Atracurium Besylate

[Section Outline]

Administration
Dosage
Dosage in Renal Impairment
Reversal of Neuromuscular Blockade

Administration

Atracurium besylate is administered IV.1 The initial intubating dose is administered by rapid IV injection;1,2 maintenance doses may be administered by intermittent IV injection or by continuous IV infusion.1,3,57,60,90,118,119 Atracurium should not be administered by IM injection since there are no clinical data to support this route of administration and tissue irritation may result.1,2

For continuous IV infusion, atracurium besylate injection should be diluted to the desired concentration (usually 0.2 or 0.5 mg/mL) in 5% dextrose, 5% dextrose and 0.9% sodium chloride, or 0.9% sodium chloride injection.1 Infusion solutions should be used within 24 hours following dilution.1 Use of a controlled-infusion device is recommended to ensure precise control of flow rate during continuous IV infusion of the drug.1,359

Atracurium should not be mixed in the same syringe nor administered simultaneously through the same needle as an alkaline solution (e.g., barbiturate solution).1 (See Chemistry and Stability: Stability.)

Atracurium besylate injection and diluted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1

Dispensing and Administration Precautions

Neuromuscular blocking agents should be administered only by individuals who are adequately trained in their use and complications.1,359 For specific procedures and techniques of administration, specialized references should be consulted. Facilities and personnel necessary for intubation, administration of oxygen, and respiratory support should be immediately available whenever these drugs are used.1,359,424 In addition, a reversal agent should be readily available in the event of a failed intubation or to accelerate neuromuscular recovery after surgery.1,359,421 (See Dosage and Administration: Reversal of Neuromuscular Blockade.)

Because neuromuscular blocking agents can cause respiratory arrest, precautions (e.g., storage segregation, warning labels, access limitations) should be taken to ensure that these drugs are not administered without adequate respiratory support.425 Affixing warning labels to storage containers and final administration containers is recommended to clearly communicate that respiratory paralysis can occur and ventilator support is required.425 The Institute for Safe Medication Practices (ISMP) recommends the following wording for these containers: “Warning: Paralyzing agent—causes respiratory arrest—patient must be ventilated.”425

Neuromuscular blocking agents have no known effect on consciousness, pain, or cerebration, and should therefore be used in conjunction with adequate levels of anesthesia, and only after appropriate analgesics and sedatives are administered.1,359,421,423 To avoid distress to the patient, atracurium should be administered only after unconsciousness has been induced.1,2,421,424

Dosage

Dosage of atracurium must be carefully adjusted according to individual requirements and response.1 The use of a peripheral nerve stimulator is recommended to accurately monitor the degree of neuromuscular blockade and recovery, determine the need for additional doses, and minimize the possibility of overdosage.1,421

The possible need for substantially increased doses of atracurium in burn patients should be considered.1,143,144,145,146,147 (See Cautions: Precautions and Contraindications.)

Initial Dose

The usual initial (intubating) adult dose of atracurium besylate is 0.4-0.5 mg/kg (1.7-2.2 times the dose necessary to induce 95% neuromuscular blockade).1,2 Following administration of this initial dose, endotracheal intubation for nonemergency surgical procedures can be performed within 2-2.5 minutes in most patients and maximum neuromuscular blockade generally occurs within 3-5 minutes.1,2 When used concomitantly with balanced anesthesia, this initial dose usually results in clinically sufficient neuromuscular blockade for about 20-35 minutes; spontaneous recovery to about 25% of baseline generally occurs within 35-45 minutes and is usually 95% complete 1 hour after administration.1,86

When used concomitantly with general anesthetics that potentiate its neuromuscular blocking activity (e.g., enflurane, isoflurane), dosage of atracurium besylate may need to be reduced.1 The manufacturers recommend that the initial adult dose of atracurium besylate be reduced by about 33% (i.e., to 0.25-0.35 mg/kg) when the drug is administered after steady-state anesthesia with enflurane or isoflurane has been achieved.1,2,37 A smaller reduction in the initial dose (e.g., about 20%) may be considered in patients in whom steady-state anesthesia has been induced with halothane, since halothane has only a minimal effect on the neuromuscular blocking activity of atracurium; in some patients receiving halothane, a reduction in atracurium besylate dosage may not be necessary.1,2,86

When used following succinylcholine, atracurium besylate should be administered at a reduced initial dose but not until the patient has recovered from the neuromuscular blockade induced by succinylcholine.1,2 Following use of succinylcholine for endotracheal intubation under balanced anesthesia, an initial atracurium besylate dose of 0.3-0.4 mg/kg is recommended for adults; a further reduction in this initial dose (e.g., to 0.2-0.3 mg/kg) may be desirable when inhalation anesthetics are also administered concomitantly.1,2,86 Insufficient data currently are available for recommendation of a specific initial dose of atracurium besylate in infants and children following the use of succinylcholine.1

The initial dose of atracurium besylate also should be reduced in patients in whom substantial histamine release would be potentially hazardous (e.g., patients with clinically important cardiovascular disease) and in patients with any history suggesting increased risk of histamine release (e.g., history of severe anaphylactoid reactions or asthma).1,2 An initial adult or pediatric dose of 0.3-0.4 mg/kg administered slowly or in fractional doses over 1 minute is recommended by the manufacturers for these patients.1,2 Although the manufacturer states that a reduction in dosage must also be considered for patients with conditions in which potentiation of neuromuscular blockade or difficulties with reversal of blockade have been demonstrated (e.g., neuromuscular diseases, severe electrolyte disturbances, carcinomatosis) (see Cautions: Precautions and Contraindications), there has been essentially no clinical experience to date with atracurium in these patients and no specific doses are recommended .1,2 Reports on the use of atracurium in several patients with myasthenia gravis suggest that the drug can be used safely and effectively in low doses and with careful monitoring in well-controlled patients whose usual therapy is continued up to the time of surgery.114,115,116,130

Maintenance Dosage

Intermittent IV Injection

For maintenance of neuromuscular blockade during prolonged surgical procedures in adults, additional atracurium besylate doses of 0.08-0.1 mg/kg may be administered by intermittent IV injection as necessary.1,2 In patients undergoing balanced anesthesia, the first maintenance dose of atracurium besylate generally is necessary 20-45 minutes after administration of the initial dose.1,2 Because the drug lacks cumulative effects at usual doses, the manufacturer states that repeated maintenance doses of atracurium besylate may be administered at relatively regular intervals, generally ranging from 15-25 minutes in patients undergoing balanced anesthesia.1,2 When enflurane or isoflurane is used for anesthesia or when higher maintenance doses of atracurium besylate (i.e., up to 0.2 mg/kg) are used, it may be possible to administer maintenance doses of atracurium besylate at longer intervals.1,2

Continuous IV Infusion During Prolonged Surgical Procedures

After the initial intubating dose is administered, patients may receive a continuous IV infusion of atracurium to maintain neuromuscular blockade for prolonged surgical procedures.1,3,57,60,79,90,118,119 The infusion should be initiated only after early spontaneous recovery from the initial IV dose is evident.1 Infusion rates should be individualized and adjusted based on patient response to peripheral nerve stimulation.1 An initial atracurium besylate infusion rate of 9-10 mcg/kg per minute may be necessary to rapidly counteract spontaneous recovery from neuromuscular blockade.1,3,57,118 A maintenance infusion rate of 5-9 mcg/kg per minute usually is adequate to maintain continuous neuromuscular blockade in the range of 89-99% of baseline in most patients receiving balanced anesthesia; however, adequate blockade may occur with infusion rates as slow as 2 mcg/kg per minute while some patients may require as much as 15 mcg/kg per minute.1 The rate of spontaneous recovery from atracurium-induced neuromuscular blockade following discontinuance of the infusion is likely to be comparable to that following administration of a single IV injection of the drug.1

A reduction in the infusion rate of atracurium besylate by about 33% may be required when the drug is administered in the presence of steady-state anesthesia with enflurane or isoflurane; a smaller reduction in the infusion rate may be considered in the presence of steady-state anesthesia with halothane.1 In patients undergoing cardiopulmonary bypass with induced hypothermia, the infusion rate of atracurium besylate required to maintain adequate surgical relaxation during hypothermia (i.e., 25-28°C) usually is approximately 50% of the infusion rate of the drug necessary in normothermic patients.1,57,79

Continuous IV Infusion in the Intensive Care Unit (ICU)

Atracurium may be administered by continuous IV infusion for maintenance of neuromuscular blockade during mechanical ventilation in the ICU.1 The degree of neuromuscular blockade should be monitored with a peripheral nerve stimulator; additional doses should not be given before there is a definite response to nerve stimulation.1

In clinical studies, average atracurium besylate infusion rates of 11-13 mcg/kg per minute were required to achieve adequate neuromuscular blockade in mechanically ventilated adults in the ICU; however, dosage requirements may vary widely among patients and also may increase or decrease over time.1 Following discontinuance of the infusion, spontaneous recovery to a train-of-four (TOF) ratio of greater than 75% generally occurred within approximately 60 minutes.1 If reinstitution of the infusion is necessary following recovery from neuromuscular blockade, administration of a direct IV (“bolus”) dose of atracurium may be necessary to reestablish neuromuscular blockade.1

Pediatric Dosage

Recommendations for initial and maintenance doses and for continuous IV infusion rates of atracurium besylate in children 2 years of age or older are the same as those for adults.1,2 (See Initial Dose and Maintenance Dosage under Dosage and Administration: Dosage.) The manufacturers recommend that children 1 month to 2 years of age who are under halothane anesthesia receive an initial atracurium besylate dose of 0.3-0.4 mg/kg.1 More frequent administration of maintenance doses may be necessary in infants and children than in adults.1,2 For doses of atracurium besylate reported to induce 50% or 95% neuromuscular blockade in children of different ages, see Pharmacology: Neuromuscular Blockade.

Dosage in Renal Impairment

The manufacturers state that it is not necessary to adjust atracurium dosage in patients with renal impairment.1,2

Reversal of Neuromuscular Blockade

Neuromuscular blockade induced by atracurium can be reversed by administering a cholinesterase inhibitor (e.g., neostigmine, pyridostigmine, edrophonium) in conjunction with an anticholinergic agent such as atropine or glycopyrrolate to block the adverse muscarinic effects of the cholinesterase inhibitor.1,9,16,17,18,19,21,23,24,26 For specific information on the uses and dosage and administration of these other drugs, see the individual monographs .

To minimize the risk of residual neuromuscular blockade, reversal should only be attempted after some degree of spontaneous recovery has occurred; patients should be closely monitored until adequate recovery of normal neuromuscular function is assured (i.e., ability to maintain satisfactory ventilation and a patent airway).1,355,356,357,358,421 Under balanced anesthesia, reversal of atracurium-induced neuromuscular blockade generally can be attempted about 20-35 minutes after administration of the initial dose or 10-30 minutes after administration of the last maintenance dose of atracurium, when recovery of muscle twitch has started.1 Complete reversal of neuromuscular blockade is generally achieved within 8-10 minutes after administration of the cholinesterase inhibitor.1

Cautions ⬆ ⬇

[Section Outline]

Adverse Effects
Precautions and Contraindications
Pediatric Precautions
Mutagenicity and Carcinogenicity
Pregnancy, Fertility, and Lactation

Adverse Effects

Adverse effects of atracurium besylate are generally mild, reportedly occur in 5% or less of patients following IV administration, and are mainly suggestive of histamine release.1,2,3,17,31,68 The manufacturer states that most adverse reactions are clinically unimportant unless associated with substantial hemodynamic changes; clinically important adverse effects reportedly occur in 0.8% of patients receiving the drug.1

Skin flush,1,2,5,9,20,31,34,41 erythema,1,2 pruritus,1,2 and urticaria,1,2 which are characteristic manifestations of cutaneous histamine release, reportedly occur in about 5, 0.6, 0.2, and 0.1% of patients, respectively, receiving atracurium.1,2 Erythema, pruritus, and urticaria have generally occurred more frequently at doses of 0.3 mg/kg or less than at higher doses.1,2 The frequency of skin flush is increased with increasing doses of the drug, reportedly occurring in about 30% of patients receiving an initial dose of 0.6 mg/kg or more.1,2 Wheals and erythema have developed occasionally at the injection site following administration of atracurium.1,17,36,68

Wheezing1,2,17 and increased bronchial secretions1,2 have been reported in about 0.2% of patients following administration of atracurium;1,2 discontinuance of the drug and initiation of appropriate therapy are rarely necessary in patients who develop increased bronchial secretions or wheezing.1,2,3 Other respiratory effects that have been reported with atracurium include bronchospasm,1,2,36 dyspnea, and laryngospasm.1,2 Angioedema has reportedly occurred in at least one patient.113

Allergic reactions, including anaphylactic or anaphylactoid reactions, have occurred in patients receiving atracurium; severe allergic reactions (e.g., resulting in cardiac arrest) have been reported rarely.1

Cardiovascular effects, including changes in heart rate,1,4,9,12,13,14,31,36,41,67 mean arterial pressure,1,9,11,12,13,14,20,31 diastolic arterial pressure,20 systemic vascular resistance,20,76 cardiac index,14,67 and cardiac output,20 have been observed occasionally following administration of atracurium; however, these effects appear to be minimal and transient.1,3,32 Some cardiovascular effects may be associated with endotracheal intubation rather than with the drug.18,68,91 In patients with no history of cardiovascular disease who were assessed in clinical studies for changes in vital signs of 30% or more from baseline values, changes in mean arterial blood pressure generally occurred more frequently as the dose of the drug was increased;1,2,3 mean arterial pressure increased or decreased by 30% or more in 2.1 or 1.9% of patients, respectively.1,2,3 In these patients, an increase in heart rate of 30% or more from baseline values occurred in 2.1% of patients receiving the drug and was more frequent with increasing dose;1,2,3 however, a decrease in heart rate of 30% or more from baseline occurred in 0.6% of patients receiving the drug and was more frequent at doses of 0.3 mg/kg or less than at higher doses.1,2,3 Although severe bradycardia (rates of 20-30 beats/minute) that was successfully treated with atropine has been reported in several patients following administration of 0.52-0.75 mg/kg of atracurium besylate,69,71,72 a causal relationship to the drug has been questioned and bradycardia may have been related to surgical manipulation or other concomitantly administered drugs.70,73,74,75 In a few patients, especially those with a history of cardiovascular disease, hypotension has been severe enough to require treatment.1,2 Cardiac arrest has been reported rarely in patients receiving atracurium.1

Although a causal relationship to atracurium or its metabolite laudanosine has not been established, seizures have been reported rarely in patients receiving continuous IV infusions of atracurium for facilitation of mechanical ventilation in intensive-care settings.1 These patients usually had predisposing factors (e.g., head trauma, cerebral edema, hypoxic encephalopathy, viral encephalitis, uremia).1 In animals receiving laudanosine (a metabolite of atracurium), cerebral excitatory effects (e.g., generalized muscle twitching, seizures) were reported.1

Serious hypersensitivity reactions, including anaphylaxis, have been reported rarely with all neuromuscular blocking agents; such reactions have been life-threatening or fatal in some cases.1,422

Precautions and Contraindications

Atracurium shares the toxic potentials of the nondepolarizing neuromuscular blocking agents, and the usual precautions of neuromuscular blocking agent administration should be observed.2 (See Cautions in the Neuromuscular Blocking Agents General Statement 12:20.20.)

When used inappropriately, neuromuscular blocking agents can severely compromise respiratory function and induce respiratory paralysis.1,80,81,82,83,86 Special precautions should be taken during and after administration of these drugs.1 (See Dispensing and Administration Precautions under Dosage and Administration: Administration.) The degree of neuromuscular blockade produced by atracurium should be monitored with a peripheral nerve stimulator, particularly in patients with conditions that may potentiate (e.g., neuromuscular diseases) or cause resistance to (e.g., burns) the neuromuscular blocking effects of the drug.1

Resistance to nondepolarizing neuromuscular blocking agents,146,149,150,151,152,153,154,155,156,157,158 including atracurium,1,143,144,145,147,148 can develop in burn patients. The magnitude of resistance depends on the extent of thermal injury and elapsed time since the burn.1,143,144,145,146,147,148,149 (see Initial Dose in Dosage and Administration: Dosage) The possibility of increased dosage requirements of atracurium in burn patients should be considered.1,143,144,145,146,147 (See Cautions: Precautions and Contraindications, in the Neuromuscular Blocking Agents General Statement 12:20.20.)

Although atracurium is a less potent stimulator of histamine release than metocurine iodide or tubocurarine chloride (both no longer commercially available in the US),1,3,11,13 the possibility of substantial histamine release must be considered.1,2 (See Pharmacology: Effects on Histamine.) Atracurium should be used with caution and at lower initial doses in patients in whom substantial histamine release would be particularly hazardous (e.g., patients with clinically important cardiovascular disease) and in patients with any history suggesting a greater risk of histamine release (e.g., a history of severe anaphylactoid reactions or asthma).1,2 The safety of atracurium in patients with asthma has not been established.1

Although limited evidence from studies and experience in malignant hyperthermia-susceptible animals (swine) and patients failed to reveal evidence of a potential for atracurium-induced precipitation of this reaction,1,77,136,138,140,142 malignant hyperthermia has been associated rarely with atracurium use.1,137,139,141 At least several such patients, however, were receiving a halogenated anesthetic agent (e.g., halothane) concomitantly,137,139 which commonly is associated with this reaction.1,137,139 Because malignant hyperthermia can occur even in the absence of a recognized precipitating factor, clinicians should be vigilant for its possible development and prepared for its management in any patient undergoing general anesthesia.1,141 (See Cautions: Adverse Effects, in the Neuromuscular Blocking Agents General Statement 12:20.20.)

Since atracurium exhibits minimal effects on heart rate,4,9,12,13,14,31,36,41,67 especially at recommended doses, the drug will not counteract the bradycardia induced by many anesthetic agents or by vagal stimulation;1,2 as a result, bradycardia may be more common when atracurium is used concomitantly during anesthesia with agents that may cause bradycardia than when certain other neuromuscular blocking agents are used concomitantly.1,2,91

Patients with neuromuscular diseases (e.g., myasthenia gravis, Eaton-Lambert syndrome) may have an exaggerated response to atracurium.1,2,86,114,115,116 In such patients, the degree of neuromuscular blockade should be monitored with a peripheral nerve stimulator.1,2,114,115,116 The degree of neuromuscular blockade produced by atracurium also should be monitored with a peripheral nerve stimulator in patients with severe electrolyte disturbances (i.e., hypermagnesemia, hypokalemia, hypocalcemia) or carcinomatosis.1,2,86 For other conditions associated with increased response to neuromuscular blocking agents, see Cautions: Precautions and Contraindications, in the Neuromuscular Blocking Agents General Statement 12:20.20 .

Long-term use of neuromuscular blocking agents to support mechanical ventilation in the intensive care unit (ICU) has been associated with prolonged paralysis and/or skeletal muscle weakness.341 The risks versus benefits of neuromuscular blockade should be considered whenever there is a need for long-term mechanical ventilation.1 Continuous monitoring of neuromuscular transmission with a peripheral nerve stimulator is recommended whenever atracurium is used in the ICU.1 Additional doses of atracurium or any other neuromuscular blocking agent should not be administered before there is a definite response to nerve stimulation tests.1 If no response is elicited, administration of the drug should be discontinued until a response returns.1

Since neuromuscular blocking agents have been reported to cause severe anaphylactic reactions, appropriate emergency treatment should be readily available whenever these drugs are administered.1 Atracurium is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation (e.g., benzyl alcohol in multiple-dose vials).1 Because of the possibility of cross-sensitivity, atracurium should be used with caution in patients who have experienced previous anaphylactic reactions to other neuromuscular blocking agents (depolarizing or nondepolarizing).1

Pediatric Precautions

Safety and efficacy of atracurium in children younger than one month of age have not been established.1 However, the drug has been used effectively and without unusual adverse effects to produce adequate neuromuscular blockade in children 1 month of age or older who were undergoing surgery.7,88,92

Each mL of atracurium besylate injection in multiple-dose vials contains 9 mg of benzyl alcohol as a preservative.1 Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.1,161,162,163,164,165,166 Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates.161,162,163,164,165,166 Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible,161,163 the American Academy of Pediatrics states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when indicated in neonates.161

Mutagenicity and Carcinogenicity

Atracurium did not exhibit mutagenic activity in the Ames microbial mutagen test, with or without metabolic activation, at concentrations up to 1 mg/plate,1,77 nor in a rat bone marrow cytogenetics assay;86 however, mutagenic activity was observed in the mouse lymphoma assay under experimental conditions which killed over 80% of the treated cells.86 The clinical importance of the positive mutagenic test result is not known; because the drug is administered for brief periods and in limited doses, this finding is probably of questionable clinical relevance.86

Studies have not been performed to date to determine the carcinogenic potential of atracurium.1

Pregnancy, Fertility, and Lactation

Pregnancy

It is not known whether administration of neuromuscular blocking agents during vaginal delivery has immediate or delayed adverse effects on the fetus or whether it increases the likelihood that resuscitation of the neonate will be necessary.1 Atracurium should be used with caution and dosage reduced as necessary in pregnant women receiving magnesium sulfate during delivery, since the neuromuscular blockade may be potentiated and its reversal impeded.1,126,127 When atracurium was administered to pregnant women during delivery by cesarean section, no adverse effects attributed to the drug were observed in neonates born to these women;1,61,63,107 however, the drug was shown to cross the placenta, and the possibility of respiratory depression in neonates should be considered following cesarean section in which a neuromuscular blocking agent is administered to the mother.1 There are no adequate and controlled studies to date using atracurium in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1

Atracurium besylate has been shown to be potentially teratogenic in rabbits when administered subcutaneously at dosages of 0.15 mg/kg daily or 0.1 mg/kg twice daily on days 6 through 18 of gestation.1 Death secondary to respiratory depression occurred in a few animals.1 Transient respiratory depression, spontaneously occurring visceral and skeletal anomalies or variations, and increased postimplantation losses also were observed.1 Following IV administration of a 0.6-mg/kg dose of atracurium besylate in pregnant cats 1-3 days before term, no effect on fetal respiration was observed at any time up to full recovery of spontaneous maternal respiration;77 a 0.6-mg/kg dose of the drug administered IV or by intraperitoneal injection to several fetuses did not appear to depress respiration.77

Fertility

It is not known if atracurium affects fertility in humans.1

Lactation

Since it is not known if atracurium is distributed into milk, the drug should be administered with caution to nursing women.1

Drug Interactions ⬆ ⬇

[Section Outline]

General Anesthetics
Skeletal Muscle Relaxants
Anti-infective Agents

Concurrent administration of some drugs, including general anesthetics (e.g., enflurane, isoflurane, halothane), antibiotics (e.g., aminoglycosides, polymyxins), lithium, skeletal muscle relaxants (e.g., succinylcholine, pancuronium), magnesium salts, procainamide, and quinidine, may affect the neuromuscular blocking activity of atracurium besylate.1,2 For additional information on potential drug interactions of atracurium, see Drug Interactions in the Neuromuscular Blocking Agents General Statement 12:20.20 .

General Anesthetics

Enflurane1,36,37 and isoflurane1,33,35 reportedly increase the potency and prolong the duration of the neuromuscular blockade induced by atracurium by about 35-50%;1,35 halothane appears to have only a marginal effect on the potency and duration of neuromuscular blockade induced by atracurium, prolonging the duration by about 20%.1,10,24,31

Skeletal Muscle Relaxants

The effects of administering succinylcholine prior to atracurium on atracurium-induced neuromuscular blockade have not been fully elucidated and are reportedly variable.78,117 Administration of succinylcholine prior to atracurium may decrease the time to maximum neuromuscular blockade by approximately 2-3 minutes and may increase the intensity of the block but does not appear to affect the duration of neuromuscular blockade induced by atracurium.1,78,117 In one study, the duration of neuromuscular blockade to 95% recovery was similar in patients receiving atracurium alone or following succinylcholine.78 In this study, a 1-mg/kg dose of succinylcholine followed 35 minutes later after complete recovery from the succinylcholine blockade by a 0.15-mg/kg dose of atracurium besylate resulted in an 84% neuromuscular blockade compared with a 52% blockade when atracurium was administered alone.78 Data from another study suggest that administration of atracurium during completed neuromuscular blockade by succinylcholine may result in a delayed onset and reduced intensity of atracurium-induced neuromuscular blockade.117 The manufacturer recommends that atracurium besylate be administered in reduced dosage (i.e., 0.2-0.4 mg/kg) and only after the patient recovers completely from succinylcholine-induced neuromuscular blockade.1

The manufacturers state that if other skeletal muscle relaxants are used during surgical procedures in which atracurium is administered, the possibility of a synergistic or antagonistic effect should be considered.1 (See Pharmacology in the Neuromuscular Blocking Agents General Statement 12:20.20.)

Anti-infective Agents

The possibility that some anti-infective agents (e.g., aminoglycosides, polymyxins) may increase or prolong skeletal muscle relaxation produced by atracurium should be considered.1 (See Drug Interactions: Anti-infective Agents, in the Neuromuscular Blocking Agents General Statement 12:20.20.) In one study, however, atracurium-induced neuromuscular blockade was not affected substantially by therapeutic plasma concentrations of gentamicin or tobramycin.159

Other Information ⬆ ⬇

[Section Outline]

Manifestations
Treatment
Neuromuscular Blockade
Effects on Histamine
Other Effects
Absorption
Distribution
Elimination
Chemistry
Stability

Acute Toxicity

There is limited experience to date with inadvertent overdosage following parenteral administration of atracurium besylate.1 The possibility of overdosage can be minimized by assessing the atracurium-induced effect on the response to peripheral nerve stimulation.1 (See Pharmacology: Neuromuscular Blockade.)

Manifestations

Overdosage of atracurium is likely to produce symptoms that are mainly extensions of the usual pharmacologic effects of the drug.1,86 The likelihood of stimulation of histamine release and adverse cardiovascular effects, especially hypotension, may be increased following acute overdose of the drug.1 The duration of neuromuscular blockade produced by an overdose of atracurium may be longer than that following usual doses,1,86 and a peripheral nerve stimulator should be used to monitor recovery from blockade.1 In a few children 3 weeks to 5 months of age who inadvertently received 0.8-1 mg/kg of the drug, the duration of blockade was prolonged and cardiovascular changes were minimal.1,86 In one adult 17 years of age who inadvertently received 1.3 mg/kg, the duration of blockade was prolonged and moderate hemodynamic changes (increases in mean arterial pressure and heart rate), which persisted about 40 minutes and required no treatment, occurred.1,86 In this patient, the time to 25% recovery from neuromuscular blockade was approximately twice as long as that usually occurring after administration of maximum recommended adult doses.1

Treatment

In atracurium overdosage, supportive and symptomatic treatment should be initiated.1 An adequate, patent airway should be maintained, using assisted or controlled respiration as necessary.1 If cardiovascular support is necessary, treatment should include proper patient positioning, fluid administration, and, if necessary, use of vasopressors.1 Reversal of the neuromuscular blockade produced by atracurium may be achieved by administration of a cholinesterase inhibitor such as neostigmine, pyridostigmine, or edrophonium.1,9,16,17,18,19,21,23,24,26 (See Dosage and Administration: Reversal of Neuromuscular Blockade.)

Pharmacology

Neuromuscular Blockade

Atracurium besylate is a nondepolarizing neuromuscular blocking agent that produces pharmacologic effects similar to those of other nondepolarizing neuromuscular blocking agents.1,2,22,23,24,26,31,56,80,81,82,83,93 (See Pharmacology in the Neuromuscular Blocking Agents General Statement 12:20.20.) On a weight basis, atracurium besylate is about 20-25% as potent as vecuronium bromide28,98 and 25-33% as potent as pancuronium bromide.9,22,97,98,99 The duration of neuromuscular blockade induced by initially equipotent doses of atracurium besylate is about 33-50% that induced by metocurine iodide (no longer commercially available in the US), pancuronium bromide, or tubocurarine chloride (no longer commercially available in the US),1,9,22,26,31,87 but similar to or slightly longer than that induced by vecuronium bromide.17,22,28,87,96,97 The neuromuscular blocking activity of atracurium is enhanced in the presence of some inhalation general anesthetics (e.g., enflurane, isoflurane).1,33,35,36,37 (See Drug Interactions: General Anesthetics.)

The degree of neuromuscular blockade and muscle paralysis induced by atracurium may be assessed by monitoring response to fast (tetanic) and slow (twitch) electrical nerve stimulation of the adductor pollicis muscles.1,15,44 As with other competitive neuromuscular blocking agents, the tetanic response is more sensitive to blockade by atracurium than is the twitch response.15 Regardless of dose, the maximum block of the tetanic response induced by atracurium has a more rapid onset than that of the twitch response; however, the duration of maximum block of the tetanic response is substantially longer than that of the twitch response after 0.2- or 0.3-mg/kg doses of the drug but not after 0.6- or 0.9-mg/kg doses.15,44 Once recovery from neuromuscular blockade begins, there does not appear to be a substantial difference in the time needed to reach 95% recovery of the tetanic response compared with that of the twitch response.15,44

In adults, patient age does not appear to affect the dose of atracurium besylate necessary to achieve and maintain steady-state neuromuscular blockade nor does it appear to affect the rate of recovery from neuromuscular blockade and muscle paralysis.3,60 Young and small children may generally require larger doses of neuromuscular blocking agents than adolescents and adults, when calculated on a weight basis, to achieve the same degree of neuromuscular blockade during comparable techniques of anesthesia;23,41 however, it has not been established whether such a relationship exists with atracurium besylate.5,22,85,88,91,92 Some clinicians report that the ED₉₅ (dose required to produce 95% suppression of the control twitch response) of atracurium besylate is greater in children 2-10 than in those 11-17 years of age when calculated on a weight basis, but is similar in these age groups when calculated on the basis of body surface area.22,41 Other clinicians report that the ED₉₅ is similar in children 4 weeks of age and older when calculated on a weight basis5,92 but lower in children 4 weeks to 1 year of age when calculated on the basis of body surface area.92 Additional study is needed to determine whether weight- or body surface area-adjusted differences in dose response to atracurium besylate exist in children of different ages and to determine the clinical importance of these potential differences.5,22,85,88,91,92

The ED₅₀ (dose required to produce 50% suppression of the control twitch response) of atracurium besylate has reportedly averaged 0.083-0.17 mg/kg in patients undergoing balanced anesthesia6,28,29,30,33,35,100,122 and 0.068-0.116 mg/kg in patients undergoing enflurane or isoflurane anesthesia.6,33,35,37,100,121 The manufacturers state that the ED₉₅ of the drug in patients undergoing balanced anesthesia averages 0.23 mg/kg;1 in multiple studies, the ED₉₅has reportedly averaged 0.12-0.35 mg/kg in patients undergoing balanced anesthesia6,9,22,33,35,37,100,121,122 and 0.10-0.28 mg/kg in patients undergoing enflurane or isoflurane anesthesia.6,33,35,37,100,121

The ED₅₀ in children 1 month to 1 year, 2-10 years, and 11-17 years of age undergoing balanced or halothane anesthesia reportedly averages 0.085-0.12,7,21,88,92 0.11-0.17,5,21,33,41,92 and 0.101-0.13 mg/kg,5,38,41,92 respectively; the ED₉₅ in these children reportedly averages 0.156-0.18,7,21,88,92 0.17-0.354,5,21,33,41,92 and 0.154-0.18 mg/kg,5,38,41,92 respectively. Based on body surface area, the ED₅₀ and ED₉₅ in children 1-6 months of age undergoing halothane anesthesia have reportedly averaged 1.6 and 3.33 mg/m², respectively;7,88 based on body surface area, the ED₅₀ and ED₉₅ in children 2-10 years of age undergoing halothane anesthesia have reportedly averaged 3.26641 and 4.7-6.628 mg/m²,41,92 respectively.

Animal studies have shown that metabolic or respiratory acidosis increases the intensity of and prolongs the recovery from neuromuscular blockade induced by atracurium;3 similarly, metabolic or respiratory alkalosis substantially reduces the intensity of neuromuscular blockade and enhances recovery.3,56 However, in one study in patients with respiratory acidosis or alkalosis and arterial pH values ranging from 7.25-7.56, the rate of recovery from atracurium-induced neuromuscular blockade did not appear to be substantially affected.3,24 In addition, the magnitude of pH change required to substantially affect atracurium-induced neuromuscular blockade would not be compatible with sustained life, and, if such fluctuations in pH did occur, immediate measures to correct the pH would be necessary.3 The usual extremes of clinical changes in pH seen in humans do not substantially affect the metabolic breakdown of atracurium.3 (See Pharmacokinetics: Elimination.)

The neuromuscular blocking activity of atracurium also appears to be affected by changes in temperature.3,57,79 (See Pharmacokinetics: Elimination.)

Effects on Histamine

Atracurium can stimulate the release of histamine release, but to a lesser extent than some older neuromuscular blocking agents (tubocurarine chloride and metocurine iodide).1,3,13 Histamine release is generally minimal with initial doses of atracurium besylate up to 0.5 mg/kg;1,10,17 however, the drug appears to stimulate the release of substantial amounts of histamine at doses greater than 0.5 mg/kg.1,3,11,13,15,97 Although attempts have been made to determine whether a correlation exists between the release of histamine and a decrease in blood pressure,1,3,13 administration of a 0.6-mg/kg dose of the drug elicited moderate histamine release and a substantial hypotensive effect but these responses were poorly correlated; in addition, these effects appeared to be transient and easily managed.1

Other Effects

Data from one study indicate that a usual dose (i.e., 0.45 mg/kg) of atracurium besylate does not appear to affect intraocular pressure in patients undergoing surgical treatment for ophthalmic trauma.101 Studies in animals and preliminary studies in humans suggest that atracurium does not affect intracranial pressure.123,124,125 Data from one study in patients anesthetized with halothane and nitrous oxide indicate that atracurium has little effect on lower esophageal sphincter pressure or barrier pressure.102

Unlike most other nondepolarizing neuromuscular blocking agents, atracurium exhibits minimal cardiovascular effects.2,5,6,7,8,9,12,13,14,15,20,22,24,25,26,27,28,88,93 The drug does not appear to substantially affect heart rate or rhythm, mean arterial pressure, systemic vascular resistance, cardiac output, or central venous pressure.2,5,6,7,8,9,12,13,14,15,20,21,22,24,25,26,27,88 However, atracurium may indirectly elicit cardiovascular effects (e.g., decreased peripheral vascular resistance) via histamine release.13,14,20,22 (See Cautions: Adverse Effects.) In animals, vagal blockade occurs at atracurium besylate doses 8-16 times greater than those required for neuromuscular blockade.56,69

Pharmacokinetics

Absorption

The onset and duration and the rate of recovery from neuromuscular blockade induced by atracurium besylate vary among individuals, are related to the dose administered, and may be altered by the anesthetic agent (e.g., enflurane, isoflurane, halothane) employed.1,6,15,24,26,31,39,47 (See Drug Interactions: General Anesthetics.) The duration of and rate of recovery from atracurium-induced neuromuscular blockade generally do not appear to be substantially altered by renal and/or hepatic dysfunction;19,40,49,103,104,105,106,131 however, the onset may be slightly delayed in patients with renal failure.40,103,105 The duration of blockade may also be prolonged in patients undergoing cardiopulmonary bypass surgery under induced hypothermia.57,79,97 (See Pharmacokinetics: Elimination.)

As with other nondepolarizing neuromuscular blocking agents, the time from injection to maximum blockade decreases as the dose of atracurium increases.1,22,24,39 Following IV administration of a 0.4- to 0.5-mg/kg dose of atracurium besylate, maximum neuromuscular blockade generally occurs within 3-5 minutes1,2 (range: 1.7-10 minutes).5,22,26,27,35,40

The duration of the maximum neuromuscular blockade increases as the dose of atracurium increases.1,22,24,35,39 In animals, the degree and duration of neuromuscular blockade have been shown to be reduced by alkalosis.3,54 The duration of neuromuscular blocking activity of atracurium is approximately 33-50% that produced by metocurine iodide (no longer commercially available in the US), pancuronium bromide, or tubocurarine chloride (no longer commercially available in the US)1,9,22,26,31,87 but similar to or slightly longer than that produced by vecuronium bromide at initially equipotent doses.17,22,28,87,96,97 The duration of neuromuscular blockade induced by atracurium besylate doses of 0.4-0.5 mg/kg under balanced anesthesia (e.g., thiopental [no longer commercially available in the US], N₂O, fentanyl) is about 20-35 minutes.1,2,17,35,86 Repeated administration of maintenance doses of atracurium does not appear to have a cumulative effect on duration of the neuromuscular blockade,1,2,9,24,42,43 provided recovery from blockade is allowed to begin prior to administering repeated maintenance doses.1 In addition, since the time necessary to recover from maintenance doses does not change with each additional dose, doses may be administered at relatively regular intervals with predictable neuromuscular blocking results.1,2,24,42

Once recovery from atracurium-induced neuromuscular blockade begins, the rate of recovery appears to be independent of the dose of the drug;24,35,39,100 recovery from the neuromuscular blocking effects of atracurium occurs more rapidly than recovery from those of metocurine iodide, pancuronium bromide, or tubocurarine chloride.1 Recovery from neuromuscular blockade may be enhanced by alkalosis.3,54 Recovery from neuromuscular blockade under balanced anesthesia generally can be expected to begin by 20-35 minutes after injection.1,35,37 The manufacturers state that following administration of atracurium besylate doses of 0.4-0.5 mg/kg under balanced anesthesia, recovery from blockade generally is 25% and 95% complete approximately 35-45 minutes and 60-70 minutes after injection, respectively.1,86 Regardless of the dose of atracurium, the time necessary for recovery from the maximum effect of neuromuscular blockade to be 95% complete is approximately 30 minutes1 (range: 12-75.7 minutes)2,6,22,24,26,31,39,100 under balanced anesthesia and approximately 40 minutes1 (range: 6-104 minutes)5,6,24,27,34,100 under anesthesia with enflurane, isoflurane, or halothane. Recovery has been reported to be more rapid in children.41,88,92 Repeated administration of maintenance doses of atracurium does not appear to have a cumulative effect on the rate of recovery from neuromuscular blockade.1,24

Good to excellent conditions for performing endotracheal intubation generally are present within 2-2.5 minutes1,2,8,17,18,36,58,59 after administration of a 0.4- to 0.5-mg/kg dose of atracurium besylate in most patients;1,2 however, intubation has been performed successfully within 0.83-1.75 minutes in some patients after administration of 0.3- or 0.6-mg/kg doses of the drug.8,18,24,59

Distribution

Distribution of atracurium into human body tissues and fluids has not been fully characterized.86 Following IV administration, atracurium distributes into the extracellular space;2,85 because the drug is ionized, it probably does not distribute into fat.2 The volume of distribution of atracurium besylate in adults with normal renal and hepatic function following administration of a single 0.3- or 0.6-mg/kg dose reportedly averages 160 mL/kg (range: 120-188 mL/kg).2,47,49,50 Although not clearly established, the volume of distribution may be slightly increased in patients with renal failure.49,104,105

Atracurium is approximately 82% protein bound.45,46 Increased protein binding (possibly to α₁-acid glycoprotein) of atracurium with subsequent decreases in the free-fraction of circulating drug may occur in patients with burns.143,144,145,147 The drug crosses the placenta in small amounts.1,2,61,107 It is not known if atracurium distributes into milk.1

Elimination

Plasma concentrations of atracurium appear to decline in a biphasic manner.47,49,50,104,106 In adults with normal renal function, the plasma half-life in the distribution phase (t_½α) averages 2-3.4 minutes47,49,50,104 and in the terminal elimination phase (t_½β) averages 20 minutes.1,2,47,48,49,50,104 The t_½α and t_½β of the drug generally are not altered substantially by renal or hepatic dysfunction.48,49,104,105,106

Following IV injection, atracurium undergoes rapid metabolism via Hofmann elimination and via nonspecific enzymatic ester hydrolysis.1,2,3,9,22,31,54,108,109,160 While some evidence suggests that the liver does not appear to play a major role in the metabolism of the drug,1,9,31 limited evidence suggests that hepatic and/or other nonrenal (besides Hofmann elimination and ester hydrolysis) pathways may contribute to elimination of the drug.160 Hofmann elimination is a base-catalyzed reaction that occurs spontaneously at physiologic pH and temperature;9,160 the metabolic products of Hofmann elimination of atracurium are laudanosine and the corresponding quaternary monoacrylate of the drug.2,54,55 Nonspecific enzymatic ester hydrolysis of atracurium is catalyzed by bases and acids and is independent of plasma pseudocholinesterase concentration;2,9,22,24,31,52,53,54 the metabolic products of ester hydrolysis are the corresponding quaternary acid and alcohol of the drug.2,54,55 The quaternary alcohol may undergo Hofmann elimination to form laudanosine or nonspecific enzymatic ester hydrolysis to form the acid.108,109,110 All metabolites of atracurium are inactive as neuromuscular blocking agents and lack cardiovascular effects at doses exceeding the usual neuromuscular blocking doses of atracurium besylate.2,54,55 In animals, laudanosine has been associated with epileptogenic effects at high doses.1

The relative roles of the degradative pathways of atracurium under the various physiologic conditions remain to be determined.54,97,104,108,109 The rate of Hofmann elimination and metabolism of atracurium besylate is enhanced by increases in physiologic pH and temperature and inhibited by decreases in pH and temperature;3,54 the rate of ester hydrolysis of the drug is enhanced by decreases in pH.31,97 In vitro studies in plasma have shown that the half-life of atracurium besylate can be increased from 18 minutes at 37°C to 49 minutes at 23°C, 15.5 hours at 5°C, and 6.5 days at -22°C.3,53 In one study in patients undergoing cardiopulmonary bypass surgery under induced hypothermia (core body temperature of 25-26°C), a substantially slower rate of infusion (0.004 mg/kg per minute) was necessary to maintain adequate neuromuscular blockade than the rate of infusion (0.0068 mg/kg per minute) necessary in patients undergoing general surgery at normothermia (35-37°C).57,79 In one study in patients 16-85 years of age, metabolism and elimination of atracurium besylate appeared to be unaffected by age.60

Atracurium besylate and its metabolites, including the metabolic products of Hofmann elimination and nonspecific enzymatic ester hydrolysis are excreted principally in urine and also in feces via biliary elimination.1,2 Approximately 70 and 90% of a dose of atracurium besylate are excreted in urine and bile within 5 and 7 hours, respectively, after injection.1,2,55 The metabolites recovered in urine and bile are similar.1 Only a small fraction of a dose is excreted unchanged in urine and bile.1

Total body clearance of atracurium besylate reportedly averages 5.1-6.1 mL/minute per kg in patients with normal renal and hepatic function47,49,50,104,105 , 6.3-6.7 mL/minute per kg in patients with renal failure,104,105 and 6.5 mL/minute per kg in patients with concomitant renal and hepatic failure.49 It is not known if atracurium and/or its metabolites are removed by hemodialysis, hemoperfusion, or hemofiltration.1

Chemistry and Stability

Chemistry

Atracurium besylate is a synthetic, nondepolarizing neuromuscular blocking agent.1,2,4 Atracurium is a bisquaternary, noncholine diester compound that is structurally similar to metocurine iodide and tubocurarine chloride (both no longer commercially available in the US) in that it contains a 1-benzyl-tetrahydroisoquinoline moiety.2 In addition, like pancuronium and succinylcholine, atracurium contains 2 quaternary ammonium groups.1,2 Atracurium is a structurally complex molecule containing 4 chemical sites at which 10 different stereochemical isomers may occur.1 During the manufacture of atracurium, isomers are produced in unequal quantities but in a consistent ratio; those forms in which the methyl group at the quaternary nitrogen projects from the plane opposite that of the adjacent substituted benzyl moiety predominate by approximately 3:1.1

Atracurium besylate occurs as a white to pale yellow powder and has solubilities of 50, 200, and 35 mg/mL in water, alcohol, and 0.9% sodium chloride, respectively, at 25°C.2 Atracurium besylate injection is a sterile solution of the drug in water for injection.1 The injection occurs as a clear, colorless solution.86 Benzene sulfonic acid is added during the manufacture of the injection to adjust the pH to 3-3.65.1,2 Commercially available multiple-dose vials of atracurium besylate injection contain 0.9% benzyl alcohol as a preservative.1

Stability

Commercially available atracurium besylate injection should be refrigerated at 2-8°C and protected from freezing.1,2 The injection is stable for 18 months following the date of manufacture when stored at 2-8°C.2 The potency of atracurium besylate injection decreases at a rate of 6% per year when stored at 5°C;1 when stored at 25°C, the loss in potency is more rapid, occurring at a rate of about 5% per month.1 Once removed from refrigeration, atracurium besylate injection should be used within 14 days, regardless of whether the injection was subsequently rerefrigerated.1

Atracurium besylate is unstable in the presence of acids and bases.2 When atracurium besylate injection is mixed with alkaline solutions (e.g., barbiturate solution), the pH of the mixture may result in inactivation of atracurium besylate and the free acid of the admixed drug may precipitate.1 Atracurium besylate injection should not be administered in the same syringe as an alkaline solution nor should atracurium besylate and an alkaline solution be administered simultaneously through the same needle.1

Atracurium besylate is susceptible to degradation in vitro when stored in blood samples, with the drug undergoing spontaneous Hoffmann elimination and ester hydrolysis.3,9,53,160 In plasma samples at physiologic pH in vitro, the degradation half-life of the drug was 18 minutes, 49 minutes, 15.5 hours, or 6.5 days at 37, 23, 5, or -22°C, respectively.3,53

Atracurium besylate is physically and chemically compatible with the following IV solutions: 5% dextrose,1,2,3 5% dextrose and 0.9% sodium chloride,1 and 0.9% sodium chloride.1,2,3 When mixed with these diluents to a final concentration of 0.2 or 0.5 mg/mL, atracurium besylate is stable for 24 hours when stored at room temperature or refrigerated;1,2,3 unused portions of the solutions should be discarded.1 Atracurium besylate injection that has been diluted to a final concentration of 0.5 mg/mL with lactated Ringer's injection is reportedly stable for 8 hours when stored at 22-25°C;3,86,95 however, since spontaneous degradation of atracurium occurs more rapidly in lactated Ringer's, it is generally recommended that the drug not be diluted in this IV solution.1,86,95

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, drug interactions, and dosage and administration of atracurium besylate, see the Neuromuscular Blocking Agents General Statement 12:20.20.

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Atracurium Besylate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for IV use	10 mg/mL*	Atracurium Besylate Injection

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

AHFS^® Drug Information. © Copyright, 1959-2024, Selected Revisions October 22, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

References ⬆

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2. Burroughs Wellcome Co. Tracrium^® pharmacist product information. Research Triangle Park, NC; 1983 Dec.

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57. Flynn PJ, Hughes R, Walton B et al. Use of atracurium infusions for general surgical procedures including cardiac surgery with induced hypothermia. Br J Anaesth . 1983; 55(Suppl 1):135-8S. [PubMed 6338893]

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section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Chemical Name:

Molecular Formula:

Uses ⬆ ⬇

Dosage and Administration ⬆ ⬇

Cautions ⬆ ⬇

Drug Interactions ⬆ ⬇

Other Information ⬆ ⬇

Preparations ⬆ ⬇

Atracurium Besylate

Copyright ⬆ ⬇

References ⬆