Pharmacological Strategies in the Prevention and Management of Bronchopulmonary Dysplasia
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.
References (110)
- et al.
Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia
Hum Pathol
(1998) - et al.
Bronchopulmonary dysplasiapossible relationship to pulmonary edema
J Pediatr
(1978) Bronchoalveolar inflammatory pathophysiology of bronchopulmonary dysplasia
Clin Perinatol
(1995)- et al.
Effect of diuresis on the performance of the failing left ventricle in man
Am J Med
(1981) - et al.
Colloid osmotic pressure in pulmonary edema clearance with furosemide
Chest
(1987) - et al.
Pulmonary effects of furosemide in preterm infants with lung disease
J Pediatr
(1983) - et al.
Controlled trial of furosemide therapy in infants with chronic lung disease
J Pediatr
(1985) - et al.
Double-blind, placebo-controlled trial of alternate-day furosemide therapy in infants with chronic bronchopulmonary dysplasia
J Pediatr
(1990) - et al.
Nebulized furosemide in infants with bronchopulmonary dysplasia
J Pediatr
(1994) - et al.
Changes in body water compartments with diuretic therapy in infants with chronic lung disease
Early Hum Dev
(1997)
Addition of metolazone to overcome tolerance to furosemide in infants with bronchopulmonary dysplasia
J Pediatr
Randomized trial of long-term diuretic therapy for infants with oxygen-dependent bronchopulmonary dysplasia
J Pediatr
Randomized, double-blind, controlled trial of long-term diuretic therapy for bronchopulmonary dysplasia
J Pediatr
Family-based association analysis of beta2-adrenergic receptor polymorphisms in the childhood asthma management program
J Allergy Clin Immunol
Strategies for prevention of neonatal chronic lung disease
Semin Perinatol
Choice and dose of corticosteroid for antenatal treatments
Am J Obstet Gynecol
Clinical trial of vitamin A supplementation in infants susceptible to bronchopulmonary dysplasia
J Pediatr
L-2-oxothiazolidine-4-carboxylate, a cysteine precursor, stimulates growth and normalizes tissue glutathione concentrations in rats fed a sulfur amino acid-deficient diet
J Nutr
N-acetylcysteine does not prevent bronchopulmonary dysplasia in immature infantsa randomized controlled trial
J Pediatr
Association of Ureaplasma urealyticum colonization with chronic lung disease of prematurityresults of a metaanalysis
J Pediatr
Ureaplasma in lung. 2. Association with bronchopulmonary dysplasia in premature newborns
Exp Mol Pathol
Lung vascular developmentimplications for the pathogenesis of bronchopulmonary dysplasia
Annu Rev Physiol
Pulmonary vascular response to oxygen in infants with severe bronchopulmonary dysplasia
Pediatrics
Oxygen-saturation targets and outcomes in extremely preterm infants
N Engl J Med
Supplemental Therapeutic Oxygen for Prethreshold Retinopathy Of Prematurity (STOP-ROP), a randomized, controlled trial. I. Primary outcomes
Pediatrics
Predisposition of infants with chronic lung disease to respiratory syncytial virus-induced respiratory failurea vascular hypothesis
Pediatr Infect Dis J
Intravenous or enteral loop diuretics for preterm infants with (or developing) chronic lung disease
Cochrane Database Syst Rev
Hydration during the first days of life and the risk of bronchopulmonary dysplasia in low birth weight infants
J Pediatr
Effect of oral diuretics on pulmonary mechanics in infants with chronic bronchopulmonary dysplasiaresults of a double-blind crossover sequential trial
Pediatrics
Effect of cyclooxygenase inhibition on the pulmonary vasodilator response to furosemide
J Pharmacol Exp Ther
Role of prostaglandins in the hemodynamic and tubular effects of furosemide
Fed Proc
The effect of furosemide on the pulmonary transvascular fluid filtration rate
Crit Care Med
Central hemodynamic effects of diuretic therapy in chronic heart failure
Cardiovasc Drugs Ther
Renal and extrarenal hemodynamic effects of furosemide in congestive heart failure after acute myocardial infarction
N Engl J Med
The effects of bumetanide and furosemide on lung liquid secretion in fetal sheep
Proc Soc Exp Biol Med
Colloid osmotic pressure of normal newborns and premature infants
Crit Care Med
Pulmonary function changes after nebulised and intravenous frusemide in ventilated premature infants
Arch Dis Child Fetal Neonatal Ed
Aerosolized diuretics for preterm infants with (or developing) chronic lung disease
Cochrane Database Syst Rev
Diuretics acting on the distal renal tubule for preterm infants with (or developing) chronic lung disease
Cochrane Database Syst Rev
Pulmonary function and electrolyte balance following spironolactone treatment in preterm infants with chronic lung diseasea double-blind, placebo-controlled, randomized trial
J Perinatol
Bronchodilators for the prevention and treatment of chronic lung disease in preterm infants
Cochrane Database Syst Rev
Respiratory response and pharmacokinetics of intravenous salbutamol in infants with bronchopulmonary dysplasia
Crit Care Med
Effects of salbutamol delivery from a metered dose inhaler versus jet nebulizer on dynamic lung mechanics in very preterm infants with chronic lung disease
Pediatr Pulmonol
Respiratory response to salbutamol (albuterol) in ventilator-dependent infants with chronic lung diseasepressurized aerosol delivery versus intravenous injection
Intensive Care Med
Beta-adrenergic receptor polymorphisms and drug responses in asthma
Pharmacogenomics
Acute systemic effects of inhaled salbutamol in asthmatic subjects expressing common homozygous beta2-adrenoceptor haplotypes at positions 16 and 27
Br J Clin Pharmacol
Inhaled salbutamol and beclomethasone for preventing broncho-pulmonary dysplasiaa randomised double-blind study
Eur J Pediatr
Pulmonary deposition of salbutamol aerosol delivered by metered dose inhaler, jet nebulizer, and ultrasonic nebulizer in mechanically ventilated rabbits
Pediatr Res
Efficiency of aerosol medication delivery from a metered dose inhaler versus jet nebulizer in infants with bronchopulmonary dysplasia
Pediatr Pulmonol
Comparison of jet and ultrasonic nebulizer pulmonary aerosol deposition during mechanical ventilation
Eur Respir J
Cited by (47)
Patent ductus arteriosus in preterm newborns: A tertiary hospital experience
2022, Revista Portuguesa de CardiologiaIntravenous fish oil containing lipid emulsion attenuates inflammatory cytokines and the development of bronchopulmonary dysplasia in very premature infants: A double-blind, randomized controlled trial
2019, Clinical NutritionCitation Excerpt :The occurrence of BPD is the most common chronic lung disease in infancy with devastating short-term and long-term consequences, causing a large financial burden on society and families [18]. Developing drugs to prevent or treat BPD has been the major goal of neonatal care over the past 20 years, but few drugs have shown favourable results [19]. Our study demonstrated that after 7 days of parenteral nutrition with fish oil containing LE for infants with VLBW, IL-1β and IL-6 levels in serum and BALF were significantly lower than in the Lipovenoes group and could be associated with the amelioration of BPD.
An update on the post-NICU discharge management of bronchopulmonary dysplasia
2018, Seminars in PerinatologyCitation Excerpt :Steroids are potent anti-inflammatory agents and when administered systemically in patients with early BPD they produce a rapid improvement in pulmonary function and gas exchange and facilitate weaning from mechanical ventilation. In animal models steroids have been shown to enhance surfactant production, decrease airway edema, stabilize capillary leakage, augment beta receptor activity and decrease overall lung fibrosis.27 Given this background, steroids have been used in preterm babies both to prevent development of BPD and to treat BPD.
Bronchopulmonary dysplasia predictor scale validation in preterm newborns in two neonatal units at 2600 m above sea level
2018, Infant Behavior and DevelopmentCitation Excerpt :In recent years, many new strategies that seek to reduce the BPD risk have been studied but only a few, like Caffeine (Schmidt et al., 2006), intratracheal Budesonide/Surfactant budesonide (Yeh et al., 2016), and quality improvement programs (Lee et al., 2014), have shown positive effects. Most other interventions have failed to show any benefit (Baveja & Christou, 2006; Castoldi et al., 2013; Ghanta, Tropea Leeman, & Christou, 2013). One possible explanation for these results is the difficulty in predicting early which patients will develop BPD who would benefit from early interventions (Beam et al., 2014; Bowen & Maxwell, 2014; Ghanta et al., 2013; Onland et al., 2013).
The use of inhaled corticosteroids in chronically ventilated preterm infants
2017, Seminars in Fetal and Neonatal Medicine