Recovery From Neuromuscular Block and Its Assessment

Residual neuromuscular block is common after the use of neuromuscular blocking drugs during anesthesia administration (1–5, 7, 8). 1 Although this has been well recognized for more than 20 years, its clinical importance has only been quantified recently (9). In addition, very small degrees of neuromuscular block may modify the respiratory response to hypoxia (10) and result in uncoordinated esophageal activity (11) that may predispose to gastric regurgitation and tracheal aspiration. Despite this, there is still some reluctance by anesthesiologists to use neuromuscular monitoring during anesthesia, in part because the clinical recognition of residual block is difficult. Residual neuromuscular block is more frequent after the use of long-acting muscle relaxants, such as pancuronium and d-tubocurarine, than after the intermediate acting drugs, atracurium and vecuronium (5). A new neuromuscular blocking drug, rapacuronium, has been introduced. In addition to a rapid onset, it has a shorter duration of action so that administration of reversal drugs, such as neostigmine, leads to prompt recovery of neuromuscular function (12). The purpose of this article is to review the frequency and means of recognition of residual neuromuscular block, to describe the use of reversal agents in avoiding the syndrome, and to compare the recovery and reversal of rapacuronium neuromuscular block with that of other contemporary agents. Residual Neuromuscular Block In 1979, Viby-Mogensen et al. (1) demonstrated a frequent incidence of residual neuromuscular blockade in patients in the postanesthesia care unit (PACU). They examined 72 patients, who had received a variety of long-acting relaxants (d-tubocurarine, gallamine and pancuronium), after the anesthesiologist had left the patient to the care of the PACU staff. In 30 patients (42%), the train-of-four (TOF) ratio after stimulation of the adductor pollicis was <0.7, although 67 had received neostigmine to reverse the block. Of the 68 who were sufficiently awake and cooperative, 16 (24%) were unable to maintain a 5-s head lift. Other studies, performed in several countries (2–8) (Table 1), have reported a similar high incidence of residual paralysis although the incidence of weakness (TOF < 0.7) was reduced to <10% when the intermediate drugs, atracurium and vecuronium, were used (5). Only in children, from 0–10 years old, studied 15–20 min after reversal of neuromuscular blockade was it not possible to demonstrate residual weakness (TOF < 0.7) (7).Table 1: Incidence of Residual Neuromuscular Block After Anesthesia AdministrationSpontaneous recovery of neuromuscular function occurs more rapidly after administration of mivacurium than after other nondepolarizing relaxants, and recovery is more rapid in children than in adults (8). It was hoped that it may not be necessary to reverse mivacurium neuromuscular blockade with anticholinesterases, and thus, the complications of reversal, such as nausea, vomiting, and abdominal pain from increased peristalsis, could be avoided. However, when neuromuscular block is maintained by continuous infusion of mivacurium, and if the block is not reversed, in adults, residual block may still be present on arrival in the PACU (8). The decreased incidence of residual block when intermediate or short duration relaxants are used has led to the gradual disappearance of relaxants such as pancuronium, d-tubocurarine, or doxacurium. The “Gold Standard”—TOF ≥ 0.7 In all these studies “residual neuromuscular block” was defined as a TOF < 0.7 because, in unanesthetized volunteers given small doses of d-tubocurarine, this value was associated with a statistically significant decrease in maximum inspired pressure that could be generated (13). Recently, it has been demonstrated that, in volunteers receiving continuous infusions of atracurium or vecuronium, mild degrees of block have been associated with ventilatory and esophageal disturbances. Eriksson et al. (10) showed, in awake volunteers receiving a continuous infusion of vecuronium to maintain constant neuromuscular block, that at TOF of 0.6–0.7, the ventilatory response to hypoxia, but not hypercapnia, was impaired and did not return to normal until TOF ≥ 0.9. The likely cause is that neuromuscular blocking drugs impair the nicotinic carotid body receptors. In a similar study (11), the same authors showed reduced pharyngeal muscle coordination and shortened pharyngeal bolus transit time during infusion of atracurium. Six of 14 volunteers demonstrated, by using videoradiography, laryngeal penetration at TOF 0.6–0.8. However, in a large, controlled study of postoperative pulmonary complications in 693 subjects randomized to receive pancuronium, vecuronium, or atracurium for abdominal, gynecological, or orthopaedic surgery, Berg et al. (9) showed that TOF < 0.7 after pancuronium administration was a potential risk factor for development of postoperative pulmonary complications (Table 2). Thus, although respiratory and alimentary effects may be seen at less intense levels of block, the index of adequate return of neuromuscular activity at the end of anesthesia should remain at TOF 0.7. There are no data evaluating postoperative neuromuscular activity after rapacuronium administration.Table 2: Postoperative Pulmonary Complications and Choice of RelaxantAssessment of Neuromuscular Blockade Clinical Evaluation In the conscious and cooperative patient, clinical testing may reveal evidence of gross weakness. Tests include the ability to lift the head of the pillow for 5 s, eye opening, tongue protrusion, jaw grip, and sustained handgrip. In children, the ability to lift the leg from the bed has been used. Sustained head lift has been recommended as a sensitive test, but all tests are crude and imprecise and of limited use during the administration of anesthesia or in the intensive care unit. Recently, Kopman et al. (14) correlated these clinical tests with the TOF ratio in volunteers. The most sensitive index is the visual symptoms seen with very mild block (Table 3).Table 3: Correlation Between Clinical Signs and TOF RatioNerve Stimulation When a current >50 mA is delivered to a motor nerve, all nerve axons propagate an action potential, and all nerve endings release acetylcholine. Such a “supramaximal stimulus” is applied, during anesthesia administration, to an accessible peripheral nerve, e.g., ulnar, median, facial, or posterior tibial nerves. The muscle response can be assessed by measuring electrical activity (electromyography [EMG]), contractile force (mechanomyography [MMG]), or acceleration (accelereomyography [AMG]). Alternatively, the response can be examined visually or by touch. In the presence of nondepolarizing muscle relaxants, there is a fade in response to repeated stimulation. Repeated stimuli >50 Hz induce sustained contraction in the muscle (tetanus). Tetanic fade is a more sensitive index of residual nondepolarizing block than single stimuli at 0.1 Hz, but high frequency stimulation (>100 Hz) produces posttetanic facilitation and, more important, leads to changes in the response to subsequent stimulation. TOF stimulation, in which trains of supramaximal stimuli with a duration of < 0.5 ms and frequency of 2 Hz are applied for 2 s every 12 s is a compromise between sensitivity and the absence of posttetanic facilitation. Double-burst stimulation (DBS) in which two, brief bursts of three impulses at 50 Hz are applied, separated by 750 ms further improves manual assessment of nondepolarizing block. The characteristics of neuromuscular monitoring for research purposes have recently been defined in the 1995 Copenhagen Consensus Conference (15). Measurement of Response MMG. Force transducers are used in research to obtain quantitative results but are too bulky for clinical practice. Most are designed to measure the force of contraction of the adductor pollicis muscle in response to ulnar nerve stimulation. EMG. Measurement of the electrical activity, EMG, is also largely a research tool. Results obtained with MMG and EMG are similar. AMG. The principle of accelerometry is Newton’s second law of motion: force = mass × acceleration. Acceleration is measured by using a small piezoelectric ceramic wafer. Although AMG monitoring has not been adequately assessed for experimental use, it is a very convenient clinical monitor. Clinical Evaluation. Using visual or tactile appreciation of the response to nerve stimulation, most clinicians are unable to detect fade to TOF stimulation when TOF ≥ 0.4 (16). Sensitivity is improved by DBS. Absence of recognizable fade to TOF is associated with a 48% chance of residual paralysis (TOF < 0.6) compared with only a 9% chance when tactile fade was absent with DBS. Accelerometry provides a written record of TOF ratio and is superior to clinical evaluation in detecting residual neuromuscular blockade (17). Although tetanic stimulation may modify the response to stimulation for several minutes and the clinician’s ability to detect fade in response to 50 Hz tetanus is no greater than his ability to detect TOF fade, a sustained response to 100 Hz tetanus for 5 s is equivalent to TOF ≥ 0.85 (18). Such a test is useful if applied at the end of surgery to determine whether reversal of neuromuscular blockade is necessary. However, tetanic stimulation is painful and may only be applied to the anesthetized patient. Influence of Monitoring Residual block after the use of neuromuscular blocking drugs during anesthesia is common even when clinical neuromuscular monitoring has been carefully applied. Complete recovery is particularly difficult to achieve when reversing pancuronium (19). Although the incidence can be reduced by using TOF monitoring or DBS and observing the adductor pollicis visually or by touch, residual block still occurs unless the response is measured quantitatively. The use of accelerometry to monitor neuromuscular block prevents residual block, at least when rocuronium was used as the relaxant (Table 4) (20–23).Table 4: Influence of Monitoring on the Incidence of Residual BlockReversal of Neuromuscular Block After the use of neuromuscular blocking drugs, reversal with anticholinesterases should be attempted unless recovery of neuromuscular block to TOF ≥ 0.7 can be demonstrated. Several regimens have been proposed. In general, recovery is achieved more rapidly after the administration of edrophonium than neostigmine. However, neostigmine is more effective in reversing an intense block. Thus, the choice and dose of reversal drugs should be based on the intensity of neuromuscular block (Table 5) (24).Table 5: Suggested Doses for the Reversal of Intermediate and Long-acting Muscle Relaxants with Edrophonium or Neostigmine According to Response to TOF StimulationThe more intense the block, the longer will it take to achieve acceptable standards of reversal (TOF ratio ≥ 0.7), and the larger the dose of reversal drug that will be required. For all drugs, reversal time is considerably prolonged when spontaneous recovery at the time of reversal is <25% the first twitch height (T1) (25). Thus, it has been recommended that the administration of reversal agents should not be attempted until this level of spontaneous recovery has been achieved. Dose-response curves for edrophonium, neostigmine, and pyridostigmine have been constructed after the reversal of 90% and 99% block and have demonstrated that the greater the dose of reversal drug, the greater the extent of recovery. By using the same dose of reversal drug, greater recovery was achieved with the intermediate than with the long-acting NMBDs (Table 6) (26–29). Thus, the time to achieve a given effect is reduced the larger the dose of reversal drug. As restoration of neuromuscular function depends on the combination of spontaneous recovery and reversal with anticholinesterases, reversal appears to be accomplished more easily with the intermediate than with the longer-acting drugs. It is probably for this reason that residual curarization is seen infrequently in the recovery room after using atracurium or vecuronium.Table 6: Potency Ratios for Edrophonium and Neostigmine in the Reversal of Atracurium, Vecuronium, Rocuronium, and MivacuriumReversal of neuromuscular blockade occurs more rapidly in infants and children than in adults. When neostigmine or edrophonium was given after bolus doses of pancuronium or vecuronium at 90% T1 block, reversal occurred more rapidly than after similar doses in adults (30). Similarly, when dose-response curves for neostigmine were determined during continuous infusion of d-tubocurarine, sufficient to maintain 90% T1 block, the dose required to produce 50% reversal was 13.1 μg/kg in infants, 15.5 μg/kg in children, and 22.9 μg/kg in adults (31). Spontaneous recovery from neuromuscular block occurs more slowly in elderly patients, perhaps as a consequence of age-related changes in hepatic metabolism and glomerular filtration. Nevertheless, it has been difficult to demonstrate impairment of reversal although this has been shown for pancuronium and d-tubocurarine but not for atracurium. Recovery and Reversal of Rapacuronium Traditionally, the rate of recovery from neuromuscular blockade after reversal is expressed as the time from administration of neostigmine or edrophonium, until recovery (TOF 0.7) has been achieved. The greater the extent of recovery when reversal is attempted, the shorter the reversal time. Thus, it is recommended that reversal should be delayed until T1 has reached 25% (T25) (25), which corresponds to the visual or tactile appearance of the response to the fourth stimulus of a TOF sequence. The more intense the block at the time of reversal, the longer the reversal time (32). However, Kirkegaard-Nielsen et al. (33) have shown that the shortest time from administration of neuromuscular relaxant until TOF 0.7 (block time) after vecuronium, was achieved when neostigmine was given at T1 of 8%. Recently, comparison of reversal times and block times after small doses (ED95 × 1.5) of vecuronium or rocuronium were compared when 0.07 mg/kg neostigmine was administered at four times (5 min after relaxant and at 1%, 10% [T10], and 25% T1) (34). Reversal times decreased the later that reversal was attempted (T25 < T10 < T1 < 5 min) (Fig. 1) but block time was independent of the extent of recovery at reversal. More important, early reversal did not prolong block time (Fig. 2). A similar pattern was observed with early reversal of vecuronium and rocuronium in children, but recovery was more rapid in children (34). Similar results were obtained when cisatracurium or atracurium block was reversed at 10% or 25% T1 (35).Figure 1: Time from administration of neostigmine to train-of-four (TOF) 0.7 after reversal of 0.45 mg/kg rocuronium with neostigmine at 5 min and first twitch height recovery of 1%, 10%, and 25% (34).Figure 2: Time from administration of rocuronium to train-of-four (TOF) 0.7 after reversal of 0.45 mg/kg rocuronium with neostigmine at 5 min and first twitch height recovery of 1%, 10% and 25% (34).Recovery of neuromuscular activity after neostigmine reversal of the new muscle relaxant, rapacuronium, follows the same principles but recovery is more rapid after rapacuronium than after vecuronium rocuronium, atracurium, or cisatracurium (Table 7). When 0.05 or 0.07 mg/kg neostigmine was given at 2 or 5 min after 1.5 or 2.5 mg/kg rapacuronium (ED95 × 1.5), at a time of complete neuromuscular block, recovery was accelerated so that block time was reduced by approximately 40% compared with spontaneous recovery (Figure 3) (36). Block time was increased with the larger dose of rapacuronium (Figure 4). The early administration of neostigmine during complete block dose not appear to prolong block time.Table 7: Time from the Administration of Relaxant to Recovery to Train-of-Four (TOF) Ratio of 0.7 (TOF 0.7 for Vecuronium, Rocuronium, Rapacuronium) or 90% First Twitch (90% T1 for succinylcholine) in Adults and ChildrenFigure 3: Time from administration of 1.5 mg/kg rapacuronium to train-of-four (TOF) 0.7 after reversal with neostigmine (0.05 or 0.07 mg/kg) given at 2 or 5 min after rapacuronium (35).Figure 4: Time from administration of 2.5 mg/kg rapacuronium to train-of-four (TOF) 0.7 after reversal with neostigmine (0.05 or 0.07 mg/kg) given at 2 or 5 min after rapacuronium (35).The time from the administration of neuromuscular relaxant until recovery to TOF 0.7 may be considered “minimum block time.” It cannot be accelerated by changing the dose or timing of neostigmine administration. Minimum block time is independent of the intensity of the block at reversal. At relaxant doses of ED95 × 1.5, block time for rapacuronium is shorter than for other intermediate duration relaxants and is shorter in children than in adults (Table 7). Thus, the poor potency and shorter duration of action of rapacuronium produces an onset of <1 min and a block time of <20 min (36). These data satisfy Bedford’s criteria for a short onset (≤1 min) and rapid recovery (TOF 0.7 < 20 min) (37). Conclusion Residual block is common after the use of neuromuscular relaxants, especially after the long-acting pancuronium. It is difficult to diagnose clinically, although AMG and tetanic stimulation may be helpful. There is some dispute about the optimal dose and drug for the reversal of neuromuscular block. Recent evidence suggests that early reversal can be attempted without the fear of impaired recovery. The new neuromuscular relaxant, rapacuronium, has a shorter duration of block and, when reversed 2 or 5 min after its administration, recovery to TOF 0.7 occurs in <20 min from its administration, which is much more rapid than with currently available intermediate acting muscle relaxants.

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