Bronchopulmonary Dysplasia

0031-3955/86 $00.00

The Newborn I

+

.20

Bronchopulmonary Dysplasia

Eduardo Bancalari, M.D.,* and Tilo Gerhardt, M.D.t

Bronchopulmonary Dysplasia (BPD) is the term introduced by Northway, Rosan, and Porter in 196763 to describe the clinical, radiographic, and pathologic changes that occur in the lungs of some newborn infants after prolonged mechanical ventilation. With the increasing number of preterm infants surviving mechanical ventilation, BPD has become one of the most common sequelae of neonatal intensive care. It is associated with increased morbidity and mortality and it is a frequent cause for prolonged hospitalization with serious social and economic consequences. The initial description by Northway et al. 63 included three stages of pulmonary changes leading to a final fourth stage characterized by severe morphological and functional lung damage. This stage occurred after several weeks of mechanical ventilation with high pressure and oxygen concentration and was associated with severe respiratory failure frequently accompanied by signs of pulmonary hypertension and cor pulmonale. In recent years, this form of BPD has become less common and has been replaced by a milder form of chronic lung damage that occurs in many of the very small pre term infants who with increasing frequency are surviving mechanical ventilation. In contrast to the earlier cases of BPD, this milder form frequently occurs in infants who initially have only mild pulmonary disease and do not require high airway pressures or inspired oxygen concentration. In fact, many of them require ventilation initially only because of apnea or respiratory depression related to their prematurity.

INCIDENCE The reported incidence of BPD varies widely.37, 49 Although part of this variation may be real and be due to differences in patient susceptibility

*Professor, Department of Pediatrics, University of Miami School of Medicine, Miami, Florida tAssociate Professor, Department of Pediatrics, University of Miami School of Medicine, Miami, Florida Pediatric Clinics of North America-Vo!. 33, No.1, February 1986

1

2

EDUARDO BANCALARI AND TILO GERHARDT

or in management, most of the differences are due to discrepancies in the way BPD is defined. While some authors include only patients with a clinical and radiographic evolution that fits the original description by Northway et aI., 63 we have adopted a more liberal definition that includes all patients who remain oxygen dependent for more than 28 days following mechanical ventilation during the first week of life and who have persistent increased densities on chest radiographs. There are also differences in the base population from which the incidence of BPD is calculated. While some reports include any infant who requires mechanical ventilation, others consider only those infants with respiratory distress syndrome (RDS). The incidence of BPD is higher in the latter group. The indications for intermittent positive pressure ventilation (IPPV) and the survival rate of ventilated infants also influence the incidence of BPD. With increasing survival of very small premature infants the number of patients at risk of developing chronic lung disease also increases. The incidence of BPD in infants with RDS who receive IPPV and survive varies between 10 per cent and 20 per cent. 4, 15, 21 Assuming the incidence ofRDS in newborns weighing less than 2.5 kg to be approximately 14 per cent,25 it can be estimated that 35,000 infants will develop RDS each year in the United States. If one third of these infants require mechanical ventilation, and 15 per cent develop BPD, approximately 1300 infants will survive with this condition each year in this country. The number of infants surviving with milder forms of chronic lung damage is much higher.

CLINICAL PRESENTATION The diagnosis of BPD is based on clinical and radiographic characteristics, but there are no specific clinical signs or laboratory alterations that confirm the diagnosis. The majority of infants who develop BPD are born prematurely, although there are also cases reported in infants born at term. 8 , 71 With rare exceptions, all of them require mechanical ventilation with intermittent positive pressure during the first days of life. Mechanical ventilation is usually indicated for respiratory failure due to RDS, but this therapy may also be for pneumonia, meconium aspiration, patent ductus arteriosis (PDA), or apnea of prematurity. 29, 49, 56, 68, 71 Once BPD has developed, infants may require mechanical ventilation and oxygen therapy for long periods of time ranging from weeks to several months. The need for respiratory assistance may be prolonged by complications such as intracranial hemorrhage, pulmonary interstitial emphysema or pneumothorax, pulmonary infection, and PDA. These complications may increase the need for high inspired oxygen concentrations and airway pressures and may start a vicious cycle in which the required therapy produces further aggravation of the pulmonary damage. Many small infants have mild respiratory disease initially requiring ventilation with low pressures and oxygen concentration, but after a few days or weeks of ventilation show progressive deterioration in their lung function and develop chronic lung disease. This deterioration may be triggered by bacterial or viral infections or heart failure secondary to a PDA.

BRONCHOPULMONARY DYSPLASIA

3

Infants with BPD may die from either progressive respiratory failure or acute complications. Most survivors show a slow but steady improvement in their lung function and, after variable periods of time, can be weaned from the ventilator. After extubation most infants persist with chest retractions and tachypnea and frequently have rales and bronchial sounds on auscultation. Many infants develop lobar or segmental atelectasis due to retained secretions and airway obstruction. Because of the respiratory failure, infants with BPD take oral feedings with difficulty and may require tube feeding. Weight gain is usually below the normal even when the amount of calories that they receive is appropriate for their age.lOO This lower weight gain may be due to the higher energy expenditure produced by the increased work of breathing. 92 With prolonged respiratory failure, some infants develop signs of right heart failure secondary to pulmonary hypertension, with cardiomegaly, hepatomegaly, and Ruid retention. 11, 37 In these cases the need for Ruid restriction further limits the amount of calories that can be given. Right ventricular failure was a frequent complication of BPD some years ago but is seen less commonly now. 26, 50 This is probably related to the milder forms of BPD seen today, and to the fact that the Pa0 2 is usually maintained at higher levels to prevent hypoxic pulmonary hypertension. Echocardiographic evaluation of infants with BPD has shown realtively normal pulmonary artery pressures as long as the Pa0 2 is maintained above 55 mmHg. 36,50 In infants with BPD, acute pulmonary infection, either bacterial or viral, is a frequent complication that worsens their course and in many cases is the precipitating cause of death. The diagnosis of BPD is based on the clinical course described above and on the radiographic findings. The four stages of BPD reported by Northway et al. 63 were based primarily on the radiographic evolution, from RDS to complete opacification to cystic appearance and finally to the typical stage IV with severe hyperinRation alternating with areas of increased density due to collapse or fibrosis. Although these different stages are present in some infants who develop BPD, most patients do not follow this course but still reach the same end stage. 22, 67, 98 Infants with conditions other than RDS may also develop BPD, and therefore their initial radiographi~ findings are varied. The radiographic changes of stage II are also nonspecific and may reRect progression of RDS, but also may be produced by pulmonary edema, hemorrhage, or infection. Not only are the changes of stage II absent in many infants who develop the advanced form of BPD, but they may be present in a large number of infants who recover without pulmonary sequelae. The radiographic changes of stage III are somewhat more specific and usually indicate more chronicity to the evolution. Yet, on some occasions the cysts correspond to severe pulmonary interstitial emphysema and may clear within a few days. This stage can also be absent in patients who ultimately develop BPD stage IV. Thus, the only changes that are required to make the diagnosis of BPD stage IV are those seen in the more advanced stages of the disease, characterized by a radiographic picture with hyperlucent areas alternating with strands of radiodensity due to collapse and/or fibrosis (Fig. 1). The radiographic course before this stage is extremely variable and depends on

4

EDUARDO BANCALARI AND TILO GERHARDT

1. radiograph Chest radiograph Figur ~ Figure 1. h st shows hyperlucency both bases shows hyperluc nco of both of base with strands of' nsity radiodensity \ ith strands of radiod mor > more the~ upper lung promin prominent nt on th onupp lung fields.pictur This ' picture is compatible fi Id . This is compatibl withstage BPDIV. stage IV. Banea(From Bancawith BPI) (From and Goldman, S. BaroandE.,~oldman , '. Barolari , E.,lari, to theIn: lung. In: Milunsky, trauma trauma to th lung. Milunsk}, A., Friedman, and Gluck, A., Friedman , E . A., E. andA., luck, in Perinatal L. ( dsL. .): (eds.): Ad ane Advances s in Pe rinatal Medicine. New York, t dicine. N \ York, Plenum Plenum Publishing perPubli
the initial the multiple complications that occur may occur th initial di asdisease and thandmultipl complications that may in th in these infants before they develop BPD. infant b for th y d v lop BPD. The aincreasing very small for long Th incr ing numbnumber r of ryofsmall infantsinfants who r who quirrequire IPPV IPPV for long periods of time and develop a milder form of chronic lung disease, p riod of tim and d v lop a mild r form of chroni lung dis as show show andlyrarely only hyp mild rhyperexpansion with diffus fine diffuse bilateral only mild xpan ion with fin bilat ral d n 'itidensities, , and rar 2). This is most likely a similar disease, but cardiomegaly22 (Fig. cardiom galy22 (Fig. 2). This is most lik ly a imilar di as , but of a I of ar lesser severity thandthat described originally by Northway s v rity than that crib d originally by orthway t al. 6.'3et al. 63 The following chronic lung diseases must be from BPD. Th following chronic lung dis a s must b diffi r differentiated ntiat d from BPD. Wilson-Mikity. The advanced thisa 'disease clinical Wilson-Mikity. Th advanc d stag sstages of thi ofdis ha have linical and and radiographic similarities to BPD, therefore ther differential is radiographic 'imilariti to BPD, and thand r for th diffi ntial diagnodiagnosis is is based mainly on the initial clinical course. While BPD occurs mainly in bas d mainly on th initial clinical cours . Whil BPD occurs mainly in the chronic lung changes described by'on Wilson infantsinfants who rwho quirrequire IPPV,IPPV, th chronic lung chang d crib d by \ViI and Mikity preterm did hay not have significant and ~1ikity occurroccurred d in print rm infantsinfants who who did not significant

radiograph of Figur Figure 2. h 2.st Chest radiograph of premature a t n-\a eten-week-old k-old pr matur infant infant persistent in showing shO'> ing peri te nt fin d fine nsitidensities sin both lungs with mild only ov mild both lungs with onl) r- overexpansion. Bancalari, E., expansion. (F rom (From Banealari , E., and Goldman, S. Barotrauma to and ~oldman , . Barotrauma to the lung. In: Milunsky, Ill : Milun 'k) , A. , FriA.,d-Friedth lung. A., and man , man, E. " E.and luck,Gluck, L. (edsL..): (eds.): Advances Perinatal Medicine. Ad ane s in Pe in rinatal t dicine. Plenum Publishing 'w New York, York, PI num Publishing orp.,Corp., 19 '2; 1982; with pwith rmi permission.) ""ion .)

BRONCHOPULMONARY DYSPLASIA

5'

pulmonary disease initially and therefore were not treated with IPPV.86. 95 It is possible that BPD and Wilson-Mikity have a similar pathogenesis, and that the differentiation based on prior use of IPPV is artificial. Although some pathological differences between these two conditions have been described, many of these differences seem to be more quantitative than qualitative. Pulmonary Interstitial Emphysema. This is a frequent complication in premature infants requiring IPPV. In the more severe cases the gas can coalesce into cystic areas that simulate focal emphysema such as seen in BPD. 9 These areas are more localized, occur early during the course of the disease, and usually disappear in a few days. When they persist for a longer time, they commonly precede the development of BPD. 83 Congenital Heart Disease. Obstruction of the pulmonary venous drainage can produce a radiographic picture similar to that of BPD. This disease occurs during the first days of life and is usually accompanied by other evidence of cardiovascular abnormalities that facilitate the differential diagnosis. Infants with left to right shunting and increased blood flow frequently develop respiratory failure that must also be differentiated from BPD. The clinical signs of heart disease and echocardiography or cardiac catheterization help in the differential diagnosis. Increased pulmonary blood flow secondary to a PDA in preterm infants is one of the factors that is associated with an increased incidence of BPD. Pneumonia. Viral pneumonia such as that produced by cytomegalovirus can lead to radiographic findings similar to those of BPD. 30.94 In other cases the pulmonary infection may produce severe respiratory failure requiring mechanical ventilation and predispose the infant to develop BPD. Viral cultures and serial antibody titers must be obtained to confirm the diagnosis of pneumonia. Recurrent aspiration of gastric content secondary to gastroesophageal reflux can also produce chronic pulmonary changes similar to BPD. 17 Cystic fibrosis may present early in life, but, like most of the conditions mentioned above, the respiratory failure and radiographic changes will precede the use ofIPPV and not follow it as in BPD.

PULMONARY FUNCTION Patients with BPD have respiratory failure with varying degrees of hypoxemia and hypercapnia. The disruption of pulmonary function is secondary to airway obstruction, fibrosis, emphysema, and areas of collapse characteristic of BPD. Minute ventilation is usually increased, but this is accomplished with a smaller tidal volume and a higher respiratory rate than normal. 20. 90 Thus, there is an increase in dead space ventilation partially explaining the alveolar hypoventilation and CO 2 retention seen in these patients. Infants with BPD characteristically have a marked increase in airway resistance. 8. 32, 55 This results in a decreased dynamic compliance, because with airway obstruction dynamic compliance becomes frequency dependent; therefore, compliance decreases at higher respiratory rates. Lung compli-

6

EDUARDO BANCALARI AND TILO GERHARDT

ance is also decreased because of fibrosis, overdistention, and collapse of lung parenchyma. The high resistance and decreased compliance result in a markedly increased work of breathing. Functional residual capacity (FRC) is initially low or normal but may be increased later in cases of severe BPD. 14, 32 Infants with advanced BPD have abnormal distribution of ventilation. Watts et al. 91 found a significant delay in the nitrogen washout in infants with BPD when they were compared with infants who received IPPV but did not develop BPD. This alteration may reflect involvement of the small airways in these patients. Ventilation studies using xenon-133 have also shown uneven distribution of ventilation in infants with severe BPD. 56 In infants with milder form of chronic lung disease the distribution of the inspired gas is usually normal as measured by nitrogen clearance delay.33 Increased airway resistance is not specific for infants with BPD, and it is observed in most infants who receive IPPV, even when they do not have clinical or radiographic evidence of residual pulmonary disease. 2, 84, 85 This increased airway resistance, which may last for several years, is not observed in infants with RDS who received oxygen therapy without IPPV. Most infants with severe BPD have marked hypoxemia and hypercapnia and require supplemental oxygen to maintain a Pa02 above 50 mmHg. The amount and duration of oxygen therapy vary with the severity of the pulmonary damage. In most cases when 100 per cent O 2 is given, the Pa02 exceeds 100 mmHg, indicating that the hypoxemia is due to a combination of an abnormal ventilation/perfusion ratio and alveolar hypoventilation, and not to anatomical right-to-left shunting. The oxygen requirement decreases gradually as the disease process improves, but increases during feedings, physical activity, or episodes of pulmonary infection or edema. The increased PaC02 is secondary to alveolar hypoventilation and to an increased alveolar-arterial CO 2 gradient produced by a mismatch of ventilation and perfusion and increased alveolar dead space. 91 The chronic hypercapnia results in an increased serum bicarbonate concentration that tends to compensate for the respiratory acidosis. This increase in base can be exaggerated by the use of diuretics that are frequently indicated in infants with BPD. Table 1 shows the results of serial pulmonary function tests performed in our laboratory in 44 infants with chronic lung disease (CLD) who have been followed up to 36 months of age. 32 As shown, weight increased slowly Table 1. Pulmonary Function in Infants with Chronic Lung Disease dUring the First Three Years of Life 6

STUDY AGE (MO?\THS)

Weight (g) Minute Ventilation (mllminlkg) Functional Residual Capacity (mllkg) Lung Compliance (mllcmH20/kg) Lung Resistance (cmH20/(l/sec)

1290 ± 430 2660 ± UOO 392 ± 123 377 ± 102

12

18

5070 ± 1270 7910 ± 1280 9490 ± 1080 280 ± 68 235 ± 54 222 ± 47

14.8 ± 2.4

14.7 ± 2.9

15.1 ± 3.5

0.74 ± 0.24

0.82 ± 0.27

0.78 ± 0.24 1.07 ± 0.25 1.10 ± 0.33

127 z 50

109 ± 31

96±30

17.5 ± 3.4

6O±17

19.2 ± 4.4

54±15

24

36

10880 ± 1500 12510 ± 1690 206 ± 44 202 ± 43 19.7 ± 3.9

21.7 ± 3.7

1.29 ± 0.33

1.29 ± 0.30

43 ± 15

35 ± 10

BRONCHOPULMONARY DYSPLASIA

7

in infants with BPD following the 10th to 25th percentiles of the normal growth curve. This degree of growth retardation in infants with chronic lung disease is characteristic of infants with very low birth weight requiring prolonged intensive care. Ventilation per kilogram decreased with advancing age mainly because of a progressive drop in respiratory rate. This is secondary to the decrease in oxygen consumption per kilogram observed with growth and to the gradual improvement in lung function in infants with chronic lung disease. FRC increased in proportion to weight (r= 0.93), but, because the regression line does not intersect at zero, FRC/kg changes from 14.8 mllkg at 1 month to 22.3 ml/kg at 3 years of age. This change with growth follows the normal pattern. Lung compliance also increased in proportion to weight (r= 0.90) but again the regression line did not intersect at zero. Compliance per kilogram was only 0.74 mllcmHzO/kg at 1 month of age and increased to 1.3 at 3 years. Specific lung compliance (compliance corrected to 1 liter FRC) was consistently 25% lower than in normal infants through the observed growth period. This suggests an intrinsic difference in the elastic properties of the lung in infants with CLD or may be due to a smaller number of more distended alveoli. Pulmonary resistance was elevated early in the disease process. At one month of age resistance was still twice the value of normal infants and showed very little change until 6 months, when the values begun to decrease faster than growth, so that at 3 years resistance was only 30 per cent above normal.

PATHOGENESIS The exact mechanisms responsible for the morphological and functional disruption of the lungs in patients with BPD has not been clearly established. Because the disease occurs almost exclusively in infants who receive mechanical ventilation with positive pressure, this mode of therapy has been considered one of the most likely causes of BPD. Other factors that may be involved in the pathogenesis of BPD include oxygen toxicity, pulmonary edema due to a patent ductus arteriosus or excessive fluid administration, increased airway resistance, prematurity, and lung damage secondary to RDS.

INTERMITTENT POSITIVE PRESSURE Most cases of BPD occur in infants who receive IPPV. Only a few cases of BPD have been reported in infants who were ventilated with intermittent negative pressure. 54, 82 This low incidence might be partially due to the lower survival of very small infants ventilated with negative pressure alone. In a long-term follow-up of infants who survived after being ventilated with negative pressure, Shepard et al. 76 described residual pulmonary changes similar to those of BPD in 6 out of 19 infants. These authors attributed these changes to the reparative process of the initial lung insult, but in fact those changes may reflect a milder form of BPD. The strongest advocates for the role of IPPV in the development of BPD are

8

EDUARDO BANCALARI AND TILO GERHARDT

Reynolds and Taghizadeh,70 who observed a decrease in the incidence of BPD in their nursery after introducing a modality of IPPV with longer inspiration, lower peak airway pressure, and lower rate. This was a ret(ospective study and the diagnosis of BPD was based on post-mortem examinations. Subsequently, the same authors87 reported results from a second pathologic study in which they examined lungs of 112 infants dying from RDS. From this analysis they concluded that more severe lesions of BPD correlated best with the use of high airway pressures. In another retrospective analysis, Moylan et al. 57 also observed a decrease in the incidence of alveolar rupture and BPD coincident with the use of lower peak airway pressures during IPPV. Similar results were published by Berg et al., 10 who reported a decrease in the incidence of BPD from 36.2 per cent to 17.2 per cent after introducing the use of positive end-expiratory pressure and lower peak inspiratory pressures in their nursery. Additional evidence for the long-term detrimental effect of positive pressure on lung function was provided by Stocks and Godfrey,84 and Stocks et al., 85 who found that infants who require mechanical ventilation with intermittent positive pressure have an increase in airway resistance that persists at least up to one year of age. Airway resistance was normal in infants with RDS treated only with oxygen or with continuous positive pressure, a finding suggesting that the intermittent positive pressure, and not the oxygen or end-expiratory pressure, was responsible for the airway damage. Most of this information comes from retrospective data; therefore it is difficult to determine whether the high pressures had a causal effect in the development of the chronic lung damage or whether these high settings were required because the lung damage was already established. No prospective study controlling for other variables that may influence the development of BPD has shown a causal relationship between positive pressure and BPD. In fact, there are studies demonstrating the opposite finding. In one of them, 110 infants with RDS were ventilated with different peak airway pressures and inspiratory durations. No significant differences were found in the incidence of chronic lung disease between infants ventilated with low pressures and prolonged inspiration and those ventilated with higher pressures and shorter inspiration. 5 Additional evidence that high peak airway pressure may not be the critical factor in the pathogenesis of BPD was presented by Brown et al., 15 who described seven infants with BPD, only one of whom received pressures above 30 cmH 20. In two subsequent prospective studies using different inspiratory to expiratory time ratios during the acute phase of RDS, no differences were found in the incidence of BPD between the two treatment groups. 39, 80 De Lemos et al.18 tried to establish the role of positive pressure and oxygen in the production of pulmonary damage in lambs. While animals exposed to 100 per cent O 2 died within 2 to 4 days with severe lung damage, those that were ventilated with air did not demonstrate any significant pulmonary changes. The relevance of these results in relation to the pathogenesis of BPD is limited because of the relatively short duration of IPPV and because the lungs in these animals were initially normal. Nilsson 59 showed that positive pressure ventilation with air produced widespread necrosis of bronchiolar epithelium in premature rabbits,

BRONCHOPULVIONARY DYSPLASIA

9

whereas no lesions occurred in mature animals. Nilsson et al. 60 were able to prevent the development of the bronchiolar lesions by depositing a surfactant solution in the upper airway before the animals were ventilated. These results suggest that the decreased compliance secondary to the increased surface tension can be an important factor in the development of bronchiolar lesions secondary to IPPV in the preterm animal. In infants with severe respiratory failure it is difficult to separate the effect of pressure from other factors that may influence the development of BPD. Most of these patients require aggressive respiratory support, including high pressures and oxygen concentrations, and they frequently have complications such as PDA and pulmonary interstitial emphysema that may predispose them to BPD. Although most likely positive pressure contributes to the damage of the small airways and to the maldistribution of the inspired gas, there is not enough clinical or experimental evidence to single out one aspect of ventilation as the critical factor in the pathogenesis of BPD. OXYGEN TOXICITY In their original report of BPD, Northway et al. 63 postulated that the pulmonary lesions were due to the effects of high oxygen concentration on a lung that was healing from severe RDS. This conclusion was based on the observation that all infants who developed BPD has received high oxygen concentrations for more than 150 hours. This concept was reinforced later by Edwards et al., 21 who found that the occurrence of BPD was directly related to the duration of exposure to oxygen concentrations above 40 per cent and not to the duration of mechanical ventilation or endotracheal intubation. Similar results and conclusions have been reported by others,7, 71 but most infants in these studies received both oxygen and positive pressure ventilation, making the interpretation of the results difficult. It is well established that a high inspired oxygen concentration can produce severe functional and morphologic changes in the lungs, some of which are similar to those observed in BPD. 96 During the first days of exposure to 100 per cent O 2 , the pulmonary changes are characterized by interstitial edema and swelling of endothelial cells followed by destruction of Type I alveolar cells. After a week of exposure to 100 per cent. O 2 , there is hyperplasia of Type II alveolar epithelial cells with further destruction of Type I cells, and marked interstitial edema with increased cellularity composed mainly of macrophages and fibroblasts. Bronchiolar changes are particularly striking; they consist of mucosal necrosis with metaplasia and proliferation of bronchiolar epithelium, and peribronchiolar edema and obstruction. 47, 58, 64 The changes in the airways are probably responsible for the uneven aeration and areas of emphysema that are observed in newborn mice after several days of oxygen exposure. 40 These changes are similar to those observed in BPD, If the animals are allowed to recover in room air, most of the changes will regress, but there may be residual thickening of the interstitium by fibrous tissue. Because of the evidence that oxygen may play an important role in the pathogenesis of BPD, interest has been focused on the susceptibility of the

10

EDUARDO BANCALARI AND TILO GERHARDT

newborn to the toxic effect of oxygen. The cytotoxicity of oxygen seems to be related to the formation of highly reactive free radicals such as superoxide anion, hydroxyl radical, singlet oxygen, and peroxide. The effects of these oxygen metabolites are neutralized by endogenous enzyme systems, such as superoxide dis mutase (SOD), glutathione peroxidase, and catalase. The neonatal animal's lung is able to respond with a larger increase in pulmonary SOD activity when exposed to high oxygen than does the lung of adult animals. This finding may explain the increased tolerance of the neonatal animal to hyperoxia compared with the mature animal. 99 Little information is available regarding these antioxidant systems in human neonatal lung. Frank et al. 28 showed that plasma of premature infants with RDS did not stimulate an increase in SOD activity in premature rat's lungs when exposed to oxygen, whereas plasma of most prematur.e infants without RDS did stimulate this enzyme activity. This deficiency in antioxidant systems in infants with RDS may increase their susceptibility to the toxic effect of oxygen. In addition, Bonta et al. 12 were able to show decreasing SOD levels in infants with RDS who developed BPD. Vitamin E may be an additional endogenous factor that can protect the lung against the effects of high oxygen. In rabbit pups, the administration of vitamin E can significantly reduce the lung changes produced by exposure to 100 per cent oxygen. 93 Although a preliminary report suggested that vitamin E could reduce the incidence of BPD in infants with RDS treated with IPPV,24 these results were not confirmed in later studies. 23 , 74 Although some of the previous data suggest the possibility that oxygen may playa role in the pathogenesis of BPD, some findings do not support its importance as a single factor. First, there is a very low incidence of BPD in infants who receive high oxygen concentrations for long periods of time but are not ventilated with positive pressure. Second, an increasing number of patients develop BPD after a brief or low level of oxygen exposure.4, 21, 68 In conclusion, exposure to high oxygen concentrations for extended periods of time may playa role in the pathogenesis of BPD, but other concomitant factors are required for the development of the chronic pulmonary changes characteristic of this disease.

PULMONARY EDEMA

Most infants with BPD have evidence of a PDA at some point during their clinical course 4, 15,49 or at post-mortem examination, 63, 87 In addition, Brown et al. 15 noted that infants who developed BPD had received greater fluid intake during the first five days of life when compared with infants who did not develop BPD. Spitzer et al. 81 published data suggesting that infants who do not increase their diuresis during the first days of life may be at greater risk for developing BPD than those who have a large diuresis. These findings suggest that an increased pulmonary blood flow and/or interstitial fluid in the lung may increase the risk of BPD in preterm infants. Increased pulmonary blood flow due to PDA and the resulting increase in interstitial fluid cause a decrease in pulmonary compliance and

BRONCHOPULMONARY DYSPLASIA

11

increase in airway resistance. 6 These two changes may prolong the need for mechanical ventilation with higher ventilation pressures and oxygen concentrations, increasing the risk for BPD. 16, 51, 52, 65 Following the development of chronic lung disease, infants with BPD continue to have a predisposition to fluid accumulation in their lungs and tolerate even a normal fluid intake very poorly. The reasons for this are not entirely known, but there are functional alterations in pulmonary vascular resistance, plasma oncotic pressure, and capillary permeability present that favor the accumulation of fluid. Pulmonary vascular pressure may be increased, because of hypoxemia and in some cases secondary to the left ventricular dysfunction that has been described in patients with chronic respiratory failure. 43 , 50 Plasma oncotic pressure may be decreased because of decreased plasma protein concentration due to poor nutrition, Capillary permeability may be increased secondary to the effects of high inspired oxygen concentration or infection on the capillary endothelium. The interstitial pressure in the lung is lower than normal because of the increased inspiratory effort made by these infants in order to overcome the low compliance and high pulmonary resistance, Finally, lymphatic drainage may be impaired because of compression of pulmonary lymphatics by interstitial fluid and fibrous tissue and also because of the increased central venous pressure in cases of cor pulmonale. The abnormal accumulation of lung fluid in infants with chronic lung disease further compromises their lung function and may initiate a cycle in which more aggressive respiratory assistance is required that produces further lung damage. INCREASED AIRWAY RESISTANCE Increased airway resistance can alter the time constant of different segments of the lung and impair the distribution of the inspired gas, favoring uneven lung expansion. In a recent study to define risk factors for BPD, pulmonary function was evaluated in a group of infants early during the course of RDS.33 Infants who subsequently developed chronic lung disease had increased pulmonary resistance from the first week of life, whereas infants who recovered had lower resistance values. This observation raises the possibility that increased airway resistance may playa significant role in the pathogenesis of BPD, and this measurement could be used to predict during the first days of life which infants are at higher risk of developing chronic lung disease. This may also open the possibility for early intervention in order to lower airway resistance and possibly reduce the incidence of chronic lung disease. Table 2 describes some of the mechanisms that may produce airway obstruction in infants with BPD. OTHER FACTORS The incidence of chronic lung disease is inversely related to gestational age and birth weight. In our service, the incidence of BPD in infants who require mechanical ventilation and survive more than 28 days is 85 per

12

EDUARDO BANCALARI AND TILO GERHARDT

Table 2. Mechanisms of Airway Obstruction in Chronic Lung Disease Bronchiolar Epithelial Hyperplasia and Metaplasia Increased Mucus Increased production Decreased elimination Mucosal Edema Inflammation: trauma, oxygen, infection Increased lung fluid: PDA, fluid overload Bronchoconstriction Smooth muscle hypertrophy Familial predisposition Small Airway Closure Decreased FRC Pulmonary interstitial emphysema

cent in those with birth weight of 500-699 g, 47 per cent at 700-999 g, 16 per cent at 1000-1300 g, and 5 per cent in infants with birth weight over 1300 g. These data suggest that prematurity plays an important role in the pathogenesis of BPD. Although most patients who develop chronic lung disease are prematures with RDS, the problem can also occur in full-term infants 63 ,71 and in newborns with diseases other than RDS. 29, 68 A decreased concentration of (Xl proteinase inhibitor may be another factor that predisposes the neonatal lung to damage secondary to the effects of proteolytic enzymes produced by neutrophils. 13 In a recent report, the possibility of a genetic predisposition to abnormal airway reactivity in infants with BPD has also been raised. Nickerson and Taussig61 found a family history of asthma stronger in infants with BPD than in controls. The possibility that vitamin A deficiency may increase the risk of chronic lung disease in preterm infants has also been suggested. Infants who developed BPD had lower vitamin A levels than did a control group who recovered without lung sequelae. 41, 75 This possible association is supported by the similarities between some of the bronchial epithelial changes observed in BPD and vitamin A deficiency. Figure 3 illustrates the interaction of some of the factors that may have a role in the pathogenesis of neonatal chronic lung disease.

PATHOLOGY The pathological changes seen in the early stages of BPD depend on the type of underlying pulmonary disease; however, in the more chronic forms of BPD, the changes become characteristic. Macroscopically the lungs have a grossly abnormal appearance; they are firm, heavy, and have a darker color than normal. The surface is irregular, many times showing emphysematous areas alternating with areas of collapse (Fig. 4). On histological examination, these lungs are characterized by areas of emphysema, sometimes coalescent into larger cystic areas, surrounded by areas of atelectasis (Fig. 5A). There are widespread bronchial and bronchiolar mucosal hyperplasia and metaplasia that reduce the lumen in many of the small airways and may interfere with mucus transport (Fig. 5B). In

13

BRONCHOPULMONARY DYSPLASIA

RESPIRATORY FAILURE

\

Mechanical Ventilation + High Inspired Oxygen Concentration

Patent ductus arteriosus Pulmonary edema Infection

Pulmonary interstitial emphysema

Prematurity Antioxidant systems deficiency? Genetic predisposition? Vitamin A deficiency? Increased proteolysis? Small Airway Damage - Obstruction Interstitial Edema - Fibrosis

+ Abnormal Distribution of Ventilation

+ Emphysema - Collapse

+ OJronic Lung Disease

Figure 3. Pathogenesis of neonatal chronic lung disease.

Figure 4. Macroscopic appearance of lungs with BPD showing areas of emphysema alternating with collapse. (From Bancalari, E., and Goldman, S. In: Milunsky, A., Friedman, E. A., and Gluck, L. (eds.): Advances in Perinatal Medicine. New York: Plenum Publishing Corp., 1982; with permission.)

14

EDUARDO BANCALARI AND TILO GERHARDT

Figure 5. A, Low-magnification view of lung with BPD showing areas of emphysema alternating with areas of partial collapse. (From Bancalari, E., and Goldman, S. In: Milunsky, A., Friedman, E. A., and Gluck, L. (eds.): Advances in Perinatal Medicine. New York: Plenum, 1982; with permission.) B, Small airways showing hyperplasia of the epithelium producing narrowing of their lumen. Peribronchial muscle is hypertrophied, most alveoli are collapsed, and there is an increase in interstitial fibrous tissue. (From Bancalari, E., and Goldman, S. In: Milunsky, A., Friedman, E. A., and Gluck, L. (eds.): Advances in Perinatal Medicine. New York: Plenum, 1982; with permission.)

BRONCHOPULMONARY DYSPLASIA

15

some cases, there may be excessive mucus secretion with exudation of alveolar macrophages. Except for the hypertrophy of the peribronchiolar smooth muscle that persists throughout the course of the disease, the involvement of the small airways is more prominent during the early stages, becoming less marked after the first months of evolution. 70 In addition, there is interstitial edema and an increase in fibrous tissue with focal thickening of the basal membrane separating capillaries from alveolar spaces (Fig. 6). Lymphatics are frequently dilated and tortuous. In many cases there are vascular changes of pulmonary hypertension, such as medial muscle hypertrophy and elastic degeneration. There may also be evidence of right ventricular hypertrophy, and in some cases left ventricular hypertrophy as well. 50 Recently the cytopathologic examination of tracheobronchial aspirate has been proposed as a tool to diagnose BPD while the infant is receiving mechanical ventilation. 53 Infants who develop BPD have a large number of bronchial epithelial exfoliated cells. These cells have prominent chromocenters and an increased nuclear/cytoplasma ratio suggestive of cell regeneration. Bronchoalveolar lavage fluid from infants with BPD has an increased number of polymorphonuclear leukocytes and also contains increased elastase/u 1 proteinase inhibitor ratio. 66 This imbalance may contribute to proteolytic lung damage.

Figure 6. Alveolar septae are thickened by edema and fibroblastic proliferation. (From Bancalari, E., and Goldman, S. In: Milunsky, A., Friedman, E. A., and Gluck, L. (eds.): Advances in Perinatal Medicine. New York, Plenum, 1982; with permission.)

16

EDUARDO BANCALARI AND TILO GERHARDT

PREVENTION As evident from the previous discussion BPD results from the interaction of multiple factors. Therefore, prevention of BPD must include avoidance of as many of these factors as possible, especially in the small premature infant who is most susceptible to develop this complication. When using mechanical ventilation, one must use the lowest peak airway pressure necessary to obtain adequate ventilation and must lower pressures rapidly as the mechanical properties of the lungs improve. Inspiratory times between 0.3 and 0.5 second are usually adequate with flow rates between 5 and 10 liters per minute. Shorter inspiratory times and higher flow rates may exaggerate the maldistribution of the inspired gas and while longer inspiratory times may increase the risk of alveolar rupture and cardiovascular side effects. The end-expiratory pressure must be adjusted so that the minimum oxygen concentration necessary to keep the Pa0 2 above 50 mmHg is used. The duration of mechanical ventilation must be limited as much as possible to reduce the risk of barotrauma and infection. Fluid administration must be carefully controlled and restricted, especially if there is evidence of a PDA. Early intervention with drugs or surgery in order to close the ductus improves lung function and limits the exposure to oxygen and IPPV, reducing the incidence of BPD. 16, 31, 51, 53

MANAGEMENT The management of infants with BPD should be directed at maintaining adequate arterial blood gases, and, at the same time, avoiding the progression of the pulmonary damage. Weaning these patients from the ventilator is difficult and has to be accomplished gradually. When the patient is able to maintain acceptable Pa0 2 and PaC0 2 with peak pressures under 25 cmH 20 and an Fi02 10wer than 0.5, the ventilator rate is gradually reduced to allow the infant to do an increasing amount of the respiratory work on his or her own. During the process of weaning, it may be necessary to increase the inspired oxygen concentration. Concurrently, the PaC0 2 may rise to values in the fifties or sixties. As long as the pH is within acceptable limits, this degree of hypercapnia may be needed to wean the patient from the ventilator. In some infants aminophylline can be used as a respiratory stimulant during the weaning phase. When the patient is able to maintain acceptable blood gas levels for at least 24 hours on a continuous positive airway pressure of 2-4 cmH 20, and without the ventilator cycling, extubation can be attempted. During the days following the extubation, it is important to maintain chest physiotherapy and, if necessary, to perform direct endotracheal suctioning to prevent airway obstruction and lung collapse due to retained secretions. Oxygen Therapy Although it is necessary to reduce the inspired oxygen concentration as soon as possible to avoid its toxic effects, it is equally important to

17

BRONCHOPULMONARY DYSPLASIA

maintain the Pa0 2 at a level sufficient to assure adequate tissue oxygenation and to avoid the pulmonary hypertension and cor pulmonale that can result from chronic hypoxemia. 1 Oxygen therapy does not produce respiratory depression in infants with chronic lung disease. 38 For this reason, the Pa0 2 must be maintained above 50-55 mmHg. Oxygen can be administered through a hood, tent, face mask, or nasal catheter. As during feedings the oxygen consumption increases and the Pa0 2 may decrease, it may be necessary to provide a higher Fi0 2 to avoid hypoxemia. In many cases, oxygen therapy is required for several months or even years. Some of these patients have received oxygen therapy at home. This practice may offer significant advantages in terms of a better environment for the patient and cost savings for the family. 69 The determination of inspired oxygen concentration should be based on arterial blood gas measurements. This is difficult because each time that an arterial or capillary blood sample is obtained these infants react with vigorous crying, which can result in hypoxemia. The fall in Pa0 2 may be avoided by the use of local anesthesia prior to arterial puncture. The use of transcutaneous oxygen monitors is helpful, but in many infants with severe BPD the results do not correlate well with the arterial P0 2 • New transcutaneous oxygen saturation monitors may be more useful to evaluate oxygenation in these infants.

Fluid Management Infants with BPD tolerate excessive or even normal amounts of fluid intake poorly and as mentioned before have a marked tendency to accumulate excessive interstitial fluid in the lung. This excess may lead to a deterioration of their pulmonary function with exaggeration of the hypoxemia and hypercapnia. In order to reduce lung fluid in infants with BPD, water and salt intake should be limited to the minimum required to provide the necessary calories for their metabolic needs and growth. When increased lung water persists despite fluid restriction, chronic diuretic therapy can be used successfully especially in patients with 'evidence of cor pulmonale. 62, 78 The use of diuretics in infants with chronic lung disease is associated with a rapid improvement in lung compliance and decrease in resistance, but the blood gases may not show significant improvement. 44, 89 The reduction in pulmonary capillary pressure observed after furosemide administration is not entirely due to the increased elimination of sodium and water but seems to be in part secondary to an increase in venous capacitance and reduced venous return. 19 Complications of chronic diuretic therapy include hypokalemia, hyponatremia, metabolic alkalosis, and hypercalciuria,

Other Therapy The use of aminophylline has been recommended in infants with BPD.72 This drug may have several beneficial effects, including diuresis, bronchodilation, respiratory center stimulation, and increased diaphrag-

18

EDUARDO BANCALARI AND TILO GERHARDT

matic strength, but there is limited experience with prolonged use of aminophylline in patients with BPD. Recent reports have shown improvement in lung function in infants with BPD during the administration of dexamethasone. 3 , 79 It is not clear whether this transient improvement in lung function justifies the use of a drug that may increase the risk of serious infection. In addition, some, experimental data have shown aggravation of acute lung injury with the administration of steroids. 46 Inhalation bronchodilators have also been used in some patients with BPD. Tal et al. 88 were unable to demonstrate improvement in lung function after nebulization of a ~2 agonist in infants with BPD, but Kao et al. 45 and Gomez-delRio et al. 35 found a marked decrease in airway resistance after isoproterenol or isoetharine was inhaled. The fact that the airway obstruction in infants with BPD is at least in part reversible with bronchodilators is important because these provide an opportunity for early intervention during the course of the disease and possibly reduce its progression. It has been suggested that breathing a helium and oxygen gas mixture may reduce pulmonary resistance and the work of breathing in infants with BPD. 97 The safety of this modality of treatment has not been evaluated and therefore cannot be recommended at this time. Recently Rosenfeld et al. 73 reported decreased clinical and radiographic evidence of BPD in infants who received subcutaneous bovine superoxide dismutase. However, there were no differences in oxygen or positive pressure ventilation requirements between infants in the treatment and placebo groups. This treatment should also be considered experimental.

NUTRITION

Most infants with severe BPD have delayed growth in weight and height but normal head circumference. lOo Nutritional needs are difficult to meet in these patients because of poor feeding tolerance, the necessity to restrict fluids, and the increased caloric demands due to the excessive work of breathing. 92 Thus, nasogastric feeding using concentrated diets for extended periods of time is necessary in most cases. Adequate nutrition may playa very important role in the tolerance of hyperoxia and in the process of pulmonary repair during the more acute phase of the disease. Frank and Groseclose 27 demonstrated a significant reduction in tolerance to oxygen exposure in undernourished newborn rats. This effect was not mediated through depression of the antioxidant systems activity but most likely resulted from improper repair of lung tissue damage produced by oxygen. A special emphasis on psychosensory stimulation is important to compensate for the lack of family influence and the abnormal environment in which these infants spend a large portion of a critical period of their development.

19

BRONCHOPULMONARY DYSPLASIA

OUTCOME Although the majority of the infants described by Northway et al. 63 died, recent studies indicate that the mortality rate has been markedly reduced. 4, 21, 49, 71 A significant proportion of the deaths of infants with BPD occur after discharge from the hospital2 1, 100 and are usually due to acute respiratory infections. The reduction in mortality over the recent years is not due to one specific modality of treatment but is a consequence of the overall improvement in the care these patients receive. Because most of the originally described infants died with right heart failure, the improved outcome may be related to closer monitoring of arterial blood gases and avoidance of hypoxemia, which reduce the risk of pulmonary hypertension and cor pulmonale. The lower mortality may also be due to the milder forms of BPD seen in recent years. The hospital stay of infants with severe BPD is frequently very long because of the need for supplemental inspired oxygen. However, this period can be reduced considerably if the patients can be given oxygen at home. 69 Growth and development may also be delayed in some infants with BPD. 49 This delay is partly due to the difficulties in providing adequate nutrition and partly because of the lack of normal sensory stimulation, as these infants spend extended periods of time in an oxygen tent, isolated from their environment. Major developmental deficits are uncommon and are usually associated with perinatal and neonatal events rather than with the presence of BPD. 34, 48, 90 Little is known regarding the long-term evolution of the pulmonary lesions in BPD. Although most infants show progressive improvement of their respiratory status, they frequently have episodes of deterioration during their first year of life. These episodes are usually due to respiratory tract infection with airway obstruction and increased hypoxemia that require readmission to the hospital. Radiographic changes also show improvement, but in some cases they persist for several years. 37, 42 There are few long-term sequential studies of pulmonary function in infants with BPD, because of the difficulty in performing these studies in children before 5 or 6 years of age. Evidence of airway obstruction with air trapping and bronchial hyperreactivity has been reported in survivors with BPD at 7 to 9 years of age. 77 Follow-up data from our institution32 shows that, although lung function improves in infants with chronic lung disease, the increased airway resistance persists for at least three years; this finding raises the possibility that infants with BPD may continue to have abnormal pulmonary function for extended periods of time. REFERENCES 1. Abman, S. H., Wolfe, R. R., Accurso, F. J., et a!.: Pulmonary vascular response to oxygen in infants with severe bronchopulmonary dysplasia. Pediatrics, 75(1):80, 1985. 2. Ahlstrom, H.: Pulmonary mechanics in infants surviving severe neonatal respiratory insuffiCiency. Acta Paediatr. Scand., 64:69, 1975. 3. Avery, C. B., Fletcher, A. B., Kaplan, M., et a!.: Controlled trial of dexamethasone in respirator-dependent infants with bronchopulmonary dysplasia. Pediatrics, 75(1): 106, 1985.

20

EDUARDO BANCALARI AND TILO GERHARDT

4. Bancalari, E., Abdenour, G. E., Feller, R., et al.: Bronchopulmonary dysplasia: Clinical presentation. J. Pediatr., 95:819, 1979. 5. Bancalari, E., Feller, R., Gerhardt, T., et al.: Prospective evaluation of different IPPV settings in infants with RDS. Clin. Res., 28:870A, 1980. 6. Bancalari, E., Jesse, M. J., Gelband, H., et al.: Lung mechanics in congenital heart disease with increased and decreased pulmonary blood flow. J. Pediatr., 90:192, 1977. 7. Banerjee, C. K., Girling, D. J., and Wigglesworth, J. S.: Pulmonary fibroplasia in newborn babies treated with oxygen and artificial ventilation. Arch. Dis. Child., 47:509, 1972. 8. Barnes, N. D., Hull, D., Glover, W. J., et al.: Effects of prolonged positive-pressure ventilation in infancy. Lancet, 2:1096, 1969. 9. Bauer, C. R., Brennan, M. J., Doyle, C., et al.: Surgical resection for pulmonary interstitial emphysema in the newborn infant. J. Pediatr., 93:656, 1978. 10. Berg, T. J., Pagtakhan, R. D., Reed, M. H., et al.: Bronchopulmonary dysplasia and lung rupture in hyaline membrane disease: Influence of continuous distending pressure. Pediatrics, 55:51, 1975. 11. Berman, W., Jr., Yabek, S. M., Dillon, T., et al.: Evaluation of infants with bronchopulmonary dysplasia using cardiac catheterization. Pediatrics, 70:708, 1982. 12. Bonta, B. W., Gawron, E. R., and Warshaw, J. B.: Neonatal red cell superoxide dismutase enzyme levels: Possible role as a cellular defense mechanism against pulmonary oxygen toxicity. Pediatr. Res., 11:754, 1977. 13. Bruce, M. C., Martin, R. J., and Boat, T. F.: Concentrations of aj-proteinase inhibitor and a 2-macroglobulin in serum and lung secretions of intubated infants. Pediatr. Res., 18(1):35, 1984. 14. Bryan, M. H., Hardie, M. J., Reilly, B. J., et al.: Pulmonary function studies during the first year of life in infants recovering from the respiratory distress syndrome. Pediatrics, 52:169, 1973. 15. Brown, E. R., Stark, A., Sosenko, I., et al.: Bronchopulmonary dysplasia: Possible relationship to pulmonary edema. J. Pediatr., 92:982, 1978. 16. Cotton, R. B., Stahlman, M. T., Bender, H. W., et al.: Randomized trial of early closure of symptomatic patent ductus arteriosus in small preterm infants. J. Pediatr., 93:647, 1978. 17. Danus, 0., Casar, C., and Larrain, A.: Esophageal reflux: An unrecognized cause of recurrent obstructive bronchitis in children. J. Pediatr., 89:220, 1976. 18. DeLemos, R., Wolfsdor, J., Nachman, R., et al.: Lung injury from oxygen in lambs: The role of artificial ventilation. Anesthesiology, 30:609, 1969. 19. Dikshit, K., Vyden, J. K., Forrester, J. S., et al.: Renal and extrarenal hemodynamic effects of furosemide in congestive heart failure after acute myocardial infarction. N. Engl. J. Med., 288:1087, 1979. 20. Durand, M., and Rigatto, H.: Tidal volume and respiratory frequency in infants with bronchopulmonary dysplasia (BPD). Early Hum. Dev., 5:66, 1981. 21. Edwards, D. K., Dyer, W. M., and Northway, W. H., Jr.: Twelve years' experience with bronchopulmonary dysplasia. Pediatrics, 59:839, 1977. 22. Edwards, D. K.: Radiographic aspects of bronchopulmonary dysplasia. J. Pediatr., 85:823, 1979. 23. Ehrenkranz, R., Ablow, R. C., and Warshaw, J. B.: Prevention of bronchopulmonary dysplasia with vitamin E administration during the acute stages of respiratory distress syndrome. J. Pediatr., 95:873, 1979. 24. Ehrenkranz, R. A., Bonta, B. W., Ablow, R. c., et a!.: Amelioration of bronchopulmonary dysplasia after vitamin E administration. N. Eng!. J. Med., 299:564, 1978. 25. Farrell, P. M., and Avery, M. E.: Hyaline membrane disease. Am. Rev. Respir. Dis., 11 :657, 1975. 26. Fouron, J. c., Le Guennec, J. C., Villemant, D., et al.: Value of echocardiography in assessing the outcome of bronchopulmonary dysplasia of the newborn. Pediatrics, 65:529, 1980. 27. Frank, L., and Groseclose, E.: Oxygen toxicity in newborn rats: The adverse effects of under nutrition. J. App!. Physiol: Respirat. Environ. Exercise Physio!. 53(5):1248, 1982. 28. Frank, L., Autor, A. P., and Roberts, R. J.: Oxygen therapy and hyaline membrane disease: The effect of hyperoxia on pulmonary superoxide dismutase activity and the mediating role of plasma or serum. J. Pediatr., 90:105, 1977.

BRONCHOPULMONARY DYSPLASIA

21

29. Friis-Hansen, B., Kamper, J., Boison-Moller, J., et al.: The incidence of pulmonary fibroplasia among 263 infants treated with intermittent positive pressure ventilation. In Stetson, J. B., and Swyer, P. R. (eds.): Neonatal Intensive Care, St. Louis, W. H. Greene, Inc., 1976, p. 445. 30. Fujimura, M., Takeuchi, T., Ando, M., et al.: Elevated immunoglobulin M levels in low birth-weight neonates with chronic respiratory insufficiency. Early Hum. Dev., 9:27, 1983. 31. Gerhardt, T., and Bancalari, E.: Lung compliance in neonates with patent ductus arteriosus before and after surgical ligation. Biol. Neonate, 38:96, 1980. 32. Gerhardt, T., Bancalari, E., Hehre, D., et al.: Changes in pulmonary mechanics with growth in infants with chronic lung disease (CLD). Pediatr. Res., 19:404A, 1985. 33. Goldman, S. L., Gerhardt, T., Sonni, R., et al.: Early prediction of chronic lung disease by pulmonary function testing. J. Pediatr., 102:613, 1983. 34. Goldson, E.: Severe bronchopulmonary dysplasia in the very low birth weight infant: Its relationship to developmental outcome. J. Dev. Behav. Pediatr., 5(4):165, 1984. 35. Gomez-delRio, M., Tapia, J. L., Goldberg, R. N., et al.: Effect ofisoetharine HCL on pulmonary function in neonates. Pediatr. Res., 17:377A, 1983. 36. Halliday, H. L., Dumpit, F. M., and Brady, J. P.: Effects of Inspired oxygen on echocardiographic assessment of pulmonary vascular resistance and myocardial contractility in bronchopulmonary dysplasia. Pediatrics, 65:536, 1980. 37. Harrod, J. R., L'Heureux, P., Wangensteen, O. D., et al.: Long-term follow-up of severe respiratory distress syndrome treated with IPPB. J. Pediatr., 84:277, 1974. 38. Hazinski, T. A., Hansen, T. N., Simon, J. A., et al.: Effect of oxygen administration during sleep on skin surface oxygen and carbon dioxide tension in patients with chronic lung disease. Pediatrics, 67:626, 1981. 39. Heicher, D. A., Kasting, D. S., and Harrod, J. R.: Prospective clinical comparison of two methods for mechanical ventilation of neonates: Rapid rate and short inspiratory time versus slow rate and long inspiratory time. J. Pediatr., 98:957, 1981. 40. Hellstrom, B., and Nergm:dh, A.: The effect of high oxygen concentrations and hypothermia on the lung of the newborn mouse. Acta Paediatr. Scand., 54:457, 1965. 41. Hustead, V. A., Gutcher, G. R., Anderson, S. A., et al.: Relationship of vitamin A (retinol) status to lung disease in the preterm infant. J. Pediatr., 105:610, 1984. 42. Johnson, J. D., Malachowski, N. C., Grobstein, R., et al.: Prognosis of children surviving with the aid of mechanical ventilation in the newborn period. J. Pediatr., 84:272, 1974. 43. Kachel, R.: Left ventricular function in chronic obstructive pulmonary disease. Chest, 74:286, 1978. 44. Kao, L. C., Warburton, D., Sargent, C. W., et al.: Furosemide acutely decreases airways resistance in chronic bronchopulmonary dysplasia. J. Pediatr., 103:624, 1983. 45. Kao, L. C., Warburton, D., Platzker, A. C. G., et al.: Effects of isoproterenol inhalation on airway resistance in chronic bronchopulmonary dysplasia. Pediatrics, 73:509, 1984. 46. Kehrer, J. P., Klein-Szanto, A. J., Sorensen, E. M. B., et al.: Enhanced acute lung damage following corticosteroid treatment. Am. Rev. Respir. Dis., 130:256, 1984. 47. Lum, H., Schwartz, L. W., Dungworth, D. L., et al.: A comparative study of cell renewal after exposure to ozone or oxygen. Am. Rev. Respir. Dis., 118:335, 1978. 48. Markestad, T., and Fitzhardinge, P. M.: Growth and development in children recovering from bronchopulmonary dysplasia. J. Pediatr., 98:597, 1981. 49. Mayes, L., Perkett, E., and Stahlman, M. T.: Severe bronchopulmonary dysplasia: A retrospective review. Acta Paediatr. Scand., 72:225, 1983. 50. Melnick, G., Pickoff, A. S., Ferrer, P. L., et al.: Normal pulmonary vascular resistance and left ventricular hypertrophy in young infants with bronchopulmonary dysplasia: An echocardiographic and pathologic study. Pediatrics, 66:589, 1980. 51. Merritt, T. A., DiSessa, T. G., Feldman, B. H., et al.: Closure of the patent ductus arteriosus with ligation and indomethacin: A consecutive experience. J. Pediatr., 93:639, 1978. 52. Merritt, T. A., Harris, J. P., Roghmann, K., et al.: Early closure of the patent ductus arteriosus in very-Iow-weight infants: A controlled trial. J. Pediatr., 99:281, 1981. 53. Merritt, T. A., Stuard, 1. D., Puccia, J., et al.: Newborn tracheal aspirate cytology: Classification during respiratory distress syndrome and bronchopulmonary dysplasia. J. Pediatr., 98:949, 1981.

22

EDUARDO BANCALARI AND TILO GERHARDT

54. Monin, P., Cashore, W. J., Hakanson, D. 0., et al.: Assisted ventilation in the neonate: CompariSon between positive and negative respirators. Pediatr. Res., 10:464, 1976. 55. Morray, J. P., Fox, W. W., Kettrick, et al.: Improvement in lung mechanics as a function of age in the infant with severe bronchopulmonary dysplasia. Pediatr. Res., 16:290, 1982. 56. Moylan, F. M. B., and Shannon, D. C.: Preferential distribution of lobar emphysema and atelectasis in bronchopulmonary dysplasia. Pediatrics, 63:130, 1979. 57. Moylan, F. M. B., Walker, A. M., Kramer, S. S., et al.: The relationship of bronchopulmonary dysplasia to the occurrence of alveolar rupture during positive pressure ventilation. Crit. Care Med., 6:140, 1978. 58. Nash, G., Blennerhassett, J. B., and Pontoppidan, H.: Pulmonary lesions associated with oxygen therapy and artificial ventilation. N. Engl. J. Med., 276:368, 1967. 59. Nilsson, R.: Lung compliance and lung morphology following artifical ventilation in the premature and full-term rabbit neonate. Scand. J. Resp. Dis., 60:206, 1979. 60. Nilsson, R., Grossmann, G., and Robertson, B.: Lung surfactant and the pathogenesis of neonatal bronchiolar lesions induced by artificial ventilation. Pediatr. Res., 12:249, 1978. 61. Nickerson, B. G., and Taussig, L. M.: Family history of asthma in infants with bronchopulmonary dysplasia. Pediatrics, 65:1140, 1980. 62. Noble, M. 1. M., Trenchard, D., and Guz, A.: The value of diuretics in respiratory failure. Lancet, 2:257, 1966. . 63. Northway, W. H., Jr., Rosan, R. C., and Porter, D. Y.: Pulmonary disease following respiratory therapy of hyaline membrane disease. N. Eng. J. Med., 276:357, 1967. 64. Northway, W. H., Jr., Rosan, R. C., Shahinian, Jr., et al.: Radiologic and histologic investigation of pulmonary oxygen toxicity in newborn guinea pigs. Invest. Radiol., 4:148, 1969. 65. Obeyesekere, H.!., Pankhurst, S., and Yu, V. Y. H.: Pharmacological closure of ductus arteriosus in preterm infants using indomethacin. Arch. Dis. Child., 55:271, 1980. 66. Ogden, B. E., Murphy, S. A., Saunders, G. C., et al.: Neonatal lung neutrophils and elastase/proteinase inhibitor imbalance. Am. Rev. Respir. Dis., 130:817, 1984. 67. Oppermann, H. C., Wille, L., Bleyl, D., et al.: Bronchopulmonary dysplasia in premature infants: A radiological and pathological correlation. Pediatr. Radiol., 5:137, 1977. 68. Philip, A. G.: Oxygen plus pressure plus time: The etiology of bronchopulmonary dysplasia. Pediatrics, 55:44, 1975. 69. Pinney, M. A., and Cotton, E. K.: Home management of bronchopulmonary dysplasia. Pediatrics, 58:856, 1976. 70. Reynolds, E. O. R., and Taghizadeh, A.: Improved prognosis of infants mechanically ventilated for hyaline membrane disease. Arch. Dis. Child., 49:505, 1974. 71. Rhodes, P. G., Hall, R. T., and Leonidas, J. C.: Chronic pulmonary disease in neonates with assisted ventilation. Pediatrics, 55:788, 1975. 72. Rooklin, A. R., Moomjian, A. S., Shutack, J. G., et al.: Theophylline therapy in bronchopulmonary dysplasia. J. Pediatr., 95:882, 1979. 73. Rosenfeld, W., Evans, H., Concepcion, L., et al.: Prevention of bronchopulmonary dysplasia by administration of bovine superoxide dismutase in preterm infants with respiratory distress syndrome. J. Pediatr., 105:781, 1984. 74. Saldanha, R. L., Cepeda, E. E., and Poland, R. L.: The effect of vitamin E prophylaxis on the incidence and severity of bronchopulmonary dysplasia. J. Pediatr., 101:89, 1982. 75. Shenai, J. P., Chytil, F., Stahlman, M. T.: Vitamin A status of neonates with bronchopulmonary dysplasia. Pediatr. Res., 19(2):185-188, 1985. 76. Shepard, F. M., Johnston, R. B., Jr., Klatte, E. C., et al.: Residual pulmonary findings in clinical hyaline membrane disease. N. Engl. J. Med., 279:1063, 1968. 77. Smyth, J. A., Tabachnik, E., Duncan, W. J., et al.: Pulmonary function and bronchial hyperreactivity in long-term survivors of bronchopulmonary dysplasia. Pediatrics, 68:336, 1981. 78. Sniderman, S., Chung, M., Roth, R., et al.: Treatment of neonatal chronic lung disease with furosemide. Clin. Res., 26:201A, 1978. 79. Sobel, D. B., Lewis, K., Deming, D. D., and McCann, E. M.: Dexamethasone improves lung function in infants with chronic lung disease. Pediatr. Res., 17:390A, 1983.

BRONCHOPULMONARY DYSPLASIA

23

80. Spahr, R. C., Klein, A. M., Brown, D. R., et al.: Hyaline membrane disease. Am. J. Dis. Child., 134:373, 1980. 81. Spitzer, A. R., Fox, W. W., and Delivoria-Papadopoulos, M.: Maximum diuresis-a factor in predicting recovery from respiratory distress syndrome and the development of bronchopulmonary dysplasia. J. Pediatr., 98:476, 1981. 82. Stem, L., Ramos, A. D., Outerbridge, E. W., et al.: Negative pressure artificial respiration: Use in treatment of respiratory failure of the newborn. Can. Med. Assoc. J., 102:595, 1970. 83. Stocker, J. T., and Madewell, J. E.: Persistent interstitial emphysema: Another complication of the respiratory distress syndrome. Pediatrics, 59:847, 1977. 84. Stocks, J., and Godfrey, S.: The role of artificial ventilation, oxygen, and CPAP in the pathogenesis of lung damage in neonates: Assessment by serial measurement of lung function. Pediatrics, 57:352, 1976. 85. Stocks, J., Godfrey, S., and Reynolds, E. O. R.: Airway resistance in infants after various treatments for hyaline membrane disease: Special emphasis on prolonged high levels of inspired oxygen. Pediatrics, 61: 178, 1978. 86. Swyer, P. R., Delivoria-Papadopoulos, M., Levison, H., et al.: Pulmonary syndrome of Wilson and Mikity. Pediatrics, 36:374, 1965. 87. Taghizadeh, A., and Reynolds, E. O. R.: Pathogenesis of bronchopulmonary dysplasia following hyaline membrane disease. Am. J. Pathol., 82:242, 1976. 88. Tal, A., Bar-Yishay, E., Eyal, F., et al.: Lack of response to bronchodilator of airway obstruction after mechanical ventilation in the newborn. Crit. Care Med., 10:361, 1982. 89. Tapia, J. L., Gerhardt, T., Goldberg, R. N., et al.: Furosemide and lung function in neonates with chronic lung diease (CLD). Pediatr. Res., 17:338A, 1983. 90. Vohr, B. R., Bell, E. F., and Oh, W.: Infants with bronchopulmonary dysplasia. Am. J. Dis. Child., 136:443, 1982. 91. Watts, J. L., Ariagno, R. L., and Brady, J. P.: Chronic pulmonary disease in neonates after artificial ventilation: Distribution of ventilation and pulmonary interstitial emphysema. Pediatrics, 60:273, 1977. 92. Weinstein, M. R., and Oh, W.: Oxygen consumption in infants with bronchopulmonary dysplasia. J. Pediatr., 99:958, 1981. 93. Wender, D. R., Thulin; G. E., Smith, G. J. W., et al.: Vitamin E affects lung morphologic response to hyperoxia. Pediatr. Res., 14:653, 1980. 94. Whitley, R. J., Brasfield, D., Reynolds, D. W., et al.: Protracted pneumonitis in young infants associated with perinatally acquired cytomegaloviral infection. J. Pediatr., 89:16, 1976. 95. Wilson, M. G., and Mikity, V. G.: A new form of respiratory disease in premature infants. Am. J. Dis. Child, 99:119, 1960. 96. Winter, P. M., and Smith, G.: The toxicity of oxygen. Anesthesiology, 37:210, 1972. 97. Wolfson, M. R., Bhutani, V. K., Shaffer, T. H., et al.: Mechanics and energetics of breathing helium in infants with bronchopulmonary dysplasia. J. Pediatr., 104:752, 1984. 98. Wung, J. T., Koons, A. H., Driscoll, J. M., et al.: Changing incidence ofbronchopulmonary dysplasia. J. Pediatr., 85:845, 1979. 99. Yam, J., Frank, L., and Roberts, R. J.: Oxygen toxicity: Comparison oflung biochemical responses in neonatal and adult rats. Pediatr. Res., 12:115, 1978. 100. Yu, V. Y. H., Orgill, A. A., Lim, S. B., et al.: Growth and development of very low birthweight infants recovering from bronchopulmonary dysplasia. Arch. Dis. Child., 58:791, 1983. Department of Pediatrics (R-131) University of Miami P.O. Box 016 960 Miami, FL 33101