Reduction in ventilator-induced lung injury improves outcome in congenital diaphragmatic hernia?

The purpose of this historical study was to compare the outcome for two treatment strategies, for neonates with congenital diaphragmatic hernia (CDH). The records of 65 infants born between 1991 and 2005 with CDH from a single tertiary care perinatal centre in the United Kingdom were retrospectively reviewed. Conventional mechanical ventilation (CMV) and systemic vasodilators were used from 1991 to 1995 (era 1). High frequency oscillatory ventilation (HFOV) and nitric oxide (NO) were used between 1996 and 2005 (era 2). Main outcome measures were survival and incidence of chronic lung disease. The results showed that the survival rate was 38% (8/21) in era 1 and 73% (32/44) in era 2, 95% CI for difference −59 to −10%. The incidence of chronic lung disease in survivors was 45% (5/11) in era 1 and 30% (9/30) in era 2, 95% CI for difference −18 to 49%. These data show significantly improved survival with elective use of HFOV and NO compared to CMV and systemic vasodilators. The survival results for CDH at St George’s Hospital are comparable to those published from other institutions. The results may reflect a reduction in ventilator-induced lung injury with HFOV compared to CMV.     

Can maternal vitamin e supplementation prevent lung hypoplasia in the nitrofen-induced rat model of congenital diaphragmatic hernia?

Recent studies suggest a role for antioxidants in the prevention of pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH). We studied the effects of vitamin E in the nitrofen-rat model of CDH. After an initial fast, timed-pregnant Sprague-Dawley rats were gavage-fed nitrofen at gestational day 11 (term is 22 d). On the same day, one group was given a s.c. injection of vitamin E in alcohol; a second group was given an injection of alcohol alone. A third group received no treatment (control). Fetuses were delivered on day 21, and static pressure-volume curves were measured by immersion. Lungs were analyzed for total DNA and protein content by standard methods. A total of 203 fetuses were studied. Of 151 nitrofen-exposed fetuses, 77% had CDH; 92% of these were right-sided. CDH was present in 82% of vehicle-treated fetuses and 71% of vitamin E-treated fetuses (p=0.17). Nitrofen-exposed fetuses not only were smaller than control fetuses but also had disproportionately smaller lungs and poorer lung function, even when CDH was absent; however, lung function was worse when CDH was present. Vitamin E treatment did not improve either lung growth or function, although there was a trend toward less CDH. We have shown, for the first time, that the lung hypoplasia seen in nitrofen-exposed rat fetuses is associated with a dramatic reduction in static lung function, even when CDH is not present. Finally, our findings support the notion that lung hypoplasia in the nitrofen-rat model is independent of CDH formation.     

Is surfactant therapy beneficial in the treatment of the term newborn infant with congenital diaphragmatic hernia?

OBJECTIVES: To determine the impact of surfactant replacement on survival, need for extracorporeal membrane oxygenation (ECMO), and chronic lung disease in term infants with prenatally diagnosed congenital diaphragmatic hernia (CDH). STUDY DESIGN: Prenatally diagnosed infants born at > or =37 weeks' gestation with immediate distress at delivery and no other major congenital anomalies, who were enrolled in the CDH Registry, were analyzed. For univariate analysis, chi 2 tests were used for categoric variables and unpaired t tests for nominal variables. Multiple logistic regression was used to calculate adjusted odds ratios. RESULTS: Eligible infants (n = 522) were identified. Demographic variables were similar between the surfactant-treated (n = 192) and nonsurfactant-treated (n = 330) groups, with the exception of race (white, 88.0% vs 71.2%; P =.0007). The use of ECMO and incidence of chronic lung disease were higher (59.8 vs 50.6, P =.04; 59.9 vs 47.6, P =.0066) and survival lower in the surfactant-treated cohort (57.3 vs 70.0, P =.0033). Adjusted logistic regression for use of ECMO, survival, and chronic lung disease resulted in odds ratios inconsistent with an improved outcome associated with surfactant use. CONCLUSIONS: This analysis shows no benefit associated with surfactant therapy for term infants with a prenatal diagnosis of isolated CDH.     

Expression of the Wilm��s tumor gene WT1 during diaphragmatic development in the nitrofen model for congenital diaphragmatic hernia

Purpose  

The nitrofen model of congenital diaphragmatic hernia (CDH) reproduces a typical diaphragmatic defect. However, the exact pathomechanism of CDH is still unknown. The Wilm’s tumor 1 gene (WT1) is crucial for diaphragmatic development. Mutations in WT1 associated with CDH have been described in humans. Additionally, WT1^−/− mice display CDH. Furthermore, WT1 is involved in the retinoid signaling pathway, a candidate pathway for CDH. We hypothesized that diaphragmatic WT1 gene expression is downregulated during diaphragmatic development in the nitrofen CDH model.     

How often is extracorporeal membrane oxygenation needed in cases of congenital diaphragmatic hernia?

Some newborns with congenital diaphragmatic hernia (CDH) and severe pulmonary hypertension cannot be saved by conventional treatment and may obtain some benefit from extracorporeal membrane oxygenation (ECMO) as a bridging measure until adequate hematosis is possible. Early prediction of the insufficiency of optimal assistance is still unclear; we reviewed our recent experience with CDH patients in an attempt to evaluate the real need for ECMO in our institution. Between 1987 and 1994, 47 newborns with CDH manifested in the first 24 h were treated with maximal ventilatory assistance (including high-frequency ventilation in 12 cases) and vasoactive drugs prior to surgical repair. In order to summarize the ventilatory and blood-gas parameters, we determined oxygenation index (OI) and ventilatory index (VI) and compared the results in survivors and nonsurvivors. Overall survival was 60% (2 cases of Fryns' syndrome were excluded from analysis). OI was 10.3±5.7 (mean ± SD) for survivors and 46.2 ± 37.8 for nonsurvivors (P < 0.01). VI was 460.9±303 and 1,532±500.6, respectively (P <0.01). Bayesian analysis and receiver operating characteristic curves enabled us to select a threshold value of OI of 20 as the best means of predicting survival in our current conditions (sensitivity: 0.7, specificity: 0.83). The generally accepted figure of 40 had a sensitivity of 1 but a specificity of only 0.44. For VI, the best threshold value was 1,100 (sensitivity: 0.93, specificity: 0.94), whereas the generally used figure of 1,000 had 0.89 and 1, respectively. According to our results, with our current management conditions, approximately 50% of our CDH patients might have obtained some benefit from ECMO.     

Increased expression of EGFR and TGF-α in segmental renal dysplasia in duplex kidney

Renal dysplasia (RD) is a disorganised development of renal parenchyma that results in a deficit of functional renal tissue. It is known that the epidermal growth factor (EGF) and the transforming growth factor- (TGF-) enhance renal cell proliferation, migration and differentiation during kidney development through binding to the same EGF receptor (EGFR). The aim of the study was to analyse the expression of TGF- and EGFR in the dysplastic kidney. The specimens of dysplstic upper poles duplex kidneys were surgically resected from 19 patients. Indirect immunohistochemistry was performed using the ABC method employing antibodies against EGFR and TGF-, and gene expression using primers specific to the human genes. There was absent or weak EGFR and TGF- immunoreactivity in normal kidney tissue. In dysplastic kidneys, there was strong TGF- and EGFR immunoreactivity in the epithelium of primitive tubules and strong EGFR immunoreactivity in the connective tissue around the primitive tubules. Our findings of markedly increased local expression of EGFR and TGF- in primitive tubules suggest that EGFR and TGF- may play an important role in altering renal morphogenesis resulting in renal dysplasia.     

Bilateral congenital diaphragmatic hernia and gastroschisis in a newborn: can low intrathoracic pressure prevent the pulmonary hypoplasia?

Congenital diaphragmatic hernia (CDH) is associated with high mortality and morbidity due to pulmonary hypoplasia (PH) and persistent pulmonary hypertension (PPH). Bilateral CDH is extremely rare with poor prognosis. It is usually accepted that PH in CDH is due to the herniation of abdominal viscera in the thorax leading to compression of the lung and preventing the normal lung development. On the other hand, some authors suggest that the PH occurs independently from the intrathoracic pressure in foetuses with CDH because of embryologic and genetic factors. We report a case of a newborn with bilateral CDH and gastroschisis born without PH, with favourable outcome. We support the hypothesis that a low intrathoracic pressure in patients with CDH allows an improved lung development.     

Evaluating the utility of the “late ECMO repair”: a congenital diaphragmatic hernia study group investigation

Purpose

Optimal timing of congenital diaphragmatic hernia (CDH) repair in patients requiring extracorporeal membrane oxygenation (ECMO) remains controversial. The “late ECMO repair” is an approach where the patient, once deemed stable for decannulation, is repaired while still on ECMO to enable expeditious return to ECMO if surgery induces instability. The goal of this study was to investigate the potential benefit of this approach by evaluating the rate of return to ECMO after repair.

Methods

The CDH Study Group database was used to analyze CDH patients requiring ECMO support. The primary outcome was return to ECMO within 72 h of CDH repair among those repaired following ECMO decannulation (“post-ECMO” patients). Secondary outcomes were death within 72 h of repair and cumulative death and return to ECMO rate.

Results

A total of 668 patients were repaired post-ECMO decannulation. Six patients (0.9%) in the post-ECMO group required return to ECMO within 72 h of surgery and a total of 19 (2.8%) died or returned to ECMO within 72 h of surgery.

Conclusion

The rate of return to ECMO and death following CDH repair is extremely low and does not justify the risks inherent to “on-ECMO” repair. Patients stable to come off ECMO should undergo repair after decannulation.

     

Is there a role for antioxidants in prevention of pulmonary hypoplasia in nitrofen-induced rat model of congenital diaphragmatic hernia?

Background/purpose  

Many studies suggest a role for antioxidants in the prevention of lung hypoplasia in nitrofen-induced rat models with congenital diaphragmatic hernia (CDH). This study investigates the oxidative status and the histological outcome of prenatal administration of vitamins E and C with synergistic effect, and effect of N-acetylcysteine (NAC) to improve lung maturation of nitrofen-induced rats.     

When primary repair is not enough: a comparison of synthetic patch and muscle flap closure in congenital diaphragmatic hernia?

Primary closure is often inadequate for large congenital diaphragmatic hernia (CDH) and necessitates repair by prosthetic patch or autologous muscle flap. Our aim was to evaluate outcomes of open patch versus flap repair, specifically diaphragmatic reherniation. A retrospective review (IRB #2017-6361) was performed on all CDH patients repaired from 2005 to 2016 at a single academic children’s hospital. Patients were excluded from final analysis if they had primary or minimally invasive repair, expired, or were lost to follow-up. Of 171 patients, 151 (88.3%) survived to discharge, 9 expired after discharge and 11 were lost to follow up, leaving 131 (86.8%) long-term survivors. Median follow-up was 5 years. Open repair was performed in 119 (90.8%) of which 28 (23.5%) underwent primary repair, 34 (28.6%) patch repair, and 57 (47.9%) flap repair. Overall, 6/119 (5%) patients reherniated, 1/28 (3.6%) in the primary group, 3/34 (8.8%) in the patch group, and 2/57 (3.5%) in the flap group. Comparing prosthetic patch to muscle flap repair, there was no significant difference in the number of patients who recurred nor time to reherniation (3 vs. 2, p = 0.295; 5.5 ± 0.00 months vs. 53.75 ± 71.06 months, p = 0.288). One patient in the patch group recurred twice. Both muscle flap and patch repair of large CDH are feasible and durable with a relatively low risk of recurrence.     

The SIS extracellular matrix scaffold—preliminary results of use in congenital diaphragmatic hernia (CDH) repair

There is no ideal bio-tensile material for tissue replacement in paediatric surgical conditions. A variety of materials have been described to replace or reinforce tissue deficits in congenital diaphragmatic hernia (CDH). The problems with these materials range from extensive surgery to body wall deformity and hernia recurrence. The ideal graft would be safe, strong, have the potential to grow and not require replacement, not affect chest wall development or produce deformity, and have minimal risk of recurrence. Surgisis is a biomaterial composed of porcine intestinal submucosa that provides inherent tensile strength as a collagen lattice and is ultimately replaced by native collagen tissue. Our objective was to prospectively assess the utility of Surgisis as a replacement graft in a cohort of 10 children undergoing primary or recurrent CDH repair. The graft was well tolerated, and there was no recurrence of herniation. We conclude that Surgisis collagen mesh may be a useful alternative for tissue replacement or reinforcement in difficult cases of CDH and diaphragmatic agenesis. The biological framework of Surgisis may also prove useful in other situations of complex tissue loss in children.     

Thoracoscopic repair of congenital diaphragmatic hernia by inflation-assisted bowel reduction, in a resuscitated neonate: a better access?

Elective endoscopic diaphragmatic hernia repairs have been reported. But endoscopic surgery was regarded unsuitable for emergency repair of diaphragmatic hernia in ventilated newborn children in bad general condition. We report a new method for inflation-assisted reduction and thoracoscopic repair of congenital diaphragmatic hernia diaphragmatic in a vitally endangered neonate. From three 2.7 mm to 5 mm accesses warmed low-pressure, low-volume CO₂ was inflated into the thorax at 100 ml/min and 2 mm mercury. This allowed spontaneous reduction of the thoracic viscera into the abdomen and diaphragmatic suture with minimal handling. The 65-min procedure was tolerated well without perioperative deterioration. The baby was weaned off the respirator and breast-fed within 2 days, mediastinal shift normalized in 6 days. In suitable infants thoracoscopic repair and inflation-assisted reduction of thoracic contents is a more physiological access to congenital diaphragmatic hernia than laparoscopy or laparotomy.     

The expression and significance of HIF-1α and VEGF in hypoxic neurons

目的 研究体外培养的新生大鼠皮质神经元缺氧不同时间后缺氧诱导因子(HIF)1α及血管内皮生长因子(VEGF)的表达规律及意义.方法 体外培养的新生大鼠皮质神经元于厌氧培养箱中缺氧0、2、4、8 h,用Western blot及real time PCR检测缺氧不同时间后神经元HIF-1α及VEGF mRNA及蛋白的表达.结果 常氧培养的神经元中几乎不表达HIF-1α,VEGF表达较低;缺氧2 h后,神经元中HIF-1α及VEGF mRNA表达均显著增加;缺氧4 h后两者mRNA及蛋白表达最高;缺氧8 h后表达降低.结论 缺氧增加神经元中HIF-1α及VEGF的表达,随着缺氧时间的增加呈先升高后降低的趋势.     

Responsiveness of intestinal epithelial cell turnover to TGF-α after bowel resection in a rat is correlated with EGF receptor expression along the villus–crypt axis

Recent evidence suggests that transforming growth factor alpha (TGF-alpha) enhances enterocyte proliferation and stimulates intestinal adaptation after massive bowel resection. In the present study, we evaluated the effects of TGF-alpha on enterocyte turnover and correlated it with epidermal-growth factor (EGF) receptor expression along the villus-crypt axis in a rat model of short bowel syndrome (SBS). Male rats were divided into three groups, sham rats underwent bowel transection (group A); SBS rats underwent a 75% bowel resection (group B); and SBS/TGF-alpha rats underwent bowel resection and were treated with TGF-alpha (75 microg/kg) (group C) from the seventh postoperative day. Parameters of intestinal adaptation, enterocyte proliferation and apoptosis were determined on day 15. Villus tips, lateral villi and crypts were separated using laser capture microdissection. EGF receptor expression for each compartment was assessed by quantitative real-time PCR (Taqman). Statistical analysis was performed using one-way ANOVA test, with P < 0.05 considered statistically significant. Treatment with TGF-alpha resulted in a significant increase in all parameters of intestinal adaptation. EGF receptor expression in crypts significantly increased in SBS rats (vs sham rats) (0.035 +/- 0.013 vs 0.010 +/- 0.002 Log ng Total RNA/18 s) and was accompanied by a significant increase in enterocyte proliferation (169 +/- 8 vs 138 +/- 5 BrdU positive cells/per 10 crypts, P < 0.05) and decreased apoptosis following TGF-alpha administration (group C). A significant decrease in EGF receptor expression at the tip of the villus (0.005 +/- 0.002 vs 0.029 +/- 0.014 Log ng Total RNA/18 s) and in the lateral villus (0.003 +/- 0.001 vs 0.028 +/- 0.006 Log ng Total RNA/18 s) in SBS (group B) rats (vs sham, group A) was accompanied by increased cell apoptosis in these compartments following treatment with TGF-alpha (group C). In a rat model of SBS, TGF-alpha increased enterocyte proliferation and stimulated intestinal adaptation. The effect of TGF-alpha on enterocyte turnover is correlated with EGF receptor expression along the villus-crypt axis.