Paul D. Losty

Value of liver herniation in prediction of outcome in fetal congenital diaphragmatic hernia: a systematic review and meta‐analysis

Intrathoracic liver herniation (ILH) is being used to estimate prognosis and hence guide antenatal interventions in fetal congenital diaphragmatic hernia (CDH). However, the literature regarding its utility in this role is conflicting. This review systematically examines the currently available evidence of ILH use in fetal CDH.

How useful is the lung-to-head ratio in predicting outcome in the fetus with congenital diaphragmatic hernia? A systematic review and meta-analysis

Fetal surgery to improve lung growth comprises tracheal occlusion in selected ‘high‐risk’ fetuses with congenital diaphragmatic hernia (CDH). Sonographically measured fetal lung‐to‐head ratio (LHR) is utilized to recruit candidates for fetal surgery. This study provides a meta‐analysis of the evidence regarding the prognostic use of lung‐to‐head ratio measurements in fetal CDH.

Prenatal glucocorticoid therapy reverses pulmonary immaturity in congenital diaphragmatic hernia in fetal sheep.

OBJECTIVE To assess the feasibility of conducting clinical trials of prenatal steroid therapy for congenital diaphragmatic hernia (CDH) in humans, the authors tested whether prenatal glucocorticoid, currently the standard treatment to minimize respiratory distress syndrome in premature infants, might improve the pulmonary immaturity in severe CDH in a large animal model. SUMMARY BACKGROUND DATA The authors have used the nitrofen-induced rat model of CDH, which demonstrates immature lungs by biochemical, morphometric, and molecular biologic criteria. They also have shown that the lethally immature lungs of the full-term CDH rats can be improved by biochemical, morphometric, physiologic, and molecular criteria by treating the mothers with parenteral steroids at doses extrapolated from the current therapy used to accelerate lung development of premature human babies. METHODS During a 3-year period in 88 fetal sheep, 1) left-sided diaphragmatic hernias were created surgically at varying gestational ages (day 78-90; term = 142-145 days) and size to maximize severity (n = 45), 2) placement and design of indwelling fetal intravenous catheters were optimized (n = 13), and 3) timing and dosage of cortisol administration were determined (n = 17). As a result, diaphragmatic hernias were created on day 80, intravenous catheters were placed on day 120, and twice-daily intravenous cortisol injections (n = 8) or saline as the control (n = 5) were administered (days 133-135). Lambs were delivered on day 136 via cesarean section to avoid steroid-induced abortion; vascular access was obtained, and the fetuses were ventilated at standard settings. Physiologic data were collected, and lungs were harvested for biochemical and histologic analysis. RESULTS Significant improvements were measured in postductal arterial oxygen pressure ([PaO2] 38 +/- 6 mmHg after cortisol therapy compared with 20 +/- 3 mmHg for saline controls; p = 0.002) and in dynamic compliance (0.42 +/- 0.05 mL/cm H2O vs. 0.29 +/- 0.01 mL/cm H2O; p = 0.01). Lung glycogen levels in the right lung of the cortisol group were significantly better than controls (4.6 +/- 0.3 mg/g lung vs. 6.8 +/- 0.4 mg/g; p = 0.002), as were protein/DNA levels (8.3 +/- 0.9 mg/mg vs. 14.5 +/- mg/mg; p < 0.05). Striking morphologic maturation of airway architecture was observed in the treated lungs. CONCLUSIONS Prenatal glucocorticoids correct the pulmonary immaturity of fetal sheep with CDH by physiologic, biochemical, and histologic criteria. These data, combined with previous small animal studies, have prompted the authors to initiate a prospective phase I/II clinical trial to examine the efficacy of prenatal glucocorticoids to improve the maturation of hypoplastic lungs associated with CDH.

Oesophageal atresia and tracheo-oesophageal fistula

Oesophageal atresia-tracheo-oesophageal fistula has featured in paediatric surgery since its beginnings. The first successful primary repair was in 1941. With overall survival now exceeding 90% in dedicated centres, the emphasis has changed to reducing morbidity and achieving improvements in the quality of life. An overview of current and emerging strategies in managing patients with this condition is presented. Advances in developmental biology and molecular genetics reflecting improved understanding of the pathogenesis are highlighted.

Neonatal endosurgical congenital diaphragmatic hernia repair: a systematic review and meta-analysis.

Objective:To compare outcomes of open and endosurgical neonatal congenital diaphragmatic hernia (CDH) repairs. Background:Historically a surgical emergency, neonatal CDH repair is now deferred pending stabilization of characteristically labile cardiopulmonary physiology. Usually accomplished via laparotomy, surgical repair may acutely worsen lung function; conversely, by reducing the visceral hernia, surgery might improve it. Theoretically, endosurgical repair could minimize deleterious effects of surgery while garnering benefits from decompressing the CDH lung. As endosurgical repair gains popularity, it is important to investigate whether or not minimally-invasive neonatal CDH repair has benefits. Methods:We searched Medline, Embase, and Cochrane Trials databases for studies comparing open with endosurgical CDH repair. Non-neonatal series and reports without comparison groups were excluded. References from papers and conference proceedings were also hand searched. Meta-analysis used a fixed effects model and was reported in accordance with PRISMA. Results:We included 3 studies (1 unpublished; none randomized); all compared thoracoscopic and open CDH repair and together described 143 patients. All studies had limitations, including use of historical controls. Demographics, CDH sidedness, APGAR and associated anomaly prevalence were similar between groups. For endosurgical repair, recurrence was higher (RR: 3.2 [1.1, 9.3], P = 0.03) and operative time longer (WMD 50 minutes [32, 69], P < 0.00001). Survival and patch usage were not different between open and endosurgical groups. Conclusions:Neonatal thoracoscopic CDH repair has greater recurrence rates and operative times but similar survival and patch usage compared with open surgery. A prospective registry for all such cases would guide development of trials (Stage 2b; IDEAL recommendations).

Early lung malformations in congenital diaphragmatic hernia

BACKGROUND/PURPOSE Lung hypoplasia, a leading contributor to the lethality of congenital diaphragmatic hernia (CDH), has been attributed to compression of the fetal lung by herniated abdominal viscera. Contested findings in experimental CDH suggest that lung malformation may precede diaphragmatic hernia. To address this unresolved question, we studied the pattern and progress of embryonic lung development in vivo and in vitro before diaphragmatic herniation in the nitrofen CDH model. METHODS Sprague-Dawley rats were fed nitrofen on day 9.5 of pregnancy to induce pulmonary hypoplasia and CDH in newborns (term, day 22). Control rats received olive oil. Embryonic lungs were microdissected on day 13.5 gestation, 24 hours after lung primordia bud from the foregut (normal diaphragmatic closure, day 16.5). In vivo airway branching was measured by counting terminal lung buds at this stage. Lungs were cultured for up to 78 hours and longitudinal in vitro development studied by serial measurements of terminal bud count, area, and perimeter. RESULTS At 13.5 days of gestation in vivo, nearly 99% of normal lungs (n = 130) had > or = 6 terminal lung buds. In contrast, 36% of the nitrofen-exposed lungs (n = 170) fell short of this developmental milestone with less than 6 terminal buds (P < .001). In vitro, the nitrofen lungs had reduced area compared with controls after 6, 30, and 54 hours (P = .001, P < .001, and P = .001, respectively). Bud count and epithelial perimeter were reduced in the nitrofen lungs after 6 and 30 hours in vitro (P < .001 and P = .01 v normal terminal bud count; P < .001 and P= .002 v normal perimeter). CONCLUSIONS Before diaphragmatic herniation, nitrofen-exposed embryos in vivo have a 36% frequency of reduced airway branching that strikingly parallels the 30% to 40% term incidence of CDH in this model. The authors propose that this early lung anomaly is restricted to a subset of nitrofen-exposed embryos in which it is integral to an emerging CDH phenotype. In vitro data confirm that nitrofen-induced pulmonary hypoplasia precedes visceral herniation and persists to allow experimental manipulation in culture. The developmental biology underlying lung hypoplasia in CDH may now be addressed using this organ culture system.

Prenatal hormonal therapy improves pulmonary compliance in the nitrofen-induced CDH rat model.

Neonates with congenital diaphragmatic hernia (CDH) experience a high mortality despite intensive medical and surgical management. The associated pulmonary hypoplasia is accompanied by an underlying biochemical deficiency that bears similarity to respiratory distress syndrome (RDS) in the premature newborn. Using therapies extrapolated from those used to treat RDS, the authors have previously shown correction of the immature pulmonary biochemical indices in the nitrofen rat CDH model. This study investigates the functional and histological outcome of prenatal hormone therapy on CDH rats. Compared with saline-treated CDH controls, dexamethasone-treated CDH animals achieved significant increases in lung distensibility (P = .0006) and functional residual capacity (P = .004); CDH rats treated with combined dexamethasone and thyrotropin-releasing hormone (TRH) showed improved functional residual capacity (P = .043) and alveolar stability (P = .025); CDH animals treated with TRH alone (TRH-CDH) showed no improvement in any parameter tested. Histologically, the lungs from dexamethasone- and dexamethasone-TRH-treated CDH animals showed changes that included narrow septal walls, increased air saccule size, and thinning of the pulmonary interstitium compared with the lungs of saline or TRH-CDH rats, which were developmentally arrested at the canalicular stage. Lung weights and lung weight-body weights ratios were similar in all CDH rats, confirming that treatment did not impair pulmonary growth. These results support the potential clinical use of prenatal pharmacological therapies to treat human fetuses with prenatally diagnosed CDH.

Recent advances in congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) is a common birth defect which continues to challenge paediatric surgeons and intensivists. Affecting approximately 1:2500 births, a baby with CDH is born every 24–36 hours in the UK.1

Congenital Diaphragmatic Hernia-Does the Side of the Defect Influence the Incidence of Associated Malformations?

BACKGROUND/PURPOSE Patients with congenital diaphragmatic hernia (CDH) frequently have associated anomalies. Experiments in the nitrofen CDH model have shown differential embryonic cell death patterns in rodents suggesting unique mechanisms in the formation of right-sided (RCDH) or left-sided (LCDH) diaphragmatic hernia. These findings provide insight into the pathogenesis of CDH and may aid our understanding on the spectrum of associated anomalies commonly observed in humans. This study therefore set out to test the hypothesis that the side of the diaphragmatic defect in humans is related to the incidence and severity of coexistent organ malformations. METHODS The medical and autopsy records of 301 CDH patients presenting to two institutions over a 23-year period were examined to analyze these factors. RESULTS One hundred patients (33%) were found to have one or more associated anomalies. The incidence of multiple-RCDH (10%) versus LCDH (7.3%) and cardiac anomalies-RCDH (10%) versus LCDH (8.5%) was similar in both groups of patients. However, the hypoplastic heart syndrome was a unique feature in 5 of 22 patients (23%) with LCDH who had cardiac abnormalities. This cardiac anomaly may be related developmentally to LCDH. CONCLUSION The cellular mechanisms underlying the genesis of this spectrum of abnormalities in humans and the nitrofen CDH model warrant further study to elucidate factors governing embryonic cell fate and phenotype expression.

Combined antenatal thyrotropin-releasing hormone and low-dose glucocorticoid therapy improves the pulmonary biochemical immaturity in congenital diaphragmatic hernia

The lungs of patients born with severe congenital diaphragmatic hernia (CDH) are biochemically and morphologically immature. Because antenatal glucocorticoid therapy can accelerate pulmonary maturation in premature neonates who have respiratory distress syndrome, we hypothesized that it may correct the pulmonary biochemical and morphological immaturity associated with CDH. We showed in previous experimental studies that antenatal low-dose dexamethasone improved the biochemical and morphological parameters of pulmonary immaturity in rats that had severe CDH. Somatic and pulmonary growth were inhibited with high doses of dexamethasone. In the present study, we examined the effects of antenatal low-dose dexamethasone and thyrotropin-releasing hormone (TRH), alone or in combination, on the pulmonary maturation in CDH. Combined antenatal low-dose dexamethasone and TRH significantly reduced mean lung glycogen concentration (P = .001), and increased mean disaturated phosphatidylcholine content (P < .005) to better than that observed with either therapy alone, without changing mean body or lung weight. Combined TRH and low-dose glucocorticoid as an antenatal therapy may reduce the morbidity and mortality of CDH.