ORIGINAL ARTICLE

Propofol Is Associated with Favorable Outcomes Compared with

Benzodiazepines in Ventilated Intensive Care Unit Patients
Nick W. Lonardo1, Mary C. Mone2, Raminder Nirula2, Edward J. Kimball2, Kyle Ludwig1, Xi Zhou3, Brian C. Sauer3,
Kevin Nechodom3, Chiachen Teng3, and Richard G. Barton2
1

Pharmacy Department, 2Department of Surgery, and 3Department of Internal Medicine, University of Utah, Salt Lake City, Utah

Abstract
Rationale: Mechanically ventilated intensive care unit (ICU)

patients are frequently managed using a continuous-infusion

sedative. Although recent guidelines suggest avoiding
benzodiazepines for sedation, this class of drugs is still widely
used. There are limited data comparing sedative agents in terms
of clinical outcomes in an ICU setting.
Objectives: Comparison of propofol to midazolam and lorazepam
in adult ICU patients.
Methods: Data were obtained from a multicenter ICU database

(20032009). Patient selection criteria included age greater than or

equal to 18 years, single ICU admission with single ventilation
event (.48 h), and treatment with continuously infused sedation
(propofol, midazolam, or lorazepam). Propensity score analysis (1:1)
was used and mortality measured. Cumulative incidence and
competing risk methodology were used to examine time to ICU
discharge and ventilator removal.
Measurements and Main Results: There were 2,250 propofolmidazolam and 1,054 propofol-lorazepam matched patients.
Hospital mortality was statistically lower in propofol-treated
patients as compared with midazolam- or lorazepam-treated
patients (risk ratio, 0.76; 95% condence interval [CI], 0.690.82
and risk ratio, 0.78; 95% CI, 0.680.89, respectively). Competing
risk analysis for 28-day ICU time period showed that propofoltreated patients had a statistically higher probability for ICU
discharge (78.9% vs. 69.5%; 79.2% vs. 71.9%; P , 0.001) and earlier

Patients are commonly admitted to the

intensive care unit (ICU) for respiratory
support and require mechanical ventilation

removal from the ventilator (84.4% vs. 75.1%; 84.3% vs. 78.8%; P ,
0.001) when compared with midazolam- and lorazepam-treated
patients, respectively.
Conclusions: In this large, propensity-matched ICU

population, patients treated with propofol had a reduced risk of

mortality and had both an increased likelihood of earlier ICU
discharge and earlier discontinuation of mechanical
ventilation.
Keywords: benzodiazepine; deep sedation; mortality rate;

delirium; comparative effective research

At a Glance Commentary
Scientic Knowledge on the Subject: Continuous sedative
infusions have been associated with intensive care unit (ICU)
complications, but there have been no studies to show
a difference in mortality when comparing propofol to
benzodiazepines.
What This Study Adds to the Field: This study is the rst

to demonstrate a statistically higher risk for mortality in

benzodiazepine-treated patients in a large cohort of ICU
patients requiring mechanical ventilation. These results are
supportive evidence for the preferential use of a
nonbenzodiazepine sedative agent.

(MV). These patients are frequently

managed using a continuous-infusion
sedative for comfort and to reduce anxiety

associated with MV. There is signicant

debate over which sedative agent or class
of agents should be used (13). The debate

( Received in original form December 30, 2013; accepted in final form April 7, 2014 )
Author Contributions: All authors participated in conception and design; analysis, data collection, and interpretation; and drafting the manuscript.
Correspondence and requests for reprints should be addressed to Nick W. Lonardo, Pharm.D., University of Utah, 50 North Medical Drive, Pharmacy
Department, A050, Salt Lake City, UT 84132. E-mail: nick.lonardo@hsc.utah.edu
This article has an online supplement, which is accessible from this issues table of contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 189, Iss 11, pp 13831394, Jun 1, 2014
Copyright 2014 by the American Thoracic Society
Originally Published in Press as DOI: 10.1164/rccm.201312-2291OC on April 10, 2014
Internet address: www.atsjournals.org

Lonardo, Mone, Nirula, et al.: Propofol vs. Benzodiazepines in Ventilated ICU Patients

1383

ORIGINAL ARTICLE
is generally centered on the likelihood of
the sedative causing delirium or resulting in
oversedation, both of which adversely
affect the patients ability to wean from
MV and have been associated with poor
patient outcomes (1, 37).
The Society of Critical Care Medicine
(SCCM) has updated the clinical practice
guidelines (CPG) for the management
of pain, agitation, and delirium in adult ICU
patients (3). The SCCM 2013 guidelines
now endorse sedation strategies that
use nonbenzodiazepine agents (propofol
and dexmedetomidine) as the preferred
choice (3), which is in contrast to the
CPG of 2002 (2), which recommended
benzodiazepines (lorazepam and midazolam).
This change from benzodiazepines to
nonbenzodiazepines is based on the results
of several recent studies that questioned
the routine use of benzodiazepines for
ICU sedation (4, 5, 810). These studies
provided evidence that benzodiazepine use
was an independent risk factor for the
development of delirium, which in turn has
been identied as an independent predictor
of increased hospital length of stay (LOS)
and increased 6-month mortality (5, 8, 9).
Despite the adverse outcomes associated
with benzodiazepines, recent surveys
suggest that their use is still widespread
(1113).
Based on the continued use of
benzodiazepines for sedation of mechanically
ventilated ICU patients and the unlikely
event of an adequately powered, randomized,
controlled trial, we studied the outcomes of
these sedatives using a large multicenter
critical care database. We selected only
patients that required MV for more than
48 hours and received exclusively propofol,
midazolam, or lorazepam via continuous
infusion. We hypothesized that in actual
clinical practice propofol would have
a measurable benet because of the
pharmacokinetic advantage of a much
shorter duration of action resulting in earlier
extubation and improved outcomes.

queried to identify any ICU patient

admitted from 2003 through 2009 that
required MV. MV is dened within PI
as any form of invasive MV delivered via
a ventilator or respirator and includes
continuous positive airway pressure via
a tracheal airway. All ICUs submitting
data to PI were included in this analysis.
The data were deidentied by patient,
participating ICU, and treatment dates
within a specic treatment year. Microsoft
Access (Microsoft Ofce 2003, Redmond,
WA) was used to delineate the study
population. This study was approved by
both the Cerner Corporation (PI) and the
University of Utah Institutional Review
Board.
Patients were included if they had
a single ICU admission with only one
MV event lasting greater than 48 hours
(see Figure E1 in the online supplement).
Patients had to have received exclusive
treatment with a single, continuous
infusion of a sedative; propofol, midazolam,
or lorazepam during the MV time period.
The sedative used must have been instituted
within 7 days of intubation to be included
in the analysis. Patients were excluded for
any of the following conditions: multiple
ICU admissions during the same hospital
admission; intubated more than once
during the ICU admission; missing Acute
Physiology and Chronic Health Evaluation
II score; treatment with a continuous
infusion of either etomidate, ketamine,
methohexital, pentobarbital, and/or
thiopental; and admission International
Classication of Diseases, 9th Revision
codes related to severe head injuries
and/or cervical spine fractures with cord
involvement (see online supplement). A
small number of patients (78) received
dexmedetomidine and were excluded from
the analysis.
Outcome Measures

identied as potential confounders and

used to build the initial logistic regression
model to predict treatment with propofol
(15). After the propensity score for
receiving propofol was calculated for each
patient, we performed 1:1 matched analysis,
without replacement, on the basis of the
log odds of the propensity score (logit).
Using the estimated logits, we rst
randomly selected a patient in the group
receiving propofol and then matched that
patient with a patient in the midazolam
group with the closest estimated logit value.
Patients in the group receiving midazolam
who had an estimated logit within 0.2 SD
of the selected patients in the propofol
group were eligible for matching (16). If no
match was found, the propofol patient
was removed from the analysis (Figures 1
and 2). This process was repeated to match
propofol-treated patients to lorazepamtreated patients.
We assessed the degree of balance in
measured covariates between the groups in
the two studies (propofol vs. midazolam)
and (propofol vs. lorazepam) by comparing
the distributions of categorical and
continuous variables using chi-squared
test and t test, respectively. Standardized
differences, expressed as a percentage
of the pooled SD of the covariates, were
also used to assess prematching and
postmatching balance of covariates;
standardized differences of less than 0.1
indicate covariates are well balanced
between groups (1719).
Analysis of Outcomes

The matched cohort was used to compute

risk ratios and 95% condence intervals
(95% CI) for dichotomous outcomes (15).
Because ICU LOS and mortality represent
competing risks, we used the cumulative
incidence function to analyze time to ICU
discharge and ventilator removal over
28 days (16). The cumulative incidence
function estimates the probability of
experiencing an ICU discharge or ventilator
removal by a given time, while allowing
for the possibility of other events to occur.

Methods

The primary outcome was ICU mortality.

Secondary outcomes included hospital
mortality, ICU and hospital LOS, MV
duration (days), tracheostomy, and
ventilator-associated pneumonia (VAP).

Study Population

Statistical Analysis

Results

Development of matched cohorts. We used

A total of 13,692 patients met study

inclusion criteria for the three sedation
agents. Propofol was the most commonly
used sedative in this study population,
comprising 73.6% of patients. Continuous

Using the critical care database Project

IMPACT (PI) (Cerner Corp., Kansas
City, MO) (14), we obtained data from
104 participating centers to perform
a retrospective, cohort study of MV
patients. The PI database was initially
1384

propensity score matching techniques to

achieve balance of the measured baseline
patient characteristics. Fifteen pretreatment
baseline covariates (Tables 1 and 2) were

American Journal of Respiratory and Critical Care Medicine Volume 189 Number 11 | June 1 2014

ORIGINAL ARTICLE
is generally centered on the likelihood of
the sedative causing delirium or resulting in
oversedation, both of which adversely
affect the patients ability to wean from
MV and have been associated with poor
patient outcomes (1, 37).
The Society of Critical Care Medicine
(SCCM) has updated the clinical practice
guidelines (CPG) for the management
of pain, agitation, and delirium in adult ICU
patients (3). The SCCM 2013 guidelines
now endorse sedation strategies that
use nonbenzodiazepine agents (propofol
and dexmedetomidine) as the preferred
choice (3), which is in contrast to the
CPG of 2002 (2), which recommended
benzodiazepines (lorazepam and midazolam).
This change from benzodiazepines to
nonbenzodiazepines is based on the results
of several recent studies that questioned
the routine use of benzodiazepines for
ICU sedation (4, 5, 810). These studies
provided evidence that benzodiazepine use
was an independent risk factor for the
development of delirium, which in turn has
been identied as an independent predictor
of increased hospital length of stay (LOS)
and increased 6-month mortality (5, 8, 9).
Despite the adverse outcomes associated
with benzodiazepines, recent surveys
suggest that their use is still widespread
(1113).
Based on the continued use of
benzodiazepines for sedation of mechanically
ventilated ICU patients and the unlikely
event of an adequately powered, randomized,
controlled trial, we studied the outcomes of
these sedatives using a large multicenter
critical care database. We selected only
patients that required MV for more than
48 hours and received exclusively propofol,
midazolam, or lorazepam via continuous
infusion. We hypothesized that in actual
clinical practice propofol would have
a measurable benet because of the
pharmacokinetic advantage of a much
shorter duration of action resulting in earlier
extubation and improved outcomes.

queried to identify any ICU patient

admitted from 2003 through 2009 that
required MV. MV is dened within PI
as any form of invasive MV delivered via
a ventilator or respirator and includes
continuous positive airway pressure via
a tracheal airway. All ICUs submitting
data to PI were included in this analysis.
The data were deidentied by patient,
participating ICU, and treatment dates
within a specic treatment year. Microsoft
Access (Microsoft Ofce 2003, Redmond,
WA) was used to delineate the study
population. This study was approved by
both the Cerner Corporation (PI) and the
University of Utah Institutional Review
Board.
Patients were included if they had
a single ICU admission with only one
MV event lasting greater than 48 hours
(see Figure E1 in the online supplement).
Patients had to have received exclusive
treatment with a single, continuous
infusion of a sedative; propofol, midazolam,
or lorazepam during the MV time period.
The sedative used must have been instituted
within 7 days of intubation to be included
in the analysis. Patients were excluded for
any of the following conditions: multiple
ICU admissions during the same hospital
admission; intubated more than once
during the ICU admission; missing Acute
Physiology and Chronic Health Evaluation
II score; treatment with a continuous
infusion of either etomidate, ketamine,
methohexital, pentobarbital, and/or
thiopental; and admission International
Classication of Diseases, 9th Revision
codes related to severe head injuries
and/or cervical spine fractures with cord
involvement (see online supplement). A
small number of patients (78) received
dexmedetomidine and were excluded from
the analysis.
Outcome Measures

identied as potential confounders and

used to build the initial logistic regression
model to predict treatment with propofol
(15). After the propensity score for
receiving propofol was calculated for each
patient, we performed 1:1 matched analysis,
without replacement, on the basis of the
log odds of the propensity score (logit).
Using the estimated logits, we rst
randomly selected a patient in the group
receiving propofol and then matched that
patient with a patient in the midazolam
group with the closest estimated logit value.
Patients in the group receiving midazolam
who had an estimated logit within 0.2 SD
of the selected patients in the propofol
group were eligible for matching (16). If no
match was found, the propofol patient
was removed from the analysis (Figures 1
and 2). This process was repeated to match
propofol-treated patients to lorazepamtreated patients.
We assessed the degree of balance in
measured covariates between the groups in
the two studies (propofol vs. midazolam)
and (propofol vs. lorazepam) by comparing
the distributions of categorical and
continuous variables using chi-squared
test and t test, respectively. Standardized
differences, expressed as a percentage
of the pooled SD of the covariates, were
also used to assess prematching and
postmatching balance of covariates;
standardized differences of less than 0.1
indicate covariates are well balanced
between groups (1719).
Analysis of Outcomes

The matched cohort was used to compute

risk ratios and 95% condence intervals
(95% CI) for dichotomous outcomes (15).
Because ICU LOS and mortality represent
competing risks, we used the cumulative
incidence function to analyze time to ICU
discharge and ventilator removal over
28 days (16). The cumulative incidence
function estimates the probability of
experiencing an ICU discharge or ventilator
removal by a given time, while allowing
for the possibility of other events to occur.

Methods

The primary outcome was ICU mortality.

Secondary outcomes included hospital
mortality, ICU and hospital LOS, MV
duration (days), tracheostomy, and
ventilator-associated pneumonia (VAP).

Study Population

Statistical Analysis

Results

Development of matched cohorts. We used

A total of 13,692 patients met study

inclusion criteria for the three sedation
agents. Propofol was the most commonly
used sedative in this study population,
comprising 73.6% of patients. Continuous

Using the critical care database Project

IMPACT (PI) (Cerner Corp., Kansas
City, MO) (14), we obtained data from
104 participating centers to perform
a retrospective, cohort study of MV
patients. The PI database was initially
1384

propensity score matching techniques to

achieve balance of the measured baseline
patient characteristics. Fifteen pretreatment
baseline covariates (Tables 1 and 2) were

American Journal of Respiratory and Critical Care Medicine Volume 189 Number 11 | June 1 2014

ORIGINAL ARTICLE
Table 1: Unmatched and Matched Covariates: Propofol versus Midazolam

Variable*
Age, yr (mean 6 SD)
Male sex
APACHE II score, mean 6 SD
Patient admission type
Medical
Scheduled surgery
Unscheduled surgery
Admission service
Trauma
General/internal medicine
Critical care (medical)
General surgery
Neurosurgery
Pulmonary
Cardiac/thoracic surgery
Vascular
Cardiology
Other medicine
Other surgery
Otolaryngology
Family practice
Nephrology
Obstetrics gynecology
Oncology-medical
Orthopedic surgery
Transplant
Other
Critical care managed unit
Chronic health condition
Cardiovascular
Gastrointestinal
Renal
Respiratory
Cardiopulmonary resuscitation 248 before ICU
Hemodynamic instability
Preadmission independent status
Hospital type
County hospital
State hospital
Community for-prot hospital
Community not-for-prot hospital
Academic
Year of treatment
2003
2004
2005
2006
2007
2008
2009

Unmatched Cohort
Midazolam
Propofol
(n = 2,390)
(n = 10,074)
P Value

Matched Cohort
Midazolam
Propofol
(n = 2,250)
(n = 2,250)

60.1 6 17.5
57.9
20.4 6 7.7

58.5 6 17.8
56.7
18.9 6 7.6

,0.001
0.27
,0.001

59.8 6 17.6
57.8
20.3 6 7.7

59.7 6 17.7
57.8
20.3 6 7.8

0.81
1.00
0.86

64.8
11.3
24.0

70.8
9.6
19.7

,0.001
0.01
,0.001

65.07
11.16
23.78

64.67
11.16
24.18

0.78
1.00
0.75

13.7
14.9
24.4
15.2
1.0
4.4
3.0
4.3
2.7
1.9
4.5
0.9
1.1
0.9
1.3
2.3
1.2
1.8
0.6
88.9

13.9
26.3
14.5
8.9
7.6
5.3
3.3
2.7
2.2
2.0
1.7
1.1
4.0
1.3
0.7
1.2
1.0
1.0
1.3
80.6

0.79
,0.001
,0.001
,0.001
,0.001
0.08
0.43
,0.001
0.16
0.80
,0.001
0.40
,0.001
0.12
0.003
,0.001
0.27
0.002
0.005
,0.001

14.18
15.73
23.47
14.89
1.022
4.71
3.16
4.27
2.8
1.96
3.78
0.93
1.11
0.93
1.24
2.0
1.29
1.87
0.67
88.58

14.22
16.04
22.31
14.93
1.022
4.22
3.07
4.31
2.89
1.73
4.4
0.84
1.29
0.98
1.2
2.58
1.42
1.78
0.76
87.87

0.97
0.78
0.36
0.97
1.00
0.43
0.86
0.94
0.86
0.58
0.29
0.75
0.58
0.88
0.89
0.20
0.70
0.82
0.72
0.46

7.0
4.8
5.3
10.3
5.0
54.6
77.3

4.3
3.9
3.9
9.8
7.1
37.8
73.3

,0.001
0.06
0.001
0.51
,0.001
,0.001
,0.001

6.76
4.98
5.33
10.27
5.11
53.24
76.84

6.18
5.51
5.6
10.31
5.02
53.64
77.24

0.43
0.42
0.69
0.96
0.89
0.79
0.75

7.2
0.5
0.6
35.0
56.7

1.4
2.4
4.8
59.0
31.9

,0.001
,0.001
,0.001
,0.001
,0.001

5.96
0.53
0.67
36.89
55.96

5.07
0.49
0.62
37.02
56.8

0.19
0.83
0.85
0.93
0.57

3.9
14.4
19.6
23.7
21.4
16.2
0.8

7.8
18.2
19.9
20.5
19.0
13.8
0.8

,0.001
,0.001
0.75
,0.001
0.006
0.002
0.97

4.09
14.4
19.38
23.24
21.47
16.58
0.84

4.84
13.6
19.29
23.64
20.89
17.11
0.62

0.22
0.44
0.94
0.75
0.64
0.63
0.38

P Value

Definition of abbreviations: APACHE = Acute Physiology and Chronic Health Evaluation; ICU = intensive care unit.
Data are given as % of patients unless otherwise indicated.
*Outcome variables defined in online supplement.

infusion midazolam was used in 17.4% of

patients and lorazepam in 9.0%. The study
population was predominantly made up
of medical admission patient types (see
Table E1) (n = 9,479; 69.2%), followed by

those who had either a planned surgery

(n = 1,305; 9.5%) or an unscheduled
surgery (n = 2,908; 21.2%). After 1:1
matching for pretreatment covariates, there
were 2,250 propofol-treated patients

Lonardo, Mone, Nirula, et al.: Propofol vs. Benzodiazepines in Ventilated ICU Patients

matched to midazolam-treated patients

(Table 1) and 1,054 propofol-treated
patients matched to patients treated with
lorazepam (Table 2). The only covariates
that remained statistically different after
1385

ORIGINAL ARTICLE
Table 2: Unmatched and Matched Covariates: Propofol versus Lorazepam

Variable*
Age, yr (mean 6 SD)
Male sex
APACHE II score, mean 6 SD
Patient admission type
Medical
Scheduled surgery
Unscheduled surgery
Admission service
Trauma
General/internal medicine
Critical care (medical)
General surgery
Neurosurgery
Pulmonary
Cardiac/thoracic surgery
Vascular
Cardiology
Other medicine
Other surgery
Otolaryngology
Family practice
Nephrology
Obstetric gynecology
Oncology-medical
Orthopedic surgery
Transplant
Other
Critical care managed unit
Chronic health condition
Cardiovascular
Gastrointestinal
Renal
Respiratory
Cardiopulmonary resuscitation 248 before to ICU
Hemodynamic instability
Preadmission independent status
Hospital type
County hospital
State hospital
Community for-prot hospital
Community not-for-prot hospital
Academic
Year of treatment
2003
2004
2005
2006
2007
2008
2009

Unmatched Cohort
Lorazepam
Propofol
(n = 1,228)
(n = 10,074)
P Value

Matched Cohort
Lorazepam
Propofol
(n = 1,054)
(n = 1,054)

55.1 6 18.6
63.4
19.4 6 7.8

58.5 6 17.8
56.7
18.9 6 7.6

,0.001
,0.001
0.04

56.6 6 18.3
61.4
19.7 6 7.8

56.1 6 19.7
59.5
19.8 6 7.8

0.58
0.37
0.87

65.5
6.0
28.5

70.8
9.6
19.7

,0.001
,0.001
,0.001

67.7
6.9
25.3

70.3
7.0
22.7

0.20
0.93
0.15

41.5
14.1
16.4
8.4
0.6
4.2
1.1
2.4
1.1
1.1
2.1
0.6
1.6
0.7
0.4
1.1
0.5
0.5
1.6
87.1

13.9
26.3
14.5
8.9
7.6
5.3
3.3
2.7
2.2
2.0
1.7
1.1
4.0
1.3
0.7
1.2
1.0
1.0
1.3
80.6

,0.001
,0.001
0.09
0.54
,0.001
0.10
,0.001
0.48
0.02
0.04
0.26
0.10
,0.001
0.09
0.28
0.68
0.10
0.06
0.38
,0.001

32.8
16.4
18.9
9.5
0.7
4.9
1.3
2.7
1.2
1.3
2.2
0.7
1.9
0.8
0.5
1.2
0.6
0.6
1.8
85.4

31.9
17.1
17.9
8.7
1.0
6.2
1.8
2.4
0.7
1.8
2.2
0.8
1.9
0.7
0.3
1.9
0.5
1.0
1.5
84.8

0.64
0.68
0.57
0.54
0.47
0.22
0.38
0.68
0.18
0.38
0.88
0.80
1.00
0.80
0.48
0.22
0.76
0.32
0.61
0.71

4.6
3.3
2.7
7.7
5.5
36.5
80.2

4.3
3.9
3.9
9.8
7.1
37.8
73.3

0.62
0.33
0.04
0.02
0.04
0.37
,0.001

4.8
3.8
3.0
8.7
5.6
38.8
77.7

4.7
3.4
2.8
7.5
5.0
41.5
76.3

0.92
0.64
0.70
0.30
0.56
0.21
0.44

1.6
17.8
5.1
29.6
45.9

1.4
2.4
4.8
59.0
31.9

0.64
,0.001
0.62
,0.001
,0.001

1.8
6.6
5.9
34.2
51.5

1.5
9.6
5.5
36.7
46.7

0.61
0.01
0.71
0.22
0.03

10.4
20.6
20.1
16.7
17.7
13.8
0.7

7.8
18.2
19.9
20.5
19.0
13.8
0.8

0.002
0.04
0.84
0.002
0.27
0.99
0.69

11.8
21.6
20.6
16.4
16.9
12.1
0.7

11.3
22.8
18.8
14.1
18.1
14.0
0.9

0.73
0.53
0.30
0.15
0.46
0.18
0.62

P Value

Definition of abbreviations: APACHE = Acute Physiology and Chronic Health Evaluation; ICU = intensive care unit.
Data are given as % of patients unless otherwise indicated.
*Outcome variables defined in online supplement.

matching were two of the ve hospital types

in the propofol versus lorazepam groups
(Table 2). Figure 3 illustrates the successful
narrowing of the standard difference of
the 15 covariates after propensity score
matching for each comparison.
1386

Study Outcomes

Mortality

Table 3 details the primary and secondary

study results in matched cohorts. Figures 4
and 5 illustrate ICU LOS and removal
from ventilator support in the presence of
the competing risk of death.

Patients receiving propofol had a

signicantly lower risk for overall ICU
mortality, with a risk ratio of 0.69 (95%
CI, 0.620.76) when compared with
midazolam and a risk ratio of 0.76 (95% CI,

American Journal of Respiratory and Critical Care Medicine Volume 189 Number 11 | June 1 2014

ORIGINAL ARTICLE

Figure 1. Propensity score distribution plot comparing initial and matched scores between midazolam- and propofol-treated patients.

0.650.90) when compared with

lorazepam-treated patients. Hospital
mortality was also lower for patients
receiving propofol, with a risk ratio of 0.76
(95% CI, 0.690.82) compared with
midazolam-treated patients and 0.78
(95% CI, 0.680.89) when compared with

lorazepam-treated patients (Table 3). By

ICU Day 28, the cumulative incidence
of death was 19.2% in propofol-treated
patients compared with 28.0% in
midazolam-treated patients (P , 0.001).
Similar results were seen when comparing
propofol with lorazepam; the cumulative

Lonardo, Mone, Nirula, et al.: Propofol vs. Benzodiazepines in Ventilated ICU Patients

incidence of death was 19.1% in propofoltreated patients compared with 24.6% of

lorazepam-treated patients (P , 0.0018).
ICU Length of Stay

By ICU Day 28, the cumulative incidence of

being discharged from the ICU was 78.9% in
1387

ORIGINAL ARTICLE

Figure 2. Propensity score distribution plot comparing initial and matched scores between lorazepam- and propofol-treated patients.

propofol-treated patients compared with

69.5% of midazolam-treated patients (P ,
0.001). When comparing ICU discharge
between propofol-treated patients and
lorazepam-treated patients, the results were

1388

similar. By ICU Day 28, the cumulative

incidence of being discharged from the ICU
was 79.2% in propofol-treated patients
versus 71.9% of lorazepam-treated patients
(P , 0.001).

Ventilator Dependence

MV use was analyzed by measuring the

cumulative incidence of ventilator
discontinuation. By ventilator Day 28,
the cumulative incidence of ventilator

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ORIGINAL ARTICLE

Figure 3. Scatter plots illustrating the standard difference of 15 pretreatment covariates before matching () and after matching (x). A significant narrowing
of the standard difference demonstrates successful propensity score matching between the sedation groups. (Left) Propofol versus midazolam; (right)
propofol versus lorazepam.

removal was 84.4% of propofol-treated

patients, compared with 75.1% of
midazolam-treated patients (P , 0.001).
Over this same period, the cumulative
incidence of ventilator removal was 84.3%
in propofol-treated patients compared
with 78.8% in lorazepam-treated patients
(P , 0.001).
Tracheostomy

There was no difference in the relative

risk of patients requiring tracheostomy
in the propofol-treated patients
compared with midazolam-treated
patients (1.00; 95% CI, 0.871.16);
however, propofol-treated patients
were signicantly less likely to
require tracheostomy compared with

lorazepam-treated patients (relative risk,

0.69; 95% CI, 0.570.80).
Ventilator-associated Pneumonia

There was a statistically higher rate of VAP

in lorazepam-treated patients, 12.7%, as
compared with propofol-treated patients,
7.9% (P , 0.001). The risk ratio for
VAP was 0.62 (95% CI, 0.480.80) for
propofol-treated patients compared with
lorazepam-treated patients.
Post-Treatment Variables

Tables E6 and ES7 detail the comparison

of post-treatment variables for midazolam
and lorazepam when compared with
propofol-treated patients. Midazolamtreated patients required 5.4 6 5.0

sedation days compared with 4.7 6 3.4 for

propofol-treated patients (P , 0.001).
Continuous-infusion opiate days while
on the ventilator were 5.2 6 5.8 for
midazolam-treated patients compared
with 2.5 6 4.0 for propofol-treated patients
(P , 0.001). Continuous-infusion
neuromuscular blocking agents were used
in 9.8% of midazolam-treated patients
compared with 6.0% of propofol-treated
patients (P , 0.001). Similar patterns
were seen in the lorazepam-treated patients.
Lorazepam-treated patients required 5.1 6 4.7
sedation days as compared with 4.8 6 3.4
for propofol-treated patients (P , 0.07).
Continuous-infusion opiate days while on
the ventilator were 4.7 6 5.5 for lorazepamtreated patients compared with 2.3 6 3.6 for

Table 3: Outcome Measures with Matching Cohorts

Outcomes
ICU mortality
Hospital mortality
Tracheostomy
Ventilator-associated
pneumonia

Midazolam
Matched
(n = 2,250)

Propofol
Matched
(n = 2,250)

P Value

28.8
37.0
14.04
6.2

19.7
27.9
14.09
6.8

,0.001
,0.001
0.967
0.43

Relative
Risk
(95% CI)
0.69
0.76
1.00
1.09

(0.620.76)
(0.690.82)
(0.871.16)
(0.881.36)

Lorazepam
Matched
(n = 1,054)

Propofol
Matched
(n = 1,054)

P Value

25.2
33.8
21.82
12.7

19.3
26.2
14.99
7.9

0.001
,0.001
,0.001
,0.001

Relative
Risk
(95% CI)
0.76
0.78
0.69
0.62

(0.650.90)
(0.680.89)
(0.570.83)
(0.480.80)

Definition of abbreviations: CI = confidence interval; ICU = intensive care unit.

Data are given as % of patients unless otherwise indicated.

Lonardo, Mone, Nirula, et al.: Propofol vs. Benzodiazepines in Ventilated ICU Patients

1389

ORIGINAL ARTICLE

Figure 4. Cumulative incidence of intensive care unit (ICU) discharge over 28 days in the presence of competing risk event (mortality) for matched
midazolam- and lorazepam-treated patients compared with propofol-treated patients.

propofol-treated patients (P , 0.001).

Continuous-infusion neuromuscular
blocking agents were used in 17.6% of
lorazepam-treated patients compared with
6.6% of propofol-treated patients (P , 0.001).

Discussion
In this multicenter, retrospective, cohort
study of mechanically ventilated adult

ICU patients who were treated with

a single sedative, we found that propofol
was associated with a statistically lower
risk for ICU mortality. Sedation with
propofol was also associated with an overall
decrease in ICU and hospital LOS and
fewer ventilator days. The results of
this propensity score analysis, which
controlled for important pretreatment
variables, support the preferential use of
propofol rather than benzodiazepines when

patients require prolonged ventilator

support.
Critical care practitioners continue
to struggle to deliver optimal sedation to
mechanically ventilated critically ill patients
(13, 1720). Although sedation can be
useful for managing extreme agitation and
optimizing pulmonary mechanics, there
is a growing body of evidence suggesting
that sedation use (21, 22), particularly
benzodiazepines (5, 8, 9), is associated with

Figure 5. Cumulative incidence of ventilator removal over 28 days in the presence of competing risk event (mortality) for matched midazolam- and
lorazepam-treated patients compared with propofol-treated patients.

1390

American Journal of Respiratory and Critical Care Medicine Volume 189 Number 11 | June 1 2014

ORIGINAL ARTICLE
negative outcomes. To address issues
surrounding adequate and safe sedation,
the SCCM updated its 1995 (1) and 2002
CPG (2) and has published comprehensive
evidence-based guidelines in 2013 (3).
These guidelines provide specic
recommendations that address comfort,
safety, pain, and agitation for patients
who require sustained use of sedatives
and analgesics. The updated CPG reect
more recent studies that have shown
benzodiazepines to be independently
associated with delirium (5, 8, 9) and
now recommend sedation strategies using
nonbenzodiazepines (propofol and/or
dexmedetomidine) (3). The occurrence of
delirium is of particular concern, because
the duration of delirium in ICU patients
has been shown to be a strong predictor
of increased mortality, ICU LOS, duration
of MV (5, 810), and long-term cognitive
impairment in survivors of critical illness
(4, 23). Because sedation is a modiable
risk factor associated with delirium
(3, 5, 8), there is considerable interest in
understanding the short- and long-term
outcomes of sedative use in the ICU.
There have been many controlled
clinical trials comparing propofol
with benzodiazepines, but none have
demonstrated a signicant mortality
difference between these agents (3, 24).
In 2008, Ho and Ng (25) published
a metaanalysis of 16 randomized trials
comparing adult ICU patients sedated with
propofol with an alternative sedative for
medium- or long-term sedation. They
reported that propofol use was associated
with a statistically signicant decrease in
ICU LOS when compared with lorazepam
and diazepam, but not for midazolam.
The mortality rate, however, was not
statistically different between propofol
and the other sedatives. The authors
acknowledged, however, that this
metaanalysis may not have been sufciently
powered to detect a difference.
Although randomized, controlled trials
are considered the standard for establishing
a causal relationship and/or efcacy
between treatments, it has been increasingly
recognized that they may not accurately
reect the outcomes seen in an actual
practice environment (2628). Studies
designed to measure the effectiveness of
common clinical options in an actual
practice setting (i.e., comparative effective
research) have been promoted by the
enactment of the American Recovery and

Reinvestment Act of 2009 (2628). This

type of study model is especially well suited
to examine the outcomes of sedatives used
in the ICU because of the well-known
variability of their use (2931) that may
not be apparent in a controlled study
environment. A limitation of randomized,
controlled sedation studies is that they
often exclude patients, such as those
with renal and/or liver dysfunction and
hemodynamic instability. These critically
ill patients are especially vulnerable to the
adverse effects of continuous-infusion
benzodiazepines because of potentially
reduced hepatic clearance, renal
insufciency, and accumulation of active
metabolites (24). In a natural ICU practice
setting, continuous-infusion sedatives are
commonly used in patients with organ
dysfunction. By comparison, in the
metaanalysis by Ho and Ng (25), patients
with renal or liver dysfunction were
excluded in half of the randomized trials.
Accumulating evidence has shown
that the occurrence of ICU delirium is
a strong predictor of increased mortality
and prolonged hospitalization (5, 3243).
Although all sedatives may cause delirium,
benzodiazepines have been independently
associated with ICU delirium (5, 8). It
has been speculated that a potential
cause of sedative-induced ICU delirium
is via activation of the g-aminobutyric
acid receptor (38). Two recent randomized
studies have demonstrated that a non
g-aminobutyric acid receptor agonist
(dexmedetomidine) was associated with less
delirium, and decreased duration of
ventilation and ICU LOS when compared
with midazolam and lorazepam (44, 45).
Because propofol and benzodiazepines
are g-aminobutyric acid receptor agonists
(46, 47), it would follow that both agents
may cause delirium and therefore be
associated with poor outcomes. However,
the complete mechanism of action of
propofol is not clearly understood (48), and
it is unknown whether delirium induced
by propofol is as noxious as that induced
by benzodiazepines. It is possible that
benzodiazepine-induced delirium persists
longer than propofol-induced delirium
because of the propensity of propofol to
rapidly redistribute out of the central
nervous system (49).
Although delirium was not the focus
of this study, it is discussed in the context
of a possible explanation for the increased
mortality seen in the benzodiazepine-

Lonardo, Mone, Nirula, et al.: Propofol vs. Benzodiazepines in Ventilated ICU Patients

treated patients. Several recent studies have

demonstrated that the duration of delirium
portends a poor prognosis in terms of
mortality, both hospital and ICU LOS, and
long-term cognitive impairment (4, 5, 10,
23). However, it remains unclear if rapidly
reversible, sedation-related delirium is
different from persistent delirium and if
the outcomes are similar. In a recent,
prospective, observational, masked study by
Patel and coworkers (50) patients were
assessed for delirium before and after daily
sedative interruption. The authors found
that measured outcomes for patients with no
delirium were not statistically different
from patients with rapidly reversible,
sedation-related delirium. In contrast,
patients with persistent delirium had more
ventilator and hospital days than those
with sedation-related delirium. In this
context, it is possible that propofol-induced
delirium does not persist as long as
benzodiazepine-induced delirium, thereby
allowing for a more rapid transition of the
patient to discharge from the ICU. Earlier
extubation and ICU discharge results in
reduction of ICU-related complications.
It is also plausible that the improved
outcomes seen in our study can be
explained by the favorable pharmacokinetic
prole of propofol. Propofol has a much
shorter duration of action than both
midazolam and lorazepam and studies
have shown that the time-to-awakening
and extubation occur more rapidly and
predictably in patients sedated with
propofol (5156).
Earlier extubation reduces the
incidence of VAP (57), which is an added
benet, because VAP has been associated
with increased hospital LOS and mortality
(58). In our analysis, lorazepam-treated
patients had a signicantly increased risk
for VAP, but those treated with midazolam
were not statistically different. Mortality
is a competing risk for VAP because death
prevents a VAP event. Relative to the
lorazepam-treated patients, the midazolamtreated patients had a greater absolute
increase mortality compared with propofoltreated patients (midazolam 9.1% vs.
lorazepam 6.0%), and this may have
lowered the overall VAP rate in the
midazolam group.
When looking at post-treatment
covariates in Tables E6 and E7, patients
that received midazolam or lorazepam
had higher rates of organ dysfunction
and ICU complications. In addition,
1391

ORIGINAL ARTICLE
benzodiazepine-treated patients had a
greater number of opiate days and required
more scheduled haloperidol. Although these
variables may affect patient outcomes, they
were unlikely to inuence the sedative
selection because these variables occurred
after the sedative was chosen. Benzodiazepinetreated patients needed more days of opiates
than propofol-treated patients. This is an
expected result given that the benzodiazepinetreated patients required more ventilator
days and remained in the ICU longer than
propofol-treated patients.
Comparing sedation agents within
a large multiinstitutional ICU database can
be difcult because of the heterogeneous
nature of patients and the variability in
treatment patterns between institutions. The
population in this study was diverse,
consisting of both medical and surgical type
admissions. The results, however, showed
a statistical difference in the mortality
risk between propofol and benzodiazepines,
which have not been found in previous
randomized, controlled trials.
The major strengths of this historical
cohort study are the relatively large
population, accurately measured clinical
variables, and the actual clinical
setting within a large number of ICUs.
Acknowledging the possibility of
confounding, we used propensity score
matched analysis to balance 15 measured
pretreatment variables that may inuence
the sedative choice and also impact
the outcomes. The measured variables
included admission service, type of
admission (medical or surgical), and the
type of hospital. Importantly, hemodynamic
instability was also included because
propofol is known to cause hypotension (24)
and may be avoided in this population.
Using propensity score matching, we were

able to achieve a balance of these important

covariates between the sedative cohorts.
The data were obtained from a wellestablished critical care database that is
specically designed to benchmark
outcomes between institutions. To best
represent treatment with a single sedative
during a single ventilator event, the study
population was carefully constructed to
minimize variance and reduce selection
bias. The choice of using patients who were
intubated more than 48 hours represents
a relevant study population that is at
risk for common ICU complications.
Because the sample size was large, we
were able to investigate the independent
inuence of sedatives on important
outcomes. The primary and secondary
study outcomes were measured in a
noncontrolled study environment from
multiple institutions and are, therefore,
more likely to represent relevant clinical
practice outcomes.
Our study has several limitations that
should be discussed. First, there is the
possibility that our results were caused
by a selection bias because the model did
not account for signicant unmeasured
covariates. Second, we could not exclude,
measure, or control for the use of
intermittent benzodiazepine dosing
given on an as-needed basis. We could
only exclude those patients that were
ordered a benzodiazepine on a scheduled
intermittent basis. We excluded propofoltreated patients that received a scheduled
intermittent benzodiazepine but retained
midazolam- and lorazepam-treated patients
provided they received the same medication.
Third, the database we used does not
collect actual drug dosages, therefore
sedative and analgesic dosing was
not available. Therefore, we could not

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American Journal of Respiratory and Critical Care Medicine Volume 189 Number 11 | June 1 2014