Resuscitation in Paediatric Sepsis Using Metabolic Resuscitation–A Randomized Controlled Pilot Study in the Paediatric Intensive Care Unit (RESPOND PICU): Study Protocol and Analysis Plan

Abstract

Introduction: Septic shock remains amongst the leading causes of childhood mortality. Therapeutic options to support children with septic shock refractory to initial resuscitation with fluids and inotropes are limited. Recently, the combination of intravenous hydrocortisone with high dose ascorbic acid and thiamine (HAT therapy), postulated to reduce sepsis-related organ dysfunction, has been proposed as a safe approach with potential for mortality benefit, but randomized trials in paediatric patients are lacking. We hypothesize that protocolised early use of HAT therapy (“metabolic resuscitation”) in children with septic shock is feasible and will lead to earlier resolution of organ dysfunction. Here, we describe the protocol of the Resuscitation in Paediatric Sepsis Using Metabolic Resuscitation–A Randomized Controlled Pilot Study in the Paediatric Intensive Care Unit (RESPOND PICU).Methods and Analysis: The RESPOND PICU study is an open label randomized-controlled, two-sided multicentre pilot study conducted in paediatric intensive care units (PICUs) in Australia and New Zealand. Sixty children aged between 28 days and 18 years treated with inotropes for presumed septic shock will be randomized in a 1:1 ratio to either metabolic resuscitation (1 mg/kg hydrocortisone q6h, 30 mg/kg ascorbic acid q6h, 4 mg/kg thiamine q12h) or standard septic shock management. Main outcomes include feasibility of the study protocol and survival free of organ dysfunction censored at 28 days. The study cohort will be followed up at 28-days and 6-months post enrolment to assess neurodevelopment, quality of life and functional status. Biobanking will allow ancillary studies on sepsis biomarkers.Ethics and Dissemination: The study received ethical clearance from Children's Health Queensland Human Research Ethics Committee (HREC/18/QCHQ/49168) and commenced enrolment on June 12th, 2019. The primary study findings will be submitted for publication in a peer-reviewed journal.Trial Registration: Australian and New Zealand Clinical Trials Registry (ACTRN12619000829112). Protocol Version: V1.8 22/7/20.

Serum Ascorbic Acid and Thiamine Concentrations in Sepsis: Secondary Analysis of the Swiss Pediatric Sepsis Study

“…Low circulating levels of VitC and VitB1 have been reported in critical illness including sepsis (4)(5)(6). VitC and VitB1 are currently under investigation as potential adjunctive treatments for sepsis (7)(8)(9).…”

Resuscitation With Early Adrenaline Infusion for Children With Septic Shock: A Randomized Pilot Trial

“…A trial powered to detect a difference of at least 12 hours in ICU-free survival censored at 7 days, assuming type I error of 0.05, power of 90%, inflation of 15% for non-normally distributed outcome (sd 1.9 d), would require 358 patients per arm (716 patients total). While the platform design allowed to optimize study education, screening, recruitment, and data collection processes for RESPOND ED with the concomitantly conducted RESPOND PICU trial, recruitment of RESPOND PICU remained substantially higher and included a much sicker cohort (13). Overall, our findings thus provide rationale to test a similar protocol in a less resourced environment.…”

Early Resuscitation in Paediatric Sepsis Using Inotropes – A Randomised Controlled Pilot Study in the Emergency Department (RESPOND ED): Study Protocol and Analysis Plan

“…We anticipate that <30% of RESPOND ED study patients will be co-enrolled into a concomitant study investigating metabolic resuscitation, named RESPOND PICU (ACTRN12619000829112) (27). Given that the study is a pilot feasibility study, analyses on RESPOND ED will occur separately from RESPOND PICU.…”