Important New Information.
Important information on colchicine poisoning

CALL US...TM

The Official Newsletter of the California Poison Control System
Volume 4, Number 2.
Summer, 2006

Diagnosis and Treatment of Colchicine Poisoning

 

Introduction

Colchicine is a widely prescribed and effective medication for the treatment of gouty arthritis. Plants such as autumn crocus or meadow saffron (Colchicum autumnale) and glory lily (gloriosa superba) contain colchicine alkaloids. Colchicine is a mitotic inhibitor that terminates cell division and is thought to have an anti-inflammatory effect as an inhibitor of leukocyte migration and the secretion of inflammatory glycoproteins. Patients with colchicine toxicity initially present with gastrointestinal symptoms of nausea, vomiting, diarrhea and abdominal pain. Delayed symptoms of colchicine toxicity include seizures, cardiac dysrhythmias, hypotension, shock, coagulopathy, pancytopenia and respiratory, renal, and hepatic failure. Death occurs most commonly at two periods following ingestion: within 48 hours due to multiorgan failure and subsequent cardiovascular collapse, or three to seven days post ingestion due to sepsis.

Case presentation

A 78 year old female presented to the Emergency Department (ED) with a history of nausea, vomiting, abdominal pain and diarrhea for three days. One week prior to arrival in the ED the patient was discharged from the hospital for an unknown illness. She was unsure of the names of her medicines but admits to taking some “pain pills”. Her past medical history is significant for arthritis and she has no known drug allergies.

While in the ED the patient became tachycardic, hypotensive with a systolic blood pressure of 50-60 mmHg, and experienced respiratory arrest. She was successfully resuscitated and transferred to the intensive care unit intubated and ventilated. Due to her hypotension, she was started on dopamine, epinephrine, and vasopressin infusions with the following vital signs: blood pressure of 116/88 mmHg, heart rate of 106 beats per minute, and temperature of 94.4 degrees. On physical examination she was unresponsive to painful stimuli, skin was cool and dry, and pupils were midposition and not reactive. Bowel sounds were normal and lungs were clear bilaterally.

Laboratory results included sodium 131 meq/L, potassium 5.0 meq/L, chloride 91 meq/L, carbon dioxide 17 meq/L, blood urea nitrogen 63 mg/dL, serum creatinine 4.4 mg/dL, glucose 91 mg/dL, white blood cell count 1700 cells/mcL, hemoglobin 13.1 gm/dL, platelets reported as clumped, CPK 834 IU/L, CK-MB 13.6 IU/L, troponin < 0.2 ng/mL, AST 129 IU/l, ALT 40 IU/L, alkaline phosphatase 153 IU/L, direct bilirubin 0.7 mg/dL, and total bilirubin 2.0 mg/dL . An arterial blood gas showed pH 7.32, pCO2 23 mmHg, pO2 477, base excess -13.2, and oxygen saturation 99%. An electrocardiogram revealed sinus tachycardia.

The following morning labs showed a sodium 135 meq/L, potassium 3.6 meq/L, chloride 101 meq/L, carbon dioxide 12 meq/L, blood urea nitrogen 47, serum creatinine 3.6 mg/dL, glucose 142 mg/dL, magnesium 3.0 meq/L, calcium 9.3 meq/L, phosphorus 7.1 mmol/L, white blood count 0.8 cell/mcL, hemoglobin 11.2 gm/dL, platelets 93,000/cmm, PT 19 seconds, PTT 39.5 seconds, INR 1.9, and CPK 2983.

Further history revealed the patient had been discharged from the hospital one week ago after an episode of acute gouty arthritis for which she was prescribed colchicine 0.6 mg twice daily. The total amount of colchicine ingested the week prior to arrival in the ED was not available. After multiple cardiac arrests, the family withdrew ventilatory support.

Questions:

1. What signs, symptoms and history should raise a clinician’s index of suspicion for colchicine toxicity in this case?

2. Were the signs and symptoms this patient experienced consistent with the different phases of colchicine toxicity?

3. Is there an antidote available for colchicine poisoning?

Epidemiology

The primary use of colchicine is in the prevention and treatment of painful exacerbations of gouty arthritis. More than two million Americans suffer from gout and risk factors include family history, obesity, and regular consumption of alcohol-containing beverages. Gout results from increased levels of urate and uric acid most commonly due to decreased renal elimination. Although patients may have high urate levels for many years, the onset of episodes of acute gouty arthritis is typically after the age of thirty. Drug-induced gout can result from diuretics, cyclosporine, niacin, or levodopa since all of these agents are known to decrease urate elimination. Excess urate results in deposition of uric acid crystals in joints and synovial fluid. This stimulates mobilization of polymorphonuclear (PMN) leukocytes and other inflammatory mediators to the affected joints, most commonly the great toe or elbow, resulting in severe pain, swelling and an episode of gout.

For the treatment of gout, the recommended dose of colchicine is 0.5 to1.2 mg orally at the onset of symptoms followed by 0.5-0.6 mg every two hours until pain is relieved or nausea, vomiting, or diarrhea develops. Symptoms generally abate within twelve hours and resolve within 48-72 hours. Colchicine is also available in an intravenous formulation given as 2 mg at the onset of symptoms, then 0.5 mg every six hours until symptom improvement up to a maximum dose of 4 mg in a 24 hour period. In the year 2000, mislabeling of IV colchicine as 0.5 mg/mL instead of 5 mg/mL resulted in two cases of significant and prolonged multiorgan toxicity. For patients who experience frequent episodes of gouty arthritis, the recommended prophylaxis dose is up to 2 mg orally daily in divided dosing two to three times per day.

Colchicine alkaloids are found in the plants Colchicum autumnale (autumn crocus, also known as meadow saffron) and Gloriosa superba (glory lily). Less toxicity is reported from colchicine-containing plants than from the medication. Autumn crocus and meadow saffron are native to England, Europe, and Africa but are cultivated throughout the United States and Canada. The seeds can contain up to 0.8% colchicine, the corm (stalk) up to 0.6%, and flowers 0.1%. Colchicine toxicity can result from ingestion of dried plant material as well. The glory lily can be cultivated in the United States but is native to Africa and tropical Asia. The tubers contain approximately 6 mg colchicine per 10 grams of tuber.

Pathophysiology

Colchicine’s effectiveness in treating gout is due to its ability to decrease the response of granulocytes and other inflammatory cells. Colchicine does not decrease urate production, increase renal urate excretion or posses any analgesic properties. Colchicine inhibits cell division early in metaphase by interfering with mitotic spindles and sol-gel transformation in dividing and non-dividing cells. This inhibits the motility, metabolism, and chemotactic ability of leukocytes and eventually results in cell death. Colchicine has also been shown to reduce levels of inflammatory mediators, such as histamine, to further decrease the painful inflammatory response to uric acid crystal deposition. The anti-mitotic effects of colchicine are not specific to granulocytes and affect all cell lines resulting in multi-organ toxicity. The fatality rate for colchicine toxicity is estimated at ten per cent with ingestions of more than 0.5 mg/kg, and may be up to 100% with ingestions greater than 0.8 mg/kg.

Clinical presentation

There are early and late phases of colchicine toxicity. As a mitotic inhibitor, colchicine’s toxic effects are first seen in the rapidly proliferating cells of the gastrointestinal epithelium. Within two to twelve hours of ingestion or administration of IV colchicine, nausea, abdominal pain, vomiting and diarrhea resulting in significant fluid losses may be seen. Electrolyte imbalance and hypotension can occur.

Multiorgan failure follows the initial phase of colchicine poisoning and generally occurs within eight to 72 hours after ingestion. Shock, delirium, seizures, myocardial infarction, cardiac dysrhythmias, pulmonary edema, rhabdomyholysis, coagulopathy, acidosis, ascending paralysis, hepatic and renal failure have all been reported. Pancytopenia develops with white blood cell count nadirs and subsequent sepsis from three to seven days after initial symptoms. Patients typically do not recover from significant toxicity until seven to ten days post ingestion.

Sensory and motor neuromyopathies, parethesias and other neurologic toxicities have all been reported after recovery from the second phase of colchicine poisoning. In some cases these symptoms have persisted longer than one year.

Diagnosis

A diagnosis of colchicine poisoning should be suspected in patients over thirty with a history of arthritis or gout presenting with early gastrointestinal symptoms of nausea, vomiting, and diarrhea or multisystem failure suggesting a late presentation. Many clinicians prescribe colchicine to be taken until gout resolves or symptoms of nausea, vomiting and diarrhea develop. This recommendation can result in unintentional overdose, and in combination with colchicine’s lack of analgesic properties and the potential 12 hour delay in gout symptom relief, many patients may not seek treatment until significant organ toxicity develops.

Laboratory values useful in the diagnosis and management of colchicine poisoning include electrolytes, blood urea nitrogen, serum creatinine, glucose and complete blood count (CBC) with differential. If significant multisystem toxicity develops, arterial blood gases, electrocardiogram, coagulation panel, liver function tests, creatine phosphokinase (CPK), troponin and urinalysis should be monitored. Asymptomatic patients should be observed for at least eight hours for the development of vomiting, diarrhea and other initial gastrointestinal symptoms. Any symptomatic patient with suspected colchicine poisoning should be placed on continuous cardiovascular monitoring until the resolution of symptoms due to the potential for significant multiorgan toxicity, including cardiac dysrhythmias. Patients who recover from initial colchicine toxicity must be monitored for signs and symptoms of infection and may need a CBC three to seven days post ingestion due to the possibility of delayed pancytopenia.

Treatment

Although charcoal is potentially beneficial in preventing colchicine absorption and significant enterohepatic recirculation, it is of limited utility due to initial symptoms of nausea, vomiting and hemorrhagic gastritis. Colchicine has rapid and excellent absorption and unless charcoal is given prior to the onset of gastrointestinal toxicity, its use may worsen symptoms and be of limited benefit. Due to colchicine’s extensive volume of distribution and excellent tissue binding, hemodialysis and hemoperfusion do not effectively remove the drug and are not recommended unless used as a supportive measure for patients in renal failure.

Aggressive supportive care is critical in the management of colchicine poisoned patients. Early fluid resuscitation and correction of electrolyte abnormalities are essential. Cardiac dysrhythmias, myocardial infarction, seizures, infections, coagulopathy, rhabdomyolysis, renal failure and hypotension should be treated symptomatically if they occur. Ventilator support and blood product transfusions are often needed in the patient severely poisoned by colchicine. Patients who develop bone marrow suppression should be placed on neutropenic precautions. Colony stimulating factors such as G-CSF have been used for the treatment of colchicine-induced leukopenia. In Europe, an experimental colchicine Fab antibody solution was used to treat patients with severe colchicine poisoning, however, this product is not currently commercially available in Europe or the United States. 

Discussion of case questions

1. What initial signs, symptoms and history should raise a clinician’s index of suspicion for colchicine toxicity in this case?

Persistent nausea, abdominal pain, vomiting and diarrhea in a patient with a history of arthritis should immediately direct the clinician to consider colchicine poisoning in the differential diagnosis.

2. Were the signs and symptoms this patient experienced consistent with the different phases of colchicine toxicity?

Initial gastrointestinal symptoms followed by hypotension then cardiovascular collapse and neutropenia are consistent with colchicine poisoning.

3. Is there an antidote available for colchicine poisoning?

No commercially available antidote is available. Aggressive supportive care is the treatment of colchicine poisoning.

Consultation assistance

Consultation with a specialist in poison information or with a medical toxicologist can be obtained free of charge by calling the California Poison Control System at 1-800-222-1222.

This issue of CALL US... was written by Kerry A. Schwarz, PharmD, CSPI, Toxicology Management Specialist, California Poison Control System, San Diego Division.


CALL US... is published by the California Poison Control System. Editorial Board: Executive Director, Stuart E. Heard, PharmD; CPCS Medical Directors: Timothy E. Albertson, MD, Richard F. Clark, MD, Richard Geller, MD, Kent R. Olson, MD; CPCS Managing Directors: Judith Alsop, PharmD, Thomas E. Kearney, PharmD, Lee Cantrell, PharmD. Assistant Editors: Binh Ly, MD, Aaron Schneir, MD. Editor: Richard F. Clark, MD.

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