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Pulmonary hypertension in bronchopulmonary dysplasia

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Abstract

Pulmonary hypertension (PH) is a common complication of neonatal respiratory diseases, including bronchopulmonary dysplasia (BPD), and recent studies have increased awareness that PH worsens the clinical course, morbidity and mortality of BPD. Recent evidence indicates that up to 18% of all extremely low-birth-weight infants will develop some degree of PH during their hospitalization, and the incidence rises to 25–40% of the infants with established BPD. Risk factors are not yet well understood, but new evidence shows that fetal growth restriction is a significant predictor of PH. Echocardiography remains the primary method for evaluation of BPD-associated PH, and the development of standardized screening timelines and techniques for identification of infants with BPD-associated PH remains an important ongoing topic of investigation. The use of pulmonary vasodilator medications, such as nitric oxide, sildenafil, and others, in the BPD population is steadily growing, but additional studies are needed regarding their long-term safety and efficacy.

Section snippets

Background

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy in the United States and complicates the course of more than 30% of extremely preterm infants, resulting in 10,000 new cases annually in the United States. While prenatal steroids and surfactants have reduced the rates of acute respiratory failure and improved survival, very limited progress has been made in reducing the rates of BPD. Multiple therapies, such as non-invasive ventilation, vitamin A, caffeine,

Pathophysiology

In contrast to the classic features of fibroproliferative BPD as originally described by Northway and others, lung disease in today's post-surfactant era is characterized by impaired alveolarization and compromised vasculogenesis which occurs when the preterm lung attempts to adapt to air breathing.13 Findings observed in both pre- and post-surfactant BPD include vascular remodeling (Fig. 1), increased vascular tone and altered vasoreactivity.14, 15 These features, along with the decreased

Screening and diagnosis

The development of standardized, clinically useful algorithms for the identification of infants with BPD-associated PH remains an important topic of investigation. Symptoms of PH often overlap those of BPD itself, including hypoxia, pulmonary instability, poor feeding and failure to thrive. Furthermore, the emergence of symptoms may indicate that the disease has already progressed to a late, less reversible phase, thereby supporting arguments for screening all infants at risk. Significant

Management

While the presence of PH does not always correlate with severity of BPD, the approach to prevention and management of PH should include optimization of respiratory function and nutritional support to limit lung injury and facilitate lung growth. While support of respiratory function may include use of diuretics, inhaled steroids and/or bronchodilators, none of these have been shown to reduce the severity of BPD-associated PH. Infants should also be evaluated for structural airway abnormalities,

Pulmonary vasodilators

The general management strategies described previously may prove insufficient for infants with severe or progressive vascular disease, prompting consideration of the use of pulmonary vasodilators. While experience with these medications in the BPD population is steadily growing, knowledge regarding their long-term safety and efficacy remains limited.

Stem cell therapies

Recent animal and human studies suggest that damage or depletion of epithelial and/or vascular stem cells in the developing lung likely contributes to the pathogenesis of BPD.75 For instance, hyperoxia-induced BPD in neonatal rats is associated with decreased circulating and resident mesenchymal stem cells (MSC).76 Administration of bone marrow-derived mesenchymal stem cells or multipotent stromal cells prevents the compromised alveolar and vascular development observed in the murine

Conclusion

While numerous questions remain unanswered with respect to optimal screening protocols and clinical management of infants with BPD-associated PH, it is clear that the condition is relatively common in ELBW or growth-restricted premature infants in the modern post-surfactant era, and that the diagnosis carries a tremendous burden of morbidity and mortality. Great efforts are being made to better characterize the prevalence, clinical course and response to acute and chronic therapy. Experience

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    Supported in part by HL54705 (RHS) and HL093302 (KKM).

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