Corticotherapy for traumatic brain-injured Patients - The Corti-TC trial: study protocol for a randomized controlled trial

Karim Asehnoune karim.asehnoune@chu- 1 3 4 Antoine Roquilly 0 4 Vronique Sebille 2 4 The Corti-TC trial group 0 4 0 Intensive care Unit , Hotel Dieu, (Place Ricordeau), Nantes (44093) , France 1 Centre Hospitalier Universitaire de Nantes, Service d'anesthesie reanimation chirurgicale, Hotel Dieu-HME , Nantes , France 2 Biostatistics Unit. EA 4275, Pharmacy University of Nantes , Nantes F-44000 France 3 Centre Hospitalier Universitaire de Nantes, Service d'anesthesie reanimation chirurgicale, Hotel Dieu-HME , Nantes , France 4 The Corti-TC trial group Background: Traumatic brain injury (TBI) is a main cause of severe prolonged disability of young patients. Hospital acquired pneumonia (HAP) add to the morbidity and mortality of traumatic brain-injured patients. In one study, hydrocortisone for treatment of traumatic-induced corticosteroid insufficiency (CI) in multiple injured patients has prevented HAP, particularly in the sub-group of patients with severe TBI. Fludrocortisone is recommended in severe brain-injured patients suffering from acute subarachnoid hemorrhage. Whether an association of hydrocortisone with fludrocortisone protects from HAP and improves neurological recovery is uncertain. The aim of the current study is to compare corticotherapy to placebo for TBI patients with CI. Methods: The CORTI-TC (Corticotherapy in traumatic brain-injured patients) trial is a multicenter, randomized, placebo controlled, double-blind, two-arms study. Three hundred and seventy six patients hospitalized in Intensive Care Unit with a severe traumatic brain injury (Glasgow Coma Scale 8) are randomized in the first 24 hours following trauma to hydrocortisone (200 mg.day-1 for 7 days, 100 mg on days 8-9 and 50 mg on day-10) with fludrocortisone (50 g for 10 days) or double placebo. The treatment is stopped if patients have an appropriate adrenal response. The primary endpoint is HAP on day-28. The endpoint of the ancillary study is the neurological status on 6 and 12 months. Discussion: The CORTI-TC trial is the first randomized controlled trial powered to investigate whether hydrocortisone with fludrocortisone in TBI patients with CI prevent HAP and improve long term recovery. Trial registration: NCT01093261 - Background Traumatic brain injury (TBI) is a leading cause of prolonged disability in young patients. The rate of hospital acquired pneumonia (HAP) varies from 30 to 50% [1-3]. Post traumatic HAP increases the risk of intracranial hypertension [4], prolongs duration of mechanical ventilation and Intensive Care Unit (ICU) length of stay [5,6] and may increase the rate of death [7]. Prevention of one episode of HAP may save 20,000$ [8]. Critical Illness Related Corticosteroid Insufficiency (CIRCI) reaches up to 50 to 70% of trauma patients [9-11]. CIRCI increases systemic inflammation and vasopressive requirement [9,12]. Hydrocortisone decreases rate of HAP and duration of mechanical ventilation in multiple trauma patients with CIRCI [10]. In a subgroup analysis of the HYPOLYTE trial, hydrocortisone appears particularly efficient in multiple trauma patients with TBI [10]. Fludrocortisone was proposed in association with hydrocortisone for the treatment of CIRCI in septic patients [13] and is recommended in BI patients with spontaneous subarachnoid hemorrhage who experience hyponatremia [14]. No data regarding fludrocortisone use in TBI patients are available to date. The CORTI-TC study aims to test the effects of prolonged low dose of hydrocortisone together with fludrocortisone for prevention of HAP and long term neurological and psychological recovery in patients with severe TBI. Methods and Design Objectives and design The Corticotherapy in traumatic brain-injured patients (CORTI-TC) study is a nationwide multicenter, randomized, double blind, placebo controlled trial. The Institutional Review Board of Tours (France) approved the study protocol. The CORTI-TC is conducted in accordance with the declaration of Helsinki and was registered on March 23 2010 at http://clinicaltrial.gov/ with trial registration NCT01093261. Study population Investigators screen consecutive severe TBI patients defined as the association of a Coma Glasgow Scale 8 together with a traumatic anomaly on tomodensitometry. Inclusions criteria are: severe traumatic BI, in the first 24 hours following trauma, age between 15 and 65 years and informed consent from a next-of-kin. Exclusions criteria are: associated tetraplegia, previous immunosuppression, corticotherapy in the previous 6 months, antibiotherapy for active sepsis at the time of inclusion. Randomization Patients eligible for inclusion should be randomized, and the study treatment is started within the first 24 hours. Patients are randomized in a 1:1 ratio in fixed blocks of 12 and stratified according to the center and MGAP score [15] by a computerized number generator list provided by a statistician not involved in the determination of eligibility or in the assessment of outcomes. All assignments are made through a dedicated, pass-word protected, SSL-encrypted website. Randomized patients are given a number corresponding to a Corti-TC treatment pack that contains: 20 100 mg vial of hydrocortisone or placebo, 10 pills of 50 g of fludrocortisone or placebo and a sheet for schedule administration. Study protocol Immediately after randomization, and before study drug administration, a short corticotropin test is performed (basal cortisolemia followed by 0.25 mg of synacthene and cortisolemia on the 60th min.). Patients are randomized to intravenous infusion of hydrocortisone (200 mg. day-1 for 7 days, 100 mg on days -8 and -9, 50 mg on day10) with enteral administration of fludrocortisone (50 g. day-1 for ten days) or to placebo. After receiving the results of the short corticotropin test (usually in the first 48 hours following inclusion), the treatment is stopped if patients have an adapted corticosteroid function. Protocol drop-out Clinicians are allowed to use corticotherapy at any time point if there is an absolute adrenal insufficiency (basal cortisolemia below 30 g.dl-1), a septic shock or an Acute Respiratory Distress Syndrome. Enteral administration of the study drug (Fludrocortisone or Placebo) can be stopped in case of hypernatremia (>155 mmol.l-1) associated with a low natriuresis (< 20 mmol.l-1). The complete follow up is always performed and patients are kept in the statistical analysis. Biological assessment Immediately before starting the treatment, but at least 8 hours after a bolus injection of etomidate [10,13], a short corticotropin test is performed: cortisolemia before and 60 minutes after an intravenous bolus of 0.25 mg of corticotropin (Novartis , Rueil-Malmaison, France). A second short corticotropin test is performed on day-11 or -12. At the same time points, plasma and serum are frozen at -80C for ancillary studies. Study end points Primary endpoint is the occurrence of HAP within 28 days of randomization (...truncated)