Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial
Nicholas Heming
(1, 2)
,
Alain Renault
(3, 4)
,
Emmanuelle Kuperminc
(5)
,
Christian Brun-Buisson
(6)
,
Bruno Megarbane
(7, 8)
,
Jean-Pierre Quenot
(9)
,
Shidasp Siami
(10)
,
Alain Cariou
(11)
,
Xavier Forceville
(3, 12, 4)
,
Carole Schwebel
(13)
,
Marc Leone
(14)
,
Jean-Francois Timsit
(15, 16)
,
Benoît Misset
(17, 18)
,
Mohamed Ali Benali
,
Gwenhael Colin
(19, 20)
,
Bertrand Souweine
(21, 22)
,
Karim Asehnoune
(23)
,
Emmanuelle Mercier
(24)
,
Loïc Chimot
(25, 26, 4)
,
Claire Charpentier
(27, 28)
,
Bruno François
(29)
,
Thierry Boulain
(30)
,
Frank Petitpas
(31)
,
Jean Michel Constantin
(32)
,
Gilles Dhonneur
(33)
,
François Baudin
(34)
,
Alain Combes
(35, 36)
,
Julien Bohé
(37)
,
Jean-François Loriferne
(38)
,
Fabrice Cook
(39)
,
Michel Slama
(40)
,
Olivier Leroy
(41)
,
Gilles Capellier
(42)
,
Auguste Dargent
(43, 44, 45)
,
Tarik Hissem
(46)
,
Rania Bounab
(47)
,
Virginie Maxime
(47)
,
Pierre Moine
(1, 47)
,
Eric Bellissant
(4)
,
Djillali Annane
(47, 1)
1
2I -
Infection et inflammation
2 Hôpital Raymond Poincaré (Garches) [GHU AP-HP Université Paris-Saclay]
3 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou]
4 CIC - Centre d'Investigation Clinique [Rennes]
5 UVSQ - Université de Versailles Saint-Quentin-en-Yvelines
6 CESP - Centre de recherche en épidémiologie et santé des populations
7 OPTeN (UMR_S 1144 / U1144) - Optimisation thérapeutique en Neuropsychopharmacologie
8 Hôpital Lariboisière-Fernand-Widal [APHP]
9 CHU Dijon
10 Centre Hospitalier Sud Francilien
11 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire
12 GHEF - Grand Hôpital de l'Est Francilien
13 Hôpital Michallon
14 Hôpital Nord [CHU - APHM]
15 Services de Maladies Infectieuses et Tropicales [CHU Bichat]
16 IAME (UMR_S_1137 / U1137) - Infection, Anti-microbiens, Modélisation, Evolution
17 CHU-Liège - Centre Hospitalier Universitaire de Liège
18 CHU Sart Tilman - Centre Hospitalier Universitaire Sart Tilman
19 CHD Vendée - Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon
20 AfterROSC - After ROSC research network [Paris, France]
21 LMGE - Laboratoire Microorganismes : Génome et Environnement
22 MIR - Service Médecine Intensive et Réanimation [CHU Clermont-Ferrand]
23 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
24 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
25 Laboratoire d'Hématologie
26 Service des maladies infectieuses et réanimation médicale [Rennes] = Infectious Disease and Intensive Care [Rennes]
27 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
28 UL - Université de Lorraine
29 CIC1435 - Centre d'Investigation Clinique de Limoges
30 CHRO - Centre Hospitalier Régional d'Orléans
31 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
32 GRC 29 - ARPE - Groupe de Recherche Clinique en Anesthésie Réanimation médecine PEriopératoire
33 Institut Curie [Paris]
34 Hôpital Cochin [AP-HP]
35 CHU Pitié-Salpêtrière [AP-HP]
36 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
37 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
38 Hôpital Saint-Camille [Bry-sur-Marne]
39 Hôpital Henri Mondor
40 CHU Amiens-Picardie
41 Centre Hospitalier Gustave Dron [Tourcoing]
42 Urgences/SAMU25
43 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
44 CIC-EC - Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques
45 LabEx LipSTIC - Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer
46 Centre Hospitalier Sud Essonnes Dourdan Etampes
47 Hôpital Raymond Poincaré [AP-HP]
2 Hôpital Raymond Poincaré (Garches) [GHU AP-HP Université Paris-Saclay]
3 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou]
4 CIC - Centre d'Investigation Clinique [Rennes]
5 UVSQ - Université de Versailles Saint-Quentin-en-Yvelines
6 CESP - Centre de recherche en épidémiologie et santé des populations
7 OPTeN (UMR_S 1144 / U1144) - Optimisation thérapeutique en Neuropsychopharmacologie
8 Hôpital Lariboisière-Fernand-Widal [APHP]
9 CHU Dijon
10 Centre Hospitalier Sud Francilien
11 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire
12 GHEF - Grand Hôpital de l'Est Francilien
13 Hôpital Michallon
14 Hôpital Nord [CHU - APHM]
15 Services de Maladies Infectieuses et Tropicales [CHU Bichat]
16 IAME (UMR_S_1137 / U1137) - Infection, Anti-microbiens, Modélisation, Evolution
17 CHU-Liège - Centre Hospitalier Universitaire de Liège
18 CHU Sart Tilman - Centre Hospitalier Universitaire Sart Tilman
19 CHD Vendée - Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon
20 AfterROSC - After ROSC research network [Paris, France]
21 LMGE - Laboratoire Microorganismes : Génome et Environnement
22 MIR - Service Médecine Intensive et Réanimation [CHU Clermont-Ferrand]
23 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
24 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
25 Laboratoire d'Hématologie
26 Service des maladies infectieuses et réanimation médicale [Rennes] = Infectious Disease and Intensive Care [Rennes]
27 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
28 UL - Université de Lorraine
29 CIC1435 - Centre d'Investigation Clinique de Limoges
30 CHRO - Centre Hospitalier Régional d'Orléans
31 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
32 GRC 29 - ARPE - Groupe de Recherche Clinique en Anesthésie Réanimation médecine PEriopératoire
33 Institut Curie [Paris]
34 Hôpital Cochin [AP-HP]
35 CHU Pitié-Salpêtrière [AP-HP]
36 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
37 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
38 Hôpital Saint-Camille [Bry-sur-Marne]
39 Hôpital Henri Mondor
40 CHU Amiens-Picardie
41 Centre Hospitalier Gustave Dron [Tourcoing]
42 Urgences/SAMU25
43 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
44 CIC-EC - Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques
45 LabEx LipSTIC - Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer
46 Centre Hospitalier Sud Essonnes Dourdan Etampes
47 Hôpital Raymond Poincaré [AP-HP]
Mohamed Ali Benali
- Fonction : Auteur
Karim Asehnoune
- Fonction : Auteur
- PersonId : 1221700
- ORCID : 0000-0003-1899-3517
François Baudin
- Fonction : Auteur
- PersonId : 12200
- IdHAL : francois-baudin
- ORCID : 0000-0003-3180-459X
- IdRef : 090172620
Michel Slama
- Fonction : Auteur
- PersonId : 940185
- ORCID : 0000-0003-4474-4282
- IdRef : 059808470
Résumé
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.