Infant Pulmonary Function in a Randomized Trial of Fetal Tracheal Occlusion for Severe Congenital Diaphragmatic Hernia

Keller, Roberta L.; Hawgood, Samuel; Neuhaus, John; Farmer, Diana L.; Lee, Hanmin; Albanese, Craig T.; Harrison, Michael R.; Kitterman, Joseph A.

doi:10.1203/01.pdr.0000141518.19721.d7

Cited by 64 publications

(44 citation statements)

References 57 publications

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“…Infants were managed with gentle ventilation, using permissive hypercapnia, pressure limitation, and permissive oxygenation (38). Details of neonatal respiratory support are available in the online data supplement.…”

Section: Neonatal Clinical Managementmentioning

confidence: 99%

Congenital Diaphragmatic Hernia

Keller

Tacy²,

Hendricks‐Muñoz³

et al. 2010

Am J Respir Crit Care Med

140

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Rationale: Endothelin-1 (ET1) is dysregulated in pulmonary hypertension (PH). It may be important in the pathobiology of congenital diaphragmatic hernia (CDH). Objectives: We hypothesized that ET1 levels in the first month would be higher in infants with CDH who subsequently expired or were discharged on oxygen (poor outcome). We further hypothesized that ET1 levels would be associated with concurrent severity of PH. Methods: We sampled plasma at 24 to 48 hours, and 1, 2, and 4 weeks of age in 40 prospectively enrolled newborns with CDH. We performed echocardiograms to estimate pulmonary artery pressure at less than 48 hours of age and weekly to 4 weeks. PH was classified in relationship to systemic blood pressure (SBP): less than 2/3 SBP, 2/3 SBP-systemic is related to pressure, or systemic-to-suprasystemic pressure. Measurements and Main Results: ET1 levels at 1 and 2 weeks were higher in infants with poor outcome compared with infants discharged on room air (median and interquartile range: 27.2 [22.6, 33.7] vs. 19.1 [16.1, 29.5] pg/ml, P 5 0. 03; and 24.9 [17.6, 39.5] vs. 17.4 [13.7, 21.8] pg/ml, P 5 0.01 at 1 and 2 weeks, respectively). Severity of PH was significantly associated with increasing ET1 levels at 2 weeks (16.1 [13.7, 21.8], 21.0 [17.4, 31.1], and 23.6 [21.9, 39.5] pg/ml for increasing PH class, P 5 0.03). Increasing severity of PH was also associated with poor outcome at that time (P 5 0.001). Conclusions: Infants with CDH and poor outcome have higher plasma ET1 levels and severity of PH than infants discharged on room air. Severity of PH is associated with ET1 levels.

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Section: Neonatal Clinical Managementmentioning

confidence: 99%

Congenital Diaphragmatic Hernia

Keller

Tacy²,

Hendricks‐Muñoz³

et al. 2010

Am J Respir Crit Care Med

140

View full text Add to dashboard Cite

show abstract

“…Effects on pulmonary function of CDH patients treated with fetal TO are preliminary. Keller et al [43] [48,[59][60][61]. Bronchodilators and inhaled steroids were, at least transiently, used by the majority of CDH patients, during the first year of life and thereafter [61,62].…”

Section: Fetal Tracheal Occlusionmentioning

confidence: 99%

“…Harrison et al [42] showed in a (small) randomized controlled trial comparing fetal endoscopic TO to standard care that mortality is equal. Data concerning long-term outcomes of fetal endoscopic TO are very scarce [43,44].…”

Section: Introductionmentioning

confidence: 99%

The long-term follow-up of patients with a congenital diaphragmatic hernia: a broad spectrum of morbidity

et al. 2008

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Congenital diaphragmatic hernia (CDH) is a life-threatening anomaly with a mortality rate of approximately 40-50%, depending on case selection. It has been suggested that new therapeutic modalities such as nitric oxide (NO), high frequency oxygenation (HFO) and extracorporal membrane oxygenation (ECMO) might decrease mortality associated with pulmonary hypertension and the sequelae of artificial ventilation. When these new therapies indeed prove to be beneficial, a larger number of children with severe forms of CDH might survive, resulting in an increase of CDH-associated complications and/or consequences. In follow-up studies of infants born with CDH, many complications including pulmonary damage, cardiovascular disease, gastro-intestinal disease, failure to thrive, neurocognitive defects and musculoskeletal abnormalities have been described. Long-term pulmonary morbidity in CDH consists of obstructive and restrictive lung function impairments due to altered lung structure and prolonged ventilatory support. CDH has also been associated with persistent pulmonary vascular abnormalities, resulting in pulmonary hypertension in the neonatal period.

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“…In the clinical setting, temporary fetoscopic endoluminal TO (FETO), a minimally invasive surgical technique intended for the most severely affected CDH fetuses (27), improved prenatal imaging findings (8) and neonatal survival rates (27,50). Nevertheless, only sparse functional and morphometric findings have been reported (16,24,31).…”

mentioning

confidence: 99%

“…Because mechanical ventilation and oxygen therapy are standard treatments for neonatal respiratory insufficiency, CDH survivors treated or not by FETO are at high risk of developing BPD (15,59). Despite increased lung growth, temporary TO did not noticeably improve neonatal respiratory function in human and experimental CDH (17,31). Since the underlying biological mechanisms are unknown, clarifying the status of TGF-␤ after TO might be clinically relevant.…”

mentioning

confidence: 99%

Increased TGF-β: a drawback of tracheal occlusion in human and experimental congenital diaphragmatic hernia?

Vuckovic

Herber-Jonat

Flemmer

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Survivors of severe congenital diaphragmatic hernia (CDH) present significant respiratory morbidity despite lung growth induced by fetal tracheal occlusion (TO). We hypothesized that the underlying mechanisms would involve changes in lung extracellular matrix and dysregulated transforming growth factor (TGF)-β pathway, a key player in lung development and repair. Pulmonary expression of TGF-β signaling components, downstream effectors, and extracellular matrix targets were evaluated in CDH neonates who died between birth and the first few weeks of life after prenatal conservative management or TO, and in rabbit pups that were prenatally randomized for surgical CDH and TO vs. sham operation. Before tissue harvesting, lung tissue mechanics in rabbits was measured using the constant-phase model during the first 30 min of life. Human CDH and control fetal lungs were also collected from midterm onwards. Human and experimental CDH did not affect TGF-β/Smad2/3 expression and activity. In human and rabbit CDH lungs, TO upregulated TGF-β transcripts. Analysis of downstream pathways indicated increased Rho-associated kinases to the detriment of Smad2/3 activation. After TO, subtle accumulation of collagen and α-smooth muscle actin within alveolar walls was detected in rabbit pups and human CDH lungs with short-term mechanical ventilation. Despite TO-induced lung growth, mediocre lung tissue mechanics in the rabbit model was associated with increased transcription of extracellular matrix components. These results suggest that prenatal TO increases TGF-β/Rho kinase pathway, myofibroblast differentiation, and matrix deposition in neonatal rabbit and human CDH lungs. Whether this might influence postnatal development of sustainably ventilated lungs remains to be determined.

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Infant Pulmonary Function in a Randomized Trial of Fetal Tracheal Occlusion for Severe Congenital Diaphragmatic Hernia

Cited by 64 publications

References 57 publications

Congenital Diaphragmatic Hernia

Congenital Diaphragmatic Hernia

The long-term follow-up of patients with a congenital diaphragmatic hernia: a broad spectrum of morbidity

Increased TGF-β: a drawback of tracheal occlusion in human and experimental congenital diaphragmatic hernia?

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