We have shown that LUS has higher diagnostic accuracy for msBPD on the 7th DOL than NT-proBNP in preterm infants. Both variables have increasing diagnostic accuracy from birth until the 14th DOL, when both have similar and adequate AUCs. However, the AUC for the LUS score is at its maximum on the 7th DOL, with similar results on the 14th DOL, and it shows good performance at this early time point. On the other hand, NT-proBNP shows maximum diagnostic accuracy on the 14th DOL, as previously published, while the AUC on the 7th DOL is still low, which makes it an unsuitable predictor at this very early stage. However, other studies have shown better results at an earlier time point, namely, birth, for predicting msBPD or death among preterm infants.
Contrary to our hypothesis, the combination of the LUS score and NT-proBNP does not increase the diagnostic accuracy of the two individual variables. The LUS score has been negatively correlated with oxygenation indexes in preterm infants with SDR and with evolving BPD, and it has a positive correlation with inflammatory markers in preterm infants with SDR. Different multicentre studies have demonstrated that the LUS score is also a good predictor of msBPD in children born before 32 weeks after the first 3–7 DOLs[17, 18, 31]. In addition, NT-proBNP is related to msBPD prediction in the first DOLs[8, 29, 32], even after adjusting for haemodynamically significant PDA[7, 8], and it remains related to pulmonary hypertension in preterm infants with BPD[33, 34].
Endothelial injury, high vascular resistance and right ventricular failure are described in the pathophysiology of BPD, and NT-proBNP is secreted by cardiac myocytes in response to volume–pressure overload. A possible explanation for the lack of improvement in the early diagnosis of BPD using both biomarkers is that the increase in vascular and myocardium pressure in these infants generates an effect in the developing lung that acts as another intermediate factor in the cascade towards lung damage in BPD, as well as mechanical ventilation, chorioamnionitis, late-onset sepsis or malnutrition. According to this hypothesis, NT-proBNP and the LUS score would detect this aberrant lung development, but from different points of view.
In the present study, we were not able to demonstrate that any biomarker alone or together increases the diagnostic accuracy of clinical variables, birth weight and the need for IMV on the 7th DOL. Many different multivariate models have been proposed to predict msBPD at birth, on the 1st DOL or on the 7th DOL[41–44] to adjust for possible treatments and ventilatory strategies for babies with a higher risk of the disease. Nevertheless, none of these models have been universally adopted in NICUs, mainly because they include subjective variables that vary between different centres. The need for IMV in preterm babies can meet the requirements of a subjective variable, as the rate of IMV or NIV is different across NICUs throughout the world. However, we believe that LUS is more objective, has high interobserver agreement, and can be performed by neonatologists with low expertise in LUS without secondary effects. We propose to study and validate BPD predictive models using the LUS score, as well as clinical variables that are not subject to variability in clinical practice between centres.
Although this is a multicentre study, which increases the external application of its results, we believe that the main limitation of this study is its sample size, as we included only twenty-seven patients with msBPD. Other variables that may influence both NT-proBNP and/or the LUS score, such as GA or pro-inflammatory conditions, cannot be addressed in a study with a small sample size. We have tried to use a practical hsPDA definition to reduce the variability detected in previous studies (size of PDA, echocardiographic score); however, the decision to treat hsPDA may be influenced by multiple variables as well as the subjective judgement of the neonatologist, which can reduce the external reproducibility of our results. More investigation in this field is warranted, as we still are not able to detect all babies who will develop msBPD as early as the 7–14th DOL to study which treatment would be more suitable to apply to these infants.
Despite these limitations, we conclude that the LUS score is a better predictor of msBPD on the 7th DOL than NT-proBNP in preterm infants born before 32 weeks, although they have similar diagnostic accuracies on the 14th DOL. Neither of them individually nor together have a better AUC for msBPD than a clinical model with birthweight and the need for IMV on the 7th DOL.