Version May 2024
INTRODUCTION — Neuromuscular blocking agents (NMBAs) paralyze skeletal muscles by blocking the transmission of nerve impulses at the myoneural junction. NMBAs may be useful in the intensive care unit (ICU) for several indications.
The clinical use, administration, and potential adverse effects of NMBAs in critically ill patients will be discussed here. The pharmacology of NMBAs and use in patients undergoing anesthesia, and intubation in the emergency department, are discussed separately. (See "Clinical use of neuromuscular blocking agents in anesthesia" and "Neuromuscular blocking agents (NMBAs) for rapid sequence intubation in adults for emergency medicine and critical care".)
CLASSIFICATION AND MECHANISM OF ACTION — Neuromuscular blocking agents (NMBAs) (table 1) block the binding of acetylcholine (ACh) to the motor endplate. They are divided into depolarizing or nondepolarizing agents based upon their mechanism of action [1-4].
●Depolarizing NMBAs bind to cholinergic receptors on the motor endplate, causing initial depolarization on the endplate membrane followed by blockade of neuromuscular transmission. Succinylcholine is the only depolarizing agent available in the United States and is utilized almost exclusively to facilitate intubation or treat laryngospasm [3,5].
●Nondepolarizing NMBAs competitively inhibit the ACh receptor on the motor endplate. Drug binding to the ACh receptor either prevents the conformational change in the receptor or physically obstructs the ion channels so that an endplate potential is not generated [6,7]. Nondepolarizing NMBAs are divided into aminosteroid compounds (eg, pancuronium, vecuronium, rocuronium) and benzylisoquinolinium compounds (eg, atracurium, cisatracurium, mivacurium).
Further details regarding the mechanism of action of NMBAs are provided separately. (See "Clinical use of neuromuscular blocking agents in anesthesia".)
CLINICAL USE — Clinical practice guidelines have been developed to help clinicians manage critically ill adults requiring sustained neuromuscular blockade [8-10]. Guidance for the use of neuromuscular blocking agents (NMBAs) in these patients is listed below:
●NMBAs are not first line agents for managing undesired movement, agitation, or ventilator asynchrony, since they do not have sedative, amnestic or analgesic properties. NMBAs for these indications are generally reserved for patients in whom conventional strategies of sedation and analgesia have failed (table 2). In such circumstances, NMBAs may be used for:
•Severe, refractory, or life-threatening hypoxemia, particularly those with severe ventilator dyssynchrony. NMBAs may help to achieve lung-protective ventilation through the prevention of spontaneous respiratory efforts and by reducing oxygen consumption through decreasing work of breathing and abolishing resting muscle tone. NMBAs may also prevent injurious regional lung overinflation and dynamic hyperinflation [11]. The role of paralysis in patients with ARDS is discussed separately. (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults", section on 'Paralysis (neuromuscular blockade)'.)
•Overt shivering due to therapeutic hypothermia following cardiac arrest. (See "Intensive care unit management of the intubated post-cardiac arrest adult patient", section on 'Adverse effects'.)
•Eliminating unwanted movement or reducing muscle tone in patients with refractory status asthmaticus, patients with raised intracranial pressure (ICP) who have unwanted muscle movement or ventilator dyssynchrony contributing to raised ICP, patients with massive hemoptysis (to prevent coughing and clot dislodgement), patients with conditions that increase muscle activity (eg, tetanus, malignant neuroleptic syndrome), patients with increased intra-abdominal pressure (IAP), or patients who need temporary paralysis to facilitate short procedures (eg, bronchoscopy, endoscopy, tracheostomy, radiologic interventions). (See "Management of acute moderate and severe traumatic brain injury", section on 'Sedation and analgesia' and "Tetanus", section on 'Control of muscle spasms'.)
•Acute respiratory failure requiring emergent intubation. (See "Clinical use of neuromuscular blocking agents in anesthesia" and "Neuromuscular blocking agents (NMBAs) for rapid sequence intubation in adults for emergency medicine and critical care".)
NMBAs should not be used for management of status epilepticus, unless necessary for intubation or short-term ventilator management, since they may mask electrical seizures. (See "Convulsive status epilepticus in adults: Management".)
SELECTING AN AGENT — There is a paucity of evidence to guide clinicians regarding agent selection in critically ill patients since most data were derived from patients who received a neuromuscular blocking agent (NMBA) during surgery. While earlier studies reported that vecuronium and pancuronium were the most commonly prescribed NMBAs in the intensive care unit (ICU) [12,13], studies since then suggest that cisatracurium is the most common agent used; accounting for two-thirds of NMBA use [14,15].
The choice between agents in the ICU depends on both the indication and the patient's comorbidities, mostly the presence or absence of renal failure, liver failure, and hyperkalemia. For continuous infusions, cisatracurium is typically the preferred agent since the metabolism is unrelated to renal or hepatic function. For endotracheal intubation in the ICU, rocuronium is commonly used as an alternative to succinylcholine given its rapid onset and intermediate duration of action, but without the high potential for hyperkalemia in the critically ill population. (See "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Adverse effects of succinylcholine'.)
While most other factors including age, sepsis, hypothermia, and electrolyte and acid base disturbances can affect the pharmacokinetics of NMBAs, they weigh less heavily on agent choice than renal and hepatic insufficiency. Nonetheless, clinicians should be aware of how such conditions affect the half-life of NMBAs (table 1).
Hepatic insufficiency — Atracurium or cisatracurium is the preferred NMBA in patients with hepatic insufficiency. Both drugs undergo spontaneous degradation at physiologic pH and temperature (via Hofmann elimination) and therefore are less dependent on hepatic (or renal) function.
In contrast, aminosteroid NMBA pharmacokinetics can be affected by liver dysfunction. Thus, because the half-life is prolonged in patients with hepatic insufficiency, pancuronium (increased volume of distribution [16]), vecuronium (reduced clearance [17]), and rocuronium (increased volume of distribution [18]) are preferably avoided. (See "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Nondepolarizing neuromuscular blocking agents'.)
Renal insufficiency — Similar to patients with liver disease, atracurium or cisatracurium is preferred in patients with renal insufficiency since both drugs undergo spontaneous degradation at physiologic pH and temperature (via Hofmann elimination) and therefore are less dependent on renal (or hepatic) function.
In contrast, aminosteroid NMBAs, pancuronium, vecuronium, and rocuronium, have variable durations of action in the setting of severe renal disease and are therefore preferably avoided [19]. The increase in elimination half-life and decreased clearance is most significant for pancuronium. Vecuronium may have a prolonged effect due to its active metabolite, 3-desacetyl vecuronium [20]. Rocuronium can have an increased volume of distribution and decreased plasma clearance in the setting of renal failure.
Older adult patients — Age-related physiologic changes, including reduction in total body water, lean body mass, and serum albumin concentration, may result in a reduction in the volume of distribution of NMBAs [21]. Decreased cardiac output may also prolong drug delivery and slow the onset of action of NMBAs. Increased age may contribute to a reduction in the rate of drug elimination via decreases in cardiac output, glomerular filtration rate, and liver function. Drug selection is dictated by age-associated decreases in cardiac, renal, and hepatic function (table 3 and table 4) [22].
Obesity — Agent selection in obese patients should be similar to nonobese patients. However dosing may be different. (See 'Dosing' below.)
Sepsis and septic shock — There is no preference for one particular NMBA in patients with sepsis. However, critically ill patients with severe sepsis may have a delayed and reduced response to standard dosing regimens of cisatracurium [23].
Hypothermia — There is no preference for one single NMBA in patients with hypothermia but clinicians should be aware that hypothermia may prolong the duration of action of all nondepolarizing NMBAs (table 1). The mechanisms underlying this prolongation include altered sensitivity of the neuromuscular junction, reduction in acetylcholine (ACh) mobilization, decreased muscle contractility, altered pH, changes in drug volumes of distributions, and reduced renal and hepatic excretion [24]. Hypothermia may also slow the Hoffmann elimination process and prolong the effect of cisatracurium and atracurium [25]. Importantly, neuromuscular monitoring is still reliable and can help guide neuromuscular blockade management in the hypothermic patient. (See 'Monitoring' below.)
Electrolyte abnormalities — Electrolyte and pH disturbances may alter the duration of action of NMBAs. Succinylcholine should not be used in those with hyperkalemia since it may worsen hyperkalemia and potentially precipitate cardiac arrest. (See "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Adverse effects of succinylcholine'.)
Hypokalemia may augment the blockade induced by nondepolarizing agents. Magnesium prolongs the duration of neuromuscular blockade. In contrast, hypercalcemia may both reduce the sensitivity to NMBA and decrease the duration of neuromuscular blockade. The blockade effect of nondepolarizing agents may be enhanced by both respiratory and metabolic acidosis. Antagonism of neuromuscular blockade by reversal agents may occur more slowly in the presence of a respiratory acidosis or metabolic alkalosis. (See "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Patient factors'.)
ADMINISTRATION — Intensive care unit (ICU) staff must be trained in the administration and monitoring of neuromuscular blocking agents (NMBAs). Appropriate equipment for assessing the degree of paralysis must also be available [5,26,27].
Bolus versus infusion — NMBAs can be administered by intermittent intravenous injection or continuous infusion, but should not be given intramuscularly due to erratic absorption (table 1) [4,28,29]. Since the depolarizing NMBA, succinylcholine, is generally only used for intubation or laryngospasm, it is administered as a bolus dose only. In contrast, nondepolarizing agents are administered as a bolus dose or an infusion, with the dose and frequency titrated to the desired clinical effect. Generally speaking, a bolus dose of long-acting NMBAs (eg, rocuronium) is preferred when transient paralysis is needed (eg, emergent intubation), while infusions of shorter-acting NMBAs (eg, cisatracurium) are generally chosen when sustained paralysis is needed (eg, post cardiac arrest following hypothermia) [29].
Dosing — Dosing and pharmacokinetics of individual NMBAs (table 1) are discussed separately. (See "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Succinylcholine' and "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Nondepolarizing neuromuscular blocking agents'.)
However, specific to critically-ill patients, sensitivity to NMBAs varies and the metabolism cannot always be accurately predicted. For example:
●Medical conditions – Specific conditions may affect the pharmacokinetics of NMBAs (table 5). For example, reduced doses may be sufficient in patients with myasthenia gravis or other muscle weakness disorders. In contrast, doses of NMBAs must be increased in burn patients, for example, due to increased protein binding and up-regulation of receptors, as well as enhanced renal and hepatic elimination [30]. (see "Anesthesia for the patient with myasthenia gravis")
●Drugs – Several drugs may interact with NMBAs, which may make dosing adjustments necessary (table 6) [2,4,29]. Drugs that inhibit presynaptic acetylcholine (ACh) release or depress postjunctional sensitivity enhance the degree and duration of neuromuscular blockade [3,6]. Conversely, phenytoin and carbamazepine significantly increase the requirement for nondepolarizing NMBAs by an unknown mechanism.
●Obesity – Given the variability among NMBAs and the overall paucity of dosing information from critically ill obese patients, we suggest starting with low doses and titrating the dose using train-of-four (TOF) or tetanic stimulation (see 'Administration' above). Limited data suggest that obesity does not appear to alter the pharmacokinetics or pharmacodynamics of succinylcholine or rocuronium [31-33]; this suggests that these agents can be dosed according to actual body weight rather than predicted body weight [31]. In contrast, atracurium and vecuronium have a prolonged duration of action if they are dosed according to actual body weight [34-36]. Effects on cisatracurium are unknown.
Target level of paralysis — The optimal level of paralysis for critically ill patients depends on the indication for NMBA use. Complete (100 percent) neuromuscular blockade may not be necessary (table 2) [4]. (See 'Clinical use' above.).
In critically ill patients when nondepolarizing NMBAs are administered, it is more appropriate to think in terms of controlling motor activity rather than completely paralyzing the patient. For example, some patients can be maintained at 50 to 70 percent blockade such that the patient maintains some modest muscle tone and even motor activity (eg, severe shivering from hypothermia where the purpose of paralysis is to eliminate shivering), whereas other patients require nearly complete paralysis (eg, 80 to 90 percent such as patients with severe abdominal paradox where the purpose of paralysis is to allow ventilator synchrony) [37].
Monitoring — For critically ill patients on NMBA infusions, most experts monitor the degree of neuromuscular blockade with regular clinical assessment (eg, triggering ventilator, degree of shivering) and peripheral nerve stimulation (PNS) using TOF counts (TOFC) or tetanic stimulation [8,28]. The targeted depth of blockade should be assessed with PNS every 2 to 3 hours until the NMBA dose is stable, then every 8 to 12 hours [38]. The dose can be adjusted to the desired target as necessary. Quantitative neuromuscular monitors (eg, accelerometers), which work by quantifying the muscle response to nerve stimulation, are increasingly used in the operating room but are not routinely used in the ICU [39]. Details regarding the practical application of PNS are described separately. (See "Monitoring neuromuscular blockade".)
The use of PNS monitoring is widely accepted, but data supporting its use in critically ill patients are limited [40,41]. The few prospective, randomized studies that have assessed the utility of PNS in critically ill patients have reported conflicting results, perhaps related to differences in drugs studied [42].
●In one randomized trial of 77 critically ill patients, vecuronium dosing was guided either by clinical assessment or PNS [43]. The PNS group used significantly less drug and recovered neuromuscular function and spontaneous ventilation approximately 55 percent faster than the control group; patients with renal insufficiency appeared to derive the most benefit for PNS-guided therapy.
●In contrast, two randomized trials of 36 patients receiving atracurium [44] and 30 patients receiving cisatracurium [45] reported no difference in the total amount of drug administered or the time to clinical recovery among patients who were monitored using TOF compared with clinical assessment.
Duration of infusions — For some indications (eg, severe ventilator dyssynchrony following intubation), one to two bolus doses of a NMBA may be all that is required while for other indications, an infusion is needed (eg, shivering) (table 2) (see 'Clinical use' above). Similar to sedative infusions, daily interruption of the NMBA infusion is suggested to assess the ongoing need for paralysis. Discontinuation should occur as early as is feasible to potentially decrease the incidence of prolonged recovery secondary to drug and metabolite accumulation and to potentially decrease the incidence of neuromuscular weakness related to critical illness [8]. (See 'Discontinuation' below and "Neuromuscular weakness related to critical illness", section on 'Critical illness myopathy'.)
Safety — Given the potential for death if an NMBA is administered to a patient without appropriate ventilatory support, the United States Pharmacopeia Safe Medication Use Expert Committee has issued recommendations [46]:
●NMBA packaging and labeling should clearly differentiate NMBAs from other medications
●Special safeguards for storage, labeling, and the use of drugs should be instituted
●Health care professionals should be especially vigilant with these drugs
Discontinuation — Tapering the dose is not necessary when neuromuscular blockade is discontinued. Sedation and analgesia adequate for patient comfort must be maintained as the NMBA is discontinued.
Reversal — The action of nondepolarizing NMBAs can be reversed, if necessary, by administration of anticholinesterase drugs such as neostigmine or edrophonium [3]. The action of the steroidal neuromuscular blocking medications rocuronium, vecuronium, and pancuronium can be reversed by administration of sugammadex sodium [47,48]. Further details regarding drug reversal are discussed separately. (See "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Reversal of neuromuscular block'.)
SUPPORTIVE CARE — Patients receiving NMBAs require meticulous care because the potential for complications is great [49]. Particular attention should be paid to the following:
●Adequate sedation and analgesia prior to, during, and following discontinuation of paralysis – Processed electroencephalography (EEG) monitoring (eg, bispectral index [BIS] monitoring) may be beneficial for assessing and controlling sedation during therapeutic musculoskeletal paralysis as in this circumstance sedation scales cannot be used [50,51]. (See "Accidental awareness during general anesthesia", section on 'Brain monitoring'.)
●Prevention of corneal injury – Lubricating eye drops or gel should be instilled every two to four hours and eyelids should be taped shut to prevent corneal drying, ulceration, infection, and scarring.
●Close monitoring for ventilator disconnect – Interruption of the ventilator circuit (eg, accidental extubation) can be fatal.
●Tracheal suctioning – The endotracheal tube should be suctioned frequently to remove accumulated secretions (NMBAs inhibit the cough reflex).
●Prevention of skin breakdown – Paralyzed patients should be turned frequently, and kept on dry, wrinkle-free bedding in order to prevent skin breakdown and decubitus ulcers.
●Venous thromboembolism prophylaxis – Paralyzed patients are at high risk of venous thromboembolism. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)
●Monitor pupillary reflexes – Pupillary reflexes should be closely monitored to assess neurologic status (but are unreliable if pancuronium is used because of its antimuscarinic effects).
Glycemic control, physical therapy strategies, aspiration precautions, and measures that avoid unintended extubation in patients receiving NMBAs are similar to that in other critically ill populations and are discussed separately. (See "Glycemic control in critically ill adult and pediatric patients" and "Post-intensive care syndrome (PICS) in adults: Clinical features and diagnostic evaluation" and "Complications of the endotracheal tube following initial placement: Prevention and management in adult intensive care unit patients", section on 'Prevention of complications in the ICU' and "Complications of the endotracheal tube following initial placement: Prevention and management in adult intensive care unit patients", section on 'Displacement and unplanned extubation' and "Extubation management in the adult intensive care unit", section on 'Patients with unplanned extubation'.)
ADVERSE EFFECTS — The adverse effects of neuromuscular blocking agents (NMBAs) in critically ill patients are similar to those experienced by patients undergoing anesthesia (table 1). The most commonly encountered side effects in critically ill patients are allergic reactions, cardiovascular side effects (hypotension and cardiac arrhythmias), prolonged paralysis, muscle weakness, and awareness during paralysis. Detailed descriptions of the adverse effects of each NMBA are discussed separately. (See "Clinical use of neuromuscular blocking agents in anesthesia".)
Allergic reactions — NMBAs are the most common cause of anaphylaxis (IgE-mediated) in the perioperative period with succinylcholine and rocuronium being the most frequent agents implicated. Cross-reactivity between NMBAs is observed in more than 60 percent of cases [52,53], thus, patients in the intensive care unit (ICU) may develop anaphylaxis due to cross reactivity with other inciting agent exposures in the past. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Neuromuscular-blocking agents' and "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions", section on 'Neuromuscular-blocking agents'.)
Cardiovascular effects — Adverse cardiovascular side effects, particularly hypotension, associated with nondepolarizing NMBAs are related to stimulation or blockade of the autonomic nervous system and vasodilatation due to histamine release. The drugs with the lowest risk of cardiovascular complications are cisatracurium, rocuronium, and vecuronium. In contrast, succinylcholine results in hypertension and tachyarrhythmias.
Prolonged paralysis and ICU-acquired skeletal muscle weakness — Prolonged paralysis (typically tetraplegia) following drug discontinuation is unusual and results from accumulation of drug or active metabolites or from ICU-acquired weakness (ICUAW) [54,55].
The risk of ICUAW from NMBA use is modest, at best, and may be greatest in sepsis or septic shock, severe illness, or concomitant use of glucocorticoids [56]. Prolonged paralysis is typically related to prolonged use (days) of paralytic agents, often in the setting of renal or hepatic insufficiency. This complication is discussed in greater detail elsewhere. (See "Neuromuscular weakness related to critical illness", section on 'Prolonged neuromuscular junction blockade'.)
Others — Other NMBA adverse effects pertinent to critically ill patients include awareness during paralysis; corneal abrasions, infection, and scarring; venous thromboembolism; and decubitus ulcers. The risk of such complications can be reduced by supportive measures. (See 'Supportive care' above.)
SUMMARY AND RECOMMENDATIONS
●Classification - Neuromuscular blocking agents (NMBAs) paralyze skeletal muscles by blocking the transmission of nerve impulses at the myoneural junction (table 1). NMBAs block the binding of acetylcholine (ACh) to the motor endplate. They are divided into depolarizing (succinylcholine) or nondepolarizing agents (steroidal nondepolarizing NMBAs: pancuronium, rocuronium, and vecuronium; benzylisoquinolinium NMBAs: atracurium, cisatracurium, mivacurium). (See 'Classification and mechanism of action' above and "Clinical use of neuromuscular blocking agents in anesthesia".)
●Indications for use - NMBAs are not first line agents for managing critically ill patients with undesired movement, agitation, or ventilator asynchrony, since they do not have sedative, amnestic, or analgesic properties. Other than emergent intubation, NMBAs are generally reserved for those in whom conventional strategies of sedation and analgesia have failed. The indications are listed in the table (table 2). (See 'Classification and mechanism of action' above and 'Clinical use' above.)
●Agent selection - In general, agent selection is affected by factors including renal and liver dysfunction and hyperkalemia. For continuous infusions cisatracurium is typically the preferred given its metabolism is unrelated to renal or hepatic function. For endotracheal intubation in the intensive care unit (ICU), rocuronium is commonly used as an alternative to succinylcholine given its rapid onset and intermediate duration of action, but without the risk of hyperkalemia. (See 'Selecting an agent' above.)
●Administration - NMBAs can be administered by intermittent intravenous injection or continuous intravenous infusion, depending upon the indication. Since complete paralysis may not be required for critically ill patients, a desired level of paralysis should be targeted. The depth of neuromuscular blockade should be monitored by clinical assessment and by peripheral nerve stimulation (eg, train-of-four count [TOFC], degree of shivering). Daily interruption of infusions is suggested to assess the ongoing need for paralysis. Discontinuation should occur as early as is feasible and tapering is not necessary. Nondepolarizing NMBAs can be reversed by an anticholinesterase agent (eg, neostigmine, edrophonium) and steroidal NMBAs can be reversed by sugammadex sodium. (See 'Administration' above.)
●Supportive care - For patients on NMBAs, particularly those receiving infusions, particular attention should be paid to the provision of adequate sedation and analgesia, eye care, avoidance of extubation, frequent suctioning and turning, and venous thromboembolism prevention measures. (See 'Supportive care' above.)
●Adverse effects - The most problematic adverse effects of NMBAs in critically ill patients are allergic reactions, cardiovascular side effects (eg, hypotension and arrhythmias), prolonged paralysis, and ICU-acquired muscle weakness. Less problematic adverse effects are awareness during paralysis, corneal abrasions, venous thromboembolism, and decubitus ulcers, many of which can be prevented by good supportive care practice. (See 'Adverse effects' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Karen Tietze, PharmD, who contributed to an earlier version of this topic review.
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