Neuromuscular blocking agents in the emergency department

The Journal of Emergency Medicine, Vol 14, No 2, pp 193-199, 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0736-4679/96 $15.00 + .OO

SSDI 0736-4679(95)02105-l

Selected Topics: Critical Care NEUROMUSCULAR

BLOCKING

AGENTS

IN THE EMERGENCY

Marcie A. Rubin, MD, FACEP* and Nicholas Sadovnikoff,

DEPARTMENT

Mot

*Department

of Emergency Medicine and TDepartment of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland Reprint Address: Marcie A. Rubin, MD, Department of Emergency Medicine, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287-2080

q Abstract-Neuromuscular blocking agents (NMBAs) are utilized frequently in the emergency department (ED). We begin with a brief history of neuromuscular blockade, then review the indications and guidelines for its use in the emergency department setting. The relevant agents will be discussed focusing on dosage, side effects, and adverse reactions. Special attention wlll be paid to succinylcholme, the drug most commonly employed in the ED setting, followed by a summary of the nondepolarizing agents currently available, in particular the four shorter-acting agents that are most appropriate for administration in the ED.

were the first to report its use with general anesthesia, observing that adequate muscle relaxation could be obtained while using much lower and less dangerous dosesof anesthetic agentsthan was previously possible (5 ) . Over the ensuing decade, the use of NMBAs for surgery became widely accepted. There are currently 11 NMBAs in clinical use in the United States, and their numbers continue to grow as advantageousstrnctural modifications are discovered.

INDICATIONS 0 Keywords-neuromuscular blockade; succinylcholine; endotracheal intubation; emergent airway management

The NMBAs are routinely used in the operating room to facilitate endotracheal intubation and to enhance skeletal muscle relaxation for surgical procedures. They are also used in intensive care units (ICUs) to facilitate both endotracheal intubation and mechanical ventilation in critically ill patients (6). Both of these are settings in which the patient’s medical condition and history are ordinarily well known to the administering physician. Relatively long-term use of the neuromuscular blockade may occur, particularly in the ICU where it may be necessaryto administer NMBAs continuously for days or even weeks. The choice of agent(s) is individualized based on the patient’s current condition, duration of anticipated requirement for relaxation, medical and anesthetic history, and underlying pathophysiology (2,7).

HISTORY The origins of neuromuscular blocking agents (NMBAs) rest in South America in the 16th century, where Sir Walter Raleigh and other explorers observed the native hunters using darts and arrows dipped in curare to paralyze their prey ( 1,2). The poison was found to come from the Strychnos plant, and its primary active component, d-tubocurarine, was ultimately identified and isolated in the 1930s (3). While this agent can now be synthesized, it is still most inexpensively prepared from the amazonian vine chondodendron tomentosum (4). Griffith and Johnson in 1942

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Critical Care is coordinatedby JosephVuron, MD, of the University of TexasM.D. AndersonCancerCenterand Baylor College of Medicine, Houston,Texas 8 March 1995; FINAL SUBMISSION RECEIVED: 4 October 1995; : 16 October 1995

193

M. A. Rubin and N. Sadovnikoff

194

In the emergency department (ED), the most common indications for utilization of NMBAs are to facilitate endotracheal intubation or to immobilize an already intubated patient to enable a procedure or imaging study to be performed (8). The ED patient is frequently acutely ill at presentation and the choice of NMBA must often be made with a minimum of information. As the requirement for use of NMBAs in the ED is usually brief, the effects of their long-term administration will not be considered here. There are few absolute contraindications to the use of NMBAs in a properly equipped and staffed setting. Reasons to consider avoiding neuromuscular blockade include status epilepticus where monitoring of seizure activity is lost, underlying neuromuscular disease, or a history of previous adverse reaction to NMBA administration (4,9,10). In a situation in which upper airway anatomy or injury makes cessation of spontaneous ventilation particularly hazardous, consideration should be given to obtaining a surgical airway without paralysis ( 11) . Whenever possible, sedative, anesthetic, and amnestic agents are used in conjunction with an NMBA. These include induction agents Sodium thiopental, etomidate, propofol and ketamine, the benzodiazepines, in particular midazolam, and rapid onset narcotic analgesics, notably fentanyl. In addition, lidocaine and esmolol have been recommended by some authors to blunt the sympathetic and consequent hemodynamic response to intubation ( 12). The choice of these drugs is largely dictated by the judgment and familiarity of the emergency physician. In the rare instance when hemodynamic instability precludes administration of amnestic agents, the likelihood of amnesia may be enhanced by scopolamine 0.4-0.6 mg IV without hemodynamic compromise ( 13). This topic is extensively reviewed elsewhere ( 14).

prolong its duration of action, this is rarely of clinical significance. In addition, there are virtually no drug-drug interactions that appreciably limit its utilization ( 1,4,16). In a truly emergent setting, as when a patient requires immediate intubation, succinylcholine is without substitute ( 17). Prolonged or excessive dosage of succinylcholine may result in a long-lived neuromuscular blockade known as Phase II block ( 1,18 ) _ This condition is not reliably antagonized by acetylcholinesterase inhibitors and must often be allowed to resolve spontaneously while the patient is supported. Succinylcholine is not an optimal choice for indications requiring protracted neuromuscular blockade. The patient requiring immediate intubation may be paralyzed first with succinylcholine followed by administration of a NMBA upon first evidence of return of neuromuscular function. Alternatively, if the patient’s condition is such that one can afford an additional 1 to 2 min until onset of adequate relaxation, then a nondepolarizing agent alone may be considered. Succinylcholine (Figure 1)) like all NMBAs, has its site of action at the motor end plate of the neuromuscular junction. Its initial action is to depolarize the postsynaptic membrane, mimicking the action of the endogenous neurotransmitter acetylcholine, whose structure it resembles ( I, 19). Unlike acetylcholine, it persists in the neuromuscular junction, causing a brief period of repetitive excitation, usually manifested clinically as muscle fasciculations ( 1,20). Following this, neuromuscular transmission is effectively blocked and flaccid paralysis ensues. Succinylcholine is then rap-

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f;

‘il

H+CH&H~OCCH,CH,CoCH,CH2N~H3 H&

+/CH3 CH3

Succinykholine DEPOLARIZING

AGENTS

The NMBAs are traditionally divided into the two categories of depolarizing and nondepolarizing agents. In fact, there is only one member of the depolarizing agents currently in common clinical use, succinylcholine, whereas there are numerous nondepolarizing agents available, each with slightly different characteristics. In general, succinylcholine is the drug of choice for truly emergent procedures ( 15). It provides superb relaxation usually within one minute of infusion, a rapidity not obtainable with any of the nondepolarizing NMBAs (1,s). It is rapidly cleared, with return of muscular function usually occurring within 5 to 10 min. While hepatic and renal failure may modestly

Cl-

Figure

1.

Neuromuscular

Blocking Agents

idly hydrolyzed by liver and plasma pseudocholinesterase, resulting in its relatively short duration of action ( 1,19-2 1) . In humans, after a bolus infusion, muscular fasciculation occurs briefly, and paralysis occurs within 1 min, is maximal at 2 min, and has resolved by 10 min ( 1,21,22). In a small subset of patients, a significant prolongation of these effects may occur. Some, but not all, of these patients have a demonstrable deficiency of pseudocholinesterase activity (23,24). The dose of succinylcholine recommended by the manufacturers for intubation is 0.6 mg/kg, but the optimal dose varies according to the individual patient from 0.3 to 1.1 mg/kg, and in emergent settings, initial doses of up to 2.0 mg/kg have been utilized. Most references cite 1.0 mg/kg as adequate for rapid sequence intubation ( l&25). If the patient has received a defasciculating dose of a NMBA (see below), the dose should be augmented by 30-50%. Second bolus doses of succinylcholine have been noted to result in profound bradycardia, most commonly in children. If a second infusion is deemed necessary, it should be preceded by a vagolytic dose of atropine (0.4 mg in an adult) (16). Succinylcholine administration is associated with a number of hazardous side effects, and if circumstances permit consideration of an alternative agent, these potential hazards must be considered prior to its use (8). Rapid, life-threatening increases in serum potassium have been observed in a number of types of patients after administration of succinylcholine, and fatal outcomes are well-documented (26-29). Hyperkalemia is a particular danger in patients with a history of massive cell damage, such as extensive burns, rhabdomyolysis, or crush injuries. Extensive, long-standing cell denervation, as with spinal cord injuries or neuromuscular disorders, predisposes to exaggerated hyperkalemic response ( 30,3 1) . In these individuals, the cause of the exaggerated hyperkalemic response to succinylcholine appears to be a marked increase in receptor density over the entire muscle surface (4,28). The danger is greatest in the period between 7 and 60 days after the injury, and the danger may persist longer if recovery from the injury is complicated by infection (4). The occurrence of fasciculations may not appear consequential, but it is this property of the agent that has been suggested as the cause for many of its undesirable side effects. Aside from causing postanesthetic muscle soreness, fasciculations may be at least partially responsible for the increases in intraocular and intragastric pressure that have been observed with this agent (4,16,32,33). Less clear is the mechanism for the welldocumented increase in intracranial pressure that occurs with its administration. The clinical significance of these

195

increases is subject to debate, but fasciculations are clearly of no benefit to the patient and are easily prevented by defasciculation (34). This involves the use of an initial small dose of a nondepolarizing NMBA (e.g., pancuronium .Ol- .015 mg/kg) followed in 90 to 120 seconds by the intubating dose of succinylcholine (augmented as above) (4). It should be noted that while this effectively prevents the occurrence of fasciculations, it has not been definitively shown to protect against development of hyperkalemia in the patient categories noted above (35). Clearly, in many emergent situations, one cannot afford to wait an additional 2 min to permit defasciculation. In these instances, the risk of postponing intubation exceeds the risk of the side effects of succinylcholine and it should be administered without delay ( 17,34). Succinylcholine also has been observed to induce histamine release, which may result in transient hypotension or bronchospasm in some patients; these effects tend to be self-limited and uncommon ( 1,36,37). Finally, a clear association exists between the use of succinylcholine and the occurrence of malignant hyperthermia (MH) in susceptible individuals. A previous history of MH is an absolute contraindication to the use of succinylcholine and, as it appears to involve genetic predisposition in most cases, a family history of MH should also preclude its use (38-41). This information of course is often not available at the time of an emergent intubation.

NONDEPOLARIZING

AGENTS

The formulary of nondepolarizing NMBAs currently available in the United States is summarized in Table 1. All of these agents contain at least two quatemary ammonium groups that mimic acetylcholine in competing for the receptor at the neuromuscular junction ( 1). All of the agents except gallamine are in one of two structurally related groups (Figure 2): the steroidal NMBAs, of which pancuronium is the prototype; and the benzylisoquinolones, of which d-tubocurarine was the first to be discovered ( 1). Neuromuscular blockade induced by all of these agents can be reversed by administration of acetylcholinesterase inhibitors such as neostigmine (.04- .07 mg/kg) or edrophonium (S-1.0 mg/kg); these are generally preceded by the anticholinergic drugs glycopyrrolate ( 7 14 pg/kg) or atropine (7-10 pg/kg), respectively, to prevent the muscarinic side effects (4,22). In general, however, reversal is not performed in the emergency department. An examination of the list of nondepolarizing NMBAs reveals that many of these agents are quite similar to one another. Six of the agents are long-acting: they are

M. A. Rubin and N. Sadovnikoff

.l 96 Table 1. Nondepolarizing Agent Long-acting pancuronium metocurine gallamine d-tubocurarine pipecuronium doxacurium Intermediate acting atracurium vecuronium rocuronium Short-acting mivacurium

Neuromuscular

Blocking

Agents

Type” (S/B)

lntubating dose mglkg

OnseP (min)

Time to 25% recovery (min)

S S B S B

0.08-0.10 0.3-0.4 3.0-5.0 0.5-0.6 0.08-0.10 0.05-0.08

3-5 3-5 3-5 3-5 3-5 3-5

80-100 80-100 80-100 80-100 80-100 80-100

B :

0.5-0.6 0.10-0.15 0.6-l .O

B

0.15-0.20

2-3 2-3 1.5-2

35-45 25-40 30-60

2-3

16-20

a S = steroidal; B = benzylisoquinolones. bTime to suitable intubating conditions. More rapid onset as short as 90 seconds may be obtained with higher doses, but time to recovery will be prolonged.

characterizedby relatively long intervals to onset of intubating conditions, and their durations of action tend not to lend them to use in acute or rapidly changing situations. The differencesbetween them include side effects, mechanisms of clearance, propensity to interact with other drugs, and cost. None of these agentshave features so compelling as to make their use in the emergency setting attractive. Of these, only pancuronium will be describedin detail. The remainder of the nondepolarizing drugs are either intermediate or short-acting. Of note is that even the shortest acting nondepolarizing agent has a duration of action at least three times that of succinylcholine. They are described individually below.

Pancuronium

Pancuronium, the oldest synthetic NMBA, is the prototypic long-acting agent and the only one that will be discussed here. When succinylcholine is contraindicated, pancuronium is an alternative that has been utilized for intubation (42). Intubating conditions can be obtained in 75 secondswith a dose of 0.15 mg/kg. This dose will result in a duration of paralysis of 120-150 min in patients with normal renal function. As pancuronium is 85% renally cleared, paralysis in patients with renal failure may last substantially longer (43,44). Pancuronium also causes a vagolytic effect that may result in significant increasesin heart rate (45 ) . Unless prolonged paralysis is desired for subsequentstudies or procedures, it seemsprudent to choose a shorter-acting agent for intubation (46).

Atracurium

Atracurium was the first nondepolarizing NMBA to become available that had a significantly shorter duration of action than its predecessors,making it particularly useful for shorter surgical procedures. While the mechanisms of its elimination are still not yet fully elucidated, it is believed that it owes its shorter halflife to two nonrenal, nonhepatic pathways; it undergoes ester hydrolysis independent of plasma cholinesterase and Hofmann elimination, a nonenzymatic process that occurs spontaneously under physiological conditions (4,13,47,48). Its primary disadvantage is its moderate propensity to cause histamine release that may result in hypotension and tachycardia or bronchospasm in someindividuals ( 13,49). These adverseeffects generally can be avoided by slow rates of infusion without significantly altering the time to intubation conditions (50). Additionally, one of its Hofmann elimination metabolites, laudanosine, is renally excreted and has been suspected to have CNS excitatory properties, as it causes seizures and EEG changes in animals. This has never been documented to be a clinical problem in humans, however (5 l-53). Nevertheless, especially in patients with cardiac disease, other agents not associated with histamine release or with even shorter durations of action are often selected (47). Its primary utility is in patients with known severe renal or hepatic impairment where there is concern about prolongation of paralysis. Vecuronium

Vecuronium, with its rate of elimination that is slightly more rapid than atracurium and its absenceof histamine-

Neuromuscular

197

Blocking Agents

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PANCUR0NlW.t

c-0 ONc ,3

VECURONIUM

c

N

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H

0

Ahcurium

OCH, Mivacurium

Rocuronium O-AC + 0 L

9

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N

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N‘3

, H

LH I. CHr Figure 2.

M. A. Rubin and N. Sadovnikoff

198

releasing properties, is frequently utilized in emergent situations (54). It causes virtually no vagolytic effects or hemodynamic alterations. Its excretion is approximately 50% renal, the remainder undergoing hepatic metabolism and biliary excretion, making it an excellent choice in patients with renal failure (4,47,55,56). Along with pancuronium, it has been associated with prolonged weakness after long-term use, particularly in critically ill patients, but this is not a consideration for problems of acute management. It is an appropriate agent in situations where succinylcholine is contraindicated (57,58).

Mivncurium Mivacurium, the shortest-acting of the NMBAs, is the only nondepolarizing agent actually classified as shortacting. It is metabolized by plasma cholinesterase, the same enzyme that metabolizes succinylcholine (59,60). As a consequence, patients with defects in activity of this enzyme may have marked prolongation of neuromuscular blockade, as they do with succinylcholine (6 1) . Like other benzylisoquinolones, mivacurium administration may result in histamine release and concomitant hypotension and tachycardia, effects that are minimized by slow infusion (36,50,59). When mivacurium is used to provide prolonged blockade, it is often given as an infusion. While the issue is controversial, anticholinesterase reversal is generally not used with mivacurium due to the theoretical possibility of actually prolonging the block by inhibiting plasma cholinesterase as well (62). It is, like vecuronium, an appropriate choice for emergent neuromuscular blockade when succinylcholine is contraindicated.

It may be prudent to use slow rates of infusion, especially in patients with known cardiac disease (62 ).

Rocuronium Rocuronium, the newest aminosteroid available, shares the intermediate duration of action of atracurium and vecuronium (63,64). The onset of action, however, is considerably faster (65). Elimination of rocuronium is predominantly via the liver, although as much as 30% has been shown to be excreted by the kidneys (66). Rocuronium, with its rapid onset and intermediate duration of action, is potentially an important agent for use in rapid-sequence intubation. As with vecuronium, hemodynamic effects are minimal and histamine release does not occur (67). At the dosage recommended for rapid-sequence intubation, a duration of action of 30-60 min is expected.

CONCLUSIONS There often are situations that occur in the emergency department for which neuromuscular blockade is indicated. The most common of these are endotracheal intubation followed by immobilization for an imaging study and immobilization for a procedure. When the patient is in need of urgent intubation, succinylcholine is the drug of choice due to its rapid onset of action. When a prolonged period of relaxation is required, as is needed to perform an imaging study, a shorter or intermediate-acting nondepolarizing agent may be more appropriate. A working knowledge of the pharmacology of the NMBAs enables their judicious and appropriate utilization.

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