Over the past five decades, quantitative neuromuscular monitoring devices have been used to examine the incidence of postoperative residual neuromuscular block in international clinical practices, and to determine their role in reducing the risk of residual neuromuscular block and associated adverse clinical outcomes. Several clinical trials and a recent meta-analysis have documented that the intraoperative application of quantitative monitoring significantly reduces the risk of residual neuromuscular blockade in the operating room and postanesthesia care unit. In addition, emerging data show that quantitative monitoring minimizes the risk of adverse clinical events, such as unplanned postoperative reintubations, hypoxemia, and postoperative episodes of airway obstruction associated with incomplete neuromuscular recovery, and may improve postoperative respiratory outcomes. Several international anesthesia societies have recommended that quantitative monitoring be performed whenever a neuromuscular blocking agent is administered. Therefore, a comprehensive review of the literature was performed to determine the potential benefits of quantitative monitoring in the perioperative setting.
“It cannot be emphasized too strongly that merely observing the movements of the rebreathing bag is not an adequate assessment of ventilation… [A] patient can have a normal tidal volume when 90% of his respiratory muscle-fibers are still paralyzed.
“The only satisfactory method of determining the degree of neuromuscular block is to stimulate a motor nerve with an electric current and observe the contraction of the muscles innervated by that nerve.” —H. C. Churchill-Davidson, 19651
None of the myriad neuromuscular blocking drugs, their antagonists, and the entire industry of medical neuromuscular monitoring devices might be available today, were it not for the experiments by Sir Henry Hallett Dale in 1913 and Otto Loewi in 1921.2 These two pioneers were awarded the 1936 Nobel Prize for “the discovery of chemical synaptic transmission.”3 In 1941, Eccles, Katz, and Kuffler demonstrated that in the presence of curare, there was a decrease in the end-plate potential at the postsynaptic muscle membrane such that the action potential could no longer be propagated in response to motor nerve stimulation.4 These findings elucidated the function of acetylcholine and the electrical events at the neuromuscular junction and opened the research gates into the physiology and pharmacology of the neuromuscular junction.5
The aim of this narrative review is to examine the published evidence supporting the use of quantitative monitoring in the perioperative setting. A brief review of the basics of neuromuscular monitoring will follow, which includes the various patterns of stimulation, the stages of neuromuscular block, and the definition of residual neuromuscular block and its perioperative incidence. The various monitoring technologies, including mechanomyography, acceleromyography, electromyography, and kinemyography, are described. Studies that have assessed the effectiveness of objective monitoring in reducing the incidence of postoperative residual neuromuscular blockade are reviewed. Additionally, clinical trials evaluating the impact of intraoperative quantitative monitoring on postoperative outcomes will be examined. For this review, we searched the National Library of Medicine’s PubMed for the terms “quantitative neuromuscular monitoring” and “objective neuromuscular monitoring” in all available years. The search terms were purposefully broad in order to retrieve all pertinent data. Applicable articles were selected by the authors for inclusion.
Basics of Neuromuscular Monitoring
Science progressed not only in physiology and pharmacology of the neuromuscular junction; understanding of physiology was facilitated by advances in technology. One hundred years ago, Gasser and Erlanger (recipients of the Nobel Prize for Physiology or Medicine in 1944) explored the action currents of nerves using the first low-voltage cathode ray oscillograph and were the first to describe that action potentials are biphasic.6 By the mid-1960s, force displacement transducers, which were initially developed to record muscle responses in experimental animals, were later adapted to measure the responses to nerve stimulation in man—usually the adductor pollicis muscle of the thumb in response to ulnar nerve stimulation.7
In the intact neuromuscular junction, neurostimulation will result in contraction of the innervated muscle. Assessment of such evoked responses involved the use of a nerve stimulator that was “designed and built for the author [RL Katz] by Burroughs Wellcome and Co. (U.S.A.) Inc.”8 The development of peripheral nerve stimulators was followed by medical devices (monitors) that not only delivered an electrical stimulus to the nerve but also could display, record, and analyze the evoked muscle responses.
Patterns of Stimulation and Depth of Neuromuscular Block
The first “new device for monitoring force of thumb adduction” was reported by Hassan Ali in 1970 (fig. 1).9 This device incorporated a new pattern of neurostimulation, the train-of-four.10 Assessment of the degree of neuromuscular block involved the delivery of a sequence of four stimuli (train-of-four) at a frequency of 2 Hz and the comparison of the amplitude of the last evoked train-of-four response (T4) to the amplitude of the first response (T1); this comparison resulted in a train-of-four ratio (T4/T1 ratio) that was indicative of the depth of nondepolarizing neuromuscular block. At the intact neuromuscular junction, a train-of-four stimulation will result in muscle responses of equal force (amplitude), such that the baseline train-of-four ratio will be 100% (1.0). When approximately 70 to 80% of postsynaptic receptors are inactivated by the nondepolarizing neuromuscular blocking agent, the amplitude of the repetitive muscle contractions starts to decrease, and the train-of-four ratio starts to “fade” (train-of-four ratio less than 1.0), until T4 = 0, and only the first, second, and third train-of-four responses (T1, T2, and T3, respectively) are present. This degree of block is assessed based on the number of train-of-four responses elicited; when T1, T2, and T3 are present, for instance, the train-of-four count is 3; when only T1 is still present, the train-of-four count is 1, and the depth of block is greater. Once train-of-four count is 0, a 5-s, 50-Hz tetanic stimulus will transiently increase the amount of acetylcholine at the neuromuscular junction, allowing for a short-lived amplification of muscle responses termed posttetanic potentiation, and resulting in transient, progressively decreasing posttetanic muscle contractions (posttetanic count). The train-of-four ratio, train-of-four count, and posttetanic count are patterns of neuromuscular responses that allow clinicians to determine the time course and depth of neuromuscular block (table 1) and adjust the timing and dosing of neuromuscular blocking agents and their antagonists.
Stages of Neuromuscular Block
While the posttetanic count is indicative of a deep neuromuscular block, the presence of a train-of-four count represents moderate block, and fade in train-of-four ratio (i.e., train-of-four ratio less than 1.0) is indicative of residual effects of neuromuscular blocking agents. It should be emphasized that there is a significant and clinically relevant difference between qualitative (subjective) evaluation of responses to neurostimulation and quantitative (objective) monitoring of neuromuscular function. The subjective evaluation of deep and intermediate levels of block using posttetanic count or train-of-four count, respectively, can be helpful if only a peripheral nerve stimulator is available to the clinician. However, adequate recovery from neuromuscular block as evidenced by a train-of-four ratio greater than 0.90 cannot be determined qualitatively with a peripheral nerve stimulator.11 Despite the common use of clinical signs of neuromuscular recovery such as presence of normal tidal volume, response to verbal commands, gagging on the tracheal tube, etc., subjective assessment of neuromuscular recovery using peripheral nerve stimulation and/or clinical testing are inadequate to ensure normal neuromuscular function recovery.12–14 The failure of clinical signs to indicate adequate neuromuscular recovery was underscored almost 20 yr ago: “It was not possible within 30 min to achieve a train-of-four ratio of 0.9 in all patients, regardless of the number of tactile responses present at neostigmine administration.”15
Residual neuromuscular block was defined in early studies using quantitative devices as a train-of-four ratio less than 0.7.16 This accepted threshold was based upon data from conscious volunteers who received tubocurarine; these data demonstrated that vital capacity and inspiratory force measured by pulmonary function tests were significantly reduced at a train-of-four ratio less than 0.7.17 However, subsequent studies reported that clinically meaningful muscle weakness was present at train-of-four ratios up to 0.9.18 At train-of-four ratios below this threshold, subjects exhibited an impairment of the hypoxic ventilatory response,19 experienced airway obstruction20 and impairment of airway protective reflexes,21 were at increased risk of aspiration,21 had an inability to breathe deeply,22 experienced unpleasant symptoms of muscle weakness,23 and had prolonged postanesthesia care unit (PACU) stays.24 Therefore, the accepted threshold for defining postoperative residual neuromuscular blockade used in the majority of studies since 1997 has been a train-of-four ratio less than 0.9.12,18,21 Recent studies have, however, documented that even return of the acceleromyographic train-of-four ratio to the baseline value of 1.00 (100%) is associated with a recovery of postoperative forced vital capacity to only 84 ± 0.11% of baseline in surgical patients,25 and a return of the acute hypoxic ventilatory response to only 86 ± 25% of baseline values in healthy volunteers.19 Therefore, despite apparent full reversal of neuromuscular block, pulmonary function and the hypoxic chemoreflex are not fully restored. These findings are not surprising, since it has been known since 1967 that 75 to 80% of the nicotinic acetylcholine receptors can be blocked while the muscle response to neurostimulation will still be normal.26
Incidence of Residual Neuromuscular Block
The development of simple and reliable patterns of neurostimulation such as the train-of-four ratio and the ability to correlate specific quantitative, repeatable recovery milestones (such as the train-of-four ratio greater than 0.90) with clinical outcomes have facilitated the introduction of perioperative neuromuscular monitoring.10,16,27,28 However, since 1979, when Viby-Mogensen first reported an incidence of residual block (defined at that time as train-of-four ratio less than 0.70),29 more than 50 studies have confirmed the high incidence (approximately 30 to 65%) of this complication.30
Neuromuscular Monitoring Technologies
Since the 1970s, a variety of quantitative devices and technologies have been utilized in clinical trials (table 2). The investigators used quantitative monitors to examine the incidence of postoperative residual neuromuscular block; to assess the effect of anesthetic interventions (type of muscle relaxant, mode of administration—bolus vs. continuous infusion, interaction with volatile and intravenous anesthetics, type of reversal agents, etc.) on the risk of incomplete neuromuscular recovery; and to determine the role of quantitative monitoring in reducing the risk of residual neuromuscular block and associated adverse clinical outcomes.30 In the initial volunteers and patient studies, both electromyography and mechanomyography were used to determine the train-of-four ratio as a “more sensitive index to the degree of curarization.”27 Mechanomyography measures the isometric force of contraction of the thumb’s adductor pollicis muscle in response to electrical ulnar nerve stimulation and was considered the accepted standard technology for decades. In a small number of later studies, electromyography was used to assess neuromuscular recovery.31 Electromyography measures the muscle action potentials after nerve stimulation, and responses recorded with this technology compare favorably with responses obtained with mechanomyography.31 In contrast to early mechanomyography and electromyography devices, acceleromyographic monitors—primarily the TOF-Watch (Schering-Plough Corp.; USA), which is no longer commercially available—were utilized intraoperatively in the majority of published investigations.30
Acceleromyography estimates the force of muscle contraction from Newton’s second law of motion, which states that force is proportional to the product of an object’s mass and its acceleration; since the mass (thumb) is constant, force and acceleration are proportional. Acceleromyographic devices measure the acceleration of a stimulated muscle using a piezoelectric transducer attached to the thumb. When a force is applied to the piezoelectric crystal, an electrical impulse is generated, which can then be analyzed and measured. The use of a hand adapter to apply a preload increases the precision of measurements.32 An important limitation of acceleromyography is that baseline train-of-four ratio measurements (i.e., those obtained before neuromuscular blocking agent administration) often exceed 1.0 (100%).33 To address this problem and prevent overestimation of neuromuscular recovery, the process of normalization has been advocated: any train-of-four ratio before tracheal extubation should be compared (normalized) to the baseline (pre–muscle relaxant administration) train-of-four ratio. Since normalization is not commonly performed in clinical practice, it is recommended that the threshold for adequate neuromuscular recovery be raised from the generally accepted threshold train-of-four ratio of 0.9 to 1.0 when using this technology.34 Despite the significant limitations of acceleromyography-based monitors, they became the predominant technology in routine clinical use and research from the 1990s until recently. Some of the explanations for the adoption of acceleromyography include the facts that mechanomyography-based monitors were cumbersome to set up, calibrate, and use, and commercially unavailable; until very recently, free-standing, portable electromyography monitors were also not commercially available; and small, battery-operated acceleromyographic devices came into use when there were few attractive alternatives.
Kinemyography utilizes a piezoelectric sensor to quantify neuromuscular function by measuring the degree of bending or deformation of the piezoelectric sensor during thumb contraction in response to ulnar nerve stimulation; the bending of the transducer between the thumb and index fingers generates an electrical signal that is converted to a train-of-four ratio. Although kinemyography has been used in clinical studies, its ability to accurately quantify the degree of neuromuscular blockade (correlation with mechanomyography) has been questioned.35–37 Other limitations include the availability of only one sensor size for all adults, and one sensor size for all pediatric patients.
Cuff pressure modality (TOFcuff; RGB Medical Devices; Spain) measures the pressure changes in a partially inflated modified noninvasive blood pressure cuff in response to stimulation of the upper arm, but no additional information is found on the company website. It is now clear that this device overestimates the train-of-four ratio obtained at the adductor pollicis in the critical range of train-of-four values greater than 0.60.38
Effect of Quantitative Monitoring on the Incidence of Postoperative Residual Neuromuscular Block
In 1979, Viby-Mogensen et al. documented with mechanomyography that 42% of patients who received long-acting muscle relaxants were admitted to the PACU with train-of-four ratio less than 0.7 (the threshold for neuromuscular recovery at that time).29 Since this initial clinical investigation, several studies have been published specifically examining the impact of objective monitoring on the incidence of residual neuromuscular block in the PACU.
Comparative Studies Examining the Effect of Quantitative Monitoring versus No Monitoring versus Peripheral Nerve Stimulator Assessment on the Incidence of Postoperative Residual Neuromuscular Block
In a 1995 study published by Mortensen et al., 40 patients given pancuronium were randomized to no intraoperative monitoring (“according to the routine of the department”) or to an acceleromyography monitoring group (table 3).39 Patients’ tracheas were extubated based on clinical criteria in the no monitoring group and when achieving a train-of-four ratio greater than 0.7 in the acceleromyography group. Postoperative train-of-four ratios less than 0.7 (the threshold that defined residual neuromuscular weakness at the time the study was performed) measured with mechanomyography were observed in 50% of the patients in the no monitoring group versus only 5.3% of those in the acceleromyography group (P = 0.03). Using a similar study design, Gätke et al. randomized 120 patients given rocuronium and neostigmine reversal to no intraoperative monitoring or to acceleromyography monitoring groups.40 Extubation was performed when clinical criteria were met, but patients in the acceleromyography group had to additionally achieve a train-of-four ratio greater than 0.8. Train-of-four ratios less than 0.8 were found in 10 patients in the no monitoring group (16.7%) compared to 2 patients in the acceleromyography group (3%; P = 0.029). However, the reduction in risk of residual neuromuscular block was achieved in the acceleromyography group at the expense of an extended time from end of surgery to tracheal extubation (12.5 min longer).
Wardhana et al.41 assessed whether an “optimal” neostigmine dosing regimen (no rocuronium dosing within 30 min of reversal, dosing based on clinical signs and using a peripheral nerve stimulator) was equivalent to a neostigmine dosing regimen based on acceleromyography monitoring. The primary outcome measure was the incidence of postoperative residual neuromuscular blockade. Of the 72 patients randomized, 6 patients (16.7%) monitored with a peripheral nerve stimulator had postoperative train-of-four ratios less than 0.9 versus 1 patient (2.8%) monitored with acceleromyography. The equivalence test showed that the 95% CI value of this study was outside the range of equivalence margins.41
In the largest to date prospective investigation examining the effect of quantitative monitoring on the incidence of postoperative residual neuromuscular blockade as a primary outcome, Murphy et al. randomized 185 patients to acceleromyography monitoring or to peripheral nerve stimulator monitoring.42 In both groups, patients’ tracheas were extubated when standard clinical criteria (sustained head lift or hand grip for more than 5 s, the ability to follow simple commands, a stable ventilatory pattern with acceptable arterial oxygen saturation, and no observation of fade during train-of-four stimulation) were met; additionally, those in the acceleromyography group had to achieve a train-of-four ratio greater than 0.8 before extubation (this threshold was selected to allow tracheal extubation of patients who were unable to tolerate the tracheal tube until a train-of-four greater than 0.9 was reached). Train-of-four ratios less than 0.9 in the PACU were observed in 30% of patients in the peripheral nerve stimulator group versus only 4.5% in the acceleromyography group (P < 0.0001).42 Another trial by the same investigators randomized 155 patients to acceleromyography or peripheral nerve stimulator monitoring, with postoperative residual neuromuscular block as a secondary measure.43 The authors observed train-of-four ratios less than 0.9 in 50% of patients monitored with peripheral nerve stimulators compared to 14.5% of those assessed with acceleromyography (P < 0.0001).43 Finally, a retrospective cohort study from Argentina examined the effect of the type of neuromuscular monitor or reversal agent on the incidence of incomplete neuromuscular recovery in 240 consecutive surgical patients.44 Train-of-four ratios less than 0.9 were present in 1.6% of patients who received quantitative monitoring versus 32% of patients who were not monitored (P < 0.01).
In a recent performance improvement initiative, 100 patients who received neuromuscular blocking agents intraoperatively and who were managed according to the local qualitative assessment practice were also tested quantitatively with an electromyography-based monitor immediately before tracheal extubation.45 The quantitative measurement was always obtained after the clinical care team declared that the block was fully antagonized, and the patient was ready for emergence and spontaneous respiration. The incidence of residual neuromuscular block was 60%. Using the local hospital’s National Surgical Quality Improvement Program database, the authors calculated that the proportion of patients with residual neuromuscular block who suffered a postoperative complication was 5.4%; the proportion of patients without residual block who suffered a postoperative complication was 1.8%. Thus, if the residual neuromuscular block were eliminated, the rate of postoperative complications would be reduced from 5.4% to 1.8%—a 66% reduction. The authors also calculated the average variable cost of care for patients without complications ($14,522) and the cost of care for patients with pneumonia and/or unplanned reintubation ($50,895). A 66% reduction in postoperative complications and associated costs would translate into a net savings to the institution of $4.6 million annually; this figure includes the cost of implementing universal quantitative monitoring.45
In summary, seven clinical trials (five randomized, one retrospective, and one observational)39–45 evaluated the incidence of postoperative residual neuromuscular block in patients monitored with a quantitative device and those who either were assessed with a peripheral nerve stimulator or received no monitoring. In each of these trials, a statistically significant reduction in the incidence of postoperative residual neuromuscular block was observed when quantitative devices were used. Although the studies were appropriately designed to examine a quantifiable outcome of interest (train-of-four ratio), limitations of the investigations were that two of the five randomized studies were relatively small (fewer than 80 patients),38,40 none of the trials were blinded, and the time of measurement of the postoperative train-of-four ratios varied.
Meta-analyses Analyzing the Effect of Quantitative Monitoring on Incidence of Postoperative Residual Neuromuscular Block
Intraoperative quantitative monitoring has been utilized in several clinical investigations in which the primary outcome was not postoperative residual neuromuscular blockade, yet postsurgical train-of-four ratios were recorded. These noncomparative studies provide further data on the efficacy of objective monitoring. Naguib et al. performed a meta-analysis of data from 24 trials involving 3,375 patients (1979 to 2005) to determine the effect of monitoring (quantitative and qualitative) on the percentage of patients with postoperative train-of-four ratios less than 0.9 and less than 0.7.46 Neuromuscular function was monitored in 823 patients, and quantitative devices were used in 280 patients. The analysis did not demonstrate that the use of “monitoring” significantly reduced the risk of postoperative residual neuromuscular block. As noted in a subsequent letter to the editor, the meta-analysis used pooled data on both qualitative and quantitative devices, making conclusions about the effectiveness of objective monitoring unclear.47 In response, Naguib et al. performed additional analyses to examine data only on quantitative monitoring, and concluded that there was no evidence that quantitative monitors were superior to peripheral nerve stimulators in reducing the incidence of incomplete neuromuscular recovery.48
A more comprehensive meta-analysis was published in 2020.30 Carvalho et al. analyzed data from 53 trials (109 study arms; 12,664 patients) published between 1979 and 2019. No monitoring was used in 4,416 patients, peripheral nerve stimulators were applied in 1,528 patients, and quantitative monitoring was used in 6,181 patients. The primary endpoint was the incidence of postoperative residual neuromuscular block, defined as train-of-four ratios less than 0.7, 0.9, and 1.0. In addition to train-of-four thresholds, models accounting for monitoring type, muscle relaxant duration, type of anesthesia, reversal agent use, and publication year were used. The investigators identified 18 studies using quantitative devices, 11 studies using peripheral nerve stimulators, and 20 studies using no monitoring when the search criteria were limited to patients who received intermediate-acting muscle relaxants and when the threshold for residual neuromuscular block was a train-of-four ratio less than 0.9. This analysis revealed the absolute risk (95% CI) for a train-of-four less than 0.9 with quantitative monitoring was 0.119 (0.061 to 0.191), which was significantly lower than that for peripheral nerve stimulator monitoring (0.311 [0.216 to 0.415]), and no monitoring (0.338 [0.243 to 0.440]). However, the authors reported that the Grading of Recommendations Assessment, Development and Evaluation global level of evidence was very low (on a “high,” “moderate,” “low,” and “very low” scale), and the refined assessment of confidence in network meta-analysis raised concerns of within- and across-study bias.30 However, the analysis did not raise significant concerns on the likelihood of the conclusions of this meta-analysis of being modified by upcoming trials. Despite these limitations, the meta-analysis by Carvalho et al.30 represented a significantly more comprehensive examination of the published data (109 study arms and 12,664 patients) than that of Naguib et al.,46 it included more recent trials (up to 2019 rather than up to 2005), and study data were subjected to a more rigorous analysis than the previous meta-analysis.46 Additionally, only eight studies using intermediate-acting muscle relaxants were included in the meta-analysis by Naguib et al., and the threshold defining residual neuromuscular block used was a train-of-four ratio of 0.7, not the currently accepted threshold of 0.9.46
In summary, data from comparative and noncomparative investigations demonstrate that the use of intraoperative quantitative monitoring results in a significant reduction in the incidence of postoperative residual neuromuscular block.
Effect of Quantitative Monitoring on Clinical Outcomes
As described in the previous section, evidence supports the use of intraoperative quantitative monitoring as a method of assuring full recovery of neuromuscular strength at the end of surgery. Additionally, several clinical investigations have documented an association between residual neuromuscular blockade in the PACU and adverse outcomes after tracheal extubation. Therefore, the application of intraoperative quantitative monitoring, by attenuating the risk of residual neuromuscular blockade, has the potential to enhance recovery from anesthesia and decrease postoperative morbidity.
During early recovery from surgery in the PACU, patients with train-of-four ratios less than 0.9 are at increased risk for adverse events. The incidences of hypoxemic events and episodes of airway obstruction are more common in patients with residual neuromuscular blockade.42,49 A multicenter study from Spain documented that patients with train-of-four ratios less than 0.9 were not only at increased risk for adverse respiratory events (odds ratio, 2.57; 95% CI, 1.23 to 5.36; P = 0.009) but also at a higher risk for unplanned reintubation.50 A similar study investigating predictors of postoperative adverse respiratory events observed that the strongest independent risk factor for these events in the PACU was residual neuromuscular block (odds ratio, 6.4; 95% CI, 3.0 to 13.4; P < 0.001).51 A systematic review of 58 studies reported that patients with residual neuromuscular block had higher rates of acute respiratory events compared to those with more complete recovery.52 Additionally, PACU length of stay was increased by 80 min in patients admitted to the PACU with train-of-four ratios less than 0.9, with only age and residual neuromuscular block independently associated with this adverse outcome.24
Residual neuromuscular blockade may also impact clinical outcomes after PACU discharge. Patrocínio et al. retrospectively analyzed data of 6,224 patients who were monitored quantitatively for postoperative respiratory complications (defined as need for invasive mechanical ventilation within 7 days or postextubation desaturation).53 The investigators observed that a low train-of-four ratio (less than 0.9) was associated with postoperative pulmonary complications (adjusted odds ratio, 1.43 [95% CI, 1.11 to 1.85]; P = 0.006). In a randomized trial enrolling 691 patients, those who received pancuronium and had residual block in the PACU had a 3.5-fold higher risk of a postoperative pulmonary complication (defined as a pneumonic infiltrate or atelectasis on a chest radiograph).54 Similarly, an observational study enrolling 558 patients reported that major critical respiratory events, defined as pneumonia or atelectasis on a chest radiograph, were significantly associated with residual neuromuscular block; 93% of patients with evidence of a major critical respiratory event had train-of-four ratios less than 0.9 in the PACU.49 In a study by Grabitz et al. that examined data from 2,233 patients, those admitted to the PACU with train-of-four ratios less than 0.9 had a threefold higher incidence of unplanned intensive care unit admission than those with train-of-four ratios 0.9 or greater.55
Quantitative Monitoring and Adverse Respiratory Events
There are fewer studies examining the effect of quantitative monitoring on respiratory outcomes than its impact on the incidence of residual neuromuscular block. However, emerging data from recent clinical trials have documented that the use of intraoperative quantitative monitoring can reduce the risk of adverse respiratory events associated with residual neuromuscular block. The following section summarizes the findings of these investigations.
Postoperative hypoxemia and airway obstruction are not uncommon events and are frequently associated with residual neuromuscular blockade.49–51,56 Three randomized clinical trials have examined the effect of quantitative monitoring on these outcome measures. In a double-blinded study, Adembesa et al. randomized 168 patients undergoing general anesthesia and neuromuscular block with cisatracurium to be extubated either when train-of-four ratios 0.9 or greater were achieved with quantitative monitoring (acceleromyography) or when standard clinical criteria (i.e., 5-s head-lift) were met.57 The primary outcome measure was the incidence of adverse respiratory events in the PACU. During the first 30 min of PACU admission, significantly fewer patients who were monitored quantitatively experienced mild hypoxia (oxygen saturation measured by pulse oximetry [Spo2] of 90 to 93%; 1% vs. 12% in clinical assessment group; P = 0.005). In addition, the incidence of upper airway obstruction was significantly lower in the patients monitored quantitatively (14%) than in patients assessed clinically (45%; P < 0.0001); fewer patients monitored quantitatively required tactile stimulation (2% vs. 21% in the clinical assessment group; P < 0.0001), and significantly fewer experienced snoring in the PACU (12% vs. 31%; P = 0.003). The two groups did not differ in the incidence of severe hypoxemic events (Spo2 less than 90%).57 Sauer et al. randomized 114 orthopedic patients to either a study group (who received neostigmine 20 μg/kg and were extubated at a train-of-four ratio of 1.0 measured with an acceleromyography quantitative monitor) or a control group (who received saline and had no fade with train-of-four or double-burst stimulation assessed with a peripheral nerve stimulator).58 The primary outcome was the incidence of critical respiratory events, defined as hypoxemia (Spo2 less than 93%), airway obstruction, tachypnea, or respiratory insufficiency. Hypoxemia developed in 40% of patients in the PACU, with significantly fewer patients in the study group having this event (28%) compared to the control group (50.9%; P = 0.021). No differences were observed between groups in other respiratory events. Although this investigation was designed to assess the effect of residual neuromuscular block on postoperative airway events, the findings illustrate that achieving a train-of-four ratio of 1.0 with acceleromyography can attenuate the risk of postoperative hypoxemia when compared to monitoring with a peripheral nerve stimulator.58
Murphy et al. randomized 185 patients to intraoperative quantitative (acceleromyographic) monitoring or a standard peripheral nerve stimulator.42 The incidence of adverse respiratory events (mild hypoxemia = Spo2 93 to 90%; severe hypoxemia = Spo2 less than 90%; airway obstruction) was one of two primary endpoints. The investigators observed that during transport from the operating room to the PACU, the percentage of patients with severe hypoxemia was lower in the group monitored with acceleromyography (0% vs. 21.1% in peripheral nerve stimulator group; P < 0.0001) and fewer patients in this monitored group required an intervention to maintain airway patency (0% vs. 11.1% in peripheral nerve stimulator group; P = 0.002). In addition, the incidence, severity, and duration of hypoxemic events during the first 30 min of PACU admission were less in the acceleromyography group (all P < 0.001; table 4).42
Patrocínio et al. analyzed 101,510 patient charts for the primary outcome of postoperative respiratory complications, defined as a composite of postoperative desaturation less than 90% within 10 min of extubation, or invasive mechanical ventilation requirement within 7 days after surgery.53 Their primary objective was to analyze the association between a recently developed prediction score (Residual Neuromuscular Block Prediction Score) and respiratory complications, while the secondary aim was to compare Residual Neuromuscular Block Prediction Score to train-of-four ratio less than 0.90 as an indicator of postoperative pulmonary complications. Of the 6,224 patients who had train-of-four ratio data available, 3,733 (60%) had a train-of-four ratio less than 0.90 before extubation; of these patients, 302 (4.9%) developed postoperative respiratory complications. Of note, only 6.1% of the 101,510 patients had undergone intraoperative quantitative monitoring. The authors concluded that quantitative monitoring to ensure a train-of-four ratio less than 0.90 was superior to Residual Neuromuscular Block Prediction Score as a predictor of postoperative respiratory complications and recommended that “clinicians use quantitative neuromuscular monitoring in patients at risk for residual neuromuscular blockade.”53
Todd et al. reported on the implementation of an electromyographic quantitative monitoring system at an academic medical center after a review of an adverse events database that revealed that two to four reintubations occurred in the PACU per year that were likely related to residual neuromuscular block.59 The investigators conducted five sampling surveys, involving 409 patients, over a 2-yr period after the electromyographic system was installed in all operating rooms. In the initial survey, quantitative monitoring was used in 51% of patients, and 31% of patients had train-of-four ratios less than 0.9 in the PACU. A fifth survey 2 yr later revealed that 93% of patients were monitored quantitatively, and only 17% of patients had train-of-four ratios less than 0.9. Most importantly, no patients required reintubation in the PACU due to residual neuromuscular weakness during the 2-yr study period.59
Surgical patients with incomplete neuromuscular recovery may also be at risk for more significant pulmonary complications, such as atelectasis and pneumonia, which are diagnosed after the patient is discharged from the PACU. An association between residual neuromuscular block in the PACU and these postoperative pulmonary complications has been documented.49,54 Furthermore, the use of sugammadex, which significantly decreases the risk of incomplete neuromuscular recovery after surgery, has been associated with a lower incidence of these postoperative pulmonary complications when compared to neostigmine.60,61 It is possible, therefore, that intraoperative strategies such as quantitative monitoring that facilitate recovery of neuromuscular function have the potential to further attenuate the risk of postoperative pulmonary complications. Currently, however, few reports (a prospective observational study62 and a subsequent reanalysis of the data from that investigation63 ) have examined this topic.
The Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR) study was a prospective observational cohort study that enrolled 22,803 noncardiac surgical patients from 211 European hospitals.62 The primary endpoint was the incidence of postoperative pulmonary complications (defined as at least one postoperative pulmonary event), observed on a postoperative visit or review of the patient’s chart, that occurred from the time of PACU admission until postoperative day 28. The analysis examined the effect of muscle relaxants, neuromuscular monitoring, and reversal agents on the primary outcome measure. The investigators reported that the use of quantitative neuromuscular monitoring (used in 4,182 patients vs. 2,686 who were assessed with a peripheral nerve stimulator and 10,282 patients with no monitoring) was not associated with a decreased risk of postoperative pulmonary complications, and that extubation at a train-of-four ratio 0.9 or greater was not associated with better pulmonary outcomes.62
A significant limitation of the POPULAR study was that the train-of-four ratio threshold for acceptable neuromuscular recovery was defined in the analysis as a train-of-four ratio of 0.9. However, acceleromyography technology was used by the majority (87%) of clinicians who used quantitative monitors.62 It is well known that baseline train-of-four ratios measured with acceleromyography before muscle relaxant administration (baseline) usually exceed 1.0 (up to 1.47),64 and that train-of-four ratio measurements should be corrected or “normalized” to this baseline value in order to accurately assess the threshold of neuromuscular recovery. If baseline values are not recorded and normalization is not performed, in order to detect a train-of-four ratio 0.9 or greater with a 95% probability, train-of-four recovery to 1.0 is recommended.34 To address this important limitation, Blobner et al. re-analyzed their original POPULAR data to determine if a higher train-of-four threshold impacted the incidence of postoperative pulmonary complications.63 Data from 3,150 patients with complete quantitative neuromuscular monitoring data were split into subcohorts of train-of-four ratios from 0.86 to 0.96 to identify an optimal train-of-four value to signify recovery (fig. 2). The investigators observed that extubating patients’ trachea when train-of-four ratio was greater than 0.95 rather than greater than 0.9 decreased the adjusted risk of postoperative pulmonary complications by 3.5% (95% CI, 0.7 to 6.0%) from the reported incidence in the POPULAR study (11.3%). Increasing the recommended train-of-four ratio threshold from 0.9 to 0.95 reduced the adjusted risk by 4.9% (95% CI, 1.2 to 8.5%).63 These findings suggest that when quantitative monitoring is used as recommended, a beneficial effect of quantitative monitoring on postoperative pulmonary complications may be observed.
In summary, several recent investigations have assessed the effect of quantitative monitoring on adverse respiratory outcomes. These studies have documented that the use of quantitative monitoring may reduce the risk of hypoxemic events and episodes of airway obstruction in the PACU, decrease the need for postoperative reintubation, and attenuate the incidence of postoperative pulmonary complications. Currently, the data are strongest for early adverse respiratory events in the PACU, with only few studies that have examined pulmonary events beyond PACU discharge. An important limitation is that there is currently no standardized definition of a “postoperative pulmonary complication.” Such a standardized definition will aid in the design of future clinical trials and allow pooling of data for meta-analyses. Additional larger investigations are also needed to assess the effect of quantitative monitoring on the more significant respiratory events such as postoperative pneumonia and other postoperative pulmonary complications that may persist beyond PACU discharge and impact patient safety and return to preoperative status.
Effect of Quantitative Monitoring on Postoperative Symptoms of Muscle Weakness
Patients admitted to the PACU are at increased risk for unpleasant symptoms of muscle weakness, which may persist for several hours. Patients commonly remember and may characterize these symptoms as “taking a long time to wake up.”23 A randomized clinical trial by Murphy et al. assessed the effect of quantitative neuromuscular monitoring on postoperative symptoms of residual paresis.43 One hundred fifty-five patients were randomized to monitoring with acceleromyography or assessment with a peripheral nerve stimulator. The primary outcome variable was the total number of symptoms of muscle weakness at four predetermined times in the PACU. The investigators reported that patients in the acceleromyography group had less overall weakness (graded on a 0 to 10 scale) and reported significantly fewer symptoms of muscle weakness during the first 60 min of PACU admission (P < 0.0001) compared to patients assessed qualitatively with a peripheral nerve stimulator.43 Additionally, overall quality of recovery in the PACU was improved in patients in the acceleromyography group. These data suggest that patient-centered outcome measures can be enhanced when quantitative neuromuscular monitoring is used intraoperatively.
While there were no differences in the number of signs of muscle weakness between the quantitative and qualitative monitoring groups in the study by Murphy et al.,43 in an investigation by Mortensen et al., 35% of patients who were not monitored intraoperatively were unable to sustain a 5-s head-lift and 25% of patients were unable to lift an arm, as compared to one and zero patients, respectively, in the acceleromyography group (P < 0.05).39
Limitations of the Studies Assessing the Effect of Quantitative Monitoring on the Incidence of Residual Neuromuscular Block and Clinical Outcomes
There are limitations to the available evidence supporting the use of quantitative monitoring in the operating room. First, apart from the POPULAR trial,62 most of the published investigations enrolled a relatively small number of subjects. When assessing the effect of monitoring on the incidence of residual neuromuscular block, the largest comparative and noncomparative studies included 240 patients44 and 602 patients,65 respectively. Similarly, the largest clinical outcome study enrolled only 185 patients.42 Future studies should be powered to assess outcomes of interest to clinicians, such as postoperative pulmonary complications. However, calculation of appropriate enrollment in these investigations is complicated by the fact that there is no standard definition of “postoperative pulmonary complication”; most studies have used a composite outcome measure that combined several adverse respiratory events. Designing trials to assess the effect of quantitative (objective) monitoring on the incidence of more specific, yet uncommon, pulmonary outcomes such pneumonia would likely necessitate study enrollment that would be large or larger than that of the POPULAR study.62 Second, there is no standardization of the time point at which postoperative residual neuromuscular block is measured. Some trials have assessed final train-of-four ratios after tracheal extubation or even immediately before extubation; at PACU admission; or 5, 10, or 15 min after PACU arrival. Others have documented that train-of-four ratio values recorded before or after extubation were significantly lower than those recorded 15 min after PACU admission.30 Third, the majority of clinical trials used acceleromyography technology, and many investigators did not calibrate the monitors, obtain baseline values, or normalize the final train-of-four ratios.30 Normalization of acceleromyographic train-of-four ratios is critical, because at a mechanomyographic train-of-four ratio of 0.9, the corresponding acceleromyographic train-of-four ratio is 0.95, with a range of 0.86 to 1.0.34 After normalization, the train-of-four ratios of mechanomyography and acceleromyography are equivalent (train-of-four ratios of 0.90 and 0.89, respectively).34 It is likely, therefore, that these acceleromyographic studies underestimated the true incidence of residual neuromuscular block. Furthermore, many researchers using acceleromyography did not calibrate the monitors, did not use a thumb preload, and did not allow for a period of signal stabilization, which are procedures needed to obtain accurate results.30,64,66 Additionally, different acceleromyographic monitors (such as the ToFscan; IDMED; France) use a modified algorithm: when the train-of-four ratio exceeds 1.0 and T2 is greater than T1, the train-of-four ratio is calculated as T4/T2; all train-of-four ratio values greater than 1.0 (100%) are truncated and displayed as 100%. This modification of the displayed raw data further increases the variability of measured responses among different manufacturers.67 Fourth, a variety of different quantitative monitors were used in various trials. Since each technology (based on measurement of force, acceleration, or electrical activity) measures a different physiologic event after neurostimulation, results obtained with different monitors may vary slightly, complicating interpretations of findings and interfering with comparisons of study data. Alternatively, the vast majority of neuromuscular monitoring studies since 2005 have used acceleromyography, but “the more practical and user-friendly nature of acceleromyography comes at a known practicality/accuracy trade-off because of its susceptibility to well-described overestimation artefacts. These could potentially overestimate the reduction of [postoperative residual neuromuscular block] over time.”30 The trade-off may well explain the reported pooled incidence of residual weakness after quantitative monitoring of 0.115 (95% CI, 0.057 to 0.188) in the meta-analysis of Carvalho et al.30 While these limitations of acceleromyography are well described and may partly explain the failure of acceleromyographic monitors to completely avoid the occurrence of residual neuromuscular block, there are no studies to indicate that the use of quantitative monitors may actually increase the incidence of residual block; this suggests that the effect of quantitative monitoring on residual neuromuscular block is not random. Finally, the great majority of the studies comparing quantitative monitoring to either no monitoring or qualitative monitoring with peripheral nerve stimulators used neostigmine as a reversal agent.30 The effect of quantitative monitoring on the incidence of residual neuromuscular block when using sugammadex is less significant, yet still poorly defined. However, although sugammadex reduces the incidence of residual neuromuscular block, the meta-analysis of Carvalho et al. concluded that “sugammadex does not eliminate postoperative residual curarization and its use and monitoring should be guided by appropriate quantitative neuromuscular monitoring.”30
Conclusions and a (Hopeful) Look to the Future
In conclusion, clinical trials have shown that the intraoperative use of quantitative monitoring significantly decreases the incidence of postoperative residual neuromuscular blockade in the operating room and PACU. Similarly, recent studies have documented that quantitative monitoring can decrease the risk of adverse postoperative events associated with incomplete neuromuscular recovery, which include hypoxemic events, episodes of airway obstruction, postoperative reintubations, and other postoperative pulmonary complications, as well as unpleasant symptoms of muscle weakness.
The authors also wish to point out several topics that are not mentioned in the literature regarding the availability and effectiveness of quantitative monitoring; the first is the “signal” that is generated by using quantitative monitoring, which either shows “no effect” on the incidence of residual neuromuscular block (and associated complications), or a “decrease” in these outcomes. To date, there are no reports of the use of quantitative monitoring being associated with an increase in the incidence of residual block and its complications. The second topic deals with the timing of the measurement of the train-of-four ratio in relation to tracheal extubation; some studies report the train-of-four ratio immediately before extubation, while others report it immediately after. If the train-of-four ratio immediately before extubation is less than 0.9, then quantitative monitoring is reported to have “failed” to prevent residual neuromuscular block. Ultimately, the monitor can only provide the quantitative information—it is the clinician who makes decisions based on these data. Third, it should be acknowledged that most peripheral neve stimulators in clinical use today are decades old and in need of replacement. However, even the newest and most feature-laden peripheral nerve stimulators are not “monitors,” since they do not measure responses—they only provide neurostimulation, and those units without a built-in digital ammeter are to be avoided. While the cost per patient of disposable electrodes associated with the use of electromyography-based quantitative monitors may be $15 to $30, the savings from more judicious use of neuromuscular blocking drugs and their antagonists may offset such costs.45,68 This topic is particularly important, because there have not been any prospective economic studies of the impact of quantitative neuromuscular monitors on the cost of care. However, we do know that the highest independent adjusted costs per adverse event derived from the American College of Surgeons National Surgical Quality Improvement Program (Chicago, Illinois) were $48,168 (for prolonged ventilation) and $26,718 (for unplanned intubation).69 These costs are comparable to those reported recently.45 If quantitative neuromuscular monitoring can help avoid such pulmonary complications, the cost of monitors and disposables is trivial.45
There is increased recognition of the adverse effects of impaired neuromuscular recovery on clinical outcomes, with the expression of expert opinion, via editorials70–72 and review articles,73,74 that quantitative monitoring should be used whenever a muscle relaxant is administered. Furthermore, national guidelines from anesthesiology societies, including the Association of Anaesthetists of Great Britain and Ireland (London, United Kingdom)75 ; the Canadian Anesthesiologists’ Society (Toronto, Ontario, Canada)76 ; the French Society of Anesthesiology and Intensive Care (Paris, France)77 ; and the Spanish Society of Anesthesiology, Intensive Care, and Pain Therapy (Madrid, Spain),78 have all recommended the use of intraoperative quantitative monitoring. Other societies’ guidelines have appeared in nonindexed, peer-reviewed publications: the Australian and New Zealand College of Anaesthetists (Melbourne, Australia); the Italian Society of Anesthesia, Analgesia, Resuscitation and Intensive Care (Rome, Italy); the Czech Society of Anesthesiology (Prague, Czech Republic); and the Portuguese Society of Anesthesiology (Lisbon, Portugal).
Additional support for the use of objective monitoring was provided in a consensus statement produced by a panel of clinical scientists with expertise in neuromuscular monitoring79 (table 5) concluding that “…whenever a neuromuscular blocker is administered, neuromuscular function must be monitored by observing the evoked muscular response to peripheral nerve stimulation. Objective monitoring (documentation of train-of-four ratio ≥0.90) is the only method of assuring that satisfactory recovery of neuromuscular function has taken place.”79 Although recommendations on management of neuromuscular blockade have not been provided by the American Society of Anesthesiologists (Schaumburg, Illinois), the development of guidelines is reportedly underway.
The reasons for clinicians’ reluctance to adopt routine use of quantitative monitoring are varied. There are several possible explanations. Surveys of anesthesiologists suggest that many practitioners believe that residual neuromuscular block is a rare event that occurs infrequently in their clinical practice.80,81 There is also poor awareness of the limited ability of clinical tests of muscle strength (i.e., 5-s head-lift, grip strength, vital capacity) and qualitative (visual, tactile) monitoring to detect full recovery of neuromuscular function. Furthermore, first-generation quantitative monitors required a relatively long time to place and calibrate before administration of muscle relaxants, and experience with use of the devices was needed to obtain accurate and reliable results.82 These time and experience requirements in the setting of the busy operating room environment likely limited the widespread adoption of first-generation monitors. There is also a significant degree of overconfidence in the clinicians’ own assessment of their knowledge and quality of care they provide, which is common among all physicians.83
It is likely that simply placing quantitative monitors in each anesthetizing location will not solve the problem of clinician avoidance of using them, or of postoperative residual neuromuscular block. Acquisition of these devices needs to be accompanied by comprehensive educational efforts that are sustained over time. Clinicians should recognize the incidence and clinical implications of incomplete neuromuscular recovery, the limitations of clinical signs of neuromuscular recovery and of peripheral nerve stimulator monitoring, and the limitations of the pharmacology of reversal agents.79 Additionally, appropriate training is required to obtain reliable results from quantitative monitoring.82,84 Successful implementation of a quantitative monitoring program into an anesthesia department requires dedicated local champions and persistence, and such efforts will increase patient safety and enhance postoperative quality of recovery of our surgical patients.
Support was provided solely from institutional and/or departmental sources.
Dr. Murphy is a consultant for Merck & Co. (Kenilworth, New Jersey) and has served on the Scientific Advisory Board for Senzime AB (Uppsala, Sweden). Dr. Brull has intellectual property assigned to Mayo Clinic (Rochester, Minnesota); has received research support (funds to Mayo Clinic) from Merck & Co., Inc.; was a consultant for Merck & Co., Inc.; is a principal shareholder and Chief Medical Officer in Senzime AB; and is a member of the Scientific/Clinical Advisory Boards for The Doctors Company (Napa, California), Coala Life Inc. (Irvine, California), NMD Pharma (Aarhus, Denmark), and Takeda Pharmaceuticals (Cambridge, Massachusetts).