Resuscitation in Paediatric Septic Shock Using Vitamin C and Hydrocortisone (RESPOND): The RESPOND Randomized Controlled Trial Protocol

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 (100mg/kg [maximum 5 g] every 6hr) and hydrocortisone (1mg/kg [maximum 50 mg] every 6hr), or IV hydrocortisone alone (1mg/kg [maximum 50 mg] every 6hr) 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.