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. 2020 Dec 2;10(12):e040931.
doi: 10.1136/bmjopen-2020-040931.

Effects of low-dose hydrocortisone and hydrocortisone plus fludrocortisone in adults with septic shock: a protocol for a systematic review and meta-analysis of individual participant data

Djillali Annane  1   2 , Romain Pirracchio  3 , Laurent Billot  4 , Andre Waschka  5 , Sylvie Chevret  6 , Jeremy Cohen  7 , Simon Finfer  8 , Anthony Gordon  9 , Naomi Hammond  10 , John Myburgh  11 , Balasubramanian Venkatesh  12 , Anthony Delaney  8 ; ULYSSES IPDMA Collaborators
Collaborators, Affiliations

Effects of low-dose hydrocortisone and hydrocortisone plus fludrocortisone in adults with septic shock: a protocol for a systematic review and meta-analysis of individual participant data

Djillali Annane et al. BMJ Open. .

Abstract

Introduction: The benefits and risks of low-dose hydrocortisone in patients with septic shock have been investigated in numerous randomised controlled trials and trial-level meta-analyses. Yet, the routine use of this treatment remains controversial. To overcome the limitations of previous meta-analyses inherent to the use of aggregate data, we will perform an individual patient data meta-analysis (IPDMA) on the effect of hydrocortisone with or without fludrocortisone compared with placebo or usual care on 90-day mortality and other outcomes in patients with septic shock.

Methods and analysis: To assess the benefits and risks of hydrocortisone, with or without fludrocortisone for adults with septic shock, we will search major electronic databases from inception to September 2020 (Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and Latin American Caribbean Health Sciences Literature), complimented by a search for unpublished trials. The primary analysis will compare hydrocortisone with or without fludrocortisone to placebo or no treatment in adult patients with septic shock. Secondary analyses will compare hydrocortisone to placebo (or usual care), hydrocortisone plus fludrocortisone to placebo (or usual care), and hydrocortisone versus hydrocortisone plus fludrocortisone. The primary outcome will be all cause mortality at 90 days. We will conduct both one-stage IPDMA using mixed-effect models and machine learning with targeted maximum likelihood analyses. We will assess the risk of bias related to unshared data and related to the quality of individual trial.

Ethics and dissemination: This IPDMA will use existing data from completed randomised clinical trials and will comply with the ethical and regulatory requirements regarding data sharing for each of the component trials. The findings of this study will be submitted for publication in a peer-review journal with straightforward policy for open access.

Prospero registration number: CRD42017062198.

Keywords: adult intensive & critical care; clinical pharmacology; clinical trials.

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Conflict of interest statement

Competing interests: DA: has received funding from French government to conduct trials that will be included in this systematic review (trials acronym: Ger-Inf-05; COIITSS, APROCCHS)—he received funding for FHU SEPSIS and RHU RECORDS research programs. The current IPDMA he was responsible for the Cochrane systematic review on corticosteroids for sepsis in children and adults, and this work will use part of data obtained in the Cochrane review. AG: has received funding from an NIHR Research Professorship (RP-2015-06-18), consulting fees paid to his institution from GlaxoSmithKline and Bristol Myers Squibb, and personal consulting fees from Baxter Healthcare. RP, LB, AW, SC, JC, SF, NH, JM, BV and AD: no conflict of interest.

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