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 becomeroutine in the operating room. The reason for the use of musclerelaxants is that deep inhalation or intravenous anesthesia, that can beused 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 intubatepatients, who are not deeply anesthetized or not paralyzed by musclerelaxants, could result in retching, vomiting, and laryngospasm.Retching and vomiting can lead to pulmonary aspiration of gastriccontents with serious consequences in any patient, but can haveparticularly dangerous consequences in burned, trauma, or criticallyill patients because of their already compromised immune system.1

In the operating room, muscle relaxants are also used to treatlaryngospasm, 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 lungfunction.2 Besides the operating room, muscle relaxants are used fortracheal intubation in the emergency room, intensive care unit(ICU), and even outside the hospital when trauma patients aretransported from the accident scene to the hospital.3–8 Musclerelaxants, therefore, are most often used for endotracheal intubationsboth in and outside operating rooms, and within and without thehospital setting.

Muscle relaxants can also be useful adjuncts to general anesthesia.For example, relaxants can be used to prevent reflex movements tosurgery during high-dose narcotic anesthesia with sedation. Experience

123

with anesthesia in unstable cardiac patients9–11 has brought advances inthe care of traumatized or critically ill patients as well. In patients forcardiac surgery, incremental doses of narcotics and muscle relaxantsgenerally 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 musclerelaxants to inhibit reflex movement produces more stable anesthesia,particularly in critically ill or trauma patients. Another indication forthe short-term (less than 12 h) use of muscle relaxants is to maintaina patient motionless for a therapeutic or diagnostic procedure (eg,placement of invasive monitors, computed tomography or magneticresonance imaging scans, pulmonary angiograms, and intestinal endo-scopy). In some other instances immobilization of critically ill patientswith muscle relaxants is required for short periods to control themovement of patients who are a danger to themselves, because theirmovement (eg, status epilepticus) may dislodge devices such as invasivemonitors or in some other way compromise their care. Relaxants in theICU can be an integral part of the management to control musclerigidity of tetanus or shivering in hypothermic patients.12 Obviously, inall the above-enumerated instances, the concomitant use of sedativesand analgesic drugs is mandatory; the use of muscle relaxants alonewould result in paralyzed and conscious patients who are unable tocommunicate their pain or discomfort.13,14

In critically ill, trauma, or burned patients, muscle relaxants can beused to facilitate mechanical ventilation as it is often associated withsustained improvement in oxygenation.15,16 This improvement inoxygenation may be related to reversal of atelectasis, reducedoxygen consumption, and decreased energy expenditure of thecritically ill patients.17–19 In some patients, the respiratory musclesaccount for as much as 50% of the total body oxygen consumption.20 Insuch circumstances, mechanical ventilation with the use of musclerelaxants will allow oxygen to be rerouted to other tissue beds thatmay be vulnerable because of increased use of oxygen by ventilatorymuscles.21 In addition, ventilatory failure related to respiratorymuscle fatigue recovers with adequate rest of the muscles for shortperiods. Prolonged use of relaxants, however, will lead to musclewasting. Muscle relaxants can be a component in the managementof neurosurgical patients to prevent the increase of intracranialpressure during suctioning and coughing.22 It is a commonly heldmisconception that muscular paralysis is a calm and painlessstate. Several reports have indicated that being paralyzed in a consciousstate is an unpleasant experience.13,14 Thus, muscle relaxants shouldnever be used alone either in the intensive care setting or in theoperating room and should always be coadministered with sedatives andnarcotics.

124 ’ Martyn et al

’ Problems Related to the Use of Muscle Relaxants

Complications have been reported with (and without) the use ofmuscle relaxants in critically ill patients, and include difficulties in themanagement of the airway, esophageal intubation, aspiration, and evendeath.8 Hypoxemia is the most common cause of death duringintubation.2,8 These complications were not always attributable to theuse of muscle relaxants. In fact, the use of muscle relaxants to facilitateprehospital or emergency room intubation improved outcomes ofpatients with trauma.4–7 In normal patients, succinylcholine producesrapid onset (less than 1 min) of neuromuscular paralysis, which thenpermits expeditious intubation of patients where full stomach orstruggling of patients poses difficulties for the caregiver in themanagement of the airway. The most serious disadvantage of the useof muscle relaxant in any patient is when one cannot ventilate orintubate a patient who has been paralyzed by a muscle relaxant. It isimperative, therefore, that one does not get into this situation whenusing relaxants. Hypoventilation during spontaneous respiration isalways better than no ventilation with iatrogenically induced muscleparalysis. Another common side effect of muscle relaxants is thehemodynamic instability; depending on the relaxant used, bradycardiaor tachycardia and hypotension or hypertension can be seen. Other sideeffects of muscle relaxants have been discussed elsewhere in this issue.

The pros and cons of the use of muscle relaxants includingsuccinylcholine during open globe (eye) injuries has been reviewedrecently.23 A dangerous side effect of succinylcholine is that it canproduce massive hyperkalemia leading to ventricular tachycardia and/orventricular fibrillation, and cardiac arrest.24,25 The normally insignif-icant rise in plasma potassium levels associated with succinylcholineadministration can become exaggerated in some burned, trauma, andcritically ill patients. In view of the unpredictability of the types ofpatients (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 andResistance to NDMRs

Upper or lower motor neuron defect (trauma to, or disease of, the central orperipheral 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 withincreased expression of gAChRs and a7AChRs throughout muscle membranes.

Relaxants in Burns, Trauma, and Critical Illness ’ 125

critical illness. In contrast to the supersensitivity to depolarizingrelaxant, these same patients (Table 1) are resistant (hyposensitive) tothe neuromuscular effects of nondepolarizing muscle relaxants(NDMRs); the dose and the plasma concentration requirements toachieve neuromuscular paralysis are increased 3 to 5-fold.24–27 Thesealtered 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 Succinylcholinehyperkalemia 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 arenicotinic AChRs, named as such because of their ability to bind to thetobacco alkaloid, nicotine. Nicotinic AChRs produce acetylcholine-mediated neurotransmission at the neuromuscular junction, autonomicganglia, and selected snyapses at the brain and spinal cord.30 There are17 nicotinic AChR subunit genes that have been cloned in vertebratesa1-a10, b1-b4, and each of d, g, and e. The schematic in Fig. 1 illustratesthe known arrangements of the subunits constituting the AChRs that areexpressed in skeletal muscle. In the normal innervated muscle, AChRsare 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 theorder 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 thee-subunit and therefore consists of two a1-subunits, and one each b1, d, g-subunits. The a7AChR isa homomeric channel composed of five a7-subunits (pentamers). All of the receptors can bedepolarized by acetylcholine. The a7AChR can be depolarized by concentrations of choline that do notdepolarize the mature and immature AChR channels. The gAChR compared with e-AChR can bedepolarized by lower concentrations of acetylcholine and succinylcholine. The gAChR and a7AChRmay have lower affinity for antagonists or neuromuscular blockers, thus requiring higherconcentrations of these drugs (ligands) to block them.


neurotransmitter, acetylcholine, and for some of the ligands (eg, musclerelaxants) that bind to the AChR are located in the a-subunits. Althoughthe innervated neuromuscular junction synthesizes only the mature typeof AChRs, the muscle nuclei have genes for the synthesis of otherisoforms of AChRs. These muscle nuclei genes do not direct thesynthesis of these other isoforms as long as there is muscle activity oractive contact with the nerve.24,30 When there is deprivation of neuralinfluence or activity, as in the fetus before innervation or afterdenervation, two other isoforms, the immature AChR or gAChR andthe neuronal a7AChR, are expressed in muscle. The immature (g)AChRhas 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 thedenervated muscle (Fig. 1). The immature or gAChR is also referred toas extrajunctional because it is expressed mostly, but not exclusively, inthe extrajunctional region of the muscle membrane.

More recently, an AChR containing five a7-subunits has beendescribed 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 thesereceptors, including the a7AChRs. Other agonists, including nicotineand 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 onlyduring denervation and in the fetus, but also during immobilization ofany form, whether it is produced by simple muscle inactivity or ischemically, iatrogenically (eg, pinning) or pathologically induced,the AChRs quantitatively and qualitatively behave as if theyare denervated.25,33–36 The most common chemical agents producingimmobilization 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) andchronic magnesium sulfate as in the treatment of preeclampsia.Preliminary and/or indirect evidence indicates that in conditionsenumerated in Table 1 there is an up-regulation of both gAChR anda7AChR throughout the muscle membrane.

The cobra toxin, a-bungarotoxin, is used to quantitate the AChRs inmuscle. This ligand, however, does not differentiate between the maturejunctional, 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 insubunit composition (g vs. e vs. a7) also change the electrophysiologiccharacteristics of these receptors. Developing or denervated extrajunc-tional gAChRs have a smaller single channel conductance and a 2 to10-fold longer open-channel time than do AChRs at the mature


end-plate (eAChR). The expression of gAChR alters the sensitivity of thisreceptor to both agonists and antagonists. Agonists such as acetylcholine,decamathonium, and succinylcholine depolarize immature receptorsmore easily and are able to lead to cationic fluxes (Na+ and Ca2+

inwards and K+ outwards) at concentrations very much smaller thanthose that would cause cationic fluxes in the mature eAChRs; comparedwith the innervated state, 1/10th to 1/100th doses of acetylcholine canaffect depolarization in the gAChR.33 The potency of competitiveantagonists such as pancuronium may also be altered. Low concentra-tions of NDMRs effectively antagonize the actions of iontophoereticallyapplied acetylcholine in the mature eAChRs, whereas the gAChRs areresistant to block by these drugs. Studies by Gu et al41 and Yost et al42 inin vitro systems, however, do not confirm this resistance of gAChRs tothe NDMRs.

The a7AChRs also display unusual functional and pharmacologiccharacteristics 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 notopen the mature and the immature AChRs will open the a7AChRchannels.31 Furthermore, no desensitization of the a7AChR occurs evenduring the continued presence of choline, a feature that contradictswhat is seen in the a7AChRs expressed in the central nervoussystem 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 theextracellular space down its concentration gradient. The a7AChR inmuscle also has a lower affinity for antagonists such as pancuroniumand a-bungarotoxin; higher concentrations of these drugs wererequired 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 electricalactivity are of vital importance for the development, maturation, andmaintenance of neuromuscular function. Multiple growth (trophic)factor signaling (eg, insulin, agrin, AChR inducing activity), and thepresence or absence of innervation control the expression of the mature(e) receptors versus the other two (g, a7) isoforms.45 Quite in contrast toother cells, muscle cells are unusual, in that they have many, usuallyhundreds of, nuclei per cell. Each of these nuclei has the genes to makeall three types of AChRs. As the fetus develops and the muscles becomeinnervated, the muscle cells begin to synthesize the mature isoformof receptors, which are inserted exclusively in the developing (future)end-plate area.


Initially, the factors released from the nerve induce the synaptic areanuclei to increase the synthesis and therefore the numbers of AChRs.Next, the nerve-induced electrical activity results in the repression ofAChRs in the extrajunctional area. The nerve-derived growth factors,agrin and AChR inducing activity/neuregulin, cause the receptors tocluster in the subsynaptic area and prompt expression of the mature ereceptor isoform.46 The gAChR and the a7AChR gradually disappearfrom the extrajunctional area. Agrin is a protein from the nerve thatstimulates postsynaptic differentiation by activating muscle specifickinase (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 thegrowth factors that control the expression of a7AChRs, except that theconditions that increase the expression of gAChRs also seem to increasethat of a7AChRs.

In conditions associated with insulin resistance, there seems to be aproliferation of AChRs beyond the junctional area. Insulin mediates itsaction via a tyrosine kinase receptor. Conditions in which insulinresistance has been observed include immobilization, burns, anddenervation.47–50 In all these conditions, there is associated up-regulation of AChRs and expression of the gAChR and possiblya7AChR in the extrajunctional region.51–53 Thus, the decreasedsignaling of agrin via muscle specific kinase and tyrosine kinase receptormay play a role in the up-regulation and altered isoform expressionof AChRs in the pathologic states enumerated in Table 1. Directelectrical stimulation of the muscle even in the absence of nerve functionor nerve-evoked muscle contraction attenuates the spread of AChRsunderscoring the importance of muscle electrical activity in the controlof AChRs.33,45

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

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


do not seem to prevent the application of these classical dogmas to theresponses observed with competitive antagonists (eg, NDMR) and ago-nists (eg, succinylcholine) of AChRs.24,25 Succinylcholine behaves like anagonist because it is really two molecules of acetylcholine joinedtogether, and therefore it initially stimulates the receptor before causingmuscle paralysis.54 The receptor theory proposes that in conditionswhere there is a proliferation of AChRs, there will be increasedsensitivity to agonists and decreased sensitivity to antagonists.55,56 Inother words, there is a shift to the left in the dose-response curves toagonist succinylcholine, and a shift to the right in the dose-responsecurves to antagonists (NDMRs) in the presence of proliferated AChRs,(Fig. 2). The increased sensitivity to agonists in the extreme form resultsin lethal hyperkalemic response to succinylcholine.

Clinical conditions in which neuromuscular responses to relaxantsbehave as if the AChRs are up-regulated are given in Table 1. Therefore,both upper and lower motor neuron injuries caused by injury or diseasewill increase AChRs. Immobilization (disuse atrophy), a conditioninvariably associated with trauma, critical illness, and burns will increaseAChRs 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 tensionsuppression 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. Theburn-injury-induced increase in AChRs in muscle was associated with proportional increases in theED95 for d-tubocurarine. Modified from Ref. 79. Similarly, the potassium response to succinylcholinewas also significantly correlated to the AChR number, as shown by Yanez and Martyn.37


neuropathies, which can up-regulate AChRs, although there is noobvious anatomic denervation.57,58 Thermal injury, direct muscletrauma, and infection, all conditions associated with systemic or localinflammation, are associated with increased AChRs, particularly at siteslocal to injury.59 Infectious organism that invariably up-regulate AChRsare the clostridial toxins (tetanus and botulinum).60,61 The clostridialtoxins produce paralysis by inhibiting the release of acetylcholine. Thus,wound infection or chronic food poisoning with clostridial toxins canaffect the release of acetylcholine at nerve endings, cause paralysis, andup-regulate AChRs. Whether other pathogenic bacterial and viralorganisms can cause up-regulation is unclear. The concomitant presenceof disease-induced immobilization may contribute to the increasedAChRs and altered sensitivity to muscle relaxants. Chronic treatmentwith neuromuscular relaxants will up-regulate AChRs not only becauseof the immobilization but also because of antagonism of the receptoritself.37–39 In all these instances the up-regulation not only involvesincreased receptor number but also appearance of new receptorproteins, the gAChRs and a7AChRs. The biologic basis for theseisoform changes has been reviewed in the previous section.

Although target organ or pharmacodynamic changes may play amajor role in the resistance to NDMRs and hyperkalemia to succinyl-choline, pharmacokinetic factors and pharmacogenetic components alsomay contribute to these variations in drug response. For example, it iswell known that several drugs including muscle relaxants haveenhanced elimination kinetics after burn injury.62,63 Additional factorsthat might contribute to the resistance to NDMRs include binding of thedrug to plasma protein components particularly a1-acid glycoprotein,which binds to cationic drugs and decreases their free concentration inplasma.64,65

’ Molecular Pharmacologic Basis for the HyperkalemiaWith Succinylcholine

During succinylcholine administration to normal patients, it depo-larizes the AChRs present only at the junctional area, resulting in effluxof intracellular potassium ions only through the junctional AChRs.Despite the high density of AChRs at the neuromuscular junction, thisdepolarization results in a change in plasma potassium concentrations ofB0.5 to 1.0 mEq/L. When there is an up-regulation of AChRs (Table 1)throughout the whole muscle membrane, these up-regulated receptorsin the extrajunctional area consist of immature (a1, b, d, g) anda7AChRs. The proportion of each of these receptor subtypes (g vs. a7)in the affected muscle is unknown, but the total AChR numberdramatically increases compared with the innervated muscle. Thesystemically administered succinylcholine depolarizes all the AChRs on


the muscle membrane releasing intracellular potassium into the plasmaand 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 thepotassium release.

There are additional factors that may compound the exaggeratedrelease of potassium from these AChRs. Because these immaturegAChRs can be depolarized with smaller than normal concentra-tions of succinylcholine,25,33,66 the depolarization will persist despitedecreasing concentrations of succinylcholine during its metabolicbreakdown. The metabolic breakdown product of succinylcholine,choline, is a strong agonist of a7AChR.31 Thus, choline can continueto 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 withconventional AChRs.31 Thus, usual doses of pancuronium, or any othernondepolarizing muscle relaxant administered before succinylcholine,would not ablate the hyperkalemic response to succinylcholine.25

’ Diagnosis and Treatment of Hyperkalemia WithSuccinylcholine

Electrocardiographic changes in association with cardiovascularinstability, occurring within 2 to 5 minutes after succinylcholineadministration, should alert the caregiver to a tentative diagnosis ofsuccinylcholine-induced hyperkalemia. The electrocardiographicchanges include tall T waves >5 mm (K+ 6 to 7 mEq/L), small broador absent P waves, wide QRS complex (K+ 7 to 8 mEq/L), sinusoidalQRST (K+ 8 to 9 mEq/L), and atrioventricular dissociation orventricular tachycardia/fibrillation (K+ >9 mEq/L).25 Electrocardio-graphic changes may not always be present with hyperkalemia.67 Severehyperkalemia, with cardiovascular collapse, is a life-threatening condi-tion that needs immediate attention. The fastest measure of the efficacyof therapy is the electrocardiogram and cardiovascular response.Whenever there is electrocardiographic evidence of hyperkalemia,including early signs of it (peaked T wave), multipronged therapyshould be initiated simultaneously.

Approaches to treatment should include antagonizing the potassiumeffects on cardiac conduction and shifting potassium from extracellularfluid to intracellular fluid.68 Calcium salt (chloride or gluconate) shouldbe administered intravenously with continuous electrocardiographicmonitoring. Calcium directly antagonizes hyperkalemia-induced depo-larization of resting membrane potential.25 The recommended dose of10% 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 severalrepetitive doses, as its effect dissipates in 15 to 30 minutes.

Drugs that promote the cellular uptake of potassium include insulinwith glucose, catecholamines, and sodium bicarbonate. Acidosisenhances the release of potassium from the cell. Repeated doses (1 to3 mL/kg) of sodium bicarbonate (8.4%) to correct the acidosis may beuseful. Glucose (50 mL of 50% dextrose) together with 10 units ofregular 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) withinsulin 0.05 units/kg is recommended.68 The effect of insulin takes atleast 10 minutes and peak effect takes 30 to 60 minutes. b-receptoragonists, such as epinephrine, will not only help with cardiopulmonaryresuscitation, but will also drive the potassium intracellularly.25 In mostpatients, the succinylcholine-induced hyperkalemia lasts less than 10 to15 minutes. In some instances, however, the reversal to normokalemiamay take very much longer. Concomitant rhabdomyolysis mayaggravate the hyperkalemia. Therefore, cardiopulmonary resuscitationshould be continued as long as required.

’ Onset and Duration of Susceptibility toHyperkalemia With Succinylcholine

Even in the absence of trauma-related or critical illness-relatedneuromyopathies, immobilization by itself with and without the use ofmuscle relaxants can lead to up-regulation of AChRs.36,37 This up-regulation is not high enough to cause hyperkalemia with succinylcholineat 48 to 72 hours of immobilization/denervation. Persistence of theperturbation, however, will lead to further up-regulation. In a study ofdenervation of a single limb, hyperkalemia was observed as early as 4 daysafter injury but the potassium levels did not reach lethal levels, probablyrelated 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 causehyperkalemic cardiac arrest as early as 5 days.24 The prolonged use ofNDMRs, infections related to the trauma or major burns, and/orquadriplegia are conditions involving many muscle fibers. These patho-logic states that lead to some form of immobilization may be sufficient toup-regulate receptors to critical levels to cause hyperkalemia even earlierthan 5 days. Thus, it may seem wise to avoid the use of succinylcholinebeyond 48 to 72 hours of denervation/immobilization and/or any otherpathologic state where AChRs are known to increase. Whether severeinfection alone, in the absence of confinement in bed, is a contraindicationto succinylcholine is unknown. Parenthetically, it should be noted, however,that hyperkalemia to succinylcholine has not been reported in patients withacquired pathologic states of less than 4 days duration.


The up-regulation of AChRs can persist as long as the condition thatinduced it continues to be present. Quadriplegics and paraplegics withpersistent 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 inAChRs. It is also unknown, however, when this AChR up-regulation, incritically ill ICU patients who have had critical illness neuropathy/myo-pathy and/or muscle relaxants, reverts to normal. Therefore, it seemsprudent to avoid succinylcholine in patients who have recoveredrecently from critical illness, major burns, or major trauma, particularlyif muscle function is still abnormal. Our experience with burned patientssuggests that AChRs return to normal levels once wounds are healed,protein catabolism has subsided, and the patient is mobile. This healingprocess may take well over 1 to 2 years after wound coverage in patientswith major (80% body surface area) burns or longer if counted fromdate of injury. If immobilization or muscle tissue catabolism persistsowing to severe contractures or other reasons, then the up-regulation ofAChRs 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 relaxantsvecuronium, atracurium, rocuronium, and cisatracurium. Except foratracurium and cisatracurium, all these enumerated muscle relaxantshave a predominant renal excretion pathway, although a greaterfraction can be eliminated by the liver in the presence of renal failure(Table 2). The trauma, critical illness, and burn-associated liver andrenal dysfunction can also complicate the administration of relaxantseliminated by the liver and/or kidney. The neuromuscular effect of asingle dose of muscle relaxant is primarily terminated by redistributionfrom the neuromuscular junction and the central compartment into theperipheral compartment. After repeated injection or continuousinfusion, however, the redistribution capacity might be saturated andthe muscle relaxants and their active metabolites can be distributed backinto the central compartment. In this case, the neuromuscular recoveryis determined primarily by elimination of the drug.70 In contrast tod-tubocurarine and metocurine, which are predominantly excreted bythe 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 beimportant during kidney dysfunction (Table 2). As for the steroidalrelaxants, the parent compound and its metabolites have musclerelaxant activity. Consequently, they can accumulate over a period of


time with repetitive doses or continuous infusions causing persistentneuromuscular 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 theusual 2�ED95 (95% effective dose) doses will produce effectiveparalysis within 3 to 5 minutes after injection (Table 2). At periodsbeyond this, however, either because of the injury and/or associatedimmobilization, these patients begin to develop resistance to the neuro-muscular effects of NDMRs.24–27 This would be evidenced as decreasedresponse to normal doses, slow onset of effect, and rapid recovery froma given dose. On the basis of the neuromuscular response, the dosesmay have to be altered. If there is associated renal and/or liverdysfunction, the doses may have to be modified accordingly on the basisof the response. Clinical observations in trauma and burns suggest thatthe initial dose requirement to achieve a given paralysis is increasedeven in the presence of kidney and liver dysfunction, but the recoveryfrom paralysis or the frequency of the dose of administration may not bethe same as in patients with normal organ function.

Atracurium and its isomer cisatracurium are unique drugs, in thatthey are independent of the kidney and liver for their elimination.They undergo spontaneous degradation by Hoffman eliminationpathway.70,71 The metabolites of both drugs are inactive, and therefore

Table 2. Muscle Relaxant Metabolism, Elimination, Onset, and Duration of Action inNormals

MuscleRelaxant Metabolism (%)

RenalElimination

(%)

2ED95

Onset(min)

Recoveryto 25%(min)

Mivacurium 95–99 (plasmapseudocholines-terase)

<5, High eliminationin pseudocholin-esterase deficiency

2.5–4.5 15–20

Atracurium 70–90 (Hofmannelimination andesterases)

10–30 (mataboliteinactive)

2–3 35–50

Cisatracurium 70–90 (Hofmannelimination andesterases)

10–30 (metaboliteinactive)

3–6 40–55

Vecuronium 30–40 (hepatic) B40 (metabolitesactive)

2–3 30–40

Pancuronium 10–20 (hepatic) 60–80 (metabolitesactive)

3.5–6 70–120

Rocuronium Minimal (hepatic) 30–40 (metabolitesactive)

1.5–2.5 35–50

2ED95 onset indicates onset time when two times ED95 was administered; Recovery of thetwitch to 25% of baseline twitch height; TOF, train of four ratio.


do not cause persistent paralysis after termination of continuousinfusion despite the continued presence of the metabolites. Hoffmanelimination takes place in the central and peripheral compartments.Atracurium can also be degraded through ester hydrolysis. It isunknown whether cisatracurium also displays the same pathway.71

Mivacurium is a drug different from all other NDMRs, in that it ismetabolized to inactive metabolites by plasma pseudocholinesterase. It iswell known that critically ill patients, including burned patients, havedecreased pseudocholinesterase activity.72 It will therefore be notsurprising that the metabolism of mivacurium will be impaired in thesecritically ill patients. Clinical studies have in fact confirmed theprolonged recovery of burned patients from mivacurium-inducedparalysis.73,74 Thus, the frequency of the administration of mivacuriummay 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 andoutside the hospital setting.3–8 The use of muscle relaxants at theaccident scene and before transport to the hospital has improvedoutcome of these patients.5–7 Rapid onset of the effect of neuromuscularparalysis is important, particularly when patients have a full stomach,because it decreases the time the airway is exposed and thereforedecreases the risk of aspiration of gastric contents. Most trauma andburned patients who are intubated shortly after the accident could beassumed to have a full stomach, and therefore the rapid onset ofparalysis is critical. Succinylcholine is not contraindicated in theimmediate period after trauma and burn injury. The spread of AChRsto a critical level to cause hyperkalemia takes more than 72 hours and isdependent on the severity of the injury. No reports of succinylcholinehyperkalemia exist before 72 hours of insult or injury. In the presence ofsevere hemorrhage and metabolic acidosis, succinylcholine may causehyperkalemia.26 Beyond 72 hours after injury, it seems prudent to avoidsuccinylcholine.

About 3 to 4 days after injury or critical illness, these patients start todevelop resistance to the neuromuscular effects of NMDRs.24–27 Thus,finding a substitute of succinylcholine that would produce rapid onset ofneuromuscular paralysis in these situations to facilitate intubation inemergency situations (eg, full stomach or laryngospasm) is an area ofneuromuscular pharmacology that has received little attention. Highdoses of drugs such as metocurine and pancuronium can induce a morerapid 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 theunacceptable cardiovascular effects of these drugs when they areadministered as a bolus in high doses.

Studies in normal adults have demonstrated significant cardiovas-cular stability and rapid onset of neuromuscular paralysis whenpancuronium and metocurine are administered in combination; theED95 dose of each drug was decreased during their combinedadministration, because of their synergistic effects.75 The efficacyof pancuronium and metocurine administered in combination to createrapid onset of paralysis in acute burned patients and in control patientshas been tested.75 When pancuronium (0.6 mg/kg) and metocurine(0.3 mg/kg) were used in combination in burned patients, 95% paralysiswas achieved in 3.1 ± 0.9 minutes. Increasing the doses to theapproximate normal 1�ED95 doses of pancuronium (0.1 mg/kg) andmetocurine (0.4 mg/kg) and administering them in combination toburned patients reduced the onset time to 1.3 ± 0.1 minutes.75 Althoughan occasional patient showed prominent changes in heart rate and bloodpressure, the overall cardiovascular stability was impressive. The mostserious disadvantage of this technique, however, was the prolongedrecovery 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 relaxantsbecause 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 anonset as fast as succinylcholine.76 Neuromuscular pharmacodynamics ofrocuronium in patients with major burns, who are resistant to theneuromuscular effects of NDMRs, has been tested.77 Rocuronium wasused 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 burnedpatients compared with nonburned patients (Table 3). Dose escalationshortened the onset time, but prolonged the duration of action. Thehigher dose also improved the intubating conditions in burned patients.All recovery profiles were significantly shorter in burned patientscompared with nonburned patients with both bolus doses. This studyconcluded that resistance to the neuromuscular effects of rocuroniumwas partially overcome by increasing doses. But it is important to notethat despite the dose of 1.2 mg/kg the onset time was still prolongedto 86 seconds for 95% paralysis. This seems too long for rapid sequenceinduction particularly in patients with poor lung function. 2,77

In another study in children and adolescents, the neuromuscularpharmacodynamics of mivacurium was studied after burn injury of lessthan 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, theonset time to maximum suppression was not different between burns


and controls. But recovery to 95% was slightly prolonged in burnedpatients with greater than 30% body surface burn irrespective of timeand magnitude of injury (Table 4). The prolonged recovery in burnedpatients was inversely related to the plasma cholinesterase activity(R = – 0.93, P<0.001), and the decreased plasma cholinesterase activitywas related to burn size and time after burn. Thus, in these 2 studies, anormal intubating dose of mivacuriaum (0.2 mg/kg) affected goodrelaxing conditions in burned patients with an onset time similar to thatof controls. These findings, therefore, contrasted with the response seenwith all other studies with NDMRs, where even with higher than normaldoses, the onset of paralysis was slower than in controls and recoveryof paralysis was faster in burns.24,77 The decreased metabolism ofmivacurium, resulting from depressed plasma cholinesterase activity,probably counteracted the receptor-mediated potential for resistance tothe neuromuscular effects. Thus, mivacurium may be an alternative tosuccinylcholine to effect rapid onset paralysis in these patients or to treatlaryngospasm. Because of the potential for release of histamine bymivacurium, the use of H1 and H2 receptor antagonists beforeadministration of mivacurium may ameliorate or completely abolishthe cardiovascular side-effects that such high doses of mivacuriumhave.78 Pretreatment with H1 and H2 antihistamine agents is notpossible when treating laryngospasm because of the urgency.

’ Conclusion

Burned, trauma, and critically ill patients have the potential toexhibit aberrant responses to neuromuscular blocking drugs. Musclerelaxants are commonly used to produce paralysis for intubation, as anadjunct to anesthesia, to prevent reflex responses to surgery and/orduring interventions, and to facilitate mechanical ventilation in the ICU.In all these instances muscle relaxants should be used in combinationwith sedatives and narcotics, otherwise one will have immobilizedpatients fully aware of their surroundings and in pain. The chronic use

Table 3. Rocuronium Onset, Recovery of TOF, and Intubating Conditions in Burns andControls

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 intubatingconditions (%)

65 38* 79 67*

Mean ± SD.*P<0.05 compared with control with same dose.


of muscle relaxants in these patients can lead to neuromusculardysfunction and persistent muscle weakness. The myopathy anddangers of the chronic use of muscle relaxants has been discussed inanother chapter in this issue. Although succinylcholine may be usedsafely within the first few days of trauma, it is inadvisable to use this drugbeyond 48 to 72 hours of trauma, particularly in the presence ofimmobilization/denervation of whatever origin. High dose rocuroniumor normal dose mivacurium may be alternative drugs for use in thesepatients, particularly for rapid intubation or for the treatment oflaryngospasm. It is unknown whether some of the newer drugs that arebeing introduced into clinical practice, AVERA 490, would be useful forintubation and maintenance of relaxation in these patients. Althoughcareful investigation of the action of muscle relaxants in burned patientshas provided guidelines for their use in trauma and critically ill patientsalso, alternative drugs to induce rapid onset of neuromuscular paralysisin these patients deserve further development and study.

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Table 4. Mivacurium Pharmacodynamics (0.2 mg/kg) in Controls and Burns

Burn size(% TBSA)

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<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.


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