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Abstract

Bilirubin-albumin binding weakens the correlation between the plasma total bilirubin concentration (TBC) and bilirubin encephalopathy (kernicterus), which has led to considerable interest over the years in measuring binding as part of the evaluation of jaundiced newborns. Despite development of several bilirubin-albumin binding tests, technical, ethical, and logistical factors have prevented the prospective studies needed to validate their routine clinical use. Consequently, it has been necessary to adopt aggressive exchange transfusion criteria based on the TBC that require the unnecessary treatment of large numbers of babies to prevent the rare case of kernicterus. Recently, early hospital discharge and arbitrary relaxation of exchange transfusion criteria have resulted in a resurgence of kernicterus. This resurgence and studies showing that nonalbumin bound or "free" bilirubin (Bf) correlates better than the TBC with bilirubin toxicity have rekindled interest in bilirubin binding tests. Technological advances in the measurement of Bf provide a convenient and economical means for integrating Bf measurements into routine clinical practice by determining the bilirubin-albumin binding parameters of various newborn populations.

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... The mainstay of therapy was an overhead array of ten Philips 40 W special blue (BB) fluorescent tubes 3 . In recent years, two other phototherapy systems were used: portable light emitting diode (LED)-based panels (Stanford PortaBed system [55]) and a custom-made "lightbox" housing 24 fluorescent tubes (combined TL52 and BB). ...
... Our treatment protocol in Table 2 is based on the pathophysiologic model illustrated in Fig. 3 [3,12,39,49,58,59] and is designed to lower total body exchangeable bilirubin and prevent its movement to extravascular sites. In jaundiced infants and adults, the total body bilirubin pool is very large and almost exclusively bound to proteins and lipid membranes, while the lower unbound bilirubin concentration [2,3] is characterized by continual flux between two competing reservoirsa finite number of intravascular binding sites and a much larger number of lower-affinity sites on endothelia of brain and other organs. ...
... Our treatment protocol in Table 2 is based on the pathophysiologic model illustrated in Fig. 3 [3,12,39,49,58,59] and is designed to lower total body exchangeable bilirubin and prevent its movement to extravascular sites. In jaundiced infants and adults, the total body bilirubin pool is very large and almost exclusively bound to proteins and lipid membranes, while the lower unbound bilirubin concentration [2,3] is characterized by continual flux between two competing reservoirsa finite number of intravascular binding sites and a much larger number of lower-affinity sites on endothelia of brain and other organs. As bilirubin passes through the circulation, the fraction deposited in the brain and other tissues depends only on its molar relationship with high-affinity albumin binding sites and the dissociation rate of the bilirubin-albumin complex relative to the time it takes blood to transit a tissue capillary bed [49,58]. ...
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We summarize the treatment of 20 patients with Crigler-Najjar disease (CND) managed at one center from 1989 to 2005 (200 patient-years). Diagnosis was confirmed by sequencing the UGTA1A gene. Nineteen patients had a severe (type 1) phenotype. Major treatment goals were to maintain the bilirubin to albumin concentration ratio at <0.5 in neonates and <0.7 in older children and adults, to avoid drugs known to displace bilirubin from albumin, and to manage temporary exacerbations of hyperbilirubinemia caused by illness or gallstones. A variety of phototherapy systems provided high irradiance over a large body surface. Mean total bilirubin for the group was 16+/-5 mg/dl and increased with age by approximately 0.8 mg/dl per year. The molar ratio of bilirubin to albumin ranged from 0.17 to 0.75 (mean: 0.44). The overall non-surgical hospitalization rate was 0.12 hospitalizations per patient per year; one-half of these were for neonatal hyperbilirubinemia and the remainder were for infectious illnesses. Ten patients (50%) underwent elective laproscopic cholecystectomy for cholelithiasis. No patient required invasive bilirubin removal or developed bilirubin-induced neurological damage under our care. Visual acuity and color discrimination did not differ between CND patients and age-matched sibling controls. Four patients treated with orthotopic liver transplantation were effectively cured of CND, although one suffered significant transplant-related complications.Conclusions. While patients await liver transplantation for CND, hyperbilirubinemia can be managed safely and effectively to prevent kernicterus. Lessons learned from CND can be applied to screening and therapy of non-hemolytic jaundice in otherwise healthy newborns.
... One entity to be considered in assessing the risk for bilirubin-induced neurologic damage is the serum albumin [24]. Investigators have observed that at physiological concentrations, bilirubin in the presence of BSA protected neonatal erythrocytes against oxidant stress in a dose-dependent fashion [25]. At higher concentration ([300 mg/l) this protection was lost, suggesting a threshold of cytoprotective effects of bilirubin. ...
... For bilirubin this may be of a great significance, since it is not only a weak sensitizer, but is also destroyed by light. In terms of a photodynamic oxidation, in the presence of a sensitizer, it is proposed that reserve albumin binding capacity may also play a protective role [25]. Albumin binding capacity was saturated with increased bilirubin concentration (Table 1), which is evidenced from a concentration-dependent oxidant stress (Table 3). ...
Article
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In vitro studies have shown unequivocally that bilirubin is an antioxidant. We hypothesized that bilirubin serves a physiological role of an antioxidant in vivo. To investigate the probable protective role of bilirubin in vivo, term babies with clinical jaundice were grouped into four categories—serum total bilirubin (STB) 200 mg/l, and kernicterus. Serum bilirubin, serum albumin, plasma glucose-6-phosphate dehydrogenase (G6PD), lipid peroxidation in blood cells, and reduced glutathione (GSH) content in whole blood were investigated. We also measured superoxide dismutase (SOD) and catalase in hemolysate and total plasma antioxidant capacity (TAC). Lipid peroxidation and antioxidant enzymes were significantly lower in babies with STB 200 mg/l and in babies with bilirubin encephalopathy. Elevated levels of MDA, SOD, and catalase and significantly decreased levels of reduced glutathione and total antioxidant capacity were observed in STB >200 mg/l group. Antioxidant enzymes were also significantly inhibited in bilirubin encephalopathy babies. Post phototherapy, MDA production and antioxidant levels were significantly increased whilst total antioxidant capacity and reduced glutathione were significantly decreased compared to pre-phototherapy values. Exchange transfusion resulted in reduced oxidative stress in subjects with encephalopathy, whereas no significant difference was observed in other babies with STB >200 mg/l. Taken together, the present study propounds that bilirubin acts as a physiological antioxidant till 200 mg/l concentration in full-term normal neonates. It is conjectured that beyond 200 mg/l, it can no longer be considered physiologic. However, the cause of pathological jaundice needs to be identified and treated. The present data documents that phototherapy also induces oxidative stress.
... A lthough physiological neonatal jaundice is believed to protect newborns against oxidative stress (1), severe unconjugated hyperbilirubinemia may cause irreversible bilirubin-induced neurologic damage (BIND) (2). Recent findings emphasize that diffusion of unconjugated bilirubin (UCB) into cells, causing neurotoxicity, is related to the unbound, free fraction of plasma UCB (Bf), rather than the total plasma UCB level (3)(4)(5). ...
... Only the unbound fraction of UCB (Bf) can enter tissues. This process becomes clinically relevant when the load of bilirubin is excessive or when agents competitively displace UCB from binding sites on albumin (3,5). Because of multiple factors affecting UCB binding and Bf, it has not been possible to define a bilirubin/albumin molar ratio (B/A) considered to be safe in protecting against BIND. ...
Article
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Few data exist on regional brain bilirubin content in the neonatal period when acute bilirubin-induced neurologic damage (BIND) may occur, and no information is available on regional brain expression of cytochrome P450 monooxygenases (Cyps) that oxidize bilirubin. Bilirubin content was analyzed by high-performance liquid chromatography and Cyp1a1, 1a2, and 2a3 mRNA expression was analyzed by quantitative PCR (qPCR) in cortex (Cx), cerebellum (Cll), superior colliculi (SC), and inferior colliculi (IC) of 17-d-old hyperbilirubinemic (jj) Gunn rat pups before and after administration of sulphadimethoxine to acutely displace bilirubin from plasma albumin. There was no difference in bilirubin content among brain regions in untreated rats. After intraperitoneal sulphadimethoxine, bilirubin content peaked at fourfold in Cx and SC at 1 h; but at 11- to 13-fold in Cll and IC at 24 h; returning to control levels at 72 h. The Cyp mRNA peaked at 30-70 times control at 1 h in Cx and SC, but at 3-9 times control at 24 h in Cll and IC. The close relationship in distinct brain regions between the extent of bilirubin accumulation and induction of mRNA of Cyps suggests Cyps may have a role in protecting selected brain areas from bilirubin neurotoxicity.
... In addition, intravenous immunoglobulin (IVIG) and albumin (IVALB) are administrated to neonates with hemolytic hyperbilirubinemia (4,5). IVALB may be effective for preventing the occurrence of complications associated with hyperbilirubinemia, including neuronal developmental abnormalities and blood transfusions (6)(7)(8)(9). However, there have been a number of previous studies indicating that neonatal hyperbilirubinemia and/or phototherapy may be associated with infant immune disorders including asthma, thrombocytopenia and arthritis (10)(11)(12), or septic shock (13,14). ...
... However, there have been a number of previous studies indicating that neonatal hyperbilirubinemia and/or phototherapy may be associated with infant immune disorders including asthma, thrombocytopenia and arthritis (10)(11)(12), or septic shock (13,14). Administration of IVALB serves a key role in preventing neonatal encephalopathy or kernicterus by binding to bilirubin and accelerating its supersession in plasma (7). Conversely, albumin (ALB) peptides may exhibit a cross-linking interaction with the neonatal Fc receptor (FcRn) and promote IgG catabolism by saturating FcRn to decrease sustained high serum IgG level (15). ...
Article
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Previous studies have indicated that phototherapy may be associated with childhood immune disorders in later life. The present study aimed to assess the effects of phototherapy as a risk factor in the decrease in serum globulin (GLB) levels during neonatal hyperbilirubinemia. A total of 430 full‑term infants aged between 1 and 28 days, diagnosed with neonatal hyperbilirubinemia, were enrolled in the present study. Neonates with intrauterine infection, genetic abnormalities and congenital diseases were excluded from the cohort. All neonates received single‑side phototherapy (halogen lamps for 12 h per day, for 3 days) and/or intravenous albumin (IVALB; 1 g/kg/day, for 2 days) and/or intravenous immunoglobulin (1 g/kg/day, for 2 days). Total serum bilirubin (TSB), albumin (ALB) and GLB levels were examined twice, on the first and fourth days of hospitalization. Neonatal TSB concentrations decreased from 299.6±83.9 to 163.6±57.6 µmol/l following 3 days of intensive treatment (P<0.001). Pearson correlative analysis indicated that TSB was significantly correlated to the GLB level (r=0.249; P<0.01), but not with ALB level. There was a significant decrease in GLB levels following phototherapy+IVALB (P<0.001). The GLB levels decreased to 2‑4 g/l (10‑20% compared with their baseline levels) and were markedly decreased in infants >16 days old compared with those in patients aged <16 days (P<0.001). The decreases in GLB levels observed were 21.3±4.1 to 18.5±4.2 g/l in the phototherapy group, and 23.0±3.9 to 16.6±4.5 g/l in the phototherapy+IVALB (P<0.001). The decrease in GLB levels was associated with age (95% confidence interval; ‑0.152, ‑0.016). The results demonstrated that phototherapy decreased serum GLB levels, particularly in infants aged >16 days, while additional IVALB treatment promoted the decrease, along with increased age.
... A lthough physiological neonatal jaundice is believed to protect newborns against oxidative stress (1), severe unconjugated hyperbilirubinemia may cause irreversible bilirubin-induced neurologic damage (BIND) (2). Recent findings emphasize that diffusion of unconjugated bilirubin (UCB) into cells, causing neurotoxicity, is related to the unbound, free fraction of plasma UCB (Bf), rather than the total plasma UCB level (3)(4)(5). ...
... Only the unbound fraction of UCB (Bf) can enter tissues. This process becomes clinically relevant when the load of bilirubin is excessive or when agents competitively displace UCB from binding sites on albumin (3,5). Because of multiple factors affecting UCB binding and Bf, it has not been possible to define a bilirubin/albumin molar ratio (B/A) considered to be safe in protecting against BIND. ...
... It is a more useful indicator of the Bf level than using the TSB level alone. [19,20] Using the B/A ratio in addition to TSB levels may lead to reducing early mortality by a mechanism that is as yet unknown. Our unexpected finding that use of the B/A ratio in the management of preterms with birth weights of .1000 ...
Article
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Background and Objective High bilirubin/albumin (B/A) ratios increase the risk of bilirubin neurotoxicity. The B/A ratio may be a valuable measure, in addition to the total serum bilirubin (TSB), in the management of hyperbilirubinemia. We aimed to assess whether the additional use of B/A ratios in the management of hyperbilirubinemia in preterm infants improved neurodevelopmental outcome. Methods In a prospective, randomized controlled trial, 615 preterm infants of 32 weeks' gestation or less were randomly assigned to treatment based on either B/A ratio and TSB thresholds (consensus-based), whichever threshold was crossed first, or on the TSB thresholds only. The primary outcome was neurodevelopment at 18 to 24 months' corrected age as assessed with the Bayley Scales of Infant Development III by investigators unaware of treatment allocation. Secondary outcomes included complications of preterm birth and death. Results Composite motor (100±13 vs. 101±12) and cognitive (101±12 vs. 101±11) scores did not differ between the B/A ratio and TSB groups. Demographic characteristics, maximal TSB levels, B/A ratios, and other secondary outcomes were similar. The rates of death and/or severe neurodevelopmental impairment for the B/A ratio versus TSB groups were 15.4% versus 15.5% (P = 1.0) and 2.8% versus 1.4% (P = 0.62) for birth weights ≤1000 g and 1.8% versus 5.8% (P = 0.03) and 4.1% versus 2.0% (P = 0.26) for birth weights of >1000 g. Conclusions The additional use of B/A ratio in the management of hyperbilirubinemia in preterm infants did not improve their neurodevelopmental outcome. Trial Registration Controlled-Trials.com ISRCTN74465643
... Disorders in the metabolism of bilirubin, especially common among newborn infants, may cause jaundice, a yellow coloration of the skin and other tissue. Free bilirubin (bilirubin IX) is the principal determinant of tissue uptake and toxicity of bilirubin, and plays a critical role in the pathogenesis of bilirubin encephalopathy in jaundiced newborn because of its lipophilic nature (Ahlfors and Wennberg, 2004;Wennberg et al., 2006). Hence free bilirubin concentration in blood serum is a better parameter to assess the risk caused by hyperbilirubemia in case of neonatal jaundice. ...
Article
We report here a fluorescence quenching based non-enzymatic method for sensitive and reliable detection of free bilirubin in blood serum samples using human serum albumin (HSA) stabilized gold nanoclusters (HSA-AuNCs) as fluorescent probe. The fluorescence of the nanoclusters was strongly quenched by bilirubin in a concentration dependent manner by virtue of the inherent specific interaction between bilirubin and HSA. A strong binding constant of 0.55×10(6)Lmole(-1) between the HSA-AuNC and bilirubin was discerned. The nano clusters each with size ~1.0nm (in diameter) and a core of Au18 were homogeneously distributed in HSA molecules as revealed from the respective high resolution transmission electron microscopic and mass spectroscopic studies. The fluorescence quenching phenomena which obeyed a simple static quenching mechanism, was utilized for interference free detection of bilirubin with minimum detection limit (DL) of 248±12nM (S/N=3). The fluorescence response of HSA-AuNCs against bilirubin was practically unaltered over a wide pH (6-9) and temperature (25-50°C) range. Additionally, peroxidase-like catalytic activity of these nanoclusters was exploited for colorimetric detection of bilirubin in serum sample with a DL of 200±19nM by following the decrease in absorbance (at λ440nm) of the reaction and its rate constant (Kp) of 2.57±0.63mLμg(-1)min(-1). Both these fluorometric and colorimetric methods have been successfully used for detection of free bilirubin in blood serum samples.
... Both newborns, of course, would receive phototherapy, but the latter would be expected to require a longer duration of treatment and experience 'rebound' jaundice as bilirubin moves back into circulation by mass action after phototherapy is stopped, and also be at a much higher risk for BIND. This supports the belief that tracking the remaining binding capacity or binding saturation might identify infants at risk for developing BIND before the BBC maximum is reached, 9 but risk threshold levels have not been well established to date. ...
Article
Hemolytic disease in newborns can result from a number of conditions, which can place such infants at an increased risk for the development of severe hyperbilirubinemia. Because the catabolism of heme produces equimolar amounts of carbon monoxide (CO) and bilirubin, measurements of end-tidal breath CO (corrected for ambient CO) or ETCOc can serve as an index of hemolysis as well as of bilirubin production from any cause. Elevated levels of ETCOc have been correlated with blood carboxyhemoglobin levels and thus hemolysis. However, the detection of hemolysis can be a clinically challenging problem in newborns. Here, we describe the importance of determining ETCOc levels and their application in identifying infants at risk for developing hyperbilirubinemia associated with hemolysis and other causes of increased bilirubin production.Journal of Perinatology advance online publication, 17 April 2014; doi:10.1038/jp.2014.66.
... The biological molecule bilirubin is an important product of the biological breakdown of heme. An excess of bilirubin in the blood (greater than 50 lM) is found in a serious disease called jaundice, [154]. In two different studies, BSA-CuNCs [155] and HSA-AuNCs [156] were successfully employed for the detection of bilirubin in blood and serum samples with high sensitivity. ...
Article
The use of protein templates for the controlled synthesis of inorganic nanostructures has gained considerable attention in multidisciplinary fields, including electronics, optics, energy, sensing, and biomedicine, owing to their biocompatibility and structural programmability. The possible synergistic combination of protein scaffolds (and other biomolecules/biopolymers) with metal nanoclusters (MNCs) has created a new class of highly photoluminescent nanoprobes and nanodevices. For the first time, we will the different types of protein templates used for MNC preparation with an emphasis on their optoelectronic properties for application. In particular, applications of protein-coated MNCs for chemosensing or biosensing of cancer biomarkers, neurotransmitters, pathogenic microorganisms, biomolecules, pharmaceutical compounds, and immunoassays are discussed in detail herein. Fluorescence-based and multimodal molecular imaging, both in vitro and in vivo based on functional proteins are also covered. Furthermore, we discuss the burgeoning growth of protein-coated MNCs (e.g., gold (Au) and silver (Ag) NCs) to develop synergistic nanotherapeutics with potential biomedical applications in chemotherapy, radiotherapy, photodynamic therapy (PDT), photothermal therapy (PTT), and antibacterial activity, as well as MNC-containing nanocomposites for enhanced bioimaging and controlled drug release. Overall, the proposed review highlights the recent progress, technical challenges and new horizons in this field, and summarizes our understanding of how MNC properties interact with the biological function of protein scaffolds to develop synergistic nanotherapeutics towards clinical translation.
... The salicylate displacement test was one of many attempting to identify the amount of dangerous "free" bilirubin. 7 Pediatric residents could be caught in the middle, as demonstrated by the example of those who worked in New York City' s Bellevue/University Hospital program.* Sanford Cohen, the head of neonatology at Bellevue and a disciple of Dr Odell' s, promoted the Prince of Dark' s paradigm. ...
... Also, it is interesting to note that the HSA-induced decrease in brain bilirubin concentrations is less pronounced than the HSAinduced decrease in plasma UCB free concentrations. These observations confirm that, apart from UCB free , other factors (e.g., changes in blood pH, BBB integrity, active transport of bilirubin across the BBB, hemolysis, inflammation) are also highly important in the pathogenesis of bilirubin-induced neurological damage [31,32]. It would be interesting to investigate these factors, as well as the accumulation of bilirubin in specific brain regions (since bilirubin predominantly accumulates in the deep nuclei of the brain) during HSA treatment in future animal experiments. ...
Article
Background & aims: Severe unconjugated hyperbilirubinemia, as occurs in Crigler-Najjar disease and neonatal jaundice, carries the risk of neurotoxicity. This neurotoxicity is related to the increased passage of free bilirubin (UCB(free)), the fraction of bilirubin that is not bound to plasma proteins, into the brain. We hypothesized that albumin treatment would lower the UCB(free) fraction, and thus decrease bilirubin accumulation in the brain. Methods: We treated chronic (e.g., as a model for Crigler-Najjar disease) and acute hemolytic (e.g., as a model for neonatal jaundice) moderate hyperbilirubinemic Gunn rats with phototherapy, human serum albumin (HSA) or phototherapy+HSA. Results: In the chronic model, adjunct HSA increased the efficacy of phototherapy; it decreased plasma UCB(free) and brain bilirubin by 88% and 67%, respectively (p<0.001). In the acute model, adjunct HSA also increased the efficacy of phototherapy; it decreased plasma UCB(free) by 76% (p<0.001) and completely prevented the hemolysis-induced deposition of bilirubin in the brain. Phototherapy alone failed to prevent the deposition of bilirubin in the brain during acute hemolytic jaundice. Conclusions: We showed that adjunct HSA treatment decreases brain bilirubin levels in phototherapy-treated Gunn rats. We hypothesize that HSA decreases these levels by lowering UCB(free) in the plasma. Our results support the feasibility of adjunct albumin treatment in patients with Crigler-Najjar disease or neonatal jaundice.
... 3,23,31-34 Among other factors, k varies as a function of sample dilution, albumin concentration, albumin species and the study medium including the presence of competing compounds. 3,23,[31][32][33][34] In this regard, the very low albumin concentration (3 mM) in the CNS of Gunn rat pups 4 relative to that in serum would be predicted to significantly increase the apparent bilirubin-albumin binding constant k (relative to serum) 33 and result in a lower calculated CNS B F than that reported using serum k values. 4 However, this effect is most likely countered, even offset, by the greatly decreased number of bilirubin-binding sites associated with the markedly lower CNS albumin concentration. ...
Article
Although most bilirubin in the circulation is bound to albumin, a relatively small fraction remains unbound. The concentration of this 'free' bilirubin (B(F)) is believed to dictate the biologic effects of bilirubin in jaundiced newborns, including its neurotoxicity. The threshold at which B(F) produces changes in cellular function culminating in permanent cell injury and cell death has been the subject of considerable debate. The objective of this study was to compare calculated central nervous system (CNS) B(F) levels in Gunn rat pups during (i) peak postnatal hyperbilirubinemia and (ii) sulfadimethoxine-induced acute bilirubin encephalopathy (ABE) previously reported from our laboratory with those predicted in human neonates with peak total serum bilirubin (TSB) levels of 35 mg per 100 ml (599 micromol l(-1)), a clinical cohort that often evidence moderate-to-severe adverse post-icteric neurodevelopmental sequelae. Homozygous j/j Gunn rat pups with neonatal hyperbilirubinemia due to a deficiency of the bilirubin conjugating enzyme uridine-diphosphate-glucuronosyl transferase 1A1 were studied along with non-jaundiced littermate heterozygous J/j controls. Sulfadimethoxine was used to displace bilirubin from albumin in hyperbilirubinemic j/j Gunn rat pups to increase their brain bilirubin content and induce ABE. Calculated Gunn rat CNS B(F) levels were determined as a function of genotype, sulfadimethoxine exposure and albumin-bilirubin binding constant. These data were compared with the human CNS B(F) predicted from the calculated serum B(F) in human neonates with a TSB of 35 mg per 100 ml as a function of albumin-bilirubin binding constant, albumin concentration and the assumption that at this hazardous bilirubin level there may be rapid equilibration of B(F) between serum and brain. There was a large gap between the upper limit of the calculated CNS B(F) 95% confidence interval (CI) range in non-jaundiced J/j pups (for example, 112 nM at k=9.2 l micromol(-1)) and the lower limit seen in the saline-treated hyperbilirubinemic j/j pups (556 nM at k=9.2 l micromol(-1)) as well as between the upper limit in saline-treated hyperbilirubinemic j/j pups (1110 nM at k=9.2 l micromol(-1)) and the lower limit seen in sulfadimethoxine-treated jaundiced j/j littermates (3461 nM at k=9.2 l micromol(-1)). There was considerable overlap and remarkable similarity between the predicted human CNS B(F) values at a TSB of 35 mg per 100 ml for a range of reported human serum bilirubin-albumin binding constants and albumin concentrations, and those calculated for saline-treated hyperbilirubinemic j/j Gunn rat pups. This exercise yielded strikingly similar apparent calculated neurotoxic B(F) levels for Gunn rat pups and human neonates rather than orders of magnitude differences that might have been predicted at the outset and add to a growing literature aimed at defining clinically germane neurotoxic B(F) thresholds.Journal of Perinatology (2009) 29, S14-S19; doi:10.1038/jp.2008.218.
... Bilirubin is neurotoxic, but the inter-individual variations in vulnerability are not fully understood. However, it is likely that part of this variation may be due to different plasma concentrations of free bilirubin even for equivalent concentrations of TSB, caused inter alia by variations in albumin concentration, avidity of bilirubin-albumin binding, presence of substances competing for the same binding site and sepsis (23,24). Unfortunately, free bilirubin concentrations were not measured in our patients. ...
Article
To show the potential for reversing acute intermediate to advanced phase bilirubin encephalopathy. Case studies. Six extremely jaundiced infants had symptoms of intermediate to advanced phase acute bilirubin encephalopathy. The infants were treated aggressively. Two patients had brain magnetic resonance imaging showing increased signals in the globus pallidus. On follow-up, all infants are neurologically normal. Intermediate-to-advanced stage acute bilirubin encephalopathy may occasionally be reversible. These cases provide a strong argument in favour of rapid and aggressive intervention in infants presenting with extreme jaundice and neurological symptoms.
... A detailed consideration of kernicterus is beyond the scope of this review. But comprehensive papers are available both on the pathogenesis and treatment particularly by Wennberg and his colleagues (e.g., Wennberg, 2000;Ahlfors and Wennberg, 2004;Wennberg et al., 2006) and in Volpe (2008). However, it is becoming increasingly clear that the mechanisms involved in whether or not kernicterus occurs in newborns are much more complex than the absolute level of unconjugated bilirubin and the binding capacity of albumin in plasma. ...
Article
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Careful examination of relevant literature shows that many of the most cherished concepts of the blood-brain barrier are incorrect. These include an almost mythological belief in its immaturity that is unfortunately often equated with absence or at least leakiness in the embryo and fetus. The original concept of a blood-brain barrier is often attributed to Ehrlich; however, he did not accept that permeability of cerebral vessels was different from other organs. Goldmann is often credited with the first experiments showing dye (trypan blue) exclusion from the brain when injected systemically, but not when injected directly into it. Rarely cited are earlier experiments of Bouffard and of Franke who showed methylene blue and trypan red stained all tissues except the brain. The term “blood-brain barrier” “Blut-Hirnschranke” is often attributed to Lewandowsky, but it does not appear in his papers. The first person to use this term seems to be Stern in the early 1920s. Studies in embryos by Stern & colleagues, Weed and Wislocki showed results similar to those in adult animals. These were well-conducted experiments made a century ago, thus the persistence of a belief in barrier immaturity is puzzling. As discussed in this review, evidence for this belief, is of poor experimental quality, often misinterpreted and often not properly cited. The functional state of blood-brain barrier mechanisms in the fetus is an important biological phenomenon with implications for normal brain development. It is also important for clinicians to have proper evidence on which to advise pregnant women who may need to take medications for serious medical conditions. Beliefs in immaturity of the blood-brain barrier have held the field back for decades. Their history illustrates the importance of taking account of all the evidence and assessing its quality, rather than selecting papers that supports a preconceived notion or intuitive belief. This review attempts to right the wrongs. Based on car
... It has been suggested that the concentration of free bilirubin might be a better prognosticator of the risk of developing kernicterus than the total concentration of bilirubin. 16,17 Unfortunately, accurately measuring the free bilirubin concentration in the presence of an overwhelmingly large background concentration of proteinbound bilirubin is difficult. Over the years, several methods have been developed but ultimately abandoned as being unreliable, inaccurate, or impractical for routine clinical use. ...
Article
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The objectives of the study were to measure the effect of 4Z,15E-bilirubin on peroxidase free bilirubin measurements and to review the literature on this topic. 4Z,15E-Bilirubin was generated in situ in serum or serum albumin solution through controlled irradiation of isomerically pure 4Z,15Z-bilirubin IXalpha, under conditions in which the total amount of bilirubin remained constant. Reactions were monitored by difference spectroscopy, to ensure that solutions were not irradiated beyond the initial photostationary state and that concentrations of other isomers were kept to a minimum. Prepared in this way, 10% to 25% of the total bilirubin in the final solutions was in the form of the 4Z,15E-isomer. Free bilirubin in the solutions was measured with a peroxidase method, before and after irradiation. The use of bovine serum albumin as a surrogate for human albumin in in vitro studies also was investigated. The findings of previous studies are not altogether consistent, with a common flaw in several being the failure to measure photoisomer concentrations. For bilirubin in serum albumin solution, conversion of approximately 25% of the 4Z,15Z-isomer to 4Z,15E-bilirubin led to a much smaller decrease (<20%) in the apparent free bilirubin concentration; for bilirubin in serum, conversion of approximately 15% of the 4Z,15Z-isomer to photoisomers resulted in a much larger increase ( approximately 40%). Irradiation of bilirubin in bovine serum albumin solution generated a very different array of photoisomers than that observed in human albumin solutions. The effect of photoisomers on the accuracy and specificity of free 4Z,15Z-bilirubin measurements remains uncertain. In a clinical setting, free bilirubin measurements need to be interpreted with caution when samples contain photoisomers. Irradiated bovine albumin solutions of isomerically impure bilirubin used in previous studies are poor models for investigating the effects of phototherapy in humans and the albumin binding of photoisomers.
... The peroxidase test is used to measure the plasma unbound (non-protein bound) or ''free'' bilirubin (B f ) in jaundiced newborns [1]. B f is the tiny but extremely important fraction of the plasma total bilirubin concentration (TBC) that plays a fundamental role in the pathogenesis of bilirubin encephalopathy (kernicterus) [2][3][4][5][6][7][8][9][10], and recent clinical studies support its use in these patients [5][6][7]9,10]. B f measurements, however, are rarely offered by clinical laboratories even though the peroxidase test was described for over 30 years ago [1], and a Federal Drug Administration-cleared commercial instrument is available [11]. ...
Article
Measuring plasma unbound bilirubin concentration by the peroxidase test is useful in the management of jaundiced newborns. However, the commercially available peroxidase technology is manual, and the unbound bilirubin may be seriously underestimated at the 42-fold sample dilution and single peroxidase concentration used. We investigated improving the test by adapting it to Zone Fluidics, which is a system for automating reactant handling that requires small sample volumes and dilution. A computer-directed Zone Fluidics system was constructed using small diameter tubing to connect in series a water-surfactant reservoir, a bi-directional pump, a multiport selection valve to which peroxidase test reactants (45 mul of sample) are attached with one port open to air, and a spectrophotometer flow cell. Test reactants and air are sequentially aspirated through the valve into the tubing connecting the pump and valve to form a reactant "zone" surrounded by air. The zone is advanced to the spectrophotometer flow cell where total and unbound bilirubin are determined (37 degrees C) from the absorbance at 460 nm at a 2-fold sample dilution and 4 peroxidase concentrations. Imprecision was assessed in artificial controls and newborn plasma. Plasma results were compared with those obtained using the commercial method. The CV for unbound bilirubin in the various controls ranged from 11% to 38% (within day) and 12% to 27% (between days). Triplicate CV measurements for newborn plasma measurements ranged from 0.6% to 31% (mean 11%, n=47). Mean unbound bilirubin by Zone Fluidics was 5-fold higher than that by the commercial method. Zone Fluidics can be used to automate the peroxidase test and overcome many of the limitations of the commercially available peroxidase technology.
... Despite these considerations, the clinical management of jaundiced newborns is conventionally based on the less reliable but readily obtainable TBC (4). Although this approach has been questioned (11), there is an often-overlooked but important paper that supports, in theory, the use of the TBC in most clinical situations. About 18 y ago, Robinson and Rapoport applied a general mathematical model they had developed for brain uptake of protein bound drugs to BBU (12,13). ...
Article
A model for brain bilirubin uptake (BBU) predicts that BBU in jaundiced newborns typically depends on the plasma total bilirubin concentration (TBC) and the bilirubin-albumin dissociation rate constant (k1) rather than the unbound bilirubin (Bf). The model's validity was tested by 1) evaluating its requirement that k3>k2, where k3 and k2 are the rate constants for BBU and Bf-albumin association, respectively, and 2) determining whether the calculated BBU is <or=5% of the bilirubin production rate, the approximate BBU expected if brain bilirubin levels are <1% of the miscible bilirubin pool as reported in the literature. The model was investigated using peroxidase test measurements of TBC, Bf, k1, and k2 from 185 jaundiced newborns. Mean k2 was compared with the reported k3 value of 0.08/s. BBU calculated from TBC and k1 was expected to be <or=0.005 microg/kg/s given the reported bilirubin production rate of 0.1 microg/kg/s. BBU calculated using Bf was also compared with the bilirubin production rate. The mean k2 of 8.9 L/micromol/s was greater than k3, and the mean BBU of 0.72 microg/kg/s exceeded the expected range of <or=0.005 microg/kg/s. However, mean BBU using Bf (0.00073 microg/kg/s) was within the expected range. A mathematical model calculating BBU as a function of TBC and k1 could not be validated. BBU calculated from Bf is consistent with the observation that <1% of the miscible bilirubin pool is distributed in the brain.
... A more sensitive index is that of unbound bilirubin. 5,6 In this report of a G-6-PD deficient premature neonate we demonstrate the development of severe hemolysis, confirmed by a high blood carboxyhemoglobin (COHb) level, but in the absence of changes in Hb, Hct and reticulocyte values. Extreme hyperbilirubinemia was accompanied by the presence of unbound bilirubin in the serum. ...
Article
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A premature glucose-6-phosphate dehydrogenase (G-6-PD) deficient neonate was readmitted for exponential rise in the plasma bilirubin concentration to 33.0 mg dl(-1). Blood carboxyhemoglobin (2.8% of total hemoglobin, >threefold normal value) confirmed the presence of hemolysis; however, hematological indices were unchanged from the birth hospitalization. Serum unbound bilirubin, although present, was probably at a concentration insufficient to cause bilirubin encephalopathy. In G-6-PD deficient neonates, severe hemolysis may occur in the absence of hematological changes typical of a hemolytic process.
... Disorders in the metabolism of bilirubin, especially common among newborn infants, may cause jaundice, a yellow coloration of the skin and other tissue. Free bilirubin (bilirubin IX) is the principal determinant of tissue uptake and toxicity of bilirubin, and plays a critical role in the pathogenesis of bilirubin encephalopathy in jaundiced newborn because of its lipophilic nature (Ahlfors and Wennberg, 2004;Wennberg et al., 2006). Hence free bilirubin concentration in blood serum is a better parameter to assess the risk caused by hyperbilirubemia in case of neonatal jaundice. ...
Conference Paper
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We report here a fluorescence quenching based non-enzymatic method for sensitive and reliable detection of free bilirubin in blood serum samples using human serum albumin (HSA) stabilized gold nanoclusters (HSA-AuNCs) as fluorescent probe. The fluorescence of the nanoclusters was strongly quenched by bilirubin in a concentration dependent manner by virtue of the inherent specific interaction between bilirubin and HSA. A strong binding constant of 0.55×106 L mole−1 between the HSA-AuNC and bilirubin was discerned. The nano clusters each with size ~1.0 nm (in diameter) and a core of Au18 were homogeneously distributed in HSA molecules as revealed from the respective high resolution transmission electron microscopic and mass spectroscopic studies. The fluorescence quenching phenomena which obeyed a simple static quenching mechanism, was utilized for interference free detection of bilirubin with minimum detection limit (DL) of 248±12 nM (S/N=3). The fluorescence response of HSA-AuNCs against bilirubin was practically unaltered over a wide pH (6–9) and temperature (25–50 °C) range. Additionally, peroxidase-like catalytic activity of these nanoclusters was exploited for colorimetric detection of bilirubin in serum sample with a DL of 200±19 nM by following the decrease in absorbance (at λ440 nm) of the reaction and its rate constant (Kp) of 2.57±0.63 mL μg−1 min−1. Both these fluorometric and colorimetric methods have been successfully used for detection of free bilirubin in blood serum samples.
... Disorders in the metabolism of bilirubin, especially common among newborn infants, may cause jaundice, a yellow coloration of the skin and other tissue. Free bilirubin (bilirubin IX) is the principal determinant of tissue uptake and toxicity of bilirubin, and plays a critical role in the pathogenesis of bilirubin encephalopathy in jaundiced newborn because of its lipophilic nature (Ahlfors and Wennberg, 2004;Wennberg et al., 2006). Hence free bilirubin concentration in blood serum is a better parameter to assess the risk caused by hyperbilirubemia in case of neonatal jaundice. ...
... The neurotoxicity of bilirubin is directly associated with the concentration of the fraction unbound to albumin (or other solubilizing substances), which is called Bf (bilirubin free) [13,14]. Bf is critically dependent on the presence of compounds that are potentially competing with bilirubin in binding to albumin [15]. Nothing is known about whether bilirubin PI may affect the bilirubin-albumin interaction. ...
Article
Full-text available
Although phototherapy was introduced as early as 1950's, the potential biological effects of bilirubin photoisomers (PI) generated during phototherapy remain unclear. The aim of our study was to isolate bilirubin PI in their pure forms and to assess their biological effects in vitro. The three major bilirubin PI (ZE- and EZ-bilirubin and Z-lumirubin) were prepared by photo-irradiation of unconjugated bilirubin. The individual photoproducts were chromatographically separated (TLC, HPLC), and their identities verified by mass spectrometry. The role of Z-lumirubin (the principle bilirubin PI) on the dissociation of bilirubin from albumin was tested by several methods: peroxidase, fluorescence quenching, and circular dichroism. The biological effects of major bilirubin PI (cell viability, expression of selected genes, cell cycle progression) were tested on the SH-SY5Y human neuroblastoma cell line. Lumirubin was found to have a binding site on human serum albumin, in the subdomain IB (or at a close distance to it); and thus, different from that of bilirubin. Its binding constant to albumin was much lower when compared with bilirubin, and lumirubin did not affect the level of unbound bilirubin (Bf). Compared to unconjugated bilirubin, bilirubin PI did not have any effect on either SH-SY5Y cell viability, the expression of genes involved in bilirubin metabolism or cell cycle progression, nor in modulation of the cell cycle phase. The principle bilirubin PI do not interfere with bilirubin albumin binding, and do not exert any toxic effect on human neuroblastoma cells.
... Very-low-density plasma lipoproteins are reported to reflect where lipids are stored, either in the liver or muscle [26]. With regard to bilirubin, unconjugated bilirubin, the predominant form in physiological conditions, is known to be ligated to albumin in mammals and with a high-density lipoprotein in Oncorhynchus keta (Walbaum, 1792) [1,28,29]. Accordingly, this reflects the relationship between TBIL and TPRO (they showed a strong linear correlation: Pearson's r, 0.566; p < 0.01) and, ultimately, Factor 1. ...
Article
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Clinical chemistry offers a valuable, affordable, moderately invasive, and nondisruptive way to assess animal physiological status and wellness within defined ranges and is widely used as a diagnostic clinical tool. Because of physiological differences between mammals, clinical correlates of blood chemistry variables are not known in detail in fish, in which tissue/organ function tests are inferred from mammal-derived clinical chemistry data. The aim of the present study was to apply exploratory factor analysis on a serum chemistry dataset from clinically healthy, reared rainbow trout Oncorhynchusmykiss (Walbaum, 1792) to select the most correlated variables and to test for possible underlying factors explaining the observed correlations as possible physiological status estimates in trout. The obtained factors were tested for correlation with hepatosomatic and splenosomatic indexes. Thirteen highly correlated variables were selected out of 18 original serum chemistry variables, and three underlying factors (Factors 1, 2, and 3) were identified that explained the observed correlations among variables. Moreover, Factor 1 correlated negatively with the hepatosomatic index and Factors 2 and 3 negatively with the splenosomatic index. The obtained factors were tentatively associated with: protein (liver) metabolism (Factor 1), cell turnover (Factor 2), and lipid (muscle) metabolism (Factor 3).
... In particular, the albumin binding of bilirubin is usually regarded as a critical factor in preventing kernicterus in newborns. 116 Bilirubin binding has been carefully investigated in a rat analbuminemic model where it was shown that lipoprotein-bilirubin binding could compensate for the albumin deficiency. 117 Analbuminemics provide inescapable evidence that either the functions of albumin are not critical to health or that these functions can be subsumed by other serum proteins. ...
Article
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David G Levitt,1,* Michael D Levitt2,* 1Department of Integrative Biology and Physiology, University of Minnesota, 2Research Service, Veterans Affairs Medical Center, Minneapolis, MN, USA *These authors contributed equally to this work Abstract: Serum albumin concentration (CP) is a remarkably strong prognostic indicator of morbidity and mortality in both sick and seemingly healthy subjects. Surprisingly, the specifics of the pathophysiology underlying the relationship between CP and ill-health are poorly understood. This review provides a summary that is not previously available in the literature, concerning how synthesis, catabolism, and renal and gastrointestinal clearance of albumin interact to bring about albumin homeostasis, with a focus on the clinical factors that influence this homeostasis. In normal humans, the albumin turnover time of about 25 days reflects a liver albumin synthesis rate of about 10.5 g/day balanced by renal (≈6%), gastrointestinal (≈10%), and catabolic (≈84%) clearances. The acute development of hypoalbuminemia with sepsis or trauma results from increased albumin capillary permeability leading to redistribution of albumin from the vascular to interstitial space. The best understood mechanism of chronic hypoalbuminemia is the decreased albumin synthesis observed in liver disease. Decreased albumin production also accounts for hypoalbuminemia observed with a low-protein and normal caloric diet. However, a calorie- and protein-deficient diet does not reduce albumin synthesis and is not associated with hypoalbuminemia, and CP is not a useful marker of malnutrition. In most disease states other than liver disease, albumin synthesis is normal or increased, and hypoalbuminemia reflects an enhanced rate of albumin turnover resulting either from an increased rate of catabolism (a poorly understood phenomenon) or enhanced loss of albumin into the urine (nephrosis) or intestine (protein-losing enteropathy). The latter may occur with subtle intestinal pathology and hence may be more prevalent than commonly appreciated. Clinically, reduced CP appears to be a result rather than a cause of ill-health, and therapy designed to increase CP has limited benefit. The ubiquitous occurrence of hypoalbuminemia in disease states limits the diagnostic utility of the CP measurement. Keywords: albumin, enteropathy, nephrosis, cirrhosis, malnutrition, clearance, synthesis
... The alternative to indomethacin, ibuprofen, was initially thought to have fewer adverse effects than indomethacin (65). However, this treatment was later found to be associated with an increased risk of chronic lung disease, pulmonary hypertension (66) and kernicterus (67). Ibuprofen interferes with bilirubin-albumin and increases the unbound bilirubin in pooled newborn plasma. ...
... UTI increases bilirubin load by causing hemolysis in erythrocytes, and causes hyperbilirubinemia by decreasing conjugation in the liver, and decreasing excretion of bilirubin [11]. In some studies, the prevalence of UTI in prolonged jaundice was as low as 5-10%, while it was found to be higher as 15-36% in other studies [1,8,[12][13][14][15][16][17]. ...
Article
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Objectives: Prolonged jaundice is a common condition among neonates. İt is defined as persisting hyperbilirubinemia after the 14th day following birth for term babies and after the 21st day for premature babies with serum bilirubin level higher than 5mg/dL. Prolonged unconjugated hyperbilirubinemia may be associated with some pathological conditions. We aimed to evaluate the etiological, clinical and laboratory findings of babies with prolonged jaundice. Methods: This descriptive cross-sectional study included 90 infants with prolonged jaundice in the pediatric outpatient clinic of Ordu University Training and Research Hospital between 1 January 2015 and 1 October 2020. Demographic characteristics, physical examination and laboratory findings of the babies were collected and analyzed to determine the etiology of neonatal hyperbilirubinemia. Results: In total 90 infants with prolonged jaundice were presented in this study, including 50 male and 40 female neonates. The most common causes of prolonged neonatal jaundice were breastfeeding, Rh or ABO incompatibility, and urinary tract infection 73%, 13% and 8% of neonates, respectively. Conclusion: Breast milk jaundice is the most common cause of prolonged jaundice in infants. Although there are some explanations for breast milk jaundice, the exact mechanism leading to breast milk jaundice is not clear. Other reasons that may affect the infants later in life should be investigated in a short time.
Chapter
Bilirubin, a degradation product of heme, circulates bound to albumin, from which it is extracted in the liver. It is translocated from blood to bile by a multistep process involving hepatocellular uptake, intracellular binding, conjugation with glucuronic acid, and active transport into bile. Hyperbilirubinemias are predominantly unconjugated, mainly conjugated, or mixed. Those with normal common liver function tests are often familial and benign; abnormalities of other hepatic tests suggest a condition with potentially serious sequelae. Studies of familial hyperbilirubinemias have identified specific proteins and pathways essential for normal liver function, including bilirubin transport and metabolism. Mutations in particular proteins underlie four of the five familial hyperbilirubinemias: the Gilbert, Crigler–Najjar types 1 and 2, and Dubin–Johnson syndromes. The basis for Rotor syndrome remains unknown. Many different mutations in three protein components of the canalicular bile secretory apparatus are likewise the basis for several familial cholestasis syndromes.
Article
Hyperbilirubinemia is the most common condition requiring evaluation and treatment in newborns. The clinical manifestation of hyperbilirubinemia-jaundice-occurs in 60% of normal newborns and nearly all preterm infants. Compared with conditions that require advanced pharmacologic and technologic treatment strategies, hyperbilirubinemia seems to be overshadowed and may lose the attention it deserves as a condition that has potentially devastating effects. Nurses must be vigilant when caring for babies with "just jaundice" by monitoring bilirubin levels, identifying infants at risk for developing severe hyperbilirubinemia, and implementing prescribed treatment effectively when indicated.
Unconjugated hyperbilirubinaemia occurs in almost all premature infants and is potentially neurotoxic. Treatment is based on total serum bilirubin (TSB), but treatment thresholds are not evidence based. Free bilirubin (Bf)-that is, not bound to albumin, seems a better parameter for bilirubin neurotoxicity, but measurements of Bf are not available in clinical practice. The bilirubin/albumin (B/A) ratio is considered a surrogate parameter for Bf and an interesting additional parameter in the management of hyperbilirubinaemia. This paper reviewed the evidence supporting the use of B/A ratios for predicting bilirubin-induced neurological dysfunction (BIND) including neurodevelopmental delay in jaundiced premature infants (gestational age less than 32 weeks). A literature search was performed and six publications reviewed regarding B/A ratios in the management and outcome of jaundiced premature infants. No prospective clinical trials had been undertaken to show whether bilirubin-induced neurotoxicity is reduced or whether unnecessary treatment is avoided by using the B/A ratio in addition to TSB. Recently, a randomised controlled trial evaluating the effect of the additional use of the B/A ratio on neurodevelopmental outcome in jaundiced premature infants has been initiated. Based on the prevailing evidence many authorities suggest that the additional use of the B/A ratio may be valuable when evaluating jaundiced premature infants.
Article
The unbound "free" bilirubin concentration (Bf), not the total bilirubin concentration, is the critical determinant of cellular uptake and toxicity of bilirubin. We compared Bf measured by a modified peroxidase method with published data obtained with ultrafiltration and examined conditions that affect the affinity (KF) of human (HSA) and bovine (BSA) serum albumin for bilirubin. The peroxidase and ultrafiltration methods yielded similar KF values that decreased with increasing HSA concentration and the presence of 50 mM chloride. When related to ionic strength, inhibition of BSA-bilirubin binding by chloride, bromide, and sulfate were similar, whereas phosphate buffer had a smaller effect. KF was lower at 37 degrees C than at 25 degrees C for HSA but not for BSA. KF for BSA was similar at pH 7.4 and 8.0. BSA and FCS had similar binding properties. The close agreement of Bf and KF values determined by the peroxidase method with published results obtained by ultrafiltration validates both methods and supports the use of the peroxidase method as a practical technique for measuring Bf under steady state conditions in minimally diluted serum or culture medium.
Article
We sought to evaluate the sensitivity and specificity of total serum bilirubin concentration (TSB) and free (unbound) bilirubin concentration (Bf) as predictors of risk for bilirubin toxicity and kernicterus and to examine consistency between these findings and proposed mechanisms of bilirubin transport and brain uptake. A review of literature was undertaken to define basic principles of bilirubin transport and brain uptake leading to neurotoxicity. We then reviewed experimental and clinical evidence that relate TSB or Bf to risk for bilirubin toxicity and kernicterus. There are insufficient published data to precisely define sensitivity and specificity of either TSB or Bf in determining risk for acute bilirubin neurotoxicity or chronic sequelae (kernicterus). However, available laboratory and clinical evidence indicate that Bf is better than TSB in discriminating risk for bilirubin toxicity in patients with severe hyperbilirubinemia. These findings are consistent with basic pharmacokinetic principles involved in bilirubin transport and tissue uptake. Experimental and clinical data strongly suggest that measurement of Bf in newborns with hyperbilirubinemia will improve risk assessment for neurotoxicity, which emphasizes the need for additional clinical evaluation relating Bf and TSB to acute bilirubin toxicity and long-term outcome. We speculate that establishing risk thresholds for neurotoxicity by using newer methods for measuring Bf in minimally diluted serum samples will improve the sensitivity and specificity of serum indicators for treating hyperbilirubinemia, thus reducing unnecessary aggressive intervention and associated cost and morbidity.
Article
Neonatal jaundice is common, and usually harmless, because of physiological jaundice or breast-feeding. In some neonates unconjugated bilirubin concentration, coupled with other risk factors, is sufficient to allow free bilirubin to cross the blood-brain barrier and cause kernicterus. Another subgroup of infants is jaundiced because of elevated conjugated bilirubin; a marker for a number of pathological conditions. Bilirubin measurement must identify those infants at risk. Transcutaneous bilirubin measurement is increasingly used in healthy infants, especially before early discharge or at home, to assess the need for laboratory bilirubin measurement. Transcutaneous measurements are not covered by laboratory quality assessment schemes. Guidelines on management of neonatal jaundice utilize age in hours and other risk factors to define bilirubin action thresholds, which may be as low as 100 micromol/L for sick premature infants, whereas early discharged babies may only present after bilirubin concentrations are extremely high. Hence, there is a requirement for accurate total bilirubin measurement from <100 to >500 micromol/L, with sufficient precision to assess the rate of bilirubin change with time. Babies presenting with late jaundice always require conjugated bilirubin measurement. It is of concern that many total and direct bilirubin automated kit methods suffer from haemolysis interference, while use of in-house methods or modification of commercial methods has virtually disappeared. External quality assessment has a vital role in providing data on different methods' performance, including accuracy, precision and susceptibility to interference. Laboratories should consider whether their adult bilirubin methods are suitable for neonates.
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The present study aimed to investigate the relationship between gestational age and increased incidence of jaundice congenital or so-called disease, yellowing of the skin in newborns, and its relationship to other causes leading to increased incidence of infection and their negative impact on children's health. The study was conducted at Al Zahra Hospital education for the birth and children in the province of Najaf since 08/01/2010 until 30/10/2010. The study included follow-up (80) The situation of newborn children of both sexes(male 54, female 26) aged (1 day to 10 days) with neonatal jaundice early and admitted to the Division of preterm infants at home. With the knowledge that children do not suffer from any medical condition, diseases such as liver, anemia, and others. After the cases were divided into groups according to gender, gestational age and weight, where comparison is made between these groups Revealed statistical analysis of the results of this study there is high significant (p <0.05) in the incidence of jaundice congenital in males 67.5% when compared with females 32.5%, was , also found high significant (p <0.05) in concentration of total bilirubin in males , but zero, the differences of the moral (p> 0.05) in pcv, weight and gestational age in patients with congenital jaundice in both sexes. The results also show a significant increase (p <0.05) in the incidence of neonatal jaundice between the groups was gestational age and gaze at the gestational age of at least 36 weeks (52.5%), which included each of the two groups (28-31) and (32-35) as reached (12.5% and 40%) when compared with gestational age (36-39) hit (47.5%), respectively, has shown a rise was not significant in the concentration of total bilirubin in gestational age (32-35) when compared with gestational age (28-31) and (36-39) hit (4.07 ± 18.13), (3.64 ± 15.12) and (3.12 ± 15.81) respectively, also made findings that there was no significant differences in pcv for both groups, respectivelyWhile statistical analysis pointed to the existence of a significant reduction in weight for the same gestational age groups was above the gestational age (28-31), amounting to 0.45 ± 1.92)) when compared with gestational age (32-35) and (36-39), where reached values (0.48 ± 2.62) and (0.58 ± 2.78), respectively, but it is not clear any significant difference between the last two sets. The results indicated the relationship between weight and the incidence of jaundice congenital to the presence of high moral in the incidence of jaundice congenital between the totals of weight increase was evident in the group at least (3> kg), which included each of the two groups (1 - 1.9) and (2 - 2.9) it reached (15% and 48.75%) when compared with the group (3>) where was (36.25%), as indicated by statistical analysis of the presence of elevated significantly in the concentration of total bilirubin between the totals of the weights and was above the group (2 - 2.9), amounting to ( 4.14 ± 17.20) when compared with the group (1 - 1.9) and (3>), which amounted to (3.40 ± 15.40) and (3.28 ± 16.44), respectively, did not show any significant differences in the pcv of the groups themselves.
Article
JPER is a multi-disciplinary journal that promotes the health of the preterm infant.
Article
Ibuprofen binds to plasma albumin and could interfere with the binding of bilirubin in jaundiced newborn infants. Most clinical studies have not shown increased concentrations of unbound bilirubin (UB) in plasma from infants treated with ibuprofen for a patent ductus arteriosus. However, studies in vitro have not been equally conclusive. Plasma were obtained from routine samples from jaundiced newborn infants and pooled. Total and UB were measured with the peroxidase method after addition of ibuprofen or sulfisoxazole as a known bilirubin displacer. Final ibuprofen concentrations varied from 0.43 to 2.6 mM. Bilirubin concentrations were varied from 176 to 708 microM by adding bilirubin to plasma samples. Ibuprofen caused a linear increase in UB up to +54% at a concentration of 1.8 mM, compared with an increase of 87% by sulfisoxazole (1.32 mM). A double reciprocal plot of molar concentrations of bound versus UB at bilirubin concentrations ranging from 176 to 708 microM showed a competitive displacement of bilirubin by ibuprofen. The data indicate that ibuprofen is a competitive displacer of bilirubin in vitro. Ibuprofen should be used with caution in premature infants with a significant hyperbilirubinemia.
Article
Objective To provide descriptive data on serum albumin levels and the bilirubin to albumin (B/A) ratio in neonates admitted to the neonatal intensive care unit, assess the effect of gestational and chronological age on serum albumin and the B/A ratio, and evaluate the association between extreme values and mortality. Study design Using a retrospective cohort design, we queried the Pediatrix clinical data warehouse for all infants born between 23 and 41 weeks of gestation from 1997 to 2014 who had a report of both a serum albumin and total serum bilirubin (TSB) level on the same day between birth and 14 days of life. Results There were 382 190 paired albumin and bilirubin levels across 164 401 neonates (15% of the 1 072 682 infants in the clinical data warehouse). Both gestational age and postnatal age were independent factors that influenced the values for serum albumin, TSB, and B/A ratio (ANOVA; P < .0001). TSB and B/A ratios values above birth weight–specific thresholds for exchange transfusions were uncommon (<6% of infants). Hypoalbuminemia (<2.5 mg/dL) was common (29% of infants). Neonates with serum albumin levels <2.5 g/dL or with B/A ratio levels exceeding exchange thresholds were at higher risk of death compared with infants who did not exceed these levels. This association was independent of other risk factors (estimated gestational age, birth weight, sex, and the presence of a major anomaly). Conclusion Both gestational age and postnatal age influence TSB, albumin, and B/A ratios; hypoalbuminemia and extreme B/A ratios are associated with an increased risk of death.
Article
Perinatal injury, prematurity, and/or congenital anomalies inflict profound long– and short–term physical, psychological, emotional, social, and financial stresses on survivors, their families, and society. Both the Annual Summary of Vital Statistics: 2007 and the National Vital Statistics Reports (April 30, 2010) list "disorders relating to short gestation and low birth weight" as the second leading cause (16–17 %) of infant death, second only to congenital malformations, deformations, and chromosomal abnormalities (19.7–21 %). In 2011, 11.7 % of the 3.95 million live births (or 462,570) were preterm (<37 weeks gestation), 8.1 % (320,241) were low birth weight (<2,500 g), and 1.44 % (56,932) were very low birth weight (<1,500 g) in the United States. In that year, two-thirds of the 23,910 infants who died (infant mortality was 6.05 per 1000 live births) died in the neonatal period, and 45 % died as a result of congenital or chromosomal abnormalities (21 %), preterm age or low birth weight (17 %), and sudden infant death syndrome (7 %). In 2006, 54 % of all infant deaths occurred in the 2 % of infants born less than 32 weeks gestation; 36 % of infant deaths were "preterm related" (Heron M et al. Pediatrics 125(1): 4–15, 2010)
Article
The aim of the present study was to clarify the in vitro potential of the purified Chinese herbal constituents LZX-A (neferine), QTJ (sinomenine), YHS (tetrahydropalmitine) and SQZG (notoginsenoside R1) to displace the highly bound bilirubin from albumin binding sites in plasma from jaundiced newborn infants. Sulfisoxazole (1.32 mM) was used as a positive control for bilirubin displacement. The displacing potential of the herbal constituents was investigated at assumed therapeutic concentrations and up to 100 times higher. Total (TB) and unbound (UB) bilirubin in plasma were measured by the peroxidase method. Sulfisoxazole increased the UB concentration in plasma by more than 60%. An increased % displacement of bilirubin was found at higher TB levels confirming the presence also of lower affinity binding sites for bilirubin in plasma. None of the purified herbal constituents showed any bilirubin displacing properties and were unaffected by the level of TB in plasma. The combination of sulfisoxazole and the herbal constituents showed no synergistic effect. It is concluded that none of the investigated purified herbal constituents possess any significant potential in vitro to increase the UB concentration in plasma from jaundiced newborn infants.
Article
Introduction: The detection, assessment, understanding and prevention of adverse drug reactions (ADRs) are the primary aims of pharmacovigilance activities. Pediatric patients, especially all newborns and infants, are particularly at risk for experiencing drug-related adverse events. Areas covered: This review briefly analyzes the physiological peculiarities of pharmacodynamic and pharmacokinetic aspects of drugs in newborns, infants and toddlers and children. It also deals with specific pediatric pharmacovigilance aspects, such as the frequent use of unlicensed and/or off-label drugs in neonatal intensive care units in European countries and in Australia. This review reports on European, American and Canadian data about the incidence and type of pediatric ADRs, particularly focusing on neonates, infants and toddlers. Expert opinion: The awareness of pediatricians about the importance of reporting ADRs should be stimulated, new reporting systems should be encouraged and pediatric pharmacovigilance activities should be improved, first, by intensifying active post-marketing surveillance methods.
Article
Background: Hyperbilirubinemia guidelines are based on total serum bilirubin (TSB), in combination with either gestational age (GA) or birth weight (BW), postnatal age and specific risk factors. However, TSB is a poor predictor of bilirubin-induced neurotoxicity (BIND). Free unconjugated bilirubin (UCBfree) and the UCBfree/TSB ratio are more directly related to BIND, but data on their postnatal courses are unknown. Aims: To characterize the postnatal courses of UCBfree and UCBfree/TSB ratio, and assess their relationships with clinical characteristics. Subjects: 72 preterm infants≤32weeks GA, admitted to the University Medical Center Groningen, The Netherlands. Study design: During the first postnatal week, bilirubin plasma parameters were analyzed and their relationship with clinical parameters was analyzed. Postnatal changes were analyzed using Generalized Estimating Equations. Data are expressed as medians [ranges]. Results: Less than 10% of the cohort (GA: 29 [26-31] weeks; BW: 1165 [600-1975] g) showed hyperbilirubinemic risk factors. We observed a large variation in UCBfree (27 [1-197] nmol/L), that could partly be explained by postnatal age and gender, but not by other risk factors. Maximal UCBfree levels of 50 [13-197] nmol/L occurred at day 4 and were higher in males. In contrast to TSB, UCBfree/TSB ratios (0.19 [0.01-1.04]) were higher in infants with low GA/BW. Conclusion: UCBfree levels vary considerably in preterm infants, despite a low incidence of hyperbilirubinemic risk factors and similar TSB-based phototherapy treatment. UCBfree could not be predicted by GA or BW, but UCBfree/TSB ratios are highest in the smallest preterms, while they have the lowest TSB levels.
Chapter
Human serum albumin (HSA) is known to bind a broad spectrum of endogenous and exogenous substances. The ligand-binding property of albumin has been utilized to remove endogenous toxins in extracorporeal blood detoxification methods such as single-pass albumin dialysis (SPAD), fractionated plasma separation and adsorption (FPSA), Prometheus®, and molecular adsorbent recirculating system (MARS). Production of recombinant HSA including individual domains has been successfully attempted by a number of researchers. The albumin domains retain similar structural characteristics of the HSA. The ligand-binding properties of albumin domains are identical to those of HSA but with lower binding affinity and percentage for most of the ligands studied. The albumin domains have an increased elimination profile compared to that of the HSA. Molecular modification of the albumin domains through site-directed mutagenesis for strengthening toxin binding is a feasible approach for improving the efficiency and effectiveness of blood detoxification treatment.
Article
A 36-week gestation newborn was admitted to the neonatal intensive care unit for treatment of primary pulmonary hypertension and possible sepsis. The infant developed hyperbilirubinemia on day 4 of life and peaked on day 5 at a total serum bilirubin of 19 mg/dL. Phototherapy was started on day 4 and continued for 5 days. On day 8 of life, ibuprofen was started for fever; a concurrent total serum bilirubin was 15.7 mg/dL. The subsequent hospital course was uneventful, and discharge occurred on day 22 of life. Because the patient failed a hearing screen at discharge, he was referred for a diagnostic audiology workup. He subsequently failed formal audiometric testing on two occasions one week apart, and was given a diagnosis of auditory dys-synchrony and/or auditory neuropathy, consistent with kernicterus. At 5½ months of age, he was reported to be hypotonic and to have frequent arching movements. Since the total serum bilirubin did not exceed 19 mg/dL, concern was raised that ibuprofen may have caused displacement of bilirubin from its albumin binding site, resulting in kernicterus due to excessive unbound bilirubin concentrations. Ibuprofen should be administered with caution in preterm infants at risk for kernicterus.
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Background: Severe neonatal hyperbilirubinemia, with consequent encephalopathy, remains a common cause of morbidity and death in many regions of the world. Poor access to clinical laboratory resources and screening programs to measure plasma bilirubin levels is a major contributor to delayed treatment in developing countries, and the cost of existing point-of-care screening instruments precludes their dissemination. Objectives: We are evaluating the accuracy of a low-cost, minimally invasive point-of-care system (Bilistick) requiring a 25-µl blood sample that could be used in low-resource environments to evaluate patients with neonatal jaundice. Methods: We compared plasma bilirubin levels in divided blood samples by clinical laboratories and by Bilistick at two medical centers serving term and near-term newborns from ethnically different populations. Results: 118 neonates with bilirubin levels ranging from 24.8 to 501.0 µmol/l were analyzed. The mean bilirubin concentration (±SD) was 215.6 ± 85.5 µmol/l for Bilistick and 226.1 ± 86.4 µmol/l by laboratory determination. Pearson's correlation coefficient between all paired results was 0.961, and the Bland-Altman analysis showed a mean difference of 10.3 µmol/l with a 95% interval of agreement of -38.0 to 58.7 µmol/l. Conclusion: Bilistick is a minimally invasive method for measuring total bilirubin concentration over a wide range of values and should provide an affordable and accurate system for pre-discharge and follow-up screening of jaundiced infants, particularly in low-resource environments.
Article
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Cleavage of the alpha-methene bridge of heme by membrane-bound heme oxygenase yields equimolar amounts of biliverdin, carbon monoxide, and reduced iron. Biliverdin is catalyzed by biliverdin reductase to bilirubin. The process occurs in all nucleated cells except mature anucleated red blood cells. Neonates in whom bilirubin production is increased tend to have higher bilirubin concentrations, and excessive bilirubin production or impairment of elimination causes dramatic deviations from the hour-specific nomogram that can be seen as “jumping” percentile tracks early in the postnatal period or later in the first week after birth. After formation, bilirubin diffuses into the circulation. In the absence of conjugates, the total bilirubin concentration in plasma is the sum of bilirubin bound to albumin plus a minimal amount of free bilirubin. Bilirubin is excreted more slowly in newborns than in adults. Although no clinical tests can measure bilirubin uptake and conjugation by the liver, an elevated hour-specific total bilirubin value when bilirubin production is normal or decreasing is a sign of impaired or abnormally delayed bilirubin excretion. The accuracy and precision of clinical laboratory total bilirubin measurements are a concern, and studies are underway to assess whether measurements of free bilirubin, the bilirubin-binding constant, the bilirubin:albumin ratio, or albumin binding capacity might improve the ability to identify infants at greater risk for bilirubin-induced neuroinjury rather than simply those at greater risk for having a higher bilirubin concentration.
Article
The clinical impact of bilirubin on collagen is investigated using various physical, chemical and biological methods. Thermo gravimetric analysis and differential scanning analysis of collagen-bilirubin complex matrices indicate that crosslinking does not alter their thermal behavior of collagen. The polydispersity of collagen-bilirubin complex increases in the reacting medium suggesting that there is an increase in the number of interacting points between them. Based on the zeta potential values, the rate of mobility of interacted complex decreases by inferring the extent of binding compared to the control collagen. Emission intensity begins to increase with increase in concentration of bilirubin which ascribes the conformational changes around the aromatic amino acids in collagen. Binding is indicated by an increase in resonance units and the responses are corrected by subtraction of those obtained for native collagen. Bilirubin showed a higher affinity for collagen at a concentration of about 25nM/mg. In this study, the association rate has been calculated which depicts the increased affinity of bilirubin to collagen. Affinity for bilirubin to collagen has been found to be 8.89×10(-3)s(-1). The greater part of binding of bilirubin to collagen is found to be electrostatic in nature. The investigation leads to comprehend the affinity of collagen-bilirubin complex during jaundice diseased tissues.
Chapter
This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the effects of pre-exchange albumin infusion on the frequency and severity of hyperbilirubinaemia, long-term neurodevelopmental outcomes, complications of exchange transfusion; and to determine the adverse effects of pre-exchange albumin infusion in infants with hyperbilirubinaemia requiring exchange transfusion. Primary comparisons • Pre-exchange albumin infusion plus exchange transfusion versus exchange transfusion alone. Phototherapy may or may not be given in the trials. • Subgroup analyses based on gestational age (term infant (≥ 37 weeks) versus preterm infant (< 37 weeks)), causes of jaundice (haemolytic disease versus non-haemolytic disease), dose of albumin, volume of exchange transfusion, and associated medical therapy (phototherapy, metalloporphyrins, barbiturates, charcoal, cholestyramine, clofibrate, D-penicillamine, glycerin, manna, riboflavin, traditional Chinese medicine, homeopathy and agar, which are used before albumin infusion).
Chapter
In the 19th century it was already known that unconjugated hyperbilirubinemia could potentially harm the central nervous system of jaundiced newborn infants. Yellow staining of deep brain nuclei in jaundiced infants was first reported in 1847. The term kernicterus (in German, kern = nucleus; in Greek, ikterus = yellow) was first denoted in 1903 to describe the pathological findings of this specific yellow staining pattern [1]. Nowadays, kernicterus is not only used to describe the pathological findings, but also to describe the clinical findings of acute and/or chronic bilirubin encephalopathy in jaundiced infants [2, 3]. Although acute kernicterus is an unambiguous clinical disorder in severely jaundiced newborn infants with the possibility of permanent sequelae, subtle forms of bilirubin encephalopathy referred to as bilirubin-induced neurological dysfunction, also known as BIND have evolved more recently [4]. This chapter aims to describe the pathophysiology of bilirubin neurotoxicity, its clinical spectrum and diagnostic tools. Novel treatment modalities to prevent infants from developing severe unconjugated hyperbilirubinemia and bilirubin neurotoxicity will be highlighted.
Article
Background: Jaundice is the quite common benign condition in neonates, but due to its potential toxicity, neonates must be monitored. This study was aimed to evaluate the effect of serum albumin level on the transcutaneous bilirubin (TcB) measurements in term neonates with unconjugated hyperbilirubinemia. Methods: Serum albumin and total serum bilirubin (TSB) of 252 jaundiced term neonates were estimated and simultaneously TcB was measured over sternum and the effect of serum albumin on TcB measurements was evaluated. Results: The correlation between TSB and TcB was linear and significant for the entire cohort. When this correlation was studied separately in the groups with different albumin levels, maximum correlation (r = 0.888, R2 linear = 0.789, p < 0.001) was observed in group 1 with hypo-albuminemia followed by in group 2 with normal albumin levels (r = 0.854, R2 linear = 0.729, p < 0.001) and group 3 with higher albumin levels (r = 0.809, R2 linear = 0.689, p < 0.001). Bland-Altman plot analysis of whole study population demonstrate good agreement between TSB and TcB [95% CI = -0.038 to 0.493 mg/dL, 17/252 = 6.75% outside the limits of agreement, Mean difference = 0.227]. This analysis in different groups also show good agreement between TSB and TcB. Conclusions: The correlation between the TSB and TcB may affected by serum albumin level. Therefore, transcutaneous bilirubinometry is not able to replace invasive TSB measurement. However, in the absence of TSB it could be an alternative to measure the level of bilirubin in term neonates.
Article
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A potential animal model of kernicterus has been developed. The blood-brain barrier was opened on one side of the brain, by brief infusion of a hypertonic solution into the carotid artery. Upon peripheral infusion of bilirubin, the animals developed unilateral yellow staining of the brain: the treated side was stained whereas the control side was not. This cerebral icterus resulted from the entry of albumin-bound bilirubin into the brain, and not from the passage of free bilirubin.
Article
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A previously reported patient with analbuminemia was re-investigated after 4 1/2 years, at age 6. The serum albumin concentration was 150 mg/L by radioimmunoassay. Most of the observed increase in total plasma protein over the 4 1/2 years was attributable to gamma-globulin. Concentrations of total and high-density lipoprotein cholesterol were increased; the esterified:free ratio and the lecithin-cholesterol acyltransferase activity were both normal. Albumin is apparently not essential for binding of lysolecithin generated by the acyltransferase-catalyzed reaction. The binding of bromphenol blue suggested that analbuminemic serum has about 25% of normal binding capacity for bilirubin (more than expected in a patient with analbuminemia), which may explain why newborns with this disorder do not develop kernicterus. Binding by the patient's plasma of diazepam (1020 mg/L) and warfarin (1040 mg/L), which bind primarily to albumin, as well as of propranolol (1.05 g/L), which binds primarily to alpha 1-acid glycoprotein, was also studied. The proportions of free diazepam (14.4%) and warfarin (4.8%) were about 10-fold normal. In contrast, the proportion of propranolol in the free form was decreased (4.5%). Evidently, other plasma proteins are partly compensating for the deficiency of albumin.
Article
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Albumin binding is a crucial determinant of bilirubin clearance in health and bilirubin toxicity in certain disease states. However, prior attempts to measure the affinity of albumin for bilirubin have yielded highly variable results, reflecting both differing conditions and the confounding influence of impurities. We therefore have devised a method based on serial ultrafiltration that successively removes impurities in [14C]bilirubin until a stable binding affinity is achieved, and then we used it to assess the effect of albumin concentration and buffer composition on binding. The apparent binding affinity of human serum albumin for [14C]bilirubin was strongly dependent on assay conditions, falling from (5.09 ± 0.24) × 107liters/mol at lower albumin concentrations (15 μm) to (0.54 ± 0.05) × 107 liters/mol at higher albumin concentrations (300 μm). To determine whether radioactive impurities were responsible for this change, we estimated impurities in the stock bilirubin using a novel modeling approach and found them to be 0.11–0.13%. Formation of new impurities during the study and their affinity for albumin were also estimated. After correction for impurities, the binding affinity remained heavily dependent on the albumin concentration (range (5.37 ± 0.26) × 107 liters/mol to (0.65 ± 0.03) × 107 liters/mol). Affinities decreased by about half in the presence of chloride (50 mm). Thus, the affinity of human albumin for bilirubin is not constant, but varies with both albumin concentration and buffer composition. Binding may be considerably less avid at physiological albumin concentrations than previously believed.
Article
Standard recommendations for evaluating and treating jaundice in term babies include following all babies closely for jaundice, obtaining several laboratory tests in those with early jaundice or bilirubin levels more than 12 to 13 mg/dL (205 to 222 µmol/L), using phototherapy to try to keep bilirubin levels below 20 mg/dL (342 µmol/L), and doing exchange transfusions if phototherapy fails, regardless of the cause of the jaundice. These recommendations are likely to lead to unnecessary testing and treatment of many jaundiced term infants. Because most jaundiced infants have no underlying illness, and the generally recommended laboratory tests lack sensitivity and specificity, they are seldom useful. In most babies, the only blood tests needed to evaluate jaundice are the blood type and group (of baby and mother) and a direct Coombs' test. A determination of direct bilirubin level should be added if jaundice is prolonged (>2 to 4 weeks) or the baby has other signs of illness. Bilirubin toxicity is rare in term babies without hemolysis. In this low-risk group, the risks and cost of identifying and treating high bilirubin levels may exceed the benefits. Such infants need not be closely followed for jaundice. If significant jaundice is nonetheless found, treatment should be deferred to relatively high levels of serum bilirubin, with a goal of keeping bilirubin levels below 400 to 500 µmol/L (23.4 to 29.2 mg/dL). Babies with hemolytic disease should be followed more closely, and their bilirubin levels kept below 300 to 400 µmol/L (17.5 to 23.4 mg/dL). These recommendations should be reevaluated as new data become available. In the meantime, currently available data justify an approach to the jaundiced term infant that is less aggressive than previously recommended.
Article
We have presented the experience of an exchange transfusion service in performing 1,139 procedures over a 7-year period. The design and practices of this service have been described in order to provide the background necessary for a critical analysis of our results. Since no definition exists for "Mortality of Exchange Transfusion," we have suggested one. The outstanding features of this experience were: 1. The umbilical vein approach proved to be an extremely easy technique by which to initiate an exchange transfusion. 2. The great majority of the procedures were completed as planned. 3. In all but a very few exchange transfusions, a volume of donor blood at least 1.5 times the infant's blood volume was infused. We could show no correlations between the volume of donor blood employed in an initial procedure and the need for a repeat exchange. 4. Most of our exchange transfusions were completed in less than 1 hour; many in less than 30 minutes. We were unable to demonstrate a higher morbidity or mortality in infants being subjected to a faster as opposed to a slower procedure. 5. The best definition of the mortality rate of exchange transfusion appears to be the number of infants dying during or within 6 hours of a procedure expressed as a percentage of the number of infants transfused and again as a percentage of the number of exchange transfusions performed. 6. The incidence of death during or within 6 hours of an exchange transfusion appeared to be more closely related to an infant's clinical status at the beginning of a procedure then to the procedure itself. Most of the deaths occurred among critically ill infants with Rh-hemolytic disease. Vigorous infants, full-term or premature, regardless of diagnosis, tolerated exchange transfusions well. Our mortality rate in vigorous infants was very low.
Article
What to do for the low-birth-weight jaundiced neonate has been a subject of debate for 30 years. It is generally agreed that the "20 mg/100 ml level" for an exchange transfusion in a full-term infant with hemolytic disease, has been effective in avoiding deaths due to kernicterus and brain damage due to bilirubin neurotoxicity. It's not perfect, but it has been effective. This is amazing because the original studies, judged by modern standards, would not be acceptable today.1 Trouble first began when this concept was extended to jaundiced low-birth-weight infants. It was assumed that "the level" should be lower in smaller infants.
Article
In July 2003, the National Institute of Child Health and Human Development convened a conference, Research on Prevention of Bilirubin-Induced Brain Injury and Kernicterus: Bench-to-Bedside. This article will provide a summary of presentations and discussions from this conference. The summary will focus on the identified knowledge gaps in 5 areas related to bilirubin-induced brain injury and kernicterus: 1) neuro-biology and neuroimaging; 2) epidemiology and issues of clinical management; 3) methodologies for assessing clinical jaundice and direct and noninvasive measurement of serum bilirubin and hemolysis; 4) therapies for management of neonatal hyperbilirubinemia; and 5) public health surveillance and systems-based approaches to prevention.
This paper describes the occurrence of kernicterus and factors which influence its development in the strain of rats * first studied by Gunn.22,23 The disease of humans designated in 1903 by Schmorl39 as kernicterus has, in our opinion, not been observed or induced in its entirety in animals. Various workers, however, have demonstrated the toxicity of indirect bilirubin.12-15,24,26,44-46 Ernster, Herlin, and Zetterström21 have caused localized pigmentation of the brain of the rabbit by treatment with bilirubin and an S-H blocking agent. Other workers17,19,20 have reported injury of brain tissue in hemolytic anemia of animals, a phenomenon not directly related to the present report, since the rats to be described do not suffer from antibody-antigen disease and have little or no hemolytic Definition of Kernicterus The following criteria are proposed as defining kernicterus: Distinctive evidence of central nervous system dysfunction during life in jaundiced subjects Canary yellow
Article
In a study of 1000 newborns jaundice of unknown aetiology was a common finding during the first week of life. In these children the bilirubin values were as follows: ≥ 10 mg% in 26 % ≥ 20 mg% in 6 % It is known from the literature that there is a causal relationship between severe jaundice occurring in the first week of lie and the subsequent development of athetosis. By carrying out exchange transfusion on children with a serum bili-rubin value of ≥ 20 mg%, and comparing the number with the frequency of athetosis reported in the literature, it is shown that the following will be exchange transfused: (a) 2140 full-term babies in order to prevent subsequent athetesis in one, but one runs the risk of 21 dying as a result of the procedure itself. (b) 92 premature infants to prevent subsequent athetosis in one, but one runs the risk of 4 dying as a result of the procedure. The limit of 20 mg% is thus not appropriate. Through systematic investigetions must be found better criteria for exchange transfusing newborn with jaundice of unknown aetiology. As opposed to this, the criteria for exchange transfusing Rhesus sensitised children are satisfactory. Admittedly it is unnecessary in the case of 44 out of every 100 children but, on the other hand, 56 will be saved from death or kernicterus, with the risk of death due to the procedure in only one case.
Article
In a study of 1000 newborns jaundice of unknown aetiology was a common finding during the first week of life. In these children the bilirubin values were as follows: ≤10 mg%in 26%of full-term 62%of premature ≤20 mg%in 6%of full-term 11%of premature It is known from the the literature that there is a causal relationship between severe jaundice occurring in the first week of life and the subsequent development of athetosis. By carrying out exchange transfusion on children with a serum bilirubin value of ≤20%, and comparing the number with frequency of athetosis reported in the literature, it is shown that the following will be exchange transfused: (a) 2140 full-term babies in order to prevent subsequent atheticsis in one, but one runs the risk of 21 dying as a result of the procedure itself. (b)92 premature infants to prevent subsequent athetosis in one, but one runs the risk of 4 dying as a result of the procedure. The limit of 20 mg%is thus not appropriate. Through systematic investigations must be found better criteria for exchange transusing new born with jaundice of unknown aetiology. As opposed to this, the criteria for exchange transfusing Rhesus sensitised children are satisfactory. Admittedly it is unnecessary in the case of 44 out of every 100 children but, on the other hand, 56 will be saved from death or kernicterus, with the risk of death due to the procedure in only one case.
Article
Fluid manipulation technologies are being invented and reinvented as researchers explore old and new approaches to automating wet chemical analysis. Most of these established techniques focus on the physical processes utilized, e.g. separation, dispersion, affinity, etc. In this paper, the focus is directed on techniques and procedures for manipulating specific fluid zones. A simple but versatile flow manifold is proposed. Examples are described that illustrate the breadth of manipulation capabilities that emerge. It is anticipated that as researchers adopt this mindset, new avenues will emerge for the established fluid manipulation technologies. We call this approach to flow-based analysis Zone Fluidics.
Article
The bilirubin-binding ability of neonatal serum was measured and compared with the serum bilirubin concentration and the serum bilirubin/albumin ratio. The bilirubin/albumin ratio correlated no better with the bilirubin-binding ability than the bilirubin concentration alone.
Article
On september 26 and 27, 1977, a workshop was held at Newport, R.I., under the sponsorship of Brown University and the National Foundation-March of Dimes, on the methodology, terminology, and clinical applications of serum bilirubin-binding determinations in the newborn infant. Participants included those involved in current research in the areas of bilirubin-albumin interactions and bilirubin encephalopathy. Bilirubin encephalopathy (kernicterus) remains a potential hazard in high-risk infants despite the use of phototherapy and of exchange transfusions to maintain serum indirect bilirubin levels in the range of 15 to 20 mg/dl or lower. Clinical and pathologic evidence of kernicterus in some high-risk infants at indirect-acting bilirubin levels below 15 mg/dl, and reports of later subtle central nervous system dysfunction in other infants with peak bilirubin concentrations between 15 and 20 mg/dl indicate that indirect bilirubin level alone is not an adequate criterion for identification of all infants at risk for bilirubin encephalopathy. It is desirable to have more sensitive indicators of risk than bilirubin concentration alone, in order to recognize infants at increased risk from presumably 'safe' bilirubin levels, and to avoid overtreatment of other infants who are at little or no risk despite moderate bilirubin elevations. The observation in animal models and in vitro that an excess of albumin prevents diffusion of bilirubin to neural structures has resulted in efforts to make clinically useful measurements of the bilirubin-binding properties of serum albumin in individual patients. The clinical use of bilirubin-binding measurements raises problems of standardization, interpretation, and follow-up which were adressed by the participants in this conference.
Article
A review of 34 autopsied infants weighing 2,250 gm or less who died on the third to seventh days of life during the 6 year period from 1971 through 1976 failed to reveal any cases of kernicterus. This contrasts with an incidence of 64% in low-birth-weight infants selected in the same manner from the same neonatal intensive care unit premature center during the period 1966 and 1967. The 34 infants in the 1971-1976 series were not significantly different with regard to their birth weights, Apgar scores, perinatal complications, or pathologic findings, other than their lack of kernicterus, from the 14 infants in the 1966-1967 series. The only significant difference between these 2 groups of infants was a lower mean peak serum bilirubin concentration in the 1971-1976 series, corresponding with the establishment in 1970 of a more aggressive policy of exchange transfusion and phototherapy. The prevention of excessive hyperbilirubinemia along with the development of more sophisticated intensive care of the neonate in recent years may be responsible for the elimination of kernicterus in the 1971-1976 series of infants.
Article
Serum unbound bilirubin concentrations (UBC) and serum total bilirubin concentrations (TBC) were measured serially in 138 low birthweight (LBW) infants treated with phototherapy for non-hemolytic hyperbilirubinemia. We attempted to assign the suitable critical UBC levels for predicting bilirubin encephalopathy into two different birthweight groups: a very low birthweight (VLBW) group (birthweight < 1,500 g) and an LBW group (birthweight between 1,500 g and 2,499 g). Twelve infants were diagnosed as 'at risk' for kernicterus, of whom 11 had signs of acute bilirubin encephalopathy and received exchange transfusion. One VLBW infant had neurological sequelae at a 3 year follow-up, although exchange transfusion was not carried out because of low TBC. Sensitivity and specificity for predicting kernicterus were calculated at different UBC levels between 0.6 microgram/dl and 1.5 micrograms/dl and TBC levels between 8 mg/dl and 26 mg/dl. The receiver-operating characteristic (ROC) curves plotted for UBC as a predictor of kernicterus were clearly shifted up and to the left compared with the curves for TBC in the VLBW and LBW groups. Thus, the UBC measurement may well provide a more rational basis for evaluating the risk of kernicterus in LBW infants. The optimal cut-off points were derived from these curves. In the VLBW group, the sensitivity was 100% and the specificity was 96% for a UBC of 0.8 microgram/dl, and 80% and 64% for a TBC of 11 mg/dl. In the LBW group, the sensitivity was 100% and the specificity was 98% for a UBC of 1.0 microgram/dl and 71% and 78% for a TBC of 16 mg/dl.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
We thank Dr Lucey for soliciting expert commentaries on our manuscript and for providing us the opportunity to respond to them. Although we do not have space to respond to each of the commentaries in depth, we will address the major points brought up by more than one author and selected points from the individual commentaries. Drs Poland and Wennberg emphasize that neurotoxicity due to bilirubin is a complicated process, with many determinants besides the serum bilirubin level; Dr Cashore's four example cases illustrate this point. We agree. A bilirubin level that may be toxic in one infant may not be hazardous in another.
Article
The auditory brainstem response (ABR) was monitored in nine infant rhesus monkeys during the intravenous infusion of 50-168 mg/kg of unconjugated bilirubin. Sulfisoxazole (200 mg/kg) was sometimes given near the end of or just before the bilirubin infusion if no obvious ABR change had yet occurred. Five of the animals were term gestation, four were preterm, and they ranged from 1 to 40 days of age at the time of study. The three oldest term animals, studied at 20, 35 and 40 days of age, respectively, showed variable changes in the ABR waves during bilirubin infusion and these changes were not altered further by sulfisoxazole administration. The other two term infants, studied at 1 and 6 days of age, respectively, showed sulfisoxazole enhanced ABR wave latency increase and amplitude reduction followed by loss of the ABR. Both of these animals became apneic following ABR loss and eventually died. The ABR reappeared in one animal prior to death. Minimal gross and microscopic changes were present in the brain of the 6-day-old animal at autopsy. The four preterm animals all had a progressive wave amplitude decrease followed by loss of the ABR with bilirubin alone. These preterm animals were sacrificed shortly after the ABR loss with only one showing yellow staining of the basal ganglia at autopsy. The infant rhesus monkey may be a useful paradigm for bilirubin-induced ototoxicity as manifested by potentially reversible ABR changes. The changes are dependent on gestational and chronological age of the animal and appear to occur in the peripheral eighth nerve or cochlea as well as in brainstem pathways.
Article
The cause of bilirubin encephalopathy has been variously ascribed to elevated total serum bilirubin concentration, high free bilirubin levels (or impaired albumin binding), and disruption of the blood-brain barrier. An experimental rat model for acute bilirubin encephalopathy was developed in which these three factors could be varied independently. Osmotic opening of the blood-brain barrier in the right hemisphere was produced by infusing a hypertonic arabinose solution into the right carotid artery. The total bilirubin level and bilirubin binding state were varied by adjusting the amount of bilirubin infused intravenously and/or by infusing human serum albumin. Brain electrical activity (EEG) served as an indicator of developing encephalopathy. Neither staining nor EEG changes occurred if the blood-brain barrier remained intact. Bilirubin staining without EEG evidence of encephalopathy sometimes occurred when the blood-brain barrier was open. Discriminant analysis showed that EEG changes were best predicted by the degree of blood-brain barrier opening (as indicated by brain bilirubin content) and by the quality of serum bilirubin binding. Serum total bilirubin concentration was not an important discriminator of encephalopathy.
Article
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)
Article
An enzymatic assay is described for non albumin bound bilirubin in the serum of newborn infants. Unbound bilirubin is oxidized to colorless compounds by ethyl hydroperoxide in the presence of horseradish peroxidase (EC 1.11.1.7), while albumin bound bilirubin is protected from oxidation. Because the equilibrium between albumin and bilirubin occurs rapidly, the oxidation step is rate limiting, and the initial oxidation velocity of total bilirubin is proportional to the unbound bilirubin concentration. By titrating serum with bilirubin in vitro, the association constant and binding capacity of high affinity sites for albumin binding can be determined. Normal human serum albumin tightly binds 1 mole of bilirubin per mole of albumin (binding constant, 2-4 X 10 8 l/mol). Although weaker secondary binding occurs, the unbound bilirubin fraction increases rapidly after the high affinity binding sites are saturated. Compromised newborns may have a decreased apparent binding capacity and (or) binding affinity. The method can be used to assess the risk of a jaundiced infant for bilirubin encephalopathy.
Article
The shape of binding isotherms for sixteen ligands to human serum albumin showed no signs of approaching saturation at high ligand concentrations. It is suggested that ligand binding to serum albumin is essentially different from saturable binding of substrates to enzymes, of oxygen to haemoglobin, etc. Binding to serum albumin appears to be non-saturable.
Article
To assess the value of free bilirubin (FB) measurements in predicting kernicterus (KI) in sick premature infants, 91 newborns weighing less than 1,500 gm at birth were observed during the first week of like with twice daily FB and total bilirubin determinations. Autopsies were performed on 30 of the 53 infants who died. Seven had KI and 23 did not. There were no differences between infants with and with out KI in the maximum FB level (KI 18.2 +/- 4.5 [SEM] nm/liter, no KI 11.1 +/- 0.9 nm/liter, P not significant) or the total bilirubin level (KI 7.3 +/- 1.3 mg/100 ml, no KI 6.1 +/- 0.5 mg/100 ml, P not significant). In fact, three kernicteric infants had very low maximum FB levels (less than 10 nm/liter). These three infants had prolonged episodes of acidosis, hypoxemia, or hypothermia during the 24 hours preceding their maximum level of FB. Although elevated levels of FB may be predictive of KI in some infants, other factors may make the blood-brain barrier more permeable to low levels of FB. This may limit the clinical applicability of FB measurements.
Article
Unbound bilirubin, bilirubin binding capacity, and bilirubin binding affinity were determined by the horseradish peroxidase method at the time of maximum hyperbilirubinemia and/or before exchange transfusions in 13 preterm infants who later died and had autopsies performed. Five of the 13 infants had kernicterus at autopsy. There were no significant differences in weight, gestational age, highest indirect bilirubin level, albumin concentration, severity of acidosis, use of assisted ventilation, sepsis, or other major clinical complications between the five infants with kernicterus and the eight infants without kernicterus. Compared with the eight nonkernicteric infants, the five kernicteric infants had significantly higher unbound bilirubin concentrations (13 +/- vs 27 +/- 9 nmoles/liter, respectively, P less than .05) and significantly lower bilirubin binding capacity and affinity. The data suggest an association between low bilirubin binding capacity and affinity, increased unbound bilirubin, and kernicterus in preterm infants with severe clinical complications.
Article
Free bilirubin concentration, bilirubin-binding capacity, and bilirubin-binding affinity were determined by peroxidase oxidation in 66 newborn infants. Twelve healthy term infants whose unconjugated bilirubin concentration was 15.8 +/- 3.7 mg/dl (mean +/- SD) had a binding capacity of 31.9 +/- 3.7 mg/dl (bilirubin: albumin molar ratio = 0.89 +/- 0.07) and Ka = 28 +/- 11 x 10(7)/M. Twelve term infants with clinical complications of asphyxia, acidosis, respiratory distress, or sepsis, and 17 preterm infants with no complications had lower serum albumin concentrations and slightly reduced binding capacity and affinity compared to the healthy term infants. Free bilirubin concentrations were similar in these three groups, averaging 8 to 9 nmol/l in each group. Twenty-five preterm infants with complications had significantly higher free bilirubin (19 +/- 11 nmol/l), lower binding capacity, and lower binding affinity than any of the other three groups (P less than 0.01 for all comparisons). Five of the 25 sick preterm infants had kernicterus at autopsy. These five infants were similar to the other 20 in birth weight, gestational age, serum bilirubin, and serum albumin level, but had significantly higher free bilirubin and significantly lower binding capacity and affinity. The data suggest that serious neonatal illness is associated with a marked reduction in bilirubin-binding capacity and affinity and an increased risk of kernicterus in preterm infants. The mechanism by which neonatal morbidity decreases bilirubin binding is not known.
Article
A widely published set of exchange transfusion criteria lowers critical bilirubin concentrations when the serum albumin falls to < 2.5 g/dL. Although acknowledging the role of bilirubin-albumin binding in bilirubin neurotoxicity, this approach may inadvertently produce two critical bilirubin concentrations. This study investigates using the bilirubin/albumin ratio instead of the single albumin concentration to eliminate this potential ambiguity in the criteria. The bilirubin/albumin ratio was defined as a reliable indicator of bilirubin-albumin binding if the frequency curves of specific unbound bilirubin concentrations are normally distributed functions of the ratio. Therefore the bilirubin/albumin ratios at which the unbound bilirubin reached 10, 15, and 20 nmol/L were determined by the peroxidase method in 35 well full-term, 10 ill full-term, and 19 ill preterm neonates. The frequency curves for each unbound bilirubin concentration plotted against the bilirubin/albumin ratio were tested for normality. The frequency of each unbound bilirubin concentration was a normally distributed function of the bilirubin/albumin ratio. Furthermore, the mean ratio at which each unbound bilirubin occurred did not differ significantly among the groups of neonates. The bilirubin/albumin ratio is a simple, nonambiguous way of incorporating the serum albumin concentration into exchange transfusion criteria.
Article
The management of nonhemolytic hyperbilirubinemia in term newborns is controversial. To evaluate the usefulness of serum unbound bilirubin concentrations (UBCs) in the management of hyperbilirubinemia, we compared the concentrations with abnormal auditory brainstem responses (ABRs). ABRs and serum UBCs in 37 hyperbilirubinemic term newborns (total bilirubin concentrations [TBCs] > or = 20 mg/dL and direct bilirubin concentrations < 2 mg/dL) were measured before treatment with either phototherapy or exchange transfusions. Eight of these newborns had blood incompatibilities. These hyperbilirubinemic newborns were divided into three groups according to the findings of ABR: group A, normal ABR (n = 18); group B, prolonged latency of wave I only (n = 8); and group C, prolonged interpeak latency of wave I-III/I-V and/or poor amplitude (n = 11). The peak TBC was significantly different between groups A and C (22.8 +/- 2.2 mg/dL and 25.4 +/- 2.5 mg/dL, respectively; P < .05), though there were no differences between groups A and B and between groups B and C. The peak UBCs in groups B (1.27 +/- 0.7 micrograms/dL) and C (1.34 +/- 0.37 micrograms/dL) were significantly higher than in group A (0.78 +/- 0.26 microgram/dL) (P < .05 and P < .01, respectively), though there was no significant difference in the peak UBC between groups B and C. Abnormal ABR findings were more clearly associated with the level of UBC at 1.0 microgram/dL than that of TBC at 23 mg/dL by multiple logistic regression analysis (odds ratio = 16.6, P = .0026, vs 4.2, P = .1272). These results suggest that measuring UBC may help in evaluating the possible risk of bilirubin encephalopathy in full-term newborns when there is vigintiphobia (fear of 20).
Article
To determine the incidence of adverse events attributable to exchange transfusion during the past 15 years and compare the incidence of severe complications between healthy and ill infants. Medical records for the past 15 years from two teaching hospitals with neonatal intensive care units were reviewed. Those newborns who underwent exchange transfusions were classified as healthy or ill. Adverse events were analyzed to determine whether they were attributable to the procedure. Of the 106 patients who underwent exchange transfusion, 81 were healthy and had no medical problems other than jaundice. The remaining 25 patients were classified as ill and had medical problems ranging from mild to severe. At least 2 (2%) of the 106 patients died of complications probably attributable to exchange transfusion. None of the 81 healthy infants died, but 1 had severe necrotizing enterocolitis requiring surgery. Of the 25 ill infants, at least 3 (12%) experienced severe complications (including 2 deaths) probably attributable to exchange transfusion. Serious complications from the most common adverse events, hypocalcemia and thrombocytopenia, were limited to the group of infants already ill with other medical problems. Because of the significantly greater rate of severe complications in ill infants, exchange transfusion should be delayed until the risk of bilirubin encephalopathy is as high as the risks of severe complications from the procedure itself (12%). These results do not support recommendations to use lower exchange levels in ill infants compared with healthy infants.
Article
A method is described for measuring the unconjugated fraction of the unbound bilirubin concentration in plasma by combining the peroxidase method for determining unbound bilirubin with a diazo method for measuring conjugated and unconjugated bilirubin. The accuracy of the unbound bilirubin determination is improved by decreasing sample dilution, eliminating interference by conjugated bilirubin, monitoring changes in bilirubin concentration using diazo derivatives, and correcting for rate-limiting dissociation of bilirubin from albumin. The unbound unconjugated bilirubin concentration by the combined method in plasma from 20 jaundiced newborns was significantly greater than and poorly correlated with the unbound bilirubin determined by the existing peroxidase method (r = 0.7), possibly due to differences in sample dilution between the methods. The unbound unconjugated bilirubin was an unpredictable fraction of the unbound bilirubin in plasma samples from patients with similar total bilirubin concentrations but varying levels of conjugated bilirubin. A bilirubin-binding competitor was readily detected at a sample dilution typically used for the combined test but not at the dilution used for the existing peroxidase method. The combined method is ideally suited to measuring unbound unconjugated bilirubin in jaundiced human newborns or animal models of kernicterus.
Article
To determine the unbound bilirubin concentration (UBC) associated with kernicterus with the use of clinical data from clusters of kernicterus after sulfisoxazole and benzyl alcohol administration. Sulfisoxazole at 12 mg/dL and benzoate at 10 mmol/L are associated with kernicterus at total bilirubins near 12 and 10 mg/dL, respectively. The concurrent UBC was estimated by first measuring the drug-induced increases in UBC in plasma and artificial sera (peroxidase-diazo method). The increases were then applied to baseline UBC, determined by linear regression analysis of binding data (peroxidase method) from 86 newborns, at total bilirubins of 12 mg/dL for sulfisoxazole and 10 mg/dL for benzoate. Sensitivity and specificity were determined with existing data. Sulfisoxazole and benzoate increased UBC in artificial sera 2.1-fold and 4.1-fold, respectively, and in plasma (sulfisoxazole) 2.4-fold. Benzoate would increase baseline UBC from 0.29 to 1.19 microg/dL and sulfisoxazole from 0.36 to 0.86 microg/dL. The sensitivity and specificity of a UBC of 0.86 microg/dL for predicting kernicterus are 79% and 92% and for 1.19 microg/dL, 50% and 98%, respectively. Historic data predict that the unbound bilirubin above which kernicterus becomes likely lies between 0.86 and 1.19 microg/dL, in good agreement with existing information.
Article
To determine the usefulness of the bilirubin-albumin (B:A) molar ratio (MR) and unbound bilirubin (UB) as compared with serum total bilirubin (TB) in predicting bilirubin encephalopathy as assessed by auditory brainstem responses (ABR) in infants of 28 to 32 weeks' gestational age. During a 2-year period, serial ABRs were obtained on 143 infants of 28 to 32 weeks' gestational age during the first postnatal week. Waveforms were categorized on the basis of response replicability and the presence of waves III and V. Wave V latencies were also serially analyzed when measurable for individual infants. Maturation of the ABR was defined as abnormal when the waveform category worsened and/or latency increased during the study interval. Serum albumin was analyzed at 48 to 72 hours of age in all patients. Serum TB was analyzed as clinically indicated. Aliquots of the same samples were also analyzed for UB in a subset of infants. The mean peak TB concentration (10.1 +/- 1.7 mg/dL) for the 71 infants with normal ABR maturation was not significantly different from the mean peak TB (10.2 +/- 2.1 mg/dL) in the 24-hour period preceding the ABR's first showing abnormal maturation in the other 55 infants. However, in infants with UB analyzed, the mean peak UB (0.62 +/- 0.20 vs 0.40 +/- 0.15 microg/dL) was significantly higher in the infants with abnormal maturation (n = 25) than in infants with normal maturation (n = 20). The B:A MR results were equivocal. In the entire study population, there was no difference in B:A MR between infants with normal versus abnormal ABR maturation. However, in the subset of infants in whom UB was measured, although TB was not different, there was a significant difference in B:A MR. Based on receiver-operating characteristic curves, a UB level of 0.5 microg/dL was the best discriminator with a sensitivity of 70% and a specificity of 75%. The proportion of infants who had UB >0.5 microg/dL and UB </=0.5 microg/dL and who had abnormal ABR, maturation was 0.81 and 0.33, respectively, with a significant difference in the incidence of transient bilirubin encephalopathy among these 2 groups. The relative risk of abnormal ABR maturation with UB >0.5 microg/dL compared with UB </=0.05 microg/dL was 2.45 (95% confidence interval: 1.33-4.49). UB is a more sensitive predictor than either serum bilirubin or B:A MR of abnormal ABR maturation, and hence transient bilirubin encephalopathy in premature newborns with hyperbilirubinemia.
Article
A prospective study in 1983 demonstrated no significant relationship between serum unbound bilirubin levels and kernicterus. The presence of benzoate (a bilirubin-binding competitor) in the serum along with sample dilution, however, may have rendered the unbound bilirubin measurements in that study inaccurate.
Article
tem-based approach to pre and postdischarge jaundice management that would minimize the potential for lapses in care and the risk of kernicterus. Such protocols need to be developed and implemented as soon as possible, with input from pediatricians, nurses, and family practitioners.
Article
A controlled clinical trial was designed to test the relative effectiveness of two prophylactic antibacterial regimens administered to premature infants in the first 5 days of life. Infants who received penicillin/sulfisoxazole (diethanolamine) died at a significantly higher rate than those who received oxytetracycline. The incidence of kernicterus was significantly higher among infants who received penicillin/sulfisoxazole (diethanolamine).
Article
Concentrations of bilirubin in the plasma of 85 premature infants weighing less than 2000 gm at birth were measured daily for the first 6 days of life. These measurements are presented and discussed. Nine cases of kernicterus which developed with relatively low concentrations of plasma bilirubin are reported. Laboratory studies are cited to support the hypothesis that the development of kernicterus in these infants was enhanced by the use of the antibacterial combination of penicillin and Gantrisin®. Attention is called to the effect which antibacterial therapy may have upon the concentration of bilirubin in the plasma of premature infants and to the lower values for plasma bilirubin which occur in dying infants.
Article
There is at present no general agreement about the relative value of different methods of treatment for hæmolytic disease of the newborn. This confusion is due to a failure to make valid comparisons between different forms of treatment. Where comparisons have been attempted, they have been between groups of cases treated not only by different methods but at different periods of time. Inevitably there is doubt whether the cases that are compared are of equal severity and whether factors other than the type of transfusion have operated to the same extent during the period of observation.
Article
To describe the incidence, etiology, treatment, and outcome of newborns with total serum bilirubin (TSB) levels >or=30 mg/dL (513 micro mol/L). Population-based case series. Eleven Northern California Kaiser Permanente Medical Care Program hospitals and 1 affiliated hospital. Eleven infants with TSB levels of >or=30 mg/dL in the first 30 days after birth, identified using computer databases from a cohort of 111,009 infants born 1995-1998. Clinical data from the birth hospitalization, rehospitalization, and outpatient visits in all infants; psychometric testing at age 5 (N = 3), neurologic examinations by child neurologists at age 5 (N = 3), or primary care providers (N = 7; mean age: 2.2 years); Parent Evaluation of Developmental Status (N = 8; mean age: 4.2 years). Maximum TSB levels of the 11 infants ranged from 30.7 to 45.5 mg/dL (525 micro mol/L to 778 micro mol/L; mean: 34.9 mg/dL [597 micro mol/L]). Four were born at 35 to 36 weeks gestation, and 7 were exclusively breastfed. Two had apparent isoimmunization; the etiology for the other 9 remained obscure, although only 4 were tested for glucose-6-phosphate dehydrogenase deficiency and 1 was bacteremic. None had acute neurologic symptoms. All received phototherapy and 5 received exchange transfusions. One infant died of sudden infant death syndrome; there was no kernicterus at autopsy. Two were lost to follow-up but were neurologically normal when last seen for checkups at 18 and 43 months. One child was receiving speech therapy at age 3. There were no significant parental concerns or abnormalities in the other children. In this setting, TSB levels >or=30 mg/dL were rare and generally unaccompanied by acute symptoms. Although we did not observe serious neurodevelopmental sequelae in this small sample, additional studies are required to quantify the known, significant risk of kernicterus in infants with very high TSB levels.
Bilirubin and serial auditory 338 C.E. Ahlfors and R.P. Wennberg brainstem responses in premature infants
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