Intrapulmonary Instillation of Perflurooctylbromide Improves Lung Growth, Alveolarization, and Lung Mechanics in a Fetal Rabbit Model of Diaphragmatic Hernia

Herber-Jonat, Susanne; Vuckovic, Aline; Mittal, Rakhi; Hilgendorff, Anne; Jani, Jacques; Flemmer, Andreas W.

doi:10.1097/pcc.0000000000000271

Cited by 5 publications

(7 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In pilot experiments, tracheal injection of BAY 41-2272 using doses up to 16 mg/kg body wt did not affect fetal survival, body weight, or organ weights (data not shown). Moreover, the safety of fibrin sealant has already been reported in rabbit fetuses (33,45). At term (31 days), living fetuses were delivered by cesarean section and weighed.…”

Section: Methodsmentioning

confidence: 92%

“…Anesthesia and general surgical procedures have been described elsewhere (65,66). The feasibility of tracheal injection of medication has already been shown in the fetal rabbit (17,33). Briefly, at 23 days of gestation (pseudoglandular stage of lung development), two ovarian-end fetuses per doe were subjected to the surgical creation of diaphragmatic hernia (DH) through a left thoracotomy (23).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Antenatal BAY 41-2272 reduces pulmonary hypertension in the rabbit model of congenital diaphragmatic hernia

Vuckovic

Herber-Jonat

Flemmer

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

View full text Add to dashboard Cite

Infants with congenital diaphragmatic hernia (CDH) fail to adapt at birth because of persistent pulmonary hypertension (PH), a condition characterized by excessive muscularization and abnormal vasoreactivity of pulmonary vessels. Activation of soluble guanylate cyclase by BAY 41-2272 prevents pulmonary vascular remodeling in neonatal rats with hypoxia-induced PH. By analogy, we hypothesized that prenatal administration of BAY 41-2272 would improve features of PH in the rabbit CDH model. Rabbit fetuses with surgically induced CDH at day 23 of gestation were randomized at day 28 for an intratracheal injection of BAY 41-2272 or vehicle. After term delivery (day 31), lung mechanics, right ventricular pressure, and serum NH2-terminal-pro-brain natriuretic peptide (NT-proBNP) levels were measured. After euthanasia, lungs were processed for biological or histological analyses. Compared with untouched fetuses, the surgical creation of CDH reduced the lung-to-body weight ratio, increased mean terminal bronchial density, and impaired lung mechanics. Typical characteristics of PH were found in the hypoplastic lungs, including increased right ventricular pressure, higher serum NT-proBNP levels, thickened adventitial and medial layers of pulmonary arteries, reduced capillary density, and lower levels of endothelial nitric oxide synthase. A single antenatal instillation of BAY 41-2272 reduced mean right ventricular pressure and medial thickness of small resistive arteries in CDH fetuses. Capillary density, endothelial cell proliferation, and transcripts of endothelial nitric oxide synthase increased, whereas airway morphometry, lung growth, and mechanics remained unchanged. These results suggest that pharmacological activation of soluble guanylate cyclase may provide a new approach to the prenatal treatment of PH associated with CDH.

show abstract

Section: Methodsmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Antenatal BAY 41-2272 reduces pulmonary hypertension in the rabbit model of congenital diaphragmatic hernia

Vuckovic

Herber-Jonat

Flemmer

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

View full text Add to dashboard Cite

show abstract

“…Also there was improvement in pulmonary function tests, airway (RAC) or vascular morphometry (reduced vessel thickness) compared to controls. Recently, it was shown that IT perfluorocytylbromide (PFOB) also improved lung mechanics …”

Section: Resultsmentioning

confidence: 99%

“…Recently, it was shown that IT perfluorocytylbromide (PFOB) also improved lung mechanics. 34 In lambs, maternal PO tadalafil (phosphodiesterase inhibitor) improved fetal pulmonary blood flow but had no impact on LBWR (Table 4). 62 A second study in the lamb model delivered a single dose of KGF IT which had little impact on RAC or LBWR.…”

Section: Isolated Studiesmentioning

confidence: 99%

Medical interventions to reverse pulmonary hypoplasia in the animal model of congenital diaphragmatic hernia: A systematic review

Eastwood

Russo

Toelen

et al. 2015

Pediatric Pulmonology

View full text Add to dashboard Cite

We aimed to systematically review all published pre-clinical research on prenatal medical treatment of pulmonary hypoplasia in congenital diaphragmatic hernia (CDH). Background The neonatal mortality due to isolated CDH remains high. Whether fetal endoscopic tracheal occlusion (FETO) reduces mortality is still to be demonstrated. Therefore more potent preferentially medical therapy would be welcomed. Methods We searched MEDLINE (Pubmed), Embase and the Web of Science including all studies from the earliest date (1951) to December 2013. Article quality was assessed using the modified CAMRADES checklist. Inclusion criteria were those animal studies addressing prenatal medical interventions and principal variables were confirmation of a diaphragmatic defect, lung to body weight ratio (LBWR), formal airway morphometry or DNA/protein content. Results In total 983 articles were identified. Following abstract review, 96 articles were assessed by two authors in agreement with a third for eligibility. Of these, 43 were included in the final analysis. The median number of study quality checklist items (maximum 10) scored was 4 (IQ range: 2-5). Thirty (69.8%) of studies were in the nitrofen rat. The majority were treated with vitamins or glucocorticoids. Single studies reported some improvement in lung morphology with alternative therapies. It was impossible to identify a pattern in animal model selection or creation, mode, time point or duration of treatment and readouts. Only one study reported a sample size calculation. Conclusion Comparison in pre-clinical studies in CDH is challenging due to methodological variation. Agreed standardized methods need to be applied in future investigation of new medical therapies.

show abstract

“…TLV use is motivated by evidence of a more homogenous lung recruitment ( Hirschl et al, 1994 ; Tooley et al, 1996 ) and its potential as an efficient technique to remove pulmonary aspiration debris ( Foust et al, 1996 ; Avoine et al, 2011 ). Moreover, PFCs have low surface tension, anti-inflammatory properties ( Thomassen et al, 1997 ; Rotta and Steinhorn, 1998 ; Khalighi et al, 2016 ) and have been shown to promote lung growth ( Nobuhara et al, 1998 ; Herber-Jonat et al, 2014 ). PFCs are known for their high solubilities for most gasses ( Riess, 2005 ) enabling them to be used for respiratory support.…”

Section: Introductionmentioning

confidence: 99%

Perflubron Distribution During Transition From Gas to Total Liquid Ventilation

et al. 2018

View full text Add to dashboard Cite

Total liquid ventilation (TLV) using perfluorocarbons has shown promising results for the management of neonatal respiratory distress. However, one important safety consideration for TLV is a better understanding of the early events during the transition to TLV, especially regarding the fate of residual air in the non-dependent-lung regions. Our objective was to assess perflubron distribution during transition to TLV using electrical impedance tomography, complemented by fluoroscopy, in a neonatal lamb model of induced surfactant deficiency. Eight lambs were anesthetized and ventilated in supine position. Surfactant deficit was induced by saline lung lavage. After deflation, lungs were filled with 25 ml/kg perflubron over 18 s, and TLV was initiated. Electrical impedance tomography data was recorded from electrodes placed around the chest, during the first 10 and at 120 min of TLV. Lung perfusion was also assessed using hypertonic saline injection during apnea. In addition, fluoroscopic sequences were recorded during initial lung filling with perfluorocarbons, then at 10 and 60 min of TLV. Twelve lambs were used as controls for histological comparisons. Transition to TLV involved a short period of increased total lung volume (p = 0.01) secondary to recruitment of the dependent lung regions. Histological analysis shows that TLV was protective of these same regions when compared to gas-ventilated lambs (p = 0.03). The non-dependent lung regions filled with perflubron over at least 10 min, without showing signs of overdistention. Tidal volume distribution was more homogenous in TLV than during the preceding gas ventilation. Perflubron filling was associated with a non-significant increase in the anterior distribution of the blood perfusion signal, from 46 ± 17% to 53 ± 6% (p = 0.4). However, combined to the effects on ventilation, TLV had an instantaneous effect on ventilation-perfusion relationship (p = 0.03), suggesting better coupling. Conclusion: transition to TLV requires at least 10 min, and involves air evacuation or dissolution in perflubron, dependent lung recruitment and rapid ventilation-perfusion coupling modifications. During that time interval, the total lung volume transiently increases. Considering the potential deleterious effect of high lung volumes, one must manage this transition phase with care and, we suggest using a real-time monitoring system such as electrical impedance tomography.

show abstract

Intrapulmonary Instillation of Perflurooctylbromide Improves Lung Growth, Alveolarization, and Lung Mechanics in a Fetal Rabbit Model of Diaphragmatic Hernia

Cited by 5 publications

References 51 publications

Antenatal BAY 41-2272 reduces pulmonary hypertension in the rabbit model of congenital diaphragmatic hernia

Antenatal BAY 41-2272 reduces pulmonary hypertension in the rabbit model of congenital diaphragmatic hernia

Medical interventions to reverse pulmonary hypoplasia in the animal model of congenital diaphragmatic hernia: A systematic review

Perflubron Distribution During Transition From Gas to Total Liquid Ventilation

Contact Info

Product

Resources

About