Cap 9

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CHAPTER 9

V O L U M E T H I R T Y - S E V E N

EDITOR: MEG A. ROSENBLATT, M.D.ASSOCIATE EDITORS: JOHN F. BUTTERWORTH IV, M.D.

JEFFREY B. GROSS, M.D.

The American Society of Anesthesiologists, Inc.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

PHYSIOLOGY ANDPHARMACOLOGY OFNEUROMUSCULARTRANSMISSION:

NEW DEVELOPMENTS THATMAY CHANGE YOUR PRACTICE

DAVID KOPMAN, M.D.ASSISTANT PROFESSOR OF ANESTHESIOLOGY

WEILL CORNELL MEDICAL CENTERNEW YORK, NEW YORK

CYNTHIA A. LIEN, M.D.PROFESSOR OF ANESTHESIOLOGYWEILL CORNELL MEDICAL CENTER

NEW YORK, NEW YORK

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Subscribers to ASA Refresher Courses in Anesthesiology are eligible to earn AMA

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a maximum of 1 AMA PRA Category 1 Credit(s)t. Physicians should only claim

credit commensurate with the extent of their participation in the activity.

Author Disclosure InformationDrs. Kopmen and Lien have disclosed that they have no financial interests in or

significant relationship with any commercial companies pertaining to this educa-

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Physiology and Pharmacology ofNeuromuscular 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 neuromuscularjunction 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

ending.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

synaptic cleft.

Both nicotinic and muscarinic receptors are found presynaptically on the motornerve 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 �2009 American Society of Anesthesiologists, Inc. 107

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 postsynapticacetylcholine 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 musclemembrane 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 membraneof 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 amountsufficient 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 asthe concentration of available acetylcholine increases relative to the concentration of

NMBA.

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

108 KOPMAN AND LIEN

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 areoccupied 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 �80 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, whichactivates muscle contraction, is started.

Neuromuscular Transmission and NeuromuscularBlocking Drugs

The depolarizing NMBA succinylcholine binds to the AchR and mimics the effects

of acetylcholine. Therefore, whether one succinylcholine molecule and oneacetylcholine 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 thebinding 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 NeuromuscularBlocking Drugs

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 theneuromuscular 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.

109PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTS

What Constitutes Adequate Clinical Recoveryfrom 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 foursupramaximal 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, andnegative 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 wereallowed 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 �25 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.

110 KOPMAN AND LIEN

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 neuromuscularblockade (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 a5-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 subjectsfelt ‘‘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 whilemanometric 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,


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 blockadewith 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 greaterincidence 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 than0.90, 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 NeuromuscularTransmission: Sugammadex and Gantacurium

Neostigmine-induced antagonism of nondepolarizing neuromuscular blockade has

its limitations. When maximal inhibition of acetylcholinesterase activity has been

112 KOPMAN AND LIEN

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

quandary.

Sugammadex

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 encapsulatesteroidal 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, amechanism 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

widespread acceptance.

Gantacurium

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

(N¼ 20, All Groups)Edrophonium(1.9 mg/kg)

Neostigmine(0.07 mg/kg)

Sugammadex(4 mg/kg)

Total dose rocuronium (mg) 73730 79726 73722Interval post last dose (minutes) 40716 35718 41719T1 at reversal (%) 1278 12714 677N with TOF Z0.90 within 5 minutes 0 1 30N with TOF Z0.70 within 30 minutes 7 9 20

Reversal of rocuronium sugammadex versus neostigmine versus edrophomium.TOF ¼ train of four.


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 orientationabout 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 neuromuscularblocking). 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 � 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 inhuman 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 � ED95). Recovery intervals are not

lengthened by increasing the dose of gantacurium (Table 3). Recovery wasaccelerated 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)

Minutes to

Maximum Block T1¼ 25% T1¼ 95%

Gantacurium 0.36 mg/kgLA 1.170.3 7.271.1 12.972.1AP 1.770.2 7.070.5 12.271.3

Gantacurium 0.54 mg/kgLA 0.970.2 9.372.9 16.174.1AP 1.570.3 9.371.5 15.273.0

Succinylcholine 1 mg/kgLA 0.870.3 6.171.7 11.371.9AP 1.570.2 8.571.5 12.172.0

AP ¼ adductor pollicis; LA ¼ laryngeal adductors.

114 KOPMAN AND LIEN

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 � ED95 gantacurium shortened the 5% to 95% recovery

interval by 212

minutes and the total duration of block (the time from administrationof gantacurium to a train-of-four ratio Z0.9) by 61

2minutes. Cysteine (10 mg/kg) will

facilitate complete recovery of the neuromuscular function even when administered

within 1 minute of gantacurium.

Summary

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 NMBAscontinues 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.

References

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2. Bowman WC: Pharmacology of Neuromuscular Function. London, Butterworth and CoLtd, 1990.

3. Naguib M, Flood P, McArdle JJ, Brenner HR: Advances in neurobiology of the neuromuscularjunction: Implications for the anesthesiologist. Anesthesiology 2002; 96:202.

4. Pedersen SE, Cohen JB: D-tubocurarine binding sites are located at alpha-gamma andalpha-delta subunit interfaces of the nicotinic acetylcholine receptor. Proc Natl Acad Sci1990; 87:2785.

5. Dilger JP, Vidal AM, Liu M, et al.: Roles of amino acids and subunits in determining theinhibition of nicotinic acetylcholine receptors by competitive antagonists. Anesthesio-logy 2007; 106:1186--95.

TABLE 3. Recovery Intervals After the Administration of Gantacurium (Mean7SD)

Dose (mg/kg)Recovery Interval(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 7.171.2T1 25--75% 2.770.5 3.370.9 2.570.3 3.471.2 3.171.2 3.071.1 3.271.1T1 25% to

TOFR Z0.95.171.1 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.


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Cap 9

Health & Medicine

Transcript of Cap 9