Influence on Retrolental Fibroplasia of intramuscular Vitamin E Administration During Respiratory Distress Syndrome

Influence on Retrolental Fibroplasia of Intramuscular Vitamin E Administration During Respiratory Distress Syndrome JAMES E. PUKLIN, MD, ROGER M. SIMON, MD, RICHARD A. EHREN KRANZ, MD

Abstract: The effect of vitamin E administered during the acute phase of therapy for respiratory distress syndrome (RDS) on the development of retinopathy of prematurity (ROP) was evaluated in a randomized double-masked study. One hundred neonates received either vitamin E or placebo intramuscularly within the first 24 hours of birth and at 24,48, and 168 hours respectively. Additional doses were given twice weekly whi Ie the infant remained in an oxygen-enriched environment and could not tolerate feedings and vitamin supplements. Parenteral vitamin Etreated infants had significantly increased serum vitamin E levels compared to placebo-treated infants. Most placebo-treated patients attained normal serum vitamin E levels during the second week of life because of nutritional sources of vitamin E. Infants in both groups had RDS of similar severity. Seventy-four infants, 37 vitamin E-treated and 37 placebotreated, survived longer than 10 days and had ophthalmologic examinations. Active changes of Stage I and Stage II ROP were noted in 17 of those patients; 9 (24.3%) vitamin E-treated and 8 (21.6%) placebotreated patients (P = 0.572). No infants developed severe cicatricial changes, and their retinal findings regressed . The incidence of risk factors associated with ROP development occurred equally in the vitamin E-treated and placebo-treated infants that developed ROP. Thus, vitamin E administration as described in this study did not result in any further reduction in the incidence of the active stages of ROP over that seen with standard neonatal care, which included daily oral Vitamin E supplements. [Key words: alpha tocopherol , bronchopulmonary dysplasia, high-risk il1fants, respiratory distress syndrome, retinopathy of prematurity, retrolental fibroplasia, Vitamin E.] Ophthalmology 89 :96103, 1982

From the Di vision of Perinatal Medicine, the Department of Pediatrics . and the Departments of Obstetrics and Gynecology, and Ophthalmology and Visual Science , Yale Uni ve rsity School of Medicine , New Haven, Connecticut. Presented at the Eighty-sixth Annual Meeting of the American Academy of Ophthalmology, Atlanta, Georgia, November 1-6, 1981 .

96

Supported in part by Visi on Center Grant EY 00785, Connecticut Lions Eye Research F oundation, Inc .. Re search to Preve nt Blindness. and grant (RR-00125 NIH) from the Children's Clinical Research Center and by grant (HD 10949) from the United States Publi c Health Service. Reprint requests to James E. Puklin. MD, Suite 3056CB, 789 Howard Avenue, New Haven, CT 06510. 0161-6420/82/0200/096/$00.90

© American Academy of Ophthalmology

PULKIN, el al • VITAMIN E RETROLENTAL FIBROPLASIA

Retrolental fibroplasia (RLF) was first described as a disorder of extreme prematurity in 1942.1 Its subsequent history has been well documented. 2 It increased as a cause of blindness, reaching almost epidemic proportions in the early 1950s. It was initially associated with oxygen therapy in 195I,3 and the subsequent curtailment of oxygen use led to a decline in RLF and an increase in infant morbidity and mortality. With improved understanding of high-risk perinatal and neonatal problems, intensive programs have been developed to care for these problems. The proliferation of this improved medical technology in the form of neonatal intensive care units has resulted in a significant decline in the mortality rate of very low birth weight high-risk newborns. 4 Because of this increased survival, an increase in the number of RLF cases has occurred,5 and it is estimated that it could be approaching the so-called "epidemic" level of RLF, which was observed in the preintensive care unit years from 1942 to 1953. 6 In 1949, Owens and Owens 7 were the first to suggest the role of vitamin E (alpha tocopherol) as a supplement to reduce the incidence of RLF. Subsequent testing of vitamin E in other institutions failed to confirm their observations. Nearly 20 years after Owens and Owens' suggestion, interest again increased regarding the potential for vitamin E to effect beneficially the pathogenesis of RLF. This was the result of increasing awareness that premature infants were relatively deficient in vitamin E, and that vitamin E was an antioxidant and free-radical scavenger having an important basic metabolic role as an organizer and stabilizer of membranes at the cellular and subcellular level. 8 A preliminary study on infants 9 and experimental work in the kitten model of RLpo,ll have suggested that vitamin E might have a beneficial effect on RLF. We have been interested in the effect of vitamin E on the development of oxygen-induced pulmonary damage. A preliminary investigation 12 suggested that the administration of vitamin E during the acute phase of therapy for respiratory distress syndrome (RDS) appeared to modify the development of bronchopulmonary dysplasia (BPD). Thus, a randomized double-masked clinical trial was initiated to verify the effect of parenteral vitamin E on BPD13 and RLF. The purpose of this report is to describe the effect of vitamin E on the development of RLF (hereafter referred to as retinopathy of prematurity-ROP) in this clinical trial population.

MATERIALS AND METHODS One hundred neonates with the diagnosis of RDS defined by standard clinical, radiographic, and laboratory criteria 14 were admitted to the study and were treated within the first 24 hours of life with either vitamin E or vitamin E-placebo (Vitamin E Injectable and the vehicle for Vitamin E Injectable, Hoffmann-

LaRoche, Inc., Nutley, NJ) in a randomized doublemasked manner. Doses of 20 mg/kg (0.4 mVkg) were administered intramuscularly upon admission to the study and 24, 48, and 168 hours later. Additional doses were given twice weekly as long as the infant remained in an oxygen-enriched environment and could not tolerate feedings and vitamin supplements. Permission to include each infant in the study was obtained by informed consent of the parents. This protocol was approved by the Human Investigation Committee, Yale University School of Medicine. Although any infant with the diagnosis of RDS was a candidate for this study, parental consent was sought primarily for those infants with moderate to severe RDS requiring early treatment with high inspiratory oxygen concentrations (F 10 2) and ventilatory assistance. Except for the investigational drug, all the infants received similar care and were managed in accordance with presently accepted methods for the treatment of RDS. The F 1 0 2 and the extent of ventilatory assistance were adjusted to maintain an arterial P02 (Pa0 2) between 50 and 75 mm Hg and an arterial PC02 (PaC02) between 30 and 45 mm Hg. An initial application of continuous distending airway pressure (CDAP) by nasal prongs was considered if an F 10 2 greater than 0.45 was required to maintain a Pa0 2 greater than 50 mm Hg and if the infant did not have apnea. An initial application of CDAP by an endotracheal tube was considered if an F 10 2 greater than 0.70 was required to maintain a P a02 greater than 50 mm Hg and if the infant did not have apnea. Positive pressure mechanical ventilation with CDAP was initiated if an F 102 = 1.00 was required to maintain a Pa0 2 greater than 50 mm Hg and/or if the infant had apnea, a persistent acidosis (pH < 7.2), or a PaC0 2 greater than or equal to 60 mm Hg or that was rising. Ventilatory assistance was provided by a time-cycled ventilator (Bourns Infant Pressure Ventilator®, model BP200, Bourns, Incorporated, Life Systems, Riverside, California) or a volume-cycled ventilator (Bourns Infant Ventilator®, model LS 104-150), both of which were pressure limited and operated in an intermittent mandatory ventilation mode. Other ventilator settings, including the respiratory frequency, the inspiratory: expiratory ratio, the peak proximal airway pressure, and the end expiratory pressure or CDAP, were adjusted according to the recommendations of Taghizadeh and Reynolds. 15,16 In addition, while requiring supplemental oxygen, each infant's hematocrit was maintained over 40% with packed red blood cell transfusions. All of the infants were exposed to nutritional sources of vitamin E. During the acute phase of RDS therapy they received an intravenous protein alimentation solution containing 2.5 IU vitamin E/liter. A lipid emulsion was administered if the infants continued to require intravenous nutrition following the acute stage of RDS, providing they were not hyperbilirubinemic or did not require an F 10 2 > 0.30. Enteral feedings with a proprietary formula designed for 97

OPHTHALMOLOGY • FEBRUARY 1982 • VOLUME 89 • NUMBER 2

the premature infant (16 IU vitamin E/liter) or human milk (approximately 3 IU vitamin E/liter) were initiated and advanced as tolerated. In addition, a daily supplement of an oral multivitamin preparation and an oral vitamin E preparation (Aquasol E®, USV Pharmaceutical Corp., Tuckahoe, NY) were started once the infants regularly tolerated feedings. The daily dose of the oral vitamin E preparation provided 50 IU vitamin E to infants weighing less than 1000 g and 25 IU to infants weighing over 1000 g.17 Clinical data relating to the entire study population are shown in Table 1. The vitamin E-treated and placebo-treated groups were compared on a variety of covariant factors. No statistically significant differences in race, gestational age, birth weight, one- and five-minute Apgar scores, patent ductus arteriosus, intraventricular hemorrhage, age at treatment, and number of doses were found. However, differences in the male:female ratio, the number of infants born at Yale-New Haven Hospital vs those transferred to the Newborn Special Care Unit, the incidence of air leaks , and the number of infants in which a patent ductus arteriosus was closed with indomethacin treatment and/or ductal ligation were noted between the groups. Of the 100 study patients, 19 died at less than 10 days of age. Sixteen of these died due to intraventricular hemorrhages: nine from the vitamin E-treated group and seven from the placebo-treated group. Three other placebo-treated infants died: one with sepsis, one with tension pneumopericardium and cardiac tamponade, and one with pulmonary hemorrhage. Ophthalmic examinations were performed on 37 of the remaining 38 vitamin E-treated and 37 of the remaining 43 placebo-treated patients . The other vitamin Etreated patient and three of the placebo-treated pa-

tients were lost to follow-up. Three other placebotreated patients expired later in the neonatal period (one as a result of an intraventricular hemorrhage and two with necrotizing enterocolitis). Table 1 also provides descriptive data about the patients in each group who had ophthalmic examinations and whose hospital courses were analyzed for this report. The composition of each of these subgroups corresponds to its respective larger group, and the similarities and differences noted between the treatment groups in the total study population remain . Serum vitamin E levels were determined by the micromethod of Fabianek et aIlS on blood samples obtained prior to treatment and during the treatment period. As shown in Table i, vitamin E-treated and placebo-treated patients received the first dose at mean ages of 14.3 and 13 .8 hours, respectively and received an average of six and five doses, respectively. The hospital course of each of the 37 vitamin Etreated and placebo-treated patients who had ophthalmic examinations was analyzed for the duration, in hours , of supplemental oxygen, positive pressure mechanical ventilation, and endotracheal CDAP. Ophthalmic examinations were performed by a retina specialist (JEP) who did not know which infants were treated with vitamin E and which with the placebo . Most initial examinations took place after the discontinuation of supplemental oxygen and prior to hospital discharge. Patients who developed ROP were followed until regression or stabilization occurred. Infants without ROP after removal from oxygen were not examined again. Mydriasis was accomplished by administering one drop of2.5% phenylephrine hydrochloride ophthalmic solution and one drop of 0.5% tropicamide ophthalmic solution to each eye at Y2-hour intervals for

Table 1. Patient Profile Study Population Variable Number Males :females White:nonWhite Gestational age (wks) Birth weight (g) Apgar score: 1 minute 5 minute Inborn:transport Air leaks Patent ductus arteriosus No . requiring Rx* Intraventricular hemorrhage Age (hr) at treatment No, of doses of vitamin E *

Vitamin E

Placebo

Vitamin E

Placebo

47 27:20 44:3 30.3 ± O.4t 1427 ± 63

53 21 :32 45:8 30 ,5 ± 0.4 1425 ± 69

37 (79) * 20:17 34:,3 30.8 ± 0.4 1484 ± 73

37 (70) 13:24 33:4 30.9 ± 0.4 1540 ± 85

4.4 ± 0.3 6.3 ± 0.3 26:21 18 (38) 29 (62) 12 (41) 16/27§ (59) 14,3 ±0,9 6.3 ± 0.9

3.9 ± 0,3 5,9 ± 0.3 36:17 27 (50) 33 (62) 25 (76) 21 /39 (54) 13 ,8 ± 0.9 4.8 ± 0.4

Figures in parentheses denote %,

t Mean ± SEM . t No, of infants in which the patent ductus arteriosus was closed with indomethacin and/or ductal ligation. § Denominator denotes no. of infants evaluated by CT scan and/or ultrasound.

98

Pati ents with Ophthalmologic Examinations

4.6 ± 0.4 6.7 ± 0.3 22:15 12 (32) 26 (70) 10 (38) 7118 (39) 14 .3 ± 1 ,0 7 ,1±1 .0

4,2 ± 0.4 6.1 ± 0.3 26:11 17 (46) 26 (70) 20 (77) 11 /26 (42) 14.0 ± 1.0 5,1 ± 0 .4

PULKIN, et al • VITAMIN E RETROLENTAL FIBROPLASIA

three doses. The eyelids were held open with a small lid speculum. Assistants stabilized the infants head and body. Topical ocular anesthesia was achieved by administering one drop of 0.5% proparacaine hydrochloride ophthalmic solution to each eye. All retinas were examined by binocular indirect ophthalmoscopy using either a 20 diopter or a 33 diopter lens. Scleral indentation was performed on each eye for 360°. Fluorescein angioscopy was performed by injecting 0.15 to 0.30 cc of 5% fluorescein into a peripheral vein. Angioscopy was performed on a selected basis on those infants where it was needed to help differentiate between immature but normally developing peripheral retinal vascularization and the earliest changes of ROP. It was also performed when there was a question of the presen,ce of preretinal .neovascularization and during certam follow-up examinations to clarify equivocal cases of regression. Since the ROP classification system described by Reese et al l9 is insufficiently precise for grading the earliest changes of ROP detected by current examination techniques, the classification system shown in Table 2 was developed and used for grading retinal findings. Eyes in which the transition between the vascular posterior and avascular anterior retina was gradual were classified as having vessel immaturity c?nsistent with prematurity and, therefore, were conSIdered normal. Such vessel immaturity frequently resulted in avascular anterior retina for 360°. Follow-up examinations of these eyes showed normal vasculogenesis. If a patient had asymmetrical retinal changes, the most severe findings were used for classification. Student's t-test for unpaired data, chi-square analysis, and the Fisher's exact test were used to test the significance of the study results. When data were not normally distributed, appropriate transformation were applied before statistical analysis.

RESULTS The effect of vitamin E administration on serum vitamin E levels is shown in Table 3. Upon admission to Table 2. Classification of Retinal Abnormalities Stage I

Stage II Stage III Stage IV Stage V

Vessels terminate at a distinct junction between avascular anterior retina and vascular posterior retina. May have some form of acquired arteriovenous shunt. There mayor may not be vessel dilatation and tortuosity at the posterior pole. Stage 1, plus extraretinal neovascularization of any degree with or without extraretinal hemorrhage. Stage II, plus one quadrant or less of peripheral retinal detachment. Stage III, plus a two or three quadrant retinal detachment. Stage IV, plus a total retinal detachment.

Table 3. Serum Vitamin E Levels Serum Vitamin E (mg/100 ml) Treatment

Pretreatment

+ 24 hours'

+ 72 hours

+ 168 hours

Vitamin E

0.45 ± 0.04t (37)

2.18±0.16 (31)

5.48 ± 0.60 (14)

3.89 ± 0.24 (30)

Placebo

0.43 ± 0.03 (46)

0.60 ± 0.05 (33)

0.60 ± 0.06 (18)

0.78 ± 0.08 (21)

*

Hours after the first dose. ± SEM of the number of determinations shown in parentheses.

t Mean

the study, the overall mean pretreated serum vitamin E level was 0.44 ± 0.03 mg/l00 ml (mean ± SEM), 0.45 ± 0.04 mg/IOO ml, and 0.43 ± 0.03 mg/IOO ml in the ,,:itamin E-treated and placebo-treated infants, respectIvely. The mean level in the placebo-treated infants was 0.78 ± 0.08 mg/IOO ml 168 hours after the first dose and 1.11 + 0.17 mg/IOO ml on the 14th day. However, in the vitamin E-treated patients, the mean value rose to 2.18 ± 0.16 mg/IOO ml (P < 0.001) 24 hours after one dose, and to 5.48 ± 0.60 mg/IOO ml (P < 0.001) 24 hours after the third dose. Serum vitamin E levels remained elevated with a mean of 3.89 ± 0.24 mg/IOO ml (P < 0.001) prior to the fourth dose of vitamin E at 168 hours after the first dose. Infants who received four doses of vitamin E had mean serum levels of 2.23 ± 0.20 mg/IOO ml on the 14th day after the first dose compared to infants who received five doses and had mean levels of 2.84 ± 0.34 mg/l00 ml on the 14th day. The total exposure to oxygen and ventilatory assistance during the hospital course was not significantly different between the vitamin E-treated and placebotreated groups (Table 4). There were also no significant differences between the peak F l 0 2 , the peak proximal inspiratory pressures and the peak CDAP to which the groups were exposed: 0.76 ± 0.05 vs 0.84 ± 0.04; 23.7 ± 1.7 vs 24.5 ± 0.9 cm H 2 0; and 5.6 ± 0.4 vS 6.2 ± 0.2 cm H 2 0, respectively, in the vitamin Etreated and t~e placebo-treated groups. Complete data for the duratlOn of oxygen exposure and of ventilatory assistance were not available for one patient because parts of the medical record had been lost. Therefore, these analyses for the vitamin E-treated group are based upon 36 instead of 37 patients. Ta?le 5.A summarizes the ROP according to the claSSIficatIOn system described in Table 2 in the infant's Table 4. Total Exposure to Oxygen and Ventilatory Assistance During the Hospital Course Variable F,02 ; , 0.21 Positive pressure mechanical ventilation Endotracheal CDAP

Vitamin E-treated (36)'

Placebo-treated (37)

565 ± 143t

348 ± 49

219 ± 61 229 ± 60

139 ± 19 146 ± 19

, No. of patients who had eye examinations. ± SEM (hrs) of inspired oxygen, positive pressure mechanical ventilation. or endotracheal CDAP.

t Mean

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OPHTHALMOLOG Y

• FEBRUARY 1982 • VOLUME 89 • NUMBER 2

Table 5A. Retinal Findings ' in Vitamin E-treated and Placebo-treated Patients Number of Patients Treatment

Normal

Stage I

Stage"

Total

Vitamin E

28 29

8

1

5

3

37 37

Placebo

• Classified according to Table 2.

Table 58 . Retinal Findings' in Vitamin E-treated and Placebo-treated Infants with Retinopathy of Prematurity Number of Eyes Treatment

Normal

Stage I

Vitamin E

16

Placebo

10

Stage"

5

• Classified according to Table 2.

who had ophthalmic examinations. Nine vitamin Etreated (24.3%) and eight placebo-treated (21.6%) infants demonstrated retinal abnormalities. Of the vitamin E-treated infants, eight developed Stage I and one developed Stage II changes compared to five infants with Stage I and three infants with Stage II changes in the placebo-treated group. There was no significant difference in the incidence of ROP between the vitamin E-treated and placebo-treated patients (X 2 = 1.71, df = 2, P = 0.572). Furthermore, although there is a suggestion that the incidence of Stage II changes might be greater in the placebo-treated infants , an analysis of the occurrence of Stage I and Stage II findings in both groups of infants with ROP (vitamin E-treated and placebo-treated) did not demonstrate a significant difference (P = 0.294, Fisher's exact test). In addition, no significant difference was found when the eyes with ROP were analyzed separately (Table 5B) (X2 = 3.95, df = 2, P = 0.136). Each of the 17 infants who developed ROP demonstrated spontaneous regression of their retinal findings and none developed more than minor cicatricial changes. The 17 vitamin E-treated and placebo-treated patients with ROP were then compared to the 57 vitamin E-treated and placebo-treated patients without ROP (Table 6). Significant differences were noted ingestational age, birth weight, one-minute Apgar score, occurrence of a patent ductus arteriosus and intraventricular hemorrhage, and in the total duration of oxygen and ventilatory assistance. No differences were noted in the five-minute Apgar score, pretreatment serum vitamin E levels, occurrence of air leaks, and in the number of infants in which a patent ductus arteriosus was closed with indomethacin treatment and/or ductal ligation. Similar findings were observed between the 9 vitamin E-treated patients with ROP and the 28 vitamin E-treated patients without ROP and between the 8 placebo-treated patients with ROP and the 29 placebo-treated patients without ROP (Table 7). 100

Furthermore, little difference was found between the 9 vitamin E-treated and 8 placebo-treated patients with ROP and between the 28 vitamin E-treated and 29 placebo-treated patients without ROP (Table 7).

DISCUSSION This report describes the effect of parenteral vitamin E administration upon the development of ROP during the acute phase of therapy for RDS. Since vitamin E is thought to function as an antioxidant, protecting lipid membranes from peroxidation by scavenging free radicals or by becoming incorporated into biologic membranes in proportion to the content of polyunsaturated fatty acids, and since vitamin E-deficient animals are more sensitive to oxygen-induced damage to the lungs , the red blood cell, and the central nervous system when compared to animals receiving a control diet, it seemed reasonable that the chemical vitamin E deficiency common in many premature infants would predispose them to such oxygen-related disorders as BPD and ROP, especially if they had RDS and required treatment with increased F t 0 2Y Therefore , early vitamin E administration might be expected to increase endogenous antioxidant protection and to reduce the incidence and/or severity of these complications of oxygen use in the neonate. As shown in Table 3, the first dose of vitamin E increased serum vitamin E levels significantly when measured 24 hours later. The other three doses, administered according to our treatment schedule 24, 48, and 168 hours afterward, maintained serum vitamin E levels over 2 mg/lOO ml throughout the first 14 days of life in the vitamin E-treated patients. The serum vitamin E level in the placebo-treated patients reached the normal adult mean of 1.05 mg/IOO ml (the 2-SD range is 0.5 to 1.6 mg/ 100 m1)20 during the second week of life, Table 6. Comparison of Infants With and Without Retinopathy of Prematurity (ROP) Variable Number Gestational age (wks) Birth weight (g) Apgar score: 1 minute 5 minute Air leaks Patent ductus arteriosus No. requiring RJC/: Intraventricular hemorrhage Pretreatment seru m vitamin E level Total 0, .'" 0.21 (hrs) Total positive pressure mechanical ventilation (hrs) Total endotracheal CDAP (hrs) • Mean

:t

ROP

No ROP

p value

17 29 .2 ± 0 .5' 1181 ± 57

57 31.4±0.3 1611 ±65

0 .001 < 0.001

3.2 ± 0.6 5.7±0.5 9 (53)t 16 (94) 10 (62) 9/10§ (90)

4.8 ± 0.3 6.7±0.2 20 (35) 36 (63) 20 (56) 9/34 (26)

0.028 NS NS 0.014 NS < 0.001

0.35 ± 0.05 722 ± 213

0.46 ± 0 .04 373 ± 72

NS 0.002

307 ±69

139 ± 34

0.023

314 ± 69

148 ± 34

0.025

SEM .

*No . inlants in which the patent ductus arteriosus was closed with indomethacin and/or ductal ligation . t Figures in parentheses denote %. of

§ Denominator denotes no. 01 infants evaluated by CT scan and/or ultrasound.

PULKIN, et al • VITAMIN E RETROLENTAL FIBROPLASIA

Table 7 Comparison of Infants With and Without Retinopathy of Prematurity Within Each Treatment Group Vitamin E-treated

*

Placebo-treated

Variable

ROP

No ROP

Number Gestational age (wks) Birth weight (g) Apgar score: 1 minute 5 minute Air leaks Patent ductus arteriosus No. requiring Rxt Intraventricu lar hemorrhage Pretreatment seru m vitamin E level Total O2 ?o 0.21 Total positive pressure mechanical ventilation Total endotracheal CDAP

9 29.8 ± 0.7t 1289 ± 78

28 31.1±0.5 1545 ± 91

8 28.6 ± 0.6 1061 ± 63

29 31.6 ± 0.5 1673 ± 93

2.8 ± 0.7 5.4 ± 0.8 5 (56)t 8 (89) 3 (33) 3/4§ (75) 0.30 ± 0.08

5.1 ±0.4 7.2 ± 0.2 7 (25) 18 (64) 7 (25) 4/14 (29) 0.49 ± 0.06

3.6 ± 1.0 6.0 ± 0.7 4 (50) 8 (100) 7 (88) 6/6 (100) 0.40 ± 0.07

4.4 ± 0.4 6.2 ± 0.4 13 (45) 18 (62) 13 (45) 5/20 (25) 0.43 ± 0.04

884 ± 389 364 ± 118

458 ± 140 170 ± 69

541 ± 125 242 ± 63

294 ± 49 111±13

369 ± 118

182 ± 69

252 ± 65

116 ± 13

ROP

No ROP

Mean ± SEM.

t Figures in parentheses denote

*§ No. of infants in which the patent ductus arteriosus was closed with indomethacin and/or ductal ligation. Denominator denotes no. of infants evaluated by CT scan and/or ultrasound. %.

apparently in response to the nutritional sources of vitamin E that all the infants received. Thus, during the initial period of exposure to increased F 10 2, the vitamin E-treated infants had serum vitamin E levels that were greater than the 2 mg/tOO ml level that Johnson et al 9 suggested was effective in reducing the incidence, severity, and duration of the acute stages of ROP. However, while the placebo-treated infants had significantly lower serum vitamin E levels during that time interval, many did not have chemical vitamin E deficiency. Furthermore, since daily oral vitamin E supplements maintain serum vitamin E levels within the normal adult range,17,21 vitamin E adequacy would be anticipated in all patients once feedings and vitamin supplements were tolerated. The similarity between the vitamin E-treated and placebo-treated groups with respect to the total duration of oxygen exposure, the positive pressure mechanical ventilation, and the endotracheal CDAP in the hospital course (Table 4) demonstrates that both groups had RDS of comparable severity. Although the vitamin E-treated group had longer mean exposures to each of those parameters, these differences did not reach statistical significance due to large variances that were related to prolonged requirements for oxygen and ventilatory assistance in several infants that developed BPD. The administration of vitamin E as described in this study did not alter the incidence of the active stages of ROP (Table 5). Furthermore, since none of the infants in whom retinal abnormalities were noted developed more severe changes, and since spontaneous regression occurs in most infants with early active changes of ROP,22 these data appear to preclude any comment

about the effect of vitamin E on the severity or healing of ROP. Although the exposure of all infants to nutritional sources of vitamin E must be considered a confounding variable in the interpretation of these data, two alternative explanations can be proposed. First, vitamin E does playa role in the prevention of ROP, but only serum vitamin E levels. within the normal adult range are necessary to achieve this effect, and levels over 2 mg/tOO ml or between 5 and 7 mg/tOO ml, as currently being studied by Schaffer et al,23 are not required. Second, vitamin E exerts a protective effect against the development of extraretinal proliferative ROP when administered after the discontinuation of oxygen exposure. Such an effect was recently described by Phelps and Rosenbaum. 11 They noted that the administration of vitamin E to kittens after the hyperoxic insult significantly inhibited the growth of intravitreal neovascularization, but did not alter the development of other aspects of oxygen-induced retinopathy in that model, and proposed that this effect might be related to vitamin E' s inhibitory effect on wound healing 24 and anti-inflammatory activity. 25 Therefore, as long as serum vitamin E levels are maintained within normal adult range until the retinal vasculature has reached maturity and/or the active stages of ROP have stabilized, then vitamin E may be able to exert its protective effect against the development of ROP. The data reported in this paper could support either or both of these explanations. Little difference was noted between the characteristics of the vitamin Etreated infants who developed ROP and placebotreated infants who developed ROP, and between those infants in each treatment group who did not tOt

OPHTHALMOLOGY • FEBRUARY 1982 • VOLUME 89 • NUMBER 2

(Table 7). Furthermore, no difference was found between the pretreatment serum vitamin E levels of the 17 infants who developed ROP and the 57 infants who did not (Table 6). However, as shown in Table 6, there are significant differences in the characteristics of those infants who had abnormal retinal findings and those who had normal retinal exams. Many of these differences have been previously described. The results of the Cooperative RLF Study, 26 performed between 1969 and 1972, suggested that the birth weight and time in oxygen were the most important risk factors with respect to the development ofROP and found that infants with birth weights less than 1,200 g had the greatest risk of developing cicatricial changes. Gunn et al 27 reported that gestational age and the duration of ventilatory assistance, but not birth weight or the duration of oxygen exposure, were significantly associated with the occurrence of active and/or cicatricial ROP. Procianoy et al 28 recently noted a significant association between the occurrence of an intraventricular hemorrhage and cicatricial ROP, but did not find any correlation with the birth weight, the gestational age, the duration of oxygen exposure, and the occurrence of a patent ductus arteriosus. Therefore, since the risk factors associated with the occurrence of ROP were present almost equally in the vitamin E-treated and placebo-treated infants who developed ROP (Table 7), and since the vitamin Etreated infants had significantly higher serum vitamin E levels than the placebo-treated infants during the first two weeks of life, the administration of vitamin E as described in this study did not appear to result in any further reduction in the incidence of the active stages of ROP over that seen with standard neonatal care, which included daily oral vitamin E supplements.

ACKNOWLEDGMENTS We are grateful to Hoffmann-LaRoche, Inc. for supplying the vitamin E and the vitamin E-placebo. We thank Arlene Nade1man and Frances Larvey for their expert technical assistance towards the completion of this study and manuscript.

REFERENCES 1. Terry TL. Extreme prematurity and fibroblastic overgrowth of perSistent vascular sheath behind each crystalline lens. I. Preliminary report. Am J Ophthalmol 1942; 25:203-4. 2. James LS, Lanman JT, eds. History of oxygen therapy and retrolental fibroplasia. Pediatrics 1976, 57:591-642. 3. Campbell K. Intensive oxygen therapy as a possible cause of retrolental fibroplasia: a clinical approach. Med J Aust 1951; 2:48-50. 4. Sinclair JC, Torrance GW, Boyle MH, et al. Evaluation of neonatal-intensive-care programs . N Engl J Med 1981 ; 305:489-94.

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5. Phelps DL. Retinopathy of prematurity: An estimate of vision loss in the United States-1979. Pediatrics 1981; 67:924-6. 6. Patz A. Symposium on retrolental fibroplasia: Introduction. Ophthalmology 1979; 86:1685-9. 7. Owens WC, Owens EU. Retrolental fibroplasia in premature infants. II. Studies on the prophylaxis of the disease: the use of alpha tocopheryl actetate. Am J Ophthalmol1949; 32: 1631-7. 8. Nair PP, Kayden HJ, eds. International Conference on Vitamin E and its role in cellular metabolism. Ann NY Acad Sci 1972; 203. 9. Johnson L. Schaffer 0 , Boggs TR Jr. The premature infant, vitamin E deficiency and retrolental fibroplasia. Am J Clin Nutr 1974; 27:1158-73. 10. Phelps DL, Rosenbaum AL. THe role of tocopherol in oxygeninduced retinopathy: kitten model. Pediatrics 1977; 59:998-1005. 11. Phelps DL, Rosenbaum AL. Vitamin E in kitten oxygen-induced retinopathy. II. Blockage of vitreal neovascularization. Arch Ophthalmol 1979; 97:1522-6. 12. Ehrenkranz RA, Bonta BW, Ablow RC, Warshaw JB. Amelioration of bronchopulmonary dysplasia after vitamin E administration . A preliminary report. N Engl J Med 1978; 299:564-9. 13. Ehrenkranz RA, Ablow RC, Warshaw JB. Prevention of bronchopulmonary dysplasia with vitamin E administration during the acute stages of respiratory distress syndrome. J Pediatr 1979; 95:873-8. 14. Farrell PM, Avery ME. Hyaline membrane disease. Am Rev Respir Dis 1975; 111:657-88. 15. Taghizadeh A, Reynolds EOR. Pathogenesis of bronchopulmonary dysplasia following hyaline membrane disease. Am J Pathol 1976; 82:241-64. 16. Reynolds EOR. Pressure waveform and ventilator settings for mechanical ventilation of severe hyaline membrane disease. Int Anesthesiol Clin 1974; 12(4):259-80. 17. Ehrenkranz RA. Vitamin E and the neonate. Am J Dis Child 1980; 134: 1157 -66. 18. Fabianek J, DeFilippi J, Richards T, et al. Micromethod for tocopherol determination in blood serum. Clin Chem 1968; 14:456-62. 19. Reese AB, King MJ, Owens WC. A classification of retrolental fibroplasia. Am J Ophthalmol 1953; 36:1333-5. 20. Bieri JG, Farrell PM. Vitamin E. Vitam Horm 1976; 34:31-75. 21 . Bell EF, Brown EJ, Milner R, et al. Vitamin E absorption in small premature infants. Pediatrics 1979; 63:830-2. 22. Kingham JD. Acute retrolental fibroplasia. Arch Ophthalmol 1977; 95:39-47. 23. Schaffer DB, Johnson L, Quinn GE, Boggs TR Jr. A classification of retrolental fibroplasia to evaluate vitamin E therapy. Ophthalmology 1979; 86:1749-60. 24. Ehrlich HP, Tarver H, Hunt TK. Inhibitory effects of vitamin E on collagen synthesis and wound repair. Ann Surg 1972 ; 175:235-40. 25. Levy L. The anti-inflammatory action of some compounds with antioxidant properties. Inflammation 1976; 1:333-45. 26. Kinsey VE, Arnold HJ, Kalina RE, et al. P.0 2 levels and retrolental fibroplasia: A report of the cooperative study. Pediatrics 1977; 60:655-68. 27. Gunn TR, Easdown J, Outerbridge EW, Aranda JV. Risk factors in retrolental fibroplasia. Pediatrics 1980; 65: 1096-1 00. 28. Procianoy RS, Garcia-Prats JA, Hittner HM, et al. An association between retinopathy of prematurity and intraventricular hemorrhage in very low birth weight infants. Acta Pediatr Scand 1981; 70:473-7.

Discussion of Two Preceding Papers

by

John T. Flynn, MD Dr. Kalina has made several points worth reemphasis. First, low birth weight infants, because of modem life support systems, are surviving in increasing numbers. Second, these low birthweight infants are the "at risk" population for acute proliferative retrolental fibroplasia (RLF). From this pool of infants with proliferative RLF, there will evolve a smaller sUbpopulation of infants with cicatricial RLF, where a real cost of the disease to the individual and society is paid in varying degrees of visual loss to blindness. The most encouraging of Dr. Kalina's results is that most of the cicatricial RLF has been mild, and that he has seen only one blind child in the last 12 years. In a comparable period of time, 1969-1980, I have seen 233 cases of proliferative RLF (Table 1), but have now 32 cases of Grade III cicatricial disease or worse. Unfortunately, my sample is not as complete as that of Dr. Kalina because I saw a select, smaller, sicker population of infants. What is noteworthy, however, is the incidence of serious cicatricial disease in my sample. It is higher than Dr. Kalina's, and I have at least nine in 32 cases. There are several explanations for this. First, it may be due to sampling error; my more select population as opposed to his. Second, it may simply be a random fluctuation in the incidence of serious disease in two nurseries at opposite poles of the country. A third and most intriguing speculation is the possibility that there may be an epidemiology of this cicatricial disease of which we are ignorant. Should the latter explanation be the case, the only way to uncover systematically these epidemiologic variables that might be implicated would be to make cicatricial RLF a reportable disease to some national health authority such as the Communicable Disease Center. That is the suggestion I would make as regards determination of the true incidence of cicatricial RLF. 1 Dr. Puklin's study has addressed another timely and important aspect of RLF, namely, its potential prevention or treatment with vitamin E. As mentioned by Dr. Puklin, the theoretic background for vitamin E usage as an oxygenradical scavenger has been known for a long time. It has received recent experimental support from the work of Phelps and Rosenbaum 2 in bringing about the suppression of the vitreous neovascularization in the kitten model of RLF. There are, to my knowledge, two National Eye Institutesupported prospective clinical trials underway to determine the efficacy of the preparation in the prevention or amelioration of the human disease. The final results of neither trial are available to us at this time. For this reason, among others, Dr. Puklin's study is most timely. Vitamin E is a From the Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami School of Medicine, Miami, Florida. Supported in part by National Institutes of Health Research Grant #EY03513-01.

Table 1. Incidence of RLF at Jackson Memorial Hospital, 1969-1980 Infants examined Proliferative RLF Grade "I cicatricial RLF +

1087 233 (21.4%) 32 (3.0%)

readily available, well-tolerated drug when given in therapeutic dosage ranges, either intramuscularly or as a dietary supplement to the premature infant. Its blood levels can be accurately determined by biochemical assay. Its actual or potential toxicity is still a matter of debate, especially when used in megadosage. 3 Adding such dosages to the current long list of powerful and potentially life-saving but toxic drugs given to tiny premature infants in today's modem neonatal intensive care unit should be undertaken with careful circumspection, if the treatment works. Unfortunately, from Dr. Puklin' s well-designed study, there are no grounds to conclude that it does. The incidence of acute proliferative RLF in the two groups-treated and controlwas the same, and the only statistically important differences noted were between those infants in both the vitamin Etreated and the placebo-treated groups who developed RLF. The smaller, sicker infants requiring more oxygen and ventilatory support were the ones in both groups who developed the disease, as compared with the more mature babies who did not. Mention here should be made ofa study by Monaco, Kretzer, and Hittner in which five times the dosage of vitamin E that Dr. Puklin employed in his study was used. They did report an effect in preventing Grade In acute retinopathy. The dosage employed was enormous, 100 mg per kg per day.4 However, on the basis of Dr. Puklin's study, I have drawn two simple conclusions. First, the search for ways to prevent RLF must continue. Vitamin E is not the answer. Second, there is no current indication to change the standard neonatal nursery practice today as far as the administration of vitamin E to premature infants is concerned. REFERENCES 1. Phelps DL. Retinopathy of prematurity: an estimate of vision loss in the United States-1979. Pediatrics 1981; 67:924-6. 2. Phelps DL, Rosenbaum AL. Vitamin E in kitten oxygen-induced retinopathy. II. Blockage of vitreal neovascularization. Arch Ophthalmol 1979; 97:1522-6. 3. Roberts HJ. Perspective on vitamin E as therapy. JAMA 1981; 246:129-31. 4. Monaco W, Kretzer F, Hittner H. Evidence that vitamin E suppresses the development of Grade III retinopathy of prematurity. ARVO Abstracts. Invest Ophthalmol Vis Sci 1981; 20 (Suppl):58.

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