Toxins Exposure Therapy/Decontamination PDF

CHAPTER 151 Toxin Exposure Therapy/Decontamination Camille DeClementi On presentation, all patients exposed to toxicants should be stabilized prior to attempts at administration of antidotal medications (Table 151-1) or patient decontamination.1 Stabilization refers to correction of life- threaten...

CHAPTER 151 Toxin Exposure Therapy/Decontamination Camille DeClementi On presentation, all patients exposed to toxicants should be stabilized prior to attempts at administration of antidotal medications (Table 151-1) or patient decontamination.1 Stabilization refers to correction of life- threatening disorders that can be hemodynamic (e.g., systemic hypotension [see ch. 127 and 159] or cardiac arrhythmias [see ch. 141 and 248]), respiratory (e.g., respiratory distress [see ch. 28, 131, and 139]), neurologic (e.g., seizures [see ch. 35, 136, and 260]), or immunologic (e.g., anaphylaxis [see ch. 137]). Once the patient is stable, decontamination of the patient should then be considered to prevent systemic absorption of the toxicant. The exposure circumstances, such as species involved, time since exposure, chemical nature of the toxicant, and amount ingested, will determine the appropriate method of patient decontamination. The clinician has multiple options for patient decontamination including dilution, induction of emesis, gastric lavage, and the use of adsorbents and cathartics. In many cases, the best treatment plan will include more than one of these methods. TABLE 151-1 Antidotal Therapies10,12 ANTIDOTAL TOXICANT DOSAGE AND COMMENTS MEDICATION INDICATIONS Acepromazine Amphetamines Dog: 0.02-0.1 mg/kg IV, IM, SC. Can cause hypotension. Atipamezole Amitraz Dog: 50 mcg/kg IM. (Antisedan) Reverses the CNS depression, bradycardia, GI stasis, and hyperglycemia associated with amitraz toxicosis. In cases of ingestion of an amitraz collar, atipamezole may need to be repeated until the collar is removed from the GI tract. Atropine Carbamates, organophosphates Dog/cat: 0.2 mg/kg, of the dose given IV and the remainder IM or SC. (OPs) Used for countering muscarinic effects (SLUDDE: salivation, lacrimation, urinary incontinence, diarrhea, dyspnea, emesis). For suspected cases, a test dose of 0.02 mg/kg can be given. If this dose results in mydriasis and tachycardia, the patient has NOT been poisoned by a carbamate or OP. Cyproheptadine Selective serotonin Dog: 1.1 mg/kg PO or per rectum up to every 8 hours if effective. (Periactin) reuptake inhibitors Used for countering serotonin syndrome (hyperthermia, tremors, seizures, (SSRIs) ataxia, excitation, depression, hyperesthesia, GI distress). 5- hydroxytryptophan (5-HTP) Baclofen Digoxin immune fab Digoxin Dog: 1-2 vials slow IV administration (over 30 minutes). (Digibind) Cardiac glycoside- Patient is expected to improve rapidly within 20-90 minutes. containing plants Monitor for hypokalemia and hypersensitivity. Bufo toad 1656  Ethanol Ethylene glycol Details provided in ch. 152: Box 152-2. Causes severe respiratory and CNS depression, and metabolic acidosis. In cats, treatment must be started within 3 hours of exposure or prognosis is grave. Flumazenil Benzodiazepines Dog/cat: 0.01-0.02 mg/kg IV. (Romazicon) Has a short half-life so may need to be repeated. Reserved for cases of severe CNS and respiratory depression. Fomepizole (4MP, 4- Ethylene glycol Dog: initial dose of 20 mg/kg IV, then subsequent doses at 12 and 24 hours with methylpyrrazole) 15 mg/kg and 36 hours with 5 mg/kg. Cat: initial dose of 125 mg/kg IV, then subsequent doses at 12, 24 and 36 hours with 31.25 mg/kg. May cause CNS depression. In cats, treatment must be started within 3 hours of exposure or prognosis is grave. Intralipid emulsion Bupivacaine Dog/cat: using a 20% solution, initial bolus of 1.5 mL/kg slowly IV, then CRI of (ILE) Verapamil 0.25 mL/kg/min IV for 30-60 minutes. Propranolol Can be useful in intoxications with other lipid-soluble toxicants including Clomipramine ivermectin, cholecalciferol, amlodipine, baclofen, diltiazem, marijuana, Lidocaine permethrin, bupropion, trazodone, barbiturates, and tricyclic antidepressants. Moxidectin Methocarbamol Permethrin Dog/cat: 55-220 mg/kg slow IV or PO. Total dosage should not exceed (Robaxin) Metaldehyde 330 mg/kg/day. Strychnine Can be useful in other intoxications causing severe tremors. Tremorgenic mycotoxins Naloxone (Narcan) Opioids Dog: 0.04 mg/kg IV, IM, SC. Cat: 0.02-0.04 mg/kg IV. Used for reversing respiratory and CNS depression. Does not reverse GI effects. N-acetylcysteine Acetaminophen Dog/cat: use a 5% solution; loading dose of 140 mg/kg PO or IV, then 70 mg/kg (NAC) PO or IV every 6 hours for 7 treatments. Can cause oral mucosal ulceration if not diluted to 5% solution. Pamidronate Cholecalciferol Dog: 1.3-2 mg/kg slow IV. (Aredia) (vitamin D3) Should not mix with calcium-containing IV fluids. Vitamin D3 analogs Most effective if given within 24-36 hours of exposure. Calcipotriene (Dovonex) Pralidoxime (2- Organophosphates Dog/cat: 20 mg/kg q 8-12 h. Initial dose IM or slow IV. Subsequent doses given PAM) (OPs) IM or SC. Used for countering nicotinic effects (tremors, muscle weakness). Works best when used in combination with atropine. Vitamin K1 Anticoagulant Dog/cat: 1.5-2.5 mg/kg PO q 12 h. rodenticides Oral route preferred. Warfarin Should be given with a fatty meal to enhance absorption. Yohimbine (Yobine) Amitraz Dog: 0.1 mg/kg IV. Has a short half-life so may need to be repeated. CNS, Central nervous system; CRI, constant rate infusion; GI, gastrointestinal; IM, intramuscular; IV, intravenous; PO, per os. Dilution using a small amount of water or milk is recommended in cases where the patient has ingested an irritant or corrosive material. A dosage of 2-6 mL/kg is suggested, which for an average-sized cat, would be approximately only 1-2 teaspoons.1 Giving only a small amount is important, since using excessive amounts could lead to vomiting and re-exposure of the esophagus to the damaging material.2 Dilution is not appropriate in patients who are at an increased risk for aspiration, including those who are actively seizuring or obtunded.2 Dilution with dairy products, such as milk, yogurt, and cottage cheese, has been useful in cases of oral irritation following ingestion of plants containing insoluble calcium oxalate crystals (e.g., Philodendron species).3 Emetics generally empty 40-60% of the stomach contents and are usually most effective if used within 2-3 1657 hours after ingestion of a toxicant.2,4 If the substance ingested could coalesce to form a bezoar in the stomach, emesis can be effective later than 3 hours after the ingestion. Chocolate and chewable medications are examples of products which may form bezoars.5 Feeding a small moist meal before inducing vomiting can increase the likelihood of adequate emesis ( Video 151-1). Induction of emesis is contraindicated with ingestion of corrosive agents including alkalis and acids, due to the risk of caustic effects on the esophageal and oral mucosa. Emesis is also not recommended after petroleum distillate ingestion due to the risk of aspiration. The clinician must take into account, when deciding whether to induce emesis, any pre-existing conditions of the patient that can cause vomiting to be hazardous; these include severe cardiac disease (risk of vagally- mediated syncope) or seizure disorder (risk of aspiration). In all instances, the attending veterinarian must carefully weigh the benefits of emesis against the risks. Emesis may not be needed if the animal has already vomited, and it is not appropriate if the animal is already exhibiting clinical signs such as coma, seizures, or recumbency, which make emesis hazardous. Additionally, if the patient has ingested a stimulant and is already agitated, the additional stimulation of vomiting could lead to seizures.2 Hydrogen peroxide (3% concentration), apomorphine hydrochloride, and xylazine hydrochloride are commonly used emetics in the veterinary clinical setting. Data from the ASPCA Animal Poison Control Center (APCC) toxicology database indicate that 3% hydrogen peroxide and apomorphine are effective emetics in dogs. Induction of emesis, with either hydrogen peroxide (2.2 mL/kg PO once; can repeat once) or apomorphine (0.03 mg/kg IV; or 0.04 mg/kg IM [least preferred]; or to tablet crushed and dissolved with a few drops of saline in a syringe [without a needle] and instilled in the conjunctival sac, then rinsed free with saline after vomiting has occurred) was successful in 92% of dogs. Hydrogen peroxide can be repeated if vomiting does not occur within 20 minutes. No significant adverse effects were reported in dogs after such use.6 Apomorphine is poorly effective as an emetic in cats and using it in cats is controversial. Xylazine (0.44 mg/kg IM [can reverse with yohimbine 0.1 mg/kg slow IV after vomiting is complete]) is an effective emetic in only 42% of cats.7 Some clinicians are also using dexmedetomidine (40 mcg/kg IM, reversed with 0.4 mg/kg atipamezole IM after vomiting is complete) as an emetic in cats.7 Gastric lavage can be considered in cases where emesis is contraindicated, is not possible, or has been unsuccessful (see ch. 112). Adsorbents may be utilized instead of, or in addition to, emetics and gastric lavage, to prevent systemic absorption of a toxicant. These agents act by adsorbing to a toxicant in the gastrointestinal (GI) tract and facilitating its excretion in the feces.2 Activated charcoal is the most commonly used adsorbent. In asymptomatic patients, activated charcoal can be given with an oral dosing syringe, or can be offered to the patient in a bowl mixed with a small amount of canned food or chicken broth. In symptomatic patients, activated charcoal is administered via an orogastric tube while the patient is under general anesthesia (see ch. 112). Repeated doses of activated charcoal should be considered if the ingested toxicant is known to undergo enterohepatic recirculation. In enterohepatic recirculation, the toxicant is carried to the liver by the portal circulation after absorption from the GI tract. Once in the liver, the toxicant enters the bile and is excreted into the GI tract where it is again available for absorption. Examples of toxicants known to undergo this type of recycling include most nonsteroidal anti-inflammatory drugs, marijuana, and digoxin. When repeated doses are indicated, half the original dosage should be given at 4- to 8-hour intervals.8 Administration of activated charcoal does carry some risks and it does not bind all compounds equally. Some chemicals that are not bound effectively include alcohols, fertilizers, petroleum distillates, most heavy metals, iodides, nitrates, nitrites, sodium chloride, and chlorate. Activated charcoal should not be given to animals that have ingested caustic materials since it is unlikely to bind these materials, can be additionally irritating to the mucosal surfaces, and can make visualization of oral and esophageal burns difficult.9 Activated charcoal administration carries a substantial risk of aspiration. The prognosis is poor for a patient that aspirates activated charcoal; therefore, proper placement of a stomach tube and a protected airway are required in symptomatic patients. Constipation can occur and black bowel movements are expected, making it difficult to determine if melena is present. If the activated charcoal resides within the GI tract for an extended period of time, it can release the toxicant. It is for this reason that activated charcoal is frequently administered with a cathartic. Many commercially-available preparations contain a cathartic like sorbitol. Hypernatremia is another possible adverse effect of activated charcoal administration. The mechanism for hypernatremia is attributed to a water shift from the intracellular and extracellular spaces into the GI tract as 1658 a result of the osmotic pull of the activated charcoal product.7 The APCC has received reports of high serum sodium concentrations following activated charcoal administration in dogs. Hypernatremia appears to be reported more often in small dogs receiving multiple doses of activated charcoal, but it has also been reported in large dogs and in cases receiving only a single dose. Furthermore, unlike human case reports, high serum sodium concentrations also have been noted in cases where no cathartic was present in the charcoal.10 With activated charcoal–associated hypernatremia, the APCC has found that administration of a warm water enema is effective at lowering the serum sodium and controlling the resultant central nervous system (CNS) effects.10 Cathartics enhance elimination of substances, including administered activated charcoal, by promoting their movement through the GI tract. Activated charcoal only binds to toxicants by weak chemical forces, so without cathartics, the bound toxicant can eventually be released and reabsorbed.2 When used with activated charcoal, the cathartic is given immediately following, or mixed with, the charcoal. Cathartics are contraindicated if the animal is dehydrated, has diarrhea, if ileus is present, or if intestinal obstruction or perforation is possible.8 There are bulk, osmotic, and lubricant cathartics. The most commonly used bulk cathartic is psyllium hydrophilic mucilloid (e.g., Metamucil). Another bulking cathartic that can be used in dogs and cats is unspiced canned pumpkin. Osmotic cathartics have limited absorption from the GI tract so they are able to draw water into the GI lumen, thereby increasing the fluid volume and stimulating motility to hasten expulsion in the feces. Sorbitol is the most commonly used osmotic cathartic; it is the cathartic of choice and frequently is combined with activated charcoal in commercially prepared charcoal products. Of the lubricant cathartics, mineral oil is the most often used. Mineral oil is not recommended following activated charcoal administration as the mineral oil can render the charcoal less effective.9,11 Since all cathartics alter the water balance in the GI tract, serum electrolyte abnormalities, especially hypernatremia, are a potential risk when using them. Hydration status should be monitored frequently and fluids administered, intravenously or via an enema, as needed. References 1. Crandell D. Toxicological emergencies. Mathews KA. Veterinary emergency and critical care management. ed 2. Lifelearn Inc.: Guelph; 2006:630–640. 2. Rosendale ME. Decontamination strategies. Vet Clin North Am Small Anim Prac. 2002;32:311–321. 3. Means C. Insoluble calcium oxalates. Plumlee KH. Clinical veterinary toxicology. Mosby: St Louis; 2004:340–341. 4. Beasley VR, Dorman DC. Management of toxicoses. Vet Clin North Am Small Anim Pract. 1990;20:307– 337. 5. Albretsen JC. Methylxanthines. Plumlee KH. Clinical veterinary toxicology. Mosby: St Louis; 2004:322– 326. 6. Khan SA, McLean MK, Slater M, et al. Effectiveness and adverse effects of the use of apomorphine and 3% hydrogen peroxide solution to induce emesis in dogs. J Am Vet Med Assoc. 2012;241:1179–1184. 7. DeClementi C. Decontamination of patients after oral exposure to toxicants. Côté E. Clinical veterinary advisor: dogs and cats. ed 3. Elsevier: St Louis; 2015:1139–1140. 8. Peterson ME. Toxicological decontamination. Peterson ME, Talcott PA. Small animal toxicology. ed 2. Elsevier: St Louis; 2006:127–141. 9. Buck WB, Bratich PM. Activated charcoal: preventing unnecessary death by poisoning. Vet Med. 1986;81:73–77. 10. DeClementi C. Prevention and treatment of poisoning. Gupta RC. Veterinary toxicology: basic and clinical principles. ed 2. Academic Press: London; 2012:1361–1368. 11. Galey FD. Diagnostic toxicology. Robinson NE. Current therapy in equine medicine. ed 3. Saunders: Philadelphia; 1992:337–340. 12. Khan SA. Common reversal agents/antidotes in small animal poisoning. Vet Clin North Am Small Anim Pract. 2012;42:403–406. 1659 CHAPTER 152 Chemical Toxicoses Justine A. Lee According to the ASPCA Animal Poison Control Center (APCC), approximately 150,000 animals are exposed to a variety of toxicants in the United States each year. Approximately 40% of the calls to the ASPCA APCCa comprise exposures to human and veterinary medications, with the remaining exposures occurring secondary to a variety of toxic foods, insecticides, rodenticides, plants, household products, herbicides, cleaning products, lawn and garden products, and miscellaneous toxicants. Ch. 13 presents ways of differentiating intoxications from nontoxicologic illness when a history is lacking. In this chapter, a review of some of the most common—or most deadly—chemical toxicants will be discussed. Rodenticides One of the top 10 toxicants affecting dogs are rodenticides. Due to U.S. Environmental Protection Agency (EPA) regulations that were mandated in 2011, second-generation anticoagulant rodenticides (ACR) such as brodifacoum and bromadiolone are being removed from the U.S. market. As a result, antidotal therapy (e.g., vitamin K1) will be less frequently required; instead, the use of non-anticoagulant rodenticides, notably bromethalin and cholecalciferol, have become more prominent as active ingredients. Bromethalin Bromethalin, a neurotoxic rodenticide, works by uncoupling oxidative phosphorylation in the brain and liver mitochondria.1 This results in decreased adenosine triphosphate (ATP) production, which affects cellular sodium and potassium pumps; as a result, lipid peroxidation occurs, resulting in sodium accumulation within the cell.1 Edema of the central nervous system (CNS) can result.1 Bromethalin is not an anticoagulant rodenticide and should not be treated with vitamin K1 as an antidote. It is sold under several popular brand names: Assault, Tomcat Mole Killer, Talpirid, Real Kill, Clout, Fastrac, Vengeance, etc. Bromethalin has a narrow margin of safety. In dogs, the LD50 of bromethalin is 2.38-3.65 mg/kg, with a minimum lethal dosage being 2.5 mg/kg (corresponding to 120 grams [4 ounces] of typical 0.01% bait consumed by a 5 kg dog).1 A typical, otherwise healthy 5 kg dog would only need to ingest approximately 12 grams (or 0.4 ounces) to develop clinical signs. Cats are more sensitive to the effects of bromethalin, and the LD50 is markedly lower (0.54 mg/kg).1 Clinical signs are dosage-dependent, and the onset of clinical signs depends on the amount ingested. Typically, with acute ingestion, signs can be seen within 2-24 hours.1 Clinical signs of CNS stimulation or depression, abnormal behavior, ataxia, hyperesthesia, seizures, and coma can be seen.1 Other common signs include paresis, hindlimb paralysis, anisocoria, nystagmus, changes in the pupillary light reflex, and tremors.1 Treatment includes early decontamination of the patient, prevention of cerebral edema, and supportive care. With recent ingestion in an asymptomatic patient, the use of appropriate decontamination (e.g., emesis induction, gastric lavage [ Video 152-1], activated charcoal; see ch. 151) is warranted. As bromethalin undergoes enterohepatic recirculation, the use of multiple oral doses of activated charcoal (without a cathartic) is recommended (e.g., q 6 h for 24 h). Patients should be monitored for signs of neurotoxicosis. The use of intravenous (IV) fluid therapy (see ch. 129), oxygen support (see ch. 131), head elevation in recumbent patients, mannitol (to decrease cerebral edema; see ch. 148), anticonvulsant therapy (see ch. 35 and 136), and thermoregulation is warranted, as needed. The use of corticosteroids to decrease intracranial pressure is no longer recommended; rather, mannitol is preferred. With bromethalin toxicosis, the prognosis varies depending on the amount ingested and the severity of clinical signs. In general, the prognosis is fair to excellent with appropriate decontamination of the patient and treatment prior to 1660 development of clinical signs. With persistent seizures or paralytic syndrome, the prognosis is poorer. Phosphides Phosphide rodenticides result in the production of phosphine gas. When zinc phosphide combines with gastric acid or moisture (or the presence of food), liberated phosphine gas is absorbed rapidly across the gastric mucosa and is distributed systemically, where it exerts its toxic effect. Phosphine gas is considered a corrosive and a direct irritant to the gastrointestinal (GI) tract. While this rodenticide has not grown in popularity compared to others (e.g., ACR, bromethalin, etc.), veterinarians must be aware of this rodenticide as it carries a public health risk to pet owners and veterinary staff. Phosphide rodenticides have been used since the 1930s and are still available on the market.3 Aluminum phosphide, a pelleted product, is used as a fumigant in grain storage. Zinc phosphide, which is more readily used, is labeled to kill mice, rats, squirrels, voles, nutria, muskrats, gophers and other vermin.3 Zinc phosphide is available as a 2-10% concentration, and comes as powder, paste, pellet or tablet formulations.3 Commercially available zinc phosphide products are sold under popular names such as Sweeney's Poison Peanut Mole, Gopha-Rid, Zinc-Tox, ZP, Arrex, Gopha-Rid, Gopher Bait II, etc.2 Formulations of phosphides have a malodorous, unique odor similar to rotten garlic, fish or acetylene.2 The toxic dosage of zinc phosphide in dogs is approximately 20-40 mg/kg, but up to 300 mg/kg on empty stomachs.3 In a patient suspected of zinc phosphide toxicosis, the administration of food (e.g., bread, milk, etc.) is contraindicated, as it triggers gastric acid secretion, promoting hydrolysis and further production of phosphine gas.3 With zinc phosphide toxicosis, clinical signs can be seen within 15 minutes to 4 hours of ingestion; while rare, death has been reported within 3-48 hours.3 Clinical signs include severe GI (e.g., vomiting, bloat, abdominal pain, hematemesis, melena), CNS (e.g., tremor, seizures, death), and rarely, cardiopulmonary signs (e.g., pulmonary edema, tachypnea, pleural effusion) or other organ dysfunction.3 Zinc phosphide carries a public health risk. Emesis—whether intentionally induced or occurring due to clinical signs—can result in secondary exposure of phosphine gas to the pet owner or the veterinary professional. In humans, clinical signs of nausea and difficulty breathing have been reported. To minimize these risks, emesis induction should always be performed in a well-ventilated area (e.g., opening the car window if the patient vomits or inducing emesis outside). Pet owners should be appropriately educated on the risks of toxic gas exposure to themselves. Pet owners should be informed not to feed their pet to prevent further production of phosphine gas. In addition, the administration of an antacid (e.g., aluminum hydroxide, milk of magnesia) prior to emesis induction or veterinary attention can help decrease the production of phosphine gas. With recent ingestion in an asymptomatic patient, the use of emesis induction (following antacid administration) and one dose of activated charcoal with a cathartic is warranted to minimize toxic effects of zinc phosphide. Supportive care, including antiemetic therapy, IV fluid therapy, and gastric protectants, is warranted. With treatment, the prognosis is excellent with supportive care.2 Cholecalciferol Cholecalciferol, the chemical name for vitamin D3, is one of the most deadly rodenticides to pets. Ingestion of toxic levels of cholecalciferol can result in severe hypercalcemia and hyperphosphatemia, with secondary acute kidney injury (AKI) developing from dystrophic mineralization of soft tissue, especially the kidneys (see ch. 322). Other common sources of vitamin D3 include over-the-counter (OTC) or prescription vitamins (typically found in a calcium/vitamin D3 combination) and psoriasis creams (in the form of calcipotriene). Cholecalciferol-containing rodenticides have a very narrow margin of safety, and only a minute amount of rodenticide needs to be ingested before clinical toxicosis occurs. In dogs, the LD50 is 85 mg/kg (based on the rodenticide concentration of 0.075%)4; however, dosages as low as >0.1-0.5 mg/kg can result in clinical signs and hypercalcemia, respectively (i.e., a 30 kg dog would only need to ingest approximately 1 ounce [30 grams] to develop clinical signs of toxicosis).4 Typically, clinical signs of toxicosis do not develop for 1-3 days, until the patient has already developed overt manifestations of AKI.4 Azotemia can develop as early as 12-36 hours following toxic ingestion. Clinical signs and clinicopathologic findings (see ch. 69) include polyuria and polydipsia, weakness, lethargy, anorexia, vomiting, generalized malaise, uremic halitosis, dehydration, hypercalcemia, hyperphosphatemia, azotemia, melena, hemorrhagic diarrhea, weight loss, and death.4 1661  With cholecalciferol toxicosis, intensive treatment is imperative due to the narrow margin of safety. Treatment should include thorough decontamination (e.g., emesis induction, gastric lavage, charcoal administration; see ch. 112 and 151). As cholecalciferol undergoes enterohepatic recirculation, the administration of multiple oral doses of activated charcoal (without a cathartic) is warranted (e.g., q 6 h × 24 h). Additional treatment includes the aggressive use of IV 0.9% saline fluid diuresis to promote calciuresis, serum calcium concentration monitoring, GI support (e.g., antiemetics, H2 blockers, sucralfate, phosphate binders, etc.), and the use of medications to increase calciuresis (e.g., prednisone, furosemide) and prevent hypercalcemia (e.g., pamidronate, calcitonin). Treatment often is expensive, and requires hospitalization for an extended period of time (e.g., 2-7 days). In hypercalcemic patients, oral therapy (e.g., furosemide, prednisone) often needs to be continued for several weeks following discharge from the hospital. Frequent monitoring of renal parameters and electrolytes is imperative. Serum calcium, phosphorus, blood urea nitrogen, creatinine, and ionized calcium should be evaluated every 12-24 hours during hospitalization, and then every 2-3 days thereafter for the next 2-4 weeks. This will allow the clinician to titrate drug therapy judiciously, and to ensure that the patient does not continue to develop hypercalcemia or azotemia. Even with intensive decontamination and therapy, chronic kidney disease (CKD) can be a secondary sequela. The prognosis for this rodenticide is poor once clinical signs and azotemia develop due to the risk of CKD. Anticoagulants First- and second-generation ACR inhibit vitamin K epoxide reductase, resulting in inactivation of clotting factors II, VII, IX, and X. First-generation rodenticides (e.g., warfarin, pindone)5 initially were replaced by more potent, longer-lasting second-generation ACR (e.g., brodifacoum, bromadiolone, diphacinone, chlorophacinone, etc.).5 However, the removal of second-generation ACR from the U.S. market was mandated by the U.S. EPA in 2011. While this will take several years to enact, veterinarians will be seeing fewer ACR cases as a result. It is important to note that the margin of safety and LD50 vary between each ACR; some have very narrow margins of safety (e.g., brodifacoum), while some have very wide margins of safety (e.g., bromadiolone). When in doubt, the toxic dosage should be calculated, or the rodenticide company directly contacted (which offer a free, 24/7 medical support line for assistance) to determine if a toxic dose has been ingested. Likewise, the ASPCA APCC can be consulted for life-saving assistance. Finally, it is worth keeping in mind that species differences exist; cats are much more resistant to the effects of ACR compared to dogs, and rarely develop toxicosis from ACR. CANINE5 LD50 FELINE5 LD50 Difethialone: 4 mg/kg >16 mg/kg Brodifacoum: 0.25-2.5 mg/kg 25 mg/kg Bromadiolone: 11-20 mg/kg >25 mg/kg Diphacinone: 3-7.5 mg/kg >15 mg/kg When a toxic ingestion of ACR has occurred, prolongation in coagulation factors (prothrombin [PT] or activated partial thromboplastin time [aPTT]) is not observed or measurable for 36-48 hours, based on the half-life of factor VII. Clinical signs typically do not develop for 3-5 days. Clinical signs are due to clotting factor depletion, resulting in generalized hemorrhage secondary to hypocoaguability. The most common clinical signs include lethargy, exercise intolerance, inappetence, pallor, dyspnea, coughing, and hemoptysis. Hemoabdomen, hemothorax, and pericardial effusion also can occur. Rarer clinical signs include gingival bleeding, epistaxis, ecchymoses, petechiae, hematuria, bleeding into the subcutaneous space or joint space, or melena.5 Optimal management depends on clinician preference and on the pet owner's commitment to follow up. Ideally, with recent ingestion, the patient should be decontaminated, if appropriate, and have a baseline PT measured at 36-48 hours post-ingestion. If PT is prolonged at that time, initiation of vitamin K1 2.5-5 mg/kg PO q 24h for 7 (first generation) to 30 (second generation) days is warranted, with rechecking of PT 2-3 days after discontinuation of vitamin K1. When client compliance is of concern, routine administration of vitamin K1 therapy for 30 days is warranted. For patients with clinical bleeding or coagulopathy, treatment should include vitamin K1 therapy; plasma transfusions; intensive care; oxygen therapy; and monitoring of PT 2-3 1662 days after discontinuation of therapy with vitamin K1. Veterinary professionals often make errors when it comes to the medical management of ACR intoxication cases. While it is often appropriate to decontaminate a patient with emesis induction and activated charcoal administration, with non-toxic ingestions (based on the LD10), this is often unnecessary (unless the patient is neonatal, geriatric, has an underlying hepatopathy, or has previously ingested an ACR). Also, the administration of a “one-time,” parenteral injection of vitamin K1 at the time of decontamination is unnecessary and potentially detrimental. As factor VII has the shortest half-life, PT will be the first blood test to be prolonged with ACR ingestion, 36-48 hours post-ingestion. Testing prior to this time is typically unnecessary (unless the patient has been chronically ingesting an ACR over several days). By administering a “one-time shot” of vitamin K1, the clinician can cause the patient's PT to be briefly normal at 36-48 hours, followed by coagulopathy and clinical bleeding days later (3-5 days, instead of 2 days). Insecticides Certain insecticides carry a wide margin of safety (e.g., pyrethrins, pyrethroids), while those with a narrower margin of safety (e.g., carbamates, organophosphates) have been predominantly removed from the market due to the severity of clinical signs seen with accidental or intentional poisonings. Pyrethrins and Pyrethroids Pyrethrins and their synthetic derivative, pyrethroids, commonly are found in household insect sprays and insecticides (e.g., permethrin, cypermethrin, cyphenothrin, etc.). Due to cats' altered liver glucuronidation metabolism, they are markedly more sensitive to pyrethrins than are dogs. While a precise toxic dosage for cats is not well established, products containing >5-10% concentration of pyrethrins can lead to systemic toxicosis. Products such as household insect sprays, topical flea sprays, and shampoos typically contain 5 mg/kg (cats), >50 mg/kg (dogs). Clinical signs: GI (e.g., hypersalivation, vomiting), CNS (e.g., ataxia, tremors, seizures, etc.), AKI and hepatotoxicosis can be seen. Treatment includes dextrose supplementation, blood glucose monitoring, fluid therapy, antiemetics, anticonvulsants, hepatoprotectants (e.g., SAMe, n-acetylcysteine, etc.). Silica Gel Packs Rarely result in toxicosis due to wide margin of safety. Rare risk of constipation or foreign body obstruction with massive ingestions in small-size patients. Food Oxidizer Packs (Commonly Found in Food Product Bags or Containers) Rarely result in toxicosis. These packages contain iron, where the powder is often black or brown in color and magnetized. Rare risks of iron toxicosis if ingestion by small-size patients. Treatment for iron toxicosis includes antacid therapy (e.g., milk of magnesia), supportive care, monitoring blood iron levels, and potentially chelation (in severe cases). Activated charcoal is not warranted (does not bind reliably to heavy metals). Amitraz A formamidine pesticide found in tick collars. Amitraz is a monoamine oxidase inhibitor and an alpha- adrenergic agonist. Toxicosis occurs when the collar is accidentally ingested, resulting in GI absorption. Lethal dosage is 100 mg/kg (dogs, PO), although toxic doses as low as 10-20 mg/kg have been reported. Clinical signs include CNS (e.g., ataxia, sedation, mydriasis, hypothermia, coma), cardiac (e.g., bradycardia, tachycardia), and GI (e.g., vomiting, diarrhea) signs. Treatment includes appropriate decontamination of the patient, removal of the collar from the GI tract (e.g., via endoscopy), alpha-2- antagonists (e.g., yohimbine or atipamezole), and supportive care. Insect Bait Stations Typically contain abamectin, hydramethylnon, or fipronil. Rarely toxic due to low-concentration of active ingredients. Rarely, plastic container can result in foreign body obstruction. Treatment is rarely indicated unless the dog has the ABCB1 gene mutation (MDR-1 polymorphism). Batteries Several types of batteries: acid dry cell, alkaline dry cell, disk-shaped, lithium. Corrosive injury or current-induced injury potentially can result in GI perforation. Clinical signs of dysphagia, anorexia, tachypnea, abdominal pain, and fever can be seen. Treatment should be aimed at radiographic 1664 confirmation of ingestion, removal (e.g., endoscopy, surgery), antacids, and supportive care. Diethylene Glycol (DEG) Used as an industrial solvent for canned cooking fuels, hydraulic fluid, lubrication, and brake fluid. With DEG toxicosis, calcium oxalate crystalluria is not observed; however, DEG can result in severe kidney injury. Clinical signs of CNS (e.g., depression, coma), GI (e.g., vomiting), renal (e.g., azotemia) dysfunction can be seen. Treatment and prognosis are similar to those of ethylene glycol. Paintballs Paintballs contain polyethylene glycol, sorbitol, glycerin, gelatin, and other ingredients that can result in free water loss and secondary, severe hypernatremia. GI (e.g., vomiting, diarrhea) and CNS signs can be seen (secondary to hypernatremia), including ataxia, tremors, head pressing, seizures, etc. Treatment is aimed at rapidly reducing blood sodium levels with IV fluids; antiemetics, electrolyte monitoring, anticonvulsants, and supportive care also are indicated. The use of activated charcoal is contraindicated with this toxicant. Tea Tree (Melaleuca) Oil Toxicosis has been reported in dogs and cats when concentrated (100%) oil is used as a holistic remedy. Clinical signs of CNS depression, weakness, ataxia, hypothermia, and muscle tremors can be seen within 1-2 hours after application. Rarely, coma, increased serum liver enzyme activities, dermal or oral irritation, or cardiorespiratory effects can occur (more often in cats). Treatment is aimed at dermal and oral decontamination (e.g., multiple doses of activated charcoal), fluid support, thermoregulation, clinicopathologic monitoring, and supportive care. Liquid Potpourri Contains essential oils. Only noted to result in toxicosis in cats, not dogs. Due to their altered glucuronidation, cats are very sensitive to cationic detergents and essential oils. Can result in severe chemical burns in the mouth, along with dermal and ocular irritation. Rarely, CNS depression, pulmonary edema, seizures, and hepatopathy can be seen in cats. Treatment includes oral and dermal decontamination, analgesics, antacids, fluid therapy, clinicopathologic monitoring, and supportive care. Metaldehyde Commonly-used pesticide for controlling snails and slugs; often used in the northwestern United States. Less commonly seen as a toxicant in the past few years due to replacement with the safer ingredient, iron phosphate. Metaldehyde toxicosis can result in GI (e.g., vomiting, diarrhea), CNS (e.g., tremors, seizures, secondary hyperthermia), and miscellaneous signs (e.g., DIC, hepatopathy). Treatment aimed at decontamination (e.g., gastric lavage, activated charcoal administration), antiemetic therapy, muscle relaxants, anticonvulsants, muscle relaxants, thermoregulation and supportive care. Plant Food and Fertilizers Wide margin of safety; contain natural elements (e.g., nitrogen, phosphorus, potassium). Clinical signs of GI disturbance with direct ingestions from the bag in moderate to large amounts. Treatment includes antiemetic therapy, fluid therapy, and supportive care. Organic Meal Fertilizers By-products from the meatpacking industry used as a soil amendment, typically made of bone, blood, feather, fish, etc. Very palatable to dogs. Clinical manifestations include GI signs (e.g., hypersalivation, abdominal distension, vomiting, bloody diarrhea), metabolic (e.g., pancreatitis), and rare risk of foreign body obstruction. Treatment is aimed at emesis induction, fluid therapy, antiemetics, bland diet, and supportive care. Compost (e.g., moldy food) Presence of tremorgenic mycotoxins (e.g., penitrem A and roquefortine), which interfere with the release of neurotransmitter amino acids. Clinical signs can be seen within 2-4 hours of ingestion and include GI (e.g., hypersalivation, vomiting, diarrhea, distended abdomen) and CNS signs (e.g., agitation, hyperesthesia, ataxia, muscle tremors, seizures, and secondary hyperthermia). Treatment should be aimed at decontamination of the patient, muscle relaxants, antiemetics, anticonvulsants, fluid therapy, thermoregulation, and supportive care. 1665  Cocoa Mulch Rarely seen as a toxicant, but can result in secondary theobromine toxicosis. Clinical signs of methylxanthine toxicosis can be seen (e.g., GI, cardiac, CNS). Treatment is aimed at decontamination (e.g., emesis induction, charcoal administration), fluid therapy, anti-emetics, sedation, anxiolytics, beta- blocker therapy, anticonvulsants, and supportive care. De-Icing Salts High concentrations of salt mixtures (e.g., sodium chloride, calcium chloride, potassium chloride, magnesium chloride hexahydrate, etc.), which is mildly toxic to dogs when exposed. Typical toxicosis due to dermal exposure (e.g., licking fur off snow-covered sidewalk). Rarely, more severe clinical signs can be seen if directly ingested from the bag. Clinical signs include GI (e.g., vomiting, diarrhea) signs; rarely, electrolyte abnormalities can be seen (e.g., hypernatremia), typically associated with large ingestions. Treatment includes IV fluid therapy, electrolyte monitoring, antiemetics, and supportive care. The use of charcoal is not recommended with salt toxicosis. AKI, Acute kidney injury; CNS, central nervous system; DIC, disseminated intravascular coagulation; GI, gastrointestinal. Household Cleaners Most household surface cleaners are generally benign, and when ingested directly from the bottle, may result in minor GI signs. However, certain concentrated cleaners can be highly toxic or corrosive. Household bleach, which typically contains 3-6% sodium hypochlorite, is a GI irritant, but “ultra” bleach, which typically contains a 5-10% sodium hypochlorite and 0.2-2% sodium hydroxide, can be corrosive, resulting in severe esophageal or upper GI damage. Concentrated lye products, toilet bowl cleaners, and oven cleaners also are corrosive, and immediate flushing of the mouth with tap water for 10-15 minutes should be performed prior to the veterinary visit to minimize tissue injury. On presentation to a veterinary clinic, additional oral flushing should be continued. The use of antacids, a bland soft diet, and analgesics (e.g., tramadol) may be warranted. Detergents Most detergents result in direct irritation to the oropharynx, esophagus and GI tract, particularly in cats. Ingestion of hand soaps, shampoos, cleaners, or laundry products can cause hypersalivation, vomiting, anorexia, and oral ulceration. Treatment is based on supportive care (e.g., flushing mouth out, antacid therapy, nutritional support, etc.). Xylitol Xylitol is a natural sweetener found in small quantities in certain fruit. Xylitol has gained popularity because it is sugar-free, and it is often found in diabetic snacks, foods, baked foods, mouthwashes, toothpastes, chewing gum, mints, candies, and chewable multivitamins.7 Sugarless products, particularly those with xylitol listed within the first 3 to 5 ingredients, can result in severe toxicosis within 15-30 minutes of ingestion. Ingestion of xylitol results in an insulin spike in non-primate species, resulting in severe hypoglycemia. Many pieces of candy and gum (e.g., Orbit, Trident, Ice Breakers) contain xylitol ranging in amounts, on average, from 2 mg to 1 g/piece (with a typical piece containing 120-170 mg). Unfortunately, xylitol content is considered proprietary information by some companies, and sources or amounts are not disclosed for all products. With xylitol toxicosis, it is imperative to calculate whether a toxic dose has been ingested whenever possible. Doses >0.1 g/kg are considered toxic and result in profound, sudden hypoglycemia from stimulation of insulin secretion.7 Higher dosages (>0.5 g/kg) of xylitol have been associated with acute hepatic necrosis.7 Clinical signs of xylitol toxicosis include lethargy, weakness, vomiting, collapse, anorexia, generalized malaise, tremors, and seizures (from hypoglycemia).7 When hepatotoxic doses are ingested, clinical signs and clinicopathologic findings can include icterus, diarrhea, melena, hypoglycemia, increased liver enzymes, hypoalbuminemia, hypocholesterolemia, and decreased blood urea nitrogen. When a patient is presented after ingesting a toxic amount of xylitol, the clinician should measure a blood glucose concentration immediately upon presentation; if the patient is hypoglycemic, a bolus of 1 mL/kg of 50% dextrose, diluted with 0.9% NaCl (in a 1 : 3 ratio of dextrose : NaCl) should be given IV over 1-2 minutes. Emesis induction should not be performed until the patient is euglycemic. Activated charcoal does not 1666 reliably bind well to xylitol, and its administration is not routinely recommended for xylitol toxicosis. Hypoglycemic patients should be hospitalized for IV fluid therapy [supplemented with dextrose (2.5-5%, CRI, IV)] for approximately 12-24 hours, and blood glucose concentrations should be measured every 1-4 hours. For patients ingesting a hepatotoxic amount of xylitol, the use of hepatoprotectants (e.g., SAMe, n- acetylcysteine), antiemetics, and supportive care (including frequent liver enzyme monitoring) are warranted (see ch. 286). Garage Toxicants Hydrocarbons Hydrocarbons consist of chemicals containing a hydrogen and carbon group as their main constituents. Examples include liquid fuels such as kerosene, engine oil, tiki-torch fuels, gasoline, diesel fuels, paint solvents, wood stains, wood strippers, liquid lighter fluids, and asphalt/roofing tar. These often are referred to as “petroleum distillates” based on their viscosity, carbon chain length, and lipid solubility. It is contraindicated to induce emesis after hydrocarbon ingestion due to the risks of aspiration pneumonia; due to the low viscosity of hydrocarbons, these compounds are more easily aspirated, resulting in respiratory injury and secondary infection. In general, hydrocarbons are GI tract irritants, but also can be irritants to the respiratory system (if inhaled), eyes, and skin. Clinical signs can include nausea/vomiting, tachypnea, and dermal or ophthalmic irritation. Typically, GI irritation is self-limiting. Patients should be treated with antiemetic therapy (e.g., maropitant), fluid therapy (e.g., SC or IV), fasting (no food per os), and a bland diet. Patients demonstrating any coughing, retching, or tachypnea post-ingestion should have thoracic radiographs performed to rule out aspiration pneumonia, for which treatment is supportive (e.g., oxygen therapy, fluid therapy, appropriate broad-spectrum antibiotic therapy, nebulization and coupage; see ch. 242). Windshield Wiper Fluid (Methanol) Most windshield wiper fluids are made up of water and methanol; however, certain types designed for extreme cold weather may contain ethylene glycol (EG), ethylene glycol monobutyl ether (EGME), ethanol, isopropyl alcohol, ammonia, or even hydrocarbons (e.g., liquefied petroleum gas). Methanol (methyl alcohol) can result in toxicosis in dogs, but does not result in the retinal toxicosis and blindness as seen with humans. When methanol is metabolized (via alcohol dehydrogenase), it creates formaldehyde, which is rapidly oxidized by aldehyde dehydrogenase to formic acid.8,9 This is then metabolized to carbon dioxide and water in non-primate species, whereas in primates, formic acid accumulates because of low tissue levels of folate, leading to acidosis and ocular toxicosis (blindness). Clinical signs include CNS (e.g., ataxia, lethargy, sedation), GI (e.g., vomiting, hypersalivation), and respiratory signs (e.g., tachypnea). With methanol toxicosis, decontamination typically is not warranted, as alcohols are rapidly absorbed from the GI tract.8 Likewise, the administration of activated charcoal is contraindicated, as it does not bind to alcohols reliably. Treatment includes IV fluid therapy, antiemetic therapy, and supportive care. Administration of fomepizole (4-methylpyrazole, 4-MP), the antidote for ethylene glycol (EG) intoxication, is not necessary with methanol toxicosis.9 Ethylene Glycol Accidental or malicious poisoning with EG can be seen in veterinary medicine, as the public generally is well aware of the narrow margin of safety with antifreeze. The minimum lethal dose in dogs is approximately 6.6 mL/kg, while in cats it is 1.4 mL/kg.9 Sources of EG include automotive antifreeze (radiator coolant, which typically contains 95% EG), windshield deicing agents, motor oils, hydraulic brake fluid, paints, solvents, etc.9 As little as one tablespoon (15 mL) can result in severe AKI in a dog, while as little as 1 teaspoon (5 mL) can result in AKI in feline patients. Ethylene glycol is metabolized by the body to highly poisonous metabolites including glycoaldehyde, glycolic acid, and oxalic acid, which lead to severe AKI secondary to development of calcium oxalate crystalluria.9 There are three clinical stages with EG toxicosis: Stage 1: This occurs within 30 minutes to 12 hours, and looks similar to alcohol poisoning. Ataxia, hypersalivating, vomiting, seizuring, and polyuria/polydipsia are seen. Stage 2: This occurs within 12-24 hours post-exposure, and clinical signs seem to “resolve” to the pet owner; however, during this time, severe internal injury is still occurring. Ataxia might seem to improve during this stage, but signs of dehydration, tachycardia, and tachypnea can be seen. 1667  Stage 3: In cats, this stage occurs 12-24 hours after EG exposure. In dogs, this stage occurs 36-72 hours post- ingestion. During this stage, severe AKI occurs secondary to calcium oxalate crystalluria. Severe anorexia, lethargy, hypersalivation, uremic halitosis, coma, depression, vomiting, and seizures can be seen. Any patient suspected of EG toxicosis should have an EG blood test, venous blood gas, and urinalysis performed. The diagnosis of EG toxicosis should be based on the combination of clinical suspicion, accurate interpretation of diagnostic testing, clinical signs, and patient history, because false positive results are well- recognized (see below). A positive EG test in a patient with known or suspected exposure can be sufficient to warrant initiating treatment immediately; metabolic acidosis, elevated anion gap, and calcium oxalate crystalluria offer further support, but confer a much worse prognosis if they already exist before treatment has been initiated.9 Importantly, EG testing is only accurate within approximately the first 24 hours after ingestion, as false negatives can be found thereafter due to complete transformation of EG to its more toxic metabolites, which are not routinely detected on EG tests. On veterinary-specific EG tests, false positive results can occur with other compounds such as propylene glycol (found in many compounds, notably oral activated charcoal products and injectable drugs including diazepam), isopropyl alcohol (at the venipuncture site), sorbitol, mannitol, etc. Currently available veterinary brands for EG testing include Kacey10 and Catachem11; the PRN test is no longer available. Due to the occurrence of false positive results with these tests, the author recommends submitting samples to a neighboring human hospital for quantitative EG levels. Treatment for EG toxicosis includes antidote therapy (e.g., fomepizole, ethanol), intensive IV fluid therapy, monitoring urine output and clinicopathologic parameters, antiemetic therapy, and supportive care. Fomepizole is an expensive but life-saving antidote that is preferred over ethanol for the treatment of EG toxicosis.9 While it is no longer being produced for dogs and cats,12 it can be compounded by certain veterinary pharmacies. The clinician must keep in mind that antidotal therapy needs to be administered quickly: in dogs, within 8-12 hours of exposure, and in cats, within 3 hours of exposure.9 If fomepizole is not available, ethanol can also be used, as it competes with alcohol dehydrogenase, thereby preventing metabolism of EG into its more toxic metabolites. Adverse effects of CNS depression, drunkenness, metabolic acidosis, hypoglycemia, bradycardia, hypoventilation, and hypothermia can be seen with ethanol treatment. Once a patient has already developed azotemia, the prognosis is generally poor to grave without hemodialysis (see ch. 110). Please see Box 152-2 for antidote dosing information. Box 152-2 A n t i d o t e s f o r E t h y l e n e G l y c o l9 Fomepizole (e.g., 4-MP, 4-Methylpyrazole) Dogs: Loading dose 20 mg/kg IV, followed by 15 mg/kg IV at 12 and 24 h. Give additional 5 mg/kg IV at 36 h. Can continue to use 3 mg/kg IV q 12 h until evidence of metabolic acidosis and clinical signs resolve. Cats: Extra-label. Loading dose 125 mg/kg IV, followed by 31.3 mg/kg IV at 12, 24, and 36 h after initial loading dose. Potential adverse reactions in dogs and cats include: anaphylaxis following second dose, CNS depression, tachypnea, hypersalivation, trembling, osmotic diuresis. Ethanol Choose a clear, non-flavored, high concentration/proof alcohol (e.g., vodka, grain alcohol, etc.). Note: With U.S. alcohol, the alcoholic proof is twice the percentage of alcohol (e.g., 100 proof = 50% ethanol = 500 mg/mL OR 190 proof = 95% alcohol = 950 mg/mL). To calculate how to make a certain percentage alcohol solution, use the formula: C1 × V1 = C2 × V2 To make a 7% ethanol solution with an 80 proof alcohol (40% alcohol), remove 175 mL from a 1 L bag of saline; add in 175 mL of an 80 proof alcohol back into the bag of saline. C1 × V1 = C2 × V2 (40)(X) = (7)(1000) X = 175 mL To make a 7% ethanol solution with a 190 proof alcohol (95% alcohol), remove 74 mL from a 1 L bag of saline; add in 74 mL of a 190 proof alcohol back into the bag of saline. 1668  C1 × V1 = C2 × V2 (95)(X) = (7)(1000) X = 74 mL There are two IV treatment recommendations for administering ethanol that are published. CRI method: Using a 7% ethanol (70 mg/mL), give 8.6 mL/kg (600 mg/kg) IV once slowly; followed immediately by 1.43 mL/kg/h (100 mg/kg/h), IV, CRI for 24-36 h. Alternative method: Using a 20% ethanol solution (200 mg/mL), give 5.5 mL/kg q 4 h × 5 doses; follow with 5.5 mL/kg q 6 h × 4 more doses. Potential adverse reactions in dogs and cats include: severe CNS depression, sedation, bradycardia, hypoventilation, metabolic acidosis, hypothermia, hypoglycemia. CNS, Central nervous system; CRI, constant rate infusion. Propylene Glycol Propylene glycol (PG), an odorless, tasteless, and colorless dihydroxy alcohol, is a component of many household products due to its hydroscopic, emollient and humectant properties.9,13 It often is found in pet- friendly antifreeze fluids, moist pet foods, disinfectants, medications (e.g., injectable diazepam, oral activated charcoal preparations), room deodorants, suntan lotions, cosmetic creams, paints and varnishes, food coloring, lubricants, and more.9,13 When ingested by animals, PG is metabolized to both D- and L-lactic acid, contributing to metabolic acidosis. PG is absorbed rapidly from the GI tract. While the LD50 for dogs is reported to be as low as 9 mL/kg,9,13 the author clinically rarely sees severe clinical signs from PG ingestion. Doses of 5 g/kg daily can result in hemolytic anemia, reticulocytosis, and hyperbilirubinemia in dogs.13 In cats, 1.6 g/kg and 8 g/kg of oral PG chronically for 2-4 weeks resulted in dose-related increases in Heinz bodies of 28% and 92%, respectively.13 Clinical signs of PG toxicosis include CNS depression, narcosis, tachypnea (secondary to metabolic acidosis), muscle twitching (cats), hypotension (cats), cardiovascular collapse, polyuria/polydipsia (secondary to an osmotic diuretic effect), and hematological changes (e.g., hemolytic anemia, Heinz body anemia).9,13 Treatment is supportive, including fluid therapy to help correct metabolic acidosis, red blood cell morphology monitoring, and rarely, red blood cell transfusions if needed. There is no need for antidotal therapy with PG exposure.9,13 Herbicides The majority of herbicides are considered to be mildly toxic to dogs and cats. There are several types of herbicides that are commonly used, including glyphosate (e.g., Roundup), pyridine herbicides, imidazolinone compounds, chlorophenoxy compounds (e.g., 2,4-D), and dicamba (a translocation herbicide similar to chlorophenoxy compounds). Typically, when herbicides are ingested, clinical signs are limited to GI abnormalities (e.g., hypersalivation, vomiting, diarrhea) or dermal irritation. Glyphosate, an aminophosphonate (non-cholinesterase inhibitor), is a nonselective post-emergent herbicide. Glyphosate has a wide margin of safety in mammals and generally is regarded as nontoxic to mammalian, aquatic, and avian species.14 It works by interfering directly with the synthesis of amino acids within the plant. When it is ingested in large amounts or directly from the container, clinical signs of hypersalivation, vomiting and diarrhea can be seen; this likely is due to the inactive surfactants found in the liquid formulation.14 Pyridine herbicides (which commonly end with “pyr”) include active ingredients such as thiazopyr, dithiopyr, fluroxypyr, triclopyr, etc. These typically are used as sprays to control the growth of broad-leafed weeds. This class of herbicides works by mimicking auxin, a natural hormone that inhibits growth in plants. Imidazolinone herbicides also are used for controlling the growth of broad-leafed weeds, and they work by inhibiting acetohydroxy acid synthase (and thereby inhibiting amino acid formation in plants). 2,4-D or chlorophenoxy compounds are some of the most commonly used herbicides, and they include the commonly known Vietnam War chemical Agent Orange. While it has a wide margin of safety in animals, this class has been shown to uncouple oxidative phosphorylation and affect ribonuclease synthesis, resulting in potential CNS affects (e.g., demyelination of peripheral nerves). In experimental studies, dogs developed GI signs and myotonia when given doses of 175 or 220 mg/kg.14 Clinical signs reported after exposure include GI (e.g., vomiting, diarrhea, signs of abdominal pain) and CNS signs (e.g., myotonia, muscle stiffness, extensor 1669 rigidity).14,15 While clinical signs rarely are seen in small animal exposures to 2,4-D, the author has concerns about chronic or large exposures due to the mechanism of action. Several published studies have postulated an association with lymphoma and phenoxy herbicides.14-17 Lastly, dicamba (which is related to the chlorophenoxy compounds such as 2,4-D) is a commonly used benzoic acid herbicide that has a wide margin of safety. With all herbicide exposures, treatment is directed towards supportive care. If large amounts are ingested, decontamination of the patient typically is sufficient. Summary In general, the prognosis for the poisoned patient is fair to excellent with immediate recognition and treatment. However, a few of these chemical toxicants have a very narrow margin of safety (e.g., OPs, carbamates, ethylene glycol), and intensive therapy is warranted. When in doubt, the clinician should consult the ASPCA Animal Poison Control Center in cases of life-threatening emergencies, or when the mechanism of action, clinical signs, and treatment are not known. References 1. Adams CA. Bromethalin. Five-minute veterinary consult clinical companion: small animal toxicology. Wiley-Blackwell: Ames, IA; 2010:769–774. 2. Gray SL, Lee JA, Hovda LR, et al. Potential zinc phosphide rodenticide toxicosis in dogs: 362 cases (2004-2009). J Am Vet Med Assoc. 2011;239(5):646–651. 3. Gray SL. Phosphides. Five-minute veterinary consult clinical companion: small animal toxicology. ed 2. Wiley-Blackwell: Ames, IA; 2016:862–870. 4. Adams CA, Poppenga RH. Cholecalciferol. Five-minute veterinary consult clinical companion: small animal toxicology. ed 2. Wiley-Blackwell: Ames, IA; 2016:850–855. 5. Murphy M. Anticoagulants. Five-minute veterinary consult clinical companion: small animal toxicology. ed 2. Wiley-Blackwell: Ames, IA; 2016:835–843. 6. Talcott PA. Insecticide toxicosis. Bonagura JD, Twedt DC. Kirk's current veterinary therapy XV. Elsevier-Saunders: St Louis; 2014:135–141. 7. Liu TY D, Lee JA. Xylitol. Osweiler G, Hovda L, Brutlag A, Lee JA. Blackwell's five-minute veterinary consult clinical companion: small animal toxicology. ed 1. Wiley-Blackwell: Iowa City; 2011:470–475. 8. Kore AM. Alcohols (ethanol, methanol, isopropanol). Osweiler G, Hovda L, Brutlag A, Lee JA. Blackwell's five-minute veterinary consult clinical companion: small animal toxicology. ed 1. Wiley- Blackwell: Iowa City; 2011:61–67. 9. Bischoff K. Automotive toxins. Bonagura JD, Twedt DC. Kirk's current veterinary therapy XV. Elsevier- Saunders: St Louis; 2014:151–155. 10. Creighton KJ, Koenigshof AM, Weder CD, et al. Evaluation of two point-of-care ethylene glycol tests for dogs. J Vet Emerg Crit Care. 2014;24(4):398–402. 11. Scherk JR, Brainard BM, Collicutt NB, et al. Preliminary evaluation of a quantitative ethylene glycol test in dogs and cats. J Vet Diagn Invest. 2013;25(2):219–225. 12. [Available at] http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm441349.htm [Accessed August 6, 2015]. 13. Osweiler GD. Propylene glycol. Osweiler G, Hovda L, Brutlag A, Lee JA. Blackwell's five-minute veterinary consult clinical companion: small animal toxicology. ed 1. Wiley-Blackwell: Iowa City; 2011:78– 85. 14. Tegzes JH. Lawn and garden product safety. Bonagura JD, Twedt DC. Kirk's current veterinary therapy XV. Elsevier-Saunders: St Louis; 2014:130–132. 15. Chen AV, Bagley RS, Talcott PA. Confirmed 2,4-dichlorophenoxyacetic acid toxicosis in a dog. J Am Anim Hosp Assoc. 2010;46:43–47. 16. Hayes HM, Tarone RE, Cantor KP, et al. Case-control study of canine malignant lymphoma: positive association with dog owner's use of 2,4-dichlorophenoxyacetic acid herbicides. J Natl Cancer Inst. 1991;8:1226–1231. 17. Glickman LT, Raghavan M, Knapp DW, et al. Herbicide exposure and the risk of transitional cell carcinoma of the urinary bladder of Scottish terriers. J Am Vet Med Assoc. 2004;224(8):1290–1297. aPersonal communication, ASPCA Animal Poison Control Center, Urbana, IL. 1670 CHAPTER 153 Prescription and Over-the-Counter Drug Toxicoses Ahna G. Brutlag Client Information Sheet: Prescription and Over-the-Counter Drug Poisonings in Dogs and Cats Collectively, exposures to human and veterinary prescription and over-the-counter drugs account for approximately 40% of all cases reported to Pet Poison Helpline, a 24/7 veterinary poison control center based out of Minneapolis, Minnesota, serving all of North America.1 Such exposures most often involve unintentional overdoses (e.g., dog chewing into a bottle of medication) but intentional administration of medication by the pet owner (e.g., giving an ailing cat a liquid children's NSAID) and iatrogenic intoxications also occur. Calcium Channel Blockers Calcium channel blockers (CCBs) or calcium channel antagonists, such as amlodipine, diltiazem, and verapamil, are commonly used in both human and veterinary medicine for the treatment of systemic hypertension, cardiac disease including hypertrophic cardiomyopathy, supraventricular tachycardia arrhythmias, and other cardiac issues. In general, CCBs inhibit the transmembrane influx of extracellular calcium through slow or long-lasting (L-type) ion channels primarily located in myocardial and arterial smooth muscle cells. This mechanism results in decreased myocardial contractility, and arterial dilation, with a subsequent decrease in peripheral resistance, blood pressure, and afterload. Slowing conduction in the SA node and reducing AV nodal conduction result in slowing of the cardiac rate, potentially precipitously. Overdose or intoxication from CCBs results in an exaggeration of therapeutic effects, predominantly sinus bradycardia, bradyarrhythmias (e.g., all degrees of heart block), and hypotension secondary to vasodilation (see ch. 159 and 248). Sinus tachycardia may occur reflexively due to severe hypotension and will typically self-correct if hypotension is resolved. Non-cardiac signs such as vomiting (especially in cats), hypothermia (see ch. 49), central nervous system (CNS) depression, non-cardiogenic pulmonary edema, hypokalemia, hyperglycemia, metabolic acidosis (secondary to hypoperfusion), and increased lactate production can also occur. Rarely, signs of CNS stimulation such as tremors or seizures occur.2 Toxic dosages for CCBs in dogs and cats have not been determined and, due to the narrow margin of safety of these agents, most overdoses are considered potentially toxic. Signs of intoxication have been noted at therapeutic dosages in both dogs and cats with additional reported intoxications occurring at 14.5 mg/kg verapamil in a cat and 95-109 mg/kg sustained-release diltiazem in an adult dog.2,3 Treatment of CCB intoxication begins with gastrointestinal decontamination if appropriate (see ch. 112 and 151). In any case of potential CCB overdose, close monitoring of heart rate, rhythm, and blood pressure (see ch. 99) should be continued for 12-24 hours after exposure. Symptomatic animals also require laboratory monitoring of electrolytes, blood glucose, acid/base status and lactate (see ch. 70 and 128). Typical first-line agents of treatment include IV crystalloids for hypotension (colloids may also be necessary—see beta-blocker section of this chapter and see ch. 129), atropine for bradycardia (0.02-0.04 mg/kg IV), and calcium gluconate (10% solution, 0.5 to 1.5 mL/kg IV slowly over 5 minutes while monitoring an electrocardiogram [ECG] or as a constant-rate infusion [CRI]; see ch. 298) or calcium chloride (10% solution, 0.1 to 0.5 mL/kg IV slowly over 5 minutes or as a CRI of 0.01 mL/kg/h) to increase transmembrane calcium flow. If the patient is refractory to this suite of therapies, other agents such as intravenous lipid emulsion (ILE) and high-dose insulin (HDI) therapy may be considered. While the exact mechanism of intravenous lipid emulsion therapy has not been fully elucidated, its beneficial effects are likely to be multifactorial. Current theories include the “lipid sink” theory which postulates that lipophilic agents (i.e., logP > 1.0) are “pulled” from their receptor sites and sequestered in the 1671 lipid compartment of the blood.4 Additional direct benefit to the myocardium is thought to result from the utilization of free fatty acids as an energy source, an increase in intracellular calcium, an alpha-adrenergic receptor mediated increased vasopressor effect, and the reduction of nitric oxide- and insulin-induced vasodilatation by ILE.4 The current recommend dosage of ILE is 1.5 mL/kg IV bolus followed immediately with a CRI of 0.25 mL/kg/min until clinical signs resolve or for 30-60 minutes, whichever is shorter. Significant improvement is expected within minutes of ILE administration. If no significant improvement occurs, additional boluses may be administered. The total amount of ILE that can be safely administered is not known and may vary greatly depending on the individual patient, the toxicant, and the severity of clinical signs. In the current human literature, a maximal daily dosing of 8 mL/kg of 20% ILE is recommended but this dosage has been safely exceeded without adverse events in both humans and animals. Experimentally, ILE has been shown to be beneficial in canine verapamil intoxications and is also often utilized in humans with CCB overdoses.5-7 High-dose insulin therapy, also referred to as hyperinsulinemia-euglycemia therapy, has also been shown to be successful in treating CCB intoxication in dogs and is currently a first-line agent of care in human medicine CCB overdosage.7-10 The proposed therapeutic mechanism of HDI is multifactorial and includes enhanced myocardial uptake of glucose, suppression of phosphodiesterase III (increases cAMP leading to increased intracellular calcium influx), and induction of mild hypokalemia resulting in enhanced cardiac ino​- tropy. Administration of HDI requires a central line and concurrent administration of dextrose to support euglycemia (see ch. 76). Prior to beginning treatment, it is important to monitor the blood glucose (BG) concentration and supplement if the BG is 80%). TPE requires standard hemodialysis equipment and is performed using renal dialysis units with hollow-fiber plasma filters. With plasmapheresis, the blood is separated into red blood cell fractions and plasma. The plasma component contains antibodies, lipoproteins, von Willebrand factor multimers, immune complexes, complement components, and toxins/endotoxins; this portion is discarded and replaced with an equal volume of replacement fluids. The blood cellular elements are returned intravenously to the patient without the plasma component. A study from 2008 (Pachtinger et al) is an excellent example of how efficient proper decontamination can be. Of 151 dogs that had ingested an anticoagulant rodenticide, and who had gastrointestinal decontamination performed within 6 hours, only 11 (8.3 %) developed prolonged PT, requiring treatment with vitamin K. Additionally, none of these dogs had evidence of clinical bleeding or required blood transfusion. Diagnostic testing Most times, when the owner suspect the animal to be “poisoned”, without having any suspicion of a specific toxin, the cause will be something else, such as metabolic, neurologic, or cardiovascular disease of some sort. It is however important to ask specific questions in regards to any possible toxin exposure, so not just ask if “there is any suspected toxin exposure”, but to ask specifically if there are any lilies in the house or on the property, if you have a cat presenting with acute kidney injury. It is also useful to know the different toxins that can cause disease in specific organs, such as renal and hepatotoxins, or cause specific signs, such as tremors. Diagnostic testing for toxins can be frustrating, as there is no one test for all toxicants, and multiple tests for specific agents may be expensive. Also, not all toxins have a test, and results can take several days. This is why we many times will end up with a “suspected” or “possible” toxin exposure, and even though this may be frustrating, it is also important to note that most treatment for toxicities are supportive and not specific in nature anyway. Many veterinary diagnostic labs offer basic screening tests for suspected rodenticide, insecticide, or heavy metal exposure, and some may also offer specialty screenings such as “convulsant” screens including toxins such as bromethalin, tremorogenic mycotoxins and strychnine etc. Toxidromes Toxidromes are recognizable syndromes resulting from toxicants or classes of toxicants. These are common ones in veterinary medicine: Ethylene glycol toxicity, xylitol toxicity, serotonin syndrome, sympathomimetic syndrome, cholinergic syndrome, and Anticholinergic syndrome. We will discuss these toxidromes in length later in this course, but I one example is the toxidrome seen with Beta-agonist toxicity (such as albuterol) where you will typically see a tachyarrhythmia, combined with severe hypokalemia, and hypophosphatemia. These signs combined should raise the concern for this specific toxicity, and owner history should be reviewed for this specifically. Symptomatic treatment As we have very few specific treatments for toxins, treatment focus should be based on monitoring and supportive care, including fluid therapy, cardiovascular, gastrointestinal, and neurologic support as needed, as well as appropriate analgesia and sedation.