Propylene glycol (PG), or 1,2-propanediol, is a clear, colorless, odorless, sweet, viscous liquid employed in numerous pharmaceuticals (Table 55–9), foods, and cosmetics. Propylene glycol is used as a solvent and preservative with antiseptic properties similar to ethanol. The WHO has set the daily allowable intake of PG at a maximum of 25 mg/kg,172 or 1.75 g/d for a 70-kg person.
TABLE 55–9.Propylene Glycol Concentration of Common Medications ||Download (.pdf) TABLE 55–9. Propylene Glycol Concentration of Common Medications
Propylene glycol is rapidly absorbed from the gastrointestinal tract following oral administration and has a volume of distribution of approximately 0.6 L/kg.108,151 When applied to intact epidermis, the absorption of PG is minimal. Percutaneous absorption may occur following application to damaged skin (eg, extensive burn surface areas). Approximately 12% to 45% of PG is excreted unchanged in the urine,46 the remainder is hepatically metabolized sequentially by alcohol dehydrogenase to lactaldehyde, which is metabolized further by aldehyde dehydrogenase to lactic acid. Lactic acid is also formed by another metabolite, methylglyoxal.120 Lactic acid may be oxidized to pyruvic acid and then to carbon dioxide and water.120 The terminal half-life of propylene glycol is reported to be between 1.4 and 5.6 hours in adults and as long as 16.9 hours in neonates.46,153
Intravenous preparations of phenytoin contain 40% PG to facilitate the dissolution of phenytoin. Nine years after intravenous phenytoin became available, several deaths were attributed to the rapid administration of phenytoin used for the treatment of cardiac dysrhythmias.63,160,182
Cardiovascular effects reported in these cases included hypotension, bradycardia, widening of the QRS interval, increased amplitude of T waves with occasional inversions, and transient ST elevations. Studies in cats100 and calves67 confirmed PG as the cardiotoxin. Bradycardia and depression of atrial conduction were not observed in cats pretreated with atropine, or in those with vagotomy following rapid intravenous infusion of PG, suggesting that these effects are vagally mediated.100 Amplification of the QRS complex was noted in these same pretreated cats, also suggesting a direct cardiotoxic effect of PG. Similar results were reported in calves pretreated with atropine that received oxytetracycline in a PG vehicle.67
Smaller infants appear to have a decreased ability to clear PG when compared with older children and adults.101 An increased frequency of seizures was reported in low-birth-weight infants who received PG 3 g daily in a parenteral multivitamin preparation.101 Seizures developed in an 11 year-old boy receiving long-term oral therapy with vitamin D dissolved in PG.7 Serum calcium, magnesium, electrolytes, and blood glucose were normal. Seizures abated after the product was discontinued. Propylene glycol possesses inebriating properties similar to ethanol. Central nervous system depression was reported following an intentional oral ingestion of a PG-containing product.108
A black-box warning was added to the product information for amprenavir (Agenerase), an oral protease inhibitor solution, because of concerns over its high PG (550 mg/mL) vehicle content.138 The recommended daily dosage of amprenavir supplies 1650 mg/kg/day of PG. A 61 year-old man experienced visual hallucinations, disorientation, tinnitus, and vertigo after receiving a 750-mg dose (474 mg/kg PG) of amprenavir solution.85
Otic preparations can contain up to 94% PG in solutions and 10% in suspensions as part of their vehicles.52 In animal studies, application of high concentrations of PG (> 10%) to the middle ear can produce hearing impairment113,114,166 and morphologic changes, including tympanic membrane perforation, middle ear adhesions, and cholesteatoma.113,154,177 Although the effects of PG in the human middle ear have not been studied, all medications applied to the external ear canal are contraindicated in patients with perforated tympanic membranes.
Fluid, Electrolyte, and Acid–Base Disturbances
Patients receiving continuous or large intermittent quantities of medications containing PG can develop high PG concentrations, particularly those with renal or hepatic insufficiency.27,46 Propylene glycol–induced electrolyte and metabolic disturbances are evidenced by hyperosmolarity, and an elevated osmolar gap attributed to the osmotically active properties of PG. In most cases, an elevated anion gap, with an otherwise unexplained elevated lactate concentration, is also present. Metabolic acidosis and hyperlactatemia result from PG metabolism.26 These adverse effects are typically reported with intravenous preparations such as lorazepam,5,80,179 diazepam,173 etomidate,163 nitroglycerin,46 pediatric multivitamins,65 and topical silver sulfadiazine.12,53,89
Systemic absorption of PG from topical application of silver sulfadiazine cream53 resulted in hyperosmolality in patients with burn surface areas greater than 35% of their body.12,53,89 In one study, nine of 15 burn patients had osmolar gaps (> 12) after application of the cream.89
Hyperosmolarity occurred in five infants receiving a parenteral multivitamin that provided a daily PG dose of 3 g.65 After 12 days, one premature infant had a PG concentration of 930 mg/dL and an osmolar gap of 136. Anion gap and lactic acid concentrations were normal. In a study, 11 intubated children aged 1 to 15 months who were receiving continuous lorazepam infusions over 3 to 14 days, accumulated serum PG concentrations of 17 to 226 mg/dL did not result in significant increases in osmolar gap or serum lactate concentrations from baseline.33 This was attributed to normal renal function and the low cumulative PG doses received (mean, 60 g).
Several small studies have found a strong correlation between elevated PG concentrations and increased osmolar gap measurements in critically ill patients receiving intravenous lorazepam and/or diazepam.6,174,178,179 An osmolar gap greater than 10 has been suggested as a marker for potential PG toxicity and also indicates when to consider obtaining a serum PG concentration.178 An osmolar gap of 20 corresponds to a serum PG concentration of approximately 48 mg/dL.6 This equation should be used cautiously, as larger, more comprehensive studies are needed to validate it. There are rare cases where PG accumulation did not result in an osmolar gap.66,179 In addition, elevated anion gap measurements and lactate concentrations occur. As PG toxicity can mimic sepsis in these critically ill patients, sepsis should always be considered as the potential etiology of increased lactate, hypotension, and worsening renal function when considering PG toxicity. Both hemodialysis and fomepizole have been used to treat PG toxicity.124,181
Human proximal tubular cells exposed in vitro to PG concentrations of 500 to 2000 mg/dL exhibited significant cellular injury and membrane damage within 15 minutes of exposure.116 Repeated exposure for up to 6 days produced dose-dependent toxic effects at lower concentrations (76, 190, and 380 mg/dL).115
The chronic administration of PG may contribute to proximal tubular cell damage and subsequent decreased kidney function. In a retrospective study of eight patients who developed elevations in serum creatinine concentration while receiving continuous lorazepam infusions, serum creatinine rose within 3 to 60 days (median, 9 days).179 The magnitude of serum creatinine rise was found to correlate with the serum PG concentration and duration of infusion. Serum creatinine decreased within 3 days of discontinuing the infusion. Patients with chronic kidney disease are at greater risk for accumulating PG because 45% of PG is eliminated unchanged by the kidneys46; the remainder is metabolized by the liver. Caution should be used when prolonged administration of a PG-containing medication is necessary in the presence of renal or hepatic dysfunction.116
Propylene glycol induced renal tubular necrosis has been reported in several cases. Daily PG vehicle dosages of 11 to 90 g/day over 14 days was associated with rising serum creatinine concentrations (0.7–2.1 mg/dL), elevated serum lactate concentrations, osmolar and anion gaps, and a serum PG concentration of 21 mg/dL.180 Urine sediment analysis revealed numerous granular, muddy-brown-colored casts and no eosinophils, suggesting an acute renal tubular necrosis. Kidney biopsy and electron microscopy showed extensive dilation of the proximal renal tubules, with swollen epithelial cells and mitochondria. Numerous vacuoles containing debris were also noted. A kidney biopsy of another case with a serum PG concentration of 30 mg/dL showed disrupted brush borders of the proximal renal tubules after a sudden rise in serum creatinine concentration (3.1 mg/dL), nonoliguric kidney failure, and metabolic acidosis. This was attributed to an average daily PG dose of 70 g for 17 days.72