title: Hydrocortisone and fludrocortisone for prevention of hospital-acquired pneumonia in patients with severe traumatic brain injury (Corti-TC): a double-blind, multicentre phase 3, randomised placebo-controlled trial.
abstract: BACKGROUND
  Hospital-acquired pneumonia is common after traumatic brain injury, and might be partly a result of traumatic brain injury-induced adrenal insufficiency. We tested the efficacy of low-dose hydrocortisone with fludrocortisone for the prevention of hospital-acquired pneumonia.
  
  
  METHODS
  We did this double-blind, phase 3, placebo-controlled trial in 19 intensive care units in France. We enrolled patients aged 15-65 years in the first 24 h after severe traumatic brain injury (Glasgow coma scale score ≤8 and trauma-associated lesion on brain CT scan). Patients were randomly assigned (1:1; fixed blocks of 12, stratified by centre and mechanism, Glasgow coma scale, age, and arterial pressure [MGAP] score) to receive either hydrocortisone (200 mg per day tapered) and fludrocortisone (50 μg tablet once per day) or matching placebo for 10 days. Before receiving study drug, adrenal function was assessed with a short corticotropin test. Treatment was stopped if patients had no adrenal insufficiency. The primary outcome was the occurrence of hospital-acquired pneumonia within 28 days after randomisation. We did an intention-to-treat analysis and a modified intention-to-treat analysis including only patients with adrenal insufficiency (adjusted for etomidate use). This study is registered with ClinicalTrials.gov, number NCT01093261.
  
  
  RESULTS
  From Sept 1, 2010, to Nov 29, 2012, we enrolled 336 patients (168 assigned to each group). Eight patients withdrew consent. At day 28, 74 of 165 patients (45%) in the steroid group and 87 of 163 (53%) in the placebo group had developed one or more episodes of hospital-acquired pneumonia (hazard ratio [HR] 0.75; 95% CI 0.55-1.03, p=0.07). In intention-to-treat analysis, we recorded 86 episodes of hospital-acquired pneumonia in the steroid group versus 110 in the placebo group (median 0, IQR 0-1 vs median 1, IQR 0-1 cases per patient, p=0.07). In modified intention-to-treat analyses, the HR for hospital-acquired pneumonia with steroids versus placebo was 0.80 (95% CI 0.56-1.14, p=0.22) in patients with adrenal insufficiency, and, in an exploratory preplanned analysis, 0·48 (0·23-1·01; p=0·05) in patients with normal adrenal function. We recorded no adverse events related to treatment.
  
  
  CONCLUSIONS
  Low-dose hydrocortisone with fludrocortisone did not improve the outcome of patients with traumatic brain injury. However, the study was underpowered because the proportion of patients with hospital-acquired pneumonia in the placebo group was lower than expected. The results were close to statistical significance for efficacy, meaning that further studies are therefore needed.
  
  
  BACKGROUND
  Société Française d'Anesthésie Réanimation.
authors: CHU Nantes, Pôle anesthésie réanimations, Service d'Anesthésie Réanimation chirurgicale, Nantes, France. Electronic address: karim.asehnoune@chu-nantes.fr.
authors: Karim
authors: K
authors: Asehnoune
authors: CHU Rennes, Service d'anesthésie réanimation 1, Université de Rennes 1, Rennes, France.
authors: Philippe
authors: P
authors: Seguin
authors: Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Service d'Anesthésie Réanimation Chirurgicale, Beaujon, France.
authors: Jeremy
authors: J
authors: Allary
authors: Plateforme de Biométrie-Cellule de promotion à la recherche clinique, CHU Nantes, Nantes, France; EA 4275 SPHERE Biostatistics, Pharmacoepidemiology & Human Sciences Research, UFR de Pharmacie, Université de Nantes, Nantes, France.
authors: Fanny
authors: F
authors: Feuillet
authors: CHU Angers, Service d'Anesthésie Réanimation, Angers, France.
authors: Sigismond
authors: S
authors: Lasocki
authors: Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Service d'Anesthésie Réanimation chirurgicale, Créteil, France.
authors: Fabrice
authors: F
authors: Cook
authors: CHU Brest, Service d'Anesthésie Réanimation, Brest, France.
authors: Hervé
authors: H
authors: Floch
authors: CHU Clermont Ferrand, Service d'Anesthésie Réanimation, Clermont Ferrand, France.
authors: Russell
authors: R
authors: Chabanne
authors: Department of Anesthesiology and Intensive Care, University Hospital of Toulouse, Equipe d'accueil Modélisation de l'agression tissulaire et nociceptive, University Toulouse 3 Paul Sabatier, Toulouse, France.
authors: Thomas
authors: T
authors: Geeraerts
authors: Service des Réanimations, Division Anesthésie Réanimation Douleur Urgence, CHU Nimes, Nimes, France.
authors: Claire
authors: C
authors: Roger
authors: CHU Montpellier, Hôpital Gui de Chauliac, Service d'Anesthésie Réanimation, Montpellier, France.
authors: Pierre F
authors: PF
authors: Perrigault
authors: CHU Caen, Service d'Anesthésie Réanimation, Caen, France.
authors: Jean L
authors: JL
authors: Hanouz
authors: Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Service d'Anesthésie Réanimation chirurgicale, Paris, France.
authors: Anne C
authors: AC
authors: Lukaszewicz
authors: CHU Bordeaux, Service d'Anesthésie Réanimation, Bordeaux, France.
authors: Matthieu
authors: M
authors: Biais
authors: CHU Grenoble, Hôpital Michallon, Service d'Anesthésie Réanimation, Grenoble, France.
authors: Perrine
authors: P
authors: Boucheix
authors: CHU Poitiers, Service d'Anesthésie Réanimation, Poitiers, France.
authors: Claire
authors: C
authors: Dahyot-Fizelier
authors: CHU Montpellier, Hôpital Lapeyronie, Service d'Anesthésie Réanimation, Montpellier, France.
authors: Xavier
authors: X
authors: Capdevila
authors: CHU Nantes, Pôle anesthésie réanimations, Service d'Anesthésie Réanimation chirurgicale, Nantes, France.
authors: Pierre J
authors: PJ
authors: Mahe
authors: CHU Rennes, Service d'anesthésie réanimation 1, Université de Rennes 1, Rennes, France.
authors: Pascale
authors: P
authors: Le Maguet
authors: Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Service d'Anesthésie Réanimation Chirurgicale, Beaujon, France.
authors: Catherine
authors: C
authors: Paugam-Burtz
authors: CHU Angers, Service d'Anesthésie Réanimation, Angers, France.
authors: Soizic
authors: S
authors: Gergaud
authors: Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Service d'Anesthésie Réanimation chirurgicale, Créteil, France.
authors: Benoit
authors: B
authors: Plaud
authors: CHU Clermont Ferrand, Service d'Anesthésie Réanimation, Clermont Ferrand, France.
authors: Jean M
authors: JM
authors: Constantin
authors: CHU Rennes, Service d'anesthésie réanimation 1, Université de Rennes 1, Rennes, France.
authors: Yannick
authors: Y
authors: Malledant
authors: CHU Nantes, Pôle Biologie Pharmacie, Service Pharmacie, Nantes, France.
authors: Laurent
authors: L
authors: Flet
authors: Plateforme de Biométrie-Cellule de promotion à la recherche clinique, CHU Nantes, Nantes, France; EA 4275 SPHERE Biostatistics, Pharmacoepidemiology & Human Sciences Research, UFR de Pharmacie, Université de Nantes, Nantes, France.
authors: Véronique
authors: V
authors: Sebille
authors: CHU Nantes, Pôle anesthésie réanimations, Service d'Anesthésie Réanimation chirurgicale, Nantes, France.
authors: Antoine
authors: A
authors: Roquilly
mesh_terms: D000293:Adolescent; D000309:Adrenal Insufficiency / Q000097:blood; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001930:Brain Injuries / Q000150:complications*; D004311:Double-Blind Method; D005260:Female; D005438:Fludrocortisone / Q000627:therapeutic use*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000627:therapeutic use*; D007362:Intensive Care Units; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D053717:Pneumonia, Ventilator-Associated / Q000209:etiology / Q000517:prevention & control*; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005438:Fludrocortisone; D006854:Hydrocortisone