Septic Shock
Conditions
Keywords
Septic Shock, Albumin, Balanced crystalloids
Brief summary
Septic shock is a devastating condition often observed in ICU. It is characterized by pro-inflammatory and immune responses, organ failures, high incidence of AKI and lethality. Fluid resuscitation is pivotal as supportive therapy. At present, there are no effective therapies to improve survival of such clinical condition, often characterized by a mortality as high as 40% during the first 90 days from diagnosis. This project proposes a large 2-by-2 factorial randomized clinical trial testing the efficacy of albumin and the low- chloride balanced crystalloid solutions (either Ringer Lactate, Ringer Acetate, or Crystalsol - BAL) in septic shock. The investigators have recently concluded a multicenter, randomized trial, the ALBIOS trial, in which, in a post-hoc analysis, albumin, in addition to crystalloids, reduced 90-day mortality in patients with septic shock, as compared to crystalloids alone (Caironi P et al, 2014). Crystalloids with supra-physiological chloride content may deteriorate renal perfusion, increasing the risk of acute kidney injury (AKI) and mortality.
Detailed description
The project will consist of a 2-by-2 factorial, investigator-initiated, open-label, multicenter, randomized, controlled trial, with PROBE design (Prospective Randomized Open Trial with Blinded Evaluation of Outcomes), in patients with septic shock, as defined according to clinical criteria. Patients will be randomized in a 1:1:1:1 ratio to one of the 4 study groups (Albumin + BAL, Albumin + NS, BAL, NS). Both the primary endpoints will include events evaluated objectively: 90-day mortality and incidence of AKI, as assessed by KDIGO criteria (KDIGO Acute Kidney Injury Work Group, 2012).
Interventions
BIOLOGICALAlbumin
Human Albumin In parallel with fluid administration for volume resuscitation, patients will receive 400 ml of 20% albumin solution both at randomization (D0) and at day 1 (D1). Subsequently, from day 2 (D2) until day 90 (D90) or ICU discharge (whichever comes first), 20% albumin will be administered on a daily basis, to maintain serum albumin concentration equal to or greater than 30 g/L, based upon serum albumin determination.
OTHERBalanced
Balanced crystalloid solutions are traditionally crystalloid solutions containing a relatively low concentration of chloride as compared to 0.9% NaCl containing solutions (Normal Saline).
Sponsors
Istituto Di Ricerche Farmacologiche Mario Negri
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
2-by-2 factorial design, open-label, multicenter, randomized, controlled trial, in patients with septic shock, as defined according to clinical criteria. Patients will be randomized in a 1:1:1:1 ratio to one of the 4 groups (Albumin + BAL, Albumin + NS, BAL, NS).
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
Patients with septic shock if they meet the two following criteria: 1. Presence of an infection (known or suspected) in at least one site: 1. Lung 2. Abdomen 3. Urinary tract 4. Others (blood, skin and soft tissues, central nervous system, bones and joints, cardiac system, reproductive organs). 2. Presence of a severe and acute, sepsis-related cardiovascular failure (as assessed by the SOFA score - see Annex 1), requiring vasopressor to maintain mean arterial pressure \>=65 mmHg, despite adequate volume resuscitation a) Cardiovascular SOFA score \> 2 (3 or 4) If the patient is unable to provide informed consent, she/he can be included in the trial provided that the requirements of ongoing laws are fulfilled; details on this approach are provided in the protocol, par 11.1 and related Annex 3. The patient will be informed about having been included in a clinical trial, as soon as she/he will regain consciousness.
Exclusion criteria
1. Age \< 18 years 2. Moribund state 3. Known or suspected adverse reaction to albumin administration 4. Septic shock in patients with traumatic brain injury or a clinically active cerebral lesion (known or suspected) 5. Severe congestive heart failure (NYHA III and IV classes) 6. Clinical situations in which the use of albumin is known or supposed to be clinically beneficial (hepatic cirrhosis with ascites, malabsorption syndrome or protein-losing enteropathy, nephrotic syndrome, burns) 7. More than 24 hours after the onset of septic shock 8. Religious objection to the administration of human blood products 9. Presence of chronic end-stage renal disease 10. Severe hyperkalemia (\> 6 mmol/L) 11. Known or suspected pregnancy based on patient information 12. Enrollment in other experimental interventional studies 13. Laboratory confirmation for SARS-CoV-2 infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause 90-day mortality | Up to 90 days | All-cause death from randomization to 90 days |
| Combined co-primary endpoint | Up to 90 days | The composite of all-cause death from randomization to 90 days and new occurrence of acute kidney injury (AKI). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| In-hospital mortality | Up to hospital discharge, a median of 20 days | All-cause death occurring during hospital stay |
| 1-year mortality | Up to 1 year | All-cause death from randomization to 1 year |
| SOFA score | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first | Severity and incidence of organ failures, as assessed by the Sequential Organ Failure Assessment (SOFA) score. SOFA score is used to determine the extent of organ function in a patient while in the intensive care unit. The score is based on 6 different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems. The scale of each score ranges from 0 (no dysfunction) to 4 (maximal dysfunction). The 6 scores are then added up to provide a global score: the highest the value, the worst the condition of the patient. |
| Incidence of AKI during ICU stay | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first | Assessed by the Kidney Disease Improving Global Outcome (KDIGO) criteria as any of the following: (1) increase in serum creatinine \>=0.3 mg/dl (26.5 mmol/l) within 48 hours; or (2) increase in SCr to \>=1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or (3) urine volume \<0.5 ml/kg/h for 6 hours. |
| RRT | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first | First use of Renal Replacement Therapy (RRT) during ICU stay |
| Mechanical ventilation | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first | Duration of mechanical ventilation during ICU stay |
| Secondary infections in ICU | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first | Incidence of secondary-acquired infections during ICU stay |
| Duration of stay in ICU | Up to ICU discharge, a median of 9 days | Duration expressed as number of days spent in ICU |
| Duration of stay in hospital | Up to hospital discharge, a median of 20 days | Duration expressed as number of days spent in hospital |
| 1-year functional and physical disability | Up to 1 year | Evaluation by specific psyco-functional tests |
| Need for vasopressors | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first | Duration of the need for vasopressors during ICU stay |
| ICU mortality | Up to ICU discharge, a median of 9 days | All-cause death occurring in Intensive Care Unit (ICU) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Severe metabolic acidosis | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first | Incidence of severe metabolic acidosis |
| Severe hyperkalemia | Up to 90 days or ICU discharge - a median of 9 days - whichever comes first | Incidence of severe hyperkalemia |
Countries
Italy
Outcome results
None listed