denica djodjeva

    Dr Denica Djodjeva

        Sofia, Bulgaria

Abstract

Colchicine is extracted from Colchicum autumnale (autumn crocus, or meadow saffron) and Gloriosa superba (glory lily). It is a lipid-soluble alkaloid that is isolated from the plant and is one of the main agents used in the treatment of crystal arthropathy gout, immune-mediated disorders such as Behçet’s disease (characterized by vasculitis), familial Mediterranean fever (characterized by polyserositis and amyloidosis), and neutrophilic dermatoses.  Because colchicine stimulates enzymes called collagenases, which break down collagen protein and inhibit liver cells from making amyloid A, in dogs and cats colchicine is used off-label to reduce scarring processes such as liver cirrhosis, amyloidosis, Shar-Pei fever, fibrosis following placement of a glaucoma drainage device, to prevent granuloma formation following tracheal stent placement and to prevent urethral stricture formation. In birds, it has also been reportedly used to treat hyperuricemia.

Colchicine is rapidly absorbed after oral administration. The pharmacokinetics involves the intestines, liver, and kidneys.  Rapidly absorbed from jejunal and ileal enterocytes, colchicine is partially locally metabolized by enterocytes. The bulk of absorbed colchicine is further metabolized by the liver and excreted in bile. The time to peak concentration in humans is 0.5 to 2.0 h, decreasing rapidly within 2 h. Colchicine undergoes extensive enterohepatic recirculation before being fecally excreted and is distributed to all tissues in the body, where it binds to intracellular tubulin and has a dissociation half-life of 20–40 hours. The accumulation in the kidney, liver, spleen, gastrointestinal wall, and leucocytes may lead to toxicity.  Because of the high degree of tissue uptake, only 10% of a single dose is eliminated within 24 hours, and elimination from the body may continue for 10 days or more. The long half-life and enterohepatic recirculation explain colchicine’s prolonged effect. However, the severity and mortality rate of the poisoning is usually related to the dose ingested. The lowest lethal oral dose reported for dogs is 0.13 mg/kg. Fatalities in the first few days result from shock, respiratory or cardiac arrest, or rapidly progressive multiple organ failure. The most common side effects start 2-5 hours after ingestion and are associated with gastrointestinal upset, vomiting, and diarrhea and are very rare but colchicine can suppress neutrophil production and can cause bone marrow suppression.

Introduction

To date, there are only a few described cases in the veterinary literature of colchicine intoxication in a dog. The main symptoms associated with ingested medication are severe abdominal pain, diarrhea, nausea, vomiting, and in more severe cases, DIC and MODS. There is no specific antidote, and the therapy is symptomatic and supportive. If

colchicine ingestion is suspected, giving active charcoal or gastric lavage would be beneficial if too much time has not passed since ingestion.

Three clinical phases of intoxication are described, each of which is associated with the corresponding expected complications and symptoms.

1. Gastrointestinal / 10-24 hours – characterized by abdominal pain, nausea, vomiting, and diarrhea. Hypovolemic state and hypotension due to severe dehydration, and peripheral leukocytosis.
2. Multiorgan phase / 2 – 7 days – bone marrow hypoplasia with strong leukopenia and thrombocytopenia; oliguric renal failure; cardiac arrhythmias and arrest; electrolyte and metabolic disorders such as hyponatremia, hypocalcemia, hypokalemia, hypophosphatemia; changes in mental status, seizures; respiratory distress, hypoxia.
3. Recovery, if death has not occurred/ after 7 days – leukocytosis; risk of alopecia.

Manifestations of Colchicine Toxicity reported in humans

The Case of Lady: A Pomeranian’s Struggle with Colchicine Toxicity

Lady’s clinical journey commenced when her owners discovered that she had ingested up to three tablets of colchicine, each containing 0.5 mg of the drug. The ingestion occurred less than 24 hours before her admission, and the rapid onset of clinical symptoms constitutes an emergency, requiring immediate veterinary intervention.

Upon evaluation, Lady presented with a constellation of acute gastrointestinal symptoms including diarrhea, nausea, vomiting, abdominal pain, fatigue, and a notable refusal to eat. Each of these symptoms indicates a severe systemic response, triggered by the colchicine overdose. Colchicine is known to affect multiple organ systems, primarily targeting the gastrointestinal tract, bone marrow, liver, and kidneys. The rapid decline in Lady’s health condition pretty good shows the nature of colchicine toxicity, which can escalate quickly if not addressed promptly.

The prognosis for Lady remains questionable due to the timing of her ingestion and the associated clinical signs. In veterinary practice, the prognosis in cases of colchicine toxicity is influenced by various factors, including the extent of ingestion, the duration since exposure, and the promptness of medical treatment. Given that less than one day has elapsed since the incident, there remains a crucial window of opportunity for effective medical intervention. Treatment protocols typically include decontamination procedures such as emesis induction and activated charcoal administration to reduce further absorption of the toxin but in a time manageable time after the ingestion. In this case, these procedures were not performed due to time elapsed since ingestion.   Supportive care, including intravenous fluids and anti-emetics, may be required to manage dehydration and electrolyte imbalances that commonly accompany gastrointestinal distress.

Test and Investigations:

In the realm of clinical diagnostics, the role of point-of-care (POC) examinations cannot be underestimated. For Lady, a range of POC exams were scheduled, including a complete blood count (CBC), basic metabolic panel (BH), and electrolytes, alongside imaging studies such as abdominal ultrasound and X-ray. Notably, Lady’s irregular vaccination status necessitated the inclusion of a CPV/CCV/G test, which ultimately returned negative results.

Laboratory findings highlighted evidence of dehydration, accompanied by increased liver enzyme levels—a possible reflection of hepatic distress or injury. These findings warrant immediate attention, as dehydration can exacerbate underlying conditions and complicate treatment protocols. Concurrently, the elevated liver enzymes may suggest an underlying metabolic or infectious process that requires further exploration.

The abdominal ultrasound provided crucial insights into Lady’s condition. Importantly, the examination did not reveal any free fluid, which often serves as a potential marker for various abdominal pathologies, such as perforation or significant intra-abdominal hemorrhage. However, the ultrasound did unveil a thickened intestinal wall and signs of inflammation in the small intestine, coupled with increased peristalsis. These findings are suggestive of an inflammatory condition, such as enteritis, which could stem from a variety of etiologies including infectious agents or inflammatory bowel disease.

Complementing the ultrasound findings, the X-ray examination corroborated the absence of any foreign body, thus eliminating a critical differential diagnosis that could account for Lady’s symptoms. The combination of these imaging modalities and laboratory tests contributes to a more comprehensive understanding of her moment health status.

Treatment and Problem-Solving Plan for Hemorrhagic Gastroenteritis due to colchicine intoxication

Hemorrhagic gastroenteritis is a serious condition characterized by inflammation and bleeding, which can lead to significant morbidity. Despite a few cases of colchicine intoxication described, Lady’s case presented a structured treatment and problem-solving plan implemented during the hospitalization and her critical condition. The approach utilized involved a combination of symptomatic therapies, intensive monitoring, nutritional support, and hygiene care tailored to address the complexities arising from her illness.

Upon admission, Lady exhibited clinical signs, including lethargy, refusal of food and water, and vital signs indicative of distress: arterial blood pressure at 150 sys (Doppler measurement), heart rate at 120 bpm, respiratory rate at 21/min, and hypothermia at 36,5 C°, MMC- pink, CRT>2sec. Immediate interventions commenced with symptomatic therapy, specifically the administration of antacids and antiemetics, complemented by antibiotics, supportive care, and warming. Regular monitoring of vital signs was imperative, enabling prompt detection of any deterioration in her condition.

The antibiotic regimen consisted of Ampicillin at a dosage of 20 mg/kg every six hours and Metronidazole at 10 mg/kg every twelve hours. This dual therapy aimed to combat potential intestinal, and bacterial translocation and infections while addressing gastrointestinal stability. Pain relief was managed through a multimodal approach, incorporating buprenorphine, metamizole sodium, hyoscine butylbreomide, and a constant rate infusion (CRI) of lidocaine at dose 1mg/kg/h, ensuring Lady’s comfort during her recovery.

Nause, vomiting, and regurgitation were challenging symptoms in this gastrointestinal upset condition. The combination of maropitant, pantoprazole, ondansetron, and metoclopramide facilitated a significant alleviation of these distressing symptoms, allowing for the resumption of feeding and subsequent recovery. Maropitant, administered at a dosage of 1 mg/kg every 24 hours, serves as a potent antiemetic, specifically targeting the neurokinin-1 (NK1) receptors in the central nervous system. Its use was instrumental in controlling nausea and vomiting episodes and also may act as mild pain control medication. In conjunction with maropitant, pantoprazole was prescribed at a dosage of 1 mg/kg every 24 hours. As a proton pump inhibitor, pantoprazole plays a crucial role in reducing gastric acid secretion, preventing the potential for gastric irritation and ulcers that may result from chronic vomiting. The synergistic effect of combining maropitant with pantoprazole not only addressed the challenges posed by nausea but also provided a protective mechanism for the gastrointestinal tract, promoting an environment for healing. Additionally, ondansetron was incorporated into Lady’s treatment regimen at a dosage of 0.3 mg/kg every 12 hours. Ondansetron’s mechanism of action, which involves blocking serotonin receptors in the central nervous system and the gastrointestinal tract, proved valuable in achieving comprehensive control over Lady’s nausea and vomiting episodes. Recognizing the importance of gastrointestinal motility in managing nausea, metoclopramide was also included in Lady’s therapy as CRI at a dosage of 2mg/kg for 24 hours. Administered to enhance peristalsis, metoclopramide not only functions as an effective antiemetic but also facilitates gastric emptying. This dual action was particularly beneficial in this case, as it mitigated the regurgitation and associated complications. Achieving coordinated motility ensured that Lady’s digestive system could efficiently process the food that would be introduced once her nausea was under control. Once adequate control of nausea and regurgitation was established, the placement of a nasoesophageal tube permitted the safe initiation of feeding and administration of additional probiotic therapy. This intervention was pivotal in delivering necessary nutrition while circumventing the challenges related to oral intake, which could have exacerbated Lady’s condition.

S-adenosyl-methionine (Transmetil ®) is known due to its hepatoprotective properties.  It’s crucial role in detoxification, metabolism, and the synthesis of various biochemicals essential for digestion, growth and potent antioxidants within hepatic tissues, can offer significant benefits in restoring liver function and mitigating cellular damage. At the moment of presence Lady’s liver enzymes were elevated (AST 549 U/I, ALP 1031 U/I). In this case dose of 10mg/kg every twelve hours was used due the hospitalization.  Colchicine is lipid- a soluble alkaloid, and to enhance its safe excretion and mitigate its adverse effects, the use of Intralipid emulsion of 20% has been included in the treatment.  Administered at a rate of 1.5 mL/kg over 15 minutes, followed by a continuous infusion of 0.25 mL/kg/min over two hours, Intralipid serves to expedite colchicine clearance. The emulsion encapsulates the lipophilic drug, facilitating its removal from the body system and subsequent elimination. Due to the hypoproteinemic and albuminemic state (ALB 28.5 g/L; TP 38.6 g/L) coupled with electrolyte imbalance (K 3.6- 3.44mmol/L; Cl 91.9mmol/L; Na 135mmol/L) the administration of amino acid solution has emerged as a vital solution. Amino acids are the building blocks of proteins and play an essential role in addressing the underlying hypoproteinemic and hypoalbuminemia state and recovery from malnutrition. The amino acid glutamine has been recognized for its role in maintaining the gut barrier and modulating electrolyte absorption in the intestines. A serum albumin level of 28.5 g/L indicates a clear departure from the normal range, which typically hovers between 30 to 40 g/L. The context of hypoproteinemia and albuminemia often underscores systemic issues such as malnutrition, liver dysfunction, or protein loss through renal or gastrointestinal pathways. The noted total protein concentration of 38.6 g/L appears low as typical total protein levels fall within the range of 60 to 80 g/L in a healthy individual. However, the focus remains on the significance of low albumin as it plays a crucial role in maintaining oncotic pressure and transporting various substances in the bloodstream. A deficit in albumin can lead to interstitial edema, impaired wound healing, and diminished immune response, exacerbating a patient’s overall clinical condition. In conjunction with hypoproteinemia, the electrolyte profile reveals imbalances: a potassium level fluctuating between 3.6 and starts dropping to 3.44 mmol/L, chloride at 91.9 mmol/L, and sodium at 135 mmol/L, which is a complication described in human clinical cases of colchicine intoxication. These values highlight a tendency to hyponatremia, which can lead to neurological disturbances, and hypokalemia, which can adversely affect cardiac function and muscle contraction.

One of the critical complications arising from HGE is anemia, often characterized by a marked decrease in red blood cell (RBC) count, hemoglobin (HGB) levels, and hematocrit (HCT). Platelet count (PLT) except as a consequence of colchicine intoxication could be indicative of starting DIC or a hypercoagulable state. Recent clinical assessments have indicated RBC levels ranging from 4.61 x 10^12/L to 3.69 x 10^12/L, HGB decreasing from 109 g/L to 89 g/L, HCT dropping from 28% to 23%, and PLT counts diminishing from 21 x 10^9/L to 18 x 10^9/L. The prevalence of anemia in HGE patients necessitates prompt and comprehensive management of potential complications, including the risk of a hypercoagulable state. In managing anemia associated with HGE, the administration of tranexamic acid at a dosage of 10 mg/kg every 12 hours has emerged as an effective therapeutic intervention. Tranexamic acid, an antifibrinolytic agent, functions by inhibiting fibrinolysis, thus promoting clot stability and reducing bleeding tendencies. In the context of HGE, where the loss of blood can lead to both acute anemia and a coagulopathy, tranexamic acid serves a dual purpose: it treats active bleeding while simultaneously preventing the progression to a hypercoagulable state that can occur due to a compensatory increase in coagulation factors. Supportive measures need to include close monitoring for signs of coagulopathy, which can arise due to microvascular changes associated with both the inflammatory response and anemia itself.  Because of that D- dimer was measured and was in normal ranges of 174ng/ml.

Fluid therapy was also critical, compensating for dehydration resulting from vomiting and diarrhea while restoring electrolyte balance; this was further supported with a per-axis supplement to correct hypokalemia and hypochloremia.

Other complications as pancreatitis were observed. The CPL measurement of 702 mcg/L indicates a severe elevation that signals significant pancreatic distress, which may correlate with the severity of pancreatitis and potential progression toward complications. Furthermore, systemic complications including acute respiratory distress syndrome (ARDS) and multi-organ failure can arise as the body attempts to respond to the inflammatory mediators released from the damaged pancreas.

Despite the initial treatment, Lady’s condition showed minimal improvement on the first days of hospitalization, characterized by persistent refusal to eat, regurgitation, and laboratory findings indicative of leukocytosis, anemia, thrombocytopenia, and hypoproteinemia. By the seventh day of hospitalization, Lady demonstrated remarkable improvement. She regained her appetite but still with the NE tube and exhibited heightened vitality and mobility, signifying a positive response to the comprehensive treatment strategy instituted. A careful transition to home care entailed a tailored prescription that included antibiotics, an anemia supplement, probiotics, and regular clinical check-ups.

Drugs affecting colchicine toxicity

Expected Outcome

In the event of colchicine overdose, the prognosis is often considered dubious, primarily due to the drug’s potent mechanism and the body’s capacity to metabolize and excrete it. Following significant exposure, patients are at considerable risk for developing disseminated intravascular coagulation (DIC), characterized by widespread activation of the coagulation cascade leading to the formation of small blood clots throughout the body’s small vessels. This pathological process can severely impact organ function and culminate in multiple organ failure. Clinically, the anticipated symptoms would include gastrointestinal distress, cardiovascular instability, and hematological anomalies. The toxicological implications of colchicine are further exacerbated by its narrow therapeutic index and long half-life, which complicates both clinical monitoring and the treatment regimen.

Actual Outcome

In a divergence from the expected prognosis, after seven days of aggressive therapy, the patient demonstrated remarkable clinical recovery. Intensive supportive care measures, including intravenous fluids, symptomatic therapy, and close monitoring of organ function, culminated in the complete restoration of health. This outcome highlights not only the resilience of the body in the face of potentially lethal drug toxicity but also underscores the critical importance of timely intervention and appropriate medical management.

Conclusion

In conclusion, this case serves as an important reminder of the unpredictable nature of drug toxicity and the potential for recovery even in seemingly dire circumstances. While the expected outcomes of colchicine overdose typically carry a grim prognosis due to all possible complications and the risk of DIC, and multiple organ failure, the actual outcome observed here emphasizes the effectiveness of proactive therapeutic measures. Given the underreported clinical cases, it is difficult to create a protocol for the treatment of colchicine poisoning, so I hope this material will help in the future creation of one and help in better management of this rare intoxication condition.