V315 Rodenticides An Oldie But a Goodie Ahna Brutlag, DVM Pet Poison Helpline, Bloomington, MN, USA

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1 82nd Western Veterinary Conference V315 Rodenticides An Oldie But a Goodie Ahna Brutlag, DVM Pet Poison Helpline, Bloomington, MN, USA KEY POINTS Do not assume all rodenticides are anti-coagulants. The active ingredient of a rodenticide cannot be determined by the color or shape of the product. Due to better absorption and less chance of reaction, the oral administration of Vitamin K1 is preferred over injectable unless the animal is coagulopathic. OVERVIEW OF THE ISSUE Rodenticides (chemicals used to kill mice, rats, moles, gophers and other vermin) have been marketed in the US for many decades. They are available in several formulations with blue or green pellets or paraffin blocks being the most common preparations. Powders and liquid products also exist. Grain and other attractants are often added to the solid formulations. While many contain bittering agents to prevent accidental ingestion by children, these agents appear to have limited effectiveness in animals. The color or formation of the rodenticide is unrelated to the active ingredient and cannot be relied upon for ingredient identification. Thus, make no assumptions about the active ingredient based on the appearance of the bait alone. Currently, anticoagulant rodenticides are the most widely used in the US. Other commonly used active ingredients include cholecalciferol, zinc or aluminum phosphides, and bromethalin. The availability of strychnine has become severely restricted and is not often available to the general public. The currently marketed array of rodenticides can lead to a wide variety of toxidromes, thereby making the management of the poisoned patient difficult and costly. Rodenticide toxicity is among the top three most common sources of toxin exposures in dogs. Cats suffer from rodenticide toxicity much less frequently. The reason for this is likely dependent on species sensitivities with cats being more resistant to the effects of many anticoagulant rodenticides as compared to dogs. These notes will review the most commonly marketed rodenticides, the clinical signs associated with poisoning, preferred diagnostic testing, and treatment recommendations for poisoning. ANTI-COAGULANTS Short acting anticoagulants: Warfarin (rarely used) Long acting anticoagulants: Bromadiolone, brodifacoum, diphacinone, difenthiolone, chlorphacinone For purposes of this lecture, anticoagulant rodenticides will be discussed as short-acting or longacting. It is the duration of action that is most important to health care providers because this dictates the duration of treatment needed. Anticoagulant rodenticides are Vitamin K antagonists and thus interfere with the production of Vitamin K dependent clotting factors in the liver (factors 2, 7, 9 and 10 or the prothrombin complex). The coagulation system generally continues to function well until about 24 to 36 hours after ingestion when the natural decay of clotting factors occurs. As a group, anticoagulant rodenticides are well absorbed orally (about 90%) with peak plasma levels occurring within 12 hours after ingestion. Warfarin, the most common short-acting anticoagulant (SAAC) has a half-life of hours and treatment with Vitamin K1 for 5 6 days is often sufficient. Due to widespread resistance amongst rats, warfarin is rarely used as a rodenticide in the US. More typical are the long-acting anticoagulants (LAACs) such as bromadiolone and brodifacoum. LAACs have an exceedingly longer half life of days to weeks; treatment is recommended for 3 4 weeks.

2 The margin of safety for anticoagulant rodenticides is quite narrow though the LD 50 varies dramatically amongst active ingredients, as well as from species to species. Cats are significantly more resistant to the effects of LAACs than dogs and rarely suffer toxicity. For an easy estimation of toxicity based on finished bait products, see Table 1. Refer to Table 4 for a listing of oral LD 50 s. Table 1. Estimates of toxicity based on 0.005% concentration of LAAC rodenticides. Active ingredient Canine toxic dose Bromadiolone* 23 gm/kg 53 gm/kg Brodifacoum** 0.99 gm/kg 132 gm/kg Diphacinone* 2.0 gm/kg 33 gm/kg * Based on 1/10 of the oral LD 50 ** Based on ¼ of the oral canine LD 50 and 1/10 of the oral feline LD 50 Animals with hepatic or renal compromise and those with GI malabsorption syndromes may be at a higher risk of toxicity. The pediatric and geriatric population, as well as those with very low body weights, also have a higher risk of toxicity and more conservative estimates of toxicity must be used. Additionally, animals taking highly protein-bound drugs (i.e., deracoxib or carprofen) may also be an increased risk of toxicity. Additionally, anticoagulant rodenticides cross the placental barrier and may lead to uterine bleeding or fetal toxicity. To a very limited extent, they are excreted in breast milk. The most common signs of toxicity in dogs and cats include generalized signs such as lethargy, exercise intolerance, inappetence, pallor, and dyspnea or wheezing. These signs typically begin 3 5 days following exposure. Gingival bleeding, epistaxis, ecchymoses, petechiae, hematuria, hemoptysis, hematemesis and melena may also be present but are often not noted by pet owners. Rarely, animals may present with generalized pain, fever, or lameness and neurologic abnormalities. As opposed to coagulopathies secondary to thrombocytopenia, bleeding is typically intracavital versus serosal. Massive blood loss into the thoracic and abdominal cavities is common and is often the cause of death. A tentative diagnosis is often made by a history of ingestion and clinical signs. This may be supported with a finding of anemia, delayed whole blood clotting times, and an ACT from 2 to 10+ times normal. These results are confirmed by prolonged PT and APPTs with normal to slightly low platelets and normal fibrin degradation products. While mild thrombocytopenia is a typical diagnostic finding, anticoagulant rodenticides do not interfere with platelet production or function. A finding of severe thrombocytopenia is either secondary to blood loss or due to other causes. For acute exposures or asymptomatic animals, a baseline PT as well as a PT performed hours post-ingestion may be performed in lieu of empirical antidotal treatment. This allows enough time for the currently present clotting factors to decay but does not (typically) provide enough time for the onset of clinical signs. Should the PT be prolonged on the subsequent test, Vitamin K1 therapy is necessary. Likewise, a PT should be performed hours following the final dose of Vitamin K1 to ensure that further treatment is no longer needed. Laboratory assays for specific LAACs may be performed on plasma, stomach contents, and kidney and liver specimens. Decontamination via emesis followed by one dose of activated charcoal is recommended following recent toxic ingestions. Vitamin K1 (phytonadione) is antidotal and is dosed at mg/kg per day or divided into two daily doses. Oral Vitamin K1 is preferred over injectable if the exposure was less than 24 hours ago and the animal is asymptomatic. Injectable Vitamin K1 given subcutaneously should be reserved for

3 coagulopathic animals. Oral Vitamin K1 should be administered for a minimum of days for LAAC toxicity and 4 6 days for SAAC toxicity. A PT should be obtained hours after treatment is discontinued to assure proper duration of treatment. If the PT is prolonged, Vitamin K1 should be reinstituted for another 21 days and rechecked at termination. Vitamin K1 has no direct effect on coagulation and it takes 6 12 hours to make new clotting factors once therapy is instituted. Animals suffering significant blood loss may need a transfusion of fresh whole blood or plasma to provide clotting factors. Animals with severely compromised respiratory systems may need a thoracocentesis. CHOLECALCIFEROL Cholecalciferol or Vitamin D3 is gaining popularity as a rodenticide. Toxicity from cholecalciferol results in life-threatening hypercalcemia and hyperphosphatemia leading to dystrophic mineralization and subsequent renal failure. Death from cardiac failure secondary to hypercalcemia may also occur though is much less likely. Estimating toxicity levels can be difficult. While the published range of oral canine LD 50 is relatively large (10 85 mg/kg), clinical signs have been documented at mg/kg. Cats are more sensitive to cholecalciferol than dogs. Refer to Table 4 for a listing of common rodenticides and their respective canine and feline oral LD 50. For an easy estimation of toxicity based on finished bait products, see Table 2. Table 2. Estimates of toxicity* based on 0.075% concentration of cholecalciferol bait. Active Ingredient Canine toxic dose (grams finished bait/kg of body weight) (grams finished bait/kg of body weight) Cholecalciferol 0.66 gm bait/kg 0.53 gm bait/kg * Based on an estimate of 0.5 mg/kg toxicity in dogs and 1/10 of the LD 50 in cats. Signs typically begin hours after ingestion and may be non-specific at the onset. While the renal system is often most acutely affected, eventually the cardiac, pulmonary GI and CNS systems may be as well hours: PU/PD, hypercalcemia, hyperphosphatemia hours: Anorexia, vomiting, weakness, lethargy, melena 2 4 days: Acute renal failure 3 5 days: Depression, frank bloody diarrhea, hematuria, prominent bradycardia, death A diagnosis is made by a history of ingestion and clinical signs, and is supported by laboratory findings of hypercalcemia and hyperphosphatemia. Additionally, azotemia, calciuria, hypothsenuria, and radiographic evidence of dystrophic mineralization support the diagnosis of cholecalciferol toxicity. A definitive diagnosis based on serum and tissue testing for cholecalciferol and its metabolites may be done but is rarely performed. Suggested laboratory monitoring: Serum phosphorous (typically rises hr post exposure) Serum calcium (typically rises hr post exposure) Ionized calcium levels (typically rises hr post exposure) BUN and creatinine (secondary to mineralization, may take 2 4 days to elevate) UA and urine specific gravity o Monitor for calcium crystalluria and hypothsenuria

4 Prevent toxin absorption by inducing emesis and administering multiple doses of activated charcoal over 1 2 days (every 4 6 hours) Keep serum calcium below 12.5 mg/dl; serum phosphorus below 7 mg/dl To increase calciuresis: o Saline diuresis: times maintenance, gradually wean down o Furosemide: 5mg/kg 3X daily initially, reduce to 3 mg/kg TID x 2 3 weeks. Administer IV while hospitalized, switch to oral upon discharge o Prednisone: 1 2 mg/kg BID x 2 3 weeks. Administer IV while hospitalized, switch to oral upon discharge and wean Additional hypercalcemic treatment (choose one): o Pamidronate (a bisphosphonate): mg/kg IV diluted in saline; give over 2 hours. o Repeat in 3 7 days if needed Salmon calcitonin: 4 6 IU/kg SQ q 2 3 hours until serum calcium is below 12.5 mg/dl. Increase dose to IU/kg if no effect Provide GI protection and support as needed (anti-emetics, sucralfate, H2 blockers, etc) Feed a low calcium diet PHOSPHIDES (ZINC, CALCIUM, AND ALUMINUM) Phosphide rodenticides are often used in mole and gopher baits. They decompose rapidly following ingestion and release phosphine gas, the true agent of toxicity. Toxicity from the elemental zinc, calcium or aluminum is rarely a concern. Phosphine gas has a characteristic garlic or rotten fish odor. It is also a potent respiratory irritant and ventilation must be present when handling emesis or performing gastric lavage! Food in the stomach greatly increases toxicity. The oral canine LD 50 with a full stomach is 20 50mg/kg while that of a fasted dog is 300mg/kg. Phosphide salts and phosphine gas cause severe gastrointestinal inflammation. Thus vomiting is often the first clinical sign and occurs soon after ingestion. Additionally, salivation, abdominal pain with distension, dyspnea, pulmonary congestion and edema, and poor cardiovascular return (secondary to bloating) are seen. Neurologic effects such as tremors, seizures and running fits have also been reported. is difficult and is typically based solely on a history of ingestion and clinical signs. The breath or emesis may smell like garlic or rotten fish. Analysis of stomach contents is available. There is no antidote and treatment options are limited. Thus, decontamination is extremely important. Because of the relatively small amount needed to cause toxicity, gastric lavage with a 5% sodium bicarbonate solution followed by activated charcoal is often recommend. Oral antacids such as Maalox may be administered by the pet owner prior to clinic presentation. This will help to reduce the amount of phosphide gas produced. Following decontamination, the animal must be observed closely. Monitor for acid/base imbalances, shock, seizures, gastric bloating, and renal and/or hepatic damage. is symptomatic and supportive and may include GI protectants, anti-emetics, sedation, and acid/base correction. BROMETHALIN Bromethalin uncouples oxidative phosphorylation. This causes a loss of sodium/potassium ATPase with resultant intracellular edema and degeneration. The CNS is the target organ of toxicity. Cerebral edema

5 causes increased pressure on nerve axons, decreased nerve conduction, paralysis and death. The plasma half-life is 5 6 days. Cats are more sensitive to the effects of bromethalin than dogs. Refer to Table 4 for a listing of the oral LD 50. For an easy estimation of toxicity based on finished bait products, see Table 3. Table 3. Estimates of bromethalin toxicity of finished bait products*. % Bromethalin Canine toxic dose 0.01% 2.5 gm/kg 1.1 gm/kg 0.025% 1.0 gm/kg 0.44 gm/kg * Based on 1/10 of the oral LD 50 Clinical signs are predominately neurologic in nature and include ataxia, paresis, depression, muscle tremors, loss of reflexes, anisocoria, hyperexcitability, and seizures. The onset of clinical signs is dose dependent and may begin in 2 24 hours. typically based on a history of ingestion and clinical signs. General laboratory results are often within normal limits. Bromethalin can be detected from stomach contents and other tissues (kidney or brain). No antidote is available. Therefore, treatment is focused on decontamination and supportive care. Bromethalin does undergo enterohepatic recirculation so multiple doses of activated charcoal may be helpful. for cerebral edema may include mannitol, head elevation of 15 30º, IV fluids to maintain cerebral perfusion pressure, oxygen therapy and thermal support. The use of dexamethasone and other steroids is controversial. POISON CONTROL RESOURCES For assistance managing a potentially poisoned patient, a number of resources are available. In the US and Canada, veterinarians or pet owners may call Pet Poison Helpline ($35/case) at (800) or the ASPCA s Animal Poison Control Center ($60/case) at (888) Both of these services are available 24/7 and are staffed with experts in the field of veterinary toxicology. The author recommends using either of these services in order to obtain the most accurate and current veterinary-specific clinical advice. Additional resources include veterinary diagnostic labs or the medical information phone number listed on the rodenticide packaging. Table 4. Reported oral LD 50 of common rodenticides in dogs and cats.* Active ingredient Canine oral LD 50 (mg/kg) Feline oral LD 50 (mg/kg) Brodifacoum Bromadiolone >25 Bromethalin Cholecalciferol Zinc Phosphide *Based on 100% concentration of active ingredient.