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J Jane Pillow

Transitional changes during the first minutes in life outside the womb: Understanding the mechanisms of lung injury. J Jane Pillow. School of Women’s and Infants’ Health, UWA, Perth, Aust. Fetal to Extrauterine Transition. Commencement of pulmonary gas exchange

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J Jane Pillow

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  1. Transitional changes during the first minutes in life outside the womb:Understanding the mechanisms of lung injury J Jane Pillow School of Women’s and Infants’ Health, UWA, Perth, Aust.

  2. Fetal to Extrauterine Transition • Commencement of pulmonary gas exchange • Pulmonary vascular bed must receive all (R) ventricular output • Ductus arteriosus must close & stay close • Fetal lung fluid must clear & allow air to enter the lungs whilst leaving a thin film of liquid to protect epithelium • Linked to processes that initiate labour • Continuous rhythmic breathing established

  3. Fetal to Extrauterine Transition • Establishment of an air-liquid interface • Mature type II alveolar epithelial cells (AEC) that produce & release surfactant into alveolar lumen to reduce surface tension • Reduce recoil pressure of the lungs • Enhance lung expansion during inspiration • Avoid collapse during expiration • Reduce work of breathing • Preterm Infants are poorly prepared for extrauterine life & primed for injury:

  4. What do we know about mechanisms of lung injury during the first minutes of life? • What remains to be understood… • Does optimal respiratory transition imply optimal transition for other body organs? • What are the important directions for future study

  5. Mechanisms of Lung Injury • Barotrauma – high pressures • Volutrauma – high static/cyclic lung volumes • Atelectotrauma – alveolar collapse and re-expansion • Biotrauma – increased inflammation Consequences of Lung Injury • Fluid, blood & protein leak into airways, alveoli & interstitium • Impaired lung mechanics • Inhibition of surfactant function • Promotion of inflammation

  6. Factors Predisposing the Preterm Lung to Injury • Not previously inflated with gas • Hypoxic in utero - potential rapid postnatal hyperoxia • Immature gas exchange structures (airway & capillary) • Less able to respond or to resist stretch • Decreased collagen & elastin • Highly compliant chest wall does not limit lung expansion • Distensible airways (limited collagen structural support) • Fluid-filled saccular distal lung units • Reduced surface area/volume • Simplified epithelium (non-pleated) easily injured by stretch

  7. Barotrauma • High ventilation pressures without high volumes are not associated with increased lung edema/injury • Dreyfuss D et al. Am Rev Respir dis 1988; 137:1159-64 • Hernandez et al J Appl Physiol, 1989;66:2364-8 • Increased intrathoracic pressure may impede pulmonary blood flow Polglase et al Pediatr Res, 2009 • Unknown effect of high ventilation pressures on other organs: • Brain • Diaphragm function?

  8. Volutrauma from Bagging Bjorklund et al, Pediatr Res 1997;42:348

  9. Adapted from Jobe et al, Neonatology, 2008;94(3):190-6.

  10. SI+PEEP5 PEEP5 • PhaseContrast X-ray • Preterm rabbit pups • End expiration • 20 s after birth No SI or PEEP SI Te Pas et al, Pediatr Res 2009:65:537-41

  11. SI+PEEP5 % variation in air volume Lung gas volume (mL) • SI effectively • opens the lung • optimises homogeneous ventilation • PEEP is required to establish FRC • SI+PEEP is additive PEEP5 0 5 10 15 20 s No SI or PEEP SI 0 20 40 60 80 100 120 s Te Pas et al, Pediatr Res 2009:65:537-41

  12. Length of Sustained Inflation & Lung Volume 1 s Lung gas volume (mL) 5 s 16 10 s 12 VT (mL/kg) 8 20 s 1 s 10 s 4 5 s 20 s 0 0 2 4 6 8 10 Breath Number 0 20 40 60 80 100 120 s Te Pas et al, Pediatr Res 2009:66:295-300

  13. Adapted from Jobe et al, Neonatology, 2008;94(3):190-6.

  14. 20 s 2 min 10 min PEEP Sigh +PEEP

  15. Does a SI at birth avoid fluidic mechanical stress-induced cellular injury? Interrupted aeration may promote microfluidic plugs that rupture in small airways and cause mechanical stress to epithelial cells Epithelial cell injury - most evident at rupture sites - present after repetitive (50-100) stresses Continuous SI may allow uninterrupted homogeneous distribution of fetal lung fluid to peripheries for absorption Surfactant prior to 1st breath would reduce pressures and shear stress and may stabilise plugs to resist rupture Pressure (a.u.) Time (ms) Huh et al, PNAS 2007; 104:18896-91

  16. Tidal Volume and Maturation: One size does not fit all! Preterm Term • Preterm lung has large deadspace/FRC ratio • Applying same tidal volume/kg will overdistend the preterm lung

  17. Tidal Volume Regulation? • Emergence of “volume guarantee” • Is this physiological? • Variability is an intrinsic component of homeokinesis * * * Variable ventilation Controlled ventilation Time (min)

  18. Flow alters rate of change in lung volume • Inspiratory flow is determined by: • tidal volume (VT) • inspiratory time (tI) Low Flow High Flow Volume delivered more quickly and lung held “open” for longer” Volume High peak inspiratory flows may cause shear stress Inspiratory flow finishes before end of set tI Flow

  19. Shear stress during ventilation in preterm lung • Bach et al: (SPR 2009) • PSV/VG using flow of 8 L/min showed • better preservation of parenchyma than 28 L/min & 18 L/min • less upregulation of early response genes Pillow et al (PSANZ 2009) – no effect of 6 L/min vs 12 L/min in SIPPV/VG IL-1β PaCO2 6 L/min 6 L/min 12 L/min mmHg UVC 12 L/min

  20. # # * # # # # # # # # * Body Temperature – Preterm Lambs # ** Fetal controls # # # * # * * * * * * NT-NI controls * * * * * * * * NT - Injury HT - Injury LT-Injury IL-6 PV Curve * IL-6 ^ ^ mL/kg * p<0.05 cf NT-NI # p<0.05 cf LT-I; Pressure (cmH2O) M Ball et al, PSANZ 2009

  21. Inspired Oxygen • High fractional inspired O2 (FiO2) is toxic to the lung tissue • Arrested alveolar development • Leukocyte activation & sequestration • Oxidative damage • Resuscitation with air reduces mortality cf 100 % O2(Davis PG et al, Lancet 2004; 364:1329-33) • Very preterm infants have immature antioxidant defences → susceptible to free-radical damage (Saugstad) • Healthy infants may take 5-10 min to oxygenate after birth …

  22. Oxygen & Humidification Pillow et al, Int Care Med (In Press)

  23. Discussion Issues • Should tidal volume be monitored at delivery? • Is “controlled hypothermia” different to uncontrolled hypothermia • Does humidification have a role in the delivery room? • Does injury minimization in the lung during transition have implications for other body organs?

  24. What else do we need to know about sustained inflations? • Does a SI at birth reduce injury? • Who should receive an SI? • How quickly should peak pressure/TLC be achieved during a SI • Immediately? • Slow ramp increase to a sustained plateau to avoid proximal overdistension • What effect does a SI have on other organs? • Brain • PDA/Heart • Do sighs have a role in maintaining lung volume after initiation of ventilation? • Does a SI alter surfactant distribution?

  25. Acknowledgements: • Alan Jobe, Suhas Kallapur, Boris Kramer, Noah Hillman, Molly Ball • Graeme Polglase, Ilias Nitsos, Gabby Musk, Carryn McLean, Richard Dalton, Andrea Lee • Fisher & Paykel Healthcare

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