Elsevier

Seminars in Perinatology

Volume 30, Issue 4, August 2006, Pages 209-218
Seminars in Perinatology

Pharmacological Strategies in the Prevention and Management of Bronchopulmonary Dysplasia

https://doi.org/10.1053/j.semperi.2006.05.008Get rights and content

Bronchopulmonary dysplasia (BPD) is a disease of complex and multifactorial etiology and a major cause of morbidity in premature infants. Contributing factors include infection, exposure to toxic oxygen levels, and ventilator-induced lung injury, resulting in arrested lung development and impaired lung function. Several preventive and therapeutic strategies have been employed and include lung protective ventilator strategies, pharmacological and nutritional interventions. These strategies target different components and stages of the disease process, and their success has been variable. This review intends to bring together prior and current pharmacological interventions and future therapeutic modalities that appear promising in the prevention and management of BPD. Better understanding of the pathogenesis has given hope for newer treatment options. Newer studies need to be designed to assess the efficacy of combination therapies that target multiple steps of the disease process.

Section snippets

Oxygen

A complicated relationship exists between vascular growth and alveolar development.2 Judicial use of oxygen to maintain oxygen saturations and pO2 levels within target range is important in preventing pulmonary hypertension and cor pulmonale in infants with BPD. Although there is general acceptance that oxygen should be used and monitored as a medication with strict guidelines, there is no agreement on the acceptable level of oxygen saturation below which oxygen should be administered to

Diuretics

Diuretics constitute one of the most common classes of drugs used in the management of BPD. BPD in premature infants is complicated by interstitial alveolar edema. Iatrogenic increase in the fluid intake, capillary leak from inflammation due to infection or from ventilator-induced lung injury, or volume overload due to left to right shunting through a patent ductus arteriosus (PDA) are some of the factors that contribute to pulmonary edema.6, 7, 8, 9, 10 The excessive interstitial edema leads

Bronchodilators

Patients with BPD have increased airway resistance due to smooth muscle hypertrophy and hyperreactivity. Bronchoconstriction in response to a hypoxic event could lead to sudden deterioration of pulmonary status. Bronchodilators have been used to relieve bronchospasm in asthmatic patients and the potential dilating effect of bronchodilators on hypertrophied muscle of the airways has validated their use in BPD patients. Studies have shown that bronchospasm contributes to elevated pulmonary

Steroids

Inflammation is a main contributor to the pathogenesis of BPD. Since corticosteroids are potent antiinflammatory agents, there was great promise in the use of steroids for the management of BPD. Systemic steroid administration reduces the inflammatory response, produces a rapid improvement in pulmonary function with better gas exchange, and facilitates weaning from mechanical ventilation. In addition to the antiinflammatory effects, steroids also enhance surfactant production, decrease airway

Mast Cell Stabilizer

Cromolyn, a mast cell stabilizer, is the first nonsteroidal antiinflammatory drug used in asthmatic patients. It targets both sensitized and nonsensitized mast cells and prevents degranulation and release of histamine. Mast cell stabilizers have been shown to decrease neutrophil migration and activation, thus minimizing inflammation.63 Two trials studied the possible role of cromolyn in prevention and treatment of evolving BPD.64 In the Watterberg study, cromolyn was given 12 hours after

Vitamin A

Vitamin A is essential for the optimal growth of cells and tissues. It is comprised of a group of compounds, which include retinal, retinaldehyde, and retinoic acid. Evidence for low levels of vitamin A in BPD patients along with its role in tissue differentiation and growth supported the hypothesis that vitamin A deficiency may contribute to the development of BPD. Details of the use of vitamin A in BPD have been discussed by Biniwale and Ehrenkranz elsewhere in this issue. Some units have

Superoxide Dismutase (SOD)

Free radicals have been implicated in the pathogenesis of BPD. Premature infants are susceptible to oxidant injury since they are relatively deficient in antioxidant enzymes while being exposed to toxic oxygen levels.74 Preliminary animal and human studies have provided evidence for a protective action of antioxidants such as SOD in hyperoxia-induced acute and chronic lung injury.75, 76, 77 A randomized controlled trial studied if recombinant CuZnSOD would decrease the incidence of BPD in

Alpha-1 Proteinase Inhibitor (α1P1)

The rationale for a therapy with exogenous protease inhibitors is to restore protease/antiprotease balance and prevent the development of BPD. Neutrophil-derived elastase has been implicated in the inflammatory process leading to BPD. Influx of neutrophils and increased neutrophil-derived elastases were detected in tracheal aspirates of preterm infants who later developed BPD.98, 99 The proteinases in the lung tissue can hydrolyze extracellular matrix, and digest surfactant proteins and

Pentoxifylline

Pentoxifylline is a methylxanthine derivative that has been used in the treatment of peripheral arterial diseases because it improves capillary blood flow by reducing blood viscosity and improving erythrocyte deformability.103 Pentoxifylline is also a phosphodiesterase inhibitor with antiinflammatory effects that decreases neutrophil sequestration and inhibits neutrophil-derived oxidation products. In rat pups, pentoxifylline reduced fibrin deposition and prolonged survival in experimental

Conclusion

Well-conducted clinical trials and meta-analyses have demonstrated no significant impact of several pharmacologic therapies. Yet, an alarming number of pharmacologic therapies are currently practiced because of transient beneficial effects and lack of alternatives. The complex and multifactorial nature of BPD makes it unlikely that targeting individual pathways will have a significant impact on outcome. Rather, a multi-drug regimen addressing several pathways simultaneously may have an impact

Acknowledgments

We thank Dr. Stella Kourembanas for useful suggestions and critical review of this manuscript.

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