Bronchopulmonary Dysplasia:
Prevention and Management
Namasivayam Ambalavanan M.D.
Assistant Professor,
Division of Neonatology,
Department of Pediatrics,
University of Alabama at Birmingham
Feb 2003
Overview of presentation
Bronchopulmonary dysplasia: a moving target?
 Pathogenesis
 Strategies for prevention of BPD
 Strategies for management of BPD
 Outcome
 Appendix

BPD vs. CLD
Initially labeled “bronchopulmonary dysplasia”
[BPD]
 Later called “neonatal chronic lung disease” or
“chronic lung disease of infancy” [CLD]
 Many experts now believe the term
“bronchopulmonary dysplasia” is more accurate
in describing the pathogenesis and that CLD is
not a specific diagnosis or description

Introduction
 Northway, Rosan, and Porter (1967) :BPD :premature
infants who developed RDS, required prolonged
mechanical ventilation with high pressures and FiO2.
Classic clinical and radiographic course had four stages:
I: RDS,
II: dense parenchymal opacification,
III: bubble-like pattern,
IV: hyperlucency of bases with strands of radiodensity in
upper lobes.
 Currently, a milder form of BPD is more commonly seen
in tiny premies who have only mild pulmonary disease not
requiring high ventilatory support
Introduction
Definitions:
1. 1980’s: Oxygen dependence for 28 days or
more after birth (Tooley WH. J Pediatr 95: 851-8, 1979)
2. 1990’s: Oxygen dependence at 36 wks’
corrected age (Shennan et al. Pediatrics 82:527-32, 1988)

3.
More correlated with abnormal pulmonary outcome at 2
years (63% PPV) vs. 28 d definition (38% PPV).
21st century: New physiologic definition of
BPD
Physiologic definition of BPD



Problem with previous definitions: The decision to
administer oxygen is not uniform and the definition
of acceptable saturation (85-98%) varies.
Development of a “room air test” to document the
need for oxygen by the NICHD Neonatal Research
Network
What is O2 requirement (failure in test)?
 Saturation <88% for 5 continuous minutes
 Any saturation <80% on an accurate pulse
oximeter reading
Study Design
Baseline phase x 5 min
 Oxygen reduction phase as per protocol every 10
min with continuous monitoring

O2 reduction phase
Rapid Pass (15 min in RA>96%)
No BPD
Rapid Fail (80-88% for 5 min
(or) <80% immediate fail
BPD
Intermediate: 88-96% in first 15 min.
Monitor for total 60 min.
Some BPD
Some No BPD
Incidence
Varies by definition, selection bias, survival
 Developed countries: NICHD Neonatal Network
for 2001
BPD-36
UAB
All centers
401-1500g 11% (n=297) 23% (n=3589)
401-1000g 19% (n=154) 39% (n=1517)
 Developing countries:
 PGI: BPD-28: <1000g: 50% ; 1000-1249g: 8%;
1250-1499g: 2.3% (Indian Pediatrics Feb 2002)

Incidence
• UAB statistics (1998-1999) of all live births <34 w
(excluding 10 deaths before admission)
GA
23
24
25
26
27
28
29
30 31
32
33
34
n
34
52
50
62
63
82
87
85 100 168 158 160
Survival
35
48
82
85
95
89
97
94 99
98
99
99
26
19
32
34
14
4
2
0
1
0
0
(%)
BPD
0
(%)
• 401-1000 g (2001; n=154): 82% IMV, 73% surf, 16%
steroids for BPD
Pathogenesis
PULMONARY IMMATURITY
Increased
Pressure/ flow
Airway
inhomogeneity
Compliance
Immature cells
Retained fluid
Barotrauma
Protein
leak
Respiratory Distress
Syndrome
Infection / Inflammation
PDA
O2 Toxicity
DIFFUSE ALVEOLAR DAMAGE
Barotrauma
surfactant
deficiency
RECOVERY
Infection / Inflammation
BRONCHOPULMONARY DYSPLASIA
Prevention of BPD

Ventilatory Strategies
Selective intubation / Avoid IMV (Prophylactic IMV
bad)
 Early CPAP
 Minimal (‘gentle”) ventilation
 Early extubation


Pharmacologic Strategies
Antenatal steroids
 Vitamin A supplementation
 Others
 Other management: PDA, Infection

Conservative Indication For CV and BPD
Percent (%)
100
Intubation
40
75
30
50
20
25
10
0
0
Control
Conservative
BPD
Control
Poets and Sens
Gitterman, et al
Lindner, et al
de Klerk and de Klerk
Conservative
Adapted from Poets and Sens*, Gitterman et al., and Lindner et al,
de Klerk and de Klerk*.
*and/or mortality
Ventilatory strategies for BPD prevention
1.
2.
3.
4.
5.
6.
7.
8.
Conservative indications for assisted ventilation
Smallest possible tidal volume
Sufficient inspiratory and expiratory times
Moderate PEEP to prevent end expiratory alveolar
collapse and maintain adequate lung volume
Early/prophylactic use of surfactant
Acceptance of hypercapnic acidosis
Aggressive weaning from assisted ventilation
Rescue with high frequency if air leak syndromes
Non-ventilatory strategies for BPD prevention




Antenatal steroids
Vitamin A supplementation (Tyson et al. NEJM 340:1962, 1999)
Avoidance of infections
Closure of PDA (but TIPP trial did not show a difference in BPD
despite a decrease in PDA from 50 to 24%. Schmidt et al. NEJM
344:1966-72, 2001)

Optimal fluid and electrolyte management: moderate water
and sodium restriction in first week of life (Tammela et al.
Acta Paediatr 81:207-12,1992; Costarino et al. J Pediatr 120: 99106, 1992; Hartnoll et al 82: F19-23, 2000)
BPD Management
 Treatment is directed towards major pathophysiology:
 Pulmonary edema => Diuretics
 Bronchoconstriction and airway hyperreactivity =>
Bronchodilators
 Airway inflammation => Steroids
 Cor pulmonale => Vasodilators
 Chronic lung injury and repair =>Antioxidants,
nutrition, prevention of infections
Management - Diuretics
 DIURETICS: Furosemide + Thiazides
 When to consider :
1 Babies >1-2 wks w/ mod-severe lung disease on
ventilator
2 BPD w/ volume overload
3 “Stalled” BPD
4 BPD w/ inadequate nutrition due to fluid
restriction
Management - Diuretics
 How?
 Therapeutic trial (Lasix): Give 1 mg/kg iv or 2 mg/kg
po/og x 4-5 doses. If no improvement, increase dose. If
improvement, give long term. If no improvement, no
long term. Eval weekly.
 Monitor for side effects: Fluid-electrolyte balance/
alkalosis/ osteopenia / ototoxic / gall stones. Alternate
day Rx may decrease side effects.
 No evidence to support any long-term benefit (Brion et al.
Cochrane Database Syst Rev (1):CD001817, 2002)
Management - Bronchodilators

Types of Bronchodilators:
 Methylxanthines ( Theophylline, caffeine )
 Bronchodilator, diuretic, resp stimulant
 weak bronchodilator, increased side effects
 b-adrenergic agonists ( mainly b2, less b1 )
 mainly smooth muscle relaxation, also enhance
mucociliary transport, redistribute pulmonary
blood flow
 Anticholinergics - Atropine, Ipratropium
Management - Bronchodilators


Results:
 Bronchodilators improve pulmonary function in the
short-term.
 No studies on long-term efficacy
 Inhaled salbutamol did not prevent BPD in a RCT
(Denjean et al. Eur J Pediatr 157:926-31, Nov 1998)
 Long term safety ? - b receptors in the brain.
Is bronchoconstriction protective ?
 Focal bronchoconstriction may have protective action
by limiting lung injury to distal units
 May maintain airway wall rigidity
Management - Vasodilators

VASODILATORS
 WHY ?
 Alveolar hypoxia leads to pulmonary vasoconstriction and
structural remodeling of the pulmonary vascular bed.
 Oxygen a potent vasodilator, main vasodilator used in BPD.
Keep PO2 60-80, SpO2 92-95%.
 Hydralazine, Diltiazem, Nifedipine used in very small trials
showed hemodynamic improvement.
 Nitric Oxide (NO) improves oxygenation in some infants
(Pilot study by Banks et al. Pediatrics 103:610-8, Mar 1999)
Management - Steroids

STEROIDS - Widespread use, different regimens
 HIGH RISK: Use is not recommended

WHY ?
Anti-inflammatory properties (early)
 Modulate lung repair (late)


HOW ?
Early vs Late use
 Short-term vs Long-term course
 PO/IV vs Inhaled route

AAP/CPS statement
Pediatrics 109: 330-8 Feb 2002
“The routine use of systemic dexamethasone for
the prevention or treatment of chronic lung
disease in infants with very low birth weight is
not recommended”
 “Outside the context of a randomized, controlled
trial, the use of corticosteroids should be limited
to exceptional clinical circumstances (eg, an
infant on maximal ventilatory and oxygen
support).”

Summary of systemic dexamethasone for BPD
BPD and BPD/Death are decreased by steroids
 However, short-term risks are significant
 No improvement in survival
 Long-term neurodevelopment is worse in infants
treated with steroids (about a 2-fold increase in CP)
 Alternatives:
 Low doses of hydrocortisone ?
 Inhaled steroids ?
 Other steroids eg. Methylprednisolone ?

RCT OF VITAMIN A IN ELBW INFANTS
Decreased Risk Increased Risk
CLD or Death
CLD in Survivors
Hospital-acquired sepsis
Grade 3/4 IVH
Death, 3/4 IVH, or PVL
0.6
Tyson et al. NEJM 340:1962, 1999
0.7
0.8
0.9
1.0
1.1
1.2
RR with 95% Cl
1.3
Prevention of infections
Routine antisepsis and hand-washing precautions
 Routine infection control measures
 Specific prophylaxis (when available, depending
on country):
 Palivizumab (Synagis): humanized monoclonal
antibody to RSV
 Pneumococcal conjugate vaccine (7-valent,
Prevnar)
 Influenza vaccine

Treatment of infections

Postnatal sepsis associated with more BPD
(Van Marter et al. J Pediatr 140:171-6, Feb 2002 )

Is Ureaplasma colonization associated with BPD?
No (Heggie et al. PIDJ 20:854-9, Sept 2001)
 Only if persistently (+) (Castro-Alcaraz et al.
Pediatrics 110:e45, Oct 2002)
 Even if associated with BPD, erythromycin treatment
may not be effective (Buhrer et al. Drugs 61:1893-9,
2001)

Summary of BPD management






Prevention is better than treatment
Oxygen therapy, avoidance of environmental and infectious
hazards. Essential not to underutilize or discontinue O2 too
early (may lead to feeding difficulty, slow growth,
bronchoconstriction, Pulmonary hypertension )
Optimize nutrition
Bronchodilators and diuretics may lead to short-term
improvements. Long-term effects unknown.
Avoid steroids as far as possible
Experimental management: Enzyme, Gene, Cytokine,
Antioxidant, Antiprotease administration, Lung transplant
Outcome

Short-term outcome
Mortality in first year is high ( Respiratory failure, sepsis,
or intractable cor pulmonale) : 11-73% (23%)
 Respiratory infections not more frequent, but earlier and
more severe. 22% risk of hospitalization in first yr for resp
illness, 40-50% for all causes.
 Higher risk of growth and developmental delay
 Gradual improvement in pulmonary function and cor
pulmonale usual, with adequate nutrition, growth and
control of infection.

Outcome (contd.)

Long-term outcome

Lung function  Poor compliance,
 increased resistance,
 expiratory airflow limitation (bronchospastic and
bronchomalacic),
 increased WOB, air trapping, reactive airway disease.
 May persist into adulthood.
Appendix
Introduction
 Indications for mechanical ventilation
 Ventilator variables for controlling
mechanical ventilation
 BPD Pathogenesis
 BPD Management

Introduction

Factors influencing incidence:
 Definition used
 Nature of patient population (Race, Sex, Antenatal
steroid use, Infection incidence etc.)
 Wide variation between different centers (Avg: 4%
of the babies req vent, 15% of RDS req vent >3 d
& surviving 30 days.)
 23-26% of VLBW survivors in USA/Canada
Introduction

Factors influencing incidence:
 Survival statistics in patient population
 Developing nations have very low CLD
since most ELBWs die within 28 days
 Surfactant improves survival of smaller
babies, but overall incidence of BPD same
[“Shift of survival and BPD curves
downward”]
Introduction (contd.)
 Clinical
presentation:
 Progression of XRay findings through 4 stages
(Northway) now rarely seen :
 I: RDS,
 II: dense parenchymal opacification,
 III: bubble-like pattern,
 IV: hyperlucency of bases with strands of
radiodensity in upper lobes.
Introduction (contd.)
 Clinical
presentation (contd.)
Many premies have mild disease initially, but
after a few days or weeks, chronic lung disease
appears - maybe triggered by infection, PDA or
barotrauma.
 Survivors show slow but steady improvement in
their lung function and XRay changes and can
be weaned from the ventilator and oxygen
therapy after weeks to months.

Introduction (contd.)
 Clinical
presentation (contd.)
 After extubation, retractions, tachypnea, and
crackles persist for variable periods.
Atelectasis occurs frequently.
 Infants with more severe lung damage may die
of progressive respiratory failure, cor
pulmonale, or infections.
Goals of mechanical ventilation


To achieve adequate gas exchange with
minimal lung injury and other adverse effects
The definitions of “adequate gas exchange”
and “minimal lung injury” will depend on the
underlying pathophysiology and the clinical
condition of the neonate
Adequate Gas Exchange
 The definition of adequate gas exchange will
determine:
 the indications for the initiation of mechanical
ventilation
 the desired blood gas values
 the ventilator adjustments to maintain the
blood gas values within the desired ranges
Indications for mechanical ventilation
I. Clinical criteria:



Respiratory distress : retractions (intercostal,
subcostal, suprasternal) and tachypnea (rate > 6070/min)
Central cyanosis (cyanosis of oral mucosa or an
oxygen saturation of <85%) on oxygen by hood
(head box) or continuous positive airway pressure
(CPAP) at FiO2 > 60-70%
persistent apnea unresponsive to medical
management (e.g. theophylline, caffeine, or CPAP)
Indications for mechanical ventilation
II. Laboratory criteria:


Severe hypercapnia: arterial carbon dioxide
tension (PaCO2) > 60 mm Hg in early RDS or >
70-80 mm Hg in resolving RDS, accompanied
by a pH of less than 7.20
Severe hypoxemia: arterial oxygen tension
(PaO2) < 40-50 mm Hg on oxygen by hood
(head box) or CPAP at FiO2 > 60-70%
Prophylactic mechanical ventilation
is not beneficial



Prophylactic mechanical ventilation not beneficial, even
for extremely premature neonates
A decrease in the rates of intubation and mechanical
ventilation for very low birth weight (VLBW) neonates
reduced bronchopulmonary dysplasia (BPD)
(Poets CF, Sens B:Pediatrics 1996;98: 24-27)
An individualized intubation strategy that restricted
intubation and mechanical ventilation did not increase
mortality or morbidity
(Lindner W et al. Pediatrics 1999; 103: 961-967 )
Prophylactic mechanical ventilation
is not beneficial (contd.)

A significant part of the variation in BPD
between two centers could be explained by an
increased incidence of BPD in the center with
more frequent use of mechanical ventilation
(Van Marter LJ et al. Pediatrics 2000, 105:1194-1201)
Ventilator controls
The ventilator controls on most pressure-controlled
time-cycled ventilators are:
 Positive end expiratory pressure (PEEP)
 Peak inspiratory pressure (PIP)
 Ventilator rate (VR)
 Inspiratory time (TI), expiratory time (TE), or
inspiratory-expiratory ratio (I:E)
 Inspired oxygen concentration (FiO2)
 Flow rate
Positive end expiratory pressure (PEEP)
PEEP maintains or improves lung volume
(functional residual capacity or FRC), prevents
alveolar collapse, and improves V/Q matching
 PEEP, rather than PIP or TI, is the main
determinant of FRC
 Low PEEP: atelectasis, low FRC, and low PaO2
 High PEEP: low VT, high FRC, and high PaCO2
 Optimal PEEP: between 3 - 6 cm H2O pressure

Peak Inspiratory Pressure (PIP)
Changes in PIP affect PaO2 by affecting the
mean airway pressure and thus influencing V/Q
matching.
 The level of PIP also affects the pressure
gradient (DP) which determines the tidal
volume
 PIP increases normally increase PaO2 and
decrease PaCO2

Peak Inspiratory Pressure (PIP) contd.
Very high PIP may lead to hyperinflation and
decreased lung perfusion and cardiac output,
leading to a decrease in oxygen transport despite
an adequate PaO2
 High levels of PIP also increase the risk of
“volutrauma”, air leak syndromes, and lung injury
 PIP required depends mainly on the compliance
of the respiratory system.

Peak Inspiratory Pressure (PIP) contd.


Clinical indicator of adequate PIP is gentle chest rise
with every ventilator-delivered breath, similar to
spontaneous breathing.
The degree of observed chest wall movement during
the ventilator-delivered breaths indicates the
compliance with fair accuracy
(Aufricht et al. Am J Perinatol 10:139-142, 1993)

Minimal effective PIP: start low (e.g. 15-20 cm H2O)
and increase slowly (in steps of 1-2 cm H2O)
Factors to be considered in selecting
PIP
Yes
Lung compliance
Blood gas derangement
Chest rise
Breath sounds
Others
No
Weight
Resistance
Time constant
PEEP
Others
Ventilator rate
The ventilator rate (frequency) determines
alveolar minute ventilation and thereby PaCO2
 alveolar minute ventilation = frequency x [tidal
volume – dead space]
 Relationship not linear: As ventilator rate
increases and TI decreases below 3 time constants,
VT decreases and minute ventilation falls

(Boros et al. Pediatrics 74: 487-492, 1984)

As time constant is low in RDS, rates > 60/min
can be used
TI , TE , and I:E
The TI and TE are normally adjusted based on the
time constant
 Changes in I:E change MAP, and thus PaO2
 When corrected for MAP, changes in I:E are not
as effective in improving PaO2 as changes in PIP
or PEEP (Stewart et al. Pediatrics 67:474-81, 1981)
 Higher ventilatory rates combined with a short TI
decrease air leaks

(Octave. Arch Dis Child 66:770-775, 1991;
Pohlandt et al. Eur J Pediatr 151:904-909, 1992)
Gas exchange
 MAP increases
with increasing PIP, PEEP, TI
to TE ratio, rate, and flow
PIP
Pressure
Rate
Flow
TI
PIP
PEEP
PEEP
TI
TE
Time
Inspired oxygen concentration (FiO2)
Changes in FiO2 alter PaO2 directly by changing
the A-a DO2
 Insufficient data to compare the roles of O2induced versus pressure-associated (or volumeassociated) lung injury in the neonate
 Generally believed that risk of O2 toxicity is less
than that of volutrauma with FiO2 < 0.6 - 0.7
 Frequent FiO2 changes are required, based on
pulse oximetry rather than occasional blood gases

Inspired oxygen concentration (FiO2)
During early RDS, FiO2 first increased to 0.6 to
0.7 before additional increases in MAP
 During weaning, first decrease PIP to relatively
safe levels, then decrease FiO2 below 0.4 to 0.5
 Maintenance of an adequate MAP and V/Q
matching may permit a reduction in FiO2
 Reduce MAP before a very low FiO2 (<0.3) is
reached, to reduce the risk of air leaks.

Flow rate
As long as a sufficient flow is used, there is
minimal effect on the pressure waveform or on
gas exchange
 Higher flow leads to a more “square wave”
pressure waveform, which increases MAP,
turbulence, and risk of air leaks
 A minimum flow rate of about 3 times the infant’s
minute ventilation is usually required, and 6-10
L/min is usually sufficient

Ventilator settings
In view of the low compliance, short time
constant, low FRC, and risk for air leaks, it is
usually preferred to use
 rapid rates (>60/min)
 moderate PEEP (4-5 cm H2O)
 low PIP (10-20 cm H2O)
 TI of 0.3-0.4 s
 VT is generally 3 - 6 mL/kg body weight

Ventilator settings

Randomized controlled trials have shown that a
rapid rates and short TI (versus slow rates and
long TI) decrease air leaks
(Octave. Arch Dis Child 66:770-775, 1991;
Pohlandt et al. Eur J Pediatr 151:904-909, 1992)

Animal models also show that rapid, shallow
ventilation produce less lung injury than slow,
deep breaths
(Albertine et al. Am J Respir Crit Care Med 159: 945958, 1999)
Clinical estimation of optimal TI and TE
Short TI
Optimal TI
Long TI
Inadeq VT Short insp. plateau Long plateau
Chest
Wall
Motion
Short TE
Air trapping
Chest
Wall
Motion
Time
Optimal TE
Short exp. plateau
Long TE
Long exp. plateau
Weaning off ventilator
When good spontaneous ventilatory attempts are
present and mechanical ventilation contributes
only minimally to total ventilation
 Normally done when ventilator rates are 15/min
or less, at a PIP <15 cm H2O and a FiO2 < 40%.
 Extubation from low rates is more successful as
compared to extubation from endotracheal CPAP
(Davis and Henderson-Smart. Cochrane Rev. CD

001078, 2000)
BPD Pathogenesis

Features of the immature lung increasing susceptibility:
 Barotrauma : Poorly compliant airspaces, but highly
compliant airways
 Hyperoxia : Poorly developed antioxidant defenses
 Infection : Altered airway clearance, immature macrophages &
WBC
 Inflammation : Poorly developed anti-oxidant, antiproteolytic
and antielastolytic systems
 Increased permeability of the alveolo-capillary membrane
with decreasing gestational age.
BPD Pathogenesis

Complications of Hyperoxia:

Cytotoxicity epithelium & endothelium
hemorrhage
Pulmonary edema and

Cytotoxicity on airway lining & macrophages
clearance and increased infection

Pulmonary edema + inhibition of surfactant synthesis leads to
worsening compliance

Inhibition of pulmonary vascular response to hypoxia leads to
shunting , V/Q mismatch

Inhibition of normal lung repair, healing by fibroblast proliferation

Inhibition of normal lung development, decreased alveolarization

Loss of pulmonary endothelial functions
Poor airway
Lung Injury During Mechanical
Ventilation
1. Chest wall restriction limits pressure-induced lung
injury (Hernandez, et al., 1988)
2. Overexpansion of the thorax with negative
pressures causes lung injury (Dreyfus, et al. 1988)
Changes in intubation rates in relation to
outcome in VLBW infants
Intubated (%)
O2 at 28d (%)
Death or O2 at 28d (%)
Death or O2 in < 1.0 kg (%)
Death or O2 in 1-1.5 kg (%)
CPAP (%)
1992
n=665
78
21
32
62
14
4
Poets and Sens. Pediatrics 98:24, 1996
1993
n=664
78
20
29
54
12
5
1994
n=672
66
17
27
52
9
6
p value
<0.05
<0.05
NS
<0.05
<0.05
NS
Ventilator-Associated Lung Injury
(VALI)
Likely mechanisms
• Volume rather than pressures
• End expiratory volume rather than VT or FRC
• Transalveolar pressure and reopening of alveoli
• Repeated collapse and reopening of alveoli
• Very low positive end expiratory pressure
• Oxidant injury
Which Volumes Cause Lung Injury?
Volume
Volutrauma Zone
Time
A
B
A High VT
B Normal VT,
high PEEP
Compliance
(cc/cmH2O•kg)
EFFECT OF TIDAL VOLUME
ON LUNG COMPLIANCE
3
8 cc/kg
2
16 cc/kg
1
32 cc/kg
0
0
60
120 180 240
Age (min)
Bjorklund et al. Pediatr Res 39:326A, 1996
Early CPAP: prophylactic or rescue?


Prophylactic CPAP (before onset of respiratory distress)
practiced at some centers.
Rescue CPAP (after onset of distress):
 Often combined with an dose of surfactant given by a
brief intubation
 May decrease the need for mechanical ventilation and
improve respiratory failure and reduce mortality
 May increase risk of pneumothorax
(Ho et al. Cochrane Rev 2000 ;(4): CD002271 )
(Verder et al. Pediatrics 1999;103: E24 )
Permissive Hypercapnia: Background
1. Maintenance of normocapnia in some patients
with severe respiratory failure necessitates high
ventilatory support.
2. Compensated respiratory acidosis is generally
well tolerated and may reduce lung injury.
Relative Risk for BPD
Variable
N
Relative risk (95% CI)
Highest PaCO2 at 48 or 96 hr
> 50 mm Hg
21
Reference group
40-49 mm Hg
52
1.35 (0.95, 1.90)
< 40 mm Hg
46
1.45 (1.04, 2.01)
Kraybill et al., J Pediatr 115:115-120, 1989
Risk for BPD in Neonates with RDS:
Variables in Logistic Regression
VE Index < 0.15
a/A Ratio < 0.15
Low PaCO2 (< 29 vs 40)
(30-39 vs >40)
Birthweight < 1000 grams
C/S Due to Fetal Distress
Odds
Ratio
3.1
2.2
5.6
3.3
5.1
4.4
Garland et al. Arch Pediatr Adolesc Med 149-617, 1995
Confidence
Interval
1.4 - 6.8
1.01 - 4.6
2.0 - 15.6
1.3 - 8.4
2.4 - 10.7
1.7 - 11.4
Volume vs. Pressure in Lung Injury
IPPV
Iron Lung
Strapping
Pulm.
Volume
High
High
Low
Epith.
Pressure
High
Low
High
Hyaline
Edema
Yes
Yes
No
Lymph
Injury
Yes
Yes
No
Filtr.
Memb. Flow Coef.
Yes Yes Yes
Yes
N/A N/A
No
No No
Dreyfus et al, 1988; Bshouty et al, 1988; Hernandez et al, 1989; Corbridge
et al, 1990; Carlton et al 1990
CPAP at Birth in VLBW Infants
Intubated (%)
Dur. intubation (d)
O2 at 28 days (%)
Nosocomial infection (%)
CPAP
n=70
30
6(3-9)
30
21
Gitterman et al. Eur J Pediatrics. 156:384, 1997
Control
n=57
53
4.5(3-7)
32
37
p value
<0.05
NS
NS
<0.05
CPAP at Birth in VLBW Infants
Percent (%)
100
Intubation
O at 28d
75
2
50
25
0
Control
CPAP
Gitterman et al. Eur J Pediatrics. 156:384, 1997
CV vs CPAP at Birth in ELBW Infants
CPAP
DR intubation (%)
Intubated (%)
Mortality (%)
O2 at 36 weeks (%)
IVH > 2 (%)
N=67
40
65
22
12
16
Lindner et al. Pediatrics 103:961, 1999
Routine
Intubation
N=56
84
93
27
32
38
p value
<0.01
<0.01
NS
<0.05
<0.01
CV VS CPAP at Birth in ELBW Infants
Intubation
O at 36 weeks
Percent (%)
100
2
75
50
25
0
Control
CPAP
Lindner et al. Pediatrics 103:961, 1999
CPAP in Infants 1-1.5 Kg
Intubated (%)
Surfactant (%)
Ventilation (d)
Oxygen suppl (d)
O2 at 28d (%)
O2 at 28d or death (%)
O2 at 36w or death (%)
CPAP
n=59
14
12
2
2
0
3
3
Control
n=57
65
40
6
4
11
16
11
de Klerk and de Klerk. J Paedr Child Health 37:161:201
p value
<0.001
<0.001
<0.05
<0.01
<0.05
<0.05
0.25
CPAP in Infants 1-1.5 Kg
Intubation
Percent (%)
100
O2 at 28d or death
75
50
25
0
Control
CPAP
de Klerk and de Klerk. J Paedr Child Health 37:161:201
Demographic Characteristics of ELBW and
BPD
Without BPD
(n=50)
28 + 2
902 + 74
34
32
1.98 + 1.25
Characteristic
Gestational age (wk)
Birth weight (gm)
Sex (% male)
Race (% white)
Roentgenographic score
*p<0.005
Kraybill et al., J. Pediatr 115:115-120, 1989
With BPD
(n=97)
27 + 2*
883 + 73
60*
43
2.77 + 1.16*
Treatment Variables of ELBW infants
and BPD
Characteristic
Pressure management
PIP (cm H2O)
At 48 hr
At 96 hr
Paw (cm H2O)
At 48 hr
At 96 hr
Without BPD
(n=29)
With BPD
(n=90)
21 + 6
18 + 5
22 + 7
19 + 5
12 + 6
6+2
12 + 5
8+3
Kraybill et al., J. Pediatr 115:115-120, 1989
Treatment Variables of ELBW infants
and BPD
Without BPD
(n=29)
Characteristic
Oxygen management
FiO2 (%)
At 48 hr
49 + 24
At 96 hr
33 + 18
PaO2 (mmHg)
At 48 hr
85 + 30
At 96 hr
72 + 17
PA-aO2 (mmHg)
At 48 hr
221 + 175
At 96 hr
127 + 128
Kraybill et al., J. Pediatr 115:115-120, 1989
With BPD
(n=90)
54 + 25
38 + 20
79 + 36
74 + 19
268 + 175
158 + 137
Relative Risk for BPD
Variable
N
Highest PaO2 at 48 or 96 hr
< 70 mm Hg
30
70-80 mm Hg
23
81-100 mm Hg
37
> 100 mg Hg
29
Kraybill et al., J Pediatr 115:115-120, 1989
Relative risk (95% CI)
Reference group
0.80 (0.60, 1.07)
0.90 (0.72, 1.13)
0.76 (0.57, 1.01)
Logistic Regression Model to
Predict BPD
Independent Variable
Sex (male)
PaCO2 at 48 hr
Roentgenographic score
Gestational age
Race
Kraybill et al., J. Pediatr 115:115-120, 1989
p
<0.01
<0.05
0.10
0.13
0.79
r
0.20
-0.14
0.07
-0.04
0.00
RANDOMIZED TRIAL OF PERMISSIVE
HYPERCAPNIA IN PRETERM INFANTS
G Mariani, J Cifuentes, WA Carlo
Department of Pediatrics, University of Alabama
at Birmingham
Pediatrics 104: 1082-8, 1999
Infants on MV (%)
Normocapnia
Permissive hypercapnia
100
80
p = 0.002 Log rank test
60
40
20
0
0
12
24
36
48
60
72
84
Duration of MV (hours)
96
SAVE
Trial
EFFECTS OF MINIMAL VENTILATION
IN A MULTICENTER RANDOMIZED CONTROLLED TRIAL
OF VENTILATOR SUPPORT AND EARLY
CORTICOSTEROID THERAPY IN EXTREMELY LOW
BIRTH WEIGHT INFANTS
The Steroid And VEntilation (SAVE) Trial
NICHD Neonatal Research Network
Carlo et al. J Pediatr 141: 370-4, Sept 2002
SAVE
Trial
Centers and Principal Investigators
Univ of Alabama at Birmingham
Harvard University
Emory University
Case Western Reserve University
Yale University
University of Tennessee-Memphis
UT Southwestern Medical Center-Dallas
Wayne State University
Brown University
University of Miami
University of Cincinnati
Stanford University
University of New Mexico
Research Triangle Institute
NICHD
Wally Carlo, MD
Ann Stark, MD
Barbara Stoll, MD
Avroy Fanaroff, MB, BCh
Richard Ehrenkranz, MD
Sheldon Korones, MD
Jon Tyson, MD
Seetha Shankaran, MD
William Oh, MD
Charles Bauer, MD
Ed Donovan, MD
David Stevenson, MD
Lu-Ann Papile, MD
Ken Poole, PhD
Linda Wright, MD
Hypothesis
A strategy
of minimal ventilation support
(defined as a PCO2 goal > 52 mmHg) in infants
501 to 1000 grams, initiated within 12 hours of
birth and maintained as long as mechanical
ventilation is needed during the first 10 days,
reduces by at least 20% the incidence of death or
chronic lung disease at 36 weeks postmenstrual
age.
SAVE
Trial
Sample Size
1200
infants
Ventilator strategy
Minimal
Steroid
strategy
Routine
Stress Dose
300 300
Placebo
300 300
SAVE
Trial
Study Design
Multicenter
 Randomized-stratified by center and birth
weight group
 2 x 2 Factorial design
 Interventions

Corticosteroid/Placebo
 Minimal/Routine ventilation

SAVE
Trial
Ventilatory Intervention (Continued)
Pressure-limited, time-cycled ventilation with or
without SIMV is preferred; HFV is discouraged.
 The preferred ventilator strategy for infants in the
minimal ventilator support group is to use the
smallest possible tidal volume with the
conventional ventilator.
 Ventilator strategy is maintained for ten days
unless extubation occurs sooner.

SAVE
Trial
Methods - Ventilatory Management
Goals: Minimal ventilation group - PCO2 > 52 mmHg
Routine ventilation group
- PCO2 < 48 mmHg
 In both groups:
 Priority was given to decrease tidal volume by
decreasing peak inspiratory pressure (PIP) or increasing
rate
 Tidal volume was measured daily
 The same extubation criteria (rate < 10/min, FiO2 <
0.50, and pH > 7.25) were used

SAVE
Trial
Ventilatory Intervention
Routine ventilator support
Minimal ventilator support
(Normocapnia)
PCO2 goal: < 48 mmHg
PaO2 goal: 50-80 mmHg
O2 sat goal: 88-95%
pH goal:
 7.20
(Permissive hypercapnia)
PCO2 goal: > 52 mmHg
PaO2 goal: 50-80 mmHg
O2 sat goal: 88-95%
pH goal:
 7.20
SAVE
Trial
Results - Primary Outcome Measure
Minimal
Ventilation
(N=109)
Mortality or CLD (%) 63
Mortality (%)
23
CLD (%)
52
Routine
Ventilation
(N=111)
68
22
60
RR
CI
0.92 (0.76-1.12)
1.06 (0.65-1.74)
0.88 (0.67-1.14)
SAVE
Trial
Results - Secondary Analyses
Minimal
Routine
Ventilation Ventilation RR
CLD or death in
501-750 gm (%)
Ventilation at
36 wk (%)
O2/CPAP/Vent
at 36 wk (%)
*p<0.05
CI
NNT
68
86
0.79
(0.65-0.96)* 6
1
18
0.09
(0.01-0.67)* 7
47
57
0.83
(0.60-1.13) —
Weighted PCO2 (mmHg)
PCO2 While on a Ventilator
Routine Ventilation
60
Minimal Ventilation
50
40
30
0
2
4
Study Day
6
8
10
TIMING OF SURFACTANT AND
LUNG VOLUTRAUMA
Compliance
(cc/cmH2O•kg)
6
Prophylactic Surfactant
“Rescue” Surfactant
4
2
0
0
60
120 180 240
Age (min)
.
Ingirmarsson et al. Pediatr Res 41:255A, 1997
Surfactant: which one to use?
Natural surfactants reduce ventilatory
requirements faster, decrease pneumothorax and
mortality risk (Soll & Blanco. Cochrane Rev 4, 2001)
 Natural surfactants: Bovine origin (e.g. Survanta,
Infasurf) or Porcine origin (e.g. Curosurf)
 Infasurf and Curosurf have a longer duration of
action and may slightly decrease ventilator
requirements compared to Survanta (Bloom et al.

Pediatrics 100; 31-38, 1997; Speer et al. Arch Dis Child Fetal
Neonatal Ed;72:F8-13, 1995)
Surfactant use: repeat doses
Repeat doses are given depending on the clinical
status and the ventilatory settings
 Higher threshold (>40% FiO2 with a MAP > 7 cm
H2O) for uncomplicated RDS
 Lower threshold (>30% FiO2) may reduce
mortality in infants with RDS complicated by
perinatal compromise or sepsis
(Kattwinkel et al. Pediatrics 106:282-288, 2000)

Surfactant use: how many doses?
Multiple doses of surfactant are normally required
for moderate to severe RDS. Multiple doses of
natural surfactant (e.g. Survanta):
 improve oxygenation
 reduce ventilator requirements
 reduce pneumothorax (RR 0.51)
 tend to reduce mortality (RR 0.63)
(Dunn et al. Pediatrics;86:564-571, 1990; Speer et al
Pediatrics. 89:13-20, 1992; Soll. Cochrane Rev. (2):
CD000141, 2000)
Surfactant use: how many doses?

Synthetic surfactant (e.g. Exosurf):
 Two doses as good as 3-4 doses
(OSIRIS. Lancet 340:1363-9,1992)
 Three doses better than one dose (lower
mortality, ventilator requirement, need for HFV)
(American Exosurf Neonatal Study. J Pediatr;126:969-78, 1995)
BPD Management - difficulties in study
Definition ; objective assessment of severity ; variable status
 confounding effect of multiple risk factors
 limited number of patients per center ; difference between
centers in patient population
 historical controls / retrospective studies of little use since rapid
changes in management techniques
 Technical limitation of PFTs ; data dropout due to death,
discharge or extubation

Elective HFOV: Meta-analysis of 8
studies (Henderson-Smart: Cochrane Rev 4, 2001)






No difference in mortality
Trends toward decreases in BPD in survivors at 36-37 weeks
(RR 0.73 (0.57, 0.93) and death or CLD at 28-30 weeks
Significant increase in severe (grades 3 & 4) IVH and in any
air leak [RR 1.19 (1.03, 1.38)] in the HFOV group
2 trials with neurodevelopmental F/U : more survivors in the
HFOV group are abnormal [RR 1.26 (1.01, 1.58)] (Ogawa
93, HiFi 89)
Sub-group with high volume strategy did not have increased
IVH or PVL
Not currently recommended
Elective HFJV: Meta-analysis of 3
studies
Carlo 90, Wiswell 96, Keszler 97
 HFJV is associated with a reduction in BPD at 36
weeks PMA in survivors [RR 0.58 (0.34, 0.98),
NNT 7 ]


Increase in PVL in the trial by Wiswell [RR 5.0
(1.19, 21.04), NNH 4.0 (2.3,14.5)] where a ‘high
volume strategy' was not the standard protocol

Requires more investigation
(Bhuta and Henderson-Smart. Cochrane Rev 4, 2001)
Rescue HFOV

Only one good trial (HIFO Study Group. J Pediatr 1993;122:609-619)

Reduction in new air leak [RR 0.73 (0.55,0.96; NNT 6]

Mortality and the use of IPPV at 30 days was similar in
the HFOV and CV groups.

The rate of IVH of any grade increased with HFOV [RR
1.77 (1.06,2.96), NNH 6]

Insufficient evidence for conclusions at present
(HIFO Study Group. J Pediatr 1993;122:609-619; Bhuta and
Henderson-Smart. Cochrane Rev 4, 2001)
Newer modes of ventilation

Patient-triggered ventilation (PTV) / Synchronized
IMV (SIMV)
 May shorten duration of IMV and weaning
(Greenough et al. Cochrane Rev 4, 2001)

Proportional Assist Ventilation (PAV)
(Schulze et al. J Pediatr 135:339-344,1999)

Continuous tracheal gas insufflation (CTGI)
(Dassieu et al. Intensive Care Med 24:1076-1082,1998)

Perflurocarbon assisted gas exchange (PAGE)
(Wolfson et al. Pediatr Pulmonol 26:42-63,1998)
Surfactant use: prophylactic vs.
selective use

Multiple clinical trials and meta-analyses performed
(Dunn 1991, Kendig 1991, Merritt 1991, Egberts 1993, Kattwinkel
1993, Walti 1995, Bevilacqua 1996 and 1997; Soll and Morley.
Cochrane Rev 4, 2001)

Prophylaxis decreases the risk of pneumothorax, PIE,
mortality, and BPD or death associated with prophylactic
surfactant administration.

Meta-analysis : For every 100 infants treated
prophylactically, there will be 2 fewer pneumothoraces,
and 5 fewer deaths.
Management - Diuretics
 DIURETICS
 WHY ?
Clinical, XRay & Histologic evidence of interstitial
& peribronchiolar pulmonary edema
 Abnormal regulation of water balance ;
hypervolemia
 Acute and short term diuretics improve pulmonary
function and occasionally gas exchange
 Benefit unrelated to urine output

Management - Diuretics
 DIURETICS:
 Types: Loop diuretics: Furosemide
Thiazides : Chloro/Hydrochlorothiazide
Spironolactone
 Results with Thiazides and Spironolactone conflicting, though
blinded studies did show some improvement
 Furosemide also increases vasodilator PG synthesis, causes
systemic and pulmonary vasodilation, increases surfactant
synthesis and decreases Cl- transport in the airway epithelium
Management - Bronchodilators
 BRONCHODILATORS
Pathways controlling airway smooth muscle tone :
1 . Parasympathetic cholinergic : contraction, increase
mucus
2 . Beta-adrenergic : relaxation
3 . Nonadrenergic, noncholinergic (NANC) or
Peptidergic :
 Bronchoconstrictor : Substance P
 Bronchodilator : VIP (possibly deficient in Asthma)
Management - Bronchodilators
 WHY ?
 Sufficient bronchial smooth muscle, even
in tiny premies
 Hyperplastic smooth muscle and
metaplastic epithelium in BPD
 Correlation with family history of Asthma
Management - Bronchodilators

Bronchodilators - How ?
 Albuterol 50 mg q 4-6 hrs for 2-3 days. If
improvement noted, continue, and reassess
weekly.
Early steroids (<96 Hours of Age)
BPD or BPD/Death at 28 d and 36 w were decreased
by steroids (NNT =10), and weaning from ventilator
was faster.
 Increase in short-term complications (hypertension,
hyperglycemia, GI bleeds, perforation). No change in
NEC, IVH, severe ROP, or infection. Borderline
increase in PVL (1.41 [0.93-2.13])
 Long-term outcome worse with steroids, with
increased risk of CP in larger studies (Shinwell et al
2000: RR 3.2; Yeh et al 1998: RR 2.32)

Moderately early steroids (7-14 days)
BPD or BPD/Death at 28 d and 36 w were decreased
by steroids (NNT =7 for BPD28 and 4 for BPD36), and
weaning from ventilator was faster.
 Duration of hospital stay same. No difference in
severe ROP, IVH, or NEC. Increase in hypertension.
 Increase in CP in steroid group in one study (O’Shea
et al 1999: 12 of 48 in steroid vs. 3 of 45 in placebo;
RR 3.75, CI 1.13-12.43)

Delayed Steroids (>3 weeks)
BPD and BPD/Death at 36 w were decreased by
steroids, but not survival or duration of hospital stay.
 No difference in NEC, GI bleeding, or infection.
 Steroids led to poor weight gain or weight loss.
 Long-term outcome similar in one large study (Jones
et al 1995: RR for CP 1.21, CI 0.68-2.16 ), but full
neurodevelopmental evaluation was not done in this
trial.

Inhaled steroids
Beclomethasone and Flunisolide have been tried by
nebulization. May decrease
 need for systemic steroids
 side effects
 Beclomethasone did not decrease BPD in RCTs
(Denjean et al. Eur J Pediatr 157:926-31, Nov 1998;
Cole et al. 340(13):1005-10, Apr 1999)
 Type, dosage, and delivery methods still need to be
optimized

Other medications: Vitamin A
Birth weight (grams)
Gestational age (weeks)
Mean airway pressure (cm H2O)
FiO2
Baseline retinol (µg/dL)
Tyson et al. NEJM 340:1962, 1999
Vitamin A
(N=405)
770  35
27  2
73
0.41  0.19
16  6
Control
(N=402)
769  138
27 2
72
0.41  0.20
16  6
Other antioxidants



No benefit demonstrated with Vit E supplementation
(Watts et al. Eur Respir J 4: 188-90, 1991)
No benefit shown with Superoxide Dismutase (SOD)
(Suresh et al. Cochrane Database Syst Rev (1): CD
001968, 2001)
Catalase, Glutathione peroxidase etc are under
investigation.
Outcome (contd.)

Long-term outcome (contd)
 Cor pulmonale - usually resolves
 Reactive Airway disease - 50% will have
exercise induced bronchospasm
 SIDS ? - BPD spells ?- acute obstructive
episodes. Some reports of increased SIDS
incidence.
Outcome (contd.)
 Long-term outcome (contd)
 Growth failure common.
– 50% < 10th centile at 6 mo.
– Only 7% > 50th at 2 yrs.
• Resistance to oral stimulation,
• forcing food,
• increased caloric consumption
Outcome (contd.)
 Long-term outcome (contd)
– Studies on developmental outcome
inconclusive. Most show no relation to
BPD but to prematurity and other risk
factors. Relationship to time hospitalized,
but not with time ventilated.
– Short stature and airflow obstruction
persist into adulthood ( Northway’s 23 yr
follow-up )