CARING FOR THE

CRITICALLY ILL PATIENT

Dexmedetomidine vs Midazolam
for Sedation of Critically Ill Patients
A Randomized Trial
Richard R. Riker, MD
Yahya Shehabi, MD
Paula M. Bokesch, MD
Daniel Ceraso, MD
Wayne Wisemandle, MA
Firas Koura, MD
Patrick Whitten, MD
Benjamin D. Margolis, MD
Daniel W. Byrne, MS
E. Wesley Ely, MD, MPH
Marcelo G. Rocha, MD
for the SEDCOM (Safety and Efficacy
of Dexmedetomidine Compared With
Midazolam) Study Group

ROVIDING SEDATION FOR PA tient comfort is an integral

component of bedside care for
nearly every patient in the intensive care unit (ICU). For decades,
-aminobutyric acid (GABA) receptor
agonists (including propofol and benzodiazepines such as midazolam) have
been the most commonly administered sedative drugs for ICU patients
worldwide.1-5 Practice guidelines for
providing sedation in the ICU have
identified the need for well-designed
randomized trials comparing the effectiveness of different sedative agents for
important clinical outcomes.1 Despite
the well-known hazards associated with
prolonged use of GABA agonists,6-12 few
investigations of ICU sedation have
compared these agents to other drug
classes.12-14 Instead, the recent focus in

For editorial comment see p 542.

Context -Aminobutyric acid receptor agonist medications are the most commonly
used sedatives for intensive care unit (ICU) patients, yet preliminary evidence indicates that the 2 agonist dexmedetomidine may have distinct advantages.
Objective To compare the efficacy and safety of prolonged sedation with dexmedetomidine vs midazolam for mechanically ventilated patients.
Design, Setting, and Patients Prospective, double-blind, randomized trial conducted in 68 centers in 5 countries between March 2005 and August 2007 among
375 medical/surgical ICU patients with expected mechanical ventilation for more than
24 hours. Sedation level and delirium were assessed using the Richmond AgitationSedation Scale (RASS) and the Confusion Assessment Method for the ICU.
Interventions Dexmedetomidine (0.2-1.4 g/kg per hour [n=244]) or midazolam
(0.02-0.1 mg/kg per hour [n=122]) titrated to achieve light sedation (RASS scores
between 2 and 1) from enrollment until extubation or 30 days.
Main Outcome Measures Percentage of time within target RASS range. Secondary end points included prevalence and duration of delirium, use of fentanyl and openlabel midazolam, and nursing assessments. Additional outcomes included duration of
mechanical ventilation, ICU length of stay, and adverse events.
Results There was no difference in percentage of time within the target RASS
range (77.3% for dexmedetomidine group vs 75.1% for midazolam group; difference, 2.2% [95% confidence interval {CI}, 3.2% to 7.5%]; P = .18). The prevalence of delirium during treatment was 54% (n = 132/244) in dexmedetomidinetreated patients vs 76.6% (n = 93/122) in midazolam-treated patients (difference,
22.6% [95% CI, 14% to 33%]; P.001). Median time to extubation was 1.9 days
shorter in dexmedetomidine-treated patients (3.7 days [95% CI, 3.1 to 4.0] vs 5.6
days [95% CI, 4.6 to 5.9]; P = .01), and ICU length of stay was similar (5.9 days
[95% CI, 5.7 to 7.0] vs 7.6 days [95% CI, 6.7 to 8.6]; P=.24). Dexmedetomidinetreated patients were more likely to develop bradycardia (42.2% [103/244] vs
18.9% [23/122]; P.001), with a nonsignificant increase in the proportion requiring treatment (4.9% [12/244] vs 0.8% [1/122]; P=.07), but had a lower likelihood
of tachycardia (25.4% [62/244] vs 44.3% [54/122]; P .001) or hypertension
requiring treatment (18.9% [46/244] vs 29.5% [36/122]; P=.02).
Conclusions There was no difference between dexmedetomidine and midazolam
in time at targeted sedation level in mechanically ventilated ICU patients. At comparable sedation levels, dexmedetomidine-treated patients spent less time on the ventilator, experienced less delirium, and developed less tachycardia and hypertension.
The most notable adverse effect of dexmedetomidine was bradycardia.
Trial Registration clinicaltrials.gov Identifier: NCT00216190
www.jama.com

JAMA. 2009;301(5):489-499
Author Affiliations and Members of the SEDCOM
Study Group are listed at the end of this article.
Corresponding Author: Richard R. Riker, MD, Neuroscience Institute, Maine Medical Center, 22 Bramhall

2009 American Medical Association. All rights reserved.

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St, Portland, ME 04102 (rikerr@mmc.org).

Caring for the Critically Ill Patient Section Editor: Derek
C. Angus, MD, MPH, Contributing Editor, JAMA
(angusdc@upmc.edu).

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DEXMEDETOMIDINE VS MIDAZOLAM FOR SEDATION OF CRITICALLY ILL PATIENTS

the practice of critical care sedation has

been on nurse-implemented algorithms and drug-interruption protocols to optimize drug delivery, regardless of class.8,15,16 These protocols and
algorithms are promising but not uniformly beneficial,17,18 and their adoption into routine practice has been
slow.3,19,20
Dexmedetomidine is an 2 adrenoreceptor agonist with a unique mechanism of action, providing sedation and
anxiolysis via receptors within the locus ceruleus, analgesia via receptors in
the spinal cord, and attenuation of the
stress response with no significant respiratory depression.21,22 We hypothesized that a sedation strategy using
dexmedetomidine would result in improved outcomes in mechanically ventilated, critically ill medical and surgical ICU patients compared with the
standard GABA agonist midazolam. To
test this hypothesis, we randomized patients in 5 countries to receive dexmedetomidine or standard sedation using
midazolam infusions for up to 30 days
of mechanical ventilation.
METHODS
Study Design

This prospective, double-blind, randomized trial was conducted in ICUs

at 68 centers in 5 countries between
March 2005 and August 2007. Because the protocol involved a dosing
strategy at doses up to twice the limits
approved by the US Food and Drug
Administration, it was considered a
phase 4 trial. The protocol was approved by the institutional review board
of the study centers, and all patients
or legally authorized representatives
provided written informed consent.
The study was designed jointly by the
sponsor and investigators. Data were
collected by the investigators and analyzed by a third-party commercial clinical research organization (Omnicare
Inc, Covington, Kentucky). For this report, all analyses were repeated as part
of an independent statistical analysis
performed by one of the authors
(D.W.B.) at Vanderbilt University.
490

Patients

Study Drug Administration

Eligible patients were 18 years or older,

intubated and mechanically ventilated for less than 96 hours prior to start
of study drug, and had an anticipated
ventilation and sedation duration of at
least 3 more days. Exclusion criteria included trauma or burns as admitting diagnoses, dialysis of all types, pregnancy or lactation, neuromuscular
blockade other than for intubation, epidural or spinal analgesia, general anesthesia 24 hours prior to or planned
after the start of study drug infusion,
serious central nervous system pathology (acute stroke, uncontrolled seizures, severe dementia), acute hepatitis or severe liver disease (Child-Pugh
class C), unstable angina or acute myocardial infarction, left ventricular ejection fraction less than 30%, heart rate
less than 50/min, second- or thirddegree heart block, or systolic blood
pressure less than 90 mm Hg despite
continuous infusions of 2 vasopressors before the start of study drug infusion. Patients with renal insufficiency were randomized and treated;
however, patients were discontinued if
they required dialysis.

Each patient received study drug within

96 hours after intubation. Sedatives
used before study enrollment were discontinued prior to the initiation of study
drug, and patients were required to be
within the Richmond Agitation and Sedation Scale (RASS)23 target range of 2
to 1 at the time of study drug initiation. Optional blinded loading doses
(up to 1 g/kg dexmedetomidine or
0.05 mg/kg midazolam) could be administered at the investigators discretion. The starting maintenance infusion dose of blinded study drug was 0.8
g/kg per hour for dexmedetomidine
and 0.06 mg/kg per hour for midazolam, corresponding to the midpoint of the allowable infusion dose
range. Dosing of study drug was adjusted by the managing clinical team
based on sedation assessment performed with the RASS a minimum of
every 4 hours. Patients in either group
not adequately sedated by study drug
titration could receive open-label midazolam bolus doses of 0.01 to 0.05
mg/kg at 10- to 15-minute intervals until adequate sedation (RASS range, 2
to 1) was achieved with a maximum
dose of 4 mg in 8 hours. If oversedation (RASS range, 3 to 5) did not respond to decreasing study drug infusion rate, the infusion was stopped until
patients returned to the acceptable sedation range.
Analgesia with fentanyl bolus doses
(0.5-1.0 g/kg) could be administered
as needed every 15 minutes. Intravenous bolus doses of fentanyl could also
be given prior to an anticipated noxious stimulation such as chest physiotherapy or suctioning. Fentanyl patches
were not permitted. No other sedatives
or analgesics were allowed during the
double-blind period. Intravenous haloperidol was permitted for treatment of
agitation or delirium in increments of 1
to 5 mg, repeated every 10 to 20 minutes as needed. Study drug infusion was
stopped at the time of extubation in both
groups (required for midazolam infusions), after a maximum of 30 days, or
if the investigator felt it was in the best
interest of the patient.

Randomization and Baseline

Data Collection

Patients and all study personnel except

the investigative pharmacist at each site
were blinded to treatment assignment.
Eligible patients were randomized 2:1 to
receive dexmedetomidine to obtain more
comprehensive safety data during prolonged dexmedetomidine use. Midazolam was selected as the comparator
medication because it is the only benzodiazepine approved for continuous infusion and is commonly used for longterm sedation in many countries,
including the United States.2-5,17-20 All patients were centrally randomized using
an interactive voice-response system and
a computer-generated schedule. Detailed information regarding sedative and
analgesic therapy prior to initiation of
study drug, baseline demographics, and
severity of illness were obtained at the
time of enrollment after consent was
signed.

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DEXMEDETOMIDINE VS MIDAZOLAM FOR SEDATION OF CRITICALLY ILL PATIENTS

Outcome Measures
and Safety End Points

The primary end point was the percentage of time within the target sedation range (RASS score 2 to 1) during the double-blind treatment period.
Secondary end points included prevalence and duration of delirium, use of
fentanyl and open-label midazolam, and
nursing shift assessments. Deliriumfree days were calculated as days alive
and free of delirium during study drug
exposure. This method of calculation
was used rather than an arbitrary 28day end point, because delirium prevalence could be confounded by administration of postprotocol sedative
medications after study drug was
stopped. Additional a priori outcomes
included duration of mechanical ventilation and length of stay in the ICU.
A daily arousal assessment was performed throughout the treatment period, during which patients within the
RASS range of 2 to 1 were asked to
perform 4 tasks (open eyes to voice command, track investigator with eyes,
squeeze hand, and stick out tongue).16
Patients were considered awake with successful completion of the assessment
when they could perform 3 of 4 tasks. If
the patients RASS score was greater than
1 at the time of a scheduled assessment, study medication was titrated until a RASS score of 2 to 1 was achieved
and then the arousal assessment was performed. If patients were oversedated to
a RASS value of 3 to 5, study drug was
interrupted until a RASS score of 2 to
0 was achieved and then the arousal assessment was performed. Delirium was
assessed daily during the arousal assessment with patients in the RASS range of
2 to 1 using the Confusion Assessment Method for the ICU (CAM-ICU).24
During each shift, the bedside nurse
assessed 3 components of patient care:
the patients ability to communicate, ability to cooperate with nursing care, and
tolerance of the ICU environment (including endotracheal tube and mechanical ventilation). Each of the 3 components was assessed using a scale of 0
to 10 (0=patient not communicating, cooperating, or tolerating; 10 = patient

communicating, cooperating, or tolerating), and a total score was defined as

the sum of the 3 component scores.
Safety was assessed by monitoring
laboratory test results, vital signs, electrocardiogram findings, physical examination findings, withdrawalrelated events, and adverse events. Vital
signs were recorded a minimum of every 4 hours, with every change of study
drug dose, and at the time of intervention for adverse events. Adverse events
were assessed and monitored by the
principal investigator and were recorded from first dose of study drug until 48 hours after study drug discontinuation. Serious adverse events were
recorded from study consent until 30
days after discontinuation of study drug.
All-cause mortality was assessed for 30
days after ICU admission.
The protocol prespecified that blood
pressure and heart rate values were considered adverse events if systolic blood
pressure was less than 80 or greater than
180 mm Hg, diastolic blood pressure was
less than 50 or greater than 100 mm Hg,
or heart rate was less than 40/min or
greater than 120/min. A greater than 30%
change from baseline heart rate or blood
pressure was also considered an adverse event. Interventions for bradycardia, tachycardia, and hypertension included titration or interruption of study
drug or administration of medication; interventions for hypotension included titration or interruption of study drug, intravenous fluid bolus, or drug therapy.
Hyperglycemia was defined as at least
1 serum glucose value greater than
8.325 mmol/L (to convert to mg/dL, divide by 0.0555). Severe sepsis was defined as known or suspected infection
with 2 or more systemic inflammatory
response syndrome criteria and at least
1 new organ system dysfunction.25 Infections with onset during the doubleblind treatment period were identified
by the clinical team managing the patient and supported by either positive
culture data or empirical antibiotic administration in response to presumed
or documented infection. Hyperglycemia and infections were not prespecified adverse events in the protocol.

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Statistical Analysis

Sample Size Determination. To address the multiple objectives of comparing safety and efficacy during prolonged exposure to dexmedetomidine
sedation, the sample size determination considered drug exposure, efficacy, and safety parameters. For the primary efficacy variable, the mean
percentage of time within target sedation range was estimated to be 85% for
dexmedetomidine and 77% for midazolam, based on a previous pilot
study.26 It was anticipated that 60% of
patients would remain intubated for 72
hours after randomization. A minimum of 150 dexmedetomidinetreated patients exposed for at least 72
hours would allow adverse events occurring in 10% of the dexmedetomidine group to be estimated with a 95%
confidence interval (CI) 5%. An estimated 100 dexmedetomidine-treated
patients were expected to remain intubated for at least 5 days. Considering
each of these requirements, enrollment of 250 patients randomized to receive dexmedetomidine and 125 randomized to receive midazolam would
have 96% power at an of .05 to detect a 7.4% difference in efficacy for the
primary outcome.
Efficacy and Safety Analysis. The
primary efficacy and safety analyses
were conducted on all randomized patients receiving any dose of study drug
(FIGURE 1). The primary efficacy analysis (percentage of time within the target sedation range during the doubleblind treatment period) was calculated
by dividing the total time that the patients remained within the target RASS
range (using linear interpolation to estimate RASS scores between assessments performed every 4 hours) by the
amount of time the patient remained in
the double-blind treatment period, multiplied by 100%. The mean difference
and 95% CI between the dexmedetomidine and midazolam treatment
groups were calculated and compared
between treatment groups with the
Mann-Whitney test. Treatment differences in nursing assessment scores were
assessed with the Wilcoxon test. Com-

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DEXMEDETOMIDINE VS MIDAZOLAM FOR SEDATION OF CRITICALLY ILL PATIENTS

parisons of treatment groups for prevalence of delirium and use of rescue

medications were performed using the
Fisher exact test. Treatment comparisons for delirium-free days, duration of
study drug, and doses of rescue medications were performed using the
Mann-Whitney test.
To account for repeated assessments during double-blind treatment
and the correlation between the
assessments, a multivariate analysis
was performed using a generalized
estimating equation (GEE) incorporating an exchangeable working correlation structure to model the prevalence of delirium (100=yes, 0=no) as
a function of treatment group and
study day. The analysis was also per-

formed including a term for the interaction of treatment group and study
day. The interaction term would be
included in the final model if P.15.
Results from the GEE analysis were
expressed as a coefficient, 95% CI,
and associated P value.27
Time to extubation and length of ICU
stay were calculated using KaplanMeier survival analysis, with differences between treatment groups assessed by the log-rank test. The log-rank
P values for time to extubation and ICU
length of stay were adjusted for multiple comparisons using the Bonferroni method. Successful extubation was
defined as no reintubation within 48
hours, and time to extubation was defined from start of study drug to suc-

Figure 1. Patient Enrollment, Randomization, and Treatment Flow

420 Patients provided consent

45 Excluded
10 Outside RASS target sedation range
9 Cardiovascular instability
5 Extubated
4 Hepatitis
4 Neuromuscular blocker use
3 Sedation not required
3 Withdrew consent
2 Investigator opiniona
2 Required anesthesia
1 Dialysis
1 Drug dependence
1 Terminally ill

cessful extubation. Length of ICU stay

was defined from start of study drug to
time of ICU transfer order. Patients
without extubation or discharge were
censored at the time of study drug discontinuation. For the safety analysis,
treatment comparisons for the incidence of adverse events were made
using the Fisher exact test.
Statistical tests were 2-sided, and
P.05 was considered statistically significant. All statistical evaluations were
conducted using SAS version 9.1 (SAS Institute Inc, Cary, North Carolina). No interim analysis was planned or performed.
A secondary analysis was conducted on the entire intent-to-treat
population. Patients randomized but
not receiving study drug (n=9) did not
have delirium or sedation assessments
performed. The analysis was performed after assigning to the missing
data a worst-case scenario (developed
delirium on day 1, 0% time in target
range, and using the 95% upper confidence limit for continuous variables).
In addition, a long-term use subgroup was defined as patients receiving study drug for more than 24 hours.
The major outcomes were also compared after restricting the analysis to
those sites enrolling 5 patients or more.
RESULTS

375 Randomized

Patient Population

250 Randomized to receive dexmedetomidine

6 Did not receive dexmedetomidine
3 Clinical deterioration
2 Died
1 Extubated

125 Randomized to receive midazolam

3 Did not receive midazolam
2 Clinical deterioration
1 Died

244 Included in primary analysis

122 Included in primary analysis

194 Included in long-term use analysis

50 Excluded (received study drug 24 h)
21 Extubated
17 Adverse event
7 Lack of efficacy
3 Withdrew consent
1 Entry criteriab
1 Investigator opiniona

103 Included in long-term use analysis

19 Excluded (received study drug 24 h)
5 Adverse event
5 Lack of efficacy
4 Withdrew consent
4 Entry criteriab
1 Investigator opiniona

Data were analyzed using the primary analysis population (n=366) as well as the long-term use population
(n=297), the group specifically requested by the US Food and Drug Administration as a means of obtaining
long-term efficacy and safety data for dexmedetomidine. RASS indicates Richmond Agitation-Sedation Scale.
a Investigator felt that patient no longer met entry criteria (eg, extubated, no longer required sedation, required deeper sedation).
b Patient had new information after consent that identified an exclusion criterion (eg, need for general anesthesia, unexpected liver or cardiac disease).
492

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A total of 375 eligible patients were randomized and 366 patients received study
drug, comprising the primary analysis
study population (244 patients received
dexmedetomidine, 122 received midazolam). Nine patients randomized (6
in the dexmedetomidine group, 3 in the
midazolam group) never received study
drug, of whom 3 died and 6 had a change
in clinical condition precluding participation. The long-term use population included 297 patients who received study
drug for longer than 24 hours (Figure 1).
Baseline characteristics were similar between treatment groups (TABLE 1). The
number of patients treated by country
were 294 (United States), 32 (Australia),
27 (Brazil), 11 (Argentina), and 2 (New
Zealand).

2009 American Medical Association. All rights reserved.

DEXMEDETOMIDINE VS MIDAZOLAM FOR SEDATION OF CRITICALLY ILL PATIENTS

Study Drug Administration
and Other Sedative/Analgesic
Medication Delivery

Themean(SD)maintenanceinfusiondose
was0.83(0.37)g/kgperhourfordexmedetomidine and 0.056 (0.028) mg/kg per
hour for midazolam. The average dexmedetomidine maintenance dose was 0.2 to
0.7 g/kg per hour in 95 of 244 patients
(39%), 0.71 to 1.1 g/kg per hour in 78
of 244 patients (32%), and greater than
1.1 g/kg per hour in 71 of 244 patients
(29%). Optional loading doses were
administered to only 20 of 244 dexmedetomidine-treatedpatients(8.2%)and
9 of 122 midazolam-treated patients
(7.4%). Open-label midazolam was administered to more dexmedetomidinetreatedpatientsonthefirststudyday(105/
244 [43%] vs 37/122 [30%]; P=.02) and
during the entire double-blind treatment
period (153/244 [63%] vs 60/122 [49%];
P=.02). The median open-label midazolam dose was similar. The percentage
of patients requiring fentanyl was similar, as was the median fentanyl dose during the double-blind period (TABLE 2).
Efficacy Analyses

Sedation Efficacy. There was no difference in the primary efficacy outcome,

percentage of time within the target
RASS range (77.3% for dexmedetomidine-treated patients and 75.1% for midazolam-treated patients; difference, 2.2%
[95% CI, 3.2% to 7.5%]; P = .18). A
similar percentage of patients successfully completed all daily arousal assessments and had study drug interrupted
to remain in target sedation range
(Table 2). The duration of study drug
treatment was shorter with dexmedetomidine (P=.01), mostly because dexmedetomidine-treated patients were extubated more rapidly.
Delirium and Nursing Assessments.
Results from the GEE analysis showed
that the treatment group and study day
were significantly associated with the
prevalence of delirium. The interaction term was not significant and was
not included in the final model. The
final model was: delirium = 68.0
(24.9 dexmedetomidine) (2.6
study day) (95% CI for dexmedetomi-

dine, 34.2 to 15.6 [P.001]; 95% CI

for study day, 4.0 to 1.2 [P .001]).
The prevalence of delirium just before
starting study drug was similar between
treatment groups (Table 1). During
study drug administration, the effect of
dexmedetomidine treatment on
delirium as measured by GEE was a
24.9% reduction (95% CI, 16% to 34%;
P .001). The prevalence of delirium
was 54% (132/244) in dexmedetomidine-treated patients vs 76.6% (93/
122) in midazolam-treated patients
(22.6% difference; 95% CI, 14% to 33%;
P .001) (FIGURE 2).
This reduction of delirium remained significant for patients who
were CAM-ICUnegative at study enrollment; the effect of dexmedetomidine treatment measured by GEE was

a 15.4% decrease (95% CI, 2% to 29%;

P =.02), with a delirium prevalence of
32.9% (25/76) in dexmedetomidinetreated patients vs 55.0% (22/40) in
midazolam-treated patients (P=.03).
For patients who were CAM-ICU
positive at baseline, the dexmedetomidine treatment effect measured by GEE
was a 32.2% reduction (95% CI, 21%
to 43%; P.001), with a prevalence of
68.7% (90/131) for dexmedetomidinetreated patients vs 95.5% (63/66) for
midazolam-treated patients (P.001).
Despite the shorter duration of study
drug treatment, the number of deliriumfree days was greater for patients treated
with dexmedetomidine (2.5 days vs 1.7
days; P=.002). Haloperidol was used to
treat delirium in 12.3% (30/244) of
dexmedetomidine-treated patients and

Table 1. Baseline Demographics and Characteristics of Study Population

No. (%)
Characteristic
Age, mean (SD), y
Men
Weight, mean (SD), kg
APACHE II score, mean (SD) a
Medical ICU patients
Surgical ICU patients
Severe sepsis b
Shock c
Pneumonia
Liver dysfunction d
Childs-Pugh A
Childs-Pugh B
Creatinine, median (IQR),
mg/dL
Prestudy drug sedative
Benzodiazepines
Propofol
Dexmedetomidine
Time from ICU admission
to start of study drug,
median (IQR), h
Delirium at enrollment
(CAM-ICUpositive) e

Dexmedetomidine
(n = 244)
61.5 (14.8)
125 (51.2)
88.1 (33.9)
19.1 (7.0)
212 (86.9)
32 (13.1)
182 (74.6)
78 (32)
156 (63.9)

Midazolam
(n = 122)
62.9 (16.8)
57 (46.7)
87.8 (31.5)
18.3 (6.2)
103 (84.4)
18 (14.7)
94 (77.1)
45 (36.9)
76 (62.3)

P
Value
.26
.44
.89
.35
.53
.53
.70
.35
.82

124 (51.0)
115 (47.3)
1.0 (0.7-1.4)

54 (44.3)
67 (54.9)
1.1 (0.8-1.4)

.27
.18
.20

195 (79.9)
125 (51.2)
1 (0.4)

100 (82.0)
56 (45.9)
2 (1.6)

.68
.38
.26

40.6 (22.2-64.9)

39.3 (24.5-72.8)

.76

138 (60.3)

70 (59.3)

.82

Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II28; CAM-ICU, Confusion Assessment Method
for the Intensive Care Unit24; ICU, intensive care unit; IQR, interquartile range.
SI conversion factor: To convert creatinine values to mmol/L, multiply by 88.4.
a APACHE II scores recorded using worst values over previous 24 hours from time of study enrollment (mean, 40 hours
following ICU admission).
b Known or suspected infection with 2 or more systemic inflammatory response syndrome criteria and at least 1 new
organ system dysfunction.
c Patients with blood pressure maintained via infusions of dopamine, dobutamine, norepinephrine, epinephrine, or vasopressin prior to start of study drug.
d Categorized using the Childs-Pugh scoring system. Childs-Pugh A corresponds to a score of 5 through 6; B corresponds to a score of 7 through 9.
e Calculated from patients treated with study drug and delirium assessments at baseline (229 with dexmedetomidine,
118 with midazolam).

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DEXMEDETOMIDINE VS MIDAZOLAM FOR SEDATION OF CRITICALLY ILL PATIENTS

14.8% (18/122) of midazolam-treated

patients during the double-blind treatment period.
The composite nursing assessment
score for patient communication, co-

operation, and tolerance of the ventilator was higher for dexmedetomidinetreated patients (21.2 [SD, 7.4] vs 19.0
[SD, 6.9]; P = .001), as were the individual scores for communication effec-

Table 2. Efficacy Outcomes in Patients Treated With Dexmedetomidine vs Midazolam

No. (%)
Dexmedetomidine
(n = 244)
77.3

Outcome
Time in target sedation range
(RASS score 2 to 1), mean, % a
Patients completing all daily arousal
assessments
Patients requiring study drug
interruption to maintain RASS score
2 to 1
Duration of study drug treatment,
median (IQR), d
Time to extubation, median (95% CI), d b
ICU length of stay, median (95% CI), d b
Delirium
Prevalence
Mean delirium-free days c
Open-label midazolam use
No. treated
Dose, median (IQR), mg/kg d
Fentanyl use
No. treated
Dose, median (IQR), g/kg d

Midazolam
(n = 122)
75.1

P
Value
.18

225 (92)

103 (84.3)

.09

222 (91)

112 (91.8)

.85

3.5 (2.0-5.2)

4.1 (2.8-6.1)

.01

3.7 (3.1-4.0)
5.9 (5.7-7.0)

5.6 (4.6-5.9)
7.6 (6.7-8.6)

.01
.24

132 (54)
2.5

93 (76.6)
1.7

.001
.002

153 (63)
0.09 (0.03-0.23)

60 (49)
0.11 (0.03-0.28)

.02
.65

180 (73.8)
6.4 (1.8-26.3)

97 (79.5)
9.6 (2.9-28.6)

.25
.27

Abbreviations: CI, confidence interval; ICU, intensive care unit; IQR, interquartile range; RASS, Richmond Agitation and
Sedation Scale.23
a The mean difference in percentage of time within target sedation range between the dexmedetomidine and midazolam treatment groups was calculated using the Mann-Whitney test.
b Calculated using Kaplan-Meier survival analysis, with differences between treatment groups assessed by the logrank test. Log-rank P values were adjusted for multiple comparisons using the Bonferroni method.
c Number of days alive without delirium during study drug treatment.
d Calculated as the total dose during study treatment divided by body mass.

Figure 2. Daily Prevalence of Delirium Among Intubated Intensive Care Unit Patients Treated
With Dexmedetomidine vs Midazolam
80
Dexmedetomidine

Delirium Prevalence, %

70

Midazolam

60
50
40
30
20
10
0
Enrollment

Treatment Day
Sample Size

229 118

206 109

175 92

134 77

92

57

60

42

44

34

Delirium was diagnosed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU).24 At
baseline, 60.3% of dexmedetomidine-treated patients and 59.3% of midazolam-treated patients were CAMICUpositive (P=.82). The effect of dexmedetomidine treatment was significant in the generalized estimating
equation27 analysis, with a 24.9% decrease (95% confidence interval,16%-34%; P.001) relative to midazolam treatment. Numbers differ from those for primary analysis because patients were extubated, discharged from the intensive care unit, or had missing delirium assessments.
494

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tiveness (6.6 [SD, 3.0] vs 5.5 [SD, 3.1];

P.001) and cooperation (7.0 [SD, 2.9]
vs 6.1 [SD, 3.0]; P = .002), while the
mean tolerance of ventilator score was
not significantly different (7.6 [SD, 2.2]
vs 7.4 [SD, 1.8]; P =.09).
Ventilator Time and ICU Length of
Stay. More patients treated with dexmedetomidine had study drug stopped because the patient was extubated (59%
[144/244] vs 45% [55/122]; P = .01).
The Kaplan-Meier estimated median
time to extubation was 1.9 days shorter
for dexmedetomidine-treated patients
(3.7 days [95% CI, 3.1 to 4.0] vs 5.6
days [95% CI, 4.6 to 5.9]; P = .01 by
log-rank) (Table 2, FIGURE 3). The
Kaplan-Meier estimated median length
of ICU stay was similar (5.9 days [95%
CI, 5.7 to 7.0] vs 7.6 days [95% CI, 6.7
to 8.6]; P = .24 by log-rank) (Table 2,
Figure 3).
Long-term Use and Subpopulations.
Results for the intent-to-treat population with assigned values (all 375 randomized patients) were similar to those
from the primary analysis for time in
target range (75.4% for dexmedetomidine-treated patients vs 73.3% for
midazolam-treated patients), reduction of delirium in dexmedetomidinetreated patients (24.9% reduction compared with midazolam), time to
extubation (3.8 days [95% CI, 3.5 to 4.0]
vs 5.7 days [95% CI, 4.6 to 6.0]), and
ICU length of stay (5.9 days [95% CI,
5.7 to 7.1] vs 7.7 [95% CI, 6.7 to 10.1]).
For the long-term use population
(receiving study drug 24 hours), the
percentage of time within the target
RASS range was similar (80.8% for
dexmedetomidine and 81% for midazolam; mean difference, 0.2% [95%
CI, 5.0 to 4.7%]; P = .54), while the
dexmedetomidine group experienced
less delirium (treatment effect by GEE
showed a 24% reduction; 95% CI,14%
to 34%; P.001), a shorter time to extubation (3.9 days [95% CI, 3.8 to 4.8]
vs 5.8 days [95% CI, 4.7 to 6.2]; P=.03),
and a similar ICU length of stay (6.4
days [95% CI, 5.8 to 7.5] vs 8.0 days
[95% CI, 6.7 to 10.1; P=.46).
When data from low-enrolling centers (5 patients) were excluded, 298

2009 American Medical Association. All rights reserved.

DEXMEDETOMIDINE VS MIDAZOLAM FOR SEDATION OF CRITICALLY ILL PATIENTS

Figure 3. Time to Extubation and Intensive Care Unit (ICU) Length of Stay Among Patients Treated With Dexmedetomidine vs Midazolam
A Time to Extubation

B ICU Length of Stay

100

100

90

90

Log-rank P = .01

80

70
Midazolam

60

Cumulative %

Cumulative %

70

50
40
30

60

Midazolam

50
40
30
Dexmedetomidine

Dexmedetomidine

20

20

10
0

Log-rank P = .24

80

10
2

Time From Start of Study Drug to Extubation, d

No. at Risk
Dexmedetomidine 244
Midazolam
122

153
91

73
60

40
29

10

12

Time From Start of Study Drug to ICU Discharge, d

21
16

194
106

244
122

137
83

75
57

50
39

40
29

28
19

A, Time to extubation was calculated from the start of study drug to the time of extubation after which no reintubation occurred. Patients not extubated were censored
at time of study drug discontinuation. The median time to extubation was 1.9 days shorter for the dexmedetomidine group than for the midazolam group (3.7 days
[95% confidence interval {CI}, 3.1-4.0] vs 5.6 days [95% CI, 4.6-5.9]; P=.01 by log-rank test). B, Length of ICU stay was calculated from start of study drug to time
of order for ICU transfer. Patients without discharge were censored at the time of study drug discontinuation. The median length of ICU stay was similar between the
dexmedetomidine and midazolam groups (5.9 days [95% CI, 5.7-7.0] vs 7.6 days [95% CI, 6.7-8.6]; P=.24 by log-rank test).

patients were enrolled at 25 centers in

4 countries. The data analyses for these
high-enrollment centers were also similar to the primary analysis. The mean
percentage of time within the RASS target range was 76.5% for dexmedetomidine-treated patients and 74% for midazolam-treated patients, a difference of
2.5% (95% CI, 3.4 to 8.5; P=.17). The
dexmedetomidine treatment effect on
delirium by GEE showed a 24.2% reduction (95% CI, 14% to 34%;
P .001). The median time to extubation was 3.8 days (95% CI, 3.1 to 4.0)
for dexmedetomidine vs 4.9 days (95%
CI, 4.2 to 6.0) for midazolam (P = .03).
The median length of ICU stay was
similar (5.8 days [95% CI, 5.1 to 6.7]
for dexmedetomidine and 7.7 days
[95% CI, 6.7 to 10.1] for midazolam;
P=.12).
Safety. All-cause 30-day mortality
from ICU admission was not different
between treatment groups (22.5%
[55/244] for dexmedetomidinetreated patients vs 25.4% [31/122] for
midazolam-treated patients; P = .60),
and no death was considered related to
study drug. The percentage of patients
transferred alive from the ICU was also
similar (81.5% [199/244] for dexme-

Table 3. Safety Outcomes During Treatment With Dexmedetomidine vs Midazolam

No. (%)
Outcome a
Cardiovascular
Bradycardia
Bradycardia with intervention
Tachycardia
Tachycardia with intervention
Hypotension
Hypotension with intervention
Hypertension
Hypertension with intervention
Metabolic (hyperglycemia)
Infections
30-d mortality b

Dexmedetomidine
(n = 244)

Midazolam
(n = 122)

P
Value

103 (42.2)
12 (4.9)
62 (25.4)
24 (9.8)
137 (56.1)
69 (28.3)
106 (43.4)
46 (18.9)
138 (56.6)
25 (10.2)
55 (22.5)

23 (18.9)
1 (0.8)
54 (44.3)
12 (9.8)
68 (55.7)
33 (27)
54 (44.3)
36 (29.5)
52 (42.6)
24 (19.7)
31 (25.4)

.001
.07
.001
.99
.99
.90
.91
.02
.02
.02
.60

a See Outcome Measures and Safety End Points for definitions and details of variables.
b Indicates mortality rate for 30 days after ICU admission.

detomidine-treated patients vs 81.9%

[100/122] for midazolam-treated
patients; P .99). A similar percentage of patients stopped study drug infusions because of adverse events (16.4%
[40/244] for dexmedetomidine vs 13.1%
[16/122] for midazolam, P =.44).
More dexmedetomidine-treated patients developed adverse events related
to treatment (40.6% [99/244] vs 28.7%
[35/122]; P = .03), primarily due to a

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greater incidence of bradycardia (42.2%

[103/244] vs 18.9% [23/122]; P.001)
(TABLE 3). This included heart rates less
than 40/ min (occurring in 5 dexmedetomidine-treated patients) and a 30%
decrease from prestudy baseline (occurring in 98 dexmedetomidine-treated patients). Among dexmedetomidinetreated patients, 4.9% (12/244) required
an intervention for bradycardia that included titration or interruption of study

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495

DEXMEDETOMIDINE VS MIDAZOLAM FOR SEDATION OF CRITICALLY ILL PATIENTS

drug infusion in 6 patients and use of

atropine in 6 patients. Among midazolam-treated patients, 1 received atropine for bradycardia. A higher incidence of tachycardia occurred in the
midazolam group (P.001), and more
hypertension requiring treatment
(P=.02) was noted in the midazolamtreated patients.
Several adverse events not identified
a priori as outcomes but monitored prospectively during the study were more
prevalent in one group or the other. The
incidence of infections with onset occurring during the double-blind period was less in dexmedetomidinetreated patients (10.2% [25/244] vs
19.7% [24/122], P = .02). These included lower rates of urinary tract infections (0% in dexmedetomidinetreated patients vs 3.3% [4/122] in
midazolam-treated patients, P=.02) and
hospital-acquired pneumonia (1.2%
[3/244] in dexmedetomidine-treated patients vs 4.9% [6/122] in midazolamtreated patients, P=.07). As shown in
Table 3, hyperglycemia occurred more
frequently among dexmedetomidinetreated patients; treatment with corticosteroids was similar (65.5% [160/
244] of dexmedetomidine-treated
patients vs 68.9% [84/122] of midazolam-treated patients), as was insulin therapy (77.8% [190/244] of dexmedetomidine-treated patients and 74.8%
[91/122] of midazolam-treated patients).
The incidence of investigatorreported adrenal insufficiency was
similar (0.4% [1/244] in dexmedetomidine-treated patients vs 0% in midazolam-treated patients). Rebound hypertension and tachycardia did not
occur following abrupt discontinuation of dexmedetomidine infusions. In
both treatment groups, few patients experienced drug-related withdrawal
events (eg, agitation, headache, hyperhidrosis, nausea, nervousness, tremor,
or vomiting) after stopping study drug.
Overall, 4.9% (12/244) of dexmedetomidine-treated patients and 8.2% (10/
122) of midazolam-treated patients experienced at least 1 event related to
withdrawal within 24 hours after discontinuing study drug (P = .25).
496

COMMENT
The primary outcome for this investigation, time in the target sedation range,
was not different between patients
treated with dexmedetomidine or midazolam, exceeding 75% with both medications. This finding contrasts with
those of previous studies, which suggested that dexmedetomidine attained the sedation target more frequently,12,26 but may be explained by
our study design, which incorporated
new standard elements for ICU sedation practice, including a light-tomoderate sedation target (RASS score
2 to 1), delirium assessment, and
study drug titration or interruption every 4 hours and as part of a daily arousal
assessment. The adherence to this approach is supported by the high frequency of study drug interruption by
more than 90% of patients in both study
groups.
Despite the similar levels of sedation attained by patients treated with
dexmedetomidine and midazolam, several important differences were noted
in this prospective, double-blind, randomized study. Bradycardia was more
common among dexmedetomidinetreated patients, while hypertension and
tachycardia were more common among
midazolam-treated patients. Patients
treated with dexmedetomidine developed delirium more than 20% less often than patients treated with midazolam and were removed from
mechanical ventilation almost 2 days
sooner.
To our knowledge, this is the first
study to show that even when the elements of best sedation practice (including daily arousal, a consistent light-tomoderate sedation level, and delirium
monitoring) are used for all patients, the
choice of dexmedetomidine as the foundation for patient sedation further improves these important outcomes. In the
context of 2 recently published smaller
studies comparing dexmedetomidine
with lorazepam and propofol,12,13 these
data suggest that 2 agonists improve
many important aspects of critical care,
namely, less delirium and shorter duration of ventilator time.

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Reductions in ventilator time, prevalence of delirium, and infection rate are

especially relevant for all who care for
ICU patients. The standard approach
to ICU sedation is associated with delirium rates of 60% to 80% and ventilator-associated pneumonia rates of 9%
to 23%.24,29 Each additional day of delirium increases the risk of prolonged
hospitalization by 20% and increases
the likelihood of a poor functional status at 3 and 6 months.30-32 Dexmedetomidine appears to be the first drug to
both reduce the development of delirium and to improve the resolution of
delirium if it develops in the ICU. Similarly, infections developing in ICU patients are associated with increased
lengths of stay, cost, and mortality.29
With the government considering limiting payments for preventable complications (such as delirium and nosocomial infections), aggressive effort is
needed to reduce all factors contributing to these conditions.33,34
Dexmedetomidine binds at 2 receptors rather than GABA receptors; this
may explain the improved outcomes we
and others have detected when comparing these two classes of medication.12,13 In addition to sedation, dexmedetomidine provides analgesic effects,
a lack of respiratory depression, sympatholytic blunting of the stress
response, preservation of neutrophil
function (compared with the neutrophil-suppressing effect of GABAagonist medications), and may establish a more natural sleep-like state.22,35-39
Several important aspects related to
dosing of dexmedetomidine and other
medications in this investigation warrant discussion. In 61% of patients,
dexmedetomidine doses exceeded the
approved maximum of 0.7 g/kg per
hour, and 80% of patients received
dexmedetomidine for longer than the
approved maximum duration of 24
hours. These initial limits were developed in 1999 from short-term studies
after general anesthesia.40 Since then,
multiple studies have suggested that patients may require higher doses and can
be treated for longer than 24 hours.41-43
This study confirms that dexmedeto-

2009 American Medical Association. All rights reserved.

DEXMEDETOMIDINE VS MIDAZOLAM FOR SEDATION OF CRITICALLY ILL PATIENTS

midine infusion rates up to 1.4 g/kg

per hour for longer than 24 hours
provides sedation similar to midazolam, are safe, and are associated with
improved outcomes. A 2-fold greater incidence of bradycardia was seen in patients treated with dexmedetomidine,
whereas midazolam-treated patients experienced a greater incidence of tachycardia and hypertension requiring treatment. Unlike the 2 agonist clonidine,
no evidence for rebound hypertension or tachycardia was detected during the 48-hour follow-up period after
stopping dexmedetomidine.
Our study design allowed enrollment up to 96 hours after ICU admission and calculated Acute Physiology
and Chronic Health Evaluation
(APACHE) scores for the 24 hours preceding study drug administration. Severity-of-illness tools designed for use
at admission underestimate the severity of illness when used 2 or 3 days after admission, and it is likely our patients were sicker than the APACHE
scores suggest.44 The high incidence of
severe sepsis and shock in our patients at baseline and mortality rates of
22.5% and 25.4% (which match those
in studies of severe sepsis and septic
shock45,46) further support that these
data were derived from a critically ill
population of patients.
Several limitations of this study warrant discussion. The primary analysis
targeted patients treated with study
drug, rather than the usual intent-totreat-as-randomized group. However,
a conservative analysis of all 375 randomized patients matched the primary analysis.
Midazolam was selected as the comparator medication owing to its frequent use for long-term sedation and
was administered as a continuous infusion owing to its short half-life and
to facilitate maintaining the blinded
nature of the study. Although midazolam is often identified as the sedative most commonly used for longterm sedation,2,5,17 common alternatives
such as lorazepam or propofol were not
tested in this study. Smaller studies with
different designs have compared

dexmedetomidine with propofol and

lorazepam, also suggesting a benefit
from dexmedetomidine.12,13
Many centers in this study enrolled
few patients, raising concern for potential bias, variability, and unbalanced center effect if only contributing to 1 study group. When centers
enrolling fewer than 5 patients were excluded, 81% of our primary analysis
population remained, and results from
these patients matched our primary
data. We excluded patients requiring renal replacement therapy to avoid the
confounding effect of accumulating
midazolam metabolites and dialysis
clearance of medication. Analyses of
dexmedetomidine and midazolam use
in patients with renal dysfunction have
concluded that the effect of both drugs
is prolonged47,48; it is unknown whether
the benefits of dexmedetomidine we
observed would be seen in these patients.
CONCLUSIONS
This investigation (which incorporated best sedation practices including a light-to-moderate sedation level
and daily arousal assessments in both
study groups) showed no difference in
the time patients spent within the sedation target range with dexmedetomidine or midazolam. Despite this
similarity in sedation levels, dexmedetomidine shortened time to removal from mechanical ventilation and
reduced the prevalence of delirium. Future studies of ICU sedation must look
beyond the quality or quantity of sedation to focus on additional important clinical outcomes, including those
we studied (prevalence of delirium and
time of mechanical ventilation) and several our study was not powered to
evaluate (ICU length of stay, rates of
nosocomial infection, mortality, and
long-term cognitive function).
In addition to the medication administration protocol and incorporation of
best sedation practices, the choice of
medication used to provide sedation for
ICU patients is a fundamental component of efforts to deliver safe and effective care. Although it did not increase

2009 American Medical Association. All rights reserved.

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the time within target sedation range,

dexmedetomidine appears to provide
several advantages for prolonged ICU
sedation compared with the GABAagonist midazolam.
Author Affiliations: University of Vermont College of
Medicine and Maine Medical Center, Portland, Maine
(Dr Riker); University of New South Wales Clinical
School, The Prince of Wales Hospital Campus, Randwick, New South Wales, Australia (Dr Shehabi); Hospira
Inc, Lake Forest, Illinois (Dr Bokesch and Mr Wisemandle); Carrera de Especialista en Medicina Crtica
de la Universidad de Buenos Aires, Hospital General
de Agudos Juan A. Fernandez, Buenos Aires, Argentina (Dr Ceraso); University of Kentucky College of
Medicine and Kentucky Lung Clinic, Hazard (Dr Koura);
University of Illinois College of Medicine at OSF St Francis Medical Center, Peoria, Illinois (Dr Whitten); Resurrection West Suburban Hospital Medical Center, Oak
Park, Illinois (Dr Margolis); Vanderbilt University Medical Center, Nashville, Tennessee (Mr Byrne and Dr Ely);
Veterans Affairs Geriatric Research Education Clinical Center for the Tennessee Valley Healthcare System VAthe VA GRECC (Dr Ely); and Pavilhao Pereira
Filho, Irmandade Santa Casa de Misericordia, Porto
Alegre, Brazil (Dr Rocha).
Published Online: February 2, 2009 (doi:10.1001/
jama.2009.56).
Author Contributions: Drs Riker and Shehabi had full
access to all of the data in the study and take responsibility for the integrity of the data and the accuracy
of the data analysis.
Study concept and design: Riker, Shehabi, Bokesch,
Ely.
Acquisition of data: Riker, Ceraso, Koura, Whitten,
Margolis, Rocha.
Analysis and interpretation of data: Riker, Bokesch,
Wisemandle, Byrne, Ely, Rocha.
Drafting of the manuscript: Riker, Shehabi, Bokesch,
Wisemandle, Byrne, Ely, Rocha.
Critical revision of the manuscript for important intellectual content: Riker, Shehabi, Bokesch, Ceraso,
Wisemandle, Koura, Whitten, Margolis, Byrne, Ely,
Rocha.
Statistical analysis: Riker, Wisemandle, Byrne, Ely.
Administrative, technical, or material support: Bokesch,
Koura, Whitten, Margolis, Ely.
Study supervision: Shehabi, Bokesch, Ceraso.
Financial Disclosures: Dr Riker reports that he has received honoraria and/or grant support from Aspect
Medical Systems Inc, AstraZeneca, Eli Lilly, Hospira, Takeda, and the Academy for Continued Healthcare Learning. Dr Shehabi reports that he has received honoraria
and/or grant support from Hospira, Edward Lifesciences, Theravance, and the Intensive Care Foundation. Dr Ceraso reports that he has received honoraria
and/or grant support from Hospira. Dr Koura reports
that he has received honoraria and/or grant support from
Altana, Artisan Pharma, Boehringer-Ingelheim, CSL,
Hospira, Ortho-McNeil, Sepracor, Schering-Plough, and
United BioScience Corp. Dr Whitten reports that he has
received honoraria and/or grant support from Hospira.
Dr Margolis reports that he has received honoraria and/or
grant support from Hospira. Mr Byrne reports that he
was paid a consulting fee for serving as the independent statistical reviewer by the sponsor. Dr Ely reports
that he has received honoraria and/or grant support from
Hospira, Pfizer, Eli Lilly, GlaxoSmithKline, and Aspect
Medical, and is an advisor to Healthways. Dr Rocha reports that he has received honoraria and/or grant support from Hospira, Theravance, Altana, Novartis and the
Canadian Institute of Health Research. Dr Bokesch and
Mr Wisemandle reported no disclosures.
Funding/Support: This study was funded by Hospira
Inc, Lake Forest, Illinois, which manufactures dexmedetomidine.

(Reprinted) JAMA, February 4, 2009Vol 301, No. 5

497

DEXMEDETOMIDINE VS MIDAZOLAM FOR SEDATION OF CRITICALLY ILL PATIENTS

Role of the Sponsor: Hospira employees worked collaboratively with the investigators in designing the
study and interpreting the data and were involved in
the conduct of the study, including the collection,
management, and initial analysis of the data. Hospira
employees reviewed the manuscript, but approval of
the Hospira was not required prior to manuscript
submission.
SEDCOM Study Group: Argentina: Buenos Aires: M.
Torres Boden (Hospital Argerich); D. Ceraso (Hospital General de Agudos Juan A. Fernandez); A. Raimondi (Sanatorio Mater Dei); Mar del Plata: M. Gonzalez (Hospital Privado de Comunidad). Australia:
Randwick, NSW: Y. Shehabi (Prince of Wales Hospital); Hobart, TAS: A. Turner (Royal Hobart Hospital);
Box Hill, VIC: D. Ernest (Box Hill Hospital); Perth, WA:
G. Dobb (Royal Perth Hospital). Brazil: Porto Alegre:
F. Dias (Hospital Sao Lucas da PUCRS), M. Rocha (Irmandade da Santa Casa de Misericordia de Porto
Alegre); Santo Andre: A. Baruzzi (Hospital Estadual
Mario CovasSanto Andre); Sao Paulo: I. da Silva (Real
e Benemerita Sociedade Portuguesa de Beneficencia
Hospital Sao Joaquim); Sao Paulo: E. Rezende (Hospital do Servidor Publico EstadualIAMSPE). United
States: Arizona: Chandler: G. Margolin (Progressive
Medical Intensivists); Phoenix: J. Feldman (Arizona Pulmonary Specialists); Scottsdale: J. Tillinghast (Arizona Pulmonary Specialists); California: Palo Alto: E.
Geller (VA Palo Alto Health Care Systems); Pasadena: N. Singla (Huntington Memorial Hospital); Redlands: J. Dexter (Beaver Medical Group); San Clemente: K. Jones (Accurate Clinical Trials); San Francisco:
J. Tang (UCSFSan Francisco General Hospital); San
Jose: E. Cheng (Santa Teresa Community Hospital);
Colorado: Denver: I. Douglas (Denver Health Medical Center); Delaware: Newark: G. Fulda (Christiana
Care Health Services); Washington, DC: D. Herr
(Washington Hospital Center); Florida: Bay Pines: L.
Anderson (Bay Pines VAMC); Miami: D. Kett ( Jackson Memorial Hospital/University of Miami); Tampa:
J. Basile (University of South Florida Anesthesiology);
Georgia: Atlanta: H. Silverboard (Northside Respiratory Care); Illinois: Arlington Heights: J. Cowen (Northwest Community Hospital); Oak Park: B. Margolis (Resurrection West Suburban Hospital); Peoria: P. Whitten
(Peoria Pulmonary Associates); Kansas: Kansas City:
S. Simpson (University of Kansas); Olathe: J. Bradley
(Consultants in Pulmonary Medicine); Kentucky: Hazard: F. Koura (Kentucky Lung Clinic); Lousiana: Shreveport: S. Conrad (LSU HSC Shreveport); Maryland: Baltimore: C. Shanholtz (University of Maryland School
of Medicine); Maine: Biddeford: R. Kahn (PrimeCare
Internal Medicine); Portland: R. Riker (Maine Medical Center); Montana: Missoula: W. Bekemeyer (Western Montana Clinic); North Carolina: Greensboro: D.
Simonds (Peidmont Respiratory Research Foundation); Nebraska: Omaha: L. Morrow (Creighton University Medical Center); New Jersey: Camden: J. Littman (Cooper University Hospital); Englewood: A.
Shander (Englewood Hospital and Medical Center);
New York: Bronx: R. Cuibotaru (St Barnabas Hospital); P. Dicpinigaitis (Montefiore Medical Center);
Brooklyn: L. George (New York Medical Hospital); Mineola: M. Groth (Winthrop-University Hospital); New
York: C. Carpati (St Vincent Catholic Medical Center); Rochester: D. Kaufman (University of Rochester, Strong Memorial Hospital); Ohio: Akron: J. Wilson (Summa Health System); Oregon: Medford: J.
Ordal, J. Schoenhals (Pulmonary Consultants Research); Pennsylvania: Danville: M. Haupt (Geisinger Medical Center); Monroeville: J. Hoyt (Forbes
Regional Hospital); South Carolina: Charleston: P.
Flume (Medical University of South Carolina); D. Handshoe (Low Country Lung and Critical Care). Tennessee: Memphis: M. Pugazhenthi (University of Tennessee Health Science Center); Texas: Dallas: M.
Ramsay (Baylor University Medical Center); Galveston: V. Cardenas (University of Texas Medical Branch);
498

Houston: H. Minkowitz (Memorial-Hermann Memorial City Hospital). Utah: Ogden: T. Fujii (McKay Dee
Hospital). Va: Lynchburg: A. Baker (Lynchburg Pulmonary Associates). New Zealand: Christchurch: S.
Henderson (Christchurch Hospital); Hastings: R. Freebairn (Hawkes Bay Regional Hospital); Palmerston
North: G. McHugh (Palmerston North Hospital).
Independent Statistical Review: Daniel Byrne, MS (Department of Biostatistics, Vanderbilt University), had
access to all of the data used in the study and performed an independent analysis of the primary and
key secondary end points reported in this article by
repeating the analyses and verifying P values and 95%
confidence intervals. The results of Mr Byrnes analysis are reported in this article. He also verified the consistency between the objectives set out in the protocol, prespecified statistical analysis plan, and results
of the statistical analysis produced by the sponsor. He
found no discrepancy in these reports, and all results
reported in this article were identical to those obtained by the sponsor.

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2. Martin J, Franck M, Fischer M, Spies C. Sedation
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As any change must begin somewhere, it is the single

individual who will experience it and carry it through.
The change must indeed begin with an individual; it
might be any one of us. Nobody can afford to look
around and to wait for somebody else to do what he
is loath to do himself.
Carl G. Jung (1875-1961)

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