Download Relationship of continuous infusion lorazepam to serum propylene

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
Objectives: The primary objective was to evaluate the relationship between high-dose lorazepam and serum propylene glycol
concentrations. Secondary objectives were a) to document the occurrence of propylene glycol accumulation associated with continuous 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 lorazepam (>10 mg/hr) infusion.
Interventions: Cumulative lorazepam dose (mg/kg) and the
rate of infusion (mg·kgⴚ1·hrⴚ1) were monitored from initiation of
lorazepam infusion until 24 hrs after discontinuation of the highdose 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.
P
ropylene glycol (PG) is used as
a solvent for intravenous, oral,
and topical pharmaceutical
preparations, including intravenous lorazepam. Chronic or large ingestions of PG have been implicated in
the development of hyperosmolar metabolic acidosis (1– 8) as well as serious
toxicities, including renal dysfunction (4,
9 –12), intravascular hemolysis (13), cardiac arrhythmias (14), seizures (15), and
*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. Gonzales, PharmD, BCPS, Cleveland Clinic Foundation, Department of Pharmacy/QQb5, 9500 Euclid Avenue,
Cleveland, OH 44195. E-mail: [email protected]
Copyright © 2004 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/01.CCM.0000134831.40466.39
Crit Care Med 2004 Vol. 32, No. 8
Measurements and Main Results: The mean cumulative highdose lorazepam received and mean high-dose lorazepam infusion rate were 8.1 mg/kg (range, 5.1–11.7) and 0.16
mg·kgⴚ1·hrⴚ1 (range, 0.11– 0.22), respectively. A significant
correlation between high-dose lorazepam infusion rate and
serum propylene glycol concentrations was observed (r2 ⴝ
.557, p ⴝ .021). Osmol gap was the strongest predictor of
serum propylene glycol concentrations (r2 ⴝ .804, p ⴝ .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 concentrations was observed (p ⴝ .637).
Conclusions: Propylene glycol accumulation, as reflected by a
hyperosmolar anion gap metabolic acidosis, was observed in critically 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
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⫺1·hr⫺1) (19). Therefore,
patients requiring large doses of lorazepam 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 lorazepaminduced 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 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– 8, 19).
To help elucidate the occurrence of
PG accumulation, we undertook a prospective, observational study in critically
ill patients receiving high-dose lorazepam (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 describing PG accumulation involve infu1709
sion periods ⬎48 hrs. The primary objective was to evaluate the relationship
between continuous infusion of HD-LZ
(ⱖ10 mg/hr) and serum PG concentrations early during therapy (at 48 hrs into
HD-LZ infusion). Secondary objectives
were a) to document the occurrence of
PG accumulation associated with continuous HD-LZ infusion; b) to assess the
relationship between lorazepam dose, serum PG concentrations, and PG accumulation; and c) to assess the relationship
between the osmol gap and serum PG
concentrations, all at 48 hrs into HD-LZ
infusion.
MATERIALS AND METHODS
This study was approved by our Institutional Review Board, and written informed
consent for participation in the study was obtained. Our medical intensive care unit
(MICU) sedation guidelines recommend lorazepam by intermittent bolus or continuous infusion as the benzodiazepine of choice for
maintenance sedation, which is consistent
with the current Society of Critical Care Medicine Sedation Guidelines (19). Sedation is
used only after the provision of adequate analgesia and is titrated and reevaluated daily
using the Motor Activity Assessment Scale
(21). By clinical observation, in our patient
population, a dose of lorazepam of ⱖ10 mg/hr
corresponds to a dose of ⱖ0.1 mg·kg⫺1·hr⫺1,
which is the upper limit suggested by the
Society of Critical Care Medicine Sedation
Guidelines (19). MICU patients receiving
HD-LZ (ⱖ10 mg/hr) were eligible for enrollment. Patients were excluded if they received
other PG-containing medications by continuous or intermittent infusion or if they were
undergoing dialysis. 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).
Patient characteristics collected at baseline
included patient age, gender, weight, admitting diagnosis, and Acute Physiology and
Chronic Health Evaluation II score at admission. Laboratory variables (serum sodium, potassium, chloride, glucose, blood urea nitrogen, creatinine, alkaline phosphatase,
bilirubin, alanine aminotransferase, aspartate
aminotransferase), as well as arterial blood
gases (pH, PaCO2, PaO2, HCO3, oxygen saturation), were monitored daily throughout the
study period. Creatinine clearance was calculated using the Cockcroft-Gault equation (22).
After enrollment, data were collected from the
time the lorazepam infusion was initiated un-
1710
Table 1. Commonly used intravenous drugs containing propylene glycol
Drug
Amount of Propylene
Glycol (% v/v)
Lorazepam, 2 mg/mL
Phenobarbital, 30–130 mg/mL
Diazepam, 5 mg/mL
Pentobarbital, 50 mg/mL
Phenytoin, 50 mg/mL
Trimethoprim-sulfamethoxazole, 16:80 mg/mL
Etomidate, 2 mg/mL
Nitroglycerin, 5 mg/mL
Esmolol, 250 mg/mL
80
67.8–75
40
20–40
40
40
35
30
25
Data adapted (2, 7, 29).
til the start of HD-LZ. Subsequent data were
collected until 24 hrs after discontinuation of
the HD-LZ infusion. Serum osmolality was
collected 48 hrs into the HD-LZ infusion and
daily thereafter. Osmol gap was calculated using the following formula: (measured osmolality) ⫺ (calculated osmolarity), where calculated osmolarity ⫽ ([2 ⫻ sodium] ⫹ [glucose/
18] ⫹ [blood urea nitrogen/2.8]) (23). Anion
gap values were corrected for serum albumin,
based on the principle that for every 1 g decline in the serum albumin, a 2.5 mmol/L
decrease in the anion gap occurs (24). Also,
serum potassium concentration was not used
to calculate the anion gap. Serum PG concentrations were drawn 48 hrs into the HD-LZ
infusion. The presence of PG accumulation, as
evidenced by a hyperosmolar, high anion gap
metabolic acidosis, was also assessed at that
time. Anion gap of ⱖ15 mmol/L and osmol
gap of ⱖ10 mOsm/L were considered clinically
significant (based on our hospital laboratory’s
reference values). All serum PG samples were
sent to an outside laboratory, and gas chromatography was used for quantitative analysis
(National Medical Services, Willow Grove, PA).
Lorazepam doses were documented daily
throughout the study period. The cumulative
dose was defined as the total amount (mg/kg)
of lorazepam received from the point the infusion started until the serum PG concentration was drawn. Cumulative HD-LZ was defined as the total amount (mg/kg) of
lorazepam received from the point the HD-LZ
infusion started until the serum PG concentration was drawn. The mean rate of infusion
(mg·kg⫺1·hr⫺1) was also calculated for the
cumulative lorazepam dose as well as the cumulative HD-LZ period. The cumulative PG
dose received was also calculated based on the
amount of PG (830 mg) found in the 2-mg/mL
injectable lorazepam formulation (Ativan,
Wyeth Laboratories, Philadelphia, PA) (20).
Statistical analyses were performed using
Sigma Stat version 2.03 (SPSS, Chicago, IL).
Changes over time, for variables measured at
multiple time points, were examined using the
one-way repeated measures analysis of variance. Correlation coefficients were calculated
using the Pearson product moment correlation. Linear regression analysis was used to
examine the relationship between lorazepam
dose, lorazepam infusion rate, osmol gap, and
serum PG.
RESULTS
From January 1, 2003, to May 9,
2003, 70 consecutive intubated patients
were initiated on a lorazepam infusion;
19 (27.1%) patients received HD-LZ.
Ten patients were excluded, seven because they were undergoing dialysis
and three patients for whom informed
consent could not be obtained. Nine
patients who received HD-LZ for ⱖ48
consecutive hours were enrolled in the
study. The majority of patients were
male (six males), with a mean age of 43
yrs (range, 20 – 62 yrs), mean weight of
95 kg (range, 73–130 kg), mean height
of 65 inches (range, 50 –73 inches), and
mean Acute Physiology and Chronic
Health Evaluation II score of 21 (range,
11–37). Acute respiratory failure due to
acute respiratory distress syndrome (n ⫽ 7)
was the predominant reason for MICU admission. Septic shock (n ⫽ 1) and fatty
liver of pregnancy (n ⫽ 1) were the other
admitting diagnoses. Patient characteristics are displayed in Table 2. All study patients had a calculated creatinine clearance
ⱖ50 mL/min at baseline. Elevated bilirubin
(⬎1.2 mg/dL) was noted in three patients.
In all patients, lorazepam was being used
for sedation, concomitantly with opiates,
during mechanical ventilation. The mean
MICU length of stay was 23.3 ⫾ 15.0 days.
Four of nine patients died in the MICU.
The mean cumulative lorazepam dose
received was 12.3 mg/kg (range, 7.5–
18.5), and the mean rate of infusion was
0.12 mg·kg⫺1·hr⫺1 (range, 0.06 – 0.21).
The mean cumulative HD-LZ received
was 8.1 mg/kg (range, 5.1–11.7), and the
mean rate of infusion during the HD inCrit Care Med 2004 Vol. 32, No. 8
fusion period was 0.16 mg·kg⫺1·hr⫺1
(range, 0.11– 0.22). The mean duration of
lorazepam infusion during the study period was 4.9 days (range, 2.1–12.4), and
all patients received HD-LZ for a mean
duration of 3.9 days (range, 2.0 – 6.8). Serum PG concentrations were obtained at
a mean of 50.4 ⫾ 3.6 hrs, and the mean
serum PG concentration was 199.6
mg/dL (range, 94 –350). The mean cumulative PG dose was 1219 mg/kg per day.
With regard to lorazepam dose, no significant correlation between cumulative
lorazepam dose (mg/kg) received and serum PG concentrations was found (p ⫽
.918). However, a significant correlation
was observed between cumulative HD-LZ
(mg/kg) and serum PG concentrations (r2
⫽ .481, p ⫽ .038) as well as HD-LZ infusion rate (mg·kg⫺1·hr⫺1) and serum PG
concentrations (r2 ⫽ .557, p ⫽ .021; Fig.
1). Also, no significant correlation between duration of lorazepam infusion and
serum PG concentrations was observed (p
⫽ .637).
Laboratory findings consistent with
PG accumulation (hyperosmolar, high
anion gap metabolic acidosis) were observed in six of nine (66.7%) patients.
Two of these patients had evidence of
elevated bilirubin at baseline. However,
all patients had an elevated osmol gap at
48 hrs, and the mean osmol gap was 48.0
(range, 24.3– 67.1; Table 3). There were
significant laboratory changes over time
in the osmol gap and corrected anion
gap. The corrected anion gap at 48 hrs
into HD-LZ was higher compared with 24
hrs after discontinuation of HD-LZ, 16.8
vs. 15.1, respectively (p ⫽ .025). Also, the
osmol gap decreased from 72 hrs into
HD-LZ compared with 24 hrs after the
discontinuation of HD-LZ, 47.7 vs. 40.1,
respectively (p ⫽ .025). The mean serum
creatinine did not change significantly
from baseline to the end of the HD-LZ
period (p ⫽ .650). The osmol gap strongly
correlated with serum PG concentrations
at 48 hrs (r2 ⫽ .804, p ⫽ .001; Fig. 2).
DISCUSSION
This is the first prospective study in
critically ill adults correlating serum PG
concentrations with the cumulative
amount of HD-LZ (mg/kg) and rate of
infusion of HD-LZ (mg·kg⫺1·hr⫺1). A very
strong and clinically important predictor
of serum PG concentrations was the osmol gap at 48 hrs into HD-LZ therapy.
These results show that PG accumulates
as early as 48 hrs into HD-LZ therapy.
Crit Care Med 2004 Vol. 32, No. 8
Table 2. Baseline patient characteristics
Patient
Age, yrs
Gender
APACHE II
Baseline CrCl,
mL/min
Bilirubin,
mg/dL
1
2
3
4
5
6
7
8
9
22
53
62
51
54
24
57
44
20
F
M
M
M
M
M
F
M
F
37
27
14
11
12
28
18
26
12
96
63
88
56
100
76
50
71
76
0.4
0.8
0.4
1.0
0.7
0.2
1.4
1.5
1.3
APACHE, Acute Physiology and Chronic Health Evaluation.
Figure 1. Correlation between high-dose lorazepam (HD-LZ) rate of infusion and serum propylene
glycol (PG) concentrations at 48 hrs.
Table 3. Laboratory variables consistent with propylene glycol (PG) accumulation
Patient
Corrected
AG
1
2
3
4
5
6
7
8
9
15.8
19.5
21.3
17.8
13.3
14.5
16.0
12.0
21.3
Osmol Gap
PG
concentration,
mg/dL
pH
Chloride,
mmol/L
HCO3,
mmol/L
Lactate,
mmol/L
44.9
29.7
49.6
43.0
52.1
36.0
24.3
43.4
67.1
252
120
210
120
320
140
94
190
350
7.26
7.43
7.35
7.18
7.43
7.40
7.21
7.29
7.20
114
96
99
108
106
115
120
110
119
21
32
21
20
24
16
19
23
13
1.9
NA
4.0
2.3
NA
NA
NA
2.0
NA
AG, anion gap; NA, not available.
All data collected 48 hrs into high-dose lorazepam infusion.
Patients should be monitored early during therapy that contains PG to help
avoid complications and toxicities associated with the compound.
Interestingly, we did not show a correlation between cumulative lorazepam
dose and serum PG concentration at 48
hrs. A pediatric intensive care unit
study showed a significant correlation
(r2 ⫽ .65, p ⬍ .005) between cumulative lorazepam dose and end-of-therapy
PG concentrations in 11 patients re1711
Figure 2. Correlation between serum propylene glycol (PG) concentrations and osmol gap at 48 hrs.
ceiving a mean lorazepam dose of 0.2
mg·kg⫺1·hr⫺1 (range, 0.1– 0.33) for a
mean of 8 days (25). In contrast to our
study, significant changes in laboratory
abnormalities consistent with PG accumulation were not observed in the pediatric population. A possible explanation
may be due to the lower mean PG concentration observed at 48 hrs. Chicella et al.
(25) showed a mean PG concentration of
51.9 mg/dL at 48 hrs, compared with our
mean PG concentration of 199 mg/dL at 48
hrs. A direct comparison between the two
studies is limited by obvious differences in
study populations and the choice of laboratory markers used to document the presence of PG accumulation.
Our correlation with HD-LZ and lack
of correlation with cumulative lorazepam
may be partially explained by the metabolism of PG. PG displays nonlinear pharmacokinetics with capacity-limited metabolism in healthy volunteers (26, 27).
Approximately 12– 45% of PG is excreted
unchanged in the urine, and the remainder is metabolized by the liver to pyruvic
acid and lactic acid. For ICU sedation,
HD-LZ may overwhelm hepatic metabolism and/or renal elimination if renal insufficiency exists, thus increasing the risk
of PG accumulation. The time frame that
we studied may also explain why we only
observed a correlation between HD-LZ
and PG concentration. The infusion of
HD-LZ may administer a PG load faster
than the patients can metabolize and/or
eliminate the compound, subsequently
leading to accumulation. This concept
was demonstrated by Hayman et al. (28),
1712
who described PG-associated toxicity only
after the addition of intravenous trimethoprim-sulfamethoxazole to a patient
receiving continuous lorazepam infusion.
We did not observe renal toxicity during our study period; however, there have
been two recent reports of PG-associated
renal toxicity. In a retrospective chart
review by Yaucher et al. (29), eight patients developed an increase in serum
creatinine while receiving continuous infusion of lorazepam. The mean cumulative dose of lorazepam in this study was
4305 mg and the median lorazepam infusion duration was 8 days. The mean PG
obtained at the peak serum creatinine
was 1103 ␮g/mL (110 mg/dL). Similar to
our findings, the authors found a correlation between the osmol gap and PG
concentration (r ⫽ .80). However, we did
not observe an increase in the serum
creatinine in our population; this may be
due to the time interval that we studied
(48 hrs of HD-LZ). In the report by
Yaucher et al., the median time to serum
creatinine increase was 9 days. At the
time of peak serum creatinine, lorazepam
dose was ⬎10 mg/hr in five of eight patients.
Hayman et al. (28) reported a case of
acute tubular necrosis secondary to the
administration of two medications that
contain propylene glycol, lorazepam and
trimethoprim-sulfamethoxazole. Acute
tubular necrosis was identified after 9
days of continuous infusion of lorazepam
and 3 days of intravenous trimethoprimsulfamethoxazole. The patient received
an average lorazepam dose of 7.5 mg/hr
but developed renal toxicity after the addition of trimethoprim-sulfamethoxazole, which separately added 123 g of
propylene glycol.
Since serum PG concentrations are
not readily available at most institutions,
theoretical formulas for predicting serum
PG concentrations from osmol gaps have
been suggested. Most of these proposed
formulas are based on the pediatric population and have not been validated in
critically ill adults (30, 31). As suggested
by our linear regression analysis, a theoretical formula for predicting serum PG
concentrations from the osmol gap is
(⫺82.1 ⫹ [osmol gap ⫻ 6.5]). This formula needs to be validated and perhaps
refined using a larger population. However, our preliminary data suggest that
osmol gap may be a clinically useful tool
to help monitor for PG accumulation
while patients are receiving HD-LZ.
Equations such as these, after validation,
may help identify as early as 48 hrs those
patients in whom PG accumulation may
be occurring.
Limitations of our study include the
criteria that were used to define PG accumulation. The presence of PG accumulation was based on laboratory abnormalities, which did not permit identification
of more serious toxicities that have been
reported in the literature. These criteria
for PG accumulation were chosen because, in combination, they correlate
strongly with organic acidosis and the
hyperosmolar state previously described
with PG accumulation. In our population, six of nine patients demonstrated
PG accumulation based on our definition.
However, all patients had an osmol gap
⬎20, which may alone be an indication of
PG accumulation and suggests that anion
gap may be a poor indication of PG accumulation. Another limitation is that only
one serum PG concentration was obtained, which did not allow us to assess
the change in serum PG concentrations
alongside the change in lorazepam dose
over the study period. Last, only patients
on HD-LZ were studied, because we believed that this was the patient population at greatest risk for PG accumulation,
due to the potential amount of PG administered. Patients who are receiving lorazepam at ⬍10 mg/hr may still be a risk for
PG accumulation, and this population
needs to be studied.
Although we found a significant correlation between HD-LZ and serum PG
concentrations, to more accurately
identify the lorazepam dosing threshold
Crit Care Med 2004 Vol. 32, No. 8
P
ropylene glycol
accumulation, as
reflected by a hyper-
osmolar anion gap metabolic
acidosis, was observed in critically ill adults receiving continuous high-dose lorazepam
infusion for ⱖ48 hrs.
elevated osmol gap, was observed in critically ill adults receiving continuous
HD-LZ (ⱖ10 mg/hr) infusion for ⱖ48
hrs. Study findings suggest, in critically
ill adults, that serum PG concentrations
may be predicted by the rate of HD-LZ
infusion (mg·kg⫺1·hr⫺1) and the osmol
gap. Furthermore, serum PG concentrations may be increased as early as 48 hrs
after the initiation of HD-LZ. Clinically,
these results may be applied to assess
patients for PG accumulation and/or toxicity when serum PG concentrations are
not readily available and to establish a
lorazepam dosing threshold for PG accumulation and PG toxicity.
ACKNOWLEDGMENTS
for PG toxicity, future studies are
needed to evaluate lorazepam at wider
dosage ranges with serial serum PG
concentrations. PG pharmacokinetic
studies are limited mainly to noncritically ill patients; however, these studies
demonstrate considerable intra- and interpatient variation in serum PG concentrations occurring over a narrow
dosage range (26, 27). The critically ill
population may display an even wider
intra- and interpatient variation in serum PG concentrations than noncritically ill patients. This stresses the importance of further studies involving
PG accumulation and toxicity in critically ill adults. Also, the relationship
between PG concentration and actual
toxicity is unknown, which suggests
that PG concentrations are a surrogate
end point of unclear significance at this
time.
Based on these findings, we recommend
that patients should be monitored for PG
accumulation and PG toxicity if they are
receiving HD-LZ for ⱖ48 hrs. We recommended calculating an osmol gap to determine whether PG is accumulating. Monitoring an osmol gap in patients who are at
risk of PG accumulation may be helpful to
avoid complications and toxicities associated with elevated PG concentrations.
Other causes of increased osmol gap should
be evaluated. Patients with renal and hepatic dysfunction may need to be monitored more closely for PG accumulation. If
PG accumulation does occur, it may be
important to use another sedative to help
avoid PG toxicities.
CONCLUSIONS
PG accumulation, as evidenced by a
high anion gap metabolic acidosis with
Crit Care Med 2004 Vol. 32, No. 8
We thank all of the medical intensive
care nurses, respiratory therapists, dietitians, and physicians for their cooperation in this study and for their daily contributions to the multidisciplinary team
and patient care.
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