Case: A 23-year-old male with no past medical history presents with abdominal pain, altered mental status, nausea, and vomiting, after ingestion of approximately 2 cups (~100cc) of antifreeze at a party two days before presentation.
Initial Vitals:
HR: 66 beats/minute | BP: 179/77 | RR: 18 | O2: 99% on RA | T: 98° F | Accucheck: 109
Labs:
UA: large blood, trace leukocyte esterase, no crystals
What is our differential?
Our focused (and non-comprehensive) differential diagnosis includes:
Toxic alcohol ingestion(ethylene glycol, methanol, or isopropyl alcohol)
Other toxicologic ingestion (eg, acetaminophen toxicity, salicylate toxicity, etc.)
Infectious process
Intra-abdominal process
Intracranial process, such as intracranial hemorrhage, CVA, etc.
We can additionally use the MUDPILES mnemonic for anion gap metabolic acidosis:
M: Methanol ingestion
U: Uremic acidosis
D: Diabetic ketoacidosis
P: Propylene glycol
I: Isoniazid or Iron tablets
L: Lactic acidosis
E: Ethylene glycol ingestion
S: Salicylate ingestion
How can we narrow down the differential?
Given our patient’s known history of antifreeze ingestion, anion gap metabolic acidosis, acute renal failure, as well as his symptoms of altered mental status and abdominal pain, the most likely explanation of our patient’s symptoms is a toxic alcohol ingestion. Ethylene glycol is the most common alcohol found in antifreeze, and our patient’s symptoms are most consistent with this ingestion. However, propylene glycol and methanol are sometimes found in antifreeze and should be considered as well. Toxic alcohol levels may be obtained, usually as stat send out tests.
The urinalysis can be helpful when evaluating for toxic alcohols, as approximately half of patients with ethylene glycol toxicity demonstrate calcium oxalate crystals on urinalysis. The absence of calcium oxalate crystals, however, should not be used to rule out ethylene glycol toxicity [1].
Calculating an osmolar gap can also be done to help support a diagnosis of a toxic alcohol ingestion. Serum osmolality is determined by the concentrations of solutes in plasma. It is calculated using patient-derived electrolyte values in the following equation:
2[Na] + [BUN]/2.8 + [Glucose]/18 + Serum ethanol/3.7
The calculated serum osmolality is then subtracted from the measured serum plasma osmolality to assess the serum osmolality gap. If this difference is greater than 10, a high serum osmolality gap exists.
High serum osmol gaps occur when additional, unmeasured solutes are present in the blood. High serum osmolality gaps are often caused by ethylene glycol, methanol, isopropyl alcohol, ketoacidosis, and lactic acidosis.
A substantially elevated anion gap (over 16 mEq/L) along with an elevated osmolar gap (>25 mosm/kg) points to an acute toxic alcohol ingestion. Nevertheless, normal osmolar gaps should not be used to rule out toxic alcohol ingestion, as high osmolar gaps may only be found immediately after ingestion (whereas our patient presented 2 days after ingestion) [2]. As such, our patient had a normal serum osmolar gap of 9, with an elevated anion gap, expected given his presentation 2 days after exposure.
Image from: Mycyk MB, Aks SE. A visual schematic for clarifying the temporal relationship between the anion and osmol gaps in toxic alcohol poisoning. Am J Emerg Med. 2003 Jul;21(4):333-5. doi: 10.1016/s0735-6757(03)00079-2. PMID: 12898493.
Nevertheless, it is important to evaluate for alternative diagnoses, which can be done with obtaining a CT head and abdomen/pelvis, chest x-ray, blood cultures, and serum and urine toxicology screen.
What did your adjunct diagnostic workup reveal?
CT head demonstrated bi-thalamic and putaminal hypo-attenuation, characteristic of encephalopathy associated with ethylene glycol poisoning. CT of the abdomen and pelvis was obtained and was within normal limits. Serum and urine toxicology screens were obtained, which were negative for all substances, including acetaminophen, salicylates, and ethanol. Toxic alcohol levels were obtained, but would not return while the patient is in the emergency department.
In the setting of known antifreeze ingestion, an anion gap metabolic acidosis, altered mental status, a negative ethanol level, and acute renal failure, a presumptive diagnosis of ethylene glycol toxicity was made.
Two Drinks Too Many
The classical clinical features of acute methanol or ethylene glycol poisoning include high serum osmolality gap with unexplained high anion gap metabolic acidosis, and early central nervous system sedation.
Methanol poisoning is primarily characterized by CNS depression, metabolic acidosis, and visual changes due to injury to the retina and the basal ganglia [3]. Methanol is metabolized to formic acid, the metabolite responsible for the toxicity and metabolic acidosis that occurs with methanol poisoning.
Ethylene glycol toxicity, in contrast, is characterized by CNS depression, metabolic acidosis, and renal failure [3], [4]. It is metabolized to glycolic acid and oxalic acid, the toxic metabolites, and their buildup is responsible for most of the metabolic acidosis. End-organ damage from ethylene glycol poisoning is thought to be due to direct cytotoxicity of glycolic acid and tissue damage from precipitation of calcium oxalate crystals in the urine [5], [6].
The first or “neurologic” stage of toxicity typically begins 30 minutes to 12 hours after ingestion due to the intoxicating effects of the ethylene glycol and can range from mild depression to coma and seizure. Ethylene glycol is directly irritating to the GI tract, so abdominal pain, nausea, and vomiting may be present, as with our patient. CNS tissue effects of glycolic acid and calcium oxalate crystals include cerebral edema, basal ganglia hemorrhagic infarction [7].
The second or “cardiopulmonary” stage begins 12 to 24 hours after ingestion and is characterized by tachycardia and may demonstrate hypertension [7].
The third or “renal” stage can be delayed 24 to 72 hours after ingestion and is characterized by renal failure from calcium oxalate crystal deposition in the proximal tubules, the most common major complication of severe ethylene glycol poisoning [7].
Management:
The main goals of treatment include the following:
Initial Resuscitation and cardiopulmonary support: This is what we are all good at: Evaluate the ABCs. These patients are frequently altered with significant nausea and vomiting, and intubation may be necessary to protect the airway. Furthermore, many of these patients are dehydrated and require volume resuscitation with crystalloids.
Block toxic metabolites:
Fomepizole is the first line treatment, as it greatly slows the elimination of ethylene glycol and its conversion to the toxic metabolites, glycolic acid and oxalic acid, by inhibition of alcohol dehydrogenase.
If ethylene glycol levels are not available, administer Fomepizole if there is a [8]:
Documented or suspected significant ethylene glycol ingestion
Coma or AMS in a patient with unclear history and either an unexplained serum osmolar gap of >10 mOsm/L, or an unexplained metabolic acidosis and ethanol level of <100 mg/dL
If ethylene glycol levels are available, administer Fomepizole if ethylene glycol level is >20 mg/dL
Fomepizole is dosed with an initial loading dose of 15 mg/kg IV over 30 minutes, followed by additional doses of 10 mg/kg IV every 12 hours. Importantly, don’t delay treatment to obtain toxic alcohol levels, as lab confirmation may take time or may not be available in certain institutions [9], [10].
Gastric decontamination is typically not recommended due to rapid gastric absorption of ethylene glycol. However if a patient presents within 60 minutes of ingestion, GI decontamination via nasogastric suction may be attempted [9], [11], [12].
If Fomepizole is unavailable, IV or PO ethanol therapy can be considered while awaiting Fomepizole or hemodialysis. Ethanol is a preferential substrate for alcohol dehydrogenase and can functionally prevent ethylene glycol from being converted into its toxic metabolites. Dosing regimens can be provided in consultation with your local poison control center.
Correct Acidosis: While there is no evidence that alkalinization is specifically beneficial in ethylene glycol toxicity, many authors recommend using a sodium bicarbonate drip if there is severe metabolic acidosis with pH <7.20 [7]. However, this should be done with caution and in consultation with a medical toxicologist as IV sodium bicarbonate can interfere with the ability to interpret serial lab trends prior to initiation of antidotal therapy.
Eliminate toxic metabolites:
Hemodialysis will rapidly remove ethylene glycol, its toxic metabolites and correct acidosis. It may be required emergently for patients with severe acidosis, hemodynamic instability, or end-organ injury, such as renal failure [9], [11], [13], [14].
Hemodialysis may not be needed if Fomepizole is started early after ingestion without acidosis or renal dysfunction.
Bonus: Adjunctive therapy with thiamine 100 mg IV every 6 hours, pyridoxine 100 mg every 6 hours, and a one time dose of magnesium 2g IV to facilitate metabolism to nontoxic metabolites [15]. This is not to be used in place of Fomepizole or hemodialysis, however.
Your local poison control center is available to assist in the diagnosis and management of suspected ethylene glycol ingestions.
What happened next?
Fluid resuscitation was initiated and the poison control center was quickly called. GI decontamination was not attempted since our patient presented 2 days after ingestion. Given the patient’s significant metabolic acidosis and acute renal failure, hemodialysis was recommended, as well as administration of Fomepizole and a bicarbonate drip.
Fomepizole was quickly administered at 15mg/kg IV, as well as the initiation of a bicarbonate infusion given his severe metabolic acidosis. A dialysis line was subsequently placed Emergently in the emergency department.
The nephrology service was consulted and agreed that emergent hemodialysis was indicated.
The patient was admitted to the medical Intensive care unit, where he had a complicated course. He remained anuric and was subsequently intubated for worsening mental status and pulmonary edema. He subsequently passed within the following week of admission to the ICU. Formal autopsy pending.
Written By:
Dr. Ishmael A Avery
PGY-4 | Cook County EM
Dr. Rayyan Kadi
PGY-4 | Cook County EM
Reviewed By:
Dr. Brian Bush
Toxicology Fellow, Cook County EM
Twitter: @BrianRBush
References:
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Mycyk MB, Aks SE. A visual schematic for clarifying the temporal relationship between the anion and osmol gaps in toxic alcohol poisoning. Am J Emerg Med. 2003 Jul;21(4):333-5. doi: 10.1016/s0735-6757(03)00079-2. PMID: 12898493.
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