Methods

Parallel‐group randomised controlled trial

Participants

Baseline characteristics

Number randomised: 10 participants

Number analysed: 10 participants

Pantoprazole

• Age (years; mean (SD)): ‐ (‐)

• Number of participants (n): 4

• Gender (male/female; n): ‐

Placebo

• Age (years, mean (SD)): ‐ (‐)

• Number of participants (n): 6

• Gender (male/female; n): ‐

Inclusion criteria

• Receiving > 5 doses of pantoprazole/placebo

• Being mechanically ventilated

Exclusion criteria: ‐

Baseline imbalances: ‐

Interventions

Pantoprazole

• Dose (total/d): 40 mg

• Duration of treatment (days): ‐

• Route: IV

• Intervention: IV pantoprazole (40 mg), mean 8.8 (0.3) doses

• Concomitant medications: mechanical ventilation

Placebo

• Dose (total/d): ‐

• Duration of treatment (days): ‐

• Route: IV

• Intervention: placebo, mean 10.7 (1.1) doses

• Concomitant medications: ‐

Adherence to regimen: ‐

Duration of trial: ‐

Duration of follow‐up: ‐

Outcomes

Outcomes sought in review and reported in trial

• Clinically important GI bleeding

Outcomes sought but not reported in trial

• VAP

• All‐cause mortality in hospital

• Duration of ICU stay

• Duration of intubation

• Blood transfusions

• Adverse events of interventions

Outcomes reported in trial but not used in review

• ‐

Notes

Setting: ICU

Source of funding: ‐

Conflicts of interest: ‐

• Ethics approval: ‐

Informed consent: ‐

Clinical trials registration: ‐

Sample size calculation: ‐

Additional notes: ‐

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: mentioned only that participants were randomised to treatment. Not enough information on method of randomisation

Allocation concealment (selection bias)

Unclear risk

Comment: no information about allocation concealment reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: mentioned only that the trial was double‐blind. No information about the method of blinding

Blinding (detection bias)
Clinically important upper GI bleeding

Low risk

Comment: mentioned that outcome assessment was done blinded to intervention. Presence of 1 or more macroscopic abnormalities (erythema or oedema, erosions, ulcerations, and nasogastric tube lesions) and GI bleeding was assessed, blinded to intervention, at endoscopy by a single experienced gastroenterologist

Quote: "assessed, blinded to intervention, at endoscopy by a single experienced gastroenterologist"

Blinding (detection bias)
Nosocomial pneumonia

Unclear risk

Comment: The outcome was not addressed in this trial

Blinding of outcome assessment (detection bias)
Adverse reactions of interventions

Low risk

Comment: mentioned that outcome assessment was done blinded to intervention

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Conference abstract reports about 10 participants from a larger prospective trial. Those who received > 5 doses of pantoprazole or placebo (n = 84) were eligible for the endoscopy substudy, but unclear why data from only 10 participants are reported

Selective reporting (reporting bias)

Low risk

Comment: Outcomes reported in Methods section are also reported in Results section

Other bias

Unclear risk

Comment: not enough information reported in conference abstract to assess other biases

Methods

Open‐label parallel‐group randomised controlled trial

Participants

Baseline characteristics

Number randomised: 34 participants

Number analysed: 34 participants

Ranitidine

• Age (years; mean (range)): 27 (10 to 55)

• Number of participants (n): 16

• Gender (male/female; n): 12/4

No prophylaxis

• Age (years, mean (range)): 26 (11 to 88)

• Number of participants (n): 18

• Gender (male/female; n): 11/7

Inclusion criteria

• Tracheotomised patients in medical ICU with tetanus

Exclusion criteria

• Pneumonia diagnosed before tracheostomy

• Ranitidine received before randomisation

Baseline imbalances: Participants were tracheotomised patients with tetanus. Maximum tetanus severity score was 11 (4 to 16) in the ranitidine group and 10 (6 to 16) in the control group. Groups were similar with respect to age and gender distribution

Interventions

Ranitidine

• Dose (total/d): 200 mg

• Duration of treatment (days): ‐

• Route: IV

• Intervention: 50 mg IV 6‐hourly

• Concomitant medications: 3 participants whose gastric pH did not increase to > 4 received additional antacids (30 mL 4‐hourly), Tetanus was treated with anti‐tetanus serum, penicillin, diazepam, and neuromuscular blockade with mechanical ventilation when indicated. All participants receivedintermittent nasogastric feeding (300 to 400 mL 4‐hourly)

No prophylaxis

• Dose (total/d): ‐

• Duration of treatment (days): ‐

• Route: ‐

• Intervention: ‐

• Concomitant medications: Tetanus was treated with anti‐tetanus serum, penicillin, diazepam, and neuromuscular blockade with mechanical ventilation when indicated. All participants receivedintermittent nasogastric feeding (300 to 400 mL 4‐hourly)

Adherence to regimen: 34 tracheotomised participants who were admitted to medical ICU with tetanus were randomly assigned to ranitidine or control group within 24 hours of tracheal intubation. Six participants who had pneumonia before tracheostomy or had ranitidine before randomisation were excluded. All remaining participants were studied until 48 hours after extubation

Duration of trial: ‐

Duration of follow‐up: studied daily until 48 hours after tracheal extubation

Outcomes

Outcomes sought in review and reported in trial

• Clinically important upper GI bleeding

  • Gross bleed (bright red or altered blood)

  • Occult bleeding (by benzidine test)

• VAP: diagnosed by appearance of new infiltrates on chest radiograph or bronchial breath sounds on examination and positive tracheal culture along with fever (axillary temperature > 38°C), leucocytes (> 13,000 cells/mm³), and purulent sputum (> 25 leucocytes per low‐power field)

• All‐cause mortality in ICU

• Duration of intubation (median and range provided)

• Number of participants requiring blood transfusion (no participant required this)

• Number of units of blood transfused (no participant required this)

Outcomes sought but not reported in trial

• All‐cause mortality in hospital

• Duration of ICU stay

• Adverse events of interventions

Outcomes reported in trial but not used in review

• Intragastric pH status (with and without enteral nutrition)

• Gastric colonisation

Notes

Setting: Medical ICU in Department of Medicine, Department of Microbiology, King Edward Memorial Hospital, Parel, Bombay, India

Source of funding: Quote: "Study supported, in part, by a grant from Seth GS medical College and KEM Hospital research Society”; Torrent Pharmaceuticals provided ranitidine

Conflicts of interest: ‐

Ethics approval: Quote: "The study was approved by the institutional ethics committee"

Informed consent: Quote: "The study was approved by the institutional ethics committee [with] waived informed consent"

Comment: not obtained, as mentioned in the trial report

Clinical trials registration: ‐

Sample size calculation: ‐

Additional notes: Trial included patients with tetanus. Trial reports that gram‐negative bacilli were the predominant organisms that caused pneumonia. Participants treated with ranitidine developed pneumonia significantly earlier (median 3 days, range 1 to 5) than participants given control (median 5 days, range 3 to 14 days)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: not enough information on method of randomisation reported

Allocation concealment (selection bias)

Unclear risk

Comment: not enough information on method of allocation concealment reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: This trial compared an intervention vs no prophylaxis (blinding was not possible)

Blinding (detection bias)
Clinically important upper GI bleeding

Low risk

Comment: GI bleeding was an objective outcome that was detected as per the definition in the trial protocol

Blinding (detection bias)
Nosocomial pneumonia

Low risk

Comment: Pneumonia was an objective outcome that was detected as per the definition in the trial protocol

Blinding of outcome assessment (detection bias)
Adverse reactions of interventions

Low risk

Comment: All other outcomes of interest were objective in nature

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: All participants who were randomised were included in analysis

Selective reporting (reporting bias)

Low risk

Comment: All intended outcomes were analysed and reported

Other bias

Low risk

Comment: This trial was supported in part by a grant from Seth GS Medical College and KEM Hospital Research Society. The role of the sponsor in the conduct and reporting of the trial is unclear. No other form of bias is suspected

Methods

Double‐blind parallel‐group randomised controlled trial

Participants

Baseline characteristics

Number randomised: 66 participants

Number analysed: 55 participants

Pirenzepine

• Age (years; mean (SD)): ‐

• Number of participants (n): 27

• Gender (male/female; n): ‐

Cimetidine

• Age (years; mean (SD)): ‐

• Number of participants (n): 28

• Gender (male/female; n): ‐

Inclusion criteria

• Age > 16 years

• Patients in surgical ICU

Exclusion criteria

• Gastroscopy not possible

• On therapy for ulcus

• Receiving operation of stomach

Baseline imbalances: baseline imbalances comparable, also in terms of severity of injury/trauma

Interventions

Pirenzepine

• Dose (total/d): 40 mg

• Duration of treatment (days): ‐

• Route: IV

• Intervention: 4 × 10 mg IV

• Concomitant medications: ‐

Cimetidine

• Dose (total/d): 800 mg

• Duration of treatment (days): ‐

• Route: IV

• Intervention: 4 × 200 mg IV

• Concomitant medications: ‐

Adherence to regimen: 11 participants withdrew from the trial. However, no reasons are mentioned in the trial report. Also no mention of which interventional group these 11 participants belonged to

Duration of trial: ‐

Duration of follow‐up: not clearly mentioned, probably until discharge

Outcomes

Outcomes sought in review and reported in trial

• Clinically important upper GI bleeding

• Adverse events of interventions

Outcomes sought but not reported in trial

• VAP

• All‐cause mortality in ICU

• All‐cause mortality in hospital

• Duration of ICU stay

• Duration of intubation

• Number of participants requiring blood transfusion

• Number of units of blood transfused

Outcomes reported in trial but not used in review

• Number of lesions on gastroscopy

Notes

Setting: Surgical ICU, Chur, Switzerland

Source of funding: ‐

Conflicts of interest: ‐

Ethics approval: ‐

Informed consent: ‐

Clinical trials registration: ‐

Sample size calculation: ‐

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: not enough information reported on method of sequence generation

Allocation concealment (selection bias)

Unclear risk

Comment: not enough information reported on method of allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: This appears to be a double‐dummy placebo‐controlled trial, in which participants from group 1 got a placebo that looks like the intervention in group 2 and vice versa. Thus personnel would have been blinded and likelihood of performance bias is low

Blinding (detection bias)
Clinically important upper GI bleeding

Unclear risk

Comment: not enough information reported on the criteria for diagnosis of upper GI bleeding

Blinding (detection bias)
Nosocomial pneumonia

Unclear risk

Comment: The trial did not address this outcome

Blinding of outcome assessment (detection bias)
Adverse reactions of interventions

Low risk

Comment: This appears to be a double‐dummy placebo‐controlled trial, in which participants from group 1 got a placebo that looks like the intervention in group 2 and vice versa. Thus the likelihood of detection bias seems low

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: 11 participants withdrew from the trial, but reasons for withdrawal and the group to which they were randomised are not clearly mentioned in the trial report

Selective reporting (reporting bias)

Unclear risk

Comment: All intended outcomes were reported but no clear mention of the number of participants in the cimetidine group who had confusion and high K levels

Other bias

Low risk

Comment: The trial report is unclear on the source of funding. No other sources of bias detected

Methods

Double‐blind parallel‐group randomised controlled trial

Participants

Baseline characteristics

Number randomised: 146 participants

Number analysed: 120 participants

Ranitidine

• Age (years; mean (SD)): 50.63 (20.78)

• Number of participants (n): 60

• Gender (male/female; n): 16/44

Pantoprazole

• Age (years; mean (SD)): 43.67 (19.58)

• Number of participants (n): 60

• Gender (male/female; n): 18/42

Inclusion criteria

• Intubated patients

• Age > 18 years

• Acute Physiology and Chronic Health Evaluation score (APACHE II) < 25

Exclusion criteria

• Pneumonia

• GI bleeding upon ICU admission

• History of gastrectomy

• Anticipated need for tracheal intubation in less than 48 hours

• Known sensitivity to the studied medication

Baseline imbalances: We found no statistically significant differences between the 2 groups regarding baseline characteristics, such as age, sex, or APACHE II

Interventions

Ranitidine

• Dose (total/d): 150 mg IV or 300 mg PO

• Duration of treatment (days): during NPO time or when oral feeding started

• Route: IV or PO

• Duration of follow‐up (days, mean (SD)): 15.67 (7.11)

• Intervention: following admission to the ICU, 50 mg intravenous ranitidine (ranitidine 50 mg, Caspian Tamin Co., Rasht, Iran) was administered 3 times daily to 1 group of participants during NPO time to prevent stress ulcers. Thereafter, the day after oral feeding initiation, 150 mg oral ranitidine tablets (ranitidine 150 mg, Darou Pakhsh, Tehran, Iran) were administered twice daily until the end of the trialT

• Concomitant medications: GI prophylaxis continued until ICU discharge. Other treatments were similarly administered to both groups according to the ICU protocol

Pantoprazole

• Dose (total/d): 40 mg IV or 40 mg PO

• Duration of treatment (days): during NPO time or when oral feeding started

• Route: IV or PO

• Duration of follow‐up (days): 17.58 (7.90) (until discharge)

• Intervention: Second group received 40 mg intravenous pantoprazole (Pepticare 40 mg, Ronak Pharmaceutical Co., Saveh, Iran) once daily during NPO time. The day after oral feeding initiation, it was replaced with 40 mg pantoprazole tablets (E.C. Tablet Pantoprazole 40 mg, Osveh, Tehran, Iran) once a day for stress ulcer prophylaxis until the end of the trial

• Concomitant medications: GI prophylaxis was continued until ICU discharge. Other treatments were similarly administered to both groups according to the ICU protocol

Adherence to regimen: ‐

Duration of trial: July 2011 to July 2012

Duration of follow‐up: ‐

Outcomes

Outcomes sought in review and reported in trial

• All‐cause mortality in ICU

• Duration of intubation

Outcomes sought in review but not reported in trial

• Clinically important GI bleeding

• VAP

• All‐cause mortality in hospital

• Duration of ICU stay

• Number of participants requiring blood transfusion

• Number of units of blood transfused

• Adverse events

Outcomes reported, but not used in the review

• Days until VAP incidence

Notes

Setting: ICU, Iran

Source of funding: ‐

Conflicts of interest: ‐

Ethics approval: Trial was approved by the Ethics Committee of Hamedan University of Medical Sciences.

Informed consent: Written informed consent was obtained from legal guardians of participants

Clinical trials registration: ‐

Sample size calculation: ‐

Conflicts of interest: ‐

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The patients were randomised using online random allocation software (www.allocationsoftware.com)"

Allocation concealment (selection bias)

Unclear risk

Comment: not enough information reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The patients and the attending intensivists responsible for data collection were blinded to the assigned groups"

Blinding (detection bias)
Clinically important upper GI bleeding

Unclear risk

Comment: Trial did not address this outcome

Blinding (detection bias)
Nosocomial pneumonia

Low risk

Quote: "Patients underwent chest radiography which was repeated at least twice a week"

Comment: Objective outcome measurement unlikely to introduce bias

Blinding of outcome assessment (detection bias)
Adverse reactions of interventions

Low risk

Quote: "The patients and intensivists responsible for data collection were blinded to the assigned groups"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: All participants were followed up until discharge

Selective reporting (reporting bias)

Low risk

Comment: All outcomes listed in the Methods section were reported in the Results section

Other bias

Low risk

Comment: no other sources of bias suspected

Methods

Single‐blind randomised controlled trial

Participants

Baseline characteristics

Number randomised: 168 participants

Number analysed: 168 participants

Cimetidine

• Age (years; mean (SD)): ‐

• Number of participants (n): 60

• Gender (male/female; n): ‐

Antacids (Maalox)

• Age (years; mean (SD)): ‐

• Number of participants (n): 52

• Gender (male/female; n): ‐

No prophylaxis

• Age (years; mean (SD)): ‐

• Number of participants (n): 56

• Gender (male/female; n): ‐

Inclusion criteria

• Patient admitted to the ICU

Exclusion criteria

• Evidence of gross upper GI bleeding before or during the 12 hours after start of the trial

• Gastric or oesophageal operations

• Age < 12 years

• Having coagulopathies

Baseline imbalances: Risk categories and risk factors in the 3 groups were comparable

Interventions

Cimetidine

• Dose (total/d): 800 mg

• Duration of treatment (days): min 10

• Route: IV or PO

• Intervention: 200 mg every 6 hours IV or orally

• Concomitant medications: ‐

Antacids (Maalox)

• Dose (total/d): 2400 mL

• Duration of treatment (days): min 10

• Route: NG tube or PO

• Intervention: 10 mL/h by NG tube or orally

• Concomitant medications: ‐

No prophylaxis

• Dose (total/d): ‐

• Duration of treatment (days): min 10

• Route: ‐

• Intervention: ‐

• Concomitant medications: ‐

Adherence to regimen: 16 participants died, 6 did not comply with therapy, and 9 were transferred to other institutions. Therefore, 31 participants did not complete 10 days of the trial

Duration of trial: March 1978 to April 1979

Duration of follow‐up: not clearly mentioned in trial report

Outcomes

Outcomes sought in review and reported in trial

• Clinically important GI bleeding diagnosed by clinical signs of haematemesis, melena, blood in NG tube or stool, or change in haematocrit

• All‐cause mortality in ICU (not reported separately for each arm)

• Number of units of blood transfused (not mentioned separately for each arm)

Outcomes sought but not reported in trial

• VAP

• All‐cause mortality in hospital

• Duration of ICU stay

• Duration of intubation

• Participants requiring blood transfusion

• Adverse events of interventions

Outcomes reported but not used in review

• Nil

Notes

Setting: ICU, University of Rome

Source of funding: ‐

Ethics approval: ‐

Informed consent: Quote: "Informed consent was obtained from either the participant or their closest relative"

Clinical trials registration: not provided

Sample size calculation: ‐

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “The study was done in a single blind manner, assigning the treatment according to a list of randomised values”

Comment: not enough information reported on method of sequence generation

Allocation concealment (selection bias)

Unclear risk

Comment: not enough information reported on method of allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: This was not a placebo‐controlled trial and personnel were not blinded

Blinding (detection bias)
Clinically important upper GI bleeding

Low risk

Quote: "The observer assessing the occurrence of gastrointestinal bleeding did not know the type of prophylactic measures the patient was receiving"

Blinding (detection bias)
Nosocomial pneumonia

Unclear risk

Comment: The trial did not address this outcome

Blinding of outcome assessment (detection bias)
Adverse reactions of interventions

Unclear risk

Comment: Unclear whether outcome assessors were blinded for other outcomes

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: All randomised participants were part of the final analysis

Selective reporting (reporting bias)

Unclear risk

Comment: All‐cause mortality in ICU and units of blood transfused were not mentioned separately for each interventional arm. Unclear whether this contributed to reporting bias

Other bias

Unclear risk

Comment: source of funding and baseline characteristics unclear

Methods

Open‐label randomised controlled trial

Participants

Baseline characteristics

Number randomised: 43 participants

Number analysed: 43 participants

Pirenzepine

• Age (years; mean (SD)): 2.62 (‐) overall

• Number of participants (n): 21

• Gender (male/female; n): 24/19 overall

Famotidine

• Age (years; mean (SD)): 2.62 (‐) overall

• Number of participants (n): 22

• Gender (male/female; n): 24/19 overall

No prophylaxis

• Age (years; mean (SD)): 2.62 (‐) overall

• Number of participants (n): 36

• Gender (male/female; n): 24/19 overall

Inclusion criteria

• Undergoing corrective or palliative surgery for congenital heart disease

Exclusion criteria

• Having operations that usually have a short and uncomplicated postoperative recovery, such as repair of an atrial septal defect, valvotomy for aortic stenosis, or repair of coarctation of the isthmus

Baseline imbalances: There were no differences between groups that did not receive any prophylaxis (not randomised) and the group that did receive prophylaxis (randomised to pirenzepine and famotidine)

Interventions

Pirenzepine

• Dose (total/d): 1 mg/kg bw

• Duration of treatment (days): until participants were fed fully by mouth

• Route: IV

• Intervention: In older participants, 2 doses were given; children who weighed less than 10 kg were given 3 doses. Daily dose was reduced to 0.5 mg/kg if serum creatinine exceeded 3 mg/dL

• Concomitant medications: Full parental nutrition was given at the time of endoscopy. All participants were treated with antibiotics after operation: cefuroxime or cefotiam at the dose of 100 mg/kg bw/d

Famotidine

• Dose (total/d): 1 mg/kg bw

• Duration of treatment (days): until participants were fed fully by mouth

• Route: IV

• Intervention: In older participants, 2 doses were given; children who weighed less than 10 kg were given 3 doses. Daily dose was reduced to 0.5 mg/kg if serum creatinine exceeded 3 mg/dL

• Concomitant medications: Full parenteral nutrition was given at the time of endoscopy. All participants were treated with antibiotics after operation: cefuroxime or cefotiam at the dose of 100 mg/kg/d

No prophylaxis

• Dose (total/d): ‐

• Duration of treatment (days): until participants were fed fully by mouth

• Route: ‐

• Intervention: ‐

• Concomitant medications: Full parenteral nutrition was given at the time of endoscopy. All participants were treated with antibiotics after operation: cefuroxime or cefotiam at the dose of 100 mg/kg/d. Intravenous

Adherence to regimen: ‐

Duration of trial: October 1988 to November 1991

Duration of follow‐up: ‐

Outcomes

Outcomes sought in review and reported in trial

• VAP: diagnosis probably based on microbiological, clinical, and radiological findings

• Adverse events of interventions

Outcomes sought but not reported in trial

• Clinically important upper GI bleeding

• All‐cause mortality in ICU

• All‐cause mortality in hospital

• Duration of ICU stay

• Duration of intubation

• Participants requiring blood transfusion

• Units of blood transfused

Outcomes reported in report but not used in review

• Severe inflammation or ulceration of the upper GI tract (no upper GI bleeding reported)

• Gastric pH values

• Relationship between GI lesions and underlying diseases

• Severe inflammation or ulceration of the upper GI tract (through endoscopy)

Notes

Setting: University Children's Hospital, Department of Pediatric Gastroenterology, Erlangen, Germany

Source of funding: ‐

Conficts of interest: ‐

Ethics approval: Quote: "The study was approved by the committee on human research of the University of Erlangen‐Nurnberg"

Informed consent: ‐

Clinical trial registration: ‐

Sample size calculation: ‐

Additional notes: Gastric cultures were positive in 95% of participants with mean gastric pH > 4 and in 80% of participants with mean gastric pH < 4. Five and 4 participants in the 2 groups required mechanical ventilation. Candida sp was the predominant species cultured from gastric and tracheal secretions of participants given pirenzepine and famotidine. In the pirenzepine and famotidine groups, an organism cultured from the stomach was grown from the tracheal secretion, 1 to 4 days later, in 6 and 5 participants, respectively

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: not enough information reported on method of sequence generation

Allocation concealment (selection bias)

Unclear risk

Comment: not enough information reported on method of allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: unclear on blinding of personnel, although regimens and mode of administration of interventions were similar

Blinding (detection bias)
Clinically important upper GI bleeding

Unclear risk

Comment: The physician who performed endoscopy to detect inflammation or ulceration of the upper GI tract was not blinded to the intervention. There is no clear definition of GI bleeding in the trial. Therefore, unclear on the likelihood of performance or detection bias

Blinding (detection bias)
Nosocomial pneumonia

Unclear risk

Comment: no mention of blinding technicians who cultured gastric secretions for pathogenic bacteria, radiologists who interpreted chest X‐rays, or physicians who performed the clinical examination. No clear definition of VAP provided in the trial

Blinding of outcome assessment (detection bias)
Adverse reactions of interventions

Unclear risk

Comment: not enough information reported on blinding of outcome assessors for other outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: All randomised participants were included in the analysis

Selective reporting (reporting bias)

Low risk

Comment: Trial compared participants who received prophylaxis vs participants who did not receive prophylaxis. In the intervention group, participants were randomised to receive either pirenzepine or famotidine. The outcome of interest (VAP) was reported separately for participants who were randomised to 2 different arms (pirenzepine and famotidine)

Other bias

Unclear risk

Comment: source of funding not clearly mentioned in the trial report. Baseline data on randomised groups unclear

Methods

Single‐blind randomised controlled trial

Participants

Baseline characteristics

Number randomised: 304 participants

Number analysed: 300 participants

Sucralfate

• Age (years; mean (SD)): 60.1 (16.8)

• Number of participants (n): 100

• Gender (male/female; n): 51/49

Cimetidine

• Age (years; mean (SD)): 59 (18.1)

• Number of participants (n): 100

• Gender (male/female; n): 51/49

Control

• Age (years; mean (SD)): 59.6 (18)

• Number of participants (n): 100

• Gender (male/female; n): 51/49

Inclusion criteria

• Age > 18 years

• Admitted to Medical ICU

• Informed consent from participant or legally authorised representative

Exclusion criteria

• Expected stay at ICU of 24 hours or less

• Evidence of gastrointestinal bleeding (haematemesis, vomiting of' "coffee grounds", haematochezia, or melena) at time of admission to the ICU

• Treatment with antacids, H2 receptor antagonists, sucralfate, or omeprazole during the 24 hours before entering the ICU

• Use of non‐steroidal anti‐inflammatory agents, systemic anticoagulants, or thrombolytic agents during previous 7 days

• Surgery requiring general anaesthesia during previous 2 weeks

• Closed head injury or clinical evidence of increased intracranial pressure

• Grade 4 hepatic encephalopathy

• Oesophageal or gastric surgery in previous year

• History of gastrointestinal bleeding during previous year

• Pregnancy or lactation

Baseline imbalances: Quote: "One hundred patients were randomly assigned to each of the treatments. The groups were similar with regard to age, gender, percentage of participants admitted from the emergency room, severity of illness, admission diagnoses, corticosteroid usage and coagulopathy. Patients often had more than one reason for ICU admission. The mean APACHE II scores for the control, sucralfate, and cimetidine groups were 16.5 ± 6.9, 16.8 ± 6.9, and 18.0 ± 8.0, respectively. Approximately one‐third of the patients in each group had APACHE II scores greater than 20.0

Comment: The 3 groups were similar with respect to demographic and other risk factors for stress haemorrhage at the beginning of the trial. The most common diagnosis on admission was pneumonia, which was reported in 89 participants. Bacterial pneumonia (control: 23; sucralfate: 26; cimetidine: 21). Non‐bacterial pneumonia was diagnosed (control: 9; sucralfate: 4; cimetidine: 6). Coagulopathy was present in 16, 14, and 21 participants in the 3 randomised groups

Interventions

Sucralfate

• Dose (total/d): 4 g

• Duration of treatment (days): ‐

• Route: nasogastric tube

• Intervention: 1 g of medication orally or as a suspension through the nasogastric tube every 6 hours. Nasogastric tube was clamped for 1 hour after sucralfate administration

• Concomitant medications: 69% of participants received enteral nutrition through a 10‐Fr feeding tube. 1% received parenteral nutrition. Corticosteroids were used in all groups

Cimetidine

• Dose (total/d): varies

• Duration of treatment (days): ‐

• Route: IV

• Intervention: 300 mg intravenous loading dose followed by continuous intravenous infusion according to creatinine clearance: more than 50 mL/min, 900 mg/d; 20 to 50 mL/min, 600 mg/d; and less than 20 mL/min, 300 mg/d. Cimetidine dose was titrated to maintain gastric pH ≥ 4.0. With 2 consecutive gastric pH values < 4.0, dose was increased by the following amounts based on creatinine clearance: 300 mg/d, 200 mg/d, and 100 mg/d. Maximum allowable cimetidine doses for participants grouped by renal function were 2400 mg/d, 1600 mg/d, and 800 mg/d

• Concomitant medications: 57% of participants received enteral nutrition through a 10‐Fr feeding tube. 7% of cimetidine group received parenteral nutrition. Corticosteroids were used in all groups

No prophylaxis

• Dose (total/d): ‐

• Duration of treatment (days): ‐

• Route: ‐

• Intervention: ‐

• Concomitant medications: 72% of participants received enteral nutrition through a 10‐Fr feeding tube. 1% received parenteral nutrition. Corticosteroids were used in all groups

Adherence to regimen: Although 304 participants were randomised, only 300 (100 in each group) were part of the trial because 1 participant died 2 hours after admission, 3 participants were randomised on 2 different occasions, and second admissions were excluded. Results for only 291 participants were available when the trial was finally reviewed by the second committee. The 8 participants who did not agree to endoscopy might have been excluded from the trial denominator (unclear on the 1 remaining participant)

Duration of trial: 1 February to 25 November 1992

Duration of follow up: until death or discharge from ICU

Outcomes

Outcomes sought in review and reported in trial

Primary outcomes

• Clinically important GI bleeding defined as:  

  • Persistent haematemesis (red blood or guaiac‐positive 'coffee grounds') that did not clear with 1.5 L saline lavage

  • 3‐Point decrease in haematocrit during 24 hours accompanied by red blood or guaiac‐positive 'coffee grounds' material that cleared with lavage, or melena, or 3 guaiac‐positive stools without evidence of lower gastrointestinal bleed

  • Any unexplained 6‐point decrease in haematocrit during a 48‐hour period (added as a safety measure because some participants would not receive prophylaxis)

Note: Median time from ICU admission to onset of stress‐related haemorrhage was 5 days

• VAP defined as:

  • Chest roentgenogram obtained 72 or more hours after ICU admission that showed a new and persistent infiltrate

  • Fever, leucocytosis, or both

  • Purulent tracheobronchial secretions

  • Gram‐stained sputum showing more than 25 polymorphonuclear leucocytes and fewer than 10 squamous epithelial cells per low‐power field

  • Recovery of an accepted nosocomial pathogen from sputum culture

• All‐cause mortality in ICU

• All‐cause mortality in hospital

• Duration of ICU stay

• Number of participants requiring blood transfusion

• Adverse events of interventions&&

Note: Noscocomial pneumonia occurred after a mean of 6.9 ± 7.2 days in the ICU (median 9 days)

Outcomes sought but not reported in trial

• Duration of intubation

• Units of blood transfused

Outcomes reported in trial but not used in review

• Duration of hospital stay

Notes

Setting: Henry Ford Hospital and Health Sciences Center, Detroit, Michigan

Source of funding: Quote: "Grant support: in part from the Henry Ford Hospital Research and Education Funds to Dr. Ben‐Menachem and to Dr. Fogel"

Conflicts of interest: ‐

Ethics approval: Quote: "This protocol was reviewed and approved by the Henry Ford Hospital Institutional Review Board"

Informed consent: Quote: "Informed consent was obtained from the patient or from legally authorized representatives when the patient could not provide consent"

Clinical trials registration: ‐

Sample size calculation: Quote: "We estimated sample size to provide 80% power to detect a 75% reduction in bleeding rate, that is, a 12% bleeding rate for the control group compared with a 3% rate in either of the two treatment groups. We used an alpha value of 0.05 (two‐tailed) adjusted for the comparison of the control group with each of the prophylaxis groups. As a result of these assumptions, 160 patients were needed in each of the three groups”

Additional notes: Mechanical ventilation was used in 65, 72, and 76 participants in the 3 respective groups. Respiratory failure and high dose of corticosteroid were independently associated with increased risk of stress‐related haemorrhage. According to the trial report, 43 participants satisfied the criteria for significant GI bleeding (as per the definition), and 19 of these participants did not have stress‐related bleeding (as determined by oesophagogastroduodenoscopy). Among them, 12 participants (4 controls, 3 receiving sucralfate, and 5 receiving cimetidine) had a normal result of endoscopy, suggesting that the change in haematocrit was due to fluid shifts. Seven participants bled from causes not due to stress ulceration, and 8 participants did not have endoscopy (5 did not give consent, 1 participant with lymphoma and thrombocytopaenia died of multiple‐organ system failure 10 days after the bleeding episode. Three of the 8 participants met criterion 3 of diagnosis

Quote: "Two of 20 patients in the control group with coagulopathy had stress‐related haemorrhage. In the cimetidine and sucralfate groups, the incidences were 1 of 22 and 2 of 17, respectively (P > 0.05)"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was by sealed envelope using the permuted block design"
Comment: Method to generate a random sequence is clearly mentioned in the trial report

Allocation concealment (selection bias)

Low risk

Quote: "Randomization was by sealed envelope using the permuted block design"

Comment: Method for allocation concealment is clearly mentioned in the trial report

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: This was a single‐blind trial, and the mode of drug administration could not have allowed blinding. Therefore, risk of performance bias is high

Blinding (detection bias)
Clinically important upper GI bleeding

Low risk

Quote: "The primary study end point was substantial haemorrhage from stress gastritis. Information regarding hematocrit, haemoccult status of stool and nasogastric aspirate, and volume status [were] presented daily to two investigators who were blinded to therapy"

Comment: Trial report mentions blinding of outcome assessors for the primary outcome of GI bleed, which was an objective outcome detected as per the definition used in the trial

Blinding (detection bias)
Nosocomial pneumonia

Low risk

Comment: Outcome assessors were not blinded. However, this was an objective outcome that was diagnosed as per the definition used in the trial protocol. Therefore, the likelihood of performance or detection bias is low

Blinding of outcome assessment (detection bias)
Adverse reactions of interventions

Low risk

Comment: All other outcomes of interest were objective in nature, so the likelihood of detection bias is low

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: Although 304 participants were randomised, only 300 were analysed, as 1 participant died 2 hours after admission, 3 were randomised on 2 different occasions, and second admissions were excluded. Results for only 291 participants were available when the trial was finally reviewed by the second committee. The 8 participants who did not agree to endoscopy might have been excluded from the trial denominator (unclear for the 1 remaining participant). However, intention‐to‐treat analysis was done with 100 participants in each of the 3 groups. Therefore, there was no attrition bias

Selective reporting (reporting bias)

Low risk

Comment: All intended outcomes are reported. A subgroup analysis was desirable for participants who received enteral feeds

Other bias

Low risk

Comment: This trial was supported in part by Henry Ford Hospital Research and Education Funds. The role of the sponsor in the conduct and reporting of this trial is unclear. No other form of bias is suspected

Methods

Stratified double‐blind randomised controlled trial

Participants

Baseline characteristics

Number randomised: 141 participants

Number analysed: 141 participants

Antacids

• Age (years; mean (SD)): 58.6 (18.6)

• Number of participants (n): 74

• Gender (male/female; n): 46/28

Sucralfate

• Age (years; mean (SD)): 57.3 (19.4)

• Number of participants (n): 67

• Gender (male/female; n): 42/25

Inclusion criteria

• Mechanically ventilated

• Expected ICU stay ≥ 3 days

• Informed consent from participants/family representative

Exclusion criteria

• Age < 15 years

• Admitted for massive gastric haemorrhage or bleeding oesophageal varices, after oesophageal or gastric surgery, when a nasogastric tube could not be placed

• Receiving H2 antagonists or H + K + ATP‐ase inhibitors

Baseline imbalances: Demographic characteristics of both groups, such as age, gender, and severity of illness, which was assessed by the APCHE score, were almost similar. Most participants were given a diagnosis of cardiovascular problems (30 in both groups). Neoplastic disease was more common among participants assigned to the antacid group when compared with the sucralfate group (12 and 5), whereas renal insufficiency and immunodeficiency were more common among participants in the sucralfate group (1 and 6 and 3 and 7, respectively). All other underlying conditions including presence of pneumonia (9 in antacid group and 10 in sucralfate group) on admission were similar between both groups

Interventions

Antacids

• Dose (total/d): 180 mL

• Duration of treatment (days; mean (SD)): 11 (16.8)

• Route: nasogastric tube

• Intervention: 30 mL every 4 hours at 2.00 through 22.00 hours + sucralfate placebo at hours when antacids were administered + 10 mL of sterile water

• Concomitant medications: antibiotics

Sucralfate 

• Dose (total/day): 5 g

• Duration of treatment (days; mean (SD)): 13.3 (12.7)

• Route: nasogastric tube

• Intervention: 1 g every 4 hours at 0.00 through 20.00 hours + antacid placebo at the hours that antacids were administered + 10 mL of sterile water

• Concomitant medications: antibiotics

Adherence to regimen: Gastric pH was determined within 24 hours after admission via continuous intragastric monitoring. Participants were stratified into 2 groups according to gastric pH value measured on the first day of admission, which was < 3 (n = 69) or ≥ 3 (n = 72) (continuous intragastric pH in 84 and indicator papers in 57 participants; for 28 in the latter group, continuous pH monitoring was performed later). Participants were later randomised to 2 treatment arms, amongst whom 74 received antacids and 67 received sucralfate

Duration of trial: August 1992 to August 1993

Duration of follow‐up: probably until discharge or death

Outcomes

Outcomes sought in review and reported in trial

• Incidence of clinically important GI bleeding; suspicion of gastrointestinal bleeding was endoscopically confirmed and treated according to standard clinical practice. Participant was excluded from the trial from that day onwards

• VAP; in case of clinical suspicion of pneumonia, bronchoscopy with protected specimen brush (PSB) and bronchoalveolar lavage (BAL) was performed. Diagnosis was established when ≥ 3 of the following criteria were established: rectal temperature > 38°C or < 35.5°C; blood leucocytosis (> 10.10³³/mm³); and/or left shift or blood leucopaenia (< 3.10³/mm³); > 10 leucocytes per high‐power stain in gamma field of tracheal aspirate; or positive culture from tracheal aspirate, in combination with a new or progressive infiltrate on chest radiograph and the presence of a sample of secretions obtained by BAL (cutoff point ≥ 10⁴ cfu/mL) or protected specimen brush (cutoff point ≥ 10³ cfu/mL), positive cultures from blood, or pleural fluid culture unrelated to another space and obtained within 48 hours before and after respiratory sampling. Episodes of pneumonia obtained within the first 24 hours of admission were considered present on admission

Note: The mean number of days before the first episode of VAP was 9.2 in the antacid group and 9.3 in the sucralfate group, respectively.

• Duration of ICU stay

• All‐cause mortality in ICU

• All‐cause mortality in hospital

Outcomes sought but not reported in trial

• Duration of intubation

• Number of participants requiring blood transfusion

• Number of units of blood transfused

• Adverse events of interventions

Outcomes reported in report but not used in review

• Gastric pH monitoring

• Colonisation

• Post hoc analysis of the role of enteral feeding

Notes

Setting: University Hospital Maastricht, Maastricht, The Netherlands

Source of funding: Quote: "Supported by grant 28‐2125 from the Praevention Foundation"

Conflicts of interest: ‐

Ethics approval: Quote: "The protocol was approved by the institutional review board of the hospital"

Informed consent: Quote: "... informed consent was obtained from all participants or if this was not possible because of the clinical condition, from a representative of the family"

Clinical trials registration: ‐

Sample size calculation: Quote: "The sample size of both groups of patients was calculated to detect a reduction in the incidence of VAP from an assumed 30% in the antacid group to an expected incidence of 10% in the sucralfate group (α = 0.05 and β = 0.2)"

Additional notes: VAP was mainly polymicrobial in nature. Pseudomonas aeruginosa and Staphylococcus aureus were the 2 predominant pathogens cultured from participants with a diagnosis of VAP. The oropharynx was the initial site for colonisation ofEnterobacteriaceae, whereas Pseudomonas aeruginosa and Staphylococcus aureus colonised in the upper respiratory tract first

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Patients were stratified into two groups according to, the gastric pH values measured on the first day of admission which were < 3 (n = 69) or ≥ 3 (n = 72). These patients were later randomised to two treatment arms"
Comment: not enough information on method of sequence generation reported

Allocation concealment (selection bias)

Unclear risk

Quote: "Sucralfate and antacids were compared in a double blind fashion and analysed according to a prospectively developed plan that used definition adopted before the treatment allocation code was broken"

Comment: Allocation concealment might have been in place but not enough information was provided on method of allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The study had a "double dummy model" design wherein participants receiving sucralfate received an antacid placebo at the same time when antacid was administered to the other group and vice versa"

Quote: "Sucralfate and antacids were compared in a double blind fashion and analysed according to a prospectively developed plan that used definition adopted before the treatment allocation code was broken. The attending physician was unaware of the cultural results of the oropharyngeal and gastric samples, or results of pH monitoring"

Comment: Personnel (and participants) were unaware of therapy and results

Blinding (detection bias)
Clinically important upper GI bleeding

Unclear risk

Quote: "The study had a "double dummy model" design wherein participants receiving sucralfate received an antacid placebo at the same time when antacid was administered to the other group and vice versa"

Comment: The trial by design inherently blinded trial personnel who were assigned to endoscopically detect upper GI bleeding; however, criteria for diagnosis of upper GI bleeding were not clearly reported

Blinding (detection bias)
Nosocomial pneumonia

Low risk

Quote: "The study had a "double dummy model" design wherein participants receiving sucralfate received an antacid placebo at the same time when antacid was administered to the other group and vice versa"

Comment: The trial by design inherently blinded trial personnel who were assigned to diagnose VAP. Criteria for diagnosis of VAP were clearly reported

Blinding of outcome assessment (detection bias)
Adverse reactions of interventions

Low risk

Quote: "The study had a "double dummy model" design wherein participants receiving sucralfate received an antacid placebo at the same time when antacid was administered to the other group and vice versa"

Comment: The trial by design inherently blinded outcome assessors. Therefore, the likelihood of detection bias is low

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: No dropouts were reported, and all randomised participants were part of the final analysis.Therefore, there might not be an attrition bias

Selective reporting (reporting bias)

Low risk

Comment: All intended outcomes were reported and were part of the analysis.. A subgroup analysis for participants who received enteral feeds was desirable

Other bias

Low risk

Comment: Trial was supported by grant 28‐2125 from the Praevention Foundation. The role of the sponsor in the conduct and reporting of the trial is unclear

Methods

Quasi‐randomised controlled trial

Participants

Baseline characteristics

Number randomised: 100 participants

Number analysed: 100 participants

Antacids

• Age (years; mean (SD)): 57 (‐)

• Number of participants (n): 52

• Gender (male/female; n): 31/21

Sucralfate

• Age (years; mean (SD)): 62.2 (‐)

• Number of participants (n): 49

• Gender (male/female; n): 27/21

Inclusion criteria

• Patient admitted to medical or surgical ICU

Exclusion criteria

• Receiving fluids or food by mouth

• Having undergone cardiac, gastric, or oesophageal surgery

• Evidence of gross upper GI bleeding upon entry into the trial

Baseline imbalances: Quote: "There was no statistically significant difference between the sucralfate treated and the antacid treated groups in number of patients, sex"

Comment: Average numbers of risk factors per group were also similar; 92.5 and 83 participants had undergone an operation just before trial entry

Interventions

Antacids (Mylanta II)

• Dose (total/d): varied

• Duration of treatment (days): Until oral feedings began, NG tube was removed and patient was discharged from the ICU

• Route: NG tube

• Intervention: initial dose of 30 mL via NG tube. With pH < 3.5, dosage was progressively doubled until subsequent pH was > 3.5. Amphojel was substituted for Mylanta II in participants with severe diarrhoea and renal failure. In case of GI bleed, the last dose was doubled and the participant continued to receive that dose every hour

• Concomitant medications: NG tube was clamped in all participants for 1 hour after administration. If regurgitation occurred around the tube, or if the volume exceeded 150 mL at the end of 1 hour, the tube was clamped for 30 minutes and suction applied for the next 30 minutes, until aspirate was < 150 mL

Sucralfate

• Dose (total/d): 4 g

• Duration of treatment (days): Until oral feedings began, NG tube was removed and participant was discharged from ICU

• Route: NG tube

• Intervention: 1 g of sucralfate was administered in 30 mL of normal saline solution through NG tube followed by an additional gram every 6 hours (no dose changes were performed based on pH determinations)

• Concomitant medications: In case of GI bleed, sucralfate was discontinued and antacids started. The NG tube was clamped in all participants for 1 hour after administration. If regurgitation occurred around the tube or if volume exceeded 150 mL at the end of 1 hour, the tube was clamped for 30 minutes and suction applied for the next 30 minutes, until aspirate was less than 150 mL

Adherence to regimen: Quote: "Of the 52 patients treated with antacids, failure to achieve a pH of 3.5 or greater occurred in 8 patients initially given 30 mL of antacid. Five subsequently required 60 mL/hour and three required 120 mL/hour. All patients receiving antacids maintained a gastric pH of mote than 5"

Comment: Iced saline solution lavage was given to all participants with diagnosis of upper GI bleed (by Gastroccult test)

Duration of trial: August 1983 to December 1983

Duration of follow up: probably until discharge or death

Outcomes

Outcomes sought in review and reported in trial

• Clinically important GI bleeding defined as occurrence of any one of the following 3 findings

  • Frank or occult bleeding every hour or 3 consecutive dark‐blue reactions (Gastroccult paper test)

• Number of participants requiring blood transfusions (nil)

• All‐cause mortality in ICU

• Adverse events of interventions

Note: antacids 9 and 10 hours after start of the drug and sucralfate; 8, 41, and 45 hours after initiation of prophylaxis

Outcomes sought but not reported in trial

• VAP

• Duration of ICU stay

• Duration of intubation

• All‐cause mortality in hospital

• Number of units of blood transfused

Outcomes reported in trial but not used in review

• Cost‐effectiveness

• Nursing time required

Notes

Setting: Queens Hospital Centre, New York, USA

Source of funding: ‐

Conflicts of interest: ‐

Ethics approval: ‐

Informed consent: ‐

Clinical trials registration: ‐

Sample size calculation: ‐

Additional notes: No deaths were due to GI bleeding

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Quote: “100 patients admitted to medical and surgical intensive care units were randomised to receive either antacids and sucralfate depending on the year of birth (odd year, sucralfate; even year, antacid)”

Comment: This was a quasi‐randomised trial

Allocation concealment (selection bias)

High risk

Comment: This was a quasi‐randomised trial, and no information on allocation concealment was reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: no information on blinding reported

Blinding (detection bias)
Clinically important upper GI bleeding

Low risk

Comment: Blinding was not done. However, the outcome was measured as per the definition used in the trial protocol. Moreover, owing to the objective nature of the outcome of interest, the likelihood of detection and performance bias is low

Blinding (detection bias)
Nosocomial pneumonia

Unclear risk

Comment: The trial did not address this outcome

Blinding of outcome assessment (detection bias)
Adverse reactions of interventions

Unclear risk

Comment: no information on blinding or criteria to diagnose other outcomes reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: All randomised participants were included in the final analysis

Selective reporting (reporting bias)

Low risk

Comment: All intended outcomes were analysed and reported 

Other bias

Low risk

Comment: Source of funding is unclear. No other source of bias detected

Methods

Quasi‐randomised trial

Participants

Baseline characteristics

Number randomised: 155 participants

Number analysed: 155 participants

Antacids

• Age (years; mean (SD)): 57 (‐)

• Number of participants (n): 75

• Gender (male/female; n): 43/32

Sucralfate

• Age (years; mean (SD)): 61 (‐)

• Number of participants (n): 80

• Gender (male/female; n): 45/35

Inclusion criteria

• Participants with 1 or more of the following risk factors for GI bleeding

  • Hypotension

  • Major surgical procedure

  • Multiple trauma

  • Renal failure

  • Jaundice

  • Respiratory failure

  • Sepsis

• Participants from whom informed consent was obtained

Exclusion criteria

• Patient not satisfying inclusion criteria

Baseline imbalances: no statistically significant difference between sucralfate‐treated and antacid‐treated groups in numbers, age, and gender of participants. 130 participants (61 and 69 in each group) had undergone a major operation just before trial entry

Interventions

Antacids (Mylanta or Maalox)

• Dose (total/d): varied

• Duration of treatment (days): 2.54

• Route: NG tube

• Intervention: hourly according to the following schedule: 30 mL if pH of the gastric aspirate was ≥ 3.5 and 60 mL if pH was < 3.5

• Concomitant medications: NG tube was clamped for 55 minutes after drug administration. There was constant monitoring of cardiac, pulmonary, renal, hepatic, haematological, metabolic, and neurological parameters. Special attention was paid to the frequency of bowel movements, serum magnesium levels, and the appearance of a skin rash

Sucralfate

• Dose (total/d): 5 g

• Duration of treatment (days): 2.9

• Route: NG tube

• Intervention: 1 g of sucralfate was administered in 10 mL of water every 6 hours

• Concomitant medications: NG tube was clamped for 55 minutes after drug administration. There was constant monitoring of cardiac, pulmonary, renal, hepatic, haematological, metabolic, and neurological parameters. Special attention was paid to the frequency of bowel movements, serum magnesium levels, and the appearance of a skin rash

Adherence to regimen: not clearly mentioned in the trial report

Duration of follow‐up: Quote: “Patients were continued in the trial until the onset of gastrointestinal bleeding, until they were discharged from the critical care unit, or until nasogastric suction was discontinued. The patients’ clinical course was followed until they were discharged from the hospital”

Outcomes

Outcomes sought in review and reported in trial

• Clinically important GI bleeding defined as the occurrence of any 1 of the following 3 findings

  • Frank blood or 'coffee ground' aspirate from the nasogastric tube

  • Melena and a decline in haematocrit

  • Three consecutive dark‐blue reactions on Gastroccult slides

• All‐cause mortality in ICU

• Participants requiring blood transfusion (nil)

• Adverse events of interventions

Note: GI bleeding was tested for antacids 9 and 10 hours after initiating prophylaxis, and for sucralfate 8, 41, and 43 hours after initiating prophylaxis

Outcomes sought but not reported in trial

• VAP

• Duration of ICU stay

• Duration of intubation

• All‐cause mortality in hospital

• Number of units of blood transfused

Outcomes reported in trial but not used in review

• Cost‐effectiveness

• Nursing time required

• Ease of administration

Notes

Setting: Long Island Jewish Medical Centre and Queens Hospital Centre

Source of funding: ‐

Conflicts of interest: ‐

Ethics approval: Quote: "The study protocol was approved by the institutional review boards at Long island Jewish Medical Centre and Queens Hospital Centre"

Informed consent: Quote: "Informed consent was obtained from the patient or immediate relative"

Clinical trials registration: ‐

Sample size calculation: ‐

Additional notes: None of the deaths were due to GI bleeding

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Quote: "Patients were randomly assigned to one of the two treatment regimens according to their date of birth"; "participants born on even days were given antacids and those born on odd days were administered sucralfate"

Comment: This was a quasi‐randomised trial

Allocation concealment (selection bias)

High risk

Comment: This was a quasi‐randomised trial; no information on method of allocation concealment was reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: This was not a placebo‐controlled trial; the different interventions and their mode of administration might not have ensured blinding of personnel

Blinding (detection bias)
Clinically important upper GI bleeding

Low risk

Comment: unclear on blinding of outcome assessors. However, the outcome was measured as per the definition used in the trial protocol. Moreover, owing to the objective nature of the outcome of interest, the likelihood of detection and performance bias was judged as low

Blinding (detection bias)
Nosocomial pneumonia

Unclear risk

Comment: The trial did not address this outcome

Blinding of outcome assessment (detection bias)
Adverse reactions of interventions

Low risk

Comment: unclear on blinding of outcome assessors. However, outcomes of interest were objective in nature, so the likelihood of detection bias is low

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: All randomised participants were part of the final analysis

Selective reporting (reporting bias)

Low risk

Comment: All intended outcomes were analysed and reported 

Other bias

Low risk

Comment: Source of funding is unclear. No other source of bias is suspected

Methods

Quasi‐randomised trial

Participants

Baseline characteristics

Number randomised: 50 participants

Number analysed: 50 participants

Antacids

• Age (years; mean (SD)): 67.1 (‐)

• Number of participants (n): 25

• Gender (male/female; n): 19/6

Sucralfate

• Age (years; mean (SD)): 67.9 (‐)

• Number of participants (n): 25

• Gender (male/female; n): 19/6

Inclusion criteria

• Underwent abdominal aortic surgery

• Admitted to surgical ICU

Exclusion criteria

• Simultaneously underwent gastric or duodenal surgery

• History of peptic ulcer disease

Baseline imbalances: Quote: "There was no statistically significant difference between the sucralfate treated and the antacid treated groups in number of patients, sex, mean age [...] or number of risk factors per patient"

Comment: All participants had undergone aortobifemoral artery Dacron graft placement

Interventions

Antacids (Mylanta II)

• Dose (total/d): 30 mL

• Duration of treatment (days): until oral feedings began, NG tube was removed, and participant was discharged from ICU

• Route: NG tube

• Intervention: Participants received 30 mL of a commercial antacid through NG tube. Each hour, the tube was clamped and participant was placed on suction for 5 minutes

• Concomitant medications: NG tube was clamped in all participants for 1 hour after administration. If regurgitation occurred around the tube, or if the volume exceeded 150 mL at the end of 1 hour, the tube was clamped for 30 minutes and suction applied for the next 30 minutes, until aspirate was less than 150 mL

Sucralfate

• Dose (total/d): 4 grams

• Duration of treatment (days): until oral feedings began, NG tube was removed, and participant was discharged from ICU

• Route: NG tube

• Intervention: 1 gram suspended in 30 mL of normal saline solution through NG tube followed by 10 mL of normal saline solution every 6 hours to clear the NG tube of any adherent sucralfate

• Concomitant medications: NG tube was clamped in all participants for 1 hour after administration. If regurgitation occurred around the tube, or if the volume exceeded 150 mL at the end of 1 hour, the tube was clamped for 30 minutes and suction applied for the next 30 minutes, until aspirate was less than 150 mL

Adherence to regimen: Comment: Iced saline solution lavage was given to all participants with diagnosed upper GI bleeding

Duration of trial: August 1983 to December 1984

Duration of follow‐up: not clearly mentioned in the trial report; probably until discharge or death

Outcomes

Outcomes sought in review and reported in trial

Primary outcomes

• Clinically important GI bleeding defined as the occurrence of

  • Frank blood in the aspirate

  • Uniformly dark blue reaction on 3 consecutive readings

• All‐cause mortality in ICU

• Participants requiring blood transfusion

• Adverse events of interventions

Outcomes sought but not reported in trial report

• VAP

• Duration of ICU stay

• Duration of intubation

• All‐cause mortality in hospital

• Number of units of blood transfused

Outcomes reported in trial but not used in review

• Cost‐effectiveness

Notes

Settings: Long island Jewish Medical Centre, New Hyde Park, NY 11042

Source of funding: ‐

Conflicts of interest: ‐

Ethics approval: ‐

Informed consent: ‐

Clinical trials registration: ‐

Sample size calculation: ‐

Additional notes: None of the deaths were due to GI bleeding

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Quote: "…were randomised to receive either antacid or sucralfate, depending on their year of birth (odd year sucralfate, even year antacid)

Comment: quasi‐randomised trial

Allocation concealment (selection bias)

High risk

Comment: This was a quasi‐randomised trial; no information on method of allocation concealment was reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: This was not a placebo‐controlled trial; the different interventions and their mode of administration might not have ensured blinding of personnel

Blinding (detection bias)
Clinically important upper GI bleeding

Low risk

Comment: unclear on blinding of outcome assessors. However, GI bleeding was an objective outcome that was detected as per the definition used in the trial report

Blinding (detection bias)
Nosocomial pneumonia

Unclear risk

Comment: The trial did not address this outcome

Blinding of outcome assessment (detection bias)
Adverse reactions of interventions

Unclear risk

Comment: unclear on blinding of outcome assessors

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: All randomised participants were included in the final analysis

Selective reporting (reporting bias)

Low risk

Comment: All intended outcomes were analysed and reported 

Other bias

Low risk

Comment: Source of funding is unclear. No other source of bias is suspected

Methods

Open‐label parallel‐group trial

Participants

Baseline characteristics

Number randomised: 83 participants

Number analysed: 74 participants

Antacids

• Age (years; mean (SD)): 50 (18)

• Number of participants (n): 36

• Gender (male/female; n): 25/11

Sucralfate

• Age (years; mean (SD)): 54 (19)

• Number of participants (n): 38

• Gender (male/female; n): 29/9

Inclusion criteria

• Admitted to surgical, medical, or burn ICU

• Having major trauma, burns injury, postoperative complications, or major medical illness

• Entering the study within 48 hours of admission to ICU

• Remaining in the study for at least 12 hours

• Having a minimum of 2 risk factors necessary to predispose patient to stress‐related mucosal injury at the time of injury, such as respiratory failure, documented respiratory insufficiency, or pneumonia requiring mechanical ventilator assistance for longer than 24 hours; hypotension/shock requiring the use of pressor agents; sepsis; burns; renal failure; hepatic failure; central nervous system injury or coma; or severe cardiac decompensation

Exclusion criteria

• Having oesophageal, gastric, or duodenal mucosal disease; oesophageal variceal bleeding; or oesophageal or gastric surgery within past 6 months

• Receiving salicylates or NSAIDs, anti‐coagulants, or H2 receptor blocking agents

• Having GI bleeding (as demonstrated through nasogastric aspirates)

• Receiving oral feedings or tube feedings greater than 50 mL/h

• Age < 18 years

• Pregnancy

Baseline imbalances: The 2 groups were almost similar with respect to age, gender, and time from entry into ICU to random selection. However, the sucralfate group had more risk factors for bleeding on admission to the study when compared with the antacid group (respiratory failure was the most common ‐ 34 and 37 participants, respectively). Three participants in the antacid group had coagulopathy vs 1 participant in the antacid group. Two participants in the antacid group were given a diagnosis of pneumonia on admission

Interventions

Antacids (Maalox Therapeutic Concentration)

• Dose (total/d): varied

• Duration of treatment (hours; mean (range)): 57 (14‐297)

• Duration of follow‐up (days; mean (SD)): 21 (20)

• Route: ‐

• Intervention: 30 mL every 2 hours for maintaining gastric pH ≥ 4. If gastric pH was < 4, dosage was increased to 30 mL every hour, 60 mL every 2 hours, or 60 mL/h as needed to maintain pH ≥ 4

• Concomitant medications: ‐

Sucralfate

• Dose (total/d): 6 g

• Duration of treatment (hours, mean (range)): 60 (12‐360)

• Duration of follow‐up (days; mean (SD)): 20 (13)

• Route: NG tube

• Intervention: 1 g (10 mL) every 4 hours per nasogastric tube

• Concomitant medications: ‐

Adherence to regimen: Six participants from the antacid group (n = 42) and 3 from the sucralfate group (n = 41) were excluded from analysis for the following reasons: < 12 hours in the study (3 died, 2 enteral feeds, 1 severe diarrhoea, with treatment discontinued), received both interventions, had evidence of GI bleed before intervention, refused participation

Duration of trial: January 1984 to September 1985

Outcomes

Outcomes sought in review and reported in trial

• Incidence of clinically relevant upper GI bleeding defined as

  • Bright red blood in the nasogastric tube that was not cleared by a 2‐liter saline lavage

  • Decrease in haematocrit by more than 3 percentage points in 24 hours, accompanied by

    • Stool that yielded positive results when tested for occult blood with Haemoccult and no evidence of lower gastrointestinal bleed, or a decrease in haematocrit level of more than 6 percentage points in 48 hours with no evidence of extra gastrointestinal source or no evidence of lower gastrointestinal bleeding

• All‐cause mortality in ICU

• Number of participants requiring blood transfusion

• Adverse events of interventions

Outcomes sought but not reported in trial

• VAP

• All‐cause mortality in hospital

• Duration of ICU stay

• Duration of intubation

Outcomes reported in trial but not used in review

• Relationship between underlying risk factors and development of upper GI bleeding

• Gastric pH values

• Medicine doses missed

Notes

Setting: surgical, medical, or burn intensive care units at San Francisco General Hospital, USA

Source of funding: ‐

Conflicts of interest: ‐

Ethics approval: Quote: "The protocol was approved by the University of California, San Fransisco, Hum and Environmental protection committees (approval number 251701‐02)"

Informed consent: "obtained from all participants. If the participant was unable to provide informed consent, then the participant's next of kin or legally authorized representative provided consent. If they could not be contacted, then the participant's attending physician was asked to provide permission"

Clinical trials registration: ‐

Sample size calculation: ‐

Additional notes: One participant in each group had significant upper GI bleeding after the trial was completed

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: no information on sequence generation reported

Allocation concealment (selection bias)

Unclear risk

Comment: no information on allocation concealment reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: Participants and personnel involved in the trial were not blinded

Blinding (detection bias)
Clinically important upper GI bleeding

Low risk

Comment: GI bleeding was an objective outcome that was diagnosed as per the definition used in the trial protocol

Blinding (detection bias)
Nosocomial pneumonia

Unclear risk

Comment: Trial did not address this outcome

Blinding of outcome assessment (detection bias)
Adverse reactions of interventions

Unclear risk

Comment: unclear whether outcome assessors were blinded. Moreover, criteria for diagnosis of other outcomes of interest not clearly reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: Not all randomised participants were included in the final analysis (83 were randomised, 74 were included in the analysis). A per‐protocol analysis was done, as 9 participants were involved in the trial for less than 12 hours. There was no imbalance between groups. Therefore, low risk of bias is due to attrition

Selective reporting (reporting bias)

Unclear risk

Comment: not enough information reported on outcomes of relevance in the trial

Other bias

High risk

Comment: Source of funding is not clearly mentioned in the trial report. No other sources of bias are suspected, but insufficient information is reported in the trial abstract

Methods

Quasi‐randomised trial

Participants

Baseline characteristics

Number randomised: 51 participants

Number analysed: 51 participants

Famotidine

• Age (years; mean (SD)): 37 (17)

• Number of participants (n): 23

• Gender (male/female; n): 20/3

Lansoprazole

• Age (years; mean (SD)): 43 (22)

• Number of participants (n): 28

• Gender (male/female; n): 17/11

Inclusion criteria

• Admitted to neurosurgery ICU

• Prescribed stress ulcer prophylactic therapy during the study period

• Gastric pH < 4.0 before first dose of lansoprazole or famotidine

• One of the following risk factors for stress‐related mucosal disease (SRMD); head injury with altered mental status, acid–base disorder, multiple trauma, coagulopathy, multiple surgical procedures, hypotension > 1 hour, sepsis

Exclusion criteria

• GI bleeding

• Prior use of an anti‐secretory agent during admission

• History of gastric or duodenal ulcer

• Age < 18 years

• Allergies to famotidine or lansoprazole; pregnancy

• Anticipated need for stress ulcer prophylaxis (SUP) for < 3 days (OR)

• Renal compromise (creatinine clearance < 50 mL/min)

Baseline imbalances: "There were significantly more males than females in the study. Over 75% of the patients had a Glasgow Coma Scale (GCS) < 9, and median GCS scores were similar between the two groups. All of the patients had at least two risk factors for SRMD, and each treatment group had a similar number of patients with traumatic brain injuries. The median baseline gastric pH was 3.0 for both famotidine and lansoprazole groups"

Comment: There were more women in the lansoprazole group than in the famotidine group

Interventions

Famotidine

• Dose (total/d): 60 mg

• Duration of treatment (days; mean (SD)): > 3 (‐)

• Route: IV or PO

• Intervention: 20 mg IV every 12 hours, or orally 20 mg every 12 hours after 72 hours

• Concomitant medications: Most patients in this study received enteral nutrition by day 2

Lansoprazole

• Dose (total/d):

• Duration of treatment (days, mean (SD)): > 3 (‐)

• Route: nasogastric tube

• Intervention: 30 mg suspended in 10 mL of an 8.4% sodium bicarbonate solution or apple juice, and administered via NG tube daily

• Concomitant medications: Most patients in this study received enteral nutrition by day 2