EDITOR'S COLUMN

Vitamin A supplementation and bronchopulmonary dysplasia revisited Very low birth weight neonates, particularly those who need mechanical ventilation and supplemental oxygen therapy in the early postnatal period, are susceptible to a form of chronic lung disease called bronchopulmonary dysplasia. 1 The development of BPD is believed to be influenced by lung immaturity, by factors promoting injury, and by factors inhibiting healing of tissues of the lung and tracheobronchial tree. 2 The lung injury can result from such insults as hyaline membrane disease, barotrauma from mechanical ventilation, prolonged high inspired oxygen concentrations, and secondary infection associated with protracted tracheal intubation, all occurring with a background of lung immaturity. 3 The healing of tissues of the lung and tracheobronchial tree is influenced by a myriad of factors, including nutrients, antioxidants, inflammatory cells, eicosanoids, growth factors, peptide hormones, and components of the extracellular matrix. 4 The role of the essential micronutrient vitamin A in the promotion of growth and in the orderly differentiation of regenerating epithelial tissues makes vitamin A an important nutrient during recovery from lung injury. Vitamin A deficiency results in a predictable sequence of progressive histopathologic changes in the epithelial lining of pulmonary conducting airways) -7 In those proximal airways, where basal and intermediate cells exist as stem cells for replacement of lining cells after natural attrition and for relining of epithelial surface cells damaged by airway injury, basal and intermediate cell proliferation is stimulated. 57 As these normally discontinuous cell populations become confluent, the normal differentiated ciliated columnar cells and nonciliated secretory cells become displaced from their basement membrane footing. These cells, having been separated from their nutritional blood supply, become necrotic, resulting in what is described in pathologic terms as necrotizing tracheobronchitis. 57 With continued proliferation, the basal and intermediate cells, apparently in the absence of the stimulus of vitamin A to differentiate into ciliated and nonciliated columnar epithelium, lose their phenotypic future and develop as layers of stratified squamous epithelium typical of squamous metaplasia) -7 The pathophysiologic consequences of these changes in9/21/39155

clude (1) loss of normal secretions of goblet cells and of other secretory cells, (2) loss of normal water homeostasis across the tracheobronchial epithelium, (3) loss of mucociliary transport with resultant predisposition to recurrent airway infection, and (4) narrowing of the lumina and loss of distensibility of the airways, with a resultant increase in airway resistance and work of breathing. The histopathologic changes seen in vitamin A deficiency are reversible with restoration of normal vitamin A status. 8, 9 Very low birth weight neonates are susceptible to acute, subacute, and chronic lung injury/ When the pulmonary conducting airways are injured, the stimulus to epithelial regeneration is triggered. It has been hypothesized 2 that if, simultaneously with injury, vitamin A deficiency were of such severity as to preclude normal differentiation of proliferating basal and intermediate ceils, normal healing would not occur and chronic lung disease would result. Conversely, the potential role of vitamin A in influencing orderly differentiation of regenerating airways could have a favorable effect on the healing process, resulting in reduced pulmonary morbidity. See related article, p. 420.

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BPD VLBW

Bronchopulmonary dysplasia Very low birth weight

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Previous clinical studies on vitamin A in relation to BPD have shown that VLBW neonates are born with low plasma concentrations of vitamin A and retinol-binding protein, l~ 12 and with low liver stores of vitamin A. 13"17 Those VLBW neonates with the development of BPD often manifest clinical, biochemical, and histopathologic evidence of vitamin A deficiency. 4, 18, 19 We have previously shown, by a randomized, double-blind, controlled clinical trial (Vanderbilt trial), 2~that vitamin A supplementation from early postnatal life in VLBW neonates not only improves their vitamin A status but also appears to promote normal regenerative healing from lung injury, as evidenced by a decreased incidence of BPD and of the associated morbidity. The same beneficial effect of vitamin A supplementation has been observed since the implementation at our institution of a pro-

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tocol of routine vitamin A supplementation in VLBW neonates at risk for BPD. 21 In this issue of THE JOURNAL,Pearson et al. 22 report their experience with vitamin A supplementation in VLBW neonates enrolled in a randomized, double-blind, controlled clinical trial. In contrast to the earlier Vanderbilt trial, this study from North Carolina showed no beneficial effect of vitamin A supplementation on the incidence of BPD a n d related morbidity. What are the possible reasons for the different results between these clinical trials? First, the patients enrolled in the two trials were not comparable. Whereas only white infants were included in the Vanderbilt trial, the patients enrolled in the North Carolina trial were not stratified by race, resulting in unbalanced groups with a preponderance of black infants in the vitamin A-supplemented group and of white infants in the unsupplemented control group. The influence of race on lung disease and morbidity in VLBW neonates has previously been documented. 23 Second, whereas none of the infants in the Vanderbilt trial received either surfactant or dexamethasone, nearly all infants in the North Carolina trial received surfactant, and approximately 50% received dexamethasone in the postnatal period. The surfactant replacement therapy can have a significant impact on the course of hyaline membrane disease, neonatal survival, and the incidence and severity of BPD among VLBW survivors.24 Postnatal dexamethasone administration causes significant increases in plasma vitamin A and retinol-binding protein concentrations in newborn infants, independent of their nutritional intakes. 25 Both surfactant and dexamethasone treatments, therefore, are confounding variables, in the presence of which any specific effect of vitamin A supplementation on pulmonary outcome is difficult to discern. Third, although the dosage of intramuscular vitamin A supplementation was similar in the two trials, the vitamin A intake from the enteral and intravenous sources was about twofold to threefold higher in the North Carolina trial. As the authors have pointed out, this higher intake of vitamin A might explain the observed low incidence of vitamin A deficiency even in the unsupplemented control infants in the North Carolina trial. Any potential beneficial effects of vitamin A supplementation might have been masked by the reduced prevalence of vitamin A deficiency in this patient population. In summary, bronchopulmonary dysplasia is a disease of multiple causes, and its incidence ~nong VLBW neonates is high. In addition to the prevention of prematurity as the primary perinatal health care goal, the strategies for reducing the occurrence of BPD among VLBW survivors are clearly warranted. These strategies involve the modulation of a delicate balance between injury and healing of the ira-

The Journal of Pediatrics September 1992

mature lung. Optimal vitamin A nutrition is but a single such strategy to complement a host of other approaches.

Jayant P. Shenai, MD Margaret G. Rush, MD Mildred T. Stahlman, MD Frank Chytil, PhD Departments of Pediatrics and Biochemistry Vanderbilt University School of Medicine Nashville, TN 37232-2370

REFERENCES

1. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease: bronchopulmonarydysplasia. N Eng! J Med 1967;276:357-68. 2. Stahlman MT, Shenai JP, Gray ME, Sundell HW, Kennedy K, Chytil F. Lung differentiation and repair in relation to vitamin A status. In: Lindblad BS, ed. Perinatal nutrition. San Diego: Academic Press, 1988:117-23. (Bristol Myers Nutrition Symposia; vol 1.) 3. Stahlman MT, Cheatham W, Gray ME. The role of air dissection in bronchopulmonary dysplasia. J PEDIATR 1979; 95:878-82. 4. Stahlman MT, Gray ME. Remodeling of airways and epithelium. In: Brigham KL, Stahlman MT, eds. Respiratory syndromes: molecules to man. Nashville: Vanderbilt University Press, 1990:188-97. 5. Wolbach SB, Howe PR. Tissue changes followingdeprivation of fat-soluble vitamin A. J Exp Med 1925;42:753-77. 6. Wong YC, Buck RC. An electron microscopicstudy of rnetaplasia of the rat tracheal epithelium in vitamin A deficiency. Lab Invest 1971;24:55-66. 7. McDowell EM, Keenan KP, Huang M. Effects of vitamin A deprivation on hamster tracheal epithelium: a quantitative morphologicstudy. VirchowsArch (Cell Pathol) 1984;45:197219. 8. Wolbach SB, Howe PR. Epithelial repair in recovery from vitamin A deficiency. J Exp Med 1933;57:511-26. 9. McDowellEM, Keenan KP, Huang M. Restoration of mucociliary tracheal epithelium followingdeprivation of vitamin A: a quantitative morphologicstudy. VirchowsArch (CellPathol) 1984;45:221-40. 10. Brandt RB, Mu~ellerDG, Schroeder JR, et al. Serum vitamin A in premature and term neonates. J PEDIATR1978;92:101-4. 11. Shenai JP, Chytil F, Jhaveri A, Stahlman MT. Plasma vitamin A and retinol-binding protein in premature and term neonates. J PEBIATR1981;99:302-5. 12. Bhatia J, Ziegler EE. Retinol-binding protein and prealbumin in cord blood of term and preterm infants. Early Hum Dev 1983;8:129-33. 13, IyemgarL, Apte SV. Nutrient stores in human foetal livers. Br J Nutr 1972;27:313-7. 14. Olson JA. Liver vitamin A reserves of neonates, preschool children and adults dying of various causes in Salvador, Brazil. Arch Latinoam Nutr 1979;26:992-7. 15. MontreewasuwatN, Olson JA. Serum and liver concentrations of vitamin A in Thai fetuses as a function of gestational age. Am J Clin Nutr 1979;32:601-6. 16. Olson JA, Gunning DB, Tilton RA. Liver concentrations of vitamin A and carotenoids, as a function of age and other pa-

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19.

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rameters, of American children who died of various causes. Am J Clin Nutr 1984;39:903-10. Shenai JP, Chytil F, Stahlman MT. Liver vitamin A reserves of very low birth weight neonates. Pediatr Res 1985;19:892-3. Hustead VA, Gutcher GA, Anderson SA, Zachman RD. Relationship of vitamin A (retinol) status to lung disease in the preterm infant. J PEDIATR1984;105:610-5. Shenai JP, Chytil F, Stahlman MT. Vitamin A status of neonates with brnnchopulmonary dysplasia. Pediatr Res 1985; 19:185-8. Shenai JP, Kennedy KA, Chytil F, Stahlman MT. Clinical trial of vitamin A supplementation in infants susceptible to bronchopulmonary dysplasia. J PEDIATR1987;111:269-77. Shenai JP, Rush MG, Stahlman MT, Chytil F. Plasma retinol-binding protein response to vitamin A administration in infants susceptible to bronchopulmonary dygplasia. J PEDIATR 1990;116:607-14.

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22. Pearson E, Bose C, Snidow T, et al. Trim of vitamin A supplementation in very low birth weight infants at risk for bronchopulmonary dysplasia. J PEDIATR1992;121:420-7. 23. Avery ME, Tooley WH, Keller JB, et al. Is chronic lung disease in low birth weight infants preventable? a survey of eight centers. Pediatrics 1987;79:26-30. 24. Shapiro DL. Surfactant replacement therapy for respiratory distress syndrome. In: Brigham KL, Stahlman MT, eds. Respiratory distress syndrome: molecules to man. Nashville: Vanderbilt University Press, 1990:236-49. 25. GeorgieffMK, Mammel MC, Mills MM, Gunter EW, Johnson DE, Thompson TR. Effect of postnatal steroid administration on serum vitamin A concentrations in newborn infants with respiratory compromise. J PED~ATR1989;114:301-4.

Intravenous immune globulin therapy for sepsis in premature neonates Although both antimicrobial therapy and intensive care have improved markedly in the last decade, the mortality rate for early-onset sepsis in premature neonates remains stubbornly high at approximately 15% to 20%. 1 Recently there has been renewed interest in immunotherapies that might augment antibiotics and further reduce the morbidity and mortality rates associated with bacterial sepsis in adults and children. These strategies include interventions designed to target the sepsis syndrome, such as antibodies (polyclonal or monoc!onal) to bacterial antigens that would opsonize the bacteria for uptake and killing by phagocytes, 2 antibodies directed to lipopolysaccharide and other bacterial products that induce harmful inflammatory mediators, 3 and antibodies directed to the inflammatory mediators themselves, such as monoclonal antitumor necrosis factor: 4 Pharmacologic interventions that interrupt the cascade of sepsis and the inflammatory response have also been tried (steroids and nonsteroidal agents), s Human trials often have been Controversial because of disparate results, difficulties in randomly assigning patients with complex problems to treatment protocols, variability in the organisms causing sepsis, and the use of antimicrobial agents that vary in their ability to lyse organisms rapidly and thus to release lipopolysaccharide and other inflammation-inducingproducts at different rates. 69 Adjunct therapies for bacterial sepsis in premature neonates have so far focused on the replacement of antibodies that normally are transferred transplacentally from mother to fetus after 32 weeks of gestation. Administration of an-

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tibody to the premature neonate makes a priori sense because the premature neonate has low levels of specific antibodies, antibodies directed to specific antigens of bacteria (such as the group B streptococcus capsule) are known to be protective, the addition of antibody to neonatal serum is known to increase its opsonophagocytic activity, and antibodies help moblhze phagocytes by increasing production of C3 and C5 fragments and other mediators that help in the maturation and release of neutrophils from the bone marrow.10, 11 The main strategy to date has utilized human antibody preparations to protect against late nosocomial infection while the neonate is in the nursery. The ability to

See related article, p. 434.

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GBS IVIG

Group B streptococcus Intravenously administered immune globulin

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perform such studies has been enhanced by the production of purified human IgG that is predominantly monomeric and thus unlikely to cause systemic reactions when administered intravenously. Several studies, for example, have attempted to determine whether intravenous administration of immune globulin to neonates reduces the rate of infection during their hospital stay. Unfortunately, these studies are complicated by the fact that multiple factors contribute to the predisposition to infection in premature neonates. Moreover, there are differences in the titers of antibody to various bacteria, particularly GBS, in different

Vitamin A supplementation and bronchopulmonary dysplasia--revisited.

EDITOR'S COLUMN Vitamin A supplementation and bronchopulmonary dysplasia revisited Very low birth weight neonates, particularly those who need mechan...
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