Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Cruickshank, 2016

Study characteristics and results are extracted from the SR (unless stated otherwise)

SR and meta-analysis of RCTs

Literature search up to November 2014

A: Abdulatif 2004, Egypt

B: Corbett 2005, USA

C: Elbaradie 2004, Egypt

E: Herr 2003, USA and Canada

F: Jakob 2012 MIDEX, 9 European countries

G: Jakob, 2012 PRODEX, Russia and 6 European countries

H: MacLaren 2013, USA

I: Maldonado 2009, USA

J: Memis 2009, Turkey

K: Pandharipande 2007, USA

L: Riker 2009, Argentina, Australia, Brazil, the

USA and New Zealand

M: Ruokonen 2009, Finland and Switzerland

N: Shah 2014, India

O: Shehabi 2013, Australia and New Zealand

P: Srivastava 2014, India

Q: Tasdogan 2009, Turkey

R: Venn 2001, UK

Study design:

All RCT (all parallel)

Setting and type of participants

A: respiratory failure requiring MV using pressure

support ventilation with or without continuous

positive airway pressure

B: single centre, after non-emergent CABG surgery

C: surgical ICU, single centre, after major thoracic,

abdominal or pelvic cancer surgeries

E: 25 centers, after scheduled CABG surgery

F: 44 centers, general ICU patients

G: 33 centers, general ICU patients

H: single center, medical and surgical ICUs patients

I: single center, following cardiac valve surgery

J: single center, all patients fulfilled clinical and laboratory criteria of septic shock

K: 2 centers, medical and surgical ICU

patients

L: 68 centers, general ICU patients

M: 2 centers, general ICU patients

N: 1 center, surgical patients

O: 6 centers, medical, operative elective

and operative emergency

P: number of centers not reported, general ICU patients

Q: single center, patients with sepsis after ileus surgery

R: single center, after complex major abdominal

or pelvic surgery (elective surgery)

Source of funding and conflicts of interest:

A: NR

B: NR

C: NR

E: NR

F: Orion Pharma, Espoo, Finland

G: Orion Pharma, Espoo, Finland

H: Hospira

I: NR

J: NR

K: Hospira

L: Hospira

M: Orion Pharma,

Finland

N: Macleods

Pharmaceuticals Ltd

O: Hospira

P: none

Q: NR

R: Abbott Laboratories

Inclusion criteria SR:

-published RCTs comparing dexmedetomidine with clonidine or

dexmedetomidine or clonidine with propofol or benzodiazepines (i.e. midazolam or lorazepam).

-critically ill adults admitted to ICUs who required MV.

Exclusion criteria SR:

-People with primary brain injuries such as trauma or intracerebral bleed/infarct

17 studies (+ secondary reports from the same study) included, with a total of 2449 patients

Important patient characteristics at baseline:

N, mean age in yrs (sd or range)

A: I: n=20, 43 (3.7) C: n=20, 40 (5.2)

B: I=43, 63.5 (10.1)

C: 46, 62.4 (10.7)

C: n=30, I:65 (6.5)

C: 67 (5.7)

E: I; 148, 61.9 (9.5)

C: 147, B: 62.4 (8.7)

F: I: n=249, median 65 (55–74)

C: n=252, median 65 (55–74)

G: I: n=251, median 65 (51–75)

n=249, median 65 (51–74)

H: I: n=11, 58.3 (15.3)

C: n=12, 57.8 (9.3)

I: I:n=40, 55 (16)

C-1:n=38, 58 (18)

C-2:n=40, 60 (16)

J: I: n=20, 60 (31–80)

C: n=20, 54 (25–78)

K:I: n=54, median 60 (IQR 49–65)

C:n=52, median 59 (IQR 45–67)

L: I: n=250, 61.5 (14.8)

C: n=125, 62.9 (62.8)

M: I: n=41, 64 (18–83)

C-1: n=28, C-2:n=16, 68 (18–83)

N: I: n=15, 49.5 (14.15)

C:n=15, 49.09 (17.17)

O: I:n=16, 61.6 (17)

C:n=21, 65 (15)

P: I: n=35, median 49 (IQR 45–63)

C:n=35, median 46 (IQR 43–59)

Q: I:n=20, 58 (21–78)

C:n=20, 50 (19–74)

R: I:n=20, median 65 (IQR 60–77)

C:n=20, median 67 (IQR 64–74)

Groups comparable at baseline?

For what is reported in the SR: yes

Describe intervention: dexmedetomidine

A: initial i.v. loading dose (1 μg/kg) over 10 min, followed by continuous i.v. infusion (5 μg/ml) at a rate of 0.5 μg/kg/hr (0.1 ml/ kg/ hr) to be increased to a maximum of 1 μg/kg/hr

B: 1 μg/kg (actual body weight) loading dose intra-venously administered over 15 min, followed by a 0.4 μg/kg/hr i.v. infusion

C: Loading infusion dose of dexmedetomidine 2.5 μg/ kg/hr over 10 min followed by maintenance infusion at a rate of 0.2–0.5 μg/kg/hr into a peripheral vein, with

the dosage adjusted to achieve the desired level

of sedation

E: Loading dose of 1.0 μg/ kg over 20 min, followed by a maintenance infusion of 0.4 μg/kg/hr. After transfer to the ICU, the infusion rate was titrated in the range of 0.2 μg/kg/hr to 0.7 mg/kg/ hr as necessary to maintain a RSS score of ≥3 before extubation, ≥2 after extubation

F: Loading dose of 1.0 μg/kg over 20 min, followed by a maintenance infusion of 0.4 μg/kg/hr. After transfer to the ICU, the infusion rate was titrated in the range of 0.2 μg/kg/hr to 0.7 μg/kg/hr as necessary to maintain a RSS score of ≥3 before extubation, ≥2 after extubation

G: Loading dose of 1.0 μg/kg over 20 min, followed by a maintenance infusion of 0.4 μg/kg/hr. After transfer to the ICU, the infusion rate was titrated in the range of 0.2 μg/kg/hr to 0.7 μg/kg/hr as necessary to maintain a RSS score of ≥3 before extubation, ≥2 after extubation

H: started at 0.15 μg/kg/ hr and adjusted by 0.15 μg/ kg/ hr to a maximum of 1.5 μg/kg/hr

I: Loading dose of 0.4 μg/kg, followed by a

maintenance drip of 0.2–0.7 μg/kg/hr

J: Loading dose at 1 μg/kg over 10 min, followed by a maintenance dose of 0.2–2.5 μg/kg per hr into a peripheral or central vein over a 24-hr infusion

K: Started at 1 ml/hr (0.15 μg/kg per hr) and titrated to a maximum of 10 ml/hr (1.5 μg/kg/hr)

L: Optional blinded loading doses (up to 1 μg/kg) administered at the

investigator’s discretion. The starting maintenance

infusion dose of the blinded study drug was 0.8 μg/kg/ hr per hr or responding to the mid-point of the allowable infusion dose range of 4mg in 8 hrs

M: Infused without a loading dose at 0.8 μg/kg/hr for 1 hr and then adjusted stepwise at 0.25, 0.5, 0.8, 1.1 and 1.4 μg/kg/hr

N: Loading dose of injection with 1 μg/kg over

10 min, followed by a maintenance infusion

of 0.2–0.7 μg/kg/hr. The rate of the maintenance infusion was adjusted to achieve the desired level of sedation.

O: Infusion at a starting dose of 1 μg/kg/hr without a loading dose. Bolus administration of

dexmedetomidine was strictly prohibited. If required, sedation could be supplemented with propofol. Dexmedetomidine

infusion was administered between a minimum of 0 μg/kg/hr and maximum of 1.5 μg/kg/ hr specified by the treating clinician and titrated to achieve the desired level of sedation

P: Loading dose of 0.7 μg/kg over a period of

10 min followed by maintenance of 0.2 μg/kg/ hr, with dosage increments titrated up to 0.7 μg/kg/hr

Q: Loading dose at 1 μg/kg over 10 min, followed by a maintenance 0.2 to 2.5 μg/kg per hr into a peripheral or central vein over a

24-hr infusion

R: Loading dose at 2.5 μg/kg/hr over 10 min, followed by a maintenance infusion of 0.2–2.5 μg/kg/hr into a peripheral or central vein

Describe control:

A: propofol: i.v. infusion (10 mg/ml) starting with a dose of 1 mg/kg/hr (0.1 ml/ hr) and increasing up to 2 mg/kg/hr

B: propofol: 5 μg/kg/minute i.v. infusion titrated within the range of 0.2–0.7 μg/ kg /hr or 5–75 μg/kg/minute

C: Propofol: undiluted as a bolus dose of 1 mg/kg

initially, followed by an infusion of 0.5–1 mg/kg/ hr, with the dosage adjusted to achieve the desired level of sedation varying the dose by 10% increase or decrease in infusion rate in order to maintain the level of sedation within the range previously considered adequate

E: Propofol: no dose or rate of propofol was

specified by the protocol. Investigators were told

to follow their usual practice with regard to propofol-based sedation

F: Midazolam: six dose levels of each study drug

covered the full dose range (dexmedetomidine, 0.2–1.4 μg/kg per hr; midazolam, 0.03–0.2 mg/kg/hr). Study treatments were infused without loading dose at a dose matching the pre-randomisation dose of midazolam for 1 hr. Thereafter, study drugs were titrated stepwise to maintain the target RASS score

G: Propofol: six dose levels of each study drug covered the full dose range (dexmedetomidine 0.2–1.4 μg/kg/hour; propofol

0.3–4.0 mg/kg/hour). Study treatments were infused without loading dose at a dose matching the prerandomisation dose of

propofol for 1 hour. Thereafter, study drugs

were titrated by the patient’s nurse stepwise to

maintain the target RASS score.

H: Midazolam: midazolam was started at 1 mg/hr

and adjusted by 1 mg/hr to a maximum of 10 mg/hr. All infusions were adjusted by

increments of 2 ml/hr to maintain blinding

I-1: Propofol: propofol drip (25 μg/kg/minute–50 μg/ kg/minute)

I-2: Midazolam: midazolam drip (0.5 mg/hr–2 mg/hr)

J: Propofol: loading dose of 1 mg/kg over 15 min, followed by a maintenance dose of 1–3 mg/kg per hr over a 24-hr infusion

K: Lorazepam: started at 1 ml/hr (1 mg/hr lorazepam) and titrated to a maximum of 10ml/hr (10mg/hr lorazepam)

L: Midazolam: optional blinded loading doses

(0.05 mg/kg ) administered at the investigator’s discretion. The starting

maintenance infusion dose of blinded study drug was 0.06 mg/kg/hr,

corresponding to the mid-point of the allowable

infusion dose range of 4 mg in 8 hrs

M-1: Propofol: infused at 2.4 mg/kg/hr for 1 hr and then adjusted stepwise at 0.8, 1.6, 2.4, 3.2 and 4.0 mg/kg/hr

M-2: Midazolam: depending on standard care at time

of randomisation, given either as i.v. boluses (1–2 mg), starting at three boluses per hr for 1 hr, and thereafter one to four

boluses per hr and, if not sufficient, as continuous infusion of 0.2 mg/kg/hr, or as a continuous infusion at 0.12 mg/kg/hr for

1 hr, followed by adjustments at 0.04, 0.08,

0.12, 0.16 and 0.20 mg/kg/hr. The initial dose

could be reduced, if considered necessary by the

treating clinician

N: Propofol: started at 5 μg/kg/minute (0.3 mg/kg/hr). The infusion rate was increased by increments of 5–10 μg/kg/minute (0.3–0.6 mg/kg/hr) until the desired level of sedation was achieved. A minimum period of 5 min between adjustments was allowed for the onset of peak drug effect

O: Standard care=Midazolam and/or propofol or other agents deemed necessary

but not dexmedetomidine. Clonidine and remifentanil could not be administered. Selected agents could be given by infusion or boluses and titrated, including cessation when necessary, to achieve the default light sedation or level of sedation deemed clinically appropriate and specified by treating clinician

P: Clonidine: i.v. infusion of clonidine 1 μg/kg/hr and titration was achieved with dosage increments up to 2 μg/kg/hr

Q: Propofol: loading dose of 1 mg/kg over 15 min, followed by a maintenance of 1 mg/kg to 3 mg/kg per hr over a 24-hr infusion

R: Propofol: undiluted as an infusion of 1–3 mg/kg/hr after a loading dose infusion of up to 1 mg/kg over 10 min, if required

End-point of follow-up:

A: 6 hrs

B: at least 24 hrs after

extubation

C: NR

E: 24 hours after

discharge from ICU

F: 45 days

G: 45 days

H: at least 72 hours after

extubation or tracheostomy but before hospital discharge

I: 3 days post-operatively

J: NR

K: until discharge from

hospital or death, and survivors were observed for vital status until one year after

enrolment

L: 48 hours after

cessation of study drug

M: 45 days

N: 24 hrs

O: 90 days after randomisation

P: 24 hours

Q: NR

R: 48–72 hours after

discharge from ICU

For how many participants were no complete outcome data available?

(intervention/control)

A: 0

B: unclear how many randomised, reported number is number analysed

C: NR

E: unclear how many randomised, reported number is number analysed

F: 1 in control group

G: 2 in control group

H: 0

I: 10 in intervention group, 8 in control-1 group and 10 in control-2 group, reasons not mentioned in SR.

J: 0

K: 2 in intervention group, 1 in control group

L: 6 in intervention group, 3 in control group

M: 0

N: 0

O: 0

P: 0

Q: 0

R: NR

Outcome measure-1: mortality (setting and period not specified)

Effect measure: RR (95% CI):

F: 1.29 (0.95 to 1.77)

G: 0.88 (0.61 to 1.28)

H: 2.18 (0.23 to 20.84)

J: 0.75 (0.19 to 2.93)

K: 0.63 (0.30 to 1.33)

L: 0.89 (0.60 to 1.30)

M:1.53 (0.64 to 3.65)

O: 1.90 (0.42 to 8.58)

Q: 0.50 (0.05 to 5.08)

Pooled effect (random effects model): 1.03 (95% CI 0.85 to 1.24) favoring control

Heterogeneity (I²): 0%

Outcome measure-2: duration of mechanical ventilation

Effect measure: MD (95% CI):

F: – 0.88 (– 2.65 to 0.88)

G: 0.12 (– 1.58 to 1.82)

M: – 2.36 (– 4.62 to – 0.10)#

Q: 1.00 (0.19 to 1.81)#

#Transformed/input data (for median/IQR)

Pooled effect (random effects model): – 0.30 (95% CI (– 1.70 to 1.11) favoring dexmedetomidine

Heterogeneity (I²): 70%

Outcome measure-3: ICU length of stay

Effect measure: MD (95% CI):

F: – 1.33 (– 2.45 to – 0.21)#

G: – 0.88 (– 2.00 to 0.25)#

J: 2.00 (– 3.12 to 7.12)

K: – 1.50 (– 3.97 to 0.97)#

L: – 1.70 (– 3.09 to – 0.31)#

M: – 1.00 (– 3.44 to 1.44)#

Q: 0.30 (– 1.42 to 2.02)#

#Transformed/input data (for median/IQR)

Pooled effect (random effects model): – 1.02 (95% CI (– 1.62 to – 042) favoring dexmedetomidine

Heterogeneity (I²): 0%

Outcome measure-4: Incidence of delirium

Effect measure: RR (95% CI):

F: 0.50 (0.26 to 0.98)

G: 0.77 (0.44 to 1.36)

H: 0.55 (0.23 to 1.31)

K: 0.96 (0.79 to 1.16)

L: 0.71 (0.61 to 0.83)

M: 1.76 (0.95 to 3.26)

O: 1.02 (0.44 to 2.34)

Pooled effect (random effects model): 0.83 (95% CI 0.65 to 1.06) favoring dexmedetomidine

Heterogeneity (I²): 60%

Outcome measure-5: Incidence of hypotension

Effect measure: RR (95% CI):

F: 1.78 (1.17 to 2.71)

G: 0.97 (0.62 to 1.53)

H: 1.82 (1.00 to 3.30)

L: 1.01 (0.83 to 1.22)

M: 2.15 (0.20 to 22.79)

Pooled effect (random effects model): 1.28 (95% CI 0.93 to 1.75) favoring control

Heterogeneity (I²): 55%

Outcome measure-5: Incidence of hypertension

Effect measure: RR (95% CI):

F: 1.03 (0.73 to 1.45)

G: 1.41 (0.96 to 2.07)

L: 0.98 (0.77 to 1.25)

Pooled effect (random effects model): 1.09 (95% CI 0.89 to 1.33) favoring control

Heterogeneity (I²): 21%

Outcome measure-6: Incidence of bradycardia

Effect measure: RR (95% CI):

F: 2.73 (1.48 to 5.02)

G: 1.29 (0.79 to 2.10)

H: 1.09 (0.57 to 2.10)

K: 4.41 (1.00 to 19.44)

L: 2.24 (1.51 to 3.33)

M: 7.50 (0.40 to 140.91)

Pooled effect (random effects model): 1.88 (95% CI 1.28 to 2.77) favoring control

Heterogeneity (I²): 46%

Outcome measure-7: Incidence of tachycardia

Effect measure: RR (95% CI):

F: 0.64 (0.43 to 0.94)

G: 1.72 (1.12 to 2.65)

H: 1.53 (0.68 to 3.42)

K: 0.95 (0.74 to 1.22)

L: 0.57 (0.43 to 0.77)

Pooled effect (random effects model): 0.93 (95% CI 0.63 to 1.39) favoring dexmedetomidine

Heterogeneity (I²): 82%

Brief description of author’s conclusion:

There is an indication that dexmedetomidine may have a better cardiovascular safety profile than clonidine,

but evidence is limited. Length of stay in ICUs and time to extubation were significantly shorter among

patients who received dexmedetomidine than among those who received other sedative agents other than clonidine. No difference was observed in time in target sedation range between dexmedetomidine and

alternative sedative interventions. Incidence of bradycardia was significantly higher for dexmedetomidine, but did not impact on mortality.

There was no clear evidence that dexmedetomidine was superior to other sedative agents in reducing the

risk of delirium. Considerable clinical heterogeneity between trials was observed, and the overall risk of

bias was high or unclear.

In original data also:

• Length of infusion of study drug
• Target sedation level
• Rescue medication
• Pain control
• Daily interruption

(not reported in this evidence table)

Study

First author, year

Appropriate and clearly focused question?¹

Yes/no/unclear

Comprehensive and systematic literature search?²

Yes/no/unclear

Description of included and excluded studies?³

Yes/no/unclear

Description of relevant characteristics of included studies?⁴

Yes/no/unclear

Appropriate adjustment for potential confounders in observational studies?⁵

Yes/no/unclear/notapplicable

Assessment of scientific quality of included studies?⁶

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?⁷

Yes/no/unclear

Potential risk of publication bias taken into account?⁸

Yes/no/unclear

Potential conflicts of interest reported?⁹

Yes/no/unclear

Cruickshank, 2016

Yes

Yes

Yes

Yes

NA

Yes

Yes

No

Yes

One author of the review received financial support of manufacturer of dexmed

nine trials declared financial support by manufacturers of sedative

agents and were, therefore, judged to be at high risk of bias by the SR