Despite current advances in neonatal care, BPD remains a heavy burden on health care resources. New treatments directed either at reducing lung injury or. Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that develops in preterm neonates treated with oxygen and. edad Gestacional con antecedentes de reanimación neonatal por SRP, necesito Ventilación mecánica DISPLASIA BRONCOPULMONAR.

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Bronchopulmonary dysplasia BPD is a chronic lung disease of infancy affecting mostly premature infants with significant morbidity and mortality. Improved survival of very immature infants bronxodisplasia led to increased numbers of infants with this disorder.

Acute and chronic lung injury and impaired postnatal lung growth are thought to be responsible for the development of BPD. While changes in clinical practice have improved the clinical course and outcomes for infants with BPD, over the last decade, the overall incidence of BPD has not nronatal. This review will describe the pre and postnatal factors that contribute to the pathogenesis of BPD as well as pulminar and experimental therapies for treatment of BPD.

The factors that contribute to the pathogenesis of BPD are well described, however recent studies have better defined how these factors modulate lung growth.

Inflammation, proinflammatory cytokines and altered angiogenic gene signaling contribute to pulmonaf injury and impair pre and postnatal lung growth resulting in BPD, however to date no therapy has been identified that potently and consistently prevents or reverses their effects on lung growth. We will discuss the cell signaling pathways affected in BPD and current therapies available for modulating these pathways.

Despite current advances in neonatal care, BPD remains a heavy burden on health care resources. New treatments directed either at reducing lung injury or improving lung growth are under study. Bronchopulmonary dysplasia BPD is a chronic lung disease that most commonly occurs in premature infants who have needed mechanical ventilation and oxygen therapy for acute respiratory distress 1 – 3but can also occur in immature infants who have had few signs of initial lung disease 4.

Although the disorder is most often associated with premature birth, it can also occur ndonatal infants born at term who need aggressive ventilator therapy for severe, acute lung disease.

The introduction of prenatal steroid use, surfactant treatment, new ventilator strategies, improved nutrition, and other treatments have resulted in major improvements broncodisplasai the clinical course and outcomes of premature newborns with respiratory distress syndrome over the past 40 years. First characterized by Northway and colleagues inBPD has traditionally pulmoar defined as the presence of persistent respiratory signs and symptoms, the need for supplemental oxygen to treat hypoxemia, and an abnormal chest radiograph at 36 weeks post menstrual age gestational age plus chronological age pulmonsr Table 1 9.

There is now phlmonar recognition that infants with chronic lung disease after premature birth have a different clinical course and pathology than had been recorded before surfactants were used. At autopsy, the lung histology of these infants with the new form has regions of more uniform and milder injury, but impaired alveolar and vascular growth remain prominent table 1.

Bronchopulmonary dysplasia – Wikipedia

Here we review the pathogenesis and of BPD, and provide an overview of existing and potential preventive treatments. Chest x-ray showing early bronchopulmonary dysplasia with showing small hazy lung fields. Chest x-ray broncodissplasia established BPD with widespread interstitial shadows in both lung fields, consistent with fibrosis. The demineralization of the ribs is consistent with osteopenia of prematurity, a frequent association of bronchopulmonary dysplasia.

NIH diagnostic criteria for bronchopulmonary dysplasia 9.

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Although BPD has a multifactorial etiology figure 2the pre and postnatal factors responsible for disrupted alveolar growth broncofisplasia fairly well defined. While the strongest association is with preterm birth, other factors such as prenatal infection and inflammation, mechanical ventilation, oxygen toxicity with decreased host antioxidant defenses, patent ductus arteriosus and postnatal infection all contribute to the pathogenesis of BPD. Recently preeclampsia alone has been defined as a risk factor for the subsequent development of BPD While antiangiogenesis is known to contribute significantly to disruption of lung development in animal models 1314recent studies have implicated impaired angiogenesis in the development of preeclampsia 1516 Etiology of bronchopulmonary dysplasia is multifactorial with pre and postnatal factors contributing to the pathogenesis of BPD.

In animal studies, hyperoxia decreases alveolar VEGF expression 24and selective VEGF receptor inhibition reduces lung vascular growth and alveolarization 14 These results suggest that endothelial-epithelial cross-talk, especially via VEGF signaling, is critical for normal lung growth following birth and that disruption of VEGF signaling impairs lung vascular growth and alveolarization. brocodisplasia

Chorioamnionitis and prenatal inflammation are well known contributors to the development of BPD 26 – More recent studies have expanded on these findings demonstrating that this inflammatory milieu can alter cell signaling pathways important in lung branching morphogenesis. Fibroblast growth factor 10 FGF is among the key mesenchymal growth factors for lung development, promoting airway extension and branching It is activated by a variety of factors, including infectious stimuli, inflammatory cytokines, deformation, oxidants, and other causes of cell stress Even in the absence of chorioamnionitis cytokines mediate acute lung injury, 36 exacerbate ventilator-associated lung injury 37 and modulate host defenses Elevated cytokine concentrations have been observed in tracheal aspirates 3940 and serum 4142 of infants with respiratory distress syndrome and predict the subsequent development of BPD.

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Postnatal hyperoxia exposure increases the production of cytotoxic oxygen free radicals, which can overwhelm the host antioxidant defense mechanisms, and cause lung injury 4647 Premature infants are deficient in antioxidant enzyme systems at birth, and have low levels of antioxidants such as vitamins C and E, increasing their vulnerability to oxygen toxicity. The need for mechanical ventilation after birth strongly correlates with the development of BPD. Antiangiogenic genes up-regulated in ventilated lungs include thrombospondin-1, collagen XVIII alpha-1, and tissue inhibitor of metalloproteinase-1 TIMP1as well as endoglin, transforming growth factor-alpha, and monocyte chemoattractant protein-1 CCL2.

Increases in proinflammatory cytokines and alterations in angiogenic genes from ventilator-associated lung injury may in part be due to volutrauma. As a consequence, high tidal volumes should be avoided during early mechanical ventilation, and even during resuscitation in the labor suite. Mechanical ventilation is an essential treatment for extremely preterm infants at the border of viability.

Recent studies comparing volume-targeted ventilation to pressure ventilation have shown some promise. The use of volume ventilation resulted in a reduction in the combined outcome of death or bronchopulmonary dysplasia, pneumothorax, days of ventilation and hypocarbia These findings were supported by decreased IL-6 and IL-8 levels from tracheal aspirates of patients treated with volume targeted ventilation when compared with pressure targeted ventilation Alternative ventilatory strategies might also play a role in the reduction of BPD.

Although the early, routine use of HFOV has not been demonstrated to improve pulmonary outcomes in premature newborns, Courtney et al showed that the use of HFOV as a rescue strategy in infants with high conventional mechanical ventilation requirements despite treatment with surfactantdecreased the incidence of BPD There may also be an association between patent ductus arteriosus PDA and bronchopulmonary dysplasia.

Long-term exposure to a symptomatic PDA, worsens pulmonary morbidity A PDA with left to right shunting increases fluid and protein efflux from the pulmonary vasculature into the lung parenchyma. The increased fluid and protein in the lung intestitium increases pulmonary microvascular filtration pressure and increased lung lymph flow eliminates excess fluid and protein from the lung.

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This compensatory increase in lung lymph inhibits fluid accumulation in the lung With persistent ductal patency, this compensatory mechanism is overloaded and pulmonary edema develops. In the presence of sepsis and RDS this mechanism is more easily overwhelmed 5. Animal models of hyperoxia induced lung injury have demonstrated a role for progenitor cells endothelial and mesenchymal in the pathogenesis of BPD and implicate these cells as contributing to repair after injury 59 In neonatal mice pups, after hyperoxia exposure bone marrow, circulating and lung EPCs are markedly reduced 59 and in extremely preterm human infants, decreased numbers of cord blood endothelial progenitor cells following extremely preterm birth may be associated with the risk for developing lung vascular immaturity characteristic of new BPD The presence of decreased circulating progenitor cells and its association with BPD may have enormous therapeutic potential for these cord blood derived cells.

Animal studies to date have shown stem cell-based therapies may offer new therapeutic avenues for lung diseases that currently lack efficient treatments. Differentiation of hemangioblasts into hematopoietic cells and endothelial cells. Bone marrow derived cells can differentiate down different cell lineages to give rise to endothelial cells that can partake in postnatal vasculogenesis or angiogenesis For this reason bone marrow derived cells have great therapeutic potential in bronchopulmonary dysplasia.

Reproduced with permission from [ 62 ]. Surfactant proteins are important for regulating surfactant activity and innate host defense and genetic variants in surfactant proteins may increase risk for BPD. For this reason, strategies aimed at preventing the development of BPD are key.

Bronchopulmonary dysplasia

Exogenous surfactant therapy reduces the rate of death from BPD, but does not prevent the disease; arguably, this could be due to the increased survival of very immature infants at high risk of BPD. The association of barotrauma or volutrauma with BPD has led to the use of strategies such as permissive hypercapnia 65 to keep lung injury to a minimum.

Recent evidence suggests some benefit to volume guarantee as a ventilator mode for preventing BPD and decreasing inflammation associated with mechanical ventilation 54 Further large randomized trials will be needed to confirm this finding.

Although no ideal ventilation mode has so far emerged, it is clear from physiological studies that tidal volumes and inspired oxygen concentrations should be kept as low as possible to avoid hypocarbia, volutrauma, and oxygen toxicity, broncodusplasia lung recruitment strategies should be used.

An neonatwl approach to reduce BPD has been to avoid intubation and mechanical ventilation by using early nasal continuous positive pressure CPAP. Many centers now minimize their use of mechanical ventilation, preferring nasal continuous positive pressure with or without exogenous surfactant, and report low incidences of BPD in high-risk infants.

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Large controlled clinical trials, however, have not yet been able neontal duplicate the broncdisplasia center experience.

This study again demonstrated the efficacy of surfactant in reducing airleak, as CPAP was associated with significantly increased risk of pneumothorax. Another recent study randomized infants to intubation and surfactant treatment within 1 hour after birth or to CPAP treatment initiated in the delivery room, with subsequent use of a protocol-driven limited ventilation strategy and also found no difference in the primary outcome of death or bronchopulmonary dysplasia as defined by the requirement for supplemental oxygen at 36 weeks Based on these findings caution should be taken in selecting a population that might benefit from this approach and adverse events, such as hemodynamic instability and necrotizing enterocolitis, should be carefully monitored.

Vitamin A levels, however, broncodisplasla be carefully monitored and while beneficial in the short term, the lack of proven beneficial long-term effects on pulmonary and neurological outcome has limited use of this therapy.

Corticosteroid therapy, although directed at reducing the lung inflammation seen in infants with evolving or established BPD, is perhaps the most controversial area of care. Clinical studies have consistently shown that steroids acutely improve lung mechanics and gas exchange, and reduce inflammatory cells and their products in tracheal samples of patients with BPD 70 A meta-analysis of randomized trials shows that corticosteroids reduce chronic oxygen dependency at 28 days, and 36 weeks post-menstrual age, if given systemically in the first 96 h, 72 but there are important concerns regarding increased pulmonaf and adverse effects on head growth, neurodevelopmental outcomes, and lung structure 72 – Broncodispkasia routine early use of high-dose steroids in premature newborns is strongly discouraged, as reflected in editorials from the American Academy of Pediatrics and others 75 The adverse findings, however, are generally based on data from studies that have used high doses of dexamethasone started in the first few days of life and administered for long periods.

Many questions persist regarding the risk-benefit relation in the use of other steroids for shorter study periods. As a result, some centers recommend use of steroids outside the first week of life at lower doses and for shorter durations 5—7 days in ventilator-dependent infants with severe, persistent lung disease. Due to the observed side effects of dexamethasone, postnatal steroid administration using hydrocortisone has been studied for the prevention of BPD. While no study has shown clear benefit with hydrocortisone administration, the direction of effect favors hydrocortisone in all studies and in the largest study to date, for infants exposed prenatally to chorioamnionitis, hydrocortisone significantly decreased mortality and increased survival without BPD No adverse short or long term effects have been demonstrated with hydrocortisone use in any studies.

The possible beneficial effects of hydrocortisone therapy need to be weighed against the increased neonatzl of gastrointestinal perforation, especially with concomitant use of indomethacin To avoid the adverse effects associated with systemic administration, steroids have also been given by inhalation, but no important benefits have been noted with this method.

The major effect of inhaled betamethasone in a multicentre randomised trial was to decrease the perceived need for the use of systemic steroids 79 – A more recent analysis demonstrated an increased rate of broncodisplaia extubation with weeks of inhaled steroid use, without a reduction in the incidence of BPD Inhaled nitric oxide NO has been shown to be effective in improving lung structure in many experimental models of BPD. These studies include neonatal mice and rat pups after hyperoxia exposure 83 neonatla, 84bleomycin induced BPD in neonatal rat pups 85 and premature lambs with RDS The first study randomized newborns less than 34 weeks gestation requiring mechanical ventilation within the first 48 hours of life to receive either NO 5ppm or placebo gas for 21 days or until extubation.

Inhaled NO also decreased the incidence of brain injury ;ulmonar premature newborns. However, a subsequent study found that the early initiation of low dose NO does not prevent the subsequent development of BPD Another study randomized infants with a birth weight less than g requiring ventilatory support between 7 and 21 days of age.

Treated infants received decreasing concentrations of nitric oxide, beginning at 20ppm for 48 to 96 hours, and the doses were subsequently decreased to doses of 10, 5, and 2 ppm at weekly intervals, for a minimum of 24 days.

Although the current evidence does not support the routine use of iNO for prevention of BPD in preterm infants 90a clinical trial of non-invasive iNO therapy in premature infants at risk for BPD and a trial designed to study the effects of iNO in infants with evolving BPD after the first week are ongoing. Neoonatal studies will further inform the debate. It is also important to recognize nepnatal for infants less than 34 weeks in the setting of pulmonary hypoplasia and pulmonary hypertension e.

Of the available strategies to treat pulmonary hypertension, iNO is the safest and most effective treatment.