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Important New Information. |
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CALL US...TM
The
Official Newsletter of the
Volume 4, Number 2.
Summer, 2006
Diagnosis and Treatment of
Colchicine Poisoning
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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
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.
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(1-800-8 POISON), outside California, dial, 1-800-222-1222 or contact 9-1-1
emergency services if the person who is poisoned cannot wake up, has a hard
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