Lung physiological and metabolic changes in lambs with congenital diaphragmatic hernia after administration of prenatal maternal corticosteroids

doi:10.1016/S0022-3468(99)90208-7

Journal of Pediatric Surgery

Volume 34, Issue 2, February 1999, Pages 354-356

https://doi.org/10.1016/S0022-3468(99)90208-7 Get rights and content

Abstract

Background/Purpose: Improved outcomes of preterm infants born to mothers treated prenatally with corticosteroids have been documented. The authors investigated the role of prenatal maternal corticosteroid therapy in congenital diaphragmatic hernia (CDH).

Methods: Five CDH lambs of ewes given 0.5 mg/kg betamethasone intravenously 24 hours before delivery (single-dose), four CDH lambs of ewes similarly dosed at 48 and 24 hours before delivery (double-dose), five untreated CDH lambs and five control lambs were studied. After 2 hours of ventilation, compliance, arterial oxygen (po₂) and carbon dioxide (pco₂) concentrations were recorded. Lavage protein and phospho-lipid levels were measured, and lung tissue was analyzed for antioxidant enzyme activity (AOE).

Results: No improvement in gas exchange was noted in either treatment group. Significant increases in compliance (P = .02) were noted in the double-dose steroid group, which were different from that of untreated CDH lambs or controls. Minimal changes in AOE activities were seen with steroid administration.

Conclusions: Although the metabolic changes were not significant, the marked improvement in compliance seen in the double-dosed steroid group suggests a potential role for prenatal maternal corticosteroids in CDH. Further timing and dosage studies are warranted in this model.

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Pathophysiology of persistent pulmonary hypertension of the newborn-cellular basis and lessons from animal studies
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Persistent pulmonary hypertension of the newborn (PPHN) is a syndrome of failed circulatory adaptation at birth due to the delay in or impairment of the normal fall in pulmonary vascular resistance that occurs following delivery. This chapter highlights the biochemical, physiological, and cellular changes during normal and abnormal cardiovascular transition at birth using information from human studies and various animal models of PPHN. The clinical relevance of these findings, applied physiology, and therapeutic strategies to correct these abnormalities are also discussed. Current treatment for infants is limited to inhaled nitric oxide and off-label use of agents approved for pulmonary hypertension in adults. Hence, there is a dire need to develop evidence-based strategies to evaluate new medications and approaches for the treatment of PPHN.
Pulmonary arteriole muscularization in lambs with diaphragmatic hernia after combined tracheal occlusion/glucocorticoid therapy
2007, American Journal of Obstetrics and Gynecology
Citation Excerpt :
In fetal sheep with severe DH, intravenous infusions of cortisol between 133 and 135 days of gestation increased arterial PO2 (DH group, 20 ± 3 mm Hg; DH-cortisol group, 38 ± 6 mm Hg) and dynamic lung compliance and reduced septal wall-thickness.44 Kapur et al45 also reported that lung compliance was increased in lambs with DH that underwent prenatal glucocorticoid therapy, although improvement in gas exchange was not observed. In a report of 3 infants with DH that underwent repetitive prenatal glucocorticoid-therapy, Ford et al46 concluded that “prolonged steroid administration over 10 weeks of pregnancy may have contributed to ease of ventilation, absence of pulmonary hypertension, and survival.”
A morphometric study was performed to examine the effects of prenatal glucocorticoids, which were administered 48 hours before birth, on muscularization of small pulmonary arterioles (<60 μm diameter) in lambs with diaphragmatic hernia (DH) after fetal tracheal occlusion (TO).
DH was created in 23 fetal sheep at 65 days gestation. TO was performed in 16 of 24 fetuses between 110 and 140 days of gestation; 9 of the fetuses were exposed prenatally to betamethasone (0.5 mg/kg body weight) 48 hours before delivery. Six sham-operated animals served as controls. Sections of paraffin that were embedded in lung tissues were stained with Elastin-Van Gieson, and the percentage of medial wall thickness (MWT) was determined.
The percentage of MWT in DH lambs (29.6% ± 1.9%) was increased compared with sham animals (18.1% ± 1.3%) and was not different from that of DH/TO animals (30.3% ± 1.7%). In DH/TO + glucocorticoid lambs, the percentage of MWT (24.6% ± 1.2%) was significantly lower than in the DH/TO group but was higher than the sham group.
In fetuses who underwent prolonged TO therapy for severe DH, prenatal glucocorticoid treatment decreased medial hypertrophy of pulmonary arterioles by approximately 19%. We speculate that such structural changes may have contributed to improve gas exchange that was observed in this model.
Antenatal vitamin A decreases ventilation-induced lung injury in the lamb model of congenital diaphragmatic hernia
2006, Asian Journal of Surgery
Infants with congenital diaphragmatic hernia (CDH) are susceptible to ventilation-induced lung injury. Vitamin A may protect the lung from injury during ventilation. The authors investigated the effects of antenatal vitamin A on ventilation-induced lung injury in CDH lambs using lung myeloperoxidase (MPO) activity as an indicator of lung injury.
Left-sided diaphragmatic defects were created in 10 lambs at 79-81 days' gestation. Six CDH lambs had right jugular venous catheters inserted at 120 days' gestation and were given vitamin A until 135 days' gestation. Four CDH lambs were not treated. Twin littermates (n = 3) served as controls. All lambs were delivered at 136-139 days of gestation and ventilated for 2 hours. Lambs were sacrificed following ventilation and samples of left lung were snap frozen. MPO was extracted from lung tissue and MPO activity was assayed.
CDH lambs treated with antenatal vitamin A demonstrated significantly lower MPO activity than untreated CDH lambs (0.0477 ± 0.0150 vs. 0.1106 ± 0.0230 units/mg protein, p < 0.05).
This is the first study to look at the effect of vitamin A on lung injury in CDH. In the lamb model of CDH, antenatal vitamin A decreases ventilation-induced lung injury.
Corticosteroids for fetuses with congenital diaphragmatic hernia: Can we show benefit?
2006, Journal of Pediatric Surgery
Prenatal corticosteroids have been used in fetuses with congenital diaphragmatic hernia (CDH). We tested the utility of steroids by 2 methods.
Mothers carrying fetuses with CDH were randomized to 3 weekly doses of betamethasone or placebo starting at 34 weeks. Patients were followed until death or discharge. In a separate cohort study, the CDH Registry was used to compare infants who received prenatal steroids to those who had not.
Thirty-four patients were enrolled at 7 centers, with 32 completing the trial. There were 15 placebo and 17 steroid patients. There was no difference in survival, length of stay, duration of ventilation, or oxygen use at 30 days. For the cohort study, we looked at infants older than 34 weeks who were born after October 2000 when data on prenatal steroids were collected. There were 1093 patients; 390 were evaluable, with 56 receiving steroids. There was no difference in survival, length of stay, ventilator days, or oxygen use at 30 days.
Neither the trial nor the CDH Registry suggest that late prenatal corticosteroids benefit fetuses with CDH. More than 1700 mothers and fetuses would need to be enrolled in a trial to show a 10% improvement in survival. It is unlikely that late steroids offer benefit to most fetuses with CDH.
Lung function in lambs with diaphragmatic hernia after reversible fetal tracheal occlusion
2004, Journal of Pediatric Surgery
Short-duration resuscitation (≤4 hours) of lambs with diaphragmatic hernia treated in utero with tracheal occlusion have shown improved lung function compared with untreated diaphragmatic hernia. This may be a transient phenomenon in the treated diaphragmatic hernia lambs because of surfactant deficiency. Our objective was to analyze the effect of fetal tracheal occlusion with or without release of the occlusion 1 week before delivery on pulmonary function during a longer period of resuscitation (8 hours) in the diaphragmatic hernia lamb model.
Four groups were compared: diaphragmatic hernia (n = 5), diaphragmatic hernia and tracheal occlusion until delivery (n = 5), diaphragmatic hernia and tracheal occlusion with release of the occlusion 1 week before delivery (n = 5), and normal controls (n = 4).
Despite persistently decreased surfactant levels, diaphragmatic hernia lambs treated with tracheal occlusion had normal-sized lungs with marked improvement in lung function and gas exchange over 8 hours when compared with untreated lambs with diaphragmatic hernia. Release of the tracheal occlusion 1 week before delivery added no benefit.
It appears that surfactant-independent mechanisms such as pulmonary growth and structural changes are of foremost importance in relating to improved compliance, oxygenation, and ventilation of diaphragmatic hernia lambs treated with tracheal occlusion.
The CDH study group and advances in the clinical care of the patient with congenital diaphragmatic hernia
2004, Seminars in Perinatology
Congenital diaphragmatic hernia (CDH) occurs in 1 of every 2,000 to 4,000 births and accounts for 8% of all major congenital anomalies. Recurrence risk for a subsequent pregnancy is estimated at 2%. The mortality rate for CDH when diagnosed antenatally, varies with fetal age and with the presence or absence of hydramnios and degree of pulmonary hypoplasia. The prognosis has improved dramatically in recent years, primarily due to advances in neonatal and surgical interventions. Neonatal survival rates with an antenatal diagnosis now exceed 80% in some centers. Treatment for infants with CDH reflects other pediatric surgical problems in that a majority of the clinical research that shapes treatment is retrospective in nature. Because CDH is a relatively rare disease, using a compilation of cases, such as the CDH database provides, greatly aids our understanding of this disease process. Moreover, the application of a quality assessment scale provides the practitioner with a knowledge base to critically evaluate the published retrospective data.

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^☆: Presented at the 45th Annual International Congress of the British Association of Paediatric Surgeons, Bristol, England, July 21–24, 1998.

^☆☆: This work was supported by a grant from The National Institutes of Health (HL 49977).

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Lung physiological and metabolic changes in lambs with congenital diaphragmatic hernia after administration of prenatal maternal corticosteroids☆,☆☆

Abstract

J Pediatr Surg

Am J Obstet Gynecol

A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants

Pediatrics

The effects of corticosteroid administration before preterm delivery: An overview of the evidence from controlled trials

Br J Obstet Gynaecol

The argument for prenatal administration of dexamethasone to prevent respiratory distress syndrome

J Pediatr

Pathophysiology of congenital diaphragmatic hernia II: The fetal lamb CDH model is surfactant deficient

J Pediatr Surg

Postnatal lung responses and surfactant function after fetal or maternal corticosteroid treatment

J Appl Physiol

Catalase