Toxicology
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Definition
Poisoning with agents containing ethylene glycol (EG) (antifreeze; aircraft de-icer;
solvents; hydraulic brake fluids; windshield washer fluids; agents in condensers, heat exchangers, and home solar units).1,2 EG is also used in portable basketball goal post bases and toilets of recreational vehicles/ homes in colder climes.

Systems. Gastrointestinal tract, CNS, cardiopulmonary, and renal. Vomiting usually within the first few hours; CNS depression, ataxia, weakness, tachypnea, polyuria/polydipsia occur within 1 to 6 hours. By 18 to 36 hours, acute renal failure develops.3,5

Relative Species Sensitivity
Most Sensitive: cat, rabbit, human
Moderately Sensitive: dog, cattle, pig, rodent
Least Sensitive: fish, poultry

Toxic Doses. Toxic dose has not been established. Lethal dose of undiluted antifreeze (95-97%) by volume is 4.4 to 6.6 ml/kg (dogs) and 1.4 ml/kg (cats).2,5 Most acute toxicity data based on doses causing early death (acidosis/intoxication) do not account for animals surviving initial stages that later succumb to kidney failure. Thus, any suspected exposure should be considered potential toxicosis, with steps to determine extent. When in doubt, treat as toxic.

SIGNS
History.

  • Exposure/possible exposure
  • Roaming or unsupervised animal
  • Evidence of exposure (radiator leaks, chewed container)
  • Vomiting, lethargy, ataxia
  • Fluorescence under Wood's lamp of urine, stomach contents, paws/muzzle

Physical Examination. Clinical signs categorized into 3 stages: neurologic (initial inebriation from alcohol), cardiopulmonary (severe acidosis/electrolyte disturbances), renal (direct injury from toxic metabolites created by breakdown of EG and from tubular injury from calcium oxalate crystals).1-4,6 However, may be asymptomatic; clinical signs often change during course; and stages can overlap, be skipped, or go unobserved. Death can occur at any stage.

Calcium oxalate crystals, shown above, can be produced as ethylene glycol is metabolized.

Stage 1-Neurologic.Typically begins ≤ 30 minutes, lasting to 12 hours.1-4,6 Vomiting common, most likely because EG irritates gastric mucosa.2,3 Initial ataxia, disorientation, stupor, polyuria/polydipsia.3,4,6 These are early indicators of possible poisoning, important because early intervention is more likely to save an animal. Coma and death possible, or animal may appear to partially/fully recover. By 6 to 12 hours,
neurologic status may worsen due to severe metabolic acidosis.3,4,6 Isosthenuria in dogs by 3 hours from osmotic diuresis/serum hyperosmolality-induced polydipsia.2,3

Stage 2-Cardiopulmonary. Generally from 12 to 24 hours. Tachypnea, tachycardia, CNS depression, seizures, pulmonary edema may occur.1-4,6 High anion gap and severe metabolic acidosis typical.3,4,6 Most deaths in humans reported at this stage.1

Stage 3-Oliguric renal failure. As early as 12 hours, especially in cats, but generally within 24 to 72 hours.2,3,5,6 Azotemia, depression, anorexia, vomiting, abdominal pain, and oliguria progressing to anuria.1,3 Low urine specific gravity and glucosuria ­with calcium oxalate crystals possible.3,4 Clinical pathologic abnormalities include increased osmolar gap/anion gap, hyperglycemia, hyperkalemia, decreased blood pH, hypocalcemia.1,3 BUN and creatinine generally do not increase until ≥ 12 hours after exposure; thus, testing has little benefit.

KINETICS AND METABOLISM
EG is rapidly absorbed, although food in stomach may slow absorption.1,3 Clinical signs may occur as early as 30 minutes; peak blood concentrations in dogs 1 to 4 hours after ingestion.6 Plasma half-life is 3 to 5 hours; therapeutic ethanol or fomepizole may increase half-time to 12 to 72 hours.1,3 Primarily eliminated through kidneys; about 50% excreted unchanged.3,4

Metabolism occurs primarily in liver, forming toxic acidic metabolites (see EG Metabol ism).1,2,5,6 Oxalic acid is directly cytotoxic to the renal tubular epithelium and induces hypocalcemia by binding to serum calcium to form calcium oxalate crystals.1-3,6 Crystals precipitate in renal tubules, causing mechanical injury and possibly obstructive uropathy.2

Diagnosis

Differentials. See algorithm on page 18 for ataxia, an early, sentinel sign of EG toxicity. Diagnostic differentials for EG toxicity can be found in standard reference texts.

Causes of Increased Anion Gap.
• Decreasing unmeasured cations (hypocalcemia, hypomagnesemia, hypokalemia)7
• Increasing unmeasured anions (ketoacids, lactate, phosphates, sulfates, salicylates, methanol, albumin)7
• Most common cause (dogs and cats) is metabolic acidosis due to lactic acidosis, renal failure, or ketoacidosis7

Ruleouts for acute renal failure.

  • Acute decompensation of chronic renal failure
  • Cholecalciferol/vitamin D3 derivatives, hypervitaminosis D, hypercalcemia
  • Glomerulonephritis
  • Grapes or raisins
  • Heavy metal intoxication (lead, mercury, cadmium, arsenic, zinc)
  • Heatstroke
  • Hemoglobinuria, myoglobinuria
  • Hypoadrenocorticism
  • Hypovolemia
  • Leptospirosis
  • Nephrotoxic antibiotics
  • NSAID overdose
  • Oxalic acid ingestion
  • Plant ingestion (Lilium species, Hemerocallis species [in cats only], rhubarb leaves, and Oxalis species)
  • Septic shock
  • Crotalid snake bite
  • Urinary obstruction

Ruleouts for metabolic acidosis

  • Acute renal failure
  • Aspirin or NSAID overdose
  • Diabetes mellitus
  • Ethanol, methanol, other short-chain alcohols
  • Metaldehyde toxicosis

BLOOD AND URINE ANALYSIS
Early diagnosis/treatment essential. Diagnosis based on history, clinical signs, laboratory testing. Peak EG levels reached ≤ 1 to 4 hours, but tests can be done from 0.5 to 12 hours.3 One kit is available for veterinary use (EGT Kit-PRN Pharmacal). Labeled for dogs with levels > 50 mg/dl, this kit can be invaluable in determining if treatment is warranted.3,4 False-positive results can occur (presence of propylene glycol in some activated charcoal solutions and injection solutions such as pentobarbital and diazepam, other glycols, or formaldehyde in the circulation).3,4,6 Blood should be taken before administering any such solutions/ agents. Products causing false positives are metaldehyde, glycerin/glycerol, or diethylene glycol. Other alcohols (e.g., ethanol, methanol, or isopropanol) do not interfere.3

Cats are more sensitive to EG than dogs, and kit may not diagnose toxicosis. Positive results are significant, but negative results do not rule out toxicosis. Some human laboratories run quantitative EG analysis. Any detectable EG warrants treatment.

Other Diagnostic Procedures.

  • Measure anion gap (>25 mEq/L) or serum osmolality (> 20 mOsm/kg).2-4,6
  • Crystalluria (not conclusive)2
  • Calcium oxalate crystals in urine can be seen 6 hours after ingestion; may be octahedral (envelope-like), prismatic (spindles, hippurate-like), or dumbbell shaped.1
  • Examine urine under Wood's lamp; will show fluorescein dye up to 6 hours.3

Diagnosing Toxicosis.

  • Increased osmolar gap (>20 mOsm/kg)
  • Decreased blood pH
  • Increased anionic gap (>25mEq/L)
  • Toxin in serum or urine
  • Hypocalcemia
  • Early-phase ataxia (1-3 hours)
  • Calcium oxalate crystalluria
  • Fluorescence of urine or vomitus on Wood's lamp

Postmortem Findings.
Renal: Proximal tubular degeneration/ necrosis, calcium oxalate deposition; calcium oxalate crystals in intestinal mucosa, liver, heart, brain3,4
CNS: Cerebral edema, multifocal hemorrhage, inflammatory cell infiltration3,4

Treatment

Must be timely and aggressive. Failure to initiate in first several hours may result in irreversible renal damage/death. Goals are to stabilize, prevent absorption, interfere with toxin metabolism, provide
supportive care.

Induction of emesis helpful only < 1 hour. Feeding dry bread before emesis may increase success. Emesis contraindicated with hyperactivity, tremor, seizures: consider gastric lavage.8 Effective emetic is 1 teaspoon 3% hydrogen peroxide per 5 lb, not to exceed 3 tablespoons.8 Usually occurs in minutes; dose can be repeated once if initially unsuccessful. Another option is apomorphine hydrochloride, administered topically to eye or parenterally at 0.03 mg/kg IV or 0.04 mg/kg IM in dogs; 0.04 mg/kg IV or 0.08 mg IM or SC in cats.8 CNS/respiratory depression, ataxia, excitement, protracted vomiting can occur, especially after IV administration.8

Activated charcoal can be given (1-3 g/kg, 1-3 hours after ingestion). Effectiveness is controversial-aliphatic alcohols may not be well adsorbed by charcoal.1,3 Take samples for EG analysis before activated charcoal to prevent false positives resulting from detection of glycols in these compounds.

Altering Kinetics. IV fomepizole and ethanol have been successful. Compounds aim to delay/prevent breakdown of toxin to more toxic metabolites, allowing excretion of unchanged parent compound in urine.

Fomepizole inhibits alcohol dehydrogenase; considered preferred treatment for dogs3,4,16 but may not be effective in cats.3,5,9,10 Unlike ethanol, does not cause hyperosmolality, metabolic acidosis, CNS depression 3,9,11,16 Administer every 12 hours for 36 hours. Dosing is 20 mg/kg slow IV over 15 to 30 minutes, then 15 mg/kg slow IV at 12 and 24 hours, then 5 mg/kg at 36 hours.3,9,10

Ethanol competes with EG as substrate for alcohol dehydrogenase; can be used in dogs and cats.3,4,6,10 Inexpensive and readily available; has serious drawbacks (worsening of metabolic acidosis and CNS depression), making evaluation of degree of toxicosis difficult.11,13 Ethanol treatments are time-intensive and require constant monitoring. Ideally, administer 8.6 ml/kg 7% ethanol solution bolus, maintain at 100 mg/kg/hr up to 200 mg/kg/hr constant-rate infusion.10 Or, make a 20% ethanol solution (dogs: 5.5 ml/kg IV every 4 hours for 5 treatments, then every 6 hours for 4 treatments; cats: 5.0 ml/kg IV every 6 hours for 5 treatments, then every 8 hours for 4 treatments.)4,5,10

For dogs, a negative EG test means treatment with fomepizole or ethanol may be discontinued; however, fluid therapy and supportive care should continue until animal fully recovers.

Supportive Care. Preventing further kidney damage/maintaining fluid, electrolyte, acid- base balance are crucial. Fluid therapy is foundation of acute renal failure treatment, comprising fluid diuresis with isotonic alkalinizing crystalloid solution (e.g. lactated Ringer's) twice maintenance rate.10,12 Goals are to correct fluid and electrolyte imbalances, improve renal blood flow, initiate diuresis. Monitor patient to avoid volume overload and possible pulmonary edema. Oliguria necessitates attempts to increase urine output (furosemide, 1 mg/kg/hr for 4 hours then 3 to 8 µg/kg/min to maintain urine flow).10 Dopamine may increase urine output (dogs); administer at 2 to 3 µg/kg/ min.11 Consider peritoneal dialysis in oliguric/anuric animals. Sodium bicarbonate can be used for acidosis (i.e., blood pH

< 7.10 to 7.15 or total CO2 < 10-12 mEq/L).3,5,10,11 Continue treatment until animal is clinically normal, with at least 24 hours' normal renal function, acid-base parameters.

Precautions.
Overhydration: Electrolyte imbalances, volume overload, possibly pulmonary edema
Overuse of sodium bicarbonate: Ionized calcium deficits, CSF acidosis, cerebral edema
Ethanol: Worsening of metabolic acidosis, CNS depression

Alternative Therapy
High doses of fomepizole may be safe and effective in cats if therapy is initiated < 3 hours after ingestion; > 4 hours, mortality rate is 100%.17 Initiating alcohol therapy at home in cases of time delay in obtaining veterinary help has been reported.10 In these cases, 2.25 ml/kg PO 40% alcohol (e.g., vodka, rum) can be administered orally.10

Hemodialysis considered superior to peritoneal dialysis in eliminating EG/metabolites in humans but limited availability in veterinary medicine.1 Pyridoxine and thiamine-cofactors for EG metabolism-recommended in human literature adjunctively.2,4

Relative Cost of Treatment*

Uncomplicated (mild or no clinical signs, no evidence of renal injury): $$-$$Includes physical examination, decontamination, EG test; baseline clinical laboratory values, ethanol or fomepizole therapy (comparable cost, $-$$, with added nursing/ acid-base monitoring and correction and hospitalization for ethanol treatment), additional serum chemistry values through treatment, and final EG test.

Complicated (severe clinical signs, acidosis +/- renal injury): $$-$$$
Includes physical examination, EG test, correction of emergent signs (e.g. seizures, acidosis), IV fluid administration, baseline clinical laboratory values, ethanol or fomepizole therapy (comparable cost, $-$$ with added nursing/acid-base monitoring and correction with ethanol treatment), additional serum chemistry values through treatment, hospitalization, treatment of acute renal failure ($-$$$), and final EG test.

Follow-Up

Patient Monitoring.

  • BUN
  • Acid-base balance
  • Creatinine
  • Urine specific gravity
  • Calcium
  • Urine production

Prognosis and Course. Depends on degree of exposure, time before treatment, aggressiveness of treatment. Good if therapy starts < 8 hours and no azotemia.4 Feline mortality rates may be as high as 97%; canine rates, 59% to 70%.3,4 Oliguria/anuria indicates grave prognosis. Animals may fully recover or have residual renal insufficiency requiring lifetime maintenance.

Advice for Owners. The veterinary community can help spread the word about antifreeze safety. Motorists can help prevent accidental EG ingestion. Among considerations are using antifreeze that contains propylene glycol, which is less toxic than EG.

Future Considerations
Researchers at Colorado State University are investigating use of fomepizole in EG-exposed cats.

EG Metabolism
1. EG oxidation to glycoaldehyde via alcohol dehydrogenase.
2. Glycoaldehyde oxidation to glycolic acid via mitochondrial aldehyde dehydrogenase.
3. Glycolic acid oxidation to glyoxylic acid, the most toxic metabolite. Short half-life of glycoxylic acid prevents accumlation of toxic concentrations.1
4. Glyoxylic acid oxidation through several pathways to produce oxalic acid, glycine, formic acid, hippurate, benzoic acid, and other compounds.
5. Oxalic acid binds to serum calcium and forms calcium oxalate crystals.

TX... at a glance

Time of Exposure

  • < 1 hour: Induce emesis
  • 1-3 hours: 1-3 g/kg activated charcoal

Then

  • Dogs: fomepizole-20 mg/kg slow IV over 15-30 mins every 12 hrs for 36 hrs; then 15 mg/kg slow IV at 12 and 24 hrs; then 5 mg/kg at 36 hrs. Tx of choice

OR

  • Cats or dogs: ethanol-8.6 ml/kg 7% ethanol solution bolus, maintain at 100 mg/kg/hr up to 200 mg/kg/hr constant-rate infusion

OR

  • 20% ethanol solution (homemade)
    • Dogs: 5.5 ml/kg IV every 4 hrs, 5X; then every 6 hrs, 4X
    • Cats: 5.0 ml/kg IV every 6 hrs, 5X; then every 8 hrs, 4X

PLUS

  • Fluid therapy (diuresis with isotonic alkalinizing crystalloid, e.g., lactated Ringer's), twice maintenance rate

ETHYLENE GLYCOL TOXICOSIS IN DOGS & CATS • Jill Richardson/ Sharon Gwaltney-Brant

References

1. Ethylene glycol (toxicologic management). Toll LL, Hurlbut KM, Poisindex editorial staff: in Rumack BH (ed): Micromedex Healthcare Series, Vol. 114. Englewood, CO, Micromedex.
2. Ethylene glycol, methanol, and isopropyl alcohol. Schiavone FM, Cantor FD, Brogan GX: in Viccellio P (ed): Emergency Toxicology, 2nd ed. Philadelphia, Lippincott-Raven, 1998, pp 269-286.
3. Ethylene glycol. Thrall MA, Grauer GF, Connally HE, Hamar D: in Peterson ME, Talcott PA (eds): Small Animal Toxicology. Philadelphia, WB Saunders, 2001, pp 484-504.
4. Ethylene glycol toxicity. Webb CB: in Wingfield WE, Raffe MR (eds): The Veterinary ICU Book. Jackson Hole, WY: Teton New Media, 2002, pp 1042-1048.
5. Household and metal toxicants. Osweiler GD, Carson TL: in Morgan RV (ed): Handbook of Small Animal Practice, 3rd ed. Philadelphia: WB Saunders, 1997, pp 1271-1278.
6. Ethylene glycol exposures managed by the ASPCA National Animal Poison Control Center from July 1995 to December 1997. Khan SA, Schell MM, Trammel HL, Hansen SR, Knight MW: Vet Hum Toxicol 41:403-406, 1999.
7. Electrolyte and acid-base abnormalities. Willard MD: Small Animal Clinical Diagnosis by Laboratory Methods. Philadelphia, WB Saunders, 1992, pp 103-120.
8. Decontamination strategies. Rosendale ME: in Poppenga RH, Volmer PA (eds): Vet Clin North Am Small Animal Pract: Toxicology 32:311-321, 2001.
9. Newer antidotal therapies. Gwaltney-Brant SM, Rumbeiha WK: in Poppenga RH, Volmer PA (eds): Vet Clin North Am Small Animal Pract: Toxicology 32:322-339, 2001.
10. Veterinary Emergency and Critical Care Manual. Mathews KA (ed). Guelph: Lifelearn Inc, 1996, pp 36-1-36-5.
11. Acute renal failure: Ischemic and chemical nephrosis. Grauer GF, Lane IF: in Osborne CA, Finco DR (eds): Canine and Feline Nephrology and Urology. Baltimore, Williams & Wilkins, 1995, pp 441-459.
12. Fomepizole. Gaddy J: Compend Contin Educ Pract Vet 23:1073-1074, 2001.
13. Inhibition of canine and feline alcohol dehydrogenase activity by fomepizole. Connally HE, Hamar DW, Thrall MA: Am J Vet Res 61:450-455, 2000.
14. Safety and efficacy of 4-methylpyrazole for treatment of suspected or confirmed ethylene glycol intoxication in dogs: 107 cases (1983-1995). Connally HE, Thrall MA, Forney SD, Grauer GF, Hamar DW: JAVMA 209:1880-1883, 1996.
15. Efficacy of 4-methylpyrazole for treatment of ethylene glycol intoxication in dogs. Dial SM, Thrall MA, Hamar DW: Am J Vet Res 55:1762-1770, 1994.
16. Comparison of the effects of ethanol and 4-methylpyrazole on the pharmacokinetics and toxicity of ethylene glycol in the dog. Grauer GF, Thrall MA, Henre BA, Hjelle JJ: Toxicol Lett 35:307-314, 1987.
17. Safety and efficacy of high dose fomepizole as therapy for ethylene glycol intoxication in cats [Abstract]. Connally, HE, Thrall MA, Hamar DW: Veterinary Emergency and Critical Care Symposium. San Antonio, Texas, 2003.

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