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Neonatal Bilirubin Nomogram: A Tool to Facilitate Practical Application of AAP Guidelines for Management of Hyperbilirubinemia in Healthy Term Newborns. † 970

Bilirubin:albumin ratio in transient bilirubin encephalopathy as evaluated by BAER in premature infants † 946

Reduced Severity and Sequelae of ROP in ≤1000g BW Infants With Vitamin E Prophylaxis & Treatment - Need for a CCT 1035

Low total protein (TP) (serum TP

Retinopathy of Prematurity (ROP), Cerebral Palsy (CP) Serum Bilirubin (SB) and Vitamin E (VE). † 925

Elevated serum bilirubin (SB) 10.9 mg/dl was noted in a six hr old, 3969g term infant with severe BO disease (Hct 29%, Hct 40%). Intensive photoRx resulted in only a modest fall in rate of SB rise; Ex appeared inevitable. Hourly BOX feedings (60 Units/kg/d), begun at 22 hrs were associated with decrease stool bile pigments and more rapid than expected fall in SB. No Ex needed. Findings in this infant are presented in comparison to those in the seven other term infants with BO disease Rx at PA H from 1991 to 1995. All needed Ex. Their SB and age at Ex (mean ± SD), were 20.2 mg/dl ± 2.4; 28.6 hs ± 7.3 resp.(See Table).

BOX, in the presence of O2, selectively destroys bilirubin and its oxidation products. During feedings, active enzyme is recovered from the stools (near 100% recovery in infant rats) and stool bilirubin and bilirubin glucuronides are markedly decreased. Since 1995, on an IND permit, after informed consent, BOX, in PO4 buffer, has been given to eight newborn infants at risk of Ex Tx because of rapidly rising serum bilirubin (SB) in spite of intensive photoRx (BW 1997 to 3960g, GA 32 to 40 wk, 60 to 120 enzyme units/kg/day in one or two hourly feedings or constant OG infusion). Oral BOX was uniformly well tolerated, with no signs of toxicity. Three of the eight were term infants and otherwise healthy; one with severe BO disease (to be described elsewhere), and two with G6PD deficiency with mild hemolysis. Hepatic bilirubin excretion was quite limited in one of these latter infants whose SB rose to 27 mg/dl (BA ratio 6.3mg/g) in spite of intensive photoRx plus BOX, and an Ex Tx was necessary. The remaining five jaundiced BOX-Rx infants had other complications. One was an IDM born at 35/36 wk GA with polycythemia, hypoglycemia, somewhat increased hemolysis (day zero Hct 68%, day 5 Hct 44%) and a rapidly rising SB. After starting oral BOX, SB rise moderated, plateaued and then fell sharply. No Ex was necessary. The four other infants, one term and three preterm, were critically ill, two with severe birth asphyxia, shock and large subgaleal/intracerebral bleeds, one with symtomatic sepsis and poor albumin bilirubin binding affinity (36 wk GA), and one (32 wk GA twin) with severe bruising, probable sepsis and respirtory distress. Only the two infants with large intracranial bleeds required Ex. No Ex was needed in the two other sick infants. A significant increase in bilirubin clearance is suggested by the more rapid than expected fall in SB. We conclude BOX Rx appears promising, completely non toxic, and deserves study in randomized clinical trials. (BOX supplied by Amano International Enzyme Co., Ltd.)}

In our study of invivo lipid peroxidation, we measured levels of expired alkane gases in preterm neonates using respiratory circuits. Ethane, pentane, butane, propane and hexane levels were measured by gas chromatography(Shimadzu 14A with a flame ionization detector, silica gel and Poropak-Q® columns, H2 carrier gas) with aliquots of 50ml collected in hydrocarbon(HC) free gas tight glass syringes. Propane cannot be distinguished by our technique unless C3-C5 analyte levels are

BILIRUBIN OXIDASE (BOX) FEEDINGS TO DELAY OR ELIMINATE THE NEED FOR EXCHANGE TRANSFUSION (EX) IN A FULL TERM G6PD DEFICIENT INFANT. 1299

PROBABILITY OF SUBSEQUENT HYPERBILIRUBINEMIA IN TERM HEALTHY NEWBORNS WITH NO ABO/Rh DISEASE. † 1165

The incidence of culture-proven neonatal sepsis and necrotizing enterocolitis (NEC) in preterm infants maintained at pharmacologic (mean 5.1 mg/dL ± 1.45 SD) serum vitamin E levels for long periods was prospectively studied as part of a double-masked clinical trial of the effect of prophylactic vitamin E v placebo treatment on the development and course of retinopathy of prematurity (ROP). Within a few days of birth, 914 preterm infants were enrolled in the study; 545 (275 placebo-treated infants, 270 vitamin E-treated infants had birth weight of 1,500 g or less. A significant difference in incidence of neonatal sepsis (17 placebo-treated infants, 37 vitamin E-treated infants) and NEC (18 placebo-treated infants, 32 vitamin E-treated infants) was observed among infants who had been treated for eight or more days and who had developed neither sepsis nor NEC before that time. The association of vitamin E treatment with increased incidence of disease was much higher with sepsis than with NEC. The most likely reason for these observations is a pharmacologic serum vitamin E-related decrease in oxygen-dependent intracellular killing ability which results in a decreased resistance to infection in preterm infants. The data suggest that, if this occurs, it is clinically significant only in the more immature infants. In view of the known variability of absorption of oral vitamin E and the association between high serum vitamin E levels and increased incidence of sepsis and late-onset NEC reported here, it can be concluded that serum vitamin E levels must be monitored when supplemental vitamin E is administered to premature infants, especially those with birth weight 1,500 g or less. The risk-benefit ratio of long-term treatment using vitamin E at high serum levels should be clearly assessed.

The incidence and severity of retinopathy of prematurity (ROP) as affected by vitamin E prophylaxis at pharmacologic serum levels (5 mg/dl) were evaluated in a double-masked clinical trial of infants with a birth weight less than or equal to 2000 gm or a gestational age less than or equal to 36 weeks. The infants were enrolled by age 5 days and randomly assigned to receive parenterally administered, and later orally administered, free alpha-tocopherol (vitamin E) or its placebo. Study medication was continued until retinal vascularization was complete or active ROP had subsided, except in infants with a diagnosis of severe disease, in whom vitamin E was substituted for study medication. Acute ROP data were collected on 755 infants. Logistic regression analysis, with control for immaturity, oxygen exposure, and other illness risk factors, showed a decrease in incidence of ROP in vitamin E-treated infants (p = 0.003, all infants; p = 0.035, infants weighing less than or equal to 1500 gm at birth). Among the 424 infants weighing less than or equal to 1500 gm at birth, the age at enrollment influenced treatment effect (age day 0 to 1, p = 0.006 (n = 288) vs age day 2 to 5, p greater than 0.1 (n = 136]. Overall, 77.6% of infants with ROP had mild disease. Moderate to severe ROP was confined to infants weighing greater than or equal to 1500 gm at birth (25 given placebo, 25 given vitamin E), with progression to severe disease in nine placebo-treated versus three vitamin E-treated infants (p = 0.048). The incidence of severe ROP per se was not significantly decreased (all birth weights, p = 0.086; less than or equal to 1500 gm birth weight, p = 0.080); the sample size was too small, however, to assess this end point adequately. An increased incidence of sepsis and late-onset necrotizing enterocolitis was found among vitamin E-treated infants weighing less than or equal to 1500 gm at birth who received study medication for greater than or equal to 8 days (p = 0.006). Because most ROP is mild in degree and regresses completely, the risk/benefit ratio of pharmacologic prophylaxis for ROP is unfavorable. Treatment of moderate and severe ROP with vitamin E above physiologic serum levels (greater than 3 mg/dl) appears promising and should be further investigated. The interpretation of cicatricial outcome was confounded by the small number of patients involved and by subsequent treatment of severe ROP in placebo-treated infants with vitamin E.

9. Hauge A, Thoresen M, Wall~e L. Changes in cerebral blood flow during hyperventilation and CO2-breathing measured transcutaneously in humans by a bidirectional, pulsed, ultrasound doppler velocitymeter. Acta Physiol Stand 1980; 110:167. 10. Pickard JD, MacKenzie ET. Inhibition of prostaglandin synthesis and the response of baboon cerebral circulation to carbon dioxide. Nature 1973;245:187. 11. Dahlgren N, Nilsson B, Sakabe T, Siesj6 BK. The effect of indomethacin on cerebral blood flow and oxygen consumption in the rat at normal and increased carbon dioxide tensions. Acta Physiol Scand 1981;111:475. 12. Friedman Z, Whitman V, Maisels M J, et al. Indomethaein disposition and indomethacin-induced platelet dysfunction in premature infants. J Clin Pharmacol 1978;18:272. 13. Yaffe S J, Friedman WF, Rogers D, et al. The disposition of indomethacin in preterm babies. J PI~DIATR 1980;97:100 [. 14. Pickard JD, MacDonell LA, MacKenzie ET, Harper AM. Response of the cerebral circulation to changing perfusion pressure after indomethacin. Circ Res 1977;40:198.

A refined classification of the stages of the retinopathy of prematurity (RLF) based on the experience of over 7500 examinations during the past decade is presented. We have been using the basic elements of this classification since 1972 in order to evaluate the influence of vitamin E on retrolental fibroplasia (RLF). It is our impression that it provides a more accurate clinical method of following the course of the retinopathy and a tool for assessing the factors other than prematurity and hyperoxia that may play a subtle role in the development of RLF.

We have developed a classification system for the acute phases of retinopathy of prematurity based on more than 13,000 ophthalmoscopic examinations of more than 3,400 premature infants between 1968 and 1982. Two forms of the active disease exist. Retinopathy of prematurity is a relatively common mild disease and retinopathy of prematurity plus is characterized by rapid progression and posterior pole vascular tortuosity and dilation. The five grades progress from peripheral vascular abnormalities (Grade 1) through a demarcation line (Grade 2) and extraretinal neovascularization (Grade 3) to partial (Grade 4) or total (Grade 5) retinal detachment. The persistence of abnormal retinal vessels during the first year of life is considered "transitional" retinopathy of prematurity unless unequivocal cicatricial changes with macular distortion develop.

Cultures of myelinating cerebellum were exposed to media containing bilirubin and human serum albumin and to identical media in which the bilirubin had been partially degraded by light. Starting concentrations of bilirubin were 30 mg. per cent. Cultures exposed to irradiated media in which the remaining diazotizable bilirubin was below 14mg. per cent (representing a bilirubin to human albumin ratio of approximately 0.8:1) did not damage the cultures. Unirradiated media produced characteristic andsevere damage.

Conjugated and unconjugated bilirubin were injected intravenously at different times into normal rats and homozygous, jaundiced Gunn rats. As was expected, Gunn rats did not excrete injected unconjugated bilirubin in the bile. After the intravenous injection of conjugated bilirubin into normal rats, approximately twice as much bilirubin appeared in the bile per 100 g of body wt within 10 min than after the injection of comparable amounts of unconjugated bilirubin. This difference probably reflects the time required for cellular uptake and conjugation of bilirubin prior to excretion. The maximal biliary bilirubin excretory rate in Gunn rats following the administration of conjugated bilirubin was 56±8.4 (S.D.) µg of bilirubin excreted/100 g body wt/min. This does not differ significantly from the maximal biliary bilirubin excretory rate observed in normal rats after infusions of either conjugated or unconjugated bilirubin. This demonstrates that conjugation alone does not limit metabolism of bilirubin by normal rat liver. These studies, when considered in the light of other investigations, suggest that the ability to excrete conjugated bilirubin is the limiting factor in metabolism of bilirubin by normal rat liver.

The clinicopathological syndrome of kernicterus observed in rats with congenital hypoglucuronyltransferasia (Gunn's strain of rats) is similar to the syndrome of human kernicterus. The earliest detectable changes in ganglion cells are associated with the presence of intracellular bilirubin. Sulfonamides, do not produce kernicterus in normal newborn rats, nor do they alter the blood-brain barrier. Their deleterious effect in Gunn's strain of rats and in premature infants may be explained by the displacement of bilirubin from the blood compartment into the extracellular fluid. It is suggested that a similar mechanism may be operative in kernicterus occurring under other circumstances. The toxic unconjugated bilirubin is probably the cause of central nervous system damage.

Pharmacokinetics of vitamin E (E, mg/dl) were evaluated in 28 preterm infants following intravenous infusion of doses of dl- tocopherol (Hoffmann-LaRoche) administered over a period of 8 hours. Blood samples were obtained from a central line immediately prior to, and at 2, 4, 6, 8, 10, 12, 18, 24, 48 and 72 hours after E infusion. Dosages were: Group I, (n=4), (BW=1218 ± 216, GA=29.5 ± 2.6) = 5 mg/kg; Group II, (n=6), (BW=1091 ± 165, GA=28.5 ± 1.2) = 10 mg/kg; Group III, (n=7), (BW=1078 ± 267, GA=27.5 ± 1.2) = 15 mg/kg; Group IV, (n=6), (BW= 941 ± 115, GA=27.5 ± 1.2) = 20 mg/kg; Group V, (n=5), (BW=1040 ± 193, GA=30.8 ± 3.7) = 30 mg/kg. Pharmokinetic parameters were obtained by independent analysis of E concentration-time profile. Mean ±SD values for serum harmonic E half life (T1/2, hrs), volume of distribution (VD, L/kg), and serum clearance (sc, ml/kg/hr) for the groups are: Infants in Group I and V had additional supplemental E (multivitamin in hyperalimentation) resulting in fluctuation of baseline values and alteration of apparent half life. These data should be useful for determination of dosage recommendations.

• Twenty-six infants with totally resolved low-grade retinopathy of prematurity (ROP) were compared with a similar group of 38 premature infants in whom no retinopathy had ever developed in the nursery. At the examination performed at a physiologic age of 1 year, the two groups were almost indistinguishable with respect to their refractive errors, strabismus, and amblyopia. The incidence and severity of mild to moderate anisometropia was increased in the resolved ROP group. It appears that there is a group of infants in whom absolute resolution occurs, with few residua of active ROP. This is especially true when there are no anatomical retinal findings consistent with low-grade cicatricial retrolental fibroplasia at 1 year of age.

The use of physical methods such as freezing point depression for the estimation of osmolality of preparations given to infants may be misleading. The reasons for this are discussed, and reference made to some other properties of preparation vehicles which may be of concern.

The long-term effect of necrotizing enterocolitis on growth, nutritional status, and gastrointestinal function was assessed in premature infants at the age of 1 year. Of the 22 of 40 infants who developed NEC, 18 were given medical treatment and four required surgical treatment consisting of intestinal resection of less than one fourth of the small bowel. Eighteen infants who did not develop NEC served as controls. At 1 year follow-up, NEC survivors and controls had normal and comparable anthropometric measurements, biochemical values (serum iron, albumin, prealbumin, retinol binding protein, liver function studies) and gastrointestinal tract function (vitamin E absorption, fasting serum bile acids concentration, lactose breath test). This study demonstrates that, in the absence of short bowel syndrome, there is no detectable long-term effect on growth, nutritional status, and gastrointestinal tract function in premature infants who had NEC in the newborn period.

The effect of high-dosage E treatment (Rx) initiated at the stage of 3-plus active disease (target serum E levels, 5-6 mg/dl) was evaluated by a standardized scoring system of visual morbidity at the one to two year eye exam among infants cared for in the University of Pennsylvania Neonatal Complex (1976-1978). The incidence of legal blindness in both eyes or worse was decreased from 71 to 40% in E Rx (n = 10) as compared to non-E Rx (n = 14) infants, and the number of infants with minimal visual morbidity was increased. Pilot studies (1972-76; target serum E level, 1.5 and 3.0 mg/dl) of the prophylactic effect of E Rx from birth on showed a decrease in mean severity of acute stage disease and a decrease in sequelae at one to two years. A strikingly difference in visual morbidity following resolved low-grade ROP was seen when prestudy infants (1968-72) who were fed early iron supplements and given formulas with low E:PUFA ratios were compared to non-E Rx as well as to E Rx 1972-76 infants. Vitamin E seems to exert a beneficial effect at all stages of ROP, perhaps because of its broadly based regulatory role.

To the Editor.— In the 1987 April issue of Pediatrics1 Dr Phelps and colleagues reported the results of their study of prophylactic vitamin E and retinopathy of prematurity and related them to those of other trials. They concluded that the evidence for efficacy of tocopherol in decreasing "severe" retinopathy of prematurity is not convincing and that its use in infants weighing ≤1,000 g at birth may be contraindicated and even produce death. With regard to toxicity, the reader needs to be reminded that the fatalities referred to followed administration of high doses of a preparation of IV tocopherol acetate (E-Ferol) which was not subjected to field testing and was not used in any of the clinical trials.

Gunn rats treated with sulfadimethoxine between 18 hours after birth and 33 days of age developed acute neurologic signs and increased yellow staining of their brains. In animals treated between the ages of 4 and 22 days, the neurologic abnormalities were proportional to the serum bilirubin levels. Animals treated from 18 to 48 hours after birth develop more severe signs than older animals with similar bilirubin levels, and those older than 22 days develop mild but definite neurologic signs. This study confirms the importance of the albumin binding of bilirubin as a protective factor in hyperbilirubinemia. We conclude that it is superfluous to postulate a blood-brain barrier to bilirubin to explain kernicterus, and that anoxia is not essential for its development. Bilirubin has access to the central nervous system beyond the newborn period. The reasons for the extreme toxicity of sulfonamides to Gunn rats in the first 2 days of life and the relatively mild effects in animals treated at 28 and 33 days are discussed. It is suggested that the characteristic pattern of yellow discoloration of the brain in kernicterus could be largely accounted for by differences in regional cerebral blood flow.

We have studied the relationship of pH and bilirubin:albumin ratio to the occurrence of bilirubin-induced damage in cerebellum cultures. Sufficient unbound bilirubin reproducibly caused a sequence of histologic changes which were observed by light microscopy. At a constant bilirubin:albumin molar ratio, a decrease in pH of the medium resulted in proportionately greater cytotoxicity. Maintenance of an average medium pH above 7.62 during the last 12 hours of the cultures' lives prevented damage in the presence of bilirubin concentrations of up to 50 mg. per 100 ml. At lower pH values an increase in the bilirubin:albumin ratio produced increasingly greater cytotoxicity. These findings support the thesis that unbound, unconjugated bilirubin is responsible for neurologic damage. Knowledge of several conditions, i.e., pH, bilirubin:albumin molar ratio, and duration of exposure, is necessary to predict the occurrence of damage. The regional pattern of bilirubin crystallization suggests that regional pH differences may play a part in determining in vivo distribution of lesions in kernicterus.

In previous papers, 20,5,55 we have described the occurrence of kernicterus in the Gunn strain of rats, as well as some of the factors which influence its incidence and pathogenesis. This paper concludes our current study of the rats and summarizes approximately 2 years of observation. Methods and Terminology As in the previous papers, the jaundice gene is designated by the small letter j and the normal gene by the capital letter J . 55 Kernicterus is defined as previously 55 and is abbreviated in tables as KI. The methods for serum bilirubin (S.B.) and sulfonamide determinations have been previously described. 55 Sodium p -aminohippurate (Na PAH) determinations were done by a micromodification of the method of Smith. 94 Sodium glucuronate (Na GA) was determined by a micromodification of the method of Fishman. 29 Total protein (T.P.) determinations were done on 20Λ of serum by an unpublished modification of the biuret

Recent studies indicate the importance of lipid substrates in normal premature infants (VAN DUYNE, 1959; PERSSON et al., 1966). To determine the relationship of acid-base status to energy substrates, sequential arterialized pH, PaCO2, BE (mEq/L) and venous FFA (mEq/L), ketones (mEq/L), and glucose (mg %) were determined in 36 newborns (1250–2500 gm) maintained in a ‘neutral’ thermal environment from ages 4 to 140 hours. Infants were fasted till after the 12–20 hour sample when feedings were begun. Mean values (±SD)

Dr. Diamond has presented important in vivo evidence reaffirming the thesis of Dr. Odell that unbound bilirubin is the toxin causing kernicterus. Unfortunately, we have not yet learned how to apply this knowledge to the management of the jaundiced newborn infant. For example, we are still left with the problem of deciding which jaundiced infant needs treatment. Recent electron microscopic studies in the Gunn rat emphasize this point. At birth, in homozygous (jj) rats born to heterozygous (Jj) mothers, no staining of the tissues is present and there are no cellular abnormalities to be found in the brain. By 4 to 8 hours of life, jj animals display slight clinical jaundice and their brains, after perfusion with saline or formalin to wash out capillary blood, exhibit equivocal localized staining.

Working with Gunn Rats as an animal model for kernicterus, it was noted that jaundiced (jj) adult females fed standard lab chow (4% fat) could rarely carry litters to term or rear healthy pups. In contrast they were as able as non-jaundiced (Jj) females when fed mouse breeder chow (11% fat). As the table shows, decreasing the litter size and feeding nursing dams breeder chow resulted in a decreased number of Purkinji cells (PC) exhibiting typical bilirubin abnormalities as assessed by phase microscopy of glutaral-dehyde-perfused, araldite-embedded sections of the cerebellar vermis. Protection seems to result from an increase in body fat and the known high affinity of fat for bilirubin. On day 16 mean S. bilirubin and protein levels were similar in all pups. Rats of breeder chow fed dams were fatter than rats of regular chow dams at both litter sizes; litters of 4 were fatter than litters of 6.

Preterm infants, at risk for retinopathy of prematurity, need to be maintained Vitamin E sufficient (range: 0.8 to 1.2 U/ml) with appropriate Vitamin E supplements. Since iron is a potent pro-oxidant and free radical donor, it effectively increases the need for Vitamin E. Based on these considerations, iron supplementation has been delayed in our ICN until retinal vasculature matures. The iron status and need for supplementation was evaluated in 50 growing preterm infants (mean ± SD birthweight = 1019 ± 23.8 gm, range: 650-1370 gm). The only presumable source of iron was packed red blood transfusion administered during the ICN stay (total mean blood received ± SD: 374 ± 255 ml). Serum Iron (SI) and transferrin saturation (SAT) were determined at birth and biweekly until eyes were mature. Mean ± SD values at 8, 10, 12 wks postnatal age appear below: These data indicate that infants in the ICN remain iron sufficient and the use of iron containing formulas may be delayed, in the occasional infant who requires little or no blood and therefor does not add to his iron stores in the nursery, the delay in providing an iron supplement can be compensated for by prescribing Poly-visol with Iron. A dosage of I ml/day for one month provides about as much iron as a daily intake of 24 oz. of iron-enriched formula over a six week period.

Incidence and severity of RLF was defined by a standard grading system in 269 premature infants with birth weight (BW)≤2000 gm or gestational age (GA) ≤36 weeks and needing oxygen (O2) therapy Prediction of mean severity of RLF (acute stage, all babies) was studied by a multiple regression equation which reports proportion of total outcome variance (cumulative R Square) accounted for by the predictor variables available. It selects independent variables in order of additional contribution to RSq, the best predictor being selected first. Very weak predictors do not enter the equation. The last RSq in the summary table represents the total variance accounted for by all risk factors considered and amounts to only 35.8%.From a clinical standpoint, only BW (or GA) is a major predictor. Carefully controlled O2 Rx seems to pose only a small risk. As yet undefined differences, probably largely genetic, (Phelp's queen effect), are of major importance. The Dependent Variable is Mean Severity of RLF for All Infants

Malondialdehyde (MDA) is a marker for lipid peroxidation of unsaturated fatty acids. The amount of MDA generated by red blood cells (RBC)exposed to a standard H2O2 stress reflects the available antioxidant protection. As such it is more specific than the H2O2 hemolysis test & provides more information than simultaneous measurement of plasma Vit E & total lipids. However, after blood transfusions, the RBC-MDA assay poorly reflects E sufficiency since for a matter of weeks, it measures donor as well as patient cells. This is illustrated in the data on Baby B presented below. Unfortunately, the smallest sickest infants who are most in need of antioxidant defenses & most in need of antioxidant protection are also most in need of frequent blood transfusions. Becausethe much shorter life span of the platelet as compared to the RBC makes it preferable as a test cell, we have developed a platelet MDA assay (1.5 ml of blood). Results, as judged by simultaneous RBC-MDA and H2O2 assays, suggest the test is clinically feasible & will be useful in defining the state of E nutrition in premature infants.

Both vitamin E and zinc deficiency continue to be observed in the very low birth-weight infants despite the use of dietary supplements. The interrelationship between vitamin E and zinc nutrition was sequentially evaluated in 58 formula fed growing preterm neonates (birth weight: X ± SD, 1043±121g, gestational age: X ± SD, 29±0.4 wks). Enteral feeds contained zinc (300mg/100ml) and supplemental vitamin E (to achieve sufficient serum E level of 1-2mg/dl). Three groups of infants were identified on data analyses. Group I (27/58) had sufficient serum zinc (>70mcg/dl) and vitamin E (1-3mg/dl) levels on mean E supplement of 55±10 SD I.U./day. Group II (15/58) were hypozincemic (

Taurine (T) is essential to normal retinal function. It is present in high concentrations in human milk but virtually absent in infant formulas and parenteral feedings. Its concentration in the retina increases until about 2 months post a term birth. Deficiency results in retinal abnormalities. T appears to regulate membrane excitability, promote homeostasis and protect membranes against oxidant damage along with Zn and vitamin E. We therefore reviewed the records of 385 infants (216≤1500g BW, 169>1500 1500g). The data suggest a protective effect of breast milk in ROP which may be related to improved taurine nutrition. Controlled clinical trials would appear to be in order.

Premature infants are vitamin E deficient at birth. Vitamin E administration by infusion is preferable to intramuscular injection because of the small muscle mass of very low blrthweight infants and the irritating nature of free tocopherol. Pharmacokinetics of intravenous vitamin E (IV) was evaluated in 9 preterm infants. 4 infants (Group 1, BW 990 ± 84 gms, GA = 29.2 ± 1.1 wks) were given a single dose of 10 mg/kg of dl-α tocopherol (Hoffmann LaRoche) by 1 hour infusion. The same dose was given to 5 infants (Group 2, BW 1138 ± 133.6 gms, GA = 28.4 ± 1.3 wks) by 8 hour infusion. Blood samples were obtained from central line immediately prior to (zero time) and at 2, 4, 6, 8, 10, 12, 15, 18, 24, 36, 48, 72 hours after vitamin E infusion. Pharmacokinetic parameters were obtained by model independent analysis of the serum vitamin E concentration time profile. Mean ± SD values for harmonic half life (T 1/2, hrs), volume of distribution (VD, liter/kg), serum clearance (SC ml/hr/kg) and selected serum vitamin E levels (E, mg/dl) for the two groups are: Infusion of vitamin E over 1 hour results in a significantly higher peak but similar steady state values as compared to 8 hours. These data can be used for dosing recommendation.

For the past 5 years we have been doing serial determinations of the activity of the flavin adenine dinucleotide(FAD) dependent enzyme, glutathione reductase (GR) in RBC's of babies undergoing phototherapy. Activity, following in vitro exposure to↑FAD, is also measured(method of Glatzle). More than 20% increase is evidence of riboflavin deficiency. A summary of data collected in our nurseries from 1971-73 is given below. Similar data have been collected since. No evidence of phototherapy related deficiency has yet been found in these 5 years. Similarly there has been no evidence of treatment related decrease in G6PD activity or GSH blood content. However low GSH levels are not infrequently found in small sick babies regardless of Rx. Beginning studies of a second FAD dependendent enzyme, methemoglobin reductase(MR) are showing similar results, except that MR activity in contrast to that of GR is lower in newborn RBC than in adult. Occasional instances of slightly lower activity following onset of Rx have all reversed themselves before cessation of Rx. These data differ from those of Gromisch et.al. perhaps because of differences in maternal nutrition.

Little is known about the factors determining the variability in response of developing retinal vessels to oxidant stress which is seen in individual premature and (rarely) in term infants.RLF fails to occur in some infants in spite of much oxygen exposure. It can occur in the absence of oxygen treatment. That genetic factors are important is emphasized by an instance of RLF seen by the authors involving a term infant never treated with oxygen whose older sibling, identical in appearance and also born without complications at term, also had severe RLF. Pregnancy complications which necessitate fetal adjustment to chronic low-grade hypoxia appear also to predispose to RLF as evidenced by the table below. Pregnancy complications included fetal growth retardation, moderate to severe toxemia, severe maternal diabetes or anemia, second or third trimester bleeding requiring treatment, heavy cigarette smoking, ruptured fetal membranes with amnionitis or exceeding 6 days. 77 Infants with Birth Weight

Coagulase-negative staphylococcus (CNSC) is an increasingly important pathogen in neonatal intensive care units, and is the causative agent for both bacteremia and focal infections (meningitis, pneumonia, osteomyelitis, UTI, septic arthritis, and shunt infections). Acute enterocolitis was the presenting symptom in 19 infants (xGA 29.9 weeks±2.2 SD; xBW 1281gm±530 SD) who, on evaluation for infection, were found to have CNSC sepsis. This CNSC-associated enterocolitis constituted 47% of the 40 cases of enterocolitis and 23% of the 81 cases of CNSC sepsis during the retrospective study period (April 1982-Aug. 1984). CNSC-associated enterocolitis was defined as 1)positive blood and stool cultures for CNSC, and 2)clinical acute enterocolitis syndrome with abdominal distension (19/19), bloody stools with mucus (gross blood 12/19, hematest + 7/19), abdominal tenderness (18/19), and gastric residuals (18/19). Abdominal x-rays showed markedly abnormal bowel gas patterns with distended bowel loops and bowel wall edema. Only one infant had pneumatosis intestinalis, and none had portal venous or free peritoneal gas. None of these infants required surgical intervention or ventilatory support. Although bloody stools often persisted for weeks, none of the neonates had prolonged feeding intolerance or development of stricture. We conclude that CNSC is a common cause of enterocolitis in the neonate, and that this association should be considered when selecting antibiotics for therapy.

To the Editor.— Phelps' commentary, "E-Ferol: What Happened and What Now?"1 is an important reminder of the danger of using untested drugs. We feel, however, some points of clarification are needed. First, Phelps cited Myers et al2 as using 1.1 mg/kg/d of E-acetate IV and raising serum E levels to 6 mg/dL in preterm infants. This is misquoted. Myers et al used 10 mg/kg of vitamin E over one hour (dl-α-tocopherol [Hoffman LaRoche] not E-acetate) and achieved levels of 0.6 mg/dL not 6 mg/dL at the end of the infusion.