Neonatal Rodent Ventilation and Clinical Correlation in Congenital Diaphragmatic Hernia

Background: Optimal ventilator management is critical to outcome in congenital diaphragmatic hernia (CDH), though data detailing the pathophysiologic and anatomic nuances of the lungs affected by CDH remain elusive. More specifically, limited data exist describing the pulmonary mechanics of CDH. Our objective was to use both a murine model and patient data to study CDH-associated differences in oxygenation, airway resistance, and pulmonary mechanics by disease severity.

Methods: We used the nitrofen rodent model of CDH. For both control and CDH rodents, data were collected within the first hour of life. Oxygen saturations (SpO2) were collected using MouseOx, and large airway resistance and inspiratory capacities were collected using FlexiVent. A single-center, retrospective review of term (35+ weeks gestation) CDH infants from 2014 to 2020 was performed. Tidal volumes (mL/kg body weight) were collected every 6 hours for the first 48 hours of life or until the patient was taken off conventional ventilation. Newborns that were mechanically ventilated but had no primary pulmonary pathology were used as controls. CDH severity was defined by the CDH Study Group classification system (Stage A/B = low risk; Stage C/D or non-repaired = high risk).

Results: Control rodents had a median SpO2 of 94.4% (IQR 87.6 – 97.5%), and CDH pups had a median SpO2 of 27.9% (IQR 22.4 - 30.4%) (p < 0.01) (Figure 1A). There was no difference in large airway resistance between CDH and control rodents (p=0.64) (Figure 1B). CDH rodents had significantly lower inspiratory capacity than control rodents (median 267L, IQR 216 – 352 vs. median 110L, IQR 70 - 170; p<0.01) (Figure 1C). Thirty CDH and ten control infants met inclusion criteria. Fourteen (46.7%) patients were CDHSG Stage A/B, thirteen (43.3%) were CDHSG Stage C/D, and three patients did not undergo CDH repair. CDH infants had a lower initial SpO2 than control infants (Figure 2A). Overall, CDH infants had lower tidal volumes than control infants (median 4.2mL/kg, IQR 3.3 – 5.0 vs. 5.4mL/kg, IQR 4.7 – 6.2; p=0.03). When risk-stratified, there was no difference in tidal volume between controls and low-risk CDH patients, but high-risk CDH infants had significantly lower tidal volumes than controls (p=0.02) (Figure 2B).

Conclusion: Newborns with CDH have significantly lower SpO2 and 25% lower tidal volumes than infants without pulmonary pathology. The nitrofen model of CDH reflects these differences, and rodent ventilation models may be useful in studying targeted therapy and ventilatory strategies for CDH infants.