Metaldehyde is a cyclic polymer of acetaldehyde that is found in a variety. Metaldehyde Toxicoses in Dogs KEY FACTS

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1 376 Vol. 25, No. 5 May 2003 CE Article #5 (1.5 contact hours) Refereed Peer Review Comments? Questions? compendium@medimedia.com Web: VetLearn.com Fax: KEY FACTS In dogs, the LD 50 of metaldehyde, a common component of snail or slug bait, is 100 mg/kg, but severe effects can occur at lower doses. The onset of clinical signs is typically within 30 minutes to 3 hours. Common signs of ingestion include tachycardia, panting, drooling, nystagmus, hyperpnea, ataxia, acidosis, cyanosis, hyperthermia, tremors, and seizures. Methocarbamol has been used successfully to treat metaldehyde-induced tremors and seizures. Metaldehyde Toxicoses in Dogs ASPCA Animal Poison Control Center Urbana, Illinois Jill A. Richardson, DVM* Sharon L. Welch, DVM Sharon M. Gwaltney-Brant, DVM, PhD, DABVT, DABT Joel D. Huffman, DVM Marcy E. Rosendale, DVM ABSTRACT: Metaldehyde is a common component of molluscacides. Commercial products are formulated in granular or liquid form and are applied around walkways and in garden areas. Dogs are exposed to metaldehyde-containing snail bait either by ingestion of bait that is scattered for snail control or by direct ingestion of bait from an inappropriately stored container. Clinical signs seen in dogs consuming metaldehyde include tachycardia, nystagmus, hyperpnea, ataxia, seizures, acidosis, cyanosis, diarrhea, dehydration, hyperthermia, and even death. Delayed hepatic failure and transient blindness have also been reported. Treatment of metaldehyde toxicoses includes use of standard decontamination procedures, such as emesis and activated charcoal, seizure control, and supportive care. IV methocarbamol has been recommended for metaldehyde-induced tremors and seizures, with consistent success noted in ASPCA Animal Poison Control Center case records. Metaldehyde is a cyclic polymer of acetaldehyde that is found in a variety of snail and slug baits. These products are commonly used in and around gardens to prevent snail- or slug-induced damage. Toxicosis in dogs most often occurs after they ingest these products. The metaldehyde concentration of most metaldehyde-containing molluscacides is 2% to 4%; liquid, powder, pellet, and granular formulations are available. 1 Although the LD 50 in dogs is 100 mg/kg, severe effects can occur at much lower doses. 2 Between January 1, 1999, and May 31, 2001, the ASPCA Animal Poison Control Center in Urbana, Illinois, consulted on 92 cases of suspected metaldehyde toxicosis in dogs. The findings were reported as follows: 53% of the dogs developed clinical signs within 30 minutes to 3 hours of exposure 96% showed clinical signs involving the central nervous system (CNS) 65% of the dogs experienced tremors *Dr. Richardson is currently affiliated with Hartz Mountain Corporation, Secaucus, New Jersey.

2 Compendium May 2003 Metaldehyde Toxicoses in Dogs % had seizures 21% experienced hyperthermia 16% had tachypnea 14% showed signs of salivation 14% had ataxia Vomiting, tachycardia, hyperesthesia, and depression were also reported. In 28% of cases, the calls involved dogs in California (Figure 1). The next most common states or provinces of call origin were New York (8.7%), Ontario (8.7%), and Texas (5.7%). Fifty-nine percent of the calls were received between May and July. METABOLISM OF METALDEHYDE In the stomach, metaldehyde undergoes acid hydrolysis to acetaldehyde, which is rapidly absorbed. 3 Metaldehyde is also absorbed intact in the stomach. This agent distributes widely throughout the body and readily crosses the blood brain barrier. 3 Metaldehyde is thought to be metabolized by mixed function oxidases because induction of cytochrome P450 has been shown to protect against metaldehyde toxicity. 4 Metaldehyde appears to be rapidly and efficiently metabolized: only 1% to 8% of ingested metaldehyde is excreted unchanged in the urine. 3 Acetaldehyde that is formed from metaldehyde is rapidly oxidized to carbon dioxide, which is probably eliminated through the lungs. The half-life of metaldehyde in dogs is unknown; in humans, however, it is estimated at 27 hours. 3 MECHANISM OF TOXICOSIS The exact mechanism of action of metaldehyde is poorly understood. Acetaldehyde derived from the hydrolysis of metaldehyde was historically thought to be the primary toxic principle. 3,5 However, more recent studies have questioned this view because studies of metaldehyde toxicosis have failed to detect acetaldehyde in the plasma, urine, or brain of intoxicated animals but have detected metaldehyde. 3 Acetaldehyde may contribute to the metabolic acidosis that is seen in metaldehyde toxicosis, but it now seems likely that the syndrome of metaldehyde toxicosis may be due primarily to the parent compound. 3 The nervous system effects of metaldehyde are theorized to result from decreases in the concentrations of neurotransmitters in the brain, primarily γ-aminobutyric acid, serotonin (5-hydroxytryptamine, or 5-HT), and norepinephrine. 6 Increases in the activity of monoamine oxidase, an enzyme involved in the metabolism of serotonin and norepinephrine, may be partly responsible for the decreased levels of these neurotransmitters. 3,6 Percentage of Calls % 8.7% 8.7% California New York Ontario Texas Location of Calls 5.7% Figure 1 Most common locations of reported suspected cases of metaldehyde toxicoses in dogs. (From ASPCA Animal Poison Control Center data collected from January 1, 1999, to May 31, 2001.) Reduced concentrations of γ-aminobutyric acid result in disinhibition of neuronal excitation, which causes seizure activity. Decreases in serotonin and norepinephrine concentrations may also contribute to seizure activity because of a lowering of the seizure threshold. 3,7 Hyperthermia, a common presentation of metaldehyde toxicosis, may be secondary to severe muscle tremors. 3 CLINICAL SIGNS Signs of toxicity may be seen as soon as 30 minutes after ingestion but typically occur within 3 to 5 hours. 2,3 The most common clinical signs reported in dogs include tachycardia, nystagmus, hyperpnea, ataxia, seizures, acidosis, cyanosis, diarrhea, dehydration, hyperthermia, and death. Delayed hepatic failure and transient blindness have also been reported, but these effects are poorly documented and their incidence is generally considered to be low. 3 The diagnosis of metaldehyde toxicosis is most commonly based on the exposure history and the development of associated clinical signs. Liver, urine, and plasma can be analyzed for the presence of metaldehyde. Gas chromatography-ion trap mass spectrometry has been successfully used to identify the compound in stomach contents, plasma, and urine. 8,9 Acetaldehyde, derived from metaldehyde, can be isolated from the stomach contents; acetaldehyde can also be detected in serum and urine. 10 Most accredited veterinary diagnostic laboratories can perform an analysis for acetaldehyde. POSTMORTEM CHANGES Lesions associated with metaldehyde toxicosis in dogs are relatively nonspecific and consist primarily of congestion of the kidneys, liver, and lungs. 5 Petechial and

3 378 Small Animal/Exotics Compendium May 2003 ecchymotic hemorrhages in the gastrointestinal mucosa, epicardium, and endocardium have also been observed. In mice and horses, fractures of the vertebral column, thought to be secondary to severe seizures, have been reported as uncommon events; no similar lesions have been described in dogs. 5,8 TREATMENT The general goals of treatment are to stabilize the clinical condition of the dog, to prevent absorption and facilitate elimination of metaldehyde, to control effects of the compound on the CNS, and to provide supportive care. Emesis may be induced in asymptomatic dogs within the first 30 minutes to 2 hours of ingestion. Feeding a small moist meal before induction of vomiting may increase the chances of an adequate emesis. Emesis is contraindicated in hyperactive dogs and in animals with tremors or seizures. A gastric lavage may be considered if emesis is contraindicated. Hydrogen peroxide (3%) at a dose of 1 teaspoon per 5 lb, not to exceed 3 tablespoons, is an effective emetic for dogs and causes vomiting as a result of mild gastric irritation. 11 Vomiting usually occurs within minutes. This treatment can be repeated once if it is not initially successful. Apomorphine hydrochloride is another option for inducing emesis. Apomorphine, a centrally acting emetic, can be administered topically to the eye or can be given parenterally at a dose of 0.03 mg/kg IV or 0.04 mg/kg IM. 12 Side effects of apomorphine are more common after IV administration and include CNS and respiratory depression, ataxia, excitement, and protracted vomiting. 12 Activated charcoal has been shown to help inhibition of metaldehyde absorption. 1,13 Activated charcoal can be given orally via a large syringe or a stomach tube. A cuffed endotracheal tube should be used in a sedated animal or an animal with depressed respiration to prevent aspiration. The recommended dose of activated charcoal is 1 to 3 g/kg. 11 The initial dose should be given in combination with a cathartic, such as 70% sorbitol at 3 ml/kg, unless the animal is dehydrated or has diarrhea. 11 Repeated doses of activated charcoal every 4 to 8 hours at half the original dose may be beneficial. Methocarbamol has been used with consistent success in Animal Poison Control Center cases for the treatment of metaldehyde-induced tremors and seizures in dogs. Seizures and tremors can best be managed with IV methocarbamol given at 55 to 220 mg/kg. 12 Half the dose should be given quickly (but no faster than 2 ml/min IV), followed by the remaining amount until the desired effect is achieved. Methocarbamol administration may be repeated if the signs recur; however, a dose of 330 mg/kg should not be exceeded in a 24-hour period. 12 Other options for seizure control include diazepam, barbiturates, and inhalant anesthetics. Diazepam can be given at 2 to 5 mg/kg IV until the desired effect is seen, or as a constant-rate infusion at 0.1 to 0.5 mg/kg/hr. 12 Diazepam is preferred to barbiturates because barbiturates compete with an enzyme that degrades acetaldehyde. 14 Unresponsive cases may require pentobarbital at 3 to 15 mg/kg IV, given slowly until the desired effect is observed and repeated, if needed, in 4 to 8 hours. 12 Other options for seizures that are refractory to all other types of therapy include propofol, given as an IV bolus or as a constant-rate infusion (0.1 to 0.6 mg/kg/min), and inhalant anesthetics. Propofol can be given to an unpremedicated healthy dog as a single injection of 6 mg/kg IV with 25% of the calculated dose given every 30 seconds until desired effects are seen. During treatment, blood gas concentrations, anion gap, and urine ph should be monitored closely for the development of metabolic acidosis. Sodium bicarbonate may be used to correct acidosis. 12 Hyperthermia, which can occur as a result of muscle fasciculation, tremors, or seizures, 15 usually resolves once tremors are controlled. Aggressive cooling, by means of ice baths or cold water enemas, should be avoided because hypothermia may result. 15 Other signs, such as gastric upset, should be treated by supportive measures as needed. Treatment should continue until clinical signs resolve and may be required for several days. Monitoring of liver values is also recommended because delayed hepatotoxicity can occur. SUMMARY Signs of metaldehyde toxicity in dogs mainly involve the CNS. Although the exact mechanism of metaldehyde toxicity is yet unknown, treatment can be successful if it is initiated early. The keys to success are early decontamination and the control of tremors and seizures. Methocarbamol has been shown to be effective in treating metaldehyde-induced tremors and seizures. REFERENCES 1. Poisindex Editorial Staff: Metaldehyde (Toxicologic Managements), in Toll LL, Hurlbut KM (eds): Poisindex System, Vol Greenwood Village, CO, Micromedex. Edition expires Booze TF, Oehme FW: Metaldehyde toxicity: A review. Vet Hum Toxicol 27(1):11 19, Puschner B: Metaldehyde, in Peterson ME, Talcott PA (eds): Small Animal Toxicology. Philadelphia, WB Saunders, 2001, pp Tardieu D, Thouvenot N, Fargier C, et al: Phenobarbital-type P-450 inducers protect rats against metaldehyde toxicity. Vet Hum Toxicol 38(6): , Knowles CO: Miscellaneous pesticides, in Hayes WJ, Laws ER (eds): Handbook of Pesticide Toxicology. San Diego, Academic Press, 1991, pp Homeida AM, Cooke RG: Pharmacological aspects of metaldehyde poisoning in mice. J Vet Pharmacol Ther 5(1):77 81, Plumlee KH: Pesticide toxicosis in the horse. Vet Clin North Am

4 Compendium May 2003 Metaldehyde Toxicoses in Dogs 379 Equine Pract 17(3): , Jones A, Charlton A: Determination of metaldehyde in suspected cases of animal poisoning using gas chromatography-ion trap mass spectrometry. J Agric Food Chem 47(11): , Booze TF, Oehme FW: Gas chromatographic analysis of metaldehyde in urine and plasma. J Anal Toxicol 9(4): , Keller KH, Shimizu G, Walter FG, et al: Acetaldehyde analysis in severe metaldehyde poisoning [abstract]. Vet Hum Toxicol 33:374, Beasley VR, Dorman DC, Fikes JD, et al: A Systems Affected Approach to Veterinary Toxicology. Urbana, IL, University of Illinois College of Veterinary Medicine, 1999, pp Plumb DC: Veterinary Drug Handbook, ed 4. Ames, Iowa State Press, Shintani S, Goto K, Endo Y, et al: Adsorption effects of activated charcoal on metaldehyde toxicity in rats. Vet Human Toxicol 41:15 18, Carson TL, Osweiller GD: Insecticides and molluscicides, in Morgan RV (ed): Handbook of Small Animal Practice, ed 3. Philadelphia, WB Saunders, 1997, pp Podell M: Seizures and sleep disorders, in Morgan RV (ed): Handbook of Small Animal Practice, ed 3. Philadelphia, WB Saunders, 1997, pp ARTICLE #5 CE TEST The article you have read qualifies for 1.5 contact hours of Continuing Education Credit from the Auburn University College of Veterinary Medicine. Choose the best answer to each of the following questions; then mark your answers on the postage-paid envelope inserted in Compendium. 4. Metaldehyde is most commonly found in a. ant and roach traps. b. household flea sprays. c. fertilizer products. d. fly baits and fly sprays. e. snail and slug baits. 5. Which sign(s) has been infrequently reported in association with metaldehyde toxicosis? a. delayed hepatic failure and transient blindness b. hemorrhage c. flaccid paralysis d. all of the above 6. Contraindications to inducing emesis in cases of suspected metaldehyde poisoning include a. dogs that are moderately to severely hyperactive. b. dogs that are demonstrating tremors or convulsions. c. dogs that are asymptomatic. d. a and b only 7. Diagnosis of metaldehyde toxicosis can be made through a. isolation of acetaldehyde from the stomach contents. b. use of the prothrombin test. c. an assay of the acetylcholinesterase level. d. screening for heavy metals. 1. Metaldehyde is a. a serotonin re-uptake inhibitor. b. a second-generation anticoagulant rodenticide. c. an atypical neuroleptic. d. a polymer of acetaldehyde. 2. The most common clinical signs reported with metaldehyde toxicosis include a. salivation, diarrhea, vomiting, bradycardia, and pulmonary edema. b. ascending paralysis. c. tremors, seizures, and metabolic acidosis. d. hemorrhage, hematuria, and thrombocytopenia. e. muscle flaccidity and generalized muscular weakness. 3. The mechanism of action of metaldehyde is a. cholinesterase inhibition. b. uncoupling of the oxidative phosphorylation process. c. blocking of the sodium channel. d. unknown. e. inhibition of the recycling of vitamin K 1.

5 380 Small Animal/Exotics Compendium May Changes associated with metaldehyde toxicosis that are found postmortem in dogs include a. nonspecific lesions. b. acute tubular necrosis and tubular mineralization. c. vacuolization of CNS tissue. d. bronchopneumonia and cardiogenic pulmonary edema. 9. Which statement most likely characterizes the metabolism of metaldehyde? a. Of ingested metaldehyde, 99% is eliminated unchanged in the urine. b. Metaldehyde does not cross the blood brain barrier. c. Of ingested metaldehyde, 1% to 8% is excreted unchanged in the urine. d. Metaldehyde is hydrolyzed to acetaldehyde. e. both c and d B 10. has been reported to be successful for treating metaldehyde-induced tremors and seizures. a. Methocarbamol b. Atropine c. Vitamin K 1 d. Calcium EDTA e. 2-PAM (pralidoxime)