Clinical use of neuromuscular blocking agents in anesthesia

INTRODUCTION — Neuromuscular blocking agents (NMBAs) are usually administered during anesthesia to facilitate endotracheal intubation and/or to improve surgical conditions. NMBAs may decrease the incidence of hoarseness and vocal cord injuries during intubation, and can facilitate mechanical ventilation in patients with poor lung compliance [1-5].

This topic will discuss the clinical use and pharmacology of the commonly used NMBAs and reversal of neuromuscular block. Monitoring neuromuscular blockade is discussed separately. (See "Monitoring neuromuscular blockade".)

SELECTION OF NEUROMUSCULAR BLOCKING AGENTS — The selection of the appropriate NMBA depends on the clinical application and patient factors. For patients without contraindications to succinylcholine (eg, hyperkalemia, burns, stroke, susceptibility to malignant hyperthermia), options include the following (see 'Adverse effects of succinylcholine' below):

●For endotracheal intubation for short procedures (<30 minutes), or if neuromonitoring will be used soon after intubation, a short duration of neuromuscular block is required. Options for endotracheal intubation include succinylcholine, intubation without an NMBA (eg, high dose remifentanil intubation, although this technique is associated with more trauma), or rocuronium or vecuronium if sugammadex is available for rapid reversal of block. (See 'Sugammadex' below.)

●For endotracheal intubation for longer procedures (≥30 minutes), succinylcholine or any of the short or intermediate acting nondepolarizing NMBAs can be used for endotracheal intubation (rocuronium, vecuronium, mivacurium, atracurium, or cisatracurium). The choice among these agents depends on availability, cost, and patient factors that affect metabolism. Pancuronium (no longer available in North America or Europe) is a rarely used, long acting alternative and should be avoided. (See 'Nondepolarizing neuromuscular blocking agents' below.)

Intraoperative relaxation can be maintained as necessary with additional doses of nondepolarizing NMBA.

●Succinylcholine provides the most reliable and fastest intubating conditions, and is therefore the preferred NMBA for rapid sequence induction and intubation (RSII). Alternatives to succinylcholine for RSII include high dose rocuronium (1.2 mg/kg which is a 4 X ED95 dose), or avoidance of NMBAs with a high dose remifentanil intubation. (See "Rapid sequence induction and intubation (RSII) for anesthesia", section on 'Neuromuscular blocking agents (NMBAs)'.)

FACTORS THAT AFFECT THE RESPONSE TO NEUROMUSCULAR BLOCKING AGENTS

Patient factors — A number of patient factors can affect the response to NMBAs or require modification of the dose or interval of administration.

●Neuromuscular disease – NMBAs should be avoided or doses should be modified in patients with some neuromuscular diseases (table 1).

•Succinylcholine may cause life threatening hyperkalemia, and should be avoided, in conditions associated with denervation and associated upregulation of nicotinic acetylcholine receptors (nAChRs). (See 'Adverse effects of succinylcholine' below.)

•Sensitivity to nondepolarizing NMBAs may be increased or variable in patients with neuromuscular diseases, and administration should be titrated, using careful monitoring.

•Patients with myasthenia gravis are resistant to succinylcholine, but extremely sensitive to nondepolarizing NMBAs. The use of NMBAs in patients with myasthenia gravis is discussed separately. (See "Anesthesia for the patient with myasthenia gravis", section on 'Neuromuscular blocking agents'.)

•Succinylcholine is contraindicated in patients with neuromuscular diseases associated with susceptibility to malignant hyperthermia (table 2). (See 'Adverse effects of succinylcholine' below and "Susceptibility to malignant hyperthermia: Evaluation and management".)

●Burns – Burn injury upregulates extrajunctional nAChRs beginning within 24 hours of injury. As a result, administration of succinylcholine after 48 hours, and for up to a year after a major burn, can cause severe hyperkalemia and life threatening arrhythmias, and should be avoided. Upregulation of nAChRs also causes resistance to nondepolarizing NMBAs and reduces duration of action. (See "Anesthesia for patients with acute burn injuries", section on 'Use of succinylcholine'.)

●Extremes of age – In older adult patients, the effects of steroidal NMBAs are prolonged due to decreased volume of distribution, changes in circulatory physiology, decreased regional renal and hepatic blood flow, and anatomic changes at the neuromuscular junction (NMJ). As such, smaller doses and less frequent dosing intervals may be warranted. The use of objective monitoring is particularly useful in this patient population (table 3 and table 4).

Administration of NMBAs in infants and children is discussed separately. (See "General anesthesia in neonates and children: Agents and techniques", section on 'Neuromuscular blocking agents'.)

●Obesity – The dose of succinylcholine should be based on total body weight for optimal intubating conditions [6]. Studies of the effects of obesity on the pharmacodynamics of various nondepolarizing NMBAs are conflicting, and the optimal method for calculating doses in very obese patients is unclear [7,8]. We calculate doses for nondepolarizing NMBAs based on ideal body weight plus 10 percent, and use objective neuromuscular monitoring to minimize the risk of prolonged paralysis [9].

●Hepatic and renal disease – Benzylisoquinolinium NMBAs are preferred for patients with hepatic or renal dysfunction, since clearance of these drugs is independent of organ function. The duration of action of the steroidal NMBAs may be prolonged in these patients because of decreased clearance (table 5).

Succinylcholine may be used for patients with renal disease, as long as serum potassium is normal. In these patients, the transient rise in potassium associated with succinylcholine is similar to patients without renal disease [10]. (See 'Adverse effects of succinylcholine' below.)

●Physiologic derangements

•Hypothermia – Hypothermia causes a prolonged response to nondepolarizing NMBAs as lower temperatures can affect excretion, volume of distribution, interactions with postjunctional nAChRs, and the pH at the NMJ [11,12]. This response is proportional to the degree of hypothermia but becomes more pronounced when muscle temperature is lower than 35.2°C [13]. It is important to note that neuromuscular monitoring is still reliable in this setting and can help guide neuromuscular blockade management in the hypothermic patient.

•Electrolyte disturbances

-Hypermagnesemia causes muscle relaxation, potentiates the effects of NMBAs, and can prolong the duration of action of rocuronium, cisatracurium, and vecuronium. Hypermagnesemia is usually iatrogenic. As an example, magnesium is routinely administered in the intrapartum and postpartum period for patients with preeclampsia to prevent seizures. If these patients require general anesthesia, nondepolarizing NMBAs are rarely necessary and should be avoided. Since magnesium does not potentiate the effects of succinylcholine, usual rapid sequence induction and intubation doses (succinylcholine 1 to 1.5 mg/kg IV) should be administered. (See "Anesthesia for the patient with preeclampsia", section on 'Intraoperative magnesium'.)

The use of magnesium to reduce dose of NMBA can result in unpredictable neuromuscular blockade and increase the incidence of residual paralysis, which can increase postoperative pulmonary complications. In a meta-analysis of 21 randomized trials, the median dose reduction of NMBA after administration of magnesium was approximately 25 percent (interquartile range 14.7 to 31 percent), without an increase in complications [14]. Here was wide variation in the dose of magnesium and the overall quality of evidence was moderate, with high statistical heterogeneity.

-Hypercalcemia causes a reduced response to the administration of nondepolarizing NMBAs as calcium triggers the release of acetylcholine into the NMJ and enhances the excitation-contraction coupling of the myocytes [15]. Thus, hypercalcemic patients may require larger doses of nondepolarizing NMBA to achieve the desired level of neuromuscular blockade.

-Hypocalcemia should be confirmed by measuring ionized calcium, and excluding falsely low levels of calcium due to low plasma albumin levels. Plasma calcium can have antagonistic actions at the neuromuscular junction; at the presynaptic membrane, it can decrease the amplitude of depolarization, thus antagonizing nondepolarizing block [16]. At the postsynaptic membrane, calcium decreases the degree of depolarization produced by acetylcholine, thus potentiating nondepolarizing block [17]. For these reasons, the overall effect of calcium on neuromuscular transmission is unpredictable [15].

-Hypokalemia may prolong the duration of nondepolarizing agents, but has no effect on the duration of depolarizing block [18].

•Acidosis – Acidosis, whether metabolic or respiratory in origin, can prolong the effects of NMBAs, by increasing NMBA affinity for postjunctional nAChRs. Acidosis also causes a relative hypocalcemia, which can prolong neuromuscular block [16,19]. Conversely, alkalosis can shorten the duration of neuromuscular blockade produced by nondepolarizing muscle relaxants, but will not affect the duration of action of depolarizing muscle relaxants [18]. These perturbations can occur once pH becomes lower than 7.3 or greater than 7.51 [19].

Drug interactions — A number of drugs can either enhance or inhibit the response to NMBAs, and may require modification of the dose or interval of administration, guided by monitoring.

●Combinations of NMBAs – In some clinical circumstances, succinylcholine may be administered before or after a nondepolarizing NMBA, or two different nondepolarizing NMBAs may be administered in sequence. Combinations of NMBAs can affect the resulting degree of neuromuscular block, and subsequent management should be guided by the use of a neuromuscular function monitor.

•Prior administration of any nondepolarizing neuromuscular blocking drug has a substantial antagonistic effect on the subsequent depolarizing block induced by succinylcholine. As an example, if a defasciculating dose of a nondepolarizing NMBA is administered prior to succinylcholine, the dose of succinylcholine must be increased [20].

•In contrast, the effect of prior administration of succinylcholine on subsequent administration of a nondepolarizing neuromuscular block depends on the drug used. Studies have reported that administration of succinylcholine prior to a nondepolarizing NMBA does not affect the potency of mivacurium [21] or rocuronium [22], but speeds the onset, increases the potency, and prolongs the duration of action of vecuronium and cisatracurium [23].

•Combining two nondepolarizing NMBAs of the same structural class, such as rocuronium and vecuronium, produces an additive interaction [24]. Combining two nondepolarizing NMBAs from different structural classes, such as rocuronium and cisatracurium, results in a synergistic response [25].

●Inhaled anesthetics – Inhaled anesthetics inhibit nAChRs and potentiate neuromuscular blockade with nondepolarizing NMBAs. This potentiation depends on the type of volatile anesthetic (desflurane > sevoflurane > isoflurane > nitrous oxide), the concentration, and the duration of exposure [26-28].

●Antibiotics – Tetracyclines, aminoglycosides, polymyxins, and clindamycin potentiate neuromuscular blockade through inhibition of acetylcholine (ACh) release or desensitization of postjunctional nAChRs to ACh [29]. In practice, this interaction is most relevant during maintenance of anesthesia. Antibiotics typically are given after a dose of NMBA has already been administered for induction of anesthesia. Thus the interaction between such antibiotics and nondepolarizing NMBAs must be considered when redosing NMBAs. Appropriate (objective) monitoring is particularly helpful in this setting.

●Antiseizure drugs – Patients receiving chronic treatment are relatively resistant to nondepolarizing NMBAs due to accelerated clearance of these drugs [30,31].

●Lithium – Patients who take lithium can have a prolonged response to both depolarizing and nondepolarizing NMBAs [32]. Lithium structurally resembles other cations, such as sodium, potassium, magnesium, and calcium. This resemblance to such cations activates potassium channels, inhibiting neuromuscular transmission.

●Antidepressants – In laboratory studies, sertraline and amitriptyline inhibit butyrylcholinesterase [33], and prolonged paralysis after administration of mivacurium has been reported in a patient who was chronically taking sertraline [34].

●Local anesthetics – Local anesthetics (LAs) may enhance the effects of both depolarizing and nondepolarizing NMBAs through pre- and post-synaptic interactions at the neuromuscular junction (NMJ) [35,36]. Administration of LAs for regional anesthesia may result in blood levels high enough to potentiate NMBA-induced neuromuscular block. Epidurally administered levobupivacaine [37] and mepivacaine [38] potentiate amino-steroidal NMBAs and delay recovery from neuromuscular blockade.

Data on the effects of lidocaine on neuromuscular block are conflicting. Whereas one study reported that epidural lidocaine potentiated vecuronium-induced neuromuscular block [39], several studies have reported no effect of intravenous (IV) lidocaine on the onset, duration, or recovery from rocuronium-induced neuromuscular block [40-42].

CLINICAL USE OF NEUROMUSCULAR BLOCKING AGENTS

Endotracheal intubation — The most common indication for the use of NMBAs in anesthesia is to facilitate endotracheal intubation. The goal of muscle paralysis for endotracheal intubation is to achieve ideal intubation conditions, which are dependent on the depth of anesthesia, airway anatomy, and the experience of the anesthesiologist, in addition to the depth of neuromuscular block (table 6). More intense block is associated with better intubation conditions; a dose of 2 X ED95 for a given NMBA should be sufficient for routine intubation [43,44].

The use of NMBAs may reduce the incidence of postintubation hoarseness and airway injury [5,45]. A 2018 meta-analysis of randomized controlled trials that compared endotracheal intubation with NMBAs and without NMBAs reported increased risks of difficult intubation and an increased risk of upper airway discomfort and injury if NMBAs were avoided for intubation, but the overall quality of the evidence was moderate to low [46].

Succinylcholine is commonly used for endotracheal intubation because of its reliable and rapid onset of neuromuscular blockade. Skeletal muscle relaxation can be assumed immediately after resolution of the fasciculations that occur with succinylcholine (see 'Adverse effects of succinylcholine' below). After administration of succinylcholine, a nondepolarizing NMBA should not be administered until return of neuromuscular function has been documented, as confirmation of normal pseudocholinesterase activity. (See 'Butyrylcholinesterase (pseudocholinesterase) deficiency' below.)

Nondepolarizing NMBAs do not cause fasciculations. Therefore, we suggest the use of an objective neuromuscular function monitor to determine when optimal neuromuscular blockade is achieved after administration of nondepolarizing NMBAs for endotracheal intubation. Central muscle groups (eg, the diaphragm and laryngeal adductors) are blocked faster than peripheral muscle groups (eg, adductor pollicis) after the administration of NMBA [47]. Therefore, if optimal neuromuscular blockade (defined as total suppression of evoked responses to train-of-four [TOF] stimulation) is confirmed by monitoring adductor pollicis stimulation, pharyngeal muscles are usually blocked as well, and optimal intubating conditions are achieved.

The onset time of nondepolarizing NMBAs can be shortened by increasing the dose. As an example, rocuronium can be used for rapid sequence induction and intubation within 60 seconds by administration of twice the usual intubation dose (or four times the ED₉₅). (See 'Rocuronium' below and "Rapid sequence induction and intubation (RSII) for anesthesia", section on 'Nondepolarizing NMBAs'.)

Rapid onset of paralysis can also be achieved by administration of a priming dose (10 percent of the intubating dose) several minutes prior to the intubating dose [48]. Since the priming dose of NMBA may cause signs of paralysis, including diplopia, blurry vision, difficulty swallowing, and risk of aspiration, we do not routinely administer a priming dose of NMBA [49].

Facilitation of surgery — Nondepolarizing NMBAs may be used to provide muscle relaxation that improves surgical conditions. However, many operations can be performed without the need to use any NMBAs, and administration of NMBAs should be individualized [50,51]. Neuromuscular blockade may improve surgical conditions during laparoscopic, robotic, abdominal, and thoracic procedures, by reducing patient movement, muscle tone, and breathing or coughing against the ventilator [2,52-55]. NMBAs also allow lower insufflation pressures during laparoscopy, but the relationship between insufflation pressure and surgical exposure is unclear. The benefits of deep versus moderate muscle relaxation during laparoscopy are also unclear [56-59]. Many of the theoretical benefits of neuromuscular blockade can be achieved by making sure that patients are adequately anesthetized at all times during surgery (table 6).

●Moderate neuromuscular block – When neuromuscular blockade is indicated, for most surgical procedures we aim for moderate levels of blockade (ie, one to three twitches using an objective peripheral nerve stimulator (figure 1)). (See "Monitoring neuromuscular blockade", section on 'Train-of-four'.)

Once neuromuscular block begins to recover from the deep level of paralysis required for endotracheal intubation, a moderate level of block may be maintained with interval dosing or an infusion of nondepolarizing NMBA, guided by monitoring. When guided by objective monitoring, administration of NMBAs by infusion may reduce the total dose required for surgical relaxation [60].

At the conclusion of abdominal surgery, a moderate level of relaxation of abdominal muscles is often sufficient to facilitate closure of the wound. A deep level of block should be avoided at this stage of the operation to allow rapid and complete reversal of the NMBA. If necessary, the anesthetic can be deepened temporarily (ie, with inhalation agent or propofol) to facilitate closure without administration of NMBA.

●Deep neuromuscular blockade – Deep levels of neuromuscular blockade (zero twitches and post tetanic count >1) may be warranted in specific settings, in addition to ensuring adequate depth of anesthesia. As an example, complete paralysis may be indicated during delicate dissection under the microscope during craniotomy, when any unexpected movement must be avoided. (See "Anesthesia for intracranial neurovascular procedures in adults", section on 'Patient immobility'.)

AVOIDANCE OF RESIDUAL NEUROMUSCULAR BLOCKADE — One primary goal for anesthetic management is to ensure complete recovery of neuromuscular function at the end of anesthesia (ie, train-of-four ratio [TOFR] ≥0.9).

Consequences of residual block — Residual neuromuscular block after administration of NMBAs is an important risk factor for anesthesia-related morbidity and mortality. Even minor degrees of residual block are associated with weakness of upper airway muscles, airway obstruction, increased risk of aspiration, and unpleasant muscle weakness. Incomplete postoperative neuromuscular recovery can also cause prolonged recovery room stay, hypoxemia and airway obstruction, awareness during emergence from anesthesia, and increased postoperative pulmonary complications [61-63].

A prospective international observational study including approximately 22,000 patients who underwent general anesthesia for noncardiac surgery at 1 of over 200 hospitals reported that the use of NMBAs was independently associated with an increase in postoperative pulmonary complications within 28 days of surgery [64]. In contrast with other literature, in this study neither the use of neuromuscular monitoring nor administration of reversal agents was associated with a reduction in postoperative pulmonary complications. The utility of this study has been questioned and a number of concerns have been raised, including poorly described reversal administration and the utilization of uncalibrated acceleromyographic data to confirm recovery [65-68]. A post hoc analysis of the study found that raising the threshold for extubation from a TOFR ≥0.9 to TOFR ≥0.95 was associated with a lower incidence of postoperative pulmonary complications [69]. These findings reinforce the need to calibrate accelerometers prior to administration of NMBAs, and support the need to increase the reversal threshold for extubation if calibration is not performed. (See "Monitoring neuromuscular blockade", section on 'Acceleromyography (AMG)'.)

Incidence of residual block — Multiple studies have reported that residual neuromuscular block is a common problem [70-72]. In a meta-analysis of 24 randomized and observational studies including 3375 patients anesthetized between 1979 and 2005, residual block (TOFR <0.9) occurred in 41 percent of patients who received intermediate acting NMBAs [73]. A 2020 meta-analysis of 53 observational and randomized trials found that for patients who received intermediate-acting NMBAs (ie, atracurium, cisatracurium, mivacurium, vecuronium, or rocuronium), the use of quantitative neuromuscular monitoring was associated with a reduced incidence of postoperative residual neuromuscular block, compared with qualitative (subjective) monitoring, or no monitoring at all (11.5 versus 30.6 versus 33.1 percent, respectively) [74]. However, the quality of evidence was judged to be very low.

Strategy for avoiding residual block — A suggested strategy for avoidance of residual neuromuscular blockade is as follows:

●Use intermediate or short acting NMBAs, rather than long acting NMBAs (eg, pancuronium) whenever possible

●Avoid deep neuromuscular blockade (ie, train-of-four count [TOFC] = 0, post tetanic count >1) when clinically appropriate

●Use objective neuromuscular monitoring whenever possible to guide administration of NMBAs and assess recovery of neuromuscular function for all patients who receive NMBAs

•If only a peripheral nerve stimulator is available, ensure electrode placement is not causing direct muscle stimulation (figure 2 and figure 3).

•Avoid monitoring facial muscles as this will overestimate the degree of recovery. If the arms are not accessible due to surgical positioning, monitor the facial muscles but transition to the arms once they become available. (See "Monitoring neuromuscular blockade", section on 'Nerves that may be monitored'.)

●Administer reversal agents in appropriate doses, and guided by the degree of recovery from neuromuscular block (table 6). (See 'Reversal of neuromuscular block' below.)

•Administer no reversal agents if adequate spontaneous recovery has been achieved, as demonstrated by a quantitative TOFR >0.9.

•Administer neostigmine, in appropriate doses, only if spontaneous recovery has reached a TOFC = 4.

●If spontaneous recovery has not reached a TOFC = 4 (as assessed at the adductor pollicis muscle), use sugammadex rather than neostigmine for reversal of steroidal NMBAs. If sugammadex is unavailable (or if using benzylisoquinolinium NMBAs), wait for spontaneous recovery to achieve a TOFC = 4 before administering neostigmine.

●Extubate the trachea only after a TOFR ≥0.9 is achieved (when objective monitors are available).

●If a quantitative monitor is not available, administer neostigmine only when TOFC = 4 (as assessed at the adductor pollicis muscle) and allow adequate time for full reversal of neuromuscular blockade, at least 10 minutes after neostigmine administration, before tracheal extubation [75,76]. (See 'Anticholinesterases' below.)

As the operation nears completion, allow the patient to recover to a TOFC of 4 by the time the surgeon starts to close the wound. When neostigmine is administered at this time, one would expect to be ready to extubate the trachea in 10 minutes or so, once the drapes are coming down. If the patient moves or became dyssynchronous with the ventilator near the end of the operation, administer propofol rather than NMBA. This timing requires familiarity with the surgeon and each individual practice.

These recommendations are consistent with 2023 guidelines from the American Society of Anesthesiologists (table 7) [77].

REVERSAL OF NEUROMUSCULAR BLOCK — A train-of-four ratio (TOFR) ≥0.9 should be achieved prior to tracheal extubation following administration of NMBAs [78]. Reversal of neuromuscular block after administration of NMBAs can occur by spontaneous recovery, or by administration of reversal agents. Reversal agents include anticholinesterases and sugammadex, the only available selective relaxant reversal agent, which is specific for aminosteroid nondepolarizing NMBAs.

The recommended doses of the commonly used reversal agents and the time course of recovery from various levels of rocuronium-induced neuromuscular block are shown in a table (table 6).

Reversal agents can rarely cause adverse effects that require treatment (bradycardia, bronchospasm, and very rarely anaphylaxis or cardiac arrest). Thus we strongly recommend physiologic monitoring and vigilance throughout emergence from anesthesia whenever reversal agents are used. (See 'Sugammadex versus neostigmine' below.)

Spontaneous recovery — Reversal agents should only be omitted when clinicians can confirm adequate recovery from neuromuscular blockade to a TOFR of 0.9 or greater using quantitative monitoring. The response to single intubating doses of NMBAs is variable among patients and responses can be difficult to predict. As an example, a large trial found that after a single intubating dose of an intermediate-acting NMBA, 37 percent of patients had not spontaneously recovered to a TOFR of 0.9 two hours after administration [79].

Anticholinesterases — Anticholinesterase agents work by increasing the availability of acetylcholine at the neuromuscular junction, to compete with nondepolarizing NMBAs for nicotinic acetylcholine receptors (nAChRs) and restore neuromuscular transmission. The anticholinesterases available for reversal of NMBA are neostigmine and edrophonium. Neostigmine is usually preferred, despite a slower onset of action than edrophonium, because neostigmine has higher affinity for acetylcholine receptors. Both drugs have a duration of action of 60 to 120 minutes [80].

Blockade of cholinesterase occurs at all cholinergic sites, including muscarinic receptors, such that these drugs have parasympathomimetic effects. Therefore, anticholinergic, antimuscarinic drugs (ie, atropine or glycopyrrolate) are administered along with anticholinesterases to prevent bradycardia and gastrointestinal side effects.

●Neostigmine – Neostigmine is the anticholinesterase agent most commonly used for reversal of neuromuscular blockade. Glycopyrrolate is routinely administered along with neostigmine (0.2 mg glycopyrrolate IV for each 1 mg neostigmine IV) as they have a similar onset of action.

The rate of reversal of neuromuscular block with neostigmine is variable. Factors that affect the speed of reversal include the depth of existing block, the dose of neostigmine, and the other factors that can affect the degree of neuromuscular block (eg, inhalation anesthesia, hypothermia, acidosis, electrolyte disturbances, hypercarbia, patient age) [81,82]. (See 'Factors that affect the response to neuromuscular blocking agents' above.)

Reversal of neuromuscular block with neostigmine takes longer during inhalation anesthesia than during intravenous (IV) anesthesia with propofol. In one study, 160 patients were randomly assigned to maintenance of anesthesia with sevoflurane or propofol, and reversal of rocuronium with neostigmine at different levels of block. The median time from administration of neostigmine at a train-of-four count (TOFC) of 3 to recovery to a TOFR of 0.9 was 15.6 minutes (7.3 to 43.9) during sevoflurane anesthesia and was 5.4 minutes (1.6 to 8.6) during propofol anesthesia [82]. The median time to recovery if neostigmine was administered at TOFC of 4 was 9.7 minutes (5.1 to 26.4) during sevoflurane anesthesia, and 4.7 minutes (1.3 to 7.2) during propofol anesthesia.

If sufficient spontaneous recovery (train-of-four [TOF] >0.9) can be confirmed through quantitative monitoring, neostigmine is unnecessary. If quantitative monitoring is not available or this level of recovery has not been achieved, neostigmine (or sugammadex) should be administered in an appropriate dose based on the degree of neuromuscular block at the time of administration (table 6).

•Neostigmine is ineffective at reversing deep levels of neuromuscular blockade (TOFC = 0, post-tetanic count [PTC] ≥1, TOFC = 0) [81].

•Neostigmine should be administered at a TOFC of 4 (shallow levels of blockade) [83], and the patient should be extubated no sooner than 10 minutes after administration of neostigmine. At a TOFC of 4, neostigmine doses of 20 to 50 mcg/kg may be sufficient to effect adequate recovery [84]. Higher doses than these are no more effective, and increase the risk of a direct neuromuscular blocking effect of the drug. A reduced dose of 15 to 30 mcg/kg may be used if there is minimal block using an objective neuromuscular monitor (ie, TOFR >0.4 and <0.9) or if there is a TOFC of 4 without fade using a peripheral nerve stimulator (table 8) [77].

•If the patient has a TOFC of 1 to 3 at the conclusion of an operation, wait for spontaneous recovery to TOFC of 4 prior to administration of neostigmine.

•If reversal is inadequate after the initial dose of neostigmine, additional neostigmine may be administered up to a total dose of 70 mcg/kg (maximum 5 mg) IV. If rocuronium or vecuronium was used, it is reasonable to administer sugammadex 1 or 2 mg/kg IV in this setting, preferably guided by quantitative neuromuscular monitoring. (See 'Sugammadex' below.)

•The use of neostigmine in the absence of NMBAs can result in paradoxical neuromuscular weakness [85,86]. Administration of neostigmine during recovery from neuromuscular blockade, even at TOFR >0.9, is unlikely to result in clinically significant weakness. It appears that nAChR occupancy by the remaining nondepolarizing molecules provides a protective effect from the depolarizing actions of excess acetylcholine. This was demonstrated by a study in which 90 anesthetized patients who had recovered to a TOFR >0.9 after a single dose of rocuronium were randomly assigned to receive neostigmine 40 mcg/kg IV or saline [87]. There were no differences in TOFR five minutes after reversal or on admission to the postanesthesia care unit, and no differences in postoperative weakness, hypoxemia, or airway obstruction. Neostigmine-induced decrements in neuromuscular function should almost never occur clinically [86].

●Edrophonium – Edrophonium has a faster onset (one to two minutes) than neostigmine and is usually coadministered with atropine (7 to 14 mcg/kg IV), which has a similar onset of action, to block antimuscarinic effects. Binding of edrophonium to acetylcholinesterases is much weaker than the neostigmine, and it should only be used at shallow levels of neuromuscular blockade. The standard dose of 0.5 to 1 mg/kg results in a similar duration of antagonism as neostigmine [80].

Sugammadex — Sugammadex is a gamma-cyclodextrin that encapsulates and subsequently inactivates steroidal NMBAs. Affinity is greatest for rocuronium, followed in decreasing order of affinity by vecuronium, and pancuronium [88]. Sugammadex has no effect on succinylcholine or the benzylisoquinolinium NMBAs.

After administration, binding occurs in plasma, leading to a rapid decrease in the plasma levels of unbound NMBA molecules. This results in a concentration gradient between the free NMBA molecules at the neuromuscular junction (NMJ) and in the plasma, leading to a net transfer of unbound NMBA back into the plasma, where it is encapsulated by unbound sugammadex. This rapid decrease in free NMBA at the NMJ results in rapid and effective antagonism and restoration of normal transmission and neuromuscular function. Sugammadex reversal produces a more complete and faster recovery than neostigmine or edrophonium reversal [89-91].

●Dosing – The dose of sugammadex should be based on the level of neuromuscular block.

•At a deep level of neuromuscular blockade (TOFC = 0, PTC 1 to 2), a dose of 4 mg/kg results in recovery to a TOFR ≥0.9 within five minutes [92].

•At a TOFC 2 to 4 a dose of sugammadex of 2 mg/kg IV results in a TOFR ≥0.9 in three to four minutes [93].

•In emergency situations in which intubation and ventilation are unexpectedly difficult or impossible, 16 mg/kg sugammadex can reverse profound rocuronium-induced blockade within three minutes [94]. Whereas rapid reversal of neuromuscular block may be helpful in this setting, a number of other factors may affect the restoration of spontaneous ventilation (eg, coadministered anesthetics and opioids, patient factors). (See "Management of the difficult airway for general anesthesia in adults", section on 'The failed airway'.)

•If reversal of aminosteroid induced block (ie, after rocuronium or vecuronium) is inadequate after administration of up to 70 mcg/kg or 5 mg IV of neostigmine, it is reasonable to administer 1 to 2 mg/kg sugammadex IV, guided by quantitative neuromuscular monitoring. Optimal dosing of sugammadex in this setting has not been determined.

•Importantly, the response to the doses of sugammadex based on the TOFC may vary. Quantitative monitoring should be used to confirm adequate reversal prior to extubation, even when reversing with sugammadex, as residual weakness is still possible. This was demonstrated in a single-center prospective dose-finding study in 97 patients who underwent cardiac surgery and received sugammadex for reversal of rocuronium-induced neuromuscular block [95]. After receiving the manufacturer recommended doses (which are described above), 13 percent of patients had residual weakness (ie, TOFR <0.9), and two patients had recurrent paralysis.

Administration of excessive doses of sugammadex should be avoided, because the incidence of anaphylaxis with sugammadex is proportional to the dose administered [96], excessive administration may prevent or delay subsequent reestablishment of neuromuscular block with steroidal NMBAs, and sugammadex is expensive.

●Elimination – The sugammadex-NMBA complex is excreted in the urine unchanged [97]. Sugammadex is not approved by the US Food and Drug Administration (FDA) for patients with severe renal impairment, primarily due to concerns about the possibility of recurrence of paralysis if the complex dissociates. There is also concern that prolonged exposure to sugammadex could increase the risk of anaphylaxis. However, a multicenter retrospective review of 158 surgical patients with end-stage kidney disease who received sugammadex reversal reported no cases of recurrence of neuromuscular blockade, and no cases of anaphylaxis [98]. In 24 patients, sugammadex was used effectively to reverse neuromuscular blockade after inadequate reversal with neostigmine. Similarly, a retrospective review of 219 patients with end stage renal disease who received sugammadex for reversal, there were no postoperative complications attributed to the use of sugammadex [99].

●Drug interactions – Sugammadex can bind and inhibit oral contraceptives. Patients should use alternative contraceptive techniques for seven days after exposure to sugammadex [100]. Reestablishing neuromuscular blockade with steroidal NMBA within three hours of sugammadex administration requires increased doses [101].

●Adverse effects – Sugammadex has been associated with several types of adverse events.

•Hypersensitivity reactions – Sugammadex has increasingly been implicated as a cause of perioperative anaphylaxis. The incidence of anaphylaxis after exposure to sugammadex is unclear, and has been reported to occur in 1:3500 to 1:64,000 exposures. (See "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions", section on 'Sugammadex'.)

Drug hypersensitivity reactions are the result of immune or inflammatory cell stimulation by the drug, and may present during anesthesia with flushing; rash; urticaria; angioedema of the face, extremities, or larynx; wheezing; and/or hypotension. Anaphylaxis is the most severe form of immediate hypersensitivity reaction. The diagnosis is clinical and based on rapid onset and progression of signs and symptoms that typically include hypotension, bronchospasm, laryngeal edema, and tachycardia. Classification and clinical manifestations of drug hypersensitivity are discussed in detail separately. (See "Drug hypersensitivity: Classification and clinical features" and "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Clinical manifestations and diagnosis'.)

Hypersensitivity reactions to sugammadex typically appear rapidly after IV administration (ie, usually within a minute but sometimes up to several minutes later) and can occur with first-time administration. Risk factors have not been identified, though the incidence of some types of reactions appears to be dose dependent [102]. Reactions can involve clinically significant airway edema and bronchospasm, and if this develops after tracheal extubation, reintubation may be required. Hypersensitivity reactions and anaphylaxis to sugammadex are discussed in several other topics. (See "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions", section on 'Sugammadex' and "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Sugammadex'.)

•Cardiac arrhythmias – Cardiac arrhythmias, including marked bradycardia and asystole, may occur after administration of sugammadex [103]. Thus, full electrocardiogram (ECG) monitoring should be continued during and after administration of sugammadex, and atropine and other vasoactive drugs should be immediately available [104]. From 2009 to 2017, 138 cases of serious cardiac adverse events with nine deaths after administration of sugammadex were reported to the US Food and Drug Administration adverse events reporting system, including bradycardia (n = 66), cardiac arrest (n = 39), ventricular fibrillation (n = 10), and ventricular tachycardia (n = 8) [105]. The reported incidence of sugammadex-induced bradycardia is approximately 1 percent [106], and the etiology is unknown. While sugammadex-induced bradycardia is typically transient, it has precipitated cardiac arrest and hemodynamic collapse in some cases [103,106,107].

•Others – Small increases in coagulation parameters have been reported after sugammadex administration, but clinically significant bleeding has not been reported [108]. There have been several reports of laryngospasm that occurred near the time of sugammadex administration [109-111]. While a direct causal relationship has not been established, vigilance is warranted in maintaining airway patency as neuromuscular function is restored.

Sugammadex versus neostigmine — For patients who receive steroidal NMBAs (eg, rocuronium or vecuronium) and require reversal, we suggest using sugammadex rather than neostigmine. However, sugammadex is significantly more expensive than neostigmine. Where cost is an issue, it is reasonable to restrict the use of sugammadex to patients who are at higher risk of complications of postoperative residual neuromuscular block (eg, patients >80 years of age or who undergo thoracic surgery), and/or patients who need reversal from TOFC ≤3.

Benefits of sugammadex compared with neostigmine include the following:

●Sugammadex reverses neuromuscular blockade more quickly and reliably than neostigmine, and can be used to reverse deeper levels of block [112].

●Sugammadex reversal is associated with reduced incidence of residual neuromuscular blockade [112,113].

●Sugammadex reversal probably reduces postoperative pulmonary complications, particularly in high risk patients.

•In a single institution randomized trial of 180 high risk older adults (ASA physical status 3 or 4, ≥75 years of age) who underwent nonemergency surgery with rocuronium induced neuromuscular blockade, there was a trend towards improved postoperative pulmonary outcomes in patients who received sugammadex, though the results did not reach statistical significance [114]. The rate of radiograph confirmed pneumonia within seven days was lower in patients who received sugammadex (2.4 versus 9.6 percent), though the number of events was small. Conclusions are limited by the timing of reversal; the agents were administered at a deeper level of block than we recommend when using neostigmine (four twitches with TOF monitoring, TOFR ≥0.4). (See 'Anticholinesterases' above.)

•In a multicenter matched cohort study of over 45,000 surgical patients, compared with neostigmine, reversal with sugammadex was associated with a lower incidence of pneumonia (1.3 versus 2.2 percent, odds ratio [OR] 0.7 [95% CI 0.44-0.62]) and reduced risk of respiratory failure (0.8 versus 1.7 percent, OR 0.45 [95% CI 0.37-0.56]) [115]. Median patient age was 58 years; 55 percent were ASA physical status 3.

•In contrast, in a single institution cohort study that compared the incidence of postoperative pulmonary complications (PPCs) before and after an institutional change from using neostigmine to using sugammadex for routine reversal of NMBAs, the incidence of PPCs was similar before and after the switch [116]. Conclusions from this study are limited by the possibility of other practice changes over time, and inconsistency or absence of data on neuromuscular monitoring.

Serious intraoperative adverse effects and complications of sugammadex and neostigmine are rare, and both drugs appear to be similarly safe. This is supported by a single institution retrospective review of clinically important adverse events in approximately 90,000 patients who underwent general, cardiac, or pediatric surgery and who received sugammadex or neostigmine for reversal of neuromuscular blockade at the end of surgery [117]. The incidence of a composite outcome of adverse events requiring pharmacologic intervention (ie, bradycardia, anaphylaxis, bronchospasm, and cardiac arrest) was slightly higher with sugammadex (3.4 percent) than neostigmine (3.0 percent), based primarily on differences in bronchospasm and bradycardia, which are usually easily treated. Anaphylaxis and cardiac arrest were extremely rare with both drugs (0.004 to 0.02 percent). The difference in the composite outcome resulted in a number needed to harm of 250 patients, meaning 250 patients would need to be given neostigmine rather than sugammadex to avoid one of these events.

In a meta-analysis of 10 randomized trials (959 patients) that compared NMBA reversal with sugammadex versus neostigmine, there was no significant difference in the incidence of one or more serious adverse event or a composite of serious adverse events [90].

CLASSIFICATION OF NEUROMUSCULAR BLOCKING AGENTS — NMBAs are classified according to their interaction with nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction (NMJ). Succinylcholine, the only depolarizing NMBA in use, produces skeletal muscle relaxation by binding directly with nAChRs to cause prolonged depolarization. Nondepolarizing NMBAs act as competitive antagonists (competing with acetylcholine [ACh] for the binding sites at the nAChRs), preventing the initiation of action potential. The type of neuromuscular block determines the response to peripheral nerve stimulation used for monitoring the effects of NMBAs. (See "Monitoring neuromuscular blockade".)

The NMJ consists of the presynaptic motor neuron, a synaptic cleft or gap, and the postsynaptic surface of the myocyte (figure 4) [15]. As an electrical signal in a motor nerve reaches the presynaptic nerve terminal, depolarization occurs, and acetylcholine (ACh) is released via calcium channel-mediated exocytosis into the synaptic cleft. This cleft is home to acetylcholinesterase, the enzyme that breaks down ACh. Fifty percent of the released ACh is cleaved by acetylcholinesterase, and the remaining molecules bind to postsynaptic nAChRs on the motor end plate, which causes ion channels to open. When enough channels are opened, the myocyte is depolarized and muscle contraction occurs. Acetylcholine remaining in the synapse is rapidly degraded by acetylcholinesterase, and the muscle is allowed to repolarize.

SUCCINYLCHOLINE — Succinylcholine (also known as diacetylcholine or suxamethonium chloride) is the only depolarizing NMBA available for clinical use.

Pharmacology of succinylcholine — Succinylcholine produces a reliable neuromuscular blockade that is the fastest in onset and shortest in duration of all NMBAs. Thus succinylcholine is often used for rapid sequence induction and intubation. (See "Rapid sequence induction and intubation (RSII) for anesthesia", section on 'Succinylcholine' and 'Endotracheal intubation' above.)

Within 30 seconds after intravenous (IV) administration, patients experience fasciculations from depolarization and antidromic activation of unparalyzed portions of the motor unit [118]; flaccid paralysis ensues seconds later. Fasciculations of varying duration and intensity occur in 94 percent of patients [119].

●Dosing/onset of action – An IV dose of 1 to 1.5 mg/kg, or 3 to 5 x ED₉₅, yields flaccid paralysis in one to two minutes. After an intubating dose, the clinical duration of action (defined as the time from drug administration until recovery of single twitch to 25 percent of baseline) is 7 to 12 minutes. If IV access is unavailable, succinylcholine can also be administered intramuscularly (3 to 4 mg/kg), and paralysis will occur in approximately four minutes.

Succinylcholine is occasionally administered by infusion, titrated to twitch depression, most often when a brief period of neuromuscular blockade is required (such as electroconvulsive therapy). Use of a succinylcholine infusion or by repeated bolus administration increase the risk of Phase II block, and prolonged paralysis. Phase II block usually occurs after total succinylcholine doses exceeding 4 mg/kg. Alternatives to succinylcholine infusion for short procedures include mivacurium (where available), or intermediate duration steroidal NMBAs (ie, rocuronium or vecuronium) followed by reversal with sugammadex. (See 'Mivacurium' below and 'Sugammadex' above.)

●Pharmacokinetics – Succinylcholine is metabolized by butyrylcholinesterase (also known as pseudocholinesterase or plasma cholinesterase) in a process that yields no active metabolites.

Phase II block — Phase II block typically develops after large doses of succinylcholine (>4 mg/kg), after repeated doses, or after a continuous infusion; some characteristics of phase II block have been described in doses as low as 0.3 mg/kg [120]. This type of block occurs when the post-junctional membrane action potential eventually returns to baseline, despite the continued activation of nAChRs in the presence of succinylcholine. Phase II block is associated with some of the features of nondepolarizing block, including train-of-four (TOF) fade and post-tetanic potentiation.

Butyrylcholinesterase (pseudocholinesterase) deficiency — In patients with atypical or deficient butyrylcholinesterase, recovery from succinylcholine (and mivacurium) can be prolonged. A variety of factors can reduce butyrylcholinesterase activity but only modestly prolong paralysis with succinylcholine, including liver disease, pregnancy, advanced age, renal failure, major burns, oral contraceptives, and echothiophate eye drops. In contrast, abnormal genetic variants of the butyrylcholinesterase enzyme can cause marked prolongation of paralysis after succinylcholine administration. Duration of paralysis may be increased by 50 to 100 percent in patients who are heterozygous for abnormal butyrylcholinesterase. Patients who are homozygous for the abnormal gene may be paralyzed for up to eight hours after an intubating dose of succinylcholine, and may require prolonged postoperative mechanical ventilation [121].

Atypical butyrylcholinesterase is often diagnosed after a patient has an unexpectedly prolonged response to succinylcholine. Objective TOF monitoring should be used, and recovery documented prior to extubation, for all patients who have received NMBAs, including those who have received succinylcholine. Some degree of recovery from succinylcholine-induced block should be documented prior to administration of a nondepolarizing NMBA, as administration of a nondepolarizing NMBA prior to documenting recovery from succinylcholine will complicate evaluation and subsequent management, should prolonged succinylcholine block occur. Principles for management of prolonged block after succinylcholine should include the following:

●Causes for prolonged block other than butyrylcholinesterase deficiency should be ruled out, including hypothermia and electrolyte disorders, or malfunctioning of the peripheral nerve stimulator or neuromuscular monitor.

●TOF fade is indicative of phase II block that is likely to occur in these patients. Reversal with neostigmine should not be attempted. Anticholinesterase agents can worsen paralysis and induce phase II block in this setting. Lack of fade may indicate resolution of phase II block, but the degree of recovery from phase I block cannot be assessed without a baseline, pre-NMBA twitch.

●The patient should be sedated and mechanically ventilated until full return of muscle strength as determined by quantitative monitoring if available. If quantitative monitoring is not available, the subjective monitoring with a peripheral nerve stimulator is warranted to confirm recovery.

After an episode of prolonged paralysis after succinylcholine, testing may be performed for the level and activity of butyrylcholinesterase. These tests are not routinely performed in hospital laboratories, and blood samples are usually sent to specialized testing centers. Two tests are performed, one for the level of enzyme activity, and if enough activity exists, another test is performed for the dibucaine number, which indicates the percent of inhibition of the enzyme under standardized test conditions. The blood sample for these tests should be drawn after the patient has recovered full muscle strength, since the enzyme activity results can vary depending on anesthetic exposure [122]. Dibucaine inhibition (ie, phenotype testing) is not affected by anesthetic exposure.

Dibucaine inhibition of 70 to 80 percent indicates a normal enzyme, whereas dibucaine inhibition of 20 to 30 percent indicates a homozygous atypical enzyme.

Adverse effects of succinylcholine — Succinylcholine is associated with a number of adverse effects, many of which are related to its depolarizing effect. Succinylcholine is contraindicated for patients with susceptibility to malignant hyperthermia, denervating conditions, major burns after 48 hours, and severe hyperkalemia.

●Hyperkalemia – Serum potassium levels increase by approximately 0.5 mEq/L after the administration of 1 mg/kg succinylcholine. This increase is exaggerated and may be life-threatening in patients who have upregulation of extrajunctional nicotinic acetylcholine receptors (nAChRs; eg, stroke with paralysis, spinal cord injury, muscle and muscle membrane disorders, muscular sclerosis, and polyneuropathies, sepsis, prolonged bed rest), or significant burns [123,124]. The administration of a small dose of a nondepolarizing NMBA prior to succinylcholine (ie, a defasciculating dose) does not reliably prevent the rise in potassium associated with succinylcholine.

Administration of succinylcholine for routine intubation in children has largely been abandoned. The Food and Drug Administration of the United States has issued a boxed warning for succinylcholine for children, except for emergency airway management, over concerns for acute rhabdomyolysis and hyperkalemia in children with undiagnosed muscular dystrophies. Despite the warning, succinylcholine can be used in carefully screened children in select circumstances (eg, for rapid sequence induction and intubation [RSII]). (See "General anesthesia in neonates and children: Agents and techniques", section on 'Intravenous induction medications'.)

●Malignant hyperthermia – Succinylcholine is a known trigger for malignant hyperthermia (MH), and its use is contraindicated in patients at risk for MH. (See "Susceptibility to malignant hyperthermia: Evaluation and management" and "Malignant hyperthermia: Diagnosis and management of acute crisis".)

●Myalgias – Nearly one-half of patients experience myalgias after receiving succinylcholine. Such myalgias were initially thought to be related to the fasciculations. However, the use of a nondepolarizing NMBA or "defasciculating" dose may attenuate, but does not reliably prevent, myalgias [15]. Nonsteroidal anti-inflammatory drugs are the most effective means of attenuating succinylcholine-induced myalgias (number-needed-to-treat of 2.5 to 3), but only prevent myalgia in one-third of patients [119].

Pretreatment with nondepolarizing NMBAs can produce partial neuromuscular blockade, which results in visual disturbances, difficulty breathing, and other adverse effects [119].

●Increased intragastric pressure – While succinylcholine increases intragastric pressure, the risk of aspiration is mitigated by a simultaneous increase in the lower esophageal sphincter tone.

●Increased intraocular pressure – Succinylcholine can cause increased intraocular pressure by up to 15 mmHg via unknown mechanisms. The optimal strategy for RSII in the setting of an open eye with a full stomach is debated, and must be individualized. (See "Anesthesia for emergency eye surgery", section on 'Induction of anesthesia'.)

●Increased intracranial pressure – Succinylcholine can produce a transient increase in intracranial pressure, which can be attenuated by administration of a defasciculating dose of nondepolarizing NMBA. (See "Anesthesia for craniotomy in adults", section on 'Neuromuscular blocking agents'.)

●Cardiac dysrhythmias – Succinylcholine may cause a variety of arrhythmias [125]. Bradycardia is the most common of these, and occurs most frequently in children, or with repeated administration. Some clinicians routinely administer atropine prior to RSII with succinylcholine in children to prevent bradycardia or asystole. (See "General anesthesia in neonates and children: Agents and techniques", section on 'Rapid sequence induction and intubation'.)

●Allergic reactions – NMBAs are among the commonly implicated triggers for perioperative anaphylaxis. The reported incidence of anaphylaxis varies, but it appears that the rates of anaphylaxis to succinylcholine and rocuronium are significantly higher than the rates of reaction to other NMBAs [126]. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Neuromuscular-blocking agents'.)

NONDEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS — Nondepolarizing, competitive NMBAs are classified by their chemical structure (steroidal versus benzylisoquinolinium) as well as their duration of action (short-, intermediate-, or long-acting agents). The properties of NMBAs are shown in tables (table 4 and table 3 and table 5).

Pharmacology of nondepolarizing neuromuscular blocking agents — In general, the speed of onset of neuromuscular block depends on the potency of the drug; greater potency is associated with slower onset of block. Thus, rocuronium, with an ED₉₅ of 0.3 mg/kg IV, has a much more rapid onset than vecuronium, which has an ED₉₅ of 0.05 mg/kg (table 4). The standard intubating dose of nondepolarizing NMBAs is 2 to 3 times the ED₉₅ for the specific drug. Higher doses of some drugs speed onset of block and may be used for rapid sequence induction and intubation (RSII), though with a prolonged duration of block.

A dose of 10 percent of the ED₉₅ may be utilized to maintain an existing level of neuromuscular block during anesthesia, guided by neuromuscular monitoring. (See 'Facilitation of surgery' above.)

●Steroidal compounds – Rocuronium and vecuronium are intermediate-acting, steroidal NMBAs. Pancuronium is the only available long-acting steroidal NMBA; it is no longer available in the United States, Canada, or Europe, but is available in several countries around the world.

●Benzylisoquinolinium compounds – Mivacurium is the only short-acting, benzylisoquinolinium NMBA. It is no longer available in the United States, but is available in some other countries.

Atracurium and its isomer cisatracurium are two intermediate-acting benzylisoquinolinium NMBAs. Curare (d-Tubocurarine) is a long-acting benzylisoquinolinium NMBA that is not available in North America.

Steroidal neuromuscular blocking agents

Rocuronium — Rocuronium has a faster onset than other nondepolarizing NMBAs. Thus rocuronium may be used at higher doses as an alternative to succinylcholine for RSII. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care".)

Rocuronium does not release histamine, nor is it vagolytic, and it causes minimal hemodynamic effects. The incidence of allergic reactions to rocuronium and succinylcholine appears to be higher than other NMBAs. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Neuromuscular-blocking agents'.)

●Dosing/onset of action – The standard intubating dose of 0.6 mg/kg (2 x ED₉₅) provides adequate intubating conditions in 1.5 to 3 minutes in most (but not all) patients. (See 'Endotracheal intubation' above.)

After an intubating dose, the clinical duration of action is 30 to 70 minutes. Thereafter, doses of 0.1 mg/kg or an infusion at a dose of 5 to 12 mcg/kg/minute can be used to maintain neuromuscular blockade, guided by neuromuscular monitoring. The RSII dose of rocuronium of 1.2 mg/kg, or 4 x ED₉₅, has a similar average onset time as succinylcholine, although the variability in onset is greater with rocuronium [127].

●Pharmacokinetics – Rocuronium has a volume of distribution of 0.3 to 0.7 L/kg. It is excreted mostly through the biliary route, although a small portion is excreted renally. Its metabolism results in 17-desacetyl-rocuronium, a compound that has 20 percent the activity of the parent compound.

Vecuronium — Vecuronium is a steroidal NMBA with minimal hemodynamic effects. It is not used as an alternative to succinylcholine for RSII because of slower onset time compared with rocuronium.

●Dosing/onset of action – An intubating dose of vecuronium of 0.1 mg/kg, or 2 x ED₉₅ provides adequate intubating conditions in three to four minutes. The maintenance dose is 0.01 mg/kg, or an infusion at 1 to 2 mcg/kg/min, guided by neuromuscular monitoring. Following an intubating dose, the clinical duration of action is 25 to 50 minutes.

●Pharmacokinetics – Vecuronium has a volume of distribution of 0.4 L/kg. It is excreted both through the biliary and renal routes. Thus patients with renal or hepatic disease may have a prolonged response to vecuronium, and maintenance doses should be carefully guided by neuromuscular monitoring. Vecuronium is metabolized to 3-desacetyl-vecuronium, a compound that has 60 percent the activity of the parent compound.

Pancuronium — Pancuronium (no longer available in North America or Europe) is a long-acting steroidal NMBA that is rarely used because of a high incidence of postoperative residual neuromuscular weakness. Pancuronium can cause tachycardia as a result of direct sympathomimetic stimulation and blockade of cardiac muscarinic receptors [128].

●Dosing/onset of action – An intubating dose of pancuronium of 0.1 mg/kg (1.5 x ED₉₅) provides adequate intubating conditions in three to five minutes. The maintenance dose is 0.02 mg/kg. Following an intubating dose, the clinical duration of action is 60 to 120 minutes.

●Pharmacokinetics – Pancuronium has a volume of distribution of 0.2 to 0.3 L/kg. It is eliminated mostly through the renal route, with approximately 20 percent biliary excretion. Pancuronium is metabolized to 17-OH-pancuronium and 3-OH- pancuronium, with the latter possessing 50 percent the activity of the parent compound. Pancuronium should generally be avoided in patients with renal and hepatic impairment. If necessary, maintenance doses should be carefully guided by neuromuscular monitoring.

Benzylisoquinolinium neuromuscular blocking agents

Atracurium — Atracurium is an intermediate-acting benzylisoquinolinium NMBA that is a mixture of 10 isomers.

●Dosing/onset of action – An intubating dose of atracurium of 0.5 mg/kg, or 2 x ED₉₅ provides adequate intubating conditions in three to five minutes. The maintenance dose of atracurium is 0.1 mg/kg, or an infusion at 10 to 20 mcg/kg/min, guided by neuromuscular monitoring. At doses higher than 0.5 mg/kg, atracurium increases plasma histamine levels, causing skin flushing, hypotension, and tachycardia [129]. Following an intubating dose, the clinical duration of atracurium is 30 to 45 minutes.

●Pharmacokinetics – Atracurium is metabolized through nonspecific plasma esterase-mediated hydrolysis and a nonenzymatic, pH- and temperature-dependent degradation called Hofmann elimination. Laudanosine is the final product of Hofmann elimination, a compound that was found to be epileptogenic in animal studies when administered in large doses [130]. Epileptogenic side effects have not been demonstrated in humans, and this byproduct has no significance at clinically relevant doses [131]. Metabolism is essentially independent of hepatic and renal function, and atracurium has no active metabolites. The volume of distribution of atracurium is 0.15 L/kg.

Cisatracurium — Cisatracurium is the cis-isomer of atracurium and is four times more potent than atracurium. In contrast with atracurium, it does not cause histamine release.

●Dosing/onset of action – The intubating dose of cisatracurium of 0.15 to 0.2 mg/kg, or 3 x ED₉₅, provides adequate intubating conditions in four to seven minutes. The maintenance dose of cisatracurium is 0.01 mg/kg or an infusion at 1 to 3 mcg/kg/min, guided by neuromuscular monitoring. Following an intubating dose of cisatracurium, the clinical duration of action is 35 to 50 minutes.

●Pharmacokinetics – Cisatracurium is also primarily metabolized through Hofmann elimination. Cisatracurium has no active metabolites, and its volume of distribution is 0.16 L/kg.

Mivacurium — Mivacurium is a short-acting nondepolarizing benzylisoquinolinium NMBA that was developed as a nondepolarizing alternative to succinylcholine. Large doses are required for intubation because of this drug's low potency. Clinical utility has been limited by the histamine release associated with these high doses [129]. Mivacurium is no longer available in the United States or Canada but is available in many other countries.

●Dosing/onset of action – An intubating dose of mivacurium of 0.2 mg/kg, or 3 x ED₉₅, provides adequate intubating conditions in three to four minutes. The maintenance dose of mivacurium is 0.1 mg/kg [132], or an infusion at 5 to 8 mcg/kg/min, guided by neuromuscular monitoring. Following an intubating dose of mivacurium, the clinical duration of action is 15 to 20 minutes.

●Pharmacokinetics – Mivacurium is mostly metabolized by butyrylcholinesterase and should not be used in patients with butyrylcholinesterase deficiency, as such patients will have unpredictable and prolonged response. Mivacurium has a volume of distribution of 0.2 L/kg. It does not have active metabolites.

Reversal (antagonism) of mivacurium with either neostigmine or edrophonium is faster than spontaneous recovery [133], although neostigmine reversal of profound mivacurium block may result in prolongation of the block [134].

Neuromuscular block that occurs after mivacurium administration in patients with pseudocholinesterase deficiency is not completely reversed by neostigmine [135], and recovery from neuromuscular block in this setting should be confirmed by objective monitoring, with a train-of-four ratio (TOFR) >0.9.

SUMMARY AND RECOMMENDATIONS

●Use and selection of neuromuscular blocking agents (NMBAs) – NMBAs are administered during anesthesia to facilitate endotracheal intubation and/or to improve surgical conditions (table 6). Selection of NMBA is based on patient factors and the clinical indication. (See 'Selection of neuromuscular blocking agents' above.)

Patient factors can affect the response to NMBAs, including neuromuscular disease (table 1), burns, extremes of age, hepatic and renal dysfunction, and physiologic disturbances. Other medications (eg, inhaled anesthetics) can also affect the response to NMBAs. (See 'Factors that affect the response to neuromuscular blocking agents' above.)

●Depth of block – Deep neuromuscular block (ie, 0 to 1 twitch, post tetanic count ≥1 with neuromuscular monitoring) is used for endotracheal intubation, and for some surgical indications. We aim for a moderate level of neuromuscular block (ie, 1 to 3 twitches) for most surgical procedures. (See 'Clinical use of neuromuscular blocking agents' above.)

●Avoiding residual block – Full recovery of neuromuscular function (ie, train-of-four [TOF] ratio of ≥0.9) must be achieved prior to extubation of the trachea. Residual neuromuscular block is associated with weakness of upper airway muscles, increased risk of aspiration, hypoxemia, awareness during emergence from anesthesia, and increased postoperative pulmonary complications.(See 'Avoidance of residual neuromuscular blockade' above.)

A strategy for avoidance of residual neuromuscular blockade should include (see 'Avoidance of residual neuromuscular blockade' above):

•Use intermediate or short acting NMBAs whenever possible

•Avoid deep neuromuscular block (ie, train-of-four count [TOFC] of zero) when clinically appropriate

•Use objective neuromuscular monitoring whenever possible to guide administration of NMBAs and assess recovery

•Administer reversal agents in appropriate doses, guided by the degree of recovery from neuromuscular block (see 'Reversal of neuromuscular block' above)

•Extubate the trachea only after a TOF ratio ≥0.9 is achieved, as indicated by objective monitoring

•If a quantitative monitor is not available, we suggest administering neostigmine only when TOFC = 4 (as assessed at the adductor pollicis muscle) (Grade 2C). We allow at least 10 minutes after neostigmine administration before tracheal extubation. (See 'Anticholinesterases' above.)

●Reversal of block – Reversal of neuromuscular blockade can occur by spontaneous recovery, or by administration of reversal agents (ie, neostigmine or sugammadex). Sugammadex can only be used to reverse block after administration of aminosteroid NMBAs (eg, rocuronium or vecuronium). For patients who have received rocuronium or vecuronium and who require reversal of block, we suggest using sugammadex rather than neostigmine (Grade 2C). Sugammadex reverses block more quickly and reliably than neostigmine, can be used to reverse deeper levels of neuromuscular block, and may be associated with reduced incidence of postoperative pulmonary complications (PPCs). (See 'Sugammadex versus neostigmine' above.)

Where cost is an issue, it is reasonable to routinely use neostigmine and restrict the use of sugammadex to patients who are at higher risk of complications of postoperative residual neuromuscular block (eg, patients >80 years of age or who undergo thoracic surgery, and/or patients who need reversal from deep levels of neuromuscular blockade (TOFC ≤3).

The doses of neostigmine and sugammadex should be based on the level of existing neuromuscular block at the time of administration (table 6). (See 'Reversal of neuromuscular block' above.)

●Classification of NMBAs – NMBAs are classified according to their interaction with nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction (NMJ). Succinylcholine produces skeletal muscle relaxation by binding directly with nAChRs to cause prolonged depolarization. Nondepolarizing NMBAs act as competitive antagonists for acetylcholine at nAChRs to prevent the initiation of an action potential (table 5). (See 'Classification of neuromuscular blocking agents' above.)

●Succinylcholine (depolarizer) – Succinylcholine is most often used for endotracheal intubation. It causes muscle fasciculations, an increase in serum potassium, and may cause postoperative myalgias. Succinylcholine is contraindicated in patients with severe burns, denervating neuromuscular diseases and stroke, susceptibility to malignant hyperthermia, and butyrylcholinesterase deficiency. (See 'Succinylcholine' above.)

●Nondepolarizers

•Rocuronium and vecuronium are the commonly used intermediate duration aminosteroid nondepolarizing NMBAs. They are used for endotracheal intubation and to facilitate surgery. Vecuronium and rocuronium have minimal cardiovascular side effects. They should be avoided or used with careful monitoring in patients with renal or hepatic dysfunction (table 4). (See 'Steroidal neuromuscular blocking agents' above.)

•Cisatracurium, atracurium, and mivacurium are benzylisoquinolinium nondepolarizing NMBAs. Cisatracurium and atracurium are intermediate duration of action NMBAs that are used for endotracheal intubation and for facilitation of surgery. They are metabolized through Hofmann elimination, and do not depend on renal or hepatic function. Atracurium, but not cisatracurium, releases histamine at higher doses and can cause hypotension (table 3). (See 'Atracurium' above and 'Cisatracurium' above.)

•Mivacurium is a short acting NMBA that is metabolized by plasma butyrylcholinesterase, and should be avoided in patients with atypical or deficient butyrylcholinesterase. At high doses, mivacurium releases histamine (table 5). (See 'Mivacurium' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Sorin Brull, MD, FCARCSI (Hon), who contributed to an earlier version of this topic review.

The UpToDate editorial staff acknowledges Mohamed Naguib, MD, now deceased, who contributed to an earlier version of this topic review.