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Sedation in the Intensive Care Unit: A Systematic Review

Article  in  JAMA The Journal of the American Medical Association · April 2000


DOI: 10.1001/jama.283.11.1451 · Source: PubMed

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CARING FOR THE
CRITICALLY ILL PATIENT

Sedation in the Intensive Care Unit


A Systematic Review
Marlies E. Ostermann, MD Context Sedation has become an integral part of critical care practice in minimizing
Sean P. Keenan, MD, FRCPC, MSc patient discomfort; however, sedatives have adverse effects and the potential to pro-
long mechanical ventilation, which may increase health care costs.
Roxanne A. Seiferling, BSP, BA
Objective To determine which form of sedation is associated with optimal seda-
William J. Sibbald, MD, FRCPC tion, the shortest time to extubation, and length of intensive care unit (ICU) stay.
Data Sources A key word search of MEDLINE, EMBASE, and the Cochrane Col-

T
O MINIMIZE PATIENT DISCOM- laboration databases and hand searches of 6 anesthesiology journals from 1980 to
fort in the intensive care unit June 1998. Experts and industry representatives were contacted, personal files were
(ICU), sedation has become an searched, and reference lists of relevant primary and review articles were reviewed.
integral part of critical care Study Selection Studies included were randomized controlled trials enrolling adult
practice. Sedation reduces the stress re- patients receiving mechanical ventilation and requiring short-term or long-term seda-
sponse, provides anxiolysis, improves tion. At least 2 sedative agents had to be compared and the quality of sedation, time
tolerance of ventilatory support, and to extubation, or length of ICU stay analyzed.
facilitates nursing care. 1-3 Unfortu- Data Extraction Data on population, intervention, outcome, and methodological
nately, sedatives have adverse effects, quality were extracted in duplicate by 2 of 3 investigators using 8 validity criteria.
have the potential to prolong mechani- Data Synthesis Of 49 identified randomized controlled trials, 32 met our selection
cal ventilation, and may increase health criteria; 20 studied short-term sedation and 14, long-term sedation. Of these, 20 com-
care costs. An ideal sedative agent pared propofol with midazolam. Most trials were not double-blind and did not report or
would have rapid onset of action, be ef- standardize important cointerventions. Propofol provides at least as effective sedation
fective at providing adequate seda- as midazolam and results in a faster time to extubation, with an increased risk of hypo-
tension and higher cost. Insufficient data exist to determine effect on length of stay in
tion, allow rapid recovery after discon-
the ICU. Isoflurane demonstrated some advantages over midazolam, and ketamine had
tinuation, be easy to administer, lack a more favorable hemodynamic profile than fentanyl in patients with head injuries.
drug accumulation, have few adverse
effects, interact minimally with other Conclusion Considering the widespread use of sedation for critically ill patients, more
large, high-quality, randomized controlled trials of the effectiveness of different agents
drugs, and be inexpensive. for short-term and long-term sedation are warranted.
The lack of a recognized ideal seda- JAMA. 2000;283:1451-1459 www.jama.com
tive has resulted in varied approaches to
sedation both among and within inten-
sive care units (ICUs). In a survey of 164 agents.1,3,7-16 In 1992, the Society of Criti- term (#24 hours) sedation, lorazepam
ICUs in the United States,4 18 different cal Care Medicine (SCCM) Task Force for longer-term (.24 hours) sedation,
sedative agents were used. The most developed practice parameters for seda- and haloperidol for delirium. The level
common agents listed were morphine tion in the ICU based on available sci- of evidence available from the litera-
sulfate, lorazepam, midazolam, diaz- entific data, clinical expertise, and ex- ture for these reviewers was somewhat
epam, and haloperidol. Intensive care perience.17 After careful review and limited at the time, and these useful clini-
unit consultants in the United King- discussion, this group recommended the cal recommendations required heavy re-
dom reported use of 11 different agents use of midazolam or propofol for short- liance on expertise. A survey by Rhoney
in another survey.5 Similarly, Dasta et al6
reported the use of 23 different drugs for
sedation, anxiety, and pain relief in their Author Affiliations: Division of Critical Care, Depart- Corresponding Author and Reprints: Sean P. Keenan,
ment of Medicine, University of Western Ontario MD, FRCPC, MSc, Centre for Health Evaluation and
surgical ICU. These surveys indicate (Drs Ostermann, Keenan, and Sibbald), Richard Ivey Outcome Sciences, St Paul’s Hospital, 620B-1081
wide practice variation in sedative ad- Critical Care Trauma Centre, Victoria Campus (Drs Burrard, Vancouver, British Columbia, Canada V6M
Keenan and Sibbald and Ms Seiferling), and Depart- 2N8 (e-mail: Sean_Keenan@telus.net).
ministration for critically ill patients. ment of Pharmacy (Ms Seiferling), London Health Caring for the Critically Ill Patient Section Editor:
A number of narrative review ar- Sciences Centre, London, Ontario; Centre for Health Deborah J. Cook, MD, Consulting Editor, JAMA.
Evaluation and Outcome Sciences, St Paul’s Hospital Advisory Board: David Bihari, MD; Christian Brun-
ticles have summarized the principles of and University of British Columbia, Vancouver (Dr Buisson, MD; Timothy Evans, MD; John Heffner, MD;
sedation and the range of available Keenan). Norman Paradis, MD.

©2000 American Medical Association. All rights reserved. JAMA, March 15, 2000—Vol 283, No. 11 1451

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SEDATION IN CRITICAL CARE

and Murry18 presented at the SCCM’s term sedation; interventions included a ferent dosing schedules or modes of ad-
meeting in 1998 found that most ICUs comparison of at least 2 sedative drugs; ministering a single agent59-68), leaving
did not use protocols, and practice of- outcomes showed quality of sedation, 32 trials for analysis.20-51
ten did not adhere to the society’s rec- time to extubation, or length of stay in
ommendations. the ICU; and study designs were ran- Study Description
There have been no recent system- domized trials. We excluded studies Short-term sedation was addressed in 20
atic reviews on sedation for critically ill available in abstract format only. Our studies,20-34,41,42,44,45,50 whereas 14 stud-
patients. While adequacy of sedation is study population did not include those ies included patients receiving sedation
an important outcome, additional out- undergoing withdrawal of life support. for more than 24 hours32,33,35-40,43,46-49,51
comes of relevance are time to extuba- (Table 2). Populations included car-
tion and length of ICU stay. The objec- Validity Assessment diac surgery 2 0 - 2 8 , 4 4 other surgical
tive of this systematic review was to Duplicate data abstraction was con- ICU, 30,31,34,45,47 trauma, 39,46 medical
answer the question: In ventilated ICU ducted by 2 of 3 investigators (M.E.O., ICU,35,40 and mixed ICU patients.* The
patients, which sedatives are associ- R.A.S., S.P.K.). In reporting informa- relative effectiveness of the anesthetic
ated with best level of sedation, short- tion on instruments used to evaluate agent propofol, and the benzodiaz-
est time to extubation, and shortest quality of sedation, we used a tax- epine midazolam, were compared in 20
length of ICU stay? We divided the in- onomy recently proposed for this pur- of these 32 clinical trials.20-39 Other agents
tervention into short-term and longer- pose by De Jonghe and colleagues.19 The included the benzodiazepine loraze-
term sedation, as suggested by the SCCM selected publications were critically pam40,41; the opiates alfentanil,44,51 pethi-
guidelines.17 We also have recorded the appraised using 8 validity criteria dine,44 papaveretum,49 fentanyl,46,47,50
hemodynamic effects of sedative agents (TABLE 1). Differences of opinion were morphine,48,51 and lytic solution45 (pethi-
when available. We divided agents us- settled by consensus after consultation dine, promethazine, and dihydroergota-
ing the following taxonomy: (1) benzo- with a third investigator. We used cri- mine); and the anesthetic agents isoflu-
diazepines (eg, diazepam, midazolam, teria applicable to most systematic re- rane42,43 and ketamine.46,50
lorazepam), (2) opiates (eg, morphine, views of randomized controlled trials A variety of scoring systems were used
fentanyl), (3) neuroleptics (haloperi- (criteria 1-4) in addition to criteria of to assess quality of sedation in 30 of the
dol, methotrimeprazine), and (4) anes- specific importance in studies of seda- 32 trials (Table 2). The Ramsay score69
thetic agents (propofol and inhala- tive agents (criteria 5-8). was used most frequently, in 18 trials
tional agents such as isoflurane). (60%). This instrument consists of 1
Analysis item and is evaluated using a numeri-
METHODS We analyzed the study results sepa- cal scale of 1 to 6. Other scoring sys-
Search Strategy rately for short- and longer-term seda- tems included 2 (6%) modified Ram-
We searched MEDLINE, EMBASE, and tion, cardiac surgery patients and other say scores (1 item, numerical scale), 3
the Cochrane Collaboration for ar- ICU patients, and by agents being com- (10%) Cook and Palma modified
ticles from 1980 to June 1998, using the pared (TABLE 2. The online version of Glasgow Coma Scales70 (4 items, nu-
key words hypnotics and sedatives, pro- Table 2 may be accessed at http:// merical scale), and 9 (30%) of 30 scor-
pofol, midazolam, benzodiazepines, halo- jama.ama-assn.org.) The studies were ing systems created for each specific
peridol, and antipsychotic agent, each too clinically heterogeneous to permit study (variable number of items, nu-
combined with intensive care unit and statistical pooling. merical scales). One trial used both the
critical care. We wrote to experts and Ramsay and the Cook and Palma score,32
first authors of selected articles as well RESULTS and another used a scoring system that
as 18 pharmaceutical companies. We Study Selection was derived from merging the Ramsay
hand searched Anesthesiology, Anesthe- We identified 49 randomized con- and Cook scores (however, the scoring
sia and Analgesia, Canadian Journal of An- trolled trials,20-68 41 from personal file, system was not provided in the article).33
aesthesia, British Journal of Anaesthesia, MEDLINE, and EMBASE searches, 7
Anaesthesia and Intensive Care, and An- more from hand searching anesthesia Assessment of Validity
aesthesia from 1980 to June 1998. Ref- journals, and 1 from an expert in the The validity of included trials is sum-
erence lists of retrieved articles were re- field. Of the 49 trials, 17 were ex- marized in Table 1. Masking of alloca-
viewed, and personal files were searched. cluded52-68 (4 addressed a different popu- tion to treatment was not documented
lation52-56 [2 normal volunteers, 1 non- in any trial. Blinding health care work-
Selection Criteria ventilated ICU patients, 1 intraoperative ers was conducted in 5 (16%) of 32 tri-
To identify published studies for inclu- cardiac surgery anesthesia patients], 2 als. Standardized cointerventions that
sion in this analysis, study populations evaluated different outcomes57,58 [renal could affect the outcomes of time to ex-
included mechanically ventilated adult function of isoflurane, urine, and plasma
patients requiring short-term or longer- catecholamines], and 6 investigated dif- *References 29,32,33,36-38,41-43,48,49,51.

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SEDATION IN CRITICAL CARE

tubation and length of ventilation or the quality of sedation achieved,31-33 azolam reported on duration of venti-
ICU stay were variably reported (wean- with the remainder reporting no dif- lation or ICU stay. While only 1 trial
ing strategy, 3 [9%] of 32 trials; anes- ference.29,30,34 All 3 trials that reported found significantly lower blood pres-
thesia for postoperative patients, 7 time to extubation found propofol to sure in the propofol arm compared with
[78%] of 9; use of analgesia, 7 [22%] be more effective than midazolam.29,32,33 midazolam (more hypotension in the
of 32; and neuromuscular blockers, 13 No trials comparing propofol with mid- first 30 minutes),34 2 other trials noted
[41%] of 32 trials). Intention-to-treat
analysis was used in 26 (81%) of
32 trials. Table 1. Validity Assessment of Studies*
Baseline Specific
Short-term Sedation Follow-up, Data Dosing
Source, y % Blinding ITT Provided† SI‡ Schedule
Cardiac Surgery Patients. Nine trials Propofol vs Midazolam (Cardiac Surgery)
were identified that examined the rela- Grounds et al,20 1987 100 No Yes 1, 2 1, 4 No
tive effectiveness of propofol to mid- McMurray et al,21 1990 100 No Yes 1, 2, 3 1 No
azolam in post–cardiac surgery pa- Snellen et al,22 1990 100 No Yes 1, 2, 3, 4, 5 1, 2, 4 Yes
tients.20-28 One trial compared the use Chaudhri et al,23 1992 NA No NA 3, 4, 5 2 No
of 2 different opiate preparations44 and Roekaerts et al,24 1993 100 No No 1, 2, 3, 4, 5 1, 2, 4 Yes
found no difference in quality of seda- Higgins et al,25 1994 100 No No 1, 2, 3, 4 None No
tion or time to extubation when either Wahr et al,26 1996 89 Yes Yes 1, 2 1, 3 No
pethidine or alfentanil was used. Searle et al,27 1997 100 Yes Yes 1, 2, 3, 4 1, 2, 3 Yes
Of the 7 trials20-22,25-28 providing data Carrasco et al,28 1998 100 Yes Yes 1, 2, 3, 4 1, 2 No
comparing quality of sedation of pro- Propofol vs Midazolam (Mixed ICU/Postoperative Patients)§
pofol vs midazolam, 5 reported no dif- Aitkenhead et al,29 1989 100 No Yes 1, 2 3 No
ference,22,25-28 and 2 found propofol to Beyer and Seyde,30 1992 100 No Yes 1, 2 2, 3 No
be more effective than midazolam.20,21 Boyd et al,311993 100 Yes Yes 1 1, 2 No
Trials reporting a difference between Carrasco et al,32 1993 100 No Yes 1, 2 3 No
propofol and midazolam were older and Costa et al,33 1994 NA No Yes 1, 2, 3, 4 3 No
fulfilled fewer validity criteria. Time to Ronan et al,34 1995 83 No No 1, 2, 3, 4 None No
extubation was shorter for patients tak- Kress et al,35 1996 66 No No 1, 2, 3, 4 None No
ing propofol than midazolam in 5 of 8 Chamorro et al,36 1996 100 No Yes 1, 2, 3, 4 None No
studies reporting this outcome20-22,24,28 Barrientos-Vega et al,37 1997 100 No Yes 1, 2, 3 2, 3 No
but was no different in the remaining Weinbroum et al,38 1997 100 No Yes 1, 2 3 No
trials.23,25,27 Six of 7 trials reported no Sanchez-Izqierdo et al,39 1998 100 No Yes 1, 3, 4 None No
difference in duration of ventilation be- Midazolam vs Lorazepam (Mixed ICU Patients)
tween propofol and midazolam,21-25,27 Pohlman et al,40 1994 100 No Yes 1, 2 None Yes
whereas 1 trial favored propofol rather Cernaianu et al,41 1996 100 No Yes 1, 3, 4 3 No
than midazolam,20 and the 2 trials re- Midazolam vs Isoflurane
porting length of ICU stay found no dif- Kong et al,42 1989 100 No Yes 1, 2 3 No
ference.27,28 One trial reported a statis- Spencer and Willatts,43 1992 100 No Yes 1, 2, 3, 4 3 No
tically significant increase in incidence
Opiate vs Opiate
of hypotension in the propofol vs the
Yate et al,44 1986 100 No Yes 1, 2, 3, 4 3 No
midazolam arm.26
Opiate vs Propofol
Surgical or Mixed ICU Patients. Nine
Heinrichs et al,45 1992 100 No Yes 2 None Yes
trials included patients from surgical or
mixed ICUs who received sedation for Opiate vs Anesthetic
less than 24 hours.29-34,41,42,45 Of these, Kolenda et al,46 1996 69 No Yes 1, 2, 3, 4 None No
6 compared the effectiveness of propo- Drug Combinations vs Drug Combinations
fol vs midazolam,29-34 1 compared mid- Adams et al,47 1988 100 No Yes 1, 2 None No
azolam to lorazepam,41 1 compared Ledingham et al,48 1988 Interim analysis Yes Yes 1 None No
midazolam to isoflurane,42 and 1 com- Harris et al,49 1990 100 No No 1, 2 None No
pared propofol to lytic solution45 (pethi- Adams et al,50 1991 100 No Yes 1, 2 None No
dine, promethazine, and dihydro- Manley et al,51 1997 100 No No 1, 3, 4 3 No
ergotamine). *ITT indicates intention to treat; SI, standardized interventions; and NA, not available.
†Baseline data available were 1, age; 2, weight; 3, hepatic function; 4, renal function; and 5, lung function.
Three of the 6 trials found propofol ‡Cointerventions included 1, anesthesia; 2, analgesia; 3, neuromuscular blockade; and 4, weaning strategy.
§ICU indicates intensive care unit. None of these studies reported masking of allocation.
to be more effective than midazolam in
©2000 American Medical Association. All rights reserved. JAMA, March 15, 2000—Vol 283, No. 11 1453

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SEDATION IN CRITICAL CARE

Table 2. Summary of Selected Trials Assessing the Effectiveness of Sedative Agents Used in the ICU*
Sedation Mean % Mean Mean
Score Time at Time to Mean ICU
Study/Patient Length of Target Mean Sedation Extubation, Length of Length of
Population† Sedation Level Sedatives‡ Dosage Target Level§ min Ventilation, h Stay, d
Propofol vs Midazolam (Cardiac Surgery Patients)
Grounds et al,20 1987
Post-CABG Short RL 3 Propofol (c) 13.1 µg/kg/min 44.6 24.9 8.08 NA
(n = 60) (,24 h) Midazolam (i) 0.3 µg/kg/min 28.1 (P,.03) 226 (P,.001) 11.12 (P,.02)
McMurray et al,21 1990
Post-CABG Short RL 2-5 Propofol (c) 19.2 µg/kg/min 86 7.6 18.56 NA
(n = 100) (,24 h) Midazolam (i) 0.6 µg/kg/min 56 (P,.001) 125 (P,.001) 20.06 (P not
tested)
Snellen et al,22 1990
Post-CABG Short RL 2-4 Propofol (c) 15.2 µg/kg/min 59.6 154 13.10 NA
(n = 40) (,24 h) Midazolam (c) 0.6 µg/kg/min 53 (NSD) 243 (P = .06) 14.63 (P not
tested)
Chaudhri et al,23 1992
Post-CABG Short 6-Point Propofol (c) 8.3-33.3 µg/kg/min 65 NSD NSD NA
patients needing (,8 h) scoring Midazolam (c) 1.7-3.3 µg/kg/min 70 (NSD) (no data) (no data)
vasodilators for system
hypertension (1 item,
(n = 40) numerical)
Roekaerts et al,24 1993
Post-CABG Short RL 5 Propofol (c) 45.2 µg/kg/min More frequent 250 14.63 NA
(n = 30) (,24 h) Midazolam (c) 1.5 µg/kg/min dose 391 (P,.01) 17.27 (P not
adjustments in tested)
M group
Higgins et al,25 1994
Post-CABG Short RL 3 Propofol (c) 12.6 µg/kg/min 58 258 17.8 No
(x = 84) (,24 h) Midazolam (c) 0.3 µg/kg/min 65 (NSD) 210 (NSD) 16.8 (P not difference
(n = 80) tested) (no data)
Wahr et al,26 1996
Post-CABG Short RL 5 Propofol (c) NA NA NA NA NA
(x = 351) Midazolam (i)
(n = 312)
Searle et al,27 1997
Post–cardiac surgery Short RL 2-4 Propofol (c) 10.6 µg/kg/min 67 87.5 5.46 3.7
(x = 44) (,8 h) Midazolam (c) 0.3 µg/kg/min 65.4 (NSD) 91.5 (NSD) 5.53 (P not 3.9 (NSD)
(n = 41) tested)
Carrasco et al,28 1998
Post-CABG Short Cook & Propofol (c) 20 µg/kg/min 93 54 NA 1.7
(n = 75) Palma level Midazolam (c) 1.3 µg/kg/min 88 (P = .10) 138 P + M, 1.8
8-11 Combined (c) 8.3 µg/kg/min (P) 90 72 (P = .01 1.8
0.5 µg/kg/min (M) for both (P..05)
comparisons)
Propofol vs Midazolam (Mixed ICU Patients)
Aitkenhead et al,29 1989
Mixed ICU Short RL 2-4 Propofol (c) 29.5 µg/kg/min 94 5 NA NA
(x = 101) (,24 h) Midazolam (c) 1.7 µg/kg/min 93 (NSD) 148 (P,.001)
(n = 100) (y = 39)
Beyer and Seyde,30 1992
Postoperative Short RL 3-4 Propofol (c) 31.7 µg/kg/min NSD NA NA NA
(n = 20) (24 h) Midazolam (c) 1.8 µg/kg/min (no data)
Boyd et al,31 1993
Postoperative Short RL 5 Propofol (c) 133 mg/h + 53.9 NA NA NA
(x = 23) (12-16 235-mg bolus
(n = 19) min) Midazolam (c) 4.0 mg/h + 25.7 (P,.001)
7.8-mg bolus
Carrasco et al,32 1993
Mixed ICU Short RL 2-5 Propofol (c) 38.3 µg/kg/min 93 18 NA NA
(x = 92) (,24 h) Midazolam (c) 2.8 µg/kg/min 82 (P,.05) 150 (P,.05)
(n = 88) (n = 40)
Medium Cook & 24 NA NA
(24 h-7 d) Palma level 810 (P,.05)
(n = 28) 8-13
Long 48 NA NA
(.7 d) 2196 (P,.05)
(n = 20)
Continued

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SEDATION IN CRITICAL CARE

Table 2. Summary of Selected Trials Assessing the Effectiveness of Sedative Agents Used in the ICU* (cont)
Sedation Mean %
Score Time at Time to Length of ICU
Study/Patient Length of Target Mean Sedation Extubation, Ventilation, Length of
Population† Sedation Level Sedatives‡ Dosage Target Level§ min h Stay, d
Propofol vs Midazolam (Mixed ICU Patients)
Costa et al,33 1994
Mixed ICU Short RC scale Propofol (c) 16.6-50 µg/kg/min 94 120 NA “Shorter
(n = 139) (,72 h) Midazolam (c) 1.7-3.3 µg/kg/min 83 (P,.05) 432 stay in
Diazepam (i) + 0.2-0.3 mg/kg 38 (no statistics)\ 594 (P,.05) P group”
Morphine (i) 0.15-0.22 mg/kg (no data)
(n = 213) (.72 h) Propofol (c) 16.6-50 µg/kg/min Better Shorter in NA NA
Midazolam (c) 1.7-3.3 µg/kg/min sedation in P group
P group (no statistics)\
(no statistics)\
Ronan et al,34 1995
Postoperative Short RL 3 Propofol (c) 24 µg/kg/min No difference NA NA NA
(n = 60) (24 h) Midazolam (c) 2.1 mg/h
Kress et al,35 1996 Time to sedation:
Medical ICU Up to 3 d Study- Propofol (c) 20.9 µg/kg/min 20.4 min NA NA NA
(n = 73) specific scale Midazolam (c) 3.1 mg/h 16 min (P = .30)
(x = 48) [n = 39]
Chamorro et al,36 1996
Mixed ICU Medium/ Study- Propofol (c) 46.7 µg/kg/min 76.5 NA NA NA
(n = 98) long specific Midazolam (c) 2.3 µg/kg/min 66.2 (P,.01)
(2-5 d) scales
Barrientos-Vega
et al,37 1997
Mixed ICU Medium/ RL 4-5 Propofol (c) 51.2-95 µg/kg/min¶ % of patients at 2088 NA NA
(x = 121) long Midazolam (c) 3.1-7.2 µg/kg/min¶ target level: 66; 5874 (P,.001)
(n = 108) (24 h-9 d) 57(NSD) [y = 52]
Weinbroum et al,38 1997
Mixed ICU 3-8 d Study- Propofol (c) 30 µg/kg/min No difference in NA NA 31
(n = 67) specific scale Midazolam (c) 1.2 µg/kg/min level of sedation, 21
in P group more agitation (No
(P,.01) statistics)\
Sanchez-Izquierdo
et al,39 1998
Trauma ICU 2-24 d Simplified RL Propofol (c) 35.3 µg/kg/min 87 NA NA 18
(x = 106) 3-4 Midazolam (c) 3.2 µg/kg/min 85 24
(n = 100) Midazolam (c)+ 2.3 µg/kg/min 90 (NSD) 17 (NSD)
Propofol (c) 26.7 µg/kg/min

Midazolam vs Lorazepam (Mixed ICU Patients)


Pohlman et al,40 1994
Medical ICU 2-10 d RL 2-3 Midazolam (c+i) 0.2 mg/kg/h No difference in NA NA NA
(n = 20) Lorazepam (c+i) 0.1 mg/kg/h time to sedation;
time to return to
baseline mental
status: M, 1815
min; L, 261 min
(NSD)
Cernaianu et al,41 1996
Mixed ICU Short Study- Midazolam (c) 1.8 mg/h NSD NA NA NA
(n = 95) (8 h) specific scale Lorazepam (i) 0.2 mg/h (no data)
Benzodiazepine vs Isoflurane
Kong et al,42 1989
Mixed ICU Short RL 2-4 Midazolam (c) 3.1 mg/h 64 195 NA NA
(n = 60) (#24 h) Isoflurane (inh) 0.2% 86 (P,.001) 60 (P,.001)
[y = 27]
Spencer and
Willatts,43 1992
Mixed ICU 4 h-6 d RL 2-4 Midazolam (c) 3.1 mg/h 67 900 NA 2.02
(n = 60) Isoflurane (inh) 0.3% 70 (NSD) 54 (P,.001) 2.08 (NSD)
[y = 43)
Opiate vs Opiate
Yate et al,44 1986
Post–cardiac surgery Short Study- Pethidine (c) 0.3 mg/kg/h NSD in sedation 36 NA NA
(n = 30) specific Alfentanil (c) 0.5 µg/kg/min score 40
score (No statistics)\
Continued

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SEDATION IN CRITICAL CARE

a greater but nonsignificant incidence did not report a difference in hemody- ics.42 Propofol and lytic solution pro-
of hypotension with propofol com- namic effects, and no other outcomes vided a similar quality of sedation and
pared with midazolam.29,31 were noted. The trial comparing iso- effect on hemodynamics; however, pro-
The trial comparing midazolam with flurane with midazolam reported a su- pofol resulted in a faster time to extu-
lorazepam did not find any difference perior quality of sedation and shorter bation.45 Finally, the combination of
in quality of sedation but did not pro- time to extubation for isoflurane with ketamine and midazolam in patients re-
vide corresponding data.41 This trial also no difference in effect on hemodynam- quiring exogenous catecholamines for

Table 2. Summary of Selected Trials Assessing the Effectiveness of Sedative Agents Used in the ICU* (cont)
Sedation Mean %
Score Time at Time to Length of ICU
Study/Patient Length of Target Mean Sedation Extubation, Ventilation, Length of
Population† Sedation Level Sedatives‡ Dosage Target Level§ min h Stay, d
Opiate vs Propofol
Heinrichs et al,45 1992
Postoperative Short RL 5 Propofol (c) 65 µg/kg/min NSD 19 NA NA
(n = 60) (6 h) Lytic solution (i) 4.2 mL/h 415 (P,.001)
(pethidine,
promethazine, and
dihydroergotamine)
Opiate vs Anesthetic
Kolenda et al,46 1996
Head-injured patients 3-14 d NA Ketamine (c+i) 104 µg/kg/d NA NA NA NA
(x = 35) Fentanyl (c) 100 µg/kg/d
(n = 24)
Drug Combinations vs Drug Combinations
Adams et al,47 1988
Surgical ICU Medium Study- Fentanyl (i) + NA Higher vigilance NA NA NA
(n = 16) (48 h) specific Midazolam (i) score in K group
score (No statistics)\
Ketamine (c) +
Midazolam (c)
Ledingham et al,48 1988
Mixed ICU 10 h-16 d Study- Morphine (c)+ NA 45 Patients fulfilling NA NA NA
(n = 60) specific Midazolam (i) sedation criteria, %
score
Morphine (i)+ 25
Midazolam (c)

Morphine (c)+ 77
Morphine (i) (no statistics)\
[interim analysis,
n = 36]
Harris et al,49 1990
Mixed ICU 10 h-10 d RL 2-5 Propofol (c)+ 22 µg/kg/min 81 NA 102 NA
(n = 27) Papaveretum (i)

Papaveretum (c)+ 0.1 mg/kg/h 90 67


Midazolam (i) (NSD) (NSD)
Adams et al,50 1991
Surgical ICU patients 48 h NA Fentanyl (i) + NA NA NA NA NA
requiring inotropic Midazolam (i)
support
(n = 20) Ketamine (c) +
Midazolam (c)
Manley et al,51 1997
Mixed ICU 1-7 d Study- Midazolam (c)+ 0.0-0.2 mg/kg/h 43.2 3000 NA 6.1
(n = 37) specific Morphine (c) 17-70 µg/kg/h 42.2 (P = .006) (P,.001)
(x = 26) score
Propofol (c)+ 1-4 mg/kg/h 180 1.7
Alfentanil (c) 0.5-2 µg/kg/h (NSD)
*ICU indicates intensive care unit; CABG, coronary artery bypass graft; RL, Ramsay level; RC, Ramsay-Cook; NSD, no significant difference; NA, not studied or data not available;
P, propofol; M, midazolam; MAP, mean arterial pressure; D, diazepam; L, lorazepam; K, ketamine; y, number of enrolled patients able to be extubated at end of study. The online
version of Table 2 contains a column listing the studies’ hemodynamic effects.
†Number of study patients: x = patients randomized, and n = patients included in study.
‡c indicates via continuous infusion; i, intermittent bolus therapy; and inh, inhalational.
§Mean percentage of time spent at target level of sedation (exceptions: studies 24, 35, 37, 38, 40, 47, 48).
\“No statistics” refers to text inferring statistically significant differences but P values not provided in the article.
¶Both agents required progressive increments in the daily dose quantities.

1456 JAMA, March 15, 2000—Vol 283, No. 11 ©2000 American Medical Association. All rights reserved.

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SEDATION IN CRITICAL CARE

blood pressure support resulted in to extubation, and decreased length of patients who received it for less than 24
lower doses of these inotropes or va- ICU stay with no difference in hemo- hours. Ketamine was as effective a seda-
sopressors than those required by pa- dynamic effects.51 tive agent as fentanyl was in head in-
tients receiving fentanyl and mid- jury patients and had a more favorable
azolam.50 COMMENT impact on blood pressure (less
The most striking finding in this re- hypotension). Ketamine may also have
Longer-term Sedation view was the relatively small portion of had a role in patients requiring higher
Of the 14 trials evaluating sedation for sedative agents reported as being used doses of inotropes or vasopressors. Both
more than 24 hours, 7 compared pro- in surveys of both North American and isoflurane and ketamine are used infre-
pofol with midazolam,32,33,35-39 1 com- European practice4-6 that have been quently in the ICU setting but may war-
pared midazolam with lorazepam,40 1 evaluated rigorously by more than 1 or rant additional study. No other firm rec-
compared midazolam with isoflu- 2 randomized controlled trials. A large ommendations can be made from this
rane,43 1 compared ketamine with fen- number of trials have been published review. The small number of trials com-
tanyl,46 and 4 studied a combination of comparing midazolam with propofol in paring any 2 agents limits the interpre-
agents.47-49,51 All studies examined sur- several patient groups, while few stud- tation of these studies.
gical or mixed ICU patients. ies have been conducted using other Cost is becoming an increasingly im-
The quality of sedation for propofol common agents. Propofol is at least as portant factor in deciding whether to
and midazolam was similar in 3 of the effective as midazolam in providing de- adopt new therapies. We did not in-
6 trials reporting this outcome.35,37,39 sired levels of sedation. In addition, once clude reported cost evaluations avail-
One trial favored midazolam rather than the decision has been made to wean pa- able in a few of these trials28,32,33,37,38,51 be-
propofol, 38 and 2 favored propofol tients from the drug, propofol appears cause of the limited generalizability of
rather than midazolam32,33; however, to consistently result in a faster time to cost data outside the study center. These
statistical analysis was provided for only extubation in patients receiving either concerns arose as a result of the rela-
1 of these trials.32 Time to extubation short-term or long-term sedation. It is tively brief descriptions available on the
was shorter in the propofol group com- not clear, however, that this shorter time costing methods. Recommendations on
pared with the midazolam group in all to extubation actually leads to a de- how to conduct economic evaluations
4 trials reporting it,32,33,37,38 although 1 crease in total time of ventilation or a that result in both internal validity (valid
trial did not report the statistical analy- shorter ICU stay. While there has been for the specific research center) and ex-
sis33 and a second did not find the dif- some suggestion that propofol may lead ternal validity (generalizability beyond
ference statistically significant.38 No tri- to lower cost in short-term sedation, the the research center) have been devel-
als of midazolam vs propofol reported opposite may occur in patients requir- oped and published.71-74 Future inves-
duration of ventilation, and the single ing longer sedation. Finally, use of pro- tigations of new and current sedative
trial reporting length of ICU stay found pofol has been consistently found to re- agents will need to incorporate valid as-
no difference between propofol and sult in more problems with hypotension sessments of both their relative effec-
midazolam.39 One of the 4 trials report- than does midazolam. How often this re- tiveness and associated costs.
ing hemodynamic effects found more sults in a clinically important adverse Strengths of this review include the
hypotension in the propofol group com- event is not clear. In summary, propo- systematic approach to searching the lit-
pared with the midazolam group.38 fol appears to offer some advantage in erature, selecting the relevant studies,
The trial comparing midazolam with the setting where rapid waking of the pa- and independent duplicate assess-
lorazepam found no difference in qual- tient is desired, but more study is re- ment of trial validity. Our inability to
ity of sedation or hemodynamic ef- quired to determine whether the in- fully assess the validity of the meth-
fects.40 Isoflurane provided a shorter creased cost and potential to cause ods of unpublished studies resulted in
time to extubation than midazolam but hypotension are outweighed by this ben- their exclusion from this review. Het-
no difference in quality of sedation, he- efit. It may be that the dosage of the drug erogeneity of patients, drugs, and dos-
modynamics, or duration of ICU stay.43 is more important, or at least as impor- ing regimens precluded meta-analysis
Ketamine resulted in higher blood pres- tant as the drug itself. of study results. As with all systematic
sure and heart rate than fentanyl in pa- No difference was found in the effec- reviews, readers are referred to the origi-
tients with head injuries.46 tiveness of midazolam compared with nal publications for further detail.
Of the 4 trials examining different lorazepam in 2 trials, suggesting more The outcome of primary interest was
combinations of sedatives, the only trial trials be conducted that examine both the quality of sedation provided to the
reporting a significant difference in out- the relative effectiveness of these 2 com- patient. While most trials assessed this
come was the combination of alfenta- monly used agents and their associated end point using the Ramsay scale* (a
nil and propofol, which, compared with costs. Isoflurane was found to lead to a 6-point scale, with measures ranging
morphine and midazolam, provided shorter time to extubation than did mid-
better quality of sedation, shorter time azolam and better quality of sedation in *References 19-26,28-33,36,39,41,42,44,48.

©2000 American Medical Association. All rights reserved. JAMA, March 15, 2000—Vol 283, No. 11 1457

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SEDATION IN CRITICAL CARE

from anxious or agitated to asleep with plicable), use of analgesics (other than cine, Department of Medicine, University of West-
ern Ontario; and by the Department of Pharmacy,
no response69), this commonly used se- those being directly studied) and neu- London Health Sciences Centre, London, Ontario. Dr
dation scale has never been rigorously romuscular blockers, and approach to Keenan is a Canadian Lung Association/Medical Re-
search Council of Canada Fellow.
validated.19 A recent systematic re- weaning from mechanical ventilation,
view 19 of sedation scoring systems con- should be standardized or at least re-
firms that some of the other scales used ported. These measures will help re- REFERENCES
in these trials also lack formal valida- duce bias in interpretation of end 1. Mazzeo AJ. Sedation for the mechanically venti-
lated patient. Crit Care Clin. 1995;11:937-955.
tion. All scales in use are numerical, and points, such as quality of sedation, time 2. Tung A, Rosenthal M. Patients requiring seda-
most assess only a single item. For ex- to extubation, and length of ventila- tion. Crit Care Clin. 1995;11:791-802.
ample, although the Ramsay scoring tion and ICU stay. These processes were 3. Durbin CG Jr. Sedation in the critically ill patient.
New Horiz. 1994;2:64-74.
system is a 6-point numerical scale that not followed in many of the trials re- 4. Hansen-Flaschen JH, Brazinsky S, Basile C, Lan-
includes measures of sedation and agi- viewed. ken PN. Use of sedating drugs and neuromuscular
blocking agents in patients requiring mechanical ven-
tation, its format restricts these to be- It is useful to consider how, with tilation for respiratory failure. JAMA. 1991;266:2870-
ing assessed as 1 item. While other time, secular changes in practice can in- 2875.
5. Reeve WG, Wallace PGM. A survey of sedation in
scales, such as the one of Cook and fluence the interpretation of study re- intensive care. Care Critically Ill. 1991;7:238.
Palma,70 have a greater number of items, sults. For example, the approach to car- 6. Dasta JF, Fuhrman TM, McCandles C. Patterns of
allowing for evaluation of an in- diac surgery patients has evolved during prescribing and administering drugs for agitation and
pain in patients in a surgical intensive care unit. Crit
creased amount of clinical informa- the past decade from a common prac- Care Med. 1994;22:974-980.
tion, they have not been validated. tice of keeping patients intubated and 7. Mendel PR, White PF. Sedation of the critically ill
patient. Int Anesthesiol Clin. 1993;1:185-200.
These aspects of scoring systems lead sedated overnight to a more aggres- 8. Kress JP, O’Connor MF, Pohlman AS, Hall JB. Se-
to concern regarding the reproducibil- sive approach of allowing patients to dating critically ill ventilated patients: a pharmaco-
logic primer. J Crit Illness. 1997;12:287-299.
ity and validity of results and diffi- awaken and be extubated as soon as 9. Louvelle JM. Sedation in the intensive care unit: an
culty in interpretation of results across possible, referred to as fast-tracking.75 overview. Can J Hosp Pharm. 1995;48:344-347.
10. Reves JG, Greenblatt DJ, Sladen RN. Drug Infu-
studies. Additional difficulty arises As a result of the potential for practice sion for Sedation in the Intensive Care Unit. Boston,
when different definitions of ideal level to change appreciably from the time a Mass: Tufts University; 1994.
of sedation are used; for example, some randomized controlled trial is con- 11. Crippen DW. The role of sedation in the ICU pa-
tient with pain and agitation. Crit Care Clin. 1990;6:
studies required Ramsay level 3, while ducted, cautious interpretation of the 369-392.
others used levels 2 to 4, 3 to 5, 2 to 5, study is necessary and sound clinical 12. Crippen DW. Pharmacologic treatment of brain fail-
ure and delirium. Crit Care Clin. 1994;10:733-766.
or 5. This review highlights the need judgment required in deciding how, or 13. Wheeler AP. Sedation, analgesia, and paralysis in
for a reliable and valid sedation scor- if, a study applies to current practice. the intensive care unit. Chest. 1993;104:566-577.
14. Berger I, Waldhorn RE. Analgesia, sedation and
ing system to improve the interpret- The lack of randomized trials for paralysis in the intensive care unit. Am Fam Physi-
ability of future studies. some of the sedative agents currently cian. 1995;51:166-172.
Blinding both patients and asses- in use in ICUs raises the issue of con- 15. Stoltzfus DP. Advantages and disadvantages of
combining sedative agents. Crit Care Clin. 1995;11:
sors to treatment is of greatest impor- sidering observational studies to ob- 903-912.
tance when subjective outcomes are tain the best evidence for such agents 16. Kovarik WD, Goldstein B. Pharmacological ap-
proach to sedation of the critically ill patient. Clin In-
used. In the trials reviewed, those as- as haloperidol or diazepam. However, tensive Care. 1996;7:248-257.
sessing quality of sedation were fre- the potential for bias increases appre- 17. Shapiro BA, Warren J, Egol AB, et al. Practice pa-
rameters for intravenous analgesia and sedation for
quently aware of the sedative agent the ciably when studies using historical or adult patients in the intensive care unit: an executive
patients were receiving. Knowing which nonrandomized controls are consid- summary. Crit Care Med. 1995;23:1596-1600.
agent a patient is receiving can intro- ered. Given the widespread use of se- 18. Rhoney DH, Murry KR. A national survey of the
use of sedating and neuromuscular blocking agents
duce the potential for bias in interpre- dation for ICU patients, there is a dearth in the intensive care unit [abstract]. Crit Care Med.
tation of the outcome of interest. While of rigorous, adequately powered ran- 1998;26:A24.
19. De Jonghe B, Cook D, Appere-De-Vecchi C, et
interpretation of quality of sedation was domized controlled trials comparing al. Using and understanding sedation scoring sys-
the most subjective outcome assessed, commonly used agents in this setting. tems: a systematic review. Intensive Care Med. In press.
20. Grounds RM, Lalor JM, Lumley J, Royston D, Mor-
time to extubation and length of ICU More economic evaluations are war- gan M. Propofol infusion for sedation in the inten-
sedation can similarly be influenced by ranted in this field, given the diverse sive care unit. BMJ. 1987;294:397-400.
21. McMurray TJ, Collier PS, Carson IW, Lyons SM,
knowing which sedative agent was re- purchasing costs of different agents and Elliott P. Propofol sedation after open heart surgery.
ceived. It is possible that blinding of as- their variable and incompletely evalu- Anaesthesia. 1990;45:322-326.
sessors had been performed in some ated effect of economic outcomes, such 22. Snellen F, Lauwers P, Demeyere R, Byttebier G, Van
Aken H. The use of midazolam versus propofol for short-
studies and not reported; however, the as duration of mechanical ventilation term sedation following coronary artery bypass graft-
importance of double-blinding has be- and duration of ICU stay. ing. Intensive Care Med. 1990;16:312-316.
23. Chaudhri S, Kenny GN. Sedation after cardiac by-
come so well recognized during the past pass surgery: comparison of propofol and midazolam
decade that most investigators will re- Funding/Support: This study was supported by The in the presence of a computerized closed loop arterial
Richard Ivey Critical Care Trauma Centre, London pressure controller. Br J Anaesth. 1992;68:98-99.
port its use if it was done. All cointer- Health Sciences Centre, Victoria Campus, University 24. Roekaerts PM, Huygen FJ, de Lange S. Infusion
ventions, including anesthesia (if ap- of Western Ontario; the Division of Critical Care Medi- of propofol versus midazolam for sedation in the in-

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SEDATION IN CRITICAL CARE

tensive care unit following coronary artery surgery. domized, prospective, multicenter study of hemody- 58. Plunkett JJ, Reeves JD, Ngo L, et al, for the Mul-
J Cardiothorac Vasc Anesth. 1993;7:142-147. namics, oxygen transport, efficacy, and cost. Crit Care ticenter Study of Perioperative Ischemia (McSPI) Re-
25. Higgins TL, Yared JP, Estafanous FG, Coyle JP, Ko Med. 1996;24:222-228. search Group, and the Ischemia Research and Edu-
HK, Goodale DB. Propofol versus midazolam for in- 42. Kong KL, Willatts SM, Prys-Roberts C. Isoflu- cation Foundation (IREF). Urine and plasma
tensive care unit sedation after coronary artery by- rane compared with midazolam for sedation in the in- catecholamine and cortisol concentrations after myo-
pass grafting. Crit Care Med. 1994;22:1415-1423. tensive care unit. BMJ. 1989;298:1277-1280. cardial revascularization. Anesthesiology. 1997;86:
26. Wahr JA, Plunkett JJ, Ramsay JG, et al, for the 43. Spencer EM, Willatts SM. Isoflurane for pro- 785-796.
Institutions of the McSPI Research Group. Cardiovas- longed sedation in the intensive care unit: efficacy and 59. Miller DR, Martineau RJ, Hull KA, Vallee F, LeBel
cular responses during sedation after coronary revas- safety. Intensive Care Med. 1992;18:415-421. M. Optimizing sedation following major vascular sur-
cularization. Anesthesiology. 1996;84:1350-1360. 44. Yate PM, Thomas D, Short SM, Sebel PS, Mor- gery. Can J Anaesth. 1994;41:782-793.
27. Searle NR, Cote S, Taillefer J, et al. Propofol or mid- ton J. Comparison of infusions of alfentanil or pethi- 60. Harper SJ, Buckley PM, Carr K. Propofol and alfen-
azolam for sedation and early extubation following car- dine for sedation for ventilated patients on the ITU. tanil infusions for sedation in intensive therapy. Eur J
diac surgery. Can J Anaesth. 1997;44:629-635. Br J Anaesth. 1986;58:1091-1099. Anaesthesiol. 1991;8:157-165.
28. Carrasco G, Cabre L, Sobrepere G, et al. Syner- 45. Heinrichs W, Tzanova I, Brost F, Weiler N, Dick 61. Westphal LM, Cheng EY, White PF, et al. Use of
gistic sedation with propofol and midazolam in inten- W. Propofol for sedation during postoperative me- midazolam infusion for sedation following cardiac sur-
sive care patients after coronary artery bypass graft- chanical ventilation [in German]. Anaesthesiol Re- gery. Anesthesiology. 1987;67:257-262.
ing. Crit Care Med. 1998;26:844-851. anim. 1992;17:77-79, 82-86. 62. Hall RI, MacLaren C, Smith MS, et al. Light ver-
29. Aitkenhead AR, Pepperman ML, Willatts SM, et 46. Kolenda H, Gremmelt A, Rading S, Braun U, sus heavy sedation after cardiac surgery. Anesth Analg.
al. Comparison of propofol and midazolam for seda- Markakis E. Ketamine for analgosedative therapy in 1997;85:971-978.
tion in critically ill patients. Lancet. 1989;2:704-709. intensive care treatment of head-injured patients. Acta 63. O’Connor M, Stow P, Mortimer A, Fisher A, Sear
30. Beyer R, Seyde WC. Propofol versus midazolam: Neurochir (Wien). 1996;138:1193-1199. JW. Propofol to provide sedation after coronary ar-
long-term sedation in the intensive care unit [in Ger- 47. Adams HA, Biscoping J, Russ W, Bachmann B, Rat- tery bypass surgery. Acta Anaesthe+siol Belg. 1992;
man]. Anaesthesist. 1992;41:335-341. they K, Hempelmann G. Sedative-analgesic medica- 43:235-241.
31. Boyd O, Mackay CJ, Rushmer F, Bennett ED, tion in intensive care patients needing ventilator treat- 64. Mathews HM, Carson IW, Collier PS, et al. Mid-
Grounds RM. Propofol or midazolam for short-term ment [in German]. Anaesthesist. 1988;37:268-276. azolam sedation following open heart surgery. Br J An-
alterations in sedation. Can J Anaesth. 1993;40: 48. Ledingham IM, Bion JF, Newman LH, McDon- aesth. 1987;59:557-560.
1142. ald JC, Wallace PG. Mortality and morbidity amongst 65. Hall RI. Sedation in the ICU: implications for the
32. Carrasco G, Molina R, Costa J, et al. Propofol vs sedated intensive care patients. Resuscitation. 1988;(16 long-stay patient. Clin Intensive Care. 1996;7:10-
midazolam in short-, medium-, and long-term seda- suppl):S69-S77. 12.
tion of critically ill patients. Chest. 1993;103:557- 49. Harris CE, Grounds RM, Murray AM, Lumley J, 66. Ewart MC, Yau KW, Morgan M. 2% Propofol for
564. Royston D, Morgan M. Propofol for long-term seda- sedation in the intensive care unit: a feasibility study.
33. Costa J, Cabre L, Molina R, Carrasco G. Cost of tion in the intensive care unit. Anaesthesia. 1990;45: Anaesthesia. 1992;47:146-148.
ICU sedation. Clin Intensive Care. 1994;5(suppl 5): 366-372. 67. Harding J, Kemper M, Weissman C. Midazolam
17-21. 50. Adams HA, Claussen E, Gebhardt B, Biscoping J, attenuates the metabolic and cardiopulmonary re-
34. Ronan KP, Gallagher TJ, George B, Hamby B. Com- Hempelmann G. The use of ketamine and midazolam sponses to an acute increase in oxygen demand. Chest.
parison of propofol and midazolam for sedation in in- for analgesia and sedation in ventilated patients sub- 1994;106:194-200.
tensive care unit patients. Crit Care Med. 1995;23: ject to obligatory treatment with catecholamines [in Ger- 68. McLeod G, Wallis C, Dick J, et al. Use of 2% pro-
286-293. man]. Anaesthesist. 1991;40:238-244. pofol to produce diurnal sedation in critically ill pa-
35. Kress JP, O’Connor MF, Pohlman AS, et al. Se- 51. Manley NM, Fitzpatrick RW, Long T, Jones PW. tients. Intensive Care Med. 1997;23:428-434.
dation of critically ill patients during mechanical ven- A cost analysis of alfentanil + propofol vs morphine + 69. Ramsay MA, Savege TM, Simpson BR, Goodwin
tilation: a comparison of propofol and midazolam. Am midazolam for the sedation of critically ill patients. Phar- R. Controlled sedation with alphaxalone-alphadolone.
J Respir Crit Care Med. 1996;153:1012-1018. macoeconomics. 1997;12(2 pt 2):247-255. BMJ. 1974;2:656-659.
36. Chamorro C, DeLatorre FJ, Montero A, et al. Com- 52. Vinik HR, Kissin I. Sedation in the ICU. Intensive 70. Cook S, Palma O. Propofol as a sole agent for pro-
parative study of propofol versus midazolam in the se- Care Med. 1991;17(suppl 1):S20-S23. longed infusion in intensive care. J Drug Dev. 1989;
dation of critically ill patients. Crit Care Med. 1996; 53. Treggiari-Venzi M, Borgeat A, Fuchs-Buder T, 4:65-67.
24:932-939. Gachoud JP, Suter PM. Overnight sedation with mid- 71. Task Force on Principles for Economic Analysis of
37. Barrientos-Vega R, Mar Sanchez-Soria M, Morales- azolam or propofol in the ICU. Intensive Care Med. Health Care Technology. Economic analysis of health
Garcia C, et al. Prolonged sedation of critically ill pa- 1996;22:1186-1190. care technology. Ann Intern Med. 1995;123:61-70.
tients with midazolam or propofol: impact on wean- 54. Sherry KM, McNamara J, Brown JS, Drummond 72. Russell LB, Gold MR, Siegel JE, Daniels N, Wein-
ing and costs. Crit Care Med. 1997;25:33-40. M. An economic evaluation of propofol/fentanyl com- stein MC, for the Panel on Cost-Effectiveness in Health
38. Weinbroum AA, Halpern P, Rudick V, Sorkine P, pared with midazolam/fentanyl on recovery in the ICU and Medicine. The role of cost-effectiveness analysis
Freedman M, Geller E. Midazolam versus propofol for following cardiac surgery. Anaesthesia. 1996;51:312. in health and medicine. JAMA. 1996;276:1172-1177.
long-term sedation in the ICU. Intensive Care Med. 55. Polster MR, Gray PA, O’Sullivan G, et al. Com- 73. Weinstein MC, Siegel JE, Gold MR, Kamlet MS,
1997;23:1258-1263. parison of the sedative and amnesic effects of mid- Russell LB. Recommendations of the Panel on Cost-
39. Sanchez-Izquierdo JA, Caballero-Cubedo RE, azolam and propofol. Br J Anaesth. 1993;70:612- Effectiveness in Health and Medicine. JAMA. 1996;
Perez-Vela JL, et al. Propofol versus midazolam: safety 616. 276:1253-1258.
and efficacy for sedating severe trauma patients. Anesth 56. Weyland W, Brauer A, Weyland A, et al. Effect 74. Siegel JE, Weinstein MC, Russell LB, Gold MR, for
Analg. 1998;86:1219-1224. of sedation on oxygen uptake during spontaneous the Panel on Cost-Effectiveness in Health and Medi-
40. Pohlman AS, Simpson KP, Hall JB. Continuous in- breathing [in German]. Anaesthesist. 1993;42:391- cine. Recommendations for reporting cost-
travenous infusions of lorazepam versus midazolam 395. effectiveness analyses. JAMA. 1996;276:1339-1341.
for sedation during mechanical ventilatory support. Crit 57. Kong KL, Tyler JE, Willatts SM, Prys-Roberts C. 75. Engelman RM, Rousou JA, Flack JE III, et al. Fast-
Care Med. 1994;22:1241-1247. Isoflurane sedation for patients undergoing mechani- track recovery of the coronary bypass patient. Ann Tho-
41. Cernaianu AC, DelRossi AJ, Flum DR, et al. Ran- cal ventilation. Br J Anaesth. 1990;64:159-162. rac Surg. 1994;58:1742-1746.

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Table 2. Summary of Selected Trials Assessing the Effectiveness of Sedative Agents Used in the ICU*
Sedation Mean % Mean Mean
Score Time at Time to Mean ICU
Study/Patient Length of Target Mean Sedation Extubation, Length of Length of
Population† Sedation Level Sedatives‡ Dosage Target Level§ min Ventilation, h Stay, d Hemodynamic Effects¶
Propofol vs Midazolam (Cardiac Surgery Patients)
Grounds et al,20 1987
Post-CABG Short RL 3 Propofol (c) 13.1 µg/kg/min 44.6 24.9 8.08 NA NSD
(n = 60) (,24 h) Midazolam (i) 0.3 µg/kg/min 28.1 (P,.03) 226 (P,.001) 11.12 (P,.02)
McMurray et al,21 1990
Post-CABG Short RL 2-5 Propofol (c) 19.2 µg/kg/min 86 7.6 18.56 NA NSD
(n = 100) (,24 h) Midazolam (i) 0.6 µg/kg/min 56 (P,.001) 125 (P,.001) 20.06 (P not
tested)
Snellen et al,22 1990
Post-CABG Short RL 2-4 Propofol (c) 15.2 µg/kg/min 59.6 154 13.10 NA Lower BP in P group after loading
(n = 40) (,24 h) Midazolam (c) 0.6 µg/kg/min 53 (NSD) 243 (P = .06) 14.63 (P not dose but NSD during
tested) maintenance
Chaudhri et al,23 1992
Post-CABG Short 6-Point Propofol (c) 8.3-33.3 µg/kg/min 65 NSD NSD NA More hypotensive periods in P
patients needing (,8 h) scoring Midazolam (c) 1.7-3.3 µg/kg/min 70 (NSD) (no data) (no data) group (no P values); HR was
vasodilators for system NSD
hypertension (1 item,
(n = 40) numerical)
Roekaerts et al,24 1993
Post-CABG Short RL 5 Propofol (c) 45.2 µg/kg/min More frequent 250 14.63 NA Increase in HR in M group
(n = 30) (,24 h) Midazolam (c) 1.5 µg/kg/min dose 391 (P,.01) 17.27 (P not ( P,.05) BP was NSD
adjustments in tested)
M group
Higgins et al,25 1994
Post-CABG Short RL 3 Propofol (c) 12.6 µg/kg/min 58 258 17.8 No NSD
(x = 84) (,24 h) Midazolam (c) 0.3 µg/kg/min 65 (NSD) 210 (NSD) 16.8 (P not difference
(n = 80) tested) (no data)
Wahr et al,26 1996
Post-CABG Short RL 5 Propofol (c) NA NA NA NA NA Higher incidence of hypotension in
(x = 351) Midazolam (i) P group (P,.05); higher
(n = 312) incidence of tachycardia
in M group (P,.05)
Searle et al,27 1997
Post–cardiac surgery Short RL 2-4 Propofol (c) 10.6 µg/kg/min 67 87.5 5.46 3.7 NSD
(x = 44) (,8 h) Midazolam (c) 0.3 µg/kg/min 65.4 (NSD) 91.5 (NSD) 5.53 (P not 3.9 (NSD)
(n = 41) tested)
Carrasco et al,28 1998
Post-CABG Short Cook & Propofol (c) 20 µg/kg/min 93 54 NA 1.7 BP decrease in both P and
(n = 75) Palma level Midazolam (c) 1.3 µg/kg/min 88 (P = .10) 138 P + M, 1.8 M vs P + M ( P,.05); HR
8-11 Combined (c) 8.3 µg/kg/min (P) 90 72 (P = .01 1.8 was NSD
0.5 µg/kg/min (M) for both (P..05)
comparisons)
Propofol vs Midazolam (Mixed ICU Patients)
Aitkenhead et al,29 1989
Mixed ICU Short RL 2-4 Propofol (c) 29.5 µg/kg/min 94 5 NA NA BP NSD overall but 4 patients vs 1
(x = 101) (,24 h) Midazolam (c) 1.7 µg/kg/min 93 (NSD) 148 (P,.001) with marked hypotension in P
(n = 100) (y = 39) vs M group; lower HR in P
group ( P,.05)
Beyer and Seyde,30 1992
Postoperative Short RL 3-4 Propofol (c) 31.7 µg/kg/min NSD NA NA NA NSD but trend to lower HR and
(n = 20) (24 h) Midazolam (c) 1.8 µg/kg/min (no data) MAP in P group
Boyd et al,31 1993
Postoperative Short RL 5 Propofol (c) 133 mg/h + 53.9 NA NA NA NSD but trend to lower MAP and
(x = 23) (12-16 235-mg bolus HR in P group
(n = 19) min) Midazolam (c) 4.0 mg/h + 25.7 (P,.001)
7.8-mg bolus
Carrasco et al,32 1993
Mixed ICU Short RL 2-5 Propofol (c) 38.3 µg/kg/min 93 18 NA NA NSD
(x = 92) (,24 h) Midazolam (c) 2.8 µg/kg/min 82 (P,.05) 150 (P,.05)
(n = 88) (n = 40)
Medium Cook & 24 NA NA
(24 h-7 d) Palma level 810 (P,.05)
(n = 28) 8-13
Long 48 NA NA
(.7 d) 2196 (P,.05)
(n = 20)
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Table 2. Summary of Selected Trials Assessing the Effectiveness of Sedative Agents Used in the ICU* (cont)
Sedation Mean % Mean Mean
Score Time at Time to Length of ICU
Study/Patient Length of Target Mean Sedation Extubation, Ventilation, Length of
Population† Sedation Level Sedatives‡ Dosage Target Level§ min h Stay, d Hemodynamic Effects¶
Propofol vs Midazolam (Mixed ICU Patients)
Costa et al,33 1994
Mixed ICU Short RC scale Propofol (c) 16.6-50 µg/kg/min 94 120 NA “Shorter NA
(n = 139) (,72 h) Midazolam (c) 1.7-3.3 µg/kg/min 83 (P,.05) 432 stay in
Diazepam (i) + 0.2-0.3 mg/kg 38 (no statistics)\ 594 (P,.05) P group”
Morphine (i) 0.15-0.22 mg/kg (no data)NA
(n = 213) (.72 h) Propofol (c) 16.6-50 µg/kg/min Better Shorter in NA NA NA
Midazolam (c) 1.7-3.3 µg/kg/min sedation in P group
P group (no statistics)\
(no statistics)\
Ronan et al,34 1995
Postoperative Short RL 3 Propofol (c) 24 µg/kg/min No difference NA NA NA Greater decrease in MAP
(n = 60) (24 h) Midazolam (c) 2.1 mg/h in P group in first 30 min, no
difference thereafter; HR was
NSD
Kress et al,35 1996 Time to sedation:
Medical ICU Up to 3 d Study- Propofol (c) 20.9 µg/kg/min 20.4 min NA NA NA NA
(n = 73) specific scale Midazolam (c) 3.1 mg/h 16 min (P = .30)
(x = 48) [n = 39]
Chamorro et al,36 1996
Mixed ICU Medium/ Study- Propofol (c) 46.7 µg/kg/min 76.5 NA NA NA NSD
(n = 98) long specific Midazolam (c) 2.3 µg/kg/min 66.2 (P,.01)
(2-5 d) scales
Barrientos-Vega
et al,37 1997
Mixed ICU Medium/ RL 4-5 Propofol (c) 51.2-95 µg/kg/min¶ % of patients at 2088 NA NA NA
(x = 121) long Midazolam (c) 3.1-7.2 µg/kg/min¶ target level: 66; 5874 (P,.001)
(n = 108) (24 h-9 d) 57 (NSD) [y = 52]
Weinbroum et al,38 1997
Mixed ICU 3-8 d Study- Propofol (c) 30 µg/kg/min No difference in NA NA 31 Greater drop in BP in P group
(n = 67) specific scale Midazolam (c) 1.2 µg/kg/min level of sedation, 21 in first 30 min; NSD during
in P group more agitation (No maintenance infusion;
(P,.01) statistics)\ HR was NSD
Sanchez-Izquierdo
et al,39 1998
Trauma ICU 2-24 d Simplified RL Propofol (c) 35.3 µg/kg/min 87 NA NA 18 NSD
(x = 106) 3-4 Midazolam (c) 3.2 µg/kg/min 85 24
(n = 100) Midazolam (c)+ 2.3 µg/kg/min 90 (NSD) 17 (NSD)
Propofol (c) 26.7 µg/kg/min

Midazolam vs Lorazepam (Mixed ICU Patients)


Pohlman et al,40 1994
Medical ICU 2-10 d RL 2-3 Midazolam (c+i) 0.2 mg/kg/h No difference in NA NA NA NSD
(n = 20) Lorazepam (c+i) 0.1 mg/kg/h time to sedation;
time to return to
baseline mental
status: M, 1815
min; L, 261 min
(NSD)
Cernaianu et al,41 1996
Mixed ICU Short Study- Midazolam (c) 1.8 mg/h NSD NA NA NA NSD
(n = 95) (8 h) specific scale Lorazepam (i) 0.2 mg/h (no data)
Benzodiazepine vs Isoflurane
Kong et al,42 1989
Mixed ICU Short RL 2-4 Midazolam (c) 3.1 mg/h 64 195 NA NA NSD
(n = 60) (#24 h) Isoflurane (inh) 0.2% 86 (P,.001) 60 (P,.001)
[y = 27]
Spencer and
Willatts,43 1992
Mixed ICU 4 h-6 d RL 2-4 Midazolam (c) 3.1 mg/h 67 900 NA 2.02 NSD
(n = 60) Isoflurane (inh) 0.3% 70 (NSD) 54 (P,.001) 2.08 (NSD)
[y = 43)
Opiate vs Opiate
Yate et al,44 1986
Post–cardiac surgery Short Study- Pethidine (c) 0.3 mg/kg/h NSD in sedation 36 NA NA NA
(n = 30) specific Alfentanil (c) 0.5 µg/kg/min score 40
score (No statistics)\
2 JAMA, March 15, 2000—Vol 283, No. 11 ©2000 American Medical Association. All rights reserved.

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Table 2. Summary of Selected Trials Assessing the Effectiveness of Sedative Agents Used in the ICU* (cont)
Sedation Mean % Mean Mean
Score Time at Time to Length of ICU
Study/Patient Length of Target Mean Sedation Extubation, Ventilation, Length of
Population† Sedation Level Sedatives‡ Dosage Target Level§ min h Stay, d Hemodynamic Effects¶
Opiate vs Propofol
Heinrichs et al,45 1992
Postoperative Short RL 5 Propofol (c) 65 µg/kg/min NSD 19 NA NA NSD
(n = 60) (6 h) Lytic solution (i) 4.2 mL/h 415 (P,.001)
(pethidine,
promethazine, and
dihydroergotamine)
Opiate vs Anesthetic
Kolenda et al,46 1996
Head-injured patients 3-14 d NA Ketamine (c + i) 104 µg/kg/d NA NA NA NA BP and HR higher in K group
(x = 35) Fentanyl (c) 100 µg/kg/d (P,.05)
(n = 24)
Drug Combinations vs Drug Combinations
Adams et al,47 1988
Surgical ICU Medium Study- Fentanyl (i) + NA Higher vigilance NA NA NA NSD
(n = 16) (48 h) specific Midazolam (i) score in K group
score (No statistics)\
Ketamine (c) +
Midazolam (c)
Ledingham et al,48 1988
Mixed ICU 10 h-16 d Study- Morphine (c) + NA 45 Patients fulfilling NA NA NA NSD
(n = 60) specific Midazolam (i) sedation criteria, %
score
Morphine (i) + 25
Midazolam (c)

Morphine (c) + 77
Morphine (i) (no statistics)\
[interim analysis,
n = 36]
Harris et al,49 1990
Mixed ICU 10 h-10 d RL 2-5 Propofol (c) + 22 µg/kg/min 81 NA 102 NA NSD
(n = 27) Papaveretum (i)

Papaveretum (c) + 0.1 mg/kg/h 90 67


Midazolam (i) (NSD) (NSD)
Adams et al,50 1991
Surgical ICU patients 48 h NA Fentanyl (i) + NA NA NA NA NA Reduced dose of inotropes
requiring inotropic Midazolam (i) in K group and increased
support dose of inotropes in fentanyl
(n = 20) Ketamine (c) + group to maintain similar BP;
Midazolam (c) HR was NSD
Manley et al,51 1997
Mixed ICU 1-7 d Study- Midazolam (c) + 0.0-0.2 mg/kg/h 43.2 3000 NA 6.1 NSD
(n = 37) specific Morphine (c) 17-70 µg/kg/h 42.2 (P = .006) (P,.001)
(x = 26) score
Propofol (c)+ 1-4 mg/kg/h 180 1.7
Alfentanil (c) 0.5-2 µg/kg/h (NSD)
*ICU indicates intensive care unit; CABG, coronary artery bypass graft; RL, Ramsay level; RC, Ramsay-Cook; NSD, no significant difference; NA, not studied or data not available; P, propofol; M, midazolam; MAP, mean
arterial pressure; D, diazepam; L, lorazepam; K, ketamine; y, number of enrolled patients able to be extubated at end of study.
†Number of study patients: x = patients randomized, and n = patients included in study.
‡c indicates via continuous infusion; i, intermittent bolus therapy; and inh, inhalational.
§Mean percentage of time spent at target level of sedation (exceptions: studies 24, 35, 37, 38, 40, 47, 48).
\“No statistics” refers to text inferring statistically significant differences but P values not provided in the article.
¶Both agents required progressive increments in the daily dose quantities.

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