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Reversal (Antagonism) of Neuromuscular Blockade
Key Points
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Appropriate reversal of a nondepolarizing neuromuscular blockade is essential to avoid adverse patient outcomes. Complete recovery of muscle strength should be present, and the residual effects of neuromuscular blocking drugs (NMBDs) should be fully pharmacologically reversed (or spontaneously recovered).
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Sufficient recovery from neuromuscular blockade for tracheal extubation can be confirmed by an adductor pollicis train-of-four (TOF) ratio of at least 0.90 (or 1.0 if acceleromyography [AMG] is used). Quantitative neuromuscular monitoring is the only method of assessing whether a safe level of recovery of muscular function has occurred.
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Residual neuromuscular blockade is not a rare event in the postanesthesia care unit (PACU). Approximately 30% to 50% of patients can have TOF ratios less than 0.90 following surgery.
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Patients with TOF ratios less than 0.90 in the PACU are at increased risk for hypoxemic events, impaired control of breathing during hypoxia, airway obstruction, postoperative pulmonary complications, symptoms of muscle weakness, and prolonged PACU admission times. Appropriate management of neuromuscular blockade can decrease the incidence of, or eliminate, residual blockade, which will reduce the risks of these adverse postoperative events.
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Neostigmine, pyridostigmine, and edrophonium inhibit the breakdown of acetylcholine, resulting in an increase in acetylcholine in the neuromuscular junction. However, there is a “ceiling” effect to the maximal concentration of acetylcholine that can be achieved with these drugs. Reversal of neuromuscular blockade with anticholinesterases should not be attempted until some evidence of spontaneous recovery is present. Neostigmine in the dose range of 30 to 70 μg/kg body weight antagonizes moderate to shallow levels of neuromuscular blockade. However, if these reversal drugs are given in the presence of full neuromuscular recovery, paradoxical muscle weakness theoretically may be induced.
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Sugammadex is a modified γ-cyclodextrin that shows a high affinity for the steroidal NMBDs rocuronium and vecuronium. Sugammadex is able to form a tight inclusion complex with either of these steroidal NMBDs, thereby inactivating the effects of rocuronium and vecuronium, resulting in rapid reversal of neuromuscular blockade.
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Sugammadex is able to reverse a moderate/shallow and a profound neuromuscular blockade with a dose of 2.0 mg/kg and 4.0 mg/kg, respectively. An immediate reversal of neuromuscular blockade induced by rocuronium is possible with a dose of sugammadex 16 mg/kg. Reversal of neuromuscular blockade by sugammadex is rapid and without many of the side effects encountered with anticholinesterase drugs.
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Fumarates (gantacurium [GW280430A, AV430A], CW002, and CW011) represent a new class of NMBDs in development that are inactivated primarily via adduction of cysteine to the double bond of the compounds, resulting in inactive breakdown products. Laboratory studies have shown that the administration of exogenous l -cysteine results in complete reversal of deep neuromuscular blockade within 2 to 3 minutes.
History
The paralytic effects of curare have been recognized since the time of Sir Walter Raleigh’s voyage on the Amazon in 1595. In 1935, the name d -tubocurarine was assigned to an alkaloid isolated from a South American vine (Chondrodendron tomentosum) . At approximately the same time, experiments from pharmacology and physiology laboratories in London suggested that acetylcholine was the chemical neurotransmitter at motor nerve endings. Investigations from these same laboratories demonstrated that eserine (physostigmine)-like substances could reverse the effects of curare at the neuromuscular junction of frog nerve-muscle preparations. In the clinical setting, Bennett (1940) described the use of curare in the prevention of traumatic complications during convulsive shock therapy. In l942, Griffith and colleagues reported on the effects of an extract of curare in 25 surgical patients; all patients appeared to recover fully without administration of an antagonist such as neostigmine.
The importance of pharmacologic reversal of neuromuscular blockade was suggested in 1945. Specifically, use of neostigmine or physostigmine to antagonize curare was recognized and was recommended to be available whenever muscle relaxants were given in the operating room. The first large case series examining the use of curare was published by Cecil Gray in 1946. A crystalline extract, d -tubocurarine chloride, was administered in 1049 general anesthesia cases. No postoperative complications directly attributable to d -tubocurarine were noted, and physostigmine was administered to only two patients in the series. However, in a later review article (1959) from the same anesthesia department, the authors concluded that “it is safer to always use neostigmine when nondepolarizing relaxants have been administered.” By the mid-1960s, significant differences in neuromuscular management existed between the United States and Europe. As noted in an editorial from this time, “In Great Britain the majority of anesthetists have arbitrarily adopted the attitude that the dangers of reversal are far less than those of latent paresis, so that most patients receive at least some anticholinesterase drug at the end of anesthesia.” In the United States, however, where smaller doses of curare were used, the emphasis was more on the mortality and morbidity associated with reversal drugs. Of greater importance was the use of muscle relaxants in smaller doses so that reversal drugs were not necessary. In fact, in the senior author’s training (Miller), the prevailing thinking was that emphasis in anesthesia should be on “properly anesthetizing rather than paralyzing” a patient; it was commonly said that “curare is not an anesthetic.”
Despite more than seven decades of research, significant differences in opinion still exist regarding management of neuromuscular blockade at the conclusion of surgery and anesthesia. On a routine basis, some clinicians pharmacologically antagonize a nondepolarizing neuromuscular blocking drug (NMBD), whereas others antagonize neuromuscular blockade only when obvious clinical muscle weakness is present. The issue is whether clinically important weakness exists when it is not clinically apparent. Will monitoring of neuromuscular blockade improve patient care? The aim of this chapter is to review the consequences of incomplete neuromuscular recovery, the use of anticholinesterase drugs in clinical practice (benefits, risks, and limitations), and the recent developments in novel drugs to reverse/antagonize residual neuromuscular blockade.
Antagonism of Neuromuscular Blockade: Current Management Practices
A number of survey studies have been conducted to determine how clinicians evaluate and manage neuromuscular blockade in the perioperative period. In the late 1950s, a survey was sent to anesthetists in Great Britain and Ireland. Forty-four percent of the respondents used neostigmine “always” or “almost always” when d -tubocurarine chloride or gallamine was used. Two thirds of respondents administered 1.25 to 2.5 mg when antagonizing these NMBDs. Despite accumulating data demonstrating a continued frequent incidence of residual neuromuscular blockade, more-recent surveys indicate that attitudes toward reversal of neuromuscular blockade have changed little over the intervening decades. A questionnaire sent to German anesthesiologists in 2003 revealed routine reversal with neostigmine at the end of surgery was not practiced in 75% of anesthesia departments. A similar survey of 1230 senior anesthetists in France reported that pharmacologic antagonism of neuromuscular blockade was “systematic” or “frequent” in only 6% and 26% of surgical cases, respectively. In contrast, reversal of nondepolarizing NMBDs was routinely performed in Great Britain.
A large-scale, comprehensive survey of neuromuscular management practices in the United States and Europe was conducted in order to better understand attitudes about doses of NMBDs, monitoring, and pharmacologic reversal. Only 18% of European respondents and 34.2% of respondents from the United States “always” administered an anticholinesterase drug when a nondepolarizing relaxant was used. The findings from these surveys suggest that there is little agreement about best practices related to reversal of neuromuscular blockade. Despite perioperative guidelines from several international and national organizations, surveys from many countries reveal that most clinicians do not monitor or reverse a neuromuscular blockade in the operating room. Surprisingly, most anesthesiologists have not witnessed obvious adverse events directly attributable to incomplete recovery from neuromuscular blockade. Therefore the potential hazards of reversal of neuromuscular blockade using an anticholinesterase drug (see later) are likely estimated to be more frequent than the risks of residual neuromuscular blockade. In the following sections, the definitions, incidence, and clinical implications of residual neuromuscular blockade are reviewed.
Residual Neuromuscular Blockade
Assessment of Residual Neuromuscular Blockade
In order to optimize patient safety, tracheal extubation in the operating room should not occur until complete recovery of muscle strength is present and the residual effects of NMBDs have been fully reversed (or spontaneously recovered). Therefore methods to detect and treat residual muscle weakness are essential in improving postoperative outcomes. Three methods are commonly used in the operating room to determine the presence or absence of residual neuromuscular blockade: clinical evaluations for signs of muscle weakness, qualitative neuromuscular monitors (peripheral nerve stimulators), and quantitative (objective) neuromuscular monitors. A more detailed description of the types of neuromuscular monitors used perioperatively is provided in Chapter 43 .
Clinical Evaluation for Signs of Muscle Weakness
Following the introduction of d -tubocurarine into clinical practice, residual paralysis and the need for neostigmine was determined primarily by the observation of “shallow, jerky movements of the diaphragm” at the end of surgery. In the absence of any clinically observable respiratory impairment, neuromuscular function was assumed to be adequate, and no reversal drugs were administered. A peripheral nerve stimulator to assess neuromuscular blockade was first used in the 1960s by Harry Churchill-Davidson in the United Kingdom and later in the United States. However, routine use of a peripheral nerve stimulator did not occur. In fact, several decades later, the most commonly applied technique for evaluation of recovery of neuromuscular function continues to be the use of clinical tests for signs of apparent muscle weakness. Furthermore, one of the primary factors that determines whether clinicians elect to administer a reversal drug at the end of surgery is the presence of signs of muscle weakness. However, for decades an array of clinical studies from different countries have consistently shown that tests of muscle strength are not sensitive or reliable indices of adequate neuromuscular recovery. The most commonly applied criteria used to determine suitability for extubation of the trachea are a “normal” pattern of ventilation and a sustained head lift. Unfortunately, the sensitivity of each test in detecting residual blockade is poor. At a level of neuromuscular recovery that allows for adequate ventilation in a patient whose trachea is intubated, the muscles responsible for maintaining airway patency and protection are significantly impaired. Other investigators have observed that the majority of subjects could maintain a 5-second head lift at a train-of-four (TOF) ratio of 0.50 or less. Additional clinical tests of muscle strength, such as sustained hand-grip, leg-lift, or eye opening, have been demonstrated to have a low sensitivity in predicting recovery of neuromuscular function ( Table 28.1 ).
TABLE 28.1
Sensitivity, Specificity, Positive, and Negative Predictive Values of an Individual Clinical Test for a Train-of-Four <90% in 640 Surgical Patients
From Cammu G, De Witte J, De Veylder J, et al. Postoperative residual paralysis in outpatients versus inpatients. Anesth Analg . 2006;102:426–429.
| Variable | Sensitivity | Specificity | Positive Predictive Value | Negative Predictive Value |
|---|---|---|---|---|
| Inability to smile | 0.29 | 0.80 | 0.47 | 0.64 |
| Inability to swallow | 0.21 | 0.85 | 0.47 | 0.63 |
| Inability to speak | 0.29 | 0.80 | 0.47 | 0.64 |
| General weakness | 0.35 | 0.78 | 0.51 | 0.66 |
| Inability to lift head for 5 s | 0.19 | 0.88 | 0.51 | 0.64 |
| Inability to lift leg for 5 s | 0.25 | 0.84 | 0.50 | 0.64 |
| Inability to sustain hand grip for 5 s | 0.18 | 0.89 | 0.51 | 0.63 |
| Inability to perform sustained tongue depressor test | 0.22 | 0.88 | 0.52 | 0.64 |
The sensitivity of a test is the number of true positives ÷ the sum of true positives + false negatives; the specificity is the number of true negatives ÷ the sum of true negatives + false positives. True positives are patients scoring positive for a test and having a train-of-four (TOF) <90%. False negatives are patients with a negative test result but a TOF <90%. True negatives have a negative test score and a TOF not <90%; false positives score positively but have a TOF not <90%. A positive test result means inability to smile, swallow and speak, general muscular weakness, and so on.
Qualitative Neuromuscular Monitoring
Qualitative neuromuscular monitors—or more accurately, peripheral nerve stimulators—deliver an electrical stimulus to a peripheral nerve, and the response to nerve stimulation is subjectively assessed by clinicians either visually or tactilely (i.e., placing a hand on the thumb to detect the muscle contraction after ulnar nerve stimulation) ( Fig. 28.1 ). Three patterns of nerve stimulation are used in the clinical setting to assess patients for residual blockade: TOF, tetanic, and double-burst stimulation. TOF stimulation delivers four supramaximal stimuli every 0.5 seconds, tetanic stimulation consists of a series of extremely rapid (usually 50 or 100 Hz) stimuli typically applied over 5 seconds, and double-burst stimulation delivers two short bursts of 50-Hz tetanic stimuli separated by 750 ms. The presence of fade with these patterns of nerve stimulation indicates incomplete neuromuscular recovery. Although qualitative monitoring may guide management during early recovery from neuromuscular blockade, the sensitivity of these devices in detecting small degrees of residual paresis (TOF ratios between 0.50 and 1.0) is limited ( Fig. 28.2 ). When using TOF stimulation, investigators have consistently observed that clinicians are unable to detect fade when TOF ratios exceed 0.30 to 0.40. Similarly, the observation of fade during a 5-second, 50-Hz tetanic stimulation is difficult when TOF ratios are greater than 0.30. The ability of clinicians to detect fade is improved with double-burst stimulation; the threshold for detection of fade is approximately 0.6 to 0.7 using this mode of stimulation. However, regardless of the mode of nerve stimulation used, residual neuromuscular blockade cannot always be reliably excluded using qualitative monitoring.
Quantitative Neuromuscular Monitoring
Quantitative neuromuscular monitors are instruments that permit both stimulation of a peripheral nerve and the quantification and recording of the evoked response to nerve stimulation. Quantitative monitors allow an accurate assessment of the degree of muscle weakness using either TOF stimulation (TOF ratio displayed) or single-twitch stimulation (response compared with control “twitch” as a percentage). Although five different methods of quantifying neuromuscular function in the operating room have been developed, only one technology, acceleromyography (AMG, available as the Stimpod, Xavant Technology, Pretoria, South Africa), is commercially obtainable as a stand-alone monitor. The portable TOF-Watch AMG monitor (Bluestar Enterprises, San Antonio, Texas), which has been used in the majority of published clinical trials, is no longer sold in the United States ( Fig. 28.3 ). In a study comparing AMG with standard qualitative tests (tactile fade to TOF, double-burst, 5-Hz tetanic, and 100-Hz tetanic stimulation), AMG was the most accurate technique in detecting residual paralysis (see Fig. 28.2 ). In addition, the use of AMG in the operating room has been demonstrated to reduce the risk of residual neuromuscular blockade in the postanesthesia care unit (PACU) and to decrease adverse respiratory events and symptoms of muscle weakness associated with incomplete neuromuscular recovery. In clinical practice, AMG is a valuable monitor in determining whether full recovery of neuromuscular function has occurred before tracheal extubation, and provides objective data to guide dosing of reversal drugs at the conclusion of surgery (see later).
A careful evaluation of the degree of residual blockade at the conclusion of a general anesthetic is essential in order to avoid the potential hazards of incomplete neuromuscular recovery following tracheal extubation. However, the methods used by most clinicians (ability to perform a head lift or maintain a stable pattern of ventilation; no fade observed to TOF or tetanic nerve stimulation) are insufficient in assuring safe recovery. At the present time, quantitative neuromuscular monitoring is the only method of determining whether full recovery of muscular function has occurred and reversal drugs safely avoided. In order to exclude with certainty the possibility of residual paresis, quantitative monitoring should be used. For a more comprehensive description of neuromuscular monitoring see Chapter 43 .
Definitions of Residual Neuromuscular Blockade
Quantitative Neuromuscular Monitoring: TOF Ratio Less than 0.70 and Less than 0.90
Traditionally, residual neuromuscular blockade has been defined using quantitative neuromuscular monitoring. Although peripheral nerve stimulation was used in the l960s, Ali and colleagues first described the application of peripheral nerve stimulation for neuromuscular monitoring using the ulnar nerve–adductor pollicis unit as the site of monitoring in the early 1970s. By comparing the amplitude of the fourth (T4) to the first (T1) evoked mechanical or electromyographic response (TOF response), the degree of neuromuscular recovery could be measured. Shortly thereafter, these same investigators performed several studies examining the association between the degree of residual blockade in the hand (defined using quantified T4/T1 ratio, i.e., TOF ratio) with symptoms of peripheral muscle weakness and spirometry measurements. At adductor pollicis TOF ratios less than 0.60, signs of muscle weakness, tracheal tug, and ptosis were observed. When TOF ratios recovered to 0.70, the majority of patients were able to sustain head lift, eye opening, hand grasp, tongue protrusion, and a vital capacity exceeding 15 mL/kg. On the basis of these data, a TOF ratio of 0.70 was previously agreed on to represent acceptable neuromuscular recovery at the end of a general anesthetic that included administration of nondepolarizing NMBDs. Yet, more recently, clinically significant muscle weakness and impaired respiratory control have been observed at TOF ratios of up to 0.90. At TOF ratios less than 0.90, awake volunteers exhibit impaired pharyngeal function, airway obstruction, an increased risk of aspiration of gastric contents, an impaired hypoxic ventilatory control, and unpleasant symptoms of muscle weakness. In surgical patients, an association between TOF ratios less than 0.90 and adverse respiratory events and prolonged PACU length of stay has been observed. At the present time, it is generally agreed that adequate recovery of neuromuscular function is represented by an adductor pollicis TOF ratio of at least 0.90 (or even 1.0 when AMG is used).
Clinical Signs and Symptoms
A variety of clinical signs may be present in patients with residual neuromuscular blockade, including the following: inability to perform a head lift, hand grip, eye opening, or tongue protrusion; inability to clench a tongue depressor between the incisor teeth; inability to smile, swallow, speak, cough, track objects with eyes; or inability to perform a deep or vital capacity breath. Symptoms of residual blockade that have been reported include subjective difficulty performing the aforementioned tests, as well as blurry vision, diplopia, facial weakness, facial numbness, and general weakness. Although the majority of patients with TOF ratios of 0.90 to 1.0 will have recovered satisfactory strength in most muscle groups, signs and symptoms of muscle weakness may be present in some of these patients. In contrast, a few patients with significant residual blockade (TOF ratios < 0.70) may exhibit no apparent muscle weakness. The most inclusive and precise definition of residual neuromuscular blockade should include not only objective and quantifiable monitoring data (a TOF ratio < 0.90 demonstrated with AMG, mechanomyography [MMG], or electromyography [EMG]) but also clinical evidence of impaired neuromuscular recovery (swallowing impairment, inability to speak or perform a head lift, diplopia, and/or general weakness).
Incidence of Residual Neuromuscular Blockade
Residual neuromuscular blockade is not a rare event in the PACU. In 1979, Viby-Mogensen examined the efficacy of neostigmine in reversing d -tubocurarine, gallamine, or pancuronium blockade. On arrival to the PACU, 42% of patients had a TOF ratio less than 0.70, and 24% were unable to perform a 5-second head lift (the majority of these subjects had TOF ratios <0.70). The authors concluded that the average dose of neostigmine given (2.5 mg) was insufficient for reversing neuromuscular blockade. Subsequent studies demonstrated a similarly frequent incidence of residual blockade in patients receiving long-acting NMBDs; 21% to 50% of patients in the early postoperative period had TOF ratios less than 0.70. Subsequently, the risk of postoperative residual blockade was reduced if intermediate-acting NMBDs were used instead of long-acting drugs. As the use of long-acting NMBDs began to decrease in clinical practices, many investigators hoped that residual blockade would become an uncommon occurrence in the PACU. However, incomplete neuromuscular recovery continues to be a common postoperative event. Large-scale studies (150–640 subjects) have demonstrated that approximately 31% to 50% of patients have clinically significant residual neuromuscular blockade with adductor pollicis TOF ratios less than 0.90 following surgery. A recent multicenter investigation enrolling 1571 patients from 32 centers documented that 58% of patients had TOF ratios less than 0.90 at the time of tracheal extubation, despite the use of neostigmine reversal in 78% of subjects. . In a metaanalysis of data from 24 clinical trials, Naguib and colleagues calculated the incidence of residual blockade by NMBD type and TOF ratio. The pooled rate of residual blockade, defined as a TOF ratio less than 0.90, was 41% when studies using intermediate-acting NMBDs were analyzed ( Table 28.2 ). In conclusion, a frequent incidence of residual neuromuscular blockade still occurs worldwide in the immediate postoperative period; with current practice and inadequate monitoring, the incidence of this complication is not decreasing over time.
TABLE 28.2
Pooled Estimated Incidence of Residual Neuromuscular Blockade by Muscle Relaxant Type and Train-of-Four Ratio
From Naguib M, Kopman AF, Ensor JE. Neuromuscular monitoring and postoperative residual curarisation: a meta-analysis. Br J Anaesth . 2007;98:302–316.
| Sub-Population | Pooled Rate of RNMB ∗ | Confidence Interval | Heterogeneity | |
|---|---|---|---|---|
| P -value | Inconsistency † (%) | |||
| Long-acting MR (TOF <0.70) | 0.351 | (0.25-0.46) | <.001 | 86.7 |
| Intermediate-acting MR (TOF <0.70) | 0.115 | (0.07-0.17) | <.001 | 85.9 |
| Long-acting MR (TOF <0.90) | 0.721 | (0.59-0.84) | <.001 | 88.1 |
| Intermediate-acting MR (TOF <0.90) | 0.413 | (0.25-0.58) | <.001 | 97.2 |
MR, Muscle relaxant; RNMB, residual neuromuscular blockade; TOF, train-of-four.
∗ Pooled rate of RNMB is the weighted average. The weight in the random-effect model takes into account both between and within studies variation.
† Inconsistency is the proportion of between studies variability that cannot be explained by chance.
The observed incidence of postoperative residual blockade varies widely between studies, ranging from 5% to 93%. A number of factors may influence the degree of neuromuscular recovery measured following tracheal extubation, accounting for the reported variability in the incidence of residual blockade ( Box 28.1 ). The observed incidence of residual blockade is more frequent if a threshold definition of 0.90 is used (vs. the previous threshold of 0.70) (see Table 28.2 ). Similarly, a frequent incidence of residual paralysis is observed if there is a short time interval between reversal of NMBDs and quantification of TOF ratios (TOF ratios measured at the time of extubation vs. measurement in the PACU). Furthermore, the technology used to quantify neuromuscular recovery may influence the percentage of patients with TOF ratios less than 0.90 following surgery. For example, when compared with MMG, AMG frequently overestimates the degree of neuromuscular recovery. Additional factors influencing the degree of residual paralysis are discussed later.
BOX 28.1
Factors Influencing the Measured Incidence of Postoperative Residual Neuromuscular Blockade
NMBD , Neuromuscular blocking drug; PACU , postanesthesia care unit; TIVA , total intravenous anesthetic; TOF , train-of-four.
Preoperative Factors
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Definition of residual neuromuscular blockade
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TOF ratio < 0.70 (before 1990)
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TOF ratio < 0.90 (after 1990)
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Presence of signs or symptoms of muscle weakness
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Patient factors
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Age (higher risk in older adults)
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Gender
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Preexisting medical conditions (renal or liver dysfunction, neuromuscular disorders)
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Medications known to affect neuromuscular transmission (antiseizure medications)
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Intraoperative Anesthetic Factors
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Type of NMBD administered intraoperatively
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Intermediate-acting NMBD (lower risk)
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Long-acting NMBD (higher risk)
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Dose of NMBD used intraoperatively
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Use of neuromuscular monitoring
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Qualitative monitoring (studies inconclusive)
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Quantitative monitoring (lower risk)
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- 4.
Depth of neuromuscular blockade maintained
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“Deeper blockade” (TOF count of 1-2) (higher risk)
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“Lighter blockade” (TOF count of 2-3) (lower risk)
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- 5.
Type of anesthesia used intraoperatively
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Inhalational agents (higher risk)
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TIVA (lower risk)
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Factors Related to Antagonism of Residual Blockade
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Use of reversal agents (lower risk)
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Neostigmine
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Pyridostigmine
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Edrophonium
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Sugammadex
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- 2.
Dosage of reversal agent used
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Time interval between reversal agent administration and quantification of residual blockade
Factors Related to Measurement of Residual Blockade
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Method of objective measurement of residual neuromuscular blockade
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Mechanomyography (MMG)
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Electromyography (EMG)
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Acceleromyography (AMG)
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Kinemyography (KMG)
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Phonomyography (PMG)
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- 2.
Time of measurement of residual neuromuscular blockade
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Immediately
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Postoperative Factors
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Respiratory acidosis and metabolic alkalosis (higher risk)
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Hypothermia (higher risk)
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Drug administration in the PACU (antibiotics, opioids) (higher risk)
Adverse Effects of Residual Blockade
Many investigations have demonstrated that approximately one half of patients will be admitted to the PACU with TOF ratios less than 0.90, as measured with AMG, MMG, or EMG. The impact of this residual muscle weakness on clinical outcomes has been less well documented. Yet even minimal levels of neuromuscular blockade may have clinical consequences. The following section reviews the effects of residual blockade in both awake volunteer studies and in postoperative surgical patients.
Adverse Effects of Residual Blockade—Awake Volunteer Studies
Surgical patients receive a variety of anesthetics in the perioperative period, which complicates an assessment of the particular effect of residual neuromuscular blockade on clinical outcomes. Conducting awake volunteer trials allows investigators to more precisely quantify the impact of NMBDs and various degrees of neuromuscular blockade on physiologic systems in the absence of anesthetics. In general, these studies have titrated NMBDs to various TOF ratios in awake subjects and measured the effects on the respiratory system and on signs and symptoms of muscle weakness.
Early volunteer investigations concluded that respiratory impairment was minimal at TOF ratios of 0.60 to 0.70. Respiratory frequency, tidal volume, vital capacity, and peak expiratory flow rates were not altered during the study, although vital capacity and inspiratory force were both significantly reduced compared with control values at a TOF ratio of 0.60. The authors concluded that these changes were of minor clinical importance. Subsequent investigations have revealed that pharyngeal and respiratory function is impaired at TOF ratios as high as 0.90 to 1.0. Return of pharyngeal muscle function is essential for airway control following tracheal extubation. In series of human studies from the Karolinska Institutet, Sweden, a functional assessment of the pharynx, upper esophageal muscles, and the integration of respiration with swallowing was performed during various levels of neuromuscular blockade. At adductor pollicis TOF ratios less than 0.90, pharyngeal dysfunction was observed in 17% to 28% of young adult volunteers ( Fig. 28.4 ), increasing more than twofold in patients older than 60 years and associated with reduced upper esophageal sphincter resting tone and misdirected swallowing and aspiration (laryngeal penetration) of oral contrast material. Eikermann and colleagues conducted a series of investigations examining the effect of residual paresis on respiratory muscle function in awake volunteers. Awake subjects were administered a rocuronium infusion, which was titrated to a TOF ratio 0.50 to 1.0. At a minimal level of residual blockade (approximately 0.80), the authors observed impaired inspiratory air flow and upper airway obstruction, a marked decrease in upper airway volumes and upper airway dilator muscle function, and increased upper airway closing pressure and collapsibility ( Fig. 28.5 ). In addition, evidence from human studies of respiratory control suggest that residual blockade inhibits hypoxic ventilatory control while leaving the ventilatory control during hypercapnia unaffected. In human volunteers, the hypoxic ventilatory response was attenuated by 30% after administration of either atracurium, vecuronium, or pancuronium at an adductor pollicis TOF ratio of 0.70, returning to normal after spontaneous recovery to a TOF ratio of greater than 0.90 ( Fig. 28.6 ). An increase in ventilatory drive during hypoxia is primarily mediated by afferent input from peripheral chemoreceptors in the carotid bodies located bilaterally at the carotid artery bifurcation, whereas ventilatory regulation during hypercapnia is mediated via CO 2 interaction with brainstem chemoreceptors. In experimental animals, the firing frequencies of carotid body chemoreceptors are almost abolished by the administration of a nondepolarizing NMBD via blockade of cholinergic neuronal subtype receptors within the carotid body oxygen signaling pathway.
Awake volunteer studies have also revealed that unpleasant symptoms of muscle weakness are present in subjects with small degrees of residual neuromuscular blockade. Conscious subjects given a small “priming” dose of pancuronium noted blurred vision, difficulty swallowing, and keeping their eyes open, and jaw weakness at a TOF ratio of 0.81. Symptoms of diplopia, dysarthria, and subjective difficulty swallowing were reported by subjects at TOF ratios of 0.60 and 0.70. Reduced clarity of vision was described in all subjects receiving a mivacurium infusion at a TOF ratio of 0.81. Kopman and associates examined 10 volunteers for symptoms and signs of residual paralysis at various TOF ratios. Testing was performed at baseline (before an infusion of mivacurium), at a TOF ratio of 0.65 to 0.75, at 0.85 to 0.95, and at full recovery (1.0). All subjects had significant signs and symptoms at a TOF ratio of 0.70 (inability to maintain incisor teeth apposition, sit without assistance, drink from a straw, visual disturbances, facial numbness, difficulty speaking and swallowing, general weakness), and in seven subjects, visual symptoms persisted for up to 90 minutes after the TOF ratio had recovered to unity.
Adverse Effects of Residual Blockade—Postoperative Surgical Patients
Awake volunteers have impairment of respiratory function and a variety of symptoms of muscle weakness at TOF ratios of 0.50 to 0.90. Similar adverse events have been observed in postoperative surgical patients with TOF ratios less than 0.90 measured in the PACU. Incomplete neuromuscular recovery is a risk factor for hypoxemic events, airway obstruction, unpleasant symptoms of muscle weakness, delayed PACU length of stay, and pulmonary complications during the early postoperative period.
Clearly, an association exists between neuromuscular management characteristics and postoperative morbidity and mortality. Beecher and colleagues collected data from 10 university hospitals between the years 1948 to 1952 to determine anesthetic-related causes of mortality. Risk of death related to anesthesia was six times more frequent in patients receiving NMBDs (primarily tubocurarine and decamethonium) compared with those administered no NMBDs (1:370 vs. 1:2100). Although the authors conclude that there is “an important increase in anesthesia death rate when muscle relaxants are added” to an anesthetic, the use or omission of pharmacologic reversal in patients receiving NMBDs was not reported or analyzed. In another large-scale study, mortality data associated with anesthesia were collected over a 10-year period (1967-1976) at a single institution in South Africa. An analysis of 240,483 anesthetics revealed that “respiratory inadequacy following myoneural blockade” was the second-most common cause of death. Again, data relating to the use of pharmacologic reversal drugs were not provided. A study from the Association of Anaesthetists of Great Britain and Ireland examined deaths that were judged “totally due to anesthesia” and reported that postoperative respiratory failure secondary to neuromuscular management was a primary cause of mortality. Rose and associates examined patient, surgical, and anesthetic factors associated with critical respiratory events in the PACU. Of the anesthetic management factors assessed, the most frequent rate of critical respiratory events was observed in patients receiving large doses of NMBDs (the use of reversal drugs was not analyzed). Two investigations of anesthetic complications resulting in admissions to the intensive care unit determined that “failure to reverse after muscle relaxants” and “ventilatory inadequacy after reversal of muscle relaxants” were the most common causes of admission. Sprung and colleagues reviewed the medical records of patients who experienced a cardiac arrest over a 10-year period (223 of 518,284 anesthetics). The most important category was the use of NMBDs, involving either hypoxia caused by inadequate pharmacologic reversal or asystole induced by anticholinesterase drugs. A large case-control investigation was performed of all patients undergoing anesthesia over a 3-year period ( n = 869,483) in The Netherlands assessing the impact of anesthetic management characteristics on the risk of coma or death within 24 hours of surgery. Reversal of the effects of NMBDs was associated with a significant reduction (odds ratio, 0.10; 95% confidence interval [CI], 0.03-0.31) in the risk of these complications. Two studies published in 2016 and 2017 examined the association between failure to reverse neuromuscular blockade and postoperative pneumonia. In an investigation examining 13,100 surgical patients, Bulka and associates observed that the risk of postoperative pneumonia was 2.26 times more likely in patients that did not receive reversal with neostigmine. Similarly, a retrospective study of 11,355 noncardiac patients revealed that the risk of respiratory complications (failure to wean from the ventilator, reintubation, or pneumonia) was significantly higher (odds ratio 1.75) in patients who were administered an NMBD without neostigmine compared to those given neostigmine. Epidemiologic studies thus suggest an association between incomplete neuromuscular recovery and adverse events in the early postoperative period. Notably, an important limitation of these outcome studies is that residual paresis was not quantified at the end of surgery. Therefore causality (residual blockade results in postoperative complications) can only be suggested but not proven.
In order to address these limitations, more recent studies have quantified TOF ratios in the PACU and documented a relationship between residual blockade and adverse outcomes. Several clinical investigations have documented an association between postoperative residual blockade and adverse respiratory events. In an observational study by Bissinger and colleagues, patients with TOF ratios less than 0.70 in the PACU had a more frequent incidence of hypoxemia (60%) compared with patients with TOF ratios 0.70 or greater (10%, P < .05). Another small study of orthopedic surgical patients randomized to receive either pancuronium or rocuronium revealed that patients with TOF ratios less than 0.90 on arrival to the PACU were more likely to develop postoperative hypoxemia (24 of 39 patients) than those with TOF ratios greater than 0.90 (7 of 30 patients, P = .003). Murphy and associates conducted a case-control study examining the incidence and severity of residual blockade in patients who developed critical respiratory events in the PACU. Seventy-four percent of patients in the group with critical respiratory events had TOF ratios less than 0.70, compared with 0% in the matched control group (matched for age, sex, and surgical procedure). Because the two cohorts did not differ in any perioperative characteristics with the exception of neuromuscular recovery, these findings suggest that unrecognized residual paralysis is an important contributing factor to postoperative adverse respiratory events. Another investigation by this same group examined the effect of AMG monitoring on postoperative respiratory events. Few patients randomized to AMG monitoring had postoperative TOF ratios less than 0.90, and a less frequent incidence of early hypoxemia and airway obstruction was observed in this group (compared with patients randomized to standard qualitative monitoring). A study of 114 patients randomized to neostigmine reversal or placebo (saline) documented a significantly more frequent incidence of both postoperative residual blockade and hypoxemia in the placebo group. Residual blockade in the PACU may also result in pulmonary complications within the first postoperative week. Berg and colleagues randomized 691 patients to receive pancuronium, atracurium, or vecuronium. TOF ratios were quantified in the PACU, and subjects were followed for 6 days for pulmonary complications. In the pancuronium group, significantly more patients with TOF ratios less than 0.70 developed a pulmonary complication (16.9%) compared with patients with TOF 0.70 or greater (4.8%). Notably, the study also demonstrated a continuously increased risk for postoperative pulmonary complications with increased age, a finding of significant clinical relevance for older adult patients, a growing part of the surgical patient population. Norton and colleagues assessed recovery characteristics in 202 consecutive patients arriving in the PACU. Thirty percent of patients had TOF ratios greater than 0.9; subjects with residual block had a significantly higher incidence of critical respiratory events, airway obstruction, hypoxemia, and respiratory failure. An observational study enrolling 150 patients ages 18 to 50 and 150 patients more than 70 years old assessed the association between incomplete neuromuscular recovery (TOF < 0.9) and adverse events from the time of tracheal extubation until hospital discharge. Elderly subjects had a higher risk of residual block (58% vs. 30%), and those elderly with TOF ratios less than 0.9 had a significantly higher incidence of airway obstruction episodes and hypoxemic events, as well as signs and symptoms of muscle weakness. A multicenter study from Spain enrolling 763 patients from 26 centers reported that 27% of patients had TOF ratios less than 0.9 and that these subjects had a higher incidence of adverse respiratory events (odds ratio 2.57) and an increased risk of reintubation. An additional study (340 patients) noted that patients with residual block had a greater than sixfold increase in postoperative adverse respiratory events.
Residual blockade causes unpleasant symptoms of muscle weakness. This symptom of “general weakness” was the most sensitive “test” for determining whether patients had a TOF ratio of less than 0.90 in the PACU. Orthopedic surgical patients given pancuronium had a more frequent risk of exhibiting both TOF ratios less than 0.90 and symptoms of blurry vision and general weakness during the PACU admission, compared with patients randomized to receive rocuronium. Similar findings were observed in a cardiac surgical patient population not receiving anticholinesterase drugs. The subjective experience of residual neuromuscular blockade after surgery was determined by examining 155 patients for 16 symptoms of muscle weakness during the PACU admission. The presence of symptoms of muscle weakness was predictive of a TOF ratio less than 0.90 (good sensitivity and specificity).
The residual effects of NMBDs on postoperative muscle strength may impair clinical recovery and prolong PACU discharge times. In a small study of patients randomized to receive either pancuronium or rocuronium, the times required to meet and achieve discharge criteria were significantly longer in the pancuronium group, and patients in the cohort as a whole with postoperative TOF ratios less than 0.90 were more likely to have a prolonged PACU stay compared with those with TOF ratios greater than 0.90. A larger investigation measured TOF ratios in 246 consecutive patients on arrival to the PACU. The PACU length of stay was significantly longer in patients with TOF ratios less than 0.90 (323 minutes) compared with patients with adequate recovery of neuromuscular function (243 minutes). Multiple regression analysis revealed that only age and residual blockade were independently associated with PACU length of stay.
In conclusion, a number of studies conducted over the past five decades have documented the effects of small degrees of residual blockade in human volunteers and surgical patients. Awake volunteer investigations have demonstrated that subjects with TOF ratios less than 0.90 have reduced upper airway tone and diameters, upper airway obstruction, pharyngeal dysfunction with impaired airway integrity, decreased upper esophageal tone, and an increased risk of aspiration, impaired hypoxic ventilatory control, and unpleasant symptoms of muscle weakness. Epidemiologic outcome investigations have suggested an association between incomplete neuromuscular recovery and major morbidity and mortality. Prospective clinical trials have revealed that patients with TOF ratios less than 0.90 in the PACU are at increased risk for hypoxemic events, airway obstruction, postoperative pulmonary complications, symptoms of muscle weakness, and prolonged PACU admission times. These data suggest that residual blockade is an important patient safety issue in the early postoperative period. Therefore appropriate management of reversal of neuromuscular blockade and assessment of recovery from neuromuscular blockade are two essential clinical components to optimize patient outcomes.
Drugs Used to Antagonize (Reverse) Neuromuscular Blockade
Reversal of neuromuscular blockade is theoretically possible by three principal mechanisms: (1) an increase in presynaptic release of acetylcholine; (2) a decrease in enzymatic metabolism of acetylcholine by cholinesterase, thereby increasing receptor binding competition; and (3) a decrease in the concentration of the NMBD at the effect-site, freeing the postsynaptic receptors.
Anticholinesterase Reversal of Neuromuscular Blockade
Nondepolarizing NMBDs inhibit neuromuscular transmission primarily by competitively antagonizing or blocking the effect of acetylcholine at the postjunctional nicotinic acetylcholine receptor (nAChR). Binding of nondepolarizing NMBDs to the nAChR occurs in a competitive fashion. If larger concentrations of acetylcholine are present at the neuromuscular junction, acetylcholine will attach to the postsynaptic receptor and facilitate neuromuscular transmission and muscle contraction. Conversely, if larger concentrations of a nondepolarizing NMBD are present at the neuromuscular junction, binding to α subunits of the receptor will preferentially occur, preventing central pore opening and muscle depolarization from occurring. A more detailed description of the neuromuscular junction is provided in Chapter 12 .
One mechanism of reversing the effects of NMBDs is by an increase in the concentration of acetylcholine at the neuromuscular junction. This can be accomplished using an inhibitor of cholinesterase, which constrains the enzyme that breaks down acetylcholine at the neuromuscular junction (acetylcholinesterase). Three anticholinesterase drugs are commonly used in clinical practice: neostigmine, edrophonium, and pyridostigmine. Neostigmine is likely the most commonly administered drug. Over the prior six decades, anticholinesterases have been the only drugs used clinically to reverse neuromuscular blockade (until the recent introduction of sugammadex).
Mechanism of Action of Anticholinesterases
Acetylcholine is the primary neurotransmitter that is synthesized, stored, and released by exocytosis at the distal motor nerve terminal. Acetylcholinesterase is the enzyme responsible for the control of neurotransmission at the neuromuscular junction by hydrolyzing acetylcholine. Rapid hydrolysis of acetylcholine removes excess neurotransmitter from the synapse, preventing overstimulation and tetanic excitation of the postsynaptic muscle. Nearly half of the acetylcholine molecules released from the presynaptic nerve membrane are hydrolyzed by acetylcholinesterase before reaching the nAChR. The action of acetylcholinesterase is quite rapid; acetylcholine molecules are hydrolyzed in approximately 80 to 100 μs (microseconds). Acetylcholinesterase is concentrated at the neuromuscular junction, and there are approximately 10 enzyme-binding sites for each molecule of acetylcholine released. However, lower concentrations of acetylcholinesterase are present along the length of the muscle fiber. Each molecule of acetylcholinesterase has an active surface with two important binding sites, an anionic site and an esteratic site. The negatively charged anionic site on the acetylcholinesterase molecule is responsible for electrostatically binding the positively charged quaternary nitrogen group on the acetylcholine molecule. The esteratic site forms covalent bonds with the carbamate group at the opposite end of the acetylcholine molecule and is responsible for the hydrolytic process ( Fig. 28.7 ). In addition, a secondary or peripheral anionic site has been proposed. Binding of ligands to the peripheral anionic site results in inactivation of the enzyme.
The anticholinesterase drugs used by anesthesiologists interact with the anionic and esteratic sites of acetylcholinesterase. These drugs are characterized as either prosthetic inhibitors (edrophonium) or oxydiaphoretic (acid-transferring) inhibitors (neostigmine, pyridostigmine) of the enzyme. Edrophonium rapidly binds to the anionic site via electrostatic forces and to the esteratic site by hydrogen bonding. Rapid binding may account for the short onset of action of edrophonium in clinical practice. During the time edrophonium is bound, the enzyme is inactive and edrophonium is not metabolized. However, the interaction between edrophonium and acetylcholinesterase is weak and short-lived. The dissociation half-life of this interaction is approximately 20 to 30 seconds, and the interaction between drug and enzyme is competitive and reversible. Because the nature of the binding is relatively brief, the efficacy of edrophonium in reversing neuromuscular blockade may be limited. Neostigmine and pyridostigmine are oxydiaphoretic inhibitors of acetylcholinesterase, which also bind to the anionic site. In addition, these drugs transfer a carbamate group to acetylcholinesterase, creating a covalent bond at the esteratic site. This reaction results in an inactivation of the enzyme, as well as the hydrolysis of the drug. The stronger interaction between neostigmine and enzyme results in dissociation half-life of approximately 7 minutes. Therefore the duration of enzyme inhibition is longer with neostigmine and pyridostigmine compared with edrophonium. These interactions at the molecular level likely have little impact on the duration of action in clinical practice. Duration of clinical effect is primarily determined by removal of anticholinesterase from the plasma.
The administration of anticholinesterases has also been reported to produce presynaptic effects. Laboratory investigations have demonstrated that these prejunctional effects may actually facilitate neuromuscular transmission. Anticholinesterases produce a reversible increase in the duration of the action potential and refractory period of the nerve terminal. Because the quantity of acetylcholine released is a function of the extent and duration of the depolarization of the terminal membrane, the period of acetylcholine release in response to nerve stimulation may be increased by anticholinesterase agents. Excessive release of acetylcholine, coupled with decreased hydrolysis due to acetylcholinesterase inhibition, results in prolonged end-plate potentials and repetitive firing of muscle fibers. These prejunctional effects appear to account for the observations that spontaneous contractions of muscles can occur when anticholinesterases are given in the absence of NMBDs.
Although neostigmine, pyridostigmine, and edrophonium inhibit the breakdown of acetylcholine, resulting in an increase in acetylcholine in the neuromuscular junction, there is a clinically relevant “ceiling” effect to the maximal concentration of acetylcholine. As concentrations of acetylcholine increase, some of the neurotransmitter diffuses away from the neuromuscular junction, while additional acetylcholine undergoes reuptake into motor nerve terminals. As the processes of diffusion and reuptake reach equilibrium with augmented release by enzyme inhibition, a “peak” level at the neuromuscular junction is reached. Once the acetylcholinesterase enzyme is maximally inhibited by an anticholinesterase agent and peak concentrations of acetylcholine are present, the administration of additional drug will not further increase acetylcholine levels or enhance recovery of neuromuscular blockade. This “ceiling” effect of anticholinesterases is an important limitation of all clinically used agents; neuromuscular blockade cannot be adequately reversed if high concentrations of NMBDs are present at the neuromuscular junction.
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