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Trials, MEDLINE, EMBASE and Latin American Caribbean Health Sciences Literature), complimented by a search for unpublished trials.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.
- adult intensive & critical care
- clinical trials
- clinical pharmacology
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Collaborators The Utility of Steroids in Septic Shock individual Patient Data Meta-Analysis (ULYSSES IPDMA) Collaborators: Yaseen Arabi: Intensive Care Department; Medical Director, Respiratory Services Professor, College of Medicine King Saud Bin Abdulaziz University for Health Sciences King Abdulaziz Medical City; Saudi Arabia. Pierre Edouard Bollaert: Service de Médecine Intensive Réanimation, CHRU de Nancy, Hôpital Central, 54035 Nancy Cedex, France. Josef Briegel: Ludwig-Maximillians-Universität München Klinik für Anaesthesiologie Marchioninistr. München; Germany. Didier Keh: Oberarzt Klinik für Anästhsiologie m.S. operative Intensimedizin CCM/CVK Canpus Virchow-Klinikum Berlin; Germany. Ling Liu: Department of critical Medicine, Zhong-Da Hospital and school of clinical Medine, Southeast University, Nanjing 210009，China. Umberto G. Meduri: University of Tennessee Health Science Center and Memphis VA Medical Center, Memphis TN, USA. Liliana Mirea: Anaesthesia and Intensive Care, Clinical Emergency Hospital of Bucharest, 2ENT, Elias Clinical Emergency Hospital, Endocrinology, National, Bucarest, Romania. Charles L. Sprung: Department of Anesthesiology, Critical Care Medicine and Pain, Hadassah Hebrew University Medical Center, Jerusalem, Israel. Nejla Tilouche : Intensive Care Unit, University Hospital Taher Sfar Mahdia 5100; University of Monastir, Research Laboratory, Tunisia. Surat Tongyoo: Faculty of Medicine, Siriraj Hospital, Mahidol University, No. 2, Prannok Road, Bangkoknoi, Bangkok, 10700, Thailand. . Ruiqiang Zheng: Department of Critical Care Medicine, the Northern Jiangsu People’s Hospital, Yangzhou 225001, Jiangsu, China.
Contributors DA is the guarantor of the study. DA and RP were responsible for the conception of the study. DA and AD made substantial contributions to the conception and design of the study, drafting of the study protocol, substantial contributions to the analysis plan, revising the work critically for important intellectual content and providing approval for the final version to be published. LB and RP made substantial contributions to the trial design and analytical plan, revising the work critically for important intellectual content and provided approval for the final version to be published. SC, AW, JC, SF, AG, NH, JM and BV made substantial contributions to the drafting of the study protocol, revised the work critically for important intellectual content and provided approval for the final version to be published.
Funding This research is part of FHU SEPSIS and RHU RECORDS, which are funded by the French government through the Programme d’Investissements d’Avenir, project number ANR-18-RHUS60004. This research received no specific grant from any agency in the commercial or not-for-profit sectors. The trial is funded by in-kind support from University of Versailles SQY- University Paris Saclay, the Imperial NIHR Biomedical Research Centre and the Division of Critical Care, The George Institute for Global Health. Funding sources will have no influence on data handling or analyses or writing of the manuscript but will be acknowledged in the principal manuscript.
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.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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