Definition of stratification variables
Site: all participating intensive care units (ICUs) will be assigned a number identifying the department.
Haematological malignancy includes any of the following:
Leukemia: acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL).
Lymphoma: Hodgkin’s disease, non-Hodgkin lymphoma (e.g. small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), hairy cell leukemia (HCL), marginal zone lymphoma (MZL), Burkitt’s lymphoma (BL), post-transplant lymphoproliferative disorder (PTLD), T-cell prolymphocytic leukemia (T-PLL), B-cell prolymphocytic leukemia (B-PLL), Waldenström’s macroglobulinemia, other NK- or T-cell lymphomas.
Multiple myeloma/plasma cell myeloma.
Definition of inclusion criteria
Acute admission to the ICU: a non-planned admission. It does not include planned recovery after surgery or similar planned admissions. ICU admission does not include admissions to semi-intensive care, intermediate intensive care or similar beds.
Age: the age of the patient in whole years at the time of randomisation. The age will be calculated from date of birth.
Shock: at least one of the following:
Systolic pressure below 90 mmHg
Mean arterial pressure below 70 mmHg
Use of vasopressors or inotropes (norepinephrine, epinephrine, phenylephrine, vasopressin or dopamine, dobutamine, milirinone or levosimendan)
Lactate level 4 mmol/l or above
Renal replacement therapy: acute or chronic intermittent or continuous renal replacement therapy.
Patients with expected duration of invasive mechanically ventilation longer than 24 hours: the treating clinician estimates that the patient will be invasively mechanically ventilated for more than 24 hours. When there is doubt about this forecast the patient should be enrolled.
Coagulopathy: platelets below 50 × 109/l or international normalised ratio (INR) above 1.5 or prothrombin time (PT) above 20 s documented within the last 24 hours.
Treatment with anticoagulant drugs: ongoing treatment with: dipyridamole, vitamin K antagonists, ADP-receptor inhibitors, therapeutic doses of low-molecular-weight heparin, new oral anticoagulant drugs, intravenous direct thrombin (II) inhibitors and similar drugs.
Acetylsalicylic acid (all doses) and low-molecular-weight heparin in prophylactic doses are not included.
History of coagulopathy: coagulopathy defined as platelets below 50 × 109/l and/or INR above 1.5 and/or PT above 20 s within the 6 months prior to hospital admission.
History of chronic liver disease: portal hypertension, cirrhosis proven by biopsy, CT scan or ultrasound, history of variceal bleeding or hepatic encephalopathy in the past medical history.
Definition of exclusion criteria
Contraindications to proton pump inhibitors (PPIs): any history of intolerance to PPIs or additives or treatment with atazanavir (HIV medication).
Ongoing treatment with PPIs and/or histamine-2-receptor antagonists (H2RAs): ongoing, documented daily treatment with the drugs in the patient charts.
Gastrointestinal (GI) bleeding during current hospital admission: GI bleeding of any origin (both upper and lower) documented in the patient charts.
Peptic ulcer: peptic ulcer confirmed by endoscopy or other method during current hospital admission.
Organ transplant: any kind of organ transplant during current hospital admission.
Withdrawal from active therapy or brain death: patients where withdrawal or brain death is documented in the patient charts.
Known pregnancy: fertile woman with a positive test for urinary or plasma human chorionic gonadotropin (hCG).
Consent not obtainable according to national regulations: patients where the clinician or investigator is unable to obtain the necessary consent before inclusion of the patient according to the national regulations.
Definition of baseline variables
Sex: the genotypic sex of the patient.
Age: defined in inclusion criteria.
Date of admission to hospital: the date of admission to the first hospital the patient was admitted to during the current hospital admission.
Elective surgery: surgery during the current hospital admission scheduled 24 hours or more in advance.
Emergency surgery: surgery during current hospital admission that was added to the operating room schedule 24 hours or less prior to that surgery.
Medical admission: when no surgery has been performed during the current hospital admission or surgery has been performed more than 1 week prior to ICU admission.
Treatment with anticoagulants at hospital admission and at ICU admission: anticoagulants are defined in the inclusion criteria.
Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid at hospital admission: treatment with all doses of these drugs at hospital admission.
Treatment with intravenous thrombolysis: treatment with all kinds of intravenous thrombolysis within 3 days prior to randomisation.
Coagulopathy: defined in the inclusion criteria.
Treatment of suspected or confirmed Clostridium difficile infection (CDI) during current hospital admission.
Coexisting illnesses must have been present in the past medical history prior to ICU admission and are defined as follows:
Chronic lung disease: chronic obstructive pulmonary disease (COPD), asthma or other chronic lung disease or treatment with any relevant drug indicating this at admission to hospital
Previous myocardial infarction: history of myocardial infarction
Chronic heart failure: New York Heart Association (NYHA) functional class III–IV. NYHA class III: the patient has marked limitations in physical activity due to symptoms (fatigue, palpitation or dyspnoea) even during less than ordinary activity (walking short distances 20–100 m or walking up one flight of stairs). The patient is only comfortable at rest. NYHA class IV: the patient is not able to carry out any physical activity (without discomfort (fatigue, palpitation or dyspnoea). Symptoms are present even at rest and the patient is mostly bedbound
History of chronic renal failure: need of any form of chronic renal replacement therapy within the last year
Liver disease: defined in baseline variables
History of coagulopathy: defined in baseline variables
Immunosuppression: patients treated with at least 0.3 mg/kg/day of prednisolone equivalent for at least 1 month in the 6 months prior to ICU admission
Metastatic cancer: proven metastasis by surgery, CT scan or any other method
Haematological malignancy: defined as stratification variable
AIDS: HIV-positive patients with one or more HIV-defining diseases such as Pneumocystis jerovechii pneumonia, Kaposi’s sarcoma, lymphoma, tuberculosis or toxoplasma infection
The Simplified Acute Physiology Score (SAPS II) is based on the most extreme (highest or lowest) values from 24 hours prior to randomisation. The score consists of 17 variables: 12 physiological variables, age, type of admission, and 3 variables related to underlying disease, to give a total score ranging from 0 to 163, with higher scores indicating greater illness severity. The score will be calculated from data from the 24 hours prior to randomisation.
The Sequential Organ Failure Assessment (SOFA) score will be calculated from raw physiology and treatment data from the 24 hours prior to randomisation. The SOFA score consists of weightings for six organ systems to give a total score ranging from 0 to 24, with higher scores indicating a greater degree of organ failure.
Definition of daily collected variables
Delivery of trial medication: confirmation of administration of the trial drug.
Treatment with a PPI or a H2RA: prescription of any of these drugs in any dose (major protocol violation if the treatment is initiated (e.g. as prophylaxis) without clinical indication (e.g. GI bleeding).
Mechanical ventilation: invasive and non-invasive mechanical ventilation including continuous mask continuous positive airway pressure (CPAP) or CPAP via a tracheotomy. Intermittent CPAP is not mechanical ventilation.
Circulatory support: continuous infusion of vasopressor or inotrope (norepinephrine, epinephrine, phenylephrine, vasopressin or dopamine, dobutamine, milirinone or levosimendan).
Renal replacement therapy: any form of renal replacement therapy on this day. In patients receiving intermittent renal replacement therapy days between treatments are included.
Clinically important GI bleeding, onset of pneumonia, CDI, and acute myocardial ischaemia in the ICU are defined as outcomes.
Treatment with enteral feeding: any dose of enteral feeding (including oral nutritional intake) during the day.
Units of red blood cells: cumulated number of units of red blood cells transfused during the day.
Serious adverse reactions (SARs) are defined below.
Definition of bleeding variables
Confirmed diagnosis: diagnosis/origin of bleeding confirmed by endoscopy or other method.
Verification of ulcer/gastritis/bleeding oesophageal varices: confirmation of one of the three specific diagnoses by endoscopy or other method.
Haemostasis achieved or attempted: documentation in patient charts of haemostasis achieved or attempted by endoscopy, open surgery or coiling.
Definitions of outcome measures
90-day mortality: death from any cause within 90 days following the day of randomisation.
proportion of patients with one or more of the following adverse events: clinically important GI bleeding, pneumonia, CDI, and acute myocardial ischaemia. The events are defined as follows:
Clinically important GI bleeding: overt GI bleeding* and at least one of the following four features within 24 hours of GI bleeding (in the absence of other causes) in the ICU:
Spontaneous drop of systolic blood pressure, mean arterial pressure or diastolic blood pressure of 20 mmHg or more
Start of vasopressor or a 20 % increase in vasopressor dose
Decrease in haemoglobin of at least 2 g/dl (1.24 mmol/l)
Transfusion of two units of packed red blood cells or more
*Overt GI bleeding: haematemesis, coffee ground emesis, melaena, haematochezia or bloody nasogastric aspirate.
Pneumonia: episodes of newly confirmed pneumonia according to the modified CDC criteria :
Two or more serial chest radiographs with at least one of the following (one radiograph is sufficient for patients with no underlying pulmonary or cardiac disease):
New or progressive and persistent infiltrate
and at least one of the following:
Fever (above 38 °C) with no other recognised cause
Leucopoenia (white cell count below 4 × 109/l) or leucocytosis (white cell count above 12 × 109/l)
and at least two of the following:
New onset of purulent sputum or change in character of sputum, or increased respiratory secretions or increased suctioning requirements
New onset or worsening cough, or dyspnoea, or tachypnoea
Rales or bronchial breath sounds
Worsening gas exchange (hypoxaemia, increased oxygen requirement, increased ventilator demand)
CDI: treatment with antibiotics (enteral vancomycin, intravenous or enteral metronidazole, enteral fidaxomicin) for suspected or proven CDI.
Acute myocardial ischemia: ST elevation myocardial infarction, non-ST elevation myocardial infarction or unstable angina pectoris according to the criteria in the clinical setting in question (e.g. elevated biomarkers, ischaemic signs on an electrocardiogram (ECG) and clinical presentation) and receiving treatment as a consequence of this (reperfusion strategies (percutaneous coronary intervention(PCI)/thrombolysis) or initiation/increased antithrombotic treatment).
Proportions of patients with clinically important GI bleeding: proportion of patients with one or more episodes of clinically important GI bleeding as defined above.
Proportion of patients with one or more infectious adverse events: proportion of patients with one or more episodes of pneumonia or CDI.
One-year mortality: landmark mortality 1 year post randomisation.
Duration of life support in the ICU: the number of days alive and free from respiratory or circulatory support and off renal replacement therapy as defined below. The outcome will be days alive without the use of mechanical ventilation, circulatory support or renal replacement therapy in the 90-day period, and will be defined as the percentage of days without mechanical ventilation, circulatory support, and renal replacement therapy (as defined in daily collected variables) in the 90 days after randomisation.
SARs: number of SARs as defined below.
The elements of all composite outcomes will be reported in the supplementary material.
A health economic analysis will be performed. The analytic details will be based on the result of the trial and specified (cost-benefit versus cost-minimisation analyses).
Definitions of serious adverse reactions (SARs)
A SAR is defined as any adverse reaction that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, or results in persistent or significant disability or incapacity.
Patients will be monitored for onset of SARs occurring between the first dose of trial medication and until discharge from the ICU. If the patient is readmitted to the ICU and trial intervention is reintroduced, data collection for SARs will be resumed. If a patient experiences a SAR the patient will be withdrawn from the trial intervention but data collection and follow-up will be continued (see section 4.3.2).
SARs will be defined as follows:
Anaphylactic reactions defined as urticaria and at least one of the following:
Worsened circulation (more than 20 % decrease in blood pressure or more than 20 % increase in vasopressor dose)
Increased airway resistance (more than 20 % increase in the peak pressure on the ventilation)
Clinical stridor or bronchospasm
Subsequent treatment with bronchodilators
Agranulocytosis is defined as any new, acute and severe drop in granulocytes to below 0.5 × 109/l requiring active monitoring or treatment.
Pancytopenia is defined as any new, severe drop in red blood cells, white blood cells and platelets requiring active monitoring or treatment.
Acute hepatic failure is defined as severe and progressing hepatic failure as judged by the treating physician or the investigator.
Stevens-Johnson syndrome and toxic epidermal necrolysis are defined as severe dermatological reactions with a skin biopsy confirming the diagnosis.
Interstitial nephritis is defined as a nephritis affecting the interstitium of the kidneys surrounding the tubules with a kidney biopsy confirming the diagnosis.
Angioedema (Quincke’s oedema) is defined as a vascular reaction involving the deep dermis, subcutaneous or submucosal tissues, resulting in a characteristic localised oedema.