Title: The efficacy and mechanism of surfactant therapy for critically ill infants with bronchiolitis: the Bronchiolitis Endotracheal Surfactant Study (BESS)
Funder: Department of Health and Social Care

Abstract: Setting: 14 Paediatric Intensive Care Units. Patient group: Term born infants age <26 weeks old and preterm born infants with corrected age < 26 weeks old; including infants with Chronic Lung Disease of Prematurity and other sequelae of premature birth. Design: Phase 2 efficacy study comprising a randomised blinded placebo-controlled trial and a nested mechanistic sub-study. Randomisation: Standard care plus intervention or standard care plus air-placebo sham procedure. Intervention: Endotracheal porcine surfactant (poractant alfa), first dose 200mg/kg, repeated 12 hourly at 100mg/kg while intubated for mechanical ventilation (MV), for a maximum of 3 doses. Control: Air-placebo sham procedure. Consent: Prospective written informed consent from a person with parental responsibility per NIHR clinical trials toolkit for trials involving critically ill children. Blinding: Usual clinical staff and investigators will be blinded to the intervention. Intervention or sham procedure will be delivered by a study respiratory therapist or other staff not otherwise involved in managing MV, or making decisions to wean or extubate. Eligibility: Infants on conventional MV for life-threatening respiratory failure due to community acquired bronchiolitis of any aetiology. Diagnosis of bronchiolitis based on clinical diagnosis per SIGN Guideline 91 & NICE NG9. Exclusions: Pre-existing co-morbidity/congenital anomaly, e.g. cyanotic heart disease, neuromuscular disease. MV for primary apnoea rather than respiratory failure. Intubated for >48 hours before recruitment. Requiring ECMO or oscillation prior to recruitment. When decision to wean to extubation has already been made. Participant discontinuation criteria: clinical judgment that intervention is futile. Primary outcome measure: Duration of MV after randomisation defined as time to final extubation in hours. Secondary outcomes measures: Parent reported outcome measure (The Liverpool Respiratory Symptom Questionnaire) at 6m & 12m. All cause mortality and readmissions to d90. Peripheral Oxygen Saturation/Fraction Inspired Oxygen (SpO2/FiO2), Ventilation Index (VI) and Oxygenation Index (OI) measured prior to and 12 hourly after intervention. Time from randomisation to readiness for Spontaneous Breathing Test. Duration of non-invasive respiratory support & supplemental oxygen. Duration of stay on PICU & in hospital. Others per Detailed Project Description (DPD) Power: please see DPD Analysis: Intention to treat. For primary outcome measure, difference between group geometric mean durations of MV. For secondary outcome measures differences between groups by: mean difference of LRSQ scores; relative risk for all cause mortality at d90; and joint modelling of the longitudinal data for SpO2/FiO2, VI and OI with the duration of MV. Duration of follow-up: 90 days for primary analysis. Mechanistic sub-study. We will explore proposed mechanisms of efficacy and failure by serial sampling of Broncho-Alveolar Lavage Fluid (BALF) while intubated. Hypotheses to test include: i) "Synthesis of endogenous surfactant is modulated by exogenous surfactant", using a non-radioactive stable isotope label protocol. ii) "Lower airway inflammation is modulated by exogenous surfactant", by focused analysis of inflammatory pathway cytokines. iii) "Treatment efficacy or failure is associated with detection of specific pathogens", by assay for bacterial and viral pathogens by multiplex PCR

Lay abstract: Bronchiolitis is a winter viral chest infection that causes breathing difficulties in babies. It is the single most common reason for hospital admission of babies in England, with over 25,000 per year. There is no vaccine or specific treatment. Breathing fails in very severe cases, and these babies need intensive care to go on a breathing machine called a mechanical ventilator. Surfactant is in the liquid produced in healthy lungs that allows the lungs to inflate more easily. Surfactant therapy has been used routinely for use in premature babies for over 30 years. We have already shown that babies with bronchiolitis have less surfactant than they need for their lungs to work normally. Three small studies that gave half the dose of surfactant that is now recommended improved babies breathing for several hours and most babies recovered and left PICU quicker. We want to find out if giving surfactant reduces the time critically ill babies with bronchiolitis spend on a mechanical ventilator. Our study will use the higher doses now recommended and involve more babies. We will give surfactant to 141 babies over two days and a dummy procedure to 141 babies. The PICU staff and research team will not know who gets what until the end of the study. We will do tests to measure how much surfactant the babies are making; how much of the surfactant that we give is staying in the lungs; which virus and bacteria are infecting the airways and how much inflammation is in the airways. Babies that have severe bronchiolitis often have more episodes of chestiness and wheeze in the months after their illness than those that did not have bronchiolitis. It is possible that the surfactant given in this study may help reduce these symptoms. We will ask parents to complete a questionnaire after their baby goes home to tell us about any respiratory symptoms they notice in their baby.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: INFECTION;REPRODUCTIVE HEALTH AND CHILDBIRTH