Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Tan, 2009

SR and meta-analysis of RCTs

Literature search up to August 2009

A: Baillard, 2005

B: Dahaba, 2004

C: Breen, 2005

D: Muellejans, 2006

E: Muellejans, 2004

Study design:

A: RCT

B: RCT

C: RCT

D: RCT

E: RCT

Setting and Country:

A: France

B: Austria

C: 15 sites in 10 countries (UK + others).

D: Germany

E: 21 sites in 5 countries.

Source of funding and conflicts of interest:

A n.r.

B: GlaxoSmithKline

C: GlaxoSmithKline

D: GlaxoSmithKline

E: GlaxoSmithKline

GlaxoSmithKline was the manufacturer of remifentayl.

The study was solely funded by Department of Intensive

Care Medicine, Royal Perth Hospital. The funding

source had no role in the collection, analysis, and

interpretation of the data or in the decision to submit

the manuscript for publication.

Inclusion criteria SR:

Only randomised controlled trials comparing remifentanil

with another opioid (sufentanil, alfentanil, fentanyl or

morphine) or hypnotic or sedative agent (propofol or

midazolam) in critically ill adult (> 18 years old) patients

were included.

Exclusion criteria SR:

n.r.

11 studies included

Important patient characteristics at baseline:

N, mean age

A 41 patients, 58-59 yrs

B: 40 patients, 54-58 yrs

C: 105 patients, 52-57 yrs
D: 80 patients, 65-67 yrs
E: 152 patients, 59-62 yrs

Sex:

A: n.r. in review

B: 60% Men

C: 67.6% Men

D: 73.6% Men

E: 70.4% Men

Groups comparable at baseline?

Yes

A: Remifentanil group (n = 21): 10 lg.kg) 1.h )1 and titrated.

B: Remifentanil group (n = 20): 9–12 lg.kg)1.h)1

C: Remifentanil group (n = 57): 6–18 ug.kg)1.h)1

D: Remifentanil group (n = 39): 6–60 lg.kg)1.h)1.

E: Remifentanil group (n = 77): 9–12 lg.kg)1.h)1.

A: Sufentanil group (n = 20): 0.125 lg.kg)1.h)1 and titrated
B: Morphine group (n = 20): 0.04–0.06 mg.kg)1.h)1

C: Midazolam ± fentanyl ⁄ morphine group (n = 48):

D: Midazolam with fentanyl group (n = 33): midazolam: 0.02– 0.04 mg.kg)1.h)1, fentanyl: 1–2 lg.kg)1.h)1

E: Fentanyl group (n = 75):

1–2 lg.kg)1.h)1

Endpoint of follow-up:

A: n.r. in review

B: until IC discharge

C: post-treatment or 10 days after administration, or death.

D: after drug administration

E: 24 hours after discontinuation of study drug

For how many participants were no complete outcome data available?

(intervention/control)

A: n.r. in review

B: 0/0

C: 0/0

D: 1/7

E: 0/0

ICU length of stay

Defined as the number of days spent at the ICU.

Effect measure: , mean difference [95% CI]:

A: 0.29 [-0.10 – 0.68]

B: -0.88 [-1.05 - -0.71]

C: -0.90 [-8.30 – 6.50]

D: 0.05 [-0.51 – 061]

E: -0.64 [-1.12 [-0.16]

Pooled effect (random effects model):

-0.32 [95% CI -0.94 to 0.30] favoring remifentanil

Heterogeneity (I²): 89%

Mortality

Effect measure: risk ratio [95% CI]:

A: 0.95 [0.60 – 152]

B: not estimatable 0/0 cases

C: 1.18 [0.40 – 3.48]

D: n.r.

E: n.r.

Pooled effect (random effects model):

0.98 [95% CI 0.64 to 1.51] favoring remifentanil

Heterogeneity (I²): 0%

Hemodynamic adverse events

Defined as the incidence of hypotension.

Effect measure: risk ratio [95% CI]:

A: n.r.

B: 3.00 [0.13 – 69.52]

C: 0.63 [0.15 – 2.68]

D: 1.11 [0.45 – 2.73]

E: 683 [0.36 – 128.02]

Pooled effect (random effects model):

1.24 [95% CI 0.62 to 2.47] favoring remifentanil

Heterogeneity (I²): 0%

Delirium

Effect measure: risk ratio [95% CI]:

A: n.r.
B: n.r.
C: n.r.
D: 0.76 [031 – 1.84]
E: n.r.

Pooled effect (random effects model):

0.76 [95% CI 0.31 to 1.84] favoring remifentanil

Heterogeneity (I²): N.A.

Duration of mechanical ventilation

Defined as the number of days on mechanical ventilation.

Effect measure: mean difference [95% CI]:

A: n.r.
B: -0.16 [-6.30 – 5.98]
C: -2.23 [-4.11 - -0.35]
D: n.r.
E: -0.15 [-0.26 - -0.04]

Pooled effect (random effects model):

-0.84 [95% CI -2.47 to 0.78] favoring remifentanil

Heterogeneity (I²): 57%

Selfextubations

Effect measure: risk ratio [95% CI]:

A: n.r.
B: n.r.
C: n.r.
D: n.r.
E: n.r.

Author’s conclusion

In conclusion, the current evidence does not support

the routine use of remifentanil as a sedative agent in

critically ill adult patients. A large randomised controlled

trial, including daily interruption of sedative drug

administration, is needed to assess whether remifentanil

with or without another short acting hypnotic agent is

cost effective in critically ill adult patients with multiple

organ failure.

Sources of funding:
A n.r. in review
B: funded by the manufacturer of remifentanil
C: funded by the manufacturer of remifentanil
D: funded by the manufacturer of remifentanil
E: funded by the manufacturer of remifentanil

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Liu, 2017

Type of study:

prospective randomized controlled

trial.

Setting and country:

Single centre, Peking.

Funding and conflicts of interest:

The authors have declared

that no competing interests exist.

Inclusion criteria:

(1) signing a consent form by the patients' legal

authorized principal; (2) admission to the surgical ICU; (3) requirement for mechanical ventilation

with the time of mechanical ventilation anticipated to be greater than 24 hours; (4)

requirement for midazolam sedation; and (5) age greater than 18 and less than 85 years.

Exclusion criteria:

1) intracranial lesions, neurosurgical

intervention, mental disabilities or coma such that they were unable to cooperate; (2)

alcohol abuse; (3) history of delirium or antipsychotic use at home described according to the

medical history or family members; (4) allergy to the investigational drug or other contraindications;

or (5) women who were pregnant or lactating.

N total at baseline:

Intervention: 35

Control: 35

Important prognostic factors²:

For example

age (SD)

I: 66.1 (11.9)

C: 62 (10.0)

Sex:

I: 60.0% M

C: 48.6% M

Groups comparable at baseline?

Yes

Remifentanil 1μg/kg/hr and midazolam. Midazolam was administered with a loading dose of 0.05 mg/kg followed

by 0.02±0.1 mg/kg/hr. The treatment administered until patients were weaned from the ventilator.

Fentanyl 1μg/

kg/hr and midazolam. Midazolam was administered with a loading dose of 0.05 mg/kg followed by 0.02±0.1 mg/kg/hr. The treatment administered until patients were weaned from the ventilator.

Length of follow-up:

Till die or the 28^th day from admission to the ICU.

Loss-to-follow-up:

Intervention: 0 (0%)

Control: 0 (0%)

Incomplete outcome data:

Intervention: 0 (0%)

Control: 0 (0%)

ICU length of stay

Defined as the number of days spent on the ICU

Effect measure: mean difference [95% CI]:

1.00 [-1.35 – 3.35] favoring remifentanil.

Mortality

Effect measure: risk ratio [95% CI]:

1.00 [0.85 – 1.18] favoring long-acting opioids.

Hemodynamic adverse events

Defined as the incidence of hypotension.

n.r.

Delirium

Effect measure: risk ratio [95% CI]:

1.29 [1.04 – 1.37] favoring remifentanil.

Duration of mechanical ventilation

Defined as the number of days on mechanical ventilation.

Effect measure: mean difference [95% CI]:

1.00 [-0.33 – 2.33] favoring remifentanil.

Selfextubations

Effect measure: risk ratio [95% CI]:

n.r.

Author’s conclusion

Patients who received benzodiazepines have a relatively greater risk of delirium; analgesics can

reduce the amount of sedatives required and can further reduce the occurrence of delirium

and improve the prognosis. Remifentanil may have an advantage over fentanyl in reducing delirium.

Spies, 2011

Type of study:

a registered clinical trial

Setting and Country: 2-Center, Germany.

Funding and conflicts of interest:

This study was

fully supported by GlaxoSmithKline GmbH & Co (manufacturer of remifentanil)

Inclusion criteria:

All patients requiring intensive care therapy were

considered for enrolment. Additional inclusion criteria

were expected ventilation for more than 24 h, ventilation

for less than 48 h at the time of enrolment, age 18 years

or older, and written informed consent.

Exclusion criteria:

included known allergy to any of the study medications;

pregnancy; World Health Organization chronic pain grade

3 or above, i.e., regular use of potent opioids such as

morphine, recent opioid analgesia via a spinal catheter,

epidural or any other regional technique; American

Society of Anesthesiologists (ASA) classification 5

patients (moribund); participation in a clinical study

within the previous 30 days; and neurotrauma or organic

brain pathology.

N total at baseline:

Intervention: 28

Control: 32

Important prognostic factors²:

age (SD):

I: 64 (15)

C: 63 (12)

Sex:

I: 71.4% M

C: 84.4% M

Groups comparable at baseline?

Yes

Remifentanil was infused at 0.1–0.4 lg/kg ideal body

weight/min. The intravenous infusion of both study agents was titrated up to the analgesia target.

The study protocol did not allow any bolus application

of either fentanyl or remifentanil. If the patient was awake,

we used the VAS and if the patient was sedated we used

the BPS. The target scores were a VAS B3 and/or a BPS

B6 at rest. Sedation was delivered by using propofol (to a

maximum of 4 mg/kg ideal body weight/h), and midazolam

(0.01–0.18 mg/kg ideal body weight/h) could be

added if required. Sedation was titrated according to the

Richmond Agitation Sedation Scale (RASS). The target

RASS was 0 to -1. There were a few exceptions where

deeper sedation (up to RASS of -4) was allowed (e.g.,

patients requiring prone positioning). Unless contraindicated,

all patients could receive the following adjuvant

analgesics: metamizole (1 g four times daily enterally or

intravenously), and/or paracetamol (1 g four times daily

enterally or intravenously), and/or clonidine (0.32–1.3 lg/

kg/h intravenously).

Patients in the remifentanil group

received a morphine bolus (0.1 mg/kg) 30 min before

ending the study medication.

Rescue pain therapy with

morphine boli was allowed at all time points for all

patients. Delirium diagnosis was performed by using the

Confusion Assessment Method for the ICU (CAM-ICU) in

all patients with a RASS[-3]

Fentanyl was infused at

0.02–0.08 lg/kg ideal body

weight/min. The intravenous infusion of both study agents

was titrated up to the analgesia target.

The study protocol did not allow any bolus application

of either fentanyl or remifentanil. If the patient was awake,

we used the VAS and if the patient was sedated we used

the BPS. The target scores were a VAS B3 and/or a BPS

B6 at rest. Sedation was delivered by using propofol (to a

maximum of 4 mg/kg ideal body weight/h), and midazolam

(0.01–0.18 mg/kg ideal body weight/h) could be

added if required. Sedation was titrated according to the

Richmond Agitation Sedation Scale (RASS). The target

RASS was 0 to -1. There were a few exceptions where

deeper sedation (up to RASS of -4) was allowed (e.g.,

patients requiring prone positioning). Unless contraindicated,

all patients could receive the following adjuvant

analgesics: metamizole (1 g four times daily enterally or

intravenously), and/or paracetamol (1 g four times daily

enterally or intravenously), and/or clonidine (0.32–1.3 lg/

kg/h intravenously).

Patients in the fentanyl group

received a placebo bolus instead of morphine 30 minutes before ending the study medication.

Rescue pain therapy with

morphine boli was allowed at all time points for all

patients. Delirium diagnosis was performed by using the

Confusion Assessment Method for the ICU (CAM-ICU) in

all patients with a RASS[-3]

Length of follow-up:

30 after the start of the study drug.

Loss-to-follow-up:

0%

Incomplete outcome data:

n.r.

ICU length of stay

Defined as the number of days spent on the ICU

Effect measure: mean difference [95% CI]:

n.r.

Mortality

Effect measure: risk ratio [95% CI]:

n.r.

Hemodynamic adverse events

Defined as the incidence of hypotension.

n.r.

Delirium

Effect measure: risk ratio [95% CI]:

1.26 [1.04 – 1.54] favoring remifentanil

Duration of mechanical ventilation

Defined as the number of days on mechanical ventilation.

Effect measure: mean difference [95% CI]:

n.r.

Selfextubations

Effect measure: risk ratio [95% CI]:

n.r.

Author’s conclusion

The use of a remifentanil-based analgesia regime in

critically ill patients was not superior regarding the

achievement and maintenance of sufficient analgesia

compared with a fentanyl-based analgesia.

Limitation

In the remifentanil group there were 16 violations

to the protocol versus 11 in the fentanyl group

(p = 0.34).

Cevik, 2011

Type of study:

prospective, randomized, open-label, and controlled trial

Setting and Country: Turkey

Funding and conflicts of interest:

n.r.

Inclusion criteria:

Age ≥ 18; patient requiring mechanical

ventilation and sedation.

Exclusion criteria:

Age ≤ 18; patients who have neuromuscular

disease; patients who are receiving neuromuscular

blockers; patients with a known or suspected allergy or

intolerance to midazolam, fentanyl, or remifentanil; patients

who die during the study period; patients who use toxic

substances; alcoholic patients; patients suspected of being

pregnant; patients who are moribund, that is, who are

classified as ASA grade V according to the American Society

of Anesthesiologists (not expected to live > 24 hours).

N total at baseline:

Intervention: 16

Control: 16

Important prognostic factors²:

age (SD):

I: 50.6 (25.2)

C: 51.9 (120.8)

Sex:

I: 43.8% M

C: 62.5% M

Groups comparable at baseline?

Yes

The R group received remifentanil

at an initial dose of 0.05 μg/kg/min and midazolam infusion at an initial dose of 0.03mg/kg/h.

No adjuvant analgesics such as paracetamol or morphine

were administered, and no rescue pain therapy was provided. Bolus doses of remifentanil, fentanyl, or midazolam were not

allowed in the protocol and therefore were not administered.

the F group received

fentanyl at an initial dose of 0.015 μg/kg/min and midazolam infusion at an initial dose of

0.03mg/kg/h.

No adjuvant analgesics such as paracetamol or morphine

were administered, and no rescue pain therapy was provided. Bolus doses of remifentanil, fentanyl, or midazolam were not

allowed in the protocol and therefore were not administered.

Length of follow-up:

n.r.

Loss-to-follow-up:

Intervention: 1/17

Control 1/17

Reason: Died before weaning

Incomplete outcome data:

n.r.

ICU length of stay

Defined as the number of days spent on the ICU

Effect measure: mean difference [95% CI]:

1.18 [ -4.69 – 7.05] favoring remifentanil.

Mortality

Effect measure: risk ratio [95% CI]:

n.r.

Hemodynamic adverse events

Defined as the incidence of hypotension.

1.00 [0.63 – 1.60] favoring remifentanil.

Delirium

Effect measure: risk ratio [95% CI]:

n.r.

Duration of mechanical ventilation

Defined as the number of days on mechanical ventilation.

Effect measure: mean difference [95% CI]:

0.00 [-1.80 – 1.80].

Selfextubations

Effect measure: risk ratio [95% CI]:

n.r.

Author’s conclusion

In conclusion, this study demonstrates that there were a small number of significant differences between remifentanil and

fentanyl statistically with respect to hemodynamic parameters, analgesic and sedative requirements, sedation time, mechanical ventilation time, ICU discharge time, organ dysfunction, or adverse effects. Compared to fentanyl, remifentanil provided significantly more potent and rapid analgesia

based on BPS measurements and a statistically non significantly shorter time to discharge. On the other hand, remifentanil caused a significantly sharper fall in heart rate within the first six hours of treatment. Differences between

groups in terms of BUN and ALT were also recorded.

Although both fentanyl-midazolam and remifentanil-midazolam can safely provide sedation and analgesia, fine

differences between the fentanyl and remifentanil should be considered when selecting a suitable regimen for individual patients.

Tan, 2009

Yes

Yes

Yes

Yes

Not applicable.

No

Yes

Yes

Yes

Study reference

(first author, publication year)

Was the allocation sequence adequately generated? ^a

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?^b

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?^c

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?^d

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?^e

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?^f

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Liu, 2017

Definitely yes;

Reason: Different treatments were offered to patients in identical vials and boxes. Each box was also labelled with a numerical code, unique to treatment allocation and again blinded from both the investigator and study participant, as an additional measure to allow review of the correct

treatment allocation by the study nurse.

Definitely yes;

Reason: Randomization was performed by the sealed envelope system, in which the study nurse randomly opened a preformed envelope containing the allocated treatment regimen.

No information;

Reason: No information was provided about the blinding of patients, healthcare providers, data collectors, outcome assessors and data analysts (except from the study nurses).

Definitely yes;

Reason: Missing data / loss to follow-up was infrequent (n=0)

Definitely yes;

Reason: All predefined outcome measures were reported.

Definitely yes;

Reason: No other problems reported.

LOW

Spies, 2011

Definitely yes;

Reason: Patients who met enrolment criteria were randomly allocated in a 1:1 ratio to the fentanyl or remifentanil group.

The randomization list was created by using computer based block randomization by a biostatistician with no

patient contact.

Definitely yes;

Reason: Allocation concealment was ensured by

pharmacy-controlled randomization: on the basis of the randomization list, the pharmacies in the respective centres

distributed patient-specific syringe pumps and bolus syringes (morphine in the remifentanil group and saline in the fentanyl group) that were identical in size, weight, and

appearance.

Definitely yes;

Reason: All study investigators, staff members, and patients were blinded to the study medication

Probably yes;

Reason: Loss to follow-up was infrequent (five patients were excluded)

Definitely yes;

Reason: All predefined outcome measures were reported.

Probably no;

Reason: The trial was

stopped early due to futility.

Even though median RASS values as well as median duration of

propofol infusion did not differ significantly between groups

we cannot exclude that ‘‘oversedation’’ might have masked a

possible outcome benefit.

LOW

Cevik, 2011

No information;

Reason: No information was provided about the generation of the allocation sequence.

No information;

Reason: No information was proved about the allocation concealment.

No information;

Reason: No information was provided about the blinding of patients, healthcare providers, data collectors, outcome assessors and data analysts.

Probably yes:

Reason: Two

patients (one patient in the fentanyl/midazolam group and one patient in the remifentanil/midazolam group) had to be

excluded because they died before weaning during the study.

Definitely yes;

Reason: All relevant outcomes were reported.

Definitely yes;

Reason: No other problems reported.

Some concerns