Respiratory course was reviewed at each meeting, including symptoms, respiratory support, respiratory rates, oxy-hemoglobin saturations, chest imaging, laboratory values, and medications. Other data reviewed included length and weight trajectories, feeding tolerance, developmental progress, and rate of overall improvement. If BPD-PH was diagnosed, BPD respiratory support strategies (invasive mechanical ventilation, noninvasive positive pressure ventilation, continuous positive airway pressure, high flow nasal cannula) were optimized to minimize work of breathing, avoid hypercapnia, decrease hyperinflation, and support optimal growth and development consistent with strategies described by the BPD collaborative (4). As a team, we implemented the high tidal volume (10–14 ml/kg), low rate (16–20 breaths per minute), and long inspiratory time (0.5–0.7 s) ventilator strategy published by Abman et al., recognizing the need for unique ventilator management due to high airway resistance in severe established BPD. PEEP was clinically titrated to the individual patients' physiology based on the presence or absence of bronchoscopy-determined central airway malacia, severity of dynamic lower airway obstruction, and frequent bedside assessment of ventilator synchrony. In patients with frequent oxygen desaturations <94% despite bedside titration to goal, a minimum supplemental oxygen level (for example 0.25–0.3 FiO₂) was considered, but carefully balanced and frequently reassessed to avoid hyperoxia. Trials of systemic and inhaled steroids, diuretics, and inhaled bronchodilators were considered on a case-by-case basis. Chest computed tomography (CT) imaging of lung parenchyma and pulmonary veins, and airway endoscopy were obtained for cases with disproportionate hypoxia or hypercapnia, or persistent evidence of BPD-PH by echocardiogram despite optimization of respiratory support. Tracheostomy was considered for chronic respiratory failure requiring long term invasive ventilation. Optimization of respiratory support continued until the patient stabilized, growth normalized, neurodevelopmental progress was established, and BPD-PH improved.

Patients with BPD-PH taking any oral feeds underwent clinical swallow evaluation and, if recommended, video fluoroscopic swallowing study. The feeding method was adjusted per feeding therapy and BPD team recommendations. Nasogastric feeding tubes were placed if needed to decrease aspiration risk and were changed from gastric to post-pyloric with concerns for significant reflux or aspiration, lack of respiratory status improvement, or worsening BPD-PH. Gastric feeds volumes and rate of delivery were adjusted to optimize feeding tolerance and minimize aspiration risk. Nissen fundoplication is not routinely performed at SCH, so all post-pyloric feeds were via nasoduodenal or gastrojejunal tubes.

PH was defined as tricuspid regurgitation jet > 2.5 m/s, interventricular septum flattened in systole, or bidirectional shunting in the presence of a patent ductus arteriosus (PDA) or ventricular septal defect. All echocardiogram images for this report were reviewed by a single cardiologist (DY). Screening echocardiograms were obtained according to our institutional protocols at or before 36 weeks PMA or at transfer to SCH for patients with BPD. Timing of echocardiograms before transfer to SCH was determined by the referring hospital, but images from most hospitals were available for our review. Available echocardiograms performed at day of life 7–14 were reviewed for early PH (19). Echocardiograms with PH, including those diagnosed before 36 weeks PMA, were repeated within 1–4 weeks depending on severity of PH and right ventricular failure. Repeat echocardiogram could also be triggered by rising B-type natriuretic peptide (BNP) levels, which were obtained concomitantly and between echocardiograms. Serial echocardiograms were also performed to follow-up PDA, atrial septal defect (ASD), and pulmonary vein stenosis (PVS), at a frequency determined by the PH specialist and cardiologist. After echocardiogram showed resolution of PH, screening echocardiograms continued every 1–6 months, depending on age and degree of respiratory and oxygen support, until patients were off all respiratory support.

Patients with a moderate or large PDA were recommended for cardiac catheterization for hemodynamic evaluation and potential closure by device at the time of BPD-PH diagnosis. Patients with moderate or large secundum ASD were recommended for device closure when BPD-PH did not resolve after optimizing respiratory support and treating aspiration. The devices used were the Amplatzer Piccolo Occluder, Medtronic Micro Vascular Plug and Siege Vascular Plug for PDA, and Amplatzer Septal Occluder device for ASD.

Patients with evidence of PVS on echocardiogram underwent chest CT angiogram and cardiac catheterization evaluation with possible intervention.

Hemodynamic diagnostic catheterization before initiation of PH vasodilators, consistent with published recommendations (12), is standard practice at SCH. Patients who met the standard definition of PH, mean pulmonary artery pressure >20 mmHg, pulmonary capillary pressure <15 mmHg, and pulmonary vascular resistance >3 Woods units*m² (20), were considered for PH medical therapy.

Sildenafil was the first line pulmonary vasodilator after confirmation of PH by catheterization. Inhaled nitric oxide (iNO) was used before 36 weeks PMA in some mechanically ventilated infants with high FiO₂ at SCH and referring hospitals prior to transfer, but due to difficulty verifying this data, iNO use was not collected. Bosentan and prostacyclins were not used in this cohort.

Our cohort of patients with severe BPD all had resolution of BPD-PH with a strategy of multidisciplinary team care including optimization of respiratory support and interventional cardiac catheterization device closure of PDA and ASD, with limited use of sildenafil (8%) and low mortality (5%). To treat BPD-PH, we employed BPD-specific ventilator strategies, including low rate, higher tidal volume, longer inspiratory time, and PEEP titrated to treat multi-level airway disease (4). A quarter of the patients in our cohort required tracheostomy. Unlike respiratory strategies for younger premature infants, only mild hypercapnia was permitted with target pCO₂ less than 55 mmHg, and oxygen was added to achieve goal saturations above 94%. Respiratory support was considered optimized if infants demonstrated acceptable growth, minimal work of breathing, and could participate in developmental therapies. Outpatients with improving BPD-PH on respiratory support continued echocardiogram screening until BPD-PH eventually resolved, some taking over 2 years. Our team was also aggressive in treating potential aspiration as recommended by PH experts (26), with 90% of study patients discharged with a feeding tube and 20% on post-pyloric feeds.

BPD-PH was diagnosed relatively early, with half diagnosed before 2.5 weeks of life and 28.1 weeks PMA, and 48% diagnosed before transfer to SCH. Resolution occurred before 36 weeks PMA for 30%, between 36 and 52 weeks PMA for 40%, and after 52 weeks for 30%. In this large series of infants who received aggressive care for PDAs, BPD-PH resolution occurred a median of 4 weeks after device closure of moderate or large PDA. We note disproportionate representation of SGA in our cohort (20%), consistent with publications identifying SGA as a risk factor for development of PH in patients with BPD (27). However, despite being implicated as risk factors for severity of disease (19, 27), neither SGA nor PH diagnosis at PMA < 36 weeks were associated with length of time to PH resolution, suggesting that our multidisciplinary care may have negated some of the risks associated with these factors.

These results are similar to a cohort reported by Altit et al. in which the “natural history” of BPD-PH was resolution, although their population was solely those with BPD-PH diagnosed after 36 weeks, with markers of more severe BPD, over a time period of nearly two decades (28). However, our cohort had lower mortality (5%) with the rare deaths unrelated to BPD-PH or heart failure. While we expect one result of our team-based approach to be lower mortality, the retrospective nature of this study and lack of an adequate historical control group makes it impossible to confirm causality. We hope with prospective data collection and improved guidelines for timing of referral for patients with severe BPD that we will be better able to address the impact of our multidisciplinary team in the future through single and multicenter studies.

Cardiology management played an important role in our management of BPD-PH, with almost half of the patients undergoing PDA or ASD device closure. Assessment and closure of both PDA and ASD were supported by recent findings that the presence of a PDA and an ASD is associated with increased risk of BPD-PH over time (29, 30). We used PDA and ASD size, not hemodynamic significance, as the indication for closure. This is because while a large PDA is not hemodynamically significant if there is high PVR, a large PDA will transmit systemic pressure to the pulmonary arteries. In addition, an ASD that causes even mild pulmonary over-circulation can lead to respiratory compromise in patients with lung dysplasia (30, 31). Historically, PDAs were surgically ligated, but newer devices make PDA and ASD closure in the cardiac catheterization lab an option with an acceptable level of risk in even very small infants. Likewise, while ASDs have not previously been considered important to the development of PH in neonates or infants and are generally recommended for closure in childhood before school age, the ability to safely close ASD in infants at SCH influenced our management recommendations and may have contributed to rapid resolution of BPD-PH. Contrary to conventional teaching to leave PDA or ASD as a “pop-off” in the setting of low velocity or bidirectional shunting, there has been no instance of right ventricular failure after closure in our cohort. This practice has been developed with the interventional cardiology team at our center, with whom we are fortunate to have a close collaboration.

Our results show much lower use of sildenafil in the BPD-PH population (8%) than in other reports, including the multicenter Children's Hospital Neonatal Consortium, in which sildenafil use averaged 60% per center (11). We suspect our lower sildenafil use was due to several factors. First, the presence of BPD-PH on the echocardiogram signaled that respiratory support was sub-optimal and would guide changes in multidisciplinary team recommendations. Also, instead of initiating sildenafil when the echocardiogram continued to show BPD-PH after respiratory optimization, we elected to watch and reassess if the echocardiogram demonstrated improvement in BPD-PH. In addition, by having a cardiology-trained BPD team member comparing echocardiogram images, subtle improvements in BPD-PH not noted in the official echocardiogram report could be observed. Lastly, we are committed to diagnosing PH by cardiac catheterization, for reasons as discussed in 4.1.4. below.

Furthermore, we speculate that even the three patients on long-term sildenafil may have resolved PH without treatment. We noted that the two patients who stopped sildenafil early due to adverse events and still eventually resolved BPD-PH were clinically similar to the third patient who was started on sildenafil by our group. In addition, BPD-PH resolved after involvement of our care in the two patients who were started on sildenafil by the referring hospital.

Whether higher use of sildenafil without diagnostic cardiac catheterization would have led to even earlier resolution of BPD-PH is unknown. However, increased sildenafil exposure would have increased risk of adverse events. The two adverse events that led to stopping sildenafil were well-documented and agreed upon by all team members. Hypoxemia in one patient after initiation of sildenafil may be due to lack of hypoxic vasoconstriction, leading to ventilation—perfusion mismatching, as others have speculated in BPD (32). Although many reports have demonstrated sildenafil safety in neonates (18, 33), we share concerns for unintended impacts of sildenafil on vascular development, such as those raised after sildenafil-exposed fetuses demonstrated increased risk of neonatal PH (34). We look forward to the results of a placebo-controlled clinical trial studying safety of sildenafil in BPD that is currently under way (35).

While our practice is to perform cardiac catheterization to diagnose PH, recently published work supports the empiric initiation of sildenafil without cardiac catheterization due to catheterization-associated risks, lack of clinical utility, and cost (17). Because we perform fewer cardiac catheterizations and initiate sildenafil less frequently, diagnostic cardiac catheterization before sildenafil initiation appears to have a beneficial role in our practice and patient population. This practice also allows for identification and treatment of other cardiac pathologies such as hemodynamically significant sinus venosus ASD as identified in one of our patients.

Standards for timing and interpretation of screening echocardiogram for BPD-PH or elevated pulmonary pressures associated with evolving BPD remain unclear (36, 37). However, echocardiogram screening for PH before 36 weeks may influence early approaches to mitigate PH, such as ventilator strategies, PDA/ASD closure, and avoidance of aspiration. In our cohort, PH at DOL 7-14 echocardiogram was not associated with late PH at 36 weeks PMA, in contrast to findings from Mourani et al. (19). However, we acknowledge that our contemporary cohort is notably smaller with variable timing of echocardiograms and therefore may not provide accurate representation of early PH in the evolving BPD population across other centers.