Transcript Document

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
PhaseContrast X-ray
• Preterm rabbit pups
• End expiration
No SI or PEEP
SI
• 20 s after birth
Te Pas et al,
Pediatr Res 2009:65:537-41
% variation in air volume
SI+PEEP5
Lung gas volume (mL)
PEEP5
0
5
10
15
20 s
• SI effectively
No SI or PEEP
– opens the lung
– optimises homogeneous
ventilation
• PEEP is required to
establish FRC
SI
• SI+PEEP is additive
0
20
40
60
80
100
120 s
Te Pas et al, Pediatr Res 2009:65:537-41
Length of Sustained Inflation & Lung Volume
Lung gas volume (mL)
1s
5s
(mL/kg)
8
VT
16
10 s
4
12
20 s
1s
5s
0
0
0
20
40
60
80
100
120 s
2
4
6
10 s
20 s
8
10
Breath Number
Te Pas et al, Pediatr Res 2009:66:295-300
Adapted from Jobe et al, Neonatology, 2008;94(3):190-6.
20 s
PEEP
Sigh
+PEEP
2 min
10 min
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
Pressure
(a.u.)
Continuous SI may allow
uninterrupted homogeneous
distribution of fetal lung fluid to
peripheries for absorption
Time (ms)
Huh et al, PNAS 2007; 104:18896-91
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 lun
Tidal Volume Regulation?
• Emergence of “volume guarantee”
– Is this physiological?
• Variability is an intrinsic component of
homeokinesis
1.00
0.75
mL/cmH2O
Tidal Volume
25
mL/kg
20
15
*
Variable ventilation
*
*
0.50
Controlled ventilation
0.25
10
5
0
5
10
15
Time (min)
20
25
0.00
0
20
40
60
80 100 120
Time (min)
Flow alters rate of change in lung
volume
• Inspiratory flow is determined by:
– tidal volume (VT)
– inspiratory time (tI)
Low Flow
Volume
High Flow
Volume delivered more
quickly and lung held
“open” for longer”
High peak inspiratory
flows may cause shear
stress
Flow
Inspiratory flow finishes
before end of set tI
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
100
IL-1β
PaCO2
PaCO2
PV Curve
60
50
100
10
5
2
6 L/min
6 L/min
*
40
12 L/min
mmHg
20
Volume (mL)
Fold Increase
50
30
20
*
80
60
UVC
10
12 L/min
1
0
40
0
UVC
6L
12 L
10
20
30
Pressure (cmH2O)
40
0
30
60
90
120
Time (min)
150
180
Body Temperature – Preterm Lambs
PIP (cmH2O)
#
#
** * #
** * * * *
*
** * * * * *
#
40
#
160
PaCO2 (mmHg)
#
#
*
#
#
120
## #
# #
*
80
80
#
20
40
40
0
0
0
mL/kg
60
60
120
180
0
0
60
120
Time (min)
PV Curve
100
50
40
20
10
5
20
0
0
10 20 30 40
Pressure (cmH2O)
OI
120
2
1
180
*
IL-6
^
^
0
60
120
180
IL-6
Fetal controls
NT-NI controls
NT - Injury
HT - Injury
LT-Injury
* p<0.05 cf NT-NI
# p<0.05 cf LT-I;
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