced with drugs
with considerably shorter durations of action, the incidence of postoperative
residual curarization remains unacceptably high today.16--19 Multiple factors are
responsible for the continued incidence of postoperative residual curarization. First,
the ability of clinicians to detect fade during train-of-four stimulation is notoriously
poor. Most trained observers lose the ability to detect fade during train-of-four
stimulation when the postoperative residual curarization exceeds 0.40.20 Thus, most
clinicians cannot detect clinically inadequate recovery from neuromuscular blockade
with a conventional peripheral nerve stimulator. Anesthesiologists today also
routinely use much greater multiples of the ED95 of intermediate-duration drugs
such as rocuronium and cisatracurium than were ever used with traditional long-
acting drugs such as tubocurarine and pancuronium. Clinicians may also have
unrealistic expectations regarding both the rate of spontaneous recovery from
nondepolarizing neuromuscular blocking as well as the ability of neostigmine to
reverse profound residual paralysis.
Postoperative Residual Curarization: Does It Really Matter?
Does postoperative residual curarization increase postoperative morbidity? Outcome
data addressing the issue are scant. Berg et al.21 randomized 691 patients scheduled
for abdominal, orthopedic, or gynecologic surgery to receive one of three NMBAs
(pancuronium, vecuronium, or atracurium). All patients had TOFR measured mechano-
myographically on arrival in the postanesthesia care unit and were then followed for
signs of pulmonary complications for 6 days postoperatively. They found that patients
in the pancuronium group, unlike those in either of the other groups, who arrived in
the postanesthesia care unit with a TOFR of less than 0.70 had a signiﬁcantly greater
incidence of radiographically demonstrable postoperative pulmonary complications
than those whose TOFR exceeded 0.70. In 2008, Murphy et al.22 published similar
ﬁndings. They collected data on 7,459 patients admitted to their postanesthesia care
unit after having received a general anesthetic and identiﬁed the occurrence of 61
critical respiratory events in those patients. Forty-two of the 61 patients noted to have
experienced a critical respiratory event were then compared with matched control
subjects. Of the 61 identiﬁed patients, only one did not receive a neuromuscular
blocking drug. Acceptable neuromuscular recovery, deﬁned as a TOFR of greater than
0.90, was present in just 9.5% of patients with a critical respiratory event as compared
with 90.5% of control subjects. Severe residual paralysis (TOFR of less than 0.70) was
present in 73.8% of the cases but in none of the matched control subjects. The authors
concluded that ‘‘unrecognized residual paresis is an important contributing factor to
postoperative critical respiratory events.’’
New Approaches to Manipulation of Neuromuscular
Transmission: Sugammadex and Gantacurium
Neostigmine-induced antagonism of nondepolarizing neuromuscular blockade has
its limitations. When maximal inhibition of acetylcholinesterase activity has been
PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTS 113
achieved, additional administration of neostigmine will not further antagonize
any remaining residual block. As long as the concentration of the NMBA at
the neuromuscular junction remains high, adequate recovery of skeletal muscle
function will remain unattainable no matter how much neostigmine is administered.
Two new drugs, currently under development, offer a possible way out of this
Sugammadex is a new reversal agent with a novel chemical structure. It is
a cyclodextrin, a member of a family of water-soluble crystalline oligosaccharides
that have long been used in the industry to solubilize lipophilic compounds.
Sugammadex (sometimes referred to in research publications as ORG 25969) is a
highly soluble g-cyclodextrin with a hydrophobic cavity that can encapsulate
steroidal neuromuscular blocking drugs.23 By encapsulating susceptible NMBAs, the
muscle relaxant is rendered unavailable to interact with the postsynaptic nicotinic
receptors of the neuromuscular junction.
Sugammadex has a very high afﬁnity for rocuronium and vecuronium (less so for
pancuronium). When given in an adequate dosage, the plasma concentration of
unbound or free relaxant decreases rapidly to very low levels. As a consequence, the
NMBA more rapidly diffuses from the myoneural junction based on the newly
established concentration gradient. Thus, we now have, for the ﬁrst time, a
mechanism by which a profound nondepolarizing block can be promptly and
satisfactorily antagonized. When 12 mg/kg sugammadex is given just 3 minutes after
a 1.2-mg/kg bolus of rocuronium, a return to a TOFR of 0.90 can be expected in less
than 3 minutes.24 The advantages of the drug vis-a-vis edrophonium or neostigmine
were clearly shown in a recent study by Sacan et al.25 (Table 1). Unfortunately,
sugammadex is not yet (December 2008) available in North America. In Europe,
where it was recently introduced, a very high acquisition cost may further limit its
Gantacurium is one of several enantiomeric bisquarternary compounds identiﬁed
as an asymmetric chlorofumarate.26--28 This class of compounds incorporates
1-benzyl and 1-phenyltetrahydroisoquinolinium groups in the same molecule.
Gantacurium was ﬁrst identiﬁed from this series of neuromuscular blockers as
TABLE 1. Reversal of Rocuronium With Sugammadex and Anticholinesterases25
Edrophonium Neostigmine Sugammadex
(N ¼ 20, All Groups) (1.9 mg/kg) (0.07 mg/kg) (4 mg/kg)
Total dose rocuronium (mg) 73730 79726 73722
Interval post last dose (minutes) 40716 35718 41719
T1 at reversal (%) 1278 12714 677
N with TOF Z0.90 within 5 minutes 0 1 30
N with TOF Z0.70 within 30 minutes 7 9 20
Reversal of rocuronium sugammadex versus neostigmine versus edrophomium.
TOF ¼ train of four.
114 KOPMAN AND LIEN
having an ultrashort duration of action and a safety margin for cardiovascular effects
similar to that of mivacurium. As opposed to mivacurium and atracurium, which are
composed of a mixture of isomers, this synthetic compound is characterized as a
single isomer. The stereochemistry of the compound is derived from its orientation
about each of its six asymmetric centers.
In rhesus monkeys, the potency of gantacurium is identical to that of mivacurium
(0.06 mg/kg).29 Its onset, however, is signiﬁcantly faster and its recovery is shorter
than that of mivacurium. Hemodynamic changes indicative of histamine release,
transient decreases in blood pressure, and increases in heart rate are observed at
doses of 3.2 mg/kg. Smaller doses caused less than a 10% change in mean arterial
pressure and heart rate. On the basis of these data, the margin of safety for histamine
release was determined to be 53 (ED for histamine release/ED95 neuromuscular
blocking). In this same study, the margin of safety for histamine release associated
with the administration of mivacurium was 13.
In humans, gantacurium has pharmacodynamic properties that mimic those of
succinylcholine. A study in anesthetized human volunteers evaluated the onset and
recovery proﬁles of 430A in the thumb and larynx.30 The pattern of blockade
resembled that of succinylcholine, with fully paralyzing doses (2--3 Â ED95 or 0.38
to 0.54 mg/kg) producing a 100% block of train-of-four within 60 to 70 seconds in the
larynx (Table 2). To date, there has been one published trial of gantacurium in
human volunteers receiving a nitrous oxide--opioid anesthetic.31 In this study of 11
individuals, the ED95 of the compound was 0.19 mg/kg. Administration of two times
the ED95 caused 100% neuromuscular blocking at the adductor pollicis within 1.7
minutes and administration of three times the ED95 caused 100% block within 1.5
minutes. Complete recovery to a train-of-four ratio of 90% after the administration of
an ED95 dose occurs within 10 minutes and within 12 to 15 minutes after the
administration of doses as large as 0.72 mg/kg (4 Â ED95). Recovery intervals are not
lengthened by increasing the dose of gantacurium (Table 3). Recovery was
accelerated by administration of edrophonium (0.5 mg/kg).
Gantacurium seems to be degraded by two chemical mechanisms, neither of
which is enzymatic.32 The chlorine in the molecule allows for a unique form of
inactivation. Preliminary studies with gantacurium in human blood indicate that the
major metabolite of the compound is mixed onium thiazolidine. This compound is
formed through the adduction of cysteine, a nonessential amino acid, to the
TABLE 2. Onset of Maximal Block and Spontaneous Recovery to 25% or 95% Twitch Height
After the Administration of Gantacurium or Succinylcholine (Mean7SD)
Maximum Block T1 ¼ 25% T1 ¼ 95%
Gantacurium 0.36 mg/kg
LA 1.170.3 7.271.1 12.972.1
AP 1.770.2 7.070.5 12.271.3
Gantacurium 0.54 mg/kg
LA 0.970.2 9.372.9 16.174.1
AP 1.570.3 9.371.5 15.273.0
Succinylcholine 1 mg/kg
LA 0.870.3 6.171.7 11.371.9
AP 1.570.2 8.571.5 12.172.0
AP ¼ adductor pollicis; LA ¼ laryngeal adductors.
PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTS 115
TABLE 3. Recovery Intervals After the Administration of Gantacurium (Mean7SD)
(minutes) 0.18 0.30 0.36 0.40 0.45 0.54 0.72
T1 5--95% 6.570.8 7.871.9 6.470.9 7.672.3 7.272.8 6.971.7 7.171.2
T1 25--75% 2.770.5 3.370.9 2.570.3 3.471.2 3.171.2 3.071.1 3.271.1
T1 25% to 5.171.1 5.471.5 4.971.1 5.472.1 5.671.8 5.071.6 5.270.8
TOFR ¼ train-of-four fade ratio.
compound at the site of the chlorine molecule. The adduction process occurs
rapidly. The second process of inactivation occurs more slowly and involves
hydrolysis of the ester bond adjacent to the chlorine substitution. This process yields
inactive hydrolysis products.
Intravenous administration of exogenous cysteine to monkeys rapidly reverses the
gantacurium-induced block.33 Administration of cysteine (10 mg/kg) 2 minutes after
the administration of 8 Â ED95 gantacurium shortened the 5% to 95% recovery
interval by 2 1 minutes and the total duration of block (the time from administration
of gantacurium to a train-of-four ratio Z0.9) by 6 1 minutes. Cysteine (10 mg/kg) will
facilitate complete recovery of the neuromuscular function even when administered
within 1 minute of gantacurium.
Both the neuromuscular junction and neuromuscular transmission have been
studied extensively. They remain incompletely understood by most clinical anesthes-
iologists. Ongoing research continues to elucidate details regarding the speciﬁcs of
neuromuscular transmission. Studies with blocking agents and compounds that
reverse their effects capitalize on these details. Inadequate recovery from NMBAs
continues to be an all-too-common occurrence after the administration of these
drugs. There is growing evidence that postoperative residual curarization places
patients at increased risk of developing postoperative pulmonary complications. We
hope that faster- and shorter-acting NMBAs and faster-acting and more effective
reversal agents will lead to improvements in safety for patients undergoing paralysis
during general anesthesia.
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