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| Name | Class |
|---|---|
| Rigshospitalet, Denmark | OTHER |
| Centre for Research in Intensive Care (CRIC) | OTHER |
| Scandinavian Critical Care Trials Group | OTHER |
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The purpose of this trial is to assess patient important benefits and harms of IV fluid restriction vs. standard care fluid therapy in patients with septic shock.
BACKGROUND:
Septic shock is common, often lethal, costly, and associated with prolonged suffering among survivors and relatives. Traditionally, intravenous (IV) fluids are used to optimise the circulation, and the use of higher volumes is recommended by international guidelines. There is, however, no high-quality evidence to support this. In contrast, data from cohort studies, small trials and systematic reviews in sepsis and large trials in other settings and patient groups suggest potential benefits from restriction of IV fluids in patients with septic shock.
OBJECTIVES:
The aim of the CLASSIC trial is to assess the benefits and harms of IV fluid restriction vs. standard care on patient-important outcome measures in adult intensive care unit (ICU) patients with septic shock.
DESIGN:
CLASSIC is an international, multicentre, parallel-grouped, open-labelled, centrally randomised, stratified, outcome assessor- and analyst-blinded trial.
POPULATION:
Adult ICU patients who have septic shock and have received at least 1 L of IV fluid in the last 24-hours.
EXPERIMENTAL INTERVENTION:
In the IV fluid restriction group no IV fluids should be given in the ICU unless extenuating circumstances occur, including signs of severe hypoperfusion, overt fluid loss or a failing GI tract with a total fluid input of less than 1 L per day. In these circumstances, IV fluid may be given in measured amounts.
CONTROL INTERVENTION:
In the standard care group there will be no upper limit for the use of IV fluids.
OUTCOMES:
The primary outcome is 90-day mortality; secondary outcomes are serious adverse events in the ICU (ischemic events or severe acute kidney injury); serious adverse reactions in the ICU; days alive without life support at day 90; days alive and out of hospital at day 90 and mortality, health-related quality of life and cognitive function at 1-year.
TRIAL SIZE:
A total of 1554 participants will be randomised to allow the detection of a 15% relative risk reduction (7% absolute) in the restrictive vs. standard care group in 90-day mortality with a power of 80%.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Fluid restriction group | Experimental | No IV fluids unless one of the extenuating circumstances occur; then, IV fluid may be given in measured amounts:
IV fluids may be given as carrier for medication, but the volume should be reduced to the lowest possible |
|
| Standard-care | Active Comparator | There will be no upper limit for the use of either IV or oral/enteral fluids. In particular:
|
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Isotonic crystalloids | Drug | Types of fluid to be used in both intervention groups:
|
| Measure | Description | Time Frame |
|---|---|---|
| 90-day Mortality | Al cause mortality at 90 days | Day 90 after randomisation |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With One or More Serious Adverse Events (SAEs) in the ICU | SAEs were defined as ischaemic events (cerebral, cardiac, intestinal or limb ischaemia) or as a new episode of severe acute kidney injury (modified KDIGO-3) | Until ICU discharge, maximum 90 days |
| Number of Participants With One or More Serious Adverse Reactions (SARs) to IV Crystalloids in the ICU. |
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Inclusion Criteria:
All the following criteria must be fulfilled:
Aged 18 years or above
Admitted to the ICU or plan to be admitted to the ICU regardless of trial participation
Septic shock defined according to the Sepsis-3 criteria:
Have received at least 1 L of IV fluid (crystalloids, colloids or blood products) in the last 24-hours prior to screening.
Exclusion Criteria:
Patients who fulfil any of the following criteria will be excluded:
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| Name | Affiliation | Role |
|---|---|---|
| Tine Sylvest Meyhoff, MD | Rigshospitalet, Denmark | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Brussels (UZB) | Brussels | Belgium | ||||
| Medical Intensive Care Unit, Fakultni Nemocnice |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27686349 | Background | Hjortrup PB, Haase N, Bundgaard H, Thomsen SL, Winding R, Pettila V, Aaen A, Lodahl D, Berthelsen RE, Christensen H, Madsen MB, Winkel P, Wetterslev J, Perner A; CLASSIC Trial Group; Scandinavian Critical Care Trials Group. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med. 2016 Nov;42(11):1695-1705. doi: 10.1007/s00134-016-4500-7. Epub 2016 Sep 30. | |
| 35709019 |
| Label | URL |
|---|---|
| Official study website | View source |
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No patients were excluded from the trial prior to group assignment.
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| ID | Title | Description |
|---|---|---|
| FG000 | Fluid Restriction Group | No IV fluids unless one of the extenuating circumstances occurred (additional details in protocol section) |
| FG001 | Standard-care | No upper limit for IV fluids (additional details in protocol section). |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Randomization |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jun 23, 2022 | Sep 27, 2022 |
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Outcome assessor- and analyst-blinded trial
|
The pre-specified SARs to IV crystalloids were: Generalized tonic-clonic seizures, anaphylactic reactions, central pontine myelinolysis, severe hypernatremia, severe hyperchloremic acidosis, and severe metabolic alkalosis. Data on the outcome measures, including SARs, were obtained from patient medical records by the trial investigators or their delegates. |
| Until ICU discharge, maximum 90 days |
| Days Alive at Day 90 Without Life Support (Vasopressor / Inotropic Support, Invasive Mechanical Ventilation or Renal Replacement Therapy) | Until ICU discharge, maximum 90 days |
| Days Alive and Out of Hospital at Day 90 | Day 90 after randomisation |
| All-cause Mortality at 1-year After Randomisation | 1-year after randomisation |
| Health-related Quality of Life 1 Year After Randomisation | Measured using the EuroQoL EQ-5D-5L questionnaire (comprising 5 questions with a score from 1 to 5 each and a visual analogue scale from 0 to 100). Participants who have died will be assigned the lowest possible scores. | 1 year after randomisation |
| Cognitive Function 1-year After Randomisation | Assessed by the Montreal Cognitive Assessment (MoCa) MINI score validated for telephone use. Mini MoCA consists of 4 cognitive dimensions: attention (immediate recall of 5 words), executive functions and language (1-min verbal fluency), orientation (6 items on date and geographic orientation), and memory (delayed recall and recognition of 5 previously learned words). The total score ranges from 0 to 30, with lower values indicating worse cognitive function. To correct for any educational effect on the cognitive test, 1 point is added for participants with 12 years of education or less (scores were truncated at the maximum upper value of 30 points) Participants who had died were assigned the value 0. | 1-year after randomisation |
| Pilsen |
| Czechia |
| Dept. of Anaesthesia and Intensive Care, Aalborg University Hospital, Denmark. | Aalborg | Denmark |
| Dept of Intensive Care,Copenhagen University Hospital Rigshospitalet | Copenhagen | 2100 | Denmark |
| Dept. of Anaesthesia and Intensive Care, Bispebjerg Hospital | Copenhagen | Denmark |
| Dept. of Anaesthesia and Intensive Care, Herning Hospital | Herning | Denmark |
| Dept. of Intensive Care, Hillerød Hospital | Hillerød | 3400 | Denmark |
| Dept. of Anaesthesia and Intensive Care, Holbæk Hospital | Holbæk | Denmark |
| Dept. of Anaesthesia and Intensive Care, Lillebaelt Hospital | Kolding | Denmark |
| Dept. of Anaesthesia and Intensive Care, Zealand University Hospital Køge | Køge | Denmark |
| Dept. of Anaesthesia and Intensive Care, Randers Hospital | Randers | Denmark |
| Dept. of Anaesthesia and Intensive Care, Zealand University Hospital Roskilde | Roskilde | Denmark |
| Dept. of Anaesthesia and Intensive Care, Viborg Hospital | Viborg | Denmark |
| Humanitas research hospital Bergamo | Bergamo | Milan | Italy |
| Dept. of Intensive Care, Humanitas Research Hospital Castelanza | Castellanza | Milan | Italy |
| Dept. of Intensive Care, Ancona Hospital | Ancona | Italy |
| Dept. of Intensive Care, Humanitas Research Hospital | Milan | Italy |
| Dept. of intensive care, Østfold, Kalnes | Grålum | Norway |
| Dept. of intensive Care, Innlandet Hamar | Hamar | Norway |
| Dept. of Intensive Care, Oslo University Hospital | Oslo | 0450 | Norway |
| Dept. of Intensive Care Medicine, Stavanger | Stavanger | Norway |
| Dept. of Intensive Care Medicine, St Göran | Gothenburg | Sweden |
| Dept. of intensive care, Huddinge | Huddinge | Sweden |
| MIMA Medicinsk intermediärvårdsavdelning | Huddinge | Sweden |
| Dept. of Intensive Care, Solna | Solna | Sweden |
| Medical ICU, Karolinska, Södersjukhuset | Stockholm | Sweden |
| Södersjukhuset | Stockholm | Sweden |
| Dept. of Intensive Care Medicine Sundsvall Hospital | Sundsvall | Sweden |
| Dept. of intensive care, Basel | Basel | Switzerland |
| Dept. of Intensive Care, University Hospital Bern | Bern | Switzerland |
| Dept. of Intensive Care Unit, Guy's and St. Thomas' Hospital | London | United Kingdom |
| Background |
| Meyhoff TS, Hjortrup PB, Wetterslev J, Sivapalan P, Laake JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M, Ostermann M, Malbrain M, Pettila V, Moller MH, Kjaer MN, Lange T, Overgaard-Steensen C, Brand BA, Winther-Olesen M, White JO, Quist L, Westergaard B, Jonsson AB, Hjortso CJS, Meier N, Jensen TS, Engstrom J, Nebrich L, Andersen-Ranberg NC, Jensen JV, Joseph NA, Poulsen LM, Herlov LS, Solling CG, Pedersen SK, Knudsen KK, Straarup TS, Vang ML, Bundgaard H, Rasmussen BS, Aagaard SR, Hildebrandt T, Russell L, Bestle MH, Schonemann-Lund M, Brochner AC, Elvander CF, Hoffmann SKL, Rasmussen ML, Martin YK, Friberg FF, Seter H, Aslam TN, Adnoy S, Seidel P, Strand K, Johnstad B, Joelsson-Alm E, Christensen J, Ahlstedt C, Pfortmueller CA, Siegemund M, Greco M, Radej J, Kriz M, Gould DW, Rowan KM, Mouncey PR, Perner A; CLASSIC Trial Group. Restriction of Intravenous Fluid in ICU Patients with Septic Shock. N Engl J Med. 2022 Jun 30;386(26):2459-2470. doi: 10.1056/NEJMoa2202707. Epub 2022 Jun 17. |
| 31276193 | Background | Meyhoff TS, Hjortrup PB, Moller MH, Wetterslev J, Lange T, Kjaer MN, Jonsson AB, Hjortso CJS, Cronhjort M, Laake JH, Jakob SM, Nalos M, Pettila V, van der Horst I, Ostermann M, Mouncey P, Rowan K, Cecconi M, Ferrer R, Malbrain MLNG, Ahlstedt C, Hoffmann S, Bestle MH, Nebrich L, Russell L, Vang M, Rasmussen ML, Solling C, Rasmussen BS, Brochner AC, Perner A. Conservative vs liberal fluid therapy in septic shock (CLASSIC) trial-Protocol and statistical analysis plan. Acta Anaesthesiol Scand. 2019 Oct;63(9):1262-1271. doi: 10.1111/aas.13434. Epub 2019 Jul 24. |
| 40272936 | Derived | Sivapalan P, Kaas-Hansen BS, Meyhoff TS, Hjortrup PB, Kjaer MN, Laake JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M, Ostermann M, Malbrain MLNG, Moller MH, Perner A, Granholm A. Effects of IV Fluid Restriction According to Standard Fluid Treatment Intensity Across Conservative Versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) Trial Sites. Crit Care Med. 2025 Aug 1;53(8):e1590-e1600. doi: 10.1097/CCM.0000000000006679. Epub 2025 Apr 24. |
| 38576165 | Derived | Sivapalan P, Kaas-Hansen BS, Meyhoff TS, Hjortrup PB, Kjaer MN, Laake JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M, Ostermann M, Malbrain MLNG, Moller MH, Perner A, Granholm A. Effects of IV fluid restriction according to site-specific intensity of standard fluid treatment-protocol. Acta Anaesthesiol Scand. 2024 Aug;68(7):975-982. doi: 10.1111/aas.14423. Epub 2024 Apr 4. |
| 37330928 | Derived | Kjaer MN, Meyhoff TS, Sivapalan P, Granholm A, Hjortrup PB, Madsen MB, Moller MH, Egerod I, Wetterslev J, Lange T, Cronhjort M, Laake JH, Jakob SM, Nalos M, Ostermann M, Gould D, Cecconi M, Malbrain MLNG, Ahlstedt C, Kiel LB, Bestle MH, Nebrich L, Hildebrandt T, Russell L, Vang M, Rasmussen ML, Solling C, Brochner AC, Krag M, Pfortmueller C, Kriz M, Siegemund M, Albano G, Aagaard SR, Bundgaard H, Crone V, Wichmann S, Johnstad B, Martin YK, Seidel P, Martensson J, Hollenberg J, Wistrand M, Donati A, Barbara E, Karvunidis T, Hollinger A, Carsetti A, Lumlertgul N, Joelsson-Alm E, Lambiris N, Aslam TN, Friberg FF, Vesterlund GK, Mortensen CB, Vestergaard SR, Caspersen SF, Jensen DB, Borup M, Rasmussen BS, Perner A. Long-term effects of restriction of intravenous fluid in adult ICU patients with septic shock. Intensive Care Med. 2023 Jul;49(7):820-830. doi: 10.1007/s00134-023-07114-8. Epub 2023 Jun 18. |
| 31982391 | Derived | Meyhoff TS, Moller MH, Hjortrup PB, Cronhjort M, Perner A, Wetterslev J. Lower vs Higher Fluid Volumes During Initial Management of Sepsis: A Systematic Review With Meta-Analysis and Trial Sequential Analysis. Chest. 2020 Jun;157(6):1478-1496. doi: 10.1016/j.chest.2019.11.050. Epub 2020 Jan 23. |
| 31828753 | Derived | Kjaer MN, Meyhoff TS, Madsen MB, Hjortrup PB, Moller MH, Egerod I, Wetterslev J, Lange T, Cronhjort M, Laake JH, Jakob SM, Nalos M, Pettila V, van der Horst ICC, Ostermann M, Mouncey P, Cecconi M, Ferrer R, Malbrain MLNG, Ahlstedt C, Hoffmann S, Bestle MH, Gyldensted L, Nebrich L, Russell L, Vang M, Solling C, Brochner AC, Rasmussen BS, Perner A. Long-term patient-important outcomes after septic shock: A protocol for 1-year follow-up of the CLASSIC trial. Acta Anaesthesiol Scand. 2020 Mar;64(3):410-416. doi: 10.1111/aas.13519. Epub 2019 Dec 26. |
| COMPLETED |
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| NOT COMPLETED |
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| 90-day Follow-up |
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| Baseline Characteristics |
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| 1-year Follow-up |
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| ID | Title | Description |
|---|---|---|
| BG000 | Fluid Restriction Group | No IV fluids unless one of the extenuating circumstances occurred (additional details in protocol section) |
| BG001 | Standard-care | No upper limit for IV fluids (additional details in protocol section). |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median | Inter-Quartile Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Volume of intravenous fluid 24 hr before randomization | Median | Inter-Quartile Range | ml |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 90-day Mortality | Al cause mortality at 90 days | Primary outcome data were missing from six patients in the restrictive-fluid group and three in the standard-fluid group. | Posted | Count of Participants | Participants | Day 90 after randomisation |
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| Secondary | Number of Participants With One or More Serious Adverse Events (SAEs) in the ICU | SAEs were defined as ischaemic events (cerebral, cardiac, intestinal or limb ischaemia) or as a new episode of severe acute kidney injury (modified KDIGO-3) | All secondary outcome data were missing for 23 patients (15 patients in the restrictive-fluid group and 8 in the standard-fluid group). In the analysis of SAEs in the ICU, additional 9 patients (5 in the restrictive-fluid group and 4 in the standard-fluid group) had missing data for severe acute kidney injury. One of the 5 patients in the restrictive-fluid group had another SAE; thus only 8 patients had missing data in the composite outcome. | Posted | Count of Participants | Participants | Until ICU discharge, maximum 90 days |
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| Secondary | Number of Participants With One or More Serious Adverse Reactions (SARs) to IV Crystalloids in the ICU. | The pre-specified SARs to IV crystalloids were: Generalized tonic-clonic seizures, anaphylactic reactions, central pontine myelinolysis, severe hypernatremia, severe hyperchloremic acidosis, and severe metabolic alkalosis. Data on the outcome measures, including SARs, were obtained from patient medical records by the trial investigators or their delegates. | All secondary outcome data were missing for 23 patients (15 patients in the restrictive-fluid group and 8 in the standard-fluid group). | Posted | Count of Participants | Participants | Until ICU discharge, maximum 90 days |
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| Secondary | Days Alive at Day 90 Without Life Support (Vasopressor / Inotropic Support, Invasive Mechanical Ventilation or Renal Replacement Therapy) | All secondary outcome data were missing for 23 patients (15 patients in the restrictive-fluid group and 8 in the standard-fluid group). | Posted | Median | Inter-Quartile Range | days | Until ICU discharge, maximum 90 days |
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| Secondary | Days Alive and Out of Hospital at Day 90 | All secondary outcome data were missing for 23 patients (15 patients in the restrictive-fluid group and 8 in the standard-fluid group). | Posted | Median | Inter-Quartile Range | days | Day 90 after randomisation |
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| Secondary | All-cause Mortality at 1-year After Randomisation | Posted | Count of Participants | Participants | 1-year after randomisation |
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| Secondary | Health-related Quality of Life 1 Year After Randomisation | Measured using the EuroQoL EQ-5D-5L questionnaire (comprising 5 questions with a score from 1 to 5 each and a visual analogue scale from 0 to 100). Participants who have died will be assigned the lowest possible scores. | In total, 46 patients in the restrictive group and 55 in the standard group had missing data (either completely missing or partially missing) for EQ-5D-5L index values. | Posted | Median | Inter-Quartile Range | EQ-5D-5L index values | 1 year after randomisation |
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| Secondary | Cognitive Function 1-year After Randomisation | Assessed by the Montreal Cognitive Assessment (MoCa) MINI score validated for telephone use. Mini MoCA consists of 4 cognitive dimensions: attention (immediate recall of 5 words), executive functions and language (1-min verbal fluency), orientation (6 items on date and geographic orientation), and memory (delayed recall and recognition of 5 previously learned words). The total score ranges from 0 to 30, with lower values indicating worse cognitive function. To correct for any educational effect on the cognitive test, 1 point is added for participants with 12 years of education or less (scores were truncated at the maximum upper value of 30 points) Participants who had died were assigned the value 0. | In total, 82 patients in the restrictive group and 98 in the standard group had missing data (either completely missing or partially missing) for Mini MOCA. | Posted | Median | Inter-Quartile Range | Units on a scale | 1-year after randomisation |
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Adverse Events were assessed until ICU discharge, maximum 90 days. All-cause mortality was assessed during ICU stay and continued following discharge from the ICU to 90 days and 1-year from randomization, respectively. "At risk" population for mortality at 90 days was 764 in the restrictive group and 781 in the standard group. At 1-year, the "at risk" population for mortality was 750 patients in the fluid restriction group, and 767 in the standard group, due to withdrawn consent.
Serious adverse events (SAEs), excluding mortality, was a secondary outcome. All secondary outcome data were missing for 15 patients in the restrictive group and 8 in the standard group. For SAEs, additional 5 patients in the restrictive group and 4 in the standard group had missing data for severe acute kidney injury. One of the 5 patients in the restrictive group had another SAE. For mortality, data were missing from 6 patients in the restrictive group and 3 in the standard group.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Fluid Restriction Group | No IV fluids unless one of the extenuating circumstances occurred (additional details in protocol section) | 385 | 764 | 221 | 755 | 0 | 755 |
| EG001 | Standard-care | No upper limit for IV fluids (additional details in protocol section). | 383 | 781 | 238 | 776 | 0 | 776 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cerebral ischemia | General disorders | Systematic Assessment |
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| Myocardial ischemia | General disorders | Systematic Assessment |
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| Intestinal ischemia | General disorders | Systematic Assessment |
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| Limb ischemia | General disorders | Systematic Assessment |
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| Severe acute kidney injury | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof. Anders Perner | Rigshospitalet, University of Copenhagen | +45 35458333 | anders.perner@regionh.dk |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Mar 1, 2022 | Sep 27, 2022 | SAP_001.pdf |
| ID | Term |
|---|---|
| D012772 | Shock, Septic |
| ID | Term |
|---|---|
| D018805 | Sepsis |
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012769 | Shock |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Units | Counts |
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| Participants |
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