Comment: Possible Toxicity from Propylene Glycol in Lorazepam Infusion

Relationship of continuous infusion lorazepam to serum propylene glycol concentration in critically ill adults*

“…Patients were also excluded if they presented with ethanol, methanol, or ethylene glycol intoxication or if they received medications or compounds that would affect the osmol gap. Table 1 lists some parenteral medications containing PG that may be administered to critically ill patients (2,7,29).…”

“…Furthermore, interpretation of the existing literature is limited by a) the diversity of patients (age, renal failure, and/or liver failure) in whom PG accumulation has been described; b) inconsistency in the criteria used to define PG accumulation; and c) variability in the lorazepam dose received and reported PG concentrations. Moreover, PG accumulation has been described over a wide range of cumulative lorazepam doses (1124 -7226 mg), serum PG concentrations (12.0 -130.8 mg/dL), and infusion periods (2-24 days) (1)(2)(3)(4)(5)(6)(7)(8)19).…”

“…Chronic or large ingestions of PG have been implicated in the development of hyperosmolar metabolic acidosis (1)(2)(3)(4)(5)(6)(7)(8) as well as serious toxicities, including renal dysfunction (4, 9 -12), intravascular hemolysis (13), cardiac arrhythmias (14), seizures (15), and central nervous system depression (16 -18). The predominant manifestation of PG accumulation is a high anion gap metabolic acidosis with elevated osmol gap, most commonly reported with lorazepam doses that exceed the upper limit of the recommended lorazepam dosage range (0.1 mg·kg Ϫ1 ·hr Ϫ1 ) (19).…”

Osmol Gap as a Surrogate Marker for Serum Propylene Glycol Concentrations in Patients Receiving Lorazepam for Sedation

“…After reviewing the range of propylene glycol concentrations (12-520 mg/dl) reported to cause toxicity during patient exposure to lorazepam, we set our potentially toxic propylene glycol concentration threshold at 25 mg/dl. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] This value represents the 25th percentile of serum propylene glycol concentrations reported in these cases of toxicity (i.e., in 75% of cases, serum propylene glycol concentrations were ≥ 25 mg/dl). Using this threshold, we evaluated the sensitivity and specificity of our linear regression equations by comparing the results with the actual serum propylene glycol concentrations determined in our laboratory.…”

Enhancement of GABAergic Activity: Neuropharmacological Effects of Benzodiazepines and Therapeutic Use in Anesthesiology

“…The dosing threshold for this effect has not been prospectively defined, but doses exceeding 20 mg/h and continued for longer than 4 weeks, and higher doses (Ͼ25 mg/h) continuing for hours to days have been proposed (Laine et al, 1995;Seay et al, 1997;Arbour, 1999). Toxicity from propylene glycol has been attributed to direct effects and its metabolites, lactate and pyruvate (generated by hepatic alcohol dehydrogenase), resulting in hyperosmolar states, cellular toxicity, metabolic acidosis, and acute tubular necrosis (Barnes et al, 2006).…”