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MONENSIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Monensin is a highly sodium-selective carboxylic, polyether ionophore antibiotic produced by Streptomyces cinnamonensis. It facilitates the transmembrane exchange of sodium for other protons, increasing intracellular sodium concentration. It is classified as an antibiotic, antifungal and antiprotozoal agent and is used in both veterinary practice and as a growth promotor for cattle.

Specific Substances

    1) A 3823A
    2) ATCC 15413
    3) Elancoban
    4) Lilly 67314
    5) Monelan
    6) Monensic acid
    7) Monensin A
    8) Monensin sodium
    9) Rumensin(R)
    10) Molecular Formula: C36-H62-O11
    11) CAS 17090-79-8 (monensin)
    12) CAS 22373-78-0 (monensin sodium)

Available Forms Sources

    A) FORMS
    1) Monensin sodium is an off-white to tan crystalline powder. It is slightly soluble in water; soluble in chloroform and in methyl alcohol; practically insoluble in mineral spirits (S Sweetman , 2001).
    B) SOURCES
    1) Monensin is a mixture of antibiotic substances produced by the fungus, Streptomyces cinnamonensis (S Sweetman , 2001).
    C) USES
    1) Monensin sodium, an antiprotozoal agent, is used in veterinary medicine for the prevention of coccidiosis in poultry and pigs and as a growth promotor for cattle. It is also used to treat toxoplasmosis in sheep (S Sweetman , 2001; Ryley & Wilson, 1975).
    2) In cattle, monensin changes rumen microbial population to increase production of propionic acid, increasing feed efficiency in confined beef and dairy cattle. It also prevents and controls coccidiosis of cattle. Continuous administration of low doses of monensin is given to cattle. It is the most widely used product of its type in cattle fed in the United States. Animals grow faster on less feed. Monensin has a relatively narrow therapeutic window, with episodes of severe and lethal intoxications reported in many animal species, e.g., cattle, poultry, sheep, horses, and dogs (Caldeira et al, 2001; Kouyoumdjian et al, 2001; Mollenhauer et al, 1990).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) HUMANS - Clinical manifestations following ingestion have included rhabdomyolysis, acute renal failure, acidosis and pulmonary edema. Initial main symptoms include muscular weakness, myalgia, malaise and fever. Death due to irreversible cardiopulmonary arrest has been reported. The major target organs for toxicity are the skeletal muscles and the heart.
    B) ANIMALS - Monensin has a relatively narrow therapeutic window, with episodes of severe and lethal intoxications reported in many animal species, e.g., cattle, poultry, sheep, horses, and dogs. One of the most striking findings of experimental or accidental monensin intoxication in animals is muscle necrosis and myoglobinuria. Target organs of monensin poisoning are skeletal and cardiac muscles. Intoxication in animals produces similar findings to those found in humans.
    0.2.5) CARDIOVASCULAR
    A) Monensin may cause an initial inotropism, followed by later cardiomyopathy with progressive negative inotropic effects; cardiac failure may occur.
    B) Tachycardia is a common finding.
    0.2.6) RESPIRATORY
    A) Pulmonary edema is a classic effect of severe monensin poisoning. Dyspnea and respiratory compromise may occur.
    0.2.7) NEUROLOGIC
    A) Effects may include hyporeflexia, weakness, flaccid paralysis and ataxia.
    0.2.8) GASTROINTESTINAL
    A) Nausea and vomiting may occur following ingestion of monensin.
    0.2.9) HEPATIC
    A) Elevated LDH, AST, ALT, and GGT may develop. In humans this has been associated with severe rhabdomyolysis. Poisoned animals have developed hepatocellular necrosis.
    0.2.10) GENITOURINARY
    A) Acute renal failure is common following poisoning in animals and humans.
    0.2.14) DERMATOLOGIC
    A) Profuse sweating may be seen in poisoning cases.
    0.2.15) MUSCULOSKELETAL
    A) Myalgias, skeletal muscle weakness and injury with rhabdomyolysis are typical in severe poisonings.
    0.2.20) REPRODUCTIVE
    A) Fetal growth retardation has been reported in experimental animals.

Laboratory Monitoring

    A) Serum levels of monensin are not readily available nor clinically useful.
    B) Monitor fluid and serum electrolyte status.
    C) Monitor kidney and liver function tests (LDH, AST, ALT, GGT) CK and myoglobin levels in symptomatic patients.
    D) Monitor urinalysis and urine output in patients with rhabdomyolysis.
    E) Obtain chest x-ray in all symptomatic patients.
    F) Monitor vital signs. Tachycardia is common. Hypotension has been reported.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) There is no antidote for monensin poisoning. Treatment is symptomatic and supportive.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    D) RHABDOMYOLYSIS: Administer sufficient 0.9% saline (10 to 15 mL/kg/hour) to maintain urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hr). Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output, but should only be considered if urine output is inadequate after volume status is restored. Urinary alkalinization is NOT routinely recommended.
    E) Fluid and electrolyte replacement may be necessary.
    F) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gas or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed. Treat volume overload with diuretics and hemodialysis if renal failure develops.
    G) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    H) Hemodialysis may be required if renal failure develops.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) Ingestion of approximately 500 mg monensin resulted in rhabdomyolysis, acute renal failure, pulmonary edema, heart failure and death in a teenager.

Clinical Effects

Summary Of Exposure

    A) HUMANS - Clinical manifestations following ingestion have included rhabdomyolysis, acute renal failure, acidosis and pulmonary edema. Initial main symptoms include muscular weakness, myalgia, malaise and fever. Death due to irreversible cardiopulmonary arrest has been reported. The major target organs for toxicity are the skeletal muscles and the heart.
    B) ANIMALS - Monensin has a relatively narrow therapeutic window, with episodes of severe and lethal intoxications reported in many animal species, e.g., cattle, poultry, sheep, horses, and dogs. One of the most striking findings of experimental or accidental monensin intoxication in animals is muscle necrosis and myoglobinuria. Target organs of monensin poisoning are skeletal and cardiac muscles. Intoxication in animals produces similar findings to those found in humans.

Vital Signs

    3.3.3) TEMPERATURE
    A) Fever may occur as an initial effect of monensin poisoning following ingestion (Kouyoumdjian et al, 2001).

Heent

    3.4.3) EYES
    A) IRRITATION - Monensin is reported to be a moderate eye irritant in the standard Draize rabbit test (Gad et al, 1985).

Cardiovascular

    3.5.1) SUMMARY
    A) Monensin may cause an initial inotropism, followed by later cardiomyopathy with progressive negative inotropic effects; cardiac failure may occur.
    B) Tachycardia is a common finding.
    3.5.2) CLINICAL EFFECTS
    A) CARDIOMYOPATHY
    1) A biphasic pattern of cardiomyopathy is reported in experimental monensin toxicology studies. An initial inotropism, likely related to intracellular calcium influx and release of catecholamines is noted. This is followed by later progressive negative inotropic effect and degenerative changes leading to cardiac failure (Oehme & Pickrell, 1999; Dacasto et al, 1999; Galitzer et al, 1986; Galitzer et al, 1986a; Muylle et al, 1981; Bassett et al, 1978; Sutko et al, 1977). The main structural changes seen in experimental studies and necropsy are cardiac muscle cellular necrosis affecting type I and type II fibers and pulmonary edema.
    a) An increase in intracellular calcium is of primary importance in injury due to monensin in the skeletal muscle and myocardial cells because toxic levels of calcium are reached leading to activation of phospholipases and proteolytic enzymes (Shier & DuBourdieu, 1992; Lattanzio et al, 1986; Bassett et al, 1978). Selective injury to atrial myocardium with extensive necrosis has been shown in animal studies (Van Vleet & Ferrans, 1984).
    2) CASE REPORT - A 16-year-old male died 11 days after ingestion of approximately 500 mg monensin. Death was due to irreversible cardiopulmonary arrest following a course of hemodynamic instability. Autopsy revealed diffuse pulmonary edema and severe skeletal muscle myocytolysis. No morphologic changes in the heart muscle were seen by optical microscopy; however, immunoperoxidase staining revealed focal deposition of C9 (Caldeira et al, 2001).
    B) TACHYARRHYTHMIA
    1) Tachycardia is a common finding in monensin poisonings among different animal species and has been reported in human poisoning cases (Caldeira et al, 2001; Kouyoumdjian et al, 2001; Bezerra et al, 1999; Novilla, 1992; Galitzer et al, 1986a).
    C) HYPOTENSIVE EPISODE
    1) Hemodynamic instability with hypotension and shock may occur following a significant ingestion. Caldeira et al (2001) reported a 16-year-old male who developed rhabdomyolysis, acute renal failure, respiratory failure and hypotension requiring norepinephrine to maintain blood pressure. The patient died 11 days postingestion despite aggressive therapy.

Respiratory

    3.6.1) SUMMARY
    A) Pulmonary edema is a classic effect of severe monensin poisoning. Dyspnea and respiratory compromise may occur.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) Pulmonary edema is a major structural change found in experimental studies and necropsy following monensin poisoning (Bila et al, 2001; Novilla, 1992; Mousa & Elsheikh, 1992; Galitzer et al, 1986; Schweitzer et al, 1984; Todd et al, 1984). Significant histologic lesions seen after poisoning include pulmonary interstitial and alveolar edema with fibrin exudation. Late onset (one week or more) pulmonary edema may be seen in human cases (Caldeira et al, 2001; Kouyoumdjian et al, 2001).
    2) CASE REPORT - Severe pulmonary congestion and edema without acute myocardial injury in a previously healthy 16-year-old male was reported about 9 days after the ingestion of approximately 500 mg monensin (Caldeira et al, 2001). The patient died 11 days after ingestion. Autopsy revealed a diffuse pulmonary edema. The pulmonary changes in this patient were probably secondary to heart failure and rhabdomyolysis, although a direct toxicity of monensin on lung structures cannot be totally ruled out.
    3) CASE REPORT - A 17-year-old male developed rhabdomyolysis with acute renal failure about 9 to 10 days after monensin ingestion. About 2 weeks after ingestion, pulmonary edema developed with death resulting, in spite of aggressive therapy, including hemodialysis (Kouyoumdjian et al, 2001).
    B) RESPIRATORY FAILURE
    1) Pulmonary congestion leading to dyspnea and respiratory compromise has been reported (Caldeira et al, 2001). Dyspnea and respiratory compromise are due to structural muscle changes from altered transport of cations (Mousa & Elsheikh, 1992).

Neurologic

    3.7.1) SUMMARY
    A) Effects may include hyporeflexia, weakness, flaccid paralysis and ataxia.
    3.7.2) CLINICAL EFFECTS
    A) HYPOREFLEXIA
    1) Global areflexia was reported in two patients with lethal overdoses, in one case 5 days after monensin ingestion (Caldeira et al, 2001) and approximately 10 days after ingestion in another case (Kouyoumdjian et al, 2001).
    B) CENTRAL NERVOUS SYSTEM FINDING
    1) The pattern of monensin poisoning in different animal species includes CNS depression, locomotor deficits, flaccid paralysis, and ataxia (Caldeira et al, 2001; Novilla, 1992; Jeffrey et al, 1989; Todd et al, 1984). Similar effects are expected in humans. Drowsiness has been reported in one human case following ingestion (Kouyoumdjian et al, 2001).
    2) CASE REPORT - Fatal rhabdomyolysis after acute ingestion is reported in a 17-year-old male. Postmortem findings of the cerebellum revealed no abnormalities. The authors suggest that ataxia and incoordination reported in animal studies may be due to the rhabdomyolysis rather than cerebellar ataxia (Kouyoumdjian et al, 2001).
    C) TREMOR
    1) A case of mild unilateral tremor, which occurred approximately one month following several days of dermal exposure to monensin, has been reported in a 67-year-old male. No progression of symptoms occurred over the next 9 months. A temporal relationship suggests monensin may be a neurotoxin and may be absorbed dermally (Blumenthal & Vance, 1988).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea and vomiting may occur following ingestion of monensin.
    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) Nausea, vomiting, abdominal pain, diarrhea and loss of appetite may occur following an ingestion (Caldeira et al, 2001). In one case, nausea and vomiting occurred within 6 hours of ingestion (Caldeira et al, 2001).

Hepatic

    3.9.1) SUMMARY
    A) Elevated LDH, AST, ALT, and GGT may develop. In humans this has been associated with severe rhabdomyolysis. Poisoned animals have developed hepatocellular necrosis.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) Significant histologic lesions found after monensin poisoning in experimental studies include hepatocellular necrosis. A similar pattern is seen in monensin intoxications in various animal species, which includes elevations in serum hepatic enzyme levels (Bezerra et al, 1999; Novilla, 1992; Mousa & Elsheikh, 1992; Dalvi & Sawant, 1990; Schweitzer et al, 1984; Todd et al, 1984; Muylle et al, 1981) Wilson, 1980).
    2) CASE REPORT - Five days after the ingestion of approximately 500 mg monensin, a 16-year-old male was reported to have elevated serum hepatic enzyme levels (AST 8970 IU/L; ALT 2166 IU/L; LDH 13100 IU/L). The patient died 11 days postingestion due to rhabdomyolysis, acute renal failure and heart failure (Caldeira et al, 2001).

Genitourinary

    3.10.1) SUMMARY
    A) Acute renal failure is common following poisoning in animals and humans.
    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) A similar pattern of intoxication occurs in various animal species and includes acute renal failure (Bezerra et al, 1999; Novilla, 1992; Todd et al, 1984; Muylle et al, 1981) Wilson, 1980), which is also reported in human poisonings (Caldeira et al, 2001; Kouyoumdjian et al, 2001).
    2) CASE REPORT - Hemoconcentration, rhabdomyolysis and acute renal failure were confirmed via laboratory tests 5 days after the ingestion of approximately 500 mg monensin by a 16-year-old male. Four days later hemodialysis was started. However, the patient deteriorated after developing hemodynamic instability and respiratory failure with progressive acidosis and hyperkalemia. The patient died 11 days postingestion with irreversible cardiopulmonary arrest. Autopsy revealed acute tubular damage (Caldeira et al, 2001).
    3) CASE REPORT - A 17-year-old male ingested an unknown amount of monensin and developed rhabdomyolysis with acute renal failure within approximately 10 days of the ingestion. Postmortem examination revealed extensive deposition of orange-brown casts, particularly in the medulla of the kidney. Several calcified tubules in the cortex, with iron, were seen. Deposition of myoglobin in casts were seen with an immunoperoxidase study. Myoglobinuria was diagnosed (Kouyoumdjian et al, 2001).
    B) ABNORMAL URINE
    1) Dark brown urine may develop following acute poisoning. This is a sign of myoglobinuria and rhabdomyolysis (Kouyoumdjian et al, 2001; Caldeira et al, 2001).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) Following a large ingestion, acute renal failure may occur followed by a progressive acidosis. Caleira et al (2001) reported acute renal failure in a 16-year-old male after a large ingestion which was followed by a progressive hyperkalemia and acidosis (pH 7.23 at 10 and 11 days postingestion). The patient died despite aggressive therapy. It was suggested that the acidosis may have been a result of monensin-induced lactate production in skeletal muscle.

Dermatologic

    3.14.1) SUMMARY
    A) Profuse sweating may be seen in poisoning cases.
    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) Profuse sweating is part of a pattern of monensin poisoning seen in different animal species and reported in human cases (Caldeira et al, 2001; Kouyoumdjian et al, 2001; Novilla, 1992).

Musculoskeletal

    3.15.1) SUMMARY
    A) Myalgias, skeletal muscle weakness and injury with rhabdomyolysis are typical in severe poisonings.
    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) A similar pattern of toxicosis is seen in different animal species, which includes elevated serum creatine kinase, myoglobinuria, acute renal failure, and skeletal muscle weakness. The major target organs for toxicity are the skeletal muscles and the heart (Dacasto et al, 1999; Bezerra et al, 1999). Muscle damage is the hallmark of monensin toxicity in animals; however, it is not pathognomonic of monensin poisoning (James et al, 1996; Jeffrey et al, 1989; Umemura et al, 1985; Todd et al, 1984) Wilson, 1980). Structural changes reported after poisoning include cardiac and skeletal muscle cellular necrosis affecting type I and type II fibers as well as pulmonary edema.
    a) In human poisonings, rhabdomyolysis followed by acute renal failure, heart failure and death have been reported (Caldeira et al, 2001; Kouyoumdjian et al, 2001). Clinical signs of rhabdomyolysis have occurred several days after ingestion.
    2) CASE REPORT - Following the ingestion of approximately 500 mg monensin, a 16-year-old male developed early onset (5 days postingestion) severe rhabdomyolysis, with myalgia, muscular weakness, dark brown urine, and extremely increased serum creatine phosphokinase (233,200 IU/L). Acute renal failure and hemodynamic instability followed. The patient died 11 days after the ingestion, despite aggressive therapy and hemodialysis. Autopsy showed a severe skeletal muscle myocytolysis and the presence of myoglobin in the lumen of renal tubules (Caldeira et al, 2001).
    3) CASE REPORT - A 17-year-old male was admitted to the ED 6 to 7 days after ingesting an unknown amount of monensin, possibly for muscle development. He was treated for nausea and abdominal pain. Two days later, weakness and severe muscle pain, mainly in the lower limbs, and a dark brown colored urine was noted. An elevated serum CPK of 233,200 U/L as well as elevated serum liver enzymes were reported on admission. Following histochemistry staining of the Deltoideus, muscle necrosis was noted. The patient died after acute rhabdomyolysis with renal failure (Kouyoumdjian et al, 2001).

Reproductive

    3.20.1) SUMMARY
    A) Fetal growth retardation has been reported in experimental animals.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Atef et al (1986) reported fetal growth retardation in rats but no teratogenicity at oral doses of 1.75 mg/kg/day on days 9-17 of pregnancy (period of fetal organogenesis). No fetal survivors were found at dosages of 3.5 mg/kg/day. De Souza Spinosa et al (1999) reported a notable adverse effect on growth of offspring (at postnatal days 10 until 21) of rat dams fed 100 to 300 ppm monensin in their diets. The pups showed no external signs of malformation.
    2) In long-term chronic reproduction studies of monensin in cattle, no detrimental effects upon reproduction were reported (Potter et al, 1984).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Serum levels of monensin are not readily available nor clinically useful.
    B) Monitor fluid and serum electrolyte status.
    C) Monitor kidney and liver function tests (LDH, AST, ALT, GGT) CK and myoglobin levels in symptomatic patients.
    D) Monitor urinalysis and urine output in patients with rhabdomyolysis.
    E) Obtain chest x-ray in all symptomatic patients.
    F) Monitor vital signs. Tachycardia is common. Hypotension has been reported.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor fluids and serum electrolytes in all symptomatic patients. An excessively high intracytoplasmatic calcium level may occur at the cellular level in poisonings (Kouyoumdjian et al, 2001). Excessive vomiting and/or diarrhea may occur.
    2) Following an ingestion, all patients should have serum creatine phosphokinase monitored for potential rhabdomyolysis.
    3) Monitor renal and hepatic function tests in all patients following exposure to monensin.
    B) ACID/BASE
    1) Follow acid/base status in all symptomatic patients following significant exposure. Severe metabolic acidosis has been reported in patients with rhabdomyolysis and renal failure (Caldeira et al, 2001).
    4.1.3) URINE
    A) URINALYSIS
    1) Monitor for myoglobinuria in all symptomatic patients. Urine may be dark brown in color. Fatal rhabdomyolysis has been reported following acute monensin ingestion (Caldeira et al, 2001; Kouyoumdjian et al, 2001).
    2) Monitor fluid intake and urine output in patients with rhabdomyolysis.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Monitor chest x-ray in all symptomatic patients. Pulmonary edema is a significant manifestation of monensin poisoning.

Methods

    A) CHROMATOGRAPHY
    1) A liquid chromatography tandem mass spectrometry (LC-MS-MS) method with electrospray (ES) for the determination of traces of monensin in chicken liver and eggs is described for the screening and determination of low concentrations of the drug (Rosen, 2001).
    2) Vanderkop & MacNeil (1989) described a thin-layer chromatography/bioautography (TLC/B) method for the detection and quantification of monensin in poultry tissues, but not in fatty tissue. Recovery from cardiac muscle, skeletal muscle, and liver and kidney tissues was reported in the range of 93% to 97%, with a detection limit of 250 mcg/kg with 99% reliability.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Serum levels of monensin are not readily available nor clinically useful.
    B) Monitor fluid and serum electrolyte status.
    C) Monitor kidney and liver function tests (LDH, AST, ALT, GGT) CK and myoglobin levels in symptomatic patients.
    D) Monitor urinalysis and urine output in patients with rhabdomyolysis.
    E) Obtain chest x-ray in all symptomatic patients.
    F) Monitor vital signs. Tachycardia is common. Hypotension has been reported.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Due to slow gastric absorption, gastric decontamination may be of benefit.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) SUPPORT
    1) There is no antidote for monensin poisoning. Treatment is symptomatic and supportive.
    B) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).
    C) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Monitor urinary output and serum electrolytes in symptomatic patients. Fluid replacement may be necessary.
    D) ACUTE LUNG INJURY
    1) NON-PHARMACOLOGIC TREATMENT: Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 milliliters/kilogram) is preferred if ARDS develops.
    2) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 milliliters/kilogram) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000).
    3) FLUIDS: Crystalloid solutions must be administered cautiously, AVOIDING a net positive fluid balance. Monitor fluid status through a central line or Swan Ganz(R) catheter.
    4) DIURETICS: May be needed, particularly in patients with renal insufficiency or rhabdomyolysis.
    5) ANTIBIOTICS: Indicated only when there is evidence of infection.
    6) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    E) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    4) DOBUTAMINE
    a) DOSE: ADULT: Infuse at 5 to 10 micrograms/kilogram/minute IV. PEDIATRIC: Infuse at 2 to 20 micrograms/kilogram/minute IV or intraosseous, titrated to desired effect (Peberdy et al, 2010; Kleinman et al, 2010).
    b) CAUTION: Decrease infusion rate if ventricular ectopy develops (Prod Info dobutamine HCl 5% dextrose intravenous injection, 2012).
    F) HEMODIALYSIS
    1) It is unknown if hemodialysis will clear monensin from the body. Acute renal failure is a prominent manifestation of poisoning, and often requires hemodialysis.
    G) CONTRAINDICATED TREATMENT
    1) Various calcium modulators were used to treat mice given different lethal doses of monensin. Verapamil, diltiazem, lidocaine, yohimbine, and tolazoline all potentiated monensin toxicity, while chlorpromazine, propranolol, and digoxin had no effect on monensin toxicity. The authors suggest that excess calcium ion influx may not be the only factor responsible for toxicity in mice (Mitema et al, 1988). Slow and fast calcium channel blockers and other drugs which antagonize calcium do not appear to be cardioselective and do not reduce monensin toxicosis, thus are NOT recommended in human poisoning cases.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) SUMMARY
    1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Abstracts

Case Reports

    A) ADULT
    1) Following the ingestion of approximately 500 mg monensin, a 16-year-old male developed early onset (5 days postingestion) severe rhabdomyolysis, with myalgia, muscular weakness, dark brown urine, and extremely increased serum creatine phosphokinase (233,200 IU/L on admission). Acute renal failure and hemodynamic instability with progressive acidosis and hyperkalemia followed about 4 days later.
    a) The patient died 11 days after the ingestion, despite aggressive therapy and hemodialysis. Autopsy showed diffuse pulmonary edema, a severe skeletal muscle myocytolysis and the presence of myoglobins in lumen tubules. No morphologic alterations were noted in the heart muscle seen by optical microscopy, but immunoperoxidase staining disclosed focal deposition of C9; no significant changes in other organs were reported (Caldeira et al, 2001).

Range Of Toxicity

Summary

    A) Ingestion of approximately 500 mg monensin resulted in rhabdomyolysis, acute renal failure, pulmonary edema, heart failure and death in a teenager.

Minimum Lethal Exposure

    A) ADULT
    1) Following the ingestion of approximately 500 mg monensin, a 16-year-old male developed early onset (5 days postingestion) and severe rhabdomyolysis (serum CPK, 233,200 IU/L). Acute renal failure and hemodynamic instability with progressive acidosis and hyperkalemia followed about 4 days later. The patient died 11 days after the ingestion, despite aggressive therapy and hemodialysis. Autopsy showed diffuse pulmonary edema, a severe skeletal muscle myocytolysis and the presence of myoglobins in lumen tubules (Caldeira et al, 2001).
    2) A 17-year-old male died about 11 days after ingesting an unknown amount of monensin with rhabdomyolysis, myoglobinuria, acute renal failure and pulmonary congestion (Kouyoumdjian et al, 2001).
    B) ANIMAL DATA
    1) ANIMALS - Monensin has a relatively narrow therapeutic window, with episodes of severe and lethal intoxications reported in many animal species, e.g., cattle, poultry, sheep, horses, and dogs (Caldeira et al, 2001). In mice, monensin caused death in a dose-dependent manner (Mitema et al, 1988). Higher doses are likely to produce cardiomyopathic changes and death due to increases in intracellular calcium ions.
    a) Severity of skeletal and cardiac muscle lesions may depend upon dose and duration of exposure to monensin. Animals dying soon after exposure may have no significant lesions, or lesions may be subtle (Bila et al, 2001).
    b) Horses have the greatest sensitivity to monensin, with an LD50 of 2 to 3 milligrams/kilogram body weight (Bezerra et al, 1999).

Maximum Tolerated Exposure

    A) ADULT
    1) DERMAL EXPOSURE to excessive monensin for several days resulted in a mild unilateral resting tremor in a 67-year-old male one month after the exposure. The authors suggest a temporal relationship with monensin (Blumenthal & Vance, 1988).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) MONENSIN
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) >10 mg/kg (RTECS, 2002)
    2) LD50- (ORAL)MOUSE:
    a) 44 mg/kg (RTECS, 2002)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 15 mg/kg (RTECS, 2002; Gad et al, 1985)
    4) LD50- (ORAL)RAT:
    a) 100 mg/kg (RTECS, 2002; Gad et al, 1985)
    B) MONENSIN SODIUM
    1) LD50- (ORAL)MOUSE:
    a) 44 mg/kg (RTECS, 2002)
    2) LD50- (ORAL)RAT:
    a) 29 mg/kg (RTECS, 2002)

Pharmacology Toxicology

Toxicologic Mechanism

    A) Toxicity of monensin is due primarily to its ability to increase intracellular sodium concentration. Monensin is a Na+-selective carboxylic ionophore which forms lipid-soluble cation complexes that can traverse cell membranes rapidly. A rise in intracellular sodium concentration can lead to a secondary increase in cytosolic calcium, most likely due to an increase in calcium influx through the Na+/Ca+ exchange pump, with release of calcium from mitochondria and sarcoplasmic reticula, and decreased efflux of calcium from the cell. The increase in intracellular calcium is a primary factor in the injury induced by monensin in the skeletal muscle and myocardial cells because toxic levels of calcium are reached leading to activation of phospholipases and proteolytic enzymes. The effect on cardiac contractility would be due in part to an increase in the availability of intracellular calcium to troponin C during a contraction (Takahashi et al, 2000; James et al, 1996; Shier & DuBourdieu, 1992; Mollenhauer et al, 1990; Lattanzio et al, 1986; Gad et al, 1985; Pressman & Fahim, 1983; Sutko et al, 1977).
    1) Various calcium modulators were used to treat mice given different lethal doses of monensin. Verapamil, diltiazem, lidocaine, yohimbine, and tolazoline all potentiated monensin toxicity, while chlorpromazine, propranolol, and digoxin had no effect on monensin toxicity. The authors suggest that excess calcium ion influx may not be the only factor responsible for toxicity in mice (Mitema et al, 1988).
    2) Monensin-induced calcium elevation is not a direct cause of coronary vasodilatation. However, a calcium-induced exocytotic release of adenosine from storage granules which activates the adenosinergic receptor of the coronary arteries, and perhaps aided by calcium-induced prostaglandin synthesis, may account for coronary vasodilatation in poisonings (Pressman & Fahim, 1983).
    B) Monensin may induce significant production of lactate in intact muscles via increased glycolysis secondary to elevated activity of Na+, K+ -ATPase. Increased lactate production may be related to acidosis seen following ingestions in humans (Caldeira et al, 2001; James et al, 1996).
    C) Monensin has been shown to induce the release of catecholamines from the adrenals and possibly nerve endings. A rise in plasma glucose induced by monensin may be attributed to an endocytotic release of glucagon from pancreatic alpha cells (Pressman & Fahim, 1983).

Physicochemical

Physical Characteristics

    A) Monensin sodium is an off-white to tan crystalline powder, which is slightly soluble in water, soluble in chloroform and in methyl alcohol, and practically insoluble in mineral spirits (S Sweetman , 2001).

Molecular Weight

    A) 670.892 (monensin)
    B) 692.9 (monensin sodium)

References

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