ABCD's of rodenticides (Proceedings)

While there are several different products that may be used as rodenticides, including strychnine, zinc phosphide, and aluminum phosphide, this presentation will focus on the rodenticides that are most often encountered: anticoagulants, bromethalin, and cholecalciferol. Just as "Kleenex" is commonly used instead of the word tissue, many owners may use the term "D-con" to refer to any rodenticide regardless of the actual brand name. Therefore it is a good idea to ask the owner to bring in the package to verify ingredients. Baits may be formulated as pellets, bars, grains, or meals. Unfortunately rodenticides are not color-coded, so the color of the rodenticide provides no insight into the type of rodenticide.

Anticoagulants

Warfarin and pindone are short-acting anticoagulants and have short half-lives (<24 hours) compared to the long acting products whose half-lives are up to 6-7 days. Long acting anticoagulants include diphacinone, difethialone, chlorophacinone, brodifacoum, and bromadiolone. First generation anticoagulants include warfarin, diphacinone, chlorphacinone, pindone and valone. Second generation anticoagulants may be longer acting and/or more potent than the first generation anticoagulants and are effective against warfarin-resistant rats. As a general guideline, the minimum toxic dosage of warfarin is >0.5 mg/kg. The minimum toxic dosage of the other anticoagulants is >0.02 mg/kg.

The anticoagulant rodenticides act by competitive inhibition of the enzyme vitamin K1 epoxide reductase thereby preventing the regeneration of inactive Vitamin K1 to its active quinone form. Vitamin K1 deficiency results in depletion of the clotting factors II, VII, IX and X. Because it has the shortest half-life, factor VII it is the first one affected. Depletion of factor VII leads to an elevation of the prothrombin time (PT). PIVKA, the collective term for the precursors of the vitamin K-dependent clotting factors, also becomes increased. The PT may be elevated within 36-72 hours, but the animal is usually still clinically normal. Beyond 72 hours, as other factors become depleted, severe hemorrhage may occur, accompanied by elevations in activated partial thromboplastin time (APTT) and activated clotting time (ACT). In rare instances (e.g. animals with pre-existing bleeding disorders or hepatic disease, etc.) depletion of coagulation factors may occur sooner, resulting in clinical evidence of hemorrhage as early as 24-48 hours following exposure.

In many cases, poisoned animals are not presented to the veterinarian until signs develop. Many patients present with vague clinical signs of lethargy, weakness and anemia without any overt external hemorrhage although some animals may present with frank external hemorrhage from surgical or traumatic wounds, the gastrointestinal tract, or other body orifices (e.g. epistaxis, vulvar bleeding). Hemorrhage into body cavities such as the joints, the peritoneal cavity or the pleural cavity is common. Weakness, pallor, abdominal distention, lameness, swollen joints, dermal bruising, muscular hematomas, dyspnea, labored breathing, or muffled heart sounds are also possible. Bleeding into the brain or spinal cord may result in severe CNS disturbances, paresis, paralysis or acute death. Tracheal constriction due to thymic, peritracheal or laryngeal bleeding may result in severe dyspnea. Clinical pathologic abnormalities may include anemia, thrombocytopenia, hypoproteinemia and decreases in CO2 and pO2.

Diagnosis is based on history, compatible clinical signs and laboratory confirmation of coagulopathy. Differential diagnoses should include congenital and acquired coagulopathies, and other causes of anemia (trauma, etc.). Coagulation panels may aid in the differentiation of anticoagulant rodenticide from other coagulopathies (e.g. disseminated intravascular coagulation, von Willebrand's disease, Hemophilia A, etc.). Serum chemistry profiles to detect hepatic or other systemic disease that might affect blood clotting are usually indicated. Anticoagulant toxicosis may be worsened in cases of significant hepatic disease due to impaired ability to synthesize coagulation factors and decreased metabolism of ingested rodenticide. Because PT is the first coagulation test to become abnormal in anticoagulant rodenticide toxicosis, it is the best choice for early detection. Elevations in PIVKA may also be used early in anticoagulant rodenticide toxicosis, as normal animals should not have PIVKA present in the circulation. Unfortunately, PIVKA proteins have been shown to be elevated in number of other acquired and congenital coagulopathies.

Stabilization of symptomatic animals is a priority. Provide oxygen as needed for dyspnea. Transfusions with whole blood or plasma may be necessary to replace blood and clotting factors. Oxyglobin may also be used.

Decontamination is only effective early (within the first 12 hours). Do not attempt emesis in a bleeding animal. Monitor prothrombin time (PT) between 36-72 hours. Any elevation in the PT warrants full treatment with Vitamin K1. No treatment is indicated if PT remains normal after 72 hours. NOTE: Recent vitamin K1 administration could result in falsely normal PT values because new clotting factor synthesis only requires 6 - 12 hours. Administer Vitamin K1 as needed, or you may opt to begin it prophylactically. Vitamin K1 should not be given intravenously and it is possible to have an anaphylactic reaction when it is given subcutaneously. Oral administration is ideal, because vitamin K1 will be delivered directly to the liver where the clotting factors are activated through the portal circulation. The dose of Vitamin K1 is 3 - 5 mg/kg/day orally. This dose should be divided BID or TID and should be given with a fatty meal to enhance absorption. The average duration of treatment is 14 days for warfarin, 21 days for bromodiolone and 30 days for the others.

Also it is advisable to check a PT at 48- 72 hours following the last dose of Vitamin K1. Vitamin K1 should be continued if the PT is still increased. If possible, avoid the use of other highly protein-bound drugs during the treatment, and instruct the owner to restrict exercise during this time.

Bromethalin

Bromethalin uncouples oxidative phosphorylation, resulting in depletion of ATP and loss of energy for sodium-potassium trans-membrane pumps. Intramyelinic edema ensues, characterized by the presence of fluid-filled vacuoles between myelin sheaths. This results in decreased nerve impulse conduction. Baits generally contain 0.01% bromethalin and come in 1.5-ounce packs. Although the literature reports a minimum toxic dose in dogs of 1.67 mg/kg, the ASPCA APCC's experience indicates that some dogs may show signs at doses as low as 0.9 m/kg. Because of this discrepancy and because treatment once signs have developed is usually unsuccessful, we recommend that decontamination be initiated at doses > 0.1 mg/kg. Cats are considered to be three times more sensitive than dogs, and we recommend decontamination for any cat exposure.

Clinical signs may begin within 24 hours or as long as 2 weeks following ingestion. Earlier onset of signs suggests higher ingested dosage and poorer prognosis. High doses (>2 mg/kg) result in a convulsant syndrome characterized by acute onset of severe tremors, hyperexcitability, seizures, rigidity, opisthotonos, decerebrate posturing, hyperthermia and death within 36 hours of ingestion. Lower doses cause a paralytic syndrome that begins as depression, +/- hyperthermia, progressive paresis originating in the rear and moving cranially and progressive CNS signs. In sub-lethal exposures, signs may arrest at some level of paresis, and the animal may recover gradually over weeks to months or may retain permanent motor impairment. Bromethalin causes spongy degeneration in the white matter of spinal tracts, brainstem, cerebellum, and cerebrum. Electron microscopy demonstrates vacoulation myelin sheaths.

There is no antidote, so aggressive decontamination is critically important. Repeated doses of activated charcoal (every 8 - 12 hours) and cathartic are recommended. Efficacy of activated charcoal in symptomatic animals is poor. Provide supportive care as needed to manage clinical signs including diazepam or barbiturates for seizures. Agents such as mannitol, furosemide, and corticosteroids have been recommended to reduce the cerebral edema, but were of little benefit in reducing the severity of signs in experimental animals. Gingko biloba at 100 mg/kg was shown to reduce the development of cerebral edema and brain lipid peroxidation in rats following a lethal dose of bromethalin. Efficacy of Gingko in other animals has not been studied. Animals exposed at lower doses exhibiting paralysis may recover. The prognosis is extremely poor for animals showing severe signs.

Cholecalciferol

Cholecalciferol (Vitamin D3) is metabolized in the liver to calcifediol (25-hydroxycholecalciferol). Calcifediol is then metabolized by the kidney to calcitriol (1,25 - dihydroxycholecalciferol). Cholecalciferol increases intestinal absorption of calcium, stimulates bone resorption, and enhances renal tubular reabsorption of calcium. This results in an increase in serum calcium. Prolonged elevation of serum calcium can lead to acute renal failure, cardiovascular abnormalities, and tissue mineralization. The minimum toxic dose of cholecalciferol ranges from 0.5 mg/kg to 3.0 mg/kg. The APCC recommends decontamination at 0.1 mg/kg. One ounce of 0.075% cholecalciferol bait contains 21.28 mg cholecalciferol.

Clinical signs may be delayed in onset and typically occur 18 - 36 hours post ingestion. The most common clinical signs seen with cholecalciferol toxicosis include vomiting, diarrhea, inappetence, depression, polyuria, polydipsia, bradycardia, and cardiac arrhythmias. An initial hyperphosphatemia is often seen within the first 12 hours, followed by hypercalcemia within 24 hours. Hypercalcemic nephropathy develops, resulting in increases in BUN and creatinine. Differential diagnoses for hypercalcemia include juvenile hypercalcemia, hypercalcemia of malignancy, hypoadrenocorticism, hypoadrenocorticism, primary hyperparathyroidism, and calcipotriene toxicosis.

Post mortem lesions seen with cholecalciferol toxicoses include diffuse hemorrhages of the gastrointestinal tract and possible streaking of the renal cortex. Upon cutting, soft tissues of the gastrointestinal tract, heart and kidney lend have a "gritty" feel to the knife. Mineralization and necrosis of gastrointestinal, cardiac, and renal tissues may be seen histologically. Elevated total kidney calcium concentrations may be detected toxicologically.

Aggressive decontamination is recommended for recent exposures. Emesis should be induced, followed by multiple doses (3-4 doses q 6-8 hours) of activated charcoal. Obtain a baseline serum calcium and BUN immediately post-exposure. Monitor serum calcium and BUN every 12-24 hours each day for three days post exposure. If the calcium level remains normal for 96 hrs, no further treatment is be needed. Treat renal effects with supportive care including fluid diuresis 2x maintenance using 0.9% saline or 0.45% saline and 2.5% dextrose. Avoid calcium-containing fluids. Normal saline fluids help to decrease tubular reabsorption of calcium. Pamidronate disodium (Aredia) inhibits osteoclastic bone resorption. The dose is 1.3- 2.0 mg/kg as a slow IV infusion over 2 hours. This dose may need to be repeated in 5-7 days. Expect normalization of serum calcium within 48 hours (often within 12-18 hours). The initial expense of pamidronate may be offset by the fact that the animal may be weaned off of IV therapy and sent home once calcium levels normalize. The dose listed is for dogs; one case of pamidronate use in a cat at 1.3 mg/kg had a very favorable outcome.

Oral prednisone at 2-3 mg/kg BID can help lower serum calcium by decreasing its gastrointestinal absorption, lowering bone resorption, and increasing renal excretion. Furosemide at 2.5 to 4.5 mg/kg TID or QID orally, or 5 mg/kg/hr via continuous intravenous infusion has been shown to decrease serum calcium levels. Salmon calcitonin 4-6 IU/kg q 2-3 hours until calcium levels stabilize has also been used. Some dogs become refractory and there is a risk of anaphylaxis. Salmon calcitonin and pamidronate should not be used together, as there is increased risk of soft-tissue mineralization.

Prolonged treatment is often required due to the long half life of Vitamin D3 (> 17 days.) Provide other supportive care as needed during treatment and monitor serum calcium, phosphorous and renal values. A low calcium diet is indicated and the patient should be kept out sunlight as much as possible. Antibiotics may be indicated if prolonged prednisone usage is anticipated.

What should I do if I don't know what this green stuff is?

Endeavor to find the type of bait. Have owner find container. If product was put out by pest control operator, an invoice is required to be left stating which pesticide(s) was/were used. If the rodenticide is still unknown, and the exposure was recent, induce emesis and administer activated charcoal. Repeat doses in case rodenticide is bromethalin or cholecalciferol. Follow decontamination with baseline PT and serum calcium and phosphorus levels. Monitor calcium and phosphorus every 12 hours for 36 hours; if normal, then can discontinue monitoring for cholecalciferol. Monitor PT at 24 and 72 hours; if normal then no treatment for anticoagulants. Educate owner to monitor for neurologic signs (paresis, depression) from bromethalin; signs could be delayed several days.