201 research outputs found
Clinical and experimental aspects of lung development and injury in congenital diaphragmatic hernia
Congenital anomalies are expressions of abnormal growth and development. They presently form the second most frequent cause of death, after immaturity, in the perinatal period. Congenital diaphragmatic hernia (CDH) is a congenital anomaly manifesting itself in about one in 3,000 total births or one in 2,700 live births. More than 95% of the diaphragmatic defects are posterolateral ones.
For a long time CDH was considered as a purely anatomical defect of the diaphragm. But it has become clear that in many cases (ranging from 39 to 47%) it is associated with other anomalies, especially cardiac defects.
Despite improved neonatal intensive care, the overall survival rate does still not exceed 55 to 58%, and is even less in patients with associated anomalies. However, higher survival rates have been reported: Wung and coworkers reported a survival rate of 94% in a group of CDH patients who were treated with very delayed surgery and a respiratory care strategy that avoids pulmonary overdistension.
The studies reported in this thesis were conducted to investigate various, related aspects of lung development and lung injury in CDH
Esophageal atresia: Long-term morbidities in adolescence and adulthood
Survival rates in esophageal atresia (EA) patients have reached 90%. In long-term follow-up studies the focus has shifted from purely surgical or gastrointestinal evaluation to a multidisciplinary approach. We evaluated the long-term morbidity in adolescent and adult EA patients and discussed mainly nonsurgical issues. Dysphagia is common and reported in up to 85% of patients. In young adults gastroesophageal reflux disease occurs frequently with development of Barrett esophagus in 6% reported in different series. It is difficult to estimate respiratory morbidity from the literature because many different definitions, questionnaires, and study designs have been used. However, many patients seem to suffer from respiratory problems even into adulthood. In conclusion, morbidity is not only restricted to surgical problems but many different domains are involved. These are all related and together determine to a large extent the quality of life of EA patients and also of their families. We assume that a multidisciplinary care approach seems best to address their special needs
Assessment and significance of long-term outcomes in pediatric surgery
Treatment modalities for newborns with anatomical congenital anomalies have greatly improved over the past decades, with a concomitant increase in survival. This review will briefly discuss specific long-term outcomes to illustrate, which domains deserve to be considered in long-term follow-up of patients with anatomical congenital anomalies. Apart from having disease-specific morbidities these children are at risk for impaired neurodevelopmental problems and school failure, which may affect participation in society in later life. There is every reason to offer them long-term multidisciplinary follow-up programs. We further provide an overview of the methodology of long-term follow-up, its significance and discuss ways to improve care for newborns with anatomical congenital anomalies from childhood into adulthood. Future initiatives should focus on transition of care, risk stratification, and multicenter collaboration
Lower respiratory tract infections in children with congenital lung abnormalities
Objective: We aimed to determine if the incidence of lower respiratory tract infections (LRTI) among children with asymptomatic, observationally managed congenital lung abnormalities (CLA) differed from that of symptomatic patients who underwent surgery. Second, we sought to compare the pre- and post-resection incidence of LRTI in patients who underwent surgery. Methods: This retrospective cohort study included patients born between 1999 and 2021 with CLA confirmed by CT scan who were enrolled in a prospective longitudinal follow-up program. The LRTI incidence rates at 1, 2, 5, 8, and 12 years were compared between surgically and observationally managed patients using incidence rate ratios (IRR). Differences in pre- and post-resection LRTI incidence rates among patients who underwent CLA-related surgery were assessed through IRR. Results: Among 217 included patients, 81 (37%) had undergone surgery and 136 (63%) had been observationally managed. The LRTI incidence rates did not significantly differ at any follow-up moment between the surgical and observational groups. Among the children who underwent CLA-related surgery, the pre-resection LRTI incidence rates were significantly higher than the post-resection LRTI incidence rates (IRR of 3.57, 95% confidence interval: [2.00; 6.33], p <.001). Conclusion: We could not demonstrate differences in LRTI incidence throughout childhood between patients with surgically and observationally managed CLA. We recommend discussing cases of LRTI in patients with CLA in a multidisciplinary setting, using additional diagnostics such as chest X-ray to screen for CLA involvement, enabling a well-considered decision on surgical resection of the lesion.</p
Lower respiratory tract infections in children with congenital lung abnormalities
Objective: We aimed to determine if the incidence of lower respiratory tract infections (LRTI) among children with asymptomatic, observationally managed congenital lung abnormalities (CLA) differed from that of symptomatic patients who underwent surgery. Second, we sought to compare the pre- and post-resection incidence of LRTI in patients who underwent surgery. Methods: This retrospective cohort study included patients born between 1999 and 2021 with CLA confirmed by CT scan who were enrolled in a prospective longitudinal follow-up program. The LRTI incidence rates at 1, 2, 5, 8, and 12 years were compared between surgically and observationally managed patients using incidence rate ratios (IRR). Differences in pre- and post-resection LRTI incidence rates among patients who underwent CLA-related surgery were assessed through IRR. Results: Among 217 included patients, 81 (37%) had undergone surgery and 136 (63%) had been observationally managed. The LRTI incidence rates did not significantly differ at any follow-up moment between the surgical and observational groups. Among the children who underwent CLA-related surgery, the pre-resection LRTI incidence rates were significantly higher than the post-resection LRTI incidence rates (IRR of 3.57, 95% confidence interval: [2.00; 6.33], p <.001). Conclusion: We could not demonstrate differences in LRTI incidence throughout childhood between patients with surgically and observationally managed CLA. We recommend discussing cases of LRTI in patients with CLA in a multidisciplinary setting, using additional diagnostics such as chest X-ray to screen for CLA involvement, enabling a well-considered decision on surgical resection of the lesion.</p
Pulmonary neuroendocrine cells in neonatal rats with congenital diaphragmatic hernia
Lung hypoplasia and persistent pulmonary hypertension are the principal causes of high mortality and morbidity in infants with congenital diaphragmatic hernia (CDH). Amine-and peptide-producing pulmonary neuroendocrine cells (PNEC), widely distributed throughout the airway mucosa, are thought to play an important role in both pulmonary development and regulation of pulmonary vascular tone. Furthermore, recent studies show increased levels of calcitonin gene-related peptide (CGRP), a pulmonary vasodilator produced by PNEC, during chronic hypoxia. The article reports data on morphometric analysis of CGRP immunoreactive PNEC clusters (neuroepithelial bodies, NEB) in a rat model of CDH. CDH was induced in neonatal Sprague Dawley rats by oral administration of 2,4-dichloro-phenyl- p-nitro-phenylether (Nitrofen; Rohm Haas, Philadelphia, PA) to the mother at 10 days of gestation. Sections of lungs from term neonatal rats with and without CDH and controls were immunostained for CGRP (marker of NEB) with specific antibody against rat CGRP. NEB size and number of NEB/area of lung were assessed using a semiautomatic image analysis system. In lungs of neonatal rats with CDH, the number of NEB per surface area of lung parenchyma was significantly increased compared with the age-matched controls. Although the mean size of NEB was larger in CDH, the differences were not significant. This is the first study of PNEC in CDH. Whether the phenomenon observed in this study results in altered NEB function including imbalance in vasoactive mediators requires further studies, especially in the human being
Calcitonin gene-related peptide expression is altered in pulmonary neuroendocrine cells in developing lungs of rats with congenital diaphragmatic hernia
Congenital diaphragmatic hernia (CDH) is associated with high neonatal
mortality from lung hypoplasia and persistent pulmonary hypertension.
Pulmonary neuroendocrine cells (PNEC) produce calcitonin gene-related
peptide (CGRP), a potent vasodilator. We previously reported altered
distribution of CGRP-positive PNEC in full-term rats with CDH, that may
lead to an imbalance in vasoactive mediators. In the present study we
examined the expression of CGRP-positive PNEC during lung development in
rats with CDH induced by 2,4-dichlorophenyl-p-nitrophenylether (Nitrofen).
Cesarean sections were performed on Days 16, 18, 20, or 22, and the lungs
were immunostained for CGRP and immunoreactive cells were quantitated
through image analysis. On Day 16, CGRP-immunoreactive staining was
negative; on Day 18, CGRP-immunoreactive cells were found in all controls
(not exposed to Nitrofen), whereas in CDH pups, CGRP-positive cells were
present in only four of six cases. On Day 20, CGRP immunoreactivity was
similar in CDH pups, Nitrofen-exposed pups without CDH, and controls. On
Day 22 (term), significantly more CGRP-positive cells (i.e., number of
positive cells per surface area [mm2] or lung volume [mm3]) were found in
ipsilateral lungs of CDH pups than in controls (P < 0.05). The difference
was even more striking in contralateral lungs of CDH pups (P < 0.001),
ruling out nonspecific effects of Nitrofen. In CDH lungs, the proportion
of immunostained epithelium and the size of the neuroendocrine cell
clusters (neuroepithelial bodies [NEB]) were not significantly different
from those of controls. On Day 22, supraoptimal dilution
immunocytochemistry yielded similar results in CDH pups and controls. We
conclude that in CDH, CGRP expression in PNEC and NEB is delayed during
early stages of lung development. Because CGRP also exhibits growth
factor-like properties for endothelium and epithelial cells, the lack of
this factor during a crucial developmental stage (canalicular period) may
be causally related to lung hypoplasia
Long-term pulmonary sequelae in children with congenital diaphragmatic hernia.
Neonates with congenital diaphragmatic hernia (CDH) often suffer from respiratory
insufficiency due to lung hypoplasia and pulmonary hypertension. Artificial
ventilation is frequently required, and this leads to a high incidence of
bronchopulmonary dysplasia. Long-term follow-up studies have shown persisting
airway obstruction. To evaluate the long-term pulmonary sequelae in CDH, we
studied 40 CDH patients of age 7 to 18 yr (median 11.7 yr) and 65 age-matched
controls without CDH and lung hypoplasia who underwent similar neonatal
treatment. Mild airway obstruction was found in both groups with more peripheral
airway obstruction in CDH patients than in control subjects. Both groups had
normal TLC and single-breath carbon monoxide diffusion capacity (DLCO). CDH
patients had increased residual volume (RV) and RV/TLC compared with controls.
Increased airway responsiveness to methacholine (MCH) was common but
bronchoconstriction to inhaled metabisulfite (MBS) was rare both in CDH and
control subjects. We conclude that this group of CDH patients has minor residual
lung function impairment. Mild airway obstruction and increased airway
responsiveness to inhaled MCH but not to MBS suggest that structural changes in
distal airways are involved and not autonomic nerve dysfunction. Both artificial
ventilation in the neonatal period and residual lung hypoplasia seem important
determinants of persistent lung function abnormalities in CDH patients
Clinical variables as indicative factors for endoscopy in adolescents with esophageal atresia
Introduction: Gastro-esophageal reflux disease (GERD) occurs frequently in patients operated for esophageal atresia (EA). Longstanding esophagitis may lead to dysphagia, strictures, columnar metaplasia, and dysplasia with an increased risk of adenocarcinoma. Are clinical factors and non-invasive assessments reliable indicators for follow-up with endoscopy? Material and method: A follow-up study with inclusion of EA adolescents in Norway born between 1996 and 2002 was conducted. Clinical assessment with pH monitoring, endoscopy with biopsies, along with interviews and questionnaires regarding gastroesophageal reflux disease (GERD) and dysphagia were performed. Results: We examined 68 EA adolescents. 62% reported GERD by interview, 22% by questionnaire. 85% reported dysphagia by interview, 71% by questionnaire. 24-hour pH monitoring detected pathological reflux index (RI) (>7%) in 7/59 (12%). By endoscopy with biopsy 62 (92%) had histologic esophagitis, of whom 3 (4%) had severe esophagitis. Gastric metaplasia was diagnosed in twelve (18%) adolescents, intestinal metaplasia in only one (1.5%). None had dysplasia or carcinoma. Dysphagia and GERD were statistically correlated to esophagitis and metaplasia, but none of the questionnaires or interviews alone were good screening instruments with high combined sensitivity and specificity. A compound variable made by simply taking the mean of rescaled RI and dysphagia by interview showed to be the best predictor of metaplasia (85% sensitivity, 67% specificity). Conclusion: The questionnaires and interviews used in the present study were not good screening instruments alone. However, combining dysphagia score by interview and RI may be helpful in assessing which patients need endoscopy with biopsy at each individual follow-up examination.</p
Evaluation of lung function changes before and after surfactant application during artificial ventilation in newborn rats with congenital diaphragmatic hernia
Patients with congenital diaphragmatic hernia (CDH) have unilateral or bilateral hypoplasia of the lungs including delayed maturation of the terminal air sacs. Because these lungs are highly susceptible to barotrauma and oxygen toxicity, even in full-term newborns, continued research into optimal ventilatory regimen is essential to improve survival rate and to prevent ongoing lung damage. Against this background, the effect of exogenous surfactant application is evaluated. In newborn rats, CDH was induced after a single dose of 2,4 dichloro-4'-nitrophenyl (Nitrofen) (400 mg/kg) on day 10 of gestation. The newborn rats were intubated immediately after hysterotomy, transferred to a heated multichambered body plethysmograph, and artificially ventilated. Inspiratory peak pressures were initially set at 17 cm H2O, with positive end-expiratory pressure at 0 cm H2O and FIO2at 1.0. The pressure was raised in steps of 5 cm H2O, from 5 to 30 cm H2O, to obtain pressure- volume diagrams at 0, 1, and 6 hours of artificial ventilation. These measurements were obtained in controls and in CDH rats with and without endotracheal installation of bovine surfactant (n = 4 to 10 in each group). Significant differences in lung volume between CDH and control rats were observed at all time-points. Surfactant application had a positive effect on lung volume, especially in control rats at t = 1 hour. No significant differences were observed between the CDH groups at t = 1 or t = 6 hours. In this animal model, the effect of artificial ventilation as well as the beneficial short-term effect of exogenous surfactant application have been evaluated. A continued positive effect on lung volume in CDH lungs could not be determined. Routine administration of exogenous surfactant in human CDH patients is not supported by these experimental results
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