Relajantes en quemados

Muscle Relaxants in Burns,
Trauma, and Critical Illness

J.A. Jeevendra Martyn, MD, FRCA, FCCM
Yuji Fukushima, MD, PhD
Jin-Young Chon, MD, PhD
Hong Seuk Yang, MD, PhD

’ Uses of Muscle Relaxants

The use of muscle relaxants for endotracheal intubation has become
routine in the operating room. The reason for the use of muscle
relaxants is that deep inhalation or intravenous anesthesia, that can be
used to produce muscle relaxation to facilitate intubation of the trachea,
would not be tolerated because of the drugs’ effects on the cardiovas-
cular system, usually hypotension and bradycardia. Attempts to intubate
patients, who are not deeply anesthetized or not paralyzed by muscle
relaxants, could result in retching, vomiting, and laryngospasm.
Retching and vomiting can lead to pulmonary aspiration of gastric
contents with serious consequences in any patient, but can have
particularly dangerous consequences in burned, trauma, or critically
ill patients because of their already compromised immune system.1
In the operating room, muscle relaxants are also used to treat
laryngospasm, particularly when it is associated with desatura-
tion. Critically ill patients desaturate faster because of their hypermeta-
bolic state, low functional residual capacity, and/or poor lung
function.2 Besides the operating room, muscle relaxants are used for
tracheal intubation in the emergency room, intensive care unit
(ICU), and even outside the hospital when trauma patients are
transported from the accident scene to the hospital.3–8 Muscle
relaxants, therefore, are most often used for endotracheal intubations
both in and outside operating rooms, and within and without the
hospital setting.
Muscle relaxants can also be useful adjuncts to general anesthesia.
For example, relaxants can be used to prevent reﬂex movements to
surgery during high-dose narcotic anesthesia with sedation. Experience
123

124 ’ Martyn et al

with anesthesia in unstable cardiac patients9–11 has brought advances in
the care of traumatized or critically ill patients as well. In patients for
cardiac surgery, incremental doses of narcotics and muscle relaxants
generally produce more cardiovascular stability than the usual inhala-
tion of anesthetic agents alone. Similarly, some clinicians feel that
‘‘balanced’’ anesthesia with nitrous oxide, narcotics, and muscle
relaxants to inhibit reﬂex movement produces more stable anesthesia,
particularly in critically ill or trauma patients. Another indication for
the short-term (less than 12 h) use of muscle relaxants is to maintain
a patient motionless for a therapeutic or diagnostic procedure (eg,
placement of invasive monitors, computed tomography or magnetic
resonance imaging scans, pulmonary angiograms, and intestinal endo-
scopy). In some other instances immobilization of critically ill patients
with muscle relaxants is required for short periods to control the
movement of patients who are a danger to themselves, because their
movement (eg, status epilepticus) may dislodge devices such as invasive
monitors or in some other way compromise their care. Relaxants in the
ICU can be an integral part of the management to control muscle
rigidity of tetanus or shivering in hypothermic patients.12 Obviously, in
all the above-enumerated instances, the concomitant use of sedatives
and analgesic drugs is mandatory; the use of muscle relaxants alone
would result in paralyzed and conscious patients who are unable to
communicate their pain or discomfort.13,14
In critically ill, trauma, or burned patients, muscle relaxants can be
used to facilitate mechanical ventilation as it is often associated with
sustained improvement in oxygenation.15,16 This improvement in
oxygenation may be related to reversal of atelectasis, reduced
oxygen consumption, and decreased energy expenditure of the
critically ill patients.17–19 In some patients, the respiratory muscles
account for as much as 50% of the total body oxygen consumption.20 In
such circumstances, mechanical ventilation with the use of muscle
relaxants will allow oxygen to be rerouted to other tissue beds that
may be vulnerable because of increased use of oxygen by ventilatory
muscles.21 In addition, ventilatory failure related to respiratory
muscle fatigue recovers with adequate rest of the muscles for short
periods. Prolonged use of relaxants, however, will lead to muscle
wasting. Muscle relaxants can be a component in the management
of neurosurgical patients to prevent the increase of intracranial
pressure during suctioning and coughing.22 It is a commonly held
misconception that muscular paralysis is a calm and painless
state. Several reports have indicated that being paralyzed in a conscious
state is an unpleasant experience.13,14 Thus, muscle relaxants should
never be used alone either in the intensive care setting or in the
operating room and should always be coadministered with sedatives and
narcotics.

Relaxants in Burns, Trauma, and Critical Illness ’ 125

’ Problems Related to the Use of Muscle Relaxants

Complications have been reported with (and without) the use of
muscle relaxants in critically ill patients, and include difficulties in the
management of the airway, esophageal intubation, aspiration, and even
death.8 Hypoxemia is the most common cause of death during
intubation.2,8 These complications were not always attributable to the
use of muscle relaxants. In fact, the use of muscle relaxants to facilitate
prehospital or emergency room intubation improved outcomes of
patients with trauma.4–7 In normal patients, succinylcholine produces
rapid onset (less than 1 min) of neuromuscular paralysis, which then
permits expeditious intubation of patients where full stomach or
struggling of patients poses difficulties for the caregiver in the
management of the airway. The most serious disadvantage of the use
of muscle relaxant in any patient is when one cannot ventilate or
intubate a patient who has been paralyzed by a muscle relaxant. It is
imperative, therefore, that one does not get into this situation when
using relaxants. Hypoventilation during spontaneous respiration is
always better than no ventilation with iatrogenically induced muscle
paralysis. Another common side effect of muscle relaxants is the
hemodynamic instability; depending on the relaxant used, bradycardia
or tachycardia and hypotension or hypertension can be seen. Other side
effects of muscle relaxants have been discussed elsewhere in this issue.
The pros and cons of the use of muscle relaxants including
succinylcholine during open globe (eye) injuries has been reviewed
recently.23 A dangerous side effect of succinylcholine is that it can
produce massive hyperkalemia leading to ventricular tachycardia and/or
ventricular fibrillation, and cardiac arrest.24,25 The normally insignif-
icant rise in plasma potassium levels associated with succinylcholine
administration can become exaggerated in some burned, trauma, and
critically ill patients. In view of the unpredictability of the types of
patients (Table 1) that would respond with hyperkalemia, succinylcho-
line is generally contraindicated 48 to 72 hours after trauma, burns, and

Table 1. Pathologic Conditions with Potential for Hyperkalemia with Succinylcholine and
Resistance to NDMRs
Upper or lower motor neuron defect (trauma to, or disease of, the central or
peripheral nervous system)
Prolonged chemical denervation (muscle relaxants, magnesium, clostridial toxins)
Direct trauma, tumor or inflammation of muscle
Major thermal trauma or electrical injury
Immobilization of several muscles with disuse atrophy
Severe infection with generalized loss of muscle mass
All of these conditions enumerated have the potential to up-regulate (increase) AChRs with
increased expression of gAChRs and a7AChRs throughout muscle membranes.


critical illness. In contrast to the supersensitivity to depolarizing
relaxant, these same patients (Table 1) are resistant (hyposensitive) to
the neuromuscular effects of nondepolarizing muscle relaxants
(NDMRs); the dose and the plasma concentration requirements to
achieve neuromuscular paralysis are increased 3 to 5-fold.24–27 These
altered responses to neuromuscular relaxants are related to both quali-
tative and quantitative changes in the acetylcholine receptors (AChRs)
expressed on the muscle membrane (see below).24,25,28 Succinylcholine
hyperkalemia can be observed even in the absence of changes in AChRs,
during profound hemorrhage in association with metabolic acidosis.29
The mechanism of this hyperkalemia is unknown.

’ Biology of the Postjunctional Nicotinic AChRs

The receptors expressed on the skeletal muscle membrane are
nicotinic AChRs, named as such because of their ability to bind to the
tobacco alkaloid, nicotine. Nicotinic AChRs produce acetylcholine-
mediated neurotransmission at the neuromuscular junction, autonomic
ganglia, and selected snyapses at the brain and spinal cord.30 There are
17 nicotinic AChR subunit genes that have been cloned in vertebrates
a1-a10, b1-b4, and each of d, g, and e. The schematic in Fig. 1 illustrates
the known arrangements of the subunits constituting the AChRs that are
expressed in skeletal muscle. In the normal innervated muscle, AChRs
are present only in the junctional area and are considered ‘‘mature’’
receptors. The mature or junctional receptor is formed by five subunits,
one consisting of two a1, and one each of b1, e, and d subunits in the
order of increasing molecular weight (Fig. 1). The binding sites for its

Figure 1. Sketch of muscle AChR channels. The mature innervated channel consists of two a1-
subunits and one each of b1, d, e-subunits. In the immature or fetal form, the g-subunit replaces the
e-subunit and therefore consists of two a1-subunits, and one each b1, d, g-subunits. The a7AChR is
a homomeric channel composed of five a7-subunits (pentamers). All of the receptors can be
depolarized by acetylcholine. The a7AChR can be depolarized by concentrations of choline that do not
depolarize the mature and immature AChR channels. The gAChR compared with e-AChR can be
depolarized by lower concentrations of acetylcholine and succinylcholine. The gAChR and a7AChR
may have lower affinity for antagonists or neuromuscular blockers, thus requiring higher
concentrations of these drugs (ligands) to block them.


neurotransmitter, acetylcholine, and for some of the ligands (eg, muscle
relaxants) that bind to the AChR are located in the a-subunits. Although
the innervated neuromuscular junction synthesizes only the mature type
of AChRs, the muscle nuclei have genes for the synthesis of other
isoforms of AChRs. These muscle nuclei genes do not direct the
synthesis of these other isoforms as long as there is muscle activity or
active contact with the nerve.24,30 When there is deprivation of neural
influence or activity, as in the fetus before innervation or after
denervation, two other isoforms, the immature AChR or gAChR and
the neuronal a7AChR, are expressed in muscle. The immature (g)AChR
has a subunit composition of a1, b, g, and d in a ratio of 2:1:1:1. Thus,
the g-subunit substitutes for the e-subunit in the immature AChR in the
denervated muscle (Fig. 1). The immature or gAChR is also referred to
as extrajunctional because it is expressed mostly, but not exclusively, in
the extrajunctional region of the muscle membrane.
More recently, an AChR containing five a7-subunits has been
described in skeletal muscle during development and denervation.31,32
These a7AChRs are homomeric (ie, formed in the same subunit)
channels formed by five subunits and referred to as pentamers (Fig. 1).
As expected, the endogenous agonist, acetylcholine, binds to all of these
receptors, including the a7AChRs. Other agonists, including nicotine
and choline, and antagonists (muscle relaxants, cobra toxin—bungar-
otoxin toxin, and snail toxins—conotoxins) also bind to these receptors,
but with different potencies. Laboratory studies indicate that not only
during denervation and in the fetus, but also during immobilization of
any form, whether it is produced by simple muscle inactivity or is
chemically, iatrogenically (eg, pinning) or pathologically induced,
the AChRs quantitatively and qualitatively behave as if they
are denervated.25,33–36 The most common chemical agents producing
immobilization and inducing a denervation-like state are the neuro-
muscular relaxants.37–40 Other chemicals that can produce a denerva-
tion-like state include clostridial toxins (tetanus and botulinum) and
chronic magnesium sulfate as in the treatment of preeclampsia.
Preliminary and/or indirect evidence indicates that in conditions
enumerated in Table 1 there is an up-regulation of both gAChR and
a7AChR throughout the muscle membrane.
The cobra toxin, a-bungarotoxin, is used to quantitate the AChRs in
muscle. This ligand, however, does not differentiate between the mature
junctional, immature (g) extrajunctional, and the a7 receptors. Electro-
physiologic, molecular biologic, and/or immunologic (monoclonal anti-
body) techniques can distinguish between them.24,30 The changes in
subunit composition (g vs. e vs. a7) also change the electrophysiologic
characteristics of these receptors. Developing or denervated extrajunc-
tional gAChRs have a smaller single channel conductance and a 2 to
10-fold longer open-channel time than do AChRs at the mature


end-plate (eAChR). The expression of gAChR alters the sensitivity of this
receptor to both agonists and antagonists. Agonists such as acetylcholine,
decamathonium, and succinylcholine depolarize immature receptors
more easily and are able to lead to cationic fluxes (Na+ and Ca2+
inwards and K+ outwards) at concentrations very much smaller than
those that would cause cationic fluxes in the mature eAChRs; compared
with the innervated state, 1/10th to 1/100th doses of acetylcholine can
affect depolarization in the gAChR.33 The potency of competitive
antagonists such as pancuronium may also be altered. Low concentra-
tions of NDMRs effectively antagonize the actions of iontophoeretically
applied acetylcholine in the mature eAChRs, whereas the gAChRs are
resistant to block by these drugs. Studies by Gu et al41 and Yost et al42 in
in vitro systems, however, do not confirm this resistance of gAChRs to
the NDMRs.
The a7AChRs also display unusual functional and pharmacologic
characteristics compared with the other 2 receptors previously de-
scribed. Choline, an extremely weak agonist of the gAChR and eAChR,
is a full agonist of the a7AChR. Concentrations of choline that do not
open the mature and the immature AChRs will open the a7AChR
channels.31 Furthermore, no desensitization of the a7AChR occurs even
during the continued presence of choline, a feature that contradicts
what is seen in the a7AChRs expressed in the central nervous
system where the a7AChRs undergo rapid desensitization with cho-
line.31 The a7AChR can be depolarized by succinylcholine also,43,44
allowing greater chance for potassium efflux from within the cell to the
extracellular space down its concentration gradient. The a7AChR in
muscle also has a lower affinity for antagonists such as pancuronium
and a-bungarotoxin; higher concentrations of these drugs were
required to block the a7AChRs compared with AChRs containing a, b,
d, and e/g-subunits.31

’ Control of Expression of Isoforms of AChRs

The trophic function of the nerve and the associated electrical
activity are of vital importance for the development, maturation, and
maintenance of neuromuscular function. Multiple growth (trophic)
factor signaling (eg, insulin, agrin, AChR inducing activity), and the
presence or absence of innervation control the expression of the mature
(e) receptors versus the other two (g, a7) isoforms.45 Quite in contrast to
other cells, muscle cells are unusual, in that they have many, usually
hundreds of, nuclei per cell. Each of these nuclei has the genes to make
all three types of AChRs. As the fetus develops and the muscles become
innervated, the muscle cells begin to synthesize the mature isoform
of receptors, which are inserted exclusively in the developing (future)
end-plate area.


Initially, the factors released from the nerve induce the synaptic area
nuclei to increase the synthesis and therefore the numbers of AChRs.
Next, the nerve-induced electrical activity results in the repression of
AChRs in the extrajunctional area. The nerve-derived growth factors,
agrin and AChR inducing activity/neuregulin, cause the receptors to
cluster in the subsynaptic area and prompt expression of the mature e
receptor isoform.46 The gAChR and the a7AChR gradually disappear
from the extrajunctional area. Agrin is a protein from the nerve that
stimulates postsynaptic differentiation by activating muscle speciﬁc
kinase (MUSK), a tyrosine kinase expressed selectively in muscle.
Sometime after birth, all the AChRs are converted into the mature e-
subunit-containing AChRs. No information is available regarding the
growth factors that control the expression of a7AChRs, except that the
conditions that increase the expression of gAChRs also seem to increase
that of a7AChRs.
In conditions associated with insulin resistance, there seems to be a
proliferation of AChRs beyond the junctional area. Insulin mediates its
action via a tyrosine kinase receptor. Conditions in which insulin
resistance has been observed include immobilization, burns, and
denervation.47–50 In all these conditions, there is associated up-
regulation of AChRs and expression of the gAChR and possibly
a7AChR in the extrajunctional region.51–53 Thus, the decreased
signaling of agrin via muscle speciﬁc kinase and tyrosine kinase receptor
may play a role in the up-regulation and altered isoform expression
of AChRs in the pathologic states enumerated in Table 1. Direct
electrical stimulation of the muscle even in the absence of nerve function
or nerve-evoked muscle contraction attenuates the spread of AChRs
underscoring the importance of muscle electrical activity in the control
of AChRs.33,45

’ The Biopharmacologic Basis for Increased Sensitivity
to Succinylcholine and Resistance to NDMRs

The classical pharmacologic theory regarding the interaction of
antagonists or agonists with up-regulated (increased) and down-
regulated (decreased) receptors is used to explain the increased and
decreased sensitivity to muscle relaxants observed in burn, trauma, and
critically ill patients. The term ‘‘up-regulation and down-regulation’’
generally refers to changes in the availability of the total number of
receptors, but these changes usually do not involve or imply a change in
isoform changes. In the muscle, however, there is also the potential for
the three (e, g, and a7AChRs) molecular species to coexist. These
isoforms that are expressed concomitantly can affect the response of
both depolarizing and NDMRs. Despite the presence of three isoforms
and their individual effects on pharmacodynamics, these differences


do not seem to prevent the application of these classical dogmas to the
responses observed with competitive antagonists (eg, NDMR) and ago-
nists (eg, succinylcholine) of AChRs.24,25 Succinylcholine behaves like an
agonist because it is really two molecules of acetylcholine joined
together, and therefore it initially stimulates the receptor before causing
muscle paralysis.54 The receptor theory proposes that in conditions
where there is a proliferation of AChRs, there will be increased
sensitivity to agonists and decreased sensitivity to antagonists.55,56 In
other words, there is a shift to the left in the dose-response curves to
agonist succinylcholine, and a shift to the right in the dose-response
curves to antagonists (NDMRs) in the presence of proliferated AChRs,
(Fig. 2). The increased sensitivity to agonists in the extreme form results
in lethal hyperkalemic response to succinylcholine.
Clinical conditions in which neuromuscular responses to relaxants
behave as if the AChRs are up-regulated are given in Table 1. Therefore,
both upper and lower motor neuron injuries caused by injury or disease
will increase AChRs. Immobilization (disuse atrophy), a condition
invariably associated with trauma, critical illness, and burns will increase
AChRs despite the anatomic integrity between nerve and muscle.
Critical illness, particularly in association with sepsis, causes generalized

Figure 2. Correlation of 95% ED95 of d-tubocurarine for gastrocnemius twitch tension
suppression to nicotinic AChRs concentration in the same muscle. Each point indicates one animal.
There was a significant positive (r = 0.8, P<0.0001) correlation between the two variables. The
burn-injury-induced increase in AChRs in muscle was associated with proportional increases in the
ED95 for d-tubocurarine. Modified from Ref. 79. Similarly, the potassium response to succinylcholine
was also significantly correlated to the AChR number, as shown by Yanez and Martyn.37


neuropathies, which can up-regulate AChRs, although there is no
obvious anatomic denervation.57,58 Thermal injury, direct muscle
trauma, and infection, all conditions associated with systemic or local
inﬂammation, are associated with increased AChRs, particularly at sites
local to injury.59 Infectious organism that invariably up-regulate AChRs
are the clostridial toxins (tetanus and botulinum).60,61 The clostridial
toxins produce paralysis by inhibiting the release of acetylcholine. Thus,
wound infection or chronic food poisoning with clostridial toxins can
affect the release of acetylcholine at nerve endings, cause paralysis, and
up-regulate AChRs. Whether other pathogenic bacterial and viral
organisms can cause up-regulation is unclear. The concomitant presence
of disease-induced immobilization may contribute to the increased
AChRs and altered sensitivity to muscle relaxants. Chronic treatment
with neuromuscular relaxants will up-regulate AChRs not only because
of the immobilization but also because of antagonism of the receptor
itself.37–39 In all these instances the up-regulation not only involves
increased receptor number but also appearance of new receptor
proteins, the gAChRs and a7AChRs. The biologic basis for these
isoform changes has been reviewed in the previous section.
Although target organ or pharmacodynamic changes may play a
major role in the resistance to NDMRs and hyperkalemia to succinyl-
choline, pharmacokinetic factors and pharmacogenetic components also
may contribute to these variations in drug response. For example, it is
well known that several drugs including muscle relaxants have
enhanced elimination kinetics after burn injury.62,63 Additional factors
that might contribute to the resistance to NDMRs include binding of the
drug to plasma protein components particularly a1-acid glycoprotein,
which binds to cationic drugs and decreases their free concentration in
plasma.64,65

’ Molecular Pharmacologic Basis for the Hyperkalemia
With Succinylcholine

During succinylcholine administration to normal patients, it depo-
larizes the AChRs present only at the junctional area, resulting in efﬂux
of intracellular potassium ions only through the junctional AChRs.
Despite the high density of AChRs at the neuromuscular junction, this
depolarization results in a change in plasma potassium concentrations of
B0.5 to 1.0 mEq/L. When there is an up-regulation of AChRs (Table 1)
throughout the whole muscle membrane, these up-regulated receptors
in the extrajunctional area consist of immature (a1, b, d, g) and
a7AChRs. The proportion of each of these receptor subtypes (g vs. a7)
in the affected muscle is unknown, but the total AChR number
dramatically increases compared with the innervated muscle. The
systemically administered succinylcholine depolarizes all the AChRs on


the muscle membrane releasing intracellular potassium into the plasma
and extracellular space.25,66 Furthermore, in contrast to acetylcholine,
because succinylcholine is metabolized more slowly (10 to 20 min),
sustained depolarization of the AChRs occurs, exaggerating the
potassium release.
There are additional factors that may compound the exaggerated
release of potassium from these AChRs. Because these immature
gAChRs can be depolarized with smaller than normal concentra-
tions of succinylcholine,25,33,66 the depolarization will persist despite
decreasing concentrations of succinylcholine during its metabolic
breakdown. The metabolic breakdown product of succinylcholine,
choline, is a strong agonist of a7AChR.31 Thus, choline can continue
to activate a7AChRs, with the release of more potassium into circulation.
The concentration of pancuronium required to attenuate choline-
evoked depolarization was higher in the presence of a7AChR than with
conventional AChRs.31 Thus, usual doses of pancuronium, or any other
nondepolarizing muscle relaxant administered before succinylcholine,
would not ablate the hyperkalemic response to succinylcholine.25

’ Diagnosis and Treatment of Hyperkalemia With
Succinylcholine

Electrocardiographic changes in association with cardiovascular
instability, occurring within 2 to 5 minutes after succinylcholine
administration, should alert the caregiver to a tentative diagnosis of
succinylcholine-induced hyperkalemia. The electrocardiographic
changes include tall T waves >5 mm (K+ 6 to 7 mEq/L), small broad
or absent P waves, wide QRS complex (K+ 7 to 8 mEq/L), sinusoidal
QRST (K+ 8 to 9 mEq/L), and atrioventricular dissociation or
ventricular tachycardia/fibrillation (K+ >9 mEq/L).25 Electrocardio-
graphic changes may not always be present with hyperkalemia.67 Severe
hyperkalemia, with cardiovascular collapse, is a life-threatening condi-
tion that needs immediate attention. The fastest measure of the efficacy
of therapy is the electrocardiogram and cardiovascular response.
Whenever there is electrocardiographic evidence of hyperkalemia,
including early signs of it (peaked T wave), multipronged therapy
should be initiated simultaneously.
Approaches to treatment should include antagonizing the potassium
effects on cardiac conduction and shifting potassium from extracellular
fluid to intracellular fluid.68 Calcium salt (chloride or gluconate) should
be administered intravenously with continuous electrocardiographic
monitoring. Calcium directly antagonizes hyperkalemia-induced depo-
larization of resting membrane potential.25 The recommended dose of
10% calcium gluconate (or chloride) is 10 mL (1 to 2 ampules)
administered as a slow bolus over 2 to 3 minutes. The dose in children


is 0.5 mL/kg.25 Calcium, even when effective, may require several
repetitive doses, as its effect dissipates in 15 to 30 minutes.
Drugs that promote the cellular uptake of potassium include insulin
with glucose, catecholamines, and sodium bicarbonate. Acidosis
enhances the release of potassium from the cell. Repeated doses (1 to
3 mL/kg) of sodium bicarbonate (8.4%) to correct the acidosis may be
useful. Glucose (50 mL of 50% dextrose) together with 10 units of
regular insulin will facilitate the redistribution of potassium into the cell.
In children, a glucose load of 0.5 g/kg (2.5 mL/kg of 50% dextrose) with
insulin 0.05 units/kg is recommended.68 The effect of insulin takes at
least 10 minutes and peak effect takes 30 to 60 minutes. b-receptor
agonists, such as epinephrine, will not only help with cardiopulmonary
resuscitation, but will also drive the potassium intracellularly.25 In most
patients, the succinylcholine-induced hyperkalemia lasts less than 10 to
15 minutes. In some instances, however, the reversal to normokalemia
may take very much longer. Concomitant rhabdomyolysis may
aggravate the hyperkalemia. Therefore, cardiopulmonary resuscitation
should be continued as long as required.

’ Onset and Duration of Susceptibility to
Hyperkalemia With Succinylcholine

Even in the absence of trauma-related or critical illness-related
neuromyopathies, immobilization by itself with and without the use of
muscle relaxants can lead to up-regulation of AChRs.36,37 This up-
regulation is not high enough to cause hyperkalemia with succinylcholine
at 48 to 72 hours of immobilization/denervation. Persistence of the
perturbation, however, will lead to further up-regulation. In a study of
denervation of a single limb, hyperkalemia was observed as early as 4 days
after injury but the potassium levels did not reach lethal levels, probably
related to the duration and limited (single limb) nature of the denerva-
tion.69 The concomitant presence of a pathologic state (eg, meningitis,
head injury) together with immobilization has been reported to cause
hyperkalemic cardiac arrest as early as 5 days.24 The prolonged use of
NDMRs, infections related to the trauma or major burns, and/or
quadriplegia are conditions involving many muscle fibers. These patho-
logic states that lead to some form of immobilization may be sufficient to
up-regulate receptors to critical levels to cause hyperkalemia even earlier
than 5 days. Thus, it may seem wise to avoid the use of succinylcholine
beyond 48 to 72 hours of denervation/immobilization and/or any other
pathologic state where AChRs are known to increase. Whether severe
infection alone, in the absence of confinement in bed, is a contraindication
to succinylcholine is unknown. Parenthetically, it should be noted, however,
that hyperkalemia to succinylcholine has not been reported in patients with
acquired pathologic states of less than 4 days duration.


The up-regulation of AChRs can persist as long as the condition that
induced it continues to be present. Quadriplegics and paraplegics with
persistent paralysis, therefore, could have the potential for succinylcho-
line hyperkalemia throughout life. Compared with simple immobiliza-
tion, the use of muscle relaxants will cause more profound increases in
AChRs. It is also unknown, however, when this AChR up-regulation, in
critically ill ICU patients who have had critical illness neuropathy/myo-
pathy and/or muscle relaxants, reverts to normal. Therefore, it seems
prudent to avoid succinylcholine in patients who have recovered
recently from critical illness, major burns, or major trauma, particularly
if muscle function is still abnormal. Our experience with burned patients
suggests that AChRs return to normal levels once wounds are healed,
protein catabolism has subsided, and the patient is mobile. This healing
process may take well over 1 to 2 years after wound coverage in patients
with major (80% body surface area) burns or longer if counted from
date of injury. If immobilization or muscle tissue catabolism persists
owing to severe contractures or other reasons, then the up-regulation of
AChRs will not abate.

’ Use of NDMRs

Drugs included in this category are the clinically available long-
acting nondepolarizing relaxants, including d-tubocurarine, metocur-
ine, and pancuronium, and the intermediate duration relaxants
vecuronium, atracurium, rocuronium, and cisatracurium. Except for
atracurium and cisatracurium, all these enumerated muscle relaxants
have a predominant renal excretion pathway, although a greater
fraction can be eliminated by the liver in the presence of renal failure
(Table 2). The trauma, critical illness, and burn-associated liver and
renal dysfunction can also complicate the administration of relaxants
eliminated by the liver and/or kidney. The neuromuscular effect of a
single dose of muscle relaxant is primarily terminated by redistribution
from the neuromuscular junction and the central compartment into the
peripheral compartment. After repeated injection or continuous
infusion, however, the redistribution capacity might be saturated and
the muscle relaxants and their active metabolites can be distributed back
into the central compartment. In this case, the neuromuscular recovery
is determined primarily by elimination of the drug.70 In contrast to
d-tubocurarine and metocurine, which are predominantly excreted by
the kidney, steroidal relaxants rocuronium, pancuronium, vecuronium,
and rocuronium are eliminated through the kidneys and the liver. Thus,
hepatic elimination of these drugs and their metabolites can be
important during kidney dysfunction (Table 2). As for the steroidal
relaxants, the parent compound and its metabolites have muscle
relaxant activity. Consequently, they can accumulate over a period of


Table 2. Muscle Relaxant Metabolism, Elimination, Onset, and Duration of Action in
Normals
Renal 2ED95 Recovery
Muscle Elimination Onset to 25%
Relaxant Metabolism (%) (%) (min) (min)
Mivacurium 95–99 (plasma <5, High elimination 2.5–4.5 15–20
pseudocholines- in pseudocholin-
terase) esterase deﬁciency
Atracurium 70–90 (Hofmann 10–30 (matabolite 2–3 35–50
elimination and inactive)
esterases)
Cisatracurium 70–90 (Hofmann 10–30 (metabolite 3–6 40–55
elimination and inactive)
esterases)
Vecuronium 30–40 (hepatic) B40 (metabolites 2–3 30–40
active)
Pancuronium 10–20 (hepatic) 60–80 (metabolites 3.5–6 70–120
active)
Rocuronium Minimal (hepatic) 30–40 (metabolites 1.5–2.5 35–50
active)
2ED95 onset indicates onset time when two times ED95 was administered; Recovery of the
twitch to 25% of baseline twitch height; TOF, train of four ratio.

time with repetitive doses or continuous infusions causing persistent
neuromuscular effects.
During the initial 3 to 4 days after critical illness, burns, or trauma,
the target organ sensitivity to the NMDRs is usually normal, in that the
usual 2 Â ED95 (95% effective dose) doses will produce effective
paralysis within 3 to 5 minutes after injection (Table 2). At periods
beyond this, however, either because of the injury and/or associated
immobilization, these patients begin to develop resistance to the neuro-
muscular effects of NDMRs.24–27 This would be evidenced as decreased
response to normal doses, slow onset of effect, and rapid recovery from
a given dose. On the basis of the neuromuscular response, the doses
may have to be altered. If there is associated renal and/or liver
dysfunction, the doses may have to be modiﬁed accordingly on the basis
of the response. Clinical observations in trauma and burns suggest that
the initial dose requirement to achieve a given paralysis is increased
even in the presence of kidney and liver dysfunction, but the recovery
from paralysis or the frequency of the dose of administration may not be
the same as in patients with normal organ function.
Atracurium and its isomer cisatracurium are unique drugs, in that
they are independent of the kidney and liver for their elimination.
They undergo spontaneous degradation by Hoffman elimination
pathway.70,71 The metabolites of both drugs are inactive, and therefore


do not cause persistent paralysis after termination of continuous
infusion despite the continued presence of the metabolites. Hoffman
elimination takes place in the central and peripheral compartments.
Atracurium can also be degraded through ester hydrolysis. It is
unknown whether cisatracurium also displays the same pathway.71
Mivacurium is a drug different from all other NDMRs, in that it is
metabolized to inactive metabolites by plasma pseudocholinesterase. It is
well known that critically ill patients, including burned patients, have
decreased pseudocholinesterase activity.72 It will therefore be not
surprising that the metabolism of mivacurium will be impaired in these
critically ill patients. Clinical studies have in fact conﬁrmed the
prolonged recovery of burned patients from mivacurium-induced
paralysis.73,74 Thus, the frequency of the administration of mivacurium
may have to be reduced in these patients on the basis of the response.

’ Use of Muscle Relaxants for Rapid (Emergency)
Intubation

Muscle relaxants are extensively used for intubation both in and
outside the hospital setting.3–8 The use of muscle relaxants at the
accident scene and before transport to the hospital has improved
outcome of these patients.5–7 Rapid onset of the effect of neuromuscular
paralysis is important, particularly when patients have a full stomach,
because it decreases the time the airway is exposed and therefore
decreases the risk of aspiration of gastric contents. Most trauma and
burned patients who are intubated shortly after the accident could be
assumed to have a full stomach, and therefore the rapid onset of
paralysis is critical. Succinylcholine is not contraindicated in the
immediate period after trauma and burn injury. The spread of AChRs
to a critical level to cause hyperkalemia takes more than 72 hours and is
dependent on the severity of the injury. No reports of succinylcholine
hyperkalemia exist before 72 hours of insult or injury. In the presence of
severe hemorrhage and metabolic acidosis, succinylcholine may cause
hyperkalemia.26 Beyond 72 hours after injury, it seems prudent to avoid
succinylcholine.
About 3 to 4 days after injury or critical illness, these patients start to
develop resistance to the neuromuscular effects of NMDRs.24–27 Thus,
ﬁnding a substitute of succinylcholine that would produce rapid onset of
neuromuscular paralysis in these situations to facilitate intubation in
emergency situations (eg, full stomach or laryngospasm) is an area of
neuromuscular pharmacology that has received little attention. High
doses of drugs such as metocurine and pancuronium can induce a more
rapid onset of paralysis in normal patients. Because of the hyposensi-
tivity (resistance) to NDMRs that one sees a few days after critical illness,
trauma, and burn, very much higher than normal doses have to be


administered. The major disadvantage of this approach is the
unacceptable cardiovascular effects of these drugs when they are
administered as a bolus in high doses.
Studies in normal adults have demonstrated significant cardiovas-
cular stability and rapid onset of neuromuscular paralysis when
pancuronium and metocurine are administered in combination; the
ED95 dose of each drug was decreased during their combined
administration, because of their synergistic effects.75 The efficacy
of pancuronium and metocurine administered in combination to create
rapid onset of paralysis in acute burned patients and in control patients
has been tested.75 When pancuronium (0.6 mg/kg) and metocurine
(0.3 mg/kg) were used in combination in burned patients, 95% paralysis
was achieved in 3.1 ± 0.9 minutes. Increasing the doses to the
approximate normal 1 Â ED95 doses of pancuronium (0.1 mg/kg) and
metocurine (0.4 mg/kg) and administering them in combination to
burned patients reduced the onset time to 1.3 ± 0.1 minutes.75 Although
an occasional patient showed prominent changes in heart rate and blood
pressure, the overall cardiovascular stability was impressive. The most
serious disadvantage of this technique, however, was the prolonged
recovery time of almost 2 hours to just 25% of baseline twitch height.75
The newer intermediate acting neuromuscular relaxants, rocur-
onium and mivacurium, offer some advantages over the older relaxants
because of their slightly faster onset or shorter duration of action,
respectively, and minimal cardiovascular effects. It must be noted,
however, that even rocuronium in normal patients does not have an
onset as fast as succinylcholine.76 Neuromuscular pharmacodynamics of
rocuronium in patients with major burns, who are resistant to the
neuromuscular effects of NDMRs, has been tested.77 Rocuronium was
used at 3 times (0.9 mg/kg) or 4 times (1.2 mg/kg) the normal ED95 dose.
The onset time to 95% neuromuscular block was prolonged in burned
patients compared with nonburned patients (Table 3). Dose escalation
shortened the onset time, but prolonged the duration of action. The
higher dose also improved the intubating conditions in burned patients.
All recovery profiles were significantly shorter in burned patients
compared with nonburned patients with both bolus doses. This study
concluded that resistance to the neuromuscular effects of rocuronium
was partially overcome by increasing doses. But it is important to note
that despite the dose of 1.2 mg/kg the onset time was still prolonged
to 86 seconds for 95% paralysis. This seems too long for rapid sequence
induction particularly in patients with poor lung function. 2,77
In another study in children and adolescents, the neuromuscular
pharmacodynamics of mivacurium was studied after burn injury of less
than 6 days duration and also at 1 to 2 weeks after the burn.73,74
Surprisingly, after the normal intubating bolus dose of 0.2 mg/kg, the
onset time to maximum suppression was not different between burns


Table 3. Rocuronium Onset, Recovery of TOF, and Intubating Conditions in Burns and
Controls
Controls Burns Controls Burns
Dose of rocuronium (mg/kg) 0.9 0.9 1.2 1.2
Onset to 95% paralysis (s) 68 ± 16 115 ± 58* 57 ± 11* 86 ± 20
Recovery to TOFZ0.8 (min) 132+ 23 103 ± 25* 162 ± 28* 126 ± 14*
Excellent intubating 65 38* 79 67*
conditions (%)
Mean ± SD.
*P<0.05 compared with control with same dose.

and controls. But recovery to 95% was slightly prolonged in burned
patients with greater than 30% body surface burn irrespective of time
and magnitude of injury (Table 4). The prolonged recovery in burned
patients was inversely related to the plasma cholinesterase activity
(R = – 0.93, P<0.001), and the decreased plasma cholinesterase activity
was related to burn size and time after burn. Thus, in these 2 studies, a
normal intubating dose of mivacuriaum (0.2 mg/kg) affected good
relaxing conditions in burned patients with an onset time similar to that
of controls. These findings, therefore, contrasted with the response seen
with all other studies with NDMRs, where even with higher than normal
doses, the onset of paralysis was slower than in controls and recovery
of paralysis was faster in burns.24,77 The decreased metabolism of
mivacurium, resulting from depressed plasma cholinesterase activity,
probably counteracted the receptor-mediated potential for resistance to
the neuromuscular effects. Thus, mivacurium may be an alternative to
succinylcholine to effect rapid onset paralysis in these patients or to treat
laryngospasm. Because of the potential for release of histamine by
mivacurium, the use of H1 and H2 receptor antagonists before
administration of mivacurium may ameliorate or completely abolish
the cardiovascular side-effects that such high doses of mivacurium
have.78 Pretreatment with H1 and H2 antihistamine agents is not
possible when treating laryngospasm because of the urgency.

’ Conclusion

Burned, trauma, and critically ill patients have the potential to
exhibit aberrant responses to neuromuscular blocking drugs. Muscle
relaxants are commonly used to produce paralysis for intubation, as an
adjunct to anesthesia, to prevent reﬂex responses to surgery and/or
during interventions, and to facilitate mechanical ventilation in the ICU.
In all these instances muscle relaxants should be used in combination
with sedatives and narcotics, otherwise one will have immobilized
patients fully aware of their surroundings and in pain. The chronic use


Table 4. Mivacurium Pharmacodynamics (0.2 mg/kg) in Controls and Burns
Maximum Time to Time to 25%
Twitch Maximum Twitch
Burn size Time After Cholinesterase Suppression Paralysis Recovery
(% TBSA) Burn Activity IU/ML (%) (Min) (Min)
10–30 r6 days 3.1 ± 1.5* 98 ± 2 3±1 12 ± 4
10–30 1–12 weeks 3.0 ± 1.3* 99 ± 1 3±1 14 ± 5
<30 <6 weeks 2.3 ± 2.2* 97 ± 7 2±1 22 ± 7*
<30 1–12 weeks 1.3 ± 0.8* 96 ± 14 2±1 20 ± 10*
Controls — 5.4 ± 1.4 95 ± 10 3±1 13 ± 14
Mean ± SEM.
TBSA indicates total body surface area.
*P<0.05 from controls.

of muscle relaxants in these patients can lead to neuromuscular
dysfunction and persistent muscle weakness. The myopathy and
dangers of the chronic use of muscle relaxants has been discussed in
another chapter in this issue. Although succinylcholine may be used
safely within the ﬁrst few days of trauma, it is inadvisable to use this drug
beyond 48 to 72 hours of trauma, particularly in the presence of
immobilization/denervation of whatever origin. High dose rocuronium
or normal dose mivacurium may be alternative drugs for use in these
patients, particularly for rapid intubation or for the treatment of
laryngospasm. It is unknown whether some of the newer drugs that are
being introduced into clinical practice, AVERA 490, would be useful for
intubation and maintenance of relaxation in these patients. Although
careful investigation of the action of muscle relaxants in burned patients
has provided guidelines for their use in trauma and critically ill patients
also, alternative drugs to induce rapid onset of neuromuscular paralysis
in these patients deserve further development and study.

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