Cases Of Congenital Diaphragmatic Hernia Research Articles

Variants in GATA4 are a rare cause of familial and sporadic congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is characterized by incomplete formation of the diaphragm occurring as either an isolated defect or in association with other anomalies. Genetic factors including aneuploidies and copy number variants are important in the pathogenesis of many cases of CDH, but few single genes have been definitively implicated in human CDH. In this study, we used whole exome sequencing (WES) to identify a paternally inherited novel missense GATA4 variant (c.754C>T; p.R252W) in a familial case of CDH with incomplete penetrance. Phenotypic characterization of the family included magnetic resonance imaging of the chest and abdomen demonstrating asymptomatic defects in the diaphragm in the two "unaffected" missense variant carriers. Screening 96 additional CDH patients identified a de novo heterozygous GATA4 variant (c.848G>A; p.R283H) in a non-isolated CDH patient. In summary, GATA4 is implicated in both familial and sporadic CDH, and our data suggests that WES may be a powerful tool to discover rare variants for CDH.

1707 Rate and Management Pattern of Congenital Diaphragmatic Hernia at Maternity Hospital, Kuwait

Introduction & Objectives:Congenital diaphragmatic hernia (CDH) occurs in around 1 in 2000 live births and associated with high mortality rate reaching up to 50%, even with prenatal diagnosis and recently...

613 Congenital Diaphragmatic Hernia Surveillance in Ireland

IntroductionThe incidence of Congenital Diaphragmatic Hernia (CDH) varies from 1 in 2,000 to 15,000 births per annum. Due to the legislation prohibiting termination of any pregnancy in the Republic of...

Hernia diafragmática congénita: criterios pronósticos y estado actual del tratamiento prenatal. Guía clínica

Congenital diaphragmatic hernia (CDH) is a severe congenital birth defect, which is commonly associated with genetic abnormalities and malformations in other systems. Once the diagnosis is made, there should be a thorough evaluation to confirm that the malformation is isolated, as well as an assessment of prognostic factors, essentially lung size and liver herniation. With these parameters an individualized and relatively accurate prognosis can be offered to parents. Management options include termination of pregnancy, conservative prenatal management and post-natal treatment, or fetal therapy. Fetal therapy consists of fetal endoscopic tracheal occlusion (FETO) and is offered in a small number of centers worldwide. Available evidence suggests that prenatal treatment might increase the chances of survival by 35-40% compared with baseline survival. Several randomized trials are now underway to assess the impact of therapy on very severe and moderate cases of CDH.

Right Sided Congenital Diaphragmatic Hernia-A Case Report with a Brief Review

Congenital diaphragmatic hernia occurs in 1 in 2000-4000 live births and accounts for 8% of all major congenital anomalies. Congenital diaphragmatic hernia (CDH) is a major surgical emergency in newborns because the key to survival depends on the prompt diagnosis and treatment. We are presenting here one such congenital diaphragmatic hernia. In North Bengal Medical College a fullterm female baby was delivered with respiratory distress, scaphoid abdomen and cyanosis. Immediately chest X-ray and CT scan of thorax and abdomen was done to assess symptomatically and clinically suspected case of congenital diaphragmatic hernia. It was a case of right sided congenital diaphragmatic hernia. The presented case report might help us to remain conscious about such congenital anomaly in a case of respiratory distress and help us to chalk out the immediate measurements accordingly to save lives of those unfortunate newborns.

Does the ex utero intrapartum treatment to extracorporeal membrane oxygenation procedure change outcomes for high-risk patients with congenital diaphragmatic hernia?

PurposeIn the most severe cases of congenital diaphragmatic hernia (CDH), significant barotrauma or death can occur before advanced therapies such as extracorporeal membrane oxygenation (ECMO) can be initiated. We have previously examined the use of the ex utero intrapartum treatment (EXIT) to ECMO procedure (EXIT with placement on ECMO) in high-risk infants and reported a survival advantage. We report our experience with EXIT to ECMO in a more recent cohort of our patients with most severe CDH. MethodsEvery patient with less than 15% predicted lung volume during January 2005 to December 2010 was included. We obtained data on prenatal imaging, size and location of the defect, and survival. ResultsSeventeen high-risk infants were identified. All 17 (100%) received ECMO and required a patch. Six children were delivered by EXIT to ECMO, and only 2 (33%) survived. An additional patient was delivered by EXIT to intubation with ECMO on standby and died. Of the 10 children who did not receive EXIT, 5 (50%) survived. ConclusionsNo clear survival benefit with the use of the EXIT to ECMO procedure was demonstrated in this updated report of our high-risk CDH population. The general application of EXIT to ECMO for CDH is not supported by our results.

A case of a patient who experienced diaphragmatic hernia after repair of inguinal hernia

To the Editor: Diaphragmatic hernia commonly occurs at birth, and the reported incidence is 1 per 2,000 live births [1]. We encountered a patient who experienced diaphragmatic hernia that was not detected at birth but after repair of an inguinal hernia. The patient was a 4-month-old female infant measuring 43.9 cm and weighing 2.4 kg who had been delivered by cesarean section at 23 weeks and 6 days, with a birth weight of 642 g. Respiratory care was provided from immediately after birth. No congenital abnormalities were observed, except for an inguinal hernia containing the prolapsed left ovary. The tracheal tube was removed at 56 days of life, and oxygen supplementation was continued thereafter until 120 days of life. At 130 days after birth (corrected age, 42 weeks and 3 days), definitive left inguinal herniorrhaphy was planned. An ilioinguinal nerveiliohypogastric nerve block was given in addition to general anesthesia for the surgery. The surgery time was 30 min and the anesthesia time 87 min. No specific problems were detected in the postoperative X-ray after the surgery (Fig. 1a). On postoperative day 4, the infant suddenly experienced cyanosis and rapid respiration with a decrease of the oxygen saturation. Chest X-ray showed a left diaphragmatic hernia, seemingly a prolapsed colon (Fig. 1b). Tracheal intubation was performed followed by mechanical ventilation, and repair of the diaphragmatic hernia was performed. General anesthesia was induced and maintained with midazolam, fentanyl, vecuronium, and remifentanil. The surgery time was 93 min, and the anesthesia time 122 min. The postoperative course was uneventful, and the tracheal tube was removed on day 3 after the diaphragmatic hernia repair. Diaphragmatic hernia normally develops at birth from respiratory failure and abdominal retraction. As a consequence of elective treatment instituted during infancy itself, the mortality rate has decreased [1]. Fetal age at the time of development of the diaphragmatic hernia determines the degree of hypoplasia of the lung. Among cases of congenital diaphragmatic hernia (CDH), the reported incidence of diaphragmatic hernia appearing after birth is 3 %, and in 80 % of these cases, it appears as a complication of cardiac anomalies before 1 month of age [2]. CDH developing within 1 year of birth is more common on the right side and is often chronic in onset. The younger infants present with more respiratory symptoms than gastrointestinal symptoms, and the symptoms are often acute in onset [2–4]. CDH develops after thoracic surgery in some cases [5]. There is a possibility of defects in the diaphragm appearing spontaneously [2]. As the present case was an extremely low-birth-weight infant with a corrected age of 42 weeks and 3 days; although she was 130 days old, there is a possibility that this could have predisposed to anatomical weakness or a preexisting hole in the diaphragm. It is thought that a lower corrected age at the time of surgery may be associated with a higher risk of occurrence of diaphragmatic Y. Osaka (&) N. Shimada M. Satou T. Masuda T. Ando Y. Kozono M. Shimada Department of Anesthesiology, Tokyo Metropolitan Ohtsuka Hospital, 2-8-1 Minami-Ohtsuka, Toshima-ku, Tokyo 170-8476, Japan e-mail: bluesapphire1226@gmail.com

Outcomes of congenital diaphragmatic hernia: a 12‐year experience

To determine outcomes for babies with congenital diaphragmatic hernia (CDH) diagnosed prenatally and postnatally presenting to a tertiary unit. Fetal medicine database and neonatal surgical unit admission books were reviewed to identify cases of CDH over a 12-year period (Jan 1998- Dec 2009). A total of 132 cases of CDH were diagnosed prenatally and 39 cases diagnosed postnatally. Mean gestation at diagnosis was 22 weeks (range 13-37 weeks). Karyotyping was abnormal in 15.9%; abnormal karyotype in 3.6% of fetuses without other structural anomalies compared with 38.9% when other anomalies were identified. In 45 cases (34.1%) pregnancy was terminated. Two stillbirths occurred (2.3% of ongoing pregnancies). One hundred twenty-four babies were live born, of whom 98 babies underwent surgery. Survival to discharge of all live born babies was 72.6%; survival following surgery was 91.8%. Birthweight had a significant effect on survival (odds ratio 0.22, 95% confidence intervals 0.08-0.66). Survival for live born babies prenatally diagnosed was significantly lower (65.9%) than those diagnosed postnatally (92.3%). Abnormal karyotype was more common when CDH was associated with other anomalies. In multivariate analysis, lower birthweight and prenatal diagnosis had a significant impact on survival. Only prenatally diagnosed CDH survival figures should be utilised in prenatal counselling.

Patch repair for congenital diaphragmatic hernia: is it really a problem?

BackgroundLarge congenital diaphragmatic hernia (CDH) defects often require the use of synthetic patches for tension-free repair. Although high rates of recurrence and other morbidities have been previously reported, our favorable perception of patch repair prompted this review. MethodsA single-center retrospective chart review of CDH cases repaired between January 1, 1999, and October 1, 2010. Patch repairs were performed by multiple surgeons with an effort to construct a tension-free dome-shaped patch. ResultsOne hundred eighty-four children underwent CDH repair of whom 99 (53.8%) required a patch. Seventy-four (74.7%) of the 99 patients who underwent patch repair survived to discharge and were compared with 75 primary repair survivors. Of those undergoing patch repair, 88% were prenatally diagnosed, 55% had liver herniation, and 22 (29.9%) were repaired on extracorporeal membrane oxygenation. Two patients experienced a recurrence after a patch repair and 3 after a primary repair for a rate of 5.4% and 4.0%, respectively (P = 1.0). ConclusionsThese results demonstrate that synthetic patch repair for CDH can be performed with a very low rate of recurrence challenging the need for alternative approaches to diaphragmatic replacement. High rates of recurrence reported for patch repair may be technical rather than intrinsic to the patch.

Outcome in fetuses with isolated congenital diaphragmatic hernia with increased nuchal translucency thickness in first trimester

To examine the possible association between increased nuchal translucency (NT) thickness in the first trimester and perinatal outcome in isolated congenital diaphragmatic hernia (CDH). We conducted a retrospective study between January 2004 and June 2010. The database was searched to identify all consecutive cases of CDH referred to the fetal medicine center of Necker Hospital in Paris. Enlarged NT was defined above the 95th centile. Only children born alive with an isolated CDH were selected for the analysis of prognostic factors. We also studied the correlation between NT thickness in the first trimester and lung-to-head ratio, observed to expected lung area-to-head ratio, lung volume estimated by magnetic resonance imaging, and other prenatal features of intrathoracic compression. Seventy-one cases of isolated CDH were available. The fetal NT was above the 95th centile in 9 of the 71 cases. Neonatal death occurred in 7/9 (78%) cases with enlarged NT, compared with 24/62 (38%) with normal NT (P = 0.035). Enlarged NT was significantly associated with prenatal features of intrathoracic compression. Enlarged NT thickness in CDH is associated with a poor outcome and is related to an early intrathoracic compression.

Congenital Diaphragmatic Hernia in a Fetus with a De novo Terminal Deletion of Chromosome 15q26.1

De novo terminal deletions of chromosome 15q26.1 are rare occurrences. Deletions of this region have been previously linked to congenital diaphragmatic hernia (CDH) as well as congenital malformations and developmental delay. This article presents a prenatal case of this de novo terminal deletion, detected by cytogenetic analysis and confirmed by fluorescence in situ hybridization (FISH), in a fetus with CDH and intrauterine growth restriction (IUGR). Genetic evaluation of pre- and postnatal cases of CDH should include at least a close examination of the terminal region of chromosome 15q26. As with any de novo substantial loss of genetic material, the prognosis is likely to include additional neurologic impairment and other congenital malformations in comparison to CDH patients without genomic alterations.

Severe Iron Deficiency Anemia due to late Presentation of Congenital Diaphragmatic Hernia in a Toddler

To the Editor, A 3-year-old female toddler was referred to our pediatric emergency unit with a 2-week history of fatigue, anorexia, progressive pallor, and vomiting. Medical history showed that iron deficiency anemia was diagnosed one year before and oral iron-sulfate was given. She also had a one year history of intermittent vomiting. Her diet seemed adequate in iron-rich foods. Chest X-ray and abdominal ultrasonographic examination performed in a medical center were normal. Complete blood count findings were as follows: Hb: 1.7 g/dL; WBC count: 8.0 x 109/L; ANC: 4.6 x 109/L; Hct: 6.9%; RBC count: 1.19 x 1012/L; RDW: 20.5; MCV: 58 fL; Plt count: 485 x 109/L; absolute reticulocyte count: 45.5 x 109/L (normal: 50-150 x 109/L). Peripheral blood smear showed hypochromic microcytic red cells, polychromasia, and nucleated red cells. Serum iron was 5 μg/dL, total iron binding capacity was 450 μg/dL, and ferritin was <1 ng/mL. She was hospitalized and given packed red cell transfusion. The following day she suddenly developed respiratory distress after breakfast. Chest X-ray showed a radiolucent lesion in the right paracardiac area (Figure). Congenital diaphragmatic hernia (CDH) was confirmed via barium gastrointestinal X-ray and computed tomography of the chest. During surgery the retrosternal diaphragmatic hernia sack was excised, and the stomach, intestines, and transverse colon were reduced to the abdominal cavity. Nissen fundoplication was also performed in an effort to prevent postoperative gastroesophageal reflux; however, another defect was noted on the left posterolateral side of the diaphragm. The defect was repaired and Thal anterior fundoplication was performed. The patient had both Morgagni and Bochdalek defects Figure X-ray of the thorax showing the radiolucent area with clear borders in the right paracardiac region. At 6 weeks post surgery the patient had no gastrointestinal symptoms, but her Hb dropped to 7.9 g/dL and fecal occult blood test findings were positive (Hct: 25.6%; RBC count: 3.63 x 1012/L; MCV: 70.5 fL; MCH: 21.9; MCHC: 31; RDW: 24; WBC count: 9.8 x 109/L; ANC: 4.3 x 109/L, Plt count: 453 x 109/L; absolute reticulocyte count: 11 x 109/L) [normal 50-150 x 109/L]). Peripheral blood smear showed hypochromic microcytic red cells. Esophagogastroduodenoscopy and esophageal biopsy showed erosions, gastroesophageal reflux, chronic inflammation, and hyperplasia of the epithelium. A proton pump inhibitor, domperidone, and anti-acid medications were started. Iron sucrose was administered twice weekly for 3 weeks and the Hb increased (Hb: 12.2 g/dL; Htc: 34.6%; RBC count: 4.76 x 109/L; MCV: 72fL; MCH: 25.6; MCHC: 35.1; RDW: 17.4; WBC count: 12.2 x 109/L; ANC: 8.2 x 109/L; Plt count: 348 x 109/L, absolute reticulocyte count: 85 x 109/L [normal: 50-150 x 109/L]; ferritin: 16 ng/mL). Blood smear showed normal red cells. At the 2-year follow-up the patient had no gastrointestinal symptoms or anemia. The coexistence of Morgagni and Bochdalek defects is rarely reported [1]. About 5%-30% of CDH cases present after the neonatal period, which poses a diagnostic challenge [2]. Such symptoms as vomiting and respiratory distress may be acute or intermittent—sometimes due to gastric volvulus or spontaneous reduction of the hernia to the abdomen. During asymptomatic periods imaging findings may be normal [3]. The presented patient had normal abdominal ultrasound and chest X-ray findings before referral to our department. The presented patient most probably had chronic occult blood loss from the gastrointestinal tract due to reflux esophagitis and mechanical trauma to the diaphragm. Sinaki et al. reported 2 patients—a 19 month-old and 6-year-old—that presented with gastrointestinal symptoms and an Hb of 5.8 g/dL and 6 g/dL, respectively [4]. Zaki et al. reported a 5-year-old patient with persistent anemia that did not respond to adequate hematinics and blood transfusion. The patient had abdominal pain, melena, an Hb of 4.8 g/dL, and multiple linear gastric erosions on the mucosal folds of the lesser curve of the stomach [5]. CDH must be included in the differential diagnosis of severe iron deficiency anemia in the absence of such obvious causes as nutritional deficiency, melena, hematochezia, and malabsorption. Physicians must be aware that a history of intermittent vomiting and/or sudden onset respiratory distress in young children are indications for imaging of the upper gastrointestinal tract and thorax.

Congenital diaphragmatic hernia in neonate: A retrospective study about 28 observations

Our purpose was to review our experience with congenital diaphragmatic hernia emphasizing diagnosis, management, and outcome. We conducted a retrospective review of all cases of babies with congenital diaphragmatic hernia diagnosed and treated in our centre from 1998 to 2010. There were 28 congenital diaphragmatic hernia cases, 13 girls and 15 boys with a mean weight birth of 3 kg. Three patients (10, 6% of cases) died within a few hours after admission. In the remaining cases, surgery was performed after a stabilization period of 2 days. The diaphragmatic defect was sitting in the posterolateral left in 23 cases and right in 2 cases. Its dimensions were on average 4,5 cm, tow cases of agenesis of the cupola were seen and required the placement of gortex prosthesis. The remaining cases are treated by direct closure of defect. Postoperative course was marked by an early death in context of respiratory distress in six cases and later with sepsis in tow cases. The outcome was favourable in 17 cases (60, 7%), despite the occurrence of sepsis in four cases and evisceration in two cases. Congenital diaphragmatic hernia remains a serious disease with high mortality and morbidity despite advances in prenatal diagnosis and neonatal resuscitation.

Outcome of fetuses with congenital diaphragmatic hernia and associated intrafetal fluid effusions managed in the era of fetal surgery

Fetuses with congenital diaphragmatic hernia (CDH) and for whom additional ultrasound findings are abnormal typically are considered to have a dismal prognosis. Our aim was to assess the outcome of fetuses with CDH and associated intrafetal fluid effusions. This was a retrospective bicentric cohort study on the perinatal management of fetuses with CDH and intrafetal fluid effusions. The incidence of effusions was 5.2% (n = 14) in 269 consecutive cases of left-sided CDH and 29.2% (n = 14) in 48 cases of right-sided CDH. Hydrothorax (n = 19 (68%)) and ascites (n = 16 (57%)) were the most common effusions. A combination of both was present in 11 (39%) fetuses. Of 20 ongoing pregnancies with CDH and fluid effusions, without other anomalies, five with moderate or mild pulmonary hypoplasia were managed without fetoscopic endoluminal tracheal occlusion (FETO). The 15 other cases underwent FETO because of severe pulmonary hypoplasia. Neonatal survival rate was similar in both groups (n = 2/5 and n = 6/15, respectively (P = 1.0)). Survival among those who underwent FETO was similar to previously published results concerning isolated cases undergoing FETO. Our observations do not support the view that intrafetal effusions are an adverse prognostic factor in fetuses with CDH. In CDH fetuses with effusions and severe pulmonary hypoplasia treated with FETO, neonatal survival is similar to that in isolated cases undergoing the intervention. Whether pleural effusions should be addressed by thoracic drainage procedures remains unproven.

Use of Endoscopic Surgical Spacer to Improve Safety During Thoracoscopic Repair of Congenital Diaphragmatic Hernia

Thoracoscopic repair of congenital diaphragmatic hernia (CDH) has recently become more common, and the challenge of managing neonatal cases is increasing. Meanwhile, there have been reported intraoperative complications or conversion to open surgery due to injury of herniated viscera and inability of organ reduction. We used the endoscopic surgical spacer SECUREA™ (Hogy Medical Co., Ltd., Tokyo, Japan), which is an elliptical sponge made of polyurethane with a radiopaque marker, for preventing these complications in three cases of CDH. The first case was a late presentation in a 10-month-old girl, and the second and third cases were prenatally diagnosed female neonates without severe pulmonary hypertension. All cases were left-sided hernias without sacs. At operation, the SECUREA was grasped using forceps, and the viscera were pushed back gently to avoid injuring the spleen or the short gastric vessels in the second and the third case. The SECUREA was intended to prevent intestinal injury during defect repair in all cases, with placement of the SECUREA between the edge of the diaphragm and the reduced intestine. The procedures in all patients were completed with no complications and without the need for conversion.

Examining the Hidden Mortality of Congenital Diaphragmatic Hernia

Background and aims: Congenital diaphragmatic hernia (CDH) poses significant medical, social and economic challenges. Our objective was to examine the impact of antenatal and perinatal management on fetal and maternal outcomes in pregnancies complicated by fetal CDH.Methods: Analysis of all pregnancies with antenatal or postnatal diagnosis of CDH in Ontario, (∽145,000 deliveries annually) between 2005 and 2009. Data were obtained from all tertiary care fetal medicine units and pediatric surgical centres in the Ontario. Maternal characteristics, antenatal information, severity of defect, surgical management and newborn outcomes were studied.Results: During the 5 year study period, 109 cases of CDH were identified by antenatal ultrasound at a mean of 22.2+7.2 weeks gestation, only 2 cases were undiagnosed antenatally. One or more significant associated anomalies were detected in 19% of fetuses, 33% being cardiovascular. Seventy eight pregnancies continued, 90% had L sided CDH and were delivered at a mean gestational age of 37.6+2.5 weeks, mean birth weight 3.1+0.6kg. Preterm delivery occurred in 17% and 14% of infants were low birth weight. Estimations of lung head ratio were available for 30 cases and were significantly greater for infants who survived, 1.55+0.5, compared to 1.17+0.25 for non-survivors, p=0.05. Mean NICU stay was 37 days, with 73% of admitted infants surviving, representing 52% of the original antenatal cohort.Conclusions: Greater understanding of the true prevalence of CDH and the factors that contribute to mortality, may identify interventions including antenatal surgery, that could be introduced to improve survival.

Delayed Presentation Of Congenital Diaphragmatic Hernia With Splenic And Caecal Herniation

The vast majority of posterolateral congenital diaphragmatic hernia (CDH) diagnosed on prenatal ultrasound screening after 24 weeks of gestation present with respiratory distress at birth. It has been observed that late presenting CDH has better outcome and is not associated with pulmonary hypoplasia. We report a case of posterolateral CDH with herniated spleen presented first in a four year old male child with chest infection. This case report highlights the fact that posterolateral CDH which presents late is not associated with pulmonary hypoplasia, but may cause respiratory symptoms.

Tetralogy of Fallot with congenital diaphragmatic hernia and left lung hypoplasia: assessment of the adequacy of the peripheral pulmonary vascular growth after hernia repair

Congenital diaphragmatic hernia is a life-threatening condition frequently associated with various congenital cardiac diseases. In congenital diaphragmatic hernia associated with tetralogy of Fallot, central pulmonary artery size of the affected side may not reflect the capacitance of peripheral pulmonary vascular beds. We report a case of congenital diaphragmatic hernia associated with tetralogy of Fallot, which was repaired after assessing the adequacy of the pulmonary vascular beds by intra-operative pulmonary blood flow study.

OP38.05: Prognostic value of first trimester nuchal translucency in isolated congenital diaphragmatic hernia

To investigate the prognostic value of increased nuchal translucency (NT) thickness in the first trimester in fetuses with isolated congenital diaphragmatic hernia (CDH). We conducted a retrospective study of all consecutives cases of CDH referred to our unit for prenatal care between January 2004 and June 2010. NT was measured at between 11 and 13 + 6 weeks during first trimester routine scan therefore blinded to the subsequent diagnosis and outcome. Cases with termination of pregnancy or associated genetic, chromosomal or anatomical anomalies were discarded. We investigated the prognostic value of enlarged NT as well as the correlation between NT (MoM) and liver location, side of CDH, lung-to-head ratio (LHR), LHR observed/expected (O/E), lung volume estimated by MRI. Perinatal outcome was defined as survival at discharge from the NICU. 83 cases were reviewed. Enlarged NT, defined as > 95th percentile occurred in 9/83 (11%) cases. Neonatal death occurred in 7/9 (78%) cases with increased nuchal translucency, compared with 35/74 (47%) cases with normal translucency. No significant correlations were found between the value of NT (MoM) and the LHR, LHR O/E, lung volume estimated by MRI. The median NT was 1 MoM and 0.9 MoM for right-sided and left-sided CDH respectively (P = 0.17). Median NT was 1 MoM and 0.86 MoM for liver-up and liver-down cases respectively (P = 0.05) Nuchal translucency may be a prognostic factor for CDH. Furthermore, the prognostic value of enlarged first trimester NT may be unrelated to other markers of lung compression except liver location.

Nitric oxide activity through guanylate cyclase and phosphodiesterase modulation is impaired in fetal lambs with congenital diaphragmatic hernia

Background Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypertension and death. Administration of nitric oxide (NO) alone remains ineffective in CDH cases. We investigated in near full-term lambs with and without CDH the role of guanylate cyclase (GC), the enzyme activated by NO in increasing cyclic 3′-5′-guanylosine monophosphate, and the role of phosphodiesterase (PDE) 5, the enzyme-degrading cyclic 3′-5′-guanylosine monophosphate. Methods Congenital diaphragmatic hernia was surgically created in fetal lambs at 85 days of gestation. Pulmonary hemodynamics were assessed by means of pressure and blood flow catheters (135 days). In vitro, we tested drugs on rings of isolated pulmonary vessels. Results In vivo, sodium nitroprusside, a direct NO donor, and methyl-2(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5trimethoxyphenyl)-3-isoquinoline carboxylate sulfate (T-1032) and Zaprinast, both PDE 5 blockers, reduced pulmonary vascular resistance in CDH and non-CDH animals. The activation of GC by sodium nitroprusside and the inhibition of PDE 5 by T-1032 were less effective in CDH animals. In vitro, the stimulation of GC by 3(5′hydroxymethyl-2′furyl)-1-benzyl indazole (YC-1) (a benzyl indazole derivative) and the inhibition of PDE 5 by T-1032 were less effective in pulmonary vascular rings from CDH animals. The YC-1–induced vasodilation in rings from CDH animals was higher when associated with the PDE 5 inhibitor T-1032. Conclusions Guanylate cyclase and PDE 5 play a role in controlling pulmonary vascular tone in fetal lambs with or without CDH. Both enzymes seem to be impaired in fetal lambs with CDH.