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La nueva bdp


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La nueva bdp

  1. 1. The new bronchopulmonary dysplasiaAlan H. JobeCincinnati Children’s Hospital, Division of Pulmonary Purpose of reviewBiology, University of Cincinnati, Cincinnati, Ohio, USA Bronchopulmonary dysplasia (BPD) remains the most common severe complication ofCorrespondence to Alan H. Jobe, MD, PhD, Division of preterm birth. A number of recent animal models and clinical studies provide newPulmonary Biology, Cincinnati Children’s Hospital,ML#7029, 3333 Burnet Avenue, Cincinnati, information about pathophysiology and treatment.OH 45229-3039, USA Recent findingsTel: +1 513 636 8563; fax: +1 513 636 8691;e-mail: The epidemiology of BPD continues to demonstrate that birth weight and gestational age are most predictive of BPD. Correlations of BPD with chorioamnionitis are cloudedCurrent Opinion in Pediatrics 2011, 23:167–172 by the complexity of the fetal exposures to inflammation. Excessive oxygen use in preterm infants can increase the risk of BPD but low saturation targets may increase death. Numerous recent trials demonstrate that many preterm infants can be initially stabilized after delivery with continuous positive airway response (CPAP) and then be selectively treated with surfactant for respiratory distress syndrome. The growth of the lungs of the infant with BPD through childhood remains poorly characterized. Summary Recent experiences in neonatology suggest that combining less invasive care strategies that avoid excessive oxygen and ventilation, decrease postnatal infections, and optimize nutrition may decrease the incidence and severity of BPD. Keywords lung injury, oxygen, prematurity, ventilation Curr Opin Pediatr 23:167–172 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-8703 14 days of oxygen exposure for 1340 infants born at 23–27Introduction weeks’ gestational age in 2002–2004 [2] (Table 1). ByBronchopulmonary dysplasia (BPD) remains the most multivariant analyses, the major predictors of BPD werecommon complication of very preterm birth. New not surprising: lower gestational age and mechanicalresearch published within the last 2 years provides ventilation on day 7. However, 33% of the persistentnew insights into the pathophysiology of BPD, primarily lung disease population (receiving 49% oxygen and 84%using animal models. New clinical trials have not pro- ventilated at 14 days) did not develop BPD, whereas 17%vided the clinician with new treatment strategies, but do of the infants in room air at 14 days of age developedprovide some guidance. The National Heart, Lung and BPD. BPD is multifactorial in causality and our abilitiesBlood Institute recently funded grants to explore child- to identify infants at risk are imperfect. I am surprisedhood outcomes of lung diseases in infants and has estab- that 81% of this population was receiving conventional orlished a five-center consortium to better characterize high frequency ventilation at 7 days of age, suggestingBPD and to identify useful biomarkers of disease pro- that the investigators did not subscribe to noninvasivegression. These research programs should benefit very ventilatory support strategies. In a second report, thesepreterm infants in the future. investigators identify fetal growth restriction in infants at 23–27 weeks’ gestation as a risk factor for BPD [3].Epidemiology of bronchopulmonary dysplasiaNew information about populations of infants with BPD The National Institutes of Child Health – Neonatalhas appeared. Stroustrup and Trasande [1] report the Research Network also has provided us with informationincidence and resource use of infants with BPD, using a on 9575 infants of 22–28 weeks gestation born from 2003US nationwide database. They conclude that the inci- to 2007 [4]. The incidence of BPD did not decreasedence of BPD decreased by 4.3% per year for the years over the 5 years in this population of well studied infants.1993–2006. There was an associated increase in nonin- The BPD outcomes are categorized for each gestationalvasive ventilation, but costs and length of hospitalizations age according to the 2000 classification of BPD as mildfor infants with BPD increased. We also learned more (oxygen use for 28 days), moderate (oxygen need atabout the pattern of disease progression from the initial 36 weeks), or severe (ventilatory support at 36 weeks)1040-8703 ß 2011 Wolters Kluwer Health | Lippincott Williams Wilkins DOI:10.1097/MOP.0b013e3283423e6bCopyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  2. 2. 168 Neonatology and perinatology Table 1 Clinical characteristics of 1346 infants grouped by patterns of lung disease to 14 days of age Consistently low FiO2 Pulmonary deterioration Persistent lung disease N 249 484 576 Percentage of population 20 38 43 Any chorioamnionitis (%) 55 54 53 Initial FiO2 0.25 029 0.38 FiO2 – 7 day 0.22 0.28 0.42 FiO2 – 14 day 0.21 0.40 0.49 Surfactant treatment (%) 78 89 97 Ã CPAP – 7 day (%) 50 30 10 Ã Mechanical ventilation – 7 day (%) 21 57 84 Ã No PDA (%) 52 36 28 Ã BPD (%) 17 51 67 BPD, bronchopulmonary dysplasia; FiO2, fractional inspired oxygen concentration; PDA, patent ductus arteriosis. Data abstracted from [2]. Ã P 0.001 for trend across groups. (Fig. 1). These curves are a useful visual reminder of the more than 50% were exposed to chorioamnionitis, but very high risk for severe BPD at the earliest gestational there was no correlation of chorioamnionitis with severity ages. However, overall, the numbers of infants with of early respiratory disease or BPD [2] (Table 1). A severe persistent BPD have decreased. multicenter study from the Canadian Neonatal Network found that clinical chorioamnionitis was associated with increased risks for intraventricular hemorrhage and early- Chorioamnionitis and bronchopulmonary onset sepsis, but not respiratory outcomes [7]. The simple dysplasia associations of chorioamnionitis with RDS and BPD are The clinical research on relationships between antenatal confounded by the unknowns – duration of fetal infection (chorioamnionitis) and respiratory distress syn- exposure, extent of fetal responses, and the organisms drome (RDS) or BPD remains unsettled. Chorioamnio- inciting the responses, factors that are important based on nitis induced in sheep by pro-inflammatory mediators animal model literature [5]. Clinical examples of the such as Escherichia coli lipopolysaccharide, IL-1, or live complexity of the relationships were provided by Been Ureaplasma induce both lung maturation and a phenotype et al. [8,9]. Chorioamnionitis isolated to the placenta and of fetal lung inflammation [5]. Chorioamnionitis in fetal chorion was associated with decreased RDS, whereas mice stimulates angiogenesis and an inflammatory profile chorioamnionitis with fetal involvement increased the comparable to the inflamed lungs of infants developing risk of RDS in early gestational age infants [9]. Infants BPD [6]. The infants in the extremely low gestational age exposed to severe chorioamnionitis had decreased newborn study - acronym for a clinical study had exten- clinical responses to surfactant treatment, and those less sive evaluations for histologic chorioamnionitis; and just favorable responses correlated with longer mechanical ventilation and more BPD [8]. Thus, simple evaluations of a clinical or histologic diagnosis of chorioamnionitis Figure 1 Percentage of population of 9575 infants categorized as to severity of BPD based on the 2000 NIH conference defi- may mask populations of infants at either increased or nition decreased risks of outcomes such as RDS and BPD. The future will be in the use of molecular microbiological techniques to better characterize the organisms causing Percentage of 60 population fetal exposures and to better define the fetal or newborn Severe BPD responses. An example is the report by Payne et al. [10] demonstrating that the presence of Ureaplasma parvum in 40 tracheal aspirates increased the odds ratio for BPD or death by 4.8. Moderate BPD 20 Mild BPD Inhaled nitric oxide The use of inhaled nitric oxide (iNO) to prevent BPD 0 22 23 24 25 26 27 28 remains controversial. A new large trial demonstrated that Gestational age at the early use of low-dose iNO had no beneficial effects birth (weeks) [11]. The National Institutes of Health (NIH) held a Consensus Conference on iNO for preterm infants in the Sixty-eight percent of these infants had BPD. Severity of BPD decreased fall of 2010, which did not recommend routine use of iNO as gestational age increased. BPD, bronchopulmonary dysplasia. Data for preterm infants at risk of BPD [12]. Research on how abstracted from [4]. iNO treatments might help preterm infants is continuing.Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  3. 3. New bronchopulmonary dysplasia Jobe 169McCurnin and colleagues [13] demonstrated in preterm risk 0.52, 95% CI 0.37–0.73) with the lower saturationbaboons that postnatal estriol supplementation improved targets. BPD defined as oxygen use at 36 weeks also waspulmonary outcomes, possibly by upregulating nitric decreased significantly for the population with the loweroxide synthase. iNO decreases the alveolar and vascular oxygen saturation target. These results, together with thegrowth abnormalities induced by oxygen exposure of Vento et al. report [17], demonstrate how carefully oxygennewborn rodents. iNO also will blunt the lung structural exposures for very preterm infants may need to beabnormalities and pulmonary hypertension caused by regulated throughout the weeks of clinical management.bleomycin in newborn rats [14]. Vadivel et al. [15] miti-gated the oxygen-induced alveolar arrest in newborn ratswith supplementation of L-citrulline, a precursor of NO. Ventilation and CPAPThe animal data strongly support a protective role of iNO As with oxygen exposure alone, mechanical ventilationfor injury of the saccular lung. The clinical challenge alone can interfere with development of the saccular lungremains to develop treatment strategies that provide in animal models. Mokres et al. [19] demonstrate thatenough benefit to justify the cost of iNO or to identify ventilation of newborn mice with room air for 24 hother drugs to increase NO in the lung. induced apoptosis, disrupted alveolar septation, and inhibited angiogenesis. Recent clinical research has explored strategies to decrease ventilation-mediatedOxygen use and bronchopulmonary dysplasia injury or to avoid mechanical ventilation entirely. AChronic exposure of the developing rodent lung to high meta-analysis of individual patient data from 10 random-oxygen concentrations uniformly causes structural ized controlled trials demonstrates no benefit from highchanges similar to the new BPD. Chronic exposure of frequency ventilation relative to conventional ventilationinfants who need oxygen after 32 weeks to a higher for BPD or other adverse outcomes [20]. Either approachoxygen saturation range will increase the incidence of to ventilatory support is effective, but avoidance ofBPD [16]. Depressed term infants can be resuscitated as mechanical ventilation is the best strategy in theory. Aeffectively with room air as with supplemental oxygen, number of studies give the clinician guidance as to howbut preterm infants are different. Preterm infants born at that can be done in practice. The same 1316 infants who24–28 weeks gestation and in need of ventilatory support were randomized to oxygen saturation ranges in theat delivery were initially resuscitated with 30 or 90% NICHD trial [18] were also randomized prior to birthoxygen by Vento et al. [17]. Oxygen exposures were to intubation at delivery and surfactant treatment withinadjusted to saturation targets of 75% at 5 min and 85% at 1 h of birth or to CPAP at delivery and surfactant as10 min. Heart rate responses were comparable and both clinically indicated [21]. The protocol specified earlygroups received about 50% oxygen by 5 min and 30% extubation when possible. Although there was no differ-oxygen by 10 min. The increased oxygen exposure for ence in the primary outcome of BPD or death, most of theinfants started at 90% oxygen from birth to 5 min of age respiratory indicators favored the CPAP group (Table 2).correlated with more ventilatory support and a significant The large decrease in use of postnatal corticosteroidsincrease in BPD. Those infants with BPD had higher with CPAP is particularly interesting with respect to theindicators of oxidant injury in blood and urine. This new policy statement from the American Academy ofprovocative report suggests that brief exposures of very Pediatrics that recommends caution for the use of post-preterm infants to high oxygen concentrations can initiate natal corticosteroids for BPD [22]. This trial randomizeda lung injury resulting in BPD, despite comparable blood infants prior to birth such that it included both depressedoxygen saturations over the period of resuscitation. The and more healthy infants. The recent COIN trial random-take home message for now is that resuscitation of very ized only infants requiring some ventilatory assistance atpreterm infants should be initiated with 30–50% oxygen. 5 min of age to CPAP or intubation, which excluded theThese results need to be replicated. depressed and ‘normal’ infants [23]. Most of the respir- atory outcomes favored CPAP in the COIN trial.A National Institute of Child Health and Development(NICHD)-Neonatal Research Network trial randomized A trial from the Vermont–Oxford Network randomizedinfants of 24–27 weeks’ gestation from Neonatal Intensive infants to three groups: intubation, surfactant, and venti-Care Unit (NICU) admission to 36 weeks to oxygen lation; intubation, surfactant, and extubation to CPAP;saturation targets of 85–89% or 91–95% [18]. The and CPAP with selective surfactant treatment [24]. Theprimary outcome for the trial was severe retinopathy of outcomes of death or BPD were not different betweenprematurity (ROP) or death, and the combined rates of groups, but qualitatively favored the CPAP groups. Onlysevere ROP or death did not differ. However, in a classic 46% of the CPAP and selective surfactant group weredemonstration of competing outcomes, the rate of death ventilated over the first 7 days vs. 99% of the ventilationincreased [relative risk 1.7, 95% confidence interval (CI) group. Other groups evaluated other wrinkles to the1.01–1.60] and the rate of severe ROP decreased (relative general theme of how to avoid mechanical ventilationCopyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  4. 4. 170 Neonatology and perinatology Table 2 Outcomes for early CPAP vs. intubation and surfactant Early CPAP Intubation and surfactant P N 663 653 Gestational age (weeks) 26.2 Æ 1.1 26.2 Æ 1.1 Death or BPD (%) 47.8 51.0 0.30 Death (%) 14.2 17.5 0.09 BPD – O2 use at 36 weeks (%) 48.7 54.1 0.07 Mechanical ventilation (days, median) 10 13 0.03 Survival without mechanical ventilation (%) 55.3 48.8 0.01 Any air leak (%) 6.8 7.4 0.56 Postnatal steroids for BPD (%) 7.2 13.2 0.01 BPD, bronchopulmonary dysplasia. Data abstracted from [21]. while using surfactant. Sandri et al. [25] randomized 208 Treatment of such infants early in their clinical course infants at birth with gestational ages of 25–28 weeks to should decrease symptoms, decrease oxygen exposure, either intubation within 30 min of birth, surfactant and decrease air leaks, and shorten the clinical course. extubation within 1 h to CPAP, or CPAP with selective surfactant treatment. These infants did not require intu- The innovations to decrease BPD are new ways to give bation following delivery and were initially stabilized surfactant and more effective methods to deliver CPAP with CPAP if needed. Fifty-one percent of the selective or noninvasive ventilation. Aerosolization of surfactant is surfactant group received surfactant. There were no an old idea that is again being evaluated [29]. Synchro- differences in the need for mechanical ventilation within nized nasal ventilation avoids the endotracheal tube and 5 days of age or in any other outcome. In contrast, Rojas can support infants with apnea [30,31]. Neural adjusted et al. [26] randomized infants of 27–31 weeks gestation ventilatory assist (NAVA) is a technique for timing and who were receiving CPAP to surfactant treatment within modulating mechanical ventilation cycles using the elec- 1 h of birth and a return to CPAP or CPAP alone, with the trical signal from the diaphragm detected with a fine primary outcome being need for mechanical ventilation. catheter in the distal esophagus. NAVA is being evalu- The subsequent need for mechanical ventilation was ated for noninvasive ventilation of infants [32]. Diblasi lower with surfactant treatment and CPAP (26%) than et al. [33] recently reported that a change in configuration with CPAP alone (39%). Air leaks also were lower in the of the pressure controller for bubble CPAP can strikingly surfactant treatment groups, but other outcomes were not increase the ability of bubble CPAP to assist ventilation different. Another approach developed in Cologne, in animal models. A package of individualized interven- Germany is to support infants with CPAP and treat with tions to support ventilation, minimize oxygen exposure, surfactant via a fine feeding tube briefly placed into the minimize apnea, and encourage growth should decrease trachea under direct vision, thus avoiding intubation both the frequency and severity of BPD, but this disease [27,28]. In a randomized study, this gentle approach to will not go away. surfactant treatment decreased the need for mechanical ventilation and decreased BPD [28]. Stem cells Taken together, a strategy of early use of CPAP with The lung injury that is BPD is complex as it involves surfactant treatment as clinically indicated is not worse epithelial surfaces, the lung matrix, and the microvascu- than, and in most studies is marginally better than, lature. A dream for the future has been the concept of routine intubation and surfactant treatment for very pre- replacing injured cells with multipotent stem cells to term infants. Strategies for respiratory support of these ‘repopulate and regrow’ the BPD lung. There are a num- tiny infants are not easily adapted to a practice guideline. ber of reports that demonstrate that stem cell treatments In the delivery room, individual assessment (clinical can mitigate oxidant injury in the developing rodent lung. judgment) will determine the intervention selected. Van Haaften et al. [34] gave bone marrow-derived Each infant should be continually assessed and given mesenchymal stem cells by intratracheal injection to oxy- just the extra support needed, and CPAP may be suffi- gen exposed newborn rats and found increased survival cient for the majority of these infants for transition out and improved exercise tolerance with less lung injury. of the delivery room. The decision about whom to treat However, few of the cells engrafted, and conditioned with surfactant, and how, remains to be refined, but the media from the cells blunted cell injury in vitro. Aslam accumulating evidence supports surfactant treatment et al. [35] gave newborn mice intravascular injections with as soon as the infant has ‘significant RDS’. For me, bone marrow-derived mesenchymal stem cells and found ‘significant’ means a chest film consistent with RDS, protection from oxygen, but with minimal engraftment of an increased work of breathing as assessed clinically, cells in the lungs. The conditioned medium from the cells and an oxygen requirement of about 35% and rising. was as protective as the cells. Stem cell therapy in infantsCopyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  5. 5. New bronchopulmonary dysplasia Jobe 171would be difficult, but the identification of products fromstem cells that blunt the injury progression in BPD has real Conclusionpotential. The good news is that perhaps the stem cells are This review is a selective sampling of progress in thenot required, just their secreted products. understanding and treatment of BPD. The controversy of management of the patent ductus arteriosis was notThere is also new information about stem cells from addressed [43]. An area of intense interest in BPD isinfants that will help frame questions about these thera- the development of biomarkers for disease progressionpeutic approaches. Baker et al. [36] isolated endothelial [44,45]. Ultimately, a decrease in BPD will depend notcolony-forming cells from cord blood of preterm infants only on new information, but also on applications ofand term infants. The cells from the preterm infants were packages of interventions that each may contribute torecovered in higher numbers but were more sensitive to decreasing the severity and incidence of BPD [46,47]. Myoxygen in vitro than cells from term infants. Borghesi et al. preferred practices are efforts to decrease the invasive[37] reported that these same endothelial progenitor cells nature of NICU care in general while empowering thewere in lower numbers in cord blood of preterm infants very preterm infant to breathe spontaneously and grow.who subsequently developed BPD. These observations Such practices include transitioning infants from thein infants at risk of BPD are starting points for recovery of delivery room with CPAP, early extubation for intubatedstem cells from infants for growth in vitro for treatment infants, minimizing oxygen exposures and vascularwith those cells or media from those cells. catheters, and maximizing enteral nutrition.Lung function in childhood and beyond Acknowledgements This work was funded in part by grants HL97064 and HL101800 fromMajor questions linger as to how the BPD lung grows the US National Institutes of Health and Human Development.through childhood and ages. We do not have definitiveanswers but several reports move these questions forward.Fakhoury et al. [38] measured lung function sequentially at References and recommended reading6, 12, and 24 months after NICU discharge in children with Papers of particular interest, published within the annual period of review, have been highlighted as:moderate to severe BPD and found that the abnormalities of special interestpersisted without improvement. Filippone et al. [39] of outstanding interest Additional references related to this topic can also be found in the Currentextended the observations to 9 and 15 years for infants World Literature section in this issue (pp. 255–256).with BPD who had lung functional abnormalities at 2 years 1 Stroustrup A, Trasande L. Epidemiological characteristics and resource use inof age. The 2-year-old children with significant airflow neonates with bronchopulmonary dysplasia: 1993–2006. Pediatrics 2010;obstruction continued to have comparable findings in late 126:291–297.childhood. Lung function also was assessed using spiro- 2 Laughon M, Allred EN, Bose C, et al. Patterns of respiratory disease during the first 2 postnatal weeks in extremely premature infants. Pediatrics 2009;metry at 11 years for infants born at less than 26 weeks’ 123:1124–1131.gestation [40]. This population of children had more A nice demonstration of the variable outcomes resulting from a 14-day history of oxygen exposure.chest deformities, more asthma, and more respiratory 3 Bose C, Van Marter LJ, Laughon M, et al. Fetal growth restriction and chronicsymptoms than did classmates born at term. Spirometry lung disease among infants born before the 28th week of gestation. Pediatricsdemonstrated airflow limitations that were most abnormal 2009; 124:e450– the children with a history of BPD. A limitation of the 4 Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;traditional measurements of lung function in infants and 126:443–456.children is that the measurements assess primarily small Recent epidemiology of outcomes of large numbers of very low birth weight infants.airway function. However, BPD causes decreased alveolar 5 Kramer BW, Kallapur S, Newnham J, Jobe AH. Prenatal inflammation and lungand vascular development – abnormalities of the distal development. Semin Fetal Neonatal Med 2009; 14:2–7.lung parenchyma. Balinotti et al. [41] combined physio- 6 Miller JD, Benjamin JT, Kelly DR, et al. Chorioamnionitis stimulates angiogen-logical techniques to measure alveolar gas volume with esis in saccular stage fetal lungs via CC chemokines. Am J Physiol Lung Cell Mol Physiol 2010; 298:637–645measurements of carbon monoxide diffusion to evaluate 7 Soraisham AS, Singhal N, McMillan DD, et al. A multicenter study on thelung parenchymal growth in normal children in the first clinical outcome of chorioamnionitis in preterm infants. Am J Obstetr Gynecol2 years of life. They found that gas diffusion increased 2009; 200:372 e371–376 e371.proportionately to alveolar volume, suggesting that alveo- 8 Been JV, Rours IG, Kornelisse RF, et al. Chorioamnionitis alters the repsonse to surfactant in preterm infants. J Pediatr 2010; 156:10.e11–15.e11.lar numbers were increasing. They then applied these A demonstration of the complex relationships between chorioamnionitis andmeasurement techniques to children who had BPD and outcomes such as RDS and BPD, using surfactant responses to evaluate lung disease.found decreased gas diffusion capacities, but normal alveo- 9 Been JV, Rours IG, Kornelisse RF, et al. Histologic chorioamnionitis, fetallar gas volumes, suggesting a persistence of impaired involvement, and antenatal steroids: effects on neonatal outcome in pretermalveolar development at 1 year of age [42]. These infants. Am J Obstet Gynecol 2009; 201:587 e581–588 e581. 10 Payne MS, Goss KC, Connett GJ, et al. Molecular microbiological character-measurements provide the first functional measurements ization of preterm neonates at risk of bronchopulmonary dysplasia. Pediatrof the distal lung in children with BPD. Res 2010; 67:412–418.Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
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