Ethylene glycol (EG) is a toxic alcohol found in antifreeze and engine coolants that is metabolized by alcohol dehydrogenase to glycolate and oxalate, causing severe high anion-gap metabolic acidosis, CNS depression, cardiopulmonary dysfunction, and acute kidney injury. The minimum lethal dose is estimated at approximately 100 mL (~1.6 g/kg) in adults, though toxicity can occur with as little as 10–30 mL of concentrated solution. [1-2] Overall mortality in treated patients is approximately 18.7%. [3]
The following figure illustrates the metabolic pathways and the characteristic inverse temporal relationship between the osmolal gap and anion gap:
1. History
- Substance and amount: What was ingested, how much, what concentration (antifreeze is typically 95% EG), and when?
- Intent: Accidental (children, pets), suicidal, or substitution for ethanol?
- Coingestants: Ethanol coingestion (present in 10–60% of cases) delays metabolism and symptom onset from 12–24 hours to 48–72 hours [4]
- Timing: Time from ingestion to presentation is critical — early presentation (before metabolism) may show only inebriation; late presentation shows acidosis and organ damage [1]
- Symptom progression: Initial inebriation → nausea/vomiting/abdominal pain → Kussmaul respirations → oliguria/anuria
- Important negatives: Absence of visual complaints (helps distinguish from methanol); absence of acetone odor (helps distinguish from isopropanol) [4]
2. Alarm Features
- Coma, seizures, or obtundation — indicate severe poisoning and poor prognosis [2]
- Severe metabolic acidosis (pH <7.0, bicarbonate <5 mEq/L)
- Hyperkalemia — associated with poor prognosis [2]
- Anuria or oliguria — indicates established AKI from oxalate crystal deposition
- Cardiovascular collapse — hypotension, tachycardia
- Kussmaul respirations — compensatory hyperventilation for profound acidosis
- Presentation with coma + hyperkalemia + seizures + severe acidosis = very poor prognosis [2]
3. Medications
Antidotes
- Fomepizole (first-line): Loading dose 15 mg/kg IV, then 10 mg/kg q12h × 4 doses, then 15 mg/kg q12h; infuse over 30 minutes. During hemodialysis, increase frequency to q4h [4-5]
- Ethanol (alternative if fomepizole unavailable): Target serum ethanol 100 mg/dL for competitive ADH inhibition; requires ICU monitoring and frequent serum ethanol levels [4]
- Sodium bicarbonate: IV for correction of metabolic acidosis [5]
- Calcium gluconate: For symptomatic hypocalcemia (from calcium oxalate precipitation)
- Thiamine and pyridoxine: Cofactors that may shunt metabolism away from oxalate (often given empirically, though evidence is limited)
Contraindicated/Cautions
- Do NOT use polycarbonate syringes or needles with fomepizole (interaction compromises syringe integrity) [5]
- Do NOT give fomepizole as undiluted bolus — causes phlebosclerosis [5]
4. Diet
- Not directly applicable in the acute setting
- NPO during acute management
- Aggressive IV hydration to maintain urine output and promote renal clearance of unmetabolized EG (elimination half-life ~17 hours with ADH inhibition and normal renal function) [2]
- Long-term: No specific dietary modifications after recovery
5. Review of Systems
- Neuro: Headache, confusion, slurred speech, ataxia, seizures, coma
- GI: Nausea, vomiting, abdominal pain (often early)
- Respiratory: Dyspnea, tachypnea (Kussmaul respirations from acidosis), pulmonary edema
- Cardiovascular: Chest pain, palpitations (from hypocalcemia or myocarditis)
- Renal: Decreased urine output, flank pain, hematuria
- Musculoskeletal: Tetany, muscle cramps (hypocalcemia)
- Psychiatric: Suicidal ideation assessment if intentional ingestion
6. Collateral History and Family History
- Collateral: Witnesses to ingestion, empty containers, suicide note, prior attempts
- Access to substances: Occupation (mechanic, industrial worker), garage/workshop access
- Psychiatric history: Depression, substance use disorder, prior self-harm
- Family history: Generally not relevant to acute toxicity; family history of substance abuse or psychiatric illness may inform disposition planning
7. Risk Factors
- Alcohol use disorder — EG may be ingested as ethanol substitute; paradoxically, concurrent ethanol delays toxicity [6]
- Suicidal intent — most fatalities are intentional ingestions [2]
- Pediatric accidental ingestion — EG has a sweet taste
- Occupational exposure — mechanics, industrial workers
- Delayed presentation — allows more complete metabolism to toxic metabolites
- Preexisting renal disease — impairs clearance of EG and metabolites
8. Differential Diagnosis
- Methanol poisoning — similar osmolal/anion gap pattern but associated with visual disturbances and formate accumulation; no oxalate crystalluria [4]
- Isopropanol poisoning — elevated osmolal gap but NO anion gap acidosis; ketonemia/ketonuria without acidosis [4]
- Diabetic ketoacidosis — elevated anion gap, ketonemia, hyperglycemia
- Alcoholic ketoacidosis — history of chronic alcohol use, starvation
- Lactic acidosis (sepsis, shock, metformin) — elevated lactate
- Uremia/CKD — elevated anion gap, elevated BUN/Cr
- Salicylate toxicity — mixed respiratory alkalosis and metabolic acidosis
- Propylene glycol toxicity — elevated osmolal gap, lactic acidosis (iatrogenic from IV lorazepam, phenobarbital) [7]
Key distinguishing feature of EG: Calcium oxalate crystalluria (dihydrate "envelope-shaped" early, monohydrate "needle-shaped" late) + hypocalcemia [4]
9. Past Medical History
- Prior toxic alcohol ingestions or suicide attempts
- Chronic kidney disease (impairs clearance)
- Hepatic disease (alters metabolism)
- Alcohol use disorder
- Psychiatric diagnoses
- Current medications (especially those affecting renal function)
10. Physical Exam
- Vitals: Tachycardia, tachypnea (Kussmaul respirations), hypotension (late/severe), hypothermia possible
- Neuro: Altered mental status ranging from inebriation to coma; ataxia, nystagmus, seizures; cranial nerve palsies (delayed, days after exposure) [4]
- Respiratory: Increased respiratory rate and depth; crackles if pulmonary edema
- Cardiovascular: Tachycardia; signs of heart failure in severe cases
- Abdomen: Epigastric/flank tenderness
- Musculoskeletal: Tetany, Chvostek/Trousseau signs (hypocalcemia)
- Skin: Diaphoresis; no characteristic odor (unlike isopropanol/acetone)
11. Lab Studies
Immediate
- BMP (Na, K, Cl, HCO₃, BUN, Cr, glucose, Ca) — calculate anion gap
- Serum osmolality (by freezing-point depression) — calculate osmolal gap
- ABG/VBG — assess pH, pCO₂
- Serum ethylene glycol level (if available; often delayed) — >20 mg/dL triggers antidote therapy [4]
- Serum ethanol level — assess for coingestion
- Lactate — both POC and lab (a discrepancy = "lactate gap", a diagnostic clue as glycolate cross-reacts with some POC lactate analyzers) [8]
- Ionized calcium — hypocalcemia from oxalate precipitation
- Urinalysis — calcium oxalate crystals (dihydrate early, monohydrate late) [4]
Key formulas
- Estimated osmolality = (2 × Na) + (BUN/2.8) + (glucose/18) + (ethanol/3.7)
- Osmolal gap = measured − calculated; normal <10–20 mOsm/kg [4]
- Anion gap = Na − (Cl + HCO₃); normal 8–12 mEq/L
Prognostic markers
- Anion gap >28 mmol/L correlates with glycolate >12 mmol/L and significantly worse outcomes [3][9]
- Glycolate <8 mmol/L (if available) has 100% negative predictive value for mortality [9]
Monitoring
- Serial BMP, ABG, osmolality q2–4h
- Hepatic enzymes and WBC (fomepizole can cause transient transaminase elevation and eosinophilia) [5]
12. Imaging
- Not routinely required in the acute setting
- CXR: If respiratory distress — assess for pulmonary edema or ARDS
- CT head: If altered mental status to rule out structural pathology or coingestant effects
- Renal ultrasound: If AKI develops — may show echogenic kidneys from oxalate deposition (typically not acutely useful)
13. Special Tests
- Osmolal gap calculation — early diagnostic clue (elevated before anion gap rises) [4]
- Lactate gap — discrepancy between POC lactate (falsely elevated due to glycolate cross-reactivity) and laboratory lactate is a highly suggestive finding [8]
- Wood's lamp of urine — fluorescein is added to some antifreeze products and may cause urine fluorescence; however, this test has poor sensitivity and specificity and should not be relied upon
- Gas chromatography / HPLC — definitive identification and quantification of EG; often not rapidly available [4]
- Serum glycolate level — best prognostic marker but rarely available in a clinically useful timeframe; anion gap is the best readily available surrogate (r = 0.73) [9]
The following algorithm from the NEJM provides a practical decision framework for diagnosis and management of toxic alcohol poisonings:
14. ECG
- Indications: Obtain on all patients — acidosis and electrolyte derangements affect the cardiovascular system [5]
- Expected findings:
- QTc prolongation — from hypocalcemia
- Peaked T waves, widened QRS — from hyperkalemia (late, severe)
- ST-segment changes — ST elevation mimicking STEMI has been reported from EG-induced myocarditis (oxalate crystal deposition in myocardium) [10]
- Dysrhythmias — from combined electrolyte abnormalities
- Pearl: ST elevation in the setting of EG poisoning should raise suspicion for toxic myocarditis rather than acute coronary syndrome [10]
15. Assessment
Three classic stages of EG toxicity: [1]
- Stage 1 (0–12 hours): CNS depression — inebriation, ataxia, slurred speech, nausea/vomiting; may appear "drunk" without ethanol odor
- Stage 2 (12–24 hours): Cardiopulmonary — tachycardia, hypertension, tachypnea, pulmonary edema, heart failure; metabolic acidosis becomes prominent
- Stage 3 (24–72 hours): Renal — flank pain, oliguria/anuria, AKI from calcium oxalate crystal deposition in renal tubules
Severity stratification
- Mild: Osmolal gap elevated, normal anion gap, no acidosis → early presentation, parent compound not yet metabolized
- Moderate: Rising anion gap, mild acidosis, no organ dysfunction
- Severe: Profound acidosis (pH <7.1), AKI, coma, seizures, cardiovascular instability
Atypical presentations: Normal anion gap with concurrent ethanol ingestion (ethanol inhibits metabolism); late presentation with normal osmolal gap but elevated anion gap (parent compound fully metabolized) [4][6]
16. Treatment Plan
Initial stabilization
- ABCs, IV access, cardiac monitoring, supplemental O₂
- Do not delay antidote for confirmatory EG levels
Antidote — Fomepizole (preferred): [4-5][11]
- Loading: 15 mg/kg IV over 30 min
- Maintenance: 10 mg/kg IV q12h × 4 doses, then 15 mg/kg q12h
- During HD: Increase to q4h dosing
- Discontinue when EG <20 mg/dL (or undetectable), asymptomatic, and normal pH
Antidote — Ethanol (if fomepizole unavailable): [4]
- Target serum ethanol 100 mg/dL
- Requires ICU-level monitoring and frequent ethanol levels
Sodium bicarbonate: IV drip for pH <7.1–7.2; corrects acidosis and promotes urinary excretion
Calcium replacement: IV calcium gluconate for symptomatic hypocalcemia (tetany, QTc prolongation); use cautiously as it may worsen oxalate deposition
Hemodialysis indications (EXTRIP 2023 recommendations): [3]
- Recommend HD if: anion gap >27 mmol/L, glycolate >12 mmol/L, severe features (coma, seizures, AKI)
- Suggest HD if: EG >50 mmol/L or osmolal gap >50 (with fomepizole); anion gap 23–27 mmol/L
- Preferred modality: Intermittent HD (high-flux membrane); CRRT if HD unavailable
- Stop HD when anion gap <18 mmol/L or EG <4 mmol/L
Fomepizole monotherapy (without HD) is safe and effective when anion gap <28 mmol/L, regardless of EG concentration [12]
Adjuncts: Thiamine 100 mg IV and pyridoxine 50 mg IV (cofactors to shunt glyoxylate metabolism away from oxalate; limited evidence but low risk)
17. Disposition
- ICU admission: All patients with significant acidosis, altered mental status, hemodynamic instability, need for HD, or IV ethanol infusion [4]
- Monitored bed: Patients with confirmed ingestion, normal labs, and early fomepizole administration who are clinically stable
- Observation: Asymptomatic patients with suspected small ingestion — serial labs q2–4h for at least 6–12 hours to monitor for delayed metabolic derangement
- Discharge: Only after EG levels undetectable or <20 mg/dL, normal pH, normal renal function, and asymptomatic [5]
- Consult triggers:
- Toxicology/Poison Control — all cases (1-800-222-1222 in the US)
- Nephrology — if HD indicated or AKI develops
- Psychiatry — all intentional ingestions before discharge
18. Follow Up / Return Precautions
- Follow-up timing: Renal function check (BMP) within 48–72 hours of discharge; repeat at 1–2 weeks
- Renal recovery: AKI from oxalate nephropathy may be prolonged; some patients require temporary or rarely permanent dialysis
- Delayed cranial neuropathy: Can appear days after exposure — counsel patients to return for new facial weakness, vision changes, or hearing loss [4]
- Return immediately for: Decreased urine output, confusion, persistent nausea/vomiting, shortness of breath, muscle cramps/spasms, seizures
- Psychiatric follow-up: Mandatory for intentional ingestions; safety planning before discharge
- Expected course: With early fomepizole treatment before significant acidosis, most patients recover without sequelae [11]
References
1. Ethylene Glycol: An Estimate of Tolerable Levels of Exposure Based on a Review of Animal and Human Data. — Hess R, Bartels MJ, Pottenger LH. Archives of Toxicology. 2004.
2. Ethylene Glycol Exposure: An Evidence-Based Consensus Guideline for Out-of-Hospital Management. — Caravati EM, Erdman AR, Christianson G, et al. Clinical Toxicology. 2005.
3. Extracorporeal Treatment for Ethylene Glycol Poisoning: Systematic Review and Recommendations From the EXTRIP Workgroup. — Ghannoum M, Gosselin S, Hoffman RS, et al. Critical Care. 2023.
4. Toxic Alcohols. — Kraut JA, Mullins ME. The New England Journal of Medicine. 2018.
5. FDA Drug Label. — Updated date: 2023-10-26. Food and Drug Administration.
6. Ethylene Glycol Poisoning With a Normal Anion Gap Caused by Concurrent Ethanol Ingestion: Importance of the Osmolal Gap. — Ammar KA, Heckerling PS. American Journal of Kidney Diseases : The Official Journal of the National Kidney Foundation. 1996.
7. Toxic Alcohol Ingestions: Clinical Features, Diagnosis, and Management. — Kraut JA, Kurtz I. Clinical Journal of the American Society of Nephrology : CJASN. 2008.
8. The Three Biological Gaps and Hyperoxaluria in Ethylene Glycol Poisoning: Case Presentation and Review. — Ahmad Y, Kissling S, Torrent C, et al. European Review for Medical and Pharmacological Sciences. 2021.
9. The Serum Glycolate Concentration: Its Prognostic Value and Its Correlation to Surrogate Markers in Ethylene Glycol Exposures. — Roberts DM, Hoffman RS, Brent J, et al. Clinical Toxicology. 2022.
10. ST-elevation in Ethylene Glycol Toxicity Mimicking Myocardial Infarction. — Dibajnia P, Sivilotti MLA, Juurlink D, Shurrab M. Journal of Electrocardiology. 2019.
11. Current Recommendations for Treatment of Severe Toxic Alcohol Poisonings. — Mégarbane B, Borron SW, Baud FJ. Intensive Care Medicine. 2005.
12. Treating Ethylene Glycol Poisoning With Alcohol Dehydrogenase Inhibition, but Without Extracorporeal Treatments: A Systematic Review. — Beaulieu J, Roberts DM, Gosselin S, et al. Clinical Toxicology. 2022.