Consumption of toxic alcohols other than ethanol continues to be a public health problem . The most common toxic alcohols are ethylene glycol, isopropanol, and methanol. All three compounds are found in products that are easily obtained (ethylene glycol in most automobile antifreezes, isopropanol in 'rubbing alcohol', and methanol in windshield cleaner fluid and some other products). Ethylene glycol and methanol are particularly dangerous in overdose, due to their metabolites that can cause severe organ damage [1–6].
Ethylene glycol is metabolized by a series of steps to glycolic acids and oxalic acid, the latter with the potential to cause severe renal injury [2–5]. Methanol is likewise metabolized by a series of enzymatic reactions to formic acid, a toxic compound that can cause blindness from permanent injury to the optic nerve. Both ethylene glycol and methanol are capable of causing marked metabolic acidosis, mainly due to their metabolites. Following ingestion of ethylene glycol or methanol, an osmolal gap appears first and an anion gap appears later after conversion to acidic metabolites [1–5]. Isopropanol is generally less toxic than ethylene glycol or methanol, as it is primarily metabolized to acetone [7, 8]. However, in addition to the organ damage caused by metabolites of ethylene glycol and methanol, all three toxic alcohols are capable of producing central nervous system (CNS) depression that in and of itself may be life-threatening [1, 4].
The definitive laboratory method for detecting and quantitating toxic alcohols in the serum/plasma is gas chromatography (GC) . However, this technique is labor-intensive and not available at most clinical laboratories associated with hospitals and medical centers, with the exception of some larger medical center laboratories. Consequently, this analysis is generally performed at remote reference laboratories, often precluding a turnaround time of 2-4 hr as recommended by a consensus panel for optimal management of patients ingesting ethylene glycol or methanol .
Diagnosis of toxic alcohol ingestion therefore often relies on clinical signs and symptoms along with indirect evidence from laboratory tests such as arterial blood gas analysis (to detect acidosis), serum osmolality (to estimate osmolal gap, OG), and common chemistry tests (to calculate anion gap). Prompt diagnosis of toxic alcohol poisoning can provide major benefit to patients. If diagnosed early enough, ethylene glycol and methanol poisonings are usually treated effectively by administration of either ethanol or fomepizole, both of which inhibit the rate-limiting first step in the metabolism of ethylene glycol or methanol by alcohol dehydrogenase and thus prevent the formation of toxic metabolites [2, 3, 9, 10]. Toxic alcohol ingestions that are not diagnosed early often require hemodialysis to clear both the parent compounds and metabolites, although end-organ damage may already have occurred. Conversely, an erroneous false diagnosis of toxic alcohol ingestion has the downside of increased expense and potential adverse effects related to antidotal therapy and/or hemodialysis.
The OG is determined by measuring serum osmolality (e.g., by freezing point depression) and then using a formula to calculate the osmolality contribution of the endogenous major contributors to serum osmolality, namely sodium, blood urea nitrogen (BUN), and glucose, which are standard chemistry tests frequently ordered in patients with potential toxic alcohol ingestions [11, 12]. The OG is the measured osmolality minus the estimated osmolality. There are also formulae to account for the presence of serum ethanol (if present). There is considerable debate over the use of OG to diagnose toxic alcohol ingestions, and also a plethora of formulae proposed for estimating the contribution of sodium, BUN, glucose, and ethanol to serum osmolality [8, 11–29]. An elevated OG (often defined as greater than a threshold between 10 and 15) suggests the presence of osmotically active substances other than sodium, BUN, glucose, and ethanol. The differential diagnosis for elevated OG includes a variety of conditions other than toxic alcohol ingestion such as alcoholic ketoacidosis [23, 30–32], mannitol infusion [33, 34], renal failure [35, 36], and shock [37, 38]. In some of these conditions (e.g., shock), the exact osmotically active compounds are not exactly known. Alcoholic ketoacidosis can produce a substantial osmolal gap even in the absence of detectable plasma ethanol due to the formation of glycerol, acetone, and the acetone metabolites acetol and 1,2-propanediol .
An additional toxic alcohol compound that can cause an elevated OG is propylene glycol [1, 39]. Although chemically similar to ethylene glycol (and also used in some automobile antifreezes), propylene glycol is generally much less toxic than ethylene glycol. Propylene glycol is found in a variety of products including cosmetics, ointments, some activated charcoal preparations, and as a diluent for intravenous preparations of poorly water-soluble drugs such as diazepam, etomidate, and lorazepam. Propylene glycol toxicity has been described in overdoses of propylene glycol-containing antifreeze . A number of studies have detailed propylene glycol toxicity from repeated intravenous administrations of medications containing propylene glycol as the diluent, particularly lorazepam used for extended sedation (e.g., for patients who are intubated for mechanical ventilation) [41–45].
In this study, we performed a retrospective analysis of toxic alcohol and OG analyses in a timespan of nearly 15 years at a tertiary care academic medical center. The primary objectives were to assess the diagnostic accuracy of OG as a test for screening for toxic alcohol ingestion and to define the common causes of elevated OG in the absence of toxic alcohol ingestion. The study conforms to the Standards for Reporting Diagnostic Accuracy (STARD) statement criteria [46, 47].