Self-reported respiratory and gastrointestinal outcomes in children with isolated congenital diaphragmatic hernia: A prospective multicentre study.

OBJECTIVE: To evaluate medium-term self-reported respiratory and gastrointestinal (GI) outcomes in children with congenital diaphragmatic hernia (CDH). DESIGN: Self-reported respiratory and GI outcomes correlated with prenatal severity indicators. SETTING: Prospective study at three fetal medicine units. POPULATION: Families of children prenatally diagnosed with isolated, left-sided CDH surviving for >1 year. METHODS: Families received validated questionnaires for GI outcomes (Infant Gastroesophageal Reflux Questionnaire Revised, I-GERQ-R, for infants aged <2 years, or Paediatric Gastro-oesophageal Symptom and Quality of Life Questionnaire, PGSQ, for children aged aged 2-8 years or >9 years) and respiratory outcomes (preschool respiratory outcome questionnaire, for children aged ≤5 years, or the International Study of Asthma and Allergies in Childhood asthma questionnaire, for children aged 6-8 years or ≥9 years). Prenatal data collected from the medical records included lung size (percentage observed/expected lung-to-head ratio, O/E LHR %), liver position, fetal endoluminal tracheal occlusion (FETO) gestational age (GA) at delivery, and perinatal data included birthweight, location, patch repair and respiratory support. MAIN OUTCOME MEASURES: The GI and respiratory scores were correlated with O/E LHR using linear and logistic regression models. Univariate analysis was used to evaluate associations with perinatal variables. RESULTS: We obtained 142 responses from 342 families (representing a response rate of 45%). The baseline characteristics of participants and non-participants were comparable. No correlations between perinatal variables and respiratory or GI scores were identified. Children aged ≤5 years with lower O/E LHR values reported higher respiratory scores (P = 0.0175); this finding was not reported in older children. Overall, the children who underwent FETO (n = 51) had GI (P = 0.290) and respiratory (P = 0.052) scores that were comparable with those of children who were expectantly managed. CONCLUSIONS: Families and children with prenatally diagnosed CDH reported fewer respiratory symptoms with increasing age. There was no correlation between O/E LHR or the use of FETO and self-reported outcomes.

Caecal Diverticulum Causing Catastrophic Gastrointestinal Bleeding in a Child: A Case Report.

Solitary caecal diverticulae are rare in children and presentation with massive gastrointestinal (GI) bleeding is seldom reported. We present the case of a 13-year-old boy with a two-year history of abdominal pain and multiple inconclusive investigations presenting with a life threating lower GI bleed. We also review the literature surrounding solitary caecal diverticulae and caecal duplication cysts (CDCs).

Complementary Effect of Maternal Sildenafil and Fetal Tracheal Occlusion Improves Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia.

OBJECTIVE: To evaluate the effect of combining antenatal sildenafil with fetal tracheal occlusion (TO) in fetal rabbits with surgically induced congenital diaphragmatic hernia (CDH). BACKGROUND: Although antenatal sildenafil administration rescues vascular abnormalities in lungs of fetal rabbits with CDH, it only partially improves airway morphometry. We hypothesized that we could additionally stimulate lung growth by combining this medical treatment with fetal TO. METHODS: CDH was created on gestational day (GD)23 (n=54). Does were randomized to receive either sildenafil 10 mg/kg/d or placebo by subcutaneous injection from GD24 to GD30. On GD28, fetuses were randomly assigned to TO or sham neck dissection. At term (GD30) fetuses were delivered, ventilated, and finally harvested for histological and molecular analyses. Unoperated littermates served as controls. RESULTS: The lung-to-body-weight ratio was significantly reduced in sham-CDH fetuses either (1.2 ±â€Š0.3% vs 2.3 ±â€Š0.3% in controls, P=0.0003). Sildenafil had no effect on this parameter, while CDH fetuses undergoing TO had a lung-to-body-weight ratio comparable to that of controls (2.5 ±â€Š0.8%, P<0.0001). Sildenafil alone induced an improvement in the mean terminal bronchiolar density (2.5 ±â€Š0.8 br/mm2 vs 3.5 ±â€Š0.9 br/mm2, P=0.043) and lung mechanics (static elastance 61 ±â€Š36 cmH2O /mL vs 113 ±â€Š40 cmH2O/mL, P=0.008), but both effects were more pronounced in fetuses undergoing additional TO (2.1 ±â€Š0.8 br/mm2, P=0.001 and 31 ±â€Š9 cmH2O/mL, P<0.0001 respectively). Both CDH-sham and CDH-TO fetuses treated with placebo had an increased medial wall thickness of peripheral pulmonary vessels (41.9 ±â€Š2.9% and 41.8 ±â€Š3.2%, vs 24.0 ±â€Š2.9% in controls, P<0.0001). CDH fetuses treated with sildenafil, either with or without TO, had a medial thickness in the normal range (29.4% ±â€Š2.6%). Finally, TO reduced gene expression of vascular endothelial growth factor and surfactant protein A and B, but this effect was counteracted by sildenafil. CONCLUSION: In the rabbit model for CDH, the combination of maternal sildenafil and TO has a complementary effect on vascular and parenchymal lung development.

Providing direction improves function: Comparison of a radial pore-orientated acellular collagen scaffold to clinical alternatives in a surgically induced rabbit diaphragmatic tissue defect model.

Gore-Tex® is a widely used durable patch for repair of congenital diaphragmatic defects yet may result in complications. We compared Gore-Tex with a composite of a radial pore-orientated collagen scaffold (RP-Composite) and clinically used porcine small intestinal submucosa (SIS; Surgisis®) in a rabbit model for diaphragmatic hernia. The growing rabbit mimics the rapid rib cage growth and reherniation rates seen in children. We created and immediately repaired left hemidiaphragmatic defects in 6-week-old rabbits with Gore-Tex, SIS, and an RP-Composite scaffold. An additional group of rabbits had a sham operation. At 90 days, survivors more than doubled in weight. We observed few reherniations or eventrations in Gore-Tex (17%) and RP-Composite (22%) implanted animals. However, SIS failed in all rabbits. Maximum transdiaphragmatic pressure was lower in Gore-Tex (71%) than RP-Composite implanted animals (112%) or sham (134%). Gore-Tex repairs were less compliant than RP-Composite, which behaved as sham diaphragm (p < 0.01). RP-Composite induced less foreign body giant cell reaction than Gore-Tex (p < 0.05) with more collagen deposition (p < 0.001), although there was a tendency for the scaffold to calcify. Unlike Gore-Tex, the compliance of diaphragms reconstructed with RP-Composite scaffolds were comparable with native diaphragm, whereas reherniation rates and transdiaphragmatic pressure measurements were similar.

MicroRNA 200b is upregulated in the lungs of fetal rabbits with surgically induced diaphragmatic hernia.

OBJECTIVE: Profiling of miR-200b expression and its targets (transforming growth factor [TGF]-ß2 and ZEB2) in the surgical rabbit congenital diaphragmatic hernia (DH) model before and after tracheal occlusion (TO). METHODS: Thirty-eight timed-pregnant rabbits had left DH creation on gestational day (GD) 23. On GD28, 17 randomly selected fetuses had TO. We harvested fetuses at GD23, GD28, or GD30. We calculated lung-to-body weight ratios, processed lungs for miR-200b in situ hybridization and real-time quantitative polymerase chain reaction, and evaluated effects on downstream targets TGF-ß2 or ZEB2. RESULTS: We obtained 16 DH fetuses (n = 7 GD28 and n = 9 GD30), 13 TO fetuses (GD30), and 38 control fetuses (n = 15 GD23, n = 11 GD28, and n = 12 GD30). Diaphragmatic hernia lungs were hypoplastic, and TO resulted in control lung-to-body weight ratio levels. Term miR-200b-3p levels were significantly upregulated in the hypoplastic compared with control ipsilateral lung (1.906 ± 0.90 vs 0.7429 ± 0.44) (P < .01). Fetal TO ipsilateral lungs displayed a variable miR-200b response on in situ hybridization and polymerase chain reaction, with levels similar to control and congenital DH lungs. The TGF-ß2 was unchanged in hypoplastic and TO lungs, and ZEB2 tended to be reduced in TO compared with DH lungs (1.79 [0.4-2.9] vs 0.73 [0.5-1.4]). CONCLUSIONS: Hypoplastic fetal rabbit lungs display upregulation of miR-200b expression although downstream targets are not different from controls. Following TO, fetal rabbit lungs display a variable miR-200b response.

Current and future antenatal management of isolated congenital diaphragmatic hernia.

Congenital diaphragmatic hernia is surgically correctable, yet the poor lung development determines mortality and morbidity. In isolated cases the outcome may be predicted prenatally by medical imaging. Cases with a poor prognosis could be treated before birth. However, prenatal modulation of lung development remains experimental. Fetoscopic endoluminal tracheal occlusion triggers lung growth and is currently being evaluated in a global clinical trial. Prenatal transplacental sildenafil administration may in due course be a therapeutic approach, reducing the occurrence of persistent pulmonary hypertension, either alone or in combination with fetal surgery.

A growing animal model for neonatal repair of large diaphragmatic defects to evaluate patch function and outcome.

OBJECTIVES: We aimed to develop a more representative model for neonatal congenital diaphragmatic hernia repair in a large animal model, by creating a large defect in a fast-growing pup, using functional pulmonary and diaphragmatic read outs. BACKGROUND: Grafts are increasingly used to repair congenital diaphragmatic hernia with the risk of local complications. Growing animal models have been used to test novel materials. METHODS: 6-week-old rabbits underwent fiberoptic intubation, left subcostal laparotomy and hemi-diaphragmatic excision (either nearly complete (n = 13) or 3*3cm (n = 9)) and primary closure (Gore-Tex patch). Survival was further increased by moving to laryngeal mask airway ventilation (n = 15). Sham operated animals were used as controls (n = 6). Survivors (90 days) underwent chest X-Ray (scoliosis), measurements of maximum transdiaphragmatic pressure and breathing pattern (tidal volume, Pdi). Rates of herniation, lung histology and right hemi-diaphragmatic fiber cross-sectional area was measured. RESULTS: Rabbits surviving 90 days doubled their weight. Only one (8%) with a complete defect survived to 90 days. In the 3*3cm defect group all survived to 48 hours, however seven (78%) died later (16-49 days) from respiratory failure secondary to tracheal stricture formation. Use of a laryngeal mask airway doubled 90-day survival, one pup displaying herniation (17%). Cobb angel measurements, breathing pattern, and lung histology were comparable to sham. Under exertion, sham animals increased their maximum transdiaphragmatic pressure 134% compared to a 71% increase in patched animals (p<0.05). Patched animals had a compensatory increase in their right hemi-diaphragmatic fiber cross-sectional area (p<0.0001). CONCLUSIONS: A primarily patched 3*3cm defect in growing rabbits, under laryngeal mask airway ventilation, enables adequate survival with normal lung function and reduced maximum transdiaphragmatic pressure compared to controls.

The Effect of Transplacental Administration of Glucagon-Like Peptide-1 on Fetal Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia.

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) increases surfactant protein expression in type 2 pneumocytes. Herein, we determine if transplacental GLP-1 treatment accelerates lung growth in the fetal rabbit model of congenital diaphragmatic hernia (DH). METHODS: Time-mated does had an induction of DH on day 23 followed by daily GLP-1 or placebo injection until term. At that time, the does were weighed, fetal blood was obtained for GLP-1 assay, and the lungs were dissected. Fetal outcome measures were lung-to-body-weight ratio (LBWR), morphometry, and Ki67 and surfactant protein B (SPB) expression. RESULTS: Maternal weight loss in the GLP-1 group was 7.1%. Fetal survival was lower in GLP-1 fetuses compared to placebo controls (27/85, 32% vs. 35/57, 61%; p < 0.05). Fetal GLP-1 levels were increased 3.6-fold. The LBWR of GLP-1 DH fetuses fell within the range of DH placebo fetuses (1.166 ± 0.207% vs. 1.312 ± 0.418%), being significantly lower than that of placebo-exposed unoperated fetuses (2.280 ± 0.522%; p < 0.001). GLP-1 did not improve airway morphometry. GLP-1 DH lungs had a reduced adventitial and medial thickness within the range of controls, and lesser muscularization of vessels measuring 30-60 µm. There were no differences in Ki67 and SPB expression. CONCLUSION: GLP-1 at this dosage improves peripheric pulmonary vessel morphology in intra-acinar vessels with no effect on airway morphometry but with significant maternal and fetal side effects. Thus, it is an unlikely medical strategy.

In vivo evidence by magnetic resonance volumetry of a gestational age dependent response to tracheal occlusion for congenital diaphragmatic hernia.

OBJECTIVE: We aimed to assess in vivo changes in lung and liver volumes in fetuses with isolated congenital diaphragmatic hernia, either expectantly managed or treated in utero. METHOD: This is a secondary analysis of prospectively collected data at two fetal therapy centers. We used archived magnetic resonance images of fetuses taken ≥7 days apart, creating paired observations in 20 expectantly managed cases, 41 with a second magnetic resonance prior to balloon reversal and 64 after balloon removal. We measured observed to expected total fetal lung volume (O/E TFLV) and liver-to-thoracic volume ratio. We calculated changes in volume as compared with the initial measurement and its rate as a function of gestational age (GA) at occlusion. RESULTS: The liver-to-thoracic volume ratio did not change in either group. In expectantly managed fetuses, O/E TFLV did not increase with gestation. In fetuses undergoing tracheal occlusion, the measured increase in volume was 2.6 times larger with balloon in place as compared with that after its removal. GA at tracheal occlusion was an independent predictor of the O/E TFLV. The net rate seems to initially increase and plateau at a maximum of 1.5% per week by 35 to 45 days after occlusion. CONCLUSIONS: Tracheal occlusion induces a net increase in volume, its magnitude essentially dependent on the GA at occlusion.

Medical interventions to reverse pulmonary hypoplasia in the animal model of congenital diaphragmatic hernia: A systematic review.

OBJECTIVE: We aimed to systematically review all published pre-clinical research on prenatal medical treatment of pulmonary hypoplasia in congenital diaphragmatic hernia (CDH). Background The neonatal mortality due to isolated CDH remains high. Whether fetal endoscopic tracheal occlusion (FETO) reduces mortality is still to be demonstrated. Therefore more potent preferentially medical therapy would be welcomed. Methods We searched MEDLINE (Pubmed), Embase and the Web of Science including all studies from the earliest date (1951) to December 2013. Article quality was assessed using the modified CAMRADES checklist. Inclusion criteria were those animal studies addressing prenatal medical interventions and principal variables were confirmation of a diaphragmatic defect, lung to body weight ratio (LBWR), formal airway morphometry or DNA/protein content. Results In total 983 articles were identified. Following abstract review, 96 articles were assessed by two authors in agreement with a third for eligibility. Of these, 43 were included in the final analysis. The median number of study quality checklist items (maximum 10) scored was 4 (IQ range: 2-5). Thirty (69.8%) of studies were in the nitrofen rat. The majority were treated with vitamins or glucocorticoids. Single studies reported some improvement in lung morphology with alternative therapies. It was impossible to identify a pattern in animal model selection or creation, mode, time point or duration of treatment and readouts. Only one study reported a sample size calculation. Conclusion Comparison in pre-clinical studies in CDH is challenging due to methodological variation. Agreed standardized methods need to be applied in future investigation of new medical therapies.