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DOI: 10.1542/neo.12-11-e6352011;12;e635Neoreviews

Robert H. Pfister and Roger F. SollBronchopulmonary Dysplasia

Pulmonary Care and Adjunctive Therapies for Prevention and Amelioration of

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PulmonaryCare and Adjunctive Therapiesfor Prevention and Ameliorationof Bronchopulmonary DysplasiaRobert H. Pfister, MD,*

Roger F. Soll, MD

Author Disclosure:

Drs Pfister and Soll

have disclosed no

financial relationships

relevant to this

article. This

commentary does not

contain a discussion

of an unapproved/investigative use of a

commercial product/

device.

AbstractShortly after the introduction of assisted ventilation in the newborn, bronchopulmo-

nary dysplasia (BPD) was first described. Northway and coworkers described a group

of preterm infants who developed chronic respiratory failure and characteristic radio-

graphic changes after prolonged mechanical ventilation. The prevention and manage-

ment of BPD in infants at risk is challenging due to the complex pathogenesis of

multiple contributing factors that include prematurity, supplemental oxygen expo-

sure, mechanical ventilation, patent ductus arterious, inflammation, genetic predispo-

sition and postnatal infection. Treatment of existing BPD requires a coordinated

approach including optimal nutrition, careful fluid management, evidence-based drug

therapy, and gentle respiratory techniques aimed at minimizing lung injury. The best

respiratory support strategy remains unclear and requires further investigation but

includes avoidance of ventilator-induced lung injury (barotraumas and volutrauma),

hyperoxemia, and hypocapnea. Among the available interventions antenatal steroids,

caffeine, and surfactant have the best risk-benefit profile. Systemic postnatal cortico-

steroids should be used only in ventilated infants unable to be weaned from the

ventilator. Quality improvement techniques may have a role towards improvement of

hospital systems geared toward reduction of BPD.

Objectives: After completing this article, readers should be able to:

1. Understand the changing definition of BPD.

2. Understand the changing appreciation of the pathophysiology of the new BPD.

3. Understand the relative efficacy and limitations of many of our therapeutic interven-

tions have in decreasing the risk of BPD.4. Understand the role of quality improvement in reducing complex multifactorial out-

comes such as BPD.

IntroductionThe introduction of mechanical ventilation in the newborn led to remarkable changes in

survival, particularly among very low birthweight infants. Shortly after the introduction of

this new technology, Northway et al (1) described a new respiratory disease termed BPD

that developed in these infants. Northway et al (1) described a group of preterm infants

who developed chronic respiratory failure and characteristic

radiographic changes after prolonged mechanical ventila-

tion. The lung damage that was seen in these infants was

thought to be due to the impact of mechanical ventilationand the attendant barotrauma as well as the toxic effects of

high inspired oxygen concentrations. Northway et al (1)

originally described four stages of the disease: an early stage,

involving necrosis; a second phase, involving repair and

inflammation; a third phase, involving dysplastic change; and

a fourth phase, occurring after many weeks, of severe cystic

change and cor pulmonale. Many factors contribute to BPD;

clearly, prematurity and the need for ventilator support lead

the list. However, a variety of other issues, such as genetic

*Assistant Professor of Pediatrics, The University of Vermont, Burlington, VT.

Professor of Pediatrics, The University of Vermont, Burlington, VT.

AbbreviationsBPD: bronchopulmonary dysplasia

CI: confidence interval

CPAP: continuous positive airway pressure

iNO: inhaled nitric oxide

INSURE: Intubate Surfactant Extubate

PDA: patent ductus arteriosus

RDS: respiratory distress syndrome

RR: relative risk

Article pulmonary care

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predisposition, perinatal asphyxia, perinatal infection,

and inflammation, may all contribute to the process.Since Northway et als (1) first description of BPD, our

understanding of the pathophysiology of BPD and even

the way we define BPD has evolved.

DefinitionThe infants originally described by Northway et al (1)

presented within the first month after birth. Based on the

original description of the disease, most of the definitions

of BPD originally focused on the neonatal period. The

first standard definition was proposed by the National

Institutes of Health sponsored workshop in 1979. BPDwas defined as continued oxygen dependency during

the first 28 days plus compatible clinical and radiographic

changes. (2) This definition, although useful in the

initial categorization of BPD, fails when we consider the

very low birthweight that is currently managed in the

neonatal intensive care unit. If a definition of oxygen

requirement at 28 days is used, well over 70% of ex-

tremely low birthweight infants would be categorized as

having BPD.

Shennan et al (3) demonstrated that simply being in

oxygen at 28 days did not routinely identify increased risk

of abnormal pulmonary follow-up. Instead of using afixed time point at 28 days, Shennan et al (3) looked at

corrected or adjusted gestational age. If infants between

25 and 32 weeks gestation were still in oxygen at

36 weeks postmenstrual gestational age, over 50% were

noted to have abnormal pulmonary follow-up. This be-

came a useful definition as it identified fewer infants who

were at measurable risk.

Newer definitions have tried to refine this approach.

In 2001 the National Institutes of Health developed a

consensus definition of BPD to help compare the inci-

dence of the disease among institutions and evaluate

potential preventive strategies and treatments. This def-inition was based on gestational age at birth, time of

assessment, and severity of disease. (2) More recently, a

simple physiologic description has been proposed: the

inability to maintain an oxygen saturation of 88% or

greater in room air for 60 minutes at 36 weeks postmen-

strual age. (4) This definition is particularly useful be-

cause of its objectivity and has been shown to decrease

variation in reported rates of BPD. However, such test-

ing is problematic in that many infants will no longer be

available for assessment by individual institutions at this

point in time as many infants will have been transferred or

discharged from the hospital.

PathophysiologyClassical BPD was noted during an era when mechan-

ical ventilation was just beginning to be employed and

was characterized by airway injury, smooth muscle hy-

pertrophy, and areas of parenchymal lung fibrosis alter-

nating with areas with emphysematous changes.

Over several decades of improvements in respiratory

care, a new BPD has emerged that often occurs after

little initial acute lung injury and is thought to be affected

by other factors such as inflammation (secondary to

sepsis or chorioamnionitis) and the presence of a patent

ductus arteriosus (PDA). (5)(6) As compared with clas-

sic BPD, preterm infants who have new BPD have

decreased fibrosis and emphysema but also have a

marked decrease in alveolar septation and microvascular

development.

The heterogeneous damage to airways and lungs re-

sults in unstable time constants and marked ventilation-

perfusion mismatch. Lung compliance is reduced sec-

ondary to fibrosis and edema. Tracheolaryngomalacia

and increased airway resistance of both small and larger

airways is common. As the course of BPD progresses,

initial low lung volumes secondary to atelectasis are often

at least partially replaced by hyperinflation.

BPD is marked by abnormal structure and function of

the pulmonary circulation in parallel to pulmonary pa-

renchymal injury. Of note, epithelial lesions, fibroblastproliferation, and smooth muscle hyperplasia have all

been observed and result in a pulmonary vascular bed

that is markedly reduced compared with normal.

Marked, abnormal vasoconstriction in response to hyp-

oxia often accompanies these anatomic changes, further

increasing pulmonary vascular resistance and in some

cases progressive pulmonary hypertension. (7) Other

cardiovascular abnormalities associated with BPD in-

clude systemic hypertension, left ventricular hypertro-

phy, and development of systemic-pulmonary collateral

vessels. (8)

Factors That Affect PathogenesisBPD has a complex multifactorial etiology. In their orig-

inal description, Northway et al (1) demonstrated the

presence of oxygen-free radicals and posited that oxygen

toxicity was a major cause of BPD. Barotrauma and

volutrauma combined with oxygen toxicity contribute to

inflammatory reactions that are implicated in the devel-

opment of BPD. (9)(10)(11) Chorioamnionitis, fetal

infection, sepsis, and pneumonia may also contribute or

amplify the development of BPD via inflammatory path-

ways. An association between fluid overload and the

presence of a symptomatic PDA with BPD can poten-

pulmonary care bronchopulmonary dysplasia

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tially be explained by increased need for mechanical

ventilation in these infants. (5) Genetic factors have been

implicated in the severity of acute respiratory disease as

well as the development of BPD. (12)(13) Finally, inad-

equate nutrition is believed to lead to decreased alveolar

development, impaired surfactant production, and a cat-

abolic state that inhibits growth and repair of the prema-

ture lung.

Antenatal Interventions to PreventBronchopulmonary Dysplasia

Prevention of Preterm BirthIn our efforts to prevent BPD, multiple interventions

have been considered, both before and after birth. Anyintervention that prevents preterm birth would be an

important improvement in decreasing the risk of devel-

opment of BPD. Unfortunately, few therapies have been

shown to prevent or postpone preterm delivery. Berk-

man et al (14) systematically reviewed the effectiveness of

tocolytics to stop uterine contractions or maintain quies-

cence. Studies of first-line tocolysis reported a small

improvement in pregnancy prolongation and birth at

term relative to placebo; however, data were insufficient

to demonstrate a decrease in neonatal morbidity or mor-

tality. These short-term benefits offer little meaningful

improvement to neonatal outcome except that the fewdays gained may act as a window in which to administer

antenatal steroids.

As mentioned above, infection and inflammation have

been implicated in the cause of BPD. Efforts to treat

mothers with urinary tract infection or bacterial coloni-

zation have been, in general, unsuccessful in minimizing

the rate of preterm labor or BPD. (15)

Antenatal GlucocorticosteroidsAdministration of glucocorticosteroids is one of the few

antenatal interventions that lead to meaningful improve-

ments in neonatal outcome. Antenatal administration ofglucocorticosteroids leads to a decrease in respiratory

distress syndrome (RDS), a decrease in respiratory sup-

port, and a decrease in mortality but only a modest

decline in BPD. (16)(17)(18) One explanation for this is

that the protective effect of antenatal steroids may be

keeping patients alive who would have otherwise died

and who go on to develop BPD. Another explanation is

that antenatal steroids may promote alveolar oversimpli-

fication. (19) Rates of the use of antenatal steroids have

risen dramatically over the past several decades. Cur-

rently, well over 70% of all very low birthweight infants

are exposed to antenatal steroid therapy (Vermont Ox-

ford Network Annual Report 2009). Antenatal beta-

methasone is preferred over dexamethasone. (20)

Postnatal InterventionsNutrition

Optimizing nutrition is key to all aspects of recuperation

and growth in preterm infants. It is known that BPD

is more common in extremely low birthweight infants

with the poorest growth. (21) However, few studies

have focused directly on the impact of nutrition on BPD

and those that have do not show significant differences,

with the possible exception of studies of vitamin A and

inositol.

Inositol is incorporated into cell membranes of the

lung and serves as a precursor for synthesis of pulmonary

surfactant. Small trials have demonstrated a significant

reduction in death or BPD in infants who received ino-

sitol. (22) These findings remain to be repeated in larger

trials.

Vitamin A plays an important role in the differentia-

tion and maintenance of the integrity of the epithelial

cells in the conducting airways. Several trials have tested

vitamin A in the prevention of BPD and demonstrated a

small but meaningful improvement in the rates of BPD

development (typical relative risk [RR]0.87, 95% con-

fidence interval [CI]0.77 to 0.98; typical risk differ-

ence0.08, 95% CI0.14 to 0.01; numberneeded to treat 13, 95% CI7 to 100). (23)

Postnatal GlucocorticosteroidsNo interventions for BPD have created more controversy

than the administration of postnatal corticosteroids to

preterm infants. Studies have demonstrated that both

inhaled and systemic steroids improve lung function and

gas exchange as well as reduce inflammation. (24)(25)

Steroid use either as an early/preventative strategy (be-

ginning at7 d) or as a later/treatment strategy (begin-

ning at7 d) significantly reduces the incidence of BPD;

however, no difference in mortality was reported.(26)(27) Although immediate pulmonary benefit is real-

ized, increased alveolar simplification is reported. Other

side effects of corticosteroids include systemic hyperten-

sion, cardiomyopathy, infection, hyperglycemia, gastro-

intestinal bleeding, and perforation. More worrisome is

the potential for adverse neurologic outcomes. Long-

term follow-up studies of infants who received high

dosage, early steroids reveal an increased risk of neuro-

developmental delay and cerebral palsy. (26) However,

major neurosensory disability and the combined rate of

death or major neurosensory disability were not signifi-

cantly different between steroid and control groups in





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infants randomized to receive late steroids. (27) Due to

concerns regarding these adverse events, the American

Academy of Pediatrics recommended against the routine

use of high-dose systemic steroids to treat or prevent

BPD. (28) A meta-regression of the studies of postnatal

steroids has revealed that in certain infants at extremely

high risk of developing BPD and its associated morbid-

ity, the benefits of postnatal steroids may outweigh the

deleterious affects. (29) Clinicians must weigh the po-

tential risks of steroids versus the potential benefits of

facilitating extubation in those infants who are still ven-

tilator dependent or on high concentrations of inspired

oxygen after several weeks of therapy.

Inhaled steroids have been tested and found to have

no significant advantage with respect to prevention or

treatment of BPD when compared with systemic ste-

roids. (30)(31) No long-term outcome data are available

regarding inhaled steroids.

Other Anti-inflammatory TherapyOutside of corticosteroids, a variety of agents that might

decrease the inflammatory response in the lung have

been tested including vitamin E, alpha-1 protease inhib-

itor, and superoxide dismutase. Unfortunately, none of

these have had an impact on BPD. (32)(33)(34)

Other novel anti-inflammatory agents that have

promise include nebulized pentoxifylline and budes-onide administered intratracheally by using surfactant as

a carrier and have been tested in ventilated preterm

infants. (35)(36) Both approaches are promising, reveal-

ing decreased BPD without adverse events and may be a

potential alternative to steroids. Further investigation in

larger clinical trials is indicated.

Surfactant TherapyThe introduction of surfactant therapy has reduced inci-

dence of pneumothorax and death in infants at risk for or

having RDS. (37) Whether used as a preventive strategy

or as treatment of established RDS, there is an approxi-mately 30% decrease in the risk of pneumothorax and

death. Given the fact that surfactant therapy decreases

the need for inspired oxygen, decreases the need for

ventilator support, decreases acute lung injury as re-

flected by pneumothorax, and leads to improved survival,

one would have assumed that there would be a decrease

in BPD. However, the situation is not that straightfor-

ward. The absolute risk of developing BPD (defined in

most of the surfactant trials as oxygen requirement at

28 d) is unchanged with therapy.

Similar to the observed effect of antenatal steroids,

perhaps the protective effect of surfactant may be keep-

ing patients alive who would have otherwise died and

who are at increased risk of BPD. Although BPD is not

reduced, prophylactic surfactant has been shown to be

beneficial in increasing survival without BPD (typical

RR0.85, 95% CI0.76 to 0.95). (38) Specific ap-

proaches or strategies to the use of surfactant may impact

on BPD. There is a slight decrease in pneumothorax

associated with the use of animal derived products. Ear-

lier treatment (within the first 2 h after birth) to infants at

risk for or having RDS may also improve outcome.

However, in the age of increased antenatal steroids and

increased knowledge of less invasive support (use of early

nasal continuous positive airway pressure), these thera-

pies have been questioned.

Oxygen TherapyGiven the toxicity associated with supplemental oxygen,

attempts to target lower saturations for oxygen are an

attractive approach to decreasing BPD. Observational

studies have suggested that lower saturation shortly after

birth is associated with better short-term outcomes. In a

study of four neonatal units, Tin et al (39) found that a

lower saturation correlated with improved short-term

outcomes in infants less than 28 weeks gestation. Practice

in these units varied greatly, ranging from saturation

targets of 80% to 90% to 94% to 98%. Surviving infants in

units that targeted the lower saturation range were ven-tilated for a shorter time and needed less oxygen at

36 weeks postmenstrual age (18% versus 46%). Survival

rates and cerebral palsy rates at 1 year follow-up were

similar.

The Surfactant Positive Airway Pressure and Pulse

Oximetry Trial in extremely low birthweight infants was

a randomized, multicenter trial conducted by the Na-

tional Institute of Child Health and Human Develop-

ment (NICHD) Neonatal Research Network. (40) One

arm of this 22 factorial design trial compared target

ranges of oxygen saturation of 85% to 89% or 91% to 95%

among 1,316 infants who were born between 24 and276 weeks gestation. Death before discharge occurred

more frequently in the 85% to 89% saturation group

(RR1.27, 95% CI1.01 to 1.60), whereas severe reti-

nopathy among survivors occurred less often in this

group (RR0.52, 95% CI0.37 to 0.73). The rate of

oxygen use at 36 weeks was reduced in the 85% to 89%

saturation group as compared with the 91% to 95%

saturation group (RR0.82, 95% CI0.79 to 0.93);

however, the rates of BPD among survivors, as deter-

mined by the physiologic test of oxygen saturation at

36 weeks, and the composite outcome of BPD or death

by 36 weeks did not differ significantly between the





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treatment groups. There were no significant differences

in the rates of other adverse events. Other trials of oxygen

saturation targeting have recently been halted due to

similar concerning findings regarding increased mortality

in the group managed with lower saturation limits. The

impact of lower saturation targeting on BPD has not as

yet been reported.

Assisted VentilationAll types of mechanical ventilation injure the premature

lung. When using conventional ventilation, one com-

mon strategy to decrease pulmonary damage is to limit

the duration of mechanical ventilation outright. While

on the ventilator, a variety of approaches to minimizing

lung injury while on respiratory support have been

tested.

The use of patient-triggered ventilation is now virtu-

ally omnipresent in neonatal intensive care. Based on

animal data, it was thought that this innovation would

decrease lung trauma and when used in the recovery

phase of infants with RDS, this technology significantly

shortens the weaning from mechanical ventilation. How-

ever, clinical trials show a marginal effect on BPD and no

effect on survival. (41)

Another conventional ventilator strategy provides op-

timal lung volumes by using gentle ventilation tech-

niques, as reflected by moderate permissive hypercapnia.Practically speaking, this entails optimal positive end

expiratory pressure (42) for lung recruitment and venti-

lation with low lung tidal volumes (4 to 6 mL/kg).

Permissive hypercapnia is unproven but popular. One

small study demonstrated that ventilation strategies for

very low birthweight infants that had received surfactant

and were maintained mildly hypercapnic (PaCO245 to

55 mm Hg) were safe (ie, no increased rates of IVH

[intraventricular hemorrhage] or PVL [periventricular

leukomalacia]) and reduced the duration of mechanical

ventilation. (43) A larger, multicenter, randomized trial

revealed that targeting a PaCO2 of 52 mm Hgresulted ina reduction in mechanical ventilation at 36 weeks post-

menstrual age but did not decrease death or BPD. (44)

Volume-targeted ventilation allows for the peak in-

flating pressure to adjust in a breath-to-breath manner to

changes in lung compliance and a patients spontaneous

respiratory effort. These modalities may deliver desired

tidal volumes more consistently at lower pressures

thereby avoiding injurious overdistention. Importantly,

a recent systematic review of studies comparing volume-

targeted ventilation compared with pressure-limited ven-

tilation demonstrated that infants ventilated by using

volume-targeted modes had reduced death and BPD

(typical RR0.73, 95% CI0.57 to 0.93; number

needed to treat

8, 95% CI

5 to 33). (45)High frequency ventilation has also been extensively

tested. Despite promising results in animal models, this

technique of ventilation does little in increasing survival

or preventing BPD. Recent meta-analyses show marginal

improvements in these outcomes, with some risk of

increased severe intraventricular hemorrhage.

Avoidance of Mechanical VentilationSome of the strongest evidence for an effective preven-

tion strategy to decrease BPD includes limiting the du-

ration of or avoiding altogether mechanical ventilation.(6) Noninvasive ventilation techniques and methylxan-

thine administration are two techniques effective at lim-

iting time spent on the ventilator.

Nasal Continuous Positive Airway PressureIn the study of Avery et al (46) it was reported that, in the

National Institute of Child Health and Human Develop-

ment lung centers, one center had a remarkably lower

rate of BPD (defined as oxygen in survivors at 28 d).

This center was in Columbia, New York City. One

obvious difference in their approach to care was theroutine and aggressive use of nasal continuous posi-

tive airway pressure (CPAP). Multiple trials have now

looked at stabilization on nasal CPAP. Recent trials

suggest that nasal CPAP may be an effective way to

stabilize infants without exposing them to mechanical

ventilation. (47)(48)(49)(50) Although statistically sig-

nificant differences did not emerge, the fact that this less

invasive approach appears to be of equal benefit may well

signal an era of less aggressive ventilator support.

Nasal intermittent positive pressure ventilation has

been shown to improve the effectiveness of CPAP in

extubated infants, leading to a decrease in reintubationrates and a reduced risk of BPD. (51) Surfactant admin-

istration followed by extubation to nasal intermittent

positive pressure ventilation has been suggested to be

synergistic in decreasing BPD. (52)

Another promising approach has been developed,

called INSURE (Intubation Surfactant Extubation). In

this approach, surfactant is administered during a brief

intubation followed by immediate extubation to CPAP.

INSURE has been reported to reduce the need for

mechanical ventilation. (53) Although these findings are

promising, larger additional studies are needed to clarify

and refine this method.





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MethylxanthinesPerhaps one of the most overlooked therapies in the

prevention of BPD has been the use of methylxanthines.

These agents function as a phosphodiesterase inhibitor,

which plays a role in regulating intracellular concentra-

tions of second messenger cyclic AMP (adenosine mono-

phosphate) and cyclic GMP (guanosine monophos-

phate). Caffeine citrate has frequently been used to

reduce apnea in preterm infants. Schmidt et al. (54)(55)

reported the effect of caffeine citrate, administered to

infants 1,250 grams, demonstrated decreased time on

the ventilator, decreased oxygen use, decreased cortico-

steroid administration, and decreased need for transfu-

sions. More importantly, a significant reduction in the

rate of development of BPD (adjusted odds ratio0.64,

95% CI0.52 to 0.78) and a composite outcome of

death, cerebral palsy, and cognitive delay (adjusted odds

ratio0.77, 95% CI0.64 to 0.93) was noted in the

treatment group. (54)(55)

Treatment of Pulmonary EdemaExcessive intravenous fluid administration increases the

risk of BPD, and infants who lose less weight and receive

more intravenous fluids immediately after birth have an

increased risk for development of BPD. (56)(57)(58) It

is not clear, however, that fluid restriction reduces theincidence of BPD. (59) Diuretics continue to be com-

monly used in the treatment of BPD. These therapies

may lead to measurable short-term changes in lung com-

pliance and pulmonary function, but little has been dem-

onstrated regarding any long-term improvement in re-

ducing BPD or mortality. Given these data, careful

restriction of water intake so physiologic needs are met

without allowing significant dehydration seems prudent.

Patent Ductus Arteriosus Treatment

The presence of a symptomatic PDA in very low birth-weight infants has been shown to lead to pulmonary

edema and be predictive of the need for supplemental

oxygen and prolonged mechanical ventilation. (60) One

might hypothesize that decreased pulmonary edema and

the ability to decrease oxygen exposure and ventilator

support would lead to less BPD. Therefore, treatment of

PDA could theoretically reduce the risk of BPD; how-

ever, neither the trials that looked at preventing PDA nor

treating PDA with cyclooxygenase inhibitors have led to

a reduced risk of BPD. (61) Surgical closure of a symp-

tomatic PDA increases the risk of BPD and is associated

with adverse neurodevelopmental outcomes. (62)

Avoiding Nosocomial InfectionNosocomial bacteremia and pneumonia contribute to

increased lung injury and BPD secondary to inflamma-

tion, polymorphonuclear leukocyte infiltration, and re-

lease of protelolytic enzymes. (63) Prevention of sepsis

or pneumonia will result in decreased inflammation and

decreased time on mechanical ventilation and should be

a goal of every center. Programs to reduce ventilator-

associated pneumonia have been advocated and com-

mercial intervention bundles are marketed; however, no

data have shown these programs reduce the incidence of

BPD.

BronchodilatorsCommonly used bronchodilators dilate small airways

with muscle hypertrophy in young children with hyper-

active airway disease. Improved compliance and de-

creased pulmonary resistance are reported with use of

bronchodilators in infants with BPD. A systematic review

of short-term studies demonstrated improved pulmonary

compliance and reduced resistance after bronchodilator

treatment in infants with established and evolving BPD,

but these short-term benefits did not translate to de-

creased need for systemic steroids or in rates of mortality

or BPD. (64)

Pulmonary Bed VasodilatorsInhaled nitric oxide (iNO) has been tested, both early in

the course of respiratory distress (on infants at risk for

respiratory distress and in infants with serious respiratory

insufficiency) and in infants with early BPD. (65) The

rationale for the use of iNO in preterm infants includes

the cardiovascular effects of iNO (decreased pulmonary

hypertension) as well as many primary effects of iNO on

lung development. None of the trials of iNO adminis-

tered early in the course of respiratory distress have

demonstrated any clinical benefit; only the trial of Ballard

et al. (66) has demonstrated a small improvement in

BPD in infants given a prolonged course of iNO begin-ning at around 1 to 2 weeks after birth. (66) iNO as

rescue therapy for the very ill preterm infant does not

appear to be effective. Early routine use of iNO in

preterm infants with respiratory disease does not improve

survival without BPD or improve neurodevelopmental

outcomes. Later use of iNO to prevent BPD might be

effective but needs further study.

Oral agents that reduce pulmonary vascular resistance

including sildenafil, prostacyclin, and bosentan have

promise in infants with established BPD, but these treat-

ments have yet to be studied in randomized controlled

trials. (67)(68)





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Delivery Room ManagementIn the delivery room, clinicians are excitably prone to

contributing to pulmonary injury secondary to overzeal-

ous ventilation of infants in transition. Uncontrolled

excessively large or small tidal volumes are injurious to

the developing lung. Measuring and controlling tidal

volumes in the delivery room, including the use of a

T-piece resuscitator, may be desirable but are unproven

in terms of prevention of BPD. (69)(70) Using a

planned, practiced, and scripted protocol for the resusci-

tation and first hour of care of infants at risk (referred to

as the Golden Hour) has been proposed to reduce the

incidence of BPD. Although these ideas have scientific

rationale, they have not been shown to reduce the inci-

dence or severity of BPD.

Role of Quality ImprovementDespite the many interventions that have been at-

tempted and tested, the incidence of BPD has remained

relatively constant over the past two decades. (71) The

Vermont Oxford Network 2009 Database Summary re-

veals a 25.2% incidence of BPD at discharge on infants

whose birthweight was 1,500 grams. This represents a

decrease of almost 3% over the previous 3 years in this

large cohort of approximately 50,000 infants from over

700 centers. Despite this modest decrease in the inci-

dence of BPD, many of the proven therapies have notbeen effectively translated into practice in many medical

centers and, perhaps because of this, large variability

exists between individual centers. In fact, BPD rates vary

by a factor of 10 within the Vermont Oxford Network

even after risk adjustment for confounders such as birth-

weight, gestational age, race, antenatal steroid adminis-

tration frequency, RDS severity, neonatal intensive care

unit volume, and even random effects. Because neither

disease severity nor random chance explains the variation

that exists between centers, treatment practices must play

a significant role in the observed variation in outcomes.

This variation is the justification for a quality improve-ment approach as a method for BPD reduction; however,

studies using these methods have had inconsistent suc-

cess. Quality improvement methods have, however, been

consistently successful when used to improve and change

individual processes rather than outcomes, and contro-

versy exists over whether these methods that implement

multiple interventions will be effective in limiting pathol-

ogy of a disease such as BPD with multiple etiologies.

ConclusionPrevention and management of BPD in infants at risk is

challenging due to the complex pathogenesis of multiple

contributing factors that include low birthweight, pre-

term birth, supplemental oxygen exposure, mechanical

ventilation, patent ductus arterious, inflammation, ge-

netic predisposition, and postnatal infection. Treatment

of existing BPD requires a coordinated approach includ-

ing optimal nutrition, careful fluid management,

evidence-based drug therapy administration, and gentle

respiratory techniques aimed at minimal lung injury. The

best respiratory support strategy remains unclear and

requires further investigation but includes avoidance of

hyperoxemia and hypocapnea. Optimal oxygen satura-

tion targeting preterm infants is being studied in several

ongoing trials. Among the available interventions, ante-

natal steroids, caffeine, and surfactant have the best risk-

benefit profile. Systemic postnatal corticosteroids should

be used only in ventilated infants unable to be weaned

from the ventilator. Quality improvement techniques

may have a role towards improvement of hospital systems

geared toward reduction of BPD.

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American Board of Pediatrics Neonatal-Perinatal

Medicine Content Specifications

Know the effects and risks of CPAP.

Know the indications for and techniques of

positive-pressure ventilation (PPV).

Know the effects and risks of PPV. Know the pathogenesis, pathophysiology,

and pathologic features of bronchopulmonary dysplasia/

chronic lung disease.

Know the prenatal and postnatal risk factors for

bronchopulmonary dysplasia/chronic lung disease and be

aware of various preventive strategies.

Know the management of bronchopulmonary dysplasia/chronic

lung disease.





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NeoReviews Quiz

12. Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease seen in preterm infant survivors.Classic BPD was originally described during an era when mechanical ventilation for neonates was justintroduced. Over several decades of improvements in respiratory care, a new BPD has emerged thatdiffers in pathologic features from classic BPD. Of the following, the mostcharacteristic pathologicfeature of the lung in new BPD is:

A. Arrested alveolar septation.B. Necrotizing tracheobronchitis.C. Parenchymal lung fibrosis.D. Smooth muscle hypertrophy.E. Squamous metaplasia.

13. BPD is a disease of many causes. Several interventions, both antenatal and postnatal, have been studied inan effort to prevent or ameliorate the development of BPD among preterm infant survivors. Of thefollowing, the postnatal intervention mostassociated with an improvement in the rate of development ofBPD involves:

A. Alpha-1 protease inhibitor.B. Inhaled glucocorticosteroid.C. Superoxide dismutase.D. Tocopherol.E. Vitamin A.

14. Mechanical ventilation predisposes the immature lung of a preterm infant to injury and subsequentdevelopment of BPD. Several strategies of mechanical ventilation have been studied in an effort toprevent or ameliorate the development of BPD among preterm infant survivors. Of the following, the

strategy of mechanical ventilationmost

associated with an improvement in the rate of development ofBPD involves:

A. Assist control ventilation.B. High frequency ventilation.C. Negative pressure ventilation.D. Pressure limited ventilation.E. Volume targeted ventilation.





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DOI: 10.1542/neo.12-11-e635

2011;12;e635NeoreviewsRobert H. Pfister and Roger F. Soll

Bronchopulmonary DysplasiaPulmonary Care and Adjunctive Therapies for Prevention and Amelioration of

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