Trial Outcomes & Findings for The Conservative vs. Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care Trial (NCT NCT03668236)
NCT ID: NCT03668236
Last Updated: 2025-02-24
Results Overview
Al cause mortality at 90 days
Recruitment status
COMPLETED
Study phase
PHASE4
Target enrollment
1554 participants
Primary outcome timeframe
Day 90 after randomisation
Results posted on
2025-02-24
Participant Flow
No patients were excluded from the trial prior to group assignment.
Participant milestones
| Measure |
Fluid Restriction Group
No IV fluids unless one of the extenuating circumstances occurred (additional details in protocol section)
|
Standard-care
No upper limit for IV fluids (additional details in protocol section).
|
|---|---|---|
|
Randomization
STARTED
|
770
|
784
|
|
Randomization
COMPLETED
|
770
|
784
|
|
Randomization
NOT COMPLETED
|
0
|
0
|
|
90-day Follow-up
STARTED
|
770
|
784
|
|
90-day Follow-up
COMPLETED
|
764
|
781
|
|
90-day Follow-up
NOT COMPLETED
|
6
|
3
|
|
Baseline Characteristics
STARTED
|
764
|
781
|
|
Baseline Characteristics
COMPLETED
|
755
|
776
|
|
Baseline Characteristics
NOT COMPLETED
|
9
|
5
|
|
1-year Follow-up
STARTED
|
767
|
782
|
|
1-year Follow-up
COMPLETED
|
750
|
767
|
|
1-year Follow-up
NOT COMPLETED
|
17
|
15
|
Reasons for withdrawal
| Measure |
Fluid Restriction Group
No IV fluids unless one of the extenuating circumstances occurred (additional details in protocol section)
|
Standard-care
No upper limit for IV fluids (additional details in protocol section).
|
|---|---|---|
|
90-day Follow-up
Withdrawal by Subject
|
3
|
2
|
|
90-day Follow-up
Lost to Follow-up
|
3
|
1
|
|
Baseline Characteristics
Lost to Follow-up
|
9
|
5
|
|
1-year Follow-up
Withdrawal by Subject
|
17
|
15
|
Baseline Characteristics
The Conservative vs. Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care Trial
Baseline characteristics by cohort
| Measure |
Fluid Restriction Group
n=755 Participants
No IV fluids unless one of the extenuating circumstances occurred (additional details in protocol section)
|
Standard-care
n=776 Participants
No upper limit for IV fluids (additional details in protocol section).
|
Total
n=1531 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
71 years
n=5 Participants
|
70 years
n=7 Participants
|
70 years
n=5 Participants
|
|
Sex: Female, Male
Female
|
303 Participants
n=5 Participants
|
324 Participants
n=7 Participants
|
627 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
452 Participants
n=5 Participants
|
452 Participants
n=7 Participants
|
904 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
755 Participants
n=5 Participants
|
776 Participants
n=7 Participants
|
1531 Participants
n=5 Participants
|
|
Volume of intravenous fluid 24 hr before randomization
|
3200 ml
n=5 Participants
|
3000 ml
n=7 Participants
|
3068 ml
n=5 Participants
|
PRIMARY outcome
Timeframe: Day 90 after randomisationPopulation: Primary outcome data were missing from six patients in the restrictive-fluid group and three in the standard-fluid group.
Al cause mortality at 90 days
Outcome measures
| Measure |
Fluid Restriction Group
n=764 Participants
No IV fluids unless one of the extenuating circumstances occurred (additional details in protocol section)
|
Standard-care
n=781 Participants
No upper limit for IV fluids (additional details in protocol section).
|
|---|---|---|
|
90-day Mortality
|
323 Participants
|
329 Participants
|
SECONDARY outcome
Timeframe: Until ICU discharge, maximum 90 daysPopulation: 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.
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)
Outcome measures
| Measure |
Fluid Restriction Group
n=751 Participants
No IV fluids unless one of the extenuating circumstances occurred (additional details in protocol section)
|
Standard-care
n=772 Participants
No upper limit for IV fluids (additional details in protocol section).
|
|---|---|---|
|
Number of Participants With One or More Serious Adverse Events (SAEs) in the ICU
|
221 Participants
|
238 Participants
|
SECONDARY outcome
Timeframe: Until ICU discharge, maximum 90 daysPopulation: All secondary outcome data were missing for 23 patients (15 patients in the restrictive-fluid group and 8 in the standard-fluid group).
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.
Outcome measures
| Measure |
Fluid Restriction Group
n=755 Participants
No IV fluids unless one of the extenuating circumstances occurred (additional details in protocol section)
|
Standard-care
n=776 Participants
No upper limit for IV fluids (additional details in protocol section).
|
|---|---|---|
|
Number of Participants With One or More Serious Adverse Reactions (SARs) to IV Crystalloids in the ICU.
|
31 Participants
|
32 Participants
|
SECONDARY outcome
Timeframe: Until ICU discharge, maximum 90 daysPopulation: All secondary outcome data were missing for 23 patients (15 patients in the restrictive-fluid group and 8 in the standard-fluid group).
Outcome measures
| Measure |
Fluid Restriction Group
n=755 Participants
No IV fluids unless one of the extenuating circumstances occurred (additional details in protocol section)
|
Standard-care
n=776 Participants
No upper limit for IV fluids (additional details in protocol section).
|
|---|---|---|
|
Days Alive at Day 90 Without Life Support (Vasopressor / Inotropic Support, Invasive Mechanical Ventilation or Renal Replacement Therapy)
|
77 days
Interval 1.0 to 87.0
|
77 days
Interval 1.0 to 87.0
|
SECONDARY outcome
Timeframe: Day 90 after randomisationPopulation: All secondary outcome data were missing for 23 patients (15 patients in the restrictive-fluid group and 8 in the standard-fluid group).
Outcome measures
| Measure |
Fluid Restriction Group
n=755 Participants
No IV fluids unless one of the extenuating circumstances occurred (additional details in protocol section)
|
Standard-care
n=776 Participants
No upper limit for IV fluids (additional details in protocol section).
|
|---|---|---|
|
Days Alive and Out of Hospital at Day 90
|
21 days
Interval 0.0 to 69.0
|
33 days
Interval 0.0 to 70.0
|
SECONDARY outcome
Timeframe: 1-year after randomisationOutcome measures
| Measure |
Fluid Restriction Group
n=750 Participants
No IV fluids unless one of the extenuating circumstances occurred (additional details in protocol section)
|
Standard-care
n=767 Participants
No upper limit for IV fluids (additional details in protocol section).
|
|---|---|---|
|
All-cause Mortality at 1-year After Randomisation
|
385 Participants
|
383 Participants
|
SECONDARY outcome
Timeframe: 1 year after randomisationPopulation: 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.
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.
Outcome measures
| Measure |
Fluid Restriction Group
n=704 Participants
No IV fluids unless one of the extenuating circumstances occurred (additional details in protocol section)
|
Standard-care
n=712 Participants
No upper limit for IV fluids (additional details in protocol section).
|
|---|---|---|
|
Health-related Quality of Life 1 Year After Randomisation
|
0 EQ-5D-5L index values
Interval 0.0 to 0.82
|
0 EQ-5D-5L index values
Interval 0.0 to 0.81
|
SECONDARY outcome
Timeframe: 1-year after randomisationPopulation: 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.
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.
Outcome measures
| Measure |
Fluid Restriction Group
n=668 Participants
No IV fluids unless one of the extenuating circumstances occurred (additional details in protocol section)
|
Standard-care
n=669 Participants
No upper limit for IV fluids (additional details in protocol section).
|
|---|---|---|
|
Cognitive Function 1-year After Randomisation
|
0 Units on a scale
Interval 0.0 to 22.0
|
0 Units on a scale
Interval 0.0 to 22.0
|
Adverse Events
Fluid Restriction Group
Serious events: 221 serious events
Other events: 0 other events
Deaths: 385 deaths
Standard-care
Serious events: 238 serious events
Other events: 0 other events
Deaths: 383 deaths
Serious adverse events
| Measure |
Fluid Restriction Group
n=755 participants at risk
No IV fluids unless one of the extenuating circumstances occurred (additional details in protocol section)
|
Standard-care
n=776 participants at risk
No upper limit for IV fluids (additional details in protocol section).
|
|---|---|---|
|
General disorders
Cerebral ischemia
|
2.3%
17/755 • 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.
|
2.3%
18/776 • 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.
|
|
General disorders
Myocardial ischemia
|
2.1%
16/755 • 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.
|
0.77%
6/776 • 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.
|
|
General disorders
Intestinal ischemia
|
5.4%
41/755 • 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.
|
5.7%
44/776 • 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.
|
|
General disorders
Limb ischemia
|
2.4%
18/755 • 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.
|
2.3%
18/776 • 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.
|
|
General disorders
Severe acute kidney injury
|
23.1%
173/750 • 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.
|
24.5%
189/772 • 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.
|
Other adverse events
Adverse event data not reported
Additional Information
Prof. Anders Perner
Rigshospitalet, University of Copenhagen
Phone: +45 35458333
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place