xix international symposium in neonatology...scheme of the presentation… •introduction. –lung...

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

SAO PAOLO 2013 2

INTRODUCTION (I)

Lung development

SAO PAOLO 2013 3

Modified from the Course in Embryology. Univ. Lausanne (Switzerland)

Antioxidant system

4 SAO PAOLO 2013

SAO PAOLO 2013 5

Canalicular phase (16th -24th week)

1. Neumocytes type I 2. Neumocytes type 2 3. Capillary vessels

Lung development

SAO PAOLO 2013 6

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

SAO PAOLO 2013 7

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


CAT activity (IU/mg Hgb)

CTRL ELBW

Vento M et al Antioxid Redox Signal 2009

Antioxidant enzyme activity

8 SAO PAOLO 2013

**

**

0

10

20

30

40

50

60


GS

H/G

SS

G X

10

0

CTRL ELBW

Vento M et al Antioxid Redox Signal 2009

Reduced to Oxidized Glutathione ratio

9 SAO PAOLO 2013

INTRODUCTION (II)

Physiology of ventilation after birth

SAO PAOLO 2013 10

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)

SAO PAOLO 2013 11

Initiation of ventilation

• Clear lung fluid

• Recruit alveolar spaces

• Establish Functional Residual Capacity (FRC)

• Avoid expiratory collapse

SAO PAOLO 2013 12

Clear lung fluid

SAO PAOLO 2013 13

PIP 35-40 cmH2O

PIP 15-20 cmH2O PEEP 2-3 cmH2O

First breath

Successive breaths

Clear lung fluid

SAO PAOLO 2013 14

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

SAO PAOLO 2013 15

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

SAO PAOLO 2013 16

O2

Avoid expiratory collapse

SAO PAOLO 2013 17

CO2

Inspiratory phase Expiratory phase

Alveolar lining fluid (Surfactant)

Mature lung Expiratory

Braking Maneuvers


SAO PAOLO 2013 18

Hooper SB et al Clin Exp Pharm Physiol 2009

Spontaneously breating

O2

Avoid expiratory collapse

SAO PAOLO 2013 19

CO2

Inspiratory phase Expiratory phase

Alveolar lining fluid lacking (Surfactant)

Immature lung

Muscle weakness Compliant chest wall Elastic resistance

SAO PAOLO 2013 20

Pressure

Volume

FRC 4-5 cmH2O

Pressure/Volume curve in term vs. preterm

(PIP) 30-35 cmH2O


SAO PAOLO 2013 21


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

SAO PAOLO 2013 22

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

SAO PAOLO 2013 23

SAO PAOLO 2013 24

Pressure

Volume

FRC 4-5 cmH2O

Pressure/Volume curve in preterm with/without PEEP

(PEEP) 4-5 cmH2O


SAO PAOLO 2013 25

Without PEEP With PEEP


SAO PAOLO 2013 26

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

SAO PAOLO 2013 27

VENTILATION in the DR (I)

Positive pressure ventilation: traumas to the lung

SAO PAOLO 2013 28

Fanaroff AA et al AJOG 2007 SAO PAOLO 2013

29

Volutrauma

SAO PAOLO 2013 30

Björklund LJ Pediatr Res 1997

Pressure – volume curves in lambs bagged 6 x with high tidal volumes

SAO PAOLO 2013 31

Lung histological findings after bagging with high tidal volume and unsatisfactory response to surfactant.

Björklund LJ Pediatr Res 1997

Bagged Non-bagged

SAO PAOLO 2013 32

HIGH TIDAL VOLUME AND LUNG INJURY

Hillman NH et al AJRCCM 2007

(IL: interleukin; MCP: monocyte chemotactic protein)

SAO PAOLO 2013 33

HIGH TIDAL VOLUME AND LUNG INJURY

Hillman NH et al AJRCCM 2007

(SAA: serum amyloid A)

SAO PAOLO 2013 34

Stretch-induce damage

SAO PAOLO 2013 35

Interstitial edema

TNFα

Protein leakage p55

Wilson MR et al AJP LCMP 2007

p75 Neutrophil recruitment

Oxidative stress

SAO PAOLO 2013 36

Stretch

Wilson MR et al AJP LCMP 2007

Pulmonary edema formation

SAO PAOLO 2013 37

SAO PAOLO 2013

Bland R et al Am J Physiol 2008

Secondary alveolar septation

38

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.

SAO PAOLO 2013 39

VENTILATION in the DR (II)

Is non-invasive ventilation protective?

SAO PAOLO 2013 40

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

SAO PAOLO 2013 41

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

SAO PAOLO 2013 42

Non-invasive ventilation in the delivery room

SAO PAOLO 2013 43

Finer NN et al Pediatrics 2004

Delivery Room – CPAP/PEEP in ELBW infants: feasibility trial.

SAO PAOLO 2013 44

ENCPAP implementation and BPD

% use CPAP

incidence of BPD

Aly H et al Pediatrics 2005

SAO PAOLO 2013 45

Morley CJ et al NEJM 2008 SAO PAOLO 2013

46

Morley CJ et al NEJM 2008

SAO PAOLO 2013 47

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

48

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!

SAO PAOLO 2013 49

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

SAO PAOLO 2013 Support Trial NEJM 2010

50

SAO PAOLO 2013 Support Trial NEJM 2010

Support Trial

51

Comments

• Infants recruited before delivery includes both good and bad postnatal adapted.

• Results seem to favor CPAP.

SAO PAOLO 2013 52

Jobe AH Lisbon 2011

VENTILATION in the DR (III)

Sustained inflations?

SAO PAOLO 2013 53

SAO PAOLO 2013

Brief inflation Sustained inflation 54

SAO PAOLO 2013 55

SAO PAOLO 2013

without SI

with SI

Te Pas AB et al Pediatr Res 2009

56

Without SI

SI for 5 sec

SI for 10 sec

SI for 20 sec

SAO PAOLO 2013

Te Pas AB et al Pediatr Res 2009

57

SAO PAOLO 2013 58

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.

SAO PAOLO 2013 59

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.

SAO PAOLO 2013

Te Pas AB et al Pediatrics 2007

60

SAO PAOLO 2013

Conventional mask CPAP

PIP

PEEP

EFURCI + ENCPAP

PPIP


PEEP

61

SAO PAOLO 2013

Total recruited

207

Conventional

103

EFURCI

104

Intubation

52 (50.5%)

Intubation

38 (36.5%)**


62

SAO PAOLO 2013 Te Pas AB et al Pediatrics 2007

Intubation in the DR and < 72 hrs

63

SAO PAOLO 2013

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


Secondary outcomes

64

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.

SAO PAOLO 2013 65

Lista G et al Neonatology 2011

SLI trial: Design

SAO PAOLO 2013 66

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


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

SAO PAOLO 2013 67

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

SAO PAOLO 2013 68

SLI trial: Conclusions

• Sustained inflations at birth in preterm infants with respiratory distress may decrease the need for mechanical ventilation without inducing adverse effects.

SAO PAOLO 2013 69


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

SAO PAOLO 2013 70

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.

SAO PAOLO 2013 71

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.

SAO PAOLO 2013 72

Klingenberg C et al Neonatology 2011

Home take message

SAO PAOLO 2013 73

SAO PAOLO 2013

■ 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)

74

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.

SAO PAOLO 2013 75

xix international symposium in neonatology...scheme of the presentation… •introduction. –lung...

Documents