JANUARY 2014

TOXICOLOGY CASE OF THE MONTH:

CASE:

58-year-old male presents to the hospital complaining of abdominal cramping, nausea, and vomiting.  He has a history of depression with suicide attempts in the past. He told his daughter he “may have taken some of his gout medication” earlier that day. His family says one of his bottles of medication, recently prescribed as needed for gout flares, is now empty. They are unsure how many pills were in the bottle.

PMH: Gout, depression, hypertension

Meds: Hydrochlorothiazide, Colchicine, Allopurinol, Buproprion

All: NKDA

VS: 105/60 110 20 99% RA 36.6

Exam remarkable for tachypnea and dry mucous membranes. Lungs are clear. No focal abdominal tenderness though the patient does complain of cramping. Rectal exam with brown stool, guaiac positive.

Labs:

CBC: WBC 3.5, Hgb/Hct 11.3/34.1, Platelets 210

Chem: 132/3.2/95/14/45/1.2/110

LFTs wnl

Lactate 4.3

APAP/Salicylate/EtOH undetectable

Applicable case questions:

1. What medications are used to treat gout flares?

• Colchicine
• NSAIDs
• Glucocorticoids (i.e. Prednisone)
• Anakinra, an interleukin-1 antagonist, is used off-label
• Note: Allopurinol is used for gout prevention, not in acute flares

2. What is the mechanism of action of colchicine? How is it prescribed?

• Colchicine acts at a cellular level by arresting dividing cells during mitosis
• It is used for treatment of gout and familial Mediterranean fever
• It is also found in certain plants (Colchicum autumnale – meadow saffron)
• It is rapidly absorbed into body tissues
• FDA-approved therapeutic dose: 1.2mg orally, followed by 0.6mg after 1 hour
• Should not be prescribed long term

3. Why should I be worried about it?

• Significant toxicity with no antidote and no effective means of elimination
• One case series described the following:
  • 0.5 mg/kg: diarrhea and vomiting
  • 0.5-0.8 mg/kg: bone marrow aplasia and 10% mortality
  • >0.8 mg/kg: uniformly resulted in death
  • Fatalities have been reported with ingestions as little as 7mg (though some have survived with ingestions >60mg)

4. What are the clinical effects of an acute colchicine overdose?

• Many organ systems effected from hours to days after exposure
• 2-12 hours after presentation: GI symptoms
  • Nausea, vomiting, abdominal pain, diarrhea (often bloody)
  • Diarrhea: common side effect of therapeutic use
  • Progresses to shock: fluid loss and depressed cardiac contractility
  • Delirium, seizures, and coma
  • Lactic acidosis due to shock and inhibition of cellular metabolism
  • Myocardial injury
  • Rhabdomyolysis
  • DIC
  • Renal failure
  • Bone marrow suppression, alopecia, polyneuropathy (late effects)
  • Death after 8-36 hours by respiratory failure, intractable shock, and cardiac arrhythmias

5. How is colchicine toxicity diagnosed?

• Clinical diagnosis
• History of gout and familial Mediaterranean fever
• Severe gastroenteritis closely followed by leukocytosis, shock, rhabdomyolysis, and acute renal failure followed by leukopenia and thrombocytopenia and general decompensation
• Levels not readily available (forensic use primarily)
• Other useful labs: CBC, CMP, CPK, UA, Troponin, EKG, Lactate

6. What is the management?

• Aggressive supportive care and shock treatment
• Anticipate respiratory and cardiac collapse
• Highly fatal overdose with no antidote and no effective means of removal (cannot use hemodialysis)
  • Colchicine-specific antibodies (Fab fragments) tested in France, not commercially available
  • Rifampin is a CYP3A4 induced – may enhance elimination in theory but no good data

• One of the only times in toxicology where aggressive decontamination is highly recommended
  • Charcoal, gastric lavage, whole bowel irrigation are considerations
  • Undergoes enterohepatic recirculation: may need multi dose activated charcoal
  • Some recommend intubation for aggressive decontamination
  • If survive initial insult may need treatment for bone marrow depression

7. What are the acute toxicities of other agents used to treat acute gout flares?

• NSAIDs
  • Pharmacologic and toxicologic effects occur via COX inhibition
  • Usually asymptomatic or GI upset
  • May develop significant CNS depression, seizures, renal failure, acidosis, hepatic dysfunction with large ingestions
  • Usual treatment is IV fluids and H2 blockers
  • Hemodialysis not effective
  • Glucocorticoids
    • Small ingestions: usually GI upset
    • Anxiety, agitation
    • Fluid retention
    • Majority of toxic effects due to chronic use (i.e. Cushing’s syndrome)

CASE CLOSURE:

• The patient developed hypovolemic shock
• Intubated and aggressive decontamination with charcoal via NG
• Ultimately death with v-fib arrest

TAKE-HOME PEARLS:

• Colchicine is a highly toxic medication used to treat gout and familial Mediterranean fever
• Presentation: gastroenteritis followed by shock, renal failure, and cardiorespiratory collapse, late bone marrow suppression
• Aggressive supportive care and decontamination recommended