Ethylene Glycol

Epidemiology

  • Ethylene Glycol Ingestion in Suicide Attempts: common
  • Degree of Toxicity: ingestion of as little as 100 mL may be fatal

Source of Ethylene Glycol Exposure

  • Antifreeze/Coolant Ingestion
  • Cosmetic Ingestion
  • Organic Solvent Ingestion: ethylene glycol is commonly used in the manufacture of several common products
    • De-Icers
    • Explosives
    • Fire Extinguishers
    • Foams
    • Hydraulic Fluids
    • Paints
    • Pharmaceuticals
    • Plastic
    • Windshield Washer Fluid

Physiology

Characteristics of Ethylene Glycol

  • Colorless, Odorless, Sweet-Tasting, Water-Soluble Liquid
  • Gastrointestinal Absorption: rapid absorption from gastrointestinal tract -> peak Levels occur about 2 hrs after ingestion
  • Toxicity: as little as 0.1 mL/kg ingestion (one swallow) may result in a potentially toxic blood level

Background on Alcohols and Their Metabolism

Ethylene Glycol

  • Ethylene Glycol is a Primary Alcohol Which is Metabolized by Alcohol Dehydrogenase and Aldehyde Dehydrogenase to Carboxylic Acids (Namely, Glycolic Acid, Glyoxylic Acid, and Oxalic Acid): these carboxylic acids cause most of the toxic effects

Methanol (see Methanol, [[Methanol]])

  • Methanol is a Primary Alcohol Which is Metabolized by Alcohol Dehydrogenase and Aldehyde Dehydrogenase to Carboxylic Acids (Namely, Formic Acid): these carboxylic acids cause most of the toxic effects

Isopropanol (see Isopropanol, [[Isopropanol]])

  • Isopropanol is a Secondary Alcohol Which is Metabolized by Alcohol Dehydrogenase Only to a Ketone (Namely, Acetone), Rather than to an Aldehyde: ketones cannot be oxidized to an aldehyde and therefore, only limited acidosis can result

Ethylene Glycol Metabolism

  • Ethylene Glycol is Hepatically Metabolized by Alcohol Dehydrogenase and Aldehyde Dehydrogenase: resulting in the formation of several toxic metabolites (glycolic acid and oxalate are the two compounds most responsible for the metabolic acidosis and renal damage)
    • Glycoaldehyde
    • Oxalate: precipitates as calcium oxalate crystals in brain, heart, kidney, pancreas, lung, and urine
    • Glyoxylic Acid: rapidly oxidized to oxalate
    • Glycolic Acid: as much as 20% is excreted unchanged in urine
  • Kinetics
    • Absence of Treatment: half-life of approximately 3-8 hrs
    • Treatment with Alcohol Dehydrogenase Inhibitor (Ethanol, Fomepizole): elimination becomes almost entirely renal (with half-life of approximately 14 hrs with normal renal function)

End Organ Toxicity

  • Central Nervous System Toxicity: due to calcium oxalate crystal precipitation
  • Elevated Anion Gap Metabolic Acidosis: due to glycolic acid (and oxalate)
  • Renal Interstitial and Tubular Damage: due to glycolic acid-induced tubular damage and calcium oxalate crystal precipitation (to a lesser extent)
  • Hypocalcemia: due to calcium oxalate formation

Diagnosis

Complete Blood Count (CBC)

  • Leukocytosis (see Leukocytosis, [[Leukocytosis]]): seen in most cases

Serum Chemistry

  • Hypocalcemia (see Hypocalcemia, [[Hypocalcemia]]): seen in 33% of cases
    • Due to calcium oxalate crystal precipitation in tissues)
  • Anion Gap Metabolic Acidosis (see Metabolic Acidosis-Elevated Anion Gap, [[Metabolic Acidosis-Elevated Anion Gap]]): anion gap is usually >20

Arterial Blood Gas (ABG) (see Arterial Blood Gas, [[Arterial Blood Gas]])

Serum Osmolality (see Serum Osmolality, [[Serum Osmolality]])

  • Elevated Osmolal Gap: >10 mOsm/kg
    • Note: the serum osmolal gap estimates the molar quantity of uncharged molecules and consequently, increases only in the presence of the parent alcohol ethylene glycol
      • The toxic ethylene glycol metabolites (glycolate/glyoxylate/oxalate), exist primarily in a dissociated/charged form at physiologic pH: as these anions are accompanied by a cation (mostly sodium), they do not contribute to the serum osmolal gap since they are accounted for in the serum sodium term in the formula for the serum osmolal gap

Lactic Acidosis

  • Lactate: may be elevated in some cases
    • However, the degree of lactate elevation is usually not sufficient to explain the degree of metabolic acidosis that is present

Urinalysis

  • Hematuria (see Hematuria, [[Hematuria]]): common
  • Casts
    • “Muddy Brown Casts” (brownish pigmented cellular casts with renal tubular epithelial cells): seen in 75% of cases
      • Pathognomonic of acute tubular necrosis (ATN)
    • RBC Casts: rare
  • Calcium Oxalate Crystalluria: not present in all cases
    • Calcium Oxalate Monohydrate Crystals: needle, biconcave, and dumbbell-shaped
    • Calcium Oxalate Dihydrate Crystals: envelope-shaped
  • Urine Wood’s Lamp Fluoroscence: may detect sodium fluorescein, which is present in antifreeze -> however, this is not sensitive or specific

Elevated Fractional Excretion of Sodium (FENa) (see Acute Kidney Injury, [[Acute Kidney Injury]])

  • Elevated: >1% (with urine sodium >20)
    • Consistent with acute tubular necrosis (ATN) as the etiology of AKI

Urine Osmolality

  • Isosthenuria: urine osm is usually around 300

Renal Biopsy

  • Not Indicated

Ethylene Glycol Level

  • Elevated
    • Level of 20 mg/dL is potentially toxic
    • Alcohol-like intoxication is seen at levels >50-100 mg/dL
    • Survival has been reported at levels as high as 650 mg/dL

Glycolic Acid Level

  • Elevated

Clinical Stages

General Comments

  • Clinical Stages: the clinical stages are not discrete, may be absent, may occur at variable times, and may overlap substantially
  • Factors Predictive of Death or Prolonged Renal Failure [MEDLINE]

Stage 1-Neurologic

General Comments

  • Timing: occurs 30 min-12 hrs post-ingestion (biphasic course)

Neurologic Manifestations

  • Altered Mental Status with Central Nervous System Depression (see Delirium, [[Delirium]] and Obtundation-Coma, [[Obtundation-Coma]]))
    • Timing: occurs within 4-12 hrs post-ingestion (symptoms associated with toxic metabolites usually predominate, but may be delayed in cases where patient has ingested large amounts of ethanol, which inhibits ethylene glycol metabolism)
    • Mechanism of Central Nervous System Depression: probably related to calcium oxalate deposition -> cerebral damage
  • Ataxia (see Ataxia, [[Ataxia]]): may occur
  • Hyporeflexia (see Hyporeflexia, [[Hyporeflexia]]): may occur in severe cases
  • Hypotonia: may occur in severe cases
  • Meningismus (see Meningismus, [[Meningismus]]): may occur in severe cases
  • Myoclonus (see Myoclonus, [[Myoclonus]]): may occur
  • Nystagmus (see Nystagmus, [[Nystagmus]]): may occur
  • Ophthalmoplegia (see Ophthalmoplegia, [[Ophthalmoplegia]]): may occur
  • Optic Fundus: usually normal (although some cases may manifest papilledema, mimicking methanol intoxication)
  • Seizures (see Seizures, [[Seizures]]): may occur in severe cases
  • Transient Inebriation/Euphoria: occurs within min-several hrs (similar to ethanol intoxication)

Renal Manifestations

  • Anion Gap Metabolic Acidosis (AGMA) (see Metabolic Acidosis-Elevated Anion Gap, [[Metabolic Acidosis-Elevated Anion Gap]]): occurs within 4-12 hrs post-ingestion
  • Elevated Osmolal Gap (see Serum Osmolality, [[Serum Osmolality]])
    • Physiology: presence of osmotically-active solute, ethylene glycol
      • Since the serum osmolal gap estimates the molar quantity of uncharged molecules, the osmolal gap is increased due to the presence of ethylene glycol itself
      • The toxic ethylene glycol metabolites glycolate/glyoxylate/oxalate exist primarily in a dissociated (charged) form at physiologic pH -> as these anions are accompanied by a cation (mostly sodium), they do not contribute to the serum osmolal gap since they are accounted for in the serum sodium term in the serum osmolal gap formula
    • Clinical: may produce a large osmolal gap (>20 mOsm/L)
      • An elevated osmolal gap may appear before the development of metabolic acidosis in cases with concomitant ethanol and ethylene glycol ingestion
      • A normal osmolal gap does not exclude ethylene glycol intoxication and a small osmolal gap can be seen with high ethylene glycol levels (the sensitivity/specificity of osmolal gap depends on timing of ingestion)
      • There are often discrepancies between the degree of osmolal gap and the severity of clinical manifestations

Other Manifestations

Stage 2-Cardiopulmonary

General Comments

  • Timing: occurs within 12-24 hrs post-ingestion (most deaths occur in this stage)

Cardiovascular Manifestations

Other Manifesttaions

  • Severe Metabolic Acidosis with Compensatory Hyperventilation (see Metabolic Acidosis-Elevated Anion Gap, [[Metabolic Acidosis-Elevated Anion Gap]]): occurs in severe cases
  • Multi-Organ Failure

Stage 3-Renal

General Comments

  • Timing: occurs within 24-72 hrs post-ingestion

Cardiovascular Manifestations

  • Hypotension/Cardiovascular Collapse (see Hypotension, [[Hypotension]])

Gastrointestinal Manifestations

  • Faint Sweet Odor on Breath
  • Hepatotoxicity (see xxxx, [[xxxx]]): serious hepatic damage rarely occurs

Pulmonary Manifestations

Renal Manifestations

  • Acute Kidney Injury (with Acute Tubular Necrosis) (see Acute Kidney Injury, [[Acute Kidney Injury]]): may occur early in course in severe cases
  • Flank Pain (see Flank Pain, [[Flank Pain]])
  • Hematuria (see Hematuria, [[Hematuria]])
  • Hypocalcemia (see Hypocalcemia, [[Hypocalcemia]])

Other Manifestations

  • Ectopic Calcification: due to oxalate precipitation in tissues
  • Hypocalcemia (see Hypocalcemia, [[Hypocalcemia]]): due to calcium oxalate formation
  • Myelosuppression: occurs in rare cases

Treatment

General Comments

  • Initiating Alcohol Dehydrogenase Inhibitor Therapy Within 6 hrs Improves Outcome [MEDLINE]
  • However, Earlier Initiation of Hemodialysis Worsens Outcome [MEDLINE]: however, this was retrospective study and there was likely sample bias (as sicker patients were more likely to undergo hemodialysis)
  • Management with Alcohol Dehydrogenase Inhibitor Monotherapy (Without Hemodialysis): patients who present with normal/near-normal initial pH and renal function likely can be safely managed without hemodialysis

Supportive Care

  • Treatment of Seizures
  • Treatment of Metabolic Acidosis
    • Sodium Bicarbonate (see Sodium Bicarbonate, [[Sodium Bicarbonate]]): may require large doses
    • Hemodialysis: indicated for refractory metabolic acidosis (see below)
  • Treatment of Hypocalcemia (see Hypocalcemia, [[Hypocalcemia]]): indicated

Intravenous Fluids + Diuretics

  • Efficacy: although intravenous fluids and diuretics may reverse oliguria due to acute kidney injury, they do not enhance ethylene glycol elimination

Gastrointestinal Decontamination

  • Gastric Emptying: effective only if performed early, as ethylene glycol is rapidly absorbed from the gastrointestinal tract
  • Activated Charcoal (see Activated Charcoal, [[Activated Charcoal]]): indicated

Alcohol Dehydrogenase Inhibitor Therapy

Ethanol (see Ethanol, [[Ethanol]])

  • Mechanism: competes with both methanol and ethylene glycol for alcohol dehydrogenase (alcohol dehydrogenase enzyme has higher affinity for ethanol and becomes saturated at an ethanol level between 13-30 mg/dL), preventing formation of toxic metabolites
    • The half-life of ethylene glycol is prolonged to about 17 hrs in the presence of ethanol infusion
  • Administration: load with 10% ethanol at 10 mL/kg IV, then infuse 10% ethanol at 1.5 mL/kg/hr IV drip -> titrate to keep ethanol level between 100-200 mg/dl
    • Concomitant Hemodialysis and Ethanol Infusion: when hemodialysis is used with ethanol infusion, increase the ethanol drip rate to account for its loss with hemodialysis -> administer 3 mL/kg/hr IV drip instead
    • Monitor: monitor ethanol and ethylene glycol levels during therapy
  • Adverse Effects
    • Inebriation
    • Hepatotoxicity (see xxxx, [[xxxx]])
    • Hypoglycemia (see Hypoglycemia, [[Hypoglycemia]])
  • Disadvantages: kinetics are unpredictable

Fomepizole (4-Methylpyrazole) (see Fomepizole, [[Fomepizole]])

  • Indications: has only been approved for ethylene glycol intoxication (but is likely also to be useful in methanol intoxication)
  • Administration: load with 15 mg/kg IV, then infuse 10 mg/kg q12hrs IV
    • Less toxic than ethanol infusion, but more expensive

Hemodialysis (see Hemodialysis, [[Hemodialysis]])

  • Efficacy: decreases ethylene glycol level and enhances elimination of toxic metabolites
  • Indications
  • Administration
    • Concomitant Hemodialysis and Ethanol Infusion: when hemodialysis is used with ethanol infusion, increase the ethanol drip rate to account for its loss with hemodialysis -> administer 3 mL/kg/hr IV drip instead

Thiamine (see Thiamine, [[Thiamine]])

  • May Be Useful

Pyridoxine (see Vitamin B6, [[Vitamin B6]])

  • May Be Useful

Charcoal Hemoperfusion (see Hemoperfusion, [[Hemoperfusion]])

  • General Indications for Charcoal Hemoperfusion: intoxication with compounds with high molecular weight, high protein binding, and large volume of distribution -> these compounds would normally be poorly removed by hemodialysis
  • Not Beneficial in Ethylene Glycol Intoxication
    • In addition, it has a higher risk of complications, since blood is in contact with activated charcoal or resin

References

  • Ethylene glycol intoxication. Semin Dialysis 1994; 7:338-345
  • Fomepizole for the treatment of ethylene glycol poisoning. N Engl J Med 1999; 340:832-838
  • Methylpyrazole for Toxic Alcohols Study Group. Fomepizole for the treatment of ethylene glycol poisoning. N Engl J Med 1999; 340:832-838
  • Ethylene glycol intoxication: pathophysiology, diagnosis, and emergency management. ANNA J 1999; 26:295-300, 355
  • American Academy of Clinical Toxicology practice guidelines on the treatment of ethylene glycol poisoning. Ad Hoc Committee. J Toxicol Clin Toxicol 1999; 37:537-560
  • Poisonings and overdoses in the intensive care unit: general and specific management issues. Crit Care Med 2003; 31:2794-2801
  • Predictors of Death and Prolonged Renal Insufficiency in Ethylene Glycol Poisoning. Crit Care Med. 2003 Dec;31(12):2794-801 [MEDLINE]