Protective effect of bilirubin in ischemia-reperfusion injury in the rat intestine.

BACKGROUND: Although bilirubin, which crosses the blood-brain barrier, can cause irreversible brain damage, it also possesses antioxidant properties that may be protective against oxidative stress. Intestinal ischemia-reperfusion (IR) injury results in cell destruction, mediated via the generation of reactive oxygen species. Although increased serum bilirubin is correlated with increased antioxidant potential in the face of hyperoxia, evidence of bilirubin-associated protective effect against IR injury remains nonspecific. We therefore sought to investigate whether hyperbilirubinemia would be protective against IR injury to the intestine. METHODS: Young adult rats were randomly assigned to one of three groups: 1) IR/control (n = 12); 2) IR/hyperbilirubinemia (n = 10), in which IR was generated while the rats were treated with a continuous infusion of bilirubin; and 3) hyperbilirubinemia controls (n = 10). Blood and intestinal tissue samples were obtained to determine serial thiobarbituric acid reducing substances (index of lipid peroxidation) and for xanthine oxidase/xanthine dehydrogenase and glutathione/glutathione disulfide ratios. Intestinal histopathology was graded from 1 (normal) to 4 (severe necrotic lesions). RESULTS: Histopathologic scoring and circulating and tissue thiobarbituric acid reducing substances were highest in the IR/control animals compared with either the IR/hyperbilirubinemics or the controls. All of these are consistent with the most severe injury in this group. Xanthine oxidase/xanthine dehydrogenase ratios were not significantly different among the groups. CONCLUSION: Hyperbilirubinemia ameliorates the extent of intestinal IR injury in our model and appears to act as an antioxidant. This study supports the concept that bilirubin possesses some beneficial properties in vivo, although no direct clinical conclusions can be drawn from these data.

Jaundice and breastfeeding.

Optimal management of breastfeeding does not eliminate neonatal jaundice and elevated serum bilirubin concentrations. Rather, it leads to a pattern of hyperbilirubinemia that is normal and, possibly, beneficial to infants. Excessive frequency of exaggerated jaundice in a hospital or community population of breastfed infants may be a warning that breastfeeding policies and support are not ideal for the establishment of good breastfeeding practices. The challenge to clinicians is to differentiate normal patterns of jaundice and hyperbilirubinemia from those that indicate an abnormality or place an infant at risk.

Breastfeeding and jaundice.

In the breastfed infant, prolongation of unconjugated hyperbilirubinemia into the third and later weeks of life in the healthy newborn is a normal and regularly occurring extension of physiologic jaundice. This is known as breastmilk jaundice. A factor in human milk increases the enterohepatic circulation of bilirubin. Insufficient caloric intake resulting from maternal and/or infant breastfeeding difficulties may also increase serum unconjugated bilirubin concentrations. This is the infantile equivalent of adult starvation jaundice. It is known as breastfeeding jaundice or "breast-nonfeeding jaundice." This increase in severity of physiologic jaundice of the newborn also results from increased enterohepatic circulation of bilirubin, but not because of a factor in human milk. In extreme cases, it may place the infant at risk for development of bilirubin encephalopathy. Optimal breastfeeding practices, which result in minimal initial weight loss and early onset of weight gain, are associated with both reduced breastfeeding jaundice and minimization of the intensity of breastmilk jaundice.

Jaundice in the breastfed infant.

Maternal perception of insufficient milk is a widespread phenomenon in modern breastfeeding. This article addresses underlying physiology, feeding patterns, growth patterns, and medical complications as they impact milk supply and infant growth. The complexity of mother-infant factors leads to a broad differential diagnosis. Problem-oriented management is discussed with the goal of preventing low milk supply, intervening promptly for feeding problems, promoting infant growth, and preserving the breastfeeding relationship.

Practice patterns in neonatal hyperbilirubinemia.

OBJECTIVE: To determine practice patterns of office-based pediatricians and neonatologists in the treatment of neonatal hyperbilirubinemia in healthy, term newborns during 1992, before the publication of the practice guideline for treatment of neonatal jaundice by the American Academy of Pediatrics (AAP). The survey was undertaken to inform the AAP's Subcommittee on Hyperbilirubinemia on current practices and to aid it in its preparation of the guidelines. It was also anticipated that this survey would serve as a basis for comparison for a second survey to be performed several years after the publication of the practice guidelines. METHODS: A self-administered questionnaire describing a single case of a jaundiced, breastfed 36-hour-old healthy, full-term infant with a total serum bilirubin concentration of 11.0 mg/dL (188 microM/L) was sent to a random sample of 600 office-based pediatricians and 606 neonatologists who were members of the AAP. The final response rate was 74%. Respondents were asked to answer questions regarding treatment of the case based on their actual practices. Ranges of total serum bilirubin concentration were provided as possible answers to questions on initiation of phototherapy and exchange transfusion, and interruption of breastfeeding. Respondents were also queried about frequency of serum bilirubin testing, locations of phototherapy administration, and factors influencing their therapeutic decisions. RESULTS: Four hundred forty-two office-based pediatricians and 444 neonatologists completed the survey. There was a tendency for neonatologists to initiate both phototherapy and exchange transfusions at lower serum bilirubin concentrations than office-based general pediatricians. At a serum bilirubin of 13 to 19 mg/dL (222 to 325 microM/L), 54% of office-based pediatricians stated they would initiate phototherapy whereas 76% of neonatologists would do so. Forty percent of office-based practitioners said they would perform exchange transfusions at serum bilirubin levels of 20 to 25 mg/dL (342 to 428 microM/L), whereas 60% of neonatologists said they would. Only a small percentage of both office-based practitioners (13%) and neonatologists (16%) indicated they would interrupt breastfeeding at 8 to 13 mg/dL (137 to 222 microM/L); but with each incremental level of serum bilirubin, an increasing proportion of neonatologists would interrupt breastfeeding. Little correlation was found between treatment practices and demographic characteristics except for years in practice; physicians with the fewest years in practice (5 years or less) differed significantly from all other groups of physicians in initiating exchange transfusions at higher serum bilirubin concentrations. CONCLUSIONS: The results of this survey indicated a wide range of variation of opinion among both groups of physicians, most likely a reflection of the uncertainty and controversy surrounding these issues. The data may also reflect a possible wide range of "acceptable practice" as opposed to a narrow treatment standard. Office-based practitioners more closely approximated the new 1994 recommendations than neonatologists.

Two thousand years of medical advice on breastfeeding: comparison of Chinese and western texts.

This discussion introduces only a few aspects of the historical writings on breastfeeding in the two cultures. Chinese writings seem to be closer in orientation to modern worldwide medical advice, approaching breastfeeding from a more natural and supportive perspective. Ancient and not-so-ancient western medical advice on breastfeeding often implies the inadequacy of the mother to breastfeed her own infant, especially in the early weeks of life. One can only speculate as to what the historical basis for this may be. European medicine emphasizes the testing of milk for its adequacy. Again, the scientific basis for this is not evident. Modern clinical science finds that the milk of virtually all mothers, even those suffering from significant malnutrition, is adequate for the growth and development of the infant. This focus on the "testing" of milk may represent an early example of the reliance on laboratory diagnosis that has so heavily dominated western medicine in recent years. Finally, western medicine seems more managerial with regard to breastfeeding than Chinese medicine, and has perhaps "medicalized" breastfeeding, a compliant often voiced even now in late 20th century America. Nonetheless, both literatures demonstrate that throughout the history of recorded medicine, physicians have been concerned with promoting optimal breastfeeding and have understood the importance of human milk for the survival, growth, and development of the infant.

PIP: Chinese and Western pediatric scholarship is compared based on published textbook material over the past 2000 years. Modern, late 20th century teachings on breastfeeding are organized around the concept that breastfeeding is a natural, biological behavior that should be initiated immediately after birth and the belief that human milk is almost always the perfect food for the infant, even when the mother is less than adequately nourished or is suffering from some disease. In contrast, ancient and not so ancient Western medical advice on breastfeeding often implies the inadequacy of the mother to breastfeed her own infant, especially in the early weeks of life. This concept continues unquestioned through 1700 years of European medical advice on breastfeeding. One the other hand, William Cadogan's advice in 1750 is remarkably similar to that of the 12th century Chinese physician: absence of medical intervention and a natural and rapid onset of nursing by the biological mother. Chinese writings seem to be closer in orientation to modern worldwide medical advice, approaching breastfeeding from a more natural and supportive perspective. The ancient Chinese medical texts, but not the early European texts, address the origins of human milk. A Chinese work by Sun Simiao (581 to 682) of the Tang Dynasty describes human milk as the product of vital energies. On the initiation of breastfeeding, a 12th century Chinese writing sounds remarkably similar to the advice one would give today to a mother who had just delivered a child. However, Chinese physicians are not without their concepts of bad milk. They describe types of milk that they associate with the induction of various diseases in nurslings. Finally, Western medicine seems more managerial with regard to breastfeeding than Chinese medicine, and has perhaps medicalized breastfeeding. Throughout the 2000 years, both literatures express concern that substitutes for human milk are being used too early and too often.

Intelligence at six years in relation to neonatal bilirubin levels: follow-up of the National Institute of Child Health and Human Development Clinical Trial of Phototherapy.

Results of the National Institute of Child Health and Human Development Randomized Controlled Trial of Phototherapy were examined for the relationship of neonatal bilirubin level to neurological and developmental outcome at 6-year follow-up. This analysis focused on 224 control children with birth weight of less than 2000 g. Bilirubin levels were maintained below previously specified levels by the use of exchange transfusion only (24%). Rates of cerebral palsy were not significantly higher for children with elevated maximum bilirubin level than for those whose level remained low. No association was evident between maximum bilirubin level and IQ (Full Scale, Verbal, or Performance) by simple correlation analysis (r = -.087, P = .2 for Full Scale) or by multiple linear regression adjusting for factors that covary with IQ (beta = -.15, P = .58). IQ was not associated with mean bilirubin level, time and duration of exposure to bilirubin, or measures of bilirubin-albumin binding. Thus, over the range of bilirubin levels permitted in this clinical trial, there was no evidence of bilirubin toxicity to the central nervous system. Measures used to control the level of bilirubin in low birth weight neonates appear to prevent effectively the risk of bilirubin-induced neurotoxicity.

Maternal age and incidence of low birth weight at term: a population study.

A total of 184,567 singleton live births with gestational ages of 40 weeks were examined from the 1980-1984 Illinois birth certificate data to determine the independent effect of maternal age on the incidence of low birth weight at term. The incidence is highest in mothers less than 17 years of age (3.2%) and gradually declines with advancing maternal age to reach 1.3% in women aged 25 to 34 years. It increases to 1.7% for those greater than 35 years of age. To separate out the independent effect of maternal age on the incidence of low birth weight infants at term, the presence of other maternal factors, such as race, education, parity, marital status, and prenatal care, were adjusted by use of a series of multiple logistic regression analyses. All of these analyses consistently demonstrated that the adjusted risk for low birth weight at term is the lowest in teenagers and increases with advancing maternal age. These results indicate that the high incidence of this factor in young mothers apparently reflects their poor sociodemographic and prenatal care status. Advancing maternal age is associated with a decreased potential for fetal growth, possibly reflecting biologic aging of maternal tissues and systems or the cumulative effects of disease.

The effect of tin (IV)-protoporphyrin-IX on bilirubin production and excretion in the rat.

Tin (IV)-protoporphyrin-IX alpha (tin-heme) may have use in treating neonatal jaundice. To evaluate its effect on bilirubin metabolism, we measured bile-bilirubin excretion in adult, male Sprague-Dawley rats (350-500 g). After a 4-h baseline period, tin-heme (100 mumol/kg) or buffer was injected subcutaneously, and bile was collected for 19 h. Bile flow, bile salt excretion, and bile-bilirubin excretion (averaging 600 +/- 60 ng/100 g/min for all animals) remained stable in the control period. Tin-heme treatment did not alter bile flow or bile salt excretion, but within 2 h bilirubin output was significantly reduced. The nadir of output was 5 h after injection when it was 380 +/- 40 ng/100 g/min (p less than 0.001). Cumulative excretion over 19 h was reduced 30.8% (p less than 0.01). To determine if tin-heme interfered with hepatic uptake or excretion of bilirubin, additional animals were administered intravenous bilirubin at 30 mg/kg/h for 3 h after tin-heme injection. Neither peak bile-bilirubin (37.4 +/- 4.68, control; 38.19 +/- 3.81 micrograms/100 g/min, treated) nor cumulative excretion (87.8 +/- 4.7, control; 88.9 +/- 4.2%, treated) were altered. Biliary excretion of tin-heme was measured under various experimental conditions. When administered alone, maximal excretion was 4 h after injection (4.41 +/- 1.58 micrograms/100 g/min); by 15 h, it fell to 0.024 +/- 0.011 microgram/100 g/min; 20-h cumulative tin-heme excretion in bile was 21.8 +/- 3.1% of the administered dose. Intravenous coadministration of albumin or albumin and bilirubin reduced the peak output but did not alter cumulative excretion of tin-heme. These data indicate that tin-heme reduces endogenous bilirubin formation but does not impair hepatic uptake and excretion. Bile is a major excretory route for tin-heme.

Breastfeeding and human milk: their association with jaundice in the neonate.

As demonstrated by this discussion, jaundice in breastfeeding infants appears to be related both to feeding-related issues and to an as-yet unidentified factor in the human milk of a small minority of women. In the case of feeding-related factors, how a mother breastfeeds; that is, how often she offers the breast and how well the baby suckles, as well as how often and how much the baby is offered complementary or supplementary feedings of water, glucose solutions, or a nonhuman mammal milk, influence serum bilirubin concentrations in the first week of postnatal life. We call this breastfeeding-related jaundice, recognizing that the feeding process is a key element in the condition. We urge that management recommendations focus on the feeding process to reduce the level of serum bilirubin concentration in the first week of life. It is appropriate to note at this juncture that hyperbilirubinemia also occurs in bottlefed infants; the frequency of feeding of these infants also may play a role in the severity of jaundice. If research findings bear out such a relationship, we may see a corollary label of "feeding-related" jaundice also applied to bottlefed babies. In a very small percentage of breastfeeding infants, a second form of jaundice occurs. Its onset appears somewhat later in the postnatal period, and it is characterized by a higher peak and a slower decline in the level of serum bilirubin concentration. We call this breast milk jaundice, recognizing that it appears to stem from the milk the baby receives rather than the manner in which he or she is fed. Eliminating other causes of jaundice prior to considering even a brief interruption of breastfeeding is appropriate when caring for the infant with this syndrome. In the breastfeeding infant, both early- and late-onset jaundice appear to be related. We suggest this because the baby with breast-feeding jaundice may be more responsive to the factor in abnormal milk, which produces breast milk jaundice. The infant with breast-feeding jaundice has a larger bilirubin load at the time the abnormal milk is being ingested. The recycling of this increased load, because of exaggerated enterohepatic circulation, results in a further late rise in serum bilirubin. If the initial bilirubin pool is smaller, the effect of the abnormal milk might well be insignificant or at least markedly diminished.(ABSTRACT TRUNCATED AT 400 WORDS)