Careful management of the depth of neuromuscular blockade in the operating room may reduce the incidence of residual paralysis in the postanesthesia care unit (PACU) or intensive care unit (ICU). Several principles related to neuromuscular blocking drug (NMBD) dosing, monitoring, and reversal have been shown to reduce the risk of incomplete neuromuscular recovery in postoperative patients. Although use of these techniques has been recommended in editorials and reviews,1–4 at this time, there are no published standards or guidelines defining optimal neuromuscular management strategies. Part II of the review provides a narrative review of the methods that can be used by clinicians to reduce the risk of complications due to residual neuromuscular blockade. The number of randomized, controlled clinical trials directly related to this topic is limited; therefore, a formal meta-analysis of the studies was not attempted. Instead, the authors provide a narrative review of the relevant literature. The recent development of several novel NMBDs that promise increased flexibility with regard to block onset time, duration of effect, and ease of reversal will also be reviewed.
METHODS TO REDUCE THE RISK OF RESIDUAL NEUROMUSCULAR BLOCKADE
Use of Shorter-Acting NMBDs
The administration of intermediate-acting NMBDs is associated with a lower incidence of residual neuromuscular blockade in the PACU and ICU compared with long-acting NMBDs. Observational and randomized clinical trials comparing the frequency of residual paralysis in patients receiving either long- or intermediate-acting NMBDs are summarized in Table 1.5–14 All of the published clinical studies have demonstrated that the risk of residual blockade is increased when patients receive long-acting NMBDs. A recent meta-analysis estimated the pooled incidence of residual neuromuscular block in patients receiving long- or intermediate-acting NMBDs.15 The use of long-acting NMBDs was associated with a 3-fold higher risk of a train-of-four (TOF) ratio <0.7 in the postoperative period (35% vs 11%, P < 0.001). Furthermore, clinical trials have demonstrated that patients receiving pancuronium have an increased incidence of hypoxemic episodes in the PACU,10,12,14 prolonged PACU admissions,14,16 longer postoperative intubation times,11,13,17,18 and an increased risk of pulmonary complications.10 These data provide compelling evidence that the use of long-acting NMBDs places the surgical patient at increased risk of complications related to residual paralysis. The role of pancuronium in contemporary anesthesia practice is limited, and many correctly argue that its clinical use should cease; in fact, its clinical benefits (long duration) can be achieved with repeated administration of intermediate-duration drugs (rocuronium, cisatracurium), but with lower risk of drug accumulation or residual paralysis.
However, the promise that NMBDs of intermediate duration might markedly reduce the incidence of residual paralysis has not been realized.6 The reason for this failure is multifactorial. First, when administered in large doses (such as 3–4 times the dose needed for 95% block, or ED95), the duration of all intermediate-acting neuromuscular blockers is prolonged (by 50%–300%) compared with the duration of action attained after administration of a 1 to 2 times ED95 dose. Second, there is a great variability among patients in response to intermediate-duration NMBDs. Third, there is great variability in the duration of neostigmine-induced reversal, even with intermediate-duration NMBDs. During cisatracurium- or rocuronium-induced block, pharmacologic reversal administration at a TOF count of 2 required at least 15 minutes, whereas some patients still had significant residual paralysis (TOF <0.90) >30 minutes after reversal.19 Thus, current clinical practice of tracheal extubation 5 to 10 minutes after administration of anticholinesterases may not allow sufficient time for adequate return of neuromuscular function, especially in patients at risk. This potentially unsafe practice (e.g., early tracheal extubation before complete neuromuscular recovery) may be a direct result of the increasingly common production pressure for “quick turnover” of surgical cases, especially in ambulatory surgery settings. The desire to expedite surgical case volume may shorten the time between administration of anticholinesterases and tracheal extubation, increasing the potential for residual block.
Last, monitoring of evoked responses intraoperatively, regardless of the NMBD used, is only a tool and may not actually decrease the incidence of residual paralysis.15 To decrease the incidence of residual paralysis, return of neuromuscular function to baseline must be documented objectively (i.e., measured) before tracheal extubation. Documentation of residual paralysis is not sufficient to solve the problem of residual neuromuscular block; acting on the available evidence is ultimately the most important step.
Clinical Tests to Exclude Residual Muscle Weakness
Ideally, clinical tests of neuromuscular recovery should not require an awake and cooperative patient. Such tests should be applicable and reliable before emergence from anesthesia and tracheal extubation. Unfortunately, most clinical tests fail to meet either of these 2 criteria. In addition, many clinical tests (leg lift, hand grip, and head lift) are not specific for the respiratory function, so they cannot be used clinically to infer adequacy of respiratory muscle function. In practice, however, most clinicians rely primarily on clinical signs or tests of muscle weakness to determine the presence or absence of residual blockade before tracheal extubation.20 Surveys have also demonstrated that most clinicians believe that it is always possible to exclude residual neuromuscular blockade using clinical tests.21,22 Available evidence does not support this belief. A 5-second head lift is the most frequently applied clinical test of residual paralysis used by clinicians.20 However, in a volunteer study, 11 of 12 subjects were able to maintain a head lift for more than 5 seconds at a TOF ratio of 0.5.23 Pedersen et al.5 observed that 16 of 19 postoperative patients were able to maintain a 5-second head lift despite having TOF ratios <0.5. Clearly, this degree of recovery (TOF of 0.5) is clinically unacceptable. Clinical studies also have demonstrated that other frequently used clinical tests of muscle weakness (sustained hand grip, leg lift, or eye opening) can be performed when significant degrees of residual neuromuscular blockade are present.24–26
The ability to maintain masseter muscle strength (clench teeth on a tongue blade or bite block) may be a more sensitive test of residual paralysis than head lift, but it is not infallible. In awake volunteers, the ability to retain a tongue depressor between the clenched incisor teeth “despite vigorous attempts to dislodge it” did not return until TOF ratios exceeded 0.86.27 However, the sensitivity of this test in predicting residual paralysis (TOF ratio <0.9) in postoperative patients was low (13%–22%).24,28 More important from a patient safety standpoint, however, is the fact that the tongue depressor test seems to be more specific; few patients with a TOF >0.9 are likely to fail this test. The sensitivity, specificity, positive predictive value, and negative predictive value of frequently used clinical tests for residual paralysis were recently examined in a cohort of 640 surgical patients.24 As noted in Table 2, the sensitivity and positive predictive values of all the tests were low for predicting TOF ratios <0.9. None of the 8 individual tests (or a sum of these tests) was able to reliably predict the occurrence of residual neuromuscular block. Another large clinical trial (n = 526 patients) noted similarly low sensitivity values (11%–14%) for clinical tests in detecting patients with TOF values <0.9.28 In summary, current evidence demonstrates that frequently used clinical tests of neuromuscular function cannot reliably exclude the presence of residual paralysis unless TOF ratios are <0.5.
Use of Neuromuscular Monitoring: Qualitative Means
A subjective (qualitative) visual or tactile assessment of a response to peripheral nerve stimulation is the most common method of neuromuscular monitoring used in the operating room, PACU, and ICU. Available data suggest that tactile evaluations may be slightly (but not significantly) more sensitive in detecting residual neuromuscular block than visual assessments. At a TOF ratio of 0.41 to 0.50, only 37% of inexperienced anesthesiologists were able to detect fade visually, compared with 57% who detected fade manually (P = not significant).29 Similarly, the ability to detect fade was comparable for visual or tactile assessments regardless of the method of neurostimulation (TOF, double-burst stimulation [DBS3,3; DBS3,2]) at both high and low currents.30 In contrast, Tammisto et al.31 observed that the tactile method (movement of the patient's thumb against the observer's fingers) was more accurate in detecting fade than visual assessment.
The most frequently used patterns of neurostimulation are TOF, DBS, and tetanic stimulation. The ability of each mode of neurostimulation to diagnose residual neuromuscular blockade (determined using mechanomyography [MMG] on the contralateral arm) has been studied extensively. In 1985, Viby-Mogensen et al.29 measured the ability of anesthesiologists to detect fade using TOF stimulation at varying levels of neuromuscular blockade. Anesthesiologists inexperienced in tactile fade detection were able to feel fade only when TOF ratios were <0.30. Although outcomes were better in observers with extensive experience in neuromuscular monitoring, these observers were unable to detect fade 80% of the time when TOF ratios were between 0.51 and 0.70. Other investigators have confirmed that the majority of evaluators are unable to detect fade when TOF ratios exceed 0.40.30,32,33 Despite this readily available information, it is likely that most clinicians are unaware of the limitations of the subjective evaluation of TOF fade.
The use of DBS seems to improve detection of residual paralysis using subjective means compared with qualitative (subjective) TOF monitoring. When using DBS monitoring, the threshold for subjective detection of fade is a TOF ratio of 0.60 to 0.70, whereas the threshold for detection of fade with TOF monitoring is 0.40.33 One of the mechanisms proposed for the apparent improvement in the ability to detect fade with DBS compared with TOF is that DBS relies on the direct comparison of 2 rapidly sequential, evoked stimuli (the muscle contraction in response to the 2 individual minitetanic bursts) rather than the indirect comparison of the fourth twitch with the first twitch in the series of 4 evoked responses of TOF. In this latter setting, the comparison of the fourth to the first twitches is likely muddled by the intervening second and third twitches that provide no useful information. Other investigators have shown that it is not the amplitude of individual responses in TOF or DBS that facilitates detection of fade (the amplitude of the individual DBS responses is greater than that of TOF responses) but the pattern of stimulation (2 responses in DBS vs 4 responses in TOF).34
In a preliminary investigation using DBS3,3, manual evaluation of the DBS response allowed detection of TOF ratios up to 0.6.33 However, probability analysis showed that when no fade was detected with either TOF or DBS, there was still a 47% risk that the “true” TOF ratio (i.e., determined by MMG) was <0.7. Other investigators have demonstrated that the ability of clinicians to detect fade in the TOF range of 0.3 to 0.7 is greater with DBS than TOF monitoring.30,32–34 The 50-Hz tetanic stimulation pattern is the least sensitive qualitative method of monitoring; fade can only be reliably detected when TOF ratios are ≤0.3.32,35 However, the threshold for detecting fade is increased using a 5-second, 100-Hz stimulating current. Although fade could be reliably detected up to TOF ratios of 0.85 to 0.88 using 100-Hz tetanus,32,36 other investigators reported no fade at MMG TOF values as low as 0.47.37 In addition, tetanic stimulation rates >70 Hz may induce neuromuscular fade (detected by MMG) even in the absence of any neuromuscular block because even normal neuromuscular transmission may fatigue at these high stimulation rates.38,39
The effect of qualitative neuromuscular monitoring on postoperative residual paralysis has been evaluated in observational and randomized trials. Three randomized clinical studies have specifically examined the usefulness of conventional peripheral nerve stimulators in reducing the occurrence of residual neuromuscular blockade in the PACU. Pedersen et al.5 randomized 80 subjects to receive either TOF monitoring (tactile evaluation of TOF stimulation) or no neuromuscular monitoring (in which clinical criteria such as spontaneous muscle activity determined the administered NMBD dose). No differences were observed between the 2 groups in TOF ratios measured in the PACU or in clinical signs of postoperative muscle weakness. The maintenance of a deep level of neuromuscular blockade in the monitored group (TOF count of 1–2 during surgery and at reversal) likely contributed to the high incidence of residual paralysis in these subjects (20 of 40 patients with TOF ratio <0.7), complicating the interpretation of findings. Shorten et al.40 randomized 39 patients to TOF monitoring (tactile assessment at the adductor pollicis) or no monitoring (clinical criteria) during anesthesia with pancuronium and enflurane. In contrast to the previous investigators, Shorten et al. determined that the proportion of patients with TOF ratios <0.7 was significantly less in a monitored group (15%) compared with unmonitored patients (47%, P < 0.05). Another randomized trial demonstrated that tactile evaluation of the response to DBS reduced, but did not eliminate, the occurrence of residual paralysis.26 In the DBS-monitored group, the trachea was extubated when no fade was detectable in both the TOF- and DBS-evoked response. Immediately after extubation, significantly fewer patients in the monitored group had TOF ratios <0.7 (24%) compared with the unmonitored group (57%). In a recent meta-analysis, investigators examined the effect of neuromuscular monitoring (qualitative and quantitative) on the incidence of postoperative residual paralysis.15 Data were analyzed on 11 observational and 13 randomized trials (total of 3375 patients) published between 1979 and 2005. The authors were unable to demonstrate that the use of monitoring decreased the incidence of residual paralysis. However, conclusions from the meta-analysis were limited by the quality of the individual studies reviewed, which were “often poorly designed to detect any advantages conferred by monitoring.” Further large-scale, well-designed randomized clinical trials are needed to assess the effect of qualitative monitoring on postoperative outcomes.
Use of Neuromuscular Monitoring: Quantitative Means
Clinicians are unable to reliably exclude residual neuromuscular blockade when using conventional peripheral nerve stimulators because fade is difficult to detect subjectively when TOF ratios are between 0.4 and 0.9.32 However, TOF ratios >0.4 can be measured accurately and displayed numerically using quantitative neuromuscular monitoring. Several methods of quantitative monitoring have been used in clinical studies: MMG, electromyography (EMG), kinemyography (KMG), phonomyography (PMG), and acceleromyography (AMG).41–43
- MMG quantitatively measures isometric contraction of a peripheral muscle (usually the adductor pollicis) in response to ulnar nerve stimulation (Fig. 1, A and B). The thumb is placed on the force transducer under mild tension (preload, usually 200–300 g) to produce an isometric contraction and improve consistency of evoked responses. The force of contraction is converted to an electrical signal and the amplitude of the signal is recorded on an interfaced pressure monitor; because the amplitude of the electrical signal is proportional to the strength of the muscle contraction, measurement of the TOF ratio will yield results that are precise and reproducible. Until the mid-1990s, MMG was used in the majority of clinical studies involving NMBDs and has been considered the “gold standard” method of assessing evoked responses. Because of the relatively elaborate set up and bulk of the equipment, today MMG is used less frequently in the clinical research setting and almost never clinically.
- EMG also has been used relatively rarely in the clinical setting because of the set up required (5 electrodes) and the expensive equipment that is necessary (Fig. 2). EMG measures the electrical activity (compound muscle action potential) of the stimulated muscle. The EMG response may be calculated by the peak amplitude of the signal (either peak-to-baseline or peak-to-peak amplitude) or by the total area under the EMG curve. The quality of the EMG signal can be affected adversely by a number of variables in the operating room (such as electrocautery), limiting the clinical utility of EMG monitoring, especially when a processed EMG monitor (such as the Datex Relaxograph, Datex Instrumentarium, Finland) was used. However, EMG responses are very consistent over time, and some experts think that the EMG should be considered the gold standard for neuromuscular monitoring because it is not subject to changes in the force of myofibril contractility (i.e., the “staircase effect”).44
- KMG relies on 2 stimulating electrodes usually placed along the ulnar nerve at the wrist and a piezoelectric polymer sensor that is placed in the groove between the thumb and the index finger; the sensor detects the degree of movement (bending) that is produced by the thumb in response to electrical stimulation of the ulnar nerve (Neuromuscular Transmission Module, E-NMT; GE Healthcare, Helsinki, Finland) (Fig. 3). When the thumb contracts and bends the piezoelectric sensor, the degree of movement is sensed, and it is converted into electrical signals that are proportional to the force of thumb contraction. Much like MMG, KMG can yield signals that can be measured and that can give an indication of the degree of neuromuscular block.45 Unlike MMG, however, KMG may be less reproducible because it may be affected by the variable positioning of the sensor on the hand, and some experts do not consider this method to be a reliable clinical monitor.46
- PMG relies on recording of the sounds that a muscle contraction evokes. A special high-fidelity and narrow-bandwidth microphone is placed alongside the monitored muscle, and the sounds from the isometric muscle contractions can be recorded; the sound intensity is proportional to the force of contraction. Studies have documented a high degree of agreement among PMG, MMG, and KMG for determination of recovery of neuromuscular function in the clinical setting.41,47 However, this technology is not used clinically, and its future development is uncertain.
- AMG calculates muscle activity using a miniature piezoelectric transducer attached to the stimulated muscle (Fig. 4). Acceleration of the muscle generates a voltage in the piezoelectric crystal that is proportional to the force of contraction (based on Newton's second law, force = mass × acceleration, or F = m × A). AMG monitors are small, portable, and relatively easy to use in the perioperative setting. In contrast, MMG and EMG were developed primarily for research purposes and are no longer commercially available. The most widely available AMG device is the TOF-Watch® (Schering-Plough Corp., Kenilworth, NJ). It is available in 3 models: (1) TOF-Watch, (2) TOF-Watch S, and (3) TOF-Watch SX (Fig. 4). Only the latter model, which is designed for research, will display a TOF ratio >1.00. The other 2 units (which are used clinically much more widely) use a modified algorithm designed for clinical use.48 As with MMG, the application of an elastic preload to the thumb during AMG monitoring will increase its precision.49,50
Three randomized clinical trials have examined the effect of intraoperative AMG monitoring on the incidence of postoperative residual neuromuscular blockade. In the first investigation, 40 surgical patients received pancuronium and were randomized to receive AMG monitoring or no neuromuscular monitoring (clinical criteria were used to determine dosing and adequacy of reversal).51 The incidence of residual neuromuscular blockade (defined as a TOF ratio <0.7 measured with MMG) was significantly lower in the AMG group (5.3%) than in the group without monitoring (50%), and the number of patients with clinical signs of muscle weakness after tracheal extubation was reduced by AMG monitoring.51 Using a similar study design, Gätke et al.52 examined the effect of AMG monitoring on the incidence of residual paralysis in 120 patients given an intermediate-acting NMBD. Postoperative MMG TOF ratios <0.8 were observed in only 3% of patients in the AMG group, compared with 16.7% of patients receiving no intraoperative monitoring. In the largest investigation, 185 patients were randomized to intraoperative AMG monitoring (AMG group) or qualitative TOF monitoring (TOF group).53 A lower frequency of residual neuromuscular blockade in the PACU (TOF ratio ≤0.9) was observed in the AMG group (4.5%) compared with the conventional, qualitative (subjective) TOF group (30.0%, P < 0.0001). In addition, during transport to the PACU and during the first 30 minutes of PACU admission, fewer AMG-monitored patients developed adverse respiratory events (hypoxemic episodes and upper airway obstruction). Of interest, the total dosing of NMBDs was unaffected by AMG monitoring in any of the 3 studies. However, the time from end of surgery until tracheal extubation was prolonged by 2 to 5 minutes in all of the AMG group patients.
Available evidence suggests that use of AMG monitoring intraoperatively reduces residual neuromuscular blockade, signs of muscle weakness, and adverse respiratory events after tracheal extubation.51–53 However, there are important limitations to the devices that are currently available commercially: TOF-Watch, TOF-Watch S, TOF-Watch SX, and Infinity Trident NMT SmartPod (Dräger Medical AG & Co., Lübeck, Germany). Control (baseline) TOF ratios obtained before administration of NMBDs usually exceed 1.0 (typically, TOF = 1.15 with a range of 0.95–1.30, compared with an MMG-derived TOF value of 0.98).54,55 Therefore, results obtained by AMG may differ significantly from those obtained by MMG or EMG. Bias among these methods can be reduced by referring all AMG-derived TOF values to baseline measurements (“normalization”).49,50 If the control TOF ratio is, for instance, 1.20, a TOF ratio of 0.9 in the PACU corresponds to a normalized TOF value of 0.75 (90 divided by 120). If AMG-derived TOF values are approximately 10% higher than MMG values, an AMG TOF measurement of at least 1.0 therefore should be achieved to exclude significant muscle weakness.56 However, because significant variability in baseline TOF measurements (0.95–1.47) has been reported with AMG,57 a TOF ratio of 1.0 at the conclusion of an anesthetic does not reliably exclude the possibility of incomplete neuromuscular recovery. Results obtained by AMG (as well as PMG) may also be influenced by an increase in the amplitude (strength) of muscle contraction in response to repetitive stimulation. This phenomenon, known as the “staircase effect,” may significantly affect the monitoring of neuromuscular transmission (single twitch but not TOF) at some peripheral muscle groups but may not be present at other muscle groups such as the corrugator supercilii.44,58 The accuracy of AMG-derived TOF values in awake postoperative patients has also been questioned; paired measurements in the PACU were discordant in 24% of patients.59 A recent systematic review examined the evidence supporting the use of AMG in clinical practice and research.49 The authors concluded that AMG could not be used interchangeably with MMG or EMG for construction of dose-response relationships or for pharmacodynamic studies. However, there was strong evidence that AMG improved detection of residual neuromuscular blockade, and that it was more sensitive than clinical tests or subjective evaluation of evoked responses in detecting residual paralysis. Available evidence suggests that AMG can reliably detect a full range of TOF ratios.
Nomenclature of Monitoring Equipment
In addition to the multiple technologies available for monitoring of evoked neuromuscular responses (MMG, AMG, EMG, KMG, and PMG), there is additional inconsistency regarding the nomenclature of the neuromuscular monitoring devices that are used clinically. For instance, “nerve stimulator,” “twitch monitor,” “qualitative monitor,” and “train-of-four monitor” may be used interchangeably, although they may well describe differing monitoring end points. The “nerve stimulator” is just a device that delivers current to a nerve; such a device should not be termed “monitor,” because it does not provide actual monitoring or physiologic data; similarly, the “twitch monitor” is certainly not a monitor, because it also delivers only an electrical current. However, the 2 (nerve stimulator and twitch monitor) are used interchangeably. At best, a nerve stimulator allows clinicians the ability to subjectively assess the presence of evoked responses, and for TOF stimulation, it allows clinicians to determine the degree of neuromuscular block by counting the number of TOF twitches present (TOF count). Such nerve stimulators are notoriously unreliable for discerning the degree of neuromuscular recovery necessary for spontaneous ventilation and tracheal extubation. To assess readiness for tracheal extubation, much more precise medical devices are needed: neuromuscular monitors that provide objective (i.e., measured or quantitative) responses to nerve stimulation. Such monitors use different methods to measure the evoked muscle responses to electrical nerve stimulation (EMG, MMG, AMG, KMG, and PMG—see above).
Routine Reversal of Neuromuscular Blockade
Surveys from Germany and France (and most recently, the United States—Brull SJ, personal communication) suggest that only a minority of clinicians routinely reverse neuromuscular blockade at the end of an anesthetic.22,60 The reasons for a relaxed view toward the use of anticholinesterases are unclear. It is likely that most clinicians believe that spontaneous recovery of neuromuscular function occurs by the end of the surgery when no NMBDs have been administered within the previous 1 to 4 hours. Available data, however, do not support this belief. Caldwell61 assessed the degree of neuromuscular blockade for up to 4 hours after a single dose of vecuronium (0.1 mg/kg). The TOF ratio was <0.75 in 4 of 20 patients at 2 hours, 3 of 10 patients at 3 hours, and 1 of 20 patients at 4 hours. A large clinical study (n = 526) examined the incidence of residual paralysis after a single intubating dose of an intermediate-acting NMBD and no reversal.28 On arrival to the PACU, TOF ratios <0.7 and <0.9 were observed in 16% and 45% of patients, respectively. In the 239 patients tested >2 hours after the administration of the NMBD, TOF ratios <0.7 and <0.9 were noted in 10% and 37% of patients, respectively. Although a high incidence of residual neuromuscular block has been reported when anticholinesterases are omitted, routine administration of reversal drugs, however, does not guarantee complete recovery of neuromuscular function in the PACU. In a study of 150 surgical patients, 60% of patients in whom neuromuscular blockade had not been reversed had TOF ratios <0.8 in the PACU, compared with 49% of those patients who received anticholinesterases (P = not significant).25 Careful management of anticholinesterase administration may further reduce the risk of incomplete neuromuscular recovery after tracheal extubation.
Based on the above, one could make the argument that routine administration of anticholinesterases should be recommended in all patients who received intraoperative nondepolarizing muscle relaxants, thus diminishing the possibility of residual paralysis. Such practice, if universal, might render the need for neuromuscular monitoring obsolete. In fact, such a practice would be far from ideal. There are several reports of neuromuscular weakness induced by the administration of neostigmine. Payne et al.62 reported that “neostigmine 2.5 mg IV given 5 minutes after exposure to halothane antagonized nondepolarizing neuromuscular block, whereas a second dose given 2 to 5 minutes later depressed the peak tetanic contraction and reestablished tetanic fade.” These investigators further reported that in patients who had received no NMBDs, administration of 2.5 mg neostigmine caused a significant reduction in peak tetanic contraction and the development of severe tetanic fade lasting for 20 minutes. Similar decreases in peak tetanic force and enhancement of tetanic fade were also reported by Goldhill et al.,63 who administered 2 doses of neostigmine 5 minutes apart once the TOF ratio had recovered to 0.5 and 0.9. The authors concluded that neostigmine, when administered after spontaneous recovery from nondepolarizing block, may adversely affect neuromuscular function, although they also acknowledged that such neostigmine effects “are probably short lived.” More recent work from Caldwell61 and Eikermann et al.64,65 confirms the effects of neostigmine on neuromuscular function during spontaneous recovery and offers specific mechanisms for the observed decrease in muscle function: impairment of genioglossus and diaphragm muscles, resulting in decreased upper airway volume.64,65 Although the causal relationship between neostigmine use and postoperative nausea and vomiting is debatable, some investigators have noted that the risk of nausea and emesis is greater with larger doses (>2.5 mg) of neostigmine than with smaller doses (1.5 mg) or placebo.66 However, omitting NMBD antagonism introduces a significant risk of residual paralysis even with short- and intermediate-acting NMBDs.66
The above data point to a single, best practical solution to the current clinical limitations: perioperative monitoring of evoked neuromuscular responses that guides the administration of anticholinesterases and documents return of neuromuscular function should be a standard of care. Only then will the clinician use quantitative criteria that indicate when it is safe to administer additional muscle relaxant; when the minimal degree of spontaneous recovery is present such that pharmacologic reversal with anticholinesterases is possible; when anticholinesterase-aided recovery is sufficient to allow safe tracheal extubation; and when the residual neuromuscular block is significant enough to warrant additional anticholinesterase therapy.
Timely Reversal of Neuromuscular Blockade/Reversal at a Higher TOF Count
Prompt recovery of satisfactory neuromuscular function may be difficult or impossible to achieve with anticholinesterases when dealing with profound block. Clinicians often underestimate the time required for reversal drugs to fully antagonize the effects of NMBDs. In a study of 120 surgical patients, TOF ratios were assessed immediately before tracheal extubation when clinicians had determined that full neuromuscular recovery had occurred using qualitative neuromuscular monitoring and clinical criteria.67 On average, clinicians were ready to perform tracheal extubation 8 minutes after neostigmine was administered; mean TOF ratios at this time were 0.67 ± 0.2. Of significance, 88% of the patients whose tracheas were extubated actually did not fulfill the extubation criteria if we consider TOF ≥0.9 to be the standard. Even if we consider a TOF ≥0.70 as the minimal threshold for extubation, 58% of the patients had failed to achieve this degree of recovery.67 Pharmacodynamic studies suggest that reversal of intermediate-acting NMBDs may require much longer time intervals. Kim et al.68 administered neostigmine 0.07 mg/kg to surgical patients at a TOF count of 1, 2, 3, and 4 to determine the time required to achieve an MMG-derived TOF ratio of 0.7, 0.8, and 0.9. The median (range) times from neostigmine administration until a TOF ratio of 0.9 was reached in patients receiving sevoflurane anesthesia were 28.6 (8.8–75.8), 22.6 (8.3–57.4), 15.6 (7.3–43.9), and 9.7 (5.1–26.4) minutes in patients with TOF counts of 1, 2, 3, and 4, respectively. At a TOF count of 4, only 55% of patients achieved a TOF of 0.9 within 10 minutes. The authors recommended a TOF count of 4 for adequate reversal from rocuronium within 15 minutes, because significant variability in neuromuscular recovery was noted among patients.68 There is 1 additional cogent reason for waiting until the TOF count is 4 before administering neostigmine. If given at a TOF count of 1, all 4 twitches may be palpable 10 minutes later with no detectable fade, even though the TOF ratio is as low as 0.40. This is followed by a prolonged period in which the clinician may erroneously think that reversal has been accomplished satisfactorily, when in fact the patient is still at risk.69
Similar findings have been observed in other investigations. Kopman et al.19 antagonized cisatracurium and rocuronium neuromuscular block at a tactile TOF count of 2. In the rocuronium group, TOF ratios 10 minutes after reversal were 0.76 ± 0.11 (range, 0.47–0.95), and 5 of 30 patients did not reach a TOF ratio ≥0.9 30 minutes after neostigmine was administered. In the cisatracurium group, TOF ratios 10 minutes after reversal averaged 0.72 ± 0.10 (range, 0.38–0.94), and 2 of the 30 patients did not reach a TOF ratio ≥0.9 within 30 minutes of reversal.19 The same investigators antagonized steady-state infusions of NMBDs at a single twitch depression of 10% of control.70 Twenty minutes after reversal with neostigmine, EMG TOF ratios of 0.89 ± 0.06 were observed in patients randomized to receive vecuronium. These studies illustrate an important limitation of anticholinesterase drugs: regardless of the TOF count at the time of reversal, it is not always possible to achieve a TOF ratio >0.9 in all patients within 30 minutes of anticholinesterase administration.19 However, it is generally true that complete recovery of neuromuscular function is more likely when neostigmine is administered early (>15–20 minutes before tracheal extubation) and at a shallower depth of block (TOF count of 4).
Avoidance of Total Twitch Suppression
Reversal of neuromuscular blockade should not be attempted until evidence of spontaneous recovery of neuromuscular function has occurred (i.e., there is at least 1 response to TOF stimulation). Anticholinesterases inhibit the enzyme that breaks down acetylcholine (ACh), allowing ACh to accumulate at the neuromuscular junction and compete with the NMBD from the nicotinic receptor recognition sites (the α subunits). The degree of ACh increase at the neuromuscular junction is, however, limited; once the cholinesterases are inhibited maximally, no further increase in ACh at the neuromuscular junction is possible. If the concentration of the NMBD at the neuromuscular junction is high, the increase in ACh levels as a result of cholinesterase inhibition will be insufficient, and thus anticholinesterases will be ineffective in competing with the NMBD for receptors. This mechanism explains why recovery times are prolonged when neostigmine is administered during intense neuromuscular blockade. At a posttetanic count of 1 to 2 during a rocuronium neuromuscular block, the geometric mean time between neostigmine administration and recovery to an AMG TOF ratio of 0.9 was >50 minutes.71 The risk of intense neuromuscular block at the end of the surgical procedure is thus increased if a TOF count of 0 is maintained intraoperatively. Fortunately, assuming sufficient anesthetic depth, surgical relaxation adequate for abdominal surgery is usually present at a TOF count of 2 to 3.72 New reversal drugs and rapidly degrading, short-acting NMBDs currently in clinical trials may in future allow clinicians to effectively antagonize deeper levels of neuromuscular blockade.
THE FUTURE: NEW DRUGS
Prevention of postoperative residual weakness and its associated complications need not involve only adequate perioperative quantitative monitoring, early reversal from shallow block, and avoidance of total twitch suppression and long-acting NMBDs. What is most likely needed is the introduction into clinical practice of NMBDs whose reversal of neuromuscular blocking activity is not dependent on acetylcholinesterase inhibition; some of these drugs (gantacurium, CW002) are currently in initial phase 1 and 2 testing,73–77 whereas the clinical development and viability of other compounds (SZ1677, cucurbituril) is more uncertain.78–81 The other potentially successful pharmacologic approach to eliminate residual neuromuscular block is the use of selective relaxant binding drugs such as sugammadex82–84 or amino acids (e.g., cysteine) that facilitate the rapid conversion of chlorofumarate muscle relaxants (gantacurium) into inactive derivatives.85–87 Unfortunately, none of these compounds are currently available clinically in the United States.
Sugammadex, a modified γ-cyclodextrin, is the first selective relaxant binding drug. Sugammadex forms very tight complexes in a 1:1 ratio with steroidal NMBDs (rocuronium > vecuronium ≫ pancuronium). This guest-host complex, which exists in equilibrium, is stable because of its very high association rate and very low dissociation rate. Sugammadex has no effect on acetylcholinesterases or on any receptor system in the body, eliminating the need for anticholinergic drugs. Phase 1 to 3 trials found that sugammadex can antagonize any level of neuromuscular blockade, including the profound blockade induced by rocuronium, adding flexibility to the use of nondepolarizing relaxants. Sugammadex, however, has no affinity for isoquinolinium drugs (atracurium, cisatracurium) or for succinylcholine, so it will not antagonize the block induced by these drugs.82 Although not yet available in the United States, sugammadex is available for clinical use in the European Union (marketed as Bridion®, Schering-Plough, Kenilworth, NJ). It is recommended for use in doses of 2, 4, and 16 mg/kg, depending on the clinical situation and the degree of spontaneous recovery at the time of administration. At doses of 2 mg/kg, sugammadex will reverse a shallow block (defined as spontaneous recovery to reappearance of the second TOF twitch); at 4 mg/kg dose, sugammadex will reverse a deep block (defined as spontaneous recovery to 1–2 posttetanic twitches); and at 16 mg/kg, sugammadex can be used for “rescue” in a failed rapid-sequence induction and intubation scenario in which very large doses of rocuronium (4 × ED95) were administered.83 In all these clinical scenarios, initial publications report reversal of neuromuscular block to a TOF >0.90 in <3 to 5 minutes.84 Sugammadex rapidly clears from most organs, except in renal failure; metabolism is at most very limited, and the drug is eliminated in the urine unchanged. Sugammadex has no effect on QT interval even in patients with severe heart disease. Although patients with pulmonary disease (asthma, bronchitis, and chronic obstructive disease) tolerated sugammadex administration without any side effects, the Food and Drug Administration did not approve its application in 2008, citing the need for more clinical information about its allergic potential.
Careful neuromuscular management may reduce the risk of postoperative residual weakness and its associated complications. Available data suggest that adherence to evidence-based practices related to NMBD dosing, monitoring, and reversal may improve patient outcomes during the early recovery period from anesthesia and surgery.
Based on the evidence presented, it seems reasonable to offer the following suggestions regarding the perioperative care of the surgical patient:
- General Principles for Avoidance of Residual Paralysis
Principles of Monitoring in Clinical Practice
- NMBDs should only be administered to patients who require this therapy. Dosing should be individualized based on surgical necessity, patient factors, and presence of coexisting disease.
- Long-acting NMBDs (e.g., pancuronium) should be avoided. Intermediate-acting NMBDs should be used whenever feasible.
- Clinical tests of muscle function (head lift, jaw clenching, grip strength, tidal volume, etc.) are unreliable predictors of recovery of neuromuscular function.
- To exclude with certainty the possibility of residual paralysis in patients at risk, clinicians should use objective (quantitative) neuromuscular monitoring tests.
- Ideally, neuromuscular function should be monitored objectively (quantitatively) in all patients receiving NMBDs.
Principles for Pharmacologic Reversal with Anticholinesterases
- Objective (quantitative) monitoring of neuromuscular function should be used.
- Peripheral nerve stimulator units should display the delivered current output, which should be at least 30 mA.
- Assessment of neuromuscular responses should take into consideration the musculature group that is monitored. The time course (onset, recovery) of muscle relaxants is different at peripheral muscles (adductor pollicis) than at central muscles (orbicularis oculi, corrugator supercilii).
- Adequate spontaneous recovery (TOF count of 4) should be established before pharmacologic antagonism of NMBD block with anticholinesterases. This requirement does not apply to reversal with sugammadex.
- Tactile evaluation of TOF and DBS fade reduces (but does not eliminate) the incidence and degree of postoperative residual paralysis compared with the use of clinical criteria to assess readiness for tracheal extubation.26,88,89
- The timing of tracheal extubation should be guided by quantitative monitoring tests such as TOF >0.9 or DBS3,3 >0.9.
Reversal Considerations in Clinical Practice
- During anesthetic techniques that do not enhance the effects of muscle relaxants (such as total IV anesthesia), a minimal TOF count of 2 should be present before administration of anticholinesterases.90
- During anesthetic techniques that enhance the effects of muscle relaxants (such as inhaled volatile anesthesia), a TOF count of 4 should be present before administration of anticholinesterases.19,90
- If recovery to TOF >0.90 is documented by MMG (quantitatively), neostigmine administration should be withheld. Administration of neostigmine to fully recovered patients may decrease upper airway muscle activity and tidal volume.64
- No neuromuscular monitor or peripheral nerve stimulator used.
Peripheral nerve stimulator—subjective (visual, tactile) assessment
- Clinical tests of adequacy of reversal are unreliable—pharmacologic reversal should be administered routinely and only when spontaneous muscle activity is present.
Quantitative evoked response monitor (e.g., AMG, KMG, and EMG)
- TOF count 1 or no TOF response—delay reversal.
- TOF count 2 or 3—administer pharmacologic reversal.
- TOF with fade (TOF <0.40)—administer pharmacologic reversal.
- TOF with no perceived fade (TOF ≥0.40)—administer pharmacologic reversal, consider low dose (20 μg/kg) of neostigmine.91
- No TOF response or TOF count of 1—delay reversal.
- TOF count 2 or 3—administer pharmacologic reversal.
- TOF <0.40—administer pharmacologic reversal.
- TOF = 0.40 to 0.90—administer pharmacologic reversal, consider low dose (20 μg/kg) of neostigmine.
- TOF >0.90—no reversal recommended.
The development of several novel NMBDs and reversal drugs represents exciting new progress in the field of neuromuscular pharmacology, and use of these drugs may significantly alter intraoperative neuromuscular management and reduce the incidence of postoperative residual paralysis and its associated morbidity.
Sorin J. Brull is the Section Editor of Patient Safety for the Journal. The manuscript was handled by Tony Gin, Section Editor of Anesthetic Clinical Pharmacology, and Dr. Brull was not involved in any way with the editorial process or decision.
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