Septic Shock
Conditions
Keywords
Fluid resuscitation, Critical care, Intensive care, Crystalloid, IV fluid therapy
Brief summary
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.
Detailed description
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%.
Interventions
Types of fluid to be used in both intervention groups: * IV fluids given for circulatory impairment: Only isotonic crystalloids are to be used as per the Scandinavian guideline for fluid resuscitation * Fluids given to substitute overt loss: Isotonic crystalloids are to be used. If large amounts of ascites are tapped, then human albumin may be used * Fluids used for dehydration: Water or isotonic glucose should be used * Fluids used for electrolyte disturbances: Fluids should be chosen to substitute the specific deficiency, including water in the case of severe hypernatremia * Blood products are only to be used on specific indications including severe bleeding, severe anaemia and prophylactic in case of severe coagulopathy
Sponsors
Rigshospitalet, Denmark
Centre for Research in Intensive Care (CRIC)
Scandinavian Critical Care Trials Group
Anders Perner, MD, PhD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Outcome assessor- and analyst-blinded trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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: * Suspected or confirmed site of infection or positive blood culture AND * Ongoing infusion of vasopressor/inotrope agent to maintain a mean arterial blood pressure of 65 mmHg or above AND * Lactate of 2 mmol/L or above in any plasma sample performed within the last 3-hours * 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: * Septic shock for more than 12 hours at the time of screening as these patients are no longer early in their course * Life-threatening bleeding as these patients need specific fluid/blood product strategies * Acute burn injury of more than 10% of the body surface area as these patients need a specific fluid strategy * Known pregnancy * Consent not obtainable as per the model approved for the specific site
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 90-day Mortality | Day 90 after randomisation | Al cause mortality at 90 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With One or More Serious Adverse Reactions (SARs) to IV Crystalloids in the ICU. | Until ICU discharge, maximum 90 days | 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. |
| 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 | — |
| Number of Participants With One or More Serious Adverse Events (SAEs) in the ICU | Until ICU discharge, maximum 90 days | 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) |
| Health-related Quality of Life 1 Year After Randomisation | 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. |
| Cognitive Function 1-year After Randomisation | 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. |
| All-cause Mortality at 1-year After Randomisation | 1-year after randomisation | — |
Countries
Belgium, Czechia, Denmark, Italy, Norway, Sweden, Switzerland, United Kingdom
Participant flow
Pre-assignment details
No patients were excluded from the trial prior to group assignment.
Participants by arm
| Arm | Count |
|---|---|
| Fluid Restriction Group No IV fluids unless one of the extenuating circumstances occurred (additional details in protocol section) | 755 |
| Standard-care No upper limit for IV fluids (additional details in protocol section). | 776 |
| Total | 1,531 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 1-year Follow-up | Withdrawal by Subject | 17 | 15 |
| 90-day Follow-up | Lost to Follow-up | 3 | 1 |
| 90-day Follow-up | Withdrawal by Subject | 3 | 2 |
| Baseline Characteristics | Lost to Follow-up | 9 | 5 |
Baseline characteristics
| Characteristic | Fluid Restriction Group | Standard-care | Total |
|---|---|---|---|
| Age, Continuous | 71 years | 70 years | 70 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 755 Participants | 776 Participants | 1531 Participants |
| Sex: Female, Male Female | 303 Participants | 324 Participants | 627 Participants |
| Sex: Female, Male Male | 452 Participants | 452 Participants | 904 Participants |
| Volume of intravenous fluid 24 hr before randomization | 3200 ml | 3000 ml | 3068 ml |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 385 / 764 | 383 / 781 |
| other Total, other adverse events | 0 / 755 | 0 / 776 |
| serious Total, serious adverse events | 221 / 755 | 238 / 776 |
Outcome results
Primary
90-day Mortality
Al cause mortality at 90 days
Time frame: Day 90 after randomisation
Population: Primary outcome data were missing from six patients in the restrictive-fluid group and three in the standard-fluid group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fluid Restriction Group | 90-day Mortality | 323 Participants |
| Standard-care | 90-day Mortality | 329 Participants |
Secondary
All-cause Mortality at 1-year After Randomisation
Time frame: 1-year after randomisation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fluid Restriction Group | All-cause Mortality at 1-year After Randomisation | 385 Participants |
| Standard-care | All-cause Mortality at 1-year After Randomisation | 383 Participants |
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.
Time frame: 1-year after randomisation
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fluid Restriction Group | Cognitive Function 1-year After Randomisation | 0 Units on a scale |
| Standard-care | Cognitive Function 1-year After Randomisation | 0 Units on a scale |
Secondary
Days Alive and Out of Hospital at Day 90
Time frame: Day 90 after randomisation
Population: All secondary outcome data were missing for 23 patients (15 patients in the restrictive-fluid group and 8 in the standard-fluid group).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fluid Restriction Group | Days Alive and Out of Hospital at Day 90 | 21 days |
| Standard-care | Days Alive and Out of Hospital at Day 90 | 33 days |
Secondary
Days Alive at Day 90 Without Life Support (Vasopressor / Inotropic Support, Invasive Mechanical Ventilation or Renal Replacement Therapy)
Time frame: Until ICU discharge, maximum 90 days
Population: All secondary outcome data were missing for 23 patients (15 patients in the restrictive-fluid group and 8 in the standard-fluid group).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fluid Restriction Group | Days Alive at Day 90 Without Life Support (Vasopressor / Inotropic Support, Invasive Mechanical Ventilation or Renal Replacement Therapy) | 77 days |
| Standard-care | Days Alive at Day 90 Without Life Support (Vasopressor / Inotropic Support, Invasive Mechanical Ventilation or Renal Replacement Therapy) | 77 days |
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.
Time frame: 1 year after randomisation
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fluid Restriction Group | Health-related Quality of Life 1 Year After Randomisation | 0 EQ-5D-5L index values |
| Standard-care | Health-related Quality of Life 1 Year After Randomisation | 0 EQ-5D-5L index values |
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)
Time frame: Until ICU discharge, maximum 90 days
Population: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fluid Restriction Group | Number of Participants With One or More Serious Adverse Events (SAEs) in the ICU | 221 Participants |
| Standard-care | Number of Participants With One or More Serious Adverse Events (SAEs) in the ICU | 238 Participants |
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.
Time frame: Until ICU discharge, maximum 90 days
Population: All secondary outcome data were missing for 23 patients (15 patients in the restrictive-fluid group and 8 in the standard-fluid group).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fluid Restriction Group | Number of Participants With One or More Serious Adverse Reactions (SARs) to IV Crystalloids in the ICU. | 31 Participants |
| Standard-care | Number of Participants With One or More Serious Adverse Reactions (SARs) to IV Crystalloids in the ICU. | 32 Participants |