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CURARE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) These drugs are non-depolarizing neuromuscular blocking agents.

Specific Substances

    A) CONSTITUENTS OF THE GROUP
    1) Atracurium (synonym)
    2) Alcuronium (synonym)
    3) Dimethyl tubocurarine iodide (synonym)
    4) Doxacurium (synonym)
    5) Gallamine (synonym)
    6) Mivacurium (synonym)
    7) Pancuronium (synonym)
    8) Pipecuronium (synonym)
    9) Rapacuronium (synonym)
    10) Rocuronium (synonym)
    11) Tubocurarine (synonym)
    12) Vecuronium (synonym)

Available Forms Sources

    A) FORMS
    1) The following preparations are available for parenteral use:
    a) Atracurium besylate 10 mg/mL (Prod Info atracurium besylate intravenous injection solution, 2011)
    b) Doxacurium Chloride 1 mg/mL (Prod Info NUROMAX(R) IV injection, 2010)
    c) Pancuronium bromide 1 mg/mL and 2 mg/mL (Prod Info pancuronium bromide intravenous injection , 2013)
    d) Rocuronium bromide 10 mg/mL (Prod Info ZEMURON(R) IV injection, 2010)
    e) Vecuronium bromide 10 mg and 20 mg intravenous powder for solution; 1 mg/mL injection solution (Prod Info vecuronium bromide IV injection, lyophilized powder for solution, 2010)
    B) USES
    1) These agents are non-depolarizing neuromuscular blocking agents, administered intravenously. They are mainly used as an adjunct to general anesthesia, to facilitate endotracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation (Prod Info pancuronium bromide intravenous injection , 2013; Prod Info atracurium besylate intravenous injection solution, 2011; Prod Info NUROMAX(R) IV injection, 2010; Prod Info ZEMURON(R) IV injection, 2010; Prod Info vecuronium bromide IV injection, lyophilized powder for solution, 2010).
    2) Rocuronium has a rapid onset of action and an intermediate duration of action that resembles the duration of action of atracurium and vecuronium (Cooper et al, 1993).
    3) Vecuronium is a monoquaternary analog of pancuronium which has a similar onset of action as pancuronium, but is 2 to 3 times shorter acting when equipotent doses are given (Engbaek et al, 1983a) and produces less cardiac effects (Engbaek et al, 1983b). The increases in heart rate and arterial pressure observed with pancuronium are not observed with vecuronium (Engbaek et al, 1983b).
    4) NOTE: Cisatracurium is covered under a separate management.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: These drugs are nondepolarizing neuromuscular blocking agents, administered intravenously. They are mainly used as an adjunct to general anesthesia, to facilitate endotracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation. NOTE: Cisatracurium is covered under a separate management.
    B) PHARMACOLOGY: These agents block myoneural transmission to skeletal muscles by competing with acetylcholine for the cholinergic receptor sites at the neuromuscular junction of skeletal muscles. By occupying the receptor sites, they block the transmitter action of acetylcholine and produce total paralysis of the muscle fibers that lasts as long as the drug remains bound at the end-plate. This competitive block may be reversed by anticholinesterase agents such as neostigmine. These agents have no or very little effect on CNS.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Therapeutic administration of these agents may cause respiratory paralysis, prolonged apnea, prolonged muscle weakness, hypotension, bradycardia, cardiac dysrhythmias, hypertension, cardiovascular collapse, and respiratory arrest. Hypersensitivity reactions, including anaphylactoid reactions, have been reported. Extravasation injuries have also been observed following the administration of atracurium and rocuronium.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Paralysis of skeletal muscle results in heaviness of the eyelids, difficulty in swallowing and talking, diplopia, progressive weakness of the extremities, the neck, intercostals, and diaphragm. Prolonged apnea and respiratory arrest may be noted due to paralysis of the intercostal muscles and diaphragm. Hypotension, bradycardia, cardiac dysrhythmias, hypertension, and cardiovascular collapse may also be observed. Although autonomic dysfunction and/or weakness may occur following the intrathecal injection of a neuromuscular blocking agent, one patient did not develop any sensory or motor block, hemodynamic changes or nerve disturbances following the intrathecal injection of atracurium. Intraarterial injection of atracurium and vecuronium were reported to cause limb ischemia. Subcutaneous injection and extravasation were reported to cause prolonged paralysis and may cause local irritation effect. It may cause tissue necrosis in severe cases.
    0.2.20) REPRODUCTIVE
    A) PANCURONIUM appears safe for use during obstetrical anesthesia. The drug crosses the placenta, but levels appear to be too low to produce detrimental effects to the fetus.

Laboratory Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor vital signs and mental status.
    D) Obtain an ECG, and institute continuous cardiac monitoring.
    E) Monitor pulse oximetry and/or arterial blood gases.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF TOXICITY
    1) Oxygenation, airway protection and ventilation support as indicated. Once airway is established and ventilation is provided, sedate patients with benzodiazepines and opioids as long as neuromuscular blockade is in effect. Monitor vital signs, especially respiration. Obtain an ECG, and institute continuous cardiac monitoring. Reverse neuromuscular blockage effect: Administer IV neostigmine (see antidote below); alternative agents include physostigmine and edrophonium. Administration of atropine sulfate with or before neostigmine has been suggested to counteract the muscarinic side effects of neostigmine. Manage mild hypotension with IV fluids. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Sedation with benzodiazepines may be helpful in agitated patients with hypertension and tachycardia. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. In most patients, sinus bradycardia is neither significant nor symptomatic, requiring no intervention. However, extreme bradycardia may result in decreased cardiac output and hypotension; IV atropine is first line treatment. If unresponsive, use beta adrenergic agonists (eg, isoproterenol) or temporary cardiac pacemaker. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Management of extravasation injuries and intrathecal injection by these agents are mainly supportive care. Refer to "extravasation injury" and "intrathecal overdose" managements for more information. For intra-arterial injection, observe signs of limb ischemia, pain, pale, paresthesia, and decrease pulse volume. Heparin and vasodilators may be helpful.
    B) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    C) AIRWAY MANAGEMENT
    1) Patients who cannot protect their own airway or have signs and symptoms of respiratory failure may need intubation for respiratory support.
    D) ANTIDOTE
    1) NEOSTIGMINE: ADULT: 0.5 to 2 mg slow IV injection, along with 0.6 to 1.2 mg of atropine sulfate IV in a separate syringe. Repeat as needed; rarely should total dose of neostigmine exceed 5 mg. PEDIATRIC: 0.02 to 0.075 mg/kg IV injection, in addition to atropine 0.01 to 0.02 mg/kg. In the presence of bradycardia, the pulse rate should be increased to about 80 beats/min with atropine before administering neostigmine. Administration of atropine sulfate with or before neostigmine has been suggested to counteract muscarinic side effects. Reversal time following intense neuromuscular blockade induced by atracurium may be prolonged. Neostigmine may not shorten the time to total recovery from an intense level of blockade. Other agents to consider include edrophonium or physostigmine in conjunction with atropine.
    E) ENHANCED ELIMINATION
    1) Hemodialysis may enhance elimination of pancuronium in patients with renal failure.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management, and these agents are only used in the hospital setting.
    2) OBSERVATION CRITERIA: Following inadvertent intravenous administrations, all asymptomatic patients should be observed for at least 1 to 2 hours for signs of systemic toxicity. Following inadvertent subcutaneous injection or extravasation, all asymptomatic patients should be observed for at least 4 to 6 hours for signs of systemic toxicity.
    3) ADMISSION CRITERIA: Patients with systemic toxicities or patients with severe symptoms following an intrathecal injection should be admitted to intensive care unit for treatment and closed monitoring.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    G) PITFALLS
    1) Failure to detect respiratory failure and compromised airway.
    H) PHARMACOKINETICS
    1) ONSET AND DURATION: Atracurium: ONSET: IV doses of 0.4 to 0.5 mg/kg produce maximal neuromuscular blockade within 3 to 5 minutes. DURATION: Recovery in 20 to 35 min. Pancuronium: ONSET: About 2 to 3 min; DURATION: About 40 to 60 min. Rocuronium: ONSET: A rapid onset of action; DURATION: An intermediate duration of action. PROTEIN BINDING: Atracurium: 82%; doxacurium: 30%; pancuronium: not highly bound; rocuronium: 30%; vecuronium: 30%. Vd: Atracurium: 120 to 188 mL/kg; pancuronium: 0.079 L/kg to 0.26 L/kg; rocuronium: 0.25 L/kg; vecuronium: 0.2 L/kg. EXCRETION: RENAL: Atracurium: More than 90% of a dose of atracurium is excreted in the urine within 7 hours following IV injection; doxacurium: It is eliminated primarily as unchanged drug in the urine and bile; pancuronium: Approximately 57% and 69% of an administered dose of pancuronium is excreted unchanged in the urine at 6 and 24 hours, respectively; vecuronium: 3% to 35% of a dose is excreted as the metabolite in the urine in 24 hours. BILE: Atracurium: Biliary excretion is also a major route of metabolite elimination of atracurium; doxacurium is eliminated primarily as unchanged drug in the urine and bile; pancuronium: 5% to 10% of a dose was excreted in the bile in 24 hours; vecuronium: 25% to 50% is eliminated via biliary excretion. ELIMINATION HALF-LIFE: Atracurium: 20 min; pancuronium: 89 to 140 min; rocuronium: 1.4 hours; vecuronium: 71 min.
    I) DIFFERENTIAL DIAGNOSIS
    1) Botulism, neurotoxic snake bite, succinylcholine toxicity, organophosphorus or carbamate toxicity, myasthenia gravis, Guillain-Barre' syndrome, tick paralysis.

Range Of Toxicity

    A) TOXICITY: A lethal dose for these agents has not been established. Parenteral administration of any dose may be sufficient to cause respiratory paralysis, hypoxia and death if respiratory assistance is not available.

Clinical Effects

Summary Of Exposure

    A) USES: These drugs are nondepolarizing neuromuscular blocking agents, administered intravenously. They are mainly used as an adjunct to general anesthesia, to facilitate endotracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation. NOTE: Cisatracurium is covered under a separate management.
    B) PHARMACOLOGY: These agents block myoneural transmission to skeletal muscles by competing with acetylcholine for the cholinergic receptor sites at the neuromuscular junction of skeletal muscles. By occupying the receptor sites, they block the transmitter action of acetylcholine and produce total paralysis of the muscle fibers that lasts as long as the drug remains bound at the end-plate. This competitive block may be reversed by anticholinesterase agents such as neostigmine. These agents have no or very little effect on CNS.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Therapeutic administration of these agents may cause respiratory paralysis, prolonged apnea, prolonged muscle weakness, hypotension, bradycardia, cardiac dysrhythmias, hypertension, cardiovascular collapse, and respiratory arrest. Hypersensitivity reactions, including anaphylactoid reactions, have been reported. Extravasation injuries have also been observed following the administration of atracurium and rocuronium.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Paralysis of skeletal muscle results in heaviness of the eyelids, difficulty in swallowing and talking, diplopia, progressive weakness of the extremities, the neck, intercostals, and diaphragm. Prolonged apnea and respiratory arrest may be noted due to paralysis of the intercostal muscles and diaphragm. Hypotension, bradycardia, cardiac dysrhythmias, hypertension, and cardiovascular collapse may also be observed. Although autonomic dysfunction and/or weakness may occur following the intrathecal injection of a neuromuscular blocking agent, one patient did not develop any sensory or motor block, hemodynamic changes or nerve disturbances following the intrathecal injection of atracurium. Intraarterial injection of atracurium and vecuronium were reported to cause limb ischemia. Subcutaneous injection and extravasation were reported to cause prolonged paralysis and may cause local irritation effect. It may cause tissue necrosis in severe cases.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) ATRACURIUM: CASE REPORT: PERIORBITAL EDEMA was seen following 0.5 mg/kg IV for 30 seconds in a 10-year-old (Cohen & Frank, 1987).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension may be observed (Hughes & Chapple, 1981).
    b) ATRACURIUM: Clinical trials involving 530 patients without cardiovascular disease revealed decreases in mean arterial pressure in 1.1%, 2.1% and 14.3% of patients receiving IV atracurium in doses of up to 0.3 mg/kg (n=365), 0.31 to 0.5 mg/kg (n=144), and 0.6 mg/kg or greater (n=21), respectively. The recommended initial dosages fall within the range of 0.31 to 0.5 mg/kg (Prod Info atracurium besylate intravenous injection solution, 2011).
    c) In studies of 875 patients receiving atracurium, 5 patients required treatment due to hypotension attributable to atracurium administration (Prod Info atracurium besylate intravenous injection solution, 2011).
    d) TUBOCURARINE can result in hypotension when given in large IV doses, as compared with minimal effects of atracurium on blood pressure, even with higher doses (Hilgenberg, 1983; Basta et al, 1982) .
    1) This is believed to be related to peripheral vasodilation secondary to histamine release. Some studies indicate that atracurium possesses fewer histamine-releasing properties than tubocurarine (less than 1/3 that of tubocurarine in one report) (Basta et al, 1983).
    2) Data by Robertson et al (1983), comparing intradermal histamine release of atracurium and tubocurarine, suggest that the degree of histamine release is similar with both agents (Robertson et al, 1983).
    e) MIVACURIUM: Hypotension has been noted during therapeutic use (Stoops et al, 1989).
    2) WITH POISONING/EXPOSURE
    a) ATRACURIUM: Hypotension may occur with overdose (Prod Info atracurium besylate intravenous injection solution, 2011).
    B) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) ATRACURIUM has insignificant effects upon heart rate and does not counteract the bradycardia induced by many anesthetic agents or vagal stimulation; thus, bradycardia during anesthesia may be more common with atracurium than other neuromuscular blocking agents.
    1) Initial studies indicate a low incidence of decreases in heart rate with atracurium treatment. Clinical trials involving 530 patients without cardiovascular disease revealed decreases in heart rate in 0.8%, 0% and 0% of patients receiving IV atracurium in doses of up to 0.3 mg/kg (n=365), 0.31 to 0.5 mg/kg (n=144), and 0.6 mg/kg or greater (n=21), respectively (Prod Info atracurium besylate intravenous injection solution, 2011). A similar report indicated a lack of significant bradycardic effects of atracurium with doses of 0.6 mg/kg IV (Barnes et al, 1983). However, reports of severe bradycardia have occurred (Carter, 1983; McHutchon & Lawler, 1983). A 15 second period of asystole occurred in one young patient (McHutchon & Lawler, 1983). All cases of bradycardia have responded adequately to atropine.
    2) CASE REPORT: A 15 second period of ASYSTOLE occurred in one young patient (McHutchon & Lawler, 1983a). All cases of bradycardia have responded adequately to atropine.
    3) CASE SERIES: Severe bradycardia was reported in 4 patients of varying ages (29 to 84 years of age) following the use of atracurium. Anesthesia was maintained with nitrous oxide-oxygen in 3 patients, with the addition of halothane in the fourth (Carter, 1983a).
    a) Doses administered were over the recommended dose in all patients (0.52 to 0.75 mg/kg), suggesting bradycardia may occur with higher doses.
    b) All cases were treated successfully with intravenous atropine. It is recommended that in surgery where vagal stimulation is expected that patients undergo full ECG monitoring and atropine be administered as part of premedication or during the induction sequence.
    c) The authors suspect that the lack of cardiovascular effects of atracurium may lead to unattenuated cholinergic effects of other anesthetic agents, resulting in bradycardia, or that a metabolite such as laudanosine may have direct effects in causing bradycardia (Carter, 1983a).
    d) This report differs from other studies, indicating lack of significant bradycardic effects of atracurium with doses of 0.6 mg/kg IV (Barnes et al, 1983a).
    C) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) PANCURONIUM: Severe hypertension has been reported during pancuronium administration (Fraley, 1978).
    1) CASE REPORT: Severe hypertensive responses to pancuronium were reported in a patient with pheochromocytoma. Ninety minutes following injection of 0.15 mg/kg in a 53-year-old woman, blood pressure increased to 230/130 mmHg and heart rate increased to 120 beats/minute. The patient responded rapidly to phentolamine (Jones & Hill, 1981).
    b) ATRACURIUM: Clinical trials involving 530 patients without cardiovascular disease revealed increases in mean arterial pressure in 1.9%, 2.8% and 0% of patients receiving IV atracurium in doses of up to 0.3 mg/kg (n=365), 0.31 to 0.5 mg/kg (n=144), and 0.6 mg/kg or greater (n=21), respectively (Prod Info atracurium besylate intravenous injection solution, 2011).
    2) WITH POISONING/EXPOSURE
    a) ATRACURIUM: CASE REPORT: A 17-year-old girl developed moderate hemodynamic changes (13% increase in mean arterial pressure and 27% increase in heart rate) after inadvertently receiving atracurium 1.3 mg/kg. She recovered 40 minutes later without requiring any treatment. The maximum recommended doses in adults produces "the time from injection to 25% recovery" of 35 to 45 minutes which is about half the time for this patient (83 minutes) (Prod Info atracurium besylate intravenous injection solution, 2011).
    D) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) ATRACURIUM: Tachycardia was reported in 5% to 8% of patients receiving doses of 0.5 to 0.6 mg/kg atracurium (Basta et al, 1982a).
    1) Clinical trials involving 530 patients without cardiovascular disease revealed increases in heart rate in 1.6%, 2.8% and 4.8% of patients receiving IV atracurium in doses of up to 0.3 mg/kg (n=365), 0.31 to 0.5 mg/kg (n=144), and 0.6 mg/kg or greater (n=21), respectively (Prod Info atracurium besylate intravenous injection solution, 2011).
    b) PANCURONIUM: Increases in heart rate and cardiac output can occur during pancuronium administration (Beam, 1973; Orkin & Pegg, 1973; Kelman & Kennedy, 1970).
    1) Atrioventricular conduction can be accelerated; however, cardiac contractility and total peripheral resistance is generally unaffected (AMA Council on Drugs, 1983; Levin & Dillon, 1971; Kelman & Kennedy, 1971).
    2) WITH POISONING/EXPOSURE
    a) ATRACURIUM: CASE REPORT: A 17-year-old girl developed moderate hemodynamic changes (13% increase in mean arterial pressure and 27% increase in heart rate) after inadvertently receiving atracurium 1.3 mg/kg. She recovered 40 minutes later without requiring any treatment. The maximum recommended doses in adults produces "the time from injection to 25% recovery" of 35 to 45 minutes which is about half the time for this patient (83 minutes) (Prod Info atracurium besylate intravenous injection solution, 2011).
    E) VENTRICULAR ARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) VENTRICULAR EXTRASYSTOLES have occurred during therapy (Brichard, 1973) and one case of cardiovascular collapse has been reported (Darwish & Challen, 1977).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH THERAPEUTIC USE
    a) PANCURONIUM: Respiratory depression can occur due to prolonged neuromuscular blockade from pancuronium. This is generally related to overdosage of the drug, interactions with other agents, and pathologic conditions such as myasthenia gravis (AMA Council on Drugs, 1983).
    1) Clindamycin, polymyxin B, tubocurarine, gentamicin, neomycin, colistin, and streptomycin have been associated with prolonged neuromuscular blockade with pancuronium resulting in respiratory insufficiency or respiratory failure (Balamoutsos et al, 1981; Regan & Perumbetti, 1980; Giala & Paradelis, 1979; Fogdall & Miller, 1974).
    2) WITH POISONING/EXPOSURE
    a) ROCURONIUM: CASE REPORT: A 57-year-old woman with residual left hemiparesis from a previous surgery was given rocuronium during a surgical procedure (total dose of 70 mg). Train-of-four stimulation, monitored at the ulnar nerve on her weak left arm, consistently showed 4 strong twitches, which served as the basis for administering additional doses of rocuronium. Following completion of the surgery and, although the patient was still intubated, she was not coughing and there was no response to pharyngeal suctioning despite administration of neostigmine. Train-of-four stimulation response was checked on the right arm, which showed only 1 weak twitch. Spontaneous respiration returned 1 hour later, after the effects of the rocuronium had worn off, and the patient was successfully extubated. It is believed that paretic limbs may be resistant to the effects of nondepolarizing muscle relaxants and therefore it is recommended that neuromuscular monitoring, in patients with hemiparesis, should be performed on the healthy, unaffected side (Whymark & MacLeod, 2004).
    B) APNEA
    1) WITH THERAPEUTIC USE
    a) PANCURONIUM: CASE REPORT: Prolonged apnea was reported in a 63-year-old man following a total of 8 mg intravenous pancuronium over 2 hours for gastric ulcer surgery. The patient was unresponsive to neostigmine administration. Cholinesterase levels were reportedly low in the patient (Kunos et al, 1975).
    C) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) Bronchospasm has been reported following PANCURONIUM and VECURONIUM administration (Prod Info pancuronium bromide intravenous injection , 2013; Prod Info PAVULON(R) IV injection, 2010; Prod Info vecuronium bromide IV injection, lyophilized powder for solution, 2010; O'Callaghan et al, 1986; Brauer & Ananthanarayan, 1978; Dick & Droh, 1970) and may be related to a hypersensitivity reaction to the medication.
    b) RAPACURONIUM has been voluntarily withdrawn from the market, by the manufacturer, due to reports of an association with rapacuronium administration and the occurrence of bronchospastic events, including the occurrence of unexplained fatalities ((Anon, 2001)).
    D) DISORDER OF RESPIRATORY SYSTEM
    1) WITH THERAPEUTIC USE
    a) PANCURONIUM: PULMONARY FUNCTION ABNORMALITIES: Pretreatment with pancuronium is used widely to attenuate some of the untoward effects of succinylcholine.
    b) Respiratory depression has been reported following pretreatment doses (0.015 mg/kg) (Rao & Jacobs, 1980; Howardy-Hansen et al, 1980).
    c) PANCURONIUM: CASE REPORT: One patient needed artificial ventilation and reversal with neostigmine following pretreatment with pancuronium (Rao & Jacobs, 1980).
    d) ROCURONIUM: In a clinical study of patients undergoing abdominal aortic surgery, transient increases (30% or greater) in pulmonary vascular resistance were reported in 24% of patients who received rocuronium bromide 0.6 or 0.9 mg/kg (Prod Info ZEMURON(R) IV injection, 2010).
    E) PARALYSIS
    1) WITH THERAPEUTIC USE
    a) TUBOCURARINE: RESPIRATORY PARALYSIS: Tubocurarine may cause the intercostal muscles and diaphragm to become paralyzed, resulting in respiratory paralysis (Gilman et al, 1990).
    F) RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) PANCURONIUM: CASE REPORT: A 46-year-old woman was found dead with a 2 mL syringe and an empty ampule of pancuronium bromide (4 mg/2 mL) in her hand. An autopsy, performed 6 days later, determined the cause of death to be respiratory failure. Initial pancuronium concentrations in her blood and liver were 81 ng/mL and 532 ng/g, respectively. Analysis of the volume of fluid residue found in the syringe estimated that the injected pancuronium bromide dose was 2.6 mg (Kala & Lechowicz, 2004).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) WITH THERAPEUTIC USE
    a) Therapeutic doses produce the following sequence of skeletal muscle depression: heaviness to the eyelids, difficulty in swallowing and talking, diplopia, progressive weakness of the extremities, the neck, trunk, spine, intercostals, and diaphragm. The paralysis recedes in the reverse order (Gilman et al, 1990).
    B) FLACCID PARALYSIS
    1) WITH THERAPEUTIC USE
    a) Profound and prolonged neuromuscular skeletal muscle paralysis leading to respiratory insufficiency or apnea may occur in patients who receive nondepolarizing blocking agents. Prolonged paralysis and/or skeletal muscle weakness have occurred rarely following long-term use of pancuronium to support mechanical ventilation in the ICU. Usually, patients are receiving other drugs, may have electrolyte imbalance, hypoxic episodes, acid-base imbalance, extreme debilitation, or have been immobilized for an extended period (Prod Info pancuronium bromide intravenous injection , 2013).
    b) TUBOCURARINE causes flaccid paralysis of all skeletal muscles. With increasing dosage, the intercostal muscles and diaphragm become paralyzed, resulting in respiratory paralysis (Gilman et al, 1990).
    c) Prolonged neuromuscular blockade was reported in 2 patients following MIVACURIUM and VECURONIUM administration, respectively. One patient had received approximately 9 grams of magnesium to treat preeclampsia and the other was homozygous for an atypical cholinesterase enzyme. Both patients gradually recovered several hours later (Vanlinthout et al, 1998; Sinatra et al, 1985) .
    2) WITH POISONING/EXPOSURE
    a) ATRACURIUM: Prolonged neuromuscular blockade may occur with overdose (Prod Info atracurium besylate intravenous injection solution, 2011).
    b) VECURONIUM: CASE REPORT: Prolonged neuromuscular blockade of approximately 4 hours in duration was reported in a patient who inadvertently received her induction medications, consisting of 1.5 mcg/kg fentanyl, 3.1 mg/kg propofol, and 0.09 mg/kg vecuronium, subcutaneously through an IV that was infiltrated. With supportive care, the patient recovered and was discharged from the intensive care unit 3 days postsurgery (Tarmey et al, 2011).
    c) VECURONIUM: CASE REPORT: A 67-year-old woman experienced prolonged neuromuscular blockade after inadvertently receiving vecuronium epidurally instead of intravenously. In this patient, the third twitch of train of 4 returned at 90 minutes after epidural dose compared with 45 minutes after intravenous dose, fourth twitch returned after 120 minutes after epidural dose compared with 90 minutes after intravenous dose (Furuya et al, 2011).
    d) PANCURONIUM: A 35-year-old woman scheduled for a cesarean section was accidentally given a subarachnoid injection of 4 mg of pancuronium bromide. After 5 minutes when no level of analgesia was achieved by pinprick, an injection of hyperbaric 1% bupivacaine, the correct drug, was administered. Approximately 15 minutes later, the patient developed generalized muscle hypotonia, hypoventilation, decreased ability to open and close eyes, difficulty with tongue movement and swallowing, and a decreased handgrip strength. Oxygen was administered along with neostigmine 2.5 mg and 1 mg of atropine IV to reverse the neuromuscular blockade. The patient recovered without neurologic sequelae. The author believes the hyperbaric 1% bupivacaine injected just after the pancuronium helped restrict diffusion of the pancuronium out of the lumbar area, thereby lessening the severity of effects (Peduto et al, 1989).
    C) LACK OF EFFECT
    1) TUBOCURARINE: CNS EFFECTS: Tubocurarine does not readily penetrate the blood-brain barrier and, therefore, has little effects in the CNS (Gilman et al, 1990).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) ATRACURIUM: Skin reactions secondary to histamine release have occurred following atracurium administration. Skin flushing, erythema, itching, and hives were reported in up to 5% of patients (n=875) receiving doses of 0.3 to 0.6 mg/kg IV (Prod Info atracurium besylate intravenous injection solution, 2011).
    b) PANCURONIUM: A transient skin rash has occurred with the use of pancuronium (Prod Info pancuronium bromide intravenous injection , 2013).
    B) FLUSHING
    1) WITH THERAPEUTIC USE
    a) ATRACURIUM: Skin flushing is the most common adverse effect observed with atracurium infusion. In clinical trials of 875 patients, skin flush was reported in 1%, 8.7% and 29.2% of patients receiving initial intravenous atracurium doses of up to 0.3 mg/kg (n=485), 0.31 to 0.5 mg/kg (n=366) and 0.6 mg/kg or greater (n=24), respectively (Prod Info atracurium besylate intravenous injection solution, 2011).
    b) MIVACURIUM: Flushing is a commonly seen side effect (25% incidence) in patients given 0.15 mg/kg over 5 to 15 seconds (Prod Info MIVACRON(R) intravenous injection solution, 2010).
    C) EXTRAVASATION INJURY
    1) WITH THERAPEUTIC USE
    a) ATRACURIUM: Extravasation injury (eg, ischemia, necrosis) has been reported following the administration of atracurium. Ischemia also developed after atracurium was injected intraarterially (Lake & Beecroft, 2010).
    b) ROCURONIUM: Extravasation with local irritation has been reported following the administration of rocuronium. Ischemia also developed after rocuronium was injected intraarterially (Lake & Beecroft, 2010).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) ATRACURIUM: An anaphylactic reaction has been reported following the administration of 0.6 mg/kg (36 mg) and 0.2 mg/kg (20 mg) atracurium (dos Santos & dos Santos, 1989; Tetzlaff & Gellman, 1986).
    b) ATRACURIUM: CASE REPORT: A anaphylactoid reaction (hypotension, skin rash, bronchospasm) occurred in a 16-year-old girl following injection of atracurium. Although thiopental was administered previous to atracurium, subsequent intradermal testing revealed positive results with atracurium but not thiopental. The data suggest a direct liberation of histamine by atracurium (Durcan & Carter, 1986; Lavery et al, 1985).
    c) PANCURONIUM: Severe allergic reactions including anaphylactic and anaphylactoid reactions, in some cases life-threatening and fatal, have been reported as part of the postmarketing surveillance of pancuronium. Cross-reactivity between both nondepolarizing and depolarizing neuromuscular blocking agents has been reported (Prod Info pancuronium bromide intravenous injection , 2013).
    d) PANCURONIUM: Generalized flushing and cardiovascular collapse occurred in a 47-year-old man approximately 1 minute after 6 mg pancuronium IV was given following anesthesia induction for elective cholecystectomy. This appears to be only the sixth report of pancuronium-induced severe anaphylactoid reaction.(Mishima & Yamamura, 1984).
    B) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) ATRACURIUM: Hypersensitivity reactions, including anaphylactic or anaphylactoid responses, and in some cases severe (eg, cardiac arrest) have rarely been reported with atracurium use (Prod Info atracurium besylate intravenous injection solution, 2011).
    b) PANCURONIUM: Hypersensitivity reactions, including bronchospasm, flushing, redness, hypotension, tachycardia, and other possible histamine release-related reactions have rarely been reported with pancuronium use (Prod Info pancuronium bromide intravenous injection , 2013).
    c) ROCURONIUM: Severe allergic reactions, including anaphylactic and anaphylactoid reactions and shock, some cases life-threatening or fatal, have been reported as part of the postmarketing surveillance of rocuronium bromide. Cross-reactivity between rocuronium bromide and both depolarizing and nondepolarizing neuromuscular blocking agents has been observed (Prod Info ZEMURON(R) IV injection, 2010).
    d) VECURONIUM: Hypersensitivity reactions (bronchospasm, hypotension, and/or tachycardia, sometimes associated with acute urticaria or erythema) have rarely been reported (Prod Info vecuronium bromide IV injection, lyophilized powder for solution, 2010).

Reproductive

    3.20.1) SUMMARY
    A) PANCURONIUM appears safe for use during obstetrical anesthesia. The drug crosses the placenta, but levels appear to be too low to produce detrimental effects to the fetus.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) ATRACURIUM has been reported safe and effective for neuromuscular blockade during cesarean section. Doses of 0.3 mg/kg were administered following induction of anesthesia, producing effective surgical relaxation and cardiovascular stability.
    a) Recovery from neuromuscular blockade occurred spontaneously in 45 of 53 patients, with neostigmine and atropine producing rapid antagonism in 8 others. No evidence of recurrence was observed (Flynn et al, 1984).
    b) There were no adverse effects on Apgar scores in neonates or on the time to sustained respiration (Flynn et al, 1984).
    c) Concentrations of atracurium in the umbilical vein range from undetectable to 0.23 mcg/mL, indicating that atracurium did not cross the placenta in amounts likely to be detrimental to the fetus (Flynn et al, 1984).
    2) PANCURONIUM appears safe for use during obstetrical anesthesia. The drug crosses the placenta, but levels appear to be too low to produce detrimental effects to the fetus (AMA Council on Drugs, 1983; Abouleish et al, 1980).
    B) ANIMAL STUDIES
    1) Animal studies have suggested the potential for teratogenic effects of ATRACURIUM when given in doses of 1/2 the human dose (Prod Info, 1985). There are no data evaluating the drug in human pregnancy.
    3.20.3) EFFECTS IN PREGNANCY
    A) PLACENTAL BARRIER
    1) Tubocurarine crosses the placenta in insignificant amounts (Gilman et al, 1990).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor vital signs and mental status.
    D) Obtain an ECG, and institute continuous cardiac monitoring.
    E) Monitor pulse oximetry and/or arterial blood gases.

Methods

    A) CHROMATOGRAPHY
    1) Liquid chromatography-mass spectrometry was performed on post-mortem blood and liver for quantification of pancuronium in a 46-year-old woman found dead with a syringe and an empty ampule of pancuronium in her hand. The limit of detection and the lower limit of quantification, using this method, were 1 ng/mL and 2 ng/mL, respectively, and did not differ between the blood and liver samples (Kala & Lechowicz, 2004).
    B) MULTIPLE ANALYTICAL METHODS
    1) Not usually available in a clinical setting, but has been done by ion-pair extraction, fluorometry, and thin layer chromatography (Poklis & Melanson, 1980; Vandenbrom & Wierda, 1988).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with systemic toxicities or patients with severe symptoms following an intrathecal injection should be admitted to intensive care unit for treatment and closed monitoring.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management, and these agents are only used in the hospital setting.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Following inadvertent intravenous administrations, all asymptomatic patients should be observed for at least 1 to 2 hours for signs of systemic toxicity. Following inadvertent subcutaneous injection or extravasation, all asymptomatic patients should be observed for at least 4 to 6 hours for signs of systemic toxicity.

Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor vital signs and mental status.
    D) Obtain an ECG, and institute continuous cardiac monitoring.
    E) Monitor pulse oximetry and/or arterial blood gases.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.

Abstracts

Case Reports

    A) SPECIFIC AGENT
    1) ATRACURIUM: Although autonomic dysfunction and/or weakness may occur following the intrathecal injection of a neuromuscular blocking agent, one patient did not develop any sensory or motor block, hemodynamic changes or nerve disturbances following the intrathecal injection of atracurium (Zirak et al, 2011).
    a) INTRATHECAL: CASE REPORT: A 38-year-old woman who was undergoing abdominal hysterectomy, inadvertently received 25 mg of atracurium intrathecally during spinal anesthesia. No sensory or motor block, hemodynamic changes or nerve disturbances were observed (Zirak et al, 2011).
    2) ATRACURIUM: Periorbital edema was described following atracurium 0.5 mg/kg IV over 30 seconds in a 10-year-old girl undergoing strabismus repair of the right eye. Administration of atracurium was preceded by thiopental and nitrous oxide. Facial flushing was evident within 45 seconds following administration of atracurium. Within 4 minutes flushing progressed to the upper chest and arms and periorbital and conjunctival edema was evident. Within 15 minutes severe periorbital, conjunctival, and lid edema were observed despite diphenhydramine 30 mg IV. The edema interfered with the surgery, and strabismus repair was delayed. Intradermal testing with atracurium 1:1000 and 1:100 revealed wheal and flare phenomenon, which was greater than that observed with histamine (0.01 mL of a 0.01% solution). More studies are indicated to determine the incidence and mechanism of this reaction; the direct release of histamine could not be ruled out in this patient; however, hypotension was not observed. The prolonged persistence of the edema could be related to a late-phase skin reaction, similar to IgG antibody in ragweed allergy. (Cohen & Frank, 1987).
    3) ATRACURIUM: Aldrete (1985) reported occurrence of a severe cutaneous allergic reaction following administration of atracurium 0.6 mg/kg IV to an 11-year-old boy. One minute later, the patient developed severe erythema and papulae on the pathway of the vein where the cannula was positioned, which progressed toward the neck, thorax, abdomen, and face. A slight increase on resistance to inspiration was observed. The patient responded to antihistamine administration. Skin testing subsequently with 0.003 mg intradermal atracurium resulted in a similar reaction. It is suggested that atracurium be avoided in patients with other drug allergies, and antihistamines may be indicated as a premedicant (Aldrete, 1985).
    4) ATRACURIUM: Accidental administration of 13.4 mg/kg of atracurium to a 59-day-old infant resulted in flushing, but no significant other signs or symptoms. Neuromuscular blockade was spontaneously reversed 2.25 hours after administration (Charlton et al, 1989).
    5) PANCURONIUM: A 33-year-old woman received 6 mg pancuronium IV in a single dose for surgical relaxation during a tubal ligation. The patient was 5 days postpartum. One minute following injection, no pulse was palpable, and cyanosis was present. External cardiac massage and IV fluids were administered as well as hydrocortisone 300 mg IV. Severe bradycardia ensued, which was treated with isoproterenol without response; methylprednisolone 1 g was administered, followed by an emergency thoracotomy. However, the patient died of total circulatory arrest. The authors suggest that pancuronium was closely associated with the cardiovascular collapse; however, there was no bronchospasm present (Darwish & Challen, 1977).
    6) PANCURONIUM: A 35-year-old woman scheduled for a cesarean section was accidentally given a subarachnoid injection of 4 mg of pancuronium bromide. After 5 minutes when no level of analgesia was achieved by pinprick, an injection of hyperbaric 1% bupivacaine, the correct drug, was administered. Approximately 15 minutes later, the patient developed generalized muscle hypotonia, hypoventilation, decreased ability to open and close eyes, difficulty with tongue movement and swallowing, and a decreased handgrip strength. Oxygen was administered along with neostigmine 2.5 mg and 1 mg of atropine IV to reverse the neuromuscular blockade. The patient recovered without neurologic sequelae. The author believes the hyperbaric 1% bupivacaine injected just after the pancuronium helped restrict diffusion of the pancuronium out of the lumbar area, thereby lessening the severity of effects (Peduto et al, 1989).
    7) PANCURONIUM: A 4-year-old girl required pancuronium bromide 1 to 1.2 mg every hour to facilitate artificial ventilation for 40 days following liver transplant surgery. The patient had liver and kidney dysfunction, which required drugs, such as gentamicin, corticosteroids, and diuretics, known to increase the neuromuscular effects of pancuronium. The patient experienced prolonged paralysis following discontinuation of pancuronium, requiring 25 days of treatment with pyridostigmine. The patient gradually returned to baseline neurologic function over 3 to 4 months (Haas et al, 1989).

Range Of Toxicity

Summary

    A) TOXICITY: A lethal dose for these agents has not been established. Parenteral administration of any dose may be sufficient to cause respiratory paralysis, hypoxia and death if respiratory assistance is not available.

Therapeutic Dose

    7.2.1) ADULT
    A) ATRACURIUM
    1) INITIAL: 0.4 to 0.5 mg/kg IV bolus (Prod Info atracurium besylate intravenous injection, 2013)
    2) MAINTENANCE: 0.08 to 0.1 mg/kg IV bolus 20 to 45 min after initial dose, then every 15 to 25 min as needed. Higher atracurium doses (up to 0.2 mg/kg) permit maintenance dosing at longer intervals (Prod Info atracurium besylate intravenous injection, 2013).
    3) MAINTENANCE: After early evidence of spontaneous recovery from the bolus dose, initial infusion rate of 9 to 10 mcg/kg/min may be required to rapidly counteract spontaneous recovery of neuromuscular function. Thereafter, 5 to 9 mcg/kg/min should maintain continuous neuromuscular block in the 89% to 99% range under balanced anesthesia. Occasionally, rates as low as 2 mcg/kg/min or as high as 15 mcg/kg/min may be needed; in ICU, 11 to 13 mcg/kg/min (range 4.5 to 29.5 mcg/kg/min) continuous IV infusion (Prod Info atracurium besylate intravenous injection, 2013).
    B) DOXACURIUM
    1) INITIAL: 0.05 mg/kg and 0.08 mg/kg IV to provide neuromuscular block for an average 100 min and 160 min, respectively (Prod Info NUROMAX(R) IV injection, 2010)
    2) MAINTENANCE: 0.005 mg/kg and 0.01 mg/kg IV to provide neuromuscular blockage for an average of 30 min and 45 min, respectively (Prod Info NUROMAX(R) IV injection, 2010)
    C) PANCURONIUM
    1) INITIAL: 0.04 to 0.1 mg/kg IV (endotracheal intubation, 0.06 to 0.1 mg/kg IV); later incremental doses starting at 0.01 mg/kg may be used (Prod Info pancuronium bromide intravenous injection , 2013).
    D) ROCURONIUM
    1) INITIAL, (REGARDLESS OF ANESTHESIC TECHNIQUE): 0.6 mg/kg IV; or a lower dose of 0.45 mg/kg IV may be used (Prod Info ZEMURON(R) intravenous injection, 2015)
    2) INITIAL, (WITH OPIOID/NITROUS OXIDE/OXYGEN ANESTHESIA): 0.9 or 1.2 mg/kg large bolus may be used (Prod Info ZEMURON(R) intravenous injection, 2015)
    3) MAINTENANCE, (ONLY AFTER SPONTANEOUS RECOVERY FROM INTUBATION DOSE): 0.1 to 0.2 mg/kg IV, repeat as needed or 0.01 to 0.012 mg/kg/minute (10 to 12 mcg/kg/min) continuous IV infusion (Prod Info ZEMURON(R) intravenous injection, 2015)
    4) MAINTENANCE: Alternatively, a continuous infusion at an initial rate of 0.01 to 0.012 mg/kg/minute (10 to 12 mcg/kg/min) is recommended after early evidence of spontaneous recovery from an incubating dose (Prod Info ZEMURON(R) intravenous injection, 2015)
    E) VECURONIUM
    1) INITIAL: 0.08 to 0.1 mg/kg IV bolus (Prod Info vecuronium bromide intravenous injection lyophilized powder for solution, 2014)
    2) MAINTENANCE: 0.01 to 0.015 mg/kg IV 25 to 40 min after initial dose, repeat every 12 to 15 min as needed (Prod Info vecuronium bromide intravenous injection lyophilized powder for solution, 2014)
    3) CONTINUOUS INFUSION: 1 mcg/kg/min continuous IV infusion 20 to 40 min after initial intubation dose, after early evidence of spontaneous recovery; then adjust to maintain 90% suppression of twitch response; range 0.8 to 1.2 mcg/kg/min (Prod Info vecuronium bromide intravenous injection lyophilized powder for solution, 2014)
    7.2.2) PEDIATRIC
    A) ATRACURIUM
    1) INFANTS (AGE 1 MONTH TO 2 YR) under halothane anesthesia: INITIAL: 0.3 to 0.4 mg/kg IV (Prod Info atracurium besylate injection, 2004)
    2) AGE 2 YR AND OLDER: INITIAL: 0.4 to 0.5 mg/kg IV bolus (Prod Info atracurium besylate injection, 2004)
    3) AGE 2 YR AND OLDER: MAINTENANCE: 0.08 to 0.1 mg/kg IV bolus 20 to 45 min after initial dose, then every 15 to 25 min as needed. Higher atracurium doses (up to 0.2 mg/kg) permit maintenance dosing at longer intervals (Prod Info atracurium besylate intravenous injection, 2013).
    4) AGE 2 YR AND OLDER: MAINTENANCE: After early evidence of spontaneous recovery from the bolus dose, initial infusion rate of 9 to 10 mcg/kg/min may be required to rapidly counteract spontaneous recovery of neuromuscular function. Thereafter, 5 to 9 mcg/kg/min should maintain continuous neuromuscular block in the 89% to 99% range under balanced anesthesia. Occasionally, rates as low as 2 mcg/kg/min or as high as 15 mcg/kg/min may be needed; in ICU, 11 to 13 mcg/kg/min (range 4.5 to 29.5 mcg/kg/min) continuous IV infusion (Prod Info atracurium besylate intravenous injection, 2013).
    B) DOXACURIUM
    1) AGE 2 YEARS AND OLDER: 0.03 mg/kg and 0.05 mg/kg IV during halothane anesthesia to provide neuromuscular blockade for an average of 30 min and 45 min, respectively (Prod Info NUROMAX(R) IV injection, 2010).
    C) PANCURONIUM
    1) ALL AGES EXCEPT NEONATES: INITIAL: 0.04 to 0.1 mg/kg IV (endotracheal intubation, 0.06 to 0.1 mg/kg IV); later incremental doses starting at 0.01 mg/kg may be used (Prod Info pancuronium bromide intravenous injection , 2013)
    2) NEONATES: Administer a test dose of 0.02 mg/kg IV to measure responsiveness (Prod Info pancuronium bromide intravenous injection , 2013)
    D) ROCURONIUM
    1) 3 MONTHS TO 14 YEARS: INITIAL: 0.45 to 0.6 mg/kg/dose IV (Prod Info ZEMURON(R) intravenous injection, 2015)
    2) 3 MONTHS TO 14 YEARS: MAINTENANCE: 0.075 to 0.15 mg/kg IV push as needed or 12 mcg/kg/min continuous IV infusion (Prod Info ZEMURON(R) intravenous injection, 2015)
    E) VECURONIUM
    1) 8 WEEKS TO 1 YEAR: more sensitive on a mg/kg basis than adults and recovery may take 1.5 times longer (Prod Info vecuronium bromide intravenous injection lyophilized powder for solution, 2014)
    2) 1 TO 10 YEARS: dosage must be individualized; may require slightly higher initial dose and slightly more frequent supplemental doses than adults (Prod Info vecuronium bromide intravenous injection lyophilized powder for solution, 2014)
    3) 10 TO 16 YEARS: INITIAL: 0.08 to 0.1 mg/kg IV bolus (Prod Info vecuronium bromide intravenous injection lyophilized powder for solution, 2014)
    4) 10 TO 16 YEARS: MAINTENANCE: 0.01 to 0.015 mg/kg IV 25 to 40 min after initial dose, repeat every 12 to 15 min as needed; may require more frequent supplementation than adults (Prod Info vecuronium bromide intravenous injection lyophilized powder for solution, 2014)
    5) 1 year of age or older: 0.1 mg/kg IV push, as needed for paralysis. Usually dosing interval is 1 to 2 hours. Adjust dose as needed based on duration of paralysis (Playfor et al, 2007; Meakin, 2001; Soriano et al, 2001; Xue et al, 1998; De & Paul, 1991; Goudsouzian et al, 1983). Less than 1 year of age, 0.06 to 0.08 mg/kg IV push (Meretoja, 1990; Meretoja et al, 1988)

Minimum Lethal Exposure

    A) No lethal doses have been established; however, any dose may be sufficient to cause respiratory paralysis, hypoxia, and death if respiratory assistance is not available.
    B) PANCURONIUM
    1) CASE REPORT: A 46-year-old woman was found dead with a 2 mL syringe and an empty ampule of pancuronium bromide (4 mg/2 mL) in her hand. An autopsy, performed six days later, determined the cause of death to be respiratory failure. Analysis of the volume of fluid residue found in the syringe estimated that the injected pancuronium bromide dose was 2.6 mg (Kala & Lechowicz, 2004).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) ATRACURIUM
    a) Doses of 0.2 to 0.4 mg/kg of atracurium may produce facial flushing but few cardiovascular effects (Anon, 1984).
    b) CASE REPORT: Inadvertent administration of 13.4 mg/kg to a 2-month-old infant resulted in flushing with no cardiovascular effects (Charlton et al, 1989).
    c) CASE REPORT: A 38-year-old woman who was undergoing abdominal hysterectomy, inadvertently received 25 mg of atracurium intrathecally during spinal anesthesia. No sensory or motor block, hemodynamic changes or nerve disturbances were observed (Zirak et al, 2011).
    d) CASE REPORT: A 17-year-old girl developed moderate hemodynamic changes (13% increase in mean arterial pressure and 27% increase in heart rate) after inadvertently receiving atracurium 1.3 mg/kg. She recovered 40 minutes later without requiring any treatment. The maximum recommended doses in adults produces "the time from injection to 25% recovery" of 35 to 45 minutes which is half the time for this patient (83 minutes) (Prod Info atracurium besylate intravenous injection solution, 2011).
    e) Three children (3 weeks, 4 and 5 months of age) developed minimal cardiovascular changes after inadvertently receiving atracurium doses of 0.8 mg/kg to 1 mg/kg (Prod Info atracurium besylate intravenous injection solution, 2011).
    2) PANCURONIUM
    a) CASE REPORT: Accidental subarachnoid injection of 4 mg of pancuronium bromide resulted in a generalized muscle hypotonia and hypoventilation within 15 minutes. The patient was given neostigmine 2.5 mg and atropine 1 mg intravenously to reverse the neuromuscular blockade. The hypoventilation reversed within minutes and the patient recovered with no neurologic sequelae (Peduto et al, 1989).
    3) RAPACURONIUM
    a) CASE REPORT: A 22-year-old pregnant woman received an overdose of rapacuronium, 5 mg/kg, during rapid sequence induction for cesarean section. Although the patient did not meet extubating criteria for greater than 2 hours after rapacuronium administration, there was no evidence of respiratory distress in the recovery room and the premature infant did not show any neuromuscular weakness (Prod Info Raplon(TM), rapacuronium bromide, 1999).
    4) VECURONIUM
    a) CASE REPORT: An accidental injection of 2 mg of vecuronium into the right radial arterial catheter in a 77-year-old man resulted in severe pain in his right hand. The arterial catheter was allowed to bleed back freely which relieved the pain. No other adverse effects were noted (Gabrielczyk & Forensky, 1988).
    b) CASE REPORT: A 9.7 kg toddler (age 23 months) inadvertently received 37 mg (3.83 mg/kg/hour) of vecuronium intravenously over 1 hour. This represents a 50-fold overdose based on the recommended infusion rate (0.5 to 0.8 mg/kg/hour). The toddler remained hemodynamically unchanged and no evidence of histamine release was noted; no change in cardiovascular support was required (Forrest & Vanner, 1990).
    c) CASE REPORT: A 5-kg 2-month-old infant received 5 mg vecuronium incrementally over 55 minutes during general anesthesia. Extubation was possible 4.5 hours after his last dose of vecuronium and he recovered uneventfully (Hiroto et al, 2005).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) PANCURONIUM: The initial postmortem blood and liver concentrations of pancuronium in a 46-year-old woman were 81 ng/mL and 532 ng/g, respectively. Storage of the samples at minus 20 degrees celsius, for seven months, showed that the pancuronium concentration of the blood sample remained stable, and the concentration of the liver sample was variable. However, storage of the blood sample at 20 degrees celsius for three months decreased the pancuronium concentration to 10% of its initial value, demonstrating that pancuronium degradation is dependent on the temperature and the biological matrix (Kala & Lechowicz, 2004).
    2) ATRACURIUM: A 45-year-old anesthesiologist was found dead with an empty syringe nearby. Analysis of the syringe, using gas chromatography-mass spectrometry, detected the presence of laudanosine, a metabolite of atracurium. Toxicological analysis of the patient's biological samples revealed the following postmortem concentrations of laudanosine (Martinez et al, 2006):
    1) Heart blood: 0.6 mg/L
    2) Urine: 0.3 mg/L
    3) Vitreous humor: 0.02 mg/L

Pharmacology Toxicology

Toxicologic Mechanism

    A) The prototype agent for this group is tubocurarine chloride, a curare alkaloid extracted from a plant Chondodendron tomentosum.
    B) These agents block myoneural transmission to skeletal muscles by competing with acetylcholine for the cholinergic receptor sites at the neuromuscular junction of skeletal muscles.
    C) By occupying the receptor sites, they block the transmitter action of acetylcholine and produce total paralysis of the muscle fibers that lasts as long as the drug remains bound at the end-plate.
    D) This competitive block may be reversed by anticholinesterase agents such as neostigmine and edrophonium.
    E) Non-depolarizing blocking agents are used to reduce the tone or contractile power of the skeletal muscle as adjuncts to general anesthesia and other operative procedures (Gilman et al, 1990).

Physicochemical

Ph

    A) ATRACURIUM: The pH of Tracarium(R) is adjusted to 3.25-3.65 with benzenesulfonic acid (Technical Information, 1985). The multiple dose vial contains 0.9% benzyl alcohol as a preservative.
    B) MIVACURIUM: 3.5-5.0 (Mivacron(R) Injection) (Prod Info, 1992)

Molecular Weight

    A) Varies

References

General Bibliography

    1) AMA Council on Drugs: AMA Drug Evaluations, 5th ed, American Medical Association, Chicago, IL, 1983.
    2) Abouleish E, Wingard LB Jr, & de la Vega S: Pancuronium in caesarean section and its placental transfer. Br J Anaesth 1980; 52:531-536.
    3) Abrams RE & Hornbein TF: Inability to reverse pancuronium blockade in a patient with renal failure and hepatic disease. Anesthesiology 1975; 42:362-364.
    4) Agoston S, Vermeer GA, & Kersten VW: The fate of pancuronium bromide in man. Acta Anesth Scand 1973b; 17:267-275.
    5) Aldrete JA: Allergic reaction after atracurium. Br J Anaesth 1985; 57:929-930.
    6) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    7) Anon: Atracurium. Med Lett 1984; 26:53-54.
    8) Anon: Voluntary Market Withdrawal. Adverse Drug Reaction. U.S. Food and Drug Administration. Rockville, MD, USA. 2001. Available from URL: http://www.fda.gov/medwatch/safety/2001/raplon_DDL.htm. As accessed Accessed April 2, 2001.
    9) Balamoutsos NG, Papastephanou C, & Skourtis HT: Potentiation and prolongation of neuromuscular blockade of pancuronium with d-tubocurarine. Anesth Analg 1981; 60:229.
    10) Barnes PK, Thomas VJE, & Boyd I: Comparison of the effects of atracurium and tubocurarine on heart rate and arterial pressure in anaesthetized man. Br J Anaesth 1983a; 55(suppl 1):91S-94S.
    11) Barnes PK, Thomas VJE, Boyd I, et al: Comparison of the effects of atracurium and tubocurarine on heart rate and arterial pressure in anaesthetized man. Br J Anaesth 1983; 55(suppl 1):91S-94S.
    12) Basta SJ, Ali HH, Savarese JJ, et al: Clinical pharmacology of atracurium besylate (BW 33A): A new non-depolarizing muscle relaxant. Anesth Analg 1982a; 61:723-729.
    13) Basta SJ, Ali J, & Savarese HH: Clinical pharmacology of atracurium besylate (BW33A): a new non-depolarizing muscle relaxant. Anesth Analg 1982; 61:723-729.
    14) Basta SJ, Savarese JJ, & Ali HH: Histamine-releasing potencies of atracurium, dimethyl tubocurarine and tubocurarine. Br J Anaesth 1983; 55(suppl 1):105S-106S.
    15) Beam LR: Pancuronium bromide side effects. JAMA 1973; 223:1044.
    16) Bevan JC, Collins L, Fowler C, et al: Early and late reversal of rocuronium and vecuronium with neostigmine in adults and children. Anesth Analg 1999; 89(2):333-339.
    17) Bevan JC, Purday JP, Reimer EJ, et al: Reversal of doxacurium and pancuronium neuromuscular blockade with neostigmine in children. Can J Anaesth 1994; 41(11):1074-1080.
    18) Brauer FS & Ananthanarayan CR: Bronchospasm after pancuronium bromide. Anesthesiology 1978; 49:434.
    19) Brichard G: Pancuronium or arrhythmogenic effect in patients under halothane. Anesth Analg 1973; 30:947-950.
    20) Bunchman TE, Lynch RE, & Wood EG: Intravenously administered labetalol for treatment of hypertension in children. J Pediatr 1992; 120(1):140-144.
    21) Buzello W: The metabolism of pancuronium in man. Anaesthesist 1975; 24:13-16.
    22) Carter ML: Bradycardia after the use of atracurium. Br Med J 1983; 287:247-248.
    23) Carter ML: Bradycardia after the use of atracurium. Br Med J 1983a; 287:247-248.
    24) Charlton AJ, Harper NJN, & Edwards D: Atracurium overdose in a small infant. Anaesthesia 1989; 44:485-486.
    25) Cohen AY & Frank G: Periorbital edema after atracurium administration. Anesthesiology 1987; 66:431-432.
    26) Coker GG, Dewar GH, & Hughes R: A preliminary assessment of atracurium, a new competitive neuromuscular blocking agent. Acta Anaesth Scand 1981; 25:67-69.
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