Septic Shock
Conditions
Keywords
Human albumin, Sepsis
Brief summary
Albumin is a key regulator of fluid distribution within the extracellular space and possesses several properties beyond its oncotic activity, including binding and transport of several endogenous molecules, anti-inflammatory and anti-oxidant actions, nitric oxide modulation, and buffer function. The accumulating evidence suggests that supplementation of albumin may provide survival advantages only when the insult is severe as in patients with septic shock. Prospective randomized trials on the possible impact of albumin replacement in these patients with septic shock are lacking. The aim of the study is to investigate whether the replacement with albumin and the maintenance of its serum levels at least at 30 g/l for 28 days improve survival in patients with septic shock compared to resuscitation and volume maintenance without albumin. In this prospective, multicenter, randomised trial, adult patients (≥18 years) with septic shock will be randomly assigned within a maximum of 24 hours after the onset of septic shock after obtaining informed consents to treatment or control groups. Patients assigned to the treatment group will receive a 60 g loading dose of human albumin 20% over 2-3 hours. Serum albumin levels will be maintained at least at 30 g/l in the ICU for a maximum of 28 days following randomization using 40-80 g human albumin 20% infusion. The control group will be treated according to the usual practice with crystalloids as the first choice for the resuscitation and maintenance phase of septic shock. The primary end point is 90 days mortality and secondary end points include 28-day, 60-day, ICU, and in-hospital mortality, organ dysfunction/failure, and length of ICU and hospital stay. In total 1412 patients need to be analyzed, 706 per group. Assuming a dropout rate of 15%, a total of 1662 patients need to be allocated.
Detailed description
This is a prospective, multicentre, randomised, controlled, parallel-grouped, open-label, interventional clinical trial in which 1662 patients are planned to be allocated. Subjects will be randomized in a 1:1 ratio to receive either Albumin or routine treatment with crystalloids. Treatment will be continued at maximum for 28 days or until the patient leaves the ICU. Primary endpoint measurement will be carried out 90 days after randomisation
Interventions
DRUGAlbutein® 200 g/L or Plasbumin® 20
The initial dose of the trial drug must be started within 6 to 24 hours after the beginning of the septic shock. Starting dose: 60 g human albumin 20% (Albutein® 200 g/L, infusion solution) over 2-3 h Daily administration of the trial drug will be based on the serum albumin concentration measured each day. Dose adjustment will follow a predetermined schedule with the aim of maintaining a serum albumin concentration of at least 30 g/l. Administration of the trial drug will continue for a maximum of 28 study days after randomisation and only as long as the participant is being treated in the ICU.
Sponsors
German Research Foundation
Instituto Grifols, S.A.
University Hospital Goettingen
SepNet - Critical Care Trials Group
Center for Sepsis Control and Care, Germany
Jena University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The presence of septic shock meeting all of the following criteria: * Clinically possible or probable or microbiologically confirmed infection taking into account the definitions of the International Sepsis Forum (ISF) * Despite adequate volume therapy, vasopressors are required to maintain mean arterial pressure (MAP) ≥ 65 mm Hg for at least 1 hour * Serum lactate level \> 2 mmol/l (18 mg/dl) despite adequate volume therapy * Start of septic shock less than 24 hours prior to inclusion, so that the start dose of the trial drug in the albumin group will be possible within 6-24 hours after the start of the septic shock * Age: ≥ 18 years * Written informed consent of the patient or his/her legal representative or confirmation of the urgency of participation in the clinical trial and possible benefit to the patient by an independent consultant or the implementation of other established procedures according to the local regulations of the contributing centre to include patients who are unable to provide informed consent in whom subsequent consent may be obtained retrospectively. * Patients of childbearing age: negative pregnancy test
Exclusion criteria
* Moribund conditions with life expectancy less than 28 days because of comorbid conditions or advanced malignant disease and palliative situations with life expectancy less than 6 months * Presence of an end of life decision prior to obtaining informed consent: Do Not Resuscitate (DNR) and Withhold/Withdraw Life-Sustaining measures * Previous participation in this study * Participation in another interventional clinical trial within the past 3 months * Shock states that can be explained by other causes, e.g. cardiogenic shock, anaphylactic shock, neurogenic shock * History of hypersensitivity to albumin or any other component of the trial drug, e.g., B., sodium caprylate, sodium N-acetyltryptophanate * Diseases in which albumin administration may be deleterious, e.g., decompensated heart failure or traumatic brain injury * Clinical conditions where albumin administration is indicated, e.g., hepatorenal syndrome, nephrosis, burns, intestinal malabsorption syndrome * Lactation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 90-day All Cause Mortality | 90 days | Mortality within 90 days after randomisation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 60-day Mortality | 60 days | Mortality within 60 days after randomisation |
| Organ Failure | 28 days | Organ failure defined as increase in the daily recorded Sequential organ Failure Assessement (SOFA) subscores; cardiovascular, respiratory, hematologic, hepatic, renal, neurologic (range 0-4 points each) from a value \<2 to a value ≥ 2 |
| Sequential Organ Failure Assessement (SOFA) Score | 28 days | The overall degree of organ dysfunction/failure assessed daily by the total Sequential Organ Failure Score (SOFA score: range 0-24 points), with higher scores indicating higher degree of overall organ dysfunction/failure). |
| ICU Length of Stay | 90 days | Intensive Care unit stay of first hospitalization after randomisation within 90 days |
| 28-day Mortality | 28 days | Mortality within 28 days after randomisation |
| Ventilation-free Days | 28 days | Ventilation-free days within 28 days after randomisation |
| Vasopressor-free Days | 28 days | Vasopressor-free days within 28 days after randomisation |
| Total Amount of Fluid of Fluid Administration and Total Fluid Balance in the ICU. | 28 days | Total amount of fluid of fluid administration and total fluid balance in the ICU within 28 days after randomisation |
| Hospital Length of Stay | 90 days | Hospital stay of first hospitalization after randomisation within 90 days |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Albumin Group Patients assigned to the Albumin group received a 60 g loading dose of human albumin 20% over 2-3 hours. Serum albumin levels were maintained at least at 30 g/l in the ICU for a maximum of 28 days following randomization using 40-80 g human albumin 20% infusion. | 222 |
| Control Group Without Albumin: The control group was treated according to the usual practice with crystalloids as the first choice for the resuscitation and maintenance phase of septic shock.
The demographic and baseline characteristics were similar between the study groups. | 218 |
| Total | 440 |
Baseline characteristics
| Characteristic | Albumin Group | Control Group Without Albumin: | Total |
|---|---|---|---|
| Age, Continuous | 69.5 years | 68.5 years | 69 years |
| Blood lactate level | 4.9 mmol/liter | 5 mmol/liter | 4.9 mmol/liter |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Germany | 222 participants | 218 participants | 440 participants |
| Serum albumin | 22 g/liter STANDARD_DEVIATION 6 | 22 g/liter STANDARD_DEVIATION 6 | 22 g/liter STANDARD_DEVIATION 6 |
| Sex: Female, Male Female | 80 Participants | 70 Participants | 150 Participants |
| Sex: Female, Male Male | 142 Participants | 148 Participants | 290 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 91 / 222 | 96 / 218 |
| other Total, other adverse events | 183 / 222 | 176 / 218 |
| serious Total, serious adverse events | 3 / 222 | 2 / 218 |
Outcome results
Primary
90-day All Cause Mortality
Mortality within 90 days after randomisation
Time frame: 90 days
Population: Informed consents were not possible to obtain within 72 hours after randomization in 14 patients, 4 patients were lost to follow up, 2 patients withdrew the informed consent, and the study was terminated in one patient due to investigator decision. Therefore, the primary outcome parameter was available for analysis in 210 patients in the albumin and 209 patients in the control groups
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Albumin Group | 90-day All Cause Mortality | 91 Participants |
| Control Group Without Albumin: | 90-day All Cause Mortality | 96 Participants |
Secondary
28-day Mortality
Mortality within 28 days after randomisation
Time frame: 28 days
Population: At 28 days after randomization, informed consent was not possible to be obtained within 72 hours of randomization in 14 patients, 2 patients withdrew consent, and the study was terminated in one patient due to investigator decision. Therefore, 28-days mortality were available in 213 vs. 210 patients in the albumin vs. control group, respectively
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Albumin Group | 28-day Mortality | 66 Participants |
| Control Group Without Albumin: | 28-day Mortality | 80 Participants |
Secondary
60-day Mortality
Mortality within 60 days after randomisation
Time frame: 60 days
Population: At 60 days after randomization, informed consent was not possible to be obtained within 72 hours of randomization in 14 patients, 2 patients withdrew consent, 2 patients were lost to follow-up, and the study was terminated in one patient due to investigator decision. Therefore, 60-days mortality were available in 211 vs. 210 patients in the albumin vs. control group, respectively
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Albumin Group | 60-day Mortality | 82 Participants |
| Control Group Without Albumin: | 60-day Mortality | 95 Participants |
Secondary
Hospital Length of Stay
Hospital stay of first hospitalization after randomisation within 90 days
Time frame: 90 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Albumin Group | Hospital Length of Stay | 24 Days |
| Control Group Without Albumin: | Hospital Length of Stay | 27 Days |
Secondary
ICU Length of Stay
Intensive Care unit stay of first hospitalization after randomisation within 90 days
Time frame: 90 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Albumin Group | ICU Length of Stay | 13 Days |
| Control Group Without Albumin: | ICU Length of Stay | 12 Days |
Secondary
Organ Failure
Organ failure defined as increase in the daily recorded Sequential organ Failure Assessement (SOFA) subscores; cardiovascular, respiratory, hematologic, hepatic, renal, neurologic (range 0-4 points each) from a value \<2 to a value ≥ 2
Time frame: 28 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Albumin Group | Organ Failure | 2 organ failures | 19 participants |
| Albumin Group | Organ Failure | 1 organ failure | 68 participants |
| Albumin Group | Organ Failure | 3 organ failures | 2 participants |
| Albumin Group | Organ Failure | 4 organ failures | 0 participants |
| Control Group Without Albumin: | Organ Failure | 4 organ failures | 1 participants |
| Control Group Without Albumin: | Organ Failure | 3 organ failures | 7 participants |
| Control Group Without Albumin: | Organ Failure | 1 organ failure | 52 participants |
| Control Group Without Albumin: | Organ Failure | 2 organ failures | 14 participants |
Secondary
Sequential Organ Failure Assessement (SOFA) Score
The overall degree of organ dysfunction/failure assessed daily by the total Sequential Organ Failure Score (SOFA score: range 0-24 points), with higher scores indicating higher degree of overall organ dysfunction/failure).
Time frame: 28 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albumin Group | Sequential Organ Failure Assessement (SOFA) Score | 9 Points | Standard Deviation 0.5 |
| Control Group Without Albumin: | Sequential Organ Failure Assessement (SOFA) Score | 8.6 Points | Standard Deviation 0.7 |
Secondary
Total Amount of Fluid of Fluid Administration and Total Fluid Balance in the ICU.
Total amount of fluid of fluid administration and total fluid balance in the ICU within 28 days after randomisation
Time frame: 28 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Albumin Group | Total Amount of Fluid of Fluid Administration and Total Fluid Balance in the ICU. | Total amount of fluid adminstration | 3200 ml/day |
| Albumin Group | Total Amount of Fluid of Fluid Administration and Total Fluid Balance in the ICU. | Total fluid balance | 234 ml/day |
| Control Group Without Albumin: | Total Amount of Fluid of Fluid Administration and Total Fluid Balance in the ICU. | Total amount of fluid adminstration | 3693 ml/day |
| Control Group Without Albumin: | Total Amount of Fluid of Fluid Administration and Total Fluid Balance in the ICU. | Total fluid balance | 355 ml/day |
Secondary
Vasopressor-free Days
Vasopressor-free days within 28 days after randomisation
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Albumin Group | Vasopressor-free Days | 2.5 Days |
| Control Group Without Albumin: | Vasopressor-free Days | 2 Days |
Secondary
Ventilation-free Days
Ventilation-free days within 28 days after randomisation
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Albumin Group | Ventilation-free Days | 4 Days |
| Control Group Without Albumin: | Ventilation-free Days | 3 Days |