A 24-year-old male caterer is admitted to the ICU approximately 24 hours after ingesting what he described as a “sweet-tasting” liquid from the canned fuel used to heat the food. Fomepizole therapy was started promptly in the emergency department and toxic alcohol levels are sent to the lab and pending. On arrival to the ICU, he complains of being “in a snowstorm.”
What is the etiology for his visual changes?
Correct Answer: B
The patient likely ingested methanol, given the description of a “sweettasting” liquid from canned fuel. Methanol is present in many commercial and industrial products including windshield washer fluid, race car fuel, model airplane fuel, and as a byproduct of illicit distillation.
Although fomepizole was started promptly in the emergency department, the patient has likely already metabolized methanol to its toxic byproducts given that the ingestion occurred over 24 hours ago. Methanol is metabolized by alcohol dehydrogenase into formaldehyde and then again by aldehyde dehydrogenase into formic acid. Both formaldehyde and formic acid are toxic to the body.
Metabolism of Methanol:
Formic acid (present in solution as formate) has direct cytotoxic action as a result of its inhibition of intramitochondrial oxygen transport, causing intracellular depletions of ATP. Formate is particularly toxic to the basal ganglia (causing hemorrhage and a Parkinsonian-type movement disorder) and to the retina and optic nerve (causing visual loss, classically described as “being in a snowstorm”).
Although ethanol withdrawal can cause seizures, they are usually generalized. Methanol can cause hemorrhage or ischemia in the basal ganglia, but this typically manifests as a Parkinsonian movement disorder. Vitamin B12 (cobalamin) deficiency is often seen in individuals with severe alcohol use disorder, but manifests as a megaloblastic anemia and a length-dependent neuronal dysfunction. Finally, the toxic alcohols can cause altered mental status, but visual changes are more likely due to retinal damage and not hallucinations or delirium.
References:
A 32-year-old male auto mechanic is transferred to your ICU from a small local hospital for consideration of dialysis. Two days prior, the patient ingested an entire jug of antifreeze at work on a dare. He was admitted to the local hospital for supportive care but developed progressive oliguric renal failure. On arrival to your hospital, a small amount of dark urine is present in the Foley catheter, which is sent to the lab for analysis. The lab calls you to tell you that there are crystals present in the urine.
What is the likely composition of these crystals?
Correct Answer: D
The patient likely ingested ethylene glycol, which lowers the boiling point of water and is a common ingredient in antifreeze. Its sweet taste contributes to a relatively high number of pediatric and pet animal overdoses. Like methanol, ethylene glycol is relatively nontoxic but is metabolized into substances that can directly harm the body.
The primary toxic metabolite of ethylene glycol is oxalic acid. Oxalic acid can bind directly to calcium in the blood and then precipitate out of solution as calcium oxalate. The most common site of precipitation is within the kidney, where it can cause renal tubular necrosis and renal failure. Calcium oxalate can also precipitate in the lungs, causing pulmonary edema, and in the heart, causing myocardial depression. In addition, precipitation of calcium out of the blood can cause hypocalcemia.
Metabolism of ethylene glycol showing production of calcium oxalate:
Uric acid and calcium pyrophosphate are common causes of gout and pseudogout, respectively, but are not typically seen with ethylene glycol overdose. Although magnesium ammonium phosphate (struvite) and cysteine are seen in some forms of kidney stones, they are not characteristic of ethylene glycol overdose.
A 28-year-old male is admitted from the emergency department after he was found unconscious at a party. The patient was given two doses of intranasal naloxone empirically with minimal improvement in his mental status. After he began to vomit, he was intubated for airway protection and placed on an infusion of propofol for sedation. His friends told the ED physicians that he ingested several tablets of crushed oxycodone, a “large number” of shots of liquor, and some of his friend’s newly distilled moonshine. His ethanol level in the ED was 453 mg/dL and a toxicology screen was positive for oxycodone. On arrival to the unit, your intern suggests treating empirically with fomepizole given the moonshine ingestion.
You reply that fomepizole therapy can be deferred at present because of the presence of:
Correct Answer: C
Fomepizole (4-methyl-1H-pyrazole) is a competitive inhibitor of alcohol dehydrogenase (ADH). For methanol and ethylene glycol, toxic effects of the alcohols occur not from the parent alcohol but from the metabolized intermediates (formic acid/formate in methanol and oxalic acid in ethylene glycol). These intermediates are typically produced from metabolism of the parent compound by ADH and then aldehyde dehydrogenase (ALDH). Further metabolism converts the toxic compounds into nontoxic breakdown products.
The purpose of fomepizole in the ingestion of a toxic alcohol is to decrease the production of toxic metabolites while allowing for later metabolic pathways to break down the toxic metabolites before they reach toxic concentrations. By inhibiting ADH, fomepizole slows the initial metabolism of the parent compound, allowing for downstream metabolism.
Like the toxic alcohols, the initial metabolism of ethanol is via ADH. In fact, ethanol has a 10- to 20-fold higher affinity for ADH than the toxic alcohols and can serve as a competitive inhibitor to the toxic alcohols at ADH. At ethanol levels above 100 mg/dL, ethanol fully saturates the ADH receptor, producing the same therapeutic effect as fomepizole. Interestingly, ethanol was traditionally used in the treatment of toxic alcohol ingestion before the creation of fomepizole; however, it is difficult to dose and sclerosing to the veins. Therefore, in the presence of ethanol co-ingestion with one of the toxic alcohols, fomepizole therapy can safely be delayed until the ethanol is metabolized to a level of approximately 100 mg/dL.
Oxycodone is likely contributing to his altered mental status and thus not a reason to defer therapy. Naloxone can serve as a reversal agent for opioids but has no effect on alcohol ingestion. Although propofol can be useful in the treatment of alcohol withdrawal, it does not affect the metabolism of the toxic alcohols and should not replace fomepizole as treatment. Finally, moonshine is likely the source of the patient’s toxic alcohol—methanol—ingestion.
A 36-year-old female is admitted to the ICU for altered mental status after ingestion of an unknown substance in a suicide attempt. Laboratory studies in the emergency department were as follows:
Which of the following calculated values most strongly supports the diagnosis of a toxic alcohol ingestion?
Correct Answer: A
Serum concentration levels of the toxic alcohols are not routinely available at most hospitals in time to guide management; they are more commonly used as confirmatory test. Therefore, the diagnosis of a toxic alcohol management depends on the clinical history, a high index of suspicion, and classic laboratory findings. The toxic alcohols are rapidly absorbed from the gastrointestinal tract to the bloodstream as osmotically active substances. Therefore, measurement of the serum osmolality at or near the time of ingestion can reveal the presence of an osmotically active substance in the blood via an elevated osmolal gap.
The osmolal gap calculates the difference in the concentration of the known osmotically active agents in the blood and the actual concentration of osmotically active agents in the blood (Osmol gap = Measured osmolality − Calculated serum osmolality). A significant difference between the measured serum osmolality and the calculated serum osmolality implies that there is an “unmeasured osmol,” which is likely a toxic alcohol. Although there is some individual variation in the osmolal gap, normal value is <10 and a gap of >25 increases specificity for a toxic ingestion in the proper clinical context.
The calculated osmolality is based on the concentration of the major osmotically active agents in blood: sodium, blood urea nitrogen (BUN), glucose, and ethanol and is calculated as follows:
In this case, the calculated osmolality would be as follows:
The osmolal gap is then calculated as:
In the context of altered mental status, known ingestion of an unknown substance, and an osmolal gap of >25, a presumptive diagnosis of toxic alcohol ingestion can be made and treatment should be initiated while awaiting levels of the toxic alcohol from the lab. Although an elevated anion gap can be present after metabolism of some of the toxic alcohols (eg, methanol, ethylene glycol, and propylene glycol), the anion gap is normal in this patient, likely because of the recent ingestion.
A 41-year-old male was admitted from the emergency department for altered mental status after drinking a bottle of an unknown liquid. A venous blood gas and measures of the serum electrolytes, renal function, and anion gap were all normal and ethanol level was 100 mg/dL. On arrival to the floor, repeat labs demonstrate a measured serum osmolality that is 40 mOsm above the calculated value. The patient is found to be hypotensive and has a pH of 7.05 and an anion gap of 30 mEq. The next osmolal gap is nearly normal.
Which of the following alcohols is NOT likely to be the ingested agent?
Correct Answer: E
On arrival to the hospital, the patient has an elevated osmolal gap but a normal pH. All of the toxic alcohols are rapidly absorbed from the gastrointestinal tract and present in the blood as osmotically active compounds, which explains the initially elevated osmolol gap. (For more explanation of the osmolal gap, please see question 4.) A high osmolal gap in the setting of an ingested liquid is highly suspicious for ingestion of a toxic alcohol. If there is a delay in treatment because of a lack of fomepizole, the patient is able to metabolize the parent compound, which decreases the measured serum osmolality, explaining the near normalization of the osmolal gap. However, all of the toxic alcohols except for isopropyl alcohol (methanol, ethylene glycol, and propylene glycol) are metabolized into organic acids (formic acid, oxalic acid, and lactic acid, respectively) and produce a metabolic acidosis. In addition, because of its interference with mitochondrial respiration, methanol can produce a profound metabolic acidosis both by direct production of formic acid and by shifting cellular metabolism to an anaerobic process. Isopropyl alcohol is metabolized to acetone, which is a ketone, and is the only toxic alcohol that does not produce a metabolic acidosis.
The characteristic laboratory findings of methanol, ethylene glycol, and propylene glycol ingestion are described through the “mountain diagram.” Initially, an elevated osmolal gap predominates whereas the anion gap is normal. Later in the ingestion, an elevated anion gap predominates whereas the osmolal gap is normal.
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