A Prospective Evaluation of Propylene Glycol Clearance and Accumulation During Continuous-Infusion Lorazepam in Critically Ill Patients

Abstract

Propylene glycol is a commonly used diluent in several pharmaceutical preparations, including the sedative lorazepam. Fifty critically ill patients receiving continuous-infusion lorazepam for a minimum of 36 hours were prospectively evaluated to determine the extent of propylene glycol accumulation over time, characterize propylene glycol clearance in the presence of critical illness, and develop a pharmacokinetic model that would predict clearance based on patient-specific clinical, laboratory, and demographic factors. In this cohort, the median lorazepam infusion rate was 2.1 mg/h (0.5-18). Propylene glycol concentration correlated poorly with osmolality, osmol gap, and lactate. In all, 8 patients (16%) had significant propylene glycol accumulation (>25mg/dL). When propylene glycol concentrations were >25 mg/dL, the median lorazepam infusion rate before sample collection was higher, 6.4 (1.9-11.3) versus 2.0 (0.5-7.4) mg/h (P =.0003). A linear first-order model with interoccasion variability on clearance adjusted for total body weight and Acute Physiology and Chronic Health Evaluation II score predicted propylene glycol concentration.

Management of acute lung injury and acute respiratory distress syndrome in children

“…Intravenous infusion of lorazepam must be used carefully in children due to the risk of propylene glycol toxicity (66). Propofol is contraindicated for long-term use in children for sedation in the intensive care unit due to the risk of potentially fatal propofol infusion syndrome leading to rhabdomyolisis, metabolic acidosis, and multiple organ failure (67).…”

Prospective assessment of short-term propylene glycol tolerance in neonates

“…The toxicity was both clinical (seizures) and biochemical (hyperosmolarity, lactic acidosis, raised plasma creatinine and bilirubin) 3 4 8. The same group estimated PG elimination half-life to be 10–31 h in neonates compared to 2–5 h in adults, but they were unable to explain the interindividual variability within their cohort of neonates 4.…”

“…Other side effects such as haemolysis, mental status changes or renal toxicity (eg, renal tubular acidosis, acute tubular necrosis resulting in increased creatinaemia and oliguria) have been reported as manifestations of PG accumulation and toxicity 2–9. Most of the case reports in adults relate to continuous intravenous administration of sedatives (ie, lorazepam, diazepam) with co-administration of PG 6–8…”

“…Toxicity to PG in preterm neonates has been reported following exposure of up to 3000 mg/day for at least 5 days 3 4 8. The toxicity was both clinical (seizures) and biochemical (hyperosmolarity, lactic acidosis, raised plasma creatinine and bilirubin) 3 4 8.…”

Determination of Propylene Glycol in Low Volume Plasma and Urine Samples of Neonates by LC with Photodiode Array Detection

“…Although it is considered safe for use in humans with a maximum exposure of 25 mg kg -1 day -1 [1], side effects as lactic acidosis, increase in anion or osmolar gap, hyponatriaemia, haemolysis, mental status changes, hepatic and renal toxicity have been increasingly reported as manifestations of PG accumulation and toxicity in adults [2][3][4][5][6]. Hyperosmolarity and lactic acidosis were also observed in pediatric patients [7,8] and American Academy of Pediatrics has identified PG as a potentially dangerous additive [9].…”