Acute management of extreme neonatal jaundice–––the potential benefits of intensified phototherapy and interruption of enterohepatic bilirubin circulation

Abstract Increasing numbers of neonates are being admitted to hospital because of extreme jaundice. Phototherapy should be very effective in such infants, because the efficacy of phototherapy is proportional to the concentration of bilirubin in the skin. Here, I report on four infants who were admitted for indirect serum bilirubin levels of >500 µmol/1 (>>30mg/dl). In one of them, unrecognized Rhesus immunization was the main cause of hyperbilirubinemia, while in the other three increased enterohepatic circulation of bilirubin was thought to be an important contributory factor. In all four infants phototherapy (11–14 µW/cm²/nm) with whole body exposure plus ad lib feeding with milk were initiated immediately upon admission to the nursery. After 2h serum bilirubin values were reduced by 170–185 µmol/1 (10-11mg/dl) in the first three infants, while in the fourth infant a reduction of 195 µmol/1 (11.3mg/dl) was seen in the 5h interval between the first and second bilirubin measurement. This experience suggests that in some infants with extreme jaundice, intensified phototherapy plus feeding with milk may be very effective in reducing serum bilirubin levels. Even if an exchange transfusion is performed, using this strategy in the waiting period may be beneficial, as both the rapid reduction in serum bilirubin levels as well as the conversion of significant amounts of bilirubin into water-soluble isomers may reduce the risk of neurotoxicity.     

Cells, bilirubin and light: formation of bilirubin photoproducts and cellular damage at defined wavelengths

Christensen T, Kinn G, Granli T, Amundsen I. Cells, bilirubin and light: formation of bilirubin photoproducts and cellular damage at defined wavelengths. Acta Paediatr 1994;83:7–12. Stockholm. ISSN 0803–5253
Cultured cells from one human and one murine cell line were treated with bilirubin and irradiated with visible light of different wavelengths, either from phototherapy lamps or from a Xenon/Mercury lamp equipped with a monochromator. Bilirubin bound to human serum albumin was also irradiated with light. After irradiation, the bilirubin and its photoisomers were extracted and analysed with High Pressure Liquid Chromatography. The formation of single strand breaks in the DNA of treated cells was studied using a fluorescence marker. Cytotoxicity in the mouse skin cell line was measured by loss of the ability to form visible colonies in vitro. Green light exposure favours the production of lumirubin, while blue light causes more DNA damage and cytotoxicity. Green light may be more efficient and safer than shorter wavelength exposure when treating jaundiced newborns with phototherapy.     

Formation of photoproducts and cytotoxicity of bilirubin irradiated with turquoise and blue phototherapy light

AIM: To compare a new turquoise ("green") fluorescent phototherapy lamp (490 nm) with a conventional blue phototherapy lamp (450 nm) with respect to cytotoxicity and photochemical effects of bilirubin. METHODS: Mouse lymphoma cells (L5178Y-R) in the presence of bilirubin solutions were exposed to phototherapy light. Occurrence of necrosis and apoptosis, reduction of mitotic index and inhibited cell growth was assayed by appropriate methods. The presence of bilirubin and its photoisomers was measured by high-pressure liquid chromatography analysis and absorption spectroscopy. RESULTS: At constant and equal light irradiances, the cytotoxic effects in the presence of bilirubin bound to human serum albumin showed that the green lamp caused significantly less necrosis (n = 4, p < 0.05) and less inhibition of cell multiplication (n = 3, p < 0.05) than the blue lamp. A slightly lower apoptotic fraction, although not statistically significant, was observed in cells exposed to the blue lamp. Photo-oxidation of bilirubin was more prominent with blue light irradiation. The photoequilibria between geometric isomers of bilirubin were different for the two lamps; more geometric photoisomers were formed by blue irradiation (n = 6, p < 0.05). The amounts of the most water-soluble isomers (presumably mainly lumirubin) were rather similar for the two lamps. CONCLUSION: The two lamps were similar in the formation of therapeutically relevant photoproducts, but the blue lamp showed potential in forming more photo-oxidation products and in causing more severe cellular damage in the presence of bilirubin.     

Change of bilirubin photoisomers in the urine and serum before and after phototherapy compared with light source

BACKGROUND: The clinical effect of phototherapy for neonatal hyperbilirubinemia is based on the production and elimination of cyclobilirubin. Generally, the clinical effect of light sources is estimated by the reduction in the total serum bilirubin level. One procedure with less invasiveness than blood collecting is urine collection. Whether the effectiveness of light sources used for phototherapy could be assessed using measurements of bilirubin photoisomers in urine was studied. METHODS: This study was a retrospective analysis of 38 term infants with hyperbilirubinemia who underwent phototherapy. Bilirubin fractions in serum and urine before and 24 h after the phototherapy were measured by high-performance liquid chromatography. The light sources used for the phototherapy were blue-white light (n = 11), Biliblanket plus high output (n = 13) or green light (n = 14). The relationships between serum and urine bilirubin photoisomers after phototherapy and whether the levels of urine bilirubin photoisomer are affected by the light sources with different wavelength characteristic were analyzed. RESULTS: There was no correlation between serum (ZE)-bilirubin and urine configurational isomers, but a weak positive correlation between serum (EZ)-cyclobilirubin and urine structural isomers after phototherapy. Although serum (ZE)-bilirubin levels depended on the wavelength characteristic of each light source during phototherapy, the urine configurational isomer levels did not depend on it. The increase in serum (EZ)-cyclobilirubin levels and the urine structural isomer levels were mostly in agreement. CONCLUSIONS: The urine bilirubin structural isomers may be used to estimate the serum (EZ)-cyclobilirubin levels and to evaluate the clinical effects of light sources.     

Prediction of the Development of Neonatal Jaundice by Increased Umbilical Cord Blood Bilirubin

ABSTRACT. Umbilical cord serum bilirubin concentration as a predictor of subsequent jaundice was studied in 291 newborns. It was possible to define subgroups of infants with significantly higher or lower risks of developing jaundice. If cord bilirubin was below 20 |imol/l, 2.9% became jaundiced as opposed to 85% if cord bilirubin was above 40 μmol/l. Furthermore, 57% of jaundiced infants with cord bilirubin above 40 nmol/1 required phototherapy, but only 9% if cord bilirubin was 40 μmol/1 or lower ( p <0.003). Knowledge of infants at risk of developing jaundice allows simple bilirubin reducing methods to be implemented before jaundice is present and could influence a decision regarding early discharge from hospital. Since the ability of plasma to bind bilirubin in cord blood from jaundiced and non-jaundiced infants showed no significant differences, the increased cord bilirubin among infants who later became jaundiced is presumably caused by increased fetal bilirubin production or decreased removal of bilirubin from the fetal circulation.     

Fibreoptic phototherapy in the management of jaundice in low birthweight neonates

A fibreoptic phototherapy device has been compared with conventional white and special blue fluorescent phototherapy lamps to evaluate its efficacy in lowering serum bilirubin levels in low-birthweight neonates. Fibreoptic phototherapy was found to be as effective 21s white light and less effective than blue light, as assessed by (i) the bilirubin concentration after 24 h of phototherapy and at the end of phototherapy, (ii) the duration of phototherapy, (iii) the percentage daily decline rate and (iv) the overall percentage decline rate ( p < 0.05). There were no failures of phototherapy and the need for re-exposure was low (4.7% of the total sample), with no difference between groups. The fibreoptic approach represents a promising way to aggregate synergically the most recent optical technologies and develop a modern, efficient and caring phototherapy system for low-birthweight infants.     

Comparison of the efficacy of conventional special blue light phototherapy and fiberoptic phototherapy in the management of neonatal hyperbilirubinaemia

The efficacy and usefulness of two types of phototherapy differing in the source, wavelength and irradiance of the light, conventional phototherapy consisting of special blue light and fiberoptic phototherapy, were compared in a relatively larger series of term newborns with non-haemolytic and more significant hyperbilirubinaemia than those in previous studies. In total, 108 newborns were allocated sequentially to receive either conventional phototherapy consisting of five special blue lamps or fiberoptic phototherapy. The average spectral irradiance measured at the skin surface level of newborns during the study period was significantly greater in the conventional phototherapy group. The special blue lamp of the conventional phototherapy unit had an emission spectrum almost identical to the bilirubin absorption spectrum, whereas the tungsten-halogen lamp of the fiberoptic phototherapy had a broad emission through the blue and green wavelengths (mainly in the green spectrum). Phototherapy was more effective in the conventional phototherapy group; the duration of exposure to phototherapy (h) was significantly shorter, and the overall bilirubin decline rate (as micromol/l/h and %/h) was significantly greater in the conventional phototherapy group. According to the nursing personnel, fiberoptic phototherapy was more comfortable than the conventional phototherapy frame because of the easier accessibility and handling of the infants during phototherapy. They complained of giddiness, nausea, glare, temporary blurring of vision and difficulty in detecting the skin colour changes of newborns with the blue light of the conventional phototherapy unit. Conventional phototherapy consisting of special blue fluorescent lamps with approximately twofold higher irradiance and an emission spectrum almost identical to the bilirubin absorption spectrum is preferable to fiberoptic phototherapy in the standard treatment of term newborns with non-haemolytic hyperbilirubinaemia.     

Screening for neonatal hyperbilirubinaemia and ABO alloimmunization at the time of testing for phenylketonuria and congenital hypothyreosis

In a population-based study including 2463 infants, serum bilirubin measurements were added to the neonatal screening programme for phenylketonuria and congenital hypothyreosis. This screening programme detected 11/17 (65%) of infants with serum bilirubin levels > 350/μmol l⁻¹, of whom 7 (3 per 1000) were readmitted from home (6 treated with phototherapy). A total of 139 infants (5.6%) received phototherapy. Maternal blood type O occurred significantly more often in term infants treated (30/54; 55.6%) compared with preterm infants treated (32/85; 37.6%) and with blood type O occurrence in the total population of mothers (906/2426; 37.3%) ( p < 0:05). The blood type constellations mother O/infant A or B showed a sensitivity of 64%, specificity 65%, positive predictive value 12% and a negative predictive value of 96% for the requirement of phototherapy for the whole material. Exchange transfusion was not required in any of the infants. No infant developed bilirubin encephalopathy (kernicterus). Adding bilirubin to a neonatal screening programme detects some cases with unexpectedly high bilirubin levels in need of intervention. Routine ABO blood typing of pregnant women, ABO cord blood typing and Coombs' test in infants of mothers with blood type O cannot be recommended because of low positive predictive value for the requirement of intervention (phototherapy) by these tests.     

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

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

Effects of bilirubin and phototherapy on osmotic fragility and haematoporphyrin-induced photohaemolysis of normal erythrocytes and spherocytes

AIM: To study the effects of phototherapy on erythrocyte haemolysis in vitro and to determine possible differences in sensitivity to phototherapy between normal erythrocytes and spherocytes. METHODS: Erythrocytes from four normal healthy donors and two donors with hereditary spherocytosis were treated with bilirubin (160 microM) in the presence of human serum albumin in the molecular ratio bilirubin/albumin 0.8. Treated cells were maintained either in the dark or in blue light (450 nm, 8 mW/cm2, 30 min). The experimental light dose was comparable to 2 h of clinical phototherapy. The osmotic fragility of the treated cells was measured by scoring haemolysis in hypo-osmolar solutions (0.10-0.90% NaCl). The sensitivity to photohaemolysis of cells pre-treated with bilirubin (BR) and/or phototherapy was tested by exposing the cell suspensions to haematoporphyrin and UVA radiation. The delayed (18 h) photohaemolysis was measured by spectrophotometry. RESULTS: Osmotic fragility, expressed as percentage haemolysis, of normal erythrocytes was more than doubled in the presence of BR combined with phototherapy (n = 6, p < 0.05). In contrast, osmotic fragility of spherocytes was unaffected by either treatment (n = 8, p < 0.05). Increased photohaemolysis was seen in spherocytes treated with BR (n = 13, p < 0.05), phototherapy (n = 13, p < 0.05) and a combination of the two agents (n = 13, p < 0.05) compared with spherocytes without BR in the dark (n = 6). CONCLUSION: Bilirubin may make the plasma membrane of normal erythrocytes more fragile. Newborns with hereditary spherocytosis may be sensitive to phototherapy.     

‘Halving the heel pricks’: Evaluation of a neonatal jaundice protocol incorporating the use of a transcutaneous bilirubinometer

Aim: This study aimed to assess the impact of implementing a new jaundice protocol incorporating the use of the Konica Minolta/Air Shields JM 103 Jaundice Meter (JM103) (Konica Minolta Sensing Inc., Osaka, Japan) in the setting of an Australian post‐natal ward. Methods: A before‐and‐after study was completed following the introduction of a protocol integrating the use of the JM103 monitor on to the post‐natal ward. Eligible infants were ≥36 weeks gestation, >24 h and <8 days of age. The number of Total Serum Bilirubin tests (TSBRs) were compared for the 12 months prior (T1) with a 6‐month period and 6 months after protocol introduction (T2). Transcutaneous bilirubin (TcBR) results were also collected in T2. Rates of phototherapy and peak TSBRs at commencement were also compared as measures of safety. Results: Four hundred and twenty‐six of the 2197 live births in T1 required one or more TSBRs compared with 119 of the 1169 live births in T2. This represents an odds ratio of 0.47 (95% confidence interval 0.38–0.58) for infants in T2 having ≥1 TSBR compared with T1. There was no difference between the groups for rates of phototherapy (3.8% vs. 3.0%; P= 0.2) nor any difference between the groups for peak SBR during phototherapy (301.9 µmol/L (standard deviation, SD 58) for T1 vs. 303.2 µmol/L (SD 54) for T2; P= 0.45). The estimated cost saving per year is $6966.00. Conclusion: TcBR measurement in conjunction with our protocol significantly reduces painful procedures and costs without increasing the risk of delaying treatment with phototherapy.     

Inhibitory action of bilirubin on superoxide production by polymorphonuclear leukocytes

To assess the interaction of bilirubin with albumin and to determine the site of bilirubin toxicity in cells, a study was made of the O2- production of neonatal neutrophils (PMNs) by two different stimulators: (1) concanavalin A (Con A) plus cytochalasin D (Cyt D), which acts on the cell surface, and (2) phorbol myristate acetate, which acts intracellularly. PMNs that had been separated from cord blood were incubated for 60 min at 37 degrees C in the solution with different molar ratios of bilirubin/albumin (unbound bilirubin, ranging from 0.35 to 3.92 micrograms/dl). The unbound bilirubin was determined by peroxidase oxidation method. A PMN viability of more than 96% was maintained after the incubation in each of solutions. The O2- production rate of PMNs stimulated by Con A plus Cyt D was inhibited in the presence of unbound bilirubin levels as low as 1.12 micrograms/dl, and the rate decreased as the levels of unbound bilirubin rose. The O2- production rate stimulated by Con A plus Cyt D was more remarkably inhibited than that by phorbol myristate acetate, which directly activates intracellular protein kinase C. These findings suggest that bilirubin toxicity to PMN can be shown at levels of unbound bilirubin as low as those in hyperbilirubinemic sera, and the critical site at which bilirubin exerts its toxicity is mainly in membrane level rather than on intracellular functions.     

严重高胆红素血症新生儿急性胆红素脑病危险因素分析

目的 探讨严重高胆红素血症新生儿急性胆红素脑病（ABE）发生的危险因素。方法选择本院2010年1月至2012年12月诊治的胎龄≥35周、血清胆红素（TSB）峰值〉425μmol/L且资料完整、进行了头颅核磁共振及脑干听觉诱发电位检查的患儿,根据是否符合ABE的诊断标准分为病例组和对照组,对一般资料、母孕期情况、合并症、围生期缺氧、黄疸的发生发展过程及实验室指标共22项临床因素进行单因素分析,对其中13项进行多因素Logistic回归分析。结果病例组43例,对照组30例,单因素分析显示,病例组出生后体重下降程度、TSB峰值、平均每日胆红素上升值及B/A值均高于对照组,差异有统计学意义（P〈0.05）;多因素分析提示,严重黄疸诊断日龄、围生期缺氧史及酸中毒与ABE的发生相关,OR（95%可信区间）分别为0.545（0.413~0.962）、36.589（1.114~1202.032）、7.963（1.294~49.010）,P均〈0.05。结论 在严重高胆红素血症新生儿中,严重黄疸诊断日龄越小,曾有围生期缺氧史和（或）伴有酸中毒者,ABE发生风险越高;而母乳喂养、出生后体重下降多、存在母子血型不合溶血、葡萄糖-6-磷酸脱氢酶缺陷则可能是严重高胆红素血症的原因。加强黄疸的监测、对严重高胆红素血症患儿积极纠正酸中毒,可能有助于预防胆红素脑病。     

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

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

Effects of albumin infusion therapy on total and unbound bilirubin values in term infants with intensive phototherapy

BACKGROUND: The purpose of the present study was to evaluate the effect of intravenous albumin administration on the serum total and unbound bilirubin values in term non-hemolytic hyperbilirubinemic neonates during intensive phototherapy. METHODS: Fifty-eight infants (gestational age 39.4 +/- 1.4 weeks; birth weight 3,245 +/- 435 g) were given phototherapy with similar light energy. Twenty infants (control group) received only phototherapy, while 38 others (albumin-treated group) were also given human albumin at 1 g/kg bodyweight, i.v., during the first 2 h of phototherapy. RESULTS: When comparing changes in total and unbound bilirubin values 0, 2, 6 and 24 h after entering the study between the albumin-treated group and the control group, there was a significant reduction in the serum unbound bilirubin values at the end of albumin treatment and at 6 and 24 h. However, there was no significant reduction in total serum bilirubin values during the study period. In the albumin-treated group, the mean serum unbound bilirubin reduction from the baseline level at the end of albumin treatment and at 6 and 24 h was 0.40 +/- 0.19, 0.41 +/- 0.20 and 0.43 +/- 0.20 microg/dL, respectively. CONCLUSIONS: The results suggest that albumin priming may be effective for an immediate reduction in serum unbound bilirubin values, the fraction that is potentially neurotoxic.