Atracurium

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Continuing Education Activity

Atracurium is a non-depolarizing neuromuscular blocking agent that facilitates endotracheal intubation and skeletal muscle relaxation during surgery or mechanical ventilation. This activity reviews the indications, mechanism of action, and contraindications of atracurium, emphasizing its role in perioperative and critical care settings. Competitive inhibition of acetylcholine at nicotinic receptors underlies the pharmacologic effect, necessitating precise dosing and vigilant monitoring to optimize neuromuscular blockade while minimizing adverse effects.

Key considerations include dosing strategies, drug interactions, and adverse event management, with a focus on histamine release and potential cardiovascular effects. Discussing toxicity, metabolism, and elimination pathways highlights patient-specific factors influencing drug selection. The role of the interprofessional healthcare team in administering and monitoring atracurium ensures safe and effective use in clinical practice. This activity enhances understanding of atracurium’s pharmacologic profile, supporting informed decision-making in anesthesia and critical care management.

Objectives:

  • Identify the FDA-approved indications and off-label uses of atracurium.

  • Screen patients for potential contraindications of atracurium administration.

  • Determine the appropriate monitoring of patients receiving atracurium therapy.

  • Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from atracurium therapy.

Indications

FDA-Approved Indications

Atracurium facilitates endotracheal intubation by inducing neuromuscular blockade, ensuring optimal conditions for the endotracheal tube insertion. This medication is also employed within the ICU to provide skeletal muscle relaxation in mechanically ventilated patients, aiding in ventilation management. Additionally, atracurium is an adjunct to general anesthesia, enhancing the effects of anesthetic agents by providing adequate neuromuscular blockade during surgical procedures.[1][2][3][4][5]

Off-Label Uses

The atracurium-vecuronium combination significantly extends the duration of deep neuromuscular blockade during laparoscopic cholecystectomy, offering potential benefits in surgeries requiring prolonged muscle relaxation. Atracurium does not affect the onset of action, intubating conditions, or the reversal time, making it a viable option for optimizing neuromuscular management in these procedures. However, further research is required.[6] 

In traumatic brain injury (TBI), controlling intracranial pressure (ICP) is crucial, and the use of neuromuscular blocking agents (NMBAs) like atracurium may be beneficial in managing ICP surges during procedures. However, continuous NMBA infusion, including atracurium, may carry risks, such as prolonged elevated ICP and extracranial complications, warranting further research.[7] 

According to one study, atracurium is a safe and non-inferior alternative to cisatracurium for acute respiratory distress syndrome (ARDS). Atracurium also offers cost-effective benefits while providing similar efficacy.[8] A dose of 1 mg/kg of atracurium provides the most effective intubating conditions for rapid sequence induction of anesthesia, with a high success rate of intubation without coughing or bucking. This dose also significantly improves vocal cord and diaphragm paralysis compared to lower doses.[9] Magnesium, dexmedetomidine, and clonidine have been shown to reduce the required dose of neuromuscular blocking agents (NMBAs) in the perioperative setting without compromising safety or recovery. These adjuncts may offer a clinically relevant sparing effect, improving the efficiency of NMBA use during anesthesia, especially during the scarcity of NMBAs during the COVID-19 pandemic.[10] While muscle relaxation is typically reserved to facilitate endotracheal intubation, studies have shown the efficacy of atracurium to facilitate the placement of a laryngeal mask airway. One study showed that when compared to laryngeal mask airway (LMA) placement with only propofol, administration of atracurium led to greater jaw relaxation and faster insertion.[11][12]

Mechanism of Action

Atracurium is a non-depolarizing neuromuscular blocking drug of the benzylisoquinoline class. As a competitive antagonist of the α subunit of the postsynaptic nicotinic receptor at the neuromuscular junction, it competes with acetylcholine for binding sites. The binding of the postsynaptic nicotinic receptor by atracurium prevents depolarization of the motor endplate and subsequent skeletal muscle contraction. Unlike depolarizing agents, binding atracurium or other non-depolarizing agents does not induce a receptor conformational change.[13]

Pharmacokinetics

Absorption: Atracurium has an onset of action of approximately 2 minutes when an intubating dose is given. This medication is classified as an intermediate-acting, non-depolarizing muscle relaxant with a duration of action of approximately 40 to 45 minutes. The elimination half-life is approximately 20 minutes. In older patients, the half-life may increase by approximately 15% due primarily to decreased clearance.[14]

Distribution: The volume of distribution is approximately 160 mL/kg, and the plasma protein binding is 82%.

Metabolism: Non-enzymatic degradation (Hofmann elimination) accounts for 45% of the metabolism of atracurium. Hoffman elimination is a temperature and pH-dependent process slowed by acidosis and hypothermia.[15] The remainder is metabolized via ester hydrolysis by non-specific esterases in the plasma that are unrelated to pseudocholinesterase. A drop in pH enhances the rate of ester hydrolysis. Neuromuscular blocking agents of the benzylisoquinoline class are preferred in critically ill patients as their metabolism is unaffected by renal or hepatic dysfunction. A primary metabolite of Hofmann's elimination of atracurium is laudanosine, which has no neuromuscular blocking activity but acts as a central nervous system (CNS) stimulant. Studies have shown that long-term infusions of atracurium in critically ill patients can cause an elevation in laudanosine levels.

Elimination: Less than 5% of atracurium is excreted in the urine. Laudanosine is hepatically and renally eliminated and has a significantly longer elimination half-life than atracurium (197 minutes).[16] Therefore, it can potentially accumulate with prolonged atracurium infusion. Animal studies have shown that laudanosine crosses the blood-brain barrier and is detectable in the cerebral spinal fluid. Laudanosine, a metabolite of atracurium, is capable of crossing the blood-brain barrier, potentially leading to excitatory effects and seizure activity. In patients undergoing liver transplantation, elevated concentrations of laudanosine are observed, while renal failure further increases plasma levels and prolongs the mean elimination half-life. Laudanosine can cross the placental barrier during pregnancy, with a mean transplacental transfer of approximately 14%. While laudanosine-associated neurotoxicity is generally unlikely in short-term use, prolonged use of atracurium, particularly in intensive care settings, can increase the risk of seizures.[16]

Administration

Available Dosage Forms and Strengths

Intravenous atracurium should not be administered intramuscularly due to excessive tissue irritation. Atracurium can be given via bolus or infusion. Studies have demonstrated that continuous infusion is a viable option to achieve a steady state of neuromuscular blockade due to its relatively predictable and organ-independent metabolism. Atracurium besylate infusion solutions can be prepared by mixing the drug with compatible diluents, such as 5% dextrose injection, 0.9% sodium chloride injection, or a combination of 5% dextrose and 0.9% sodium chloride injection.

Adult Dosage

  • ED95 and intubation: Doses of 0.23 mg/kg and 0.5 mg/kg for adults and children older than 2, 0.3 to 0.4 mg/kg for children younger than 2. In morbidly obese patients, an atracurium dose should be administered based on ideal body weight.[17]
  • Initial dosing and recovery profile: The recommended initial dose of atracurium for nonemergency intubation is 0.4 to 0.5 mg/kg. This dose typically achieves adequate conditions for intubation within 2 to 2.5 minutes, with peak neuromuscular block occurring approximately 3 to 5 minutes post-injection. Under balanced anesthesia, the clinically effective neuromuscular blockade persists for 20 to 35 minutes. Recovery to 25% of baseline neuromuscular function is observed after 35 to 45 minutes, and full recovery (95%) is typically achieved within 60 minutes.
  • Adjusted dosing in the presence of anesthetic agents: In the presence of isoflurane or enflurane, which potentiates the effects of atracurium, the initial dose should be reduced by approximately one-third to account for enhanced neuromuscular blockade. Only minimal dose reduction may be necessary for halothane, which exerts a marginal potentiating effect (around 20%).
  • Maintenance dosing for prolonged procedures: Atracurium dosages of 0.08 to 0.10 mg/kg are recommended to maintain sustained neuromuscular blockade during extended surgical procedures. The first maintenance dose is typically required 20 to 45 minutes after the initial dose, with subsequent dosing intervals determined by clinical monitoring of neuromuscular function. Maintenance doses may be administered within 25 minutes under balanced anesthesia.
  • Cardiovascular disease or a history of asthma/anaphylactoid reactions: To minimize potential adverse effects, it is recommended that adults, children, or infants with significant cardiovascular conditions or a history suggesting a higher risk for histamine release (eg, severe allergic reactions, asthma) be administered a starting dose of 0.3 to 0.4 mg/kg of atracurium slowly or in divided doses over 1 minute.
  • Neuromuscular disease, electrolyte imbalances: Patients with conditions that may potentiate neuromuscular blockade or complicate reversal, such as neuromuscular disease, severe electrolyte disturbances, or carcinomatosis, may require careful dose adjustments. While there is limited clinical experience in these groups, no specific dosing guidelines are available.
  • Post-succinylcholine administration: Following succinylcholine administration for intubation under balanced anesthesia, an initial dose of 0.3 to 0.4 mg/kg of atracurium is recommended for adults. If potent inhalational anesthetics are used, further dose reductions may be needed. Atracurium should only be administered after the effects of succinylcholine have entirely worn off.
  • Continuous infusion in the operating room: For prolonged surgical procedures, atracurium can be administered by continuous infusion after an initial bolus dosage of 0.3 to 0.5 mg/kg. The infusion rate should be adjusted based on patient response, starting at 9 to 10 μg/kg/min to counteract spontaneous recovery from neuromuscular function. Maintenance rates of 5 to 9 μg/kg/min are generally adequate for most patients.
  • Cardiopulmonary bypass: In patients undergoing cardiopulmonary bypass with induced hypothermia (25 °C to 28 °C), the required infusion rate of atracurium is approximately half that required during normothermic conditions to maintain adequate muscle relaxation.
  • Use in the intensive care unit (ICU): The recommended continuous infusion rate for adult patients in ICU settings is between 11 and 13 μg/kg/min, ranging from 4.5 to 29.5 μg/kg/min. Pediatric ICU patients may require higher infusion rates. Dosing may vary over time, and frequent adjustments based on the clinical response are necessary. If a neuromuscular block is lost, a bolus dose may be required to quickly reestablish the block before continuing the infusion.

Specific Patient Populations

Hepatic impairment: No dosage adjustment is required.

Renal impairment: No dosage adjustment is required.

Pregnancy considerations: Atracurium is a favorable neuromuscular blocking agent for pregnant patients undergoing cesarean sections due to its minimal placental transfer, which reduces fetal exposure compared to other non-depolarizing muscle relaxants. However, the pharmacokinetics of non-depolarizing muscle relaxants may be altered in pregnancy, with increased drug permeability across the placenta in certain pathological conditions. While atracurium does not significantly affect mean arterial pressure, it may induce a notable bradycardic response in pregnant patients, necessitating careful cardiovascular monitoring during administration.[18] A systematic review shows no significant pharmacokinetic differences between pregnant and non-pregnant women in atracurium.[19]  

Pediatric patients: Atracurium dosages generally do not require adjustment for patients aged 2 and older. For infants aged 1 month to 2 years, the suggested starting dose of atracurium besylate is 0.3 to 0.4 mg/kg when used under halothane anesthesia. Safety and efficacy in patients younger than 1 month have not been verified.

Older patients: Older patients may exhibit slightly altered pharmacokinetics, including a modest decrease in total plasma clearance, which is compensated by an increase in the volume of distribution. These alterations do not significantly differ in the clinical duration or recovery from neuromuscular blockade compared to younger patients. However, caution is advised due to concomitant comorbidities and medications.

Adverse Effects

Most adverse reactions associated with atracurium administration are related to histamine release. Flushing and erythema are the most common adverse effects associated with histamine release related to atracurium administration. Less commonly, more severe adverse effects can occur, including bradycardia, bronchospasm, dyspnea, hypotension, laryngospasm, tachycardia, urticaria, and wheezing. Studies have previously demonstrated that a mean arterial pressure fall of 30 mm Hg can be seen within 2 minutes of administration. Histamine receptor type-1 and type-2 blocking agents have been used to attenuate this hypotensive response effectively. A slower injection speed (ie, 30 to 60 seconds) has also reduced histamine release and the associated adverse effects.[20][21] Atracurium-induced bronchospasm with a flat capnograph has been reported.[22]

Drug-Drug Interactions

  • Inhalational anesthetics: These volatile anesthetics (eg, enflurane, isoflurane, halothane) enhance the neuromuscular blocking action of atracurium, potentially leading to more profound and longer-lasting muscle relaxation. Careful monitoring is essential during anesthesia.

  • Aminoglycosides and polymyxins: Aminoglycosides like gentamicin and polymyxins can potentiate the effects of atracurium, impairing neuromuscular transmission and increasing the risk of prolonged paralysis.[23]

  • Lithium: Lithium may enhance the neuromuscular blocking effects of atracurium, leading to increased muscle weakness or prolonged neuromuscular blockade.

  • Magnesium: Magnesium can enhance the effects of atracurium by reducing neuromuscular transmission and increasing the intensity and duration of neuromuscular blockade.

  • Procainamide: Procainamide may potentiate the effects of atracurium by inhibiting neuromuscular transmission, which can lead to prolonged paralysis.

  • Quinidine: Quinidine can similarly enhance the neuromuscular blocking action of atracurium, increasing the risk of muscle weakness and prolonged paralysis.[24]

  • Succinylcholine (depolarizing muscle relaxant): According to product labeling, succinylcholine administration before atracurium does not extend the duration of the neuromuscular blockade but accelerates its onset and may increase its depth. Recovery from a succinylcholine-induced block is essential before administering atracurium.

  • Ringer lactate: Ringer lactate should not be used as a diluent, as atracurium degrades more rapidly in this solution than in a 0.9% sodium chloride solution.

Contraindications

The primary contraindication to administration is hypersensitivity to atracurium besylate or excipients.[25] Multiple-dose vials contain benzyl alcohol as a preservative; hypersensitivity to benzyl alcohol is a contraindication to administration. Documented cross-reactivity to neuromuscular blockade drugs is limited, but atracurium should be used cautiously in patients with previous anaphylactic reactions to other neuromuscular blocking agents.[26][27]

Warnings and Precautions

  • Risk of allergic reactions and cross-reactivity with other neuromuscular blocking agents: Atracurium may trigger allergic reactions (including anaphylaxis) in susceptible individuals, especially if the patient has had prior reactions to neuromuscular blocking agents. Cross-reactivity between different agents in this class increases the need for careful monitoring and patient history-taking before administration. The American College of Allergy, Asthma & Immunology has recommended 1 mg/mL for skin prick tests and 0.01 mg/mL for intradermal tests. Positive results may indicate a higher risk of IgE-mediated reactions upon re-exposure, guiding anesthesia drug selection and suggesting structurally unrelated alternatives if needed.[25]

  • Cardiovascular disease, asthma, or history of anaphylactoid reactions: Atracurium is less likely to release histamine than other agents. However, histamine release can still occur, particularly in patients with cardiovascular disease or a history of asthma and anaphylaxis. In these cases, a reduced dose of 0.3 to 0.4 mg/kg should be administered slowly to minimize adverse effects.

  • Risk of bradycardia: Unlike other neuromuscular blockers, atracurium does not counteract bradycardia induced by anesthesia or vagal stimulation. Therefore, patients may experience bradycardia during anesthesia, necessitating closer monitoring and possible intervention.

  • Myasthenia gravis, Lambert-Eaton myasthenic syndrome, or neuromuscular diseases: Patients with neuromuscular disorders, including myasthenia gravis and Lambert-Eaton myasthenic syndrome, are particularly sensitive to non-depolarizing muscle relaxants like atracurium.[28][29] Neuromuscular function must be closely monitored using a peripheral nerve stimulator to prevent overdose and adverse drug reactions.

  • Malignant hyperthermia: Although malignant hyperthermia (MH) is extremely rare when using atracurium, vigilance remains essential. MH has been primarily linked to halogenated anesthetics and succinylcholine, but clinicians should remain vigilant against this potentially fatal condition when administering anesthesia.

  • Resistance in burn patients: Burn patients may develop resistance to non-depolarizing neuromuscular blocking agents like atracurium, requiring higher doses. The exact dosing adjustments depend on the size of the burn and the time since the injury. Resistance to non-depolarizing neuromuscular blocking agents (NMBA) like rocuronium and atracurium has been associated with conditions such as denervation injury, infections, and metabolic disorders.[30]

  • Safety concerns in bronchial asthma: The safety of atracurium in patients with bronchial asthma has not been well established. Due to the potential for bronchospasm or histamine release, caution is required when administering atracurium to these individuals.

  • Long-term use in ICU patients: In ICU patients requiring prolonged mechanical ventilation, the dosing requirements for atracurium vary significantly between individuals. After prolonged use, spontaneous recovery of neuromuscular function can range from 15 to 75 minutes, necessitating close monitoring and individualized care.

  • Laudanosine and risk of seizures: Laudanosine, a metabolite of atracurium, has been linked to transient hypotension and, in higher doses, seizures in animal studies. While rare, ICU patients receiving long-term atracurium may experience seizures, particularly if they have predisposing conditions such as head trauma or uremia. Further research is required to identify risk factors and mitigate neurotoxicity.[31][32][33]

Monitoring

There are several methods to monitor neuromuscular blockade following administration of atracurium. Clinical signs are often used to attempt to determine the depth of neuromuscular blockade, as well as a reversal. These could include eye-opening, sustained handgrip, leg lift, or sustained head lift for longer than 5 seconds. Unfortunately, these are not accurate determinants of the presence or absence of residual neuromuscular blockade. Nerve stimulation is a method frequently used for monitoring neuromuscular blockade intraoperatively. ECG electrodes are applied at the ulnar, facial, or tibial nerve. Then, a "train-of-four" stimulation pattern is applied. Four stimuli are applied at the chosen nerve at a frequency of 2 Hz, provoking a twitch response. When atracurium or another non-depolarizing neuromuscular blocking agent is given, there is a reduction in the amplitude of the evoked responses; the final twitch of the train-of-four sequences (T4) is affected first, then the third (T3), followed by the second (T2), then the first (T1). This sequential decrease in twitch height is known as fade. Lack of response in 3 of 4 twitches indicates 90% to 95% blockade.

As the intensity of the neuromuscular blockade increases, the twitches begin to disappear in the same sequence as the fade occurs. As neuromuscular blockade is reversed, the reverse order is true, with T1 being the first to reappear. The ratio of twitch intensity when comparing T4 to T1 is a significant value; a ratio of 0.9 indicates sufficient neuromuscular blockade reversal.[34][35]

Toxicity

Signs and Symptoms of Overdose

In cases involving atracurium overdose, pharmacological effects are enhanced. Histamine release and cardiovascular effects, such as hypotension, may occur. In pediatric patients, unintentional doses up to 1 mg/kg (5 to 6 times the ED95) lead to delayed recovery (50 to 55 minutes), with minimal cardiovascular changes. In adults, a dose of 1.3 mg/kg results in a prolonged recovery time (83 minutes) and moderate hemodynamic effects, including increased mean arterial pressure and heart rate (13% and 27%, respectively), which persist for about 40 minutes but do not require specific intervention.

Management of Overdose

The primary focus in managing an atracurium overdose is ensuring proper airway and ventilation. Emergency medicine physicians maintain manual or mechanical ventilation when necessary. Peripheral nerve stimulation is used to monitor neuromuscular block recovery. Recovery can be enhanced with anticholinesterase agents like neostigmine, edrophonium, or pyridostigmine combined with anticholinergic drugs such as atropine or glycopyrrolate. If cardiovascular support is needed, fluids and vasopressors should be administered. Critical care physicians should closely monitor the patient's hemodynamic status and respiratory function. Due to the potential for prolonged recovery, intensive care support is provided until the patient stabilizes and fully recovers from the neuromuscular block. Lethal self-administration in healthcare providers remains a concern.[36]

Enhancing Healthcare Team Outcomes

Atracurium is a neuromuscular blocking agent commonly used in anesthesia. This medication is known to cause histamine release, which can lead to various adverse drug reactions. Anesthesiologists must determine the appropriate use and dosage of atracurium and communicate their plan to nurse anesthetists (CRNAs). Surgeons should ensure that the timing of atracurium administration aligns with the surgical procedure and maintain communication with the anesthesia team. Pharmacists can verify potential drug interactions and recommend dosage adjustments as needed. Nurses are responsible for monitoring the patient's condition and alerting the CRNA to complications. Nurses and residents should closely monitor patients in the medical intensive care unit (MICU), surgical intensive care unit (SICU), and post-anesthesia care unit (PACU). A large retrospective cohort study reveals significant provider variability in the use of neuromuscular blocking agents (NMBAs) during general anesthesia, with nurse anesthetists (CRNAs) adapting their practice more precisely to the preferences of individual surgeons. This highlights the importance of developing standardized guidelines to optimize NMBA use, improve patient safety, and enhance clinical outcomes through better interprofessional collaboration.[37] An evidence-based approach is essential to optimize treatment outcomes and minimize adverse effects. Effective interprofessional communication and coordination are crucial for excellent care from induction to recovery. An interprofessional team approach involving clinicians, pharmacists, and nurses is vital for reducing potential adverse effects and improving patient outcomes related to atracurium.


Details

Editor:

Armen Derian

Updated:

2/6/2025 1:48:31 AM

References


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