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The Roentgenographic Course and Complications of Hyaline Membrane Disease
Symposium on Respiratory Disorders in the Newborn
The Roentgenographic Course and Complications of Hyaline Membrane Disease Michael H. Weller, MD.*
The classical radiologic pattern of hyaline membrane disease is well known, and experience has shown considerable accuracy in the radiologic diagnosis of this condition. 4 1, 45 Occasional asymmetry of involvement and atypism of the roentgenographic pattern have been documented.!·39 In recent years, the typical radiologic course of hyaline membrane disease has been modified somewhat by the introduction of various forms of assisted ventilation. With the increasing incidence of iatrogenic complications, a dilemma occasionally exists between maintenance of adequate blood gas values and the production of even more lifethreatening complications of ventilatory manipulation. It is therefore vital for both the radiologist and the pediatrician to be aware of the radiologic variations occurring in hyaline membrane disease with assisted ventilation, and to understand the implications of extra-alveolar air collections. The purpose of this report is to review the radiologic appearance of both the typical and modified course of hyaline membrane disease, and to illustrate some of the patterns and complications observed on the standard portable chest examination.
COURSE OF THE DISEASE The clinical features of hyaline membrane disease have been extensively discussed elsewhere. 4 , 5. !3. 37 The disease is seen in the premature infant between 27 and 36 weeks gestation, and is more common in infants born by cesarean section. The incidence is also increased with maternal diabetes, prepartum and intrapartum asphyxia, and in the second of twins. Even though the onset of respiratory distress is usually within the first few hours of life, there may be a few hours delay before the typical roentgen picture becomes evident. Rarely, the onset of roentgenogra':'Assistant Clinical Professor of Radiology and Pediatrics; Head, Division of Pediatric Radiology, University of California, San Diego, School of Medicine, La Jolla, California
Pediatric Clinics of North America- Vol. 20, No.2, May 1973
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Figure 1. A, Premature infant with minimal respiratory distress shortly after birth. The chest film is normal at 7 hours. The prominent right superior mediastinal shadow is cast by the thymus, accentuated owing to mild obliquity of the chest. B, At3'12 days, respiratory distress had increased considerably, and the radiograph now shows classical hyaline membrane disease of moderate degree.
phic changes is delayed to 24 hours (Fig. 1). Generally, the more severe the disease, the sooner the typical pattern appears. 45 The classic radiologic picture of hyaline membrane disease is one of generalized reticulogranular density throughout both lungs, with airfilled major bronchi projected in bold relief through partially opaque
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lungs - the "air-bronchogram" effect (Fig. 2). Because of the small volumes involved in the premature chest, a word of caution should be said against over-reading air-bronchograms. Air-filled bronchi may be normally visible within the confines of the cardiac silhouette and should be considered definitely abnormal only when they extend beyond the cardiac silhouette and into partially opacified pulmonary parenchyma. The reticulogranular pattern is the most reliable finding. The histology of hyaline membrane disease provides excellent radiologic-pathologic correlationY" as There is variable atelectasis of terminal saccules or air sacs, with maintenance of aeration and frequent overdistention of alveolar ducts and terminal bronchioles. The roentgenographic summation of all these microfoci of atelectasis and bronchiolar overdistention leads to the "frosted-glass" reticulogranularity. In the first few hours of life, the radiograph may show opaque or almost opaque lungs. This picture may then be replaced by the typical pattern several hours after therapy is instituted. The diffuse opacity is due to either massive atelectasis or to retained lung fluid, since it is known that delayed clearance of normal lung fluid occurs with some frequency in hyaline membrane disease lfl • 2R. :!O.:l7 (Fig. 3). The pulmonary opacity may also be related to rather constant pulmonary edema resulting from transudation from distended lymphatic and blood capillaries, in turn due to altered capillary integrity from neonatal asphyxia. 19 • 28 The most severe cases may never show clearing of opaque lungs, and it is usually these infants in whom widespread pulmonary hemorrhage is found at postmortem examination.
Figure 2. Classical pattern of hyaline membrane disease in a 60 hour old premature infant. Reticulogranularity is prominent throughout both lungs and there are "air bronchograms" as well as air-filled bronchi seen on end, especially in the right upper lobe. Mild mesocardia is present.
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Figure 3. Premature infant with respiratory distress syndrome. A, At 6 hours, there are streaky densities radiating out from both hila as well as reticulogranular densities throughout both lungs. B, After 5 hours of CPAP, the lung fluid has cleared, leaving behind the typical pattern of hyaline membrane disease. Several small artifacts are present to the right of the spine.
Massive pulmonary hemorrhage is a common terminal event in hyaline membrane disease and may be heralded by sudden re-opacification of previously clearing lungs - the so-called "white-out" effect. Suctioning of blood from the trachea may often complete the correlation. Atypical patterns of hyaline membrane disease occur, and these may be
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related to persistent lymphatic distention, and resultant obscuring of residual aeration. Radiology provides no clues to the underlying cause of hyaline membrane disease. The pathologic hallmark of the disease, hyaline membranes, are oriented along the axes of terminal respiratory pathways and line alveoli. They average 50 microns in thickness, and are not of the
Figure 4. A, At 3 days, there is typical reticulogranularity distributed evenly in both the upper and lower lobes bilaterally. B, On day 5, the infant had improved and the upper lobes are now clear. Residual hyaline membrane disease changes are prominent in both lower lobes.
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physical dimensions to contribute appreciably to the roentgen image. Histologic examination may disclose absence of hyaline membranes in one lobe, but if diffuse atelectasis is present, the roentgen picture shows no corresponding lobar sparing. 39 While controversy still exists as to the specific roles of surfactant depletion,2' 4. 5. la. 2H. 37 pulmonary arteriolar vasoconstriction,2H.37 and asphyxia with amniotic fluid aspiration,5. 17 the radiograph reflects only the resultant multifocal atelectasis, bronchiolar overdistention, and occasional alveolar fluid. The pattern of resolution of mild or moderate hyaline membrane disease is one of 4 to 7 days in the uncomplicated case,l2· 14.:17 In experiments with premature animals, this interval corresponds to the time of surfactant reappearance. The upper lobes usually clear first, and within 24 to 48 hours from the inception of healing, the upper lobes become entirely normal. This is in keeping with experimental evidence that surfactant production resumes first in the upper lobes in animal models. I. 17 The lower lobes usually take longer to clear, and the reticulogranularity may be replaced by confluent, nonspecific densities which may remain as long as 2 weeksaH (Figs. 4 and 5). The nature of these slowly disappearing opacities is uncertain, but they are probably related to persistent atelectasis, which in turn may be due to compression of the lower lobes by the upper lobes which expand earlier.31l The avoidance of constant supine positioning of such babies might alleviate this sequence of events. We have observed a small number of babies who have been maintained on only very low amounts of continuous end-expiratory pressure (2 to 4 cm. of water), in whom there has been a definite lag in radiographic resolution compared with the clinical course. When clearing does occur, the transition is much more abrupt than usual, with all traces of disease disappearing in a few days. There is mounting evidence that the concept can no longer be accepted that hyaline membrane disease clears completely without residual pulmonary disease. Recent studies suggest that a significant number of such patients have an increased susceptibility to respiratory illness in the first years of life/ 5, 21, a3 and some have residual radiologic abnormalities of a nonspecific nature, including focal or diffuse hyperaeration and parenchymal fibrosis. This has been almost exclusively in those treated with positive pressure ventilation. 15 , 21. a3, 34, 38. 40 In patients who do not recover, the course may be marked by sudden and complete reopacification of the lungs. This pattern is due to either massive bilateral pulmonary hemorrhage 5 • 7. 19 (Fig. 6), or severe pulmonary edema of central nervous system origin when intracerebral or intraventricular bleeding causes a sudden increase in intracranial pressure'" 5, 7, 10,37 When reopacification is not sudden but definitely progressive, the postmortem examination has been nonspecific in our experience, and merely discloses massive atelectasis. Finally, the entire course may be complicated by sepsis, usually showing a more patchy or focal pattern corresponding to areas of pneumonia (Fig. 7). Aspiration may also produce similar roentgen changes. Knowledge of the clinical course is indispensable in the evaluation of the radiographs. Text continues on p. 390.
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Figure 5. Moderate respiratory distress is present at 24 hours, and the roentgen pattern is that of typical hyaline membrane disease. B, At 96 hours, the infant is significantly improved, and both upper lobes are clear. The lower lobes contain confluent densities bilaterally which probably represent atelectasis. The infant recovered and did not manifest signs of sepsis at any time.
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Figure 6. A, On day 2 at 8:00 A.M., the pattern of resolving hyaline membrane disease is seen. Note the residual changes in the lower lobes, while the upper lobes have cleared. B, Five hours later, the infant became apneic and died, with copious amounts of blood aspirated from the trachea. Note the sudden "white-out" change since the film at 8:00 A.M. Massive bilateral pulmonary hemorrhage was confirmed at postmortem examination.
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Figure 7. A, Typical roentgen appearance of hyaline membrane disease at 5 days. The appearance is replaced at 8 days (B) with patchy pneumonia in both lungs. This premature infant was grossly septic and eventually died with abscesses in both lungs. No pulmonary hemorrhage was found at postmortem examination.
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COMPLICATIONS The course of hyaline membrane disease has been altered somewhat with new therapeutic approaches. Since surfactant depletion appears to be a significant causative factor in the production of respiratory distress, various methods of assisted ventilation have been introduced to prevent complete alveolar collapse during expiration. Since alveoli then remain partially open at the end of expiration, there is no longer need for generation of high inspiratory pressures to re-open collapsed alveoli devoid of surface-tension-active phospholipids. Maintenance of the continuous positive airway pressure (CP AP), especially during expiration, improves the situation also by matching ventilation with perfusion and allowing reduction in the concentration of inspired oxygen. There is additional evidence that with CP AP, right-to-Ieft shunting (mainly intrapulmonary but also across the patent ductus and foramen ovale) is diminished, thereby decreasing cyanosis.1 5 Complications involving extra-alveolar air collections are most common with maintenance of positive-end-expiratory pressure (PEEP) plus mechanical ventilation that delivers significant peak pressures during inspiration. This therapeutic approach is employed only in infants who have poor or no spontaneous respirations. In our experience, radiologic and clinical complications occur in at least half of such cases. The incidence of pneumothorax and other extra-alveolar air collections diminishes appreciably in infants who show spontaneous respirations, and in whom continuous positive airway pressure (CPAP) alone can be employed to maintain a constant airway pressure throughout the respiratory cycle and prevent end-expiratory alveolar collapse. 15 The same is true for maintenance of positive end-expiratory pressure through creation of constant negative extrathoracic pressure (CNP)7 It is most important for the radiologist and pediatrician to realize that the roentgen image of hyaline membrane disease, modified by the various forms of positive airway pressure, is an artificially optimistic one. It is vital to bear in mind that one is seeing a more favorable degree of expansion than would exist without positive airway pressure. This realization will help avoid great discomfiture at the temporary radiologic appearance of the chest should an endotracheal tube become dislodged (Fig. 8). Pneumonia and pulmonary hemorrhage are complications of hyaline membrane disease which have already been mentioned. With positive airway pressure therapy, delayed closure of the ductus arteriosus is being seen as an increasingly common complicating occurrence during the healing phase of hyaline membrane disease l5 . 16 (Fig. 9). Occasionally, the patent ductus requires surgical closure. Because of the marked pulmonary vasoconstriction invariably present, right-to-Ieft shunting through underperfused lung, as well as through the ductus and foramen ovale, is common during the active stages of hyaline membrane disease. 5. 28. 37. 43 As the systemic hypotension resolves and pulmonary arteriolar vasoconstriction lessens, the flow through the ductus reverses and becomes leftto-right. If left-to-right shunting is prolonged and becomes massive enough, congestive heart failure ensues. The radiologic picture is one of increasing cardiac diameter as well as increasing tortuosity of pulmonary
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Figure 8. A, The endotracheal tube became dislodged in this premature infant with hyaline membrane disease, just prior to the taking of this radiograph. B. Note the apparent dramatic improvement only 20 minutes later after reintubation and administration of CP AP (2 cm. H 2 0). Interstitial emphysema is present in the right upper lobe.
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Figure 9. A, At day 2, moderate hyaline membrane disease changes are present radiologically. B, By day 9, a characteristic patent ductus murmur became obvious, and the pulses took on a bounding character. Note the interval cardiomegaly and nodular shadows of enlarged and tortuous vessels seen on end (arrows). Some pulmonary edema is present and the vessels are hazy. The infant improved on digitalis, and a week later the murmur was gone and chest films returned to normal.
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vessels now carrying an excess blood flow. Many more areas of the nowtortuous vessels are seen on end, almost resembling at times granulomatous nodules in the peri-hilar areas. Once congestive heart failure ensues, the margins of individual vessels become indistinct and peri-hilar pulmonary edema may obscure central vessels completely. With digitalization and diuretics, the vessels once again become distinct, though still enlarged and tortuous. Concomitant cardiomegaly may not necessarily occur.H Abnormal Air Collections With the classic experiments of the Macklins,2:J. 24 the pathogenesis of pneumomediastinum with and without pneumothorax became clear. Air which escapes from ruptured alveoli dissects along the perivascular spaces, probably milked along toward the hila with changes in bronchiolar length during respiration. The air finally gains entry to the mediastinum. As the use of all variations of positive airway pressure have increased, so have abnormal air collections in both the chest and extrathoracic locations. The abnormal air collections have been most common with respirator-driven inspiratory pressures plus maintenance of end-expiratory pressure (PEEP) occurring in at least half of such cases. The extra-alveolar air collections have been much less common with CP AP alone, but still occur with some regularity. Interstitial Pulmonary Emphysema If radiographs could be taken often enough, and at critical times, almost every pneumothorax occurring during the course of hyaline membrane disease would be preceded by interstitial pulmonary emphysema. This phenomenon represents air which has dissected along perivascular spaces within the pulmonary interstitium, but which has not yet escaped into the pleural space or mediastinum. Interstitial pulmonary emphysema has been produced experimentally/3.24 and the microscopic examination of such lungs confirms the interstitial location. 6 • 11 Radiologically, interstitial pulmonary emphysema is characterized by short, nonbranching linear or ovoid lucencies which are quite black on the radiograph (Figs. 10 to 12). The distribution of air does not conform to the anatomic arborization of the bronchial tree. One of the most useful criteria has been the marked lucency of these minute air collections. They are characteristically blacker than the normal air bronchogram seen behind the heart and beyond the confines of the cardiac silhouette in the midst of atelectatic lung. Interstitial pulmonary emphysema can be seen in hyaline membrane disease without positive airway pressure therapy, but is far more common when this mode of ventilatory manipulation is employed. The extent of interstitial pulmonary emphysema is apparently quite sensitive to small variations in positive end-expiratory pressure applied, and such changes in pressure can often be guessed at, upon inspection of interval radiographs (Fig. 10). The importance of interstitial pulmonary emphysema is twofold. First, there is probably a splinting effect on the lung, further compromising pulmonary compliance. Perhaps more important, however, is the rec-
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Figure 10. A, This premature infant with hyaline membrane disease had suffered a bilateral pneumothorax on day 3 and bilateral chest tubes were placed. Note the characteristic short, nonbranching linear and ovoid lucencies on the right, characteristic of pulmonary interstitial emphysema. PEEP (8 em. H, O) is being administered via endotracheal tube. B, After pulmonary interstitial emphysema had been noted, the PEEP was decreased to 3 em. of H, O and there is now less pulmonary interstitial emphysema. C, The chest tubes were removed but the infant continued to do poorly and increased interstitial emphysema is seen on the right. 9 em. of H, O of PEEP were required to maintain the p02 • Residual hyaline membrane disease changes remain on the left.
ognition of this entity as the precursor of more catastrophic complications including pneumothorax and/or pneumomediastinum. This is particularly true when the interstitial emphysema is unilateral, allowing prediction of the location of the impending pneumothorax. Unilateral interstitial emphysema may reappear in the re-expanding lung, as a pneumothorax is treated (Fig. 11). Pseudocyst Occasionally, air which escapes after alveolar rupture may remain localized within the pulmonary parenchyma. This lesion has been called a "pseudocyst" of hyaline membrane disease. 6 The radiographic picture is one of a round or oval lucency entirely within pulmonary parenchyma, with a well demarcated wall composed of compressed alveoli around the expanding cyst (Fig. 12). It is likely that some degree of air-trapping exists to permit the enlargement of the pseudocyst. Compared to pneumothorax, this complication is not commonly seen, although 5 of 84 cases in Campbell's series developed this complication.6 The lesion should not be misinterpreted as a pneumatocele secondary to staphyloccal pneumonia. Spontaneous resolution usually occurs, but occasionally the pseudocyst may-enlarge to the point of rupturing into either the pleural space or
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the mediastinum and producing a pneumothorax or pneumomediastinum , respectively (Fig. 13).
Pneumothorax and Pneumomediastinum The occurrence of pneumothorax and pneumomediastinum is fairly common in hyaline membrane disease, with an increased incidence in infants maintained on assisted ventilation.111 • 2 " Pneumothoraces which occur in hyaline membrane disease usually manifest some signs of tension, and require removal of air from the pleural space, either by needle aspiration or tube drainage. The cardinal roentgen signs include collapse of the lung to a highly variable degree, an expanded pleural space with shift of the heart and mediastinum to the contra-lateral side, flaring of the intercostal spaces with bulging of the parietal pleura, and depression or inversion of the ipsolateral hemidiaphragm (Fig. liB). The lung affected with hyaline membrane disease is a stiff, noncompliant lung which may be even further splinted owing to the presence of interstitial pulmonary emphysema. The lung may therefore appear to "float" in the air in the pleural space. Care must be taken not to
Figure 11. A, A chest tube has been placed on the right owing to previous pneumothorax with some residual air remaining medial to the right lung. Marked interstitial emphysema is seen on the left and left pneumothorax was predicted on the basis of this radiograph. B, Five hours later, a tension pneumothorax has occurred. Note the characteristic expansion of the left hemithorax with mediastinal and cardiac shift to the left, bulging of the inters paces on the left, and inversion of the left hemidiaphragm. There is also a pneumomediastinum present. Air is present either under the right lun g or under the right diaphragmatic pleura from the pneumomediastinum (see Fig. 17). C. Following removal of air from the left pleural space, there is still residual interstitial emphysema 5 hours later.
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Figure 12. A, At 8 hours, there is homogenous opacification of both lungs owing to markedly delayed clearance of lung fluid. Often, delayed clearance of this degree will eventually reveal hyaline membrane disease in underlying lungs. B, At 28 hours, the lung fluid has cleared and the typical picture of hyaline membrane disease is present. There is a large "pseudocyst" with well demarcated walls in the right lung (arrow).
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Figure 13. A large "pseudocyst" (open arrows) is present in the right lung, and has ruptured into the mediastinum. There is air outlining the right pulmonary artery (solid arrows), and air in the neck. Changes of hyaline membrane disease are seen in both lungs. A nasogastric tube is present in the esophagus.
Figure 14. Congenital lobar emphysema of the right upper lobe. The open arrows indicate herniation of the overexpanded right upper lobe across midline. The right'middle lobe and right lower lobe are compressed inferiorly with characteristic triangular densities (solid arrow). There is marked cardiac and mediastinal shift to the left. Note that a few bronchovascular markings are seen in the emphysematous lobe, in contrast to the absence of these markings in a tension pneumothorax (see Figure lIB).
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Figure 15. This premature infant with hyaline membrane disease had already developed a left pneumothorax on PEEP for which a tube was placed in the left pleural space. There is now a small right pneumothorax present (small arrows), as well as a pneumomediastinum with elevation of the right lobe of the thymus producing the "spinnaker sign" (large solid arrow). There is also air in the neck (open arrow). There may be a sub-pleural bleb on the right also (see Fig. 17).
confuse the picture with that of congenital lobar emphysema, where broncho-vascular markings can be seen out to the periphery of the hyperaerated lobe, and compression atelectasis of the lower lobe is manifest by a triangle of density adjacent to or behind the heart (Fig. 14). Occasionally, air may accumulate medial to the lung and peel away the lung laterally, mimicking pneumomediastinum. This may be impossible to differentiate from mediastinal air unless decubitus films are obtained. Pneumomediastinum in the neonate can usually be detected by the presence of air anterior to the heart on the lateral film, as well as by elevation of the thymus off the cardiac silhouette both in the anteroposterior and lateral projections. Oblique films may occasionally be needed. This thymic elevation has been referred to as the "spinnaker sign"27 (Figs. 15 and 17). The mediastinal air may occasionally be seen pushing the mediastinal pleurae laterally on both sides of the heart. It has been said that mediastinal air rarely escapes from the chest in the newborn. However, we have seen dissection of air into the soft tissues of the neck not uncommonly and in direct proportion to the severity of the pneumomediastinum (Figs. 15, 16, 17). On the anteroposterior radiograph, one may occasionally see air in a subpulmonic location (Fig. 17). The location of this air is not completely certain. Apparently, it may dissect under the parietal pleura, and be situated between the parietal pleura and muscle of the hemidiaphragm. This finding was present in 6 of 25 cases reported by O'Gorman et al.,32 although neither their cases nor
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Figure 16. A, At 24 hours this premature infant with hyaline membrane disease has developed pulmonary interstitial emphysema on the left and a pneumomediastinum manifest by lucency superimposed on the cardiac silhouette. Note the air in the soft tissues of the neck (open arrow). B, Shortly before death, at 48 hours, there is a pneumopericardium present. Note the diminution in cardiac size and the fine shadow of the pericardium. The endotracheal tube is well down into the right lower lobe bronchus, but at autopsy, the chest was opened under water and no escape of air from the pericardium occurred. There was no tear in the tracheobronchial tree.
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Figure 17. The anteroposterior (A) and lateral (B) chest films show hyaline membrane disease with a right pneumothorax and a pneumomediastinum, with air in the soft tissues of the neck (open arrows). The pneumomediastinum has produced the "spinnaker sign" in the lateral view (curved arrow). There is a large pneumoperitoneum present also, with clear delineation of the anterosuperior surface of the liver (straight arrows). A large subpulmonic or subpleural air collection is seen on the right. Pulmonary interstitial emphysema is also present in the right lung medially. A chest tube was placed on the right, between the taking of the anteroposterior and the lateral films.
those of Lilliard and Allen22 were autopsy-proven. This finding has been disputed by McSweeney,25 who feels that the air is subpulmonic, within the pleural space, and that films in the decubitus projection will reveal a shift of this air out from under the lung. It may be that both possibilities can occur. Pneumopericardium Pneumopericardium is an extremely rare complication of hyaline membrane disease. We have seen this complication only once in an infant on assisted ventilation. There is no anatomic continuity between the mediastinum and pericardial space and it has been speculated that air may be in the precardial mediastinal space.32 Nevertheless, when the abnormal gas is seen completely encircling the heart and causing some diminution in size of the heart as in Figure 16, it is hard to deny the fact that pneumopericardium does occasionally occur. Campbe1l6 reports 3 of 84 cases of hyaline membrane disease with this complication. Pneumoperitoneum This complication of hyaline membrane disease is also uncommon (Fig. 17). Presumably, air gains entry to the peritoneal cavity through dissection into the mediastinum and from there to the retroperitoneal space. Theoretically, defects in the posterior parietal peritoneum must also be present for air to escape into the peritoneal cavity. It is also possible for air toent~ the peritoneal cavity through the venal caval or aortic hiatus
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of the diaphragm, or through persistent anterior or posterior diaphragmatic closure defects.:l When pneumoperitoneum is present, exclusion of a perforated viscus is impossible radiologically. If the pneumoperitoneum does not resolve coincident with resolution of the invariably-present pneumomediastinum or pneumothorax, surgical exploration becomes necessary. Pneumatosis cystoides intestinalis has been reported due to dissection of air from the mediastinum to the retroperitoneal space and then along the perivascular spaces in the root of the mesentery to the subserosa of the gut.20 Presumably, rupture of subserosal air bubbles might then provide yet another alternative route for the production of pneumoperitoneum from pneumomediastinum. Oxygen Toxicity The radiologic diagnosis of oxygen damage to the lung is far from specific. As outlined by Northway,'lI the factors involved in the production of oxygen toxicity include individual susceptibility, the concentration of inspired oxygen, and the duration of exposure. In Northway's cases, greater than 150 continuous hours of 80 to 100 per cent oxygen concentration were required to produce chronic changes in the lung. The changes noted include cystic and bullous changes interspersed with linear and confluent atelectasis and/or fibrosis (Fig. 18). Chronic interstitial pneumonia and fibrosis are noted microscopically. It is not clear what relationship mechanical ventilation utilizing lower concentrations of ox-
Figure 18. This premature infant had required high concentrations of inspired oxygen as well as high end-expiratory pressures since birth, and died shortly after this radiograph. Note the coarse areas of fibrosis interspersed with areas of alveolar breakdown .and coalescence. Pulmonary interstitial emphysema is present in the right lung. Histologic sections disclosed marked interstitial fibrosis, suggestive of oxygen toxicity. No gross inflammatory disease was noted. The individual roles of oxygen and respirator therapy cannot be separated.
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Figure 19. A, This markedly immature baby (800 gm.) had respiratory distress from birth and a picture suggestive of hyaline membrane disease. This cleared quickly and neither high oxygen concentrations nor respirator therapy was needed. B, At 72 days, there is marked hyperaeration and coarse densities throughout both lungs. Healing rib fractures are present on the right from previous resuscitative efforts earlier in life. The picture fits that of WilsonMikity syndrome, but a lung biopsy was not done.
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ygen has to pulmonary disease, and whether or not similar changes are produced. It is usually impossible to separate out the two factors clinically. In addition, the relationship between bronchopulmonary dysplasia (oxygen toxicity) and pulmonary dysmaturity (Wilson-Mikity syndrome) is not certain, especially since an appreciable percentage of patients with pulmonary dysmaturity have a history of early respiratory distress and hyaline membrane disease 18 • 26 • 44 (Fig. 19). McSweeney 25 has suggested that these entities may form a common complex of changes and terms both "chronic pulmonary disease of prematurity."
UNUSUAL SEQUELAE OF HYALINE MEMBRANE DISEASE OF UNCERTAIN RELATIONSHIP Right-Sided Bochdalek Diaphragmatic Hernia We have had occasion to watch the development of a right-sided Bochdalek hernia in a child with hyaline membrane disease and a pre-
Figure 20. A , Hyaline membrane disease at 2 days. Note the normal position of the liver and the right hemidiaphragm. Respiratory distress cleared in approximately 4 to 5 days. B and C, At 15 days, respiratory distress recurred and the radiograph displayed herniation of the bowel loops up into the right chest with compression atelectasis of the left lung. At surgery there was herniation of the liver, small bowel, and colon through the foramen of Bochdalek. The hernia was successfully reduced.
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viously normal position of the abdominal viscera and right hemidiaphragm (Fig. 20). The hernia did not become manifest until the seventeenth day of life, although intermediate radiographs disclosed opacification of both lungs of uncertain cause. The hernia was confirmed surgically and repaired with no subsequent problems. Faure et al." reported 3 cases of delayed right-sided diaphragmatic hernias and have reviewed the literature. One of their 3 cases presented initially with respiratory distress. McSweeney has commented also on the delayed appearance of right-sided Bochdalek hernias. 25 The relationship of antecedent hyaline membrane disease and continuous positive airway pressure therapy in our patient is not clear. Congenital Lobar Emphysema We have seen an infant with hyaline membrane disease who continued to have respiratory distress after clinical and radiologic manifestations of hyaline membrane disease had cleared. At approximately 5 weeks, congenital lobar emphysema involving the right middle lobe became obvious radiographically (Fig. 21). Although congenital lobar emphysema and congestive heart disease have some association,42 we are unable to locate any reports linking congenital lobar emphysema and hyaline membrane disease.
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Figure 21. A, At 3 days only mild hyaline membrane disease changes are present. Despite clearing of the chest rum, mild respir· atory distress persisted. B and C, At 65 days massive lobar emphysema of the right middl~ lobe is evident. The large solid arrow indicates probable coaptation of the right and left mediastinal pleurae anterior to the heart. The right upper lobe (small solid arrow) and right lower lobe (open arrow) are both compressed by the grossly emphysematous right middle lobe. At surgery, right middle lobe emphysema was confirmed, and a right middle lobectomy was performed.
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SUMMARY The typical radiologic course of hyaline membrane disease has been reviewed and the natural history of this disease has been stressed. The changing pattern of evolution of hyaline membrane disease since the advent of assisted ventilation and positive airway pressure has been reviewed. The complications of the disease, both spontaneous and iatrogenic, have been commented upon, with emphasis on extra-alveolar air collections seen more commonly in patients with all forms of ventilatory manipulation. The increasing frequency of delayed closure of the ductus arteriosus with positive airway pressure therapy is being seen in a significant number of centers. The subsequent development of a rightsided Bochdalek hernia and congenital lobar emphysema in 2 unusual patients has been described. It is imperative that the radiologist, the neonatologist, and the general pediatrician be aware of the roentgen picture and evolution of hyaline membrane disease, in which the radiologic and clinical courses are so often closely parallel.
REFERENCES 1. Ablow, R. C., and Orzalesi, M. M.: Localized roentgenographic pattern of hyaline membrane disease. Evidence that the upper lobes of human lung mature earlier than the lower lobes. Amer. J. Roentgen., 112:23-27, 1971. 2. Adams, F. J., Fujiwara, T., Emmanouilides, G., et al.: Surface properties and lipids from lungs of infants with hyaline membrane disease. J. Pediat., 66:357-364, 1965. 3. Aranda, J. V., Stern, L., and Dunbar, J. S.: Pneumothorax with penumoperitoneum in a newborn infant. Amer. J. Dis. Child., 123:163-166,1972. 4. Auld, P., Hodson, A., and Usher, R.: Hyaline membrane disease: A discussion. J. Pediat., 80:129-140,1972. 5. Avery, M. E.: Hyaline membrane disease. In The Lung and Its Disorders in the Newborn Infant. Philadelphia, W. B. Saunders, 2nd ed., 1968. 6. Campbell, R. E.: Intrapulmonary interstitial emphysema: A complication of hyaline membrane disease. Amer. J. Roentgen., 110:449-456, 1970. 7. Chernick, V., and Vidyasagar, D.: Continuous negative chest wall pressure in hyaline membrane disease: One year experience. Pediatrics, 49:753-760,1972. 8. Dunbar, J. S.: Plain film diagnosis of congenital heart disease in the newborn. In Mosely, R. D., ed.: Current Problems in Radiology, Vol. 1, No.6, Nov.-Dec. 1971. Chicago, Illinois, Medical Year Book Publishers, Inc. 9. Faure, C. Sauvegrain, J., and Bomsel, F.: Hernie congenitale du diaphragme droit avec coupole diaphragmatique en place normale ala naissance. Ann. de Radiol., 14:305-313, 1971. 10. Felman, A. H.: Neurogenic pulmonary edema. Observations in six patients. Amer. J. Roentgen., 112:393-396, 1971. 11. Fletcher, B. D., Outerbridge, E. W., and Dunbar, J. S.: Pulmonary interstitial emphysema in the newborn. J. Canad. Assoc. Radiol., 21 :273-279, 1970. 12. Gluck, L.: Biochemical development of the lung: Clinical aspects of surfactant development, RDS, and the intrauterine assessment of lung maturity. Clin. Obstet. Gynec., 14:710-721,1971. 13. Gluck, L.: Pulmonary surfactant and neonatal respiratory distress. Hosp. Pract., 45-56, November 1971. 14. Gluck, L.: Surfactant: 1972 PEDIAT. CLIN. N. AMER., 19:325-331, 1972. 15. Gregory, G. A., Kitterman, J. A., Phibbs, R. H., et al.: Treatment of the idiopathic respiratory distress syndrome with continuous positive airway pressure. New Eng. J. Med., 284:1333-1340, 1971. 16. Gregory, G. A.: Ventilating the infant with RDS. Presented to the American Academy of Pediatrics, San Diego, California, Spring Session April 26, 1972. 17. Howatt, W. F., Avery, M. E., Humphreys, P. W., et al.: Factors affecting pulmonary surface properties in the foetal lamb. Clin. Sci., 29:239-248, 1965.
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18. Krauss, A. N., Levin, A. R., Grossman, H., et al.: Physiologic studies on infants with Wilson-Mikity Syndrome. J. Pediat., 77:27-36, 1970. 19. Lauweryns, J. M.: Hyaline membrane disease in newborn infants. Macroscopic, radiographic and light and electron microscopic studies. Human Pathol., 1 : 1 75-204, 1970. 20. Lee, S. B., and Kuhn, J. P.: Pneumatosis intestinalis following pneumomediastinum in a newborn infant. J. Pediat., 79:813-815, 1971. 21. Lewis, S.: A follow-up study of the respiratory distress syndrome. Proc. Roy. Soc. Med., 61 :771-773, 1968. 22. Liillard, R L., and Allen, R P.: The extrapleural air sign in pneumomediastinum. Radiology, 85:1093-1098,1965. 23. Macklin, C. C.: Transport of air along sheaths of pulmonic blood vessels from alveoli to mediastinum. Arch. Int. Med., 64:913, 1939. 24. Macklin, M. T., and Macklin, C. C.: Malignant interstitial emphysema of the lung and mediastinum as an important occult complication in many respiratory diseases and other conditions. Medicine, 23:281, 1944. 25. McSweeney, W. J.: Radiologic evaluation of the newborn with respiratory distress. Seminars Roentgen., 7:65-83, 1972. 26. Mikity, V. G., Hodgman, J. E., and Tatter, D.: The radiological findings in delayed pulmonary maturation in premature infants. Prof. Ped. Radiol., 1: 149-159, 1967. 27. Moseley, J. E.: Loculated pneumomediastinum in the newborn. A thymic "spinnaker sail" sign. Radiology, 75:788-790,1960. 28. Nelson, N. M.: On the etiology of hyaline membrane disease. PEDIAT. CLIN. N. AMER., 17:943-965, 1970. 29. Newman, H., and Thoeny, R. H.: Pneumoperitoneum in the newborn. Brit. J. Radiol., 40:780-782,1967. 30. Normand, I. C. S., Reynolds, E. O. R, Strang, L. B., et al.: Flow and protein concentration of lymph from lungs of lambs developing hyaline membrane disease. Arch. Dis. Child., 43:334-339, 1968. 31. Northway, W. H., and Rosan, R. C.: Radiographic features of pulmonary oxygen toxicity in the newborn: Bronchopulmonary dysplasia. Radiology, 91 :49-58, 1968. 32. O'Gorman, L. D., Cottingham, R A., Sargen, E. N., et al.: Mediastinal emphysema in the newborn: A review and description of the new extrapleural gas sign. Dis. Chest, 53 :30 1308,1968. 33. Outerbridge, E. W., Nogrady, M. B., Beaudry, P. H., et al.: Idiopathic respiratory distress syndrome. Recurrent respiratory illness in survivors. Amer. J. Dis. Child., 123:99-104, 1972. 34. Pusey, V. A., Macpherson, R. I., and Chernick, V.: Pulmonary fibroplasia following prolonged artificial ventilation of newborn infants. Canad. Med. Assoc. J., 100:451-457, 1969. 35. Recavarren, S., Benton, C., and Gall, E. A.: The pathology of acute alveolar diseases of the lung. Seminars Roentgen., 2:22-32, 1967. 36. Reilly, B. J.: Patterns of pulmonary involvement in the idiopathic respiratory distress syndrome. Presented to the Society for Pediatric Radiology, Boston, Massachusetts, September 27, 1971. 37. Reynolds, E. O. R: Hyaline membrane disease. Amer. J. Obstet. Gynec., 106:780-797, 1970. 38. Rudhe, J., and Broberger, U.: Roentgenological observations in survivors of clinical hyaline membrane disease of the newborn. Ann. Radiol., 10:284-294, 1967. 39. Rudhe, U., Margolin, F. R, and Robertson, B.: Atypical roentgen appearances of the lung in hyaline membrane disease of the newborn. Acta Radiol. (Diag.), 10:57-68, 1970. 40. Shepard, F. M., Johnston, R B., Klatte, E. C., et al.: Residual pulmonary findings in clinical hyaline membrane disease. New Eng. J. Med., 279:1063-1071,1968. 41. Singleton, E. B.: Respiratory distress syndrome. Pro gr. Ped. Radiol., 1 :135,1967. 42. Stanger, P., Lucas, R. V., and Edwards, J. E.: Anatomic factors causing respiratory distress in acyanotic congenital cardiac disease. Special reference to bronchial obstruction. Pediatrics, 43:760-769, 1969. 43. Strang, L. B., and MacLeish, M. H.: Ventilatory failure and right-to-left shunt in newborn infants with respiratory distress. Pediatrics, 28:17-27,1961. 44. Wilson, M. G., and Mikity, V. G.: A new form of respiratory disease in premature infants. Amer. J. Dis. Child., 99:489-499,1960. 45. Wolfson, S. L., Frech, R, Hewitt, C., et al.: Radiographic diagnosis of hyaline membrane disease. Radiology, 93:339-343,1969.
Department of Radiology University Hospital 225 West Dickinson Street San Diego, California 92103
The Roentgenographic Course and Complications of Hyaline Membrane Disease Michael H. Weller, MD.*
The classical radiologic pattern of hyaline membrane disease is well known, and experience has shown considerable accuracy in the radiologic diagnosis of this condition. 4 1, 45 Occasional asymmetry of involvement and atypism of the roentgenographic pattern have been documented.!·39 In recent years, the typical radiologic course of hyaline membrane disease has been modified somewhat by the introduction of various forms of assisted ventilation. With the increasing incidence of iatrogenic complications, a dilemma occasionally exists between maintenance of adequate blood gas values and the production of even more lifethreatening complications of ventilatory manipulation. It is therefore vital for both the radiologist and the pediatrician to be aware of the radiologic variations occurring in hyaline membrane disease with assisted ventilation, and to understand the implications of extra-alveolar air collections. The purpose of this report is to review the radiologic appearance of both the typical and modified course of hyaline membrane disease, and to illustrate some of the patterns and complications observed on the standard portable chest examination.
COURSE OF THE DISEASE The clinical features of hyaline membrane disease have been extensively discussed elsewhere. 4 , 5. !3. 37 The disease is seen in the premature infant between 27 and 36 weeks gestation, and is more common in infants born by cesarean section. The incidence is also increased with maternal diabetes, prepartum and intrapartum asphyxia, and in the second of twins. Even though the onset of respiratory distress is usually within the first few hours of life, there may be a few hours delay before the typical roentgen picture becomes evident. Rarely, the onset of roentgenogra':'Assistant Clinical Professor of Radiology and Pediatrics; Head, Division of Pediatric Radiology, University of California, San Diego, School of Medicine, La Jolla, California
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Figure 1. A, Premature infant with minimal respiratory distress shortly after birth. The chest film is normal at 7 hours. The prominent right superior mediastinal shadow is cast by the thymus, accentuated owing to mild obliquity of the chest. B, At3'12 days, respiratory distress had increased considerably, and the radiograph now shows classical hyaline membrane disease of moderate degree.
phic changes is delayed to 24 hours (Fig. 1). Generally, the more severe the disease, the sooner the typical pattern appears. 45 The classic radiologic picture of hyaline membrane disease is one of generalized reticulogranular density throughout both lungs, with airfilled major bronchi projected in bold relief through partially opaque
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lungs - the "air-bronchogram" effect (Fig. 2). Because of the small volumes involved in the premature chest, a word of caution should be said against over-reading air-bronchograms. Air-filled bronchi may be normally visible within the confines of the cardiac silhouette and should be considered definitely abnormal only when they extend beyond the cardiac silhouette and into partially opacified pulmonary parenchyma. The reticulogranular pattern is the most reliable finding. The histology of hyaline membrane disease provides excellent radiologic-pathologic correlationY" as There is variable atelectasis of terminal saccules or air sacs, with maintenance of aeration and frequent overdistention of alveolar ducts and terminal bronchioles. The roentgenographic summation of all these microfoci of atelectasis and bronchiolar overdistention leads to the "frosted-glass" reticulogranularity. In the first few hours of life, the radiograph may show opaque or almost opaque lungs. This picture may then be replaced by the typical pattern several hours after therapy is instituted. The diffuse opacity is due to either massive atelectasis or to retained lung fluid, since it is known that delayed clearance of normal lung fluid occurs with some frequency in hyaline membrane disease lfl • 2R. :!O.:l7 (Fig. 3). The pulmonary opacity may also be related to rather constant pulmonary edema resulting from transudation from distended lymphatic and blood capillaries, in turn due to altered capillary integrity from neonatal asphyxia. 19 • 28 The most severe cases may never show clearing of opaque lungs, and it is usually these infants in whom widespread pulmonary hemorrhage is found at postmortem examination.
Figure 2. Classical pattern of hyaline membrane disease in a 60 hour old premature infant. Reticulogranularity is prominent throughout both lungs and there are "air bronchograms" as well as air-filled bronchi seen on end, especially in the right upper lobe. Mild mesocardia is present.
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Figure 3. Premature infant with respiratory distress syndrome. A, At 6 hours, there are streaky densities radiating out from both hila as well as reticulogranular densities throughout both lungs. B, After 5 hours of CPAP, the lung fluid has cleared, leaving behind the typical pattern of hyaline membrane disease. Several small artifacts are present to the right of the spine.
Massive pulmonary hemorrhage is a common terminal event in hyaline membrane disease and may be heralded by sudden re-opacification of previously clearing lungs - the so-called "white-out" effect. Suctioning of blood from the trachea may often complete the correlation. Atypical patterns of hyaline membrane disease occur, and these may be
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related to persistent lymphatic distention, and resultant obscuring of residual aeration. Radiology provides no clues to the underlying cause of hyaline membrane disease. The pathologic hallmark of the disease, hyaline membranes, are oriented along the axes of terminal respiratory pathways and line alveoli. They average 50 microns in thickness, and are not of the
Figure 4. A, At 3 days, there is typical reticulogranularity distributed evenly in both the upper and lower lobes bilaterally. B, On day 5, the infant had improved and the upper lobes are now clear. Residual hyaline membrane disease changes are prominent in both lower lobes.
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physical dimensions to contribute appreciably to the roentgen image. Histologic examination may disclose absence of hyaline membranes in one lobe, but if diffuse atelectasis is present, the roentgen picture shows no corresponding lobar sparing. 39 While controversy still exists as to the specific roles of surfactant depletion,2' 4. 5. la. 2H. 37 pulmonary arteriolar vasoconstriction,2H.37 and asphyxia with amniotic fluid aspiration,5. 17 the radiograph reflects only the resultant multifocal atelectasis, bronchiolar overdistention, and occasional alveolar fluid. The pattern of resolution of mild or moderate hyaline membrane disease is one of 4 to 7 days in the uncomplicated case,l2· 14.:17 In experiments with premature animals, this interval corresponds to the time of surfactant reappearance. The upper lobes usually clear first, and within 24 to 48 hours from the inception of healing, the upper lobes become entirely normal. This is in keeping with experimental evidence that surfactant production resumes first in the upper lobes in animal models. I. 17 The lower lobes usually take longer to clear, and the reticulogranularity may be replaced by confluent, nonspecific densities which may remain as long as 2 weeksaH (Figs. 4 and 5). The nature of these slowly disappearing opacities is uncertain, but they are probably related to persistent atelectasis, which in turn may be due to compression of the lower lobes by the upper lobes which expand earlier.31l The avoidance of constant supine positioning of such babies might alleviate this sequence of events. We have observed a small number of babies who have been maintained on only very low amounts of continuous end-expiratory pressure (2 to 4 cm. of water), in whom there has been a definite lag in radiographic resolution compared with the clinical course. When clearing does occur, the transition is much more abrupt than usual, with all traces of disease disappearing in a few days. There is mounting evidence that the concept can no longer be accepted that hyaline membrane disease clears completely without residual pulmonary disease. Recent studies suggest that a significant number of such patients have an increased susceptibility to respiratory illness in the first years of life/ 5, 21, a3 and some have residual radiologic abnormalities of a nonspecific nature, including focal or diffuse hyperaeration and parenchymal fibrosis. This has been almost exclusively in those treated with positive pressure ventilation. 15 , 21. a3, 34, 38. 40 In patients who do not recover, the course may be marked by sudden and complete reopacification of the lungs. This pattern is due to either massive bilateral pulmonary hemorrhage 5 • 7. 19 (Fig. 6), or severe pulmonary edema of central nervous system origin when intracerebral or intraventricular bleeding causes a sudden increase in intracranial pressure'" 5, 7, 10,37 When reopacification is not sudden but definitely progressive, the postmortem examination has been nonspecific in our experience, and merely discloses massive atelectasis. Finally, the entire course may be complicated by sepsis, usually showing a more patchy or focal pattern corresponding to areas of pneumonia (Fig. 7). Aspiration may also produce similar roentgen changes. Knowledge of the clinical course is indispensable in the evaluation of the radiographs. Text continues on p. 390.
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Figure 5. Moderate respiratory distress is present at 24 hours, and the roentgen pattern is that of typical hyaline membrane disease. B, At 96 hours, the infant is significantly improved, and both upper lobes are clear. The lower lobes contain confluent densities bilaterally which probably represent atelectasis. The infant recovered and did not manifest signs of sepsis at any time.
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Figure 6. A, On day 2 at 8:00 A.M., the pattern of resolving hyaline membrane disease is seen. Note the residual changes in the lower lobes, while the upper lobes have cleared. B, Five hours later, the infant became apneic and died, with copious amounts of blood aspirated from the trachea. Note the sudden "white-out" change since the film at 8:00 A.M. Massive bilateral pulmonary hemorrhage was confirmed at postmortem examination.
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Figure 7. A, Typical roentgen appearance of hyaline membrane disease at 5 days. The appearance is replaced at 8 days (B) with patchy pneumonia in both lungs. This premature infant was grossly septic and eventually died with abscesses in both lungs. No pulmonary hemorrhage was found at postmortem examination.
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COMPLICATIONS The course of hyaline membrane disease has been altered somewhat with new therapeutic approaches. Since surfactant depletion appears to be a significant causative factor in the production of respiratory distress, various methods of assisted ventilation have been introduced to prevent complete alveolar collapse during expiration. Since alveoli then remain partially open at the end of expiration, there is no longer need for generation of high inspiratory pressures to re-open collapsed alveoli devoid of surface-tension-active phospholipids. Maintenance of the continuous positive airway pressure (CP AP), especially during expiration, improves the situation also by matching ventilation with perfusion and allowing reduction in the concentration of inspired oxygen. There is additional evidence that with CP AP, right-to-Ieft shunting (mainly intrapulmonary but also across the patent ductus and foramen ovale) is diminished, thereby decreasing cyanosis.1 5 Complications involving extra-alveolar air collections are most common with maintenance of positive-end-expiratory pressure (PEEP) plus mechanical ventilation that delivers significant peak pressures during inspiration. This therapeutic approach is employed only in infants who have poor or no spontaneous respirations. In our experience, radiologic and clinical complications occur in at least half of such cases. The incidence of pneumothorax and other extra-alveolar air collections diminishes appreciably in infants who show spontaneous respirations, and in whom continuous positive airway pressure (CPAP) alone can be employed to maintain a constant airway pressure throughout the respiratory cycle and prevent end-expiratory alveolar collapse. 15 The same is true for maintenance of positive end-expiratory pressure through creation of constant negative extrathoracic pressure (CNP)7 It is most important for the radiologist and pediatrician to realize that the roentgen image of hyaline membrane disease, modified by the various forms of positive airway pressure, is an artificially optimistic one. It is vital to bear in mind that one is seeing a more favorable degree of expansion than would exist without positive airway pressure. This realization will help avoid great discomfiture at the temporary radiologic appearance of the chest should an endotracheal tube become dislodged (Fig. 8). Pneumonia and pulmonary hemorrhage are complications of hyaline membrane disease which have already been mentioned. With positive airway pressure therapy, delayed closure of the ductus arteriosus is being seen as an increasingly common complicating occurrence during the healing phase of hyaline membrane disease l5 . 16 (Fig. 9). Occasionally, the patent ductus requires surgical closure. Because of the marked pulmonary vasoconstriction invariably present, right-to-Ieft shunting through underperfused lung, as well as through the ductus and foramen ovale, is common during the active stages of hyaline membrane disease. 5. 28. 37. 43 As the systemic hypotension resolves and pulmonary arteriolar vasoconstriction lessens, the flow through the ductus reverses and becomes leftto-right. If left-to-right shunting is prolonged and becomes massive enough, congestive heart failure ensues. The radiologic picture is one of increasing cardiac diameter as well as increasing tortuosity of pulmonary
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Figure 8. A, The endotracheal tube became dislodged in this premature infant with hyaline membrane disease, just prior to the taking of this radiograph. B. Note the apparent dramatic improvement only 20 minutes later after reintubation and administration of CP AP (2 cm. H 2 0). Interstitial emphysema is present in the right upper lobe.
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Figure 9. A, At day 2, moderate hyaline membrane disease changes are present radiologically. B, By day 9, a characteristic patent ductus murmur became obvious, and the pulses took on a bounding character. Note the interval cardiomegaly and nodular shadows of enlarged and tortuous vessels seen on end (arrows). Some pulmonary edema is present and the vessels are hazy. The infant improved on digitalis, and a week later the murmur was gone and chest films returned to normal.
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vessels now carrying an excess blood flow. Many more areas of the nowtortuous vessels are seen on end, almost resembling at times granulomatous nodules in the peri-hilar areas. Once congestive heart failure ensues, the margins of individual vessels become indistinct and peri-hilar pulmonary edema may obscure central vessels completely. With digitalization and diuretics, the vessels once again become distinct, though still enlarged and tortuous. Concomitant cardiomegaly may not necessarily occur.H Abnormal Air Collections With the classic experiments of the Macklins,2:J. 24 the pathogenesis of pneumomediastinum with and without pneumothorax became clear. Air which escapes from ruptured alveoli dissects along the perivascular spaces, probably milked along toward the hila with changes in bronchiolar length during respiration. The air finally gains entry to the mediastinum. As the use of all variations of positive airway pressure have increased, so have abnormal air collections in both the chest and extrathoracic locations. The abnormal air collections have been most common with respirator-driven inspiratory pressures plus maintenance of end-expiratory pressure (PEEP) occurring in at least half of such cases. The extra-alveolar air collections have been much less common with CP AP alone, but still occur with some regularity. Interstitial Pulmonary Emphysema If radiographs could be taken often enough, and at critical times, almost every pneumothorax occurring during the course of hyaline membrane disease would be preceded by interstitial pulmonary emphysema. This phenomenon represents air which has dissected along perivascular spaces within the pulmonary interstitium, but which has not yet escaped into the pleural space or mediastinum. Interstitial pulmonary emphysema has been produced experimentally/3.24 and the microscopic examination of such lungs confirms the interstitial location. 6 • 11 Radiologically, interstitial pulmonary emphysema is characterized by short, nonbranching linear or ovoid lucencies which are quite black on the radiograph (Figs. 10 to 12). The distribution of air does not conform to the anatomic arborization of the bronchial tree. One of the most useful criteria has been the marked lucency of these minute air collections. They are characteristically blacker than the normal air bronchogram seen behind the heart and beyond the confines of the cardiac silhouette in the midst of atelectatic lung. Interstitial pulmonary emphysema can be seen in hyaline membrane disease without positive airway pressure therapy, but is far more common when this mode of ventilatory manipulation is employed. The extent of interstitial pulmonary emphysema is apparently quite sensitive to small variations in positive end-expiratory pressure applied, and such changes in pressure can often be guessed at, upon inspection of interval radiographs (Fig. 10). The importance of interstitial pulmonary emphysema is twofold. First, there is probably a splinting effect on the lung, further compromising pulmonary compliance. Perhaps more important, however, is the rec-
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Figure 10. A, This premature infant with hyaline membrane disease had suffered a bilateral pneumothorax on day 3 and bilateral chest tubes were placed. Note the characteristic short, nonbranching linear and ovoid lucencies on the right, characteristic of pulmonary interstitial emphysema. PEEP (8 em. H, O) is being administered via endotracheal tube. B, After pulmonary interstitial emphysema had been noted, the PEEP was decreased to 3 em. of H, O and there is now less pulmonary interstitial emphysema. C, The chest tubes were removed but the infant continued to do poorly and increased interstitial emphysema is seen on the right. 9 em. of H, O of PEEP were required to maintain the p02 • Residual hyaline membrane disease changes remain on the left.
ognition of this entity as the precursor of more catastrophic complications including pneumothorax and/or pneumomediastinum. This is particularly true when the interstitial emphysema is unilateral, allowing prediction of the location of the impending pneumothorax. Unilateral interstitial emphysema may reappear in the re-expanding lung, as a pneumothorax is treated (Fig. 11). Pseudocyst Occasionally, air which escapes after alveolar rupture may remain localized within the pulmonary parenchyma. This lesion has been called a "pseudocyst" of hyaline membrane disease. 6 The radiographic picture is one of a round or oval lucency entirely within pulmonary parenchyma, with a well demarcated wall composed of compressed alveoli around the expanding cyst (Fig. 12). It is likely that some degree of air-trapping exists to permit the enlargement of the pseudocyst. Compared to pneumothorax, this complication is not commonly seen, although 5 of 84 cases in Campbell's series developed this complication.6 The lesion should not be misinterpreted as a pneumatocele secondary to staphyloccal pneumonia. Spontaneous resolution usually occurs, but occasionally the pseudocyst may-enlarge to the point of rupturing into either the pleural space or
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the mediastinum and producing a pneumothorax or pneumomediastinum , respectively (Fig. 13).
Pneumothorax and Pneumomediastinum The occurrence of pneumothorax and pneumomediastinum is fairly common in hyaline membrane disease, with an increased incidence in infants maintained on assisted ventilation.111 • 2 " Pneumothoraces which occur in hyaline membrane disease usually manifest some signs of tension, and require removal of air from the pleural space, either by needle aspiration or tube drainage. The cardinal roentgen signs include collapse of the lung to a highly variable degree, an expanded pleural space with shift of the heart and mediastinum to the contra-lateral side, flaring of the intercostal spaces with bulging of the parietal pleura, and depression or inversion of the ipsolateral hemidiaphragm (Fig. liB). The lung affected with hyaline membrane disease is a stiff, noncompliant lung which may be even further splinted owing to the presence of interstitial pulmonary emphysema. The lung may therefore appear to "float" in the air in the pleural space. Care must be taken not to
Figure 11. A, A chest tube has been placed on the right owing to previous pneumothorax with some residual air remaining medial to the right lung. Marked interstitial emphysema is seen on the left and left pneumothorax was predicted on the basis of this radiograph. B, Five hours later, a tension pneumothorax has occurred. Note the characteristic expansion of the left hemithorax with mediastinal and cardiac shift to the left, bulging of the inters paces on the left, and inversion of the left hemidiaphragm. There is also a pneumomediastinum present. Air is present either under the right lun g or under the right diaphragmatic pleura from the pneumomediastinum (see Fig. 17). C. Following removal of air from the left pleural space, there is still residual interstitial emphysema 5 hours later.
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Figure 12. A, At 8 hours, there is homogenous opacification of both lungs owing to markedly delayed clearance of lung fluid. Often, delayed clearance of this degree will eventually reveal hyaline membrane disease in underlying lungs. B, At 28 hours, the lung fluid has cleared and the typical picture of hyaline membrane disease is present. There is a large "pseudocyst" with well demarcated walls in the right lung (arrow).
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Figure 13. A large "pseudocyst" (open arrows) is present in the right lung, and has ruptured into the mediastinum. There is air outlining the right pulmonary artery (solid arrows), and air in the neck. Changes of hyaline membrane disease are seen in both lungs. A nasogastric tube is present in the esophagus.
Figure 14. Congenital lobar emphysema of the right upper lobe. The open arrows indicate herniation of the overexpanded right upper lobe across midline. The right'middle lobe and right lower lobe are compressed inferiorly with characteristic triangular densities (solid arrow). There is marked cardiac and mediastinal shift to the left. Note that a few bronchovascular markings are seen in the emphysematous lobe, in contrast to the absence of these markings in a tension pneumothorax (see Figure lIB).
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Figure 15. This premature infant with hyaline membrane disease had already developed a left pneumothorax on PEEP for which a tube was placed in the left pleural space. There is now a small right pneumothorax present (small arrows), as well as a pneumomediastinum with elevation of the right lobe of the thymus producing the "spinnaker sign" (large solid arrow). There is also air in the neck (open arrow). There may be a sub-pleural bleb on the right also (see Fig. 17).
confuse the picture with that of congenital lobar emphysema, where broncho-vascular markings can be seen out to the periphery of the hyperaerated lobe, and compression atelectasis of the lower lobe is manifest by a triangle of density adjacent to or behind the heart (Fig. 14). Occasionally, air may accumulate medial to the lung and peel away the lung laterally, mimicking pneumomediastinum. This may be impossible to differentiate from mediastinal air unless decubitus films are obtained. Pneumomediastinum in the neonate can usually be detected by the presence of air anterior to the heart on the lateral film, as well as by elevation of the thymus off the cardiac silhouette both in the anteroposterior and lateral projections. Oblique films may occasionally be needed. This thymic elevation has been referred to as the "spinnaker sign"27 (Figs. 15 and 17). The mediastinal air may occasionally be seen pushing the mediastinal pleurae laterally on both sides of the heart. It has been said that mediastinal air rarely escapes from the chest in the newborn. However, we have seen dissection of air into the soft tissues of the neck not uncommonly and in direct proportion to the severity of the pneumomediastinum (Figs. 15, 16, 17). On the anteroposterior radiograph, one may occasionally see air in a subpulmonic location (Fig. 17). The location of this air is not completely certain. Apparently, it may dissect under the parietal pleura, and be situated between the parietal pleura and muscle of the hemidiaphragm. This finding was present in 6 of 25 cases reported by O'Gorman et al.,32 although neither their cases nor
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Figure 16. A, At 24 hours this premature infant with hyaline membrane disease has developed pulmonary interstitial emphysema on the left and a pneumomediastinum manifest by lucency superimposed on the cardiac silhouette. Note the air in the soft tissues of the neck (open arrow). B, Shortly before death, at 48 hours, there is a pneumopericardium present. Note the diminution in cardiac size and the fine shadow of the pericardium. The endotracheal tube is well down into the right lower lobe bronchus, but at autopsy, the chest was opened under water and no escape of air from the pericardium occurred. There was no tear in the tracheobronchial tree.
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Figure 17. The anteroposterior (A) and lateral (B) chest films show hyaline membrane disease with a right pneumothorax and a pneumomediastinum, with air in the soft tissues of the neck (open arrows). The pneumomediastinum has produced the "spinnaker sign" in the lateral view (curved arrow). There is a large pneumoperitoneum present also, with clear delineation of the anterosuperior surface of the liver (straight arrows). A large subpulmonic or subpleural air collection is seen on the right. Pulmonary interstitial emphysema is also present in the right lung medially. A chest tube was placed on the right, between the taking of the anteroposterior and the lateral films.
those of Lilliard and Allen22 were autopsy-proven. This finding has been disputed by McSweeney,25 who feels that the air is subpulmonic, within the pleural space, and that films in the decubitus projection will reveal a shift of this air out from under the lung. It may be that both possibilities can occur. Pneumopericardium Pneumopericardium is an extremely rare complication of hyaline membrane disease. We have seen this complication only once in an infant on assisted ventilation. There is no anatomic continuity between the mediastinum and pericardial space and it has been speculated that air may be in the precardial mediastinal space.32 Nevertheless, when the abnormal gas is seen completely encircling the heart and causing some diminution in size of the heart as in Figure 16, it is hard to deny the fact that pneumopericardium does occasionally occur. Campbe1l6 reports 3 of 84 cases of hyaline membrane disease with this complication. Pneumoperitoneum This complication of hyaline membrane disease is also uncommon (Fig. 17). Presumably, air gains entry to the peritoneal cavity through dissection into the mediastinum and from there to the retroperitoneal space. Theoretically, defects in the posterior parietal peritoneum must also be present for air to escape into the peritoneal cavity. It is also possible for air toent~ the peritoneal cavity through the venal caval or aortic hiatus
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of the diaphragm, or through persistent anterior or posterior diaphragmatic closure defects.:l When pneumoperitoneum is present, exclusion of a perforated viscus is impossible radiologically. If the pneumoperitoneum does not resolve coincident with resolution of the invariably-present pneumomediastinum or pneumothorax, surgical exploration becomes necessary. Pneumatosis cystoides intestinalis has been reported due to dissection of air from the mediastinum to the retroperitoneal space and then along the perivascular spaces in the root of the mesentery to the subserosa of the gut.20 Presumably, rupture of subserosal air bubbles might then provide yet another alternative route for the production of pneumoperitoneum from pneumomediastinum. Oxygen Toxicity The radiologic diagnosis of oxygen damage to the lung is far from specific. As outlined by Northway,'lI the factors involved in the production of oxygen toxicity include individual susceptibility, the concentration of inspired oxygen, and the duration of exposure. In Northway's cases, greater than 150 continuous hours of 80 to 100 per cent oxygen concentration were required to produce chronic changes in the lung. The changes noted include cystic and bullous changes interspersed with linear and confluent atelectasis and/or fibrosis (Fig. 18). Chronic interstitial pneumonia and fibrosis are noted microscopically. It is not clear what relationship mechanical ventilation utilizing lower concentrations of ox-
Figure 18. This premature infant had required high concentrations of inspired oxygen as well as high end-expiratory pressures since birth, and died shortly after this radiograph. Note the coarse areas of fibrosis interspersed with areas of alveolar breakdown .and coalescence. Pulmonary interstitial emphysema is present in the right lung. Histologic sections disclosed marked interstitial fibrosis, suggestive of oxygen toxicity. No gross inflammatory disease was noted. The individual roles of oxygen and respirator therapy cannot be separated.
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Figure 19. A, This markedly immature baby (800 gm.) had respiratory distress from birth and a picture suggestive of hyaline membrane disease. This cleared quickly and neither high oxygen concentrations nor respirator therapy was needed. B, At 72 days, there is marked hyperaeration and coarse densities throughout both lungs. Healing rib fractures are present on the right from previous resuscitative efforts earlier in life. The picture fits that of WilsonMikity syndrome, but a lung biopsy was not done.
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ygen has to pulmonary disease, and whether or not similar changes are produced. It is usually impossible to separate out the two factors clinically. In addition, the relationship between bronchopulmonary dysplasia (oxygen toxicity) and pulmonary dysmaturity (Wilson-Mikity syndrome) is not certain, especially since an appreciable percentage of patients with pulmonary dysmaturity have a history of early respiratory distress and hyaline membrane disease 18 • 26 • 44 (Fig. 19). McSweeney 25 has suggested that these entities may form a common complex of changes and terms both "chronic pulmonary disease of prematurity."
UNUSUAL SEQUELAE OF HYALINE MEMBRANE DISEASE OF UNCERTAIN RELATIONSHIP Right-Sided Bochdalek Diaphragmatic Hernia We have had occasion to watch the development of a right-sided Bochdalek hernia in a child with hyaline membrane disease and a pre-
Figure 20. A , Hyaline membrane disease at 2 days. Note the normal position of the liver and the right hemidiaphragm. Respiratory distress cleared in approximately 4 to 5 days. B and C, At 15 days, respiratory distress recurred and the radiograph displayed herniation of the bowel loops up into the right chest with compression atelectasis of the left lung. At surgery there was herniation of the liver, small bowel, and colon through the foramen of Bochdalek. The hernia was successfully reduced.
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viously normal position of the abdominal viscera and right hemidiaphragm (Fig. 20). The hernia did not become manifest until the seventeenth day of life, although intermediate radiographs disclosed opacification of both lungs of uncertain cause. The hernia was confirmed surgically and repaired with no subsequent problems. Faure et al." reported 3 cases of delayed right-sided diaphragmatic hernias and have reviewed the literature. One of their 3 cases presented initially with respiratory distress. McSweeney has commented also on the delayed appearance of right-sided Bochdalek hernias. 25 The relationship of antecedent hyaline membrane disease and continuous positive airway pressure therapy in our patient is not clear. Congenital Lobar Emphysema We have seen an infant with hyaline membrane disease who continued to have respiratory distress after clinical and radiologic manifestations of hyaline membrane disease had cleared. At approximately 5 weeks, congenital lobar emphysema involving the right middle lobe became obvious radiographically (Fig. 21). Although congenital lobar emphysema and congestive heart disease have some association,42 we are unable to locate any reports linking congenital lobar emphysema and hyaline membrane disease.
65 days
65 days
Figure 21. A, At 3 days only mild hyaline membrane disease changes are present. Despite clearing of the chest rum, mild respir· atory distress persisted. B and C, At 65 days massive lobar emphysema of the right middl~ lobe is evident. The large solid arrow indicates probable coaptation of the right and left mediastinal pleurae anterior to the heart. The right upper lobe (small solid arrow) and right lower lobe (open arrow) are both compressed by the grossly emphysematous right middle lobe. At surgery, right middle lobe emphysema was confirmed, and a right middle lobectomy was performed.
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SUMMARY The typical radiologic course of hyaline membrane disease has been reviewed and the natural history of this disease has been stressed. The changing pattern of evolution of hyaline membrane disease since the advent of assisted ventilation and positive airway pressure has been reviewed. The complications of the disease, both spontaneous and iatrogenic, have been commented upon, with emphasis on extra-alveolar air collections seen more commonly in patients with all forms of ventilatory manipulation. The increasing frequency of delayed closure of the ductus arteriosus with positive airway pressure therapy is being seen in a significant number of centers. The subsequent development of a rightsided Bochdalek hernia and congenital lobar emphysema in 2 unusual patients has been described. It is imperative that the radiologist, the neonatologist, and the general pediatrician be aware of the roentgen picture and evolution of hyaline membrane disease, in which the radiologic and clinical courses are so often closely parallel.
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18. Krauss, A. N., Levin, A. R., Grossman, H., et al.: Physiologic studies on infants with Wilson-Mikity Syndrome. J. Pediat., 77:27-36, 1970. 19. Lauweryns, J. M.: Hyaline membrane disease in newborn infants. Macroscopic, radiographic and light and electron microscopic studies. Human Pathol., 1 : 1 75-204, 1970. 20. Lee, S. B., and Kuhn, J. P.: Pneumatosis intestinalis following pneumomediastinum in a newborn infant. J. Pediat., 79:813-815, 1971. 21. Lewis, S.: A follow-up study of the respiratory distress syndrome. Proc. Roy. Soc. Med., 61 :771-773, 1968. 22. Liillard, R L., and Allen, R P.: The extrapleural air sign in pneumomediastinum. Radiology, 85:1093-1098,1965. 23. Macklin, C. C.: Transport of air along sheaths of pulmonic blood vessels from alveoli to mediastinum. Arch. Int. Med., 64:913, 1939. 24. Macklin, M. T., and Macklin, C. C.: Malignant interstitial emphysema of the lung and mediastinum as an important occult complication in many respiratory diseases and other conditions. Medicine, 23:281, 1944. 25. McSweeney, W. J.: Radiologic evaluation of the newborn with respiratory distress. Seminars Roentgen., 7:65-83, 1972. 26. Mikity, V. G., Hodgman, J. E., and Tatter, D.: The radiological findings in delayed pulmonary maturation in premature infants. Prof. Ped. Radiol., 1: 149-159, 1967. 27. Moseley, J. E.: Loculated pneumomediastinum in the newborn. A thymic "spinnaker sail" sign. Radiology, 75:788-790,1960. 28. Nelson, N. M.: On the etiology of hyaline membrane disease. PEDIAT. CLIN. N. AMER., 17:943-965, 1970. 29. Newman, H., and Thoeny, R. H.: Pneumoperitoneum in the newborn. Brit. J. Radiol., 40:780-782,1967. 30. Normand, I. C. S., Reynolds, E. O. R, Strang, L. B., et al.: Flow and protein concentration of lymph from lungs of lambs developing hyaline membrane disease. Arch. Dis. Child., 43:334-339, 1968. 31. Northway, W. H., and Rosan, R. C.: Radiographic features of pulmonary oxygen toxicity in the newborn: Bronchopulmonary dysplasia. Radiology, 91 :49-58, 1968. 32. O'Gorman, L. D., Cottingham, R A., Sargen, E. N., et al.: Mediastinal emphysema in the newborn: A review and description of the new extrapleural gas sign. Dis. Chest, 53 :30 1308,1968. 33. Outerbridge, E. W., Nogrady, M. B., Beaudry, P. H., et al.: Idiopathic respiratory distress syndrome. Recurrent respiratory illness in survivors. Amer. J. Dis. Child., 123:99-104, 1972. 34. Pusey, V. A., Macpherson, R. I., and Chernick, V.: Pulmonary fibroplasia following prolonged artificial ventilation of newborn infants. Canad. Med. Assoc. J., 100:451-457, 1969. 35. Recavarren, S., Benton, C., and Gall, E. A.: The pathology of acute alveolar diseases of the lung. Seminars Roentgen., 2:22-32, 1967. 36. Reilly, B. J.: Patterns of pulmonary involvement in the idiopathic respiratory distress syndrome. Presented to the Society for Pediatric Radiology, Boston, Massachusetts, September 27, 1971. 37. Reynolds, E. O. R: Hyaline membrane disease. Amer. J. Obstet. Gynec., 106:780-797, 1970. 38. Rudhe, J., and Broberger, U.: Roentgenological observations in survivors of clinical hyaline membrane disease of the newborn. Ann. Radiol., 10:284-294, 1967. 39. Rudhe, U., Margolin, F. R, and Robertson, B.: Atypical roentgen appearances of the lung in hyaline membrane disease of the newborn. Acta Radiol. (Diag.), 10:57-68, 1970. 40. Shepard, F. M., Johnston, R B., Klatte, E. C., et al.: Residual pulmonary findings in clinical hyaline membrane disease. New Eng. J. Med., 279:1063-1071,1968. 41. Singleton, E. B.: Respiratory distress syndrome. Pro gr. Ped. Radiol., 1 :135,1967. 42. Stanger, P., Lucas, R. V., and Edwards, J. E.: Anatomic factors causing respiratory distress in acyanotic congenital cardiac disease. Special reference to bronchial obstruction. Pediatrics, 43:760-769, 1969. 43. Strang, L. B., and MacLeish, M. H.: Ventilatory failure and right-to-left shunt in newborn infants with respiratory distress. Pediatrics, 28:17-27,1961. 44. Wilson, M. G., and Mikity, V. G.: A new form of respiratory disease in premature infants. Amer. J. Dis. Child., 99:489-499,1960. 45. Wolfson, S. L., Frech, R, Hewitt, C., et al.: Radiographic diagnosis of hyaline membrane disease. Radiology, 93:339-343,1969.
Department of Radiology University Hospital 225 West Dickinson Street San Diego, California 92103