Strategies for the Prevention of Bronchopulmonary Dysplasia: Wishful Thinking or Reality?

Strategies for the Prevention of

Bronchopulmonary Dysplasia:

Wishful Thinking or Reality?

S. David Rubenstein, MD

Chronic Pulmonary Disorder which is

Consequence of Lung Injury that is

Abnormally Repaired

Bronchopulmonary

Dysplasia (BPD)

Old Definition of BPD

Need for supplemental oxygen at

> 28 days or > 36 wks gestation.

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

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

“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.

“Old” BPD

“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.

“New” BPD

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

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].

7. Lung injury with the initiation of ventilation

Vyas et al. [48] measured lung expansion after term birth and observed high

negative esophageal pressures with inspiration and high positive esophageal pressures

with expiration. Adequate tidal volumes and functional residual capacities were

achieved most effectively in asphyxiated term infants when long inspiratory times (5

s) were used to initiate ventilation [49]. The long inspiratory times and relatively high

pressures overcome the resistance of fluid movement down the airways, a process

facilitated by high surfactant concentrations in fetal lung fluid at term. There have

been no systematic studies of the initiation of ventilation in VLBW infants. In animal

models, air opening pressures for fluid filled fetal lungs decrease as fetal lung fluid

volumes decrease and decrease as surfactant concentrations increase [50,51]. How-

ever, if fetal lung fluid volumes are very low, opening pressures increase because of

airway collapse [50], a situation that can occur after prolonged rupture of membranes.

Initiation of ventilation in VLBW infants often requires pressures greater than 30

cmH 0, probably because surfactant concentrations are low and fetal lung fluid2

volumes are high as a result of immature fluid clearance pathways. The generally

accepted goal for ventilation of the VLBW infant after delivery is to achieve a pink

infant with a P of about 40 mmHg as soon as possible, and this may not be easilyCO 2

achievable without risking lung injury. The VLBW infant destined to have RDS may

have a total lung capacity of only 20 ml /kg (Fig. 2). The lungs will inflate poorly and

nonuniformly because of surfactant deficiency despite the use of high pressures, and

ventilation in the midst of a resuscitation may not effectively limit tidal volumes to

volumes that will not enter the high volume injury zone. In practice this injury zone

Jobe et al, Early Human Development: 53 (1998) 81-94

Factors Contributing to Lung Injury

Jobe: Neoreviews 2006

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)

Goldenberg et al NEJM 342: 1500-07, 2000

Incidence of positive chorioamniotic cultures in

women with intact membranes undergoing cesarean

section after spontaneous preterm labor

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

Intrauterine Infection and Preterm Labor

Goldenberg,

NEJM: May, 2000

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

There is a strong relationship between markers of

inflammation in amniotic fluid and BPD

Yoon, Am J Ob Gyn; Oct 1997, 825-830

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

Intrauterine Inflammation & Risk of Chronic Lung

Disease

Chorioamnionitis No chorioamnionitis

RDS 33% 73%

BPD 63% 27%

Watterberg K. Ped. 1996 & 1997

* p< 0.003 * p<0.01

*

* *

*

*

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

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

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.

• Ventilation at low lung volumes (atelectrauma) also

causes release of cytokines and influx of white blood

cells.

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).

Lung Injury Zones

Jobe and Ikegami 1998

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)

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.

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.

Delivery Room Management

Can lung damage occur immediately after

birth by giving a few large breaths?

If yes, will surfactant still be effective?

Neonatal Resuscitation

& Lung Injury

Bjorkland et al Ped. Res. 42: 348, 1997

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.

Neonatal Resuscitation

& Lung Injury

Bjorkland et al Ped. Res. 42: 348, 1997

• Blood gases and pressure volume curves were

then recorded until the lambs were sacrificed at age

four hours.

• Lung histopathology was then examined

Neonatal Resuscitation

& Lung Injury

Bjorkland et al Ped. Res. 42: 348, 1997)

Pressure (cm H2O)

Control lambs Experimental group

15 15 30 30

Volu

me

(ml/

kg)

Volume (ml/kg

5 5

30

10 10 Before surfactant Before surfactant

45-135 min. 45 min.

75 min.

135 min.

20

Resuscitation & Lung Injury

Bjorkland et al Ped. Res. 42: 348, 1997

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

•Flux of fluid into the air spaces

Lung Overdistension Jobe

Am J Respir Crit Care Med 176: 575-581 (2007)

(PIP = 45-50 cm H2O)

Lung Overdistension Jobe

Am J Respir Crit Care Med 176: 575-581 (2007)

Bronchoalveolar lavage fluid: TP and cell count

Increased 5-fold, 11-fold, 14-fold

Increased 300-fold

* p < 0.01

Lung Overdistension Jobe

Am J Respir Crit Care Med 176: 575-581 (2007)

Cytokine mRNA in lung tissue

• 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.

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

Fluid Therapy & BPD

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)

Antenatal Steroids & BPD (True or False?)

• Antenatal steroids decrease the incidence

of bronchopulmonary dysplasia.

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

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.

Surfactant Delivery room prophylaxis

Mortality

BPD

Pneumothorax

Treatment of RDS

Mortality

BPD

Pneumothorax

Natural Synthetic

•

•

•

•

•

•

• •

•

•

•

1.0 1.0

Continuous Positive

Airway Pressure

If you do not ventilate neonates

it’s hard to cause BPD!

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

Gregory et al. N Engl J Med 284: 1333, 1971

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

Treatment of idiopathic respiratory distress

syndrome with continuous positive airway pressure

Gregory et al. N Engl J Med 284: 1333, 1971

Nasal CPAP

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

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

• 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

Columbia vs. Boston

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

Long-Term Neurocognitive

Development

vLong-Term Neurocognitive

Development

Sanocka et al PAS 2002

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

Permissive Hypercapnia

• Intentional hypoventilation to avoid volutrauma

and diminish lung injury.

• Limited controlled data in infants to support its

efficacy & safety.

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

Lung Inflammatory Markers:

Effect of FiCO2

0

0.5

1

1.5

Protein Total WBC PMN H2O2

nl PCO2

hi PCO2

Strand et al., Peds Research 2003

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.

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.

CPAP started infants in 2 epochs, BW<1000g

1999-2002

(n=138)

2008-11

(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

Infants ≤1000g with RDS requiring

intubation after a trial of CPAP

Time of intubation pH PaCO2 PaO2/FiO2

(hrs)

CPAP-failure 29.7±18 7.19±.09 63±16

133±86

Blood gases at time of failure

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)

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

Lung Inflammatory Markers:

Effect of CPAP

7.1

7.2

7.3

7.4

7.5

0 15 30 60 120

time (minutes)

pH IPPV

CPAP

*

Jobe et al., Peds Research 2002

Lung Inflammatory Markers:

Effect of CPAP

30

40

50

60

70

80

0 15 30 60 120

time (minutes)

pC

O2

(m

m H

g)

IPPV

CPAP

Jobe et al., Peds Research 2002

Lung Inflammatory Markers:

Effect of CPAP

0

20

40

60

80

0 5 10 15 20 25 30 35 40

pressure (cm H2O)

volu

me (

ml/

kg)

IPPV

CPAP

Jobe et al., Peds Research 2002

Lung Inflammatory Markers:

Effect of CPAP

0

10

20

30

40

cell

s x

10

5/k

g

No IPPV IPPV CPAP

lymphs

mono

Jobe et al., Peds Research 2002

Lung Inflammatory Markers:

Effect of CPAP

0

2

4

6

8

neu

tro

ph

ils

x 1

05/k

g

No IPPV IPPV CPAP

PMN

Jobe et al., Peds Research 2002

Lung Inflammatory Markers:

Effect of CPAP

0

25

50

75

100

125

H2

O2

(m

icro

mo

les/

kg)

No IPPV IPPV CPAP

H2O2

Jobe et al., Peds Research 2002

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

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

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

Nasal CPAP Application (2)

4. Choose FiO2 to keep

PaO2 at 50’s or

O2 saturation at

83 – 93%

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)

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

Neonatal Resuscitation

& Lung Injury

Neonatal resuscitation bags can deliver

high volumes at very high pressures.

ComplianceLung = Δ Volume/Δ Pressure

Factors Contributing to Lung Injury

Jobe and Ikegami 1998

Effects of High TV Ventilation

Wada et al., J Appl Phys 1997

• Recovery from RDS is heralded by the onset of

diuresis.

• A delay in 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.

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

Fluid Therapy & BPD

*NEJM 1980, **J Ped 1982, @ Eur J Ped 1992, # Arch. Dis Child 2000

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