Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Yavagal, 2000

Type of study:

RCT

Setting and country:

ICU of a university hospital in India

Funding and conflicts of interest:

Not reported

Inclusion criteria:

nasogastric tube for >24 hrs

Exclusion criteria:

pneumonia or who had a nasogastric tube placed before ICU admission

N total at baseline:

Intervention: 131

Control: 174

Important prognostic factors²:

For example

age ± SD:

I: 38.1 (17.4)

C: 34.8 (15.2)

Sex:

I: 79/131 M

C: 110/174 M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Metoclopramide 10 mg

NG q8h;

Describe control (treatment/procedure/test):

Placebo

Length of follow-up:

Until death, ICU discharge or ng tube removal or development of nosocomial pneumonia

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Nosocomial pneumonia

I: 22/131

C: 24/174

Mortality

I: 56%

C: 53%

Author’s conclusion

Metoclopramide in the

dose of 10 mg every 8 hrs did not reduce the risk of nosocomial pneumonia in ICU

patients receiving nasogastric tube feeds.

Although it delayed the onset of pneumonia by 1.5 days, this is of little clinical

significance because it did not have any effect on the mortality rate or the length of

ICU stay.

Makkar, 2016

Type of study:

RCT

Setting and country:

India

Funding and conflicts of interest:

None

Inclusion criteria:

TBI patients with Glasgow coma score (GCS) of more than 5 admitted to trauma intensive care within 72 h of injury

Exclusion criteria:

blunt trauma abdomen, severe thoracic injury with associated hemothorax, allergy to macrolide

or metoclopramide, abnormal liver function, and renal

dysfunction

N total at baseline:

Intervention 1: 39

I2: 38

Control: 38

Important prognostic factors²:

For example

age ± SD:

I1: 37.26±16.2

I2: 34.92±13.6

C: 39.03±14.5

Sex:

I1: 34/39 M

I2: 33/38 M

C: 32/38 M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

1) Metoclopramide 10 mg

2) Erythromycin 250 mg

Every 8 hours for 5 days through NG tube

Describe control (treatment/procedure/test):

Placebo

Every 8 hours for 5 days through NG tube

Length of follow-up:

5 days

Loss-to-follow-up:

I1:

N=2 (5%)

Reasons: protocol deviation

I2:

N= 3 (7.3%)

Reasons: protocol deviation

Control:

N=2 (4.9%)

Reasons: protocol deviation

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality

I1: 6/39

I2: 4/38

C: 3/38

Target calories met mean%, SD

I1: 83.16 ± 16.25

I2: 90.13 ± 15.88

C: 80.42 ± 19.78

Author’s conclusion

The incidence of high GAV in TBI patients was

60.5%, and there was a significant decrease in the incidence

of high GRV with the use of erythromycin when compared

to metoclopramide and placebo. The combination

of erythromycin and metoclopramide was associated with acceptance of greater percentage of target calories in the control group

Reignier, 2002

Type of study:

RCT

Setting and country:

France

Funding and conflicts of interest:

Not reported

Inclusion criteria:

require

mechanical ventilation and early nutritional support for >5

days

Exclusion criteria:

treatment with erythromycin within 48 hrs

before ICU admission; pregnancy; diabetes mellitus; current acute pancreatitis, bleeding from the stomach or esophageal varices;

facial trauma; a history of esophageal or

gastric surgery; intolerance or sensitivity to

erythromycin; or a need for droperidol, a

tricyclic antidepressant, cisapride, atropine,

or metoclopramide

N total at baseline:

Intervention: 25

Control:23

Important prognostic factors²:

For example

age ± SD:

I: 70 ± 2

C: 66 ± 3

Sex:

I: 9/20 M

C: 11/20 M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Erythromycin 250 mg in 50 mL of 5% dextrose (i.v.) given at 6-hr intervals for 5

days

Describe control (treatment/procedure/test):

Placebo

Length of follow-up:

5 days

Loss-to-follow-up:

Intervention:

N=5 (20%)

Reasons: no MV for >5 days

Control:

N=3 (13%)

Reasons: no MV for >5 days

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality

I: 30%

C: 40%

Vomiting

I: 0/20

C: 3/20

Pneumonia

I: 3/20

C: 3/20

Feeding intolerance

(defined as: 6-hr GRV > 250 mL or if the patient vomited)

I: 7/20

C: 14/20

Author’s conclusion

In critically ill patients receiving invasive mechanical ventilation, erythromycin promotes gastric emptying and improves the chances of successful early enteral nutrition.

Nursal 2007

Type of study:

RCT

Setting and country:

Turkey

Funding and conflicts of interest:

Not reported

Inclusion criteria:

sustained TBI and had been admitted to the hospital within 48 hours with an initial Glasgow Coma

Scale score of 3–11

Exclusion criteria:

additional

abdominal and pelvic injuries, severe thoracic injuries with hemo/pneumothorax who required chest-tube drainage or surgery

N total at baseline:

Intervention: 10

Control:10

Important prognostic factors²:

For example

age ± SD:

I: 43.8 (24.5)

C: 43.0 (18.5)

Sex:

I: 8/10 M

C: 8/9 M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Metoclopramide 10 mg iv, 3x daily for 5 days

Describe control (treatment/procedure/test):

Saline

Length of follow-up:

5 days

Loss-to-follow-up:

Intervention:

N=0

Control:

N=1 (10%)

Reasons: protocol violation

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality

I: 3/10

C:3/9

Vomiting

I: 1/10

C:2/9

Diarrhea

I: 1/10

C: 1/9

Feeding intolerance

(defined as abdominal distension, vomiting, or diarrhea resulting in a decreased feeding infusion

rate or cessation of infusion)

I: 4/10

C: 2/9

Length of hospital stay (days) mean (SD)

I: 15.6 (11.1)

C: 16.8 (8.5)

Author’s conclusion

We do not suggest use of metoclopramide as an aid to

enteral nutrition in TBI patients. Simple intragastric enteral feeding, with close monitoring for possible complications, seems to be sufficient, with acceptable morbidity rates

Berne 2002

Type of study:

RCT

Setting and country:

USA

Funding and conflicts of interest:

Not reported

Inclusion criteria:

critically injured

patients who received intragastric tube feedings within 72 hours of admission and failure to  tolerate feedings at any time during the first 48 hours, as determined by a GRV > 150 mL

Exclusion criteria:

age < 17 years;

pregnancy; contraindication to use of erythromycin,

specifically, concomitant use of drugs known to interact with

erythromycin (warfarin, cyclosporine, theophylline, carbamazepine, or digoxin); known allergic reaction to erythromycin or macrolide antibiotics;  use of a prokinetic agent within the prior 2 weeks; or  evidence of severe liver

dysfunction

N total at baseline:

Intervention: 32

Control:36

Important prognostic factors²:

age:

I: 40.0

C: 34.1

Sex:

I: 21/32 M

C: 23/36 M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

250 mg erythromycin iv every 6 hours

Describe control (treatment/procedure/test):

Placebo

Length of follow-up:

48 hours (% total nutrition goal, feeding intolerance)

Until discharge/death (VAP, mortality, hospital days)

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality

I: 2/32

C: 2/36

% total nutrition goal met

I: 65

C: 59

Hospital days

I: 25.5

C: 22.2

VAP

I: 13/32

C: 18/36

Feeding intolerance (defined as GRV > 150 mL)

I: 13/32   

C: 20/36

Author’s conclusion

Intravenous erythromycin reduces delayed gastric emptying in critically ill trauma patients during the first 48 hours. The use of eythromycin in trauma patients does not affect the rate of nosocomial infection.

Nassaji 2010

Type of study:

RCT

Setting and country:

Surgical ICU in Islamic Republic of Iran

Funding and conflicts of interest:

Not reported

Inclusion criteria:

Admitted to the ICU and required nasogastric tube feeding for more than 24 hours

Exclusion criteria:

Those s who already had pneumonia,

had received a nasogastric tube before ICU admission or who were discharged or died within 48 hours after admission

N total at baseline:

Intervention: 68

Control: 152

Important prognostic factors²:

age ± SD:

I: s 41.5 (23.9)

C: 46.4 (24.8)

Sex:

I: 49/68 M

C: 95/152 M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

metoclopramide 10 mg every 8 hours through NG tube (max. 5 days)

Describe control (treatment/procedure/test):

No metoclopramide

Length of follow-up:

Until ICU discharge or death

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Pneumonia

I: 23/68

C: 51/152

Mortality

I: 23/68

C: 51/152

Hospitalization, mean

I: 9.0

C: 10.5

Author’s conclusion

oral metoclopramide

in the dose used in this study (10 mg every 8 hours) did not reduce the risk

of developing NP in ICU patients with

nasogastric feeding.

Vijayaraghavan 2021

Type of study:

RCT

Setting and country:

Critically ill cirrhotic

patients in a liver ICU in India

Funding and conflicts of interest:

Not reported

Inclusion criteria

Patients of chronic liver disease and of age ≥ 18 and ≤ 70 years who were admitted in ICU, patients with cirrhosis, with decompensation, and with acute on chronic liver failure (ACLF), as defined by Asia Pacific association for the study of the liver (APASL) definition were enrolled

Exclusion criteria

Patients who were requiring dual vasopressor, on high vasopressors (> 0.64 mcg/kg/min), uncontrolled sepsis, DIC, and patients with GI bleed at the time of development of feed intolerance, have current or past history of surgical abdomen, including mechanical obstruction, mesenteric ischemia, perforation or requiring abdominal surgery, patients receiving nutrition through gastrostomy or feeding jejunostomy, prior comorbid illnesses like advanced cardiopulmonary disease, prior episodes of arrhythmia, structural heart diseases, traumatic brain injury, cerebrovascular accidents, raised intracranial pressures, history of myasthenia gravis, endocrinological illnesses like uncontrolled hypothyroidism, hypoparathyroidism, previously diagnosed diabetic gastroparesis, connective tissue disorders including systemic sclerosis, dermatomyositis or polymyositis, systemic lupus erythematosus, amyloidosis were excluded. Patients were excluded if they had received prokinetic medication during ICU stay or were allergic to  metoclopramide or erythromycin, pregnant and refusal to give consent.

N total at baseline:

I1: 28

I2: 27

C: 28

Important prognostic factors²:

age ± SD:

I1: 46.4 ± 11.01

I2: 46.3 ± 14.04

C: 45.7 ± 12.3

Sex:

I1: 82% M

I2: 85% M

C: 64% M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

1. metoclopromide 10 mg iv every 8 hours

2. erythromycin 70 mg iv every 12 hours

Describe control (treatment/procedure/test):

Placebo

Length of follow-up:

Until death or ICU discharge (max. 7 days)

Loss-to-follow-up:

I1: 0

I2: 0

C: 0

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality

I1: 12/28

I2: 8/27

C: 16/28

Author’s conclusion

Early detection and the addition of prokinetics facilitate the resolution of feeding intolerance in critically ill cirrhotic patients.

Erythromycin is safe and superior to metoclopramide for early resolution of gut paralysis in critically ill

cirrhotic patients.

Critical note:

Only patients with high (>500 mL) GRV were randomized, which may have been reflected in high mortality rates

Griffith 2003

Type of study:

RCT

Setting and country:

Adult patients requiring enteral tube feeding admitted to the medical or surgical ICUs of Emory University Hospital, USA.

Funding and conflicts of interest:

Not reported

Inclusion criteria

Patients who exhibited one or more of the following indications for postpyloric feeding: evidence of delayed gastric emptying with repeatedly high gastric aspirates; history of pulmonary aspiration of tube feeds or clinical high risk for aspiration; severe acute pulmonary disease; or head elevation not possible (e.g., orthopedic patients)

Exclusion criteria

history of allergy to erythromycin; current administration of prokinetic drugs; current hemodynamic instability, with or without pressor agents; active gastrointestinal bleeding or recently active gastric or esophageal varices; severe thrombocytopenia; gastric outlet or intestinal obstruction; history of gastric surgery; agitation; or requirement for face mask oxygen delivery.

N total at baseline:

I: 14

C: 22

Important prognostic factors²:

age ± SD:

I: 54.6 ± 3.4

C: 59.7 ± 3.8

Sex:

I: 79% M

C: 64% M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

100-mL intravenous infusion of erythromycin mixed in normal saline

Describe control (treatment/procedure/test):

Placebo (100-mL intravenous infusion of normal saline)

Length of follow-up:

Not reported

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Successful postpyloric feeding tube placement:

I: 13/14

C: 12/22

Author’s conclusion

A single bolus dose of intravenous erythromycin facilitates active bedside placement of postpyloric feeding tubes in critically ill adult patients.

Heiselman 1995

Type of study:

RCT

Setting and country:

medical and surgical ICU patients at a community teaching hospital, USA.

Funding and conflicts of interest:

Not reported

Inclusion criteria

1) admission to the critical care unit, (2) the need for enteral nutrition, and (3) an age of at least 18 years

Exclusion criteria

1) upper GI hemorrhage, gastric malignancy, pheochromocytoma, gastroparesis, gastric outlet obstruction, or active GI disease affecting normal upper tract anatomy or motility; 2) surgery for peptic ulcer disease, vagotomy, or surgery affecting normal upper tract anatomy or motility; 3) prescriptions for metoclopramide, MAO inhibitors, tricyclic antidepressants, sympathomimetic amines, terbutaline sulfate, norepinephrine bitartrate, isoproterenol hydrochloride, albuterol, or medications which interact with metoclopramide; and 4) known adverse reactions to metoclopramide

N total at baseline:

I: 59

C: 46

Important prognostic factors²:

No baseline characteristics of included patients described

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

10 mg of metoclopramide IV

Describe control (treatment/procedure/test):

no medication

Length of follow-up:

Not reported

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Successful postpyloric feeding tube placement:

I: 32/59

C: 21/46

Author’s conclusion

Intravenous metoclopramide, 10 mg, administered 10 min prior to intubation with a small-bore feeding tube (10F), was ineffective in facilitating transpyloric intubation.

Critical note:

Baseline characteristics of included patients were not described.

Hu 2015

Type of study:

RCT

Setting and country:

ICUs of seven university hospitals, China

Funding and conflicts of interest:

No conflicts of interest reported, Nutricia provided spiral nasojejunal tubes and supporting this study partly.

Inclusion criteria

patients admitted to the ICU; age ≥18 years; and requiring enteral nutrition for more than 3 days.

Exclusion criteria

history of percutaneous gastrostomy or gastrojejunostomy; intubation intolerance; esophageal varices or strictures; previous major gastroesophageal surgery (for example, esophagectomy or gastrectomy); pregnant; or history of allergy to metoclopramide, domperidone, or meglumine diatrizoate

N total at baseline:

I1: 103

I2: 100

C: 104

Important prognostic factors²:

age ± SD:

I1: 62.1 ± 18.6

I2: 65.2 ± 15.1

C: 61.3 ± 17.4                               

Sex:

I1: 67.0% M

I2: 58.6% M

C: 72.7% M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

1) 20 mg (or 10 mg in cases of renal insufficiency) metoclopramide intravenously

2) 20 mg domperidone ( × 4/day) was administered by the tube

Describe control (treatment/procedure/test):

No intervention

Length of follow-up:

24h

Loss-to-follow-up:

I1: 0

I2: 0

C: 0

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Successful postpyloric feeding tube placement:

I1: 55/100

I2: 51/99

C: 27/99

Author’s conclusion

Prokinetic agents, such as metoclopramide or domperidone, are effective at improving the success rate of post-pyloric placement of spiral nasojejunal tubes in critically ill patients.

 Critical note:

Healthcare providers could not be blinded due to the absence of a placebo with an identical appearance to domperidone suspension, and because of the different dosing regimen of the two drugs

Kalliafas 1996

Type of study:

RCT

Setting and country:

surgical intensive care units of The Ohio State University Hospitals, USA

Funding and conflicts of interest:

Not reported

Inclusion criteria

All patients admitted to the surgical ICU who required enteral nutrition

Exclusion criteria

Pregnant women, minors (less than 18 years old), prisoners, and patients with known allergic reactions to erythromycin

N total at baseline:

I: 31

C: 26

Important prognostic factors²:

Age (range):

I: 54.7 (19-84)

C: 57.3 (19-84)

Sex:

I: 58.1% M

C: 46.2% M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

200 mg erythromycin intravenously

Describe control (treatment/procedure/test):

Placebo

Length of follow-up:

Not reported

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Successful postpyloric feeding tube placement:

I: 19/31

C: 9/26

Author’s conclusion

Overall, erythromycin is effective in facilitating placement of a nasoenteric feeding tube into the duodenum in ICU patients. It is clearly beneficial in those patients with normal

mental status and may be useful in patients with diabetes mellitus.

Paz 1996

Type of study:

RCT

Setting and country:

medical and surgical acute and intermediate critical care services at Hahnemann University Hospital, USA

Funding and conflicts of interest:

Supported in part by a gift from Ross laboratories

Inclusion criteria

requiring enteral nutritional support

Exclusion criteria

unconscious or too ill to provide informed

consent

N total at baseline:

I1: 21

I2: 20

C1: 26

C2: 16

Important prognostic factors²:

age ± SD:

I1: 58.9 ± 18.6

I2: 58.8 ± 21.0

C1: 57.0 ± 17.6

C2: 68.4 ± 15.9

Sex:

I1: 61.9% M

I2: 40% M

C1: 46.2% M

C2: 68.8% M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

1. 200 mg of erythromycin i.v. over

15 min prior to passage of a weighted 10-french "Flexiflo" feeding tube

2. 10 mg of metoclopramide i.v. over 15 min prior to having a weighted 10-french "Flexiflo" tube placed

Describe control (treatment/procedure/test):

1. Normal saline, unweighted tube
2. Normal saline, weighted tube

Length of follow-up:

24 h

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Successful postpyloric feeding tube placement:

I1: 0/21

I2: 0/20

C1: 3/26

C2: 2/16

Author’s conclusion

Weighted enteral feeding tubes are

preferred because they can be intubated into the stomach

with less difficulty. Neither metoclopramide nor erythromycin was effective in improving transpyloric placement

of the feeding tubes, and indeed may hinder duodenal intubation.

Whatley 1984

Type of study:

RCT

Setting and country:

ICU (including e Surgical Intensive Care

or Neurosurgical Units), USA

Funding and conflicts of interest:

Not reported

Inclusion criteria

patients had failed to achieve spontaneous duodenal

intubation within 24 hrs

Exclusion criteria

-

N total at baseline:

I: 5

C:5

Important prognostic factors²:

Not reported

Groups comparable at baseline?

Unknown

Describe intervention (treatment/procedure/test):

20 mg of metoclopramide

intravenously

Describe control (treatment/procedure/test):

No premedication

Length of follow-up:

24 hrs

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Successful postpyloric feeding tube placement:

I: 4/5

C: 0/5

Author’s conclusion

Metoclopramide, administered after nasogastric intubation, is ineffective in promoting transpyloric advancement of weighted feeding tubes. There is a significant

increase in transpyloric intubation when metoclopramide

is administered prior to weighed feeding tube insertion.

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

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?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

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?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Yavagal, 2000

Probably no;

Reason: randomization method is not discussed

Probably no;

Reason: not specified

Probably yes;

Reason: double-blinded study, with blinding of patients and one other group. Unsure whether that is healthcare providers or outcome assessors

Probably yes

Reason: no loss to follow-up reported

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes;

Reason: No other problems noted

Some concerns

(all outcomes except mortality)

Unknown randomization method

Nursal, 2007

Probably yes;

Reason: separated by blocked rank randomization

into two groups. Details are lacking.

Probably yes;

Reason: not specified but no indications of the problems with concealment.

Probably yes

Reason: Patients, health care providers, outcome assessors are blinded (data collectors and analysts were not discussed)

Probably yes

Reason: loss to follow-up was only present in the control group and was infrequent

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes;

Reason: No other problems noted

LOW

Makkar, 2016

Definitely yes;

Reason: Randomization with computer generated random numbers

Probably yes;

Reason: not specified but no indications of the problems with concealment.

Definitely yes;

Reason: Patients, health care providers, outcome assessors and data collectors are blinded

Probably yes

Reason: Loss to follow-up was infrequent in intervention and control group. Authors anticipated to possible dropouts beforehand.

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes;

Reason: No other problems noted

LOW

Reignier, 2002

Probably yes;

Reason: sealed envelope randomization procedure

Probably yes;

Reason: not specified but no indications of the problems with concealment

Probably no;

Reason: Patients were blinded, health care providers and data collectors were not

Probably yes

Reason: loss to follow-up was infrequent in both groups. Unknown whether power is sufficient.

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes;

Reason: No other problems noted

Some concerns

(all outcomes except mortality)

Lack of blinding

Berne 2002

Probably no;

Reason: randomization method is not discussed

Probably no;

Reason: allocation concealment is not discussed

Definitely yes;

Reason: Patients, health care providers, outcome assessors and data collectors are blinded

Probably yes

Reason: no loss to follow-up reported

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes;

Reason: No other problems noted

Some concerns

(all outcomes except mortality)

Unknown randomization method

Nassaji 2010

Probably no;

Reason: generation of allocation sequences by alternation

Probably no;

Reason: not discussed and inadequate randomization method

Probably yes;

Reason: double-blinded study, with blinding of patients and data collectors. Unsure whether that is healthcare providers or outcome assessors

Probably yes

Reason: no loss to follow-up reported

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes;

Reason: No other problems noted

Some concerns

(all outcomes except mortality)

Inadequate randomization

Acosta-Escribano 2014

Definitely yes;

Reason: Randomization with computer generated random numbers

Probably yes;

Reason: not specified but no indications of the problems with concealment.

Probably yes;

Reason: blinding of patients and one other group. Unsure whether that is healthcare providers or outcome assessors

Probably no;

Reason: equal loss to follow-up in both groups, but power of the control group is insufficient

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes;

Reason: No other problems noted

Some concerns

(all outcomes except mortality)

Loss to follow-up

Vijayaraghavan 2021

Definitely yes;

Reason: randomization using computer generated block randomization with a block size of 15

Definitely yes:

Reason: Allocation concealment using sequentially numbered opaque sealed envelope (SNOSE) technique

Definitely no

Reason: this is an open-label study

Definitely yes

Reason: No loss to follow-up occurred

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes;

Reason: No other problems noted

HIGH

(all outcomes except mortality)

Lack of blinding

Griffith 2003

Probably no;

Reason: study is randomized, but randomization method is not discussed

Probably no;

Reason: allocation concealment is not discussed

Probably yes;

Reason: study was double-blinded (patients and healthcare providers).

Probably yes

Reason: no loss to follow-up reported

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes;

Reason: No other problems noted

Some concerns

(all outcomes except mortality)

Unknown randomization method

Heiselman 1995

Probably no;

Reason: study is randomized, but randomization method is not discussed

Probably no;

Reason: allocation concealment is not discussed

Probably no;

Reason: blinding was not reported

Probably yes

Reason: no loss to follow-up reported

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes;

Reason: No other problems noted

Some concerns

(all outcomes except mortality)

Unknown randomization method and blinding

Hu 2015

Probably no;

Reason: study is randomized by fixed block randomization, no additional details described

Probably no;

Reason: allocation concealment is not discussed

Definitely no

Reason: only the patients and the data analyst were blinded

Definitely yes

Reason: No loss to follow-up occurred

Definitely yes

Reason: All relevant outcomes were reported;

Probably no;

Reason: Sponsoring by industry (Nutricia)

HIGH

(all outcomes except mortality)

Lack of blinding, industry sponsoring

Kalliafas 1996

Probably yes;

Reason: stratified randomization, details are lacking

Probably yes;

Reason: allocation concealment is not discussed

Probably yes

Reason: study was double-blinded but no details were provided

Probably yes

Reason: no loss to follow-up reported

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes;

Reason: No other problems noted

LOW

Paz 1996

Probably yes;

Reason: randomization by a random number table

Probably yes;

Reason: allocation concealment is not discussed

Probably yes;

Reason: patients and healthcare providers were blinded to the investigational drug.

Probably yes

Reason: no loss to follow-up reported

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes;

Reason: No other problems noted

LOW

Whatley 1984

Probably yes;

Reason: randomization by a random number table

Probably yes;

Reason: allocation concealment is not discussed

Probably no;

Reason: blinding was not reported

Probably yes

Reason: no loss to follow-up reported

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes;

Reason: No other problems noted

Some concerns

(all outcomes except mortality)

Lack of blinding