As early as 1942, Levine and Gordon felt that respiratory difficulties should lead the list of various handicaps faced by the premature infant. Table 1 lists the systems involved in respiratory difficulties as discussed by Levine during the past thirty years.28*29 Ten years ago, when lecturing in Hawaii, I reviewed 360 cases of premature births at the New York Hospital (November, 1960 to March, 1962). 38 Of these, 100 cases with a diagnosis of respiratory distress syndrome as defined clinically by Usher44 were further analyzed. Very few authors agreed about the exact diagnosis of this disease.
It is now generally accepted that immaturity is nearly always present with the respiratory distress syndrome of the newborn.13 Nelson,31 reviewing both facts and theories, lists 275 references in his 12-page article on the etiology of hyaline membrane disease, and over 50 different causes have been proposed for the respiratory distress syndrome. 19 Avery4 probably offers the most detailed and yet simple explanation of it in her book. Usher,45 whom we quoted 10 years ago, has recently again reviewed the factors related to the disease. He and others agree that it rarely occurs after 38 weeks of gestation. He analyzed 11,792 deliveries in the Royal Victoria Hospital in Montreal, Canada, and found that of these, 10,335 were vaginal deliveries whereas 1,457 were delivered by caesarean section. He believes that delivery by caesarean section increases both the incidence and severity of RDS at all gestational ages. There is no explanation for this, but lack of placental transfusion and aspiration of blood from the incision may contribute. Also, when the airway is not squeezed by chest compression as in vaginal delivery, there may be aspiration of amniotic fluid from vomiting of gastric contents, which may contribute to RDS. We have not seen an increase of respiratory distress syndrome related to delivery by caesarean section per se, but agree that it is probably related to the indication for caesarean section.42 Usher45 also points out that RDS is a disease of prematurity. Among infants delivered vaginally, the incidence rose from 0.8 per cent at 37-38 weeks to 64 per cent at 29-30 weeks of gestation. RDS occurred in only three of 6,023 infants delivered vaginally after 38 weeks.
As early as 1959, Gellis and Hsia17 felt that maternal diabetes is not a predisposing factor. Usher45 agreed that RDS probably results from infants being delivered prematurely rather than from their mothers having diabetes.
Systems Involved In Respiratory Difficulties
The mortality of RDS increases with the degree of prematurity. Usher's45 study shows that no infant delivered vaginally after 36 weeks of gestation died from RDS, but for affected infants delivered at 29-30 weeks, the mortality was 37 per cent. Ten years ago, Strang41 reported that the mortality was in excess of 50 per cent, and our findings were similar.38 Later in this issue the entire pathology will be discussed separately.
In Hawaii, we also quoted Usher38,44 that the symptoms are chest retractions, an increase in respiratory rate, expiratory grunting and decreased air entry on auscultation, present during and persisting beyond the first three hours of life. In the mid 1960s35 and very often since then, the infant with RDS has been described as being edematous, dyspneic, tachypneic, cyanotic in air with an expiratory grunt and poor breath sounds heard on auscultation. We feel that if an infant has these symptoms, a chest film is essential. Classically, the chest x-ray shows a diffuse fine reticulogranular pattern of the lung fields, a superimposed air bronchogram and distinct cardiac borders which are occasionally enlarged.12-40 The x-ray is important not only to help make the diagnosis of RDS but especially to rule out other conditions in the newborn that might produce similar symptoms.
Today we feel very strongly that decreased or absent pulmonary surfactant which develops and matures during fetal life is the major etiologic factor in RDS. Avery and Mead5 were among the first to expound this hypothesis; Scarpelli37 reviewed the known data about pulmonary surfactant and Gluck19,21 even feels that one can discover by amniocentesis whether a baby's lungs are mature and ready for the first breath of life. Gluck19 again reviewed our knowledge of surfactant in 1972. He believes that RDS occurs when there is lack of pulmonary surfactant. It is now fairly well-established that pulmonary surfactant is necessary for alveolar stability. We know that pulmonary surfactant lines the alveoli of the lungs and is composed of a variety of substances; of these lecithin, a phospholipid, is present in the largest amount and is the major substance which imparts stability to the normal pulmonary alveolus.27,37 Many other surfactant substances including sphingomyelin are also present.37 Gluck18 feels that the key to fetal lung maturity is the ratio of one phospholipid to another. Lecithin values change during the development of the human embryo.22,23 When lecithin has a lower value than sphingomyelin, the alveoli cannot stay patent between inhalations. Lecithin begins to exceed sphingomyelin as early as the 24th week of gestation and may be high enough to support breathing from then until the 35th week. At about this time lecithin increases markedly and is present at a ten to one ratio over sphingomyelin.18 Infants who develop the respiratory distress syndrome also contain less lecithin.33 Therefore, respiratory distress syndrome is believed to occur in infants where there is an inadequate synthesis of surfactant after birth and atelectasis occurs.19 The maturity of the fetal lung and its ability not to develop the respiratory distress syndrome can be determined by measurement of phospholipids "leaked" from the fetal alveoli into the maternal amniotic fluid; this has become a useful determination in predicting the state of maturation of the unborn fetal lung. When surface active lecithin is extracted from amniotic fluid and compared with the amount of sphingomyelin at about 35 weeks of gestation, there is a ratio of lecithin to sphingomyelin greater than two. Once this ratio is reached, the baby will be born without respiratory distress.19,21 If the ratio is less than 1.5, all babies develop respiratory distress syndrome. A convenient modified method for the routine determination of amniotic fluid lecithin: sphingomyelin ratio is now available.36 Others have also developed simple tests to determine lung maturity.11,30 One of these tests depends on the ability of the pulmonary surfactant to generate stable foam in the presence of ethanol.
As the main pathology in the respiratory distress syndrome is atelectasis due to lack of alveolar stability, all therapy must be directed towards correcting symptoms produced by this pathologic process. We recommend that the following blood gases should be maintained if possible:
POz:40-60 mm. Hg.
PCO2 :35-45 mm. Hg.
To remedy a decreased arterial PO2 or clinical cyanosis, we use oxygen. We feel that oxygen is so important that its use will be discussed later in this issue by Dr. Krauss,3 who works with Dr. AuId at the New York Hospital. An increased PCO2 may require assisted ventilation by any of several means. Dr. Driscoll will discuss this aspect of therapy later in this issue. We have been impressed with the technique described by Gregory,24 where a continuous positive pressure of five to 10 cm. water is supplied against which the infant must breathe during expiration. Nearly all cases of the respiratory distress syndrome are associated with acidosis - both respiratory as well as metabolic - leading to a lower pH. Usher43 was one of the first to advocate sodium bicarbonate (NaHCOa) therapy to correct acidosis. We feel therefore that frequent measurement of pH and PCO2 is necessary. The dose of NaHCO3 given depends on the base deficit derived from the Andersen monogram.2 The most frequently used formula is:20
ml.7.5% NaHCO3 = mEq./L. of Base Deficit x wgt.(kg.) x 0.3
In many instances, especially if apnea is present at birth, the physician will not have time to measure the pH and pCCh. We feel that in such cases one can give NaHCO3 (7.5 per cent) in a dose of three-five ml. /kg. over a five-minute period rather than adding five-25 mEq. per 100 ml. of NaHCO3 to a 10 per cent glucose and water solution. The infant with respiratory distress will require an intravenous solution in a peripheral vein to give him both calories and fluid. We use 10 per cent glucose and water in a dose of 100 ml./kg./day for about two days, and then add V4 to V2 N. saline to the glucose solution on the third day. We frequently measure blood gases but only insist on an initial chest film to rule out other causes of respiratory distress. If the clinical condition worsens, we repeat chest films to make sure that complications like pneumothorax and pneumomediastinum have not developed.
We also feel that it is essential to maintain the infant's body temperature with added heat, if necessary. Low temperature increases acidosis and increase the effect of hypoxia.32 We try to maintain the infant's skin temperature at 36-37° C. and use an incubator in all such cases. We do not use antibiotics unless an indwelling umbilical catheter is used or the maternal history and the appearance of the amniotic fluid suggest intrauterine infection. Dr. Shinefield has discussed the management of infection earlier in this issue.
We are often asked about sequelae of the respiratory distress syndrome. Thirty years ago we knew it would lead to either death or complete recovery. We have been taught that survivors of hyaline membrane disease would have no residual aftereffects. Let us examine three important sequelae:
1) PULMONARY SEQUELAE.
In 1960, Wilson and Mikity47 for the first time described a respiratory disease in premature infants characterized by cyanosis, hyperpnea and retractions which usually appear between one and three weeks of age and become progressively more severe during the following two to four weeks. Occasionally, these symptoms may start as late as two to three months.10 There also is a decrease in lung volume and in lung compliance. Grossman25 and his associates described the typical x-ray features which in the early stages show a reticular pattern throughout both lung fields and a bubbly appearance that represents focal areas of overaeration; this picture usually develops during the first month of life. Later the lung fields have heavy markings radiating from the hylum, which are greater in the upper areas with an increase of overaeration in the lungs. Hodgman26 reports that 34 premature infants were seen during a seven-year period with this syndrome. At onset, the symptoms were mild. The disease reached a maximum intensity from four to eight weeks after onset. Signs and symptoms then slowly cleared during the following weeks to months. Twelve of 34 died during the period of severe respiratory distress. In the 22 surviving infants, the abnormal signs cleared completely in three to 24 months. Eleven lung biopsies were performed on 10 infants, and autopsies were done on all who died. The pathologic material showed a progression from an early immature pattern of the lungs through areas of hyperinflation and collapse in the early stage to overinflation in infants dying during the second stage. We share Auld's3 belief that pulmonary tissue is particularly susceptible to injury from a high concentration of oxygen. Thus, the Wilson-Mikity syndrome may well be due to oxygen toxicity in some patients. Bronchopulmonary dysplasia, the Wilson-Mikity syndrome and pulmonary lesions secondary to oxygen toxicity in animals have similar microscopic lesions. Sheperd29 found radiologic evidence suggestive of pulmonary fibrosis in six of 70 infants with hyaline membrane disease followed for two to five years. It was the belief of his group that oxygen toxicity alone was not the cause of this process. On the other hand, Westgate46 suggests that too much oxygen may be harmful in the respiratory distress syndrome, but that the situation is complicated by the fact that many of the patients with symptoms of hyaline membrane disease need the oxygen to survive.
Obstetrical Aids Aimed At Lowering Premature Mortality
2) NEUROLOGIC SEQUELAE.
The New England Journal of Medicine14 in an editorial asks this very important question: "Does vigorous therapeutic intervention spare the brain from harm, or are infants being kept alive only at the expense of irreversible central nervous system damage?" Fisch 1S feels that neurological abnormalities in the first year of life are more frequent in survivors of the respiratory distress syndrome than in subjects of similar weight. His study involved 34,792 single live-born infants, including 59 survivors of the respiratory distress syndrome. The editor of the 2970 Yearbook of Pediatrics16 commented that, "The factors in the premature infant which are responsible for the production of respiratory distress may also be responsible for direct damage to the central nervous system." Robertson34 did not find a statistically significant increase in neurological abnormalities in children who survived the respiratory distress syndrome. She compared such children at sixand-one-half years with matched controls.
3) DEVELOPMENTAL SEQUELAE.
Psychological examination was done as part of follow-up studies in 77 children.1 Physical, neurological and psychological examination showed the same proportion of abnormalities in the controls as in the ones who survived RDS, which would indicate that RDS does not increase the handicaps associated with prematurity.
Levine always concluded his lectures on handicaps of the premature infant by showing Tables 2 and 3 in which he summarized his views on obstetrical aids aimed at lowering premature mortality and essentials of good postnatal care.28 Most of the observations listed have been discussed in the October issue oiPediatnc Annals. I will comment merely on three points:
1) General measures to prolong gestation period. Zlatnik and Fuchs48 have advocated the use of I.V. alcohol to inhibit premature labor. They reported 21 patients who received ethanol and found that the median postponement in the ethanol group was 19 days compared with less than one day in a control group. No deleterious effects were seen in infants where the mother received ethanol.
2) Premature accommodations. Whereas a special premature unit was advocated in the 1940s, 1950s and even 1960s, we now firmly believe in the concept of neonatal special care units discussed by Dr. Howard Fox in the October issue of Pediatric Annals. Let me emphasize my own feeling that all ill neonates belong in such a unit. Obviously, the majority of patients will be the small low birth weight babies requiring special care. We feel that such a unit must have an adequate number of incubators, facilities for phototherapy, heating devices, as well as all types of monitoring equipment ranging from apnea to cardiac and even blood pressure devices. Infusion pumps to give small amounts of intravenous fluids must be available. There must be an adequate number of medical and nursing personnel to take care of all infants in such a unit. A neonatology - or I should say - a perinatology team must be available
3) Preparations for discharge. Berg8,9 and I6,7 have lectured and written extensively about discharging babies at weights lower than five to five-and-one-half pounds. We feel very strongly that there is no need for highly specialized hospital care for small infants once the following three criteria have been met: 1) The medical staff thinks that babies have no disease or disabilities and can maintain themselves in a room air environment; 2) The nursing staff believes that parents have been instructed in the proper care and handling of the low birth weight baby including proper amount and type of feeding; 3) A proper home environment exists as determined by visiting nurse and/or social service departments. If the above criteria are met, babies with a weight of 41Zz lb. and even less can be discharged safely. The lowest discharge weight in our series was three lb. and 13 oz.7
Essentials of Good Postnatal Premature Care
If early discharge of low birth weight babies from the hospital is found possible, we insist on adequate follow-up care of these infants.
1. Ambrus. CM.; Weintraub, D.; Niswander, K.; Fischer. L; Fleishman, J.; Bross, I. and Ambrus. J. L. Evaluation of respiratory distress syndrome at 4 years of age. Am, J. Dis. Child. 120 (1970), 296-302.
2. Astrup, P.; Jorgensen, K.; Andersen. 0.; Sigaard and Engel, K. Acid-base metabolism: new approach. Lancet 1 (1960), 1035.
3. Auld, P. Oxygen therapy for premature infants. J. Pediat. 78 (1971). 705-709.
4. Avery. M. The Lung and Its Disorders in the Newborn Infant. Philadelphia: W.B. Saunders, 1968.
5. Avery. M. and Mead. J. Surface properties in relation to atelectasis and hyaline membrane disease. Am. J. Dis. Child. 97 (1959), 517
6. Bauer, C. Low birth weight babies - changes in procedure. XIII. Int. Congress of Pediatrics, Vienna, Austria, 1971.
7. Bauer. C. and Tinklepaugh, W. Low birth weight babies in the hospital. A survey of recent changes in their care, with special emphasis on early discharge. Clinical Ped. 10 (1971). 467-469.
8. Berg, R. and Salisbury. A. Discharging infants of low birth weight. Am. J. Dis. Child. 122 (1971), 414417.
9. Berg, R.; Salisbury, A. and Kahan, R. "Early" discharge of low birth weight infants. J.A.M.A. 210 (1969), 1892.
10. Bernard, E. The pulmonary syndrome of Wilson and Mikity, and respiratory function in very small premature infants. Pediat. Clin. N. Amer. 13 (1966). 999.
11. Clements, J.; Platzker, A.; Tierney, D.; Hobel. C; Creasy, R.; Margolis. A.; Thibeault, D.; Tooley, W. and Oh, W. Assessment of the risk of the respiratorydistress syndrome by a rapid test for surfactant in amniotic fluid. W. Eng. J. Med. 286 (1972). 1077-1081.
12. Donald, I. Radiology in neonatal respiratory disorders. Brit. J. Radiol. 27 (1954), 500.
13. Dunn, P. The respiratory distress syndrome of the newborn: immaturity vs. prematurity. Arch. Dis. Child. 40(1965). 62.
14. Editorial. Fate of survivors of hyaline membrane disease. We w Eng. J. Med. 279 (1968), 111-112.
15. Fisch, R.; Gravem, H. and Engel, R. Neurologic status of survivors of neonatal respiratory distress syndrome: preliminary report from the collaborative study. J. Pediat. 73 (1968), 395-403.
16. Gellis, S. Neurologic Status of Survivors of Neonatal Respiratory Distress Syndrome. In Yearbook of Pediatrics, S. Gellis. ed. New York: Yearbook Medical Publishers, 1970. 431.
17. Gellis. S. and Hsia. D. The infant of the diabetic mother. Amer. J. Dis. Child. 97 (1959). 1.
18. Gluck. L. Foretelling - and averting - hyaline disease. Medical World News 11 (1970), 4.
19. Gluck. I. Surfactant: 1972. Pediat. Clin. N. Amer. 19 (1972). 325.
20. Gluck. L. The respiratory distress syndrome. Pediatric Portfolio 1:16 (1971).
21. Gluck. L.; Kulovich, M.; Borer. R.; Brenner, P.; Anderson, G. and Spellacy. W. Diagnosis of the respiratory distress syndrome by amniocentersis. Amer. J. Obstet. Gynec. 109 (1971), 440.
22. Gluck. L; Motoyama, E.; Smits, H. and Kulovich, M. The biochemical development of surface activity in mammalian lung. I. Ped. Res. 1 (1967), 237.
23. Gluck. L.; Scribney. M. and Kulovich. M. The biochemical development of surface activity in mammalian lung. II. Ped. Res. 1 (1967). 247.
24 Gregory. G.. Kitterman, J.; Phibbs, R.; Tooley. W. and Hamilton, W. Treatment of idiopathic respiratory distress syndrome with continuous positive airway pressure. N. Eng. J. Med. 284 (1971). 1333.
25. Grossman. H.; Berdon, W.; Migraki. A. and Baker, D Neonatal focal hyperaeration of the lung (Wilson-Mikity syndrome). Radiology 85 (1965). 409.
26. Hodgman, J.; Mikity. V.; Tatter, D. and Cleveland, R. Chronic respiratory distress in the premature infant. Pediatrics 44 (1969). 179-195.
27. Klaus, M.; Clements, J. and Havel, R. Composition of surface-active material isolated from beef lung. Proc. Natl. Acad. Sci. 47 (1961), 1858.
28. Levine. S. and Bauer. C. From lectures to Institute in Care of Premature Infants at the New York Hospital-Cornel! Medical Center, 1948-1968.
29. Levine. S. and Gordon, H. Physiologic handicaps of the premature infant. J. Dis. Child. 64 (1942), 274
30. Nelson, G. Relationship between amniotic fluid lecithin concentration and respiratory distress syndrome. Am. J. Obst. Gyn. 112 (1972), 827-833.
31 . Nelson, N. On the etiology of hyaline membrane disease. Ped. Clin. N. Amer. 17 (1970). 943.
32. Oliver. R. Temperature regulation and heat production in the newborn. Ped. Clin. N. Amer. 12 (1965), 765.
33. Pattle, R.; Claireaux, A.; Davies, D. and Cameron, A. Inability to form a lung lining film as a cause of respiratory distress syndrome in the newborn. Lancet 2 (1962). 469.
34. Robertson, A. and Crichton, J. Neurological sequelae in children with neonatal respiratory distress. Am. J. Dis. Child. 117 (1969), 271-275.
35. Rudolph, A.; Desmond, M. and Pineda, R. Clinical diagnosis of respiratory difficulty in the newborn. Pediat. Clin. N. Amer. 13 (1966), 669.
36. Sarkozi, L.; Kovacs. H.; Fox. H. and Kerenyi. T. A modified method for the estimation of phosphatidyl chlorine: sphingomyelin ratio in amniotic fluid and its use in the assessment of fetal lung maturity. Clinical Chemistry (Sep. 1972).
37. Scarpelli, E. Pulmonary Surfactants and their Role in Lung Disease In Advances in Pediatrics, I. Schulman, ed. Vol. 16. New York: Yearbook Medical Publishers, 1969. 177.
38. Schwartz. M. and Bauer, C. Respiratory distress syndrome of the newborn. Hawaii Med. J. 24 (1965). 195.
39. Shepard. F.; Johnston. R.; Klatte, E.; Burko, H. and Stahlman, M. Residual pulmonary findings in clinicai hyaline membrane disease. New Eng. J. Med. 279 (1968), 1063-71.
40. Steiner, R, The radiology of respiratory distress in the newborn. Brit. J. Radiol. 27 (1954), 491.
41. Strang, L.B. Respiratory distress syndrome in newborn infants. Brit. Med. Bull. 19 (1963). 45.
42. Strang, L.; Anderson, G. and Piatt, J. Neonatal death and elective caesarean section. Lancet 1 (1957), 594.
43. Usher, R. Reduction of mortality from respiratory distress syndrome of prematurity with early administration of glucose and sodium bicarbonate. Pediatrics 32 (1963). 966.
44. Usher, R. The respiratory distress syndrome of prematurity. Ped. Clin. N. Amer, ß (1961), 525.
45. Usher, R.; Allen. A. and McLean, F. Risk of respiratory distress syndrome related to gestational age, route of delivery, and maternal diabetes. Amer. J. Obst. Gyn. 111 (1971). 826.
46. Westgate. H.; Fisch. R.; Lander, L. and Staub. H Pulmonary and respiratory function changes in survivors of hyaline membrane disease. Dis. Chest 55 (1969). 465-470.
47. Wilson. MG. and Mikity, V. A. new form of respiratory disease in premature infants. Amer. J. Dis. Child. 99 (1960), 489
48. Zlatnik, F. and Fuchs. F. Controlled study of ethanol in threatened premature labor. Am. J. Obst. Gyn 112 (1972) 610-612.
Systems Involved In Respiratory Difficulties
Obstetrical Aids Aimed At Lowering Premature Mortality
Essentials of Good Postnatal Premature Care