The effects of prenatal intraamniotic surfactant or dexamethasone administration on lung development are comparable to changes induced by tracheal ligation in an animal model of congenital diaphragmatic hernia.
OBJECTIVE
Lung surfactant deficiency contributes to the pathophysiology of congenital diaphragmatic hernia (CDH) and the high neonatal mortality rate. Acceleration of lung surfactant system maturation by prenatal administration of hormones has been described in animal models of CDH. However, in utero tracheal ligation (TL) is the best method to accelerate lung growth and reverse the pulmonary hypoplasia associated with CDH. Although this method offers promise, its application in humans is limited. The aim of this study was to investigate a new noninvasive therapeutic strategy, that is, the prenatal intraamniotic administration of exogenous porcine surfactant or dexamethasone, and compare it with the effects of TL in an animal model of CDH.


METHODS
Twenty-four pregnant New Zealand rabbits underwent surgery on gestational day 24 or 25 to create CDH in 26 fetuses. Five groups of animals were studied: (1) Control, nonoperated fetuses (n=14), (2) CDH (n=6), (3) CDH plus TL (n 6), (4) CDH plus intraamniotic administration of Curosurf (40 mg; n=6), and (5) CDH plus intraamniotic infusion of dexamethasone (0.4 mg; n=8). On gestational day 30, the fetuses were delivered by cesarean section. Functional studies (lung hysteresis curves and lung distensibility), weight and volume of lungs, histopathologic and histomorphometric analysis of lungs were performed.


RESULTS
The authors demonstrated that the hysteresis curve of CDH animals was shifted downward in comparison with controls. The analyses of curves standardized for lung weight indicated that intraamniotic administration of surfactant or dexamethasone improved lung compliance in comparison with controls and CDH fetuses, but TL had no effect on this parameter. Lung distensibility (maximum lung volume at 32 cm of water pressure per gram of lung) was reduced by CDH, but this parameter was increased by intraamniotic administration of drugs and not by TL (P< .05). CDH decreased the weight and volume of lungs (P< .05), and these changes were reversed only by TL, which prevented the herniation of the liver from the abdomen to the thorax. Histologically, CDH lungs treated with TL or intraamniotic administration of drugs demonstrated structural patterns similar to those of controls. Histomorphometric studies proved that CDH promoted significant thickening of septa walls (P< .05), and all the therapeutic methods could reverse this alteration to control values. The alveolar number per area in control lungs, CDH, and CDH plus TL lungs were similar, but in CDH plus surfactant and CDH plus dexamethasone lungs, the decreased number per area (P< .05) demonstrated that the alveolar airspace was increased.


CONCLUSIONS
From these data the authors conclude that intraamniotic surfactant or dexamethasone administration is capable of preventing pulmonary hypoplasia in fetuses with CDH, and thus, this method may be a substitute for TL.
Pediatric Surgery Division, University of São Paulo Medical School, Brazil.
U
U
Tannuri
J G
JG
Maksoud-Filho
M M
MM
Santos
A C
AC
Tannuri
C J
CJ
Rodrigues
A J
AJ
Rodrigues
D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D003907:Dexamethasone / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D065630:Hernias, Diaphragmatic, Congenital; D015552:Injections, Intralesional; D008026:Ligation; D008168:Lung / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology* / Q000473:pathology; D008171:Lung Diseases / Q000151:congenital / Q000517:prevention & control*; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011817:Rabbits; D012016:Reference Values; D013501:Surface-Active Agents / Q000008:administration & dosage*; D014132:Trachea / Q000601:surgery
D000893:Anti-Inflammatory Agents; D013501:Surface-Active Agents; D003907:Dexamethasone