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

– 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

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:

• 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

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

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

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?

Volutrauma from Bagging

Bjorklund et al, Pediatr Res 1997;42:348

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

SI+PEEP5 PEEP5

No SI or PEEP SI

Te Pas et al,Pediatr Res 2009:65:537-41

PhaseContrast X-ray

•Preterm rabbit pups

•End expiration

•20 s after birth

0 20 40 60 80 100 120 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+PEEP5

PEEP5

No SI or PEEP

SI

0 5 10 15 20 s

Length of Sustained Inflation & Lung Volume

0 20 40 60 80 100 120 s

1 s

5 s

10 s

20 s

0

4

8

12

16

0 2 4 6 8 10

Breath NumberTe Pas et al, Pediatr Res

2009:66:295-300

20 s10 s

5 s1 s

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

PEEP

Sigh +PEEP

20 s 2 min 10 min

Does a SI at birth avoid fluidic mechanical stress-induced cellular injury?

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 1st breath would reduce pressures and shear stress and may stabilise plugs to resist rupture

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

Tidal Volume Regulation?

• Emergence of “volume guarantee”– Is this physiological?

• Variability is an intrinsic component of homeokinesis

0 20 40 60 80 100 120

mL/

cmH

2O

0.00

0.25

0.50

0.75

1.00 ** *

Time (min)

Variable ventilation

Controlled ventilation

Tidal Volume

Time (min)

0 5 10 15 20 25

mL/

kg

5

10

15

20

25

Flow alters rate of change in lung volume

• Inspiratory flow is determined by:– tidal volume (VT) – inspiratory time (tI)

Inspiratory flow finishes before end of set tI Flow

Low Flow High Flow

High peak inspiratory flows may cause shear stress

Volume

Volume delivered more quickly and lung held “open” for longer”

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

UVC 6 L 12 L

Fol

d In

crea

se

2

5

20

50

1

10

100 IL-1β PaCO2

Time (min)

0 30 60 90 120 150 180

40

60

80

100

**

PV Curve

Pressure (cmH2O)

0 10 20 30 40

Vol

ume

(mL)

0

10

20

30

40

50

60PaCO2

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

0 10 20 30 400

20

40

60

PaCO2 (mmHg)

Time (min)0 60 120 180

0

40

80

120

160

*# #

###

#

##

#

*#

Body Temperature – Preterm LambsPIP (cmH2O)

0 60 120 1800

20

40

********* **

#

*

#

**

#

*

#

*

#

*

2

5

20

50

1

10

100

IL-6

OI

0 60 120 1800

40

80

120

Pressure (cmH2O)

*̂

^

IL-6PV Curve

* p<0.05 cf NT-NI# p<0.05 cf LT-I;

Fetal controlsNT-NI controlsNT - InjuryHT - InjuryLT-Injury

M Ball et al, PSANZ 2009

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 …

Oxygen & Humidification

Pillow et al, Int Care Med (In Press)

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?

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?

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