clinical investigations in critical care

Propofol vs Midazolam for ICU Sedation*

A Canadian Multicenter Randomized Trial
Richard I. Hall, MD, FCCP; Dean Sandham, MD, FCCP; Pierre Cardinal, MD;
Martin Tweeddale, MD; David Moher, MSc; Xiaohua Wang, MSc STAT; and
Aslam H. Anis, PhD; for the Study Investigators†

Study objectives: To determine whether sedation with propofol would lead to shorter times to
tracheal extubation and ICU length of stay than sedation with midazolam.
Design: Multicenter, randomized, open label.
Setting: Four academic tertiary-care ICUs in Canada.
Patients: Critically ill patients requiring continuous sedation while receiving mechanical ventilation.
Interventions: Random allocation by predicted requirement for mechanical ventilation (short
sedation stratum, < 24 h; medium sedation stratum, > 24 and < 72 h; and long sedation stratum,
> 72 h) to sedation regimens utilizing propofol or midazolam.
Measurements and results: Using an intention-to-treat analysis, patients randomized to receive
propofol in the short sedation stratum (propofol, 21 patients; midazolam, 26 patients) and the
long sedation stratum (propofol, 4 patients; midazolam, 10 patients) were extubated earlier (short
sedation stratum: propofol, 5.6 h; midazolam, 11.9 h; long sedation stratum: propofol, 8.4 h;
midazolam, 46.8 h; p < 0.05). Pooled results showed that patients treated with propofol (n ⴝ 46)
were extubated earlier than those treated with midazolam (n ⴝ 53) (6.7 vs 24.7 h, respectively;
p < 0.05) following discontinuation of the sedation but were not discharged from ICU earlier
(94.0 vs 63.7 h, respectively; p ⴝ 0.26). Propofol-treated patients spent a larger percentage of
time at the target Ramsay sedation level than midazolam-treated patients (60.2% vs 44.0%,
respectively; p < 0.05). Using a treatment-received analysis, propofol sedation either did not
differ from midazolam sedation in time to tracheal extubation or ICU discharge (sedation
duration, < 24 h) or was associated with earlier tracheal extubation but longer time to ICU
discharge (sedation duration, > 24 h, < 72 h, or > 72 h).
Conclusions: The use of propofol sedation allowed for more rapid tracheal extubation than when
midazolam sedation was employed. This did not result in earlier ICU discharge.
(CHEST 2001; 119:1151–1159)
Key words: ICU; mechanical ventilation; midazolam; multicenter; propofol; randomized clinical trial; sedation;
Abbreviations: APACHE ⫽ acute physiology and chronic health evaluation; CI ⫽ confidence interval

*From the Queen Elizabeth II Health Sciences Centre (Dr.
Hall), Halifax, Nova Scotia, Canada; Foothills Hospital (Dr.
Sandham), University of Calgary, Calgary, Alberta, Canada;
Ottawa General Hospital (Dr. Cardinal), Ottawa, Ontario, Can-
ada; Vancouver General Hospital (Dr. Tweeddale), Vancouver,
British Columbia, Canada; Ottawa Civic Hospital (Mr. Moher),
Ottawa, Ontario, Canada; St. Paul’s Hospital (Mrs. Wang),
Vancouver, British Columbia, Canada; and the Department of
Health Care and Epidemiology (Dr. Anis), University of British
Columbia, Vancouver, British Columbia, Canada.
†A list of additional study investigators is located in Appendix 1.
Presented in part to the American College of Chest Physicians
Annual Meeting, New Orleans, LA, October 26 –30, 1997.
This research was supported by Zeneca Pharma Inc. Canada.
Dr. Hall has received consultation fees from Zeneca Pharma Inc.
and Hoffman-LaRoche Limited. He has no equity interest in
either company. Drs. Sandham, Cardinal, Tweeddale, and Anis,
and Mr. Moher and Mrs. Wang have no financial relationship
with either company.
Manuscript received March 11, 1999; revision accepted Septem-
ber 7, 2000.
Correspondence to: Richard I. Hall, MD, FCCP, Department of
Anesthesia, Queen Elizabeth II Health Sciences Centre, 1796
Summer St, Halifax, Nova Scotia, Canada B3H 3A7; e-mail:
rihall@is.dal.ca

CHEST / 119 / 4 / APRIL, 2001 1151

P noxious
atients in an ICU are exposed to a variety of
stimuli including pain after surgery, fre-
quent venipuncture, and discomfort from the pres-
ence of an endotracheal tube.1,2 Sedation is fre-
quently required as a component of compassionate
care in these patients. While a variety of agents have
been employed for the provision of sedation, two
currently popular ones are midazolam and propo-
fol.3–5 Both are rapid-acting drugs and do not sup-
press adrenal function when administered to the
critically ill patient.6,7 Randomized studies, largely
from European centers, comparing propofol to mi-
dazolam for the sedation of ICU patients suggest that
propofol is as good as midazolam for this purpose
and that its pharmacokinetic profile may permit
more rapid dissipation of effects, thus allowing rapid
weaning from mechanical ventilation and tracheal
extubation.8 –17 Data regarding the safety and effi-
cacy of propofol when used for prolonged sedation
(ie, ⬎ 72 h) are limited,8,11,12,15,16,18,19 and it is not
currently recommended for long-term sedation due
to lack of such information.20
This multicenter study conducted in four Cana-
dian ICUs sought to examine whether, given that
midazolam is a longer-acting4 agent than propofol,
this difference in pharmacokinetic properties would
lead to significant differences in time to tracheal
extubation and ICU discharge. Because the benefits
of a shorter-acting sedative might be offset by the
duration of infusion21 (ie, patients requiring pro-
longed infusions during mechanical ventilation re-
ceive more sedation and have prolonged recovery
times), a secondary question was in which segment
of the ICU population (ie, those requiring sedation
for short-term, medium-term, or long-term mechan-
ical ventilation) did this benefit apply? Our null
hypothesis was that there would be no difference in
time to tracheal extubation or ICU length of stay
when propofol was compared to midazolam as the
primary sedative agent in patients requiring mechan-
ical ventilation.
Materials and Methods
Trial Design
This study was a multicenter, randomized, open-label trial
conducted in four ICUs in academic medical centers across
Canada. These centers were characterized as follows: center 1, a
surgical and trauma ICU; center 2, a mixed population of
medical-surgical patients and the regional trauma unit; center 3,
a mixed medical-surgical unit that also admitted postoperative
cardiac surgical cases; and center 4, a mixed medical-surgical unit
that was a referral center for patients with difficult, long-term
mechanical ventilation problems. All centers had 24-h coverage
by staff intensivists and in-house coverage by resident house staff.
The research review board of each institution approved the
1152
protocol and consent process. Physicians made an assessment as
to whether patients would require sedation for short-term (ⱕ 24
h), medium-term (⬎ 24 and ⬍ 72 h), or long-term (ⱖ 72 h)
mechanical ventilation on admission to the ICU. Patients then
were stratified by predicted sedation time while receiving me-
chanical ventilation, were randomized, and were entered into the
trial.
Eligibility Criteria
Inclusion Criteria: Patients were of either gender, ⱖ 18 years
of age, and required immediate sedation so as to permit the
initiation and tolerance of mechanical ventilation.
Exclusion Criteria: Exclusion criteria included a known or
suspected allergy or intolerance to propofol or midazolam,
suspected pregnancy, coma due to a cerebrovascular accident or
unknown etiology, cranial trauma or neurosurgical intervention,
or status epilepticus. In situations in which patients could not give
consent, surrogate consent was obtained from next-of-kin at the
earliest possible time following ICU admission.
Randomization and Stratification
Patients were individually assigned to treatment group by a
random allocation process using a computer-generated (Zeneca
Pharma Inc; Mississauga, Ontario, Canada) random block design.
Groups of four opaque, sealed, sequentially numbered envelopes
with the group allocation coded for each center were provided for
each of the three strata based on predicted sedation time while
the patient was receiving mechanical ventilation as follows: short
term (expected duration, ⬍ 24 h); medium term (ⱖ 24 h but
⬍ 72 h); and long term (ⱖ 72 h).
Infusion Regimens
Once randomized, patients allocated to the propofol group
received an infusion of 0.3 to 0.6 mg/kg/h initially, which was
subsequently titrated to achieve a target Ramsay sedation score22
(see Appendix 2) that was specified for each patient at least daily
and was adjusted based on the patient’s response to therapy.
When necessary to achieve a very rapid induction of sedation (eg,
to treat acute agitation), the infusion rate could be increased so as
to provide a bolus dose prior to adjustment of the standard
infusion regimen.
Patients randomized to the midazolam group received an
infusion of 0.012 to 0.024 mg/kg/h adjusted to achieve the target
Ramsay sedation score. As for the propofol group, in situations in
which the rapid control of sedation was desired, an infusion bolus
could be administered.
No restrictions were placed on the type or amount of analgesia
required to achieve patient comfort.
Masking
We elected not to mask the treatment groups. The physical
appearance of propofol (formulated in a white lipid emulsion) is
different from midazolam (clear liquid), and any leakage of
solution would unmask the study. We also reasoned that there are
sufficient differences in the onset of drug effect that knowledge-
able caregivers would likely recognize treatments on this basis
alone. Furthermore, when necessary to administer bolus infu-
sions for acute agitation, knowledge of the treatment groups
would prevent potentially hazardous hemodynamic changes
through appropriate care with drug infusion rates. The practical-
ity of masking infusions by wrapping bags and tubing, for
example, at all hours of the day or night was limited. Indeed,
Clinical Investigations in Critical Care
 Figure 1. Trial flow diagram.
when sedation was required to rapidly achieve patient control of,
eg, postoperative emergence delirium, the time factor required to
prepare and mask solutions was thought to be such as to be
detrimental to patient care. The purpose of our study was to
inquire whether real-world use of the agents in a diverse group of
Canadian ICUs would lead to measurable differences in out-
comes.23
Once patients were entered into the study, all investigators
agreed in advance that patient crossover between sedative regi-
mens was prohibited unless a clear treatment failure could be
demonstrated (eg, increasing paradoxical excitement in response
to benzodiazepine administration or hyperlipidemia in response
to propofol administration). Patients who died or crossed over
were eliminated from the study, and the data were censured.
Measurement Scales
The Ramsay sedation score22 was utilized to quantitate the
desired degree of sedation specified at regular intervals and
adjusted as the patient’s condition (ie, recovery or deterioration)
dictated. Patients receiving muscle relaxants and sedation were
given a Ramsay sedation score of 6. Recovery of consciousness
was determined by measurement of the acute physiology and
chronic health evaluation (APACHE) III modification of the
Glasgow coma score to allow for scoring of the verbal component
in intubated patients.24,25 Patients were judged to be awake when
the Glasgow coma score was ⱖ 12.
Measurements
The Ramsay score (target and actual) was recorded hourly for
the first 72 h or up to the time of discharge from ICU if this
occurred prior to 72 h. After 72 h, it was recorded as the patient’s
condition or infusion rate was altered. Time to tracheal extuba-
tion, time to ICU discharge, and requirements for reintubation
were recorded. A record of vital signs was maintained every 20
min for 40 min, then every 6 h for 48 h following extubation or
until ICU discharge, whichever came first. Admission therapeutic
intervention scoring system score26 and APACHE II score27 were
recorded.
Decisions as to when a patient was ready for a trial of
extubation or for discharge from the ICU were left to the
attending intensivists.
Primary Outcome Measures: The time from withdrawal of
sedation until tracheal extubation and ICU discharge for each
stratum was taken as the primary outcome measures. In situa-
tions in which patients required multiple independent periods of
sedation or reintubation due to alterations in their disease
process, the first period of sedation accompanied by tracheal
extubation was utilized for data collection surrounding this event.
CHEST / 119 / 4 / APRIL, 2001 1153
Data were collected for the duration of the patient’s ICU stay. leading to death developed in one patient receiving
ICU length of stay was recorded as the time from admission to propofol, and propofol administration was thought to
ICU until the patient was discharged to the floor.
Secondary Outcome Measures: The time when the patient was
have possibly contributed to that death by the safety
deemed ready for extubation (as assessed by attending physicians review board. Hypertriglyceridemia developed in
clinically and by use of weaning parameters in most cases) was one propofol-treated patient who subsequently died.
recorded as well as the interval between when the patient was Lack of response to sedation occurred in four mida-
deemed ready for discharge and when discharge actually oc- zolam-treated patients (one of whom died) and in
curred.
seven propofol-treated patients (four of whom died)
(p ⫽ 0.30). Lack of response to sedation was attrib-
Safety Review Board uted to paradoxical excitement and agitation in three
All reports of deaths and serious adverse events, as identified midazolam-treated patients and in one propofol-
by site investigators, were examined by a blinded safety review treated patient. Unacceptable hypotension devel-
board that determined whether the event was attributable to oped in two propofol-treated patients.
study drug treatment or not. Diagnostic categories for the remaining 124 pa-
tients who survived and were discharged from the
Sample Size Calculation ICU are presented in Table 1. Demographic infor-
Statistical power was estimated using reduction in recovery
mation is provided in Table 2. There were more
time as the primary outcome. The recovery time for patients women in the midazolam group with a tendency to a
assigned to midazolam treatment was taken from the data of lower weight distribution. There were no differences
Carrasco et al.11 In that study, the mean (⫾ SD) recovery time for
midazolam was 3.6 ⫾ 0.8 h in the short-term sedation group (ie,
⬍ 24 h) 21.0 ⫾ 5.8 h in the medium-term sedation group (ie, ⬍ 7
days), and 54.7 ⫾ 12.3 h in the long-term sedation group (ie, ⬎ 7 Table 1—Distribution of Study Population by Center,
days). We assumed an interest in detecting a 20% relative Group, and Diagnosis*
reduction in recovery time using propofol (␤ ⫽ 0.1; ␣ ⫽ 0.05;
2-sided). The statistical power was calculated for each stratum Center 1 Center 2 Center 3 Center 4
separately (short term [⬍ 24 h], 22 per group to detect a Diagnosis Mid Prop Mid Prop Mid Prop Mid Prop
difference of 0.95 h; medium term [⬎ 24 and ⬍ 72 h], 31 patients
per group to detect a difference of 4.95 h; and long term [⬎ 72 Surgical
h], 22 patients per group to detect a difference of 12.97 h). Elective 2 4 1 2 5 1 1 0
postoperative
Vascular 1 3 3 3 2 1 0 1
Statistical Analysis surgery
Cardiac 0 0 0 0 13 14 0 0
The primary analysis was by intention-to-treat and was based
surgery
on differences in time to tracheal extubation and time to ICU
Trauma 1 2 4 1 0 0 1 0
discharge from the withdrawal of sedation using data from
Liver 0 1 0 0 0 0 0 0
patients as assigned to the original stratum. Probability values
transplant
ⱕ 0.05 were considered to be statistically significant. Ninety-five
Intra-abdominal 4 1 3 4 0 3 1 0
percent confidence intervals (CIs) were constructed for all data.
sepsis
A two-way analysis of variance was used to assess differences in
Necrotizing 0 0 0 1 0 1 1 0
tracheal extubation time by treatment group and sedation stra-
fasciitis
tum. A similar analysis was used to compare differences in the
Mediastinitis 1 0 0 0 0 0 0 0
time of ICU length of stay. The incidence of adverse events and
Burn 0 0 0 0 0 1 1 0
mortality was compared using a contingency table analysis.
Aspiration 2 2 1 0 0 0 0 1
A second analysis was performed post hoc to determine
pneumonia
differences between groups based on the time from sedation
Medical
reduction to tracheal extubation and ICU discharge using the
Pulmonary 0 0 1 1 0 0 0 0
data for patients as actually sedated (ie, those patients sedated for
edema
ⱕ 24 h, 24 to 72 h, or ⱖ 72 h regardless of initial randomization
(CHF)
assignment).
COPD 0 0 2 2 0 0 0 0
Acute MI 0 0 2 0 1 0 0 0
Pneumonia 0 1 4 4 1 1 0 0
Results Guillain-Barré 0 0 0 0 0 1 1 0
Pancreatitis 2 0 0 0 1 0 0 0
The trial flow diagram28 is presented in Figure 1. Hemorrhage 0 1 1 0 0 1 0 0
(GI bleed)
Initial treatment assignment and stratification were
Diagnosis 0 0 0 0 1 0 0 0
equally distributed among centers (data not shown). unknown
The trial was terminated prematurely for fiscal reasons. Total 13 15 22 18 24 24 6 2
There were 11 deaths in the midazolam group *Excluding patients who died or were sedation failures.
(13.9%) and 15 deaths (19.5%) in the propofol group CHF ⫽ congestive heart failure; MI ⫽ myocardial infarction;
(p ⫽ 0.37). Hypotension and ventricular tachycardia Mid ⫽ midazolam; Prop ⫽ propofol.

1154 Clinical Investigations in Critical Care

 Table 2—Demographic Information*

Midazolam Propofol
Variables (n ⫽ 65) (n ⫽ 59) p Value

Age, yr 59.8 (55.3–64.4) 60.3 (55.2–66.0) 0.82

Weight, kg 72.1 (68.2–75.9) 78.0 (73.2–82.8) 0.06
Gender, No.
M 34 40 0.05
F 29 16
TISS score† 40 (35.7–45.0) 43 (37.7–48.4) 0.45
APACHE II score† 22 (20.4–24.0) 21 (18.6–22.6) 0.23
SBP,† mm Hg 124 (116.3–131.4) 126 (119.3–133.6) 0.62
DBP,† mm Hg 67 (62.4–71.2) 68 (62.8–73.0) 0.74
Heart rate,† beats/min 98 (92.1–104.6) 92 (86.4–98.2) 0.16
Respiratory rate,† beats/min 15 (13.1–16.3) 16 (13.2–18.0) 0.50
Pao2,† mm Hg 134 (113.0–155.2) 115 (100.4–130.4) 0.15
Paco2, mm Hg 42 (36.0–47.7) 39 (35.6–42.1) 0.36
Repeated tracheal intubation, No. 6 12 0.07
Median length of stay, h 72.7 69.8 0.94
*Excluding data from patients who died or did not respond to sedation. Values given as mean (95% CI), unless otherwise indicated.
TISS ⫽ therapeutic intervention scoring system; SBP ⫽ systolic BP; DBP ⫽ diastolic BP.
†At admission.

between groups for baseline hemodynamic parame- ated with earlier tracheal extubation and longer
ters of BP, heart rate, respiratory rate, or arterial times to ICU discharge. Propofol-treated patients
blood gas levels. had lower diastolic BP, heart rate, and respiratory
Center analysis showed that the average length of rate than did midazolam-treated patients at the time
stay was shorter for center 3 but that there was no of tracheal extubation (data not shown). Respiratory
difference in length of stay between treatment rate continued to be lower over the next 12 h.
groups within each center. Therefore, data were Otherwise, no differences were detected.
pooled (Table 3). Individual data are given for duration of sedation
Tracheal extubation occurred while continuous vs time from end of sedation to tracheal extubation
sedation was ongoing in 25 patients (midazolam, 12 (Fig 2, top) and vs time from end of sedation to ICU
patients; propofol, 13 patients), preventing the ascer- discharge (Fig 2, bottom). Of the four patients whose
tainment of extubation time. Data for the primary time from end of sedation to tracheal extubation
outcome variables for the remaining 99 patients by exceeded 80 h (Fig 2, top), all were treated with
stratum, as determined using an intention-to-treat midazolam. One of these patients required repeated
analysis, are listed in Table 4. Significant differences tracheal intubation. Of the patients who had a time
between groups for the short-term and long-term from end of sedation to ICU discharge of ⬎ 300 h
strata for time to extubation, but not for time to ICU (Fig 2, bottom), three were sedated with propofol
discharge, were noted. When the data were pooled,
the mean time from reduction of sedation to tracheal
extubation was shorter for propofol-treated patients
than for midazolam-treated patients (midazolam, Table 3—Overall Length of Stay by Stratum*
24.7 h [95% CI, 14.5 to 35.0]; propofol, 6.7 h [95% Sedation Strata Midazolam Propofol p Value
CI, 4.2 to 9.1]) but not the time to ICU discharge
ⱕ 24 h
(midazolam, 63.7 h [44.3 to 83.0]; propofol, 94.0 h
Mean 59.56 70.82 0.606
[44.0 to 143.9]). Patients treated with propofol spent 95% CI 40.9–78.1 29.9–111.7
more time at the target mean Ramsay sedation score Median 46.25 46.67 0.940
level (propofol, 60.2% [range, 52.6 to 67.9]; midazo- 24–72 h
lam, 44.0% [range, 35.0 to 52.9]; p ⬍ 0.05). Mean 151.45 158.26 0.897
95% CI 83.5–219.4 72.6–243.9
Data for the post hoc secondary analysis using
Median 94.67 117.17 0.800
treatment received stratification are given in Table 5. ⱖ 72 h
Using this analysis, no differences in either extuba- Mean 219.28 202.94 0.727
tion time or time to ICU discharge were detected 95% CI 159.8–278.7 89.4–316.5
between groups for the short sedation stratum. In Median 207.50 207.33 0.990
the other two strata, the use of propofol was associ- *Excluding data from patients who died or were sedation failures.

CHEST / 119 / 4 / APRIL, 2001 1155

 Table 4 —Time From Sedation Reduction to Tracheal Extubation and ICU Discharge by Strata*

Sedation
Stratum End Point Midazolam Propofol p Value

ⱕ 24 h Extubation (n ⫽ 26) (n ⫽ 21)

ICUdischarge 11.9 (7.0–16.8) 5.6 (2.6–8.6) 0.029
32.7 (23.7–41.7) 49.5 (10.2–88.9) 0.394

24–72 h Extubation (n ⫽ 17) (n ⫽ 21)

ICUdischarge 31.3 (5.7–57.0) 7.4 (3.1–11.7) 0.068
72.6 (41.5–103.7) 147.2 (44.9–249.5) 0.158

ⱖ 72 h Extubation (n ⫽ 10) (n ⫽ 4)
ICUdischarge 46.8 (14.4–79.3) 8.4 (0–25.0) 0.03
129.0 (47.5–210.5) 47.6 (0–108.1) 0.20
*Positive values only were used with an intention-to-treat analysis. Values given as mean (95% CI), unless otherwise indicated.

and one with midazolam. All of these patients re-
quired repeated tracheal intubation.
Discussion
In this multicenter randomized trial, the use of
propofol compared to midazolam for sedation of
patients in the ICU was associated with a reduced
time to tracheal extubation in evaluable patients, but
there was either no difference or a prolonged time to
ICU discharge.
We can only speculate as to why ICU discharge
was delayed. It could perhaps be explained by
problems in the systematic handling of patients
within these institutions. For example, any pharma-
cokinetic advantage to earlier tracheal extubation
associated with propofol use will be lost if there are
routine difficulties associated with discharging pa-
tients from the ICU due to, for example, lack of floor
beds available to receive these patients. Alterna-
tively, propofol-treated patients, although they were
extubated earlier (and perhaps prematurely), may
have required more ongoing care in the ICU than
patients treated with midazolam. Propofol-treated
patients had lower respiratory rates following extu-
bation. Perhaps the ongoing release of propofol from
fat stores4 contributed to residual sedation leading to
an impairment of cough, atelectasis, and pulmonary
dysfunction, thus necessitating retention of patients
in the ICU for longer periods of time. Both propo-
fol29,30 and midazolam31 have been demonstrated to
reduce neutrophil function in vitro. The degree to
which this may have contributed to the results is
unknown. Although not statistically significant, there
were more deaths among the propofol-treated pa-
tients, and they required reintubation more fre-
quently than midazolam-treated patients. Unfortu-
nately, we did not capture the reason for
reintubation in our data set.
Our trial confirms the findings of the majority of
previous randomized studies, which have demon-
strated more rapid times to awakening9,11–14,16,17 and
reduced times to tracheal extubation11,15 with the
use of propofol for ICU sedation. However, Higgins

Table 5—Time From Sedation Reduction to Tracheal Extubation and ICU Discharge by Stratum as
Determined by Post Hoc Analysis*

Sedation
Stratum End Point Midazolam Propofol p Value

ⱕ 24 h Extubation (n ⫽ 30) (n ⫽ 28)

ICUdischarge 9.1 (5.5–12.7) 6.3 (3.4–9.2) 0.17
33.7 (24.3–43.0) 43.4 (30.9–55.9) 0.22

24–72 h Extubation (n ⫽ 8) (n ⫽ 7)
ICUdischarge 31.0 (6.3–55.7) 9.9 (1.3–18.5) 0.014
76.7 (29.7–123.7) 156.5 (0–335.8) 0.008

ⱖ 72 h Extubation (n ⫽ 15) (n ⫽ 11)

ICUdischarge 52.7 (25.6–79.8) 5.3 (1.4–9.2) 0
121.7 (63.1–180.3) 154.7 (0–316.6) 0.004
*Positive values only were used. Values given as mean (95% CI).
1156 Clinical Investigations in Critical Care

Figure 2. Top: time from the end of sedation to tracheal
extubation vs duration of sedation. Note the increased variability
for patients who received midazolam for sedation. Each point
represents results for an individual patient. Bottom: time from
the end of sedation to ICU discharge vs duration of sedation.
Each point represents results for an individual patient. No
differences between groups were identified.
et al10 did not find a difference in time to tracheal
extubation when comparing propofol to midazolam
for sedation in a cardiac surgical patient population.
Comparative studies reporting the role of propofol
sedation to accelerate ICU discharge have produced
mixed results. Our findings were that the use of
propofol for sedation did not shorten ICU length of
stay. In contrast, Carrasco et al11 demonstrated that
the use of propofol was associated with earlier ICU
discharge and, consequently, with cost savings in
patients having ICU stays of ⬍ 1 day. Barrientos-
Vega and colleagues15 also were able to show cost
savings due to earlier ICU discharge in patients
sedated with propofol for approximately 150 h. Both
studies were conducted in Spain and may reflect
differences in ICU practice and patient mix in that
country vs Canada. However, another Spanish trial,
conducted in a trauma population, showed an in-
creased ICU length of stay for propofol-treated
patients (propofol-treated patients, 24 days; midazo-
lam-treated patients, 18 days).16 A study conducted
by Weinbroum et al17 in Israel, while able to show a
difference in time to awakening, did not measure a
significant difference in ICU discharge time (mida-
zolam-treated patients, 31 days; propofol-treated pa-
tients, 21 days) when patients were sedated for ⬎ 24
h. ICU costs were five times higher in propofol-
treated patients in that study. It would appear,
therefore, that to capitalize on the more rapid awak-
ening and tracheal extubation produced by the use of
propofol sedation, the ability to rapidly discharge the
patient once tracheal extubation occurs is essential.
In situations in which this is not possible (ie, those in
which the patient’s disease process will require
further ICU stay after extubation [eg, trauma pa-
tients]) or those in which there are systematic diffi-
culties in arranging the timely transfer of patients
once they are extubated out of the ICU (as exists in
the Canadian health-care system as a consequence of
bed closures), the use of propofol may not be
cost-effective.
The Society of Critical Care Medicine has pub-
lished guidelines for sedation in the ICU.20 They
recommend propofol or midazolam for sedation
intervals of ⬍ 24 h and lorazepam for sedation
intervals of ⬎ 24 h. In part, their recommendations
are predicated on a lack of information concerning
the safety of propofol for long-term sedation. A
recent meta-analysis32 suggested a need for more
randomized trials of ICU sedation. Our study adds to
a growing body of knowledge concerning the safety
of propofol for ICU sedation in adults.8,11,12,15,16,18,19
In the current study, hypertriglyceridemia developed
in one patient receiving propofol who subsequently
died, and significant hypotension developed in three
others (one of whom died), prompting a change in
the sedation regimen. Our results suggest that, while
propofol may be a satisfactory agent for ICU seda-
tion, attention should be given to the monitoring of
hemodynamics and serum triglyceride levels on a
regular basis as a proportion of patients will develop
hemodynamic and metabolic complications.
Prolonged tracheal intubation may be associated
with adverse clinical events, including development
of nosocomial pneumonia33 and barotrauma.34 Intu-
itively, drugs that reduce the time that a patient
receives mechanical ventilation should lead to reduc-
tions in such adverse events. In this study, no
differences in adverse events were detected between
the two drug regimens, but the study was not
designed to detect measurable differences.
The strengths of our study include its randomized
nature, size, multicenter design, and differences in
CHEST / 119 / 4 / APRIL, 2001 1157
case mix. A weakness is the lack of masking, but, for
reasons already expounded, we did not think that we
could mask the study treatments in any practical
fashion. By chance alone, more women were ran-
domized to the midazolam treatment group. Un-
known gender differences in pharmacokinetics may
have played a role in the results. For budgetary
reasons, we did not complete the recruitment of
sufficient numbers of patients in the medium-term
sedation stratum (24 patients) and the long-term
sedation stratum (40 patients), which may have
affected our ability to detect differences within the
medium-term sedation stratum and suggests that
caution should be exercised in the interpretation of
the data from the long-term stratum.
Conclusion
Propofol was a satisfactory agent for ICU sedation
in this randomized multicenter trial. It permitted
earlier tracheal extubation compared to midazolam
but did not permit earlier ICU discharge.
Appendix 1: Additional Study Investigators
David Stewart, MSc, Study Monitor, Ottawa Civic Hospital,
Ottawa, Ontario, Canada; Hugh Devitt, MD, Safety Review
Committee, Sunnybrook Health Sciences Centre, Toronto, On-
tario, Canada; Craig Guenther, MD, Safety Review Committee,
University of Alberta Hospitals, Edmonton, Alberta, Canada;
Mauricio Calero, MD, Commercial Products Manager, Zeneca
Pharma Inc., Mississauga, Ontario, Canada; and Hector Leon,
BSc STAT, Data Entry and Statistical Analysis, St. Paul’s Hospi-
tal, Vancouver, British Columbia, Canada.
Appendix 2: Ramsay Sedation Scale
1. Anxious and agitated, or restless, or both22
2. Cooperative, oriented, and tranquil
3. Responding to commands only
4. Brisk response to glabellar tap
5. Sluggish response to glabellar tap
6. No response to light glabellar tap
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