Diagnostics: Toxic Alcohols
/The term “toxic alcohols” refers to a group of substances which, when metabolized, form toxic metabolites that can lead to organ dysfunction or death. Of the many toxic alcohols, the most commonly ingested and therefore most clinically relevant are methanol, ethylene glycol, propylene glycol, and isopropanol.
These substances are considered “volatile” because they have fewer hydrogen bonds, and therefore less energy is needed for these liquids to turn to gas [1]. Clinically, this is significant because it allows for rapid absorption of these substances from the GI tract. These compounds also readily cross the alveoli [2]. Therefore, early identification and intervention is key, as these compounds reach peak plasma levels soon after ingestion. Methanol reaches this level within 30 to 60 minutes, and ethylene glycol reaches peak plasma level one to four hours after ingestion [3]. Additionally, the high vapor pressure of methanol allows it to be absorbed through intact skin or by inhalation as well [3].
These substances may be ingested accidentally or intentionally. Intentional ingestion may occur in patients with suicidal ideation or in desperate alcoholic patients without access to ethanol. Accidental ingestion typically occurs in children, given ethylene glycol’s sweet taste, or in cases where the substance has been stored in an alternate container suggesting its potability. There have also been several reported incidents of surreptitious administration as a homicide attempt [3]. The following represents the metabolic breakdown of each of these compounds.
Clinical Presentation and Laboratory Markers
Methanol is present in windshield wiper fluid, paint, paint thinners, and wood stains, as well as other household and industrial agents [3,4]. It has also been noted to cause toxicity by inhalation from food-warming cans used in catering (i.e. Sterno brand) [3]. The accumulation of its metabolite, formic acid, leads to retinal and optic nerve toxicity and subsequent blurred (“snowstorm”) vision and ultimately blindness [2]. Although rare, bilateral basal ganglia hemorrhage, most commonly in the putamen, may be seen on CT, and can produce Parkinsonian symptoms [5]. Methanol is eventually broken down to formic acid, which inhibits cytochrome c in the mitochondria. This inhibits aerobic respiration and therefore creates a significant lactic acidosis [6].
Ethylene glycol is most commonly present in antifreeze, but can also be found in several other substances, such as engine coolants and industrial solvents [3]. There are three distinct phases of ethylene glycol toxicity: (1) dose-dependent inebriation, (2) cardiopulmonary phase 12-24 hours after ingestion, and (3) nephrotoxic phase 24-72 hours after ingestion [2]. In ethylene glycol ingestion, dumbbell and needle-shaped calcium oxalate monohydrate or envelope-shaped calcium oxalate dihydrate crystals may be seen in the urine [7]. As ethylene glycol metabolizes to oxalate, oxalate binds calcium and precipitates to form stones. These stones can accumulate in the body, most often in the kidneys, and cause acute renal failure. This is thought to be due to obstructive nephropathy as well as direct toxicity and acute tubular necrosis secondary to oxalate [3]. In order to assess for calcium oxalate crystals in the urine, order a urinalysis with microscopy. Consider assessing for hypocalcemia in suspected ethylene glycol toxicity, as precipitation of calcium oxalate crystals has been reported to decrease serum calcium levels [3]. Ethylene glycol can also prolong the QRS or QTc due to its effects on serum calcium. In ethylene glycol ingestion, the patient’s urine may appear fluorescent under Wood’s lamp [3]. This is due to the presence of sodium fluorescein that is added to antifreeze to help assess for radiator leaks. The clinician may also use this method to assess the patient’s mouth, vomitus, or clothing for the presence of fluorescence [8]. This finding, however, has poor sensitivity and specificity for ethylene glycol toxicity, and therefore should not be used to rule toxicity in or out [9].
Propylene glycol toxicity can be seen in patients receiving parenteral medications for which propylene glycol is used as a diluent, including diazepam, lorazepam, phenobarbital, phenytoin, and nitroglycerin. This is one of the reasons that fosphenytoin is preferred to phenytoin for use as a loading dose, as it does not contain propylene glycol [10]. Additionally, propylene glycol is now also being used in some formulations of antifreeze, as it has a more unpleasant taste and is less toxic than ethylene glycol. This is because it metabolizes to lactic acid rather than other, more toxic metabolites [3]. In contrast with methanol, lactic acidosis in propylene glycol toxicity occurs because lactic acid is produced as a direct metabolite.
Isopropanol can be found in hand sanitizer and rubbing alcohol. Isopropanol is broken down to acetone, and therefore the clinician may test for ketones if there is high suspicion for isopropanol ingestion. Some institutions have the ability to test for acetone directly, a more indirect measure may be obtained by testing serum ketones if direct laboratory testing is unavailable. This is due to the fact that high levels of acetone may cause a positive nitroprusside reaction when testing for acetoacetate [5].
Intoxication with each of these substances can produce CNS depression, GI distress in those ingested orally, and increased osmolar gap. The following table highlights the key differences in clinical presentation and laboratory testing specific to each of these substances [5].
Testing
In an acutely altered patient, assess the patient’s airway, breathing, and circulation. Obtain basic initial testing as you otherwise would in a patient with altered mental status, including vital signs, fingerstick glucose and EKG.
Ingestion and intoxication with these substances can be detected by a number of laboratory studies. These compounds are osmotically active, and therefore osmolar gap >10 mOsm/kg can provide a surrogate marker for the presence of unmetabolized toxic alcohols.
These substances are often co-ingested with ethanol, which can affect the patient’s osmolar gap. Alcohol dehydrogenase is responsible for the breakdown of ethanol as well as the toxic alcohols, so its co-ingestion will actually compete for the enzyme and delay the metabolism of the toxic alcohol. Obtain an ethanol level in order to assess for co-ingestion as well as to accurately calculate the patient’s osmolar gap.
Calculating Osmolar Gap
Calculated Osmolality = [2 x Na] + [Glu/18] + [BUN/2.8] + [Ethanol/3.7]
Osmolar Gap= measured serum osmolality – calculated serum osmolality
Be sure to use caution when using osmolar gap to assess for toxic alcohol ingestion. Other conditions or circumstances may increase the osmolar gap due to an increased level of osmotically active solute, including hyperglycemia, mannitol therapy, and renal failure (due to increased levels of urea) [11]. Other conditions may cause a decrease in the measured serum osmolality. These examples include hyperlipidemia and hyperproteinemia, as they cause pseudohyponatremia, which in turn affects the measured serum osmolality.
Another difficulty in using osmolar gap is that it assesses the presence of unmetabolized toxic alcohols. As these compounds are metabolized to acids, the osmolar gap begins to close and a high anion gap metabolic acidosis begins to form [3]. Be sure to obtain a basic metabolic panel (BMP) in order to calculate anion gap, as well as a blood gas in order to determine the patient’s pH status. Testing for APAP and salicylates should be performed to assess for co-ingestion, especially in an altered patient who is not able to provide a history.
Gas chromatography is the gold standard laboratory test to evaluate for the presence and degree of toxic alcohol intoxication. This test provides a quantitative value of the unmetabolized alcohol. However, if the parent compound has already metabolized at the time of patient presentation, this could produce a false negative [11]. This test should result in approximately 45-60 minutes, depending on the availability of a toxicology-trained laboratory technician.
There may be a panel of individual orders available for ethanol, methanol, isopropyl alcohol, acetone, and ethylene glycol [12]. Order serum osmolality, which will provide the patient’s measured osmolar gap. Compare this to your calculated osmolar gap, either using your renal panel or by calculating it using the equation. If the patient has an ethanol co-ingestion, the calculated osmolar gap that comes in your renal panel will be inaccurate.
Management
If you suspect intoxication with one of these substances, contact your local poison control center.
American Association of Poison Control Centers - (800) 222-1222
Historically, intravenous ethanol has been administered to these patients as a competing substrate for alcohol dehydrogenase. While some facilities maintain this practice, there has been a shift towards using fomepizole, as the dosing is more consistent and it has a more favorable side effect profile [13]. Fomepizole acts as an alcohol dehydrogenase inhibitor [14]. The use of ethanol or fomepizole does not prevent the formation of toxic metabolites, but rather works by slowing the breakdown of these compounds and allowing for elimination of these metabolites before they reach toxic levels. At our facility, treatment of fomepizole is initiated for documented cases of ingestion when serum ethylene glycol or methanol concentration ≥20 mg/dL or when osmolal gap >25 mOsm/L. In cases of suspected ingestion, the patient must have two of the following: arterial pH <7.3, osmolal gap >25 mOsm/L, serum carbon dioxide <20 mmol/L, or oxalate crystals (if ethylene glycol is suspected). Dosing of this medication is weight-based and depends on whether or not the patient is on hemodialysis. For further details, refer to your institutional guideline on treatment of ethylene glycol and methanol toxicity, for an example here is ours.
In the case of methanol and ethylene glycol, the most lethal of the compounds discussed, hemodialysis can be used to eliminate both the parent compound and the toxic metabolites [3]. A typical protocol may have hemodialysis initiated in these patients if the glycolic acid level is >8 mmol/L15.
Other criteria for the initiation of hemodialysis have also been described, including serum methanol or ethylene glycol level >50 mg/dL, arterial blood pH <7.3, renal failure, visual disturbance (if methanol intoxication is suspected), worsening clinical status, or electrolyte abnormality [3].
Cofactor therapy may also be added to the treatment regimen in order to accelerate the metabolism of toxic compounds. According to guidelines, in ethylene glycol toxicity, the recommended regimen includes pyridoxine 50 mg IV q6h, thiamine 100 mg IV q6h, and magnesium 1 g IV. For methanol toxicity, leucovorin 50 mg IV q4h (preferred) or folate 50 mg IV q4h [15] can facilitate metabolization.
In contrast with the above treatment methods for methanol and ethylene glycol, the management of propylene glycol and isopropanol varies. Both may be managed with supportive care, and the clinician may consider hemodialysis based on the severity. In propylene glycol toxicity, treatment must also include discontinuation of the offending agent. [5]
As in other acidotic conditions, approach the topic of intubation in these conditions with extreme caution. If the patient’s respirations cannot be matched with ventilator settings, intubation and mechanical ventilation will worsen the patient’s acidosis.
Quick Hits
Consider toxic alcohol ingestion in patients whose history supports this intoxication, those whose inebriation is inconsistent with ethanol ingestion or who have additional symptoms, and in children
Calculate the patient’s osmolar gap
Test for co-ingestions
Contact poison control
Discontinue offending agent
Initiate fomepizole per guidelines
Consider hemodialysis if patient meets criteria
Consider cofactor administration
Post by Alexis Kimmel, MD
Dr. Kimmel is a PGY-1 resident in Emergency Medicine at the University of Cincinnati
Editing and Peer Review by Susan Owens, MD and Ryan LaFollette, MD
Dr. Owens is a PGY-4 at the University of Cincinnati and Dr. LaFollette is a PGY-8 and APD
References
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Busti, A. J., PharmD. (2015, August). Medications Containing Propylene Glycol and Risk of Anion Gap Metabolic Acidosis. Retrieved from https://www.ebmconsult.com/articles/medications-containing-propylene-glycol-risk-anion-gap-metabolic-acidosis
Mcquade, D. J., Dargan, P. I., & Wood, D. M. (2014). Challenges in the diagnosis of ethylene glycol poisoning. Annals of Clinical Biochemistry, 51(2), 167-178. doi:10.1177/0004563213506697
Toxicology. (n.d.). Retrieved from https://www.uchealth.com/laboratory/services-departments/clinical-lab/toxicology/
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