In this episode, I’ll discuss iatrogenic propylene glycol toxicity.
Propylene glycol is a diluent for several medications commonly used in critical care – especially diazepam, lorazepam, and phenytoin.
Although propylene glycol is considered safe to use as a diluent by the FDA, the potential for toxicity exists.
The potential consequences of propylene glycol toxicity include agitation, seizure, coma, cardiac arrhythmias, hyperosmolarity, lactic acidosis, hypotension, and multisystem organ dysfunction. There are several case reports and a review of the potential for medications like diazepam and lorazepam to cause propylene glycol toxicity.
In one observational study, out of a group of 21 patients who received propylene glycol containing medications, 19% went on to develop an unexplained anion gap and/or decreased bicarbonate that resolved after stopping propylene glycol containing medications.
A proposed definition of propylene glycol accumulation is the coexistence of both an increased anion gap (>15) and an osmolar gap (>10 mOsm/L) in the presence of a positive propylene glycol level.
One study has suggested that patients are more likely to experience toxicity when the serum propylene glycol concentrations accumulate beyond 25 mg/dL. The study authors proposed a threshold of lorazepam 1mg/kg/day before evaluating patients for the potential for propylene glycol toxicity.
According to current prescribing information, 2 mg of IV lorazepam contains 0.8 mL of propylene glycol. This puts the potentially toxic dose of propylene glycol at 0.4 mL/kg/day.
In addition, 5 mg IV diazepam contains 0.4 ml propylene glycol. This implies that a dose of 5 mg/kg/day of IV diazepam would have the same potential for toxicity as 1 mg/kg/day of lorazepam.
Although phenytoin also contains propylene glycol, toxicity from therapeutic doses of phenytoin due to propylene glycol is unlikely because the dose needed would be 50mg/kg/day of phenytoin, and this is far above what would therapeutically be administered.
These toxicity thresholds may change if a patient has severe renal or hepatic insufficiency. A little less than half of propylene glycol is eliminated by the kidneys, and the rest is metabolized by alcohol dehydrogenase to lactate, pyruvate and acetic acid.
One proposed screening method for patients over the 0.4 ml/kg/day threshold of propylene glycol administration is to check a serum osmol gap. An osmol gap of at least 10 is associated with elevated propylene glycol levels, and an osmol gap of at least 12 is associated with propylene glycol toxicity.
Treatment of known or suspected propylene glycol toxicity involves discontinuing the involved medications and dialysis, either intermittent or continuous renal replacement therapy.
Whether or not fomepizole should be used for propylene glycol toxicity is unknown. A single unsuccessful case report describes fomepizole use in massive IV lorazepam overdose.
Fomepizole would inhibit alcohol dehydrogenase from metabolizing propylene glycol. But what is not determined is what is the mechanism of toxicity? The propylene glycol itself or the metabolites of pyruvate, lactate, and acetic acid? Fomepizole would be either harmful or helpful, respectively depending on the mechanism of toxicity. Until more data is known I would not use fomepizole in a patient with propylene glycol toxicity.
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