Reserve Albumin Concentration Research Articles

The increase of yellow skin colour beyond that of serum bilirubin: a proposed indicator of risk for bilirubin encephalopathy in the newborn.

Forty-seven newborn infants with 1 min Apgar score < 7 were studied. On the third postnatal day the following measurements were made: yellow skin colour, serum bilirubin concentration, reserve albumin concentration and plasma pH. Given the bilirubin concentration and the regression curve between the yellow skin colour and the bilirubin concentration, delta-TcB was calculated as the difference between measured yellow skin colour and the expected yellow skin colour. There was a negative correlation between delta-TcB and Apgar score (P = 0.003), pH (P = 0.026) and reserve albumin concentration (P = 0.045). Fourteen of the included newborns had central nervous system symptoms in the days just following birth. A tendency towards higher delta-TcB was noted in this group (P = 0.08). The results suggest that further study of delta-TcB determination as a tool in the assessment of the icteric newborn infant is justified.

Ceftriaxone-bilirubin-albumin interactions in the neonate: An in vivo study

The in vivo bilirubin-albumin binding interaction of ceftriaxone (CRO) was investigated in 14 non-jaundiced newborns, aged 33-42 weeks of gestation, during the first few days of life after they had reached stable clinical condition. CRO (50 mg/kg) was infused intravenously over 30 min. The competitive binding effect of CRO on the bilirubin-albumin complex was estimated by determining the reserve albumin concentration (RAC) at baseline, at the end of CRO infusion, and at 15 and 60 min thereafter. Immediately after the end of drug administration, RAC decreased from 91.9 (+/- 25.1) mumol/l to 38.6 (+/- 10.1) mumol/l (P = 0.0001). At the same time the plasma bilirubin toxicity index (PBTI) increased from 0.64 (+/- 0.40) before drug infusion to 0.96 (+/- 0.44) thereafter (P = 0.0001). The highest displacement factor (DF) was calculated to be 2.8 (+/- 0.6) at the end of drug infusion. Average total serum bilirubin concentrations decreased from a baseline value of 59.6 (+/- 27.0) mumol/l to 55.2 (+/- 27.1) mumol/l (P = 0.026). Sixty minutes after the end of CRO infusion, RAC was 58.3 (+/- 21.7) mumol/l, PBTI regained baseline, but DF was still 1.9 (+/- 0.2). No adverse events were recorded. Our results demonstrate significant competitive interaction of CRO with bilirubin-albumin binding in vivo. Thus, ceftriaxone should not be given to the neonate at risk of developing bilirubin encephalopathy.

The risk of bilirubin encephalopathy, as estimated by plasma parameters, in neonates strongly suspected of having sepsis.

The study comprises 18 mature newborns, strongly suspected of having sepsis, and a control group of 18 mature, healthy newborns with the same postnatal age. The object of the investigation was to compare the risk of development of bilirubin encephalopathy between the two groups, as estimated by plasma parameters. The sepsis group had significantly lower reserve albumin concentration for binding of MADDS (p < 0.01) and significantly lower total albumin concentration (p < 0.01). No significant differences were observed in unconjugated bilirubin concentration and plasma pH. It is suggested that mature newborns with sepsis have a slightly increased risk of developing bilirubin encephalopathy.

Reduced albumin binding of MADDS — a measure of bilirubin binding — during pregnancy and delivery

It was the purpose of the present study to investigate whether the decrease in the ability of plasma albumin to bind bilirubin, noted in pregnancy and during delivery, takes place in one step, during pregnancy alone, or in two steps, during both pregnancy and delivery. Furthermore, it was investigated whether a possible decrease during labor was related to the method of delivery itself. The material comprised (a) 17 pregnant women who delivered vaginally; (b) 25 women who were delivered by Cesarian Section; and (c) a group of 25 non-pregnant women. The reserve albumin concentration for binding of MADDS (a measure of the binding of unconjugated bilirubin), the total albumin concentration and the ratio between them were constant in the 6-week period up to birth and were significantly lower than the corresponding values in the non-pregnant group. During labor a significant decrease in reserve albumin and ratio of reserve albumin to total albumin was observed, while no change in the total albumin concentration was noted. No significant difference in reserve albumin concentration, total albumin concentration and ratio between them was found when the group of mothers who delivered vaginally was compared to the Cesarian Section group. It is concluded that the decrease in the ability of plasma albumin to bind unconjugated bilirubin takes place stepwise. The first step is a significant reduction during pregnancy followed by a further decrease during labor. The method of delivery is of no significance.

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.

Cefmenoxime and Bilirubin: Competition for Albumin Binding

Certain drugs are known to compete with bilirubin for albumin binding; therefore, all drugs administered to neonates should be tested to determine the degree of competition. The effect of cefmenoxime on bilirubin-albumin binding was determined by comparing the oxidation rate of free bilirubin in the presence and absence of drug. The reserve albumin concentration (RAC) of pooled cord serum was also measured using the MADDS dialysis rate method. We show that cefmenoxime competes with bilirubin for albumin binding with a displacement constant, of 3.1 x 10(3) l/mol. The maximal displacement factor (MDF) is used to determine the clinical effect of the drug at usual serum concentrations. The MDF for cefmenoxime is 1.10, representing approximately a 10% increase in free bilirubin concentration. In comparison, the MDF for a known bilirubin displacing drug, sulfisoxazole, is 2.43. The MADDS method showed an estimated 28% decrease in the RAC at 150 mumol/l, the mean peak serum concentration (MPSC) of cefmenoxime. These results show while cefmenoxime affects bilirubin-albumin binding, the degree of the effect is relatively small. However, cefmenoxime may pose a hazard to very sick, premature infants, especially if the infant is jaundiced.

Binding of long‐chain fatty acids to serum albumin in healthy humans Relationship to obesity

Equilibria of the binding of palmitate to serum albumin in adults are studied by dialysis-exchange-rate determinations. The results are used for a description of binding equilibria of fatty acids in general, as follows. 1. The reserve albumin concentration, p, for binding of palmitate is used as an approximate measure of p*, the reserve albumin concentration for binding of mixed fatty acids present in serum. 2. The total availability of fatty acids is defined as C*/p*, where C* is the total concentration of non-esterified fatty acid. 3. The fatty-acid-binding property of albumin is described by L* = p*/P = alpha C*/P, where P is the albumin concentration. The numerical value of alpha is -0.05. The above parameters are measured in sera from four healthy volunteers, in whom large variations of serum fatty acid concentration occurred. A group of 64 healthy students showed considerable variation of L* from one individual to another. It is found that L* decrease significantly with increasing body mass index (body mass divided by the square of the body length). In 42 patients with diabetes type I, L* was independent of body mass index. These findings are consistent with a previously formulated hypothesis of mechanism of obesity.

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.

The Serum Reserve Albumin Concentration for Monoacetyldiaminodiphenyl Sulphone and Auditory Evoked Responses during Neonatal Hyperbilirubinaemia

Auditory brainstem evoked responses (ABR) were recorded in 9 neonates with hyperbilirubinaemia. Pathological recordings were found in two children showing absence of waves and prolonged latencies. There was no correlation between latencies to waves and the total serum bilirubin concentration. The serum reserve albumin concentration for monoacetyldiaminodiphenyl sulphone (MADDS) was, however, inversely related to the latencies in the ABR recordings. Our findings suggest that the binding properties of serum albumin contribute to the risk of bilirubin toxicity and that, in this study, the reserve albumin concentration for MADDS seemed to be of greater significance than the total bilirubin concentration.

The influence of the reserve albumin concentration and pH on the cephalocaudal progression of jaundice in newborns

The relationship between cephalocaudal progression of jaundice and bilirubin concentration, reserve albumin concentration and plasma pH was studied in 47 newborn infants. Furthermore, the cephalocaudal progression of the yellow colour of the skin was measured in 131 newborns at birth and on the third postnatal day. The cephalocaudal colour difference correlated positively to the bilirubin concentration ( P < 0.001), to the reciprocal of the reserve albumin concentration ( P < 0.05) and to the squared hydrogen ion concentration ( P = 0.04). The cephalocaudal colour gradient at birth correlated positively to the gradient at the third postnatal day ( P < 0.0004). The results support the hypothesis that the cephalocaudal progression of jaundice in icteric newborn infants may be explained by conformational changes in the young bilirubin-albumin complex.

Fatty acid binding to serum albumin in Type I insulin-dependent diabetes mellitus

Equilibria of binding of long-chain fatty acids to albumin in sera from type I diabetic patients and healthy adults were studied by dialysis exchange rate determinations and described by, p*, the reserve albumin concentration for binding of fatty acid, C*/p*, the total availability of fatty acids, where C* is the total concentration of non-esterified fatty acid, and L*, the fatty acid binding property of albumin, which is L* = p*/P + 0.05 C*/P, where P is the albumin concentration. Studies in samples from 81 diabetic patients and 99 healthy adults showed that availability of fatty acids increased with increasing fatty acid concentrations, equally in the two groups. Some diabetics had higher fatty acid concentrations, and thus higher fatty acid availabilities, than the normals. It is shown that the fatty acid binding property of serum albumin is individually variable, ranging about the same mean value in normal and diabetic persons but with a larger variation in the latter. The fatty acid binding property of albumin in serum, L*, and sixteen clinical parameters were measured in 42 of the 81 diabetic patients. Regression analysis indicated that L* was correlated to serum cholesterol concentration (probability of 0-hypothesis, p = 0.01) and to serum triglyceride concentration (p = 0.05). Values of L* were slightly correlated to age, age on diagnosis, duration, Body Mass Index (BMI), diastolic blood pressure, albumin excretion rate, serum creatinine concentration, and serum non-esterified fatty acid concentration with p-values varying from 0.10 to 0.50. For sex, retinopathy, hemoglobin A1c, systolic blood pressure, daily insulin dose, and blood glucose concentration no correlation to L* was found, p-values ranging from 0.56 to 0.96. Non-enzymatic glycosylation of serum albumin did not decrease binding affinity for fatty acid in vitro.

Valproate Competes with Palmitate for Binding to Serum Albumin

Addition of sodium valproate (VPA) to a buffered solution of human serum albumin (HSA) or to serum reduces binding affinity for palmitate. A maximal pharmacologic VPA concentration, 700 microM, added to a 300-microM albumin solution, reduces the reserve albumin concentration for binding of palmitate by a factor of 0.64. One possible site model explaining these findings may be that VPA competes strongly with one among three palmitate molecules, bound to albumin with high affinity, and induces a weaker displacement of a second palmitate.

Skin colour and bilirubin in neonates.

The correlation between the yellow colour of the skin and serum bilirubin concentration, reserve albumin concentration, and pH was investigated in 76 icteric neonates. Significant linear correlation existed between yellow colour of the skin and serum bilirubin concentration, reciprocal of the reserve albumin concentration, and the squared hydrogen ion concentration. Furthermore, the basic yellowness of the skin at birth correlated linearily with the yellow colour of the skin measured when the child became jaundiced. The results support the proposed hypothesis that bilirubin is transferred from plasma to skin through two different mechanisms: (a) leakage of bilirubin-albumin complexes into extravascular spaces and (b) precipitation of bilirubin acid in phospholipid membranes. The latter mechanism suggests that measurement of the yellow colour of the skin may be a better predictor of brain damage than the serum bilirubin concentration and thus be of clinical utility. Measurement of the yellow colour of the skin as a method of obtaining serum bilirubin concentration is unreliable.

Effect of cephalosporins on bilirubin-albumin binding

The effect of parenterally administered cephalosporins on bilirubin-albumin binding was measured in vitro by means of the peroxidase method with human serum albumin and by means of a dialysis rate method with newborn infants' serum. Ceftriaxone and cefoperazone have been shown to affect bilirubin-albumin binding. In this study, 13 additional cephalosporins were tested. Cefonicid, cefotetan, and cefmetazole competed with bilirubin for albumin binding and, at reported mean peak serum levels, decreased the reserve albumin concentration by 75%, 56%, and 40%, respectively. We suggest that these five cephalosporins may increase the risk of bilirubin encephalopathy in jaundiced neonates.

Reduced albumin binding of MADDS--a measure for bilirubin binding--in sick children.

The reserve albumin concentration for binding of MADDS (monoacetyldiaminodiphenyl sulphone) in plasma is used as a measure of the reserve albumin concentration for binding of unconjugated bilirubin. The aim of the present study was to investigate whether a reduction in the reserve albumin concentration for binding of MADDS could exist in sick children after 5 months of age, where the bilirubin binding properties of the albumin has reached the adult level. The material included 75 children, 1-15 years of age with mild infections, severe bacterial infections, acute viral hepatitis, chronic hepatic diseases or uraemia, and a control group of 22 healthy children. The reserve albumin concentration was significantly lower in children with severe bacterial infections, acute viral hepatitis, and uraemia, than in healthy children (p less than 0.01), while the reserve albumin concentration in children with mild infections and chronic hepatic diseases did not differ significantly from that of the control group (p greater than 0.05). The total albumin concentration in plasma in either of the groups of sick children did not differ significantly from that of the healthy children. The plasma concentration of unconjugated bilirubin was elevated in the group of children with acute viral hepatitis, but not enough to influence the concentration of reserve albumin for binding of MADDS to a significant degree. The reserve albumin concentration was significantly lower in children with acute viral hepatitis than in children with severe bacterial infections (p less than 0.05).

Warfarin binding to plasma albumin, measured in patients and related to fatty acid concentrations

A method for determination of reserve albumin equivalent for binding of warfarin as previously described [1] has been used for assessing the influence of non-esterified fatty acid concentration (NEFA) on binding of warfarin to human serum albumin (HSA). Reserve albumin concentration can be used for calculation of the expected fraction of bound warfarin in serum. It is shown in vitro that binding of warfarin increases with added oleate up to 4 mol of oleate per mol of albumin and then decreases. Twenty-four patients on permanent warfarin treatment showed no correlation of serum albumin and reserve albumin concentrations (r = 0.10, P greater than 0.50) indicating that warfarin binding is governed by other factors. However, in the same patients there was a significant correlation between reserve albumin concentration and NEFA/HSA (r = 0.54, P less than 0.01). In one human volunteer changes of NEFA were provoked by strenuous work and it was found that reserve albumin concentration increased with NEFA concentration as expected from the in vitro findings (r = 0.90, P less than 0.001). Five uraemic patients on permanent warfarin treatment showed increasing reserve albumin concentration with increasing NEFA concentration induced by heparin. These findings indicate that, both in vitro and in vivo, the reserve albumin concentration for binding of warfarin and hence the free warfarin concentration is markedly influenced by NEFA concentration. This may add to the understanding of warfarin dose requirement during anticoagulant therapy.

Reserve albumin and bilirubin toxicity index in infant serum.

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.

Bilirubin-displacing effect of furosemide and sulfisoxazole. An in vitro and in vivo study in neonatal serum.

Sulfisoxazole and furosemide, 0.1-1.0 mM, both decreased reserve albumin concentration for bilirubin binding in pooled cord serum as estimated by rate of dialysis of 14C-monoacetyl-diamino-diphenylsulfone (MADDS) in undiluted serum at 37 degrees C. Peroxidase oxidation at a bilirubin:albumin ratio of 0.5 also showed that both drugs were capable of displacing bilirubin in vitro when added in molar excess of the albumin present. However, when aliquots of the same treated sera which had been used undiluted in the MADDS assay were diluted 40-fold and titrated with bilirubin and peroxidase, no drug-related increase in free bilirubin or decrease in reserve albumin could be shown. In vivo administration of 1 mg/kg furosemide showed no change in total bilirubin or reserve albumin by the MADDS technique in 8 infants. Estimation of the peak plasma level theoretically achievable with 1 mg/kg of furosemide suggests that peak plasma levels achieved with that dose are probably not high enough to produce significant reduction of reserve albumin, in agreement with the in vivo findings. In testing neonatal serum for bilirubin displacement by drugs, the choice of method, drug concentration, and dilution of the sample may influence the interpretation of results.

Albumin reserve for binding of bilirubin in maternal and cord serum under treatment with sulphasalazine.

Twelve pregnant patients with ulcerative colitis or Crohn's disease who were being treated with sulphasalazine (SASP) were studied together with their newborn, full-term babies. An earlier study had shown almost identical concentrations of SASP and its metabolic sulphapyridine (SP) in maternal and cord serum. As controls, blood samples were collected from 25 healthy women and their newborn infants. Sera from mothers and infants were analysed for the vacant amount of high-affinity bilirubin binding site on albumin (reserve albumin) by the MADDS method. The mean reserve albumin concentration of the SASP-treated mothers was 9% lower than that of the controls, which is probably insignificant. No difference was observed in the corresponding two groups of infants. In vitro studies showed that neither SASP nor SP in therapeutic plasma concentrations had a significant bilirubin-displacing capacity. It seems that SASP preferentially is bound to other sites on albumin than to the high-affinity binding site for bilirubin. The risk of kernicterus in the full-term newborn does not seem to be increased by treatment of the mother with sulphasalazine.

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

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 [14C]-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.