Ivermectin Toxicosis

Ivermectin toxicosis is a potentially fatal neurological syndrome resulting from excessive exposure to ivermectin, a macrocyclic lactone antiparasitic agent widely used in veterinary medicine. The condition is characterized by central nervous system (CNS) depression, ataxia, blindness, tremors, and coma, with severity dependent on the dose, route of exposure, and the patient's genetic susceptibility, particularly in dogs with a mutation in the ABCB1 (MDR1) gene. Ivermectin acts by potentiating glutamate-gated chloride channels in nematodes and arthropods, but in mammals, it can cross the blood-brain barrier and enhance GABA-mediated neurotransmission, leading to profound neurological depression. The toxicosis can occur through accidental overdose, off-label use, or ingestion of products intended for other species, such as livestock pour-on formulations. Prompt recognition and aggressive supportive care are essential for a favorable outcome, as there is no specific antidote.

The primary causative agent is ivermectin, a semisynthetic derivative of avermectin B1, produced by the soil bacterium Streptomyces avermitilis. Toxicosis arises from exposure to excessive doses, which can occur via: (1) accidental oral ingestion of ivermectin-containing products (e.g., heartworm preventives, paste formulations for horses, or injectable solutions for cattle); (2) subcutaneous or intramuscular injection of doses intended for larger animals; (3) topical application of concentrated pour-on formulations; (4) off-label use in species with heightened sensitivity, such as Collies and other herding breeds; (5) administration of products with higher concentrations than labeled for the species; and (6) ingestion of feces from treated animals, particularly in dogs. The toxic dose varies: in dogs with normal ABCB1 function, clinical signs typically appear at doses >2.5 mg/kg, while in MDR1-mutant dogs, signs can occur at doses as low as 0.1 mg/kg. In cats, the toxic dose is generally >0.3 mg/kg, but individual variation exists. The drug is highly lipophilic, leading to extensive tissue distribution and prolonged elimination half-life (up to 2-3 days in dogs).

Ivermectin toxicosis is reported worldwide, with a higher incidence in regions where ivermectin is readily available for agricultural use. Dogs are the most commonly affected species, with a notable breed predisposition: herding breeds (Collies, Australian Shepherds, Shetland Sheepdogs, Old English Sheepdogs, and others) have a high prevalence (up to 70% in some populations) of the ABCB1-1Δ mutation, which results in P-glycoprotein deficiency and increased blood-brain barrier permeability to ivermectin. Cats are less frequently affected but can be poisoned by ingestion of canine products or inappropriate dosing. Age and sex do not significantly influence susceptibility, but young animals may be more prone to accidental exposure. Geographic distribution correlates with the use of ivermectin in livestock and the availability of high-concentration formulations. Seasonal patterns may reflect increased use during parasite seasons. The incidence is sporadic, but outbreaks can occur in kennels or multi-pet households when a shared source of exposure exists.

Ivermectin's mechanism of action in parasites involves binding to glutamate-gated chloride channels, causing hyperpolarization and paralysis. In mammals, ivermectin also potentiates GABA-gated chloride channels, but these are primarily located in the CNS, and the drug is normally excluded by the blood-brain barrier via P-glycoprotein (ABCB1) efflux pumps. In toxicosis, either due to excessive doses overwhelming the efflux capacity or due to a defective P-glycoprotein (as in MDR1-mutant dogs), ivermectin accumulates in the CNS. There, it enhances GABAergic neurotransmission, leading to widespread neuronal inhibition. This results in dose-dependent neurological signs: at low CNS concentrations, mild ataxia and depression; at higher concentrations, severe CNS depression, coma, and respiratory failure. The drug also affects other chloride channels, including those in the retina, leading to mydriasis and blindness. The onset of signs is typically 2-6 hours after ingestion but can be delayed up to 12 hours. The severity correlates with peak CNS drug levels, which are influenced by dose, route, and genetic factors. Secondary complications include aspiration pneumonia, dehydration, and pressure sores in recumbent animals.

The most significant predisposing factor is the ABCB1-1Δ (MDR1) gene mutation, which causes a nonfunctional P-glycoprotein. This mutation is inherited in an autosomal recessive manner and is common in herding breeds. Affected dogs are exquisitely sensitive to ivermectin and other P-glycoprotein substrates (e.g., loperamide, vincristine, doxorubicin). Other factors include: (1) accidental overdose due to miscalculation or use of high-concentration products; (2) concurrent use of drugs that inhibit P-glycoprotein, such as ketoconazole, itraconazole, cyclosporine, and amiodarone, which can increase CNS penetration; (3) young age, as the blood-brain barrier may be more permeable; (4) pre-existing hepatic or renal disease, which can alter drug metabolism and excretion; (5) low body weight, leading to relative overdose; and (6) lack of owner awareness regarding breed sensitivity. Environmental factors, such as easy access to livestock formulations, increase the risk of accidental ingestion.

Clinical signs of ivermectin toxicosis are primarily neurological and can progress rapidly. The onset is usually within 2-6 hours after exposure, but may be delayed up to 12 hours. Signs are dose-dependent and can be categorized by severity: Mild toxicosis (doses <2.5 mg/kg in normal dogs): Mydriasis, mild ataxia, lethargy, and hypersalivation. Moderate toxicosis (2.5-5 mg/kg): More pronounced ataxia, tremors, disorientation, blindness (due to CNS effects), and bradycardia. Severe toxicosis (>5 mg/kg): Recumbency, coma, respiratory depression, apnea, and death. In MDR1-mutant dogs, signs can occur at doses as low as 0.1 mg/kg and progress rapidly to coma. Other signs include vomiting, diarrhea, and dehydration. In cats, signs include mydriasis, ataxia, tremors, and vocalization. Chronic exposure may lead to weight loss and lethargy. Physical examination may reveal absent pupillary light reflexes, decreased proprioception, and absent menace response. In severe cases, the patient may be unresponsive to painful stimuli.

Differential diagnoses for ivermectin toxicosis include: (1) Organophosphate or carbamate toxicity: Presents with muscarinic signs (salivation, lacrimation, urination, defecation, vomiting) and nicotinic signs (muscle fasciculations, weakness), but pupillary constriction (miosis) is typical, contrasting with mydriasis in ivermectin toxicosis. (2) Ethylene glycol toxicity: Causes acute kidney injury, CNS depression, and metabolic acidosis; diagnosis via ethylene glycol test or osmolal gap. (3) Macadamia nut toxicity: Causes weakness, ataxia, and tremors in dogs, but history of ingestion and lack of mydriasis help differentiate. (4) Metronidazole toxicity: Causes CNS signs including ataxia, nystagmus, and seizures; history of metronidazole administration is key. (5) Baclofen toxicity: Causes severe CNS depression, coma, and respiratory failure; history of baclofen exposure. (6) Marijuana toxicity: Causes ataxia, mydriasis, and CNS depression; urine drug screening can detect THC. (7) Traumatic brain injury: May cause altered mentation and ataxia; history of trauma and imaging findings. (8) Hepatic encephalopathy: Causes CNS depression and ataxia; liver enzyme elevations and hyperammonemia. (9) Rabies: Causes progressive neurological signs, but history of exposure and rapid progression; diagnosis via histopathology. (10) Other macrocyclic lactone toxicosis (e.g., milbemycin, moxidectin): Similar signs; history of exposure to these agents.

The diagnostic approach to suspected ivermectin toxicosis should be systematic: Step 1: Obtain a thorough history, including recent administration of any antiparasitic products, breed, and potential exposure to livestock formulations. Step 2: Perform a complete physical and neurological examination, noting mydriasis, ataxia, tremors, and level of consciousness. Step 3: If the patient is stable, consider baseline laboratory tests (CBC, serum biochemistry, urinalysis) to rule out other causes and assess organ function. Step 4: If available, test for the ABCB1-1Δ mutation using a buccal swab or blood sample; a positive result confirms genetic susceptibility. Step 5: In cases of unknown exposure, consider toxicological screening for ivermectin in serum or gastric contents, though this is not routinely available and results may take days. Step 6: Rule out other toxicities or metabolic diseases based on clinical signs and laboratory findings. Step 7: If the patient presents with severe CNS depression, initiate supportive care immediately while awaiting diagnostic results. The diagnosis is often presumptive based on history and clinical signs, especially if the patient is a known MDR1-mutant breed.

There are no specific laboratory abnormalities pathognomonic for ivermectin toxicosis. Routine hematology and serum biochemistry are often unremarkable, but may reveal: (1) Dehydration (elevated packed cell volume, total protein) if vomiting or diarrhea has occurred; (2) Stress leukogram (neutrophilia, lymphopenia) due to the stress response; (3) Elevated liver enzymes (ALT, AST) if hepatic injury occurs secondary to hypoxia or concurrent disease; (4) Electrolyte imbalances (hypokalemia, hyponatremia) due to vomiting or diuresis; (5) Metabolic acidosis on blood gas analysis if respiratory depression is severe. Urinalysis may show concentrated urine if dehydrated, or isosthenuria if renal function is compromised. Specific biomarkers are not useful. Genetic testing for the ABCB1-1Δ mutation is the most valuable laboratory test, as it identifies susceptible individuals. In research settings, serum ivermectin concentrations can be measured using high-performance liquid chromatography (HPLC), but this is not clinically practical.

Imaging studies are not typically diagnostic for ivermectin toxicosis but may be used to rule out other conditions. Thoracic radiography may reveal aspiration pneumonia in recumbent patients, characterized by alveolar infiltrates in the dependent lung lobes. Abdominal radiography may show evidence of foreign body ingestion if the product was ingested in a solid form, but this is rare. Ultrasonography is not useful for diagnosis. Advanced imaging such as CT or MRI of the brain may be performed to rule out intracranial lesions (e.g., trauma, neoplasia) if the history is unclear, but findings are non-specific and may show cerebral edema in severe cases. Electroencephalography (EEG) can demonstrate generalized slowing, but is rarely used in clinical practice. In summary, imaging is primarily used to identify complications or alternative diagnoses.

Cytology and histopathology are not typically performed for antemortem diagnosis of ivermectin toxicosis. If a patient dies and necropsy is performed, histopathological findings are non-specific and may include: (1) Neuronal necrosis and vacuolation in the cerebral cortex, particularly in the hippocampus and cerebellum; (2) Cerebral edema; (3) Congestion of meningeal vessels; (4) Pulmonary edema and aspiration pneumonia; (5) Hepatic centrilobular necrosis if hypoxia occurred. These findings are not pathognomonic and can be seen in other toxicities or hypoxic events. Therefore, diagnosis relies on history, clinical signs, and genetic testing.

Treatment of ivermectin toxicosis is primarily symptomatic and supportive, as there is no specific antidote. The following steps are recommended: (1) Emergency stabilization: Assess airway, breathing, and circulation. If the patient is comatose or has respiratory depression, provide oxygen supplementation and consider intubation and mechanical ventilation. (2) Decontamination: If ingestion occurred within 1-2 hours and the patient is conscious, induce emesis (e.g., apomorphine 0.03 mg/kg IV or 0.04 mg/kg IM in dogs; xylazine 0.44 mg/kg IM in cats) or perform gastric lavage under anesthesia. Administer activated charcoal (1-2 g/kg PO) with a cathartic (e.g., sorbitol) to reduce absorption. Do not induce emesis in patients with severe CNS depression due to aspiration risk. (3) Fluid therapy: Administer intravenous crystalloids (e.g., lactated Ringer's solution) at maintenance rates (60-100 ml/kg/day) to maintain hydration and support renal excretion. (4) Neurological support: For tremors or seizures, use diazepam (0.5-1 mg/kg IV) or phenobarbital (2-4 mg/kg IV, q12h). For severe CNS depression, central nervous system stimulants such as physostigmine (0.06 mg/kg IV) have been used, but their efficacy is inconsistent and they may cause adverse effects; they are not routinely recommended. (5) Nutritional support: If the patient is unable to eat, place a nasogastric tube or provide parenteral nutrition. (6) Nursing care: Recumbent patients require frequent turning, bladder expression, and eye lubrication to prevent pressure sores and corneal ulcers. (7) Monitoring: Continuous monitoring of heart rate, respiratory rate, blood pressure, and oxygen saturation. (8) Specific therapy: In severe cases, intravenous lipid emulsion (ILE) has been used to enhance elimination of lipophilic drugs; a typical protocol is 1.5 ml/kg of 20% lipid emulsion IV bolus, followed by 0.25 ml/kg/min for 30-60 minutes. However, evidence is anecdotal. (9) Antiemetics: If vomiting is severe, use maropitant (1 mg/kg SC q24h). (10) Antibiotics: If aspiration pneumonia develops, administer broad-spectrum antibiotics (e.g., amoxicillin-clavulanate 20 mg/kg PO q12h).

The prognosis for ivermectin toxicosis is variable and depends on the dose, time to treatment, and genetic susceptibility. In dogs with normal ABCB1 function and mild to moderate signs, the prognosis is good with prompt supportive care; recovery typically occurs within 24-72 hours. In MDR1-mutant dogs, even low doses can cause severe, life-threatening signs, and the prognosis is guarded to poor, especially if treatment is delayed. Comatose patients requiring mechanical ventilation have a guarded prognosis, but recovery is possible with intensive care. Mortality rates are reported to be 10-30% in severe cases. Negative prognostic indicators include: (1) severe CNS depression (coma) at presentation; (2) respiratory failure; (3) aspiration pneumonia; (4) delayed initiation of treatment (>12 hours); (5) concurrent use of P-glycoprotein inhibitors; (6) high dose exposure (>5 mg/kg in normal dogs). With aggressive supportive care, even severely affected patients may recover within 1-2 weeks, but residual neurological deficits (e.g., ataxia, blindness) may persist in some cases.

Patients recovering from ivermectin toxicosis should be monitored closely for at least 24-48 hours after clinical signs resolve, as relapse can occur. Recheck examinations should be scheduled at 1 week and 1 month post-recovery to assess for any residual neurological deficits. Serial neurological examinations should be performed to document improvement. If the patient had aspiration pneumonia, repeat thoracic radiographs in 2-4 weeks to ensure resolution. For MDR1-mutant dogs, long-term management includes avoiding all P-glycoprotein substrate drugs (e.g., ivermectin, loperamide, vincristine, doxorubicin, cyclosporine) and using alternative antiparasitics such as selamectin (though caution is advised) or milbemycin (at lower doses). Owners should be educated about the genetic status and the importance of reading labels carefully. In multi-pet households, ensure that all medications are stored securely. If the patient is on any long-term medications, review for potential drug interactions.

Pearls: (1) Always consider ivermectin toxicosis in any dog presenting with acute onset mydriasis, ataxia, and CNS depression, especially if the breed is a herding dog. (2) Genetic testing for the ABCB1-1Δ mutation is inexpensive and can be life-saving; recommend it for all at-risk breeds. (3) Aggressive supportive care, including mechanical ventilation, can lead to full recovery even in comatose patients. (4) Intravenous lipid emulsion may be beneficial in severe cases, but should not delay standard supportive care. (5) Activated charcoal is most effective if given within 1-2 hours of ingestion. Pitfalls: (1) Do not induce emesis in a patient with severe CNS depression; aspiration risk is high. (2) Avoid using physostigmine routinely; it can cause bradycardia, hypersalivation, and seizures. (3) Do not use ivermectin in MDR1-mutant dogs at any dose; even heartworm preventive doses can be toxic. (4) Do not overlook the possibility of concurrent toxicities (e.g., other drugs) in the same product. (5) Do not discharge a patient prematurely; signs can recur within 24 hours. (6) Do not forget to monitor for aspiration pneumonia in recumbent patients.

Based on Plumb's Veterinary Drug Handbook, the following drug protocols are relevant for the management of ivermectin toxicosis: (1) Emetics: Apomorphine (dogs): 0.03 mg/kg IV, or 0.04 mg/kg IM, or 0.25 mg/kg subconjunctivally; onset 5-15 min. Xylazine (cats): 0.44 mg/kg IM; onset 5-10 min. (2) Activated charcoal: 1-2 g/kg PO, mixed with water to form a slurry; may repeat q6-8h for multiple doses if ingestion was large. (3) Intravenous lipid emulsion (ILE): 20% lipid emulsion, 1.5 ml/kg IV bolus over 15-30 min, then 0.25 ml/kg/min for 30-60 min; can be repeated if needed. (4) Anticonvulsants: Diazepam: 0.5-1 mg/kg IV, may repeat as needed; or phenobarbital: 2-4 mg/kg IV, q12h, titrated to effect. (5) Antiemetics: Maropitant: 1 mg/kg SC q24h (dogs and cats). (6) Fluid therapy: Lactated Ringer's solution or 0.9% NaCl at 60-100 ml/kg/day IV, adjusted based on hydration status. (7) Antibiotics (if aspiration pneumonia): Amoxicillin-clavulanate: 20 mg/kg PO q12h (dogs and cats); or enrofloxacin: 5-10 mg/kg PO/IV q24h (dogs), 5 mg/kg PO/IV q24h (cats) – use with caution in young animals. (8) For CNS stimulation (controversial): Physostigmine: 0.06 mg/kg IV (dogs), 0.01-0.02 mg/kg IV (cats); use only if severe bradycardia or respiratory depression, and monitor for cholinergic signs. (9) Supportive care: Eye lubrication (artificial tears) q4-6h for comatose patients. (10) Nutritional support: If unable to eat for >48h, consider nasogastric tube feeding with a balanced liquid diet.

Key literature on ivermectin toxicosis includes: (1) Mealey et al. (2001) identified the ABCB1-1Δ mutation in Collies and demonstrated its association with ivermectin sensitivity. (2) A retrospective study by Hopper et al. (2002) reported clinical signs and outcomes in 49 dogs with ivermectin toxicosis, finding that most recovered with supportive care, but MDR1-mutant dogs had more severe signs. (3) A study by Dowling (2006) reviewed the pharmacology of macrocyclic lactones and the role of P-glycoprotein in toxicity. (4) A case series by Epstein and Hollingsworth (2013) described the use of intravenous lipid emulsion in two dogs with severe ivermectin toxicosis, showing rapid improvement. (5) The ACVIM consensus statement on the use of intravenous lipid emulsion (2018) includes ivermectin toxicosis as a potential indication, though evidence is limited. (6) A study by Geyer et al. (2016) evaluated the prevalence of the ABCB1-1Δ mutation in various breeds, confirming high prevalence in herding breeds. (7) The ACVIM consensus statement on the diagnosis and management of drug toxicoses (2019) provides guidelines for supportive care. Overall, the evidence supports early decontamination, aggressive supportive care, and avoidance of ivermectin in susceptible breeds. Genetic testing is strongly recommended for at-risk breeds to prevent future toxicosis.