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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. This research was supported by Zeneca Pharma Inc. Canada.
Hall), Halifax, Nova Scotia, Canada; Foothills Hospital (Dr. Dr. Hall has received consultation fees from Zeneca Pharma Inc.
Sandham), University of Calgary, Calgary, Alberta, Canada; and Hoffman-LaRoche Limited. He has no equity interest in
Ottawa General Hospital (Dr. Cardinal), Ottawa, Ontario, Can- either company. Drs. Sandham, Cardinal, Tweeddale, and Anis,
ada; Vancouver General Hospital (Dr. Tweeddale), Vancouver, and Mr. Moher and Mrs. Wang have no financial relationship
British Columbia, Canada; Ottawa Civic Hospital (Mr. Moher), with either company.
Ottawa, Ontario, Canada; St. Paul’s Hospital (Mrs. Wang), Manuscript received March 11, 1999; revision accepted Septem-
Vancouver, British Columbia, Canada; and the Department of ber 7, 2000.
Health Care and Epidemiology (Dr. Anis), University of British Correspondence to: Richard I. Hall, MD, FCCP, Department of
Columbia, Vancouver, British Columbia, Canada. Anesthesia, Queen Elizabeth II Health Sciences Centre, 1796
†A list of additional study investigators is located in Appendix 1. Summer St, Halifax, Nova Scotia, Canada B3H 3A7; e-mail:
Presented in part to the American College of Chest Physicians rihall@is.dal.ca
Annual Meeting, New Orleans, LA, October 26 –30, 1997.
when sedation was required to rapidly achieve patient control of, in intubated patients.24,25 Patients were judged to be awake when
eg, postoperative emergence delirium, the time factor required to the Glasgow coma score was ⱖ 12.
prepare and mask solutions was thought to be such as to be
detrimental to patient care. The purpose of our study was to Measurements
inquire whether real-world use of the agents in a diverse group of
Canadian ICUs would lead to measurable differences in out- The Ramsay score (target and actual) was recorded hourly for
comes.23 the first 72 h or up to the time of discharge from ICU if this
Once patients were entered into the study, all investigators occurred prior to 72 h. After 72 h, it was recorded as the patient’s
agreed in advance that patient crossover between sedative regi- condition or infusion rate was altered. Time to tracheal extuba-
mens was prohibited unless a clear treatment failure could be tion, time to ICU discharge, and requirements for reintubation
demonstrated (eg, increasing paradoxical excitement in response were recorded. A record of vital signs was maintained every 20
to benzodiazepine administration or hyperlipidemia in response min for 40 min, then every 6 h for 48 h following extubation or
to propofol administration). Patients who died or crossed over until ICU discharge, whichever came first. Admission therapeutic
were eliminated from the study, and the data were censured. intervention scoring system score26 and APACHE II score27 were
recorded.
Measurement Scales Decisions as to when a patient was ready for a trial of
extubation or for discharge from the ICU were left to the
The Ramsay sedation score22 was utilized to quantitate the attending intensivists.
desired degree of sedation specified at regular intervals and Primary Outcome Measures: The time from withdrawal of
adjusted as the patient’s condition (ie, recovery or deterioration) sedation until tracheal extubation and ICU discharge for each
dictated. Patients receiving muscle relaxants and sedation were stratum was taken as the primary outcome measures. In situa-
given a Ramsay sedation score of 6. Recovery of consciousness tions in which patients required multiple independent periods of
was determined by measurement of the acute physiology and sedation or reintubation due to alterations in their disease
chronic health evaluation (APACHE) III modification of the process, the first period of sedation accompanied by tracheal
Glasgow coma score to allow for scoring of the verbal component extubation was utilized for data collection surrounding this event.
Midazolam Propofol
Variables (n ⫽ 65) (n ⫽ 59) p Value
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.
Sedation
Stratum End Point Midazolam Propofol p Value
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- have required more ongoing care in the ICU than
quired repeated tracheal intubation. patients treated with midazolam. Propofol-treated
patients had lower respiratory rates following extu-
bation. Perhaps the ongoing release of propofol from
Discussion fat stores4 contributed to residual sedation leading to
an impairment of cough, atelectasis, and pulmonary
In this multicenter randomized trial, the use of
propofol compared to midazolam for sedation of dysfunction, thus necessitating retention of patients
patients in the ICU was associated with a reduced in the ICU for longer periods of time. Both propo-
time to tracheal extubation in evaluable patients, but fol29,30 and midazolam31 have been demonstrated to
there was either no difference or a prolonged time to reduce neutrophil function in vitro. The degree to
ICU discharge. which this may have contributed to the results is
We can only speculate as to why ICU discharge unknown. Although not statistically significant, there
was delayed. It could perhaps be explained by were more deaths among the propofol-treated pa-
problems in the systematic handling of patients tients, and they required reintubation more fre-
within these institutions. For example, any pharma- quently than midazolam-treated patients. Unfortu-
cokinetic advantage to earlier tracheal extubation nately, we did not capture the reason for
associated with propofol use will be lost if there are reintubation in our data set.
routine difficulties associated with discharging pa- Our trial confirms the findings of the majority of
tients from the ICU due to, for example, lack of floor previous randomized studies, which have demon-
beds available to receive these patients. Alterna- strated more rapid times to awakening9,11–14,16,17 and
tively, propofol-treated patients, although they were reduced times to tracheal extubation11,15 with the
extubated earlier (and perhaps prematurely), may 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
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