Rapid Recognition of Corticosteroid Resistant or Sensitive Sepsis (RECORDS)

  • STATUS
    Recruiting
  • End date
    Oct 23, 2024
  • participants needed
    1800
  • sponsor
    Assistance Publique - Hôpitaux de Paris
Updated on 23 May 2022
pneumonia
corticosteroids
dopamine
mechanical ventilation
epinephrine
FIO2
pao2
positive end expiratory pressure
norepinephrine
shock
septic shock
acute respiratory distress syndrome
lactate level
vasoconstrictors
secondary infection

Summary

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).

Description

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.

Details
Condition Sepsis
Treatment Administration procedures
Clinical Study IdentifierNCT04280497
SponsorAssistance Publique - Hôpitaux de Paris
Last Modified on23 May 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Patient ≥18 years old
Admitted to ICU with proven or suspected infection as the main diagnosis
Patients who have been tested for one or more RECORDS specific biomarkers
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
CIRCI
Endocan
GILZ
DUSP-1
MDW
lymphopenia
Transcriptomic SRS2
Endotype B
PCR COVID-19
Patient affiliated to a social security system or to an universal health coverage (Couverture Maladie Universelle (CMU) in France
PCR Influenza
Patient under guardianship or curatorship will be included
Patient in case of simple emergency (legal definition) will be included
PCR other respiratory virus
Cutaneous vasoconstrictor response to glucocorticoids
Patient who has signed an informed and written consent whevener he/she is able of
consent, if not, if not ascent from his/her representant whenever he/she is
present at time of screening for inclusion
Patients managed with covid 19 and having biological samples available

Exclusion Criteria

Expected death or withdrawal of life-sustaining treatments within 48 hours
Previously enrolled in this study
Pregnancy
Formal indication for corticosteroids according to most recent international guidelines
Vaccination with live virus within past 6 months
Hypersensitivity to hydrocortisone or fludrocortisone or (microsined betamethasone dipropionate) or any of their excipients (spc)
Women of childbearing potential not using contraception
Nursing women For patients included in this stratum, if applicable, do not apply the cream to an infected or ulcerated area
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