Antifreeze toxicosis (Proceedings)

Methanol

Methanol (also known as methyl alcohol or wood alcohol) is found most commonly in "antifreeze" windshield washer fluid and varies in concentration from 20-100% (with 20-30% being the most common form.) Methanol's metabolite, formaldehyde, is rapidly oxidized by the enzyme aldehyde dehydrogenase to formic acid, which can cause metabolic acidosis if significant quantities of methanol are ingested. Formic acid is subsequently converted to carbon dioxide and water. In humans and some non-human primates, formic acid is inefficiently metabolized and accumulates causing injury to the retina and central nervous system. Even very small amounts of methanol can be extremely dangerous to humans, but this is not an issue in non-primates. The minimum lethal dose in dogs is 8.0 ml/kg of 100 % methanol.

According to the ASPCA Animal Poison Control Center (APCC) database, the most common methanol exposures occur in dogs and usually involve chewing on containers or licking up spills. In general, alcohols are rapidly absorbed from gastrointestinal tract, so in order to be effective decontamination needs to be done within 20-30 minutes of an oral exposure. With small exposures in dogs and cats, only mild gastric upset may be seen. Larger exposures result in vomiting, diarrhea, ataxia, disorientation (inebriation), depression, hypothermia, tremors and dyspnea; in severe cases seizures, bradycardia or ventricular premature contractions, metabolic acidosis, coma, and respiratory depression may occur. Death is usually due to respiratory depression, hypothermia, or aspiration.

A recent small ingestion should be treated with dilution (milk or water) to minimize gastric upset. Large ingestions warrant decontamination via emesis if less than 30 minutes have passed and the animal is asymptomatic. Activated charcoal is of questionable value in binding small alcohols and is generally not used. Symptomatic animals should be monitored until recovered. Treatment may entail IV fluids to enhance elimination of methanol, thermoregulation, correction of acid/base imbalances, management of cardiac abnormalities, ventilatory support, and seizure control (anticonvulsants should be used with care as they can worsen the CNS depression). Anecdotally, yohimbine has been used to aid in reversal of coma in alcohol-intoxicated dogs. Given prompt and aggressive care, most dogs and cats will recover within 4-36 hours.

Propylene Glycol

Propylene glycol is the primary ingredient in some forms of automotive antifreezes and coolants, as well as many recreational vehicle antifreezes (be sure to check the label). Propylene glycol is also present in a variety of food, pharmaceutical, and cosmetic agents, generally at low concentrations (< than 12-15%). Propylene glycol in injectable medications or activated charcoal formulations may interfere with ethylene glycol test kits (i.e. result in false-positives, see ethylene glycol below). Products containing less than 20-30% propylene glycol should not pose an acute toxicity hazard to pets if ingested. Newer automotive antifreezes containing 50% or more propylene glycol (i.e. Prestone's Low Tox® and Sierra ®) are indeed "safer" than ethylene glycol-based antifreezes in that they will not cause the serious kidney damage that is seen with ethylene glycol toxicosis. However, it is important to remember that ingestion of propylene glycol-containing antifreezes may result in serious intoxication similar to that seen with other alcohols. A dog given propylene glycol at 10 ml/kg displayed no clinical signs; however the LD50 (experimental dose at which 50% of dogs died) in dogs is 22 ml/kg. Therefore, doses over 10 ml/kg of 100% propylene glycol should be considered potentially toxic and justify veterinary intervention.

Like methanol, propylene glycol is rapidly absorbed from the gastrointestinal tract. Decontamination must therefore be accomplished within 20-30 minutes of ingestion to be of benefit. Clinical signs can occur as early as 20 minutes following ingestion. Due to the risk of aspiration of vomitus, induction of vomiting is NOT recommended in animals that are already symptomatic. As with other alcohols, propylene glycol can cause severe intoxication, ataxia, inebriation, and metabolic acidosis (see methanol clinical signs above). Treatment recommendations are similar to those described for methanol toxicosis—fluids to promote excretion, treatment of CNS effects (seizures, coma) as needed, thermoregulation (hypothermia is a significant risk in comatose patients), and management of metabolic acidosis. As with methanol, the overall prognosis is generally good provided the animal receives prompt and appropriate veterinary care. Recovery usually occurs within 24-36 hours of ingestion.

Ethylene Glycol

Ethylene glycol is most commonly thought of as an automotive radiator antifreeze, but it is also present in high concentrations in many brake fluids and aircraft deicers. In addition, ethylene glycol is often used in condensers, heat exchangers, home solar units and portable basketball goal post bases. Ethylene glycol may also be used to winterize toilets in recreational vehicles and summer homes in colder climates. Ethylene glycol is commonly present as a component in household paints, but it is rarely present in concentrations above 10% and significant ethylene glycol exposure is unlikely unless very large quantities of paint are ingested. Inks, ink pad, polishes, finger moistening compounds (e.g. Tacky Finger®), and other stationery supplies may contain ethylene glycol. Some ink pens contain relatively high levels of ethylene glycol, but the total volume of ink is only a few milliliters, so ink pens would only pose an ethylene glycol risk to very small animals such as birds, pocket pets, or dogs/cats less than 2-3 pounds.

Unfortunately, reliable toxic doses of ethylene glycol have not been established for most animals, including dogs and cats. Much of the acute toxicity data available is based on doses that cause early deaths from acidosis and inebriation and do not take into account the fact that many animals may survive the initial stages of toxicosis only to succumb to kidney failure days later. Because of this, any suspected oral exposure of an animal to radiator antifreeze should be considered a potential toxicosis, and steps should be taken, through historical and diagnostic information, to attempt to determine the extent of the exposure. When doubt still exists, the only prudent recourse is to treat as if the ingestion was potentially toxic.

It is important to remember that ethylene glycol is a very potent alcohol; for that reason, many of the signs of ethylene glycol toxicosis will relate to severe alcohol intoxication. In addition, ethylene glycol is broken down to metabolites (e.g. oxalic acid) that cause damage to the kidney tubules, resulting in renal failure. Because of the different mechanisms involved in ethylene glycol toxicosis, clinical signs frequently change throughout the course of the toxicosis. The clinical signs can be broken down into 3 different stages, although considerable overlap between these stages may be seen and some animals will not experience each stage. Death can occur at any stage. The stages are 1) neurologic, the initial inebriation due to the effects of alcohol on the CNS, 2) cardiopulmonary, due to severe acidosis and electrolyte disturbances, and 3) renal, due to renal tubular injury from calcium oxalate crystals.

Stage 1: Neurologic. Generally begins within 30 minutes of exposure and lasts up to 12 hours. In mild to moderate cases, this stage may pass quickly and may not be noted by the pet owner or veterinary staff. Animals are initially ataxic, disoriented, "drunk," stuporous, hypothermic (especially cats), polyuric, and polydipsic (PD/PU more pronounced in dogs). Coma and death may occur during this stage, or the animal may appear to partially or fully recover over 3-6 hours. By 6-12 hours, the neurologic status of the animal may again deteriorate due to development of severe metabolic acidosis from ethylene glycol metabolites. You may see marked CNS depression, stupor or coma and seizures are possible.

Stage 2: Cardiopulmonary. This stage generally occurs 12 to 24 hours following exposure. Signs may be more recognizable in dogs than cats. Tachypnea, tachycardia, depression, +/- seizures, and pulmonary edema may occur. At this time, a high anion gap and severe metabolic acidosis are generally present.

Stage 3: Oliguric renal failure. This stage can be seen as early as 12 hours, especially in cats, but generally within 24-72 hours following exposure. Clinical signs may include azotemia, depression, anorexia, vomiting, abdominal pain, oral ulcers, and oliguria progressing to anuria. Laboratory findings may include low urine specific gravity, glucosuria and calcium oxalate crystals may be visualized in the urine (absence of crystalluria does NOT rule out the possibility of EG toxicosis). Seizures are possible.

Clinical pathologic abnormalities include increased osmolal gap and anion gap, hyperglycemia, hyperkalemia, decreased blood pH, and hypocalcemia. BUN and creatinine become elevated but usually not before 12 hours post exposure; therefore BUN and creatinine are of minimal benefit in diagnosing early exposures.

Diagnosis is based on history, clinical signs, and confirmatory laboratory testing. There are two in-house ethylene glycol tests presently on the market. Both tests have benefits and disadvantages which will be discussed below. The PRN ethylene glycol test is no longer sold. PRN now sells the PRN REACT Test kit. Cats are much more sensitive to ethylene glycol toxicosis than dogs. The level requiring treatment in cats is > 20 mg/dL while the level for treatment in dogs is > 50 mg/dL. The PRN test is appropriate to use in both dogs and cats but it has to be read at 60 seconds in the cat. False positives occur from propylene glycol, glycerol, sorbitol, mannitol and isopropyl alcohol (which is frequently used to wet the hair when drawing blood) and hemolyzed serum samples. The use of 4-MP (fomepizole) can lead to a false negative therefore, unlike the previous PRN ethylene glycol test, this test cannot be used to judge when treatment with fomepizole can be concluded. The manufacturer PRN has been responsive to APCC suggestions for improvement of this new test and have indicated an improved test will be released soon.

Another ethylene glycol test, produced by Kacey, Inc. uses a test strip onto which a drop of plasma is deposited and a color change indicates whether the sample contains ethylene glycol. Advantages to this test include ease of use, short time to finish (8 minutes), and separate indicator pads for cats (measuring > 20 mg/dL) and dogs (measuring >50 mg/dL). Disadvantages of the test as it currently exists include it gives a false positive with any alcohol (glycerol, sorbitol, mannitol, formaldehyde, methanol, ethanol, etc) and since the color change involves green dyes, people with red-green color blindness might not be able to distinguish color changes.

Other means of diagnosing ethylene glycol exposure in pets include having levels run at a human hospital on a STAT basis. Many human hospitals are willing to do this, although sometimes it takes talking to the laboratory technician rather than a receptionist. Levels of 50 mg/dl (or 5 μg/ml, be sure to check the units reported) or greater in dogs would be considered significant. In cats, any level above zero should be considered significant. Measuring anion gap (>25 mEq/L) or serum osmolality (> 20 mOsm/kg) may assist in diagnosing ethylene glycol toxicosis. Observation, via Wood's lamp, of fluorescence in urine, stomach contents or on paws/muzzle may suggest exposure (fluorescein dye is added to automotive antifreeze to help in detecting radiator leaks).

Treatment of ethylene glycol toxicosis must be timely and aggressive. Failure to institute appropriate therapy within the first several hours may result in irreversible renal damage or death of the animal. For recent (within 45 minutes) exposures and asymptomatic animals, induce vomiting or perform gastric lavage; because food in the stomach may slow absorption, emesis or lavage may be of benefit up to 1 hour in animals that have recently eaten. The use of activated charcoal is not likely to be useful since aliphatic alcohols are not well adsorbed by charcoal. Additionally, activated charcoal products can interfere with in-house tests and the animals may have significant CNS depression and nausea putting them at risk for aspiration. Based on exposure history and/or diagnostic test results, the use of either fomepizole or ethanol infusion (see below) may be indicated.

Symptomatic animals should be stabilized as needed. Seizures can be controlled with diazepam or barbiturates, but care must be taken to minimize any further CNS depression. Intravenous fluids are the cornerstone of treatment, especially in symptomatic animals. High infusion rates of crystalloids are necessary to correct dehydration and hypoperfusion; fluid ins and outs should be monitored to avoid fluid overload and possibly pulmonary edema. Treatment of acidosis and renal failure may be required. Oliguric or anuric animals may require peritoneal dialysis.

Intravenous ethanol and, more recently fomepizole (4-MP, 4-methylpyrazole, Antizol-Vet™), have been used successfully in the management of ethylene glycol toxicosis in animals and man. The primary goal of using these compounds is to delay the breakdown of ethylene glycol to its more toxic metabolites, allowing the parent compound to be excreted in the urine unchanged. Best results with either of these treatments require initiation of treatment as soon as possible following ingestion, preferably within the first 6-8 hours for dogs and first 3 hours for cats.

Ethanol has the advantages of being inexpensive and readily available, but it has some serious drawbacks, including worsening of metabolic acidosis and CNS depression, making evaluation of the degree of ethylene glycol toxicosis difficult. Additionally, ethanol treatments are time-intensive and require constant patient monitoring because of the severe side effects. Ethanol can be used in both cats and dogs. The preferred treatment regime is to administer 8.6 ml/kg (600 mg/kg) of a 7% (70 mg/ml) ethanol solution and then maintain at 1.43 ml/kg/hr (100 mg/kg/hour), up to 200 mg/kg/hr as a constant rate infusion. The animal must be constantly monitored and the dosage adjusted to prevent severe respiratory depression and acidosis. The other method of ethylene glycol treatment would be to make a 20% ethanol solution. Dogs are given 5.5 ml/kg every 4 hours for 5 treatments then every 6 hours for 4 treatments. Cats are given 5.0 ml/kg every 6 hours for 5 treatments, then every 8 hours for 4 treatments.

Fomepizole will not cause hyperosmolality or metabolic acidosis. In contrast to ethanol, which is administered every 4 hours or as a constant-rate infusion, fomepizole is administered every 12 hours for 36 hours. The initial dosage in dogs is 20 mg/kg (slow IV over 15-30 minutes), then 15mg/kg (slow IV) at 12 and 24 hours, and then 5mg/kg is given at 36 hours. Fomepizole is not expected to cause sedation in dogs. The main drawbacks with fomepizole are the cost of the medication and the fact that fomepizole is only useful in cats if given within 3 hours of exposure. In cats, the dosage is 125 mg/kg initially, followed by 31.25 mg/kg at 12, 24 and 36 hours. Sedation is expected with this protocol in cats but it is expected to produce better results than ethanol treatment in cats. In one study, fomepizole used within first 3 hrs of administration of a lethal ethylene glycol dose resulted in a 75% recovery rate (versus a 25% recovery rate with ethanol). At 4 hrs post ethylene glycol dosing, there was 100% mortality with fomepizole and ethanol.

Treatment should be continued until the patient is clinically normal and has had at least 24 hours with normal renal function and acid base parameters. The prognosis for recovery depends on degree of exposure, length of time between exposure and treatment, and aggressiveness of treatment. Surviving animals may fully recover or may have residual renal insufficiency requiring lifetime maintenance. The presence of oliguria/anuria indicates a grave prognosis.