Embryology of congenital diaphragmatic hernia

It is still generally believed that the defect in congenital diaphragmatic hernia results from failure of the so-called pleuroperitoneal canals (PPCs) to close at the end of the embryonic period (8th gestational week). Furthermore, it is assumed that gut could enter the thoracic cavity through this defect, causing compression and finally hypoplasia of the lung. However, this sequence of embryological events has never been studied, and many details even of normal diaphragmatic development are still unknown. Using scanning electron microscopy and a new animal model of congenital diaphragmatic hernia (CDH), the nitrofen rat model, the normal embryology of the diaphragm was reinvestigated and, for the first time, the crucial developmental steps of congenital diaphragmatic hernia formation were studied. The basic results were: (1) In normal development, the PPCs are never wide enough to allow herniation of gut loops. (2) The formation of the defect happens in an early embryonic period. (3) The early ingrowth of liver through the defect is of major importance for the formation of CDH. In another set of experiments, the nitrofen rat model of congenital diaphragmatic hernias was used to study the cellular mechanisms involved during epithelial and mesenchymal growth and differentiation in normal and in abnormal lungs. These results, combined with selected culture techniques (eg, branching morphogenesis and epithelio-mesenchymal interaction) probably open new ways to a better understanding of the mechanisms that finally lead to an abnormal lung in CDH.     

Prediction of outcome in congenital diaphragmatic hernia

The case records of 59 patients with congenital diaphragmatic hernia (CDH) who presented between 1984 and 1997 were studied retrospectively. Included in the study were infants born with CDH who required respiratory support within the first 6 h of life. Twenty-three were excluded from the study for various reasons; 36 were enrolled in the study; the male-to-female ratio was 18:18. Twenty-nine hernias were left-sided and 7 were right-sided. All patients were ventilated using conventional techniques. Arterial blood gases were measured on average 1.76 h following admission and the initial period of resuscitation (range 1-4 h). Three formulae were applied in an attempt to predict outcome: ventilation index against PCO2, alveolar-arterial oxygen gradient, and a newly derived formula from this institution (Red Cross formula) that comprises respiratory rate x PCO2 x FiO2 x mean airway pressure/PaO2 x 6000. Seventeen patients (47.2%) survived and 19 died (52.8%); 21 became stable enough to undergo surgery. The average time from presentation until surgery was 1.98 days (range 6 h to 4 days). The Red Cross formula, with a 100% predictive value for mortality, 85% predictive value for survival, and an overall predictive value of 91.6%, appeared to be superior to the other formulae studied. The availability of a highly accurate predictive formula may facilitate management of this frequently lethal disease.     

Contemporary controversies in the management of congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) has remained the most frustrating of the major birth defects to manage successfully. Despite the earlier detection of severe diaphragmatic defects by prenatal ultrasound, and the early recognition of CDH as a cause for respiratory distress presenting at birth, current mortality has improved little from the original series presented in 1940 by Ladd and Gross. This article discusses the difficulty in defining population with congenital diaphragmatic hernia, current controversies in the medical and surgical management of these patients, appropriate timing and usage of ECMO, a review of current, experimental therapies, and short-term and long-term outcomes of these patients.     

Improved survival in congenital diaphragmatic hernia with evolving therapeutic strategies

OBJECTIVE: To compare the survival rates for 3 therapeutic eras, each using different treatment strategies for the management of newborns with congenital diaphragmatic hernia (CDH). DESIGN: Retrospective review of all infants with CDH from 1970 through 1997. SETTING: Tertiary care children's hospital. PARTICIPANTS: A total of 203 newborns with CDH. INTERVENTIONS: Extracorporeal membrane oxygenation (ECMO) was performed with arterial and venous cannulation connected to a membrane oxygenatorroller pump perfusion apparatus, using systemic heparinization. Delayed operative therapy involved operative repair 2 to 5 days after birth using preoperative ventilation support only. Since 1970, 203 newborns with CDH were managed in 3 therapeutic eras: era 1 (1970-1983, 102 patients) was immediate CDH repair with postoperative ventilator and pharmacologic support; era 2 (1984-1988, 45 patients) was immediate repair with postoperative ventilator support (18 patients), immediate ECMO with CDH repair on ECMO (4 patients), or immediate repair with postoperative ECMO (23 patients); and era 3 (1989-1997, 56 patients) was immediate ECMO with repair on ECMO (23 patients), immediate repair with postoperative ECMO (9 patients), or delayed (2-5 days) CDH repair (24 patients). MAIN OUTCOME MEASURES: Survival, defined as discharge from the hospital, and morbidity. RESULTS: Survival was 42% (43/102 patients) in era 1, 58% (26/45 patients) in era 2, and 79% (44/56 patients) in era 3 (P<.02 vs eras 1 and 2). In era 3, the survival for immediate ECMO with repair on ECMO was 57% (13/23 patients), 89% (8/9 patients) for immediate repair with postoperative ECMO, and 96% (23/24 patients) for delayed repair. Eight late deaths were caused by pulmonary hypertension (1 death), sudden infant death syndrome (1 death), and other causes (6 deaths). Morbidity in survivors included mild neurologic deficit (5 patients) and pulmonary disease (3 patients). CONCLUSION: These data demonstrate a significant improvement in survival in CDH with preoperative ECMO and with delayed repair with and without ECMO support and suggest that immediate repair of CDH without the availability of ECMO support should be abandoned.     

Two cases of the congenital posterolateral diaphragmatic hernia were reported

Case 1, a 9-year-old woman, was admitted to our hospital because of nausea, vomiting, and epigastralgia. Diagnosis of Bochdalek hernia was made by the unusual course of naso-gastric tube. At surgery through the left posterorateral thoracotomy, the herniation of the stomach, small intestine, and colon to the thoracic cavity through the dorsolateral defect of the diaphragm were revealed. Case 2, a 35-year-old man, was admitted to our hospital because of dyspnea. Similar diagnosis was made by the examination of upper G1 series and barium enema, which demonstrated the presence of multiple loops of the small intestine and colon in the left thoracic cavity. Their postoperative courses were uneventful. Most of Bochdalek hernia is observed in infancy, and adolescent or adult case is is rarely reported (approximately 10% of all cases). Since this often misdiagnosed as pleuritis or pulmonary tuberculosis, a cautious examination is necessary for the establishment of the correct diagnosis.     

Management of congenital diaphragmatic hernia diagnosed prenatally: an update

EBV-associated lymphoproliferative disorder (LPD) is a rare but serious complication in marrow transplant recipients. A 31-year-old Japanese woman in the second chronic phase of CML received an allogeneic BMT from her HLA 2-locus-incompatible 62-year-old father. Around day +200, she developed EBV-LPD of the right parieto-temporal lobe which caused slowly progressive left hemiparesis. Two courses of donor lymphocyte transfusions (DLT) of 10(6)CD3+ T cells/kg of body weight failed to suppress her central nervous system (CNS) EBV-LPD. The patient died of recurrent blastic crisis of CML. This case suggests that DLT may be ineffective for the treatment of CNS EBV-LPD.     

Pulmonary artery structural changes in pulmonary hypertension complicating congenital diaphragmatic hernia

Primary pulmonary hypertension is characterized by the presence of smooth muscle cells in nonmuscular compartments or segments of the vessel and the abnormal deposition of collagen in both the small muscular arteries and arterioles and the large elastic arteries. Victorian blue van Gieson staining and Immunostaining with anti-alpha smooth muscle actin (ASMA) were performed on lung tissues obtained during autopsy from 21 patients who had congenital diaphragmatic hernia (CDH) complicated by persistent pulmonary hypertension (PPH) and 10 control patients who died of sudden infant death syndrome (SIDS). The degree of medial thickening and adventitial thickening was measured in pulmonary arteries by image analysis and compared statistically. There was a significant increase in adventitial as well as medial thickness in arteries of all sizes in CDH patients compared with control patients (P < .001). The most striking increase occurred in arteries with an external diameter (ED) of less than 75 microns. Calculation of the areas of the various components in the wall of each vessel showed that for smaller vessels (< 75 microns ED), the area of the lumen was smaller and the area of the media and adventitia was larger in CDH patients compared with control patients (P < < .001). In vessels greater than 75 microns ED, the areas of media in CDH was the same as in controls and the area of adventitia in CDH was significantly larger than controls (P < .001). The present study provides evidence that an increase in adventitial thickness and adventitial area occurs in pulmonary arteries in CDH patients complicated by PPH. The structural changes in the adventitia of the pulmonary arteries may be an important factor in the development of PPH in patients with CDH.     

Patterns of fetal perinasal fluid flow in cases of congenital diaphragmatic hernia

OBJECTIVE(S): Our purpose was to expand the previous reported series of observations of fetal perinasal fluid flow in cases of antenatally diagnosed congenital diaphragmatic hernia, characterize the timing parameters of the fetal breath cycle, and define the relationship of fetal perinasal fluid flow and the diaphragmatic component of fetal breathing movements. Our hypothesis was that characteristics of diaphragm-related and nondiaphragm-related perinasal fluid flow and other breath cycle characteristics differ in cases of congenital diaphragmatic hernia compared with controls. STUDY DESIGN: Fetal perinasal fluid flow velocity and fetal chest wall movements were studied in 24 cases of uncomplicated pregnancy, and flow was studied in 24 cases of antenatally diagnosed congenital diaphragmatic hernia at gestational ages ranging from 30 to 41 weeks. The examination of fetal perinasal fluid flow velocity was performed with use of an ultrasonography system applying color flow and spectral Doppler analysis. Breath-to-breath interval, time of inspiration, time of expiration, and peak inspiratory and expiratory velocities were determined for each type of perinasal flow. RESULTS: The study revealed that the time of expiration in cases of congenital diaphragmatic hernia at 30 to 36 and 37 to 41 weeks of gestation was significantly shorter than in cases of uncomplicated pregnancy. The ratio of time of inspiration and breath-to-breath interval in cases of diaphragmatic hernia was approximately 30% higher (p = 0.001) at 30 to 36 weeks of gestation than in cases of uncomplicated pregnancy. The study also showed that in cases of congenital diaphragmatic hernia the expiratory peak velocity ratio at 30 to 36 weeks of gestation was significantly lower than in cases of uncomplicated pregnancy. CONCLUSIONS: We conclude that by Doppler ultrasonography measurements of fetal perinasal fluid flow, in cases of congenital diaphragmatic hernia, we can evaluate the timing parameters of fetal diaphragm-related breath cycles, the relationship of intraalveolar and intraamniotic pressures, and fetal upper respiratory tract resistance. Fetuses with diaphragmatic hernia spent significantly more time with diaphragm-nonrelated perinasal flow than did fetuses in cases of uncomplicated pregnancy, which can cause the increased loss of lung liquid and consequently be associated with pulmonary insufficiency in the early neonatal period.     

Prediction of morbidity during infancy after repair of congenital diaphragmatic hernia

Recent studies have suggested there may be a high incidence of pulmonary and extrapulmonary sequelae among infants who have undergone repair of congenital diaphragmatic hernia (CDH). The aim of this study was to identify factors that predict high-risk cases to facilitate counseling of parents. Morbidity, defined as conditions requiring treatment and/or hospitalization during follow-up, was documented. Only five of 15 cases that had been diagnosed antenatally (at 16 to 26 weeks' gestation) and underwent surgical repair after preoperative stabilization were without morbidity at the time of follow-up. Respiratory problems were identified in seven (chylothorax in 3, recurrent infections in 4) and failure to thrive in four; three infants required further gastrointestinal surgery. A comparison of infants with and without morbidity showed that the only significant difference between the groups was in the duration of respiratory support. A requirement for respiratory support for more than 10 days had 90% sensitivity, 100% specificity, and a positive predictive value for morbidity at follow-up of 100%.     

Epidemiology of congenital diaphragmatic hernia, Hawaii, 1987-1996

Congenital diaphragmatic hernias (CDHs) in Hawaii between 1987 and 1996 were examined with data from a birth defects surveillance system. There were 51 cases of CDH (prevalence 2.45 per 10,000 births). Forty-nine percent of livebirths survived, an increase over the rate reported in Hawaii in 1975-1982. These results are similar to those reported by other population-based studies.     

Epidemiological studies on 321 children with congenital diaphragmatic hernia in China]

Perinatal babies delivered in hospitals with gestation of 28 weeks to seven days after birth were monitored by National Birth Defects Monitoring Network from September 1986 to December 1993 to study the prevalence of congenital diaphragmatic hernia in China and the risk factors contributing to their prognosis. Results showed that 321 cases of congenital diaphragmatic hernia in 4,777,220 perinatal babies were detected with an incidence of 0.7 per ten thousand, a case-fatality ratio of 84.1 percent and, fetal death and stillbirth accounting for 28.1 percent of the total perinatal deaths. There was significant difference in birth weight between perinatal deaths and survival perinatal. And, 54.4 percent of the cases complicated with other congenital deformities and severe deformities in heart, lung and central nervous system accounted for the most proportion of them, which were the most important factors contributing to death. A case-fatality ratio of cases with single malformation was 74.7 percent and that of those with multiple malformation 92 percent, with a statistically significant difference. The cases diagnosed antenatally accounted for 11.3 percent of the total, and multiple malformation accounted for a large proportion of them. It indicated that proportion of antenatal diagnosis for congenital diaphragmatic hernia deformity was lower, and their perinatal case-fatality ratio was higher and their prognosis worse.     

Hypoxic pulmonary vasoconstriction is impaired in rats with nitrofen-induced congenital diaphragmatic hernia

The aim of this study was to determine the efficacy and toxicity of topotecan administered as a 21-day continuous intravenous infusion in patients with advanced or metastatic adenocarcinoma of the pancreas. 26 previously untreated patients with advanced or metastatic pancreatic adenocarcinoma received topotecan at a dose of 0.5 mg/m2/day or 0.6 mg/m2/day as a continuous intravenous infusion for 21 days. Courses were repeated every 28 days. 26 patients were assessable for response and toxicity on an intent-to-treat basis. The initial 8 patients at a starting dose of 0.6 mg/m2/day experienced unacceptable myelosuppression and dose delays. The subsequent 18 patients, therefore began therapy at a dose of 0.5 mg/m2/day. The major toxicity of topotecan at this dose and schedule was myelosuppression, which was reversible and non-cumulative. There were no complete responses and two partial responses for a total response rate of 8% (95% confidence interval, 1-25%). Response durations were 17 and 45 weeks. Stable disease was seen in 3 patients. The median time to progression for all patients was 8 weeks and the median survival was 20 weeks. Topotecan given as a 21-day continuous intravenous infusion has a similar response rate and median survival to our previously reported study of the 5-day short infusion regimen in pancreatic carcinoma.     

Airway muscle in infants with congenital diaphragmatic hernia: response to treatment

BACKGROUND/PURPOSE: Airway muscle hyperactivity and chronic lung disease frequently follow congenital diaphragmatic hernia (CDH) treatment. The aim of this study was to compare the quantity of airway muscle and alveolar ductal artery muscle in CDH infants after various treatments. METHODS: Five groups were studied postmortem: CDH, died within 24 hours, without high ventilatory assistance (n = 3); CDH, various extracorporeal membrane oxgenation (ECMO) durations, without high ventilatory assistance (n = 4); CDH, various ECMO durations, with high ventilatory assistance (n = 7); no CDH, without high ventilatory assistance (n = 12); and no CDH, with high ventilatory assistance and bronchopulmonary dysplasia (BPD) (n = 5). Sections from standardized fixed lungs were immunohistochemically stained for alpha-smooth muscle actin. Muscle surrounding conducting airways from small preterminal bronchioles to bronchi was quantitated in both the ipsilateral and contralateral lungs with computerized image analysis. Similarly, muscle mass was quantitated in alveolar ductal arteries. RESULTS: CDH infants with low ventilatory assistance, regardless of postnatal age, had the same quantity of airway muscle as low ventilatory assistance controls. Infants with CDH and prolonged high ventilatory assistance had significantly more muscle throughout the conducting airways, similar to BPD infants without CDH, even though the CDH infants had significantly less exposure to high ventilatory assistance. With both low and high ventilatory assistance, the quantity of muscle in both the ipsilateral and contralateral lungs was similar. In contrast, small acinar arteries in CDH infants have increased muscle mass at birth. This muscle is decreased by ECMO but persists in CDH infants with high ventilatory assistance. CONCLUSIONS: The authors show that postnatally, CDH infants acquire increased muscle quantity throughout the conducting airways, in both the ipsilateral and contralateral lungs, with relatively short exposure to high ventilatory assistance. The normal decrease in acinar arterial mass that occurs postnatally is delayed in CDH infants with high ventilatory assistance.     

Tracheal ligation: the dark side of in utero congenital diaphragmatic hernia treatment

This retrospective study investigates the clinical characteristics of gestational diabetes mellitus (GDM) (time of diagnosis, different treatment, metabolic parameters, etc.) in relation to prepregnancy body mass index (BMI) and the influence of BMI on neonatal outcome. 93 GDM women and 110 control subjects were divided into three groups in relation to their prepregnancy BMI: normalweight (Nw), overweight (Ow) and obese (Ob). GDM was diagnosed significantly (p < 0.01) earlier in Ow and Ob than in Nw. Preterm deliveries and cesarean sections resulted significantly (p < 0.01) increased in all BMI categories of GDM respect to matched controls. Prevalence of neonatal macrosomia was higher in GDM patients (44.6%) compared with normal controls (15.4%) and correlated (p < 0.01) with prepregnancy BMI in both groups. Nevertheless in each BMI category the prevalence of macrosomia was significantly higher in GDM patients. The body weight increase during pregnancy was not associated with neonatal macrosomia. This study shows that prepregnancy BMI is an important risk factor for GDM and is predictive for macrosomia specially in women suffering from GDM.     

Effect of dexamethasone on endothelial nitric oxide synthase in experimental congenital diaphragmatic hernia

AIMS: To study the effect of prenatal glucocorticoid treatment on endothelial nitric oxide synthase (eNOS) expression in rats with congenital diaphragmatic hernia (CDH). METHODS: CDH was induced in fetal rats by the maternal administration of nitrofen on day 9.5 of gestation. Dexamethasone was administered on days 18.5 and 19.5 before delivery of the fetuses on days 20.5 and 21.5. Pulmonary eNOS protein expression was studied by western immunoblotting and immunohistochemistry. RESULTS: On day 20.5, eNOS expression was significantly reduced in CDH pups compared with normal control rats. Dexamethasone treated CDH pups had eNOS concentrations equivalent to those of normal animals. By day 21.5, however, there was no detectable difference in eNOS expression between the experimental groups. CONCLUSIONS: eNOS is deficient in near term (day 20.5) CDH rats. Dexamethasone restores eNOS expression in these animals to that seen in normal rat lungs. At term, the precise role of eNOS in the pathophysiology of CDH remains uncertain.