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PRACTICAL TOXICOLOGY The Decontamination Dilemma: Bromethalin Ingestion

Renee Tourdot, DVM, ASPCA Animal Poison Control Center

shutterstock.com/Ysbrand Cosijn

Bromethalin-based bait exposures have become increasingly common since the Welcome to Practical Toxicology, brought to you in 1 partnership between Today’s Veterinary Practice and product became available in 1985. In 2015, the ASPCA Animal Poison Control Center (APCC) the American Society for the Prevention of (www.aspcapro.org/poison). This column provides practical clinical information about diagnosing and Cruelty to Animals Animal Poison Control treating pets that have been exposed to potentially Center received 2791 calls regarding exposures harmful substances. to bromethalin-based .2 The APCC: • Provides 24-hour diagnostic and treatment Exposures to this present a unique challenge recommendations by specially trained veterinary to clinicians. Once signs of syndrome—a toxicologists neurologic syndrome caused by bromethalin • Protects and improves animal lives through toxicology toxicosis—have developed, prognosis for recovery is education, consulting services, and case data review poor.3,4 Therefore, most clinicians seem aware that • Developed and maintains AnTox, an animal toxicology database system that identifies and characterizes prompt and aggressive decontamination measures toxic effects of substances in animals must be taken. However, if decontamination • Works closely with human poison control centers to is too aggressive, iatrogenic hypernatremia can provide animal poisoning information develop, and clinical hypernatremia can be just as • Offers extensive veterinary life-threatening as a large bromethalin exposure. toxicology consulting to organizations in industry, government, and agriculture. To further complicate matters, clinical signs of hypernatremia can appear similar to the neurologic If treating a patient that 5 requires emergency care for signs caused by bromethalin. If clinicians are not poisoning, call the APCC at aware of, or monitoring for, a significant rise in 888-426-4435. the patient’s serum sodium level, hypernatremia may be mistaken for bromethalin toxicosis,

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resulting in incorrect treatment being instituted, Based on patient history, it can be determined which can worsen the patient’s prognosis. that Dusty was exposed to up to 6.75 ounces of the rodenticide (12−5.25 = 6.75 blocks). This This article provides guidance on how to treat is the worst-case scenario: the largest amount patients with bromethalin exposure, while of bait that Dusty may have ingested is the taking these challenges into consideration. missing portion of the block he was discovered carrying plus the missing blocks from the box. CONSIDER THIS CASE: EVALUATION To calculate the dosage ingested, the concentration Dusty, a 6-year-old, 21-kg male castrated hound of bromethalin in the bait needs to be determined. mix, is presented to an emergency hospital. • It is important to verify the rodenticide History product, active ingredient, and concentration. This information should be taken directly Shortly before presentation, Dusty’s owner found from the packaging whenever possible. him carrying part of a rodenticide bait block and • While most bromethalin-based rodenticides have subsequently discovered a box of bait blocks on a concentration of 0.01%, some commercial the basement floor. The owner believes the box products have higher concentrations. of bait blocks was stored in the basement when • A bromethalin concentration of 0.01% equals she purchased the home 5 years ago, and she 0.1 mg of bromethalin in each gram of bait. knows the box was not on the floor yesterday evening—the last time the owner was in the Using a concentration of 0.01%, the potential basement. There are no other pets in the home. dosage ingested by Dusty can then be calculated:

1. There are 28.4 grams in 1 ounce; therefore, Dusty Learn More may have ingested up to 192 grams of bait. The Animal Poison Control Center (APCC) provides 24-hour diagnostic and treatment 6.75 oz × 28.4 g/oz = 192 g recommendations by specially trained veterinary toxicologists. If treating a patient that requires emergency care for poisoning, 2. If each gram of bait has 0.1 mg of call the APCC at 888-426-4435. bromethalin, Dusty may have ingested up to 19 mg of bromethalin.

0.1 mg/g × 192 g = 19.2 mg Rodenticide Evaluation 3. Finally, when 19 mg bromethalin is Evaluation of the box label suggests that it once converted to mg/kg, Dusty may have held 12 rodenticide bait blocks, each weighing 1 ingested up to 0.9 mg/kg of bromethalin. ounce. The box now contains 5 blocks plus the portion of the block the owner recovered from 19 mg / 21 kg = 0.9 mg/kg the dog’s mouth, which appears to be no larger than one quarter of a block. The label on the box What does this mean? Is this a concerning says the active ingredient is 0.01% bromethalin. exposure and, if so, how concerning? How aggressive does decontamination need to be? Calculating Rodenticide Dosage To answer these questions, the kinetics and After evaluating patient history and the toxicity of bromethalin need to be discussed. rodenticide itself, the dosage of bromethalin ingested needs to be calculated.

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BROMETHALIN TOXICITY Cats demonstrate a similar clinical course to dogs, but are much more sensitive Mechanism of Action & Kinetics to bromethalin. The LD50 in cats is 0.54 mg/kg.4 Cats may also demonstrate ileus Bromethalin’s metabolite, desmethyl bromethalin, and resultant abdominal distention.1,5 is primarily responsible for the uncoupling of oxidative phosphorylation in neuronal Range of Dosages mitochondria.4 This results in a depletion of from the cell, causing The dosages cited for dogs and cats are impairment of the sodium potassium pump. medians, and any individual patient may be more sensitive to the effects of bromethalin. When pump function is poor, sodium and fluid accumulate within the sheaths. This The APCC has recorded hindlimb weakness edema accounts for the neurologic signs seen occurring, although rarely, at dosages as low as with bromethalin ingestion. Because the edema 0.15 mg/kg in dogs, and tremors, depression, is within the myelin, this may also explain why anorexia, and death occurring at dosages as low traditional medical management of central as 0.95 mg/kg, even though the experimental nervous system edema, such as administration of minimum lethal dose is reported to be 2.5 mg/kg.1,2 diuretics and mannitol, has limited success.3 In cats, signs have occurred at dosages Bromethalin is excreted primarily through the less than 0.24 mg/kg,2 and depression, bile, and it is suspected to undergo enterohepatic ataxia, paresis, and death have occurred recycling because experimental studies have at dosages as low as 0.45 mg/kg.3 shown that multiple doses of activated charcoal are more effective at preventing the neurologic It also appears that dogs younger than 1 year syndrome rather than a single dose.4 of age may be more susceptible to the effects of bromethalin, which may be due to the Clinical Presentation immature blood–brain barrier in juveniles.

The clinical presentation of bromethalin MANAGEMENT OF toxicosis is dose dependent. BROMETHALIN EXPOSURES

At lower exposure dosages (below the 50% Based on the kinetics and toxicity of bromethalin, lethal dose [LD50] of 3.65 mg/kg for dogs), clinicians must take a conservative approach a paralytic syndrome can develop, typically when deciding at what dosage to begin within 24 to 86 hours after exposure. This decontamination efforts and how aggressively to syndrome can cause hindlimb paresis and decontaminate. In addition, the time that has ataxia, and patients may recover from these elapsed between exposure and decontamination signs over a period of weeks to months. must be taken into account (Table, page 98).

The signs of paralytic syndrome may progress, with ADMINISTRATION OF development of absent deep pain sensation, upper ACTIVATED CHARCOAL motor bladder paralysis, central nervous system depression, tremors, hyperesthesia, , Prior to decontamination with activated charcoal, and death.1,4 This convulsant syndrome is usually, consider administering an antiemetic. This may but not always, associated with larger exposures to help reduce the risk for aspiration secondary bromethalin (above the LD50), and signs typically to vomiting, as well as treat any nausea, which develop within 4 to 36 hours after ingestion.1,6,7 may encourage the patient to drink water.

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The first dose of activated charcoal should be the largest dose (1 to 2 g/kg)2 and, ideally, contain Decontamination Measures: Not Recommended a cathartic agent, such as sorbitol, unless the patient already has diarrhea. Subsequent doses Alternative decontamination measures have been should be half the original dose, with no cathartic proposed and tried, yet no published evidence included. If there is no evidence of charcoal in supports a recommendation for their clinical use at this time. The following measures are not recommended as the rectum within 8 hours after the first dose, the standard of care for bromethalin exposures. consider administering a warm water enema.6 Intralipid Emulsion Bromethalin is very lipophilic; therefore, in theory, The potential for activated charcoal to cause intralipid emulsion therapy has the potential to reduce potentially lethal hypernatremia should not bromethalin concentrations in the body.9 If this therapy is to benefit the patient at all, it would likely be underestimated. The mechanism for this be within the first several hours after an exposure effect is not definitively understood but is because bromethalin is rapidly absorbed (peak plasma thought to result from the osmotic effect of concentrations occur in 4 hours in rats).1,4 Reversal of the neurologic syndrome by intralipid emulsion is the activated charcoal pulling water into the unlikely once the are damaged. There is no solid gastrointestinal tract.8 When administering evidence to support the routine use of intralipid therapy for bromethalin exposures at this time. activated charcoal (especially in repeated doses): • It is vital to closely monitor the patient for Cholestyramine Cholestyramine is an indigestible ion exchange resin hypernatremia: obtain a baseline serum sodium that has been successfully used for decontamination level prior to administering activated charcoal and with other agents that undergo extensive recheck it before administering the next dose. enterohepatic recirculation, such as and certain nonsteroidal anti-inflammatory drugs.10-13 • Maintain the patient on intravenous balanced Cholestyramine binds with bile acids in the intestine, preventing their reabsorption and producing an crystalloid fluids—such as lactated Ringer’s insoluble complex that is excreted in the feces.14 It is solution, Normosol R (hospira.com), or unknown at this time whether cholestyramine can be Plasma-Lyte (baxterhealthcare.com)—and used successfully for bromethalin decontamination. provide unlimited access to oral water to help prevent hypernatremia.

TABLE Decontamination Recommendations for Bromethalin Ingestion

DOSE INGESTED (MG/KG) TIME SINCE EXPOSURE ACTION

DOGS

< 4 H Emesis or 1 dose activated charcoal 0.1–0.49 > 4 H 1 dose activated charcoal

< 4 H Emesis + activated charcoal Q 8 H for 24 H (3 doses total) 0.5–0.75 > 4 H Activated charcoal Q 8 H for 24 H (3 doses total)

< 4 H Emesis + activated charcoal Q 8 H for 48 H (6 doses total) > 0.75 > 4 H Activated charcoal Q 8 H for 48 H (6 doses total)

CATS

< 4 H Emesis or 1 dose activated charcoal 0.05–0.09 > 4 H 1 dose activated charcoal

< 4 H Emesis + activated charcoal Q 8 H for 24 H (3 doses total) 0.1–0.3 > 4 H Activated charcoal Q 8 H for 24 H (3 doses total)

< 4 H Emesis + activated charcoal Q 8 H for 48 H (6 doses total) > 0.3 > 4 H Activated charcoal Q 8 H for 48 H (6 doses total)

Table information based on ASPCA APCC recommendations for bromethalin ingestion

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• If a patient’s sodium level increases 5 mmol/L or Activated Charcoal more from baseline, provide free water (oral, enema, or 5% dextrose solution in water) and postpone the Dusty then receives 230 mL of 10% activated following dose until the sodium level has decreased. charcoal with sorbitol. His baseline sodium is 146 mmol/L. Seven hours after this treatment, CONSIDER THIS CASE: THERAPY Dusty’s sodium level is 151 mmol/L (mEq/L); his fluid rate is increased to 2 times the Decontamination Method6,7 maintenance rate and he is given an enema.

To summarize the information known about One hour later, his serum sodium decreases Dusty’s exposure, he was exposed to bromethalin to 148 mmol/L. Dusty is administered while carrying the rodenticide block (< 4 H) and 115 mL of 10% activated charcoal without his worst-case-scenario exposure dosage is 0.9 sorbitol. The remaining doses of charcoal mg/kg bromethalin. The Table recommends: are administered without complication. • Induction of emesis and Outcome • Administration of activated charcoal Q 8 H for 48 H (6 doses total). Dusty is discharged from the hospital 54 hours after admission without developing Because exposure may have taken place as signs of bromethalin toxicosis. early as the previous evening, it is important to

perform a rectal examination and/or to evaluate LD50 = 50% lethal dose. the feces. If the feces are the color of the bait, a gentle warm water enema (5–10 mL/kg) to help decontaminate the colon is recommended. References

Therapeutic Approach 1. Dorman DC, Parker AJ, Buck WB. Bromethalin toxicosis in the dog. Part I: Clinical effects. JAAHA 1990; 26:589-594. Emesis 2. ASPCA Animal Poison Control Center database, unpublished data, 2015. Dusty is admitted to the hospital, and emesis is 3. Dorman DC, Parker AJ, Buck WB. Bromethalin toxicosis in the dog. Part II: Selected treatments for the toxic syndrome. JAAHA 1990; induced with apomorphine (0.04 mg/kg IV). 26:595-598. A few small pieces of green material, suspected 4. Dorman DC. Bromethalin. In Peterson ME, Talcott PA (eds): Small Animal Toxicology, 3rd ed. St. Louis: Elsevier Saunders, 2013, pp 471- to be the bait, are seen in the vomitus. He is 478. administered maropitant (1 mg/kg SC) as well 5. Bates MC, Roady P, Lehner AF, et al. Atypical bromethalin intoxication in a dog: Pathologic features and identification of an as lactated Ringer’s solution IV at 1.5 times isomeric breakdown product. BMC Vet Res 2015; 11:244. the maintenance rate of 60 mL/kg/day. 6. DeClementi C, Sobczak BR. Common rodenticide toxicoses in small animals. Vet Clin North Am Small Anim Pract 2012; 42:349-360. 7. Dunayer E. Bromethalin: The other rodenticide. Vet Med 2003; 98:732-736. 8. Plumb DC. Plumb’s Veterinary Drug Handbook, 7th ed. Stockholm, WI: PharmaVet Inc, 2011, pp 193-195. Renee Tourdot 9. Dorman DC, Simon J, Harlin KA, Buck WB. Diagnosis of bromethalin Renee Tourdot, DVM, is a consulting veterinarian in toxicosis in the dog. J Vet Diagn Invest 1990; 2:123-128. clinical toxicology with the ASPCA Animal Poison 10. Ferry DG, Grazeley LR, Busby WJ. Enhanced elimination of piroxicam Control Center (APCC). Dr. Tourdot received her by administration of activated charcoal or cholestyramine. Eur J Clin Pharmacol 1990; 39:599-601. DVM from University of Wisconsin–Madison and completed an internship in small animal medicine 11. Calvo M, Dominguez-Gil A. Interaction of naproxen with cholestyramine. Biopharmaceut Drug Dispos 1984; 5:33-42. and surgery at Coral Springs Animal Hospital 12. Busch U, Heinzel G, Narjes H. The effect of cholestyramine on in Coral Springs, Florida. Dr. Tourdot practiced the pharmacokinetics of meloxicam, a new non-steroidal anti- emergency medicine and surgery at Wisconsin inflammatory drug (NSAID), in man. Eur J Clin Pharmacol 1995; Veterinary Referral Center before joining the APCC 48:269-272. in 2015. 13. Thompson WG, Thompson GR. Effect of cholestyramine on the absorption of vitamin D3 and calcium. Gut 1969; 10:717-722. 14. Questran oral suspension, cholestyramine oral suspension. Spring Valley, NY: Par Pharmaceutical Co, Inc, 2006.

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