Neuromuscular Blocking Agents

Mechanism of Action

NMBAs act at the neuromuscular junction (NMJ), which consists of 3 parts:

• Presynaptic nerve terminal
• Synaptic cleft
• Postsynaptic nicotinic receptors

When an electric impulse transmits along the motor neuron, it causes the release of acetylcholine (ACh) from the presynaptic membrane, which travels across the synaptic cleft and acts on nicotinic receptors on the postsynaptic membrane, causing muscle contraction.

Presynaptic Nerve Terminal

The presynaptic nerve terminal consists of motor neurons originating from the ventral horn of the spinal cord. The motor neuron loses its myelin sheath as it embeds in muscle tissue and secretes trophic and growth factors. The nicotinic acetylcholine receptors (nAChRs) are located on the surface of the presynaptic nerve terminal membrane.[16]

Acetylcholine is stored in vesicles that are readily releasable or gathered in a reserve pool. Readily-released ACh activates sodium channels in the presynaptic membrane, which activate voltage-dependent calcium channels (P-type fast), allowing an inward movement of calcium into the cytoplasm of the motor neuron.[16]

The Synaptic Cleft

The synaptic cleft is the space between the presynaptic and postsynaptic membranes, typically measuring about 50 nm across. Several biologically active substances interact in the cleft to promote and enhance nerve impulse transmission. These substances include acetylcholine esterase (AChE), lipoprotein receptor protein 4 (LRP4), and agrin. A glycoprotein binds LRP4 in the cleft, activating muscle-specific tyrosine kinase (MuSK), which helps differentiate acetylcholine receptors.

The Postsynaptic Membrane

This membrane comprises multiple shoulders densely populated with acetylcholine receptors (AChRs) and voltage-gated sodium channels. This density is possible due to rapsyn and other proteins serving as anchors, enabling a neurotransmitter signal to elicit sufficient depolarization for muscle contraction.[17]

AChR receptors exist in 2 forms:

Mature (adult) junctional receptors are pentametric proteins with 5 subunits. They have high conductivity, remain open for a short period, and have a half-life of approximately 14 days.

Immature (fetal) junctional receptors are primarily found in fetal tissue but can increase in conditions like sepsis, burns, and upper and lower motor neuron diseases. They have a pentameric structure, a half-life of 24 hours, and appear within 24 hours after injury. These receptors are resistant to non-depolarizing neuromuscular blocking agents but are sensitive to succinylcholine. Stimulation of these receptors can cause potassium efflux, predisposing to hyperkalemia.

Depolarizing Neuromuscular Blocking Agents

Depolarizing NMBAs (eg, succinylcholine) act on receptors at the motor endplate of the neuromuscular junction (NMJ), causing depolarization of the membrane; this induces a refractory period. These drugs have an onset of action of 1 minute and a duration of 6 minutes and are rapidly metabolized by plasma butyrylcholinesterase.[18] The continued disruption of ACh-mediated effects causes muscular fasciculation and twitching. Succinylcholine, or suxamethonium, is the only depolarizing NMBA used clinically.

Nondepolarizing Neuromuscular Blocking Agents

Nondepolarizing NMDAs prevent acetylcholine from binding to the motor plate at the NMJ by competing for the ACh binding site on the α subunit of nicotinic receptors. As the concentration of non-depolarizing NMBAs at the junction increases relative to ACh, a neuromuscular blockade becomes established.[19]

There are 2 major structural classes of non-depolarizing NMBAs:

Aminosteroids Neuromuscular Blockers 

• Vecuronium
• Pancuronium
• Rocuronium

Benzylisoquinolinium Neuromuscular Blockers

• Benzylisoquinolinium
• Mivacurium
• Atracurium
• Cis–atracurium [19] 
• Gantacurium [20] (not FDA-approved)

Based on duration of action, NMBDs may be classified as:

• Short-acting (eg, mivacurium, succinylcholine)
• Intermediate-acting (eg, vecuronium, rocuronium, atracurium)
• Long-acting (eg, pancuronium, gallamine, tubocurarine) [21]

Administration

Available Dosage Forms and Strengths

Neuromuscular blocking agents (NMBAs) are most effective when administered intravenously or intramuscularly. They are poorly absorbed if administered orally.[22] The administration route is determined by the patient's clinical condition, desired action speed, and clinical effect duration. NMBA administration is typically intravenous through boluses or continuous infusion. Continuous infusion is usually preferred in the ICU, where prolonged paralysis may be necessary, or in the OR, where a surgical procedure requires significant time.

Adult Dosage

NMBA dosing is based on ideal body weight to prevent overdosing or prolonged paralysis.[23] Adequate sedation and analgesia should be established before NMBA administration. The Society of Critical Care Medicine Clinical Practice Guidelines for Rapid Sequence Intubation recommends administering a neuromuscular blocking agent with a sedative-hypnotic induction agent in critically ill adult patients. Five studies have demonstrated improved first-pass intubation success (FPS) and reduced respiratory arrest, cardiovascular collapse, and vomiting/aspiration occurrences with NMBA use. Due to their widespread availability, NMBAs should be reserved for airway management in critically ill patients when an induction agent is planned to induce unconsciousness.[15] These dosages serve as general guidelines and may require modification depending on individual patient characteristics and use in the ICU vs surgery. For precise dosing, providers should refer to the FDA-approved labeling for each medication and carefully assess the patient's clinical situation. This approach ensures the safe and tailored administration of drugs, aligning with best healthcare practices.

• Succinylcholine: 0.6 mg/kg, Maintenance: 0.04 to 0.07 mg/kg 

• Atracurium: Initial bolus: 0.4 to 0.5 mg/kg, Maintenance: 0.08 to 0.1 mg/kg 

• Cisatracurium: Initial bolus: 0.15 to 0.2 mg/kg, Maintenance: 0.03 mg/kg IV 

• Rocuronium: Intubation (RSI): 0.6 to 1.2 mg/kg, Maintenance: 0.01 to 0.012 mg/kg/min

• Vecuronium: Initial bolus: 0.08 to 0.1 mg/kg, Maintenance:0.8 to 1.2 μg/kg/min

Specific Patient Populations

Hepatic impairment: Liver disease can reduce plasma cholinesterase activity, leading to prolonged neuromuscular blockade after succinylcholine administration.[24]

Renal impairment: Atracurium is the preferred neuromuscular blocking agent for chronic kidney disease (CKD) due to its metabolism via ester hydrolysis and Hofmann degradation, which are independent of renal function. Cisatracurium is also suitable, as it is metabolized by Hofmann degradation, though its clearance is reduced by 13% in CKD. Vecuronium and rocuronium undergo significant renal excretion, leading to prolonged action and reduced clearance in CKD; they require careful monitoring. Pancuronium should be avoided due to decreased clearance.[25] 

Pregnancy considerations: Succinylcholine is preferred for its rapid elimination and minimal transfer to breast milk during pregnancy and postpartum. Other non-depolarizing muscle relaxants, such as pipecuronium and vecuronium, are considered safe alternatives for a caesarian section due to their limited placental transfer and minimal fetal effects. Rocuronium is widely used during pregnancy, as it has a shorter onset and is reversed with sugammadex. Atracurium and cisatracurium are safe options with low placental transfer and minimal cardiovascular effects. Mivacurium, while having the shortest duration, should be used cautiously in patients at risk of eclampsia. Depolarizing and non-depolarizing neuromuscular blocking drugs are ionized and water-soluble, preventing placental transfer at clinically relevant doses. Rocuronium and succinylcholine are classified by the FDA as previous Pregnancy Categories B and C, respectively. These drugs do not cause neonatal skeletal muscle weakness or paralysis. Pregnancy decreases plasma cholinesterase concentration due to increased plasma volume, affecting the onset and duration of these drugs. Therefore, careful monitoring of neuromuscular function and cautious use of reversal agents are essential to prevent rapid increases in circulating acetylcholine, which may induce uterine contractions.[26][27]

Breastfeeding considerations: Non-depolarizing neuromuscular blocking drugs are quaternary ammonium compounds with limited lipid solubility and oral absorption. They are primarily ionized at physiological pH, making them unlikely to pass into breast milk in significant quantities. Due to its ionization at physiological pH and poor oral absorption, succinylcholine is unlikely to be present in notable amounts in breast milk. Breastfeeding can resume once the woman has recovered from anesthesia. Limited clinical data is available on rocuronium during breastfeeding. Rocuronium's short action, high polarity, and poor oral absorption suggest minimal transfer to breast milk and a low risk to the infant.[28] Neostigmine is a quaternary ammonium with a half-life of 15 to 30 minutes that may be transferred to breast milk in nonsignificant quantities. Although excreted in breast milk based on animal studies, sugammadex is a large, polar molecule with minimal likelihood of oral absorption by the infant. Sugammadex is considered safe for use during breastfeeding.[29]

Pediatric patients: Pediatric patients exhibit different responses to neuromuscular blocking agents than adults due to developmental changes in neuromuscular transmission and body composition. Infants are particularly sensitive to non-depolarizing neuromuscular blocking agents because of deficient acetylcholine levels in developing motor nerves. However, this sensitivity is primarily offset by the distribution of these drugs into a larger extracellular fluid volume. When performing rapid sequence intubation in pediatric patients, succinylcholine or rocuronium should be considered (due to their rapid onset), with sugammadex available for reversal.[30]

Older patients: Older patients are more susceptible to postoperative residual neuromuscular blockade (PRNB) and its associated complications, including airway obstruction, hypoxemic events, muscle weakness symptoms, postoperative pulmonary complications, and extended stays in the PACU and hospital. In these patients, PRNB was linked to higher rates of adverse events.[31]

Adverse Effects

The different NMBA types have various adverse effects associated with their use.

Depolarizing NMBAs

Succinylcholine administration correlates with a significant elevation in serum potassium levels. Therefore, succinylcholine should be avoided for patients with chronic kidney disease, rhabdomyolysis, burns, or crush injuries. Elevated potassium levels can lead to fatal arrhythmias.

Succinylcholine can cause bradycardia, especially in pediatric patients. Activation of the nicotinic receptor can stimulate an associated muscarinic receptor, resulting in bradycardia. Administering succinylcholine with atropine or glycopyrrolate can mitigate this effect.

Succinylcholine can cause increased intracranial and intraocular pressure. The administration of adequate age-appropriate sedation in conjunction with succinylcholine can minimize this unwanted adverse effect.[18]

Succinylcholine can also cause malignant hyperthermia, a pharmacogenetic disorder triggered by the concurrent administration of volatile inhalation anesthetics and succinylcholine. Malignant hyperthermia clinically presents as hypercarbia, metabolic acidosis, hyperventilation, hyperthermia, and rhabdomyolysis. This condition is associated with RYR1 and CACNA1S gene mutations.[32]

Other adverse effects of succinylcholine include jaw rigidity, hypersalivation, and hypersensitivity reactions.

Nondepolarizing NMBAs

Benzylisoquinolinium Derivatives

Benzylisoquinolinium, mivacurium, atracurium, cisatracurium, and doxacurium can stimulate histamine release, causing bronchospasm, hypotension, and tachycardia due to peripheral vasodilation.

Laudanosine, a metabolite of atracurium, can accumulate in the central nervous system (CNS) and cause seizures.[33]

Amino Steroids

Prolonged infusion of vecuronium, pancuronium, or rocuronium with concurrent steroids can cause muscular weakness, a condition called "critical illness polyneuropathy."[34]

Potentiating Conditions

Some conditions can prolong the effects of neuromuscular blocking agents:

• Hypothermia
• Metabolic derangements
• Hypercalcemia
• Hypermagnesemia
• Hypokalemia
• Hypothermia
• Respiratory acidosis
• Metabolic alkalosis [35]

Drug-Drug Interactions

• The administration of aminoglycosides (eg, neomycin, gentamicin, tobramycin) or clindamycin potentiates neuromuscular blockade and can enhance the blockade effect induced by rocuronium.[36]
• Inhaled anesthetic agents act at the neuromuscular junction to potentiate neuromuscular blockade in a dose-dependent manner. Desflurane, sevoflurane, and isoflurane can enhance the effect of non-depolarizing neuromuscular blocking agents.[37]
• The concentration-dependent modulatory effect of magnesium enhances and prolongs the action of non-depolarizing NMBAs.[38]
• Medications like calcium channel blockers, lithium, cyclosporine, and anti-arrhythmic drugs such as procainamide and quinidine can increase sensitivity to neuromuscular blocking agents.[39]

Contraindications

Patients with a history of a severe allergic reaction to an NMBA or anaphylaxis should not take NMBAs. Pancuronium and vecuronium undergo deacetylation in the liver; these drugs should be administered to patients with liver failure cautiously. NMBAs are among the most common allergens responsible for hypersensitivity reactions during anesthesia, accounting for 70% of cases.[40]

Pseudocholinesterase deficiency impairs the body's ability to metabolize succinylcholine. The dibucaine inhibition test aids in diagnosing this condition by measuring enzyme activity inhibition after administering dibucaine; higher inhibition percentages indicate greater deficiency severity. The dibucaine number refers to the inhibition percentage.[2]

Box Warning

Succinylcholine can trigger rhabdomyolysis, a rare but critical complication in pediatric anesthesia. In young patients with undiagnosed Duchenne muscular dystrophy (DMD), this condition causes hyperkalemia, increasing the risk of life-threatening ventricular dysrhythmias and cardiac arrest. Management focuses on aggressive interventions for hyperkalemia, including the administration of intravenous calcium, bicarbonate, and glucose with insulin. To minimize the risk of rhabdomyolysis, succinylcholine use in pediatrics should be reserved for emergencies requiring immediate airway control.[41]

Warning and Precautions

• Rocuronium and vecuronium are excreted via the hepatobiliary system and should be avoided in patients with liver failure if an alternative agent is available.
• Pancuronium, doxacurium, and pipecuronium should be avoided in patients with kidney failure as these drugs are excreted renally.
• Atracurium and cisatracurium may be used in patients with kidney or liver failure. These NMDAs get eliminated by a unique process called Hoffman elimination, a spontaneous degradation process independent of liver or kidney function.[42]
• The extravasation of neuromuscular blocking agents can cause unpredictable neuromuscular blockades. Absorption from the subcutaneous depot is slower and influenced by lipid solubility, protein binding, and local tissue perfusion. The extravasation site affects pharmacokinetics, as faster onset and recovery are expected in more vascularized regions. Conditions such as diabetes and atherosclerosis can further influence absorption.[43]
• Caution should be exercised for patients with myasthenia gravis due to their increased sensitivity to neuromuscular blockers. Reversal of rocuronium or vecuronium is achieved with sugammadex administration.[44]
• Per the American Society of Anesthesiologists (ASA) guidelines for obstructive sleep apnea, a complete reversal of neuromuscular block must be confirmed before extubation.[45]

Monitoring

Patients on NMDAs are usually undergoing treatment in the intensive care unit. Monitoring parameters for these patients include pulse oximetry for oxygen saturation and continuous end-tidal CO₂ (ETCO₂). A subsequent elevation in carbon dioxide may suggest developing malignant hyperthermia.

Assessment of neuromuscular blockage involves measuring the "train-of-4" ratio. Typically, the ulnar, median, or facial nerves are stimulated to monitor the effect of neuromuscular blockade. Four electric impulses are delivered at a frequency of 2 Hz. The fourth-to-first twitch ratio is used to assess the blockade effect. The disappearance of the fourth twitch signifies a blockage of 75%, the disappearance of the third twitch signifies a blockage of 85%, the second twitch for 90%, and if only the first twitch is observable, the blockade is near 100%.[46][47][48] The American Society of Anesthesiologists 2023 guidelines recommend quantitative neuromuscular monitoring at the adductor pollicis muscle and confirmed recovery of the "train-of-4" to ≥90% before proceeding with extubation.[49]

The bispectral index monitor (BIS) is a type of quantitative electroencephalography (EEG) used to assess sedation of patients on continuous infusion of NMBAs using bi-spectrality and time domain.[50] In patients who are deeply sedated or under general anesthesia, the BIS is sensitive to changes in the patient's electromyogram (EMG).[51][52][53]

Toxicity

Signs and Symptoms of Toxicity

NMBA dosing should be based on ideal body weight. Excessive NMBA dosing results in paralysis for longer than required and may present with prolonged muscular weakness, decreased respiratory drive, and apnea. Certain conditions mentioned above can prolong the effect of NMBA. Inadequate recovery from neuromuscular blocking drugs is associated with adverse outcomes, including pneumonia, upper airway obstruction, reintubation, atelectasis, and prolonged stay in the postanesthesia care unit (PACU).

Antagonism of Neuromuscular Blockade

Residual neuromuscular blockade is defined as a "train-of-4" (TOF) ratio <0.9 at the adductor pollicis muscle, making it essential to confirm recovery at this site. Precise measurement of the blockade effect aids in selecting the appropriate antagonist drug and determining its dose. If intraoperative monitoring was performed using the eye muscles, the adductor pollicis muscle should be used to confirm the TOF ratio before administering an antagonist. Antagonist dosages are based on adductor pollicis responses, and FDA-approved sugammadex dosages do not apply to corrugator supercilii monitoring.

According to ASA guidelines, sugammadex is recommended for the neuromuscular blockade induced by vecuronium or rocuronium. Sugammadex encapsulates the neuromuscular blocking agent, rendering it inactive. Sugammadex dosing is based on actual body weight (not ideal) and is not recommended for patients with a creatinine clearance (CrCl) <30 mL/min. 

Selecting neostigmine or sugammadex is determined by the likelihood of effective reversal, the type of neuromuscular blocker, blockade depth, and antagonist efficacy. Proper use of antagonists and monitoring is crucial to prevent residual blockade.

Successful antagonism with neostigmine is best achieved when significant spontaneous recovery occurs, specifically at a TOF count of 4 twitches. Studies have demonstrated that administering neostigmine after observing a fourth twitch is associated with better outcomes than lower counts. However, effective NBMA reversal is only confirmed if the fourth twitch is strong. Neostigmine may be used for deeper blocks with an understanding of longer recovery times.

For an initial TOF ratio of 0.4, neostigmine administration achieves a TOF ratio of ≥0.9 within 10 minutes. For a TOF ratio of 0.4 to <0.9, neostigmine should not exceed a 40 µg/kg dose. Neostigmine at 30 µg/kg is recommended for minimal blockade. Higher doses can cause weakness if the TOF ratio is ≥0.9. Neostigmine reaches its maximum effect within 10 minutes; if a TOF ratio ≥0.9 is not observed in this timeframe, providers can wait for further recovery or administer sugammadex or additional neostigmine (no more than 50 µg/kg). 

In the absence of quantitative monitoring and given a TOF count of 4, 15 to 30 µg/kg of neostigmine may be administered, after which providers must wait 10 minutes before extubation. With quantitative monitoring, extubation can occur at a TOF ratio ≥0.9. 

The FDA-approved sugammadex dosages are also based on train-of-4 counts. These guidelines recommend 2 mg/kg for a TOF count of 2 (or ratio <0.9), 4 mg/kg for a TOF count of 1 (or a post-tetanic count of 1), and 16 mg/kg for immediate reversal after 1.2 mg/kg rocuronium administration. Women using hormonal contraceptives require contraception for 7 days after sugammadex administration.

Both neostigmine and sugammadex are effective at a TOF ratio of 0.5. Adverse effects of sugammadex and neostigmine (with glycopyrrolate) are similar, with no significant differences in the incidence of anaphylaxis, bradycardia, tachycardia, postoperative nausea, or vomiting.[49] 

Management of Extravasation

If extravasation is suspected, a new intravenous line for safe anesthesia should be secured promptly. After an accidental subcutaneous injection, a prolonged and unpredictable duration of neuromuscular blockade should be presumed, especially with additional intravenous doses of NMBDs. Quantitative monitoring to detect ongoing block risk should be regularly performed, with TOF monitoring ideally beginning at anesthesia induction to assess block onset. Before administering additional intravenous NMBA doses, the TOF should be measured to align with best practices for anesthesia. Due to potentially delayed absorption from subcutaneous tissue, spontaneous patient recovery may be observed, or active blockade may be further stabilized. Prolonged ventilation and sedation may be necessary post-surgery.

If an increase in TOF count or ratio is observed, sugammadex or neostigmine can reverse the effect of NMBAs. Sugammadex is preferred for aminosteroid NMBDs due to its pharmacological profile, neutralizing capability, lack of muscarinic effects, less residual paralysis, and longer half-life elimination than neostigmine. Sugammadex rarely causes perioperative anaphylaxis. Extubation is safe to perform when the TOF ratio exceeds 0.9. Post-extubation monitoring should include regular neuromuscular block measurement, full ASA monitoring, and a minimum PACU stay of 4 hours, particularly with long-acting NMBAs. Additional sugammadex may be given to reverse aminosteroid NMBD administration if the TOF ratio declines during the PACU observation period. Additional doses must not be given if neostigmine inadequately reverses a non-aminosteroid blockade. Instead, the patient should be observed in the ICU under prolonged sedation and ventilation.[43]

Enhancing Healthcare Team Outcomes

After a surgical procedure is completed or when a patient is weaning towards extubation, NMBAs may be reversed pharmacologically to prevent adverse effects and facilitate quick extubation. Traditionally, neostigmine is used to reverse the effect of NMBAs. Neostigmine's mechanism of action involves the inhibition of acetylcholinesterase (AChE), the enzyme responsible for the breakdown of acetylcholine (ACh). Elevated levels of ACh will compete with the NMBA and stimulate the nicotinic receptors at the neuromuscular junction, enhancing signal transmission.

Recent advances in anesthesia have introduced sugammadex, a cyclodextrin that selectively binds to NMBAs in the plasma. The encapsulation process rapidly nullifies the effect of the NMBA as it is unavailable to act at the neuromuscular junction.[54]

Sugammadex produces a safe and quick reversal of commonly used NMBAs like rocuronium, vecuronium, and pancuronium. Sugammadex can quickly reverse both moderate and deep neuromuscular blockade (NMB).[55][56][57]

With the introduction of sugammadex, deeper and longer NMB may be maintained during surgical procedures without fear of prolonged recovery. Deep NMB improves working conditions for surgeons with less insufflation pressure required during laparoscopic surgery.[58][59][60][61] 

NMBAs should be administered only by adequately trained professionals (eg, anesthesiologists, certified registered nurse anesthetists (CRNA), intensivists, and emergency physicians). The administration of NMBAs should not occur without personnel and facilities for resuscitation and life support, and an antagonist must be readily available. The pharmacist must ensure that dosage is appropriate for the clinical scenario and report any disparities. Respiratory therapists are essential in implementing weaning protocols for mechanical ventilation and ensuring lung-protective ventilation.[62] An interprofessional team approach and open communication between clinicians (MDs, DOs, NPs, PAs), CRNAs, respiratory therapists, pharmacists, and nurses is necessary to optimize patient outcomes related to neuromuscular blocking agents.