Protocol for a prospective cohort study exploring the gut microbiota of infants with congenital heart disease undergoing cardiopulmonary bypass (the GuMiBear study).

The gut microbiota develops from birth and matures significantly during the first 24 months of life, playing a major role in infant health and development. The composition of the gut microbiota is influenced by several factors including mode of delivery, gestational age, feed type and treatment with antibiotics. Alterations in the pattern of gut microbiota development and composition can be associated with illness and compromised health outcomes.Infants diagnosed with 'congenital heart disease' (CHD) often require surgery involving cardiopulmonary bypass (CPB) early in life. The impact of this type of surgery on the integrity of the gut microbiome is poorly understood. In addition, these infants are at significant risk of developing the potentially devastating intestinal condition necrotising enterocolitis. This study will employ a prospective cohort study methodology to investigate the gut microbiota and urine metabolome of infants with CHD undergoing surgery involving CPB. Stool and urine samples, demographic and clinical data will be collected from eligible infants based at the National Centre for Paediatric Cardiac Surgery in Ireland. Shotgun metagenome sequencing will be performed on stool samples and urine metabolomic analysis will identify metabolic biomarkers. The impact of the underlying diagnosis, surgery involving CPB, and the influence of environmental factors will be explored. Data from healthy age-matched infants from the INFANTMET study will serve as a control for this study. This study has received full ethical approval from the Clinical Research Ethics Committee of Children's Health Ireland, GEN/826/20.

Magner C ，Jenkins D ，Koc F ，Tan MH ，O'Toole M ，Boyle J ，Maguire N ，Duignan S ，Murphy K ，Ross P ，Stanton C ，McMahon CJ ... -  《BMJ Open》

Gut Microbiome in Children with Congenital Heart Disease After Cardiopulmonary Bypass Surgery (GuMiBear Study).

The gut microbiome of infants with congenital heart disease (CHD) undergoing cardiopulmonary bypass surgery (CPB) is at risk of profound alteration. The aim of this study was to examine the gut microbiome pre- and post-bypass surgery to explore potential implications of altered gut biodiversity. A prospective cohort study involving infants with CHD who underwent CPB was performed. Faecal samples were collected from infants alongside the collection of demographic and clinical data in order to examine gut microbiome changes before and after surgery. 16S rRNA sequencing analysis was performed on DNA isolated from stool samples to determine changes in gut microbiome composition. Thirty-three patients were recruited, with samples from thirteen of these available for final analysis. Compared with healthy, matched controls, at a genus level, pre-operative samples for infants with CHD demonstrated a higher relative abundance of Escherichia-Shigella (31% vs 2-6%) and a lower relative abundance of Bifidobacterium (13% vs 40-60%). In post-operative samples, the relative abundance of Escherichia-Shigella (35%), Enterococcus (11%), Akkermansia (6%), and Staphylococcus (5%) were higher than pre-op samples. One infant developed post-operative necrotising-enterocolitis (NEC). They displayed a marked abundance of the Enterococcus (93%) genus pre-operatively. This study demonstrates that infants with CHD have an altered gut microbiome when compared with healthy controls and there might be a possible link between an abundance of virulent species and NEC.

Koc F ，Magner C ，Murphy K ，Kelleher ST ，Tan MH ，O'Toole M ，Jenkins D ，Boyle J ，Lavelle M ，Maguire N ，Ross PR ，Stanton C ，McMahon CJ ... -  《-》

Study protocol: NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC trial): a randomised controlled trial.

Congenital heart disease (CHD) is a major cause of infant mortality. Many infants with CHD require corrective surgery with most operations requiring cardiopulmonary bypass (CPB). CPB triggers a systemic inflammatory response which is associated with low cardiac output syndrome (LCOS), postoperative morbidity and mortality. Delivery of nitric oxide (NO) into CPB circuits can provide myocardial protection and reduce bypass-induced inflammation, leading to less LCOS and improved recovery. We hypothesised that using NO during CPB increases ventilator-free days (VFD) (the number of days patients spend alive and free from invasive mechanical ventilation up until day 28) compared with standard care. Here, we describe the NITRIC trial protocol. The NITRIC trial is a randomised, double-blind, controlled, parallel-group, two-sided superiority trial to be conducted in six paediatric cardiac surgical centres. One thousand three-hundred and twenty infants <2 years of age undergoing cardiac surgery with CPB will be randomly assigned to NO at 20 ppm administered into the CPB oxygenator for the duration of CPB or standard care (no NO) in a 1:1 ratio with stratification by age (<6 and ≥6 weeks), single ventricle physiology (Y/N) and study centre. The primary outcome will be VFD to day 28. Secondary outcomes include a composite of LCOS, need for extracorporeal membrane oxygenation or death within 28 days of surgery; length of stay in intensive care and in hospital; and, healthcare costs. Analyses will be conducted on an intention-to-treat basis. Preplanned secondary analyses will investigate the impact of NO on host inflammatory profiles postsurgery. The study has ethical approval (HREC/17/QRCH/43, dated 26 April 2017), is registered in the Australian New Zealand Clinical Trials Registry (ACTRN12617000821392) and commenced recruitment in July 2017. The primary manuscript will be submitted for publication in a peer-reviewed journal. ACTRN12617000821392.

Schlapbach LJ ，Horton SB ，Long DA ，Beca J ，Erickson S ，Festa M ，d'Udekem Y ，Alphonso N ，Winlaw D ，Johnson K ，Delzoppo C ，van Loon K ，Gannon B ，Fooken J ，Blumenthal A ，Young P ，Jones M ，Butt W ，Schibler A ，NITRIC Study Group, the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG), the Paediatric Critical Care Research group (PCCRG) and the ANZICS Paediatric Study Group (PSG) ... -  《BMJ Open》

Feeding intolerance after pediatric cardiac surgery is associated with dysbiosis, barrier dysfunction, and reduced short-chain fatty acids.

Owens J ，Qiu H ，Knoblich C ，Gerjevic L ，Izard J ，Xu L ，Lee J ，Kollala SS ，Murry DJ ，Riethoven JJ ，Davidson JA ，Singh AB ，Ibrahimiye A ，Ortmann L ，Salomon JD ... -  《-》

Longitudinal cohort study investigating neurodevelopmental and socioemotional outcomes in school-entry aged children after open heart surgery in Australia and New Zealand: the NITRIC follow-up study protocol.

Despite growing awareness of neurodevelopmental impairments in children with congenital heart disease (CHD), there is a lack of large, longitudinal, population-based cohorts. Little is known about the contemporary neurodevelopmental profile and the emergence of specific impairments in children with CHD entering school. The performance of standardised screening tools to predict neurodevelopmental outcomes at school age in this high-risk population remains poorly understood. The NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) trial randomised 1371 children <2 years of age, investigating the effect of gaseous nitric oxide applied into the cardiopulmonary bypass oxygenator during heart surgery. The NITRIC follow-up study will follow this cohort annually until 5 years of age to assess outcomes related to cognition and socioemotional behaviour at school entry, identify risk factors for adverse outcomes and evaluate the performance of screening tools. Approximately 1150 children from the NITRIC trial across five sites in Australia and New Zealand will be eligible. Follow-up assessments will occur in two stages: (1) annual online screening of global neurodevelopment, socioemotional and executive functioning, health-related quality of life and parenting stress at ages 2-5 years; and (2) face-to-face assessment at age 5 years assessing intellectual ability, attention, memory and processing speed; fine motor skills; language and communication; and socioemotional outcomes. Cognitive and socioemotional outcomes and trajectories of neurodevelopment will be described and demographic, clinical, genetic and environmental predictors of these outcomes will be explored. Ethical approval has been obtained from the Children's Health Queensland (HREC/20/QCHQ/70626) and New Zealand Health and Disability (21/NTA/83) Research Ethics Committees. The findings will inform the development of clinical decision tools and improve preventative and intervention strategies in children with CHD. Dissemination of the outcomes of the study is expected via publications in peer-reviewed journals, presentation at conferences, via social media, podcast presentations and medical education resources, and through CHD family partners. The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry as 'Gene Expression to Predict Long-Term Neurodevelopmental Outcome in Infants from the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) Study - A Multicentre Prospective Trial'. ACTRN12621000904875.

Long D ，Anderson VA ，Crossley L ，Sood NT ，Charles KR ，MacDonald AD ，Bora S ，Pestell CF ，Murrell K ，Pride NA ，Anderson PJ ，Badawi N ，Rose B ，Baillie H ，Masterson K ，Chumbes Flores J ，Sherring C ，Raman S ，Beca J ，Erickson S ，Festa M ，Anderson BW ，Venugopal P ，Yim D ，Andrews D ，Cheung M ，Brizard C ，Gentles TL ，Iyengar A ，Nicholson I ，Ayer J ，Butt W ，Schlapbach LJ ，Gibbons KS ... -  《BMJ Open》