Multicentre prospective observational study exploring the predictive value of functional echocardiographic indices for early identification of preterm neonates at risk of developing chronic pulmonary hypertension secondary to chronic neonatal lung disease

Laura Thomas, Michelle Baczynski, Poorva Deshpande, Ashraf Kharrat, Sébastien Joye, Faith Zhu, Daniel Ibarra-Rios, Prakesh S Shah, Luc Mertens, Robert P Jankov, Xiang Y Ye, Elaine Neary, Joseph Ting, Michael Castaldo, Philip Levy, Aisling Smith, Afif F El-Khuffash, Regan E Giesinger, Patrick J McNamara, Dany E Weisz, Amish Jain, Laura Thomas, Michelle Baczynski, Poorva Deshpande, Ashraf Kharrat, Sébastien Joye, Faith Zhu, Daniel Ibarra-Rios, Prakesh S Shah, Luc Mertens, Robert P Jankov, Xiang Y Ye, Elaine Neary, Joseph Ting, Michael Castaldo, Philip Levy, Aisling Smith, Afif F El-Khuffash, Regan E Giesinger, Patrick J McNamara, Dany E Weisz, Amish Jain

Abstract

Introduction: Although chronic pulmonary hypertension (cPH) secondary to chronic neonatal lung disease is associated with increased mortality and respiratory and neurodevelopmental morbidities, late diagnosis (typically ≥36 weeks postmenstrual age, PMA) and the use of qualitative echocardiographic diagnostic criterion (flat interventricular septum in systole) remain significant limitations in clinical care. Our objective in this study is to evaluate the utility of relevant quantitative echocardiographic indices to identify cPH in preterm neonates, early in postnatal course and to develop a diagnostic test based on the best combination of markers.

Methods and analysis: In this ongoing international prospective multicentre observational diagnostic accuracy study, we aim to recruit 350 neonates born <27 weeks PMA and/or birth weight <1000 g and perform echocardiograms in the third week of age and at 32 weeks PMA (early diagnostic assessments, EDA) in addition to the standard diagnostic assessment (SDA) for cPH at 36 weeks PMA. Predefined echocardiographic markers under investigation will be measured at each EDA and examined to create a scoring system to identify neonates who subsequently meet the primary outcome of cPH/death at SDA. Diagnostic test characteristics will be defined for each EDA. Pulmonary artery acceleration time and tricuspid annular plane systolic excursion are the primary markers of interest.

Ethics and dissemination: Ethics approval has been received by the Mount Sinai Hospital Research Ethics Board (REB) (#16-0111-E), Sunnybrook Health Sciences Centre REB (#228-2016), NHS Health Research Authority (IRAS 266498), University of Iowa Human Subjects Office/Institutional Review Board (201903736), Rotunda Hospital Research and Ethics Committee (REC-2019-008), and UBC Children's and Women's REB (H19-02738), and is under review at Boston Children's Hospital Institutional Review Board. Study results will be disseminated to participating families in lay format, presented to the scientific community at paediatric and critical care conferences and published in relevant peer-reviewed journals.

Trail registration number: NCT04402645.

Keywords: echocardiography; neonatal intensive & critical care; paediatric cardiology.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
In early stage of chronic pulmonary hypertension (cPH), the disease is expected to be more functional, determined by sustained pulmonary vasoconstriction and relatively less by ‘fixed’ anatomical remodelling, hence, may be more amenable to treatments. The overall aim of this study is to develop new diagnostic criteria sensitive enough to identify extreme premature neonates with significant pulmonary vascular disease, who subsequently will be diagnosed with cPH secondary to chronic neonatal lung disease. CNLD, chronic neonatal lung disease; PVR, pulmonary vascular resistance
Figure 2
Figure 2
Schematic representation of planned study interventions. Each infant, after obtaining informed parental consent, will undergo two sequential early diagnostic assessments (EDAs) at predefined time points, followed by a standard diagnostic assessment (SDA) to categorise study cohort as chronic pulmonary hypertension (cPH) or no cPH, as per the standard currently used clinical definition. Blinded measurements will be performed for tricuspid annular plane systolic excursion (TAPSE, a marker of right ventricular function) and pulmonary artery acceleration time (PAAT, a marker of pulmonary vascular resistance) at both EDAs to calculate their early diagnostic characteristics (sensitivity, specificity and positive and negative likelihood ratios) to diagnose cPH by comparing to eventual diagnosis made at SDA. GA, gestational age; NICU, neonatal intensive care unit; PMA, postmenstrual age.

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