xix international symposium in neonatology...scheme of the presentation… •introduction. –lung...
TRANSCRIPT
Non-invasive ventilation in the delivery
room of the extreme preterm infant.
Máximo Vento MD PhD Director Neonatal Research Unit
Division of Neonatology & Health Research Institute
University and Polytechnic Hospital La Fe
(Valencia; Spain)
XIX International Symposium in Neonatology
Scheme of the presentation…
• Introduction. – Lung development
– Physiology of ventilation after birth
• Ventilation in the Delivery Room. – Traumas to the lung with positive pressure ventilation
– Non invasive ventilation in the DR : RCT’s
– Sustained inflations? Basic concepts and experimental and clinical experience.
• Take home message
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INTRODUCTION (I)
Lung development
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Modified from the Course in Embryology. Univ. Lausanne (Switzerland)
Antioxidant system
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Canalicular phase (16th -24th week)
1. Neumocytes type I 2. Neumocytes type 2 3. Capillary vessels
Lung development
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Saccular phase (24th -36th week)
1. Neumocytes type I 2. Pseudoalveolar spacer 3. Neumocytes type 2 4. Elastic fibers 5. Mesoderm 6. Vascular endothelium
Lung development
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Saccular phase: formation of the alveolar lining fluid
Surfactant is detected
▲ non-enzymatic antioxidants’ synthesis rate
▲ enzymatic antioxidants’ expression
*
** IU
/g H
gb
IU
/g H
gb
*
**
0,00
0,50
1,00
1,50
2,00
2,50
3,00
3,50
Umbilical cord Day 1
SOD activity (IU/g Hgb)
CTRL ELBW
0,00
50,00
100,00
150,00
200,00
250,00
300,00
Umbilical cord Day 1
CAT activity (IU/mg Hgb)
CTRL ELBW
Vento M et al Antioxid Redox Signal 2009
Antioxidant enzyme activity
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**
**
0
10
20
30
40
50
60
Umbilical cord Day 1
GS
H/G
SS
G X
10
0
CTRL ELBW
Vento M et al Antioxid Redox Signal 2009
Reduced to Oxidized Glutathione ratio
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INTRODUCTION (II)
Physiology of ventilation after birth
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Surfactant
Fetal lung Onset of breathing Established breathing
PIP (30-40 cmH2O)
Glotis
Negative thoracic pressure
PIP (20-25 cmH2O)
4-5 cm H2O
PEEP
FROM LIQUID TO AIR BREATHING
(-52 cmH2O)
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Initiation of ventilation
• Clear lung fluid
• Recruit alveolar spaces
• Establish Functional Residual Capacity (FRC)
• Avoid expiratory collapse
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Clear lung fluid
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PIP 35-40 cmH2O
PIP 15-20 cmH2O PEEP 2-3 cmH2O
First breath
Successive breaths
Clear lung fluid
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Mechanical forces imposed on the fetus during labor.
Activation of epithelial Na+ channels (ENaCs)
Adrenaline Vasopressin
Na+
Am
ilori
de
-sen
siti
ve
ENaC
s
Cl-
H2O + Na+ +
-
Clear lung fluid
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Aquaporins
Relative gene expression of aquaporins in chorial vellosity and placenta. mRNA fold
expression was determined by the ct method. The mRNA of AQP2 and AQP6 were not
amplified neither in chorial villus nor in placenta. ** p<0,01 & * p<0,05 vs placenta.
0,0
0,5
1,0
1,5
2,0
0,0
1,0
2,0
3,0
4,0
5,0
6,0
mRN
A fo
ld e
xpre
ssio
n (v
s 18S
)
AQPs in chorial vellosity
Placenta
Chorial Vellosity
0,0
1,0
2,0
3,0
4,0
5,0
6,0
mRN
A fo
ld e
xpre
ssio
n (v
s 18S
)
AQPs in chorial vellosity
Placenta
Chorial Vellosity
Placenta
Chorial Villosity
**
p=0.08
*
**
AQUAPORIN GENES EXPRESSION IN CHORIAL VILLOSITY AND PLACENTA
First vs. third trimester AQP’s expression
Escobar JJ et al EAPS 2011
**
Establishment of FRC
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O2
Avoid expiratory collapse
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CO2
Inspiratory phase Expiratory phase
Alveolar lining fluid (Surfactant)
Mature lung Expiratory
Braking Maneuvers
Establishment of FRC
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Hooper SB et al Clin Exp Pharm Physiol 2009
Spontaneously breating
O2
Avoid expiratory collapse
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CO2
Inspiratory phase Expiratory phase
Alveolar lining fluid lacking (Surfactant)
Immature lung
Muscle weakness Compliant chest wall Elastic resistance
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Pressure
Volume
FRC 4-5 cmH2O
Pressure/Volume curve in term vs. preterm
(PIP) 30-35 cmH2O
Establishment of FRC
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Hooper SB et al Clin Exp Pharm Physiol 2009
Mechanically ventilated preterm rabbits
Without PEEP
With PEEP
Compliance
Probyn ME et al Pediatr Res 2004
arterio-venous O2
PEEP during resuscitation of premature lambs
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0 PEEP
4 cm H2O
8 cm H2O
12 cm H2O
0 PEEP
4 cm H2O
8 cm H2O
12 cm H2O
Oxygen saturation and PEEP
Probyn ME et al Pediatr Res 2004
FiO2 needed and PEEP
PEEP during resuscitation of premature lambs
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Pressure
Volume
FRC 4-5 cmH2O
Pressure/Volume curve in preterm with/without PEEP
(PEEP) 4-5 cmH2O
Establishment of FRC
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Without PEEP With PEEP
Hooper SB et al Clin Exp Pharm Physiol 2009
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Initial breathing difficulties associated to prematurity
• Low lung compliance • Compliant chest wall • Surfactant deficiency • Immature antioxidant defenses • Impaired liquid clearance • Muscular weakness • Inefficient grunting • Double-walled interstitium • Incompletely developed capillary bed • Incipient septation (low exchange surface)
Vento M et al Neonatology 2009
501 – 749 g
(n: 4046)
750 – 999 g
(n: 4266)
Respiratory Distress Syndrome 71 (51-98) 55 (39-75)
Oxygen at 28 d 66 (39-90) 37 (15-70)
Bronchopulmonary dysplasia 46 (25-81) 33 (11-62)
Pneumothorax 13 (1-19) 6 (3-10)
MORBIDITY % (RANGE)
Respiratory morbidity in ELGAN’s
Fanaroff AA et al AJOG 2007
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VENTILATION in the DR (I)
Positive pressure ventilation: traumas to the lung
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Fanaroff AA et al AJOG 2007 SAO PAOLO 2013
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Volutrauma
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Björklund LJ Pediatr Res 1997
Pressure – volume curves in lambs bagged 6 x with high tidal volumes
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Lung histological findings after bagging with high tidal volume and unsatisfactory response to surfactant.
Björklund LJ Pediatr Res 1997
Bagged Non-bagged
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HIGH TIDAL VOLUME AND LUNG INJURY
Hillman NH et al AJRCCM 2007
(IL: interleukin; MCP: monocyte chemotactic protein)
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HIGH TIDAL VOLUME AND LUNG INJURY
Hillman NH et al AJRCCM 2007
(SAA: serum amyloid A)
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Stretch-induce damage
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Interstitial edema
TNFα
Protein leakage p55
Wilson MR et al AJP LCMP 2007
p75 Neutrophil recruitment
Oxidative stress
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Stretch
Wilson MR et al AJP LCMP 2007
Pulmonary edema formation
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Bland R et al Am J Physiol 2008
Secondary alveolar septation
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Formation of secondary septae Blunting of secondary septae formation by PPV.
We conclude…
● A brief period of high tidal volume (VT) ventilation (e.g.: resuscitation) may injure the fetal lung.
● Mechanical ventilation, thereafter, selectively amplifies injury markers.
● The brief initial ventilation period also triggers a systemic response in the preterm modulated by temperature and endogenous surfactant, and not by NFkB, IL1 or IL8.
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VENTILATION in the DR (II)
Is non-invasive ventilation protective?
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CPAP applied to the airway (+)
● Improves lung expansion & increases lung volume, FRC and compliance.
● Improves ventilation/perfusion matching & oxygenation
● Decreases pulmonary vascular resistance & atelectasis
● Enhances release and conservation of surfactant
● Reduces inspiratory resistance by dilating the airways
● Improves work of breathing and reduces CO2 retention
Halamek LP & Morley Clin Perinatol 2006
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CPAP applied to the airway (-)
● Exact pressure applied is unknown due to leakage (if lungs are compliant over distension may occur)
● Associated with air leaks (e.g.: pneumothorax)
● Local tissue injury
● Does not allow to instillate surfactant
Halamek LP & Morley Clin Perinatol 2006
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Non-invasive ventilation in the delivery room
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Finer NN et al Pediatrics 2004
Delivery Room – CPAP/PEEP in ELBW infants: feasibility trial.
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ENCPAP implementation and BPD
% use CPAP
incidence of BPD
Aly H et al Pediatrics 2005
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Morley CJ et al NEJM 2008 SAO PAOLO 2013
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Morley CJ et al NEJM 2008
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Morley CJ et al NEJM 2008 SAO PAOLO 2013
0
1
2
3
4
5
6
7
8
9
10
Pneumothorax Death BPD - 28 d O2 BPD - 36 wksO2CPAP INTUBATION
*
*
COIN Trial – 36 weeks outcomes
x 10
x 10
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Comments
● Only patients breathing spontaneously at 5 min were randomized (“good vs. bad”)
● High CPAP pressure (8 cm H2O) caused significant increase in pneumothorax after resuscitation.
● Median ventilatory days for both were low!
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Support Trial
• Infants between 24+0 and 27 + 6 weeks gestation.
• Randomized “prior” to delivery.
• Protocol limited ventilation strategy.
• Primary outcome: death and/or BPD
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Support Trial
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Comments
• Infants recruited before delivery includes both good and bad postnatal adapted.
• Results seem to favor CPAP.
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Jobe AH Lisbon 2011
VENTILATION in the DR (III)
Sustained inflations?
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Brief inflation Sustained inflation 54
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without SI
with SI
Te Pas AB et al Pediatr Res 2009
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Without SI
SI for 5 sec
SI for 10 sec
SI for 20 sec
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Te Pas AB et al Pediatr Res 2009
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Effect of 20 sec SI on achievement of tidal volume & FRC
Hooper SB et al Neoreviews 2010
Effectiveness of SI
• Maturity of the lung
• Amount of fluid present in the lung
• Total cross-sectional area of the small distal airways
• Duration of SI
• Pressure applied to the airways
• Combination of SI + PEEP was the best approach in the experimental setting.
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Hooper SB et al Neoreviews 2010
Early functional residual capacity (EFURCI) – UH Leiden (Netherlands)
• To determine whether early nasal continuous positive airway pressure (ENCPAP) preceded by a sustained inflation is more effective and less injurious than conventional mask ventilation followed by CPAP in babies ≤ 29 weeks gestation.
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Te Pas AB et al Pediatrics 2007
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Conventional mask CPAP
PIP
PEEP
EFURCI + ENCPAP
PPIP
Te Pas AB et al Pediatrics 2007
PEEP
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Total recruited
207
Conventional
103
EFURCI
104
Intubation
52 (50.5%)
Intubation
38 (36.5%)**
Te Pas AB et al Pediatrics 2007
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Intubation in the DR and < 72 hrs
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Secondary outcomes EFURCI CONVENTIONAL Univariate analysis
OR
Surfactant >1 dose, n(%) 10/103 (10%)
22/104 (21%)
0.02 0.39 (0.18-0.88)
BPD TOTAL, n(%) 22 (22a ) 34 (34) 0.05
BPD MODERATE – SEVERE n (%)
21 (20) 16 (16) 0.04 0.41 (0.18-0.96)
Mortality, n (%) 2 (2) 4 (4) 0.4
Te Pas AB et al Pediatrics 2007
Secondary outcomes
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SLI V Buzzi Hospital (Milan) trial: Objectives
• To verify if the application of SI applied at birth in preterm infants may reduce the need for mechanical ventilation and improve respiratory outcome.
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Lista G et al Neonatology 2011
SLI trial: Design
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Control group (n: 119)
GA: 28.1±2.0
(2004-6)
SLI group (n: 89)
GA: 28.12.2
(2007-9)
Bag & mask
PEEP 5%
FiO2 for Sat 80-85%
Bag & mask
PIP 25 cmH2O x 15 sec
Repeated if HR<100 bpm or SpO2<<
PEEP 5%
FiO2 for Sat 80-85%
AAP GUIDELINES
Lista G et al Neonatology 2011
SLI trial: Results without statistical significance
Outcome SLI GROUP CONTROL P
Pneumothorax 8 (9%) 10 (8%) NS
PDA 24 (27%) 29 (24%) NS
Grade 3-4 IVH 1 (1%) 5 (4%) NS
PVL 4 (4%) 11 (9%) NS
ROP > grade 3 10 (11%) 7 (6%) NS
NEC 4 (4%) 0 NS
Hospital stay (days) 54±29 55±32 NS
MORTALITY 8 (9%) 17 (14%) NS
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SLI trial: Results with statistical significance
Outcome SLI GROUP CONTROL P
INSURE 14(16%) 3 (3%) 0.001
MV (days) 5±11 11±19 0.008
Exclusive NCPAP 44 (49%) 29 (24%) 0.0001
Surfactant 40 (45%) 73 (61%) 0.029
Oxygen therapy (days) 21±27 31±31 0.016
BPD (O2 at 36 wks) 6 (7%) 25 (25%) 0.004
Postnatal steroids 9 (10%) 30 (25%) 0.01
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SLI trial: Conclusions
• Sustained inflations at birth in preterm infants with respiratory distress may decrease the need for mechanical ventilation without inducing adverse effects.
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Lista G et al Neonatology 2011
SLI : unanswered questions
• Duration and intensity of inflations
• Hemodynamic consequences of increased thoracic pressure
• Short-lasting beneficial effect
• Individually adjustment of SI
• Titration of oxygen during SI
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SLI: comparison of 3 devices UN Norway & U Melbourne
• Objective: Provide SI 10 sec & 30 cmH2O to a leak free manikin with SIB, FIB and T-piece.
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Klingenberg C et al Neonatology 2011
SLI: comparison of 3 devices UN Norway & U Melbourne
• Conclusions
– T-piece provided consistent PIP during a single 10 s sustained inflation with less variation in pressure compared to the flow-inflating bag.
– SI > 3 s were difficult to achieve with the self-inflating bag.
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Klingenberg C et al Neonatology 2011
Home take message
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■ CPAP is comparable to (or even a bit better) than intubation +/- surfactant for initial stabilization in DR. ■ Perhaps 50% of ELBW infants do not have RDS (“good responders”). ■ Some infants will not respond to our interventions because of immaturity or unknown factors (“bad responders”). ■ Death or BPD are outcomes with casualties not necessarily related to the interventions.
Conclusions from RCT’s
adapted from Dr AH Jobe ( International Neonatal Meeting; Lisbon 2011)
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Postnatal interventions
• If the baby is spontaneously breathing initiate non-invasive ventilation – Mask or ENCPAP applied with T-piece if possible (or bag with EV)
– Apply PEEP 4-6 cmH2O
– Flow 4-8 l/min
– Sustained inflation of 30 cmH2O for 15 sec if you are confident with the technique and repeat 2nd time if no response seem to be beneficial (National Guidelines Holland; Norway; ERC)
– Titrate oxygen according to SpO2 and HR.
• If the baby is not spontaneously breathing and does not respond to non-invasive ventilation proceed to intubate and ventilate with PIP+PEEP.
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