Relationship of continuous infusion lorazepam to serum propylene
glycol concentration in critically ill adults*
Alejandro C. Arroliga, MD; Nadine Shehab, PharmD; Kevin McCarthy, RCPT;
Jeffrey P. Gonzales, PharmD, BCPS
P
ropylene glycol (PG) is used as
a solvent for intravenous, oral,
and topical pharmaceutical
preparations, including intra-
venous lorazepam. Chronic or large in-
gestions of PG have been implicated in
the development of hyperosmolar meta-
bolic acidosis (1– 8) as well as serious
toxicities, including renal dysfunction (4,
9 –12), intravascular hemolysis (13), car-
diac 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 loraz-
epam doses that exceed the upper limit of
the recommended lorazepam dosage
range (0.1 mg·kg
-1
·hr
-1
) (19). Therefore,
patients requiring large doses of loraz-
epam for sedation may be at risk for PG
accumulation. Each vial of lorazepam (2
mg/mL) contains 0.8 mL (830 mg) of
PG/mL, and critically ill patients could
receive more than the recommended
daily amount of PG (25 mg·kg
-1
·day
-1
)
(20).
Lorazepam is the medication of choice
for maintenance sedation in the critically
ill population (19). Currently, there is a
paucity of data describing lorazepam-
induced PG accumulation and/or toxicity
in critically ill adults, with the majority of
literature consisting of case reports or
case series. Furthermore, interpretation
of the existing literature is limited by a)
the diversity of patients (age, renal fail-
ure, and/or liver failure) in whom PG
accumulation has been described; b) in-
consistency in the criteria used to define
PG accumulation; and c) variability in the
lorazepam dose received and reported PG
concentrations. Moreover, PG accumula-
tion 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– 8, 19).
To help elucidate the occurrence of
PG accumulation, we undertook a pro-
spective, observational study in critically
ill patients receiving high-dose loraz-
epam (HD-LZ) by continuous infusion.
We also wanted to determine whether PG
accumulation occurred early in therapy
(at 48 hrs) because most of the data de-
scribing PG accumulation involve infu-
*See also p. 1800.
From The Cleveland Clinic Foundation, Department
of Pulmonary and Critical Care Medicine (ACA, KM) and
Department of Pharmacy (NS, JPG), Cleveland, OH.
Address request for reprints to: Jeffrey P. Gonza-
les, PharmD, BCPS, Cleveland Clinic Foundation, De-
partment of Pharmacy/QQb5, 9500 Euclid Avenue,
Cleveland, OH 44195. E-mail: gonzalj@ccf.org
Copyright © 2004 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/01.CCM.0000134831.40466.39
Objectives: The primary objective was to evaluate the relation-
ship between high-dose lorazepam and serum propylene glycol
concentrations. Secondary objectives were a) to document the oc-
currence of propylene glycol accumulation associated with continu-
ous high-dose lorazepam infusion; b) to assess the relationship
between lorazepam dose, serum propylene glycol concentrations,
and propylene glycol accumulation; and c) to assess the relationship
between the osmol gap and serum propylene glycol concentrations.
Design: Prospective, observational study.
Setting: Tertiary care, medical intensive care unit.
Patients: Nine critically ill adults receiving high-dose loraz-
epam (>10 mg/hr) infusion.
Interventions: Cumulative lorazepam dose (mg/kg) and the
rate of infusion (mg·kg
1
·hr
1
) were monitored from initiation of
lorazepam infusion until 24 hrs after discontinuation of the high-
dose lorazepam infusion. Serum osmolarity was collected at 48
hrs into the high-dose lorazepam infusion and daily thereafter.
Serum propylene glycol concentrations were drawn at 48 hrs into
the high-dose lorazepam infusion, and the presence of propylene
glycol accumulation, as evidenced by a high anion gap (>15
mmol/L) metabolic acidosis with elevated osmol gap (>10 mOsm/
L), was assessed at that time.
Measurements and Main Results: The mean cumulative high-
dose lorazepam received and mean high-dose lorazepam in-
fusion rate were 8.1 mg/kg (range, 5.1–11.7) and 0.16
mg·kg
1
·hr
1
(range, 0.11– 0.22), respectively. A significant
correlation between high-dose lorazepam infusion rate and
serum propylene glycol concentrations was observed (r
2
.557, p .021). Osmol gap was the strongest predictor of
serum propylene glycol concentrations (r
2
.804, p .001).
Propylene glycol accumulation was observed in six of nine
patients at 48 hrs. No significant correlation between duration
of lorazepam infusion and serum propylene glycol concentra-
tions was observed (p .637).
Conclusions: Propylene glycol accumulation, as reflected by a
hyperosmolar anion gap metabolic acidosis, was observed in criti-
cally ill adults receiving continuous high-dose lorazepam infusion for
>48 hrs. Study findings suggest that in critically ill adults with
normal renal function, serum propylene glycol concentrations may be
predicted by the high-dose lorazepam infusion rate and osmol gap.
(Crit Care Med 2004; 32:1709 –1714)
KEY WORDS: lorazepam; propylene glycol; toxicity; sedation;
adults; osmol gap
1709 Crit Care Med 2004 Vol. 32, No. 8