Confirmed Fatal Colchicine Poisoning in an Adolescent with Blood and Bile Concentrations—Implications for GI Decontamination?

Abstract

Introduction

Colchicine is commonly used to treat diseases like acute gouty arthritis. However, colchicine has a very narrow therapeutic index, and ingestions of > 0.5mg/kg can be deadly. We report a fatal acute colchicine overdose in an adolescent. Blood and postmortem bile colchicine concentrations were obtained to better understand the degree of enterohepatic circulation of colchicine.

Case Report

A 13-year-old boy presented to the emergency department after acute colchicine poisoning. A single dose of activated charcoal was administered early but no other doses were attempted. Despite aggressive interventions such as exchange transfusion and veno-arterial extracorporeal membrane oxygenation (VA-ECMO), the patient died 8 days later. Postmortem histology was notable for centrilobular necrosis of the liver and a cardiac septal microinfarct. The patient’s blood colchicine concentration on hospital days 1 (~30 hours post-ingestion), 5, and 7 was 12ng/mL, 11ng/mL, and 9.5ng/mL, respectively. A postmortem bile concentration obtained during autopsy was 27ng/mL.

Discussion

Humans produce approximately 600mL of bile daily. Assuming that activated charcoal would be able to adsorb 100% of biliary colchicine, using the bile concentration obtained above, only 0.0162mg of colchicine per day would be able to be adsorbed and eliminated by activated charcoal in this patient.

Conclusion

Despite supportive care, activated charcoal, VA-ECMO, and exchange transfusion, modern medicine may not be enough to prevent death in severely poisoned colchicine patients. Although targeting enterohepatic circulation with activated charcoal to enhance elimination of colchicine sounds attractive, the patient’s low postmortem bile concentration of colchicine suggests a limited role of activated charcoal in enhancing elimination of a consequential amount of colchicine.

Introduction

Colchicine is a medication used for conditions such as acute gouty arthritis, pericarditis, and familial Mediterranean fever, among others. Despite its efficacy, colchicine has a very narrow therapeutic index and small amounts can be deadly, especially in children [1]. A typical dose that can cause mortality or significant toxicity is >0.5mg/kg, although some cases report fatalities at doses <0.5mg/kg [2].

We report an adolescent patient with fatal acute colchicine poisoning who died 8 days post-ingestion despite use of aggressive interventions, including exchange transfusion and veno-arterial extracorporeal membrane oxygenation (VA-ECMO). A postmortem gallbladder concentration of colchicine was obtained to further evaluate the potential role of multidose-activated charcoal in colchicine poisoning due to its known enterohepatic circulation.

Case Report

A 13-year-old, 55kg, adolescent boy with a past psychiatric history of a mood disorder presented to the emergency department (ED) roughly 24 hours after an intentional overdose of an unknown amount of colchicine. It was unclear how the patient obtained the pills, but a family member was able to find a residual pill. The pill was then identified as colchicine by its markings using an online pill identifier. The patient admitted to taking an overdose of an unknown amount of pills on subsequent questioning but he did not know that the pills were colchicine.

On arrival at the ED, the patient had profound nausea, vomiting, abdominal pain, and diarrhea. His initial vital signs were as follows: BP, 102/71 mm Hg; HR, 121 beats/minute; respiratory rate, 14 breaths/minute; temperature, 97.9°F (36.6 °C), O₂ saturation, 96% (room air). His mental status was normal; physical examination was notable for an ill-appearing child with diffuse abdominal tenderness. His initial electrocardiogram showed sinus tachycardia and a QT (Bazett correction) duration of 486ms. A chest radiograph demonstrated vascular congestion but no other acute pulmonary processes. A bedside echocardiogram demonstrated an ejection fraction of 35%. Laboratory tests obtained on initial ED presentation (hospital day 1) were notable for white blood cell 27.1/mm³ (ref. range: 4.5–11.0×10³/mm3), lactate 3.92 mmol/L (ref. range: 0.6–1.7mmol/L), and troponin 0.11ng/mL (ref range: 0–0.4ng/mL). Due to concern for infection, the patient was administered vancomycin, piperacillin/tazobactam, and ceftriaxone in addition to intravenous fluids.

Four hours into his ED stay, the patient developed altered mental status, acute hypoxic respiratory failure, and cardiogenic shock. He required endotracheal intubation for airway protection and was administered epinephrine 0.02 mcg/kg/minute and dopamine 7.5 mcg/kg/minute for hemodynamic support. A nasogastric tube was placed and a single dose of 50g of activated charcoal was administered. A formal echocardiogram demonstrated globally decreased systolic function, with an ejection fraction of 38%.

Approximately 10 hours into his hospital stay, the patient experienced a bradycardic cardiac arrest followed by a return of spontaneous circulation after epinephrine administration and 3 minutes of cardiopulmonary resuscitation (CPR). Post-arrest, both VA-ECMO and continuous kidney replacement therapy (CKRT) were initiated. Although he was able to have his hemodynamics temporized with vasopressors (epinephrine, milrinone, vasopressin, norepinephrine), he experienced progressively worsening multisystem organ failure and anasarca. His WBC count dropped progressively (to a nadir of 0.6/mm³) and serum troponin I increased (peak of 3.71ng/mL) (see Table 1). The patient received filgrastim for pancytopenia. Due to the sequestration of colchicine into red blood cells, an exchange transfusion was initiated on hospital day 6 but was discontinued after he became hemodynamically unstable during the procedure. Colchicine antibody fragments were attempted to be obtained for compassionate use but were unavailable. On hospital day 8, the patient experienced a cardiac arrest and was pronounced dead.

Table 1.

Laboratory values trend

	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7	Day 8
WBC (/mm3) (Ref. range: 4.5–11.0 × 103/mm3)	27.1	14.0	3.9	0.8	0.7	0.5	0.8	0.6
Troponin (ng/mL) (Ref. range: 0–0.4 ng/mL)	0.11	8.53	4.19	2.80	2.33	1.63	1.43	3.71
Creatinine (mg/dL) (Ref. range: 0.5–1.0 mg/dL)	0.9	1.13	0.80	1.35	1.30	1.05	1.06	0.94
Creatine kinase (U/L) (Ref. range: (29–168 U/L)	562	1422	17,090	45,640	46,220	1,028,640	85,030	20,9990
Colchicine (ng/mL) (Ref. range*)	12	-	-	-	11	-	9.5	-

*The highest peak colchicine concentration reported from a 1mg dose in an adult was 8.52ng/mL. The colchicine concentration 24 hours after a 1mg dose was 0.38ng/mL [3]

Postmortem histology was notable for centrilobular necrosis of the liver and a microinfarct in the septum of the heart. The patient’s blood colchicine concentrations are shown in Table 1. A postmortem gallbladder bile concentration obtained during autopsy was 27ng/mL.

Discussion

Colchicine is a microtubule inhibitor medication used for a variety of conditions including acute gouty arthritis, pericarditis, and familial Mediterranean fever. Microtubules are present in all eukaryotic cells and are necessary for intracellular transport, maintaining cell structure/shape, cellular mitosis, and other normal cell functions [4]. Colchicine toxicity is classically described in a triphasic presentation, although in actual clinical practice, these phases can have significant overlap. Phase 1 occurs within the first 24 hours and is characterized by leukocytosis, nausea, vomiting, and diarrhea. Phase 2 occurs within 1–7 days and is notable for profound pancytopenia, sepsis, kidney injury, acute respiratory distress syndrome, and the risk of sudden cardiac death. Phase 3 occurs after 7 days and is characterized by alopecia, myopathy, and neuropathy. Although there is a lack of rigorous epidemiologic studies regarding colchicine poisoning, data suggest ingestion of >0.5mg/kg colchicine is associated with systemic toxicity and death, with some data suggesting that doses smaller than 0.5mg/kg can be fatal [4]. Colchicine has a narrow therapeutic index and toxicity occurs in the context of poisoning, drug interactions (CYP enzyme, p-glycoprotein), and/or hepatic dysfunction.

There is currently no commercially available antidote for colchicine toxicity and despite a previous successful case report using colchicine-specific antibody fragments, this treatment has not been widely studied or mass-produced [5]. Consequently, supportive care is the mainstay of treatment. In addition to traditional supportive care (IV fluids, empiric antibiotics, antiemetics, pressors), this patient also received activated charcoal, VA-ECMO, and exchange transfusion.

Gastrointestinal (GI) decontamination interventions aimed at limiting absorption, such as gastric lavage and activated charcoal, are reasonable to perform in patients with colchicine toxicity. In this case, given that the patient presented to healthcare 24 hours after ingestion of pills, gastric lavage was not performed. In contrast to gastric lavage, activated charcoal as a method of GI decontamination is less invasive and can usually be easily administered. Activated charcoal is effective at mitigating toxicity by adsorbing xenobiotics in the GI tract after acute ingestion and further adsorbing select drugs in the GI tract that are enterohepatically circulated. Colchicine exhibits enterohepatic circulation with elimination in the bile and because of this, some sources recommend the administration of multidose-activated charcoal [1, 6]. The postmortem bile concentration in this patient (obtained during autopsy) was 27ng/mL.

To provide some context for the interpretation of the bile colchicine concentration, on average, humans produce approximately 600mL of bile produced daily [7]. Assuming that 600mL of bile is produced per day and that activated charcoal would be able to adsorb 100% of bile colchicine, only 0.0162mg of colchicine per day would be adsorbed and eliminated by activated charcoal. This amount is equivalent to 2.7% of a typical single therapeutic 0.6mg dose of colchicine. One previous study documented a higher postmortem biliary colchicine concentration of 2921ng/mL, but even if activated charcoal were administered and this adsorbed 100% of biliary colchicine, the calculated amount of colchicine removed by interruption of enterohepatic recycling would be 1.8mg [8]. These findings suggest that there may be a limited role in activated charcoal treating colchicine toxicity by targeting enterohepatic circulation.

Colchicine is sequestered into red blood cells—this can result in an intracellular concentration that is five to ten times higher than plasma. As a result, whole blood exchange transfusion may have some theoretical benefits to reduce body burden and enhance elimination [6]. However, there are limited data surrounding the benefit and indications for exchange transfusion in patients with colchicine poisoning. One case reports a patient who consumed >0.8mg/kg of colchicine and received a whole blood exchange transfusion and survived [6]. In another case report of a patient with colchicine poisoning who had whole blood exchange performed, whole blood colchicine concentrations of 17ng/mL and 7.6ng/mL pre- and post-whole blood exchange transfusion, respectively, were documented [9]. Because some studies suggest that up to 30% of colchicine is renally cleared, whole blood exchange transfusion may have a role in the removal of colchicine in patients who are anuric [9]. Despite these cases, however, it should be noted that colchicine has a large Vd (7L/kg) and this would suggest that whole blood exchange transfusion is likely of limited utility.

Extracorporeal membrane oxygenation (ECMO) is a supportive modality that maintains perfusion to vital organs until the body metabolizes the drug and hopefully recovers from drug toxicity. Although VA-ECMO has been reported to help at least one patient survive colchicine toxicity, colchicine toxicity (as we have seen with this case) can prove fatal even despite the early initiation of VA-ECMO therapy [10]. There are multiple possible explanations for the failure of ECMO in this case, including the irreversible and/or profound cytotoxicity of colchicine on the myocardium and other organs, inability to initiate ECMO in a timely fashion because of the patient delay in hospital presentation, and hypoxic injury sustained during cardiac arrest, to name a few.

There are many limitations to this case report. First, this patient only received a single dose of activated charcoal, and we were unable to assess the role or potential benefit of multiple-activated charcoal (MDAC). However, based on our calculation above, we do not believe that MDAC would have changed the patient’s outcome. Second, this patient presented to healthcare 24 hours after the initial ingestion, so it is possible that the lack of improvement after the above treatment strategies could be related to late presentation to healthcare. Third, the history obtained for this case was that the patient ingested an overdose of colchicine. Although this was confirmed with colchicine blood testing, we did not perform comprehensive toxicologic testing for other xenobiotics outside of acetaminophen and salicylate (which were both negative). The bile colchicine concentration used for our theoretical calculations was obtained during autopsy—it is possible that a higher bile colchicine concentration present earlier in the patient’s course could have changed the calculation. Furthermore, it is possible that if the patient presented sooner after their time of ingestion, the outcome could have been different. Gastrointestinal decontamination with activated charcoal may not have had any consequential effect at the time the patient presented to care due to the amount of time that had already passed and the amount of colchicine that had already been systemically absorbed. Lastly, the toxicity of colchicine could have been irreversible at the time the patient presented.

Conclusion

Deliberate and significant colchicine poisonings can result in severe end-organ dysfunction and fatality. This is particularly true in patients who have delayed presentation to the hospital, when GI decontamination is likely to be of limited utility and/or there is established end-organ damage. Death can result despite initiation of aggressive support care measures including VA-ECMO, attempts at limiting enterohepatic recirculation of colchicine, use of colony-stimulating factor, and exchange transfusion. Given that there are limited management options, no true antidote, and inability to obtain colchicine antibody fragments, patients may still die despite all available supportive interventions. The focus therefore should be on the prevention of colchicine poisonings.

Declarations

Conflicts of Interest

None

Sources of Funding

None

Disclosure

Consent for publication of this case was obtained from the family and provided to the journal in accordance with JMT policy.