International conference «Actual approaches to the extremely preterm babies: International experience and Ukrainian realities» (Kyiv, Ukraine, March 5-6, 2013)

1. Strategies for the Prevention of
Bronchopulmonary Dysplasia:
Wishful Thinking or Reality?
S. David Rubenstein, MD

2. Bronchopulmonary
Dysplasia (BPD)
Chronic Pulmonary Disorder which is
Consequence of Lung Injury that is
Abnormally Repaired

3. Old Definition of BPD
Need for supplemental oxygen at
> 28 days or > 36 wks gestation.

4. New Definition of BPD
•Mild BPD: need for supplemental oxygen > 28
days but not at 36 weeks gestation PMA
•Moderate BPD: need for supplemental oxygen >
28 days and < 30% at 36 weeks PMA
•Severe BPD: need for supplemental oxygen > 28
days, and > 30% at 36 weeks PMA and/or
positive pressure at 36 weeks PMA

5. Incidence of BPD at Columbia
BW(g) GA(wks) O2 (36 wks) Mild Mod. Severe
< 750 25.4±2.0 18.3% 31.6% 15.0% 3.3%
750-1000 26.9±1.8 1.4% 16.9% 1.4% 0
1001-1250 29.0±1.8 1.1% 0 1.1% 0
<1250 27.4±2.4 5.9% 14.1% 5.0% 0.9%
Sahni R., PAS 2003

6. “Old” BPD
• Disorder related to lung injury.
•Common in term & near term infants ventilated with
high pressures and O2 .
•Chest x-ray demonstrates areas of over-inflation, cystic
emphysema and fibrosis.
• Histopathology demonstrates interstitial and alveolar
edema, small airway disease, extensive inflammation and
fibrosis.

7. “Old” BPD

8. “New” BPD
• More of a disorder resulting from processes that
interfere with lung development, not injury.
•Common in VLBW infants with modest ventilatory
and oxygen needs.
• Chest x-ray: diffuse haziness which progresses to a
fine lacy pattern.
•Histopathology: decreased alveolarization, minimal
small airway disease and less inflammation/fibrosis.

9. “New” BPD

10. New BPD:
Diminished Alveolarization
• Normal alveolarization begins about 28 weeks
gestation: infants at term gestation have 20-50% of the adult
number of alveoli
• A variety of processes interfere with alveolarization
including: poor nutrition, hypoxia, hyperoxia, inflammation
and glucocorticoids

11. New BPD:
Diminished Alveolarization
88 A.H. Jobe, M. Ikegami / Early Human Development 53 (1998) 81 –94
Fig. 4. Alveolar numbers for human infants at birth and for ventilated infants. The curve indicates the
normal increase in alveolar number with gestation age. Ventilation of the preterm lung results in decreased
alveolar numbers. Data from Hislop and co-workers [46,47].
Jobe et al, Early Human Development: 53 (1998) 81-94

12. Factors Contributing to Lung Injury
Jobe: Neoreviews 2006

13. Intrauterine Inflammation Increases the Risk of
Preterm Birth
• Histopathological evidence of chorioamnionitis is
present in 40-70% of preterm births (vs. 4-18% of
term deliveries)
•Incidence of infection (positive AF culture) is
32-35% with pPROM and 10-15% (spontaneous
onset of preterm labor with intact membranes)

14. Incidence of positive chorioamniotic cultures in
women with intact membranes undergoing cesarean
section after spontaneous preterm labor
Goldenberg et al NEJM 342: 1500-07, 2000

15. Percent of placentas harboring a microorganism
Biopsy of the chorion from 1,083 placentas (initiator of delivery: preterm
labor, preeclampsia) before the 28th week (Culture/PCR)
Week of pregnancy 23 24 25 26 27
Initiator of Delivery Route
Preterm labor: CS 56 62 42 46 34
vaginal 87 74 68 48 58
Preeclampsia: CS 33 24 21 28 22
Onderdonk and the ELGAN study group Am. J Obstet. Gynecol: July 2008

16. Intrauterine Infection and Preterm Labor
Goldenberg,
NEJM: May, 2000

17. There is a strong relationship between markers of
inflammation and BPD
• Amniotic fluid proinflammatory cytokine levels are
increased in infants who develop BPD
•Cord blood IL-6 concentration is an independent risk
factor for BPD and a better predictor than amniotic fluid
IL-6 levels.
Ghezzi 1998 & Yoon 1997, Yoon 1999

18. There is a strong relationship between markers of
inflammation in amniotic fluid and BPD
Yoon, Am J Ob Gyn; Oct 1997, 825-830

19. Intrauterine Infection, MMP-8 and CLD
Romero et. al., Am J Ob Gyn 2001, 185: (5)1149-1155
Halliday et. al., Arch Dis Child Fetal Neonatal ed 2004; 89: F61-64 2001; 84: F168-171

20. Intrauterine Inflammation & Risk of Chronic Lung
Disease
Chorioamnionitis No chorioamnionitis
RDS 33% 73%
BPD 63% 27%
* *
* *
*
* p< 0.003 * p<0.01
Watterberg K. Ped. 1996 & 1997

21. Antenatal Administration of
Endotoxin in Fetal sheep
• Promotes lung maturation
• Increases proinflammatory cytokine expression (5 hrs)
• Increases influx of leucocytes
• Interferes with alveolar development
• Augments the inflammatory response when ventilated
Newnham 2001, Newnham 2002, Kramer 2001,
Kramer 2002, Moss 2002, Jobe 2001

22. Chorioamnionitis, Mechanical Ventilation &
Postnatal Sepsis: Modulators of Chronic Lung
Disease
• Chorioamnionitis 0.2 (0.0-0.5)
• Postnatal sepsis 1.3 (0.2-2.3)
• Ventilation> 7 d 1.6 (0.9-2.9)
•Ventilation > 7d and 3.2 (0.9-11)
chorioamnionitis
•Ventilation > 7d and 2.9 (1.1-7.4)
postnatal sepsis
Van Marter J Ped. 2002

23. Mechanical Ventilation
Inflammation & Alveolarization
•Mechanical ventilation in experimental animals
with or without high O2 concentrations injures the
lung (and decreases alveolarization)
•Infants that progress to chronic lung disease have
persistence of leukocytes in alveolar lavages with
high concentrations of inflammatory mediators.

24. Mechanical Ventilation
Inflammation & Alveolarization
•Over distention of the lung during mechanical
ventilation (volutrauma) disrupts structural elements
and leads to production of inflammatory mediators
(cytokines and chemokines).
•Ventilation at low lung volumes (atelectrauma) also
causes release of cytokines and influx of white blood
cells.

25. Lung Injury Zones
Jobe and Ikegami 1998

26. Delivery Room Management
“Chronic Lung disease in preterm neonates may result
more from antepartum or delivery room events than
postnatal management.” (Jobe, J. Peds 1998)
“There is perhaps nothing more dangerous for the
preterm lung than an anxious physician with an
endotracheal tube and a bag” (Jobe, J Peds. 2005)

27. Delivery Room Management
•In infants with RDS, total lung capacity is
reduced by a widespread proteinaceous edema
•Mechanical ventilation aggravates the edema
(probably by epithelial disruption); surfactants
decrease the edema.

28. Delivery Room Management
•Surfactant instilled after mechanical ventilation
may be inactivated by leaking protein and may
fail to enter collapsed or fluid filled regions.
•This suggests that surfactant should be given as
early as possible. However, clinical trials have
not shown a consistent benefit to prophylaxis.

29. Delivery Room Management
Can lung damage occur immediately after
birth by giving a few large breaths?
If yes, will surfactant still be effective?

30. Neonatal Resuscitation
& Lung Injury
Five pairs of lamb siblings were delivered at 127-128 d
gestation and one lamb in each pair was randomly
selected to receive 6 manual inflations at a volume
equal to inspiratory capacity (35-40 ml) before the start
of mechanical ventilation. All lambs then received
surfactant at 30 minutes of age.
Bjorkland et al Ped. Res. 42: 348, 1997

31. Neonatal Resuscitation
& Lung Injury
•Blood gases and pressure volume curves were
then recorded until the lambs were sacrificed at age
four hours.
• Lung histopathology was then examined
Bjorkland et al Ped. Res. 42: 348, 1997

32. Neonatal Resuscitation
& Lung Injury
Control lambs Experimental group
135 min.
Volume (ml/kg)
30
75 min.
Volume
20 45 min. (ml/kg
45-135 min.
10 Before surfactant
Before surfactant 10
5 5
15 30 15 30
Pressure (cm H2O)
Bjorkland et al Ped. Res. 42: 348, 1997)

33. Resuscitation & Lung Injury
Bjorkland et al Ped. Res. 42: 348, 1997

34. Neonatal Resuscitation
& Lung Injury
•Ventilation with large breaths in an immature lung
may cause:
• Epithelial and microvascular injury
• Increased production of inflammatory mediators
• Flux of fluid into the air spaces

35. Lung Overdistension
Jobe
(PIP = 45-50 cm H2O)
Am J Respir Crit Care Med 176: 575-581 (2007)

36. Lung Overdistension
Jobe
Bronchoalveolar lavage fluid: TP and cell count
Increased 5-fold, 11-fold, 14-fold
Increased 300-fold
* p < 0.01
Am J Respir Crit Care Med 176: 575-581 (2007)

37. Lung Overdistension
Jobe
Cytokine mRNA in lung tissue
Am J Respir Crit Care Med 176: 575-581 (2007)

38. Fluid Therapy & BPD
•All newborn infants exhibit an increase in urine
output postnatally (usually in the first day of life).
•In infants with RDS, the diuretic phase is delayed
and commonly occurs between 24 & 48 hours of life.
• A delay in the onset of diuresis until 5-7 days is
associated with an increased risk of BPD.

39. Fluid Therapy & BPD
Study Source Design N Outcome
Van Marter J Ped 1990 CCS 223 Infants with BPD
received amounts of
crystalloid & colloid
Van Marter J Ped 1992 MVA 223 Incidence of BPD
strongly correlated
with volume of
colloid received

40. Randomized Trials of Postnatal
Na+ Supplementation
•Costarino et al: (N=17) Na+ restriction during the first
3-5 days of life significantly decreased the incidence of
BPD (J Pediatr 1992)
•Hartnoll et al: (N=46) Delaying Na+ supplementation
until 6% of the body weight was lost had a beneficial
effect on the risk for continuing O2 requirement
(Arch Dis Child F19 1999)

41. Antenatal Steroids & BPD
(True or False?)
• Antenatal
steroids decrease the incidence
of bronchopulmonary dysplasia.

42. Antenatal Glucocorticoid Treatment
Does Not Reduce Chronic Lung Disease
Among Surviving Preterm Infants
Study Design: Case-referent study of 1454 LBW infants
born between 1991-93 at four university hospitals
Outcome: In multivariate logistic regression analyses
antenatal steroid Rx did not significantly decrease the rate
of CLD. OR .98 (.66-1.5)
Van Marter J Ped. 2001

43. Surfactant & BPD
True or False?
• The use of surfactant has decreased the likelihood
of chronic lung disease.
•Surfactants work best when given before the first
breath.

44. Surfactant
Natural Synthetic
Delivery room prophylaxis 1.0 1.0
Mortality
• •
BPD •
•
Pneumothorax
• •
Treatment of RDS
Mortality
•
BPD
• •
Pneumothorax
• •

45. Continuous Positive
Airway Pressure

46. If you do not ventilate neonates
it’s hard to cause BPD!

47. The Significance of Grunting in
Hyaline Membrane Disease
•In infants with HMD, grunting is a protective
maneuver resulting from contraction of the
abdominal muscles and closure of the glottis
• Grunting can be prevented by intubation
•Intubation (and elimination of grunting) resulted
in a fall in oxygenation
Harrison et al Ped. 1968

48. Treatment of idiopathic respiratory distress
syndrome with continuous positive airway pressure
Gregory et al. N Engl J Med 284: 1333, 1971

49. Treatment of idiopathic respiratory distress
syndrome with continuous positive airway pressure
Weight N PaO2 (pre) PaO2 (post)
930-1500 10 37.1 116.4
1501-2000 5 38.1 114.8
2001-3830 5 48.6 96.0
Gregory et al. N Engl J Med 284: 1333, 1971

53. Nasal CPAP

54. Survey of Infants Admitted to 8
Neonatal ICU’s
• No significant differences in survival
•Columbia had the lowest incidence of O2 use at
28 days and 3 months of age in survivors
•Observations: early use of CPAP, permissive
hypercapnia, no muscle relaxants, “J Wung”
Avery et al Pediatrics 79: 77, 1987

55. Do clinical markers of
barotrauma and oxygen
toxicity explain interhospital
variation in rates of chronic
lung disease?
Van Marter et al Pediatrics: 105, 1194, 2000

56. Columbia vs. Boston
•Case-cohort study to evaluate the relationship between
NICU practices and the occurrence of BPD
• Birth weight 500-1500g (1991-93)
•Three NICUs: Babies, Beth Israel Hospital & Brigham
and Women’s Hospital
• Outcome: O2 at 36 weeks PMA

57. Babies Boston
BPD 4% 22%*
CPAP 63% 11%*
Ventilation 29% 75%*
# days MV 13 d 27 d *
Surfactant 10% 45%*
Indomethacin 2% 28%*
Sedation 0% 46%*
Mortality 9% 10%
Postnatal Steroids 3% 4%
No significant differences in IVH, PVL, NEC or ROP

58. Long-Term Neurocognitive
Development

59. vLong-Term Neurocognitive
Development
Sanocka et al PAS 2002

60. Long-Term Neurocognitive
Development
Hypocarbia on day one was associated with a two-
fold increase in CP [odds ratio of 2.2 (1.0-4.0)]
Hypercarbia (PaCO2 > 55, < 65) had no effect on the
prevalence of CP, IQ or behavioral scores
Sanocka et al PAS 2002

61. Permissive Hypercapnia
•Intentional hypoventilation to avoid volutrauma
and diminish lung injury.
• Limited controlled data in infants to support its
efficacy & safety.

62. Lung Inflammatory Markers:
Effect of FiCO2
• Premature lambs studied at 132 days
Exogenous surfactant to all (n=14)
High TV and PIP for 30 minutes (10.8ml/kg, 40cm H2O)
• Group I
IPPV (TV 6-8ml/kg): pCO2 of 40mm Hg for 5.5 hours
• Group II
Same TV, PIP and F as group I; IPPV for 5.5 hours
FiCO2 increased to maintain pCO2 of 95mm Hg.
• Alveolar wash after IPPV
Strand et al., Peds Research 2003

63. Lung Inflammatory Markers:
Effect of FiCO2
1.5
1
nl PCO2
0.5 hi PCO2
0
Protein Total WBC PMN H2O2
Strand et al., Peds Research 2003

64. Protective Effects: Hypercapnia
• Hypercapnic acidosis protects the heart and brain
against ischemic injury and protects the lung against
ischemic-reperfusion injury in experimental animals.
• Hypercapnia increases cardiac output and oxygen
delivery, decreases oxygen consumption, increases
mesenteric blood flow, attenuates oxygen induced
retinal neovascularization.

65. Protective Effects: Hypercapnia
• Hypercapnia upregulates pulmonary nitric oxide,
decreases inflammatory processes, and attenuates
production of free radicals.
• Human beings can tolerate exceptionally high
concentrations of CO2 and recover completely.
• Hypothesis: Hypercapnia may be protective in the
setting of acute organ injury.

66. CPAP started infants in 2 epochs, BW<1000g
1999-2002 2008-11
(n=138) (n=235)
CPAP failure (%) 35 36
Surfactant given on failure (%) 52 63
Pneumothorax (%) 7.2 9.8
Mortality (%) 14.5 13.6
BPD (O2 at 36wk) (%) 10.9 8.1

67. Infants ≤1000g with RDS requiring
intubation after a trial of CPAP
Blood gases at time of failure
Time of intubation pH PaCO2 PaO2/FiO2
(hrs)
CPAP-failure 29.7±18 7.19±.09 63±16
133±86

68. Why is Columbia Successful with CPAP?
• Early use of NPCPAP
• Use of permissive hypercapnia
• Acceptance by nursing staff
• Bubble CPAP
• Meticulous attention to CPAP circuit
• Frequent suctioning; check prong position frequently
• Jen T. Wung, MD (be patient; give the baby a chance)

69. Lung Inflammatory Markers:
Effect of CPAP
• Premature lambs studied at 134 days
labor induced with epostane and betamethasone
vaginal delivery allows spontaneous breathing
• Lambs divided into 3 groups
no IPPV
IPPV at F = 40, PIP (maintain pCO2 at 40), PEEP 4
bubble CPAP, 5 cm H2O
• Evaluate lungs at 2 hours
Jobe et al., Peds Research 2002

70. Lung Inflammatory Markers:
Effect of CPAP
7.5
*
7.4
IPPV
pH
7.3
CPAP
7.2
7.1
0 15 30 60 120
time (minutes)
Jobe et al., Peds Research 2002

71. Lung Inflammatory Markers:
Effect of CPAP
80
70
pCO2 (mm Hg)
60
IPPV
50 CPAP
40
30
0 15 30 60 120
time (minutes)
Jobe et al., Peds Research 2002

72. Lung Inflammatory Markers:
Effect of CPAP
80
60
volume (ml/kg)
IPPV
40
CPAP
20
0
0 5 10 15 20 25 30 35 40
pressure (cm H2O)
Jobe et al., Peds Research 2002

73. Lung Inflammatory Markers:
Effect of CPAP
40
30
cells x 10 /kg
5
lymphs
20
mono
10
0
No IPPV IPPV CPAP
Jobe et al., Peds Research 2002

74. Lung Inflammatory Markers:
Effect of CPAP
8
neutrophils x 10 /kg
6
5
4 PMN
2
0
No IPPV IPPV CPAP
Jobe et al., Peds Research 2002

75. Lung Inflammatory Markers:
Effect of CPAP
125
H2O2 (micromoles/kg)
100
75
H2O2
50
25
0
No IPPV IPPV CPAP
Jobe et al., Peds Research 2002

76. The BPD Scorecard
Intervention Relative Evidence
Importance
Antenatal steroids - strong
Surfactant + strong
DR management ++++ animal data
Fluid restriction ++ moderate
Early use of CPAP +++ minimal
Permissive CO2 +++ minimal

83. Nasal CPAP
Set up ( 1 )
1. Oxygen blender
2. Flowmeter(5-10 LPM)
3. Heated humidifier
4. Thermometer
5. Inspiratory tubing
6. Nasal cannulae
7. Velcro

84. Nasal CPAP
Set up ( 2 )
8. Manometer (optional)
9. Expiratory tubing
10. A bottle containing a
solution of 0.25% acetic
acid filled up to a depth of
7 cm. Distal tubing
immersed to a depth of 5
cm to create +5 cmH2O

87. Nasal CPAP
Application (2)
4. Choose FiO2 to keep
PaO2 at 50’s or
O2 saturation at
83 – 93%

88. Nasal CPAP
Application (3)
5. Adjust a flow rate 5-10
lpm to:
a) provide adequate flow to
prevent rebreathings CO2
b) compensate leakage from
tubing connectors and
around CPAP prongs
c) generate desired CPAP
pressure (usually 5
cmH2O)

90. Nasal CPAP
Application (5)
7. Insert the lightweight
corrugated tubing
(preferrably with heating
wire inside) in a bottle of
0.25% acetic acid solution
or sterile water filled up to
a height of 7 cm. The tube
is immersed to a depth of
5 cm to create 5 cmH2O
CPAP as long as air
bubbling out of solution

91. Neonatal Resuscitation
& Lung Injury
Neonatal resuscitation bags can deliver
high volumes at very high pressures.
ComplianceLung = Δ Volume/Δ Pressure

92. Factors Contributing to Lung Injury
Jobe and Ikegami 1998

93. Effects of High TV Ventilation
Wada et al., J Appl Phys 1997

94. Fluid Therapy & BPD
•Recovery from RDS is heralded by the onset of
diuresis.
• A delayin the onset of diuresis until 5-7 days is
associated with an increased risk of BPD.
•Diuretics may facilitate extubation in infants with
RDS who are not exhibiting a spontaneous diuresis.

95. Fluid Therapy & BPD
Study Design N BW Outcome
Bell et al* RCT 170 ~1430g No difference
Lorenz et al** RCT 88 ~1180g No difference
Tammela@ RCT 100 ~1300g BPD (4 wks)
Kavvadia # RCT 168 ~ 900g No difference
*NEJM 1980, **J Ped 1982, @ Eur J Ped 1992, # Arch. Dis Child 2000

96. Permissive Hypercapnia
•VLBW infants with RDS (n= 49) randomized to a
hypercapnia group (PHC) (PCO2 45-55) or normo-
capnia group (NC) (PCO2 35-45).
•The total number of days on assisted ventilation was
2.5 in the PHC group and 9.5 in the NC group (P=.17).
• No difference in BPD, IVH, PVL or air leak
Mariani et al Pediatrics 1999