Rapid Recognition of Corticosteroid Resistant or Sensitive Sepsis
Rapid Recognition of Corticosteroid Resistant or Sensitive Sepsis
Main objective and primary endpoint: To compare the effect hydrocortisone plus
 fludrocortisone vs. placebo on a composite of death or persistent organ dysfunction - defined
 as continued dependency on mechanical ventilation, new renal replacement therapy, or
 vasopressors - assessed at 90 days on intensive care unit (ICU) adults and having different
 biological profiles for immune responses and corticosteroids bioactivity.

 Secondary objectives and endpoints:

 -  Mortality and health-related quality of life at 6 months;

 -  Daily organ function (SOFA score days 1, 2, 3, 4, 7, 10, 14, 28, and 90);

 -  Daily secondary infections (up to 90 days)

 -  Daily blood and urinary levels of glucose, sodium and potassium (up to 28 day)

 -  Daily gastroduodenal bleeding (up to 28 day)

 -  Daily cognitive function and muscles' strength (days 1 to 28, 90 and 180 days).
The potential benefits of a lower dose ( ≤ 400 mg of hydrocortisone or equivalent per day),
 and a longer duration at full dose ( ≥ three days) of treatment, have been investigated in
 numerous randomized controlled trials over the past three decades. In the past two years,
 guidelines for clinical practices about corticosteroids use in sepsis have been released. All
 but one of the guidelines, recommended against the use of corticosteroids in sepsis, except
 in patients with septic shock and poorly responsive to fluid replacement and vasopressor
 therapy. Some guidelines suggested that corticosteroids should be given as a continuous
 infusion rather than intermittent boluses.

 Corticosteroids survival benefit is not affected by age, gender, disease severity, type of
 infection, source of infection, or type of pathogens. There is currently no diagnostic test
 for CS sensitivity/resistance in sepsis. The scientific community is competing to identify
 markers delineating between patients who draw survival benefit from corticosteroids
 (CS-sensitive sepsis) and those who may be harmed (CS-resistant sepsis). In sepsis, the
 deregulated response may result in systemic inflammation and organs damage, or immune paresis
 and secondary infections. Obviously, patients with systemic inflammation may benefit from CS
 whereas those with immune paresis may deteriorate. The study team had have looked for an
 interaction between survival in response to corticosteroids and the presence of CIRCI
 according to the ACTH test results (cortisol increment of less than 9µg/dL). The benefits
 from corticosteroids were more important in patients with CIRCI in the Ger-Inf-05 trial but
 not in the APROCCHS trial. Thus, current sepsis guidelines suggest that the ACTH test may not
 reliably guide the use of corticosteroids. Indeed, this test provides information neither on
 corticosteroids bioactivity nor on patient's immune status, when this information should
 precede any corticotherapy. Recent studies suggested that a transcriptomic signature based on
 100 genes may identify a subset of paediatric sepsis that had increased risk of death when
 exposed to corticosteroids. Another study found transcriptomic based sepsis response
 signatures (SRS) associated with immune paresis (SRS1) or with systemic inflammation (SRS 2).
 In this study, patients with a SRS 2 transcriptomic signature had significantly higher
 mortality when treated with hydrocortisone. Thus, we have started exploring the mechanisms of
 sensitivity/resistance to corticosteroids in sepsis, namely by investigating endocan, as a
 surrogate of patient's inflammatory status, and GILZ expression as a marker of
 corticosteroids bioactivity.

 This is a new multicentre concealed-allocation multi-arms, parallel-group, adaptive blinded
 randomized controlled trial. The overall objective of the trial is to determine whether
 different signatures of immune status and/or corticosteroids biological activity influence
 the responses to hydrocortisone plus fludrocortisone of adults with sepsis. To remain
 pragmatic, this trial has broad eligibility criteria and includes all patients admitted to
 the ICU with a primary diagnosis of sepsis. Patients will be randomly assigned to
 hydrocortisone plus fludrocortisone or placebo for 7 days, targeting 1800 patients with full
 follow-up up to 6 months.
Inclusion Criteria:

 -  Patient ≥18 years old;

 -  Admitted to ICU;

 -  Patient with proven or suspected infection as the main diagnosis;

 -  Community acquired pneumonia related sepsis or vasopressors dependency
 (norepinephrine, epinephrine, vasopressin, dopamine, phenylephrine) or septic shock
 (vasopressor to maintain mean blood pressure of at least 65 mmHg and lactate levels
 above 2 mmol/l) or acute respiratory distress syndrome (ARDS: a- acute onset, i.e.
 within one week of an apparent clinical insult and with progression of respiratory
 syndrome, b- bilateral opacities on chest imaging not explained by other pulmonary
 pathologies, e.g. pleural effusion, atelectasis, nodules etc, c- no evidence for heart
 failure or volume overload, d- PaO2/FiO2 ≤ 300 mm Hg, - PEEP ≥ 5 cm H2O;

 -  Patients who have been tested for RECORDS specific biomarkers:

 1. CIRCI neg

 2. Endocan < 2 ng/L

 3. GILZ < x (to be defined)

 4. CPD pos

 5. Transcriptomic SRS2

 6. Endotype B;

 -  Patient who has signed the informed consent whenever he/she is able to consent, if
 not, patient's representative signed ascent whenever he/she is present at inclusion;

 -  Patient affiliated to a social security system or to an universal health coverage
 (Couverture Maladie Universelle (CMU) in France;

 -  Patient under guardianship or curatorship will be included;

 -  Patient in case of simple emergency (legal definition) will be included.

 Exclusion Criteria:

 -  Pregnant woman;

 -  Expected death or withdrawal of life-sustaining treatments within 48 hours;

 -  Previously enrolled in this study.