Morbidity In Congenital Diaphragmatic Hernia Research Articles

Fetal Lung Volume Appears to Predict Respiratory Morbidity in Congenital Diaphragmatic Hernia.

Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypoplasia and respiratory morbidity. To assess whether respiratory morbidity during the first 2 years of life in infants with left-sided CDH is associated with fetal lung volume (FLV) evaluated by the observed-to-expected FLV ratio (o/e FLV) on antenatal magnetic resonance imaging (MRI). In this retrospective study, o/e FLV measures were collected. Respiratory morbidity in the first 2 years of life was studied according to two endpoints: treatment with inhaled corticosteroids for >3 consecutive months and hospitalization for any acute respiratory disease. The primary outcome was a favorable progression defined by the absence of either endpoint. Forty-seven patients were included. The median o/e FLV was 39% (interquartile range, 33-49). Sixteen (34%) infants were treated with inhaled corticosteroids and 13 (28%) were hospitalized. The most efficient threshold for a favorable outcome was an o/e FLV ≥ 44% with a sensitivity of 57%, specificity of 79%, negative predictive value of 56%, and positive predictive value of 80%. An o/e FLV ≥ 44% was associated with a favorable outcome in 80% of cases. These data suggest that lung volume measurement on fetal MRI may help to identify children at lower respiratory risk and improve information during pregnancy, patient characterization, decisions about treatment strategy and research, and personalized follow-up.

Upregulated TSP1 and CD47 expression in the lung in nitrofen-induced congenital diaphragmatic hernia.

Persistent pulmonary hypertension remains a major cause of mortality and morbidity in congenital diaphragmatic hernia (CDH). The secreted glycoprotein thrombospondin-1 (TSP1), a ligand for receptor CD47, is widely expressed on both systemic and pulmonary vascular cells. TSP1-CD47 signaling has been reported to be one of the pathogeneses of pulmonary hypertension (PH). After creating a nitrofen-induced CDH rat model, fetuses were sacrificed on D17, D19 and D21 and divided into a control group and a CDH group. Quantitative real-time polymerase chain reaction was performed to determine the pulmonary gene expression of TSP1, CD47 and Runx3 (a regulator of TSP1). An immunofluorescence study was performed to evaluate the expression and localization of TSP1, CD47 and Runx3. The relative mRNA expression of pulmonary TSP1, CD47 and Runx3 on D21 was significantly increased in the CDH group (p=0.005, p=0.001, p=0.046, and p=0.002, respectively). The immunofluorescence study also confirmed the overexpression of TSP1, CD47 and Runx3 in the CDH group. Our results provide evidence that TSP1-CD47 signaling is involved in the pathogenesis of PH in a nitrofen-induced CDH model. Our data suggest that anti-CD47 antibodies can be novel therapeutic targets for the treatment of PH in CDH.

Impact of Time Point of Extracorporeal Membrane Oxygenation on Mortality and Morbidity in Congenital Diaphragmatic Hernia: A Single-Center Case Series.

Since there are no data available on the influence of the time point of ECMO initiation on morbidity and mortality in patients with congenital diaphragmatic hernia (CDH), we investigated whether early initiation of ECMO after birth is associated with a beneficial outcome in severe forms of CDH. All neonates with CDH admitted to our institution between 2010 until 2020 and undergoing ECMO treatment were included in this study and divided into four different groups: (1) ECMO initiation < 12 h after birth (n = 143), (2) ECMO initiation between 12–24 h after birth (n = 31), (3) ECMO initiation between 24–120 h after birth (n = 48) and (4) ECMO initiation > 120 h after birth (n = 14). The mortality rate in the first (34%) and fourth group (43%) was high and in the second group (23%) and third group (12%) rather low. The morbidity, characterized by chronic lung disease (CLD), did not differ significantly in the three groups; only patients in which ECMO was initiated >120 h after birth had an increased rate of severe CLD. Our data, although not randomized and limited due to small study groups, suggest that very early need for ECMO and ECMO initiation > 120 h after birth is associated with increased mortality.

Anti-reflux surgery in children with congenital diaphragmatic hernia: A prospective cohort study on a controversial practice

IntroductionGastro-esophageal reflux disease (GERD) is the most frequent long-term morbidity of congenital diaphragmatic hernia (CDH) survivors. Performing a preventive fundoplication during CDH repair remains controversial. This study aimed to: (1) Analyze the variability in practices regarding preventive fundoplication; (2) Identify predictive factors for fundoplication.(3) Evaluate the impact of preventive fundoplication on gastro-intestinal outcomes in children with a CDH patch repair; MethodsThis prospective multi-institutional cohort study (French CDH Registry) included CDH neonates born in France between January 1st, 2010-December 31st, 2018. Patch CDH was defined as need for synthetic patch or muscle flap repair. Main outcome measures included need for curative fundoplication, tube feed supplementation, failure to thrive, and oral aversion. ResultsOf 762 CDH neonates included, 81 underwent fundoplication (10.6%), either preventive or curative. Median follow-up was 3.0 years (IQR: 1.0–5.0).(1) Preventive fundoplication is considered in only 31% of centers. The rates of both curative fundoplication (9% vs 3%, p = 0.01) and overall fundoplication (20% vs 3%, p < 0.0001) are higher in centers that perform preventive fundoplication compared to those that do not.(2) Predictive factors for preventive fundoplication were: prenatal diagnosis (p = 0.006), intra-thoracic liver (p = 0.005), fetal tracheal occlusion (p = 0.002), CDH-grade C-D (p < 0.0001), patch repair (p < 0.0001). After CDH repair, 8% (n = 51) required curative fundoplication (median age: 101 days), for which a patch repair was the only independent predictive factors identified upon multivariate analysis.(3) In neonates with patch CDH, preventive fundoplication did not decrease the need for curative fundoplication (15% vs 11%, p = 0.53), and was associated with higher rates of failure to thrive (discharge: 81% vs 51%, p = 0.03; 6-months: 81% vs 45%, p = 0.008), tube feeds (6-months: 50% vs 21%, p = 0.02; 2-years: 65% vs 26%, p = 0.004), and oral aversion (6-months: 67% vs 37%, p = 0.02; 1-year: 71% vs 40%, p = 0.03). ConclusionsChildren undergoing a CDH patch repair are at high risk of requiring a curative fundoplication. However, preventive fundoplication during a patch repair does not decrease the need for curative fundoplication and is associated with worse gastro-intestinal outcomes in children. Level of evidenceII – Prospective Study.

Birth weight predicts patient outcomes in infants who undergo congenital diaphragmatic hernia repair

Purpose The purpose of this study was to analyze the clinical characteristics and outcomes of low birthweight (LBW) infants with congenital diaphragmatic hernia (CDH) compared to normal birthweight (NBW) infants with CDH. We hypothesized that LBW was associated with increased mortality, decreased extracorporeal life support (ECLS) utilization, and increased pulmonary morbidity in CDH patients. Methods Patients in the CDH Study Group from 2007 to 2018 were included. LBW was defined as <2.5 kg. Clinical characteristics and outcomes for LBW patients were compared to normal birthweight (NBW) patients using univariate and multivariable analyses. Results Of 5,586 patients, 1,157 (21%) were LBW. LBW infants had more congenital anomalies and larger diaphragmatic defects than NBW infants. ECLS utilization was decreased, and overall mortality was increased among LBW infants compared to NBW infants. A 1 kg increase in birthweight was associated with 34% higher odds of survival after repair (adjusted Odds Ratio 1.34, 95% CI 1.03–1.76; p = .03). LBW infants had longer durations of mechanical ventilation and were more likely to require supplemental oxygen at 30 days and at the time of discharge. Conclusion LBW is a risk factor for mortality and pulmonary morbidity in CDH. Prolonged oxygen requirement and increased length of stay are important considerations when managing this population.

Prenatal Imaging Features and Postnatal Factors Associated with Gastrointestinal Morbidity in Congenital Diaphragmatic Hernia

Background: To perform a comprehensive assessment of postnatal gastrointestinal (GI) morbidity and determine the prenatal imaging features and postnatal factors associated with its development in patients with congenital diaphragmatic hernia (CDH). Materials and Methods: A retrospective review was conducted of all infants evaluated for CDH at a quaternary fetal center from February 2004 to May 2017. Prenatal imaging features and postnatal variables were analyzed. GI morbidity was the primary outcome. The Mann-Whitney U test, the Kruskal-Wallis test with Dunnett’s T3 post hoc analysis and logistic regression, and the χ² test were performed when appropriate. Results: We evaluated 256 infants; 191 (75%) underwent CDH repair and had at least 6 months of follow-up. Of this cohort, 60% had gastroesophageal reflux disease (GERD), 13% had gastroparesis, 32% received a gastrostomy tube (G-tube), and 17% needed a fundoplication. Large defect, patch repair, extracorporeal membrane oxygenation (ECMO), and prolonged use of mechanical ventilation were significantly associated with having GERD, gastroparesis, G-tube placement, and fundoplication (p < 0.05). Fetuses with stomach grades 3 and 4 were most likely to have GERD, a G-tube, and a long-term need for supplemental nutrition than fetuses with stomach grades 1 and 2 (p < 0.05). Conclusion: Survivors of CDH with large defects, prolonged use of mechanical ventilation, or that have received ECMO may be at an increased risk for having GERD, gastroparesis, and major GI surgery. Marked stomach displacement on prenatal imaging is significantly associated with GI morbidity in left-sided CDH.

The proportion of alveolar type 1 cells decreases in murine hypoplastic congenital diaphragmatic hernia lungs.

BackgroundPulmonary hypoplasia, characterized by incomplete alveolar development, remains a major cause of mortality and morbidity in congenital diaphragmatic hernia. Recently demonstrated to differentiate from a common bipotent progenitor during development, the two cell types that line the alveoli type 1 and type 2 alveolar cells have shown to alter their relative ratio in congenital diaphragmatic hernia lungs.ObjectiveWe used the nitrofen/bisdiamine mouse model to induce congenital diaphragmatic hernia and accurately assess the status of alveolar epithelial cell differentiation in relation to the common bipotent progenitors.Study designPregnant Swiss mice were gavage-fed with nitrofen/bisdiamine or vehicle at embryonic day 8.5. The administered dose was optimized by assessing the survival, congenital diaphragmatic hernia and facial abnormality rates of the exposed mouse pups. NanoCT was performed on embryonic day 11.5 and 16.5 to assess the embryonic and early canalicular stages of lung development. At embryonic day 17.5 corresponding to late canalicular stage, congenital diaphragmatic hernia lungs were characterized by measuring the lung weight/body weight ratio, morphometry, epithelial cell marker gene expression levels and alveolar cell type quantification.ResultsNitrofen/bisdiamine associated congenital diaphragmatic hernia lungs showed delayed development, hypoplasia with morphologic immaturity and thickened alveolar walls. Expression levels of distal epithelial progenitor marker Id2 increased, alveolar type 1 cell markers Pdpn and Hopx decreased, while type 2 cell markers pro-SPC and Muc1 remained constant during the canalicular stage. The number of Pdpn+ type 1 alveolar cells also decreased in congenital diaphragmatic hernia lungs.ConclusionThe mouse nitrofen/bisdiamine model is a potential model allowing the study of congenital diaphragmatic hernia lung development from early stages using a wide array of methods. Based on this model, the alveolar epithelium showed a decrease in the number of alveolar type 1 cell in congenital diaphragmatic hernia lungs while type 2 cell population remains unchanged.

Lowest PaCO2 on the first day of life predicts mortality and morbidity among infants with congenital diaphragmatic hernia.

To evaluate the association between hypercarbia in the first 24 h of life and clinical outcomes in infants with congenital diaphragmatic hernia (CDH). Retrospective review of patients entered into the CDHSG registry between 2007-2014. Half of the identified patients were analyzed to identify the PaCO2 value most predictive of mortality. Prediction models for outcomes of death, ECMO, and respiratory support at 30 days of life (DOL) were developed using PaCO2. Remaining half of data was used for validation of study findings. 1878 and 1875 patients were analyzed in the testing and validation groups. Lowest PaCO2≥60 mmHg in the first DOL is highly predictive of death prior to discharge. Prediction models including this variable demonstrate good discrimination for outcomes of death, ECMO, and respiratory support (AUC 0.8808, 0.8279, 0.8065). Lowest PaCO2 in the first DOL is an independent risk factor of mortality and morbidity in CDH.

Long-term morbidity of congenital diaphragmatic hernia: A plea for standardization

Congenital diaphragmatic hernia (CDH) survivors present long-term morbidities in several systems, including the neurodevelopmental, gastrointestinal, pulmonary, and musculoskeletal ones, and CDH long-term sequelae are increasingly being recognized. Due to high co-morbidity, health related quality of life in a significant proportion of CDH patients might be compromised. As a consequence of consciousness on the long-term sequelae of CDH survivors, and their consequences for life, several follow-up programs were brought to life worldwide. In this review, we will summarize the long-term sequelae of CDH survivors, the impact of new treatments, and analyze the consistency of follow-up programs.

Antenatal assessment of liver position, rather than lung-to-head ratio (LHR) or observed/expected LHR, is predictive of outcome in fetuses with isolated left-sided congenital diaphragmatic hernia

Objectives: Respiratory morbidity in congenital diaphragmatic hernia (CDH) is associated with high mortality and adverse outcome. Accurate prenatal diagnosis is essential for prognosis and potential treatment in utero. The aim was to evaluate the prenatal ultrasound findings in assessing the respiratory prognosis in fetuses with isolated left-sided CDH.Methods: We retrospectively analyzed the medical records of 59 prenatally diagnosed left-sided CDH cases managed at a tertiary perinatal center.Results: Survival rate in the study group was 73% (43/59). We found no statistically significant relationship between survival and the presence of polyhydramnios, gestational age at diagnosis, lung-to-head ratio (LHR) and observed/expected LHR (O/E LHR) values, gestational age at birth and birth weight. Intrathoracic liver herniation was a statistically significant parameter adversely affecting survival (37.2% in survivors, 68.8% in non-survivors, p = 0.031) and logistic regression confirmed this relationship. The presence of pneumothorax and severe pulmonary hypertension were significantly associated with mortality (82% non-survivors versus 15% in survivors, p = 0.0001).Conclusion: Intrathoracic liver herniation seems to be a reliable parameter in the prediction of survival and neonatal respiratory morbidity in fetuses with isolated left-sided CDH. In contrast, we found no significant correlation between perinatal outcome and LHR, O/E LHR values, birth weight and gestational age.

A morphometric investigation of pulmonary sympathetic innervation in nitrofen-induced congenital diaphragmatic hernia rats

1) Abstract Pulmonary hypoplasia influences prognosis in congenital diaphragmatic hernia (CDH) . However the abnormality of pulmonary innervation is not clearly understood. We immunohistochemically examined the lungs of CDH model rats with special reference to sympathetic innervation. Pregnant rats were received nitrofen on gestational day 9 and the fetuses were recovered on gestational day 22. Control animals received only olive oil. Fetal lungs were dissected and the weight was measured. Whole mount sections at the level of main bronchus were immunostained using anti‑tyrosine hydroxylase (TH) antibody as a sympathetic marker. The proportion of area of TH‑immunoreactive nerve fi bers relative to the total lung area was calculated. The mean lung weight of CDH aff ected side was signifi cantly lower than that of ipsilateral side of controls. The percentage of TH‑positive area of CDH affected side was significantly lower than that of unaffected side. The reduction of pulmonary sympathetic innervation may play an important role in respiratory morbidity in CDH.

Hernie de coupole diaphragmatique : devenir à long terme

The increased survival rate reached in infants with congenital diaphragmatic hernia (CDH) has shown a concomitant increase in late morbidity. Many complications including pulmonary damage, cardiovascular disease, gastro-intestinal disease, failure to thrive, neurocognitive defects and musculoskeletal abnormalities have been described. Long-term pulmonary morbidity in CDH consists of obstructive and restrictive lung function impairments due to altered lung structure and prolonged ventilatory support. Long-term consequences of pulmonary hypertension are unknown. Gastro-esophageal reflux disease (GERD) is also an important contributor to overall morbidity. Failure to thrive may be caused by GERD, insufficient intake due to oral aversion and increased caloric requirements due to pulmonary morbidity. Neurological outcome is determined by an increased risk of perinatal and neonatal hypoxemia in the first days of life of CDH patients. Many studies have addressed the substantial impact of the health problems described above, on the overall well-being of CDH patients, but only a few studies focus on the health-related quality of life. Considering the scattered data indicating substantial morbidity in long-term survivors of CDH, follow-up studies that systematically assess long-term sequelae are needed. Based on such studies, a more focused approach for routine multidisciplinary follow-up programs could be established. It is the goal of the French Collaborative Network to promote exchange of knowledge, future research and development of treatment protocols.

Disruption of the Bone Morphogenetic Protein Receptor 2 Pathway in Nitrofen‐Induced Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia (CDH) remains a major therapeutic challenge despite advances in neonatal resuscitation and intensive care. The high mortality and morbidity in CDH has been attributed to pulmonary hypoplasia and persistent pulmonary hypertension (PH). Bone morphogenetic protein receptor 2 (BMPR2) plays a key role in pulmonary vasculogenesis during the late stages of fetal lung development. BMPR2 is essential for control of endothelial and smooth muscle cell proliferation. Dysfunction of BMPR2 and downstream signaling have been shown to disturb the crucial balance of proliferation of smooth muscle cells contributing to the pathogenesis of human and experimental PH. We designed this study to investigate the hypothesis that BMPR2 signaling is disrupted in nitrofen-induced CDH. Pregnant rats were treated with nitrofen or vehicle on gestational day 9 (D9). Fetuses were sacrificed on D21 and divided into CDH and control. Quantitative real-time polymerase chain reaction, Western blotting, and confocal-immunofluorescence were performed to determine pulmonary gene expression levels and protein expression of BMPR2 and related proteins. Pulmonary Bmpr2 gene expression levels were significantly decreased in nitrofen-induced CDH compared to controls. Western blotting and confocal microscopy revealed decreased pulmonary BMPR2 protein expression and increased activation of p38(MAPK) in CDH compared to controls. The observed disruption of the BMPR2 signaling pathway may lead to extensive vascular remodeling and contribute to PH in the nitrofen-induced CDH model. BMPR2 may therefore represent a potential target for the treatment of PH in CDH.

Fetal outcome of cases with diaphragmatic hernia

Objective: The aim of this study is to report the short-term morbidity of congenital diaphragmatic hernia at a tertiary referral center in Karachi, Pakistan.Methods: It is a retrospective cohort study of fetuses with congenital diaphragmatic hernia from January 2001 to December 2011. This includes all cases with prenatal diagnosis and those presenting in the postnatal period. This study analyses the survival of these cases and assesses the prognostic factors associated with the mortality of this condition.Results: During the 11 year study period, 65 cases of diaphragmatic hernia were identified. Among these, 41 cases were diagnosed in the antenatal period while the rest of the 24 presented in the postnatal period. Fifty-eight out of the 65 (89%) were born alive. Only 38% of these survived beyond 28 days of life. Factors like antenatal diagnosis and birthweight significantly influenced the outcome while mode of delivery, site of lesion and gestational age at delivery did not affect the prognosis.Conclusion: The overall mortality of congenital diaphragmatic hernia remains high. Survival rate of isolated hernia was substantially higher than those who had associated anomalies. The data from this study will provide the basis for counseling women in our setup.

Increased activation of NADPH oxidase 4 in the pulmonary vasculature in experimental diaphragmatic hernia

Persistent pulmonary hypertension remains a major cause of mortality and morbidity in congenital diaphragmatic hernia (CDH). NADPH oxidases (Nox) are the main source of superoxide production in vasculature. Nox4 is highly expressed in the smooth muscle and endothelial cells of the vascular wall and increased activity has been reported in the pulmonary vasculature of both experimental and human pulmonary hypertension. Peroxisome proliferator-activated receptor (PPARγ) is a key regulator of Nox4 expression. Targeted depletion of PPARγ results in pulmonary hypertension phenotype whereas activation of PPARγ attenuates pulmonary hypertension and reduces Nox4 production. The nitrofen-induced CDH model is an established model to study the pathogenesis of pulmonary hypertension in CDH. It has been previously reported that PPARγ-signaling is disrupted during late gestation and H(2)O(2) production is increased in nitrofen-induced CDH. We designed this study to investigate the hypothesis that Nox4 expression and activation is increased and vascular PPARγ is decreased in nitrofen-induced CDH. Pregnant rats were treated with either nitrofen or vehicle on gestational day 9 (D9). Fetuses were sacrificed on D21 and divided into control and CDH. RT-PCR, western blotting and confocal-immunofluorescence-double-staining were performed to determine pulmonary expression levels of PPARγ, Nox4 and Nox4-activation (p22(phox)). There was a marked increase in medial and adventitial thickness in pulmonary arteries of all sizes in CDH compared to controls. Pulmonary Nox4 levels were significantly increased whereas PPARγ levels were decreased in nitrofen-induced CDH compared to controls. Western blotting revealed increased pulmonary protein expression of the Nox4-activating subunit p22(phox) and decreased protein expression of PPARγ in CDH compared to controls. Confocal-microscopy confirmed markedly increased pulmonary expression of the Nox4 activating subunit p22(phox) accompanied by decreased perivascular PPARγ expression in lungs of nitrofen-exposed fetuses compared to controls. To our knowledge, the present study is the first to report increased Nox4 production in the pulmonary vasculature of nitrofen-induced CDH. Down-regulation of the PPARγ-signaling pathway may lead to increased superoxide production, resulting in pulmonary vascular dysfunction and contributing to pulmonary hypertension in the nitrofen-induced CDH model. PPARγ-activation inhibiting Nox4 production may therefore represent a potential therapeutic approach for the treatment of pulmonary hypertension in CDH.

Gene expression analysis in hypoplastic lungs in the nitrofen model of congenital diaphragmatic hernia

Background Pulmonary hypoplasia and persistent pulmonary hypertension are the main causes of mortality and morbidity in newborns with congenital diaphragmatic hernia (CDH). Nitrofen is well known to induce CDH and lung hypoplasia in a rat model, but the mechanism remains unknown. To increase the understanding of the underlying pathogenesis of CDH, we performed a global gene expression analysis using microarray technology. Methods Pregnant rats were given 100 mg nitrofen on gestational day 9.5 to create CDH. On day 21, fetuses after nitrofen administration and control fetuses were removed; and lungs were harvested. Global gene expression analysis was performed using Affymetrix Platform and the RAE 230 set arrays. For validation of microarray data, we performed real-time polymerase chain reaction and Western blot analysis. Results Significantly decreased genes after nitrofen administration included several growth factors and growth factors receptors involved in lung development, transcription factors, water and ion channels, and genes involved in angiogenesis and extracellular matrix. These results could be confirmed with real-time polymerase chain reaction and protein expression studies. Conclusions The pathogenesis of lung hypoplasia and CDH in the nitrofen model includes alteration at a molecular level of several pathways involved in lung development. The complexity of the nitrofen mechanism of action reminds of human CDH; and the picture is consistent with lung hypoplasia and vascular disease, both important contributors to the high mortality and morbidity in CDH. Increased understanding of the molecular mechanisms that control lung growth may be the key to develop novel therapeutic techniques to stimulate pre- and postnatal lung growth.

Bronchopulmonary innervation defects in infants and rats with congenital diaphragmatic hernia

Introduction Pulmonary morbidity in survivors of congenital diaphragmatic hernia (CDH) is caused by hypoplasia, barotraumas, or other reasons. We have previously shown deficient tracheal innervation in rats with CDH. Now we examine whether bronchopulmonary innervation is also abnormal in both infants and rats with CDH. Material and Methods Sections of E15, E18, and E21 rat lungs were immunostained for Protein gene product 9.5 and S100 antibodies. Similar immunostaining was performed on tissue from infants dying from CDH (n = 6) and other causes (n = 6) with Neurofilament, S100, and Rearranged during transfection antibodies. Nerve trunks/bronchus were counted, and the proportion of glial and RET-positive cells/bronchial surface was calculated. Glial cell-line derived neurotrophic factor protein and mRNA were measured in rat lungs. Results Nerve trunks/bronchus were decreased in infants and rat fetuses with CDH. In contrast, glial and RET-positive cells/bronchial surface were increased in infants and rats with CDH. Both lungs were equally affected. GDNF protein was high, whereas GDNF mRNA was decreased in preterm animals with CDH. Conclusions The lungs of infants and rats with CDH have decreased neural components compensated by increased supporting glial cells and persistence high expression of RET and GDNF protein. Because bronchopulmonary innervation controls airway smooth muscle, vessels, and glandular secretions, it is tempting to hypothesize that these deficiencies might play a role in respiratory morbidity in CDH.

The long-term follow-up of patients with a congenital diaphragmatic hernia: a broad spectrum of morbidity

Congenital diaphragmatic hernia (CDH) is a life-threatening anomaly with a mortality rate of approximately 40-50%, depending on case selection. It has been suggested that new therapeutic modalities such as nitric oxide (NO), high frequency oxygenation (HFO) and extracorporal membrane oxygenation (ECMO) might decrease mortality associated with pulmonary hypertension and the sequelae of artificial ventilation. When these new therapies indeed prove to be beneficial, a larger number of children with severe forms of CDH might survive, resulting in an increase of CDH-associated complications and/or consequences. In follow-up studies of infants born with CDH, many complications including pulmonary damage, cardiovascular disease, gastro-intestinal disease, failure to thrive, neurocognitive defects and musculoskeletal abnormalities have been described. Long-term pulmonary morbidity in CDH consists of obstructive and restrictive lung function impairments due to altered lung structure and prolonged ventilatory support. CDH has also been associated with persistent pulmonary vascular abnormalities, resulting in pulmonary hypertension in the neonatal period. Long-term consequences of pulmonary hypertension are unknown. Gastro-esophageal reflux disease (GERD) is also an important contributor to overall morbidity, although the underlying mechanism has not been fully understood yet. In adult CDH survivors incidence of esophagitis is high and even Barrett's esophagus may ensue. Yet, in many CDH patients a clinical history compatible with GERD seems to be lacking, which may result in missing patients with pathologic reflux disease. Prolonged unrecognized GERD may eventually result in failure to thrive. This has been found in many young CDH patients, which may also be caused by insufficient intake due to oral aversion and increased caloric requirements due to pulmonary morbidity. Neurological outcome is determined by an increased risk of perinatal and neonatal hypoxemia in the first days of life of CDH patients. In patients treated with ECMO, the incidence of neurological deficits is even higher, probably reflecting more severe hypoxemia and the risk of ECMO associated complications. Many studies have addressed the substantial impact of the health problems described above, on the overall well-being of CDH patients, but most of them concentrate on the first years after repair and only a few studies focus on the health-related quality of life in CDH patients. Considering the scattered data indicating substantial morbidity in long-term survivors of CDH, follow-up studies that systematically assess long-term sequelae are mandatory. Based on such studies a more focused approach for routine follow-up programs may be established.

The impact of strict infection control on survival rate of prenatally diagnosed isolated congenital diaphragmatic hernia

Although the prognosis of congenital diaphragmatic hernia (CDH) is determined by the degree of pulmonary hypoplasia, there may be an occult contribution of infection to outcomes. The purpose of this study is to evaluate the effects of our new supportive therapy to prevent infectious complications on mortality and morbidity of CDH. Among 57 cases with CDH treated between 2002 and 2007, 43 prenatally diagnosed isolated cases were enrolled in this study. All patients were managed by a lung-protective strategy and delayed surgery. Since January 2006, we have optimized our perioperative care to reduce infectious complications by using peripherally inserted central catheters and restriction of invasive procedures including extracorporeal membranous oxygenation (ECMO). The survival rate, intubation period, maximum serum C-reactive protein (CRP) level, and complications were compared before and after the introduction of refined supportive therapy. There were 25 cases (12 liver-up, 13 liver-down) treated before 2006 and 18 cases (8 liver-up, 10 liver-down) after 2006. ECMO was required for stabilization in five cases before 2006. The survival rates of total, liver-up, and liver-down cases improved from 60, 42, 77, to 83, 63, 100% after 2006, respectively. The intubation period was shortened from 37.8 +/- 24.3 to 22.2 +/- 10.8 days, and the maximum serum CRP level declined from 12.8 +/- 11.5 to 2.2 +/- 1.6 mg/dl after 2006. Nine cases developed sepsis before 2006 whereas no patients suffered from sepsis or pneumonia after 2006. The new supportive therapy with strict infection control improved survival rate of prenatally diagnosed CDH without using ECMO.

Lung Morphology After Late Fetal Tracheal Ligation in Rats

Pulmonary hypoplasia and persistent pulmonary hypertension are the main causes of mortality and morbidity in congenital diaphragmatic hernia (CDH). Prenatal tracheal occlusion accelerates lung growth, but the mechanism remains unknown. In order to be able to establish the accuracy of our experimental model for further molecular biological examinations, we evaluated the histologic structure of 1. fetal lungs subjected to tracheal occlusion compared to 2. normal fetal lungs, 3. hypoplastic lungs in CDH, and 4. normal neonatal lungs. One group of Sprague-Dawley rat fetuses were subjected to intrauterine tracheal ligation (TL) on gestational day 19 (n = 7). Control fetuses were obtained from the same litters as those subjected to TL (n = 8). Another group of pregnant Sprague-Dawley rats were given 100 mg nitrofen on gestational day 9.5 to create CDH (n = 8). All fetuses were delivered by cesarean section on day 21. Lungs from 1-day-old, healthy, non-operated, newborn Sprague-Dawley rats were also examined (n = 6). Lung weight to body weight ratio was significantly higher in the TL lungs (5.0 +/- 0.36 %), compared to control lungs (2.8 +/- 0.15 %), CDH lungs (1.9 +/- 0.12 %), and normal neonatal lungs (4.2 +/- 0.18 %). Volume density of alveolar air space and radial alveolar count (RAC) in TL lungs (52 +/- 1.4 %) (3.3 +/- 0.25) were significantly higher than in control lungs (34 +/- 3.4 %) (2.2 +/- 0.17) and in CDH lungs (16 +/- 1.7 %) (1.7 +/- 0.07). No significant differences were found between the TL and the normal neonatal group (59 +/- 1.4 %) (3.6 +/- 0.11). Fetal lungs after TL showed evidence of growth stimulation with increased volume density of alveolar air space and increased RAC, comparable to findings in normal neonatal lungs.