ALBumin Italian Outcome Septic Shock-BALANCED Trial (ALBIOSS-BALANCED)

Efficacy of Albumin Replacement and Balanced Solution in Patients With Septic Shock (the ALBIOSS-BALANCED Trial): a 2-by-2 Factorial, Investigator-initiated, Open- Label, Multicenter, Randomized, Controlled Trial

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.

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).

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