Neuromuscular Blockers and Tracheal Intubation

Speed of onset of a neuromuscular block is one of the requirements to rapidly secure the airway, and it is affected by several factors, including the rate of delivery of the drug to the neuromuscular junction, receptor affinity, plasma clearance, and the mechanism of neuromuscular blockade (depolarizing versus nondepolarizing). ^{[176] [259] [260]} The speed of onset is inversely proportional to the potency of nondepolarizing neuromuscular blockers.^{[176] [259]} A high ED₉₅ (low potency) is predictive of rapid onset and vice versa (see Table 13-8 and Fig. 13-18 ). Except for atracurium,^[261] molar potency (the ED₅₀ or ED₉₅ expressed in µM/kg) is highly predictive of a drug's initial rate of

Figure 13-18 Linear regression of the onset of neuromuscular blockade (ordinate) versus potency of a series of steroidal relaxants studied in the cat model by Bowman and colleagues.^[176] The data show that onset may be increased in compounds with low potency and encouraged the eventual development of rocuronium and rapacuronium. A, pipecuronium; C, pancuronium; D, vecuronium.

Donati and Meistelman^[260] proposed a model to explain the inversed potency-onset relationship. Nondepolarizing neuromuscular blockers of low potency (such as rocuronium and rapacuronium) have more molecules to diffuse from the central compartment into the effect compartment. Once in the effect compartment, all molecules act promptly. Weaker binding of low-potency drugs to receptors prevents buffered diffusion,^[260] a process that occurs with potent drug. Buffered diffusion causes repetitive binding and unbinding to receptors, thereby keeping potent drugs in the neighborhood of effector sites and potentially lengthening the duration of effect.

The times to 95% block at the adductor pollicis after a 1 × ED₉₅ dose of succinylcholine, rocuronium, rapacuronium, vecuronium, atracurium, mivacurium, and cisatracurium are shown in Figure 13-19 .^{[220] [259] [261]} The figure shows that the most potent compound, cisatracurium, has the slowest onset and that the least potent, rocuronium and rapacuronium, are the most rapid ( Fig. 13-19 ). ^{[220] [259] [261]} Bevan^[263] also proposed that rapid plasma clearance is associated with a rapid onset of action. The fast onset of succinylcholine is related to its rapid metabolism and plasma clearance.

The onset of neuromuscular blockade is much more rapid in the muscles that are relevant to obtaining optimal intubating conditions (laryngeal adductors, diaphragm, and masseter) than in the muscle typically monitored

Figure 13-19 Percentage of peak effect after a 1 × ED₉₅ dose of succinylcholine, rapacuronium, rocuronium, atracurium, mivacurium, vecuronium, and cisatracurium at the adductor pollicis muscle. Times (mean ± SD) in seconds to 95% of peak effect are shown in parentheses. (Redrawn from Kopman and associates.^{[220] [259] [261]} )

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Onset of block in the larynx occurs 1 to 2 minutes earlier than at the adductor pollicis after the administration of nondepolarizing neuromuscular blocking agents. The pattern of blockade (onset, depth, speed of recovery) in the orbicularis oculi is similar to that in the larynx.^[271] By monitoring the onset of neuromuscular blockade at the orbicularis oculi, the quality of intubating conditions can be predicted. The onset of maximal block in the larynx also corresponds to the point at which the adductor pollicis is beginning to show palpable evidence of weakening. Furthermore, return of thumb responses to normal suggests that the efferent muscular arc of protective airway reflexes is intact.

Rapid Tracheal Intubation

Succinylcholine remains the drug of choice when rapid tracheal intubation is needed because it consistently provides muscle relaxation within 60 to 90 seconds. When succinylcholine is considered undesirable or contraindicated, the onset of nondepolarizing neuromuscular blocking drugs can be accelerated by preceding the intubating dose with a priming dose of neuromuscular blocker,^{[272] [273] [274] [275]} by the use of high doses of an individual agent,^{[250] [276]} or by combinations of neuromuscular blockers. ^{[251] [277] [278]} Although some combinations of mivacurium and rocuronium can achieve rapid onset without undue prolongation of action and without undesirable effects,^[251] combination therapy may not consistently result in rapid onset of effect.^[277]

The Priming Technique

Since the introduction of rocuronium, the use of priming has significantly decreased. Several groups of investigators have recommended that a small subparalyzing dose of the nondepolarizer (about 20% of the ED₉₅ or about 10% of the intubating dose) be given 2 to 4 minutes before administering a second large dose for tracheal intubation.^{[272] [273] [274] [275]} This procedure, termed priming, has been shown to accelerate the onset of block of most nondepolarizing neuromuscular blockers by about 30 to 60 seconds, with the result that intubation can be performed within approximately 90 seconds after the second dose. However, intubating conditions after priming do not match those after succinylcholine.^[279] Moreover, priming carries the risk of aspiration and difficulty swallowing, and the visual disturbances associated with subtle degrees of block are uncomfortable for the patient. ^{[280] [281]}

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High-Dose Regimen for Rapid Tracheal Intubation

Larger doses of neuromuscular blockers are usually recommended when intubation must be accomplished in less than 90 seconds. High-dose regimens, however, are associated with considerable prolongation of the duration of action and potentially increased cardiovascular side effects (see Table 13-8 ).^{[250] [276] [282] [283]} Increasing the dose of rocuronium from 0.6 (2 × ED₉₅ ) to 1.2 (4 × ED₉₅ ) mg/kg shortened the onset time of complete neuromuscular blockade from 89 ± 33 seconds (mean ± SD) to 55 ± 14 seconds but significantly prolonged the clinical duration (recovery of T1 to 25% of baseline) from 37 ± 15 to 73 ± 32 minutes, respectively. ^[250]

Whatever technique of rapid-sequence induction of anesthesia and intubation is elected, the following four principles are important: (1) preoxygenation must be performed, (2) an adequate dosage of intravenous drugs must be administered to ensure that the patient is adequately anesthetized, (3) intubation within 60 to 90 seconds must be considered acceptable, and (4) cricoid pressure should be applied subsequent to injection of the induction agent.

Low-Dose Relaxants for Tracheal Intubation

This low-dose technique is not suitable for rapid-sequence induction. Several studies have demonstrated that low doses of neuromuscular blocking drugs can be used for routine tracheal intubation. A low-dose neuromuscular blocker has several advantages: (1) it shortens the time to recovery from neuromuscular blockade, and (2) it reduces the requirement for anticholinesterase drugs. Rocuronium has the shortest onset time of all the nondepolarizing neuromuscular blocking drugs currently available.^{[264] [266]} The maximal effect of either 0.25 or 0.5 mg/kg rocuronium at laryngeal muscles was observed after 1.5 minutes.^[264] This interval was shorter than the 3.3 minutes reported after the administration of equipotent doses of vecuronium (0.04 or 0.07 mg/kg)^[46] and only slightly more than the 0.9 minute reported after 0.25 or 0.5 mg/kg succinylcholine (see Table 13-9 ).^[284]

With a better understanding of the multiple factors that contribute to satisfactory conditions for intubation, it is now possible to take full advantage of the onset profile for rocuronium. Intubating conditions are related more closely to the degree of neuromuscular blockade of the laryngeal adductor muscles than to the degree of blockade typically monitored at the adductor pollicis. Figure 13-20 demonstrates this principle.^[262] Complete block at the larynx or diaphragm, or at both, may not be a prerequisite for satisfactory tracheal intubating conditions.

Kopman and colleagues^[286] noted that 0.5 mg/kg rocuronium (1.5 × ED₉₅ ) provided very satisfactory conditions for intubation (25 intubations were rated as excellent and 5 were rated as good) in patients anesthetized with 12.5 µg/kg alfentanil and 2.0 mg/kg propofol if laryngoscopy is delayed for 75 seconds after drug administration. They estimated that a 1.5 × ED₉₅ dose (0.5 mg/kg) of rocuronium will produce a 95% block or greater in 98% of the population. ^[286] Others have reported the same observation. ^[287] It has also been shown that a similar or lower ED₉₅ multiple of rocuronium has a more rapid onset and shorter duration than does either atracurium^[288] or

Figure 13-20 A computer simulation based on Sheiner and colleagues' model^[224] and data reported by Wierda et al.^[285] The ED₉₅ of rocuronium at the adductor pollicis from this model is 0.33 mg/kg. Rocuronium, 0.45 mg/kg, is given as a bolus at time zero. Muscle X represents a muscle (such as the diaphragm or the laryngeal adductors) that is less sensitive to the effects of nondepolarizing relaxants than the adductor pollicis is but has greater blood flow. In this example, the concentration of rocuronium producing a 50% block (EC₅₀ ) of muscle X is 2.5 times that of the adductor pollicis, but the half-life of transport between plasma and the effect compartment (t_½ k_e0 ) of muscle X is only half as long. The rapid equilibration between concentrations of rocuronium in plasma and muscle X results in a more rapid onset of blockade of muscle X than the adductor pollicis. The greater EC₅₀ at muscle X explains the faster recovery of this muscle from neuromuscular blockade than the adductor pollicis. Lower blood concentrations of rocuronium must be achieved at the adductor pollicis than at muscle X before recovery begins. (Redrawn from Naguib M, Kopman AF: Low dose rocuronium for tracheal intubation. Middle East J Anesthesiol 17:193–204, 2003.)

In the vast majority of patients receiving alfentanil, 15 µg/kg, followed by propofol, 2.0 mg/kg, and rocuronium, 0.45 mg/kg, good to excellent conditions for intubation will be present 75 to 90 seconds after the completion of drug administration. ^[286]