Reference: PRODEX, MIDEX
Clinical Question posed by the trial: Whether dex is noninferior to midazolam and propofol in maintaining mild to
moderate sedation and offers benefits in terms of reduced mech vent in the ICU
Methodology
Participants
Study Design
MC, R, active control, non-inferiority trial
Setting
ICU mech vented patients
Sequence
Generation
Allocation
Concealment
1:1 by central interactive voice response system.
Stratified by study center for blocks of 4.
Inclusion
criteria
>18, invasive mech vent
goal RASS 0 to -3
using midaz or propofol expected to last >24 hrs
Enrolled w/in 24 hours of ICU admit and within 48
hours of sedation
Severe neurological disorder
MAP less than 55 despite fluids/pressors
HR less than 50/min, AVB II/III w/o PM
Use of alpha-2 agonists-antagonists w/in 24 hours
Blinding
Loss to
follow-up
Population
analyzed
Intervention
“central interactive voiceresponse system”
Relavent
exclusion
criteria
“All patients and study personnel were masked
to treatment allocation”
“double-dummy design with NS as dummy, but
propofol and dummy was prepared with non
transparent black syringes, infusion tubing and
connectors”
~10% of pts were excluded from per-protocol”
Only 4 pts in PRODEX study were lost to f/up
1 Pt in MIDEX and 2 pt in PRODEX withdrew
consent
“Primary analysis performed as per-protocol as
it was non-inferiority”
All others as ITT
Dexmedetomidine 0.2 to 1.4 ug/kg/hour
Midazolam 0.03 to 0.2 mg/kg/hour
Propofol 0.3 to 4 mg/kg/hour
Study size
Planned 500 in each study
MIDEX 249 and 251
PRODEX 251 and 247
“Average
patient”
Intubated, male (60%) age 65 with SAPS II score 45
admitted for medical (73%) reason to ICU. Has
respiratory and cardio failure (60% each) and an
infection (~50%)
Most patients 90% had sedation stops performed
Other
Reasons
for
exclusion
Most d/t expected sedation <24 hours or acute
neurological disorder
Study drugs were infused w/out loading dose at
a dose matching pre-randomization sedation
Outcomes
Adjudication
Pain treated with fentanyl boli. Rescue sedation
with prop in MIDEX and midaz in PRODEX
Primary: proportion of time RASS 0-3 without
use of rescue therapy
Secondary: length of ICU stay from
randomization, nurses assessment of
arousal/ability to cooperate using VAS
No independent group
Assessment
Duration
Funding
Maximum study meds for 14 days
Continued only until extubated
Patients followed for 45 days
Pharma
MIDEX
Time at RASS
Death
Drug d/c due to
lack of efficacy
Dex
60.7%
27.3%
9%
Midazolam
56.6%
21.1%
4%
RR
ARD
NNT
p-value
Non-infer
0.02
Mech Vent Hours
ICU stay
Hypotension
Bradycardia
Duration of drug
use (median)
101 hrs
211
20.6%
14.2%
42 hours
147 hrs
243
11.6%
5.2%
43 hours
0.01
NSS
0.007
<0.001
0.15
PRODEX
Time at RASS
Death
Drug d/c due to
lack of efficacy
Mech Vent Hours
ICU stay
Hypotension
Duration of drug
use (median)
Critical Illness
Polyneuropathy



Dex
64.6%
17.1%
14%
Propofol
64.7%
19.4%
5%
RR
ARD
NNT
p-value
Non-infer
69
164
93
185
42 hours
47 hours
0.04
NSS
NSS
<0.001
2
11
0.02
<0.01
Nurses VAS assessments indicated that patients were more arousable, more cooperative and beter able to
communicate their pain than patients receiving either midazolam or propofol
Dex patients received less treatments for delirium
Patients in the Dex group had more spontaneous breathing trials performed
Major Limitations
Methods:





Did not confirm that blinding was maintained. They blinded propofol but would be easy to imagine this could be
broken.
No independent group adjudicated outcomes. Means that if blinding was broken the results would be more
easily biased.
Would have preferred primary outcome to be duration of ICU stay, mech vent or hospital stay rather than time
in RASS target.
In PRODEX, 36 patients in the dex group had treatment stopped for lack of efficacy (15 in 1st 24 hrs) and 29 for
AE. It appears that these patients were still included in the per-protocol analysis but it is not clear how there
data would have been included.
NO standardized mechanical ventilation weaning protocol or criteria for extubation.
Results


Why did the patients in the PRODEX study require twice as much dex? (0.925 ug/kg/h vs 0.45 ug/kg/h)
Included only health care workers assessment of sedation rather than patients.
Generalizability

Only applies to patients on continuous infusions of sedative medications which is somewhat rare now.
Assessment
Dexmedetomidine is similar in effectiveness to midazolam and propofol for maintaining target RASS in this group of
study includable patients. Dex may reduce the duration of mech vent compared to midazolam and propofol (p=0.01 and
0.04 respectively), but had no significant difference in duration of ICU stay. Nurses assessments seemed to indicate that
patients were better behaved and more interactive. No information on patients satisfaction with sedation.
Higher rates of bradycardia and hypotension but less delirium.
Conclusion
Dex appears may reduce mechanical ventilation duration and delirium but does not reduce ICU stay. May be a useful
sedative for some patients at high risk of delirium who will not be adversely affected by Dex side effects.
Not sure that it would be easy to determine a priori in which patients the use of dex would be cost effective.
Notes:
o
SAPS II
 http://www.sfar.org/scores2/saps2.html
 Patients in this study had a 35% predicted mortality