Clinical trial of tin mesoporphyrin to prevent neonatal hyperbilirubinemia.

OBJECTIVE: To assess the efficacy of the heme oxygenase inhibitor, tin mesoporphyrin (SnMP), to reduce total bilirubin (TB) levels. STUDY DESIGN: Masked, SnMP (4.5 mg kg(-1)), placebo-controlled, multicenter trial of single intramuscular injection to newborns ⩾35 weeks gestational age whose predischarge screening transcutaneous bilirubin (TcB) was >75th percentile. RESULTS: Two hundred and thirteen newborns (median age 30 h) were randomized to treatment with SnMP (n=87) or 'sham' (n=89). We found that the duration of phototherapy was halved. Within 12 h of SnMP administration, the natural TB trajectory was reversed. At age 3 to 5 days, TB in the SnMP-treated group was +8% but sixfold lower than the 47% increase in the sham-treated group (P<0.001). At age 7 to 10 days, mean TB declined 18% (P<0.001) compared with a 7.1% increase among controls. No short-term adverse events from SnMP treatment were noted other than photoreactivity due to inadvertent exposure to white light phototherapy. CONCLUSION: Early, predischarge SnMP administration decreased the duration of phototherapy, reversed TB trajectory and reduced the severity of subsequent hyperbilirubinemia.

A multicenter long-term safety and efficacy trial of preterm formula supplemented with long-chain polyunsaturated fatty acids.

BACKGROUND: The tissue accretion of long-chain polyunsaturated fatty acids is compromised in infants born prematurely. Human milk contains long-chain polyunsaturated fatty acids, but most preterm infant formulas do not. The long-term effects of preterm formula supplemented with arachidonic acid and docosahexaenoic acid, in proportions typical of those in human milk, were therefore investigated. METHODS: In this double-blind, randomized study, 288 preterm infants received experimental formula (n = 77), unsupplemented (control) formula (n = 78), or human milk (n = 133) until 48 weeks postconceptional age (PCA). Term formula, without supplemental long-chain polyunsaturated fatty acids, was administered from 48 to 92 weeks PCA to formula-fed infants and to infants weaned from human milk. Anthropometric and fatty acid data were assessed by using analysis of variance. RESULTS: At 92 weeks PCA, no statistically significant anthropometric measurement differences were found except for midarm circumference, which was smaller in human milk-fed infants than in those fed formula. Phospholipid concentrations were similar in the experimental and human milk-fed groups, and docosahexaenoic acid levels were significantly greater than in the control group. The types and incidences of adverse events were similar among the feeding groups. CONCLUSIONS: The results of this study demonstrate the efficacy and long-term safety of preterm formula supplemented with long-chain polyunsaturated fatty acids.

A multi-centre safety and efficacy trial of a preterm infant formula supplemented with long chain polyunsaturated fatty acids (LCP) (48 weeks PCA analysis)

LCP supplementation of premature infant formula has been shown to produce plasma and erythrocyte lipid profiles similar to human milk (HM)-fed preterm infants. Previous studies reported decreased growth with LCP supplemented formula. This prospective, double-blind, randomised, controlled, parallel trial compared safety, growth and phospholipid fatty acid (PFA) levels in preterm infants fed preterms formula with (L+) or without (Lo) LCP. The study consisted of Phase I: enrolment to 40 weeks (wk) postconceptual age (PCA); and Phase II: 40 to 48 wk PCA. Infants (birth weight 750-2000 g, 0-28 days of age) were fed L+ or L preterm formula, 24 Kcal/oz during Phase I, and 20 Kcal/oz during Phase II. A control group was exclusively HM-fed preterms who, if weaned at the end of Phase I, received L. HM and formula intake were unrestricted. Weight (wt), length (Lt), head circumference (OFC) and upper mid-arm circumference (MAC), and phospholipid profiles were measured at 40 and 48 wk PCA. Adverse events were monitored. 183/288 infants completed Phase II. There were no difference in growth rates between formula groups. At 48 wk PCA, mean PFA levels in infants fed L+ were similar to HM-fed and were significantly higher than the L fed group. Adverse events were similar between the 2 formula groups. The number of infants who were discontinued because of an adverse event was similar among all groups. In conclusion the LCP preterm infant formula is safe, support normal growth and maintains phospholipid profiles similar to HM-fed infants.(AU)

The protective role of bilirubin in oxygen-radical diseases of the preterm infant.

We hypothesized that because bilirubin is a potent free-radical quencher, infants without disorders that have oxygen-radical disease (ORD)-mediated mechanisms may have higher bilirubin levels than infants suffering from conditions possibly associated with ORD-mediated mechanisms (e.g., necrotizing enterocolitis, broncopulmonary dysplasia, intraventricular hemorrhage, and retinopathy of prematurity). We identified 25 infants (birth weight 912 +/- 208 gm, gestational age 27 +/- 3 weeks) who comprised the ORD group and compared them with 57 controls (birth weight 1242 +/- 248 gm, gestational age 31 +/- 3 weeks). Infants with ORD had lower peak serum bilirubin concentrations, later ages at peak, and lower incidence of peak bilirubin concentrations exceeding 10 or 15 mg/dl. In addition, these infants exhibited a slower rate of bilirubin rise and a smaller area under the bilirubin-time curve measure compared with controls. To control for different birth weights, we analyzed subgroups weighing < 1000 gm. Significant differences were again identified in peak bilirubin concentrations, age at peak, phototherapy duration, and area under the curve. In this population of preterm infants, higher bilirubin levels were associated with a lower incidence of oxygen radical-mediated injury.

The course of hyperbilirubinemia in the very low birth weight infant treated with phenobarbital.

We examined the effect of early phenobarbital therapy on the course of jaundice in 57 infants with birth weight below 1,500 g. The study group of 28 infants was treated with a phenobarbital loading dose of 20 mg/kg at 4.2 (3.6) [mean (SD)] hours of age, followed by a maintenance dose of 5 mg/kg/day for one week; 29 infants served as controls. Seventeen study and 19 control infants suffered from periventricular-intraventricular hemorrhage (IVH). The two groups had comparable risk factors that can potentially affect the course of hyperbilirubinemia. Peak serum bilirubin concentration was 7.9 (1.8) mg/dl in the treated group and 8.6 (2.2) mg/dl in the control group. Three infants in the treated group and seven infants in the control group had peak serum bilirubin concentration above 10 mg/dl. These differences in the peak serum bilirubin concentration or in the number of infants with peak serum bilirubin concentrations above 10 mg/dl are not statistically significant. However, treated infants achieved peak serum bilirubin concentration earlier (mean age 90 hours as compared to 138 hours in control infants), and required phototherapy for a shorter duration of time (5.5 days in the treated group as compared to 7.5 days in the control group). While these differences in the two groups with regard to age of peak serum bilirubin concentration and duration of phototherapy are statistically significant, they do not seem to be clinically important. Thus, in our group of very low birth infants phenobarbital failed to show any clinically important effects on the course of jaundice when used in conjunction with phototherapy.

Transcutaneous bilirubinometry. III. Dermal bilirubin kinetics under green and blue light phototherapy.

Using the transcutaneous bilirubinometer, we studied the response of cutaneous bilirubin to different colors of light during phototherapy. Three groups of ten infants were exposed to blue, green, and blue-green lights at a mean postnatal age ranging from 50 to 77 hours. Patched areas served as controls. Every 15 minutes during four hours of phototherapy, we obtained simultaneous measurements from exposed and covered areas. After the onset of phototherapy, transcutaneous bilirubinometer values from the covered areas in all groups remained stable. The overall rate of bleaching was lowest in the green light group and highest in the blue-green combination group. In this group of infants, green light appeared to enhance the effectiveness of blue light in reducing dermal bilirubin concentrations as measured by the transcutaneous bilirubinometer.

Transcutaneous bilirubinometry II. Dermal bilirubin kinetics during phototherapy.

We examined the effect of phototherapy on cutaneous bilirubin using the transcutaneous bilirubinometer (TcB) in 14 white infants at a mean postnatal age of 30 h. Six infants were treated with blue light, eight with white light. An opaque patch, 2.5 cm in diameter, covered the skin and served as a source for TcB control values. Simultaneous TcB measurements were obtained from exposed and patched areas every 15 min during 4 h of phototherapy. After the start of phototherapy, TcB index obtained from patched skin did not change during the course of treatment. Data from exposed skin showed that the initial rate of TcB index fall during the first hour was significantly faster than the successive values during the next 3 h in both groups studied. During the first 2 h of therapy the TcB index decreased faster among infants treated with blue light. Correlation studies indicate that TcB measurements from exposed skin areas may not be clinically useful in predicting serum bilirubin response to phototherapy but data obtained from unexposed sites may fill this role.

The effects of shielding the hepatic area on the clinical response to phototherapy.

The changes in serum bilirubin concentration in response to phototherapy were studied in 26 infants with and without an opaque patch on the liver area. Fifteen infants in the patched group were treated at a mean age of 50.7 h, and 11 control infants at 49.1 h. No significant differences were demonstrated between the two groups in duration of phototherapy, peak bilirubin concentration and rates of bilirubin decrement. Shielding the hepatic area during illumination does not alter the clinical response to phototherapy which suggests that the main site of action of phototherapy is in the skin.

Transcutaneous bilirubinometry. I. Correlations in term infants.

The transcutaneous bilirubinometer was evaluated in 43 white infants, eight black infants, and in nine white infants treated with phototherapy. The reproducibility of the instruments was determined after trials consisting of both five and 100 repetitions. Among the infants not being treated with phototherapy, TcB index and serum bilirubin concentration correlated at 0.90 level in both white and black infants. Phototherapy reduced the accuracy of the TcB and, at the present time, the use of this index in infants under light therapy cannot be recommended. Otherwise the TcB is a valuable tool in screening healthy term infants for hyperbilirubinemia.

Intermediate phototherapy in the treatment of jaundice in the premature infant.

A controlled trial of the use of intermittent phototherapy for the treatment of hyperbilirubinemia in newborn infants is reported. Periods of illumination of (1) 15 minutes light on, 15 minutes light off, (2) 15 minutes on, 30 minutes off, and (3) 15 minutes on, 60 minutes off are as effective as is continuous illumunation. A comparison with previous trials of intermittent phototherapy is made and differences in results are explained using as a model the action of light on bilirubin.