Don't eat that! Toxicities in cats (Proceedings)

Cats are great patients because they are less likely to ingest large amounts of bad stuff just because. However, their unique metabolism presents other challenges as it contributes to the toxicities that we do see in cats and changes, often lowering, the toxic dose we can expect. Also, substances that are safe in other species can be deadly in cats. The substances discussed are by no means complete, but do address the most common toxicities. Even with the oldies still on our list, there may be some new information which helps further define or treat the toxicity.

Acetaminophen

Acetominophen is a (paracetamol) is a synthetic non-opiate derivative of p-aminophenol that can produce both hepatotoxicity and hematotoxicity, specifically, methemoglobinemia. Although the majority of acetaminophen is conjugated with sulfate and glucuronide to form inactive metabolites, a small amount is processed via the cytochrome P450 enzyme system to form N-acetyl-p-benzo-quinone imine (NAPQI). This intermediary metabolite is then conjugated with glutathione to an inactive product. Because NAPQI is highly reactive it can cause hepatocellular damage once glutathione has been depleted.

A unique feature of acetaminophen toxicity in cats, and dogs to a lesser degree, however, is methemoglobinemia. A recent study determined that a different metabolite may be responsible for this hematotoxicity that is not present in other species. This metabolite, para-Aminophenol (PAP), is conjugated with glutathione and N-acetyl to detoxify it. The enzyme, N-acetyltransferase, is deficient is both cats and dogs resulting in the hematotoxicity in these two species.As little as 10 mg/kg can result in toxicity in cats. A regular strength Tylenol is 325 mg (extra strength tablets are 500 mg), children's suspension liquid is 32 mg/ml, and infant's suspension liquid is 100 mg/ml. By way of comparison, a dose of 100 mg/kg in dogs is required for hepatotoxicity and 200 mg/kg to produce methemoglobinemia.

Clinical signs of methemoglobinemia accompanied by hepatotoxicity in cats include increased respiratory rate, pale-muddy mucous membranes, hypothermia, and tachycardia. Other signs are CNS depression, anorexia, vomiting, facial edema and edema of the extremities, salivation, diarrhea, coma and death. Heinz body anemia, hemoglobinuria and hematuria as methemoglobin levels rise in the bloodstream. Elevated liver enzymes will occur if hepatotoxicity is present. Death occurs within hours after methemoglobin levels reach greater than 50%.

The goals of therapy are to:

     1. Scavenge the reactive metabolites by replenishing glutathione: N-acetylcysteine (NAC) [5% solution PO or IV (using a bacteriostatic filter): loading dose of 140 mg/kg, then 70 mg/kg every q 4 h for at least 3-5 treatments]. Ascorbic Acid [30 mg/kg TID-QID PO or IV] for additional anti-oxidant scavenging can also be given.

     2. Slow metabolism of parent substance to reactive metabolite: Cimetadine [5-10 mg/kg TID-QID PO or IV] interferes with the P450 enzyme system.

     3. Protect the liver from oxidant damage: SamE [180 mg BID PO x 3 days then 90 mg BID x 14 days – protocol from recent study (Webb et al, 2003)]

Though methylene blue can be used to treat methemoglobinemia, it causes Heinz body anemia in cats and, therefore, should not be used.

Lily toxicity

They're lovely with their curling petals standing tall above their slender leaves, but Easter lilies, tiger lilies, Asiatic hybrid lilies and daylilies, (genera Lilium and Hemerocallis) are deadly to cats, even in small amounts. Ingestion of a couple of leaves or part of a single flower can cause death. In experimental studies of Easter lilies specifically, the flower is more toxic than the leaves. In severe intoxications (~8 flowers) in this same study, cats died (or were euthanized due to severity of clinical signs) within 4-8 hours of ingestion. The specific parts of the plants that are nephrotoxic have not been elucidated in Hemerocallis spp.

Not all plants designated as "lilies", however, are nephrotoxic. Calla lilies and peace lilies (Arum genus) are not true lilies and though they can cause GI upset, they are not nephrotoxic. "Lily of the Valley" (Convallaria genus) contains cardiac glycosides and can produce clinical signs similar to digitalis, but is not nephrotoxic. Therefore, it is important to identify the type of lily ingested.

The primary histopathologic abnormality is acute tubular necrosis. Epithelial cell death can occur within hours of ingestion depending on the dose ingested. In some cases of Easter lily intoxication, pancreatitis and pancreatic fibrosis have also been documented.

Initial clinical signs – within 1-3 hours – include salivation, vomiting and anorexia. This is followed over the next 12-36 hours with polyuria/polydipsia, dehydration and eventual anuric renal failure. Biochemical parameters are consistent with acute renal failure and the urinalysis often reveals the presence of casts, glucose and protein, suggestive of tubular damage.

If a patient is presented during the first 6 hours post-ingestion, it is imperative to induce vomiting to empty gastric contents and to administer activated charcoal to limit further absorption of the toxin. Fluid therapy with normal saline at 2-3 times maintenance rates should be initiated and continue over the next 48 – 72 hours. If an owner has witnessed lily ingestion in the previous 6-8 hours, beyond the usefulness of decontamination, but the patient is not clinical and azotemia is not present, it is a deadly mistake to assume a toxic level has not been consumed. Aggressive fluid therapy is crucial to prevent anuric renal failure as dehydration will occur rapidly once the patient becomes polyuric. Dehydration coupled with concurrent tubular damage hastens the descent into anuric renal failure. During therapy, daily urinalyses and renal parameter assessment is essential to gauge progression of renal failure and adjust fluid and electrolyte therapy. ARF management discussions are available in other journal reviews.

Unfortunately, most patients present long after GI decontamination is useful. Many are already in polyuric, oliguric or anuric renal failure. Hemo- or peritoneal dialysis should be considered in cats in anuric renal failure. Even with dialysis to give time for renal tubular repair, prognosis is guarded. In one case series of 6 cats with lily toxicity (2 of which received hemodialysis), 50% died or were euthanized within 30 days of presentation.

Phosphate enemas

Owners are only trying to do their best when they administer an enema to their constipated cat, but the consequences are still tragic. Fleet® enemas, the most common product available for children ages 2 to 9 years, contain sodium phosphate and biphosphate. Owners often assume that a child's product must be safe for their cats. Many physicians incorrectly assume that the phosphate is not absorbed extensively and that the high concentration within the solution is therefore safe. There are, however, several case reports of children and adults with severe electrolyte imbalances after Fleet® enema administration; thus, the acute hyperphosphatemia is not unique to the cat. However, in the majority of toxicity reports in humans, patients were compromised in some way, e.g., pre-existing nephropathy or colonic mucosal disease, which likely contributed to the adverse effects.

It should be noted that not all Fleet® enemas are created equal. There are several adult preparations (Fleet® Mineral Oil Enema, Fleet® Bisocodyl Enema) that contain no phosphate. Unfortunately, owners often reach for the only children's product available – Pedialax Enema by Fleet® — which does contain phosphate.

Acute absorption of sodium and phosphate results in serum hypernatremia, hyperphosphatemia and — by the Mass Law Effect that governs calcium-phosphate homeostasis — hypocalcemia. The rapid shift in electrolytes within the brain causes cerebral dehydration. Other biochemical abnormalities include hypokalemia, hyperglycemia, acidosis and hyperlactatemia. Clinical signs, which are apparent within an hour post-enema, are attributable to cerebral dehydration and hypocalcemia: lethargy, ataxia, miosis, arrhythmias, muscle tremors, and seizures.

Treatment is supportive only and must be administered promptly.

     1. Low-sodium fluids: If given soon after the enema is administered, the fluids can be given rapidly without concern of cerebral edema because the onset of enema-induced hypernatremia was also rapid, i.e., no time for neurogenic osmoles to form. If therapy is not begun for several hours, isotonic fluids must be used judiciously to bring down serum sodium levels slowly and avoid cerebral edema.

     2. Phosphorus will decrease secondary to fluid diuresis and normalization of other electrolytes.

     3. If life-threatening arrhythmias are present due to hypocalcemia, monitor ECG while giving calcium gluconate (10 mg/kg IV slowly) to effect.

Kaopectate and Pepto-Bismol®Toxicity

Prior to 2002, Kaopectate® contained kaolin, pectin and attapulgate. These substances are not absorbed into the bloodstream, working locally to adsorb bacteria and other toxics and decrease water loss. After 2002, bismuth subsalicylate was added. Cats are relatively deficient in glucuronosyltransferase, which conjugates salicylate with glucuronic acid. A tablespoon of regular-strength Kaopectate® and extra-strength Kaopectate® contains 130 mg aspirin equivalent and 230 mg aspirin equivalent, respectively. Toxicity in cats occurs at >25 mg/kg/day. A tablespoon of extra-strength Kaopectate® in a 5 kg cat would be a dose of 46 mg/kg. Clinical signs of toxicity include lethargy, vomiting, diarrhea, hematemesis, melena and abdominal pain. Severe gastric ulceration with rupture can occur.

Meloxicam

Meloxicam (Metacam®) is a popular COX-1 sparing NSAID that is used world-wide for managing a variety of painful conditions, such as degenerative joint disease, feline gingivostomatitis, idiopathic cystitis, uveitis and neoplasia, among others. It was touted for its safety when given at oral doses of 0.025 – 0.5 mg/kg daily. However, on Sept. 17, 2010, Boehringer Ingelheim Vetmedic announced that there have been adverse events, including renal failure and death, associated with the oral suspension formulation. The company recommended that it be used as a one-time only injection post-elective surgical procedure. There are other NSAIDs available that are approved for use in cats, all of which are discussed in the International Society of Feline Medicine and American Association of Feline Practitioners's Consensus Statement on Long-Term NSAID Use in Cats.

Benzocaine toxicity

Benzocaine is another OTC drug that can result in toxicity if it is absorbed into the skin or ingested. The toxicity observed is methemoglobinemia and although it has been documented in a number of species, cats are particularly susceptible to hemoglobin oxidation. In one study, a single spray application of a benzocaine-containing topical anesthetic produced significant methemoglobinemia within 20-30 minutes of application. The clinical signs and treatment of methemoglobinemia are covered elsewhere in these proceedings. Benzocaine can also cause Heinz body hemolytic anemia, further reducing oxygen carrying capacity. Bathing an animal with a mild soap if skin absorption has occurred or decontamination of the GI tract may be necessary.

References

Murphy MJ. Rodenticides. Vet Clin North Am Small Anim Prac. 2002;32(2):469-84.

McKonkey SE, Grant DM, Cribb AE. The role of para-aminophenol in acetaminophen-induced methemoglobinemia in dogs and cats. J Vet Pharmcol Therap 2009;32:585–595.

Avizeh R, Najafzadeh H, Razijalali M, et al. Evaluation of prophylactic and therapeutic effects of silymarin and N-acetylcysteine in acetaminophen-induced hepatotoxicity in cats. J Vet Pharmcol Therap 2009;33:95–99.

Welch SL. Oral toxicity of topical preparations. Vet Clin Small Anim 2002;32:443–453.

Taylor NS, Dhupa N. Acetominophen toxicity in dogs and cats. Compend Contin Educ Pract Vet 2000;22:160-169.

Webb CB, Twedt DC, Fettman MJ, Mason G. S-adenosylmethionine (SAMe) in a feline acetaminophen model of oxidative injury. J Feline Med Surg 2003;5[2]:69-75.

Fitzgerald KT. Lily toxicity in the cat. Top Companion Anim Med 2010;25(4):213-7.

Rumbeiha WK, Francis JA, Fitzgerald SD, et al. A comprehensive study of Easter lily poisoning in cats. J Vet Diagn Invest 2004;16:527–541.

Sparkes AH, Heiene R, Lascelles DBX, et al. ISFM and AAFP Consensus Guidelines: Long-term NSAID use in cats. J Fel Med Surg 2010;12:521-538.

Davis JA, Greenfield RE, Brewer TG. Benzocaine-induced methemoglobinemia attributed to topical application of the anesthetic in several laboratory animal species. Am J Vet Res 1993;54:1322-6.

Wilkie DA, Kirby R. Methemoglobinemia associated with dermal application of benzocaine cream in a cat. J Amer Vet Med Assoc 1988;192(1):85-6.