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Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial

2024; Elsevier BV; Volume: 12; Issue: 5 Linguagem: Inglês

10.1016/s2213-2600(23)00430-7

2213-2619

Nicholas Heming, Alain Renault, Emmanuelle Kuperminc, Christian Brun‐Buisson, Bruno Mégarbane, Jean‐Pierre Quenot, Shidasp Siami, Alain Cariou, Xavier Forceville, Carole Schwebel, Marc Léone, Jean‐François Timsit, Benoît Misset, Mohamed Ali Benali, Gwenhaël Colin, Bertrand Souweine, Karim Asehnoune, Emmanuelle Mercier, Loïc Chimot, Claire Charpentier, Bruno François, Thierry Boulain, Frank Petitpas, Jean Michel Constantin, Gilles Dhonneur, François Baudin, Alain Combes, Julien Bohé, Jean-François Loriferne, Fabrice Cook, Michel Slama, O. Leroy, Gilles Capellier, Auguste Dargent, Tarik Hissem, Rania Bounab, Virginie Maxime, Pierre Moine, Éric Bellissant, Djillali Annane, Djillali Annane, B. Christian, MISSET Benoit, CHASTRE Jean, BRIVET François, B. Julien, SCHWEBEL Carole, SIAMI Shidasp, SLAMA Michel, LEROY Olivier, CAPELLIER Gilles, W Michel, ALI BEN ALI Mohamed, ANTONINI François, LORIFERNE Jean-François, PETITPAS Franck, CHARPENTIER Claire, Constantin Jean-Michel, D'HONNEUR Gilles, S. Bertrand, F. Xavier, Mégarbane Bruno, BAUDIN Francois, COLIN Gwenhaël, Karim Asehnoune, QUENOT Jean-Pierre, François Bruno, B. Thierry, MERCIER Emmanuelle, Jean Reignier, A Carvalho Roland, COOK Fabrice, CARIOU Alain, CHIMOT Loic, F Fouad, Polito Andrea, Clair Bernard, Virginie Maxime, L David, Tarek Sharshar, David Orlikowski, RAZAZI Keyvan, DE PROST Nicolas, CARTEAUX Guillaume, GARROUSTE ORGEAS Maité, Philippart François, Alain Combes, Nieszkowska Ania, Jacobs Frédéric, Prat Dominique, Lafforgue Patrick, ARA SOMOHANO Claire, MINET Clémence, LUGOSI Maxime, Maizel Julien, Navellou Jean Christophe, Mourvillier Bruno, Lila Bouadma, Timsit Jean François, Martin Claude Denis, Julien Textoris, Wiramus Sandrine, BRUN Clément, R. Benoit, Ali Ait Hssain, Alain Combes, Touati Samia, K. J. Jean, W S Wong Vincent, Lahillaire Pierre, Lassi Mohammed, ANTONA Marion, M. Alia, DEMESMAY Marine, Boulet Eric, LOUTREL Olivier, D R Romain, Antoine Roquilly, MAHE Pierre-Joachim, DEMEURE dit LATTE Dominique, CHAMPIN Philippe, ARNOULD Jean François, Raphaël Cinotti, Le FLOCH Ronan, M. Clavel, Philippe Vignon, Nicolas Pichon, BEGOT Emmanuelle, Fedou Anne-Laure, CHAPELLAS Catherine, G Antoine, Benzekri Lefevre Dalila, Mathonnet Armelle, Bretagnol Anne, Runge Isabelle, Barbier Francois, Muller Gregoire, Garot Denis, DEQUIN Pierre François, PERROTIN Dominique, LEGRAS Annick, Mankikian Julie, T. Patrice, Ehrmann Stephan, JORET Aurélie, L St Claire, JORET Aurélie, L St Claire, ROUVE Emmanuelle, BODET-CONTENTIN Laetitia, JOUAN Youenn, S Charlotte, COLIN Gwenhaël, MARTIN-LEFEVRE Laurent, Matthieu Henry-Lagarrigue, YEHIA Aihem, LASCARROU Jean-Baptiste, Christine Lebert, LACHERADE Jean-Claude, LEVESQUE Eric, NGUYEN Yen-Lan, DAVIAUD Fabrice, B Taylor Adrien, MIRA Jean Paul, CHICHE Jean Daniel, Pène Frédéric, M. Soria Tristán, GERI Guillaume, DESSALLES Pierre Henri, MONSEAU Yannick, SAINT-LEGER Mélanie, BEDON-CARTE Sandrine, Bodet-Contentin Laetitia, Darwiche Walid, Ehrmann Stephan, Garot Denis, Guillon Antoine, Jouan Youenn, Legras Annick, Mankikian Julie, Mercier Emmanuelle, Morisseau Marlene, Perez Yonatan, Rouve Emmanuelle, S Charlotte, Helms Julie, Rahmani Hassene, M Revynthi Alexandra, Merdji Hamid, Clere-Jehl Raphael, Stiel Laure, Studer Antoine, Andreu Pascal, Jean-Baptiste Roudaut, Labruyere Marie, J Marine, Barbier Francois, Benzekri Dalila, Boulain Thierry, Jacquier Sophie, Mathonnet Armelle, Muller Gregoire, Nai Mai-Anh, Runge Isabelle, Tisi Sophie, Roux Damien, Jonathan Messika, Vuillard Constance, Dumont Louis-Marie, Federici Laura, Zucman Noemie, Amouretti Marc, Djillali Annane, Pierre Moine, Paris Meng, Bouchikhi Rania, Fartoukh Muriel-Sarah, Djibre Michel, Elabbadi Alexandre, Azais Marie-Ange, Bachoumas Konstantinos, B. Arthur, Bernardon Remi, Blonz Gauthier, Desmedt Luc, E. Brian, Fiancette Maud, Henry Matthieu, Lacherade Jean-Claude, Lascarrou Jean-Baptiste, Christine Lebert, Lorber Julien, Lefevre Laurent Martin-, Pouplet Caroline, Vinatier Isabelle, Yehia Aihem, Benghanem Sarah, Charpentier Julien, Clara Vigneron, Nicolas Pichon, Fedou Anne-Laure, Mancia Claire, Begot Emmanuelle, Daix Thomas, Philippe Vignon, G Antoine, Greitens Celine, Goudelin Marine, E Bruno, Desachy Arnaud, Julien Vaidie, Gilbert Guillaume, Darreau Cédric, Derrien Benoit, Saint-Martin Marjorie, Tirot Patrice, Landais Mickael, Chudeau Nicolas, Callahan Jean Christophe, V O D O V A R Dominique, Le Moal Charlene, Olivier Pierre-Yves, Marnai Remy, Schneider Francis, Sedillot Nicolas, Tchenio Xavier, Robine Adrien, Poncelin Yves, Bruyere Remi,

Adrenal Hormones and Disorders

Summary Background Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock. Methods APROCCHSS was a randomised controlled trial that investigated the effects of hydrocortisone plus fludrocortisone, drotrecogin-alfa (activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups. It was conducted in 34 centres in France. In this subgroup study, patients with CAP were a preselected subgroup for an exploratory secondary analysis of the APROCCHSS trial of hydrocortisone plus fludrocortisone in septic shock. Adults with septic shock were randomised 1:1 to receive, in a double-blind manner, a 7-day treatment with daily administration of intravenous hydrocortisone 50 mg bolus every 6h and a tablet of 50 μg of fludrocortisone via the nasogastric tube, or their placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included all-cause mortality at intensive care unit (ICU) and hospital discharge, 28-day and 180-day mortality, the number of days alive and free of vasopressors, mechanical ventilation, or organ failure, and ICU and hospital free-days to 90-days. Analysis was done in the intention-to-treat population. The trial was registered at ClinicalTrials.gov (NCT00625209). Findings Of 1241 patients included in the APROCCHSS trial, CAP could not be ruled in or out in 31 patients, 562 had a diagnosis of CAP (279 in the placebo group and 283 in the corticosteroid group), and 648 patients did not have CAP (329 in the placebo group and 319 in the corticosteroid group). In patients with CAP, there were 109 (39%) deaths of 283 patients at day 90 with hydrocortisone plus fludrocortisone and 143 (51%) of 279 patients receiving placebo (odds ratio [OR] 0·60, 95% CI 0·43–0·83). In patients without CAP, there were 148 (46%) deaths of 319 patients at day 90 in the hydrocortisone and fludrocortisone group and 157 (48%) of 329 patients in the placebo group (OR 0·95, 95% CI 0·70–1·29). There was significant heterogeneity in corticosteroid effects on 90-day mortality across subgroups with CAP and without CAP (p=0·046 for both multiplicative and additive interaction tests; moderate credibility). Of 1241 patients included in the APROCCHSS trial, 648 (52%) had ARDS (328 in the placebo group and 320 in the corticosteroid group). There were 155 (48%) deaths of 320 patients at day 90 in the corticosteroid group and 186 (57%) of 328 patients in the placebo group. The OR for death at day 90 was 0·72 (95% CI 0·53–0·98) in patients with ARDS and 0·85 (0·61–1·20) in patients without ARDS (p=0·45 for multiplicative interaction and p=0·42 for additive interaction). The OR for observing at least one serious adverse event (corticosteroid group vs placebo) within 180 days post randomisation was 0·64 (95% CI 0·46–0·89) in the CAP subgroup and 1·02 (0·75–1·39) in the non-CAP subgroup (p=0·044 for multiplicative interaction and p=0·042 for additive interaction). Interpretation In a pre-specified subgroup analysis of the APROCCHSS trial of patients with CAP and septic shock, hydrocortisone plus fludrocortisone reduced mortality as compared with placebo. Although a large proportion of patients with CAP also met criteria for ARDS, the subgroup analysis was underpowered to fully discriminate between ARDS and CAP modifying effects on mortality reduction with corticosteroids. There was no evidence of a significant treatment effect of corticosteroids in the non-CAP subgroup. Funding Programme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d'Investissements d'Avenir, France 2030, and IAHU-ANR-0004.