FETAL AND NEONATAL MEDICINE
Trial of vitamin A supplementation in very low birth weight infants at risk for bronchopulmonary dysplasia E. Pearson, MD, C. Bose, MD, T. Snidow, MD, L. Ransom, MD, T. Y o u n g , MD, G. Bose, RN, a n d A. Stiles, MD From the Department of Pediatrics, University of North Carolina Hospital, Chapel Hill, Moses Cone Memorial Hospital, Greensboro, North Carolina, and Wake Medical Center, Raleigh, North Carolina We performed a randomized, double-blind, controlled trial to determine whether vitamin A supplementation in a group of very low birth weight infants would red u c e the i n c i d e n c e of b r o n c h o p u l m o n a r y dysplasia. Forty-nine infants (birth weight 700 to 1100 gm) requiring m e c h a n i c a l ventilation and supplemental oxygen at 96 hours a g e were randomly assigned to receive either 2000 IU retinyl palmitate (n = 27) or saline p l a c e b o (n = 22) intramuscularly every other d a y for up to 14 doses. There were no differences b e t w e e n treatment groups in the i n c i d e n c e s of b r o n c h o p u l m o n a r y dysplasia at 31 days of postnatal a g e (vitamin A group 48%, p l a c e b o group 55%; p - 0.776), supplemental o x y g e n requirement at 34 weeks of p o s t c o n c e p t i o n a l age, or other complications of prematurity. The vitamin A group had higher mean plasma vitamin A concentrations than the p l a c e b o group, but mean plasma vitamin A concentrations were greater than 20/~g/dl (suggesting sufficiency) in both groups after the first study week. By study d a y 28, only one fourth of the infants in either group had plasma vitamin A concentrations less than 20 ~g/dl. In contrast to an earlier report, we found no c h a n g e in the i n c i d e n c e of BPD with vitamin A supplementation. Our findings may reflect a low baseline i n c i d e n c e of vitamin A d e f i c i e n c y in the study population and recent changes in the respiratory care of very low birth weight infants. Thelatter may have lessened the potential impact of vitamin A d e f i c i e n c y on lung disease. (J PEDIATR1992;121:420-7)
Multiple factors have been implicated in the pathogenesis of bronchopulmonary dysplasia, including oxygen toxicity, barotrauma, infection, lung maturation in an extrauterine environment, and nutritional deficiency. Deficiency of one specific nutrient, vitamin A, has been described as an important contributing cause.1 Vitamin A is crucial to normal growth and differentiation of epithelial cells. InsuffiSupported by the North Carolina Chapter of the American Lung Association. Submitted for publication Jan. 24, 1992f4aeceptedMarch 31, 1992. Reprint requests: Ellyn Pearson, MD, Division of Neonatal/Perinatal Medicine, CB 7596, Fourth Floor, UNC Hospitals, University of North Carolina at Chapel Hill, Chapel Hill, NC 275997596. 9/23/38262
420
cient amounts .oay impair normal reepithelialization of lung tissue after acute injury, such as barotrauma and oxygen toxicity. Previous studies of premature infants have documented a high risk for vitamin A deficiency in this group 2, 3 and have I
BPD RBP RDS
Bronchopulmonary dysplasia Retinol-bindingprotein Respiratory distress syndrome
[
See commentary, p. 399. shown an association between vitamin A deficiency and the development of bronchopulmonary dysplasia. 4, 5 A previous clinical trial reported a 40% reduction in the incidence of
Volume 121 Number 3
BPD with intramuscular vitamin A supplementation. 6 Since this trial, several changes have occurred in the nutritional and respiratory care of premature infants, including the earlier initiation of parenteral and enteral feedings, an increase in the amount of vitamin A administered in formulas and parenteral nutrition, the introduction of exogenous surfactant treatment, and the more widespread use of steroid therapy. Because these changes may have reduced the impact of vitamin A deficiency on BPD, we performed a clinical trial to determine whether the administration of intramuscular vitamin A supplementation reduces the likelihood of BPD after acute lung disease. METHODS This study was a multicenter, double-blind, placebo-controlled trial to test the hypotheses that supplemental intramuscular vitamin A given in the first month of life to very low birth rate infants at risk for BPD would (1) reduce the incidence of BPD, (2) reduce the need for oxygen supplementation at 34 weeks of postconceptional age, and (3) raise plasma vitamin A concentrations to >20 #g/dl. Study population. The study sites included the neonatal intensive care units at North Carolina Children's Hospital (NCCH), Chapel Hill, N.C., Moses Cone Memorial Hospital (MCMH), Greensboro, N.C., and Wake Medical Center (WMC), Raleigh, N.C. Infants cared for at these centers with birth weights between 700 and 1100 gm and at risk for BPD were eligible for study enrollment unless an exclusion criterion was present. Risk of BPD was defined as (1) the need for mechanical ventilation and oxygen between 72 and 96 hours of age, with (2) previous cumulative duration of mechanical ventilation and oxygen longer than 48 hours. Exclusion criteria included (1) growth retardation, (2) congenital anomalies or chromosomal abnormalities, (3) hydrops fetalis, (4) congenital infection, (5) neonatal hepatitis~ or (6) presence of a "do not resuscitate" order on the infant's chart at 72 hours of age. Infants eligible for study entry were enrolled between 72 and 96 hours of age after parental consent. This study was approved by the committee for the protection of the rights of human subjects at each participating hospital. Randomization. After enrollment and before randomization, infants were stratified into four groups according to birth weight and gender: (1) 700 to 900 gm boys, (2) 901 to 1100 gm boys, (3) 700 to 900 gm girls, and (4) 901 to 1100 gm girls. Within each stratum at each hospital, infants were randomly assigned to receive either vitamin A or placebo. Randomization was performed with the use of sequential, sealed envelopes. Drug preparation and administration. Investigational pharmacists at N C C H and M C M H and one study nurse at W M C carried out the randomization and study drug (vita-
Vitamin A for prevention o f BPD
421
min A and placebo) preparation. A water-miscible vitamin A preparation (Aquasol A Parenteral; Rorer Hospital Products, Blue Bell, Pa.) containing 50,000 I U / m l retinyl palmitate was used. Each dose (0.04 ml containing 2000 IU) was administered within 30 minutes of preparation. The solution was shielded from light at all times. A similar volume of 0.9% saline solution was used as a placebo. Opaque tape concealed the contents of syringes to ensure blinding. At N C C H and M C M H , each patient's bedside nurse administered the study drug. At WMC, the study nurse administered the study drug behind a screen. Each infant in the treatment group received 2000 IU supplemental vitamin A by intramuscular injection on study day 1 (postnatal day 4) and every other day thereafter for up to 14 doses for 28 days. At N C C H and MCMH, each infant in the placebo group received 0.04 ml 0.9% saline solution by intramuscular injection on study day 1 (postnatal day 4) and every other day thereafter for up to 14 doses for 28 days. At W M C a study nurse prepared the placebo in the manner described for N C C H and M C M H but administered it by mock injection behind a screen. If a patient was weaned to room air before the fourteenth dose, study drug was discontinued. At all three sites, staff responsible for patient care had no knowledge of group designation. General patient management. The usual staff of each neonatal intensive care unit was responsible for the clinical care of infants enrolled in the study. The standards of care for respiratory management were similar at each center. During the acute phase of lung disease, arterial oxygen pressure was maintained at 50 to 70 mm Hg and arterial carbon dioxide pressure at 45 to 55 mm Hg. Oxygen saturation by pulse oximetry was maintained at 92% to 98% during the recovery phase. As is routine in these units, most infants enrolled in the study received exogenous surfactant (Exosurf Neonatal; Burroughs Wellcome Co., Research Triangle Park, N.C.), 5 ml/kg per dose, on the first day of life. All infants received intravenously administered glucose solutions beginning at birth. In most cases a proteindextrose solution (TrophAmine; Kendall-McGaw, Irvine, Calif.) was started by postnatal day 4 and lipid emulsion (Intralipid; KabiVitrum Inc., Alameda, Calif.) by postnatal day 7. Vitamin A in the form of M.V.I. Pediatric (Astra Pharmaceutical Products, Inc., Westborough, Mass.) was routinely added to the protein-dextrose solution to give a dose of 1200 to 1500 IU per day. All infants were begun and advanced on orogastric tube feedings of human milk or formula as soon as tolerated. The vitamin A content of the formulas ranged from 250 to 1030 IU per 100 ml. Data collection Initial characteristics. Maternal and infant demographic
422
Pearson et al.
The Journal of Pediatrics September 1992
3,000 A V'ff.amlnA Group
P PlaceboGroup Intramuscular Intraveflous
9 ~] [] *
2,500 "O
Enteral p < 0.001 )
..~ 2,000
1,5o0 r" < r 1.0oo m
.m
E 500
A
P 1
A 2
P
A
P 3
A
P 4
Study Week Fig. t. Vitamin A intake. Each infant's average daily vitamin A intake was calculated. Within the two study groups, these values were averaged for each week of the study to calculate the average daily vitamin A intake for that week. Intake by intramuscular, enteral, and intravenous routes are indicated. Intramuscular intake accounted for the significant difference in total intake between groups.
information, maternal medical and obstetric history, and infant clinical status at study entry were recorded. The initial respiratory disease was classified as respiratory distress syndrome, as pulmonary insufficiency of the premature infant, or as "other." RDS was diagnosed if characteristic chest radiograph findings were present (decreased lung volume, air bronchograms, and a reticulogranular pattern) and if more than 0.30 fractional inspired oxygen was required on the first day of life to maintain arterial oxygen pressure >60 mm Hg. Pulmonary insufficiency of the premature infant was diagnosed in infants up to 28 weeks of gestational age who had normal chest radiographs and who required less than 0.30 fractional inspired oxygen to maintain arterial oxygen pressure >60 mm Hg on the first day of life. Clinical course. During the 28-day study period, respiratory status, nutritional intake, and weight were recorded daily. Evidence of toxic reactions to vitamin A was monitored with weekly serologic liver function tests (alanine aminotransferase and aspartate aminotransferase). Respiratory status was recorded at 24-hour anniversary times from study enrollment and included the following measurements: oxygen concentration, peak inspiratory pressure, positive end-expiratory pressure, yentilator rate, and mean airway pressure. Nutritional data collected daily included intakes of vitamin A, calories, carbohydrate, protein, and fat. The average daily intake of each nutrient was calculated by study group. Intake was then expressed for each study week as the average daily value for the week.
On study day 28, the clinical course of each infant was reviewed for complications of prematurity. The following diagnoses, based on prospectively established criteria, were assigned as appropriate: pulmonary infection, nonpulmonary infection, patent ductus arteriosus, pulmonary air leak, necrotizing enterocolitis, hyperbilirubinemia (total and direct), intraventricular hemorrhage, seizures, and apnea. Each infant's respiratory status was recorded at 34 weeks of postconceptional age. At hospital discharge the infant's course was reviewed for total duration of mechanical ventilation or supplemental oxygen or both, and for total duration of hospital stay. Results of ophthalmologic examinations for retinopathy of prematurity were recorded. Chest radiogrii~)hs. Radiographs of the chest were obtained for each infant on study day 1 and for each infant receiving supplemental oxygen or mechanical ventilation or both on study day 28. One investigator (C.L.B.) scored the radiographs in a blinded fashion according to the Edwards classification scheme for RDS severity (study day 1) and for BPD severity (study day 28). 7 Outc6mes. On study day 28 (postnatal day 31), the presence or absence of BPD was assessed for each surviving patient. We defined BPD as present if an infant had an oxygen requirement and an Edwards score of three or more on a chest radiograph. A second outcome, the presence or absence of a supplemental oxygen requirement at 34 weeks of postconceptional age, was also noted. Vitamin A status. Blood was drawn from each patient for plasma retinol and retinol-binding protein concentrations
Volume 121 Number 3
Vitamin A for prevention of BPD
423
T a b l e I. Demographic and physical characteristics of 9 Vitamin A group
the study groups
Birth weight (gm)* Gestational age (wk)* Gender: No. (%) Male Female Race: No. (%) Black White Other Prenatal steroids Weight at study entry (gm)*
9
60 Vitamin A (n = 27)
Placebo (n = 22)
885 +_ 118 27 +_ 1
887 _+ 102 27 + 1
14 (52) 13 (48)
11 (50) 11 (50)
16 (59) 10 (37) 1 (4) 7 (26) 832 _+ 133
7 (32) 14 (64) 1 (4) 9 (41) 828 _+ 107
.=_
E
40
20
0 i
~ t'-
Placebo group
I
Patient population. Study enrollment began at N C C H and M C M H on Jan. 1, 1990, and at W M C on Jan. 1, 1991. Enrollment ended at all three sites on June 15, 1991, after a blinded interim analysis of 49 patients showed no significant divergence in outcome between treatment groups.
I
I 24
I 31
I :~
RESULTS
I
4
All p values are not significant. *Values are expressed as mean _+ SD.
on study days 1, 7, 14, 21, and 28 (postnatal days 4, 10, 17, 24, and 31 ). Plasma was stored at - 2 0 ~ C until assay by the Vanderbilt University Department of Biochemistry by means of previously described methods. 6, 8 Statistical analysis Sample size calculation. In 1989, using a retrospective analysis o f infants in our nurseries who met eligibility criteria, we determined a 75% incidence of BPD. To judge the intervention effective, we desired a 30% reduction in the incidence of BPD. On the basis of an alpha of 0.05 and a beta of 0.2, the estimated sample size to show a reduction from 75% to 45% in the incidence of BPD was 41 subjects per treatment group. Data analysis. Data were analyzed with the InStat (GraphPAD Software, San Diego, Calif.) and Statistical Analysis Systems (SAS Institute, Inc., Cary, N.C.) computer program packages. Initial population characteristics were compared with the Student t test for continuous variables and the Pearson chi-square test for discrete variables. Outcomes were compared with the Fisher Exact Test and the Pearson chi-square test. Variables involving repeated measurements (nutritional intake, plasma levels of retinol, and RBP) were compared by the Wilcoxon Rank-Sum test. Relationship between BPD and plasma vitamin A concentrations was analyzed with the Fisher Exact Test for univariate analysis and logistic regression for multivariable analysis of risk factors. All p values were based on two-tailed tests. A p value less than 0.05 was considered significant.
I
t--
2
Q. 0
I 4
I 10
I 17
P o s t n a t a l A g e (days) Fig. 2. Plasma concentrations of vitamin A and RBP. Mean plasma concentrations of vitamin A and RBP on postnatal day 4 reflect pretreatment values and were similar in both groups.
One hundred sixty-one infants with birth weights between 700 and 1100 gm were admitted to the three study sites during the study period. Eighty-seven infants were ineligible for study enrollment (exclusion criteria, n = 25; death before 72 hours age, n = 9; no mechanical ventilation requirement by 72 hours age, n = 53). Seventy-four infants met study entry criteria. Parental consent was obtained for 49 infants (thirteen 700 to 900 gm boys, twelve 901 to 1100 gm boys, seventeen 700 to 900 gm girls, and seven 901 to 1100 gm girls). Thirty-two infants were enrolled at N C C H , eleven at M C M H , and six at W M C . Twenty-seven infants were randomly assigned to the vitamin A group ( N C C H , n = 16; M C M H , n = 8; W M C , n = 3), and 22 infants to the placebo group ( N C C H , n = 16; M C M H , n = 3; W M C , n = 3). The two treatment groups did not differ in demographic and physical features (Table I), in cardiorespiratory status at study entry (Table II), or in other prenatal and perinatal factors (parity, maternal hypertension, placental abruption, multiple birth status, duration of rupture of membranes, inborn or outborn status, type of delivery, and Apgar scores). Outcomes. There was no difference in the incidence of BPD between treatment groups nor in the incidence of BPD or death at study day 28 (Table III). Likewise, there was no difference in the incidence of supplemental oxygen require-
424
Pearson et al.
The Journal of Pediatrics September 1992
T a b l e II. Cardiorespiratory status of study groups at study entry V i t a m i n A (n = 27)
Diagnosis: No. (%) RDS Pulmonary insufficiency of prematurity Pulmonary air leak Patent ductus arteriosus Exogenous surfactant: No. (%) Respiratory measurements* Fraction of inspired oxygen Peak inspiratory pressure (cm H20) Positive end-expiratory pressure (cm H20) Ventilator rate (breaths/min) Mean airway pressure (cm H20) Oxygenation index~" Initial chest radiograph score*
24 3 7 6 25
(89) (11) (26) (22) (93)
0.37 _+ 0.16 18_+5 4_+1 27 _+ 13 6___2 3.6 _+ 3.9 9.6 _+ 3.7
P l a c e b o (n = 22)
19 (86) 3 (14) 7 (32) 9 (41) 21 (95) 0.39 + 0.21 19_+4 4_+1 28 _+ 17 7_+2 3.7 _+ 2.6 8.1 _+ 3.1
All p values are not significant. *Values are expressed as mean +- SD. ]'Oxygenation index = (MAP • FI02 X 100)/Pa02, where MAP is the mean airway pressure, FI02 is fractional inspired oxygen, and Pa02 is partial pressure of arterial oxygen.
T a b l e 111. Outcomes of study groups V i t a m i n A (n = 27)
Study day 28 (postnatal day 31): No. (%) Dead Alive BPD* BPD or dead Supplemental oxygen requirement* Ventilator requirement* At 34 weeks PCA: No. (%) Total dead at 34 weeks PCA Alive at 34 weeks PCA Supplemental oxygen requirement* Supplemental oxygen requirement or dead Ventilator requirement* Hospital discharger Duration of oxygen therapy (days) Duration of mechanical ventilation (days) Duration of hospitalization (days)
P l a c e b o (n = 22)
1/27 26/27 12/26 13/27 20/26 10/26
(4) (96) (46) (48) (77) (38)
4/22 18/22 8/18 12/22 13/18 7/18
(18) (82) (44) (55) (72) (39)
5/27 22/27 14/22 19/27 4/22
(19) (81) (64) (70) (18)
4/22 18/22 12/18 16/22 2/18
(18) (82) (67) (73) (11)
58 _+ 38 27 + 22 84 +_ 31
42 _+ 29 20 _+ 14 81 _+ 19
All p values are not significant. PCA, Postconceptional age. *Denominator for percentages is number of survivors. tValues are expressed as mean + SD.
ment at 34 weeks of postconceptional age nor in the incidence of supplemental oxygen requirement or death. In addition, there were no differences between the treatment groups in respiratory measurements at weekly intervals, weights at weekly intervals, need for oxygen on study day 28, need for mechanical ventilation on study day 28, or use of bronchodilators or diuretics on study day 28. Both groups had a similar incidence of steroid use during the 28day study period (46% in the vitamin A group, 44% in the placebo group). Total duration of oxygen use, total duration
of mechanical ventilation, and duration of hospitalization were similar between the treatment groups (Table III). There were no differences in the incidences of retinopathy of prematurity (61% in each group, mostly stage 1 or 2), patent ductus arteriosus, pulmonary air leak, infections, necrotizing enterocolitis, hyperbilirubinemia, intraventricular hemorrhage, seizures, or apnea. There was no difference in mortality rates between treatment groups. All deaths in the placebo group occurred before study day 28 (one death at 10 days from necrotizing
Volume 121 Number 3
Vitamin A f o r prevention o f BPD
< 20~g/dL
loo
9 Vitamin A [ ] Placebo
80
0
< 15Fg/dL
u
4
i|
10
Jn
in
17 2 4 " 3 1 '
< 10#,g/dL 9 Vitamin A [ ] Placebo
9 Vitamin A [ ] Placebo
4 10 17 24 31 Postnatal A g e (Days)
425
H.n,
4
10
17"24"31'
Fig, 3.. Percentageofinfantswith plasma vitamin A concentrations consistent witb deficiency.Percentage ofinfants with plasma vitamin A concentrations consistent with deficiency declined during the study period in both groups. Concentrations
Trial of vitamin A supplementation in very low birth weight infants at risk for bronchopulmonary dysplasia E. Pearson, MD, C. Bose, MD, T. Snidow, MD, L. Ransom, MD, T. Y o u n g , MD, G. Bose, RN, a n d A. Stiles, MD From the Department of Pediatrics, University of North Carolina Hospital, Chapel Hill, Moses Cone Memorial Hospital, Greensboro, North Carolina, and Wake Medical Center, Raleigh, North Carolina We performed a randomized, double-blind, controlled trial to determine whether vitamin A supplementation in a group of very low birth weight infants would red u c e the i n c i d e n c e of b r o n c h o p u l m o n a r y dysplasia. Forty-nine infants (birth weight 700 to 1100 gm) requiring m e c h a n i c a l ventilation and supplemental oxygen at 96 hours a g e were randomly assigned to receive either 2000 IU retinyl palmitate (n = 27) or saline p l a c e b o (n = 22) intramuscularly every other d a y for up to 14 doses. There were no differences b e t w e e n treatment groups in the i n c i d e n c e s of b r o n c h o p u l m o n a r y dysplasia at 31 days of postnatal a g e (vitamin A group 48%, p l a c e b o group 55%; p - 0.776), supplemental o x y g e n requirement at 34 weeks of p o s t c o n c e p t i o n a l age, or other complications of prematurity. The vitamin A group had higher mean plasma vitamin A concentrations than the p l a c e b o group, but mean plasma vitamin A concentrations were greater than 20/~g/dl (suggesting sufficiency) in both groups after the first study week. By study d a y 28, only one fourth of the infants in either group had plasma vitamin A concentrations less than 20 ~g/dl. In contrast to an earlier report, we found no c h a n g e in the i n c i d e n c e of BPD with vitamin A supplementation. Our findings may reflect a low baseline i n c i d e n c e of vitamin A d e f i c i e n c y in the study population and recent changes in the respiratory care of very low birth weight infants. Thelatter may have lessened the potential impact of vitamin A d e f i c i e n c y on lung disease. (J PEDIATR1992;121:420-7)
Multiple factors have been implicated in the pathogenesis of bronchopulmonary dysplasia, including oxygen toxicity, barotrauma, infection, lung maturation in an extrauterine environment, and nutritional deficiency. Deficiency of one specific nutrient, vitamin A, has been described as an important contributing cause.1 Vitamin A is crucial to normal growth and differentiation of epithelial cells. InsuffiSupported by the North Carolina Chapter of the American Lung Association. Submitted for publication Jan. 24, 1992f4aeceptedMarch 31, 1992. Reprint requests: Ellyn Pearson, MD, Division of Neonatal/Perinatal Medicine, CB 7596, Fourth Floor, UNC Hospitals, University of North Carolina at Chapel Hill, Chapel Hill, NC 275997596. 9/23/38262
420
cient amounts .oay impair normal reepithelialization of lung tissue after acute injury, such as barotrauma and oxygen toxicity. Previous studies of premature infants have documented a high risk for vitamin A deficiency in this group 2, 3 and have I
BPD RBP RDS
Bronchopulmonary dysplasia Retinol-bindingprotein Respiratory distress syndrome
[
See commentary, p. 399. shown an association between vitamin A deficiency and the development of bronchopulmonary dysplasia. 4, 5 A previous clinical trial reported a 40% reduction in the incidence of
Volume 121 Number 3
BPD with intramuscular vitamin A supplementation. 6 Since this trial, several changes have occurred in the nutritional and respiratory care of premature infants, including the earlier initiation of parenteral and enteral feedings, an increase in the amount of vitamin A administered in formulas and parenteral nutrition, the introduction of exogenous surfactant treatment, and the more widespread use of steroid therapy. Because these changes may have reduced the impact of vitamin A deficiency on BPD, we performed a clinical trial to determine whether the administration of intramuscular vitamin A supplementation reduces the likelihood of BPD after acute lung disease. METHODS This study was a multicenter, double-blind, placebo-controlled trial to test the hypotheses that supplemental intramuscular vitamin A given in the first month of life to very low birth rate infants at risk for BPD would (1) reduce the incidence of BPD, (2) reduce the need for oxygen supplementation at 34 weeks of postconceptional age, and (3) raise plasma vitamin A concentrations to >20 #g/dl. Study population. The study sites included the neonatal intensive care units at North Carolina Children's Hospital (NCCH), Chapel Hill, N.C., Moses Cone Memorial Hospital (MCMH), Greensboro, N.C., and Wake Medical Center (WMC), Raleigh, N.C. Infants cared for at these centers with birth weights between 700 and 1100 gm and at risk for BPD were eligible for study enrollment unless an exclusion criterion was present. Risk of BPD was defined as (1) the need for mechanical ventilation and oxygen between 72 and 96 hours of age, with (2) previous cumulative duration of mechanical ventilation and oxygen longer than 48 hours. Exclusion criteria included (1) growth retardation, (2) congenital anomalies or chromosomal abnormalities, (3) hydrops fetalis, (4) congenital infection, (5) neonatal hepatitis~ or (6) presence of a "do not resuscitate" order on the infant's chart at 72 hours of age. Infants eligible for study entry were enrolled between 72 and 96 hours of age after parental consent. This study was approved by the committee for the protection of the rights of human subjects at each participating hospital. Randomization. After enrollment and before randomization, infants were stratified into four groups according to birth weight and gender: (1) 700 to 900 gm boys, (2) 901 to 1100 gm boys, (3) 700 to 900 gm girls, and (4) 901 to 1100 gm girls. Within each stratum at each hospital, infants were randomly assigned to receive either vitamin A or placebo. Randomization was performed with the use of sequential, sealed envelopes. Drug preparation and administration. Investigational pharmacists at N C C H and M C M H and one study nurse at W M C carried out the randomization and study drug (vita-
Vitamin A for prevention o f BPD
421
min A and placebo) preparation. A water-miscible vitamin A preparation (Aquasol A Parenteral; Rorer Hospital Products, Blue Bell, Pa.) containing 50,000 I U / m l retinyl palmitate was used. Each dose (0.04 ml containing 2000 IU) was administered within 30 minutes of preparation. The solution was shielded from light at all times. A similar volume of 0.9% saline solution was used as a placebo. Opaque tape concealed the contents of syringes to ensure blinding. At N C C H and M C M H , each patient's bedside nurse administered the study drug. At WMC, the study nurse administered the study drug behind a screen. Each infant in the treatment group received 2000 IU supplemental vitamin A by intramuscular injection on study day 1 (postnatal day 4) and every other day thereafter for up to 14 doses for 28 days. At N C C H and MCMH, each infant in the placebo group received 0.04 ml 0.9% saline solution by intramuscular injection on study day 1 (postnatal day 4) and every other day thereafter for up to 14 doses for 28 days. At W M C a study nurse prepared the placebo in the manner described for N C C H and M C M H but administered it by mock injection behind a screen. If a patient was weaned to room air before the fourteenth dose, study drug was discontinued. At all three sites, staff responsible for patient care had no knowledge of group designation. General patient management. The usual staff of each neonatal intensive care unit was responsible for the clinical care of infants enrolled in the study. The standards of care for respiratory management were similar at each center. During the acute phase of lung disease, arterial oxygen pressure was maintained at 50 to 70 mm Hg and arterial carbon dioxide pressure at 45 to 55 mm Hg. Oxygen saturation by pulse oximetry was maintained at 92% to 98% during the recovery phase. As is routine in these units, most infants enrolled in the study received exogenous surfactant (Exosurf Neonatal; Burroughs Wellcome Co., Research Triangle Park, N.C.), 5 ml/kg per dose, on the first day of life. All infants received intravenously administered glucose solutions beginning at birth. In most cases a proteindextrose solution (TrophAmine; Kendall-McGaw, Irvine, Calif.) was started by postnatal day 4 and lipid emulsion (Intralipid; KabiVitrum Inc., Alameda, Calif.) by postnatal day 7. Vitamin A in the form of M.V.I. Pediatric (Astra Pharmaceutical Products, Inc., Westborough, Mass.) was routinely added to the protein-dextrose solution to give a dose of 1200 to 1500 IU per day. All infants were begun and advanced on orogastric tube feedings of human milk or formula as soon as tolerated. The vitamin A content of the formulas ranged from 250 to 1030 IU per 100 ml. Data collection Initial characteristics. Maternal and infant demographic
422
Pearson et al.
The Journal of Pediatrics September 1992
3,000 A V'ff.amlnA Group
P PlaceboGroup Intramuscular Intraveflous
9 ~] [] *
2,500 "O
Enteral p < 0.001 )
..~ 2,000
1,5o0 r" < r 1.0oo m
.m
E 500
A
P 1
A 2
P
A
P 3
A
P 4
Study Week Fig. t. Vitamin A intake. Each infant's average daily vitamin A intake was calculated. Within the two study groups, these values were averaged for each week of the study to calculate the average daily vitamin A intake for that week. Intake by intramuscular, enteral, and intravenous routes are indicated. Intramuscular intake accounted for the significant difference in total intake between groups.
information, maternal medical and obstetric history, and infant clinical status at study entry were recorded. The initial respiratory disease was classified as respiratory distress syndrome, as pulmonary insufficiency of the premature infant, or as "other." RDS was diagnosed if characteristic chest radiograph findings were present (decreased lung volume, air bronchograms, and a reticulogranular pattern) and if more than 0.30 fractional inspired oxygen was required on the first day of life to maintain arterial oxygen pressure >60 mm Hg. Pulmonary insufficiency of the premature infant was diagnosed in infants up to 28 weeks of gestational age who had normal chest radiographs and who required less than 0.30 fractional inspired oxygen to maintain arterial oxygen pressure >60 mm Hg on the first day of life. Clinical course. During the 28-day study period, respiratory status, nutritional intake, and weight were recorded daily. Evidence of toxic reactions to vitamin A was monitored with weekly serologic liver function tests (alanine aminotransferase and aspartate aminotransferase). Respiratory status was recorded at 24-hour anniversary times from study enrollment and included the following measurements: oxygen concentration, peak inspiratory pressure, positive end-expiratory pressure, yentilator rate, and mean airway pressure. Nutritional data collected daily included intakes of vitamin A, calories, carbohydrate, protein, and fat. The average daily intake of each nutrient was calculated by study group. Intake was then expressed for each study week as the average daily value for the week.
On study day 28, the clinical course of each infant was reviewed for complications of prematurity. The following diagnoses, based on prospectively established criteria, were assigned as appropriate: pulmonary infection, nonpulmonary infection, patent ductus arteriosus, pulmonary air leak, necrotizing enterocolitis, hyperbilirubinemia (total and direct), intraventricular hemorrhage, seizures, and apnea. Each infant's respiratory status was recorded at 34 weeks of postconceptional age. At hospital discharge the infant's course was reviewed for total duration of mechanical ventilation or supplemental oxygen or both, and for total duration of hospital stay. Results of ophthalmologic examinations for retinopathy of prematurity were recorded. Chest radiogrii~)hs. Radiographs of the chest were obtained for each infant on study day 1 and for each infant receiving supplemental oxygen or mechanical ventilation or both on study day 28. One investigator (C.L.B.) scored the radiographs in a blinded fashion according to the Edwards classification scheme for RDS severity (study day 1) and for BPD severity (study day 28). 7 Outc6mes. On study day 28 (postnatal day 31), the presence or absence of BPD was assessed for each surviving patient. We defined BPD as present if an infant had an oxygen requirement and an Edwards score of three or more on a chest radiograph. A second outcome, the presence or absence of a supplemental oxygen requirement at 34 weeks of postconceptional age, was also noted. Vitamin A status. Blood was drawn from each patient for plasma retinol and retinol-binding protein concentrations
Volume 121 Number 3
Vitamin A for prevention of BPD
423
T a b l e I. Demographic and physical characteristics of 9 Vitamin A group
the study groups
Birth weight (gm)* Gestational age (wk)* Gender: No. (%) Male Female Race: No. (%) Black White Other Prenatal steroids Weight at study entry (gm)*
9
60 Vitamin A (n = 27)
Placebo (n = 22)
885 +_ 118 27 +_ 1
887 _+ 102 27 + 1
14 (52) 13 (48)
11 (50) 11 (50)
16 (59) 10 (37) 1 (4) 7 (26) 832 _+ 133
7 (32) 14 (64) 1 (4) 9 (41) 828 _+ 107
.=_
E
40
20
0 i
~ t'-
Placebo group
I
Patient population. Study enrollment began at N C C H and M C M H on Jan. 1, 1990, and at W M C on Jan. 1, 1991. Enrollment ended at all three sites on June 15, 1991, after a blinded interim analysis of 49 patients showed no significant divergence in outcome between treatment groups.
I
I 24
I 31
I :~
RESULTS
I
4
All p values are not significant. *Values are expressed as mean _+ SD.
on study days 1, 7, 14, 21, and 28 (postnatal days 4, 10, 17, 24, and 31 ). Plasma was stored at - 2 0 ~ C until assay by the Vanderbilt University Department of Biochemistry by means of previously described methods. 6, 8 Statistical analysis Sample size calculation. In 1989, using a retrospective analysis o f infants in our nurseries who met eligibility criteria, we determined a 75% incidence of BPD. To judge the intervention effective, we desired a 30% reduction in the incidence of BPD. On the basis of an alpha of 0.05 and a beta of 0.2, the estimated sample size to show a reduction from 75% to 45% in the incidence of BPD was 41 subjects per treatment group. Data analysis. Data were analyzed with the InStat (GraphPAD Software, San Diego, Calif.) and Statistical Analysis Systems (SAS Institute, Inc., Cary, N.C.) computer program packages. Initial population characteristics were compared with the Student t test for continuous variables and the Pearson chi-square test for discrete variables. Outcomes were compared with the Fisher Exact Test and the Pearson chi-square test. Variables involving repeated measurements (nutritional intake, plasma levels of retinol, and RBP) were compared by the Wilcoxon Rank-Sum test. Relationship between BPD and plasma vitamin A concentrations was analyzed with the Fisher Exact Test for univariate analysis and logistic regression for multivariable analysis of risk factors. All p values were based on two-tailed tests. A p value less than 0.05 was considered significant.
I
t--
2
Q. 0
I 4
I 10
I 17
P o s t n a t a l A g e (days) Fig. 2. Plasma concentrations of vitamin A and RBP. Mean plasma concentrations of vitamin A and RBP on postnatal day 4 reflect pretreatment values and were similar in both groups.
One hundred sixty-one infants with birth weights between 700 and 1100 gm were admitted to the three study sites during the study period. Eighty-seven infants were ineligible for study enrollment (exclusion criteria, n = 25; death before 72 hours age, n = 9; no mechanical ventilation requirement by 72 hours age, n = 53). Seventy-four infants met study entry criteria. Parental consent was obtained for 49 infants (thirteen 700 to 900 gm boys, twelve 901 to 1100 gm boys, seventeen 700 to 900 gm girls, and seven 901 to 1100 gm girls). Thirty-two infants were enrolled at N C C H , eleven at M C M H , and six at W M C . Twenty-seven infants were randomly assigned to the vitamin A group ( N C C H , n = 16; M C M H , n = 8; W M C , n = 3), and 22 infants to the placebo group ( N C C H , n = 16; M C M H , n = 3; W M C , n = 3). The two treatment groups did not differ in demographic and physical features (Table I), in cardiorespiratory status at study entry (Table II), or in other prenatal and perinatal factors (parity, maternal hypertension, placental abruption, multiple birth status, duration of rupture of membranes, inborn or outborn status, type of delivery, and Apgar scores). Outcomes. There was no difference in the incidence of BPD between treatment groups nor in the incidence of BPD or death at study day 28 (Table III). Likewise, there was no difference in the incidence of supplemental oxygen require-
424
Pearson et al.
The Journal of Pediatrics September 1992
T a b l e II. Cardiorespiratory status of study groups at study entry V i t a m i n A (n = 27)
Diagnosis: No. (%) RDS Pulmonary insufficiency of prematurity Pulmonary air leak Patent ductus arteriosus Exogenous surfactant: No. (%) Respiratory measurements* Fraction of inspired oxygen Peak inspiratory pressure (cm H20) Positive end-expiratory pressure (cm H20) Ventilator rate (breaths/min) Mean airway pressure (cm H20) Oxygenation index~" Initial chest radiograph score*
24 3 7 6 25
(89) (11) (26) (22) (93)
0.37 _+ 0.16 18_+5 4_+1 27 _+ 13 6___2 3.6 _+ 3.9 9.6 _+ 3.7
P l a c e b o (n = 22)
19 (86) 3 (14) 7 (32) 9 (41) 21 (95) 0.39 + 0.21 19_+4 4_+1 28 _+ 17 7_+2 3.7 _+ 2.6 8.1 _+ 3.1
All p values are not significant. *Values are expressed as mean +- SD. ]'Oxygenation index = (MAP • FI02 X 100)/Pa02, where MAP is the mean airway pressure, FI02 is fractional inspired oxygen, and Pa02 is partial pressure of arterial oxygen.
T a b l e 111. Outcomes of study groups V i t a m i n A (n = 27)
Study day 28 (postnatal day 31): No. (%) Dead Alive BPD* BPD or dead Supplemental oxygen requirement* Ventilator requirement* At 34 weeks PCA: No. (%) Total dead at 34 weeks PCA Alive at 34 weeks PCA Supplemental oxygen requirement* Supplemental oxygen requirement or dead Ventilator requirement* Hospital discharger Duration of oxygen therapy (days) Duration of mechanical ventilation (days) Duration of hospitalization (days)
P l a c e b o (n = 22)
1/27 26/27 12/26 13/27 20/26 10/26
(4) (96) (46) (48) (77) (38)
4/22 18/22 8/18 12/22 13/18 7/18
(18) (82) (44) (55) (72) (39)
5/27 22/27 14/22 19/27 4/22
(19) (81) (64) (70) (18)
4/22 18/22 12/18 16/22 2/18
(18) (82) (67) (73) (11)
58 _+ 38 27 + 22 84 +_ 31
42 _+ 29 20 _+ 14 81 _+ 19
All p values are not significant. PCA, Postconceptional age. *Denominator for percentages is number of survivors. tValues are expressed as mean + SD.
ment at 34 weeks of postconceptional age nor in the incidence of supplemental oxygen requirement or death. In addition, there were no differences between the treatment groups in respiratory measurements at weekly intervals, weights at weekly intervals, need for oxygen on study day 28, need for mechanical ventilation on study day 28, or use of bronchodilators or diuretics on study day 28. Both groups had a similar incidence of steroid use during the 28day study period (46% in the vitamin A group, 44% in the placebo group). Total duration of oxygen use, total duration
of mechanical ventilation, and duration of hospitalization were similar between the treatment groups (Table III). There were no differences in the incidences of retinopathy of prematurity (61% in each group, mostly stage 1 or 2), patent ductus arteriosus, pulmonary air leak, infections, necrotizing enterocolitis, hyperbilirubinemia, intraventricular hemorrhage, seizures, or apnea. There was no difference in mortality rates between treatment groups. All deaths in the placebo group occurred before study day 28 (one death at 10 days from necrotizing
Volume 121 Number 3
Vitamin A f o r prevention o f BPD
< 20~g/dL
loo
9 Vitamin A [ ] Placebo
80
0
< 15Fg/dL
u
4
i|
10
Jn
in
17 2 4 " 3 1 '
< 10#,g/dL 9 Vitamin A [ ] Placebo
9 Vitamin A [ ] Placebo
4 10 17 24 31 Postnatal A g e (Days)
425
H.n,
4
10
17"24"31'
Fig, 3.. Percentageofinfantswith plasma vitamin A concentrations consistent witb deficiency.Percentage ofinfants with plasma vitamin A concentrations consistent with deficiency declined during the study period in both groups. Concentrations
