CHAPTER 65 • INHALATIONAL ANESTHETICS 1017
■■ Nitrous oxide abuse, typically in the form of “whippets,” is common and 25. Inman WH, Mushin WW. Jaundice after repeated exposure to halothane: a further analy-
can lead acutely to life-threatening hypoxia. It causes bone marrow sup-
pression and disabling polyneuropathy with chronic abuse. Treatment
is supportive in acute setting, and patients with long-term hematologic
and neurologic sequelae are treated with vitamin B12, methionine, and
folinic acid.
■■ Halothane, an older halogenated hydrocarbon, is no longer used in
North America but is still in widespread use around the world and is
associated with fulminant hepatitis.
■■ Sevoflurane is associated with production of compound A, which can
cause renal tubular necrosis; however, it is not shown to cause acute
kidney injury in vivo.
■■ Abuse of halogenated volatile anesthetics is rare; treatment is
supportive.
Acknowledgment
Martin Griffel, MD, contributed to this chapter in previous editions.
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20. Frink EJ Jr, et al. Renal concentrating function with prolonged sevoflurane or enflurane
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23. Hoft RH, et al. Halothane hepatitis in three pairs of closely related women. N Engl J Med.
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ficiency. Anesthesiology. 2002;97:1133-1136.
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37. Meyer KH. Contributions to the theory of narcosis. Trans Faraday Soc. 1937;33:1062-1063.
38. Myles PS, et al. Avoidance of nitrous oxide for patients undergoing major surgery: a ran-
domized controlled trial. Anesthesiology. 2007;107:221-231.
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41. Neuberger J, Williams R. Halothane hepatitis. Dig Dis. 1988;6:52-64.
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43. Nunn JF, et al. Megaloblastic bone marrow changes after repeated nitrous oxide anaes-
thesia. Reversal with folinic acid. Br J Anaesth. 1986;58:1469-1470.
44. O’Sullivan H, et al. Human bone marrow biochemical function and megaloblastic hema-
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45. Pohl LR, Gillette JR. A perspective on halothane-induced hepatotoxicity. Anesth Analg.
1982;61:809-811.
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58. Versichelen LF, et al. Only carbon dioxide absorbents free of both NaOH and KOH do
not generate compound A during in vitro closed-system sevoflurane: evaluation of five
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08/11/18 11:18 AM
 66 NEUROMUSCULAR BLOCKERS
Caitlin J. Guo and Kenneth M. Sutin
HISTORY AND EPIDEMIOLOGY
Curare is the generic term for the resinous arrowhead poisons used to para-
lyze hunted animals.116 The curare alkaloids are derived from the bark of the
Strychnos vine, and the most potent alkaloids, the toxiferines, are derived
from Strychnos toxifera. Fortunately for the hunters who used curare, inges-
tion of their prey did not cause paralysis. Sir Walter Raleigh discovered the
use of curare in Guyana in 1595, and he was the first person to bring curare
to Europe. Curare played a pivotal role in the discovery of the mechanism
of neuromuscular transmission. In 1844, Claude Bernard placed a small
piece of dry curare under the skin of a live frog and observed that the frog
became limp and died.8 He performed an immediate autopsy and discovered
that the heart was beating. Because direct muscle stimulation produced
contraction but nerve stimulation did not, Bernard concluded that curare
paralyzed the motor nerves. He later observed, however, that bathing the
isolated nerve did not affect neuromuscular transmission, leading him to
conclude: “Curare must act on the terminal plates of motor nerves.”18 Curare
was used by Nobel Laureate physiologists Charles Sherrington, John Eccles,
and ­Bernard Katz to further elucidate neuromuscular physiology. Its first
clinical use was described in 1878 when Hunter used curare to treat patients
with tetanus and seizures.116 In 1932, Raynard West used curare to reduce the
muscular rigidity of hemiplegia.116
Curare (d-tubocurarine) was introduced into clinical anesthesia in 1943 by
Harold Griffith and Enid Johnson.43 Endotracheal intubation during general
anesthesia was not common those days, so d-tubocurarine was administered
in a dose that spared the diaphragm and maintained spontaneous ventila-
tion. It was not until 1954 when Henry Beecher found that patients receiv-
ing d-tubocurarine had a sixfold increase in respiratory-related anesthesia
mortality that artificial ventilation and reversal of residual d-­tubocurarine
became a routine practice.9 Use of d-tubocurarine spanned almost 40 years
until it was replaced by superior nondepolarizing neuromuscular blockers
that caused less histamine release and hypotension.
Around the same time in the 1950s that curare gained popularity in the
operating room, succinylcholine also came to clinical use to facilitate orotra-
cheal intubation.9 In the nonmedical world, succinylcholine carried a repu-
tation of being the “person poison.”3 This came to media attention when a
high-profile killing case involving an anesthesiologist Dr. Carl Coppolino
and his mistress were accused of murdering his wife and the mistress’s hus-
band in 1966 and 1967, respectively, by injecting succinylcholine.77 In 1983,
shortly after Dr. Michael Swango began his internship at Ohio State University
­Hospital, patients began dying inexplicably, and he was relieved of his duties.109
Following switching residencies and jobs for 14 years, prosecutors secured
Swango’s guilty plea for the murder of three victims. The toxicological analy-
sis of the 7-year-old remains of Thomas Sammarco revealed succinylcholine in
the liver and gallbladder and its metabolite succinylmonocholine in multiple
organs, which assisted in the conviction.
With the advent of new modalities of drug delivery, toxicologists must be
attuned to possible malicious intent. Emergency personnel responding to a
911 call observed the widow removing an insulin pump reservoir from her
dead husband’s body with the stated intent to donate the costly equipment.5
A natural cause of death was presumed, yet surprisingly, forensic analysis
revealed etomidate and laudanosine (a metabolite of atracurium) in the
v­ ictim’s liver.
Understanding the pharmacokinetics and pharmacodynamics of the
depolarizing and nondepolarizing neuromuscular blockers (NDNMBs) is
critical to maximizing benefit while minimizing toxicity.
1018
97-Goldfrank_Ch66_p1018-p1028.indd 1018
MECHANISM OF NEUROMUSCULAR TRANSMISSION AND BLOCK
The purpose of a NMB is to selectively and reversibly inhibit signal trans-
mission at the skeletal neuromuscular junction (NMJ). All NMBs possess at
least one positively charged quaternary ammonium moiety that binds to the
postsynaptic nicotinic acetylcholine (nACh) receptor at the NMJ, inhibiting
its normal activation by acetylcholine (ACh). The nACh receptor is a ligand-
gated ion channel that consists of 4 different protein subunits in a pentam-
eric structure surrounding a central channel. The nACh receptor found in
human skeletal muscle is present in 2 primary forms: a mature type found
at the NMJ (α12βεδ) or as a fetal (immature) type found on muscle at extra-
junctional regions of the muscle fiber (α12βγδ). Figure 66–1 provides an
overview normal neuromuscular transmission and excitation–­contraction
coupling.
Skeletal muscle paralysis can occur by several mechanisms. For example,
tetrodotoxin blocks voltage-sensitive sodium channels, preventing action
potential conduction in the motor neuron (Chap. 39). On the other hand,
botulinum toxin blocks ACh release from the presynaptic neuron by inhib-
iting the binding of ACh-containing vesicles to the neuronal membrane in
the region of the synaptic cleft (Chap. 38). Modulation of postsynaptic ACh
receptor activity at the NMJ may produce paralysis by one of two mecha-
nisms: depolarizing (phase I block) and nondepolarizing (phase II block).
Succinylcholine is the only depolarizing neuromuscular blocker (DNMB) in
current clinical use. High doses of nicotine also cause a depolarizing block.
All other drugs discussed are NDNMBs.
The process of DNMB requires several steps. First, two molecules of succi-
nylcholine must bind to each α site of the nACh receptor. This action causes
a prolonged open state of the nACh receptor ion channel. The initial depolar-
ization generates a muscle action potential and usually causes brief contrac-
tions (fasciculations). In contrast to ACh, succinylcholine is not hydrolyzed
efficiently by acetylcholinesterase (AChE) located in the synaptic cleft. Thus,
the effect of succinylcholine lasts much longer than ACh. Succinylcholine
persistence at the ACh receptor causes a sustained local muscle endplate
depolarization that, in turn, causes the voltage-gated sodium channel in
the perijunctional region to remain in a prolonged inactive state, inducing
a desensitization block. The muscle is temporarily refractory to presynaptic
release of further ACh (phase I block).
The NDNMBs cause skeletal muscle paralysis by competitively inhibiting
the effects of ACh and thus preventing muscle depolarization. One molecule
of an NDNMB bound to a single nACh receptor (also on the α site) is sufficient
to competitively inhibit normal channel activation. Because the NDNMBs do
not block voltage-gated sodium channels on the skeletal muscle membrane,
direct electrical stimulation with a current sufficient to cause membrane
depolarization will still elicit a muscular contraction. The NDNMBs are clas-
sified by duration of action as ultra-short, short, intermediate, and long. They
are also classified by chemical structure as either a synthetic benzylisoquino-
linium or an aminosteroid (Table 66–1).
The NDNMBs also block nACh receptors on the prejunctional nerve ter-
minal and inhibit ACh-stimulated ACh production and release by blocking
local autoregulation of available ACh.98 This effect reduces the available pool
of ACh and augments the extent of neuromuscular block.11
PHARMACOKINETICS
The NMBs are highly water soluble and relatively insoluble in lipids. Thus,
they are rapidly distributed in the extracellular space and very slowly perme-
ate lipid membranes such as the gut, placenta, and the normal blood–brain
25/10/18 4:40 PM

FIGURE 66–1. Excitation–contraction coupling in skeletal muscle. At the
neuromuscular junction, acetylcholine (2) released from the presynaptic nerve
terminal crosses the 50-nm synaptic cleft to reach the nicotinic acetylcholine
(nACh) receptor (1). When an agonist simultaneously occupies both receptor
sites, this ion channel opens, becoming nonselectively permeable to
monovalent cations, resulting in an influx of Na+ and an efflux of K+. This
produces local membrane depolarization (endplate potential), which in
turn opens voltage-gated Na+ channels (3). A depolarization of sufficient
amplitude generates a propagated muscle action potential (MAP), which is
conducted along the muscle membrane and down the transverse (T) tubules
(4). In the T tubule, the MAP triggers a voltage-gated calcium channel (7) and
the dihydropyridine receptor (5), which then activates the skeletal muscle
ryanodine receptor/channel (6). To allow the fastest activation of mammalian
skeletal muscle, calcium diffusion is not necessary for activation of the type 1
ryanodine receptor (RyR-1); instead, there is a direct electrical (protein) linkage
between the dihydropyridine (DHP) receptor and the ryanodine receptor.33
Active ATPase-driven calcium reuptake terminates muscle contraction. Many
factors influence the activity of the RyR-1 channel, including Ca2+, Mg2+, and
xenobiotics such as inhalational anesthetics that accelerate Ca2+ release
in persons susceptible to malignant hyperthermia. Antagonists such as
conotoxin are red and agonists such as nicotine are green.
barrier. For this reason, they are devoid of central nervous system (CNS)
effects. Because these drugs distribute in the extracellular space, their dose
is based on ideal body mass. Thus, in obese patients, estimation of drug
requirement based on total body mass results in the administration of an
excessive dose.
The speed of onset of an NMB is inversely related to its molar potency
(ie, ED95 expressed as moles NMB drug per kilogram body weight).59,60 Stated
differently, the greater the affinity of the NDNMB for the ACh receptor, the
fewer molecules per kilogram of tissue are required to produce a given degree
of ACh receptor occupancy. Atracurium is the only NDNMB that does not
97-Goldfrank_Ch66_p1018-p1028.indd 1019
CHAPTER 66 • NEUROMUSCULAR BLOCKERS 1019
follow this generalization because it is a mixture of 10 isomers, each having a
unique receptor affinity (cisatracurium consists of only one isomer).
In general, small, fast-contracting muscles such as the extraocular mus-
cles are more susceptible to neuromuscular block than are larger, slower
muscles such as the diaphragm. This is the so-called respiratory-sparing
effect. After an intravenous (IV) bolus of NDNMB, paralysis of the diaphragm
is coincident with paralysis of laryngeal muscles because high tissue per-
fusion results in rapid drug distribution and diffusion into the NMJ of all
tissues.25 However, recovery from NMB is fastest for the diaphragm and inter-
costal muscles; intermediate for the large muscles of the trunk and extremi-
ties; and slowest for the adductor pollicis, larynx, pharynx, and extraocular
muscles.25
COMPLICATIONS OF NEUROMUSCULAR BLOCKERS
Complications associated with the use of NMBs include (1) problems asso-
ciated with the care of a paralyzed patient (eg, inability to secure a defini-
tive airway, undetected hypoventilation resulting from ventilator or airway
problems, impaired ability to monitor neurologic function, unintentional
patient awareness, peripheral nerve injury, deep vein thrombosis, and skin
breakdown); (2) immediate side effects; and (3) delayed effects occurring
after prolonged drug exposure.85,86
Consciousness
Even though NMBs do not affect consciousness, misconceptions about these
drugs persist.73 The pupillary light reflex, an important indicator of midbrain
function, is preserved in healthy subjects who receive NDNMBs because
pupillary function is mediated by muscarinic cholinergic receptors, for
which the NMBs have no affinity.42
Histamine Release
Neuromuscular blockers may elicit dose- and injection rate–related nonim-
munologic (non–IgE-mediated) histamine release from tissue mast cells by
an uncertain mechanism (Table 66–1). The NMBs most commonly associ-
ated with histamine release are atracurium and succinylcholine.81
Anaphylaxis
Anaphylactic reactions are rare, with an incidence of 1 in 3,500 to 1 in 20,000
and up to 60% are related to NMBs.81 Part of this variability is due to difficulty
in determining the exact exposures in the operative setting when numerous
xenobiotics and, blood products NMBs are administered simultaneously.
Rocuronium and succinylcholine are the two most cited offenders among all
NMB-associated anaphylaxis.66,115
Control of Respiration
At subparalyzing doses, NDNMBs blunt the peripheral hypoxic ventilatory
response (HVR) but not the ventilatory response to hypercapnia.30,31 Hypoxic
ventilatory response returns to normal when chemical paralysis is com-
pletely reversed. Hypoventilation resulting from blunting of the HVR, espe-
cially when combined with the residual effects of other xenobiotics used
during anesthesia such as opioids or inhalational anesthetics, causes delayed
respiratory failure after general anesthesia.
Autonomic Side Effects
Nicotinic ACh receptors found in autonomic ganglia, similar to those at the
NMJ, are pentamers composed of α and β subunits. In general, they are less
susceptible to block by NMBs.74 There is one notable exception. At the same
dose that produces neuromuscular block, tubocurarine also blocks nACh
receptors at the parasympathetic ganglia, causing tachycardia, and at the
sympathetic ganglia, blunting the sympathetic response.102 In combination
with tubocurarine-related histamine release, the sympathetic block causes
significant hypotension, particularly in patients with heart failure or hypovo-
lemia.11 This is an important reason why tubocurarine is no longer available
in the United States.
The muscarinic receptors (M1−M5) are members of the seven-­
transmembrane G-protein–coupled receptor family. As such, they are struc-
turally unique and mostly unaffected by NMBs. At clinical doses, pancuronium
25/10/18 4:40 PM
 1020 PART C • THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

TABLE 66–1 Pharmacology of Selected Neuromuscular Blockers

Generic Name Class Duration Initial Dose (mg/kg)a,b Onset (min)c Clinical Duration (min)d

Succinylcholine Depolarizer Ultrashort 0.6–1 1–1.5 3–7

Atracurium Nondepolarizer, benzylisoquinolinium Intermediate 0.4 2–4 20–40
Cisatracurium Intermediate 0.1 2–4 20–40
Pancuronium Nondepolarizer, aminosteroid Long 0.1 3–6 60–90
Rocuronium Intermediate 0.6 1.5–3 30–40
Vecuronium Intermediate 0.1 2–4 20–40
Renal Excretion (%)e Biliary Excretion (%)f Metabolite Histamine Release Effect on Heart Rate

Succinylcholine <10 Minimal Succinic acid Minimal Bradycardia (rare)

Atracurium 5–10 Minimal Laudanosine Minimal No
Cisatracurium 10–20 Minimal Laudanosine No No
Pancuronium 40–60 10–20 3-Desacetyl-pancuroniumg No Tachycardia
Rocuronium 10–20 50–70 No No Tachycardia at high dose
Vecuronium 15–25 40–70 3-Desacetyl-vecuroniumc No No
a
Cisatracurium is labeled as milligram of base per milliliter. Other drugs are labeled and packaged as milligram of salt per milliliter. Typical initial dose is approximately 2 × ED95 (mg/kg). cOnset is time from bolus to
b

100% block. dClinical duration is time from drug injection until 25% recovery of single twitch height. ePercent renal excretion in the first 24 h of unchanged drug; if high, associated with prolongation of clinical effect.
f
Percent biliary excretion in first 24 h of unchanged drug; if high, associated with prolongation of clinical effect. gActive metabolite.
Data from Donati F. Neuromuscular blocking drugs for the new millennium: current practice, future trends—comparative pharmacology of neuromuscular blocking drugs. Anesth Analg. 2000;90(suppl):S2-S6;
McManus MC. Neuromuscular blockers in surgery and intensive care, part 1. Am J Health Syst Pharm. 2001;58:2287-2299; and Murray MJ, et al. Clinical practice guidelines for sustained neuromuscular blockade in the
adult critically ill patient. Crit Care Med. 2002:30:142-156.

elicits dose- and injection rate–related increases in heart rate, blood pressure,
cardiac output, and sympathetic tone.26,103,110 This is attributed to a selective
block of parasympathetic transmission at the cardiac muscarinic recep-
tors, an atropine-like effect,103 block of presynaptic (feedback) muscarinic
­receptors at sympathetic nerve terminals, and perhaps an indirect norepi-
nephrine-releasing effect at postganglionic fibers.26
Dysrhythmias such as bradycardia, junctional rhythms, ventricu-
lar ­dysrhythmias, and asystole occur rarely after use of succinylcholine.
­Dysrhythmias most likely result from stimulation of the cardiac musca-
rinic receptors and can be prevented by pretreatment with 15 to 20 mcg/kg
of IV atropine. Bradycardia is uncommon, but it may be especially severe
in ­children during anesthetic induction when large or repeated doses of
­succinylcholine are given.
INTERACTIONS OF NEUROMUSCULAR BLOCKERS WITH OTHER
XENOBIOTICS AND PATHOLOGIC CONDITIONS
The NMBs have significant interactions with many xenobiotics and coexist-
ing medical conditions. These interactions affect the neuromuscular system
at any level from the CNS to the muscle itself (Table 66–2).94,114
In most neuromuscular diseases, such as muscular dystrophy,
­Guillain-Barré syndrome, myasthenia gravis, and postpolio syndrome, the
sensitivity to NDNMB is increased, so a small dose of NMB produces a pro-
found degree of block.2,13,45 However, persons with myasthenia gravis typically
demonstrate resistance to the effects of succinylcholine.2,13 In individuals
with myopathy in whom the specific cause is not yet known, succinylcholine
should be avoided because of the possible sensitivity to malignant hyperther-
mia (MH), hyperkalemia, or rhabdomyolysis. In place of succinylcholine, a
short-acting NDNMB can be used to lessen the chance of prolonged weakness.
Many pathologic conditions potentiate the duration or intensity of
NDNMB, such as respiratory acidosis, hypokalemia, hypocalcemia, hyper-
magnesemia, hypophosphatemia, hypothermia, shock, and liver or kidney
failure.97 Alternatively, acute sepsis and inflammatory conditions are associ-
ated with mild resistance to the effect of NDNMB.88
PHARMACOLOGY OF SUCCINYLCHOLINE
Succinylcholine is a bis-quaternary ammonium ion composed of two mole-
cules of ACh joined end to end at the acetate groups.28 After a conventional IV
induction dose of 1 mg/kg, typical plasma concentrations are approximately
62 mcg/mL.90
Succinylcholine is hydrolyzed primarily by plasma cholinesterase
(PChE, also known as pseudocholinesterase or butyrylcholinesterase;
BChE, EC 3.1.1.8) and to a slight extent by alkaline hydrolysis. Hydrolysis
is a two-step reaction; first succinylmonocholine and choline are formed,
and then succinic acid and choline are formed. The latter two are normal
products of intermediary metabolism. The first reaction is approximately
six times faster than the second reaction. Less than 3% of the adminis-
tered dose is excreted unchanged in the urine.40 After an IV bolus, the
plasma succinylcholine concentration increases abruptly, and there is a
rapid onset of NMJ block. Later, the plasma succinylcholine concentra-
tion undergoes a rapid decline as a result of drug redistribution to extra-
vascular tissues and hydrolysis in plasma. Finally, succinylcholine leaves
the NMJ to reenter the plasma as a result of reversal of the concentration
gradient.39,55
At an induction dose of 1 mg/kg IV, succinylcholine theoretically increases
cerebral blood flow, cortical electrical activity, intracranial pressure (ICP),61
and intraocular pressure, but the clinical implication is unclear. Most data
come from small nonrandomized studies involving ICP, and results are
mixed. In addition, there has not been sufficient evidence that supports rou-
tine use of NDMBs as a pretreatment for succinylcholine.
TOXICITY OF SUCCINYLCHOLINE
The important adverse drug reactions associated with succinylcholine
include anaphylaxis, prolonged drug effect, hyperkalemia, acute rhabdomy-
olysis in patients with muscular dystrophy, MH in susceptible patients, mas-
seter spasms or trismus in patients with congenital myopathies, and cardiac
dysrhythmias. This is especially relevant for children who present with undi-
agnosed or a cyclically subtle myopathy.

97-Goldfrank_Ch66_p1018-p1028.indd 1020 25/10/18 4:40 PM

 CHAPTER 66 • NEUROMUSCULAR BLOCKERS 1021

TABLE 66–2  Effect of Prior Administration of Xenobiotics on Subsequent Response to Succinylcholine or Nondepolarizing Neuromuscular
Blockers
Xenobiotic Response to Succinylcholine Response to Nondepolarizer Comments

Aminoglycosides (eg, amikacin, Potentiates Potentiates Dose-related decrease in presynaptic ACh release. Decrease postjunctional response
gentamicin) to ACh. Partially reversible with calcium administration. The ability of neostigmine
to reverse this effect is unpredictable.
Anticholinesterase, peripherally Prolongs succinylcholine No effect Neostigmine, pyridostigmine, and physostigmine inhibit plasma AChE and ­prolong
­acting: neostigmine, edrophonium (except edrophonium) succinylcholine block. Edrophonium does not inhibit plasma cholinesterase.
Anticholinesterase, centrally Potentiates No effect Inhibits AChE (junctional >> plasma); long half-life (70 h).
­acting: donepezil
β-Adrenergic antagonist: Potentiates in cats, effects in Potentiates When given alone, unmasks myasthenic syndrome. Blocks ACh binding at postsyn-
propranolol humans uncertain aptic membrane. Reversal of block with neostigmine causes severe bradycardia.
β-Adrenergic antagonist: esmolol ? Mild prolongation Slows onset of rocuronium Competes for PChE or red blood cell cholinesterase.
Botulinum toxin ? Early potentiation, delayed Subclinical systemic denervation leads to hypersensitivity.
resistance
Calcium channel blockers Potentiates Potentiates Causes calcium channel block pre- and postjunctionally. Verapamil has local
cholinesterase inhibitor effect on nerve. Inhibits block reversal of NDNMBs by cho-
linesterase inhibitors.
Carbamazepine ? Inhibits, shortened duration Chronic therapy causes resistance to NDNMB, except for atracurium.
Cardioactive steroids More prone to cardiac Pancuronium increases
dysrhythmias ­catecholamines and causes
dysrhythmias
Dantrolene ? Potentiates Blocks excitation–contraction coupling by blocking ryanodine receptor channel in
sarcoplasmic reticulum of skeletal muscle.
Furosemide <10 mcg/kg Potentiates or inhibits Potentiates or inhibits Biphasic dose response in cats; protein kinase inhibition at low doses and
1–4 mg/kg ­phosphodiesterase inhibition at high doses. Diuretic-related hypokalemia
­potentiates pancuronium in cats.
Glucocorticoids ? Inhibits Chronic steroid use induces resistance to pancuronium and decrease plasma
­cholinesterase activity by 50%. Steroids ± NDNMB associated with myopathies.
Inhalational anesthetics: Potentiates Potentiates Decrease CNS activity and potentiates NMB in anesthetic doses: dependent fashion
isoflurane (postsynaptic and muscle effects). Halothane causes less muscle relaxation than
isoflurane.
Lidocaine Potentiates Low dose potentiates block; high The fast Na+ channel blockers decrease action potential propagation, ACh release,
dose inhibits nerve terminals postsynaptic membrane sensitivity, and muscle excitability. Weak inhibitor of PChE.
and blocks ACh binding site at This potentially is observed with all local anesthetic, but practically lidocaine one
­postsynaptic membrane. that is intravenously administered.
Lithium Prolongs onset and duration Prolongs effect of pancuronium Inhibits synthesis and release of ACh. Lithium alone causes myasthenic reaction.
Magnesium Potentiates; blocks Potentiates or prolongs blocks Decreases prejunctional ACh release, postjunctional membrane sensitivity, and
fasciculations muscle excitability.
NDNMB: pancuronium, “Precurarization” with Chronic NDNMB induces resistance Prior NDNMB inhibits plasma PChE and prolongs mivacurium and succinylcholine
vecuronium, rocuronium NDNMB shortens the onset to their effect; mixing different block. Rank order: pancuronium > vecuronium > atracurium. Heterozygote
and decreases side effects of NDNMBs causes greater than addi- for atypical PChE develops phase II block when given succinylcholine and
succinylcholine; pancuronium tive effects, especially combining pancuronium.
increases block duration. pancuronium with tubocurarine or
metocurine.
Organic phosphorus compounds Potentiates ? Irreversible PChE inhibitor. Which totally blocks enzyme activity.
Phenelzine (MAOI) Prolongs ? Decreases PChE activity.
Phenytoin ? Resistant, shortened duration Acutely, potentiates NDNMB paralysis. With chronic use (except for atracurium),
phenytoin induces resistance to NDNMB and increases metabolism. This increases
the initial dose and decreases the repeat dosing interval.
Polypeptide antibiotics: polymyxin Potentiates Potentiates Causes severe weakness and induces postsynaptic neuromuscular block.
­Neostigmine increases block.

(Continued)

97-Goldfrank_Ch66_p1018-p1028.indd 1021 25/10/18 4:40 PM

 1022 PART C • THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

TABLE 66–2  Effect of Prior Administration of Xenobiotics on Subsequent Response to Succinylcholine or Nondepolarizing Neuromuscular
Blockers (Continued)
Xenobiotic Response to Succinylcholine Response to Nondepolarizer Comments

Succinylcholine Small initial dose of Pancuronium and vecuronium

­succinylcholine are used to slightly prolonged by prior
limit muscular fasciculations. succinylcholine.
Theophylline Inhibits The combination of pancuronium and theophylline increases cardiac dysrhythmias.
Cyclic antidepressants (CA) The combination of pancuronium and CA cause cardiac dysrhythmias due to
sympathetic effects.
ACh = acetylcholine; AChE = acetylcholinesterase; CNS = central nervous system; MAOI = monoamine oxidase inhibitor; NDNMB = nondepolarizing neuromuscular blocker; NMB = neuromuscular blocker;
NMJ = neuromuscular junction; PChE = plasma cholinesterase.
Data from Crowe S, Collins L. Suxamethonium and donepezil: a cause of prolonged paralysis. Anesthesiology. 2003;98:574-575; Flacchino F, et al. Sensitivity to vecuronium after botulinum toxin administration.
J Neurosurg Anesthesiol. 1997;9:1491153; Fleming NW, et al. Neuromuscular blocking action of suxamethonium after antagonism of vecuronium by edrophonium, pyridostigmine or neostigmine. Br J Anaesth.
1996;77:492-495; Kaeser HE. Drug-induced myasthenic syndromes. Acta Neurol Scand Suppl. 1984;100:39-47; Kato M, et al. Inhibition of human plasma cholinesterase and erythrocyte acetylcholinesterase by nonde-
polarizing neuromuscular blocking agents. J Anesth. 2000;14:30-34; Ostergaard D, et al. Adverse reactions and interactions of the neuromuscular blocking drugs. Med Toxicol Adverse Drug Exp. 1989; 4:351-368; and
Viby-Mogensen J. Interaction of other drugs with muscle relaxants. In: Katz RL, ed. Muscle Relaxants: Basic and Clinical Aspects. New York, NY: Grune & Stratton; 1985:233-256.

PROLONGED EFFECT hyperkalemic response to succinylcholine is greatly exaggerated with coex-

The effects of succinylcholine last for several hours if metabolism is signifi-
cantly slowed because of decreased PChE concentration, abnormal PChE
activity (genetic variant or drug inhibition), or a phase II block.20 Acquired
PChE deficiency is caused by hepatic disease, malnutrition, plasmapheresis,
or pregnancy.20 Inactivation of PChE results from fluoride poisoning, organic
phosphorus compounds, or carbamates. However, even with only 20% to 30%
of normal PChE activity, the clinical duration of succinylcholine is less than
doubled.35
Many genetic variants of PChE are known. The most common atypi-
cal PChE (atypical type, homozygous; incidence 1:3,000) can be assayed by
its resistance to inhibition by the local anesthetic dibucaine.95 A history of
uneventful exposure to succinylcholine excludes the possibility of atypical
PChE except in the case of hepatic transplantation. Dibucaine inhibits the
ability of normal PChE to hydrolyze benzoylcholine by more than 70% (ie,
dibucaine number >70), heterozygous atypical PChE by 40% to 60%, and
homozygous atypical PChE by 30% or less. Dibucaine number is an effec-
tive method of identifying patients at increased risk for prolonged neuro-
muscular blockade from succinylcholine. The lower the number, the greater
likelihood there will be prolonged neuromuscular blockade from atypical
reasonable PChE activity. Fresh-frozen plasma or PChE concentrates are
infused to hasten recovery in the case of a genetic enzyme defect or an
acquired PChE deficiency. However, to avoid the risks of transfusion, it is
best to provide supportive care, simply keep the patient sedated, intubated,
and ventilated until the drug is metabolized. In this setting, spontaneous
reversal usually occurs within 3 to 4 hours, although in rare cases, full recov-
ery requires up to 12 hours.20 When the duration of succinylcholine is very
prolonged, blood samples should be drawn for measurement of PChE con-
centration and activity.
Prolonged nondepolarizing block also occurs when unusually large IV
doses of succinylcholine (3–5 mg/kg) are given over minutes.68 This is called
phase II block, and it can be partially reversed by neostigmine.
Interestingly, pseudocholinesterase is also involved in metabolism of
cocaine. Plasma cholinesterase catalyzes the hydrolysis of cocaine, and low
PChE concentrations are associated with increased risk of cocaine toxic-
ity.24,51,92 There have been few small studies demonstrating that exogenously
administered PChE degrades cocaine more quickly and is theoretically able
to treat cocaine-induced toxicity.16,75,78,105
HYPERKALEMIA
Succinylcholine 1 mg/kg IV typically causes a transient serum K+ concentra-
tion increase of approximately 0.5 mEq/L within minutes of administration
both in normal individuals and in persons with kidney failure. The acute
isting myopathy or proliferation of extrajunctional muscle ACh receptors.
However, the mortality rate is highest (approaching 30%) when rhabdomy-
olysis is present.44 Severe, precipitous, potentially life-threatening hyperka-
lemia also occurs after succinylcholine administration in several conditions
associated with proliferation of ACh receptors. These conditions include
denervation caused by head or spinal cord injury, stroke, neuropathy, pro-
longed use of NDNMBs because of muscle pathology direct trauma, crush or
compartment syndrome, or muscular dystrophy; critical illness due to hem-
orrhagic shock, neuropathy, myopathy, or prolonged immobility; thermal
burn or cold injury; and sepsis lasting several days. After a neurologic injury,
susceptibility to hyperkalemia begins within 4 to 7 days and persist for an
extended period of time. In patients who have been in the intensive care unit
(ICU) for more than 1 week, succinylcholine should be avoided altogether
because of the risk of hyperkalemic cardiac arrest, which is associated with a
mortality rate of at least 19%.7,10,44 Severe hyperkalemia can be mitigated, but
not prevented, by a small dose of an NDNMB (10%–30% ED95 of the NDNMB
or 5%–15% of the intubation dose). This dose should be sufficient to prevent
succinylcholine-­induced muscle fasciculations.106
Severe or even fatal hyperkalemia is reported in a few patients who
received succinylcholine immediately after exsanguinating hemorrhage or
massive trauma. The mechanism for this condition differs from that after
neurologic injury because of inadequate time for proliferation of extrajunc-
tional ACh receptors. Succinic acid, a tricarboxylic acid cycle intermediate
that is also a metabolite of succinylcholine, facilitates activation of voltage-
gated sodium channels in a dose-dependent fashion, increasing skeletal
muscle excitability.46 In hemorrhagic shock, accumulation of succinic acid as
a result of cell breakdown and anaerobic metabolism possibly augments the
potassium-releasing effect of succinylcholine.
RHABDOMYOLYSIS
Severe hyperkalemia rarely occurs in the absence of a clinical history that
readily discloses an obvious risk factor, with one important exception. Acute
or delayed onset of rhabdomyolysis, hyperkalemia, ventricular dysrhythmias,
cardiac arrest, and death are reported in apparently healthy children who
were subsequently found to have an undiagnosed myopathy.64 Since March
1995, a black box warning on the package insert has stated that succinylcho-
line should be avoided in elective surgery in children, particularly in children
younger than 8 years of age, because of the risk of a previously undiagnosed
skeletal myopathy, especially Duchenne muscular dystrophy. Sudden cardiac
arrest occurring immediately after succinylcholine administration should
always be assumed to be caused by hyperkalemia. If fever, muscle rigidity,
and elevated lactate concentration or metabolic and respiratory acidosis are

97-Goldfrank_Ch66_p1018-p1028.indd 1022 25/10/18 4:40 PM


also present, the presumptive diagnosis of MH should prompt immediate
therapy with dantrolene.
MALIGNANT HYPERTHERMIA
Malignant hyperthermia is a syndrome characterized by extreme skeletal
muscle hypermetabolism. It is most often initiated after exposure to an
anesthetic that triggers a cycle of abnormal calcium release from the skel-
etal muscle sarcoplasmic reticulum and can have a variable presentation.100
Malignant hyperthermia is observed in patients with underlying muscle dis-
eases, such as muscular dystrophy and myotonia. It is also strongly linked to
three rare genetic myopathies, central core disease, King Denborough syn-
drome, and multiminicore disease.
Although MH is linked with rare congenital myopathies, it typically
affects individuals who are otherwise healthy.63 It is inherited as an autoso-
mal dominant trait with variable penetrance.76 Triggering xenobiotics that
can precipitate an attack of MH include succinylcholine and volatile inha-
lational anesthetics (the prototypical xenobiotic is halothane). In individu-
als considered MH susceptible, xenobiotics that can be administered safely
include NDNMBs, nitrous oxide, propofol, ketamine, etomidate, benzodiaz-
epines, barbiturates, opioids, and local anesthetics.
In human MH, there is a causal association with several unique defects
involving a skeletal muscle receptor or regulatory protein, especially defects
involving the voltage sensitive calcium release channel found in skeletal
muscle; the type 1 ryanodine receptor (or RYR1, chromosome 19q13.1).
Mutations of the RYR1 receptor are detected in 50% to 70% of patients with
MH, and more than 200 different mutations are described12,50 (Fig. 66–1).
The structurally distinct type 2 ryanodine receptor (RYR2) is the primary
type expressed in cardiac muscle, and this could explain why the myocar-
dium is relatively spared in the early phase of MH (with the exception of
an acute hyperdynamic response).99 The existence of multiple mutations
across multiple alleles means that genetic testing is not likely to prove use-
ful in detecting all individuals who are MH susceptible or to exclude the
risk of MH.
Although the prevalence of a genetic disorder associated with MH is
between 1 in 3,000 and 1 in 8,500, the observed incidence of fulminant MH in
patients exposed to general anesthesia when triggering anesthetic agents are
used is 1 in 62,000 and 1 in 84,000.93,100 Each year in the United States, there
are an estimated 700 cases of MH.62 Even in those who are MH susceptible
after exposure to anesthesia with known triggers, clinical manifestations
develop less than half the time. For this reason, a previous uneventful anes-
thetic exposure does not preclude development of MH on a subsequent expo-
sure.4 In the operating room, MH most often presents abruptly soon after
initial exposure to a triggering anesthetic, although the onset of MH may be
delayed several hours during the anesthesia84 or occur as long as 12 hours
after surgery. In addition, recrudescence of MH occurs within 24 to 36 hours
after an initial episode in up to 25% of patients.
The immediate systemic manifestations of MH result from extreme skel-
etal muscle hypermetabolism. The uncontrolled release of calcium from the
terminal cisternae of the sarcoplasmic reticulum causes skeletal muscle
contraction. Although generalized muscular rigidity is a specific sign of MH,
it is only observed in 40%; masseter spasm is a finding observed in 27% of
MH patients.63 Futile calcium cycling by sarcoplasmic Ca2+-ATPase rapidly
depletes intracellular adenosine triphosphate and leads to anaerobic metab-
olism. Clinically, MH presents as skeletal muscle hypermetabolism with an
increase in cardiac output and sinus tachycardia; increased CO2 production
causes hypercapnia; increased O2 consumption can cause: mixed venous O2
desaturation (below the normal value of 75%), arterial hypoxemia, anaerobic
metabolism, metabolic acidosis, elevated lactate concentration, cyanosis,
and skin mottling; and excess heat production that leads to a rapid increase
in core temperature with hyperthermia.47 Other clinical findings include
tachycardia, cardiac dysrhythmias, hyperkalemia, rhabdomyolysis, and dis-
seminated intravascular coagulopathy.
The earliest signs of MH include an early and rapid increase in CO2 pro-
duction, causing an increase in arterial, venous, and end-tidal CO2, followed
97-Goldfrank_Ch66_p1018-p1028.indd 1023
CHAPTER 66 • NEUROMUSCULAR BLOCKERS 1023
by or associated with tachycardia; tachypnea; hypertension or labile blood
pressure; and skeletal and jaw muscle rigidity. Despite the name of the syn-
drome, hyperthermia is not a universal finding in MH, and moreover, it may
be a late sign.113 Acute potassium release from skeletal muscle cells produce
life-threatening hyperkalemia. Subsequent rhabdomyolysis exacerbates the
elevation of potassium by causing acute kidney injury. In late-stage MH,
cardiac decompensation results from hyperkalemia, heart failure, vascular
collapse, or myocardial ischemia (especially with coexisting coronary artery
disease).
The differential diagnosis of MH includes antipsychotic malignant
syndrome, propofol infusion syndrome, serotonin toxicity, thyroid storm,
pheochromocytoma, baclofen withdrawal, tetanus, meningitis, poisoning
by salicylates, amphetamines, cocaine, or antimuscarinics, unintentional
intraoperative hyperthermia, environmental heat stroke, and transfusion
reactions (Chap. 29). Of note, early septic shock is also associated with
hypermetabolism, increased cardiac output, and fever; however, in contrast
to MH, early septic shock is associated with an elevated mixed venous O2
saturation (typically >75%).
Rarely, MH is triggered by severe exercise in a hot climate, IV potassium
(which depolarizes the muscle membrane), antipsychotics, or infection.23,54
There is of a possible link between MH and exertional heat illness (EHI) or
exertional rhabdomyolysis (eg, a patient with exertional rhabdomyolysis
who at a later time develops MH).14,15 There is no evidence that patients with
heat-related illness have MH, even if, on occasion, some patients appear to
improve following many interventions including dantrolene. Furthermore,
a presumptive diagnosis of heat-related illness does not necessarily exclude
the diagnosis of MH, and one must maintain clinical suspicion for possible
MH, especially because environmental factors can be a sole precipitating fac-
tor in the absence of anesthetics.50
One theory of the pathogenesis of MH suggests that MH-triggering xeno-
biotics interact with an abnormal RYR1 channel, causing it to stay in a pro-
longed open state and leading to rapid efflux of calcium from the skeletal
muscle sarcoplasmic reticulum into the myoplasm. Succinylcholine pro-
longs muscle depolarization, leading to an elevated myoplasmic calcium
concentration. This action initiates the voltage sensitive calcium release
channel of the sarcoplasmic reticulum.44 However, not all cases of MH can
be explained by an RYR1 mutation.36 For example, MH is also associated with
defects in the CACNA1S protein that encodes a subunit of the skeletal muscle
L-type calcium channel (known as the dihydropyridine receptor) and pos-
sibly with certain disorders of sodium channels (observed in the myotonic
disorders).36,83
The antidote for MH is dantrolene, and the key aspects of MH therapy
are rapid initial diagnosis, discontinuation of triggering anesthetics, active
cooling, and immediate therapy with dantrolene (within minutes). By par-
tially blocking calcium release from skeletal muscle sarcoplasmic reticulum,
­dantrolene rapidly reverses the signs and symptoms of hypermetabolism
(Antidotes in Depth: A24). The precise mechanism of dantrolene activity is
not known, but it modulates several calcium pathways.50 Before the intro-
duction of dantrolene, the mortality rate of MH was 64%.62 When patients
with acute MH are treated immediately with dantrolene, removal of trigger-
ing agents, and supportive measures (volume resuscitation, active cooling,
control of hyperkalemia), the mortality rate is less than 5%.62 Factors associ-
ated with an increase in mortality rate are a muscular body habitus, devel-
opment of disseminated intravascular coagulation, and a longer duration of
anesthesia before the peak in end-tidal carbon dioxide.62 Even if administra-
tion is delayed for hours or days, dantrolene still improves survival after an
acute episode of MH. Patients with significant dysrhythmias can be treated
with standard antidysrhythmics; however, calcium channel blockers must
not be given with dantrolene because they precipitate h­ yperkalemia and
severe hypotension101 (Table 66–3).
Persons who have experienced a possible episode of MH or have a positive
family history should be referred to the Malignant Hyperthermia Registry and
may be considered for muscle biopsy or genetic sequencing of the RYR1 gene.
The muscle biopsy is considered to be the gold standard, but patients must
25/10/18 4:40 PM
 1024 PART C • THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

TABLE 66–3 Therapy for Malignant Hyperthermia (MH)a

Acute Phase Treatment of MH
1. Call for help. Immediately summon experienced help when MH is suspected. Call MH ­hotline, 800-644-9737.
2. Discontinue triggers: volatile inhalational anesthetics and succinylcholine.
3. Hyperventilate with 100% O2 with flow ≥10 L/min and monitor end-tidal CO2.
4. Halt procedure as soon as possible and continue sedation and analgesia with nontriggering agents: opioids and benzodiazepines.
5. Administer dantrolene, initial IV bolus of 2.5 mg/kg followed by additional boluses (every 15 minutes), until signs of MH are controlled (tachycardia, rigidity, increased end-tidal CO2,
­hyperthermia). Typically, a total dose of 10 mg/kg IV controls symptoms, but occasionally 30 mg/kg is required.
• Dantrium/Revonto:b Each 20-mg vial is reconstituted by adding 60 mL of sterile water.
• Ryanodex: Each 250-mg vial is reconstituted by adding 5 mL of sterile water.
6. Monitor core temperature closely (tympanic membrane, nasopharynx, esophagus, rectal, or pulmonary artery) and actively cool the patient with core temperature >39°C (immersion in
­ice-water slurry is preferred, cooling by peritoneal or gastric lavage, surface cool or surface cooling techniques are also reasonable).
7. Hyperkalemia is common and should be treated aggressively with hyperventilation, IV calcium gluconate (30 mg/kg up to 3 g) or chloride (10 mg/kg up to 1 g), sodium bicarbonate,
IV dextrose, and insulin. Hypokalemia should be treated with caution because of the potential for rhabdomyolysis induced hyperkalemia.c
8. Sodium bicarbonate. 1–2 mEq/kg (up to 50 mEq/kg) is reasonable if blood gas values have not yet been obtained or if clinically indicated.
9. Monitor continuously: ECG, pulse oximetry, end-tidal CO2, core temperature, CVP, urine output; and serially measure: arterial and mixed venous blood gases, metabolic profile (especially
­potassium), calcium, CBC, coagulation indices, and creatine kinase.
10. Dysrhythmias usually respond to dantrolene, cooling, and correction of acidosis and hyperkalemia. If dysrhythmias persist or are life threatening, standard antidysrhythmics are indicated,
including amiodarone, magnesium, and procainamide.
• Calcium channel blockers (verapamil or diltiazem) should not be used to treat dysrhythmias because they may cause hyperkalemia and cardiac arrest.
11. Ensure adequate urine output by restoration of intravascular volume followed by administration of mannitol or furosemide. Insert a urinary bladder catheter and consider central venous or
pulmonary artery catheterization.
12. For emergency consultation, refer to the MHAUS at http://www.mhaus.org/. Call the MH Emergency Hotline:
• Inside the United States or Canada, call 800-MH-HYPER (800-644-9737).
• Outside the United States and Canada, call 001 315-464-7079.
Postacute Phase Treatment of MH
1. Observe the patient in an ICU setting for at least 24 h because recrudescence of MH occurs in 25% of cases, particularly after a fulminant case resistant to treatment. Observe for pulmonary
edema, kidney failure, and compartment syndrome.
2. Administer dantrolene 1 mg/kg IV q4–6h or 0.25 mg/kg/h by infusion for at least 24 h after the episode.
3. Serially monitor arterial blood gases, metabolic profile, CBC, creatine kinase, calcium, phosphorus, coagulation indices, urine and serum myoglobin, and core body temperature until they
return to normal values.
4. Counsel the patient and family regarding MH and further precautions.
• For nonemergency patient referrals, contact the MHAUS at 800-644-9737, 1 North Main Street, PO Box 1069, Sherburne, NY 13460.
• Report patients who have had an acute MH episode to the North American MH Registry of MHAUS at 888-274-7899.
• Alert family members to the possible dangers of MH and anesthesia.
5. Recommend an MH medical identification tag or bracelet for the patient, which should be worn at all times.
a
The guidelines may not apply to every patient and of necessity must be altered according to specific patient needs. bThere are two formulation of dantrolene, Dantrium/Revonto and Ryanodex. cSudden unexpected
cardiac arrest in children: Children younger than about 10 years of age who experience sudden cardiac arrest after succinylcholine administration in the absence of hypoxemia and anesthetic overdose should be
treated for acute hyperkalemia first. In this situation, calcium chloride should be administered along with means to reduce serum potassium. They should be presumed to have subclinical muscular dystrophy, and
a pediatric neurologist should be consulted.
CBC = complete blood count; CVP = central venous pressure; ECG = electrocardiogram; ICU = intensive care unit; IV = intravenous; MHAUS = Malignant Hyperthermia Association of the United States.
Modified with permission from Malignant Hyperthermia Association of the United States (mhaus.org).

travel to an authorized testing center for biopsy. There are currently four
centers in the United States and one center in Canada. A fresh tissue speci-
men is placed in a tissue bath perfused with Krebs solution, and halothane
or caffeine is added. According to the North America Malignant Hyperther-
mia Group, an MH-susceptible individual is one who demonstrates a p­ ositive
muscle contraction in response to either halothane or caffeine. On the other
hand, genetic testing can be performed. Additional information regarding
testing options can be found on the w­ ebsite of the ­Malignant Hyperthermia
Association of the United States (www.mhaus.org).
MUSCLE SPASMS
Masseter muscle rigidity was observed in 0.3% to 1.0% of children when
general anesthesia was induced with succinylcholine and halothane (a tech-
nique now obsolete) and currently is much less frequently encountered. Mas-
seter muscle rigidity is clinically significant because it will complicate airway
management and herald the onset of MH.91
When administered to persons genetically predisposed to myotonia,
succinylcholine precipitates tonic muscular contractions, ranging from
trismus (which prevents orotracheal intubation) to severe generalized
myoclonus and chest wall rigidity (which prevent ventilation).32 Because the
myotonic contractions are independent of neural activity, they cannot be
aborted by an NDNMB. Usually the contractions are self-limited, but occa-
sionally they will be life threatening if an airway cannot be established and
hypoxemia ensues.
PHARMACOLOGY OF NONDEPOLARIZING
NEUROMUSCULAR BLOCKERS
Table 66–1 summarizes the pharmacology and toxicity of the NDNMBs.53,79,80,86
Whereas atracurium is composed of 10 different isomers, each having its
unique pharmacokinetic and pharmacodynamic profile, cisatracurium
contains only the 1R-cis and 1′R-cis isomers. Both atracurium and cisatra-
curium exhibit organ-independent elimination and are rapidly metabolized

97-Goldfrank_Ch66_p1018-p1028.indd 1024 25/10/18 4:40 PM


by spontaneous (nonenzymatic) temperature- and pH-dependent Hoffmann
degradation and, to a lesser extent, by ester hydrolysis. The latter is catalyzed
by nonspecific plasma esterases distinct from the PChE that hydrolyzes suc-
cinylcholine. In addition, significant drug metabolism or elimination occurs
in the liver and kidney.34
TOXICITY OF NONDEPOLARIZING NEUROMUSCULAR BLOCKERS
The most important toxic effects of the NDNMBs are accumulation of lau-
danosine and persistent weakness. In general, limiting the drug dose and
monitoring the drug effect with a portable nerve stimulator reduce the inci-
dence of prolonged weakness.
Laudanosine
Metabolism of atracurium and cisatracurium generates laudanosine, which
crosses the blood–brain and placental barriers and may cause neuroexcita-
tion but lacks any neuromuscular blocking activity.29 Metabolism of each
atracurium molecule generates one molecule of laudanosine.89 Cisatracu-
rium is an improvement over atracurium because it produces one-third as
much laudanosine (and is three times more potent).38,58
In the CNS, laudanosine has an inhibitory effect at the γ-aminobutyric
acid, nACh, and opioid receptors. At high serum concentrations in experi-
mental animals, laudanosine causes dose-related neuroexcitation, myo-
clonic activity (>14 mcg/mL), and generalized seizures (>17 mcg/mL).17,38
In humans, the toxic serum laudanosine concentration is unknown, and
seizures directly attributable to atracurium are not reported even after
prolonged infusion in the ICU.38,117 In ICU patients who received a 72-hour
infusion of atracurium (1 mg/kg/h), the highest serum laudanosine concen-
trations (10–20 mcg/mL) were observed in patients with impaired glomer-
ular filtration rate.69 Laudanosine is excreted primarily in the bile, and its
elimination is prolonged in patients with liver disease, biliary obstruction,
and kidney disease.96
Persistent Weakness Associated with Nondepolarizing
Neuromuscular Blockers
Short-term blockade with a NDNMB usually resolves promptly upon discon-
tinuation. When an NDNMB is administered for more than 48 hours, there is
a risk that weakness will persist longer than anticipated based on the kinet-
ics of drug elimination. In addition, critical illness is associated with dys-
function of the peripheral nerve, NMJ, and muscle (Table 66–4). For instance,
in the ICU, persistent weakness is observed in 68% to 100% of patients with
sepsis or multiorgan failure22,37,112 and in 20% to 30% of patients who receive
NDNMB for only 48 to 72 hours.71 Persistent weakness is multifactorial and
associated with illness severity; sepsis; acute respiratory distress syndrome;
multiorgan failure; hyperglycemia; NDNMB; use of systemic corticosteroids;
TABLE 66–4 Acute Neuromuscular Pathology Associated With Critical Illness or Nondepolarizing Neuromuscular Blockers
Critical Illness Polyneuropathy
Sensory Moderate to severe, distal > proximal
Motor Symmetric weakness, lower > upper
­extremity, proximal > distal or diffuse,
­respiratory failure
Creatine phosphokinase Normal
Electrodiagnostic studies Axonal degeneration of motor > sensory, Fatigue at NMJ assessed by fade on
(EMG, NCV) reduced sensory and motor compound action repetitive nerve stimulation
potentials, normal NCV
Muscle biopsy Denervation atrophy
EMG = electromyography; NCV = nerve conduction velocity; NMJ = neuromuscular junction.
Data from Bolton CF. Critical illness polyneuropathy and myopathy. Crit Care Med. 2001;29:2388-2390; Lacomis D. Critical illness myopathy. Curr Rheumatol Rep. 2002;4:403-408; Lacomis D, Campellone JV. Critical ill-
ness neuromyopathies. Adv Neurol. 2002;88:325-335; and Leijten FSS, de Weerd AW. Critical illness polyneuropathy: a review the literature, definition and pathophysiology. Clin Neurol Neurosurg. 1994;96:10-19.
97-Goldfrank_Ch66_p1018-p1028.indd 1025
CHAPTER 66 • NEUROMUSCULAR BLOCKERS 1025
muscle injury; thermal injury, and electrolyte, endocrine, and nutritional
disorders.21,27,49,70 Many xenobiotics given to patients in the ICU can cause
weakness by themselves or potentiate the effects of NDNMB.52,94 Progressive
weakness and acute respiratory failure are even described after discharge
from the ICU and will be life threatening if not immediately recognized.65
Patients who develop persistent weakness have a 2.5- to 3.5-fold increase in
ICU mortality and ICU stay.71
PHARMACOLOGIC REVERSAL OF NEUROMUSCULAR BLOCKADE
Acetylcholinesterase Inhibitors
Termination of NMB effect initially results from drug redistribution and later
from drug elimination, metabolism, or chemical antagonism. Pharmacologic
antagonism of a partial NDNMB is achieved by giving a reversal agent that
inhibits junctional AChE and thereby increases ACh at the NMJ. This increase
in ACh can overcome the competitive inhibition caused by residual NDNMB.
The commonly used anti-ChEs are polar molecules that possess a quaternary
ammonium (Table 66–5). Neostigmine and pyridostigmine are hydrolyzed
by ChE and form short-lived carbamyl complexes (half-life, 15–20 minutes)
with the esteratic site of the enzyme.6 In contrast, edrophonium is not hydro-
lyzed by ChE; rather, it forms an electrostatic interaction and a hydrogen
bond with the cationic site of ChE that is both competitive and reversible.
Neostigmine and pyridostigmine, but not edrophonium, inhibit PChE and
thus prolong the effects of xenobiotics metabolized by this enzyme, such as
succinylcholine.35
The most common and troublesome clinical side effect of ChE inhibi-
tion is bradycardia, which usually is prevented by coadministration of an
antimuscarinic such as atropine.19 Bradydysrhythmias are severe and lead
to nodal or idioventricular rhythm, complete heart block, or even asystole.72
These side effects occur more frequently in patients with preexisting brady-
cardia and those receiving chronic β-adrenergic antagonist therapy. They
are not necessarily prevented by prior administration of atropine.108 Other
problems that result from excess ChE inhibition are hypersalivation, lacrima-
tion, bronchospasm, increased bronchial secretions, abdominal cramping
from intestinal hyperperistalsis, and increased bladder tone. After general
anesthesia, use of anti-ChE pharmacologic reversal increases the incidence
of nausea, vomiting, and abdominal cramps.57 Because atropine crosses the
blood–brain barrier, it may produce central anticholinergic syndrome.
Sugammadex
Sugammadex (Bridion) is a selective NDNMB binder that was developed spe-
cifically for rapid and complete reversal of neuromuscular blockage induced
by rocuronium and vecuronium (Fig. 66–2). Approved by the ­European
Union in 2008 for use, the US Food and Drug Administration initially rejected
Residual Neuromuscular Block Disuse (Cachectic) Myopathy Critical Illness Myopathy
Normal Normal Normal
Diffuse symmetric weakness, Diffuse weakness, Symmetric weakness, proximal > distal
­respiratory failure proximal > distal or diffuse, respiratory failure
Normal Normal Elevated in ≤50%
Normal EMG and NCV Myopathic changes, muscle membrane
inexcitability, normal NCV
Normal Atrophy of type 2 fibers, Atrophy of type 2 fibers, myosin loss,
no ­myosin loss, no necrosis mild myonecrosis, no inflammatory
infiltration
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 1026 PART C • THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

TABLE 66–5 Pharmacology of Intravenous Neuromuscular Blockade Reversal Drugs and Coadministered Antimuscarinics
Anticholinesterases

Neostigmine Pyridostigmine Edrophonium

Initial dose (mg/kg) 0.04–0.08 0.2–0.4 0.5–1.0

Onset (min) 7–11 10–16 1–2
Duration (min) 60–120 60–120 60–120
Recommended antimuscarinic Glycopyrrolate Glycopyrrolate Atropine (preferred because of time of onset is better paired
with edrophonium)
Antimuscarinics

Glycopyrrolate Atropine

Structure Quaternary ammonium Tertiary amine

Initial dose (mg/kg) 0.01–0.02 0.02–0.03
Onset (min) 2–3 1
Duration (min) 30–60 30–60
Elimination Renal Renal
Crosses blood–brain barrier No Yes

sugammadex because of concerns of hypersensitivity and allergic reactions
but it was approved in December 2015.
Sugammadex reverses the effect of steroidal NMBs by directly binding
to the steroidal NMB at 1:1 ratio to form sugammadex–NMB complex, thus
preventing the binding of NMBs to the nicotinic receptors. Although sugam-
madex can bind to all steroidal NMBs, its affinity is greatest for rocuronium
followed by vecuronium and least with pancuronium.87 Administration of
IV sugammadex results in rapid removal of NMB from plasma, which facili-
tates the movement of NMBs from the NMJ into plasma through a concen-
tration gradient effect, where they bind to any free remaining sugammadex.
Thus, sugammadex can reverse any depth of neuromuscular blockade in a
dose-dependent fashion. After the sugammadex–NMB complex is formed, it
is eliminated through biliary (75%) and renal (25%) clearance and excreted
via the urine (65%–97%).48 In addition, the sugammadex–NMB complex is
inert and does not cause any muscarinic effect. There are some concerns
over hypersensitivity and allergic reactions, which occurred in 0.3% of
healthy ­volunteers, which delayed its approval in the United States. A par-
ticular precaution for sugammadex exists on utilizing women on hormonal
contraceptives. In vitro studies indicate sugammadex binds to progesterone
and decreases the concentration. Administration of sugammadex is consid-
ered to be equivalent to missing a dose (or doses) of an oral contraceptive.
Therefore, patients must be counseled regarding the use additional non-
hormonal or back-up method of contraception for the subsequent 7 days if
they received the sugammadex and are receiving hormonal contraceptives.
The doses of sugammadex based on actual body weight are:1
■■ 2 mg/kg for shallow blockade: if spontaneous recovery has been
reached up to the reappearance of the second twitch to train-of-four
stimulation after rocuronium and vecuronium blockage
■■ 4 mg/kg for profound blockage: if 1 or 2 posttetanic counts and response
to train-of-four stimulation after rocuronium and vecuronium blockade
■■ 16 mg/kg for immediate reversal: 3 minutes after administration of
1.2 mg/kg of rocuronium. Immediate reversal of vecuronium is unstudied.
Sugammadex is not effective for nonsteroidal NMBS such as mivacu-
rium, atracurium, and cisatracurium. Therefore, if neuromuscular blockage
needs to be reestablished after sugammadex, succinylcholine or one of the
nonsteroidal neuromuscular blockers should be used. In the meantime, sup-
portive management is continued with establishing a definitive airway and
mechanical ventilation.

FIGURE 66–2. Sugammadex encapsulating a molecule of rocuronium.
(Reproduced with permission from Hemmerling TM, Zaouter C, Geldner G, et al.
Sugammadex—a short review and clinical recommendations for the cardiac
anesthesiologist. Ann Card Anaesth. 2010;Sep-Dec;13(3):206-216.)
CHOICE OF REVERSAL
Choice of reversal between sugammadex versus acetylcholinesterase inhibi-
tor is complex. Although sugammadex has been available in Europe since
2008, experience has been limited in the United States due to availability and
cost, largely because of its very recent approval.
Sugammadex offers two major advantages: rapid reversal and lack of cho-
linergic side effects. Its disadvantages include a lack of affinity for nonsteroidal
NDNMB and a variable affinity for steroidal NMB (rocuronium > vecuronium
>> pancuronium). Thus, it is unlikely to replace acetylcholinesterase inhibi-
tors completely. In routine anesthesia care, rapid reversal of NDNMB is rarely
needed, and the anticholinergic effects are well tolerated when administered
with an antimuscarinic. However, there are clearly situations when rapid
reversal of an NDNMB with sugammadex can be beneficial such as difficult
airway management, brief surgical procedures that require deep neuromus-
cular blockade, patients with cardiac comorbidities who do not tolerate
dysrhythmias from AChE inhibition, and pediatric patients in whom neuro-
muscular blockage have been avoided because of unknown myopathy.

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