Neuromuscular blockade is an integral part of the rapid sequence induction and intubation protocol. The combination of a paralytic agent and a sedative or an analgesic is superior to the use of any single agent. The use of a neuromuscular blocking (NMB) agent to facilitate intubation provides for control of the airway and better visualization of the vocal cords than does sedation without paralysis.50 It is also well documented that, in the Emergency Department setting, rapid sequence induction with an NMB agent allows for faster intubations with fewer complications than sedation alone.1 The use of a sedative without a NMB should be reserved for the awake oral intubation of a patient with a difficult airway.
NMBs are classified as either depolarizing or nondepolarizing, depending on their action at the nicotinic acetylcholine receptor of the motor end plate. The optimal NMB agent has a rapid onset of action, a predictably short duration of action, and no side effects. As with induction agents, the optimal NMB agent has yet to be found. Until a better agent is developed, succinylcholine (Anectine™) remains the standard NMB agent for Emergency Department intubations.51
Succinylcholine is the only depolarizing NMB agent in clinical use. Introduced in 1952, it is a chemical combination of two acetylcholine molecules. It is the most widely used NMB in the Emergency Department because its onset of action is faster and its duration of action is shorter than that of any other NMB agent. This is particularly important in patients who cannot be intubated after neuromuscular blockade and where the resumption of spontaneous respirations is vital.
After a paralytic dose of succinylcholine, adequate intubating conditions are usually achieved in 60 seconds.53 The duration of apnea following a single dose of succinylcholine is 3 to 5 minutes and reflects the rapid degradation of the drug by pseudocholinesterase, also known as plasma cholinesterase or butyrylcholinesterase.53 Repeated doses or infusion of succinylcholine may produce tachyphylaxis, prolonged paralysis, and repolarization of the neuromuscular membrane, a condition referred to as phase II block.53 If this condition develops, it can be partially reversed by administration of an anticholinesterase agent, similar to the reversal of a nondepolarizing block. If paralysis of greater than 3 to 5 minutes is desired, a nondepolarizing agent can be administered after the patient is intubated.
The structure of succinylcholine allows it to bind noncompetitively to acetylcholine receptors, causing depolarization of the postjunctional neuromuscular membrane. This initial depolarization is seen as a brief period of muscle fasciculation following the administration of the drug. Unlike acetylcholine, which is hydrolyzed within milliseconds, succinylcholine remains intact for several minutes. It produces paralysis by occupying the acetylcholine receptors, and making the motor end plates refractory, so that muscle contraction cannot occur. Muscle relaxation proceeds from the distal muscles to the proximal muscles, and thus the diaphragm is one of the last muscles to become paralyzed.52
Succinylcholine is rapidly hydrolyzed by plasma pseudocholinesterase to succinylmonocholine. Only a small fraction of the IV administered dose reaches the neuromuscular junction. Succinylmonocholine, which also has some neuromuscular blocking properties, is further hydrolyzed to succinic acid and choline. These end products are rapidly taken up by cells and reused in various biochemical molecules. The rapid degradation of succinylcholine provides a concentration gradient that causes the diffusion of succinylcholine away from the acetylcholine receptors and allows repolarization of the myocyte membrane.
In patients with atypical pseudocholinesterase enzyme, a genetic variant with autosomal semidominant transmission, the duration of action of succinylcholine is markedly prolonged due to decreased enzyme activity. In patients homozygous for the atypical allele, a condition that occurs with an incidence of 1 in 3200, a single intubating dose of succinylcholine may last up to 8 hours.53
The recommended dose of succinylcholine to produce optimal intubating conditions is 1.0 to 1.5 mg/kg IV bolus in adults and 1.5 to 2.0 mg/kg in infants, with the twofold increased dose in this population explained by their higher volume of distribution.53,83 This dose should be increased by 50% in patients who have received a defasciculating dose of a nondepolarizing neuromuscular blocker (see below under “Adverse Effects” section) prior to the administration of succinylcholine.53 Intramuscular administration is also possible, which may become important for use in an emergency when control of the airway is necessary and the patient has no IV access. The intramuscular dose is two to four times the IV dose.54
Although relatively uncommon, a number of potential adverse effects are associated with the administration of succinylcholine. These include muscular fasciculations and myalgia, autonomic stimulation, histamine release, prolonged apnea, elevated intracranial and intraocular pressure, hyperkalemia, and malignant hyperthermia.53 The use of succinylcholine is recommended for rapid sequence induction and intubation as the risk of a compromised airway far outweighs the potential harm from these side effects.
The fine, chaotic muscle contractions that are often observed at the onset of paralysis are associated with several side effects, most commonly myalgia, but also increased intraocular pressure (IOP), increased intracranial pressure (ICP), and increased intragastric pressure. Muscle pain 24 to 48 hours after the administration of succinylcholine is most prominent in young, muscular men, while it is unlikely in children, the elderly, and those with undeveloped or diminished muscle mass. Muscle fasciculations may be prevented by the administration of a defasciculating dose (10% of the paralytic dose, a phenomenon known as “precurarization”) of a nondepolarizing NMB agent given 3 to 5 minutes prior to the succinylcholine.55
Increased ICP may also occur with the use of succinylcholine. While the magnitude and clinical significance of this increase remains unclear, defasciculation with a nondepolarizing NMB agent has been shown to prevent this rise in ICP.58
To omit the use of a paralyzing agent entirely during the rapid sequence induction of patients with penetrating eye injuries or intracranial pathology for fear of the potential increase in IOP or ICP is a decision that must be made for each individual patient. Any attempt to intubate a nonparalyzed, lightly anesthetized patient could result in gagging or “bucking,” which has been shown to increase both IOP and ICP far more than that which would be achieved from an intubating dose of succinylcholine. In most patients, muscle fasciculations are benign and precurarization is unnecessary. In patients with eye injuries or suspected intracranial pathology, however, it is prudent to either use a nondepolarizing NMB agent or utilize precurarization with succinylcholine to prevent worsening of an injury to these areas.56 Rocuronium is a nondepolarizing agent that has been shown to significantly decrease IOP during rapid sequence induction.57 Its use may be indicated in patients with penetrating eye injuries.57
Increased intragastric pressure, which is also lessened by precurarization, may increase the risk of aspiration. On the other hand, succinylcholine favorably increases the tone of the lower esophageal sphincter, which may mitigate the risk of aspiration.59 Regurgitation of stomach contents during intubation is more likely the result of distention from overzealous mask ventilation.
Succinylcholine binds to acetylcholine receptors throughout the body, including those of the autonomic ganglia. Succinylcholine may have direct muscarinic effects on the heart. It is difficult to characterize a specific cardiovascular effect typical of succinylcholine. It may produce tachycardia, bradycardia, or dysrhythmias.53 Children are particularly susceptible to bradycardia following succinylcholine administration. It is recommended that all children be given 0.01 mg/kg IV of atropine prior to administration of succinylcholine.54
Prolonged apnea following succinylcholine is a sign of decreased plasma pseudocholinesterase levels. This may occur in patients with hepatic disease, anemia, renal failure, cancer, connective tissue disorders, pregnancy, cocaine intoxication, genetically deficient enzyme activity, or taking cytotoxic drugs. In most cases, apnea rarely exceeds 20 minutes.60
Succinylcholine may produce an increase in serum potassium level, which is typically less than 0.5 meq/L. It should be used with caution in patients with significant hyperkalemia. Its use is not contraindicated in patients with renal failure, but caution must be taken if their serum potassium level is elevated. It has been associated with cases of massive hyperkalemia (>5 meq/L) and cardiac arrest in patients who have had digoxin toxicity, myasthenia gravis, massive muscle trauma, crush injuries, severe burns, and major nerve or spinal cord injury at least 1 week prior to receiving succinylcholine.53 In such patients, succinylcholine should not be used starting 24 hours after the insult.
Malignant hyperthermia (MH) is an extremely rare and life-threatening autosomal dominant condition that can develop following exposure to certain inhaled anesthetics and/or succinylcholine in genetically susceptible individuals. It is characterized by intense, sustained skeletal muscle contraction leading to severe acidosis, rhabdomyolysis, hyperthermia, hyperkalemia, arrhythmias and, if left untreated, death. The triggering exposure is not dose-dependent, can occur following any single dose or combination of offending agents, and may occur even in individuals who have been exposed to the agents in the past without an adverse effect. The incidence of MH during anesthesia is estimated to be 1 in 15,000 in children and 1 in 50,000 in adults.82 Although it is most notoriously characterized by a rapid elevation in temperature, the earliest signs of the condition are usually profound tachycardia, tachypnea, and generalized skeletal muscle rigidity. Laboratory blood analysis reveals severe respiratory and metabolic acidosis, hyperkalemia, and elevation of serum creatine kinase.
Early and aggressive treatment is the key to patient survival. This involves active cooling measures, volume resuscitation, correction of acid–base and electrolyte disturbances, and rapid administration of dantrolene (2 to 3 mg/kg IV bolus with additional increments up to 10 mg/kg).53,82 Dantrolene sodium is a muscle relaxant that is supplied as a lyophilized powder in 20 mg vials. Prior to administration, each vial must be reconstituted with 60 mL of water.82 It is emphasized that rapid and early administration of dantrolene is important to abort the reaction and greatly increases the chance of survival. Dantrolene administration should be continued until all signs of MH have stabilized. Admit the patient to the intensive care unit for observation of any recurrence following the acute phase.
Isolated masseter muscle rigidity is a benign side effect in most cases. It has been reported mainly in children receiving succinylcholine. In several reported cases of fatal malignant hyperthermia, however, masseter muscle rigidity was the first sign of an abnormal reaction.61 Masseter rigidity occur following the administration of succinylcholine requires the patient to be closely monitored for other signs of MH.
Patients of families with MH, those with suspected reactions, and other selected high-risk patients can undergo a muscle biopsy test known as the caffeine-halothane contracture test, which carries a 100% sensitivity and 85% to 90% specificity for MH susceptibility.82 Patients who develop suspected MH reactions should be referred immediately to their primary physicians for testing and follow-up, as documented positive susceptibility and patient education could prevent a future potentially lethal exposure to offending agents.
Despite the lengthy list of potential adverse effects, the benefits of intubation with a rapidly acting and short-lasting paralytic agent such as succinylcholine provide the safest conditions for intubation in the Emergency Department. If prolonged paralysis is required in an agitated patient, a nondepolarizing agent should be administered for maintenance following intubation with succinylcholine.
Nondepolarizing NMB agents act by competitive inhibition of the acetylcholine receptors at the motor end plate. They weakly bind to the receptor and block the binding site for acetylcholine without producing any effect on the postsynaptic neuromuscular membrane. Following the kinetics of competitive inhibition, this blockade is dependent on the relative concentrations of acetylcholine and NMB available in the synaptic cleft. As the ratio returns in favor of acetylcholine, normal neuromuscular transmission is restored. Thus, return of muscle function can be hastened by the use of a cholinesterase inhibitor such as neostigmine or edrophonium, but only after some muscular contraction can be observed. Nondepolarizing agents have not only the potential for reversal, but also for fewer side effects than succinylcholine. Their longer time to onset and much longer duration of action make them less useful for rapid sequence induction, especially in the Emergency Department.53
Nondepolarizing NMB agents can be grouped by chemical structure. The steroid-based agents include pancuronium, vecuronium, and rocuronium. The oldest nondepolarizing agent, d-tubocurarine, is a benzylisoquinoline, as are atracurium, cisatracurium, and mivacurium.53 Pancuronium, vecuronium, and rocuronium have been extensively studied for use in rapid sequence intubation.62 Of these, rocuronium (Zemuron™) has become established as the nondepolarizing NMB of choice for rapid sequence induction in situations where succinylcholine is contraindicated. For this reason, rocuronium is discussed separately from the other nondepolarizing NMB agents.
When succinylcholine is contraindicated, rocuronium has been used at a dose of 1.2 mg/kg. This dose is twice the standard intubating dose to yield an onset of action in approximately 60 seconds and intubating conditions that are comparable to succinylcholine.72 This has been demonstrated both in adult and pediatric populations.72,84 It should be noted, however, that at this increased dosage, the duration of action is also prolonged to greater than 1 hour, which far exceeds the 3 to 5 minutes provided by succinylcholine.53,63 The nondepolarizing, competitive blockade produced by rocuronium cannot be immediately reversed by anticholinesterases such as neostigmine until a partial competitive antagonism by acetylcholine has taken place naturally at the motor end plate. This may take an average of 20 minutes to occur, and must be measured by the return of muscular twitch using a neuromuscular twitch monitor, a device often used by anesthesia personnel in the operating room to monitor the level of intraoperative motor blockade.84 Therefore, should unexpected difficulties with intubation or ventilation be encountered, it is recommended that the practice of using high-dose rocuronium during rapid sequence induction be limited in the Emergency Department as much as possible. Should all attempts at intubation and ventilation fail, staff experienced in the attainment of a surgical airway must be immediately available.
Rocuronium is eliminated primarily by the liver and<10% by the kidneys.53 Its duration of action, therefore, is significantly prolonged in liver failure and only slightly in renal failure. There are no active metabolites, making it a good choice for prolonged infusions. Nondepolarizing NMB agents as a class are highly ionized, water-soluble compounds that cannot easily cross lipid membranes such as the blood–brain barrier and the placenta. As a result, they have no central nervous system effects and do not affect the fetus when administered to pregnant women.53
Rocuronium binds nicotinic acetylcholine receptors at the neuromuscular end plate and, once bound, it is unable to induce the conformational change necessary to open the ion channels and allow subsequent depolarization. This results in a competitive and antagonistic block.
Several drugs including volatile anesthetics, aminoglycosides, magnesium, lithium, dantrolene, and certain antiarrhythmics will augment the neuromuscular blockade produced by nondepolarizers. In contrast, corticosteroids, certain anticonvulsants, and calcium will diminish their effect. Patients with myasthenia gravis, Lambert–Eaton myasthenic syndrome, and Duchenne's muscular dystrophy exhibit varying sensitivity to nondepolarizing neuromuscular blockers. Burn patients, on the other hand, are resistant to their effects. Careful titration of dosages, dosing intervals, and infusion rates are necessary in these patient populations.
Rocuronium is administered at a usual intubating dose of 0.6 mg/kg, providing a clinical duration of roughly 45 minutes. Rapid sequence induction with rocuronium is most rapidly achieved with a dose of 1.2 mg/kg and is associated with an accompanying increase in duration. Following intubation, maintenance of paralysis can be achieved with intermittent 0.1 mg/kg boluses or by infusion rates of 5 to 12 mcg/kg/min, titrated to effect.
Other than the potential for a severe anaphylactic reaction in allergic patients, rocuronium is essentially devoid of any serious side effects. This should not be taken lightly, however, as neuromuscular blocking drugs are responsible for >50% of all life-threatening anaphylactic or anaphylactoid reactions occurring during anesthesia administration.53 While succinylcholine is the most common offending agent, the nondepolarizers are the second.
As a class, the steroidal nondepolarizers possess varying degrees of vagolytic activity and, fortunately, are not associated with histamine release. The vagolytic action of rocuronium is weak and rarely of clinical significance. This is in contrast to pancuronium, another steroidal nondepolarizer, which can cause significant tachycardia fol-lowing administration. Patients may report pain on injection of rocuronium due to venous irritation. This may be reduced by prior administration of IV lidocaine, but is usually not a problem as patients are unconscious or sedated at the time of rocuronium injection.
Other Nondepolarizing Agents
Pancuronium, in use since 1972, is classified as a long-acting, bisquaternary steroidal nondepolarizing agent. At a dose of 0.08 to 0.12 mg/kg, it produces paralysis in 2 to 5 minutes and lasts approximately 60 to 90 minutes. Following intubation, supplemental doses of 0.02 mg/kg can be given intermittently to maintain paralysis.53 Its use is associated with an increased heart rate, blood pressure, and cardiac output through a postganglionic vagolytic effect. It is not associated with the release of histamine. An estimated 80% to 85% of a dose of pancuronium is eliminated unchanged in the urine. Therefore, in patients with renal failure its duration may be significantly prolonged.53 Pancuronium's low cost and familiarity have made it popular, but its slow onset of action and extended duration limit its usefulness in facilitating emergent endotracheal intubation.
Removing a quaternary methyl group from pancuronium yields vecuronium, a monoquaternary steroidal nondepolarizer. This small change does little to affect potency, but favorably alters the side effect profile of the drug, most notably the vagolytic action. Similar to rocuronium, the vagolytic effects of vecuronium are negligible and do not cause histamine release. This molecular change also alters the metabolism and excretion of the drug when compared with pancuronium. Vecuronium is metabolized to a small extent by the liver and depends primarily on biliary excretion and secondarily on renal excretion. Vecuronium is unstable in solution. It is prepared as a lyophilized powder that must be hydrated prior to use.
The normal intubating dose of vecuronium (0.1 mg/kg) takes 3 minutes to produce adequate paralysis for intubation, and the patient will remain apneic for 30 to 35 minutes. Although it can produce good intubating conditions within 1 minute at 2.5 times the normal dose, this unfortunately results in paralysis for 1 to 2 hours. Maintenance of paralysis can be achieved with boluses of 0.02 mg/kg. The most troublesome side effect of this drug is prolonged paralysis (up to several days) following an infusion, a side effect attributed possibly to accumulation of its active 3-hydroxy metabolite.53
Rapacuronium is a newer nondepolarizing NMB agent with onset times and duration of action similar to those of succinylcholine. It was developed as a replacement for succinylcholine in the rapid sequence protocol. Due to reported incidences of fatal bronchospasm in patients, rapacuronium was voluntarily withdrawn from the US market by its manufacturer in March, 2001. At present, succinylcholine is firmly in place as the muscle relaxant of choice for rapid sequence emergency intubations.64