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Diaphragm Muscle Weakness Contributes to Ventilatory Deficits in an Animal Model of Congenital Diaphragmatic Hernia
Author(s) -
Fogarty Matthew J.,
Enninga Elizabeth A. L.,
Ibrogba Eniola R.,
Ruano Rodrigo R.,
Sieck Gary C.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06043
Subject(s) - medicine , congenital diaphragmatic hernia , pulmonary hypoplasia , diaphragm (acoustics) , diaphragmatic breathing , lung volumes , isometric exercise , ventilation (architecture) , plethysmograph , pulmonary function testing , functional residual capacity , pulmonary hypertension , cardiology , lung , anesthesia , fetus , pregnancy , pathology , mechanical engineering , genetics , physics , alternative medicine , acoustics , loudspeaker , engineering , biology
Congenital diaphragmatic hernia (CDH) occurs in approximately 1 in 2,500 live births; it is associated with high rates of neonatal mortality, especially in cases with severe pulmonary hypoplasia and pulmonary arterial hypertension. Treatments have focused on hernia repair and ameliorating lung hypoplasia, with the precise pathophysiological mechanisms of CDH remain unknown. We investigated whether or not diaphragm muscle (DIAm) weakness is apparent in CDH, evaluating DIAm force generation and ventilatory function in a Nitrofen rat model. 7 pregnant rats received 100 mg of Nitrofen in 2 mL of olive oil at 9 days gestational age and rat pups were collected at birth. Ventilatory function was assessed in isolated plethysmography chambers (Buxco). Following these functional assessments, neonatal pups were euthanized, and the DIAm with its rib attachments excised. The presence or absence of a CDH was confirmed and a DIAm strip was obtained either from control pups, or from the unaffected side in CDH pups. The isometric force generation of these DIAm strips and their fatigueability was assessed using field stimulation of muscle at various frequencies (5–100 Hz) and normalized to DIAm cross‐sectional area. Statistical significance was determined using a Student’s t‐test or Mann‐Whitney u test at the P <0.05 level. A marked reduction in both neonatal respiratory rate (−42%) and respiratory minute ventilation (−43%) was observed in CDH pups compared to controls ( P <0.01). We observed reduced DIAm twitch (−40%), maximum tetanic (−72%) and residual force following fatigue (−69%) in CDH pups compared to controls ( P <0.05). CDH neonatal rat pups exhibit DIAm weakness and ventilatory disturbances. Based on previous modelling of ventilatory function, it is possible that DIAm weakness contributes to the poor ventilation, as CDH DIAm forces following fatigue were less than control groups. This work has important considerations when assessing novel treatment outcomes in clinical CDH.