Effects of prenatal glucocorticoids and postnatal nitric oxide inhalation on the survival and lung maturation of newborn rats with congenital diaphragmatic hernia

Abstract

Introduction: Pulmonary hypertension and pulmonary hypoplasia account for the high mortality associated with congenital diaphragmatic hernia (CDH). In animal models of CDH postnatal nitric oxide (NO) inhalation has resulted in significantly better survival, and antenatal glucocorticoid administration has shown to improve lung compliance. The objective of this study was to further evaluate the single and combined effect of prenatal glucocorticoid administration and postnatal NO-inhalation on pulmonary morphology and survival of newborn rats with nitrofen-induced CDH. Methods: CDH was induced by maternal application of a single oral dose (100mg) of nitrofen on day 11.5 of pregnancy. Dexamethasone (DEX: 0.25mg/kg) was given in group III and IV by intraperitoneal injection on day 18.5 and 19.5 of pregnancy. Control animals (groups I) and further test group (III) received vehicle alone. After spontaneous delivery, animals were exposed to either NO (80 ppm) (groups II and IV) or room air (groups I and III). Hernia size was estimated in percentage of total thoracic content. Results: CDH was observed in 398 out of 491 newborn rats (81%). Animals with large hernias (> 50%) died within 3 hours after birth irrespective of treatment. Hernias with less than < 50% were considered as clinically relevant hernias. Therapy effects for groups II and III showed similar results: box plots of the histology score mean showed a similar distribution of data, and the mean histology score was almost identical at 2.16 and 2.15, respectively. Survival analysis also gave similar results with a mean of 639 and 585, respectively; survival probability was roughly 80% for both groups, and there was an almost equal tendency of significance in comparison to the control group (p=0.073, p=0.075) on survival. The combined effect of dexamethasone prenatally and nitric oxide postnatally, as in group IV, showed a further improvement in survival and lung maturation in comparison to groups II and III. The histology score mean was 1.57 in group IV with little variation of data, and the survival analysis gave a mean of 709 minutes. Conclusion: In this study it was shown that the combined therapy of antenatal dexamethasone and postnatal nitric oxide was successful in improving lung maturation and length of survival for a subgroup (large hernias excluded) of newborn rat litter. This combined therapy in the nitrofen induced CDH rat resulted in improved pulmonary compliance, narrowed septal walls, increased air saccule size, and thinning of the pulmonary interstitium. The greatest benefit of NO may be as adjunctive short term therapy in the preoperative stabilisation and delayed repair of infants with CDH to allow improvement of respiratory mechanics and reduction of operative risk.