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(Chest. 2001;119:1151-1159.)
© 2001 American College of Chest Physicians

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; Aslam H. Anis, PhD and for the Study Investigators{dagger}

* 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, Canada; 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. {dagger} A list of additional study investigators is located in Appendix 1.

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{at}is.dal.ca


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Appendix 1
 Appendix 2
 References
 
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 = 46) were extubated earlier than those treated with midazolam (n = 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 = 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.

Key Words: ICU • mechanical ventilation • midazolam • multicenter • propofol • randomized clinical trial • sedation


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 Appendix 1
 Appendix 2
 References
 
Patients in an ICU are exposed to a variety of noxious stimuli including pain after surgery, frequent venipuncture, and discomfort from the presence of an endotracheal tube.1 2 Sedation is frequently 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 propofol.3 4 5 Both are rapid-acting drugs and do not suppress adrenal function when administered to the critically ill patient.6 7 Randomized studies, largely from European centers, comparing propofol to midazolam 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 9 10 11 12 13 14 15 16 17 Data regarding the safety and efficacy 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 Canadian 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 prolonged infusions during mechanical ventilation receive 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 mechanical 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 mechanical ventilation.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 Appendix 1
 Appendix 2
 References
 
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 protocol and consent process. Physicians made an assessment as to whether patients would require sedation for short-term (<= 24 h), medium-term (> 24 and < 72 h), or long-term (>= 72 h) mechanical ventilation on admission to the ICU. Patients then were stratified by predicted sedation time while receiving mechanical ventilation, were randomized, and were entered into the trial.

Eligibility Criteria
Inclusion Criteria: Patients were of either gender, >= 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 (>= 24 h but < 72 h); and long term (>= 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 knowledgeable caregivers would likely recognize treatments on this basis alone. Furthermore, when necessary to administer bolus infusions for acute agitation, knowledge of the treatment groups would prevent potentially hazardous hemodynamic changes through appropriate care with drug infusion rates. The practicality of masking infusions by wrapping bags and tubing, for example, at all hours of the day or night was limited. Indeed, 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 outcomes.23

Once patients were entered into the study, all investigators agreed in advance that patient crossover between sedative regimens 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 >= 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 extubation, 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 situations 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. Data were collected for the duration of the patient’s ICU stay. ICU length of stay was recorded as the time from admission to ICU until the patient was discharged to the floor.

Secondary Outcome Measures: The time when the patient was deemed ready for extubation (as assessed by attending physicians clinically and by use of weaning parameters in most cases) was recorded as well as the interval between when the patient was deemed ready for discharge and when discharge actually occurred.

Safety Review Board
All reports of deaths and serious adverse events, as identified by site investigators, were examined by a blinded safety review board that determined whether the event was attributable to study drug treatment or not.

Sample Size Calculation
Statistical power was estimated using reduction in recovery time as the primary outcome. The recovery time for patients assigned to midazolam treatment was taken from the data of 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 days). We assumed an interest in detecting a 20% relative reduction in recovery time using propofol (ß = 0.1; {alpha} = 0.05; 2-sided). The statistical power was calculated for each stratum separately (short term [< 24 h], 22 per group to detect a 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 h], 22 patients per group to detect a difference of 12.97 h).

Statistical Analysis
The primary analysis was by intention-to-treat and was based on differences in time to tracheal extubation and time to ICU discharge from the withdrawal of sedation using data from patients as assigned to the original stratum. Probability values <= 0.05 were considered to be statistically significant. Ninety-five percent confidence intervals (CIs) were constructed for all data.

A two-way analysis of variance was used to assess differences in tracheal extubation time by treatment group and sedation stratum. A similar analysis was used to compare differences in the time of ICU length of stay. The incidence of adverse events and mortality was compared using a contingency table analysis.

A second analysis was performed post hoc to determine differences between groups based on the time from sedation reduction to tracheal extubation and ICU discharge using the data for patients as actually sedated (ie, those patients sedated for <= 24 h, 24 to 72 h, or >= 72 h regardless of initial randomization assignment).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 Appendix 1
 Appendix 2
 References
 
The trial flow diagram28 is presented in Figure 1 . Initial treatment assignment and stratification were equally distributed among centers (data not shown). The trial was terminated prematurely for fiscal reasons.



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  		Figure 1.. Trial flow diagram.

 
There were 11 deaths in the midazolam group (13.9%) and 15 deaths (19.5%) in the propofol group (p = 0.37). Hypotension and ventricular tachycardia leading to death developed in one patient receiving propofol, and propofol administration was thought to have possibly contributed to that death by the safety review board. Hypertriglyceridemia developed in one propofol-treated patient who subsequently died. Lack of response to sedation occurred in four midazolam-treated patients (one of whom died) and in seven propofol-treated patients (four of whom died) (p = 0.30). Lack of response to sedation was attributed to paradoxical excitement and agitation in three midazolam-treated patients and in one propofol-treated patient. Unacceptable hypotension developed in two propofol-treated patients.

Diagnostic categories for the remaining 124 patients who survived and were discharged from the ICU are presented in Table 1 . Demographic information is provided in Table 2 . There were more women in the midazolam group with a tendency to a lower weight distribution. There were no differences between groups for baseline hemodynamic parameters of BP, heart rate, respiratory rate, or arterial blood gas levels.


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  		Table 1.. Distribution of Study Population by Center, Group, and Diagnosis*

 

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  		Table 2.. Demographic Information*

 
Center analysis showed that the average length of stay was shorter for center 3 but that there was no difference in length of stay between treatment groups within each center. Therefore, data were pooled (Table 3 ).


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  		Table 3.. Overall Length of Stay by Stratum*

 
Tracheal extubation occurred while continuous sedation was ongoing in 25 patients (midazolam, 12 patients; propofol, 13 patients), preventing the ascertainment of extubation time. Data for the primary outcome variables for the remaining 99 patients by stratum, as determined using an intention-to-treat analysis, are listed in Table 4 . Significant differences between groups for the short-term and long-term strata for time to extubation, but not for time to ICU 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, 24.7 h [95% CI, 14.5 to 35.0]; propofol, 6.7 h [95% CI, 4.2 to 9.1]) but not the time to ICU discharge (midazolam, 63.7 h [44.3 to 83.0]; propofol, 94.0 h [44.0 to 143.9]). Patients treated with propofol spent more time at the target mean Ramsay sedation score level (propofol, 60.2% [range, 52.6 to 67.9]; midazolam, 44.0% [range, 35.0 to 52.9]; p < 0.05).


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

 
Data for the post hoc secondary analysis using treatment received stratification are given in Table 5 . Using this analysis, no differences in either extubation time or time to ICU discharge were detected between groups for the short sedation stratum. In the other two strata, the use of propofol was associated with earlier tracheal extubation and longer times to ICU discharge. Propofol-treated patients had lower diastolic BP, heart rate, and respiratory rate than did midazolam-treated patients at the time of tracheal extubation (data not shown). Respiratory rate continued to be lower over the next 12 h. Otherwise, no differences were detected.


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

 
Individual data are given for duration of sedation vs time from end of sedation to tracheal extubation (Fig 2 , top) and vs time from end of sedation to ICU discharge (Fig 2 , bottom). Of the four patients whose time from end of sedation to tracheal extubation exceeded 80 h (Fig 2 , top), all were treated with midazolam. One of these patients required repeated tracheal intubation. Of the patients who had a time from end of sedation to ICU discharge of > 300 h (Fig 2 , bottom), three were sedated with propofol and one with midazolam. All of these patients required repeated tracheal intubation.



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  		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.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 Appendix 1
 Appendix 2
 References
 
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 pharmacokinetic advantage to earlier tracheal extubation associated with propofol use will be lost if there are routine difficulties associated with discharging patients from the ICU due to, for example, lack of floor beds available to receive these patients. Alternatively, 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 extubation. 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 propofol29 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 patients, and they required reintubation more frequently than midazolam-treated patients. Unfortunately, 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 demonstrated more rapid times to awakening9 11 12 13 14 16 17 and reduced times to tracheal extubation11 15 with the use of propofol for ICU sedation. However, Higgins 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 increased ICU length of stay for propofol-treated patients (propofol-treated patients, 24 days; midazolam-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 (midazolam-treated patients, 31 days; propofol-treated patients, 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 awakening 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 patients]) or those in which there are systematic difficulties 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 published 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 sedation, 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 Intuitively, drugs that reduce the time that a patient receives mechanical ventilation should lead to reductions 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 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 randomized to the midazolam treatment group. Unknown 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
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
Appendix 1
 Appendix 2
 References
 
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
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Appendix 1
Appendix 2
 References
 
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, Ontario, 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 Hospital, Vancouver, British Columbia, Canada.


   Appendix 2
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Appendix 1
 Appendix 2
References
 
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


   Footnotes
 
Abbreviations: APACHE = acute physiology and chronic health evaluation; CI = confidence interval

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.

Received for publication March 11, 1999. Accepted for publication September 7, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Appendix 1
 Appendix 2
 References
 

  1. Aitkenhead, AR (1989) Analgesia and sedation in intensive care. Br J Anaesth 63,196-206[Free Full Text]
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  9. Boyd, O, Mackay, CJ, Rushmer, F, et al (1993) Propofol or midazolam for short-term alterations in sedation. Can J Anaesth 40,1142-1147[Abstract/Free Full Text]
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  16. Sanchez-Izquierdo-Riera, JA, Caballero-Cubedo, RE, Perez-Vela, JL, et al (1998) Propofol versus midazolam: safety and efficacy for sedating the severe trauma patient. Anesth Analg 86,1219-1224[Abstract]
  17. Weinbroum, AA, Halpern, P, Rudick, V, et al (1997) Midazolam versus propofol for long-term sedation in the ICU: a randomized prospective comparison. Intensive Care Med 23,1258-1263[CrossRef][ISI][Medline]
  18. Beller, JP, Pottecher, T, Lugnier, A, et al (1988) Prolonged sedation with propofol in ICU patients: recovery and blood concentration changes during periodic interruptions in infusion. Br J Anaesth 61,583-588[Abstract/Free Full Text]
  19. Valente, JF, Anderson, GL, Branson, RD, et al (1994) Disadvantages of prolonged propofol sedation in the critical care unit. Crit Care Med 22,710-712[ISI][Medline]
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