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Background: Survival rates of patients with congenital diaphragmatic hernia (CDH) have improved to up to 80%. Little is known about long-term consequences of the disease and its treatment. We evaluated lung function and respiratory symptoms longitudinally in a previously studied cohort of CDH patients and age-matched non-CDH patients who underwent similar neonatal intensive care treatment., Study Design: We tested 27 young adults [mean (SD) age: 26.8 years (2.9)] with CDH and 30 non-CDH patients. Dynamic and static lung volumes, midexpiratory flows, and diffusion capacity were expressed as mean (SD) standard deviation scores. Prevalence of respiratory symptoms was evaluated with the European Community Respiratory Health Survey., Results: All data are expressed as mean (SD). FEF(25-75) in CDH patients had slightly deteriorated since childhood (CDH: -0.7 (1.4) vs. -1.6 (1.5), P < 0.001; non-CDH patients: 0.2 (1.4) vs. -0.3 (1.6), P = 0.038, ns). Diffusion capacity decreased in both groups (CDH: DL(CO) c 0.2 (1.1) vs. -1.5 (1.1), P <0.001; non-CDH: DL(CO) c 0.1 (0.4) vs. -1.1 (1.1), P < 0.001). Lung volumes were normal in both groups. The prevalence of asthma was higher than in the normal population (27.6% in patients and 30% in controls, P < 0.001)., Conclusions: Airflow obstruction and diffusion capacity deteriorated mildly from childhood into adulthood in survivors of CDH. The improved survival of patients with more severe forms of diaphragmatic hernia calls for long-term follow-up of lung function., (Copyright © 2012 Wiley Periodicals, Inc.)

Infants with congenital diaphragmatic hernia (CDH) or anterior wall defects (AWD) can suffer abnormal antenatal lung growth, the risk, however, may be greater for CDH infants. The objectives of this study were to test the hypothesis that following surgical correction, CDH infants would have worse lung function at follow-up than AWD infants and to determine whether fetal lung volume (FLV) results correlated with the lung function results at follow-up. Thirteen infants with CDH and 13 infants with AWD had lung function measurements at a median age of 11 (range 6-24) months; 17 of the infants had had their FLV assessed. Lung function was assessed by plethysmographic measurement of lung volume (FRCpleth) and airway resistance (Raw). In addition, functional residual capacity was assessed by a helium gas dilution technique (FRCHe); tidal breathing parameters (T(PTEF) :Te) and compliance and resistance of the respiratory system (Crs and Rrs, respectively) were also determined. FLV was assessed using three-dimensional (3D) ultrasound and virtual organ computer aided analysis. The CDH compared to the AWD infants had a higher median FRCpleth (41 ml/kg vs. 37 ml/kg, P = 0.043) and a lower median Crs (1.45 ml/cm H(2) O/kg vs. 2.78 ml/cm H(2) O/kg, P = 0.041). FRCpleth results correlated significantly with FLV results (r = 0.721, P < 0.001). In conclusion, infants with CDH had significantly different lung function at follow-up than AWD infants. Our findings suggest FLV results may predict lung function abnormalities at follow-up in infants with surgically correctable anomalies., (Copyright © 2012 Wiley Periodicals, Inc.)

Aim: The aim of this study was to determine the presence of the neuronal nitric oxide synthase (nNOS) in near full-term lambs with congenital diaphragmatic hernia (CDH) and its role in the modulation of pulmonary vascular basal tone., Methods: We surgically created diaphragmatic hernia on the 85th day of gestation. On the 135th, catheters were used to measure pulmonary pressure and blood flow. We tested the effects of 7-nitroindazole (7-NINA), a specific nNOS antagonist and of N-nitro-L-arginine (L-NNA), a nonspecific nitric oxide synthase antagonist. In vitro, we tested the effects of the same drugs on isolated pulmonary vessels. The presence of nNOS protein in the lungs was detected by Western blot analysis., Results: Neither 7-NINA nor L-NNA modified pulmonary vascular basal tone in vivo. After L-NNA injection, acetylcholine (ACh) did not decrease significantly pulmonary vascular resistance (PVR). In vitro, L-NNA increased the cholinergic contractile-response elicited by electric field stimulation (EFS) of vascular rings from lambs with diaphragmatic hernia., Conclusion: We conclude that nNOS protein is present in the lungs and pulmonary artery of near full-term lamb fetuses with diaphragmatic hernia, but that it does not contribute to the reduction of pulmonary vascular tone at birth.

Unlabelled: The assessment of lung volumes, particularly functional residual capacity (FRC), is crucial for understanding lung development during infancy in CDH patients., Aim: To evaluate changes in lung function during infancy in subjects with CDH treated with a "gentle ventilation" technique and delayed surgery strategy in the neonatal period., Methods: 13 CDH infants were studied twice and compared with a population of 28 healthy infants (HI). Tidal-Volume (Vt), respiratory rate (RR) and time to peak expiratory flow/expiratory time ratio (tPTEF/Te) were measured with an ultrasonic flow meter; Compliance (Crs) and Resistance (Rrs) of the respiratory system were studied with the single occlusion technique; FRC and Lung Clearance Index (LCI), were assessed with the sulfur hexafluoride (SF6) wash-in/wash-out technique. The differences between the first (T1) and second (T2) measurement in the CDH group were assessed by the Student's t-test for paired values. For each set of measurement (T1 and T2) the values were compared with HI by Student's t-test., Results: Mean age at test was 7.5 +/- 5.2 months for HI, 4.5 +/- 2.5 at T1 and 11.9 +/- 4.5 months at T2 for CDH infants. At T1 there were no significant differences between CDH infants and HI in Vt, Crs, and FRC, while tPTEF/te ratio was lower and RR, Rrs, and LCI were higher in CDH patients than in HI. At T2 Vt, Crs, and FRC remained normal in CDH patients as well as RR that, at this time was not different between CDH and healthy infants; tPTEF/te remained below and Rrs and LCI remained above normal ranges, indicating a persistent impairment in lower airways patency., Conclusions: Lung function in infants with severe CDH is characterized by a persistent impairment in airways patency and significant inhomogeneity of ventilation, suggesting a peripheral bronchial obstruction even if the other lung function tests are within normal ranges.

Several animal models have been proposed to study the pathophysiology of congenital diaphragmatic hernia (CDH). Surgical induction of CDH in fetal rabbits during the pseudoglandular phase has been shown to induce severe pulmonary hypoplasia, but functional studies in this model are scarce. We aimed to measure neonatal pulmonary impedance and related it to the severity of lung hypoplasia. CDH was surgically created in rabbits at 23 days of gestation. Following cesarean delivery at term (31 days) pups were subjected to measurement of total lung capacity (TLC), lung to body weight ratio (LBWR) and lung impedance by forced oscillation technique (FOT). Airway resistance (R(aw)), tissue elastance (H(L)), tissue damping (G(L)), and hysteresivity (eta) (G(L)/H(L)) were calculated from impedance data. Twelve CDH fetuses and 15 controls were available for final analysis. LBWR and TLC were significantly lower in the CDH group compared to gestational and age matched controls (P<0.001). R(aw), H(L), and G(L) were significantly increased in CCDH fetuses. eta and H(L) best reflected lung hypoplasia (LBWR) (r(2) = 0.42 and 0.43; P=0.001), indicating a dominant contribution of lung tissue mechanics to CDH-induced lung hypoplasia. We successfully introduced lung impedance measurement by FOT in neonatal rabbits. Following surgical induction of CDH in the pseudoglandular phase, they have, next to morphological evidence of pulmonary hypoplasia, changes in lung mechanics. Our results for lung tissue mechanics support the concept of delayed pulmonary tissue modeling. We propose to employ functional studies in future experiments when evaluating prenatal interventions aimed at reversing pulmonary hypoplasia., ((c) 2007 Wiley-Liss, Inc.)

Congenital diaphragmatic hernia (CDH) is accompanied by pulmonary hypoplasia and structural abnormalities of the pulmonary vascular bed. It is unknown whether pulmonary function, exercise capacity, and gas exchange during exercise are impaired in adult CDH survivors. The objective of this study was to assess the long-term pulmonary function, exercise capacity, and gas exchange during exercise and relate these findings with quality of life. Of the 23 patients eligible for this study, 12 adult CDH survivors (mean age, 24.3 +/- 4.1 years) with high-risk CDH agreed to participate. Pulmonary function tests, diffusion capacity, and a cardiopulmonary exercise test (CPET) were performed. The FEV1 (mean z-score +/- SD; -1.30 +/- 1.37), FEF25-75% (-1.49 +/- 1.14), and the KCO (-1.03 +/- 1.24) were found to be lower in CDH survivors. The RV/TLC ratio (28.2% +/- 5.0%) was found to be higher. Despite these abnormalities, percent predicted work load (102% +/- 17.2%) and percent predicted maximal oxygen uptake (90.8% +/- 18.9%) were normal in most of the patients. The quality of life of CDH survivors, assessed with the SF-36 questionnaire, is comparable to the general population. Comparison of participants to non-participants did not reveal significant differences in clinical characteristics. In this first study assessing pulmonary function in adult survivors of CDH, mild airway obstruction was observed in most of the patients together with a slightly reduced diffusion capacity for CO. Exercise capacity and gas exchange parameters were normal in this group, indicating that patients do not have a physical impairment, as reflected by a normal quality of life of CDH patients., ((c) 2007 Wiley-Liss, Inc.)

Our objective was to study exercise capacity and cardiorespiratory response to exertion in survivors of congenital diaphragmatic hernia (CDH). This was a cross-sectional cohort study of 23 CDH survivors, aged 10-16 years, and 23 gender- and age-matched controls. Exercise testing was performed on a cycle ergometer, with cardiac output measurements made using exponential CO2 rebreathing. Pretest cardiorespiratory assessment was done by echocardiography and pulmonary function testing. Statistical analysis was performed using Student's t-test, regression analysis, and longitudinal model computing with spatial covariance structure. No echocardiographic evidence for pulmonary hypertension was found at rest (right ventricular systolic pressures, 27 +/- 6 mmHg). Mean pulmonary artery diameter on the side of the CDH was significantly smaller than contralaterally, but was within normal range (z-score, 0 +/- 1.1 vs. 1.2 +/- 1.6, P < 0.01). Exercise capacity was mildly reduced in CDH compared to controls and predictive data (maximum workload, 77% +/- 12% vs. 91% +/- 16% of predicted, P < 0.01). Cardiorespiratory response to exertion was not significantly different between groups. In conclusion, most adolescent CDH survivors have nearly normal exercise capacity and cardiorespiratory response to exertion. This study may prove useful in comparisons with future cohorts comprising more severely affected individuals now surviving due to improved neonatal care., (Copyright 2006 Wiley-Liss, Inc.)

Infants born with severe congenital diaphragmatic hernia (DH) characteristically have pulmonary hypoplasia. Airway hyperresponsiveness during the first 4 weeks of life can be demonstrated in most of these neonates. Early postnatal pulmonary development in infants with severe DH has not been well characterized. We examined lung growth in patients with congenital DH by using the forced deflation method to study pulmonary function in 18 infants on mechanical ventilation who survived neonatal repair of their congenital DH. Thirteen infants without primary pulmonary pathology who required general anesthesia for other surgery served as controls. Infants were further divided according to age at the time of testing into early (age < or = 7 days at time of testing) and late (age > or = 29 days) groups, yielding four groups of subjects: early diaphragmatic hernia (EDH): n = 9; mean age, 4.2 days; range, 1-7 days; early controls (EC): n = 8; mean age, 3.1 days; range, 1-6 days; late diaphragmatic hernia (LDH): n = 11; mean age, 57.7 days, range, 28-120 days; and late controls (LC); n = 5; mean age, 52.2 days; range 32-90 days. All infants were studied once, with the exception of two infants with DH who were studied on two occasions at EDH and LDH stages. A marked reduction in weight-corrected forced vital capacity (FVC) was seen in the EDH group (13.9 +/- 3.9 ml/kg) as compared to the EC group (44.4 +/- 4.9 ml/kg). During the ensuing 4 months of life, FVC in patients with LDH (24.5 +/- 1.9 ml/kg) was much higher than FVC in patients with EDH (P < 0.05). These findings demonstrate the presence of pulmonary hypoplasia in the EDH group and suggest subsequent rapid postnatal lung growth. An index of rate constant, MEF25/FVC, as compared with control groups was abnormally elevated in EDH subjects (1.87 +/- 0.30/second vs 1.16 +/- 0.32/ second, P < 0.05), indicating significantly increased lower airway caliber relative to lung volume. The severe reduction of the rate constant in the LDH group (0.36 +/- 0.05/second vs 0.73 +/- 0.07/second, P < 0.05) suggests the development of lower airway obstruction. After the administration of a nebulized bronchodilator (BD), an increase in MEF25 (32.9%) in the EDH group was not significant, but an increase of 134.7% in the LDH group was significant (P < 0.05). Although the study utilized a cross-sectional design with most of the infants in either the early or late group, present findings suggest that infants with EDH have lung restriction reflecting pulmonary hypoplasia. These infants developed lower airway obstruction and airway hyperresponsiveness with only mild fixed obstruction over the first 4 months of life.

Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypoplasia that limits survival, but the nature and extent of pulmonary dysfunction in neonates with CDH have not been studied. We performed pulmonary function tests (PFTs) in eight intubated infants who survived neonatal repair of CDH (wt, 3.33 +/- 0.15 kg; age, 20.1 +/- 2.7 d; mean +/- S.E.M.). PFTs obtained from six full-term infants (wt, 3.56 +/- 0.15 kg; age, 25.0 +/- 3.3 d) with no respiratory illness served as controls. The deflation flow-volume curve technique produced maximum expiratory flow-volume (MEFV) curves, giving reproducible measurements of forced vital capacity (FVC) and maximal expiratory flow at 25% of FVC (MEF25). Respiratory system compliance (Crs) and resistance (Rrs) were obtained with a modified passive mechanics technique. In seven of eight infants PFTs were repeated after nebulized bronchodilator (0.1% isoetharine). In neonates surviving CDH repair, as compared to those with normal lung function, FVC was significantly reduced (20.78 +/- 3.32 vs. 39.83 +/- 3.30 mL.kg-1, P less than 0.05). MEF25 was also markedly reduced (20.78 +/- 3.32 vs. 39.83 +/- 3.30 mL.kg-1.s-1, P less than 0.05), indicating lower airway obstruction. After administration of nebulized bronchodilator, PFTs showed significant increases from control values in both FVC (15.9%) and MEF25 (200%) without changes in Crs and Rrs. These findings indicate that neonates with CDH have restrictive lung defects, reflecting hypoplasia. After surgical repair and mechanical ventilation airway reactivity develops, primarily in smaller airways, and this may complicate the postoperative course.

Deciding when to wean neonates from extracorporal membrane oxygenation (ECMO) can be difficult. The usefulness of simple measurements of pulmonary mechanics e.g., dynamic compliance (Cdyn) has been questioned. We investigated the pulmonary mechanics of eight neonates using the interrupter technique, which allows the partitioning of pulmonary mechanics into compartments representing the conducting airways and more peripheral phenomena (viscoelastic properties and "pendelluft"). Three neonates required ECMO for a congenital diaphragmatic hernia (CDH), two for hyaline membrane disease (HMO), two for meconium aspiration syndrome (MAS), and one for pneumonia. All neonates with MAS, HMD, and pneumonia were successfully weaned from ECMO when their Cdyn was 0.3 mL/cmH2O/kg or greater [mean 0.34 +/- 0.06 (SEM)]. All three neonates with CDH died and their highest Cdyn was 0.21, 0.19, and 0.09 mL/cmH2O/kg respectively (mean, 0.16 +/- 0.037). The airway resistance (Raw) and the slower component of pressure change after interruption (delta Pdiff), a measure of the more peripheral phenomena of the lung, were not significantly different in those neonates who survived and those who did not. The values for delta Pdiff in all patients were higher than those in healthy neonates. However, the Raw was not different. This suggests that the major disturbance in pulmonary mechanics was distal to the conducting airways. Those neonates who were successfully weaned from ECMO had a significantly higher Cdyn 24-48 hours prior to decannulation. Considering the lung as a two-compartment model offers no advantages when compared to the one-compartment model for the prediction of the outcome of a neonate on ECMO.