Neuromuscular Blocking Agents
David A. Caro
Erik G. Laurin
INTRODUCTION
Neuromuscular blockade is the cornerstone of rapid sequence intubation (RSI), optimizing conditions for tracheal intubation while minimizing the risks of aspiration or other adverse physiologic events. Compared to sedation alone, RSI with a neuromuscular blocking agent (NMBA) is the current standard of care for emergent intubation. Multiple prospective studies and emergency airway registry data confirm the high success rate of RSI with NMBAs when performed by experienced operators in both adult and pediatric emergency patients.1 NMBAs do not provide analgesia, sedation, or amnesia. As a result, they are paired with a sedative induction agent for RSI. Similarly, appropriate sedation is essential when maintaining neuromuscular blockade postintubation.
Cholinergic nicotinic receptors on the postjunctional membrane of the motor endplate play the primary role in stimulating muscular contraction. Under normal circumstances, the presynaptic neuron synthesizes acetylcholine (ACH) and stores it in small packages (vesicles). Nerve stimulation results in these vesicles migrating to the prejunctional nerve surface, rupturing and discharging ACH into the cleft of the motor endplate. The ACH attaches to the nicotinic receptors, promoting depolarization that culminates in a muscle cell action potential and muscular contraction. As the ACH diffuses away from the receptor, the majority of the neurotransmitter is hydrolyzed by acetylcholinesterase (ACHE). The remainder undergoes reuptake by the prejunctional neuron.
NMBAs are either agonists (“depolarizers” of the motor endplate) or antagonists (competitive agents, also known as “nondepolarizers”). Agonists work by persistent depolarization of the endplate, exhausting the ability of the receptor to respond. On the other hand, antagonists attach to the receptors and competitively block access of ACH to the receptor while attached. Because they are in competition with ACH for the motor endplate, antagonists can be displaced from the endplate by increasing concentrations of ACH, the end result of reversal agents (cholinesterase inhibitors such as neostigmine, edrophonium, and pyridostigmine) that inhibit ACHE and allow ACH to accumulate and reverse the block. The ideal muscle relaxant to facilitate RSI would have a rapid onset of action, rendering the patient paralyzed within seconds; a short duration of action, returning the patient’s normal protective reflexes within 3 to 4 minutes; no significant adverse side effects; and metabolism and excretion independent of liver and kidney function.
SUCCINYLCHOLINE
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Succinylcholine (SCh) comes closest to meeting the desirable goals listed earlier; however, it has the potential for adverse effects such as hyperkalemia. Rocuronium’s popularity is increasing as a result of potential adverse effects of SCh and, in pediatric patients, the specter of hyperkalemia from administering SCh to a child with an undiagnosed degenerative neuromuscular disorder. In fact, recent registry data suggest that rocuronium is now the most common NMBA in emergency department (ED) RSI.2
Clinical Pharmacology
SCh is comprised of two molecules of ACH linked by an ester bridge and, as such, is chemically similar to ACH. It stimulates all nicotinic and muscarinic cholinergic receptors of the sympathetic and parasympathetic nervous system to varying degrees, not just those at the neuromuscular junction. Rarely, stimulation of cardiac muscarinic receptors by SCh can cause bradycardia, especially when repeated doses are given to small children.3 Although SCh can be a negative inotrope, this effect is so minimal as to have no clinical relevance. SCh causes the release of trace amounts of histamine, but this effect is also not clinically significant. Initially, SCh depolarization manifests as fasciculations which are followed rapidly by complete motor paralysis. The onset, activity, and duration of action of SCh are independent of the activity of ACHE and instead depend on rapid hydrolysis by pseudocholinesterase (PCHE), an enzyme of the liver and plasma that is not present at the neuromuscular junction, before excretion in the urine. Therefore, diffusion away from the neuromuscular junction motor endplate and back into the vascular compartment is ultimately responsible for SCh metabolism. This extremely important pharmacologic concept explains why only a fraction of the initial intravenous (IV) dose of SCh ever reaches the motor endplate to promote paralysis. As a result, larger, rather than smaller, doses of SCh are used for RSI.2 Incomplete paralysis may jeopardize the patient by compromising respiration while failing to provide adequate relaxation to facilitate tracheal intubation.
Succinylmonocholine, the initial metabolite of SCh, sensitizes the cardiac muscarinic receptors in the sinus node to repeat doses of SCh, which may cause bradycardia that is responsive to atropine. At room temperature, SCh retains 90% of its activity for up to 3 months. Refrigeration mitigates this degradation. Therefore, if SCh is stored at room temperature, it should be dated and stock should be rotated regularly.
Indications and Contraindications
SCh is frequently used as an NMBA for RSI because of its rapid onset and relatively brief duration of action.2,3,4 A personal or family history of malignant hyperthermia (MH) is an absolute contraindication to using SCh.5,6 Inherited disorders that lead to abnormal or insufficient cholinesterases prolong the duration of paralysis and contraindicate SCh use in elective anesthesia, but are not ordinarily an issue in emergency airway management. Certain conditions, described in the “Adverse Effects” section, place patients at risk for SCh-related hyperkalemia and represent absolute contraindications to SCh. These patients should be intubated using rocuronium. Relative contraindications to the use of SCh are dependent on the skill and proficiency of the intubator and the individual patient’s clinical circumstance. The role of difficult airway assessment in the decision regarding whether a patient should undergo RSI is discussed in Chapter 9, ‘Developing your strategy’.
Dosage and Clinical Use
In the normal-sized adult patient, the recommended dose of SCh for RSI is 1.5 mg per kg IV. Intubating conditions are directly related to the dose of SCh used, with excellent intubating conditions in more than 80% of patients receiving 1.5 mg per kg IV or more of SCh.2,3,7 There is sufficient evidence that decreasing doses of SCh produce inferior intubating conditions. Therefore, we firmly recommend 1.5 mg per kg IV (or more) of SCh for RSI. During cardiac arrest intubations and in shock states when both residual muscular tone and impaired circulation may be present, we recommend increasing the dose to 2.0 mg per kg IV to compensate for reduced IV drug delivery. Increasing the dose of SCh from 1.5 to 2 mg per kg IV increases the duration of action only from 5.2 to 7.5 minutes, reinforcing the notion that the half-life of SCh in vivo is approximately 1 minute. In a rare, life-threatening circumstance when SCh must be given intramuscularly (IM) because of the inability to secure venous access, a dose of 4 mg per kg IM may be used. The drug’s absorption and delivery will then depend on the patient’s circulatory status. IM administration may result in a prolonged period of vulnerability for the patient, during which respirations will be compromised, but relaxation is not sufficient to permit intubation. Active bag-mask ventilation will usually be required before laryngoscopy in this circumstance.
SCh is dosed on a total body weight basis.2,8 In emergencies, it may be impossible to know the exact weight of a patient, and weight estimates, especially of supine patients, have been shown to be notoriously inaccurate. In those uncertain circumstances, it is better to err on the side of a higher
dose of SCh to ensure adequate patient paralysis. The serum half-life of SCh is less than 1 minute, so doubling the dose increases the duration of block by only 60 seconds. SCh is safe up to a cumulative dose of 6 mg per kg. At doses greater than 6 mg per kg, the typical phase 1 depolarization block of SCh becomes a phase 2 block, which changes the pharmacokinetic displacement of SCh from the motor endplate. Although the electrophysiologic features of a phase 2 block resemble that of a nondepolarizing or competitive block (train-of-four fade and post-tetanic potentiation), the block remains nonreversible. This prolongs the duration of paralysis but is otherwise clinically irrelevant. The risk of an inadequately paralyzed patient who is difficult to intubate because of an inadequate dose of SCh greatly outweighs the minimal potential for adverse effects from excessive dosing.
dose of SCh to ensure adequate patient paralysis. The serum half-life of SCh is less than 1 minute, so doubling the dose increases the duration of block by only 60 seconds. SCh is safe up to a cumulative dose of 6 mg per kg. At doses greater than 6 mg per kg, the typical phase 1 depolarization block of SCh becomes a phase 2 block, which changes the pharmacokinetic displacement of SCh from the motor endplate. Although the electrophysiologic features of a phase 2 block resemble that of a nondepolarizing or competitive block (train-of-four fade and post-tetanic potentiation), the block remains nonreversible. This prolongs the duration of paralysis but is otherwise clinically irrelevant. The risk of an inadequately paralyzed patient who is difficult to intubate because of an inadequate dose of SCh greatly outweighs the minimal potential for adverse effects from excessive dosing.
In children younger than 10 years, length-based dosing is recommended, but if weight is used as the determinant, the recommended dose of SCh for RSI is 2 mg per kg IV, and in the infant (younger than 12 months), the appropriate dose is 3 mg per kg IV. Some practitioners routinely administer atropine (0.02 mg per kg IV) to children younger than 12 months who are receiving SCh, but there is no high-quality evidence to support this practice.9 There is similarly no evidence that it is harmful. When adults or children of any age receive a second dose of SCh, bradycardia may occur, and atropine should be readily available.
Adverse Effects
The recognized side effects of SCh include fasciculations, hyperkalemia, bradycardia, prolonged neuromuscular blockade, MH, and trismus/masseter muscle spasm. Each is discussed separately and some are specifically relevant to RSI in intensive care unit (ICU) settings.
Fasciculations
Fasciculations are believed to be produced by stimulation of the nicotinic ACH receptors. Fasciculations occur simultaneously with increases in intracranial pressure (ICP), intraocular pressure, and intragastric pressure, but these are not the result of concerted muscle activity. The exact mechanisms by which these effects occur are not well elucidated. In the past, it was recommended that nondepolarizing agents be given in advance of SCh to mitigate these side effects, but there is insufficient evidence to support this practice.
Hyperkalemia
Under normal circumstances, serum potassium increases minimally (0 to 0.5 mEq per L) when SCh is administered. Few studies to date have examined the risk of SCh administration in hyperkalemic patients. In a meta-analysis, Thapa and Brull identified four controlled studies of patients with and without renal failure, and there were no cases in which serum potassium increased by more than 0.5 mEq per L.10 The largest series, involving more than 40,000 patients undergoing general anesthesia, identified 38 adults and children with hyperkalemia (5.6 to 7.6 mEq per L) at the time they received SCh. None of these patients had an adverse event, and the authors calculated that the maximum likelihood of an adverse event related to SCh in hyperkalemic patients is 7.9%.11 The long-held dogma to avoid SCh in any patient with renal failure is questionable at best, and SCh’s independence of renal excretion makes it an excellent, viable agent to consider when renal function is impaired. A reasonable recommendation for the instance when hyperkalemia is present, or believed to be present (e.g., patient with end-stage renal disease), and electrocardiogram (ECG) stigmata of cardiac instability from hyperkalemia (e.g., peaked T-waves or increased QRS duration) are present, an alternative agent, such as rocuronium, should be used for RSI. Otherwise, renal failure, or nominal hyperkalemia (i.e., without ECG changes), is not a contraindication to SCh.
In certain pathologic conditions, however, a rapid and dramatic increase in serum potassium can occur in response to SCh. These pathologic hyperkalemic responses occur by two distinct mechanisms: receptor upregulation and rhabdomyolysis. In either situation, potassium increase may approach 5 to 10 mEq per L within a few minutes, resulting in hyperkalemic dysrhythmias or cardiac arrest.
Two forms of postjunctional ACH receptors exist: mature (junctional) and immature (extrajunctional). Each receptor is composed of five proteins arranged in a circular fashion around a common channel. Both types of receptors contain two α-subunits. ACH must attach to both α-subunits to open the channel and effect depolarization and muscle contraction. When receptor upregulation
occurs, the mature receptors at and around the motor endplate are gradually converted over a 3- to 5-day period to immature receptors that propagate throughout the entire muscle membrane. Immature receptors are characterized by low conductance and prolonged channel opening times (four times longer than mature receptors), resulting in increasing release of potassium.12 Most of the entities associated with hyperkalemia during emergency use of SCh are the result of conditions that cause receptor upregulation. Interestingly, these same extrajunctional nicotinic receptors are relatively refractory to nondepolarizing agents, so larger doses of vecuronium, pancuronium, or rocuronium may be required to produce paralysis. This is not an issue in emergency RSI, where full intubating doses several times greater than the 95% effective dose (ED95) for paralysis are used.
occurs, the mature receptors at and around the motor endplate are gradually converted over a 3- to 5-day period to immature receptors that propagate throughout the entire muscle membrane. Immature receptors are characterized by low conductance and prolonged channel opening times (four times longer than mature receptors), resulting in increasing release of potassium.12 Most of the entities associated with hyperkalemia during emergency use of SCh are the result of conditions that cause receptor upregulation. Interestingly, these same extrajunctional nicotinic receptors are relatively refractory to nondepolarizing agents, so larger doses of vecuronium, pancuronium, or rocuronium may be required to produce paralysis. This is not an issue in emergency RSI, where full intubating doses several times greater than the 95% effective dose (ED95) for paralysis are used.
Hyperkalemia may also occur with rhabdomyolysis, most often associated with myopathies, especially inherited forms of muscular dystrophy. When severe hyperkalemia occurs related to rhabdomyolysis, the mortality approaches 30%, almost three times higher than that in cases of receptor upregulation. This mortality increase may be related to coexisting cardiomyopathy. SCh is a toxin to unstable membranes in any patient with a myopathy and should be avoided.13
Patients with the following conditions are at risk of SCh-induced hyperkalemia:
Receptor Upregulation
Burns—In burn victims, the extrajunctional receptor sensitization becomes clinically significant 3 to 5 days postburn. It lasts an indefinite period of time, at least until there is complete healing of the burned area. If the burn becomes infected or healing is delayed, the patient remains at risk for hyperkalemia. It is prudent to avoid SCh in burned patients beyond this window if any question exists regarding the status of their burn. The percent of body surface area burned does not correlate well with the magnitude of hyperkalemia. Significant hyperkalemia has been reported in patients with as little as 8% total body surface area burn (less than the surface of one arm), but this is rare. The majority of emergent intubations for burn patients are performed well within the safe 3- to 5-day window period. Should a later intubation become necessary, however, rocuronium provides an excellent alternative.14,15Related posts:
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