Resuscitation in Paediatric Septic Shock Using Vitamin C and Hydrocortisone (RESPOND): The RESPOND Randomized Controlled Trial Protocol
Sainath Raman, Kristen Gibbons, Muralidharan Jayashree, A. V. Lalitha, Rinaldo Bellomo, Robin Blythe, David Buckley, Warwick Butt, Hwa Jin Cho, Michele Cree, Daniela Carla de Souza, Simon Erickson, Marino S. Festa, Subodh Ganu, Shane George, Ebor Jacob James, Kerry Johnson, Renate Le Marsney, Paula Lister, Trang Pham, Puneet Singh, Balasubramanian Venkatesh, Renee Wall, Debbie Long, Luregn J. Schlapbach, on behalf of the Resuscitation in Paediatric Septic Shock using Vitamin C and Hydrocortisone (RESPOND) Study Group and the Australian and New Zealand Intensive Care Society Paediatric Study Group (ANZICS PSG)
Abstract
OBJECTIVES: Pediatric sepsis results in significant morbidity and mortality worldwide. There is an urgent need to investigate adjunctive therapies that can be administered early. We hypothesize that using vitamin C combined with hydrocortisone increases survival free of inotropes/vasopressors support until day 7 compared with standard care. Here we describe the Resuscitation in Paediatric Septic Shock using Vitamin C and Hydrocortisone (RESPOND) trial protocol, which aims to address this hypothesis. DESIGN: Randomized, open label, controlled, parallel-group, three-arm trial with integrated economic evaluation. SETTING: Nine Australia and New Zealand PICUs, with interest from additional international sites. PATIENTS: Children between 7 days and younger than 18 years old who are treated for suspected or confirmed sepsis and receiving inotropes/vasopressors for greater than 1 hour. INTERVENTIONS: IV vitamin C (100 mg/kg [maximum 5 g] every 6 hr) and hydrocortisone (1 mg/kg [maximum 50 mg] every 6 hr), or IV hydrocortisone alone (1 mg/kg [maximum 50 mg] every 6 hr) or standard care. MEASUREMENTS AND MAIN RESULTS: Three hundred eighty-four children will be randomly assigned to receive the interventions, or standard care in a 1:1:1 ratio with stratification by steroid administration pre-randomization and hospital site. The primary outcome is time alive and free of inotropes/vasopressors, censored at 7 days. Secondary outcomes include 28-day mortality, survival free of organ support, PICU length of stay, quality of life, functional status and neurodevelopmental vulnerability at 6 months post-enrollment, and hospitalization-related costs. Statistical analysis will be based on an intention-to-treat principle. The study has ethical approval (HREC/20/QCHQ/69922, dated December 21, 2020), is registered in the Australian New Zealand Clinical Trials Registry (ACTRN12621000247875), commenced recruitment on December 8, 2021, and is expected to finish recruitment by mid-2026. CONCLUSIONS: Dissemination of the results will occur through publication in peer-reviewed journals, presentations at international conferences, and additional consumer-informed pathways.