B-Type Natriuretic Peptide and Novel Cardiac Ultrasound in Very Preterm Neonates: Potential Markers for the Detection of Pulmonary Hypertension and for Risk Stratification

Abstract

Very premature birth causes an interruption of cardiorespiratory development. Successful pulmonary adaptation requires synchronous development of alveoli and pulmonary capillary networks. Very premature birth threatens this process. Exposure to excess oxygen, combined with the modifying effects of growth and inflammation, can cause bronchopulmonary dysplasia characterised by maldevelopment of alveoli and pulmonary vasculature. This may be complicated by pulmonary hypertension causing right heart dysfunction which may persist to adulthood. As pulmonary hypertension develops insidiously, and is associated with significant morbidity and mortality, screening is recommended. However, there are no consensus diagnostic criteria and a paucity of validated heart ultrasound parameters in the very preterm population. N-Terminal proB-type Natriuretic Peptide (NTproBNP), a cardiac hormone, is a promising biomarker as it is a sensitive marker of ventricular wall pressure and volume stress and predicts pulmonary hypertension in other settings. There is limited data in very preterm infants. Premature infants have unstable oxygen saturations due to multifactorial causes which may be exacerbated by pulmonary hypertension. Oxygen saturation targeting attempts to reduce hypoxia and hyperoxia. Modern oximeters allow detailed analysis of oxygen saturation patterns but optimal measures of instability have not been established. We investigated temporal changes in NTproBNP and factors influencing levels, in a cohort of very preterm infants. We evaluated NTproBNP as a biomarker for pulmonary hypertension by pairing NTproBNP with heart ultrasound and pulse oximetry data in the neonatal period and report clinical and neurodevelopmental outcomes at two years. Quantitative measures of right heart function and compliance with oxygen saturation alarm limits in our unit were evaluated. Current screening recommendations were reviewed. We demonstrated high NTproBNP on days 3 and 10 then decreasing NTproBNP beyond the period of cardiac transition. NTproBNP was a highly sensitive and specific marker of haemodynamically significant patent ductus arteriosus and a modest predictor of severe bronchopulmonary dysplasia. None of our cohort had evidence of pulmonary hypertension at 36 weeks post menstrual age by predefined conventional heart ultrasound criteria. However, we demonstrated it is feasible for more advanced quantitative measures of right heart function to be incorporated into clinician performed heart ultrasound that may be of value to screening programmes. We showed changes in these parameters over time, reviewed their reliability, and investigated differences in infants with and without bronchopulmonary dysplasia. Oxygen saturation instability increased in our cohort over time peaking at day 28 and was greater in infants with bronchopulmonary dysplasia. We identified oxygen saturation coefficient of variation and percentage time less than 88% as useful measures of instability. Compliance with oxygen saturation alarm limits in our unit was low despite high levels of nursing experience potentially exposing extremely premature infants to iatrogenic hyperoxia which may contribute to pulmonary hypertension. In summary, we found a lower than expected rate pulmonary hypertension in our very preterm cohort. There is insufficient evidence for NTproBNP as a standalone biomarker for pulmonary hypertension but it may be useful as an adjunct to comprehensive heart ultrasound evaluation. To reduce pulmonary hypertension, surveillance of at risk infants and oxygen saturation stewardship is needed.