Pediatrics
VOLUME 19 MARCH 1957 Nuxtnui 3
AMERICAN ACADEMY OF PEDIATRICS PROCEEDINGS
THE ROLE OF OXYGEN IN RETROLENTAL FIBROPLASIA E. Mead Johnson Award Address
By Arnall Patz, M.D. Departments of Ophthalmology and Pediatrics, District of Columbia General Hospital and the Hofiberger Research Laboratories, Sinai Hospital, Baltimore, Maryland
[ In presenting an E. Mead Johnson award problem of retrolental fibroplasia than I)i. Patz. to Dr. Patz, Dr. Bakwin, President of the Acad- His contributions are considered to be a beauti- cmv, made the following remarks: “Dr. Arnall fiil exercise in experimental medicine, the more Patz, Recipient of the Second E. NIead Johnson noteworthy 1)ecause he made them while en- Award, was born in Elberton, Georgia, in 1920. gaging in the private practice of ophthalmol- He attended Emory University at Atlanta and ogy. graduated from the Medical School at that Uni- [“It is for these works that the Academy’s versitv in 1945. Dr. Patz interned at Sinai Committee on Awards has selected 1)r. Patz as Hospital in Baltimore; served in the Medical the recipient of an E. \lead Johnson Award Corps of the Army for 2 years; following which for 1956. This award consists of a handsome he became resident in Ophthalmology at the scroll amid a check for $1000 which we take District of Columbia General Hospital. In 1950 pleasure in iio\v presenting to Dr. Patz. and 1951 Dr. Patz was Research Fellow in [“Dr. Patz will honor us by giving a r -suni ’
Ophthalmology at the Armed Forces Institute of his work which has contributed SO miiticli to of Pathology. pe(liatricS. [“Dr. Patz is certified b ’ the American Board [ Dii. P Tz: “I should like to exj ress my of Ophthalmology and serves as an instructor in thanks to the American Academy of Pediatrics
Ophthalmology at Georgetown Umiiversitv and for the honor ou have accorded nie. As an Johns Hopkins University. During the past 9 ophthalmologist it is particularly gratifying to \ears Dr. Patz has published 15 papers, 10 of know that the work (lone in con( ueriI1g retro- them relating to his clinical studies, backed up lental fibroplasia has received recognition from by animal experimentation, which have clearly this distinguished group. demonstrated the adverse effects of oxygen [“Although I have been named as the recipi- administration in relation to retrolental fibro- ent of this a vard, it is, in fact, a tribute to all plasia in small infants. No one in this coun- the prominent scientists who have contributed try has been more influential in solving the to the ultimate victors’ against retroleutal fibro-
Presented at the Annual Meeting, October 10, 1956. These studies were aided by grants from the E. Matilda Ziegler Foundation for the Blind, The Na- tional Society for the Prevention of Blindness, and the National Institute of Neurological Diseases and Blindness, United States Public Health Service. ADDRESS: 1212 Eutaw Place, Baltimore 17, Maryland. 504
Downloaded from www.aappublications.org/news by guest on October 1, 2021 AMERICAN ACADEMY OF PEDIATRICS - PROCEEDINGS 505 plasia. The work of Owens and Owens in iden- oxygen therapy and incidence of cicatricial tifying the true clinical course and of Frieden- RLF. Chart I summarizes these uncon- wald and Reese in clarifying the histopathology trolled data collected between July, 1948, of the disease deserve special recognition. Im- and December, 1950, and shows the con- portant contributions have been made by Boe relation between number of days of oxygen Hellstr#{246}m and Lars Gyllensten of Sweden, Nor- therapy and incidence of retnolental fibro- man Ashton and Mary Crosse of England, Kate plasia (residual membrane cases only). Campbell of Australia, Harry Gordon, Everett In 1949, Kinsey and Zachanias2 reported Kinsev, and Jonathan Lanman of this country, that three changes in pediatric cane, namely, and several others. [“I have been fortunate in having a loyal addition of iron medication, use of water- group join me in these studies. Dr. Leroy Hoeck miscible vitamins and increased use of oxy- has collaborated in the nursery study. Dr. gen were associated with the increased in- Edgar de Ia Cruz and Dr. Thomas Kleh as- cidence of RLF. I think it is fain to state that sisted in the eve examinations. Mrs. Ann East- between 1948 and 1950 most pediatric and ham, Dr. Miriam Reiner and Dr. Don Higgen- ophthalmologic authorities did not consider botham contributed to the animal studies. In that overuse of oxygen was related etio- accepting this award I thank you in the name logically to retrolental fibroplasia in spite of my entire research team and I thank you for of this epidemiologic report. Because of the privilege of addressing this assembly.”] this lack of suspicion of oxygen by leading authorities on the subject, it was extremely O BSERVATIONS on the role of oxygen ad- difficult to convince ourselves of the justifi- ministration in retrolental fibroplasia cation of restricting oxygen for a certain (RLF) have been conducted in the pre- number of infants, as would be necessary in mature nursery of the District of Columbia a controlled randomized study. Hospital with Dr. Leroy Hoeck, Depart- Fortunately for us, Dr. Harry H. Gordon, ment of Pediatrics, since 1948.1 Our atten- then Professor of Pediatrics at the Univer- tion was first focused on oxygen by one of sity of Colorado, spoke before the pediatric our first cases of RLF occurring in an in- staff of the Johns Hopkins Hospital in fant where special measures were utilized November, 1950. He stated that at the Pre- to deliver a high oxygen concentration for mature Center of the Colorado General several days after birth. This incidental Hospital, oxygen therapy routine was cur- observation suggested, what then appeared tailed considerably for several months, and an extremely remote possibility, that oxy- coincidental with this change in policy a gen therapy might in some way be related sharp decrease in RLF cases occurred. Of to the disease. more importance to us, he reported that The infants in the premature nursery during this period the smaller premature were examined at intervals in the nursery infants were apparently thriving with much and afterwards in a special clinic during less added oxygen, as they used to do be- a period between July, 1948, and December, fore efficient methods of giving high con- 1950. However, during this period, there centrations of oxygen were available. This were no rigid controls on oxygen administra- gave us the first reassurance that a rigid tion and indeed the only recording of oxy- curtailment of oxygen might be a safe pro- gen that was available for some premature cedune. In January, 1951, our controlled infants was that on the nursing notes where study was started, placing alternate infants the number of days of oxygen therapy was under 3.5 lb birth weight, into either a recorded; occasionally the flow rate was “high” or “low” oxygen routine. It was still also mentioned. with considerable anxiety on our part that Even from this poorly supervised method the small infants who drew a “low” oxygen of administering and recording oxygen ad- routine were entered into that regimen in ministration, there was noted a strong as- the study. The nursing staff also shared this sociation between the number of days of anxiety and it was not uncommon, early in
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ChAnT I. Showing correlation of retrolental fibroplasia with number of days in continuous oxygen according to birth weight. X represents infant with cicatricial retrolental fibroplasia niembranes and dot represents infant with normal eyes. (Nonrandomized data, July, 1948, through I)ecember, 1950.)
the study, to find that the night nurse had (1,590 gm), entered the study during the turned the oxygen on on increased that al- first year and under :3 lb 5 oz (1,500 gui) ready flowing to an infant in the “low” during the second year. group, just to feel more secure. On an alternate admission basis, the in- The controlled study was carried out in fants were placed into either a high oxygemi the nursery from January, 1951, until May, group on a curtailed oxygen group on ad- 1953. At this latter date, we first observed mission to the nursery. Those infants in high in our laboratory ocular lesions that were oxygen received 60 to 70% oxygen concen- indistinguishable from those of early hu- trations for 28 days on longer; whereas, m n RLF following the administration of those in restricted oxygen received concen- oxygen to young animals. Our controlled trations usually under 40% an(l only for nursery data involving 120 infants under specific clinical indications. The nursery 3.5 lb birth weight implicated oxygen and, routine was otherwise identical in the two with the added incrimination of oxygen groups. from the animal data, we felt that our own Oxygen tensions were controlled by imi- controlled study should be terminated. A cubator samplings at 8-hour intervals with brief r#{233}sum#{233}ofthe nursery study which has a panamagnetic analyzer (accurate within
been previously neportedl 3 is cited. 2% concentration). The infants in each group were examimied PREMATURE NURSERY STUDY ophthalmoscopically at regular intervals With five exceptions all infants included and followed after discharge from the nun- iii the controlled investigation were de- seny in a special clinic until they were 6 livered in the District of Columbia General months of age. Hospital Obstetrical Division. Premature The ocular findings were classified to con- infants with birth weights under 3.5 lb form to the standard classification recom-
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z 10 LU (-) a: 0 LU 0 5 i ci- - - -. - -ri- - - ---- UNDER 1001-S 1251- 1501- 1000 1250 1500 1590
BIRTH WEIGHT IN GRAMS
CIIAII1 II. Showing striking difference in incidence of cicatricial retrolental (ibm-
l)l L511t l)etWeen higli_ and low-oxygen casts vitliin each bimth ‘eigl t group. 11111111t5 with birth weights over 1,500 gui were included (luring the first year only. (Randomized contmolle(l (hlt l, January, 1951, to January, 195:3.) mended by Reese, Owens, and King.4 Chart fants shown in Chart II shows a chi2 of 1.44 II shows the miuml)er of cases in the con- with a p- ’altie of 0.01. trolled study develo1)ing advanced residual During the controlled Stu(ly 21 cases of retrolental niembranes (cicatricial stages C, active disease (active stages 1 and 2) whichi D, amid E) according to birth weight after regressed to normal in the high oxygen dropping the 15 infants oven 1,500 gm in group and 9 cases of active disease (active the first year. From this chart one notes stages 1 and 2) which regressed to normiial that 12 of 60 infants with birth weights in the low oxygen group were noted. under 1,500 gin in the high oxygen group This controlled nursery data is now sup- developed advanced retrolental fibroplasia. ported by the controlled study of Lanman In the curtailed oxygen group, 1 of 60 in- and co-workers5 and the larger co-operative fants (IevelOpe(I the advanced disease. This study of Kinsey and associates.’ There are infant, however, received oxygen for 10 also several excellent nonranclomized clays. studies7ul further incriminating oxygen in
There was fl() indication of any pediatric the etiology of retnolental fibroplasia. The difficulties arising from the rigid curtailment report of Gordon and co-workers’ deserves of oxygen administration. No significant special mention in view of the long -follow- difference iii mortality rate was noted be- up and large number of cases involved. tween the infants in the high and in the EXPERIMENTAL OBSERVATIONS low oxygen groups. A statistical appraisal of the data obtained We were mnost fortunate in the expeni- in the first 24 months of the controlled mental phase of this study in finding that randomized study based on these 120 in- at birth the retinas of mouse, rat, kitten and
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GESTATIONAL AGE OF FETUS
7 Months 6 Months 5 Months ;hS Retinal V
OPTIC Newborn Kitten NERVE Newborn puppy ORA SERRATA 4 day old rat.
0 Schematic drawing showing chronology of retrool vascuIar zaton in human fetus. The retinal vessels advance from the Disc to the Ora between the 4th and 8th months of gestation. The relationship to retinal vessel devel- opment in the rat, cat, and dog are indicated.
Fic. 1. dog were incompletely vascularized and satisfactory solution for protecting the (hiffenentiated so that we were dealing with mother against pulmonary oxygen poisoning retinas comparable to that of the small pre- evolved. This was accomplished by main- mature infant as depicted in Figure 1. Sev- taming a nursing mother animal with her eral experiments were then instituted in young in room air for every litter in the 1951 to evaluate primarily the ocular, but oxygen chamber. At 24-hour intervals the also the systemic effects of added oxygen on mother animals in oxygen were exchanged these species. The newborn opossum in the with those in room air. This provided a 24- pouch stage was also studied. Due to many hour rest in air and eliminated pulmonary pitfalls and failures it was not until May, oxygen poisoning in the mothers. A healthy 1953, that the animal counterpart of human foster mother animal was then always avail- RLF was successfully produced. able to nurse the young animals which were The greatest obstacle during the early maintained continuously in oxygen. In some experiments was pulmonary oxygen poison- experiments the young were divided be- ing in the nursing mother animals. It is tween the two mothers at the start so that well established that oxygen above 70% con- each mother animal was assigned half hen centration after 48 hours causes irritation own litter and half of her control partner’s of the adult human or animal pulmonary litter. This provided litter mates as controls alveolar epithelium. Pulmonary edema, and insured practically identical nutritional hemorrhages and ultimate asphyxia result factors from maternal lactation in oxygen from the pulmonary engorgement. The treated and control young animals in air alveolar epithelium of the newborn animal (Fig. 2). The opossum in the pouch stage or premature infant is much more resistant was studied in view of the extreme pre- to the pulmonary toxicity of oxygen, and maturity of newborn pouch opossums. The these young subjects can withstand oxygen newborn opossum is known to enter the at 70% to 100% concentrations for much maternal pouch in an extremely premature longer periods without alveolar damage state and incubate there for several weeks. resulting. Several months lapsed before a However, the mother animals showed a
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