| Methods |
Multi‐centre open‐label randomised controlled trial |
| Participants |
Baseline characteristics
Number randomised: 202 participants
Number analysed: 202 participants
Pantoprazole (40 mg per 24 hours)
Age (years; mean (SD)): 42.3 (21.8) Number of participants (n): 32 Gender (male/female; n): 22/10
Pantoprazole (40 mg per 12 hours)
Age (years; mean (SD)): 38.7 (18) Number of participants (n): 38 Gender (male/female; n): 24/14
Pantoprazole (80 mg per 24 hours)
Age (years; mean (SD)): 33.5 (15.5) Number of participants (n): 23 Gender (male/female; n): 15/8
Pantoprazole (80 mg per 12 hours)
Age (years; mean (SD)): 42.3 (19.2) Number of participants (n): 39 Gender (male/female; n): 29/10
Pantoprazole (80 mg per 8 hours)
Age (years; mean (SD)): 41.3 (16.4) Number of participants (n): 35 Gender (male/female; n): 28/7
Cimetidine
Age (years; mean (SD)): 44.5 (17.5) Number of participants (n): 35 Gender (male/female; n): 27/8
Inclusion criteria
Written informed consent obtained Unique patient ID assigned Male or non‐pregnant female Age ≥ 18 years One of the risk factors for stress‐related upper GI bleeding Postoperative major surgery Major trauma (head, chest, abdomen, or limbs) Hypovolumic shock defined clinically as a syndrome of inadequate tissue perfusion characterised by systolic blood pressure < 90 mmHg (or a decrease of 30 mmHg in previously hypertensive patients) and metabolic acidosis Sepsis, including peritonitis, confirmed or suspected bacteraemia, complex of fever, increased leucocyte count -
Acute respiratory failure, defined as 1 of the following:
Need for mechanically assisted ventilation Severe hypoxaemia with an oxygen deficit great enough to require a fraction of inspired oxygen (FiO2) of 0.31 by mask or at least 2 L/min of oxygen by nasal prongs to maintain 90% oxygen saturation Acute hypoventilation resulting in an arterial blood pH < 7.34
Burns involving ≥ 30% of body surface area Coagulopathy defined as a platelet count < 50,000 mm² or increased international normalised ratio or partial thromboplastin time > 1.5 times upper normal limit Baseline gastric aspirate that was clear (defined as no particulate matter, clots, or 'coffee grounds' and no red or brown colour, bile‐tinged fluid was allowed) with no more than moderate positivity for occult blood on Gastroccult testing
Exclusion criteria
Known hypersensitivity to PPIs Pregnancy Any condition known to compromise patient safety, according to the investigator Intubated for more than 24 hours at the time of drug administration ICU admission following oesophageal, gastric, or duodenal surgery or acute illicit drug overdose History of gastrectomy or UGI lesion with the potential for haemorrhage History of hypersecretory conditions like Zollnger‐Ellison Syndrome Existence of peptic ulcer diseases within 1 year of study entry (on any of the study drugs immediately before or during the study) Inability to tolerate NG tube Previous participation in the study Clinical signs and symptoms/documentation of aspiration (or documentation of aspiration on the screening chest X‐ray) Suspected/documented pneumonia
Baseline characteristics: Groups were similar with respect to age, gender, and race. Trauma was the main cause for admission, and coagulopathy was present in 2 participants from the pantoprazole group |
| Interventions |
Pantoprazole
Dose (total/d): 200 mg Duration of treatment (days): 2 to 7 Route: ‐ Intervention: 40 mg per 24 hours, 40 mg per 12 hours, 80 mg per 24 hours, 80 mg per 12 hours, 80 mg per 8 hours Concomitant medications: Enteral feeding was given to 50 participants
Cimetidine
Dose (total/d): (300mg bolus +) 120 mg Duration of treatment (days): 2 to 7 Route: IV Intervention: continuous infusion of cimetidine (300‐mg bolus followed by 5‐mg/h infusion) simultaneous intervention of external feeding for selected patients based on physician's opinion Concomitant medications: Enteral feeding was given to 4 participants
Adherence to regimen: Quote: "Subjects received study medication within 24 hours of the precipitating stress event and treatment was to be continued for at least 48 hours and up to 7 days. Patients were considered as completers if they received the study medication as described and participated in the study for at least 48 hours"
Of 202 participants, 144 remained NPO, while 58 participants were switched over to enterally feed, mainly on day 2 (48 participants)
"32 patients (16%) prematurely discontinued from the study. The most frequent reason for premature discontinuation was removal or inability to maintain tolerate NG/OG tube. Other reasons for premature discontinuation from the study included adverse events (3 in total, 2 in pantoprazole and 1 in cimetidine) or legal guardian request"
Duration of trial: June 2000 to September 2001
Duration of follow up: up to 30 days |
| Outcomes |
Outcomes sought in review and reported in trial (none of these were primary outcomes of interest for this study)
Incidence of upper GI bleeding occurring anytime during the study up to the last dose of study medication. Defined mainly as presence of haematemesis or bright red blood in gastric aspirate that did not clear after adjustment of nasogastric or orogastric tube and a 5 to 10 minute lavage with iced water or saline. Persistant 'coffee ground' material for 8 consecutive hours that did not clear with 100 mL of lavage, or was accompanied by 5% decrease in haematocrit. A decrease in haematocrit requiring one or more transfusions that occurred in the absence of any obvious source and required further diagnostic studies. Malena or frank bloody stools from upper gastrointestinal sources Incidence of ventilator‐associated pneumonia defined as radiographic findings of a new or evolving infiltrate in the chest X ray, fever, elevated white blood cell count > 15% immature neutrophils (band) or leucopaenia, presence of at least 3 of the following: new or increased cough, new onset of purulent sputum production or a change in the character of the sputum, auscultatory findings on pulmonary examination of rales or evidence of pulmonary consolidation Dyspnoea, tachypnoea, or respiratory rates ≥ 20 breaths/min Hypoxaemia with PaO2 < 60 mmHg or oxygen saturation < 90%, while the patient was breathing room air, or respiratory failure requiring mechanical ventilation, tachycardia, pleuritic chest pain, new or worsened confusion All‐cause mortality in ICU Adverse events of interventions
Outcomes sought but not reported in trial
All‐cause mortality in hospital Duration of ICU stay Duration of intubation Participants requiring blood transfusions Units of blood transfused
Outcomes reported but not used in review
|
| Notes |
Setting: 14 ICU centres across the United States
Source of funding: Quote: "Supported by Wyeth Pharmaceuticals, Collegeville, PA"
Ethics approval: Quote: "The study conducted according to declaration of Helsinki and its amendments. and was approved by the independent ethics committee or institutional review board at each ICU centre"
Informed consent: Quote: "Written informed consent was obtained from all patients or their legal representatives before enrolment"
Clinical trials registration: ‐
Sample size calculation: The sample size of 30 patients per group was chosen based on a common standard deviation of 24% for the primary end point (pH response associated with each treatment group), and there was approximately 80% power to detect a mean difference of 18% for treatment group comparisons
Additonal notes:H influenzae was one of the most common bacterial isolates among participants who developed pneumonia. The pantoprazole arms were combined to form a common interventional arm vs the H2 receptor antagonist as the review did not aim to investigate efficacy on the basis of dose or mode of administration in the same drug |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Low risk |
Quote: "...the study centre called the central randomisation centre to obtain the treatment assignment..."
Comment: Sequence generation was probably done |
| Allocation concealment (selection bias) |
Low risk |
Quote: "...the study centre called the central randomisation centre to obtain the treatment assignment..."
Comment: Allocation was probably concealed |
| Blinding of participants and personnel (performance bias)
All outcomes |
Unclear risk |
Quote: "One physician per patient remained blinded to the patients treatment assignment and pH data to assess patient’s safety”
Comment: Each patient had a physician in charge, who was blinded. Unclear on how this was possible, as it is not a placebo‐controlled trial, and all other personnel were aware of the intervention |
| Blinding (detection bias)
Clinically important upper GI bleeding |
Low risk |
Comment: unclear on blinding of outcome assessors. GI bleeding was an objective outcome detected as per the definition in the study protocol |
| Blinding (detection bias)
Nosocomial pneumonia |
Low risk |
Comment: unclear on blinding of outcome assessors. VAP was detected as per the definition in the study protocol |
| Blinding of outcome assessment (detection bias)
Adverse reactions of interventions |
Low risk |
Comment: unclear on blinding of outcome assessors. However, owing to the objective nature of the outcomes of interest, the likelihood of detection bias is low |
| Incomplete outcome data (attrition bias)
All outcomes |
Low risk |
Comment: All randomised participants completed the trial and were included in the final analysis. There were no treatment withdrawals and no trial group changes |
| Selective reporting (reporting bias) |
Low risk |
Comment: All intended outcomes were analysed and reported |
| Other bias |
Low risk |
Comment: Study was supported by Wyeth Pharmaceuticals, Collegeville, PA. The role of the sponsor in the conduct and reporting of the trial is unclear |
