Ethylene Glycol Toxicity

10 Interesting Facts of Ethylene Glycol Toxicity 

  1. Ethylene glycol toxicity results from accumulation of toxic metabolites that form after ingestion of products containing ethylene glycol (eg, antifreeze, brake fluid, radiator coolant, deicing solution)
  2. Toxicity can manifest with altered mental status, increased osmolal gap, severe metabolic acidosis with increased anion gap, hypocalcemia, and calcium oxalate crystalluria
  3. Approximately 1 mL/kg or 100 mL of ethylene glycol in an adult is potentially lethal 1
  4. Early symptoms of ethylene glycol ingestion mimic ethanol intoxication with inebriation, euphoria, and gastric irritation (eg, nausea, vomiting)
  5. Ethylene glycol causes an increased osmolal gap early after ingestion; with time, as metabolites start to form, the osmolal gap disappears and anion gap increases 2
  6. Toxic metabolites are responsible for metabolic acidosis, central nervous system depression, coma, renal failure, cardiovascular collapse, and death
  7. Serum ethylene glycol concentration confirms diagnosis; however, results are not always readily available
    • Diagnosis relies on high index of suspicion and additional laboratory testing, such as:
      • Elevated osmolal gap early after ingestion serves as a surrogate marker for presence of ethylene glycol 3
      • Elevated anion gap metabolic acidosis later after ingestion serves as a surrogate marker for presence of toxic metabolites 3
      • Hypocalcemia and calcium oxalate crystals in urine may provide additional clues to suggest diagnosis
  8. Administration of antidote prevents toxic metabolite formation and development of renal failure
    • Fomepizole (4-methylpyrazole) is first line antidote; ethanol is second line treatment
    • Early administration of antidote can prevent need for hemodialysis
  9. Hemodialysis may be indicated; hemodialysis is effective in removing ethylene glycol and metabolites in critically ill patients or in cases of significant exposure
  10. Death is uncommon in patients who present early after ingestion and receive prompt diagnosis and treatment

Pitfalls

  • Failure to maintain a high level of suspicion for ethylene glycol ingestion in patients who appear intoxicated can delay diagnosis
  • When calculating serum osmolality, use correct units (mg/dL) for ethanol (ie, use 80 mg/dL instead of 0.08 g/dL) to avoid error in calculation
  • Do not rely on a single laboratory value (eg, osmolal gap, anion gap) to definitively exclude ethylene glycol ingestion; appearance of typical laboratory findings is dynamic; anion gap may be within reference range in early exposure, and osmolal gap may be within reference range in late exposure
  • Failure to recognize that an ethylene glycol metabolite, glycolate, commonly causes false elevation in lactate level that can lead to missed diagnosis; maintain high level of suspicion for ethylene glycol poisoning in any patient with increased anion gap metabolic acidosis despite presence of high measured lactate level
  • Failure to start alcohol dehydrogenase–blocking antidotal therapy immediately when ethylene glycol poisoning is suspected leads to harm from increased exposure to toxic metabolites
  • Avoid reliance on presence or absence of urinary fluorescence to assist in diagnosis; unacceptable rates of false-positive and false-negative results render this test an unreliable screening tool

Terminology

Clinical Clarification

  • Ethylene glycol toxicity results from accumulation of toxic metabolites that form after ingestion of products containing ethylene glycol (eg, antifreeze, brake fluid, radiator coolant, deicing solution) 4
  • Toxicity can manifest with altered mental status, increased osmolal gap, severe metabolic acidosis with increased anion gap, hypocalcemia, and calcium oxalate crystalluria 2

Classification

  • Classification based on severity of poisoning
    • Mild to moderate intoxication 5
      • Characterized by presentation similar to alcohol intoxication with inebriation without progression to severe manifestations of intoxication
    • Severe intoxication 1 5
      • Characterized by presence of the following clinical findings:
        • Obtundation
        • Coma
        • Seizures
        • Hemodynamic instability
        • Severe anion gap
        • Metabolic acidosis
        • Hypocalcemia
        • Renal failure
  • Classification based on clinical stages of poisoning 1 5
    • Stage 1: neurologic 1
      • Occurs 30 minutes to 12 hours after exposure 1
      • Hallmark of this phase is osmolal gap due to presence of ethylene glycol parent compound 6
      • Initial manifestations (eg, inebriation, vomiting) develop secondary to presence of ethylene glycol parent compound 2
      • Progressive central nervous system depression and coma develop as metabolism of ethylene glycol ensues 2
    • Stage 2: cardiopulmonary 1
      • Occurs 12 to 24 hours after exposure 1
      • Hallmark of this phase is development of metabolic acidosis secondary to toxic metabolite accumulation 2
      • Deposition of oxalate crystals (in heart, lungs, and vasculature) and direct effects of toxic metabolites result in acute tissue necrosis 5
      • Most deaths occur at this stage 2
    • Stage 3: renal 1
      • Occurs 24 to 72 hours after exposure 1
      • Progressive accumulation of calcium oxalate in kidneys and direct effects of toxic metabolites result in acute tubular necrosis and/or renal failure

Diagnosis

Clinical Presentation

History

  • Background
    • Diagnosis is challenging when accurate history is not obtainable owing to altered mental status, age, or poor cooperation 5
    • History of possible ingestion of ethylene glycol– or methanol-containing products 5
      • Majority of exposures are unintentional
        • Toxic alcohols may be inappropriately stored in unlabeled containers or beverage containers (eg, water bottles, soda bottles), leading to unintentional exposure
        • Ethylene glycol has a sweet taste that may lead to larger ingested volumes
        • Children who ingest more than a witnessed taste or lick are at risk for toxicity 7
        • Adults who ingest a swallow (10-30 mL) are at risk for toxicity 7
      • Intentional ingestions
        • Up to 13% of ethylene glycol exposures are intentional 8
          • People who attempt suicide
          • People with long-term excessive alcohol use
            • May substitute ethylene glycol for ethanol owing to availability or cost
      • Coingestion of ethanol
        • Delays development of toxic metabolites and symptoms related to toxic metabolite formation
  • Classic stages of clinical presentation
    • Represent a framework to describe possible progression of toxicity
      • Symptoms correlate with metabolism of ethylene glycol to toxic metabolites via action of alcohol dehydrogenase
    • Inconsistent and unpredictable onset and clinical course is common
      • Development, timing, and severity of each stage widely vary; significant overlap often occurs among stages
      • 1 stage may predominate while another stage may not develop
        • Rarely, patient presents with acute renal failure in the absence of other stigmata of toxicity 9
      • Symptom manifestations vary depending on timing of exposure, ingested dose, and coingestion of other substances
        • Many hours after ingestion, patients manifest coma, respiratory distress, and renal insufficiency
        • Coingestion of ethanol may result in delayed symptom manifestations (several hours of delay) 9
    • Stage 1: neurologic
      • Occurs 30 minutes to 12 hours after ingestion 2
      • Gastrointestinal symptoms are common in the first few hours 2
        • Secondary to irritation to gastrointestinal mucosa
        • Abdominal pain, nausea, and vomiting
      • Initial neurologic symptoms
        • Occur secondary to ethylene glycol parent compound
        • May mimic ethanol intoxication without odor of alcohol on the breath 5
          • Inebriation (eg, mild confusion, stupor)
          • Euphoria
          • Headache and dizziness
        • Absence of inebriation or intoxication does not exclude an ingestion 10
          • People who use alcohol may have a higher tolerance to the effects of ethylene glycol
      • Neurologic symptoms progressively worsen with severe poisoning
        • Occur secondary to toxic metabolite accumulation 2
          • Metabolic encephalopathy can occur owing to severe metabolic acidosis
          • Central nervous system edema can occur owing to deposition of oxalate crystals
        • Significant alteration in mental status 5
          • Agitation or combative behavior
          • Somnolence
          • Obtundation or stupor
          • Coma
        • Seizures and status epilepticus are common 2
  • Stage 2: cardiopulmonary 5
    • Occurs 12 to 24 hours after exposure 2
    • Respiratory symptoms
      • May range from hyperpnea and tachypnea to respiratory failure
    • Cardiovascular symptoms
      • May range from mild (eg, tachycardia) to heart failure (eg, dyspnea) and frank cardiovascular instability
    • Persistent central nervous system abnormalities
      • Obtundation and coma are often a result of cerebral edema, metabolic encephalopathy, and/or central nervous system hemorrhage 6
      • Seizures may occur
  • Stage 3: renal 5
    • Late manifestations occur 24 to 72 hours after ingestion 2
    • Oliguria or anuria
    • Flank pain
    • Gross hematuria
  • Delayed cranial nerve manifestations
    • Rare and may occur weeks after presentation
    • Cranial nerve (ll, V, Vll-X, Xll) dysfunction 5
      • Bilateral facial paralysis
      • Facial sensory loss
      • Deafness
      • Dysarthria
      • Diplopia
      • Dysphagia

Physical examination

  • Stage 1: neurologic 5
    • Mild manifestations may include:
      • Somnolence
      • Ataxia
      • Dysarthria
      • Nystagmus
    • Progressive signs with severe intoxication may include:
      • Obtundation and coma 2
      • Ophthalmoplegia
      • Myoclonus or tetany
      • Hypotonia
      • Hyporeflexia, areflexia, or hyperreflexia
      • Meningismus
      • Quadriplegia
      • Extensor plantar responses and decerebrate posturing
      • Brain death
  • Stage 2: cardiopulmonary
    • Respiratory findings 5
      • Tachypnea or hyperpnea are common early findings
        • Kussmaul respirations are a compensatory mechanism for developing metabolic acidosis
      • Findings consistent with pulmonary edema (eg, crackles, increased work of breathing) can occur
        • Often an early manifestation of acute respiratory distress syndrome
    • Cardiovascular findings
      • Tachycardia or bradycardia
      • Hypotension or hypertension
      • Circulatory collapse
    • Hypoxia can occur with severe toxicity
      • Can progress to acute respiratory distress syndrome, heart failure, multiorgan failure, and circulatory collapse
  • Stage 3: renal
    • Flank tenderness
  • Delayed cranial nerve deficits
    • Dysfunction can include cranial nerves ll, V, Vll to X, and Xll 5
    • Diplegia is most common
    • Absent corneal reflex

Causes and Risk Factors

Causes

  • Sources of exposure 5
    • Most exposures are attributable to automotive products
      • 2014 National Poison Data System reported 87% of ethylene glycol exposures as secondary to automotive products 8
        • Antifreeze
        • Brake fluid
        • Coolants
        • Hydraulic fluid
        • Car wash fluid
    • Other sources include:
      • Aircraft deicing fluids
      • Refrigerating fluids
      • Ink solvent
      • Stamp pads
      • Pesticides
  • Route of exposure
    • Significant toxicity is caused by ingestion of ethylene glycol–containing products
    • Inhalational exposure may cause mild mucosal irritation but no systemic toxicity 7
    • Dermal exposure is clinically insignificant 7
  • Toxic dose
    • Minimum toxic dose varies among individuals 1
    • 1 mL/kg or 100 mL of ethylene glycol in an adult is potentially lethal 1 2
      • This toxic dose is used as an overall guideline; death can occur after consumption of less than 1 mL/kg while survival can occur after consuming more than the presumed toxic dose 9
      • Ethylene glycol–containing products have variable amounts of ethylene glycol; therefore, all ethylene glycol ingestions are potentially toxic
        • A child’s typical mouthful or swallow (5-10 mL) is potentially toxic 7
        • An adult’s typical mouthful or swallow (10-30 mL) is potentially toxic 7
      • Material safety data sheet contains specific information on the ethylene glycol content, if the product is known
    • Coingestion of ethanol
      • Ethanol may be initially protective and delay the metabolism of ethylene glycol to toxic metabolites
  • Ethylene glycol pharmacokinetics
    • Rapidly absorbed from gastrointestinal tract; 80% is metabolized by liver; 20% of ethylene glycol parent compound is eliminated in urine 5 6
    • Peak concentrations occur 1 to 4 hours after ingestion; half-life is 3 to 8 hours without treatment 5
      • Half-life is markedly prolonged (17-18 hours) with alcohol dehydrogenase competitor such as ethanol 6
    • Alcohol dehydrogenase oxidizes ethylene glycol to several toxic metabolites (eg, glycolic acid, oxalic acid)
    • Pyridoxine, thiamine, and magnesium are cofactors in metabolism 2
    • Accumulation of ethylene glycol metabolites, rather than parent compound, causes most significant toxicity 2
      • Profound metabolic acidosis, tissue deposition of calcium oxalate crystals, and cellular dysfunction may result in end-organ dysfunction (eg, neurologic, cardiovascular, pulmonary, renal)
    • Ethylene glycol parent compound alters extracellular osmolality, adding to potential toxic effects 2

Risk factors and/or associations

Age
  • Most exposures occur in adults
  • Children younger than 13 years account for up to 10% of all exposures 8
Other risk factors/associations
  • Risk factor for toxicity
    • Intentional ingestion is more dangerous than unintentional ingestion
      • Intentional ingestion is up to 37 times more likely to have moderate to severe toxicity compared with unintentional ingestions; amounts are usually higher 7

Diagnostic Procedures

  • Calcium oxalate monohydrate crystals.From Jammalamadaka D et al: Ethylene glycol, methanol and isopropyl alcohol intoxication. Am J Med Sci. 339(3):276-81, 2010, Figure 2.
  • Calcium oxalate dihydrate crystals.From Jammalamadaka D et al: Ethylene glycol, methanol and isopropyl alcohol intoxication. Am J Med Sci. 339(3):276-81, 2010, Figure 3.

Primary diagnostic tools

  • Suspect diagnosis based on clinical presentation; there is heightened concern for ingestion in the following scenarios:
    • Any exposure to ethylene glycol–containing products
      • Absence of symptoms shortly after ingestion does not exclude potentially toxic dose 7
    • Signs of alcohol intoxication without smell of ethanol or corroborating serum ethanol concentration
  • Diagnosis is typically based on a high index of suspicion with proper interpretation of adjunct laboratory diagnostics
    • Common early finding is an increased osmolal gap due to ethylene glycol parent compound
    • Hallmark of toxic metabolite formation is increased anion gap metabolic acidosis 3
    • Crystalluria and hypocalcemia commonly develop with time; renal failure may result
  • Serum ethylene glycol concentration confirms diagnosis; however, clinical utility of test is low because of time required for sending specimens out to reference laboratory for testing 10
    • Do not wait for confirmatory results to start treatment when indicated in patients with suspected poisoning
  • Obtain the following laboratory tests when ethylene glycol poisoning is suspected: 5
    • Electrolyte levels with anion gap calculation
    • Serum calcium and magnesium levels 1
    • Renal function test (BUN and creatinine levels)
    • Serum osmolality
    • Serum ethanol and glucose levels; use to calculate serum osmolality
    • Urinalysis with microscopy to assess for crystalluria or hematuria
    • Arterial or venous blood gas levels
    • Ethylene glycol concentration when readily available
  • Obtain other routine tests indicated during the evaluation of a potential poisoning victim, especially with intentional ingestion, to evaluate for any coingestion that may require concomitant treatment or conditions that may require treatment modification
    • Serum acetaminophen concentration
    • ECG to assess for conduction delays requiring immediate intervention
    • Glucose level in patients with mental status depression
    • Urine/serum hCG level in women of childbearing age
    • Head CT with any significant alteration in sensorium, prolonged or focal seizures, signs of increased intracranial pressure, or focal neurologic deficit 5

Laboratory

  • Serum osmolality with calculated osmolal gap
    • Measured serum osmolality by freezing point depression 9
      • Measures the total molal concentration of all osmotically active solutes in plasma 5
      • General reference range for serum osmolality is 285 to 290 mOsm/L 9
      • Abnormally high measured serum osmolality not explained by increased urea, increased glucose, increased sodium, or ethanol indicates the accumulation of low-molecular-weight osmotically active substances in the plasma 9
      • Measured osmolality is often highest in the first several hours after ingestion 9
    • Calculated osmolality = (2 × Na⁺) + (BUN/2.8) + (glucose/18) + (ethanol/4.6) 11
      • Calculation takes into account that azotemia, hyperglycemia, hypernatremia, and ethanol are common causes for hyperosmolality
      • Of note, units for ethanol are mg/dL (use 80 mg/dL instead of 0.08 g/dL); units for BUN and glucose are mg/dL; and units for Na⁺ are mEq/L 12 13
      • Calculators are available online 13
    • Osmolal gap = measured serum osmolality − calculated osmolality
      • Screening test for presence of unmeasured, osmotically active substances in serum 5
      • Reference range for osmolal gap can vary, but generally, values more than 10 mOsm/L are considered elevated 11
      • Normal osmolal gap does not exclude ethylene glycol toxicity
        • Ethylene glycol is the unmeasured solute causing elevation of the osmolal gap
        • Osmolal gap will normalize with time as ethylene glycol is metabolized; metabolites do not contribute to an osmolal gap
      • Additional causes of an elevated osmolal gap can include methanol, isopropanol, propylene glycol, glycerol, mannitol, acetone, sorbitol, ketoacidosis, and unknown osmotically active solutes in critical illness (eg, multiorgan failure, renal failure, circulatory shock) 3 14
        • Of note, isopropanol does not cause acidosis; mannitol, sorbitol, and propylene glycol rarely cause acidosis
  • Serum electrolyte levels with calculated anion gap
    • Metabolic acidosis (with bicarbonate level less than 22 mEq/L) with increased anion gap develops over time after a toxic exposure 9
      • Glycolate is the primary metabolite responsible for development of acidosis and anion gap 5 6
      • Acidosis is often severe and increase in anion gap is often strikingly high when toxic metabolites begin to accumulate 5
        • Coingestion of ethanol delays development of anion gap 6
        • Low bicarbonate levels (increasingly severe metabolic acidosis) are associated with increase in mortality 9
      • Anion gap = (Na⁺) − (Cl⁻ + HCO₃⁻) 12
        • Reference range for anion gap is 6 to 17 mEq/L 12
        • Excess anion gap approximates glycolic acid concentration 5
        • Normal anion gap does not exclude exposure, particularly early in course of poisoning, with ethanol coingestion, and with low ingested ethylene glycol dose 3
        • Increased anion gap with normal pH after administration of sodium bicarbonate may indicate continued circulating toxic metabolites 5
        • Anion gap greater than 20 mEq/L is predictive of renal failure in a patient with ethylene glycol poisoning (without any intervention) 15
        • Some other causes for an increased anion gap metabolic acidosis include uremia, lactic acidosis, diabetic or alcoholic ketoacidosis, inborn errors of metabolism, toxic alcohols (eg, methanol, propylene glycol, diethylene glycol), and salicylate intoxication 16
    • Hypocalcemia 1
      • Common in serious toxicity and most profound many hours after ingestion 3 9
      • May result from calcium oxalate formation
    • Hyperkalemia
      • Can result from renal failure 6
  • Arterial or venous blood gas levels
    • Metabolic acidosis (pH less than 7.35 and bicarbonate level less than 22 mEq/L) develops in up to 86% with toxicity 9
      • Acidosis is typically a direct result of toxic metabolites, particularly of glycolate
      • Acidosis may lead to increased central nervous system penetration of toxic metabolites 5
      • High risk of mortality and acute renal failure is associated with bicarbonate level of 5 mEq/L or lower, blood pH less than 7.1, or serum glycolate 8 to 10 mmol/L or higher 9
      • Metabolic acidosis unresponsive to standard treatment is an indication for hemodialysis
  • Urinalysis with microscopy
    • Calcium oxalate crystals
      • Finding supports the diagnosis given the appropriate clinical context 5
      • Calcium oxalate crystals may be present in the urine approximately 4 to 8 hours after ingestion 9
      • Crystalluria is noted in over half of cases (up to 63%) with ingestion; 2 types are associated with intoxication 17
        • Calcium oxalate monohydrate crystals appear as prisms or dumbbells 2
        • Calcium oxalate dihydrate crystals are tentlike, or resemble envelopes or octahedra 2
          • Closely resemble hippurate crystals 3
      • Finding is nonspecific, and absence of crystals does not exclude the diagnosis
      • Crystalluria can persist for up to 40 hours in the absence of renal failure and up to 4 days if renal failure is present
Calcium oxalate monohydrateCalcium oxalate dihydrate
Mineral nameWhewelliteWeddellite
FormulaCaC₂O₄⋅H₂OCaC₂O₄⋅2H₂O
Crystal systemMonoclinicTetragonal
Thermodynamic stabilityStableMetastable
Crystal habitPleomorphic (any of the following)Monomorphic
– Needlelike shapes– Dipyramidal (octahedral)
– Elongated hexagons⋅ Tentlike shapes
– Cigarlike shapes⋅ Appear as square circumscribing an × (envelopelike shape) or cross pattée pattern
– Hempseed (orzolike) shapes⋅ Interpenetrant twinning may occur
– Biconcave ovoid shapes
– Short prisms
– Sheaf shapes
– Dumbbell shapes
Crystal aggregationNeedle-shaped crystals may orient with 1 end directed to a central point forming a spheroidal aggregateCrystals may be scattered or may appear in compactly interlocking aggregates
Crystal size¹ (μm)9 ± 1612 ± 8
BirefringenceStrongWeak
Prevalence in ethylene glycol poisoning²More commonLess common
Overall clinical prevalence³Less commonMore common
OtherNeedle, prism. and elongated hexagonal forms may be misidentified as hippuric acid crystalsGreater tendency to form at higher calcium oxalate concentrations; may spontaneously transform to the monohydrate form

Caption: ¹Crystal size (mean ± standard deviation) data from freshly voided urine specimens of 27 unselected outpatients with incidental oxalate crystalluria and no know urologic or toxicologic disorders. ²Relative prevalence from animal models and some clinical reports of ethylene glycol poisoning. ³Relative clinical prevalence of isolated crystalluria without stone formation, outside the context of ethylene glycol poisoning.

Citation: Data from Kruse JA: Ethanol, methanol, and ethylene glycol. In: Vincent JL et al, eds: Textbook of Critical Care. Philadelphia, PA: Elsevier; 2011:1270-81; Kruse JA: 

  • Other possible abnormal urinalysis findings include:
    • Microscopic hematuria 2 associated with early renal damage or acute tubular necrosis
    • Blood, protein, and casts in urine associated with significant renal damage
    • Myoglobinuria (ie, heme-positive urine without RBCs on microscopy) consistent with rhabdomyolysis 6

Imaging

  • Neuroimaging (CT or MRI)
    • Findings are usually normal despite significant central nervous system symptoms and physical findings 6
    • Used in acute setting to:
      • Exclude other causes of altered mental status
      • Assess for hemorrhage and cerebral edema
    • Several patterns of injury are seen with ethylene glycol toxicity
      • Diffuse cerebral edema
      • Intraparenchymal hemorrhage or petechiae
      • Localized hypodense areas involving the brain, brainstem, and cerebellum
  • Chest radiography
    • Obtain in patients experiencing respiratory symptoms associated with toxicity to assess for ethylene glycol–induced pulmonary edema 26

Functional testing

  • ECG
    • Hypocalcemia may cause QT interval prolongation predisposing to arrhythmia 2

Differential Diagnosis

Most common

  • Methanol toxicity
    • Results from ingestion of methanol-containing products (eg, denatured alcohol, automotive fluids, embalming fluids, paints, varnishes, wood stains, lacquer, paint thinner)
    • May be difficult to clinically distinguish methanol and ethylene glycol poisoning
      • Patients may initially appear intoxicated and subsequently develop metabolic acidosis and multiorgan failure
      • Often similar laboratory findings as for ethylene glycol toxicity, including metabolic acidosis with elevated anion gap and/or osmolal gap
    • Methanol causes more prominent ocular symptoms including visual impairment, altered color perception, or “snowfield” vision
    • Ethylene glycol is more likely to cause renal failure than methanol, secondary to oxalic acid production
    • Differentiating test is serum methanol concentration by gas chromatography
      • Initial treatment of methanol and ethylene glycol poisoning is the same; therefore, do not delay treatment while awaiting differentiating test results
  • Ethanol toxicity (Related: Acute Ethanol Toxicity)
    • Presentation is often similar to early ethylene glycol toxicity with signs of altered mental status, nystagmus, ataxia, slurred speech, and/or euphoria
    • Ethanol is the most common cause of elevated osmolal gap and must be accounted for when performing calculation
    • Patients with ethanol toxicity often present with a distinct odor of ethanol; in contrast, ethylene glycol is odorless
    • Ethanol does not cause a metabolic acidosis with elevated anion gap or signs of organ dysfunction
    • Of note, coingestion of both ethanol and ethylene glycol can be protective
      • Ethanol concentration of 100 mg/dL preferentially uses alcohol dehydrogenase, which is an enzyme necessary to metabolize ethylene glycol 18
    • Serum ethanol concentration confirms exposure
  • Ketoacidosis (starvation, diabetic, or alcoholic) (Related: Diabetic Ketoacidosis)
    • Signs and symptoms may mimic ethylene glycol toxicity including altered mental status, tachypnea, and overall ill appearance 27
    • Alcoholic ketoacidosis is typically associated with history of recurrently excessive alcohol use followed by abrupt alcohol cessation (Related: Alcohol Withdrawal)
    • Metabolic acidosis with elevated anion gap develops; circulating acetone may result in elevated osmolal gap 3 28
    • Differentiate by clinical presentation, laboratory findings, and clinical course; elevated serum ketone levels (eg, acetone, β-hydroxybutyrate) are more predictive of ketoacidosis and rapid reversal with fluid administration 9 28
  • Isopropanol toxicity 2
    • Isopropyl alcohol constitutes the common solvent in household rubbing alcohol
    • Initial manifestations can mimic ethylene glycol toxicity with inebriation, central nervous system depression, and hyperosmolarity (ie, increased osmolal gap) without increased anion gap metabolic acidosis 2
    • Clinical clues to isopropyl alcohol intoxication are fruity breath odor with ketone-positive urine without antecedent hyperglycemia, elevated blood or urine acetone concentration, and absence of significant β-hydroxybutyrate ketone production
    • Differentiate based on clinical presentation with ketone-positive blood or urine (ie, positive nitroprusside reaction), elevated acetone level without β-hydroxybutyrate elevation, absence of anion gap metabolic acidosis, and absence of renal toxicity
    • Of note, very high acetone concentrations can falsely elevate serum creatinine level; however, BUN level remains within reference range
    • Confirm ingestion with serum isopropanol concentration by gas chromatography if the diagnosis remains in question

Treatment

Goals

  • Prevent toxic metabolite formation with administration of antidote to inhibit alcohol dehydrogenase
  • Enhance elimination of ethylene glycol and toxic metabolites with hemodialysis when indicated

Disposition

Admission criteria

Confirmed or suspected ethylene glycol poisoning 29

Fomepizole antidotal treatment

Criteria for ICU admission
  • Persistent metabolic acidosis
  • Persistent or significant central nervous system depression or seizures
  • Cardiovascular instability
  • Signs of organ dysfunction
  • Ethanol infusion antidotal treatment
  • Dialysis requirement

Recommendations for specialist referral

  • Early consultation with a medical toxicologist or poison control center is advised for all suspected ingestion (for further diagnostic and treatment recommendations) 15
  • Early consultation with a nephrologist is beneficial in the event that immediate dialysis is necessary

Treatment Options

Immediate critical supportive measures include:

  • Airway management, hemodynamic resuscitation, and IV fluids for volume depletion 1
  • Treat acidosis (pH less than 7.3) 1
    • Administer sodium bicarbonate as a bolus followed by infusion; goal pH is between 7.35 and 7.45 5
    • Large amounts of sodium bicarbonate may be required 5
    • Acidic pH favors central nervous system penetration of toxic metabolites 5
  • Seizure management
    • First line medications are benzodiazepines (eg, lorazepam, diazepam, midazolam) 1
    • Second line medications include barbiturates (ie, phenobarbital) 1 30 31
    • Third line medications include levetiracetam and propofol (limited data, expert opinion) 32
    • Seizures refractory to standard management
      • If hypocalcemia is a cause, administer IV calcium gluconate or calcium chloride
  • Electrolyte replacement as needed 1
    • Replace magnesium for significant hypomagnesemia 1
      • Magnesium is a cofactor for the metabolism of glycolic acid
    • Calcium replacement for severe symptomatic hypocalcemia (eg, intractable seizures, tetany, QT prolongation) 5
      • Avoid routine calcium supplementation without significant manifestations of hypocalcemia because of risk for increase calcium oxalate formation 1 5 15

Specific treatment involves administration of antidote and potentially hemodialysis

  • Antidotes (ie, fomepizole or ethanol)
    • Prevent metabolism of ethylene glycol to toxic metabolites, allowing time for renal elimination of parent compound
    • Fomepizole is effective alone without hemodialysis in the absence of metabolic acidosis and renal insufficiency 2
  • Hemodialysis
    • Removes both ethylene glycol and toxic metabolites; often required after toxic metabolites have begun to form
    • General indications include: 2
      • Deteriorating clinical status despite supportive therapy
      • Recalcitrant metabolic acidosis and electrolyte abnormalities
      • Worsening renal function or acute renal failure

Antidotal treatment

  • Fomepizole is a potent competitive inhibitor of alcohol dehydrogenase 15
  • Ethanol is a competitive substrate with higher affinity for alcohol dehydrogenase than ethylene glycol 5 15
  • Either antidote is effective; do not use together in the same patient 5
  • Early initiation of antidotal therapy can prevent renal failure and the need for hemodialysis 15
  • Indications for fomepizole (preferred) or ethanol include any of the following: 1 5
    • Ethylene glycol concentration over 20 mg/dL 1
    • History of ingestion of toxic amount of ethylene glycol and osmolal gap above 10 mOsm/L 1
    • History or strong clinical suspicion of ethylene glycol poisoning and at least 2 of the following: 1
      • Arterial pH less than 7.3
      • Serum bicarbonate less than 20 mEq/L
      • Osmolal gap more than 10 mOsm/L
      • Presence of calcium oxalate crystalluria
  • Fomepizole is first line treatment of choice
    • Advantages of fomepizole compared with ethanol 5 9
      • Fewer adverse effects 33 compared with ethanol; fomepizole does not cause sedation, inebriation, or hypoglycemia
      • No monitoring or dosing titration required; does not necessitate ICU level of care
      • Does not increase serum osmolality; allows accurate measurement of serum osmolality when monitoring response to treatment 9
      • Safe for most people who have a contraindication to ethanol (eg, liver disease)
      • Ethanol requires compounding by pharmacy; dosing is complex and requires additional fluid volume administration, and pharmacokinetics are unpredictable
    • Contraindications
      • Absolute: severe allergy to pyrazole derivatives 6 15
      • Relative: pregnancy 6
        • Lack of safety data; administer only with clear medical necessity
        • Never withhold antidotal treatment with fomepizole owing to pregnancy, per expert consensus 34
    • Acidosis and anion gap will resolve within 4 hours with effective treatment 12
  • Ethanol is second line antidote
    • Maintain care with dosing of ethanol because frequent dosing errors occur 5
      • Of note, in the United States, alcohol concentration in any given product is noted by proof (ie, 100 proof = 50% ethanol)
    • Blood ethanol concentration needs to be 100 mg/dL to saturate alcohol dehydrogenase
      • Serum ethanol concentration requires close monitoring every 1 to 2 hours 1
      • Infusion rates may need to be adjusted to achieve target goal ethanol concentration between 100 mg/dL and 150 mg/dL 1
    • Use ethanol when fomepizole is not available or is contraindicated 1
    • Relative contraindications include: 1
      • Recent administration of disulfiram or medications causing central nervous system depression
      • History of gastric ulcers if using oral alcohol
      • History of alcoholism
      • Hepatic disease
      • First trimester of pregnancy 1
  • Treatment duration 5
    • Continue until patient is asymptomatic and either of the following criteria are met:
      • Ethylene glycol is undetectable, or
      • Ethylene glycol concentration is less than 20 mg/dL with normal pH and anion gap
    • Osmolal gap serves as a surrogate marker in lieu of direct measurement of ethylene glycol concentration, when the latter is not available
      • Osmolal gap should be within reference range before discontinuation of therapy 5
    • Anion gap serves as a surrogate marker in lieu of direct measurement of toxic metabolites (eg, glycolate concentration)
      • Anion gap should be within reference range before discontinuation of therapy 5

Renal protection

  • Volume expansion with maintenance of adequate urine output may increase urinary excretion of ethylene glycol and toxic metabolites 9
  • Sodium bicarbonate therapy may augment urinary excretion of organic acid anions (eg, glycolate) and inhibit renal precipitation of calcium oxalate crystals 9 15
    • Goal urine pH is greater than 7 12
  • Early dialysis in conjunction with antidotal treatment prevents calcium oxalate deposition and renal failure 9

Vitamin cofactor

  • Recommended in patients with long-term excessive alcohol use and in those with nutrient deficiency 5
    • Thiamine (vitamin B₁) 12
      • Promotes metabolism of glycolic acid to α-hydroxy-β-ketoadipate (nontoxic) 9
    • Pyridoxine (vitamin B₆) 5
      • Promotes metabolism of glyoxylate to glycine (nontoxic) 9

Gastrointestinal decontamination has limited role

  • Activated charcoal is indicated if there is suspicion or known presence of applicable coingestant 5
  • Charcoal is not recommended for ethylene glycol ingestion alone owing to rapid absorption and poor binding characteristics of ethylene glycol
  • Gastric lavage is controversial and not routine
    • Many experts advise that gastric lavage is not indicated; rapid administration of antidote is priority over gastric lavage 7
    • May have some potential benefit if done within 30 minutes of ingestion 6

Drug therapy

  • Fomepizole (4-methylpyrazole)
    • NOTE: The same dosing regimen is used for pediatric patients as for adults. 35
      • Fomepizole Solution for injection; Adults: 15 mg/kg IV once, followed by 10 mg/kg IV every 12 hours for 4 doses, then 15 mg/kg every 12 hours until ethylene glycol or methanol concentrations are undetectable or less than 20 mg/dL and patient is asymptomatic with normal pH. All doses infused over 30 minutes.
      • Fomepizole Solution for injection; Adult patients requiring intermittent hemodialysis: Dosing interval should be changed to every 4 hour during hemodialysis. Once off hemodialysis, give the next scheduled dose 12 hours from last dose administered.
  • Ethanol
    • NOTE: The same dosing regimen is used for pediatric patients as for adults.
    • IV therapy with 10% ethanol
      • NOTE: Special compounding is required and may delay time to administration.
      • Loading dose:
        • Alcohol, Dehydrated, Dextrose Solution for injection; Adults: 7.6 to10 mL/kg IV.
      • Maintenance dose:
        • Alcohol, Dehydrated, Dextrose Solution for injection; Adults, nondrinker: 0.89 mL/kg/hour IV for at least 5 days in methanol poisoning and 3 days in ethylene glycol poisoning.
        • Alcohol, Dehydrated, Dextrose Solution for injection; Adults, moderate drinker: 1.39 mL/kg/hour IV for at least 5 days in methanol poisoning and 3 days in ethylene glycol poisoning.
        • Alcohol, Dehydrated, Dextrose Solution for injection; Adults, chronic drinker: 1.95 mL/kg/hour IV for at least 5 days in methanol poisoning and 3 days in ethylene glycol poisoning.
    • Oral therapy with 20% ethanol (approximately 200 mg/mL)
      • Loading dose:
        • Oral: Adults: 4 mL/kg PO of a 20% ethanol solution (may dilute in juice).
      • Maintenance dose:
        • Adults nondrinker: Administer 0.4 to 0.65 mL/kg/hour PO of a 20% ethanol solution.
        • Adults moderate/tolerant drinker: Administer 0.75 mL/kg/hour PO of a 20% ethanol solution.
  • Vitamin cofactors
    • Thiamine (vitamin B₁) 12
      • Vitamin B₁ (thiamine hydrochloride) Solution for injection; Adults: 100 mg IV every 6 hours until ethylene glycol is no longer measurable in the serum. 36
    • Pyridoxine (vitamin B₆) 12
      • Vitamin B₆ (pyridoxine) Solution for injection; Adults: 50 mg IV every 6 hours for up to 24 hours. 36
  • Sodium bicarbonate
    • Sodium Bicarbonate Solution for injection; Adults: 0.5 to 1 mEq/kg IV bolus; repeat as needed to correct to a serum pH of 7.4. 5

Nondrug and supportive care

Procedures
Hemodialysis

General explanation

  • Eliminates ethylene glycol and toxic metabolites
  • Corrects acid-base and electrolyte disturbances
  • Antidotes (ie, fomepizole and ethanol) are removed by dialysis 5
    • Maintenance dose of fomepizole requires adjustment 15
      • Options include more frequent dosing (every 4 hours) or low-dose continuous infusion
      • Dosing schedule may require alteration at time of transition onto and off of dialysis 5
    • Maintenance rate of ethanol requires adjustment
      • Increase rate of infusion and titrate to goal ethanol concentration
      • Alternatively, ethanol can be added to dialysate 5
      • Frequent monitoring of ethanol concentrations during hemodialysis is required
  • Continue antidotal treatment after discontinuation of dialysis
    • Rebound increase in plasma ethylene glycol concentration can occur within 12 to 36 hours from tissue compartment redistribution to plasma 5

Indication 1

  • Definitive indications
    • Deteriorating clinical status despite supportive therapy 5
    • Acute renal injury with creatinine level greater than 3 mg/dL or increased beyond baseline by 1 mg/dL or more 2
    • Metabolic acidosis (pH less than 7.25-7.3) unresponsive to standard treatment 5 9
    • Electrolyte abnormalities unresponsive to standard treatment 5
  • Possible indication
    • Ethylene glycol concentration greater than 50 mg/dL (controversial) 5
      • May not be necessary if patient is receiving fomepizole and is asymptomatic without acidosis 5
    • Glycolic acid concentration greater than 8 to 10 mmol/L 9

Contraindications

  • No absolute contraindications

Complications

  • Interference with antidote administration owing to removal of fomepizole and ethanol via dialysis
  • Complications associated with invasive procedure of placing dialysis catheter
  • Hypotension
  • Infection

Interpretation of results

  • Effective dialysis is indicated by:
    • Improvement in clinical status
    • Resolution of acid-base status abnormalities and elevated anion gap
    • Resolution of electrolyte abnormalities
    • Normalization of osmolal gap
    • Ethylene glycol concentration less than 20 mg/dL 15
  • Rebound increase in plasma ethylene glycol concentration may occur in some patients after cessation of dialysis; therefore, patients require continued monitoring for rebound

Special populations

  • Pregnant patients
    • Use of ethanol as treatment during pregnancy is controversial owing to potential risk for fetal alcohol syndrome 1
  • Children
    • Caution with administration of ethanol because of risk for hypoglycemia in children

Monitoring

  • Monitoring in patients with evidence of ethylene glycol toxicity
    • Closely monitor vital signs and clinical status to determine need for intubation
    • Closely monitor renal function, urinalysis parameters, and urine output
    • Closely monitor electrolyte, calcium, and glucose levels; acid-base status; anion gap; and osmolal gap
    • Monitor clinically for pulmonary edema and cardiac dysrhythmia during sodium bicarbonate treatment
      • Rapid infusion of large volume may precipitate volume overload, especially in oliguric patients
      • Sodium bicarbonate therapy may cause hypokalemia, and potassium level should be monitored
      • Sodium bicarbonate therapy may promote or worsen hypocalcemia 5
    • Monitoring for patients who require antidotal treatment
      • Assess for laboratory criteria for safe discontinuation of therapy
        • Ethylene glycol concentration (or osmolal gap when ethylene glycol concentration is not available)
        • Anion gap with pH (or glycolate concentration when available)
  • Monitoring for patients treated with ethanol
    • Monitor ethanol concentration every 1 to 2 hours until dosing is near steady state 5
    • After maintenance dose has been established, monitor ethanol concentration every 2 to 3 hours 5
    • Increase frequency of monitoring to every 1 to 2 hours if ethanol concentration is not within target range (ie, 100-150 mg/dL), if maintenance dose is interrupted, or if dialysis is started 5
    • Closely monitor fluid balance, owing to high volume that is often necessary with ethanol infusion 5
    • Monitor for hypoglycemia, particularly in sedated patients and pediatric patients
  • Monitoring for rebound after cessation of dialysis
    • After discontinuation of dialysis, continue to monitor serum osmolality, osmolal gap, electrolyte levels, anion gap, and renal function at 2- to 4-hour intervals for 12 to 36 hours 5
    • Redevelopment of an osmolal gap or increased anion gap is concerning for a rebound increase in serum ethylene glycol concentration or toxic metabolite formation; continuation of antidote and possibly repeated hemodialysis are indicated 5

Complications and Prognosis

Complications

  • Short-term complications of severe poisoning
    • Deposition of calcium oxalate in various organ systems
      • Pulmonary 9
        • Pulmonary edema and infiltrates
        • Pneumonitis
        • Acute respiratory distress syndrome
      • Cardiovascular 9
        • Myocardial dysfunction and heart failure
        • Myocarditis
      • Renal
        • Oliguric, anuric, or nonoliguric renal failure 5
        • High risk of acute renal failure is associated with bicarbonate level of 5 mEq/L or less, anion gap more than 20 mmol/L, blood pH less than 7.1, or serum glycolate concentration of 8 to 10 mmol/L or higher 3 9
      • Central nervous system 9
        • Aseptic meningitis and encephalitis
        • Diffuse cerebral edema, with or without herniation
        • Cerebral infarction
        • Multiorgan failure
    • Death
      • May occur if severe complications are recalcitrant to supportive care
      • Untreated, severe poisoning is often fatal within 24 to 36 hours 12
  • Potential long-term sequelae
    • Renal impairment
      • Renal function recovers in most patients within months 5 12
      • Permanent renal impairment requiring renal replacement therapy is rare 2 5
    • Cerebral infarction
      • Neurologic deficits often resolve with time 5
    • Delayed cranial nerve deficits can occur
      • Facial and auditory nerves are most commonly affected 5
      • May develop several weeks after initial exposure
      • Resolution may take up to 1 year 37

Prognosis

  • Death is uncommon in patients who present early after ingestion and receive prompt diagnosis and treatment 12
    • Early fomepizole administration (ie, before toxic metabolite formation) prevents toxicity
  • Overall mortality is variable, ranging from 1% to 22% 9
    • Highest risk for mortality is among patients with:
      • Treatment started more than 10 hours after ingestion 9
      • Severe acidosis (pH less than 7.1) 9
    • Additional predictors of mortality include hyperkalemia, seizures, and coma 38
  • End-organ toxicity (eg, renal, central nervous system)
    • Often slowly resolves among survivors of severe intoxication over several months 6

Prevention

  • Ethylene glycol–containing products should be clearly labeled and kept out of reach of children
    • Avoid storing ethylene glycol in inappropriate containers (eg, soda bottles, juice bottles) to prevent accidental ingestion
  • Avoid storing drinking containers near ethylene glycol–containing products, as most ingestions are accidental

References

Barceloux DG et al: American Academy of Clinical Toxicology practice guidelines on the treatment of ethylene glycol poisoning. Ad Hoc Committee. J Toxicol Clin Toxicol. 37(5):537-60, 1999

Cross Reference

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