A 37-year-old woman is brought into the emergency department by EMS after being found down next to a bottle of an unknown substance. (See photo.) Her family said she was initially tearful and repeatedly mumbling, “I’m sorry,” and became progressively less responsive.
She was obtunded and intubated for airway protection upon arrival to the ED. Her initial vital signs were a temperature of 98.8°F, heart rate 110 bpm, blood pressure 187/118 mm Hg, respiratory rate 22 bpm, and pulse oximetry 98% on ventilator. Initial ABG reveals a pH 6.89, pCO2 16, pO2 174, and bicarbonate 3.1. Pertinent lab results include a metabolic panel with an anion gap of 24, creatinine 1.23, ammonia of 103, and a positive urine drug screen for THC.
What is the differential diagnosis for a patient with a large anion gap? For this patient, we considered the possible etiologies included in the mnemonic MUDPILES.
M Methanol, metformin
D DKA, AKA, or any ketoacidosis
P Paracetamol, paraldehyde
I Iron, isoniazid
E Ethylene glycol, ethanol
Acetaminophen, salicylate, and ethanol levels were negative. Initial lactate is 5.6 mmol/L, and serum osmolality is 354. Her metabolic panel is below:
What is this patient’s osmolal gap? Osmolal gap= serum osmolality - calculated osmolality [(2 x serum Na) + (serum glucose/18) + (serum BUN/2.8) + (serum ethanol/4.6)]. In this case: Calculated osmolality = (2x135) + (200/18) + (14/2.8) + (0/4.6) = 286
Osmolal gap = 354 - 286 = 68
What products contain methanol or ethylene glycol?
n De-icing solutions
n Windshield washer fluid
n Engine coolant antifreeze
n Paint removers
n Shoe dyes
n Solid cooking fuel used in camping
n Embalming fluid
n Contaminant in moonshine or fermented beverages
Methanol and ethylene glycol themselves are relatively nontoxic and primarily cause CNS sedation. Toxicity stems from their metabolism to toxic metabolites.
The toxic metabolite of methanol formic acid causes retinal and optic nerve injury, and may lead to permanent blindness. Ischemic or hemorrhagic injury to the basal ganglia have also been described.
The toxic metabolites of ethylene glycol lead to acute renal injury and ultimately to renal failure by tubule damage and by the formation of calcium oxalate crystals, which lead to tubule obstruction. Systemic hypocalcemia may also occur as the oxalic acid metabolite precipitates with calcium.
The parent compounds initially cause an elevation of the osmolal gap after ingestion. As they are metabolized to their toxic acid metabolites, the osmolal gap decreases and the anion gap increases, causing a profound anion gap metabolic acidosis.
Treatment should begin immediately based on history, clinical exam, elevated osmolal gap, or a metabolic of unknown cause. Confirmatory testing done by measuring serum ethylene glycol or methanol levels should not delay treatment because these tests are generally sent to outside laboratories and may take some time to provide results. Consultation with a medical toxicologist or poison control center is recommended because these patients are a potentially serious medical emergency.
Initial treatment of a toxic alcohol ingestion requires the use of an inhibitor of alcohol dehydrogenase. Prior to the discovery of fomepizole in 1963, ethanol had been used to block the metabolism of methanol and ethylene glycol to their toxic metabolites. Alcohol dehydrogenase preferentially metabolizes ethanol, and therefore would not be available to metabolize methanol or ethylene glycol.
In fact, a patient who has ingested ethanol and a toxic alcohol has unknowingly protected himself from metabolizing the toxic alcohol to a toxic metabolite while his ethanol level remains greater than 100 mg/dL. Fomepizole has now replaced ethanol as the antidote of choice for toxic alcohol ingestion in the United States, and it has no contraindications and no known adverse effects. A 15 mg/kg IV loading dose of fomepizole should be administered followed by 10 mg/kg doses every 12 hours if a toxic alcohol ingestion is suspected. Repeated doses of fomepizole induce cytochrome P450 metabolism, so clinical guidelines recommend increasing fomepizole dosing to 15 mg/kg every 12 hours after 48 hours. No dose adjustments are needed for patients with renal or hepatic disease. Treatment should continue until methanol or ethylene glycol levels are less than 20 mg/dL.
Hemodialysis should be considered in those patients with end-organ toxicity or severe acidosis. The severe acidosis indicates that a majority of the toxic alcohol has already been metabolized, in which case the efficacy of fomepizole is minimal. Clinical guidelines also recommend initiating hemodialysis with a methanol level higher than 50 mg/dL because toxic levels of methanol, along with inhibition of metabolism from fomepizole, will lead to a prolonged half-life. It is important to remember that hemodialysis will not only remove the toxic alcohols and their metabolites but will remove the antidote as well, making it necessary to increase fomepizole dosing to 10 mg/kg every four hours during hemodialysis.
A recent challenge to the treatment of toxic alcohol poisoning is the current national shortage of fomepizole. Hospitals have begun to develop or revisit protocols for the therapeutic use of ethanol for toxic alcohol poisoning. This nationwide shortage makes it important to know how to dose and treat with both antidotes.
Dosing may be challenging because of variability in metabolism between patients, so frequent monitoring is required. Most pharmacies have a 10% ethanol solution available. Administration via a central venous catheter is preferred because of the risk of phlebitis, but a large vein may also be considered for administration of IV ethanol.
IV ethanol dosing (initial blood ethanol concentration=0):
n Loading dose:
n 8 mL/kg ethanol 10% intravenous solution
n Give over 20 to 60 min as tolerated.
n Loading dose may be omitted if serum ethanol level is higher than 100.
n If serum ethanol level is detected, decrease loading dose proportionally.
n Maintenance dose (non-drinkers)
n 1 mL/kg/hr ethanol 10% solution
n Maintenance dose (drinkers)
n 2 mL/kg/hr ethanol 10% solution
n Maintenance dose during hemodialysis
n 2 to 3.5 mL/kg/hr ethanol 10% solution
n Obtain serum ethanol levels after the loading dose and frequently during maintenance therapy.
n Target blood ethanol concentration: 100–150 mg/dL
n Monitor every two hours until goal is achieved or after a change in the infusion rate.
n Once stable, monitor every four to six hours.
n Blood glucose
n Every two hours and immediately if any signs/symptoms of hypoglycemia
n Metabolic panel & acid-base status
n Every six hours
n Acute drop in serum bicarbonate or increase in anion gap should prompt immediate evaluation of blood gas and ethanol concentration.
n Observe for adverse effects
n Inebriation or sedation
n Local phlebitis
n Acute flushing, palpitations, postural hypotension in those with atypical aldehyde dehydrogenase enzyme
n Use of interacting drugs that may cause disulfiram-type reactions (metronidazole, furazolidone, procarbazine, chlorpropamide, some cephalosporins, and Coprinus mushrooms)
n Pregnancy category C. Administration should be done in consultation with toxicologist/obstetrician.
Consider adjunctive therapies in treating toxic alcohol patients, such as bicarbonate for significant acidosis in methanol poisoning or ethylene glycol toxicity. Bicarbonate functions by shifting methanol’s toxic metabolite formic acid to the less toxic dissociated form, formate, which has a lower affinity for target sites for toxicity.
The administration of cofactors is thought to have a theoretical advantage for producing nontoxic metabolites, but has not been proven in clinical studies. Folinic acid and folic acid (50 mg IV every four to six hours) enhance the metabolism of methanol’s toxic metabolite formate because it is metabolized to water and carbon dioxide. As cofactors, pyridoxine (50 mg IV every six hours) and thiamine (100 mg IV every six hours) enhance the metabolism of ethylene glycol to nontoxic metabolites, limiting accumulation of the metabolite responsible for renal toxicity and metabolic acidosis.
Our patient was treated with intravenous ethanol (because of the fomepizole shortage), sodium bicarbonate infusion, pyridoxine, thiamine, and folic acid. Nephrology was consulted, and hemodialysis was initiated within six hours of ED presentation. The patient had a prolonged hospital course and returned to baseline by hospital day 8. Although the patient’s initial ethylene glycol level at presentation returned at only 45 mg/dL, the significant metabolic acidosis and acute kidney injury on presentation suggest a significant amount of ethylene glycol had been metabolized by the time she presented.
1. Kearney TE. Chapter 187. Ethanol. In: Olson KR. ed. Poisoning & Drug Overdose, 6th edition. New York, NY: McGraw-Hill; 2012.
2. Brent J. Fomepizole for ethylene glycol and methanol poisoning. New Engl J Med 2009;360(21):2216.
3. Headline: Matt Groening via Homer Simpson, The Simpsons, Episode 171; March 16, 1997.