The effect of multiple exchange transfusions on bilirubin binding

Three bilirubin binding tests (hydroxybenzene-azobenzoic acid dye binding method, the estimation of unbound bilirubin by horseradish peroxidase assay and the saturation of albumin by the salicylate saturation index) were performed on pre-exchange samples of blood and repeated 24 hours after the procedure. No significant improvement in bilirubin binding was found even in infants receiving as many as four exchange transfusions. Based on these bilirubin binding tests, we find no evidence that the criteria for subsequent exchange transfusions should be different from the first exchange transfusion.     

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.     

High-dose intravenous immune globulin therapy for hyperbilirubinemia caused by Rh hemolytic disease.

We conducted a multicenter controlled trial to test the hypothesis that high-dose intravenous immune globulin (HDivIG) therapy can modulate bilirubin production and reduce the frequency of exchange transfusions in newborn infants with Rh hemolytic disease. Thirty-four patients with Rh incompatibility proved by positive direct antiglobulin test (Coombs test) results were randomly assigned to receive conventional treatment including phototherapy, with or without additional HDivIG therapy at 500 mg/kg given for a 2-hour period as soon as the diagnosis was established. Exchange transfusions were performed if serum bilirubin concentrations exceeded the modified curves of Polácek by more than 2 mg/dl. Two patients were excluded because of protocol violations. The results in 32 infants were analyzed. In the HDivIG group, 2 (12.5%) of 16 children required exchange transfusions, whereas it became necessary in 11 (69%) of 16 children in the control group (p less than 0.005). Bilirubin levels in the HDivIG group were lower despite reduced frequency of exchange transfusions. No side effects of HDivIG treatment were observed. We conclude that HDivIG therapy by a yet unknown mechanism reduces serum bilirubin levels and the need for blood exchange transfusions in children with Rh hemolytic disease.     

Die Bedeutung des Albuminsättigungsindex für Bilirubin bei der Beurteilung des Neugeborenenikterus

The saturation of serum albumin with bilirubin (saturation index) was determined in 81 serum samples of 32 icteric newborn infants by means of the salicylate displacement technique [10, 12]. The saturation index was directly related to the serum bilirubin concentration in 17 icteric newborns without hemolytic disease (r=0.665, p<0.001). The same result was obtained in newborns with Rh-erythroblastosis who had had an exchange transfusion (r=0.63, p<0.005). No significant correlation between saturation index and bilirubin concentration was found in children with hemolytic disease. For a bilirubin concentration of 20 mg% we determined saturation indices of 7.95±1.48% (nonhemolytic hyperbilirubinemia) and 7.81±1.3% (hemolytic disease, post-exchange sera) by interpolation with the regression lines. This corresponds to the dangerous saturation index level of 8% reported by Odell et al. [13]. The salicylate method is a simple, rapid micromethod which may be usefull, in combination with serum bilirubin determination, as a test for the indication of exchange transfusion. The reserve albumin binding capacity (HABA-binding) was evaluated in 10 newborns with nonhemolytic hyperbilirubinemia. There was no significant correlation between reserve binding capacity and bilirubin concentration. Evaluation of reserve binding capacity does not appear to offer a satisfactory criterion for exchange transfusion. Bilirubin concentration was assayed in 50 serum samples using two different spectrophotometric micro-methods (White et al. [18] and Chiamori et al. [2]) and one diazomethod. It is possible to use both spectrophotometric methods simultaneously with the salicylate method, but we suggest the method of White et al. [18]. White's method showed a greater correlation coefficient (r=0.97) than the method of Chiamori et al. (r=0.94). Correction for heme pigments by reading the absorbance at 575 nm is more reliable than the use of a correction based on a reading at 415 nm. The spectrophotometric determination of bilirubin can be used to check the bilirubin concentration determined by a diazomethod.     

Superiority of intensive phototherapy — Blue double light —in rhesus haemolytic disease

The purpose of the study was to investigate whether intensive phototherapy (blue double light) is superior to ordinary white single light in the treatment of rhesus haemolytic disease (RHD). 71 newborn infants suffering from RHD and with strongly positive direct Coombs' tests were illuminated with blue double light, and 104 infants illuminated with white single light. With the double light treatment, the number of late exchange transfusions was reduced to 1/6 of the number in single light treated infants thereby halving the total number of exchange transfusions. This reduction was significant in infants with mild-to-moderate RHD, as well as in infants with severe RHD. The mean maximum serum bilirubin concentration was significantly lower in the double light treated infants than in the single light treated infants. Correspondingly, significantly fewer double light treated infants than single light treated infants developed moderate or high serum bilirubin concentrations. There were no significant side effects during the phototherapy. To prevent a marked increase of the serum bilirubin concentration after discontinuation of the double light treatment, this therapy was followed by single light treatment. It can be concluded that intensive phototherapy is superior to ordinary phototherapy in the treatment of RHD.     

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目的探讨全自动换血术对高胆红素血症新生儿血液学指标的影响,评估其疗效与安全性以及间接胆红素和白蛋白比值的临床意义。方法 2008年1月至2010年5月南方医科大学南方医院对74例重症高胆红素血症患儿均采用周围动静脉同步换血术,监测换血前后胆红素、白蛋白、间接胆红素与白蛋白比值、电解质、血常规。结果血中胆红素、白蛋白、间接胆红素与白蛋白比值、电解质(Na+、K+、Cl-、Mg2+)、血常规换血后均较换血前明显下降,但Ca2+、P3+浓度换血后较换血前升高,差异均有统计学意义。换血术后无患儿发生不良反应。结论换血对胆红素、白蛋白、间接胆红素与白蛋白比值、Na+、K+、Cl-、Mg2+、Ca2+、P3+、白细胞、红细胞、血红蛋白、红细胞压积、血小板均有影响,应注意监测。特别要注意监测间接胆红素与白蛋白比值,该比值是评估胆红素毒性的危险指标。比值越高,其危险性越高,越需要输注白蛋白。     

Reserve albumin binding capacity,salicylate saturation index,and red cell binding of bilirubin in neonatal jaundice

105 blood samples from 72 infants, mostly with jaundice due to haemolytic disease, were analysed for reserve albumin binding capacity (HBABA method), salicylate saturation index (SI), and red cell binding of bilirubin. 2 infants with clinical symptoms of bilirubin encephalopathy had abnormally large amounts of red cell bound bilirubin, though the HBABA binding capacity and salicylate saturation index did not suggest a risk of bilirubin encephalopathy. On the other hand, 48 of the other samples showed `risk values'' for saturation index and 2 of the other samples showed such values as judged by the HBABA method. The discrepancies between these findings are discussed. It is suggested that determination of red cell bound bilirubin may have clinical value in patients with neonatal jaundice, especially in cases of suggested kernicterus.     

Intravenous immune globulin in neonatal immune hemolytic disease: does it reduce hemolysis?

We studied the effect of intravenous immune globulin (IVIG) on hemolysis in term, hyperbilirubinemia, Coombs'positive infants utilizing measurement of carboxyhemoglobin fraction corrected for inhaled carbon monoxide (COHbc), a sensitive indicator of hemolysis. COHbc values were determined before and after IVIG infusion. In those babies who responded with a decrease in serum total bilirubin ( n = 19). no exchange transfusions were required and COHbc levels decreased significantly by 24 h post-IVIG from 1.37 ± 0.31 to 1.12 ± 0.26% tHb ( p < 0.0001). There were no corresponding decreases in COHbc levels (1.89 ± 0.54 to 1.82 ± 0.48% tHb; ( p > 0.05) among those whose serum bilirubin levels did not decrease in response to IVIG ( n = 7), and all of these infants required exchange transfusions. Furthermore, the extent of the decrease in COHbc was related to the degree of decrease in serum bilirubin levels, such that the percentage decrease of bilirubin at 24 h was directly correlated with the percentage decrease of COHbc at 24 h ( p = 0.007). We conclude that IVIG, when successful, inhibits hemolysis in these infants.     

Intravenous immunoglobulins in rhesus hemolytic disease

Objective: To evaluate the role of intravenous immunoglobulins in Rh hemolytic disease of newborn.Methods: The study included all DCT positive Rh isoimmunized babies admitted in the unit from August 2000 to February 2001. Intravenous immunoglobulins in the dose of 500 mg/kg on day 1 and day 2 of life in addition to the standard therapy. Babies who received IVIG were compared with those who did not receive IVIG for the peak bilirubin levels, duration of phototherapy, number of exchange transfusions, discharge PCV and the need for blood transfusions for late anemia till 1 months of age.Results: A total of 34 babies were eligible for the study. 8 babies received IVIG and 26 babies only standard treatment. The mean maximum bilirubin levels were significantly lower in the IVIG group compared to the group who received NO IVIG (16.52 ± 2.96 Vs 22.72 ± 8.84, p=0.004). Five babies in the IVIG group (62.5%) and 23 babies in the NO IVIG group required exchange transfusions (88.5%, p=0.014). 12 of the 26 babies in the NO IVIG group required multiple exchange transfusions while none of the babies in IVIG group required more one exchange transfusion (p=0.03). The mean duration of phototherapy was 165 ± 109 hours in the IVIG group as against 119 ± 56 hours in the NO IVIG group (p=0.29). Blood transfusion for anemia was more common in the IVIG group (37.5 % Vs 11.5% p=0.126) though the packed cell volumes at discharge were similar in both the groups (39.5 ±11 Vs 40 ± 5.1, P=0.92).Conclusion; Intravenous immunoglobulins is effective in decreasing the maximum bilirubin levels and the need for repeated exchange transfusions in Rh hemolytic disease of newborn. There is however an increased need for blood transfusions for late anemia in the babies treated with IVIG.     

Intensive phototherapy with a blue double lamp in the treatment of neonatal hyperbilirubinemia

The purpose of this study was to investigate the effect of "intensive phototherapy" (blue double light, 2 X 30 microW/cm2) on neonatal hyperbilirubinemia in 41 infants, compared to a control group treated with "single light" phototherapy (1 X 30 microW/cm2). The double light treatment enhances the photodegradation of bilirubin. The number of exchange transfusions was reduced, and no further exchange transfusions had to be carried out. No significant clinical side effects during the phototherapy were observed.     

Excessively high bilirubin and exchange transfusion in very low birth weight infants

Aim: To evaluate the performance of exchange transfusion in very low birth weight (VLBW) infants with excessively high serum bilirubin levels. Methods: A population‐based observational study using data collected by the Israel National VLBW Infant Database. The study sample comprised 13 499 infants. Two definitions of excessively high‐peak bilirubin levels that might be considered as threshold levels for performance of exchange transfusion were used. First, a bilirubin level of ≥15 mg/dL for all infants (PSB‐15), and second, incremental bilirubin levels ranging from 12 to 17 mg/dL according to gestational age (PSB‐GA). Results: Four hundreds sixty‐eight (3.5%) and 1035 infants (7.7%) infants in the PSB‐15 and in the PSB‐GA groups respectively had peak serum bilirubin levels above thresholds for exchange transfusion. Exchange transfusions were performed in 66 (14.1%) of these infants in the PSB‐15 group and 91 (8.8%) in the PSB‐GA group. Using logistic regression analysis, peak serum bilirubin was found as an independent factor for performing exchange transfusion. Conclusion: Exchange transfusion was performed in only 9–14% of VLBW infants with excessively high bilirubin levels. We speculate that this may be a result of an absence of definitive guidelines or the possible belief that the risks of exchange transfusion outweigh the potential risk of bilirubin‐induced neurological injuries.     

Rhesus disease: postnatal management and outcome

The incidence of rhesus haemolytic disease has been markedly reduced. Affected infants who have had intrauterine transfusions suffer a late hyporegenerative anaemia. Postnatal haemolysis and hence treatment for hyperbilirubinaemia is less commonly needed. Optimal phototherapy reduces the need for postnatal exchange transfusions, but data on the efficacy of inhibitors of bilirubin production such as haem oxygenase inhibitors or immunoglobulin are less secure. Even hydropic infants have less than 20% mortality and bilirubin encephalopathy is uncommon. There is, however, very limited information on the long-term outcome of infants with rhesus haemolytic disease. Conclusion Multicentre collaboration is required to test strategies to improve the management of affected individuals further and to provide meaningful data on their prognosis. Received and accepted: 13 January 1999     

Late neurological sequelae of non-hemolytic hyperbilirubinemia of healthy term neonates

Records of the only children's hospital equipped to perform exchange transfusions in West Berlin were used to identify all 29 non-hemolytic healthy term newborns with total serum bilirubin between 20 and 30 mg/dL, 16 of whom were available for follow-up neurological examination according to Touwen. Compared to 18 case controls with bilirubin <12 mg/dL, jaundiced children scored significantly worse only on the choreiform dyskinesia scale.     

THE DECREASE IN THE SERUM BILIRUBIN LEVEL IN PREMATURE INFANTS BY OROTIC ACID

The influence of higher doses of orotic acid on the serum bilirubin level of premature infants was investigated following studies with a lower dose. 102 premature infants were treated with a daily dose of 300 mg of orotic acid from the 1st-6th day after birth. An equal number of children served as a control group. The serum level for the indirect bilirubin that was analysed from the 3rd-6th day of life could be statistical significantly decreased by the administration of orotic acid. Blood exchange transfusions were necessary only four times with the administration of orotic acid, whereas blood exchange transfusions were required in 30 premature infants of the control group. The question of eventual side effects and the supposed mode of action of the orotic acid are discussed.     

Salicylate saturation index in neonatal jaundice.

30 serum samples from premature and newborn infants with non-haemolytic hyperbilirubinaemia were analyzed to prove the accuracy of determination of albumin binding capacity for bilirubin. The salicylate method of Odell was used to determine the saturation index of albumin indicated by a decrease in optical density through displaced bilirubin. Bilirubin is stoichometrically displaced from albumin by the addition of salicylate. The values of the sautration index correspond to free binding sites. Analysis of our data demonstrated that there is no direct correlation between the saturation index (SI) and total serum bilirubin/albumin concentration quotient. Methodical errors, problems in statistics and other theoretical concepts are discussed. The salicylate method is not suitable for accurate determination of albumin binding capacity for bilirubin.     

新生儿高胆红素血症换血术与预后

目的　探讨新生儿高胆红素血症换血术与预后的相关因素。方法　对入住我科重症高胆红素血症患儿采用双通道同步换血术 ,并追踪随访预后。根据预后分为异常组、对照组 ,对相关因素进行比较。结果　高胆红素血症患儿换血后胆红素水平显著下降 (P <0 0 1)。追踪随访 6 8例 ,7例失访 ,余 6 1例中 2 5例异常 ,36例作为对照组。对照组与异常组比较 ,日龄、体重、胆红素水平、B/A(胆红素白蛋白 )比值、BAEP(脑干听觉诱发电位 )均有显著差异 (P <0 0 5 )。结论　新生儿高胆红素血症强调早期诊断、早期治疗。就诊时间越晚 ,胆红素水平越高 ,越易发生核黄疸。早产儿、低体重儿较足月正常体重儿 ,对胆红素的毒性更加敏感。对于高胆红素血症患儿 ,可参考血清胆红素水平 ,BAEP及B :A比值早期评估预后     

Phenobarbitone in neonatal jaundice

Eighty-three jaundiced newborn infants were studied, 41 received phenobarbitone, and 42 served as controls. 48 hours after starting treatment the mean serum bilirubin level of the group of normal birthweight infants was significantly lower than that of controls. Exchange transfusions were required in 6 of the 32 control cases and in none of the 28 treated cases.There were no significant differences in the mean serum bilirubin levels or in the exchange transfusion rates between treated and control low birthweight infants.     

High-dose intravenous immunoglobulin therapy in neonatal immune haemolytic jaundice

A controlled study was conducted to assess the role of high-dose i.v. immunoglobulin (HDIVIG) therapy in neonatal immune haemolytic jaundice. Patients with ABO and/or Rh incompatibilities proved by significant hyperbilirubinaemia (>204 mmol l(-1)), positive direct antiglobulin test and high reticulocyte count (> or =10%) were randomly assigned to receive either conventional phototherapy alone or phototherapy with high-dose i.v. immunoglobulin (1 g kg(-1), over 4 h) as soon as the diagnosis was established. Exchange transfusions were performed if serum bilirubin concentrations exceeded 290 mmol l(-1) and increased by more than 17 mmol l(-1) per h despite both treatment manoeuvres. Eight of 58 patients in the HDIVIG group required exchange transfusions, whereas it became necessary in 22 of 58 patients in the control group (p<0.001). The durations of phototherapy and hospitalization in terms of hours were significantly shorter in the HDIVIG group (p<0.05). No side effects of HDIVIG therapy were observed. In conclusion, HDIVIG therapy in newborns with ABO or Rh haemolytic diseases reduces haemolysis, serum bilirubin levels and the need for blood exchange transfusion, a procedure which has potential complications and carries a risk of mortality.     

Auditory nerve and brainstem responses in newborn infants with hyperbilirubinemia

To assess early bilirubin toxicity, a study was made of auditory brainstem responses in relation to total bilirubin levels as well as unbound bilirubin levels in 56 hyperbilirubinemic infants (total bilirubin greater than or equal to 15.0 mg/dL) and 24 infants who did not have jaundice. The latencies of wave I at 85 dB HL (hearing level) in hyperbilirubinemic infants were significantly greater than those in the control group. The latencies of wave I and V in hyperbilirubinemic infants with unbound bilirubin levels greater than or equal to 1.0 microgram/dL (group C) were greater than those in the control group and in the hyperbilirubinemic infants with unbound bilirubin levels less than 0.5 microgram/dL (group A) and with unbound bilirubin levels less than 1.0 microgram/dL (group B). There were no significant differences of the wave I-V interpeak latency between the control infants and the hyperbilirubinemic infants. Thirty of the 80 infants showed prolonged peak latencies (greater than the mean +/- 2 SD for the control infants) of wave I and/or V in one or both ears. The incidences of the prolonged peak latencies in group B (42%) and group C (89%) were significantly greater than that in the control group (12%). The serial determinations of auditory brainstem responses in infants treated with exchange transfusions revealed that the prolonged peak latencies before exchange transfusion improved at 48 and 96 hours after the procedure for wave I, and at 24, 48, and 96 hours after the procedure for wave V. The interpeak latency of wave I-V did not change with exchange transfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Normal neurological outcome in two infants treated with exchange transfusions born to mothers with Crigler-Najjar Type 1 disorder

Patients with Crigler-Najjar Type 1 (CN-1) disorder have an unconjugated hyperbilirubinaemia due to the complete absence in activity of uridinediphosphate glucuronosyltransferase, a bilirubin-conjugating enzyme. In pregnant women with CN-1, the foetus is at high risk of being adversely affected by the bilirubin, as unconjugated bilirubin can cross the placenta and is potentially neurotoxic. We report the long-term outcomes of two infants born to women with CN-1. These infants had exchange transfusions soon after birth and have normal neurodevelopmental outcomes at 18 months and four years of age, respectively. We propose that this intervention might have improved the neurological outcome of these infants. There are no conflicts of interest reported by any of the authors. Funding was not required.