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Sustained inflation improves initial lung aeration in newborn rabbits with a diaphragmatic hernia

Pediatric Research volume 95, pages 660–667 (2024)Cite this article

Abstract

Background

Infants with a congenital diaphragmatic hernia (DH) have underdeveloped lungs and require mechanical ventilation after birth, but the optimal approach is unknown. We hypothesised that sustained inflation (SI) increases lung aeration in newborn kittens with a DH.

Methods

In pregnant New Zealand white rabbits, a left-sided DH was induced in two fetal kittens per doe at 24-days gestation (term = 32 days); litter mates acted as controls. DH and control kittens were delivered by caesarean section at 30 days, intubated and mechanically ventilated (7–10 min) with either an SI followed by intermittent positive pressure ventilation (IPPV) or IPPV throughout. The rate and uniformity of lung aeration was measured using phase-contrast X-ray imaging.

Results

Lung weights in DH kittens were ~57% of controls. An SI increased the rate and uniformity of lung aeration in DH kittens, compared to IPPV, and increased dynamic lung compliance in both control and DH kittens. However, this effect of the SI was lost when ventilation changed to IPPV.

Conclusion

While an SI improved the rate and uniformity of lung aeration in both DH and control kittens, greater consideration of the post-SI ventilation strategy is required to sustain this benefit.

Impact

  • Compared to intermittent positive pressure ventilation (IPPV), an initial sustained inflation (SI) increased the rate and uniformity of lung aeration after birth. However, this initial benefit is rapidly lost following the switch to IPPV.

  • The optimal approach for ventilating CDH infants at birth is unknown. While an SI improves lung aeration in immature lungs, its effect on the hypoplastic lung is unknown. This study has shown that an SI greatly improves lung aeration in the hypoplastic lung.

  • This study will guide future studies examining whether an SI can improve lung aeration in infants with a CDH.

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Fig. 1: Phase-contrast X-ray images acquired from near-term diaphragmatic hernia (DH) and control kittens at the end of phase one of ventilation.
Fig. 2: Physiological recordings of lung air volumes and airway pressures in ventilated near-kittens with a diaphragmatic hernia.
Fig. 3: Dynamic lung compliance during Phase 1 of ventilation in control kittens and kittens with a diaphragmatic hernia.
Fig. 4: Dynamic lung compliance during phase 2 (shaded region) when both diaphragmatic hernia (DH) and control kittens received IPPV.
Fig. 5: Regional lung aeration rates.
Fig. 6: Uniformity of lung aeration.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author upon reasonable request.

References

  1. Langham, M. R. et al. Congenital diaphragmatic hernia: epidemiology and outcome. Clin. Perinatol. 23, 671–688 (1996).

    Article  PubMed  Google Scholar 

  2. DeKoninck, P. L. J. et al. Effects of tracheal occlusion on the neonatal cardiopulmonary transition in an ovine model of diaphragmatic hernia. Arch. Dis. Child. Fetal Neonatal Ed. 104, F609–F616 (2019).

    Article  PubMed  Google Scholar 

  3. Kashyap, A. J. et al. Neonatal cardiopulmonary transition in an ovine model of congenital diaphragmatic hernia. Arch. Dis. Child. Fetal Neonatal Ed. 104, F617–F623 (2019).

  4. Kotecha, S. et al. Congenital diaphragmatic hernia. Eur. Respir. J. 39, 820 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Mous, D. S., Kool, H. M., Wijnen, R., Tibboel, D. & Rottier, R. J. Pulmonary vascular development in congenital diaphragmatic hernia. Eur. Respir. Rev. 27, 170104 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Hooper, S. B. et al. Imaging lung aeration and lung liquid clearance at birth using phase contrast X-ray imaging. Clin. Exp. Pharmacol. Physiol. 36, 117–125 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Siew, M. L. et al. Inspiration regulates the rate and temporal pattern of lung liquid clearance and lung aeration at birth. J. Appl Physiol. (1985) 106, 1888–1895 (2009).

    Article  PubMed  Google Scholar 

  8. Snoek, K. G. et al. Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: The CDH EURO Consortium Consensus – 2015 Update. Neonatology 110, 66–74 (2016).

    Article  PubMed  Google Scholar 

  9. Lally, K. P. Congenital diaphragmatic hernia; the past 25 (or so) years. J. Pediatr. Surg. 51, 695–698 (2016).

    Article  PubMed  Google Scholar 

  10. Flemmer, A. W. et al. Lung hypoplasia in newborn rabbits with a diaphragmatic hernia affects pulmonary ventilation but not perfusion. Pediatr. Res 82, 536–543 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pryor, E. J. et al. Improving lung aeration in ventilated newborn preterm rabbits with a partially aerated lung. J. Appl Physiol. (1985) 129, 891–900 (2020).

    Article  PubMed  Google Scholar 

  12. Sobotka, K. S. et al. An initial sustained inflation improves the respiratory and cardiovascular transition at birth in preterm lambs. Pediatr. Res. 70, 56 (2011).

    Article  PubMed  Google Scholar 

  13. te Pas, A. B. et al. Optimizing lung aeration at birth using a sustained inflation and positive pressure ventilation in preterm rabbits. Translational investigation. Pediatr. Res. 80, 85 (2016).

    Article  Google Scholar 

  14. te Pas, A. B. et al. Establishing functional residual capacity at birth: the effect of sustained inflation and positive end expiratory pressure in a preterm rabbit model. Pediatr. Res. 65, 537–541 (2009).

    Article  Google Scholar 

  15. Lang, J. A. R. et al. Increase in pulmonary blood flow at birth: role of oxygen and lung aeration. J. Physiol. 594, 1389–1398 (2016).

    Article  CAS  PubMed  Google Scholar 

  16. Lang, J. A. R. et al. Ventilation/perfusion mismatch during lung aeration at birth. J. Appl. Physiol. 117, 535–543 (2014).

    Article  ADS  PubMed  Google Scholar 

  17. Flemmer, A. W. et al. Lung tissue mechanics predict lung hypoplasia in a rabbit model for congenital diaphragmatic hernia. Pediatr. Pulmonol. 42, 505–512 (2007).

    Article  PubMed  Google Scholar 

  18. Kitchen, M. J. et al. A new design for high stability pressure-controlled ventilation for small animal lung imaging. J. Instrum. 5, T02002 (2010).

    Article  Google Scholar 

  19. McGillick, E. V. et al. Elevated airway liquid volumes at birth: a potential cause of transient tachypnea of the newborn. J. Appl Physiol. (1985) 123, 1204–1213 (2017).

    Article  PubMed  Google Scholar 

  20. Kitchen, M. J. et al. Dynamic measures of regional lung air volume using phase contrast x-ray imaging. Phys. Med. Biol. 53, 6065–6077 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Hooper, S. B. et al. Imaging lung aeration and lung liquid clearance at birth. FASEB J. 21, 3329–3337 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Hooper, S. B., Te Pas, A. B. & Kitchen, M. J. Respiratory transition in the newborn: a three-phase process. Arch. Dis. Child. Fetal Neonatal Ed. 101, F266–F271 (2016).

    Article  PubMed  Google Scholar 

  23. Tan, J. K. et al. Long-term medical and psychosocial outcomes in congenital diaphragmatic hernia survivors. Arch. Dis. Child 104, 761–767 (2019).

    Article  PubMed  Google Scholar 

  24. Stainsby, A. V. et al. Effect of prenatal diaphragmatic hernia on pulmonary arterial morphology. Anat. Rec. https://doi.org/10.1002/ar.25159 (Hoboken) 2023.

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Acknowledgements

This research was undertaken on the Imaging Beamline at the Japanese Synchrotron facility, SPring-8, and we gratefully acknowledge the infrastructure support they provided.

Funding

This research was supported by an NHMRC Program Grant (APP113902) and the Victorian Government’s Operational Infrastructure Support Program. E.V.M. was a NHMRC Peter Doherty Biomedical Early Career Fellowship (APP1138049). S.B.H. was supported by an NHMRC Senior Principal Research Fellowship (APP1154914). A.B.t.P. was the recipient of a Vidi grant, The Netherlands Organisation for Health Research and Development (ZonMw), part of the Innovational Research Incentives Scheme Veni-Vidi-Vici (NWO-Vidi 2015/2016). M.J.K. was supported by an ARC Future Fellowship (FT160100454).

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Authors and Affiliations

  1. Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia

    Lauren Hadley, Marcus J. Kitchen, Kelly J. Crossley, Erin McGillick, Megan J. Wallace, Philip DeKoninck, Ryan Hodges & Stuart B. Hooper

  2. Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia

    Lauren Hadley, Kelly J. Crossley, Erin McGillick, Megan J. Wallace, Ryan Hodges & Stuart B. Hooper

  3. Division of Neonatology, University Children’s Hospital and Perinatal Center, LMU Hospital, Munich, Germany

    Andreas W. Flemmer

  4. School of Physics and Astronomy, Monash University, Melbourne, VIC, Australia

    Marcus J. Kitchen, Michelle K. Croughan & Katie L. Lee

  5. National Cerebral and Cardiovascular Center, Suita, Japan

    James T. Pearson

  6. Department of Physiology, Victoria Heart Institute and Monash Biomedicine Institute, Monash University, Melbourne, VIC, Australia

    James T. Pearson

  7. Department of Obstetrics and Gynaecology, Division of Obstetrics and Fetal Medicine, Erasmus MC University Medical Center – Sophia Children’s Hospital, Rotterdam, The Netherlands

    Philip DeKoninck

  8. Division of Neonatology, Willem Alexander Children’s Hospital, Leiden University Medical Center, Leiden, The Netherlands

    Arjan B. te Pas

  9. Newborn Research Centre, The Royal Women’s Hospital, Melbourne, VIC, Australia

    Marta Thio

  10. Department of Obstetrics and Gynaecology, The University of Melbourne, Melbourne, VIC, Australia

    Marta Thio

  11. The Murdoch Children’s Research Institute, Melbourne, VIC, Australia

    Marta Thio

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  1. Lauren Hadley
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Contributions

L.H., A.W.F., A.B.t.P., S.B.H. and M.T. conceived and designed the research project. All authors performed the experiments. L.H., M.K.C. and L.K.L. analysed the data. L.H., S.B.H., M.T., P.D. and A.W.F. interpreted the results of experiments, prepared figures and drafted the manuscript. All authors edited, revised and approved the final version of the manuscript.

Corresponding author

Correspondence to Stuart B. Hooper.

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Hadley, L., Flemmer, A.W., Kitchen, M.J. et al. Sustained inflation improves initial lung aeration in newborn rabbits with a diaphragmatic hernia. Pediatr Res 95, 660–667 (2024). https://doi.org/10.1038/s41390-023-02874-x

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