Neonatal Respiratory Distress: Experience at The Hospital for Sick Children, Toronto,

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1 AUGUST 31, 1963 * VOL. 89, NO. 9 Neonatal Respiratory Distress: Experience at The Hospital for Sick Children, Toronto, W. B. HANLEY, M.D.,* M. BRAUDO, M.B., M.R.C.P.(Ed.) and P. R. SWYER, M.B., M.R.C.P.(Lond.), Toronto INFANTS with respiratory distress admitted to the Neonatal Unit of The Hospital for Sick Children, Toronto, over the 24-month period January 1, 1960, to December 31, 1961, were studied with particular reference to diagnosis, morbidity and mortality. Clinical and special studies and an analysis of certain possible perinatal factors in the causation of the "idiopathic respiratory distress syndrome" (IRDS) will be reported separately. MATERIAL, METHODS AND NOMENCLATURE The Hospital for Sick Children admits newborn infants from hospitals in the city of Toronto and neighbourhood for whom special care is thought necessary by the physician concerned. Thus infants admitted to the Neonatal Unit are a selected group and probably include fewer of the milder cases who are not transferred. On the other hand, the unit attracts many problem cases. TABLE 1.-NEONATAL UNIT, TUE HOSPITAL FOR SICK CHILDREN, Admissions Deaths 1.Hemolytic Respiratory distress (symptomatic) Other In the 24 months of the years 1960 and 1961, 1981 patients aged seven days and under were admitted to the Neonatal Unit (Table I). Nine hundred and sixty-four of these infants were diagnosed as having hemolytic disease of the newborn. Of the remainder, 430 had the symptom of respiratory distress beginning before the age of 48 hours; of these, 228 died. These constituted approximately ABSTRACT Four hundred and thirty infants selectively referred to the Newborn Unit of The Hospital for Sick Children, Toronto, with the symptom of respiratory distress, were reviewed. There were 142 cases of the "idiopathic respiratory distress syndrome" (IRDS), of which 67 were fatal. The remainder included 100 cardiac (76 deaths), 63 extrapulmonary (28 deaths) and 109 other specffic pulmonary conditions (54 deaths). Of the 109, half were due to massive aspiration. Serial observations and radiographs led to correct clinical diagnosis in 85% of necropsy-proved cases of IRDS and in a comparable proportion of all other conditions. The incidence and mortality rate of IRDS were twice as high in males as in females. A significant number of premature infants have transient respiratory distress after birth. and diagnostic criteria for inclusion in any study should be defined in detail. This study emphasized the large contribution of disorders of the respiratory and cardiac systems to neonatal mortality and led to the formation of a special department for intensive care and research. in these conditions. From The Research Institute, The Hospital for Sick Children, and the Department of Pediatrics, University of Toronto. This work was supported by a grant from the Department of *Mead National Johnson Health Research and Welfare. Fellow.

2 376 HANLEY AND OTHERS: NEONATAL RESPIRATORY DismEss Canad. Med. Ass. J. (IRDS) are usually premature by weight. There is a high incidence as well in offspring of diabetic mothers and in those delivered by Cesarean section. Clinically they present with gradually worsening, rapid laboured respirations, grunting and marked chest-wall retractions. Peripheral edema is frequently present. The peak of the disease occurs at hours of age. The infant, if he survives, gradually improves to complete recovery. Most, but not all,2.4 of the infants who die from this syndrome are found to have hyaline membrane formation in the lungs at necropsy. They all have a distinctive pattern of "resorption atelectasis" with dilated alveolar ducts and terminal bronchioles. The remainder of these infants with symptomatic respiratory distress fall into well-defined groups, though, as reported by others,55 mixed clinicalpathological pictures are not uncommon. Emphasis will be placed on the major lesion, and associated problems will be indicated as necessary. RESULTS TABLE II. NEONATAL RESPIRATORY DISTRESS (SYMPTOMATIC), THE HOSPITAL FOR SICK CHILDREN, Cases Deaths* mortality A. Pulmonary-IRDS % Other specific causes % B. Extrapulmonary % C. Cardiac.10076% 76 D. Undiagnosed % *The diagnoses in Groups A to C were all proved post mortem, except in five of the cardiac deaths (see Table III). Table II presents our experience with 430 cases of symptomatic respiratory distress and Table III depicts the detailed differential diagnosis. There were 142 patients with IRDS, of whom 67 died. The diagnosis of IRDS was made on clinical grounds only in 19; from clinical and radiological Cl3 w C, as. 10. I i50i ZSooI Hot )3000 WT. IN CRAMS Fig. 1.-Prognosis in relation to birth weight. TABLE 111.-NEONATAL RESPIRATORY DISTRESS, THE HOSPITAL FOR SICK CHILDREN, CLASSIFICATION A. Pulmonary- I Idiopathic-IRDS Cases Deaths II Specific causes (a) Surgical 1. Spontaneous pneumothorax Congenital cystic lung 1 3. Lobar.mphysema Thoracic mass..2 0 (b) Medical 1. Massive aspiration (i) Squames and mecomum (ii) Maternal blood Pneumonia Pulmonary hemorrhage "Aspiration pneumonia "Primary atelectasis" Congenital stridor Segmental atelectasis 4 0 S. Mucus-plug syndrome Interstitial emphysema B. Extrapulmonary- (a) Surgical 1. Esophageal atresia Diaphragmatic hernia Choanal atresia Vascular ring.1 0 (b) Medical 1. Primarily CNS Renal disease Pierre-Robin syndrome Congenital methemoglobinemia 1 0 C. Cardiac- (a) Functional Paroxysmal tachycardia.3 0 (b) Anatomical 1. Transposition of great D. Undiagnosed.16 3 vessels ti2% (2. Aortic atresia Coarctation of aorta X4. Pulmonary atresia Patent ductus and ventricular septal defect TetralogyofFallot Ventricular septal defect Truncus arteriosus Tricuspid atresia Patent ductus Pulmonary stenosis Endocardial fibroelastosis Others Undiagnosed evidence in 58, and by clinical (and/or radiological) and necropsy findings in 65. Six of the infants in whom this diagnosis was made on clinical grounds alone were delivered by Cesarean section and two were infants of diabetic mothers. Fig. 1 gives the prognosis in relation to birth weight. The incidence and mortality of IRDS in

3 Canad. Med. Ass. J. Hanley and others: Neonatal Respiratory Distress 377 infants over 2500 g. are high. This reflects the selected nature of our material. Approximately half of the infants over 2500 g. with IRDS were delivered by Cesarean section and seven were infants of diabetic mothers. Sex Incidence In common with others911 we have found that two-thirds of our cases of IRDS were males (Fig. 2). Furthermore, the mortality rate was twice as high in males as females. 90H 63.5%.S X INCIDENCE Fig. 2..Mortality rate, by sex. DlFFERENTIAL DlAGNOSIS Radiographs In our experience one of the more useful diagnostic aids was the chest radiograph. Radiographs were taken in the incubator with minimal disturb- Fig. 3b..IRDS.opaque chest film sometimes seen in the early stages. Fig. 3a..IRDS.typical reticulogranular radiograph. Fig. 3c..The homogeneous or "ground glass" density sometimes seen in IRDS.

4 378 HANLEY AND OTHERS: NEONATAL RESPIRATORY DIsmEss canad. Med. Ass. J. ance to the infant. The typical picture of IRDS (Fig 3a) is that of a well-expanded thorax with a fine reticulogranular pattern often showing a good "air bronchogram" far out to the periphery. Fortytwo of the infants who died, and in whom IRDS was noted histologically as the primary disease, had technically satisfactory radiographs (Table IV). In TABLE IV.-RADIOGRAPHS IN IRDS IRDS Proved Radiograph Lived post mortem A. Diagnostic of IRDS B. Not typical of IRDS.11 6 C. Not taken.7 21 Results of radiographs taken in 69 of 76 cases of IRDS who lived and 42 of 63 cases who died. A "diagnostic" radiological picture was present in 58 of 69 (84%) who lived and 36 of 42 (86%) who died. 36 the radiological picture was typical of IRDS, while six radiographs were equivocal Five of the equivocal radiographs were taken before the age of five, hours and showed a generalized opacity (Fig. 3b) or "ground-glass" appearance (Fig. 3c). One radiograph taken at four hours showed a pneumothorax, but the lung fields were otherwise clear. Of the infants with IRDS who survived, 58 of 69 (84%) had "diagnostic" radiographs. This confirms the experience of other workers." 1216 Four other infants, who died in respiratory distress and had "diagnostic" radiographs, had hyaline membrane formation, but the major disease was interpreted pathologically as pneumonia in two, aspiration of squames and meconium in another, and intra-alveolar hemorrhage in the fourth. The remaining infants who died of causes other than IRDS had a distinctly different radiological picture Other Pulinanary Causes of Respiratory Distress The 109 patients in this group are classified in Table III. Difficulty in categorizing these cases and the overlap with the IRDS group are shown by the following groups: 1. Of the 50 who died of massive aspiration, six had some hyaline membrane formation, two had pneumothoraces, and one had extensive pulmonary hemorrhage. 2. Of the seven who died of pneumonia, three had hyaline membranes, two had many squames in thefr respiratory passages, and two had extensive intra-alveolar hemorrhage. 3. Of the 11 patients with fatal massive pulmonary hemorrhage, two had hyaline membrane formation, two had aspiration of squames and meconium, one of these had a pneumomediastinum as well, and two suffered from generalized hemorrhagic disease of the newborn. 4. The one patient who died of massive aspiration of maternal blood also had some hyaline membrane formation. 5. Five patients with a major central nervous system hemorrhage as the immediate cause of death had hyaline membrane formation; one of these also had evidence of squames and hemorrhage in the lung section. 6. Of the 67 infants in whom death was due primarily to IRDS, 19 suffered from relatively minor anoxic subarachnoid hemorrhage, six had pneumothoraces, one aspirated squames and meconium, three had secondary pneumonia, four had some pulmonary hemorrhage, and eight had some other associated disease. Massive Aspiration The group of 50 patients with massive aspiration were, as a rule, easily distinguished clinically. They were usually full-term by weight, often had a history of a birth characterized by meconium-stained liquor amnii and the radiographs revealed a characteristic picture (Fig. 3d). This consisted of a Fig. 3d.-Massive aspiration syndrome (meconium.). coarse, non-uniform streaking and heavy mottling, with a "barrel chest" suggesting obstructive emphysema.'2 This contrasts with the fine reticulogranular pattern and normal-sized thorax of those with IRDS. Clinically the emphysematous "barrel" chest was usually discernible. Respirations were rapid and shallow, rather than indrawing as in IRDS. Rales were frequently present. Pneumonia Seven of the 13 patients whose major clinical condition was pneumonia died. The survivors had

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6 380. AND 0Th.s: NEONATAL RESPIEATORY DIsmEss Canad. Med. Ass. J. gests coarctation of the aorta in any baby who is not moribund. The size of the heart should be interpreted cautiously in six-foot radiographs of the chest. A degree of cardiomegaly is common in IRDS. Gross cardiomegaly suggests the presence of a cardiac lesion, particularly if pulmonary vascularity is reduced. We have not encountered the typical radiological features of IRDS in any infant with cardiac disease except two babies with proved transposition of the great vessels who had IRDS as well. The value of the electrocardiogram in differential diagnosis is being studied at present. One useful sign we have noticed so far is that a qr pattern in lead V1 has always been associated with a cardiac lesion. By paying careful attention to all features, we were able to distinguish patients with congenital heart disease from those with IRDS at the time of the first examination in all except two babies. In these exceptional cases the correct diagnosis of transposition of the great vessels became clear with continued observation, though hyaline membrane formation was observed in the lungs at necropsy in addition to the cardiac malformation. DISCUSSION Incidence and Differential Diagnosis Over 40 different specffic conditions were found producing neonatal respiratory distress (Table III). This list is not exhaustive and other causes may be found.2' An accurate clinical diagnosis was possible in the great majority of cases after a careful evaluation of the history, clinical picture and radiographs. The true incidence and mortality of IRDS are uncertain. A survey of the literature22 revealed an incidence in prematures ranging from 10% to 42% and a mortality ranging from 17% to 55%. However, on close analysis of these figures one concludes that the incidence and mortality would be similar in all centres if uniform criteria for diagnosis were used. A great many newborns, especially those under 2000 g. and those born by Cesarean section, have transient mild to moderate dyspnea lasting for one to six hours or more, and recover spontaneously. These probably should be excluded from any study directed toward determining incidence or evaluating therapy. Indeed, in reviewing a group of prematures at the Toronto General Hospital over a two-year period we found that virtually all infants with birth weights of less than 1500 g. had some degree of respiratory distress for at least the first one to two hours of life. Our own experience is highly selective and includes many of the more severe cases. Usher's9 experience (Fig. 4) probably reflects more accurately the true incidence in the general nursery population. Our incidence of IRDS in relation to other causes of respiratory distress (Table II) also reflects the selected nature of our material. From observations in the nurseries for the newborn in < Birth weight in grams Fig. 4.-IRDS. Adapted with permission, from figures suppiled by Dr. R. Usher (Personal communication, 1962; see also Usher. R.: Pediat. Olin. N. America, 8: 525, 1961.) the general hospitals of Toronto, and from perusal of the available literature,3' 5, 7, 2325 we would estimate that 70% to 80% of neonates in respiratory distress suffer from IRDS. Radiographs Radiographs were taken of the infants in the incubator, with minimal disturbance, by techniques described by Bauman and Nadelhaft'3 and Steiner.'4 A few authors4' 8 contend that a definitive diagnosis of IRDS depends on pathological examination. However, many now feel that a clinical and radiological diagnosis can be made in 85% or more of cases." 1246 Feinberg and Goldberg'6 found that in the first one to three hours of life the radiological picture often is not classical but by taking serial films the diagnosis usually becomes evident. The early radiographs often show varying degrees of uniform opacity of the lung fields (Fig. 3b, c). Peterson and Pendleton'2 described a few cases in which the typical pattern was not present until 16 to 18 hours of age. Schaffer2' stated that he had seen several patients who lacked the typical roentgen pattern; however, his illustrative radiograph of an eighthour-old infant showed the homogeneous opacity mentioned above. Bauman'3 found that eight of 10 prematures with hyaline membranes at necropsy had typical radiographs; the other two apparently had normal films. He also found a large number of false positives, 16 out of 35, i.e. typical "reticulogranular" radiographs with no associated clinical distress. The reticulogranular pattern was absent in the few non-distressed prematures in our unit who had radiographs, but was seen in two transiently distressed infants. However, most of our infants with transient respiratory distress did not have a radiographic examination.

7 Canad. Med. Ass. J. HANLEY AND OTHERS: NEONATAL RESPIRATORY DIsTI.Ess 381 It is probable that some normal or transiently distressed prematures have a reticulogranular pattern in their chest radiographs. Our conclusion is that the radiograph is a valuable adjunct in the diagnosis of IRDS but should not be the sole diagnostic criterion. Clinical Significance This survey has emphasized the size and scope of the problem of neonatal morbidity and mortality in this hospital with special reference to respiratory distress. Approximately 160 (40%) of the 400 postmortem examinations performed annually were on neonates within the first week of life. One hundred and twenty (30%) had some condition causing respiratory distress and of these 35 (9%) had IRDS. As a result, a special neonatal unit has been organized specifically for research and intensive care in an effort to reduce mortality and the incidence of serious neuropsychiatric sequels. SUMMARY AND CONCLUSIONS A group of 430 newborn infants referred to the Newborn Unit of The Hospital for Sick Children, Toronto, with the symptom of respiratory distress are reviewed. In 142 of these the IRDS (idiopathic respiratory distress syndrome) was diagnosed; of these 67 died. The incidence, differential diagnosis and mortality of respiratory distress are discussed and the following conclusions reached: This group is a selected one and does not provide a true cross-section of the incidence of IRDS in the general nursery population. A definite clinical diagnosis of IRDS is possible in over 85% of cases. Radiographs are an essential adjunct in the differential diagnosis of neonatal respiratory distress and the taking of them is not disturbing to the infant. A significant number of premature infants have transient respiratory distress after birth and the diagnostic criteria for inclusion of subjects in studies of incidence, mortality or therapy of this condition should be defined in detail. As noted by others, the incidence and mortality of IRDS were considerably higher in males. As a result of this survey a special neonatal research and treatment unit has been set up at this hospital. The authors would like to thank Dr. C. E. Snelling for his support and encouragement the staff doctors of the hospital for allowing us to see their patients, and Miss W. A. Hannah and her nursing staff for their co-operation and patience. REFERENCES 1. RUDOLPH, A. J. AND SMITH, C. A.: J. Pediat., 57: 905, BRIGGS, J. N. AND HOGG, G.: Pediatrics, 22: 41, CLAIREAUX, A. E.: Neonatal pathology. In: Modern trends in paediatrics, second series, edited by A. Hoizel and J. P. M. Tizard, Butterworth & Co., Ltd., London, 1958, p GRUENWALD, P.: J. A. M. A., 166: 621, BOUND, J. P., BUTLER, N. R. AND SPECTATOR, W. G.: Brit. Med J , LANDING, 13. H.: Pediatrics, 19: 217, AHVENAINEN, E. K.: J. Pediat., 55: 691, WADE-EVANS, T.: Arch. Dis. Child., 36: 293, USHER, R.: Pediat. Olin. N. Amer., 8: 525, islam, N.: New York 1'. Med., 61: 3419, COMBES, M. A., WIGGINS, K. M. AND FACKLER, W. R.: Comparison of oral fluid and human fibrinolysin regimens in the management of the respiratory stress syndrome of premature Infants. In: American Pediatric Society, report of 72nd annual meeting, programs and abstracts, May 10-12, 1962, Atlantic City, p. 60 (abstract) 12. PETERSON, H. G., JR. AND PENDLETON, M. E.: Amer,T. Roentgen., 74: 800, BAUMAN, W. A. AND NADELHAFT, J.: Pediatrics, 21: 813, STEINER, R. E.: Brit. J. Radiol., 27: 491, GELLIS, 5. 5.: Year Book of pediatrics, , Year Book Publishers, Inc., Chicago, 1959, p FEINBERG, S. B. AND GOLDBERG, M. E.: Radiology, 68: 185, BERNSTEIN J AND WANG, J.: Amer. J. Dis. Child., 101: 350, 19S RowE. R. D. AND CLEARY, T. E.: Canad. Med. Ass.,f., 83: 299, BURNARD, E. D.: Brit. Med. J., 1: 806, BRAUDO, M. AND RowE, R. D.: Amer. J. Dis. Child., 101: 575, SCHAEFER, A. J.: Diseases of the newborn, W. B. Saunders Company, Philadelphia, HANLEY, W. B.: To be published. 23. BOWDEN, D. H., GOODEELLOW, A. M. AND SNELLING C. E.: Canad. Med. Ass. J., 75: 1000, DONALD, I.: J. Obstet. Gynec. Brit. Emp., 61: 725, MILLER, H. C.:,f. Pediat., 61: 9, PAGES OUT OF THE PAST: FROM THE JOURNAL OF FIFTY YEARS AGO The authors consider the nervous system to include the will find this work within their comprehension. They have mind, and maintain that disturbances of any and all of its produced a work in philosophy rather than a text-book in functions, mental as well as physical, are the proper subjects for therapeutics. They have not confined themselves amalgamation which is now going on in the United States, medicine; and they have faced boldly the problem of race to details, important as these are, but have laid most stress which is indeed "a prodigious biological experiment." They upon "the larger human problem of the individual, the are quite logical and have taken the position that the word man, the biological unit and his social relations." They are "insanity" should be eliminated from medicine, as a relic less concerned, as they mention in the preface, to patch of that time when all brain disorders with predominant up broken machinery, but rather to give directions for mental symptoms were considered as one disease. With avoiding the wrecks. They lay emphasis upon the psychical nineteen contributors it is obvious that the contributions side of life as being worth quite as much consideration as will not be of equal value, and we would select the chapter the physical. In the face of much "pessimistic nihilism" on Alcoholism and the Alcoholic Psychoses as being the they affirm that "neurology and psychiatry offer the widest least satisfactory. The chapter which deals with possible opportunities for preventive medicine, as well as "Immigration and the Mixture of Races in Relation to the for therapeutic optimism." Accordingly the work is not Mental Health of the Nation" is one of grave signfficance, and the problem concems Canada just as much as it addressed to the medical practitioner alone. It is written concerns the United States. The book is a most important for him principally, but the authors appeal to a wider one, and is suggestive of the wide extension that medicine audience: the educator, the legislator, the judge, the lawyer, has had in recent years in the fields which were previously the student of the problems of criminology, of immigration, considered closed to it.-book review: "The Modem Treatment of Nervous and Mental Diseases", Canad. Med. Ass. of dangerous trades, the hospital superintendent, the social worker, the military man, even the intelligent layman, all 1., 3: 608, 1913.