displasia broncopulmonar la nueva

DOI: 10.1542/neo.7-10-e531 2006;7;e531-e545 NeoReviews

Alan H. Jobe The New BPD

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The New BPDAlan H. Jobe, MD, PhD*

Author Disclosure

Dr Jobe did not

disclose any financial

relationships relevant

to this article.

Objectives After completing this article, readers should be able to:1. Explain the anatomy of the new bronchopulmonary dysplasia (BPD).2. List the factors that contribute to BPD.3. Explain the effect of corticosteroids on alveolarization.4. Explain the contribution of mechanical ventilation and supplemental oxygen to BPD.

IntroductionBPD was described by Northway and associates in 1967 as a syndrome of severe lung injuryin preterm infants receiving mechanical ventilation and high levels of supplementaloxygen. (1) The mean birthweight of the infants who survived mechanical ventilation withBPD was 2.3 kg, and the mean gestational age was 34 weeks. Subsequently, Bonikos andcolleagues demonstrated that oxygen exposure alone could cause many of the anatomicchanges of BPD in newborn mice. (2) The initial description of BPD occurred in the erawhen mechanical ventilation was just beginning to be used for preterm infants and fewinfants whose birthweights were less than 1 kg survived. This classical BPD wascharacterized by prominent airway injury, epithelial metaplasia, smooth muscle hypertro-phy, and parenchymal fibrosis alternating with emphysema. The experimental work duringthat era demonstrated that the causes of BPD were primarily mechanical ventilation andoxygen exposure of the preterm lung. (3)

Fortunately, neonatal care practices and outcomes have changed over the last 25 years,with the use of continuous positive airway pressure, antenatal corticosteroids, surfactant,improved ventilation equipment and strategies, and improvements in nutrition and othercare practices. Now many infants whose birthweights are less than 1 kg and gestational agesare less than 28 weeks survive. The infants described by Northway have almost nolong-term lung-related morbidity in 2006. However, the incidence of BPD in survivors ofpreterm birth has not decreased because of the survival of large numbers of extremely lowbirthweight (ELBW) infants whose gestational ages are less than 28 weeks and birth-weights are less than 1 kg. The epidemiology of BPD has changed. With the improvementsin care, factors other than mechanical ventilation and oxygen exposure contribute to theoccurrence of BPD in ELBW infants, including postnatal sepsis, patent ductus arteriosus,and antenatal chorioamnionitis. (4) Some ELBW infants now develop BPD withoutinitially having severe respiratory distress syndrome (RDS) or initially requiring muchsupplemental oxygen or mechanical ventilation. (5)

In 1999, I reviewed the clinical associations with BPD and relevant experimental studiesand used the term new BPD to describe the arrest in lung development that is prominentin this new form of the disease in ELBW infants. (6) The term now is being used frequentlyto describe a progressive lung injury syndrome in ELBW infants characterized clinically byhazy lungs, minimal cystic emphysema or hyperinflation that is apparent on chest radio-graphs, a persistent oxygen requirement that slowly resolves, less airway reactivity, and lesspulmonary hypertension (blue spells) than in the past. Infants who have died of the newBPD have minimal fibrosis or airway injury but a striking decrease in normal alveolarseptation and microvascular development. (7) These anatomic findings demonstrate thatthe new BPD is less of an injury syndrome and more of a syndrome resulting from processesthat interfere with lung development. This review highlights the multiple factors that canalter lung development to yield the new BPD.

*Professor of Pediatrics, Division of Pulmonary Biology, Cincinnati Childrens Hospital, University of Cincinnati School ofMedicine, Cincinnati, Ohio.

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Diagnosis of BPDThe diagnosis of BPD is confounded by a series ofdefinitions that have been used over the years and bychanges in the patients at risk. (8) The diagnosis of BPDas characteristic changes on the chest radiograph andoxygen need at 28 days after birth initially used for largeinfants does not apply well to ELBW infants because fewhave normal chest radiograph findings and most arereceiving some oxygen at this time point. The diagnosisof BPD as oxygen need at 36 weeks postmenstrual age(PMA) has been used in most recent reports. A NationalInstitutes of Health Workshop in 2000 recommended agraded diagnosis for BPD to describe better the clinicalstatus of affected infants (Table). (8) Because cliniciansdo not have evidence-based criteria for the use of supple-mental oxygen, oxygen use and tar-get saturations vary widely in clini-cal practice. Walsh and colleagues(9) developed an oxygen needs testto make the diagnosis of BPD moreconsistent across clinical services.The physiologic test for oxygenneed also is described in the Table.When evaluated across 17 clinicalunits in the National Institute ofChild Health and Human Develop-ment Neonatal Research Network,the diagnosis of BPD decreasedfrom 35% to 25% of the infants

whose birthweights were less than1,250 g surviving to 36 weeks ges-tation. (9)

The most commonly used diag-nosis of BPD as oxygen need at36 weeks PMA does not requireantecedent exposures as part of thediagnosis (eg, RDS, mechanicalventilation), abnormalities on achest radiograph, or any laboratorytest. Therefore, the diagnosis issimply based on the need for oxy-gen in ELBW infants who have sur-vived to 36 weeks gestation. This isa soft diagnosis relative to mostdiagnoses in medicine that gener-ally include specific clinical associa-tions and laboratory findings. Cer-tainly part of the problem resultsfrom the progressive nature of andmultiple associations with BPD inthis unique group of infants. Per-

haps it is helpful to think about the stages of BPD that areclinically relevant to developing and testing therapies forBPD (Fig. 1). Although the diagnosis of BPD presently ismade at 36 weeks PMA, efforts to prevent BPD need tobegin with antenatal exposures and to focus on theknown associations with BPD in the minutes to days afterpreterm birth (Fig. 2). The factors associated with BPDin ELBW infants or in animal models that have a BPDphenotype are discussed in this article. However, animportant caveat is that the clinical diagnosis of BPDdoes not have a direct link to the developmentalabnormalities that cause the lung structural changesidentified as the new BPD. Although we know thatinfants who die of the new BPD have a severe arrest inlung development, we know virtually nothing about

Figure 1. Stages of bronchopulmonary dysplasia (BPD). BPD may be initiated with aninjury phase that may begin prior to preterm birth. The early injury generally occursfollowing preterm birth at 23 to 28 weeks gestation. The acute progression of BPDprobably occurs after the initial injuries over the first several weeks after preterm birth.An infant is given a diagnosis of BPD at 36 weeks postmenstrual age. The chronic stagesmay last for months, and very little is known about the time frame required for partial orcomplete resolution of BPD.

Table. Bronchopulmonary Dysplasia (BPD)Workshop Definition of BPD for Infants atGestational Ages of Less than 32 WeeksTreatment with oxygen >21% for at least 28 days plus

Mild BPD: Breathing room air at 36 weeks postmenstrual age (PMA) ordischarge

Moderate BPD: Need for 30% oxygen and/or positive pressure (ventilation or

continuous positive airway pressure) at 36 weeks PMA

Physiologic Test for Diagnosis of BPD

Infants at 35 to 37 weeks PMA receiving mechanical ventilation, continuouspositive airway pressure, or >30% O2 with saturation of 96% tested forO2 need O2 progressively decreased gradually to room air No BPD if saturation is >90% in room air for 30 min

Adapted from Jobe and Bancalari (8) and Walsh, et al (9).

respiratory disorders bronchopulmonary dysplasia

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the lungs of the majority of infants who survive withmilder forms of BPD.

Developmental Context forthe New BPDThe human lung has completedabout 16 generations of dichoto-mous airway branching by about16 to 18 weeks gestation to yieldapproximately 65,000 saccules atthe end of terminal bronchioles(Fig. 3). (10) Considerable mecha-nistic information is known aboutthis airway branching, termed pri-mary septation. Genes that are crit-ical for primary septation includefibroblast growth factor (FGF), epi-dermal growth factor, and the tran-scription factor. Secondary septa-tion is the process of alveolarizationof the distal lung saccules. Alveolar-ization is the anatomic descriptionof the protrusion of an elastin fiberand mesenchyme containing a dou-ble capillary network into the saccu-lar lumen, resulting in subdivisionof that saccule. (11) In humans,alveolarization normally begins at32 to 36 weeks gestation and con-tinues for several years. Alveolariza-

tion is being studied intensively be-cause of its relevance to BPD ininfants and to emphysema in adults.Factors known to regulate alveolar-ization are FGF-18 and platelet-derived growth factor-A as well aspathways for collagen and elastinmetabolism. However, BPD occursmost frequently between 23 weeksand 28 weeks gestation in the hu-man, about 1 month after airwaybranching has finished and as muchas 3 months before alveolarizationbegins.

Burri (11) describes a process ofthree generations of saccular septa-tions after 20 weeks gestation toform 524,000 respiratory bronchi-oles. These distal saccules furtherdivide into three generations of al-veolar ducts. These six branching

generations yield about 4106 saccules that subse-quently alveolarize after 32 to 36 weeks gestation. This64 times increase in saccular structures that occurs be-tween about 20 weeks and about 32 to 36 weeks is a

Figure 2. Flow chart for some of the clinical interventions and occurrences thatcontribute to BPD. Extremely low-birthweight infants experience many of these events.The progression to BPD should be viewed as a multiple hit sequence resulting in abnormallung development.

Figure 3. Anatomic development of the human lung. The human lung goes through about23 generations of dichotomous branching. Airway branching is complete by about18 weeks gestation to yield about 65,000 distal structures. These saccules divide furtherto form respiratory bronchioles and alveolar ducts by 32 to 36 weeks gestation, whenalveolarization begins. Z indicates branching generation number. Figure modified fromBurri. (10)



complex phase of lung development between airwaybranching and alveolarization that does not have a name.The new BPD may result primarily from interferencewith the generation of respiratory bronchioles and alve-olar ducts. Concurrently with the expansion of the gassurface areas of the fetal lung and alveolarization, there isa large expansion of the pulmonary microvasculature.The essential development of the pulmonary microstruc-ture occurs during the onset, progression, and healing ofBPD.

Pathology of BPDThe anatomic information available for infants who diedof BPD is biased toward the most severe changes, withthe anatomy demonstrating multiple changes that areconsistent with altered lung development. The lungshave increased alveolar (saccular) diameters and feweralveoli (saccules). (12) The collagen network around thesaccules is disrupted, and elastin is not localized to fibersin sites for future secondary septation. (13) Acute severeinflammation is not apparent unless there has been asecondary infection. The saccules are lined with dysplas-tic type II cells that express increased amounts of mRNAfor surfactant protein C. Several reports have describeddecreased platelet/endothelial cell adhesion molecule-1(PECAM) staining as a marker for the endothelium of adecreased pulmonary microvasculature. (14) A recentreport showed increased levels of PECAM protein andprominent staining of the pulmonary microvasculature inlungs of infants who died of BPD. (15) Certainly, infantswho die of BPD have pulmonary hypertension and mi-crovascular disease. These contrasting pathologic find-ings may represent true variability in the pathophysiologyof BPD, perhaps related to the major inciting factors, or

different stages in the progressionof the lung abnormalities. The moststriking abnormality in the lungs ofinfants who have BPD is the arrestof alveolarization, resulting in theappearance of emphysema (Fig. 4).However, there is very little ana-tomic information available formost infants who survive BPD.These lungs may have differentfindings.

Alveolarization: Lessonsfrom Animal ModelsMice and other rodents are born atterm with a saccular lung that be-gins to alveolarize at about 3 days of

age. This postnatal timing of alveolarization, when com-bined with the transgenic technology available for mice,is ideal for investigating factors that can interfere withalveolarization. Mice made to overexpress proinflamma-tory cytokines such as tumor necrosis factor-alpha, trans-forming growth factor-alpha, interleukin (IL)-6, IL-1,and IL-13 during the period of alveolarization experi-ence the development of emphysema because of afailure of alveolarization. (6) Alveolarization also can beinhibited by exposure of mice to hyperoxia, and hyper-oxia causes inflammation. In preterm ventilated lambsand baboons, conventional or high-frequency ventilationdisrupts alveolar septation (Fig. 5). (16) These animalsalso were exposed to increased oxygen levels, and oxygenalone can inhibit alveolarization. Supplemental oxygenand mechanical ventilation probably represent the com-bination of two hits to the fetal lung: one an oxidantinjury and the other a stretch injury. Both injuries aretransduced to activate inflammatory cascades. In venti-lated baboons, the proinflammatory mediators IL-6 andIL-8 were chronically elevated in airway samples about10-fold above values measured in term newborn ba-boons (Fig. 6). (17) Thus, the common theme for theinhibition of alveolarization is inflammation, suggestingthat inflammation caused by any mechanism will inter-fere with alveolar septation.

Other factors that can interfere with lung develop-ment are corticosteroids and starvation. Newborn rabbitsthat are fed less calories have increased sensitivity tooxidant damage, and adult rodents that are starved de-velop an emphysematous lung, which returns to normalwith refeeding. (18) There is no information in newbornhumans about the effects of low calorie intake on lungdevelopment. However, nutritional status may be an

Figure 4. Comparison of lungs of an infant who has BPD and a normal infant. A. This lungsection is from a 5-month-old infant born at term. B. This lung section is from an infantwho has BPD, was born at 28 weeks gestation, and had a lung biopsy at 8 months of age.The lungs of the infant who has BPD have enlarged alveolar ducts and few alveoli.Jacqueline Coalson, University of Texas San Antonio, provided new photomicrographs thatare similar to photomicrographs originally published by Coalson, et al. (7)



important and underappreciated variable on the pathwayto BPD.

Both antenatal and postnatal corticosteroids inhibitalveolarization and pulmonary microvascular complexityin developing animals. (19) Fetal sheep and monkeysexposed to antenatal corticosteroids have a decrease inthe mesenchyme and increased airspace volumes within24 hours. Subsequently, the alveoli are larger and the

lung has decreased numbers of al-veoli. In sheep, the corticosteroid-induced changes that occur in thepreterm lung have disappeared byterm. Rodents that alveolarize afterterm birth have arrested alveolarseptation when treated with corti-costeroids. The corticosteroid ef-fects on alveolarization are inde-pendent of inflammation. There isno information about how cortico-steroid effects might interact withinflammation to influence alveolar-ization. Nevertheless, infants at riskof severe BPD are treated with cor-ticosteroids, presumably to de-crease inflammation. The risk-to-benefit ratio for a single antenatalcourse of betamethasone certainlyfavors corticosteroid therapy. (20)Infants likely to develop severeBPD also may benefit from postna-tal corticosteroid treatments, butthose treatments may adversely af-fect alveolarization. (21) Clinicalbenefit may depend on the impor-tance of inflammation to the pro-cess that is being treated in the in-fant.

Chorioamnionitis:A Pathway to BPDMost infants born prior to30 weeks gestation have been ex-posed to inflammation because ofan often subclinical ascending in-trauterine infection caused by low-grade pathogens. The most fre-quent organisms associated withchorioamnionitis, which is definedas inflammation of the fetal mem-branes, inflammatory cells, or or-ganisms in amniotic fluid, areUrea-

plasma and Mycoplasma sp. (22) Infants exposed tochorioamnionitis or delivered after preterm prolongedrupture of membranes (a surrogate marker for chorioam-nionitis) have a decreased incidence of RDS but also havean increased risk of BPD in some clinical series. In otherseries, the increased risk of BPD occurred in infantsexposed to chorioamnionitis who then were ventilated ordeveloped postnatal sepsis. (23) Consistent clinical cor-

Figure 5. Effect of conventional mechanical ventilation on alveolarization of pretermlamb lungs. Preterm lambs delivered at 126 days gestation (term is 150 d) were treatedwith surfactant and ventilated at rates of 20 or 60 breaths/min for 3 weeks. The ventilatedlambs were similar to gestation-matched fetal lambs and had not alveolarized over3 weeks in comparison to measurements for airspace area and radial alveolar count interm lambs. Redrawn from data of Albertine, et al. (16)



relates no doubt are confounded bythe imprecision of the diagnosis ofchorioamnionitis where, in mostcases, there is no information onthe duration, intensity, or the or-ganisms responsible for the clinicalor histopathologic diagnosis. Fur-thermore, the contrasting effects ofclinical lung maturation with lessRDS may tend to protect the infantfrom BPD, while the inflammationalready present at birth may con-tribute to BPD.

The responses of fetal sheep toinflammatory mediators providesome insight about how the fetuscopes with inflammation. Intra-amniotic injections of Escherichiacoli endotoxin, the proinflamma-tory cytokine IL-1-alpha, or endo-toxin from periodontal organismscause chorioamnionitis (inflamedmembranes, inflammatory cells,and increased IL-8 concentrationsin amniotic fluid). (24) Withinhours, the fetal lung becomes in-flamed and the numbers of inflam-matory cells increase in the air-spaces over several days. The lunginflammation/injury responseprogresses with cytokine expressionin the fetal lung, cell apoptosis andproliferation, and microvascular in-jury. (25)(26) Within 7 days, alve-olar number decreases and alveolarsize increases (Fig. 7). (27) Thiscombination of microvascular in-jury and inhibition of alveolariza-tion is a mild BPD phenotype caused by inflammation ofthe fetal lung. (29) Thus, inflammation in the absence ofsupplemental oxygen and ventilation can cause changessimilar to BPD in the fetal lung. The clinical outcome ofthese fetal exposures is lung maturation characterized bylarger lung gas volumes and large increases in surfactantlipids and proteins. (28) Fetal sheep lungs colonized byintra-amniotic injection of live Ureaplasma have minimalinflammation but striking lung maturation. (30) Theseresults replicate the clinical experience that many ELBWinfants do not have severe RDS, especially after chorioam-nionitis or ruptured membranes.

Fetal sheep exposed continuously to intra-amniotic

endotoxin for 28 days prior to preterm delivery havealveolar simplification but no progression of lung injury.Prolonged fetal exposure to endotoxin did not causepersistent lung abnormalities when the lambs were deliv-ered close to term. (31) This surprising result demon-strates that the fetal lung can mount a rapid inflammatoryresponse to inflammation/infection but that the inflam-matory response need not be progressive or severe. Thefetus copes with the inflammation with reversible effectson lung alveolarization and microvascular development,and induced lung maturation is the most clinically appar-ent outcome after preterm birth. However, antenatalexposure to inflammation has resulted in the recruitment

Figure 6. Interleukin (IL)-6 and IL-8 levels in airway samples from preterm ventilatedbaboons. The cytokines were increased at all time intervals relative to values for termnewborn or adult baboons. Median values for multiple measurements were adapted fromCoalson, et al. (17)



of monocytes to the airspaces that can mature to macro-phages that have an increased inflammatory potential.(32) Fetal sheep exposed to intra-amniotic endotoxin30 days before preterm delivery had increased numbersof inflammatory cells in their airspaces after mechanicalventilation, indicating that the antenatal exposurechanged the postnatal inflammatory response to me-

chanical ventilation. (33) The clin-ical implication is that antenatal ex-posure to inflammation likely willnot cause BPD, but antenatal in-flammation may potentiate postna-tal inflammatory events. Althoughno specific information is availablefor infants, most ELBW infants areexposed to antenatal corticoste-roids and many will be exposed si-multaneously to chorioamnionitis.Each exposure can cause BPD-typestructural changes in the develop-ing lung.

Neonatal Resuscitation/Initiation of Air BreathingThe previous discussion of chorio-amnionitis described how antenatalexposure to inflammation or corti-costeroids may promote the initia-tion of injury. The antenatal expo-sures may occur over days, weeks,or even months. The initiation ofair breathing after preterm birth is arapid transition that must occurquickly for the infant to survive,and most ELBW infants receiveventilatory support to facilitate thetransition. The scheme of clinical

variables that may contribute to BPD shown in Figure 2has been modified in Figure 8 to emphasize the brief, butimportant, period of delivery room management. Thefetal preterm lung is fluid-filled, often surfactant-deficient, and very easy to injure because lung structure isimmature and the potential gas volume (total lung ca-pacity) is small. For example, the total lung capacity for

infants who have RDS is only 20 to30 mL/kg in contrast to volumesof about 50 mL/kg for term infantsand 80 mL/kg for adults. Lunginjury occurs if the lung is venti-lated from lung volumes below theideal functional residual capacity(FRC) (a frequent occurrence withsurfactant deficiency) or to volumesclose to or above the total lungcapacity (TLC). (34) The ELBWinfant has great difficulty establish-ing a reasonable FRC because ofsurfactant deficiency, inadequate

Figure 7. Effects of intra-amniotic endotoxin on the fetal sheep lung. Intra-amnioticendotoxin increased inflammatory cells and cytokine mRNA expression in the fetal lung.Maximal expression of IL-1-beta mRNA occurred with lung injury, as indicated byincreased apoptosis. A proliferative response followed the apoptosis. The lung vasculaturealso was injured, as indicated by decreased endothelial nitric oxide xynthase (eNOS)protein and the mRNA for the vascular endothelial growth factor (VEGF) 188 isoform inthe fetal lung tissue at 2 and 4 days relative to controls. At 7 days, the mcmol/kg ofsaturated phosphatidylcholine (Sat PC) in bronchoalveolar lungs (BAL) increased and themL/kg lung gas volume measured at 40 cm H2O distending pressure increased, indicatingbiochemical and functional lung maturation. However, alveolar number decreased by 31%relative to the control value. Data redrawn from (25)(27)(28). *P

respiratory drive, and a compliant chest wall. The clini-cian attempting to ventilate the infant cannot establishand maintain a reasonable FRC without consistent posi-tive end-expiratory pressure (PEEP) or continuous pos-itive airway pressure (CPAP). Unfortunately, the FRCcannot be measured in clinical practice. Compliance ofthe preterm lung is highly variable because of the rangeof surfactant amounts and the TLC, which depend onsurfactant amount and the amount of induced lung matu-ration. Thus, mechanical ventilation is very likely to injurethe lung of the ELBW infant.

Injury is most likely to occur during neonatal resusci-tation because of the physiologic difficulties of establish-ing an FRC while avoiding overdistention of the lung.The anxieties of clinicians to ventilate the infant quicklypromote excessive ventilation. Bjorklund and associates(35) demonstrated that just six large tidal volume breathscould injure the preterm lamb lung severely and thatsurfactant treatment prior to high tidal volume ventila-tion minimized the injury. Wada and colleagues (36)demonstrated that 30 minutes of tidal volume ventilation

with 15 to 20 mL/kg was requiredto normalize PCO2 values using aventilation rate of 30 breaths/min,but these tidal volumes also severelyinjured the preterm lamb lung. In-jury was minimized by use of lowertidal volumes for initial ventilationafter preterm birth, but the lowtidal volumes resulted in hypercar-bia. The use of low tidal volumes,but no PEEP, increases the injurythat develops after preterm birth(Fig. 9). (37)

Other potential sources of injuryto the preterm lung are the gasesand the conditioning (temperature,humidity) of the gases used for re-suscitation of the preterm. The newInternational Liaison Committeeon Resuscitation (ILCOR) recom-mendations for neonatal resuscita-tion suggest that room air or anoxygen concentration of less than100% are options, but caution issuggested for using less than 100%oxygen for the preterm infant. (38)However, the preterm infant maybe more susceptible to oxidant-mediated injury than the term in-fant because protective antioxidant

systems are less well developed. The term infant hasdelayed onset of spontaneous breathing and biochemicalindicators of oxidant injury even after a brief exposure to100% oxygen. The possible contribution of 100% oxygento the initiation of lung injury in the preterm infantpresently is not known. Many delivery rooms use only100% oxygen that is neither heated nor humidified.There is no information about the potential of unhu-midified and unheated air or oxygen to injure the airwaysof term or preterm infants.

Surfactant treatment before the initiation of breathingcan decrease lung injury strikingly in preterm animalsthat have surfactant deficiency. (35)(36) The humansituation is more complex because many preterm infantshave some degree of early lung maturation, and intuba-tion and ventilation, when not necessary, can increase therisk of injury to the preterm lung. The relative merits ofearly surfactant treatment are discussed in another articlein NeoReviews. (39) The optimal timing of surfactanttreatment for ELBW infants remains unresolved withinthe context of delivery room management.

Figure 9. Cytokine mRNA expression in lung tissue of preterm lambs 2 hours afterdelivery and ventilation. The animals were ventilated after surfactant treatment at birthwith either 0 or 4 cm H2O positive end-expiratory pressure (PEEP) with a goal to keep thePCO2 greater than 50 mm Hg. The fetal lung expressed very low cytokine mRNA levels.Ventilation with PEEP resulted in increased IL-1beta and IL-6 mRNA levels, which weremuch higher when ventilation was without PEEP. Data redrawn from Naik (37). tP

The recent ILCOR guidelinesdo not address resuscitation of thepreterm infant other than to saythat the lung can be easily injured,PEEP/CPAP may be helpful, andmaintenance of body temperatureis important. (38) The lack of spe-cific guidelines results from the al-most total lack of evidence-basedinformation concerning resuscita-tion of the preterm infant. The re-sults from animal models suggeststrongly that PEEP/CPAP are im-portant, as is limiting tidal volumesto perhaps no more than 5 mL/kg;100% oxygen seldom is required.Avoidance of hyperventilation is animportant first step in minimizinglung injury. The contribution oflung injury at delivery to the ulti-mate outcome of BPD may neverbe defined clearly because this briefopportunity to injure the lung soonis overtaken clinically by prolongedpostnatal management. However,it is clear that in the extreme, pul-monary interstitial emphysema canbe initiated in the delivery roomand can be a strong indicator ofsubsequent poor lung function andultimately BPD.

Ventilatory Support as aCause of BPDThe two primary associations withthe new BPD in ELBW infants are gestational age (birth-weight) and exposure to ventilatory support. The associ-ation of ventilatory support with BPD has been domi-nant since the initial description of the disease in 1967.(3) With each improvement in ventilatory technique, thenew technique initially was believed to be a (partial)solution to the BPD problem. The introduction of CPAPand PEEP improved mortality, and negative pressureventilation was promoted as the solution to lung injury.Unfortunately, small infants who have significant lungdisease cannot be supported with negative pressure ven-tilators, and those are the infants now at significant risk ofdeveloping BPD. High-frequency oscillatory ventilation(HFOV) had been promoted as the solution to the BPDproblem, initially because of the remarkable demonstra-tions of decreased injury relative to conventional ventila-

tion of preterm baboons that had RDS. (40) However,the favorable BPD outcomes initially reported from clin-ical trials are much less compelling in more recent trials,and a meta-analysis demonstrates convergence of theBPD outcome for HFOV and conventional ventilation(Fig. 10). (41) Because the trials were conducted overabout 15 years, the techniques, equipment, and clinicalgoals for all approaches to mechanical ventilation wereimproving, and survival of more immature infants wasincreasing. The incidence of BPD has not changed, butthe severity of BPD has decreased. (42) Clark made thepoint in an editorial that outcomes with ventilatory sup-port depend on both the tool (ventilator) and thecarpenter (clinician). (43)

The physiologic model for ventilator-induced lunginjury in the adult lung is shown in Figure 11. (44) The

Figure 10. Meta-analyses of randomized trials comparing high-frequency ventilation(HFV) and conventional ventilation (CMV) for the outcome of bronchopulmonarydysplasia. The earlier studies favored HFV, but that benefit has not been maintained inmore recent trials. Explanations for the change in responses include the introduction ofsurfactant into clinical care and the use of different ventilation approaches andequipment. Reprinted with permission from Bollen, et al (41). American ThoracicSociety.



pressure-volume curve for the normal lung has regions ofinjury on the inflation and deflation limbs. Lung injuryoccurs below a normal FRC of about 30 mL/kg and forvolumes approaching or above a normal TLC. Less pres-

sure is required to ventilate the lungon the deflation limb of thepressure-volume curve than on theinflation limb. The preterm lung isa challenge to ventilate because theTLC is low, and although FRC alsois less (15 to 20 mL/kg) than in theadult lung, there is a much smallervolume range in which injury willnot occur. (45) This model is over-simplified primarily because lunginflation is not uniform if the lung isdiseased or injured. Surfactant defi-ciency increases the pressuresneeded to achieve the volumes inthe preterm lung and cause nonuni-form inflation. The assumptions ofthis model and the clinical experi-ences in older children and adultsare that if mechanical ventilation

occurs in the safe pressure-volume range on the deflationlimb of the pressure-volume curve, no lung injury occurs.The goal of HFOV is to keep the lung volume relativelyhigh on the deflation limb of the pressure-volume curve

and use small tidal volumes that donot approach TLC. Conventionalventilation of the preterm infantwith sufficient PEEP to hold thelung at or above FRC and with theuse of small tidal volumes may re-sult in a risk of ventilation-mediatedinjury that is similar to that ofHFOV.

CPAP is the ventilatory supporttechnique now claimed to decreaseBPD when used to avoid intuba-tion and mechanical ventilation.(46) CPAP should recruit andmaintain the FRC and allow theinfant to breathe, presumably usingtidal volumes that do not approachTLC. With experience, CPAP canbe used to transition infants suc-cessfully from the delivery room tothe neonatal intensive care unit,and many such infants do not re-quire intubation and surfactanttreatment. The clinical experienceof Aly and colleagues (47) is shownin Figure 12. The larger infantsusually required only CPAP. The

Figure 11. Hypothetical pressure-volume curves for adult and preterm lungs. Injuryoccurs if the lung is ventilated from below functional residual capacity (FRC) or tovolumes close to total lung capacity (TLC). When the graphs are scaled such that the80-mL/kg TLC of the adult lung is shown to be similar to the 30-mL/kg TLC for thepreterm lung, the large difference in the lung volume available for ventilation is notapparent. As indicated, this volume is about 50 mL/kg in the adult and about 15 mL/kgin the preterm infant who has respiratory distress syndrome. Also note that higherpressures are required to recruit volume for the preterm than for the adult lung.

Figure 12. Clinical experience with a trial of CPAP in the delivery room. Infants weremanaged with CPAP when possible in the delivery room, and their need for intubation bythe second postnatal day was documented. A CPAP success was defined as not needingCPAP for the first 7 days after birth. The table gives the percent of overall population ineach group, mean values for the birthweights, the percent of infants in each outcomegroup treated with surfactant, and the occurrence of BPD, defined as oxygen use at36 weeks postmenstrual age. Adapted from Aly, et al. (47)



incidence of BPD was higher in infants who were intu-bated in the delivery room than in infants managed byCPAP. However, the occurrence of BPD was still 28% ininfants who were extubated to CPAP soon after delivery.The infants were not randomized to care strategies, sothis and other clinical experiences do not demonstratethat CPAP can prevent BPD.

Some experimental observations indicate that a CPAPstrategy preserves lung structure and allows alveolariza-tion to occur. Thomson and associates (48) demon-strated preservation of lung structure for preterm ba-boons supported with CPAP after an initial period ofsurfactant treatment and stabilization with mechanicalventilation. Preterm lambs have fewer biochemical indi-cators of lung injury on CPAP than on conventionalventilation. (49) These experimental results are proof ofprincipal that CPAP can cause less injury to the pretermlung than conventional ventilation. However, similarmodels were used to show that HFOV was superior toconventional ventilation, an outcome that has not trans-lated to clinical practice.

My assessment of the controversies about the bestways to avoid BPD combines concepts of lung injury,lung development, and reasonable clinical care strategies.Important advantages of CPAP are the avoidance ofoverinflation and inflation without control of PEEP,especially in the delivery room. The preterm lung is easyto injure, and the more injury, the more likely that BPDwill develop. However, CPAP, PEEP, and the highermean airway pressures used for HFOV stretch the lung,and stretch can transduce inflammation. The require-ments for an FRC and a tidal volume sufficient for gasexchange, no matter how accomplished, may be suffi-cient to alter the subsequent development of the saccularlung. Injury and the other associations with BPD onlymake the developmental abnormalities worse.

Oxygen and BPDIn the clinical setting, oxygen has not been disentangledfrom ventilation in terms of relative importance for caus-ing BPD. Infants who require ventilatory support alsousually receive supplemental oxygen. The anatomicchanges of delayed alveolar septation and an arrest inmicrovascular development occur simply with oxygenexposure in newborn rodents. (50) There is no informa-tion on the importance of oxygen to lung injury imme-diately after delivery or within the first days after birth ininfants. However, infants who had retinopathy of prema-turity and were randomized to a high oxygen saturationtarget had more severe BPD that persisted for a longerperiod of time than infants randomized to a lower oxy-

gen saturation range in one study. (51) The recentemphasis on keeping oxygen saturations to a reasonablerange (perhaps 85% to 95%) for oxygen-exposed ELBWinfants should help decrease the severity of BPD, al-though the optimal oxygen saturation range remainsunknown.

Sepsis and BPDAs reviewed previously, chorioamnionitis is an associa-tion with BPD. Infants exposed to chorioamnionitisrange in exposure from mild lung inflammation to asystemic inflammatory response and sepsis. The lunginflammation prior to birth is the start of an inflammatoryresponse that can be amplified by postnatal care thatincludes ventilation and oxygen. Infants exposed to cho-rioamnionitis also have early tracheal colonization withorganisms, which also is an association with BPD. (52)Postnatal sepsis is a similar insult that occurs after thelung injury/developmental abnormality sequence hasbeen initiated. The experimental literature clearly dem-onstrates that most any cause of inflammation can stopalveolar septation in newborn rodents. Whenever it oc-curs, infection with its associated inflammation is likely tointerfere with lung development. Postnatal sepsis is animportant variable that confounds studies of the relativebenefits of different ventilatory support strategies be-cause infection is so common in ELBW infants.

Postnatal CorticosteroidsCorticosteroids have pleotropic effects on the fetus andnewborn, and the lung is a target of corticosteroid ac-tion. Corticosteroids mature the fetal lung, primarily bydecreasing the amount of mesenchymal tissue and in-creasing potential airspace volume. Such anatomicchanges result in an arrest in alveolar (saccular) septationin fetal monkeys and sheep. (27) Similarly, postnatalcorticosteroids arrest alveolar septation and microvascu-lar development in rodents. (19) Thus, corticosteroidsinduce the anatomic equivalent of a mild new BPD. Thefetal exposures are of low dose and short duration relativeto the exposures often provided postnatally. The matu-rational benefits exceed the risks for fetal exposures.Postnatal treatments to prevent or treat BPD are primar-ily used for anti-inflammatory effects. Postnatal cortico-steroids are controversial and generally not recom-mended because of concerns about adverse effects onneurodevelopment. The recent meta-analysis by Doyleand colleagues (21) demonstrated that for infants at highrisk of developing BPD, corticosteroid treatments afterapproximately 1 week of age may be of benefit (Fig. 13).



Outcome of Infants Who Have BPDThe long-term lung outcomes for ELBW infants are aconcern. ELBW infants who do not have BPD requirefrequent hospitalizations and lung-related medicationsin the first 2 postnatal years. (53) ELBW infants who

have BPD have increased pulmo-nary problems and poorer neurode-velopment than unaffected ELBWinfants. My interpretation is that allELBW infants have some degree ofabnormal lung development, andBPD is the clinical manifestation ofincreased severity of developmentalabnormalities. Preterm infants havemore airway restriction than terminfants at term, and the preterminfant has more airway reactivitylater in life. Children who survivedthe old BPD have some restrictiveairway disease and increased airwayreactivity. (54) There is very littleinformation about if and how in-fants who have the new BPD re-model their alveoli and microvascu-lature with growth. Of concern is theobservation that adolescent monkeysthat were ventilated after pretermbirth continued to have lungs thathad decreased alveolar numbers (Fig.14). (55) Most infants who havemilder forms of BPD seem to haveminimal residual lung disease, butnormally there is a large respiratoryreserve that decreases after adoles-cence throughout life. A concern ishow such BPD lungs will age.

ACKNOWLEDGMENTS. This workwas supported in part by grantsHD-12714 and HL-65397 fromthe National Institutes of Health.

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newborn: the effect of prolonged 100% O2 exposure in the lungs ofnewborn mice. Lab Invest. 1975;32:6196353. OBrodovich HM, Mellins RB. Bronchopulmonary dysplasia.Unresolved neonatal acute lung injury. Am Rev Respir Dis. 1985;132:6947094. Bancalari E. Changes in the pathogenesis and prevention of

Figure 13. Possible benefits of postnatal corticosteroids (CS) depend on risk of chronic lungdisease (CLD). This graph compares the risk difference (RD) for death or cerebral palsy (CP) forinfants randomized to postnatal corticosteroids relative to the percent of control infants whohave CLD. The size of the circle is proportionate to study size. The regression line with 95%confidence intervals demonstrates that for infants at a high risk of CLD, postnatal cortico-steroids may decrease death and CP. Reprinted with permission from Doyle, et al. (21)

Figure 14. Decreased alveolar septation in baboon survivors of BPD. Preterm baboonswere delivered and randomized to ventilation with low or high supplemental oxygen for21 days. The high oxygen plus ventilation-exposed group developed BPD. The BPD animalssurvived until 33 weeks of age, and biopsies of the lungs (A) demonstrated larger distalairspaces than for the comparison preterm ventilated animals exposed to less supplemen-tal oxygen (B). Jacqueline Coalson, University Texas San Antonio, provided micrographsthat are similar to those published by Coalson, et al. (55)



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chronic lung disease in preterm infants. J Pediatr. 2002;140:17117624. Jobe A. Antenatal factors and the development of bronchopul-monary dysplasia. Semin Neonatol. 2003;8:91725. Kramer BW, Kramer S, Ikegami M, Jobe A. Injury, inflamma-tion and remodeling in fetal sheep lung after intra-amniotic endo-toxin. Am J Physiol Lung Cell Mol Physiol. 2002;283:L452L45926. Kallapur SG, Willet KE, Jobe AH, Ikegami M, Bachurski C.Intra-amniotic endotoxin: chorioamnionitis precedes lung matura-tion in preterm lambs. Am J Physiol. 2001;280:L527L53627. Willet K, Jobe A, Ikegami M, Brennan S, Newnham J, Sly P.Antenatal endotoxin and glucocorticoid effects on lung morphom-etry in preterm lambs. Pediatr Res. 2000;48:78278828. Jobe AH, Newnham JP, Willet KE, et al. Endotoxin inducedlung maturation in preterm lambs is not mediated by cortisol. Am JRespir Crit Care Med. 2000;162:1656166129. Kallapur SG, Bachurski CJ, Le Cras TD, Joshi SN, Ikegami M,Jobe AH. Vascular changes following intra-amniotic endotoxin inpreterm lamb lungs. Am J Physiol Lung Cell Mol Physiol. 2004;287:L1178L118530. Moss TJM, Nitsos I, Ikegami M, Jobe AH, Newnham JP.Experimental intra-uterine Ureaplasma infection in sheep. Am JObstet Gynecol. 2005;192:1179118631. Kallapur SG, Nitsos I, Moss TJM, et al. Chronic endotoxinexposure does not cause sustained structural abnormalities in thefetal sheep lungs. Am J Physiol Lung Cell Mol Physiol. 2005;288:L966L97432. Kramer BW, Ikegami M, Moss TJ, Nitsos I, Newnham JP,Jobe AH. Endotoxin-induced chorioamnionitis modulates innateimmunity of monocytes in preterm sheep. Am J Respir Crit CareMed. 2005;171:737733. Ikegami M, Jobe A. Postnatal lung inflammation increased byventilation of preterm lambs exposed antenatally to E. coli endo-toxin. Pediatr Res. 2002;52:35636234. Dreyfuss D, Saumon G. Ventilator-induced lung injury. Am JRespir Crit Care Med. 1998;157:29432335. Bjorklund LL, Ingimarsson J, Curstedt T, et al. Manual venti-lation with a few large breaths at birth compromises the therapeuticeffect of subsequent surfactant replacement in immature lambs.Pediatr Res. 1997;42:34835536. Wada K, Jobe AH, Ikegami M. Tidal volume effects on surfac-tant treatment responses with the initiation of ventilation in pretermlambs. J Appl Physiol. 1997;83:1054106137. Naik AS, Kallapur SG, Bachurski CJ, et al. Effects of ventilationwith different positive end-expiratory pressures on cytokine expres-sion in the preterm lamb lung. Am J Respir Crit Care Med. 2001;164:49449838. International Liaison Committee on Resuscitation. 2005 In-ternational consensus on cardiopulmonary resuscitation and emer-gency cardiovascular care science with treatment recommendations.Part 7: Neonatal resuscitation. Resuscitation. 2005;67:29330339. Jobe AH. Pharmacology review: why surfactant works forrespiratory distress syndrome. NeoReviews. 2006;7:e95e106.Availableat:http://neoreviews.aappublications.org/cgi/content/full/7/2/e9540. Coalson JJ, Kuehl TJ, Prihoda TJ, deLemos RA. Diffusealveolar damage in the evolution of bronchopulmonary dysplasia inthe baboon. Pediatr Res. 1988;24:35736641. Bollen CW, Uiterwaal CS, van Vught AJ. Cumulative meta-analysis of high-frequency versus conventional ventilation in prema-ture neonates. Am J Respir Crit Care Med. 2003;168:11501155



42. Smith VC, Zupancic JA, McCormick MC, et al. Trends insevere bronchopulmonary dysplasia rates between 1994 and 2002.J Pediatr. 2005;146:46947343. Clark RH. Both the tool and the carpenter are important.J Pediatr. 1997;131:79679844. Froese AB, McCullouch PR, Sugiura M, Vaclavik S, PossmayerF, Moller F. Optimizing alveolar expansion prolongs the effective-ness of exogenous surfactant therapy in the adult rabbit. Am RevRespir Dis. 1993;148:56957745. Jobe AH, Ikegami M. Mechanisms initiating lung injury in thepreterm. Early Hum Dev. 1998;53:819446. Ammari A, Suri MS, Milisavljevic V, et al. Variables associatedwith the early failure of nasal CPAP in very low birth weight infants.J Pediatr. 2005;147:34134747. Aly H, Massaro AN, Patel K, El-Mohandes AA. Is it safer tointubate premature infants in the delivery room? Pediatrics. 2005;115:1660166548. Thomson MA, Yoder BA, Winter VT, et al. Treatment ofimmature baboons for 28 days with early nasal continuous positiveairway pressure.Am JRespir Crit CareMed. 2004;169:1054106249. Jobe A, Kramer BW, Moss TJ, Newnham J, Ikegami M.

Decreased indicators of lung injury with continuous positive expi-ratory pressure in preterm lambs. Pediatr Res. 2002;52:38739250. Warner BB, Stuart LA, Papes RA, Wispe JR. Functional andpathological effects of prolonged hyperoxia in neonatal mice. Am JPhysiol. 1998;275:L110L11751. Supplemental Therapeutic Oxygen for Prethreshold Retinop-athy of Prematurity (STOP-ROP), a randomized, controlled trial. I:Primary outcomes. Pediatrics. 2000;105:29531052. Young KC, Del Moral T, Claure N, Vanbuskirk S, Bancalari E.The association between early tracheal colonization and broncho-pulmonary dysplasia. J Perinatol. 2005;25:40340753. Ehrenkranz RA, Walsh MC, Vohr BR, et al. Validation of theNational Institutes of Health consensus definition of bronchopul-monary dysplasia. Pediatrics. 2005;116:1353136054. Northway W, Moss R, Carlisle K, et al. Late pulmonary se-quelae of bronchopulmonary dysplasia. N Engl J Med. 1990;323:1793179955. Coalson JJ, Winter V, deLemos RA. Decreased alveolarizationin baboon survivors with bronchopulmonary dysplasia. Am J RespirCrit Care Med. 1995;152:640646



NeoReviews Quiz

9. In contrast to classic bronchopulmonary dysplasia (BPD), initially described in 1967, the new BPD inthe more contemporary clinical setting is characterized by different histopathologic findings onexamination of the lung tissue. Of the following, the most striking abnormality in the lungs of infantswho have new BPD is:

A. Decrease in alveolar septation.B. Diffuse leukocytic infiltration.C. Epithelial squamous metaplasia.D. Hypertrophy of airway smooth muscle.E. Lung parenchymal fibrosis.

10. Maternal chorioamnionitis, defined as inflammation of the fetal membranes and the presence ofinflammatory cells or organisms in the amniotic fluid, often is a pathway for the development of BPD inpreterm infants. Of the following, the most frequent organism associated with maternal chorioamnionitisas a cause of neonatal BPD is:

A. Escherichia coli.B. Group B Streptococcus.C. Listeria monocytogenes.D. Staphylococcal species.E. Ureaplasma urealyticum.

11. The pathogenesis of new BPD in extremely low-birthweight (ELBW) infants involves a complex interplayof several factors. Of the following, one of the primary associations with the development of new BPD inELBW infants is:

A. Exposure to ventilator support.B. Genetic predisposition.C. Nutritional deficit.D. Postnatal sepsis.E. Surfactant deficiency.

12. Corticosteroids have pleiotropic effects on the fetus and newborn, and the lung is a target ofcorticosteroid action. Of the following, the most striking anatomic change in the lung in relation topostnatal corticosteroid treatment is:

A. Arrested microvascular development.B. Decreased airspace volume.C. Dysplastic epithelial type 2 cells.D. Increased mesenchymal tissue.E. Infiltration with inflammatory cells.



DOI: 10.1542/neo.7-10-e531 2006;7;e531-e545 NeoReviews

Alan H. Jobe The New BPD

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