Friday May 29, 2009 (pediatric pearl)
What is the risk of excepient toxicity in critically ill children?

Background: Excipients like benzyl alcohol (BA), a preservative, and propylene glycol (PG), the therapeutically inactive components of pharmaceutical products, are increasingly being used in medications routinely administered to critically ill neonates. Generally regarded as inert, prolonged, or large exposures to excipients can be harmful especially of concern in critically ill neonates given their limited metabolic capacity, and the frequency with which they are exposed to medications formulated with BA and PG.

Clinical Presentation: In neonates, BA toxicity has been strongly associated with metabolic acidosis, seizures, and gasping respirations, and PG toxicity has resulted in serum hyperosmolality, seizures, and respiratory arrest. PG and BA are osmotically active and produce a concentration-dependent increase in serum osmolality. For this reason, monitoring of the osmolal gap has been suggested as a means of assessing potential accumulation in patients receiving PG-containing medications at high doses or by continuous infusion.

In a retrospective study the mdian (range) cumulative dose was 4.5 mg/kg/day (0.6–319.5 mg/kg/day) for BA, and 204.9 mg/kg/day (17.3–9472.7 mg/kg/day) for PG. Patients who received medications via continuous infusion received significantly higher excipient doses than patients who received medications intermittently. In this subset of patients, median cumulative excipient doses (BA, 106.3 mg/kg/day and PG, 4554.5 mg/kg/day) were approximately 21 and 180 times the acceptable daily intakes of BA and PG (5 and 25 mg/kg/day), respectively, and exceeded the doses above which toxicity has been reported in infants. Midazolam and lorazepam were involved in over two-thirds of BA and PG exposures, respectively.

Conclusions: Critically ill neonates, especially those receiving medications by continuous infusion, are at risk of being exposed to BA and PG at potentially toxic doses during routine medication administration. Given the serious adverse reactions known to be associated with BA and PG, future studies are warranted to determine the clinical consequences associated with this degree of excipient exposure.

Both BA and PG partially undergo oxidative metabolism in the liver to benzoic acid and lactic acid by-products, respectively. A reduced metabolic capacity to inactivate benzoic acid to hippuric acid in newborns, especially preterm infants, has been suggested as the underlying mechanism of BA toxicity. PG undergoes dose and concentration-dependant clearance and may accumulate, along with is metabolites, in the presence of limited hepatic and renal elimination capacity. The half-life of PG has been reported to be 10–31 hours in neonates compared with 2–5 hours in adults.



Reference: click to get reference

Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. - Pediatric Critical Care Medicine. 10(2):256-259, March 2009.