POSTNATAL CHANGES IN THE ABILITY OF PLASMA ALBUMIN TO BIND BILIRUBIN

ABSTRACT. The plasma concentrations of total albumin, unconjugated bilirubin and reserve albumin for bilirubin binding were determined in 407 healthy infants of various age up to eight days. The albumin reserve was measured using monoacetyldiaminodiphenyl-sulfone (MADDS) as a deputy ligand for bilirubin. The fraction of albumin capable of binding bilirubin was calculated as the sum of the concentrations of bilirubin and reserve albumin, divided by the total albumin concentration. Our data showed that this fraction was low (average 0.36) and did not change during the first 24 hours of life, and in this period it was independent of the maturity of the infant, as expressed by its birth weight or gestational age. From about 24 hours of life, the fraction began to increase. This increase came to an end about 60 hours after birth, and no further changes were seen during the following five days. The level of the bilirubin-binding fraction reached 60 hours after birth was related to the maturity of the infant: It increased with increasing birth weight up to 3000 g and with increasing gestational age up to 275 days, when on an average it was about 0.58. The fraction of binding albumin was independent of the sex.     

新生儿高胆红素血症的风险预测

目的探讨一种无创性、按每小时计的经皮胆红素(TcB)百分位列线图,以预测新生儿高胆红素血症的发生风险。方法选择2010年1月至2010年3月出生、胎龄≥35周且出生体质量≥2 000 g的健康新生儿679例,测定其出生后152 h内的TcB值。将出生后68 h内对应最高危区域的胆红素测定值作为预测指标,利用以小时为单位的胆红素曲线图评估其高胆红素血症的危险度,利用诊断试验特征曲线(ROC曲线)分析胆红素百分位列线图预测高胆红素血症的发生风险。结果将679例新生儿7 482个对应不同小时龄的TcB值纳入分析。42例新生儿出生后68 h内的胆红素水平处于高危区,预测高胆红素血症的灵敏度为34.52%,特异度为97.82%;212例新生儿胆红素水平处于高危区和中高危区,预测高胆红素血症的灵敏度为80.95%,特异度为75.80%;213例新生儿胆红素水平处于低危区,预测高胆红素血症的灵敏度为98.81%,特异度为35.63%。以TcB百分位列线图危险区域表示的出院前胆红素水平预测高胆红素血症发生风险的ROC曲线下面积(AUC)为0.846;胎龄与出生68 h内的胆红素水平结合预测高胆红素血症发生风险的ROC曲线下面积(AUC)为0.857;出生后前3 d的生理性体质量下降与出院前胆红素水平结合预测高胆红素血症发生风险的AUC为0.859。结论根据新生儿出院前胆红素水平结合胎龄、出生后前3天的生理性体质量下降能简单而准确地预测新生儿高胆红素血症的发生风险。     

The influence of the basal yellow colour of the skin at birth on later jaundice meter readings in mature newborn infants

The yellow colour of the skin was measured just after birth in 100 mature newborns using a jaundice meter. The skin colour was significantly correlated to the cord bilirubin concentration (rho = 0.26, p = 0.009), but unrelated to cord reserve albumin concentration, cord albumin concentration, cord haemoglobin concentration, birth weight and gestational age. In 123 other mature newborns, the basal yellow colour of the skin was estimated on the basis of meter readings taken just after birth. Correction of meter readings taken on the third postnatal day for the basal yellow skin colour improved neither the correlation between the meter readings and the bilirubin concentration nor the ability of the meter readings to predict hyperbilirubinaemia.     

Plasma protein binding of theophylline during development in the rabbit.

The plasma protein binding profile of theophylline was investigated in the rabbit during the perinatal and developmental period. The roles of unbound plasma theophylline fraction (THu), albumin, nonesterified fatty acids (NEFA) and plasma bilirubin levels were analyzed. Plasma total protein and albumin levels doubled with age from the 1st day of life to maturity (from 3.1 to 5.3 and 1.6 to 3.7 g/l, respectively). THu, NEFA and bilirubin levels were inversely related to age, and decreased from 81 to 37%, 2,136 to 239 microEq/l and 2.4 to 0.20 mg/dl, respectively. A linear correlation was shown between THu and albumin, NEFA, and bilirubin plasma concentrations. Stepwise multiple linear regression analysis, including albumin, NEFA and bilirubin values as independent variables, identified NEFA as the variable explaining most of the variability in plasma protein binding of theophylline. Findings support the need for careful interpretation (with a view to therapeutic utilization) of estimates of plasma protein unbound fraction of a drug during development. This fact highlights the importance of considering not only protein but NEFA concentrations too.     

EFFECT OF EXCHANGE TRANSFUSION ON SERUM RESERVE ALBUMIN FOR BINDING OF BILIRUBIN AND INDEX OF SERUM BILIRUBIN TOXICITY

ABSTRACT. Ebbesen F. (Department of Neonatology, Rigshospitalet, Copenhagen, Denmark). Effect of exchange transfusion on serum reserve albumin for binding of bilirubin and index of serum bilirubin toxicity. Acta Paediatr Scand, 70:643,.–Seventeen newborn infants, who received their first exchange transfusion due to hyperbilirubinaemia and/or rhesus haemolytic disease, were studied. The exchange transfusions were performed with fresh, citrated blood. During the exchange transfusion a marked increase in the serum reserve albumin concentration for binding of bilirubin measured by the [^,4C]-MADDS method was observed, followed by a smaller decrease after the transfusion. Plasma pH increased both during and after the exchange transfusion. During the exchange transfusion a drastic fall in index of serum bilirubin toxicity was observed, followed by a smaller increase after the transfusion. Citrate was not found to interfere in the binding of bilirubin to albumin. The results are in agreement with the clinical finding that an exchange transfusion performed with fresh, citrated blood effectively reduces the risk of bilirubin encephalopathy. The ratio in serum of binding albumin, i.e. bilirubin plus reserve albumin, to total albumin failed to be increased by the exchange transfusion, and a decrease occurred after the transfusion. These findings indicate the presence in infant serum of non-binding albumin. Donor albumin with intact binding potential is partly transformed into the non-binding variety in the course of one hour after the transfusion. In the most severely rhesus sensitized infant a drastic decline of the serum albumin binding capacity was seen during the first day of life.     

ALBUMIN ADMINISTRATION COMBINED WITH PHOTOTHERAPY IN TREATMENT OF HYPERBILIRUBINAEMIA IN LOW-BIRTH-WEIGHT INFANTS

ABSTRACT. Ebbesen, F., and Brodersen, R. (Department of Neonatology, Rigshospitalet, Copenhagen and Institute of Medical Biochemistry, Aarhus, Denmark). Albumin administration combined with phototherapy in treatment of hyperbilirubinaemia in low-birth-weight infants. Acta Paediatr Scand, 70:649,.–Fifty-nine jaundiced light treated newborn infants with low birth weight were studied. At onset of phototherapy 30 infants received 1 g human serum albumin per kg body weight as a 9 % solution containing sodium caprylate and N-acetyltryptophan as stabilizers. 29 infants did not receive human serum albumin and served as controls. Blood samples were taken before initiation of the therapy and again 24 and 48 h thereafter, and the following determinations were made: Serum concentrations of unconjugated bilirubin, albumin, reserve albumin for binding of bilirubin by the [^l4C]-MADDS method, packed cell volume and pH. Before infusion of albumin it was found that the binding fraction of serum albumin, i.e. the sum of the serum concentrations of bilirubin-albumin and reserve albumin, constituted about half of the total serum albumin concentration. The other half was non-binding, in agreement with previous findings in neonates. The effect of albumin therapy was mainly an unexpected increase of the non-binding fraction of serum albumin, while the increase of the serum reserve albumin concentration was small and the concentration of bilirubin-albumin was not changed.     

Albumin binding properties in relation to bilirubin and albumin concentrations during the first week of life

In 19 non-jaundiced and 22 jaundiced neonates, the serum albumin and bilirubin concentrations were measured during the first week of life. Some of the neonates were followed longitudinally. The albumin binding properties were evaluated by determining the reserve albumin concentration for monoacetyldiaminodiphenyl sulphone (MADDS), a deputy ligand for bilirubin. The reserve albumin concentration for MADDS increased with postnatal age. The reason for this increase is still unexplained. There was an inverse relation between the bilirubin and the reserve albumin concentrations, but when the bilirubin concentration increased by 1 mumol/l, the reserve albumin concentration for MADDS decreased by only 0.2 mumol/l. This shows that the reserve albumin concentration for MADDS does not give a direct measure of the bilirubin binding ability of the serum albumin molecule. In spite of this, it is still possible that a low reserve albumin concentration for MADDS is a risk factor for bilirubin encephalopathy.     

RESERVE ALBUMIN AND BILIRUBIN TOXICITY INDEX IN INFANT SERUM

ABSTRACT. Reserve albumin concentration (the concentration of albumin available for binding of unconjugated bilirubin) was determined in 95 sera from 76 subjects by dialysis with ¹⁴C-monoacetyl diamino diphenyl sulfone (MADDS). An index, I of bilirubin toxicity in the plasma was calculated for each subject, based on the bilirubin and reserve albumin concentrations, the affinity of bilirubin for serum albumin, and the pH-dependent solubility of bilirubin in the plasma. The values of reserve albumin and of I varied significantly with gestational age, clinical condition (whether sick or well), and serum bilirubin level. The value of reserve albumin was decreased and I was increased in association with clinical factors (e. g., hyperbilirubinemia, hypoxia, acidosis, or sepsis) recognized as increasing the risk for bilirubin encephalopathy. The lowest values of reserve albumin and the highest values of I were found in the least mature and sickest infants.     

Albumin Binding Properties in Relation to Bilirubin and Albumin Concentrations during the First Week of Life

ABSTRACT. In 19 non-jaundiced and 22 jaundiced neonates, the serum albumin and bilirubin concentrations were measured during the first week of life. Some of the neonates were followed longitudinally. The albumin binding properties were evaluated by determining the reserve albumin concentration for monoacetyldiaminodiphenyl sulphone (MADDS), a deputy ligand for bilirubin. The reserve albumin concentration for MADDS increased with postnatal age. The reason for this increase is still unexplained. There was an inverse relation between the bilirubin and the reserve albumin concentrations, but when the bilirubin concentration increased by 1 μmol/l, the reserve albumin concentration for MADDS decreased by only 0.2 μmol/l. This shows that the reserve albumin concentration for MADDS does not give a direct measure of the bilirubin binding ability of the serum albumin molecule. In spite of this, it is still possible that a low reserve albumin concentration for MADDS is a risk factor for bilirubin encephalopathy.     

LOW RESERVE ALBUMIN FOR BINDING OF BILIRUBIN IN NEONATES WITH DEFICIENCY OF BILIRUBIN EXCRETION AND BRONZE BABY SYNDROME

ABSTRACT. The plasma reserve albumin concentration for binding of bilirubin was found to be low in four newborn infants with deficiency of bilirubin excretion, of whom two had the bronze baby syndrome. Thus, the risk of bilirubin encephalopathy was increased. Also the ratio of binding fraction of albumin, i. e. unconjugated bilirubin plus reserve albumin, to total albumin was low. Possible causes of the low reserve albumin concentration and the ratio are discussed.     

BILIRUBIN, RESERVE ALBUMIN FOR BINDING OF BILIRUBIN AND pH IN PLASMA DURING PHOTOTHERAPY (ORDINARY AND DOUBLE LIGHT) OF TERM NEWBORN INFANTS

ABSTRACT. Ebbesen, F. (Department of Neonatology, Rigshospitalet, Copenhagen, Denmark). Bilirubin, reserve albumin for binding of bilirubin and pH in plasma during phototherapy (ordinary and double light) of term newborn infants. Acta Paediatr Scand, 70:223, 1981. –Forty-five term newborn infants with uncomplicated hyperbilirubinaemia were treated continuously with phototherapy for 24 hours. Twenty-eight infants received double light treatment and 17 infants ordinary phototherapy. During both treatments a significant decrease in the serum unconjugated bilirubin concentration, a significant increase in the serum reserve albumin concentration for binding of bilirubin determined by the [¹⁴C] MADDS method, and a significant decrease in the index of serum bilirubin toxicity occurred. The changes in these parameters were significantly greater during the double light treatment than during the ordinary phototherapy. During the treatment the fall in index was constant. No significant change in plasma pH was seen. Thus, the study gives further evidence that the risk of bilirubin encephalopathy is reduced by phototherapy and that double light treatment is in the respect superior to ordinary phototherapy. Prior to phototherapy the molar ratio in serum of unconjugated bilirubin plus reserved albumin for binding of bilirubin to albumin was only 0.60, on average, and during the treatment the increase in the serum reserve albumin concentration was less than the decrease in the serum bilirubin concentration. This can be explained either by the presence in infant serum of an unknown ligand interfering competitively or allosterically in the binding of MADDS and bilirubin to albumin, or by the existence of a foetal albumin with a lower affinity for MADDS than adult albumin.     

Birth weight gestational age correlates of neonatal mortality

Two hundred and fifty five neonatal deaths out of 6,222 live born babies born at All-India Institute of Medical Sciences hospital during a period of 4 years were analysed for their birth weight and gestational age. The neonatal mortality data by birth weight and gestational age parameters is presented in a variety of ways to indicate their usefulness in everyday practice. The overall neonatal mortality rate was 4.1 per cent. Preterm and low birth weight babies accounted for 66.6 per cent and 75.2 per cent of total deaths respectively. Although neonatal mortality rate is reduced with higher birth weight and longer gestational age, the gestational maturity influences the survival of infants irrespective of other factors. The significance and utility of the data when expressed in large and small weightgestational age groupings and their routine use in evaluating an individual pregnancy outcome or assessing an individual newborn infant is discussed.     

Bilirubin binding and acid-base equilibrium in newborn infants with low birthweight

Acidosis is known as a risk factor for the development of bilirubin encephalopathy in neonatal jaundice. However, few attempts have been made to evaluate the influence of acid-base state on bilirubin-albumin binding state in blood of newborn infants. Therefore, in 171 appropriate and 83 small for gestational age newborns (birthweight less than 2,500 g) the acid-base state in blood and bilirubin (BR) binding state in serum was measured at the ages of 3, 4, 5, and 8 days. There is a weak but significant correlation between standard base deficit and the ratio BR/reserve albumin as well as the toxic potential of serum BR. The results suggest that the higher risk in acidosis is not only caused by increased tissue binding of BR but also--at least partially--attributable to decreased BR binding in serum.     

Phototherapy for neonatal jaundice: clinical equivalence of fluorescent green and "special" blue lamps

The relative efficacy of fluorescent green (Sylvania F20T12/G) and "special" blue (Westinghouse F20T12/BB) lamps in the phototherapy of jaundiced neonates was investigated. Two groups of low birth weight infants with a mean gestational age of 35 weeks and mean birth weight of 1930 gm, who developed hyperbilirubinemia within the first 5 days of life, were given green or blue lamp phototherapy under the same irradiation conditions. No statistically significant difference in plasma bilirubin concentrations was found between the two groups after 24 or 48 hours of treatment. Because recent measurements indicate that green lamps are much less efficient than special blue lamps for the production of Z, E isomers of bilirubin in vitro and in vivo, the clinical equivalence of these two types of lamps seems to support the hypothesis that production of structural photoisomers of bilirubin is the main mechanism of phototherapy in humans. Therefore, fluorescent green lamps provide an alternative to special blue lamps for treatment of neonatal hyperbilirubinemia.     

Hyperbilirubinemia in preterm infants in Japan: New treatment criteria

In 1992, Kobe University proposed treatment criteria for hyperbilirubinemia in newborns using total serum bilirubin and serum unbound bilirubin reference values. In the last decade, chronic bilirubin encephalopathy has been found to develop in preterm infants in Japan because it can now be clinically diagnosed based on an abnormal signal of the globus pallidus on T2‐weighted magnetic resonance imaging and abnormal auditory brainstem response with or without apparent hearing loss, along with physical findings of kinetic disorders with athetosis. We therefore revised the Kobe University treatment criteria for preterm hyperbilirubinemic infants in 2017. The three revised points are as follows: (i) newborns are classified under gestational age at birth or corrected gestational age, not birthweight; (ii) three treatment options were created: standard phototherapy, intensive phototherapy, and albumin therapy and/or exchange blood transfusion; and (iii) initiation of standard phototherapy, intensive phototherapy, and albumin therapy and/or exchange blood transfusion is decided based on the total serum bilirubin and serum unbound bilirubin reference values for gestational weeks at birth at <7 days of age, and on the reference values for corrected gestational age at ≥7 days of age. Studies are needed to establish whether chronic bilirubin encephalopathy can be prevented using the 2017 revised Kobe University treatment criteria for preterm infants in Japan.     

26. Premature Infants Treated with Human Albumin

Total serum protein content was determined in the cord blood of 79 premature infants. There was a tendecy for the serum protein values to rise with the birth weight and gestational age. Boys had, on average, lower serum protein values than girls. 31 infants with serum protein content less than 5 g/100 ml were treated with albumin solution, 2 g per kg of body weight intravenously, on the first day of life. 27 infants, serving as controls, were not treated with albumin. The two groups showed the same frequency of "respiratory distress". One infant died in connection with the administration of albumin.     

Bilirubin Binding and Acid-Base Equilibrium in Newborn Infants with Low Birthweight

ABSTRACT. Acidosis is known as a risk factor for the development of bilirubin encephalopathy in neonatal jaundice. However, few attempts have been made to evaluate the influence of acid-base state on bilirubin-albumin binding state in blood of newborn infants. Therefore, in 171 appropriate and 83 small for gestational age newborns (birthweight less than 2500 g) the acid-base state in blood and bilirubin (BR) binding state in serum was measured at the ages of 3, 4, 5, and 8 days. There is a weak but significant correlation between standard base deficit and the ratio BR/reserve albumin as well as the toxic potential of serum BR. The results suggest that the higher risk in acidosis is not only caused by increased tissue binding of BR but also—at least partially—attributable to decreased BR binding in serum.     

Transient neonatal diabetes mellitus in extremely preterm infant

A report of transient neonatal diabetes mellitus in an extremely preterm infant (gestational age 27 weeks, birth weight 718 g). The patient had intrauterine growth retardation and developed hyperglycaemia on the first day of life. Insulin administration was discontinued on the 89th day of life, which was 1 day before the original due date. This case suggests that (a) insufficient insulin secretion started at least from the second trimester of the pregnancy; (b) the duration needed for recovery of insulin secretion was not dependent on the maturity.     

The relative contribution of birth weight and gestational age to physical traits of newborn infants

The present study establishes anthropometric standards for newborn infants, born between 26-41 weeks of gestational age. The measurement of 10 standard anthropometric traits was made within the first 72 hours of life in 224 preterm (26-36 weeks) and 190 term (37-41 weeks) infants. Multiple regression analysis was carried out for each of these anthropometric traits (dependent variables) on gestational age, birth weight and sex (independent variables). It was found that the prediction of several traits, namely, body length, body mass index, body surface area, interocular diameter, ear length and palm length, can be done solely via the information on birth weight; cephalic index is better predicted on the basis of gestational age, while for the prediction of such cranial traits as the circumference, length and breadth of head, both birth weight and gestational age are desirable.     

Influence of gestational age on cord serum bilirubin binding studies

The effect of gestational age on bilirubin binding was studied using cord serum from 22 preterm infants and 13 term infants and serum from 17 adults. Using the peroxidase oxidation method, a bilirubin titration curve was obtained by adding bilirubin to serum and measuring the apparent unbound bilirubin concentration. The resultant curve was analyzed using the least-squares fit of the empiric equation Y = aXb. After correction for albumin concentration by plotting the apparent unbound bilirubin concentration against the molar ratio of total bilirubin/albumin, term and preterm infants had identical titration curves, which remained inferior to that of adults. In addition, the apparent primary bilirubin association constant Ka'1 was similar for all infants but was two to three times less than that for adults. We conclude that bilirubin binding by cord serum is equivalent regardless of gestational age. However, adult serum binds bilirubin qualitatively better than does serum from infants of all gestational ages. We suggest that the adverse effect of prematurity on bilirubin binding noted in previous studies may have reflected postnatal complications rather than gestational age as such.