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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.

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Presentation on theme: "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."— Presentation transcript:

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 Environmental Influences Chorioamnionitis Pre-eclampsia Nutrition Steroids 9 months Pregnancy Antenatal smoke exposure Postnatal Care Birth PDA Sepsis Steroids/ Anti-inflammatory drugs Nutrition Ventilation Strategy Oxygen Outcomes Passive smoke exposure Adapted from Jobe et al, Neonatology, 2008;94(3):190-6. 15 minmonths → years Caffeine iNO

3 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

4 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:

5 Injurious Exposures During Initial Postnatal Transition Birth +/- Resuscitation Adapted from Jobe et al, Neonatology, 2008;94(3):190-6. O2O2 Flow VTVT Cold & Dry Gas PEEP Surfactant Temp Control Fluid Volume Drugs

6 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

7 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

8 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

9 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?

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

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

12 SI+PEEP 5 PEEP 5 No SI or PEEPSI Te Pas et al, Pediatr Res 2009:65:537-41 PhaseContrast X-ray Preterm rabbit pups End expiration 20 s after birth

13 Lung gas volume (mL) 020406080100120 s SI effectively –opens the lung –optimises homogeneous ventilation PEEP is required to establish FRC SI+PEEP is additive Te Pas et al, Pediatr Res 2009:65:537-41 SI+PEEP 5 PEEP 5 No SI or PEEP SI % variation in air volume 05101520 s

14 Length of Sustained Inflation & Lung Volume Lung gas volume (mL) 020406080100120 s 1 s 5 s 10 s 20 s 0 4 8 12 16 V T (mL/kg) 0246810 Breath Number Te Pas et al, Pediatr Res 2009:66:295-300 20 s 10 s 5 s 1 s

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

16 PEEP Sigh +PEEP 20 s 2 min 10 min

17 Does a SI at birth avoid fluidic mechanical stress-induced cellular injury? Pressure (a.u.) Time (ms) Huh et al, PNAS 2007; 104:18896-91 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 1 st breath would reduce pressures and shear stress and may stabilise plugs to resist rupture

18 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

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

20 Flow alters rate of change in lung volume Inspiratory flow is determined by: –tidal volume (V T ) –inspiratory time (t I) Inspiratory flow finishes before end of set t I Flow Low FlowHigh Flow High peak inspiratory flows may cause shear stress Volume Volume delivered more quickly and lung held “open” for longer”

21 Shear stress during ventilation In modelling studies, maximum shear stress is evident in the bronchioles, just before the acinus (Nucci G, J Appl Physiol, 2003;95:348-356) trachea alveolus Shear stress (mm) 0.05 0.04 0.03 0.02 0.01 0.00 Baseline airway diameter (mm) 0.05 maximum shear stress

22 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 IL-1β PaCO 2 mmHg UVC 12 L/min 6 L/min 12 L/min 6 L/min Pillow et al (PSANZ 2009) – no effect of 6 L/min vs 12 L/min in SIPPV/VG

23 * ##### #### # #### # * # Body Temperature – Preterm Lambs * * * * * * * * * * # * # * * # * # * # * IL-6 mL/kg Pressure (cmH 2 O) * ^ ^ IL-6 PV Curve * p<0.05 cf NT-NI # p<0.05 cf LT-I; Fetal controls NT-NI controls NT - Injury HT - Injury LT-Injury M Ball et al, PSANZ 2009

24 Inspired Oxygen High fractional inspired O 2 (FiO 2 ) is toxic to the lung tissue –Arrested alveolar development –Leukocyte activation & sequestration –Oxidative damage Resuscitation with air reduces mortality cf 100 % O 2 (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 …

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

26 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?

27 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?

28 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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