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Ethylene Glycol Poisoning

Ethylene Glycol Poisoning

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Ethylene glycol poisoning

Ethylene glycol poisoning is extremely serious in cats. A small dose can result in signs which are initially non-specific and may be easily missed. Ethanol is the antidote to ethylene glycol toxicity and works by preventing to toxic compounds. However, it is generally only worthwhile if started within a few hours of ingestion. Although a potentially lethal dose of ethylene glycol can be survived if treatment is prompt, Nicola Bates many cats with ethylene glycol poisoning present late BSc (Brunel) BSc (Open) MSc MA and as a result most cases have a fatal outcome. Nicola Bates has worked in human and veterinary toxicology for 25 years and has thylene glycol (also known amongst other been with the Veterinary Poisons Information Enames as ethanediol) is a common Service (VPIS) since it started. As well as ingredient of antifreeze; it is also found in providing emergency advice via the some screenwashes or more rarely de-icers telephone she has written extensively on (Figure 1). Most antifreezes contain ethylene veterinary toxicology. In addition to service glycol (or occasionally methanol), and are provision, she is involved in training of VPIS liquids which are added to in engine staff and veterinary professionals. She is radiators to prevent freezing and improve cold currently the congress abstract editor for the weather performance. The usual final dilution European Association of Poisons Centres and is approximately 1:1. Clinical Toxicologists (EAPCCT).

Exposure Cats may be exposed by neat Key point antifreeze from a spill, but are more As with many commonly exposed after drinking the diluted poisoning cases in fluid from drained vehicle radiators. Most cats, ingestion is exposures are not witnessed. rarely witnessed. Prevention by informing owners of the dangers of leaving antifreeze around is far preferable, as mortality from ingestion is high.

Mechanisms of toxicity The major toxic agent in ethylene Figure 1: glycol poisoning is not the parent Ethylene glycol is highly toxic compound but the metabolites to cats produced by the action of alcohol

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dehydrogenase (Figure 2). This Toxic dose enzyme oxidises ethylene glycol to Cats are more susceptible to glycoaldehyde. This is then ethylene glycol than dogs and signs metabolised to glycolic acid which progress more rapidly, but it is not appears to be the principle cause of clear why. It may be that toxic the observed with ethylene metabolites are eliminated more glycol toxicity. Further metabolites slowly, or metabolites are of glycolic acid are glyoxylic acid metabolised more rapidly to other and then oxalate; the latter causes more toxic compounds. 1 renal damage and hypocalcaemia by binding to calcium to form calcium The lethal dose of ethylene glycol in oxalate (crystals of which may be cats is commonly reported as present in ). 1.5 ml/kg. 2 In another study 1 g/kg (where 1 ml is approximately 1 g) Toxicokinetics was fatal to cats within 48 h, Ethylene glycol is rapidly absorbed whereas this dose did not affect rats, from the ; in rabbits or guinea pigs. 3 Undiluted cats the peak plasma concentration ethylene glycol-containing occurs about 1 h after ingestion and antifreezes generally contain 95% or the urine concentration peaks about more, with ‘ready to use’ products 3 h after ingestion. 1 being approximately 50%.

Figure 2: Mechanism of ethylene glycol toxicity

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How the antidotes work Key point The aim of antidotal therapy in the management of ethylene glycol The longer the time toxicosis is to prevent formation of between ingestion and the toxic metabolites (Figure 2). treatment, the poorer This is achieved through the prognosis. If acute administration of ethanol or kidney injury has fomepizole (4-methylpyrazole, 4- occurred then the prognosis is poor. MP), both of which are competitive inhibitors of alcohol dehydrogenase, with a higher affinity for the enzyme than ethylene glycol. Fomepizole is early signs may be easily missed, the more potent inhibitor. Inhibition particularly in an outdoor cat. of ethylene glycol metabolism allows , dehydration, tachypnoea, time for renal excretion of the acidosis and may unchanged parent compound. occur. Polydipsia, although common in dogs, is generally not seen in cats. In the study by Connally et al, 4 cats Convulsions can occur at this stage only survived lethal doses of in severe cases. ethylene glycol if treated with fomepizole or ethanol at or before From 12 –24 h cats remain depressed 3 h. In an earlier study, of nine cats and develop cardiopulmonary signs given lethal doses of ethylene glycol with tachypnoea, , (4, 6 or 8 ml/kg) and treated with acidosis, hyper- or hypotension, ethanol at 4 h, five (55.5%) survived pulmonary oedema, arrhythmias, compared to only one (8%) survivor congestive failure and of 12 cats treated at 8 h. 5 These circulatory . Cerebral oedema studies therefore suggest that may occur. Death can occur at this survival is most likely in cats if stage in some cases. treatment with ethanol or fomepizole is started within 3 –4 h of Renal system signs including ingestion. , azotaemia and/or uraemia develop and the renal impairment Fomepizole is effective in cats but exacerbates acid/base and the drug is expensive and the cost of disturbances. Kidneys treatment is cats is increased further may be swollen and painful and because they require a much higher there may be , , dose (6 x dose) than dogs or oral ulcers, severe depression, humans. In addition, this high dose lethargy, coma and convulsions due causes sedation, ataxia and to uraemia. 6 hypothermia in cats. 4 As a result ethanol is more commonly used and Laboratory changes is much more readily available. There is raised urea and creatinine, which is generally seen from about Clinical signs 12 h in cats, 7 low In the early stages of ethylene glycol (due to osmotic induced by poisoning, which occurs from 30 ethylene glycol), proteinuria, minutes to 12 h, there are central glucosuria, haematuria and nervous system signs due to albuminuria. Calcium oxalate crystals unmetabolised ethylene glycol. can appear in the urine within 3 h of These include vomiting, ataxia, ingestion (Figure 3), 4 but the tachycardia and weakness. These absence of oxalate crystals does not

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by 3 h after ingestion, and markedly decreased by 12 h. 7 Neutrophil leukocytosis may also be observed. 6

Prognosis Prognosis should be based on an animal’s response to treatment, 9 but the longer the time to treatment the less favourable the prognosis. Recovery may take 3 –5 days if treated aggressively within a few hours of ingestion, 4 but in most cases unless the ingestion was witnessed, animals usually present in the final stage of poisoning. Coma or Figure 3: Calcium oxalate monohydrate crystals (x500 magnification, Kovastain): in acute renal injury indicates a poor this image the crystals have a rounded ovoid prognosis. appearance but they can be more hexagonal (picture courtesy of Kathleen Tennant ) In a study of 25 cases of ingestion of ethylene glycol in cats the mortality rate was 96%. 10 In another report of Key point 26 cats and 24 dogs with ethylene glycol poisoning only six animals Cats with ethylene glycol (12%) survived. Half of the survivors toxicity may have calcium were admitted within 12 h. 6 In a oxalate monohydrate review of all fatal cases of poisoning crystals in their urine reported to the Veterinary Poisons but the absence of Information Service (VPIS) the most these crystals common agent to result in a fatal does not rule out outcome in cats was presumed to be poisoning. (few cases had laboratory confirmation) ethylene glycol. Of 213 cats with suspected or confirmed ethylene glycol poisoning with known outcome, 38 died (17.8%) and rule out ethylene glycol poisoning. 159 were euthanased (74.6); this is There may also be hyperglycaemia, an overall fatality rate of 92.5%. 11 hypocalcaemia (due to binding of calcium to oxalate), Diagnosis hyperphosphataemia and Diagnosis is generally based on hyperkalaemia (due to acute kidney history, clinical signs and laboratory injury and acidosis). Clinical signs of findings. Ethylene glycol poisoning hypocalcaemia generally do not should be suspected in any animal occur in ethylene glycol poisoning with acute onset of signs, raised because of the shift to the active, urea, creatinine and low urine ionised form of calcium when specific gravity. 9 occurs. 6,8 Test kits are available for confirming There is acidosis, typically with a ethylene glycol in but they blood pH of <7.3 and acidic urine have some limitations. Cats can be with a pH <6.5. 9 The blood pH and poisoned at concentrations below plasma bicarbonate are decreased that detected by the kits (usually

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Keeping cats safe

500 mg/l) and some kits also give essential to ensure adequate false positives in the presence of hydration and therefore renal alcohol (such as ethanol). These kits perfusion and to promote diuresis. If only detect ethylene glycol not its possible, the central venous pressure metabolites. Therefore, in late and urine output should be presenting animals the test may be monitored in cats with acute kidney negative because the ethylene injury because of the risk of fluid glycol has been metabolised or is overload and subsequent pulmonary below the limit of detection. oedema. If there is oliguria or anuria, diuretics such as or Many antifreeze products contain can be given if there is fluorescein (a green or red dye no response to fluid therapy alone. depending on the pH of the There is a significant risk of volume medium), which fluoresces under overload in cats with acute kidney ultraviolet light. Sometimes the dye injury and advice on treatment may be detected in urine or vomitus should be taken from a specialist using a Wood’s lamp and and, ideally, the cat referred to a examination of the paws, mouth and specialist centre. Peritoneal dialysis face may be useful. 12 However, this is or haemodialysis can be used in not a reliable test, 13 as it is difficult to acidotic cats with oliguria, but are detect fluorescence in a test sample rarely available. without a positive and negative control for comparison. 14 Other treatments may include treatment of hyperkalaemia, Treatment management of and The aim of therapy in ethylene glycol vomiting and specific treatment of poisoning is to prevent metabolism severe acidosis. Treatment of and the production of toxic hypocalcaemia is rarely required. metabolites, reverse electrolyte and acid/base disturbances and maintain Antidotal treatment the glomerular filtration rate. Advice After ingestion of ethylene glycol should be sought from a poisons the sooner antidotal therapy is information service and a specialist started the better the outcome. A centre to optimise treatment of potentially lethal dose of ethylene affected cats. glycol can be survived if treatment is prompt. Survival is most likely if Decontamination treated within 3 –4 h of ingestion. Treatment is recommended for any There is no point giving ethanol or quantity but gut decontamination is fomepizole to block metabolism if probably only worthwhile within 1 h the ethylene glycol has been of ingestion. Adsorbents such as metabolised. Unfortunately, cats activated charcoal are not useful. In most cases cats do not present until the onset of signs, hours after Tip ingestion. Antidotes must be given Monitoring, investigations within 3 –4 h of ingestion and initial treatment and, unfortunately, there In symptomatic cats the blood pH, is no point giving them and renal function to cats already suffering should be monitored. Intravenous . fluids (2 –3 times maintenance) are

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often present late by which time such should not be used in cats with antidotal therapy is no longer of use. acute kidney injury as antidotes Management in these cases is increase the half-life of ethylene supportive/palliative. Antidotes glycol and if renal damage has already occurred the kidneys may not be able to effectively eliminate Box 1: Ethanol regimen for it. ethylene glycol poisoning Ethanol is the most readily available and commonly used antidote for Intravenous dosage ethylene glycol toxicity (Box 1). It 5% solution as a constant rate infusion • can be given orally or intravenously at a rate of 5 ml/kg/h for 48 h or but use of a constant rate infusion is longer preferred as it will result in more OR stable blood ethanol concentration. 4 5 ml/kg body weight 20% ethanol in • The dose of ethanol required will IV every 6 h for 5 doses then cause significant central nervous every 8 h for 4 doses. system (CNS) depression and hypothermia. Nursing care for a Ideally, a pharmaceutical grade of recumbent patient will be required. ethanol should be used but if not Ethanol may also worsen acidosis available oral ethanol can be given or an and can cause hypoglycaemia. The IV solution made up using 40% vodka, as blood glucose should be monitored follows:* every 4 –6 h, because of the risk of hypoglycaemia. 7 The airway should To make a 5% solution : add 125 ml of • be protected if there is significant vodka to 875 ml of IV fluid lactated CNS depression. If the cat survives it Ringer’s or saline, that is remove will be depressed and lethargic (that about 125 ml from the bag and replace is, hung over) during recovery from with vodka. An in-line filter should be ethanol therapy and require further used for the IV. supportive care (eg, nutritional support and fluid therapy). To make a 20% solution: dilute an

equal volume of vodka with IV fluids Conclusions such as lactated Ringer’s or saline (eg, Ethylene glycol ingestion is 500 ml with 500 ml). An in-line filter commonly lethal in cats, but prompt should be used for the IV. diagnosis and treatment with ethanol therapy can be life-saving. Oral dosage In many cases, however, the early 2.4 ml/kg orally of a 40% solution (eg, • signs may be missed or vague and vodka, whisky, suitably diluted; non-specific resulting in late equated to 750 mg/kg) over the first presentation. Clients should be hour, followed by 0.5 ml/kg/h educated on avoiding exposing cats, (equates to 150 mg/kg/h). for example, in the garage. This is best given via an indwelling nasogastric tube, periodically over the References treatment period (that is, not all at once, 1 Connally HE, Hamar DW and Thrall MA. Inhibition of canine and feline alcohol as it is irritant and could result in dehydrogenase activity by fomepizole. Am J vomiting). Vet Res 2000; 61: 450 –455. 2 Miles G. Ethylene glycol poisoning with suggestions for its treatment as oxalate *From Plumbs (2008) 15 poisoning. Arch Path 1946; 41: 631. 3 Gessnser PK, Parke DV and Williams RT.

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Studies in detoxication. The metabolism of 14C-labelled ethylene glycol . Biochem J 1961;

79: 482.

4 Connally HE, Thrall MA and Hamar DW. S afety

and efficacy of high-dose fomepizole

compared with ethanol as therapy for

ethylene glycol intoxication in cats. J Vet

Emerg Crit Care 2010; 20: 191 –206.

5 Penumarthy L and Oehme FW. Treatment of Feline Nursing

ethylene glycol toxicosis in cats. Am J Vet Res

1975; 36: 209 –212. Distance Education Courses

6 Thrall MA, Grauer GF and Mero KN.

Clinicopathologic findings in dogs and cats

with ethylene glycol intoxication . J Am Vet

Med Assoc 1984; 184: 37 –41. ISFM is pleased to offer 7 Osweiler GD, Hovda LR, Brutlag AG and Lee JA

(eds). Blackwell’s five-minute veterinary two qualifications in feline

consult clinical companion small animal veterinary nursing: toxicology. Ames, Iowa, Wiley-Blackwell, 2011.

8 Winek CL, Shingleton DP and Shanor SP.

Ethylene and toxicity. Clin ISFM Certificate in Feline Nursing Toxicol 1978; 13: 297 –324.

9 Grauer GF and Thrall MA. Ethylene glycol

(antifreeze) poisoning in the dog and cat.

J Am Anim Hosp Assoc 1982; 18: 492 –497. ISFM Diploma in Feline Nursing 10 Rowland J. Incidence of ethylene glycol

intoxication in dogs and cats seen at Colorado

State University Veterinary Teaching Hospital. Do you want to be a feline friendly nurse? Vet Hum Toxicol 1987; 29: 41 –44. ❖

11 Bates N and Edwards N. Toxic deaths in cats Do you want to learn more about cats? ❖ and dogs reported to the Veterinary Poisons Information Service (VPIS) [abstract]. Clin ❖ Do you want to study from home? Toxicol 2015; 53: 273. 12 Winter ML, Ellis MD and Snodgrass WR. Urine fluorescence using a Wood's lamp to detect    the antifreeze additive fluorescein: a qualitative adjunctive test in suspected ethylene glycol ingestions. Ann Emerg Med 1990; 19: 663 –667. 13 Parsa T, Cunningham SJ, Wall SP, Almo SC and Crain EF. The usefulness of urine fluorescence for suspected antifreeze ingestion in children. Am J Emerg Med 2005; 23: 787 –792. Erratum in: Am J Emerg Med 2006; 24: 396. 14 Wallace KL, Suchard JR, Curry SC and Reagan C. Diagnostic use of physicians' detection of urine fluorescence in a simulated ingestion of sodium fluorescein-containing antifreeze. Ann Emerg Med 2001; 38: 49 –54. 15 Plumb DC. Plumb’s veterinary drug handbook, 6th ed. Ames, Iowa; Blackwell Publishing, 2008.

Many cases of poisoning are preventable by raising owner The courses are online with workbooks to awareness, one of the aims of the complete and marked by our experts. Keeping Cats Safe Campaign. For full details go to: The Campaign is run by International Cat Care in www.icatcare.org/learn conjunction with the Veterinary Poisons Information Service and Agria Pet Insurance.        For more information see: http://icatcare.org/keeping-cats-    safe

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