SUPPLEMENT ARTICLE |
a Department of Pediatrics, Case Western Reserve University, Rainbow Babies & Childrens Hospital, Cleveland, Ohio
b National Jewish Center for Immunology and Respiratory Medicine, Department of Pediatrics, University of Colorado Health Science Center, Denver, Colorado
c CardioPulmonary Research Institute Winthrop University Hospital, State University of New York, Stony Brook School of Medicine, Mineola, New York
d Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland
e Division of Newborn Medicine, Department of Pediatrics, Childrens Hospital of Boston and Harvard Medical School, Boston, Massachusetts
f Department of Pediatrics, Childrens Hospital, University of Colorado School of Medicine, Denver, Colorado
g Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
h Department of Pediatrics, Childrens Hospital Medical Center, Cincinnati, Ohio
| ABSTRACT |
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Key Words: bronchopulmonary dysplasia therapeutics
Abbreviations: BPDbronchopulmonary dysplasia
Bronchopulmonary dysplasia (BPD) is an evolving process of lung injury and recovery that can result in chronic pulmonary impairment requiring oxygen therapy. The incidence of BPD varies according to birth weight, with BPD increasing as birth weight decreases.1 Infants who weigh <1250 g at birth constitute 97% of the infants with this condition. The development of BPD is a multifactorial process. The impact of injury and repair on immature lungs and any imbalance in the processes leads to BPD that may have lifelong consequences for the infant.
Although neonatal care has improved substantially over the past 3 decades, BPD continues to occur in
30% of newborns with birth weights of <1000 g and contributes to significant morbidity in this population.2 Because of the gaps in knowledge about the prevention and treatment of BPD in newborns, children treated in NICUs may develop unintended short- and long-term sequelae. For example, in addition to the chronic lung disease of BPD, preterm newborns with BPD are more likely to develop language delay, cerebral palsy, minor neuromotor dysfunction, and cognitive impairments than are preterm newborns who do not develop BPD.
| STUDY-DESIGN ISSUES |
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Three Stages of BPD
Because BPD is an evolving process of lung injury, the pathophysiology is likely to differ at different times. Therefore, optimal therapeutic agents may differ at different stages of the disease (see Table 1). The pulmonary group found it useful to conceptualize BPD in 3 stages and agreed that trials are needed in all 3 stages.
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After birth, corticosteroids may play a role. However, the use of high-dose dexamethasone (0.5 mg/kg) for short or longer intervals is associated with adverse short-term outcomes (gastrointestinal bleeding, intestinal perforation, hyperglycemia, hypertension, hypertrophic cardiomyopathy, and growth failure) and long-term outcomes (adverse neurosensory outcome) without a clear reduction in BPD.6 Lower-dose dexamethasone (
0.15 mg/kg) and hydrocortisone treatments begun shortly after birth have been associated with gastrointestinal perforations, which may result from an apparent drug interaction with the simultaneous use of indomethacin.7 Nevertheless, some very low birth weight infants have low cortisol levels, and the logic of replacing what seems to be a physiologic deficit resulting from adrenal immaturity is compelling.8 The choice of corticosteroid, the dose, patient selection (possibly to include screening for inadequate cortisol levels before treatment), and the potential for drug interactions need to be considered carefully. In designing such studies, it is important to prospectively collect data about the severity and chronicity of chorioamnionitis and other antenatal conditions that may contribute to postnatal corticosteroid responses and adverse events.
Infants with evolving BPD who are oxygen- and ventilator-dependent have rapid and often dramatic responses to corticosteroid treatments that permit achievement of important short-term clinical goals such as extubation.3,9 Corticosteroids may also decrease mortality. Concerns about their potential for neurodevelopmental impairment have limited their use. The available follow-up data on neurodevelopmental impairment are concerning but selective, incomplete, and inadequate. Nevertheless, the recent statement from the American Academy of Pediatrics and Canadian Paediatric Society that suggests limiting the use of postnatal steroids may make future studies more difficult to perform.8
In stage 2, the goal is treatment of evolving BPD in an attempt to abort the development of the disease. Therapies that are directed at controlling inflammation and lung water might have the most impact on this stage. Therapeutic agents of interest include systemic or inhaled corticosteroids, other antiinflammatory agents, and diuretics. It is currently unknown whether some patients have a major component of the disease from excess lung water while others have inflammation as the predominate feature. It is logical to assume that patients with different predominate disease pathophysiology might respond to different directed therapies. Trial design must include an assessment of these different pathophysiologic mechanisms.
In stage 3, BPD is established. The underlying predominate mechanisms may include overly reactive airways, lung fluid retention, and an oxygenation defect. Methods to identify the extent to which any component is contributing to established BPD in an individual patient do not currently exist. The development of such techniques would allow the use of more targeted therapies. Neonates with established BPD are frequently managed with systemic and/or inhaled corticosteroids during their initial hospitalization and after hospital discharge. The use of corticosteroids for this indication is essentially unstudied. Another commonly used treatment in established BPD is the use of ß-adrenergic aerosolized bronchodilators.10 Virtually all evaluations of bronchodilators have been of short-term duration in small numbers of infants. There are no trials that have assessed the ability of bronchodilators to modify the course of disease.
Definition of BPD
The pulmonary group agreed to use the definition developed by the National Institute of Child Health and Human Development (NICHD) Workshop on BPD in 2001.1 The NICHD definition is stratified by postmenstrual age with different end points for infants who are born at <32 weeks' and those who are born at
32 weeks' postmenstrual age. The following end points are for infants who are born at <32 weeks' postmenstrual age:
The definitions for infants who are born at >32 weeks' postmenstrual age is adjusted for the time end point of 56 days of life rather than 36 weeks' postmenstrual age.2 The group agreed that this definition should be augmented with a physiologic definition of BPD in selected infants with oxygen-saturation monitoring during a room-air challenge to adjust for differences in the diagnosis that are introduced by differences in oxygen-prescription practices.11 The group felt that these 2 definitions worked well together to provide information on the severity of disease at 36 weeks' postmenstrual age as a short-term end point.
Subgroups Within BPD
The pulmonary group identified opportunities to study subgroups among those with BPD. Infants with a high likelihood of mortality or very severe morbidity might qualify for studies of agents with a higher-risk adverse-effect profile, such as systemic corticosteroids. Another subgroup is those infants with BPD who have a strong family history of asthma. It is possible that their response to therapeutic agents may differ from those without such a history. Finally, there is a need to evaluate groups for potential maternal protective factors and risk factors (eg, antenatal steroids, tobacco, asthma, chorioamnionitis).
| GAPS IN KNOWLEDGE |
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Basic Science
Knowledge is limited in the following areas of basic science:
Pharmacologic Knowledge
Current gaps in pharmacologic knowledge are extensive. Data are lacking on safety, efficacy, pharmacokinetics, and potential drug interactions of even the most commonly used agents. The safety of drug excipients (vehicles, emulsifiers, or preservatives) in preterm infants needs to be evaluated. Because some common metabolic pathways are immature in premature infants, ingredients that are inactive in term infants and older children may produce toxicities in preterm infants. A notorious example of this is benzyl alcohol, which produced a gasping syndrome, metabolic alkalosis, and death in preterm infants in the 1980s. Among infants at risk of BPD, the use of inhaled bronchodilators and chronic diuretics is widespread, but evidence for efficacy and safety is lacking. Patients with established BPD are frequently treated with multiple drugs simultaneously with no understanding of drug interactions. Furthermore, similarities in pathophysiology to asthma and extensive preclinical work on the role of inflammation in BPD suggest that antiinflammatory strategies may be beneficial. However, these strategies remain largely unstudied, and with the exception of corticosteroids, major drug classes have not been explored for use in this patient population.
Specific areas worthy of additional study include:
| DRUG PRIORITIES |
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Clinical trials of these drug classes should use parallel groups and placebo controls. The use of open-label drugs and the potential for drug-drug interactions will need to be addressed in the study design. Stratification by postmenstrual age and disease severity is desirable. To ensure that trials do not produce short-term benefits with long-term harm, trials should assess long-term pulmonary and neurodevelopmental outcomes including language development.
| PROPOSED CLINICAL-TRIAL FRAMEWORK |
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| TRIAL-DESIGN ISSUES COMMON TO ALL NEONATAL STUDIES |
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| FUTURE DIRECTIONS |
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antagonists, and inhaled nitric oxide;
| ACKNOWLEDGMENTS |
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Our thanks go to the reviewers for helpful comments.
| FOOTNOTES |
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Address correspondence to Michele C. Walsh, MD, Division of Neonatology, Rainbow Babies & Children's Hospital, Case Western Reserve University, 11100 Euclid Ave, Mailstop 6010, Cleveland, OH 44106-6010. E-mail: msw3{at}po.cwru.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
The views presented in this article do not necessarily reflect those of the Food and Drug Administration (FDA). This article reflects discussions of designing clinical trials in newborns and should not be construed as an agreement or guidance from the FDA. Drug development and clinical-trial design must be discussed with the relevant review division within the FDA.
| REFERENCES |
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A A Hutchison and S Bignall Non-invasive positive pressure ventilation in the preterm neonate: reducing endotrauma and the incidence of bronchopulmonary dysplasia Arch. Dis. Child. Fetal Neonatal Ed., January 1, 2008; 93(1): F64 - F68. [Full Text] [PDF] |
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E. Baraldi and M. Filippone Chronic Lung Disease after Premature Birth N. Engl. J. Med., November 8, 2007; 357(19): 1946 - 1955. [Full Text] [PDF] |
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T. R. Grover The diverse role of inhaled nitric oxide in experimental BPD: reduced fibrin deposition and improved lung growth Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L33 - L34. [Full Text] [PDF] |
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T. R. Grover, T. M. Asikainen, J. P. Kinsella, S. H. Abman, and C. W. White Hypoxia-inducible factors HIF-1{alpha} and HIF-2{alpha} are decreased in an experimental model of severe respiratory distress syndrome in preterm lambs Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1345 - L1351. [Abstract] [Full Text] [PDF] |
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