Transcutaneous bilirubin measurement in evaluating neonatal jaundice among Saudi newborns

Transcutaneous bilirubin measurements, using the Minolta transcutaneous bilirubinometer (TcB), were performed in 68 full-term, healthy Saudi infants. Infants who had exchange transfusion and those under phototherapy were excluded. One hundred and twenty measurements were obtained and compared with serum bilirubin levels measured by the American Optics (A.O.) bilirubinometer. The serum bilirubin range was 3.8-18.4 mg/dl. The results showed that the TcB index correlates well with the serum bilirubin measurement: the regression analysis was: r = 0.878, y = 10.78 + 0.909 x, P less than 0.001. However, the regression line showed that at a serum bilirubin level above 12.9 mg/dl the sensitivity of the TcB was 69% and the specificity 92%, while its positive and negative predictive values were 58% and 95% respectively. There was a fair amount of variability around the regression line which may lead to significant errors in clinical decision-making. Thus, the TcB at present has grave limitations which restrict its usefulness in the newborn.     

The laboratory method as a variable in the diagnosis of hyperbilirubinemia

Algorithms based on fractionation of bilirubin into direct-reacting and indirect-reacting fractions by diazo methods are frequently utilized for investigation of hyperbilirubinemia. Unfortunately, direct-reacting and indirect-reacting fractions do not correspond precisely with conjugated and unconjugated pigment. Advances in analytical methods allow accurate quantitation of the individual fractions of bilirubin in serum. Three cases of hyperbilirubinemia are presented in which bilirubin fractionation by diazo methods suggested an erroneous diagnosis. Analysis of the serum samples by high-performance liquid chromatography for bilirubin conjugates confirmed the correct clinical diagnosis. Diazo methods for bilirubin analysis are subject to marked discrepancies. While the new methodology utilizing high-performance liquid chromatography is not practical for routine bilirubin analysis, optimization of diazo methods utilizing rigid and meticulous protocol is suggested. Laboratories performing diazo bilirubin determinations should correlate their results with those of other laboratories and clinical data. Clinicians need to be aware of the reliability of a particular test result before embarking on a lengthy and expensive evaluation.     

Value and limitations of bilirubin binding capacity in predicting the development of kernicterus

The serum bilirubin (SBR) and the bilirubin binding capacity (BBC) were determined on hospital admission in 181 consecutive neonates with neonatal jaundice. Twenty-three babies were less than 2500 g and two were of birth weight less than 2000 g. Fifteen babies were preterm. There were eight cases of kernicterus. Although the serum bilirubin was generally higher in infants with a BBC less than 34 mumol/l, there was no correlation between the bilirubin binding capacity and the presence of kernicterus (r = 0.28, P greater than 0.05). However, when both the serum bilirubin and the bilirubin binding capacity were used, a low value of BBC less than 34 mumol/l increased the risk of kernicterus. Higher values of BBC, on the other hand, did not mean that there was less risk of kernicterus, other factors being equal. This, while the bilirubin binding capacity may provide an additional source of information, its limitations should always be borne in mind.     

Is it worthwhile using a transcutaneous bilirubinometer in the nursery?

Jaundice is a potential threat to neonatal health and/or life. The advantages and limitations of transcutaneous determination of bilirubin concentration and current devices are briefly discussed in this paper.     

Value and limitations of bilirubin binding capacity in predicting the development of kernicterus

The serum bilirubin (SBR) and the bilirubin binding capacity (BBC) were determined on hospital admission in 181 consecutive neonates with neonatal Jaundice. Twenty-three babies were less than 2500 g and two were of birth weight less than 2000 g. Fifteen babies were preterm. There were eight cases of kernicterus. Although the serum bilirubin was generally higher in infants with a BBC < 34 μmol/l, there was no correlation between the bilirubin binding capacity and the presence of kernicterus (r = 0.28, P > 0.05). However, when both the serum bilirubin and the bilirubin binding capacity were used, a tow value of BBC < 34 μmol/l increased the risk of kernicterus. Higher values of BBC, on the other hand, did not mean that there was less risk of kernicterus, other factors being equal. This, while the bilirubin binding capacity may provide an additional source of information, its limitations should always be borne in mind.     

Transcutaneous bilirubinometry in preterm infants

The aim of this study was to evaluate the accuracy and safety of transcutaneous bilirubinometry in preterm infants using the new bilirubin analyser BiliCheck^±. The study included 145 preterm children (23–36 wk gestation). Capillary blood sampling for determination of serum bilirubin (BS) was combined with transcutaneous bilirubin measurement (BTc) every morning until the sixth postnatal day and related to several clinical data (phototherapy (PT), infection signs, breathing disturbances, skin bleeding, etc.). Overall bilirubin concentration ranged from 17 to 371 μmol/l, and from 21 to 325 μmol/l for BS and BTc, respectively. Mean values obtained by BTc were significantly higher than BS values. The correlation coefficient between BS and BTc was r= 0.64 for the whole group, and r= 0.73 in infants without PT. As demonstrated by multiple regression analysis, BS‐BTc correlations were related only to gestational age (beta ‐0.32) and breathing disturbances (beta 0.29), indicating that the lower the gestational age and the more seriously ill the baby, the higher the incoherence between BS and BTc. Conclusion: BiliCheck^±provides a convenient, non‐invasive possibility for bilirubin estimation in preterm infants. However, there are limitations: the method gives reliable results only in newborns older than 30 wk gestation, without PT and artificial ventilation.     

Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants

Objectives: To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18–22 months corrected age in extremely low birth weight infants. Method: Total plasma bilirubin and unbound bilirubin were measured in 1101 extremely low birth weight infants at 5 ± 1 days of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18–22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow‐up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors. Results: Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow‐up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow‐up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants. Conclusions: In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma bilirubin and death or adverse neurodevelopmental outcomes at 18–22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.     

Phototherapy in the management of neonatal hyperbilirubinemia: efficacy with light sources emitting more than 500 nanometers

The clinical action of green fluorescent lamps, properly filtered to remove wavelengths of less than 500 nm, was investigated in a group of 23 newborns with different initial serum bilirubin concentrations. The serum bilirubin levels were measured at 6, 12, 24, and 48 hours after the beginning of phototherapy. These results are compared with those obtained, under the same experimental conditions, in a group exposed to commercial green lamps. Similar bilirubin decline rates were observed in the two experiments. In general, these data confirm the satisfactory clinical efficacy of the green light in phototherapy and prove, in particular, that the blue component present in the emission spectrum of the commercial green lamps has a negligible effect on the bilirubin degradation process.     

Managing the assessment of neonatal jaundice : Importance of timing

In view of the limitations in the accurate visual assessment of jaundice and its potential role as a predictive vector for serious neurologic sequelae, we propose that a universal screening of bilirubin be considered concurrent to the routine pre-disharge metabolic screening. Universal bilirubin screening in the term and near-term newborns when plotted on “Hour-specific Bilirubin Nomogram” in lieu of the usual “day-specific” value will predict the high-risk and the low-risk groups and facilitate cost-effective and individualized follow-up of those babies at risk. A percentile based bilirubin nomogram for the first week of age was constructed from hour-specific pre-and post-discharge bilirubin values of 2840 healthy term and near-term babies. The accuracy of the pre-discharge bilirubin values was determined as a predictive vector. Pre-discharge (18–72 hours age), 6.1% of the study population had bilirubin values in the high-risk zone (>95th percentile). Of these, 39.5% remained in that zone (likelihood ratio {LR}=14.08). Pre-discharge, 32.1% of the study population had bilirubin values in the intermediate risk zone (40–75th percentiles). In a clinically significant minority of these babies (6.4%), the post-discharge values moved to the high-risk zone (L−R=3.2 for the move from the upper-intermediate zone and 0.48 from the lower-intermediate zone). In the remainder 61.8% of the population who were identified to be at low risk, there was no measurable risk for significant hyperbilirubinemia (L–R =0). The bilirubin nomogram can predict which infant is at high, intermediate, and low risk for subsequent excessive hyperbilirubinemia and allows for the individualized follow-up of these high-risk babies with particular attention to those who may need evaluation and intervention. Whereas, identification of the low risk group allows for a less intense bilirubin follow-up and in whom a visual check by an experienced care-provider may suffice.     

Ex uno plures: the concealed complexity of bilirubin species in neonatal blood samples

Blood from jaundiced neonates often contains several isomers of bilirubin in addition to the biosynthetic isomer that causes kernicterus. These isomers are generated during phototherapy or during normal exposure of infants to ambient light. Their presence is generally overlooked or ignored in clinical measurements of circulating bilirubin concentrations and the interpretation of these values. Whether this is justified or clinically important is presently uncertain. However, the presence of isomers may complicate the accurate measurement of free bilirubin concentrations in blood and the use of such values for identifying jaundiced infants at most risk of kernicterus.     

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.     

Bilirubin beyond the blood-brain barrier

We evaluated the utility of recording neural signals, such as auditory brainstem responses, as potential new criteria for treatment of neonatal jaundice. Findings from recent studies of auditory brainstem responses and behavior of jaundiced infants reinforce the notion that asymptomatic and even symptomatic neurotoxicity caused by bilirubin may occur relatively frequently at relatively low serum bilirubin concentrations. Evidence suggests that this is transient and reversible. Whereas current criteria for the prevention of kernicterus are based on the idea that bilirubin entry to the CNS should be averted, the existence of transient subclinical and clinical bilirubin-induced neurotoxicity suggests that the focus of prevention might be shifted to events beyond the blood-brain barrier. With the use of "finer tools" to detect neurotoxicity, it may be possible to recognize a prior stage of neurotoxicity, described here as "transient subclinical bilirubin-induced neurotoxicity." Recordings of neural signals might be used as either predictors of kernicterus or as immediately available "outcomes" or end points with which biochemical predictors (serum bilirubin and "unbound" bilirubin concentrations) might be correlated, to determine their relative value as predictors of entry of bilirubin to the CNS. It is suggested that the results of studies to determine the relative risks associated with the various predictive criteria, namely, a prospective cohort analysis, may not be available for many years and that randomized controlled trials of new criteria for exchange transfusion are even further removed from reality.     

Micro-invasive management of neonatal bilirubinemia.

The present study aims at analyzing the suitability of transcutaneous approach and filter paper technique using Minolta Jaundicemeter in the management of neonatal bilirubinemia. I compared serially measured values of Serum Bilirubin Index (SBI) by using filter paper technique and transcutaneous bilirubin index (TcBI) with serum bilirubin level determined by Diazo Method in 100 clinically jaundiced newborns and in 25 neonates at birth. The estimation of TcBI is simple, quick, reliable and non-traumatic to the newborn with no workload on the laboratory and technician. However, different nomograms are to be prepared for different laboratories, as also for the newborns with difference in skin pigmentation, gestational age and after phototherapy. SBI determined by filter paper technique eliminates these limitations. Moreover, the linear correlation was stronger between SBI and Diazo values (r = 0.9343, p < 0.001) in comparison to TcBI with Diazo values (r = 0.9090, p < 0.001). Further SBI readings almost correspond with actual serum bilirubin levels while corresponding TcBI values were much higher especially at higher diazo values. Thus TcBI can be used routinely for the surveillance of neonatal jaundice till it reaches a level corresponding to critical serum bilirubin level at which active management is required. At this point, serum bilirubin level may be confirmed by SBI.     

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

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

The effect of shielding the hepatic area on the clinical response to phototherapy

The changes in serum bilirubin concentration in response to phototherapy were studied in 26 infants with and without an opaque patch on the liver area. Fifteen infants in the patched group were treated at a mean age of 50.7 h, and 11 control infants at 49.1 h. No significant differences were demonstrated between the two groups in duration of phototherapy, peak bilirubin concentration and rates of bilirubin decrement.Shielding the hepatic area during illumination does not alter the clinical response to phototherapy which suggests that the main site of action of phototherapy is in the skin.     

Usefulness of the bilirubin/albumin ratio for predicting bilirubin-induced neurotoxicity in premature infants

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.     

Assessment of jaundice in preterm neonates: comparison between clinical assessment, two transcutaneous bilirubinometers and serum bilirubin values

Aim: 1) To compare the clinical assessment of craniocaudal progression of jaundice and two transcutaneous bilirubinometers with serum bilirubin values in preterm neonates; 2) to identify factors affecting the difference between non-invasive bilirubin estimation and serum bilirubin. Methods: Serum bilirubin was clinically estimated in healthy preterm newborn infants (34 to 36.9 gestational weeks) independently by a primary investigator and by nurses, and subsequently compared with separate measures of two transcutaneous bilirubinometers. Results: A total of 107 measurements were performed on 69 infants. Minolta JM-102 showed the best performance, with ROC area under the curve of 0.96, followed by BiliCheck™ over the sternum (0.89) and over the forehead (0.88), clinical assessment by nurses (0.73) and by a physician (0.70). Serum bilirubin >190 μmol/l can be detected with 95% sensitivity with Minolta JM-102 ≥19 units, with BiliCheck™ ≥145 μmol/l over the sternum and ≥165 μmol/l over the forehead and with jaundice progression to the trunk or further (Kramer zone ≥2). Gestational age affects all non-invasive methods in the estimation of serum bilirubin, whereas skin colour affects both BiliCheck™ and clinical assessment. Ambient light affects only clinical assessment.

Conclusion: Minolta JM-102 showed the best performance, closely followed by BiliCheck™, with clinical assessment performing far worse than either transcutaneous method. None of the three methods are recommended as complete substitutes for serum bilirubin values in jaundiced preterm infants.     

Randomized trial of prophylactic phototherapy in the infant with very low birth weight

Twenty-two preterm infants (birth weight 850 +/- 220 gm) were randomly assigned to receive phototherapy either soon after birth or after the serum bilirubin concentration reached 5 mg/dl. Infants receiving prophylactic phototherapy were placed under lights at a significantly earlier age and lower serum bilirubin concentration than infants in the routine group (P less than 0.001). There was no significant difference between groups in peak serum bilirubin concentration, age at which it peaked, rate of rise in serum bilirubin concentration, or serum bilirubin concentration at any time during the study. Infants assigned to the prophylactic phototherapy group were under lights for a significantly longer time than those in the routine group (P less than 0.05). There was a significant rise in both configurational and structural photo-isomers (P less than 0.005) independent of serum bilirubin concentration after phototherapy in all patients. These data suggest that the clinical course of hyperbilirubinemia is not altered in infants with very low birth weight receiving prophylactic phototherapy compared with infants with phototherapy begun at a bilirubin concentration of 5 mg/dl.     

Clinical evaluation of Sephadex gel filtration in estimation of bilirubin binding in serum in neonatal jaundice

Clinical experience with a Sephadex gel filtration test-kit for the evaluation of bilirubin binding affinity of serum in neonatal jaundice is reported. In serial serum specimens from 166 jaundiced neonates the results of the test in most cases were in accord with the independent clinical decision to perform exchange transfusion. In all 9 cases with clinical kernicterus the Sephadex test was strongly positive (very low bilirubin binding affinity of serum).The test was positive at lower bilirubin levels and bilirubin/albumin molar ratios in preterm as compared with term neonates, especially in those in poor clinical condition. Among term infants the test indicated an increase in bilirubin binding affinity after the 5th day of life.     

新生儿黄疸的研究进展

新生儿黄疸为新生儿常见病,但在黄疽的诊断标准、高胆红素血症预测及干预、胆红素脑病的早期诊断及后遗症的防治等方面均存在诸多问题,需要我们进一步解决和完善.

Abstract：

Neonatal jaundice is one of the common diseases in preterm neonates. But there are still some problems to be determined,for example,the clinical diagnosis criteria for neonatal jaundice,the prediction,diagnosis and therapies for hyperbilirubinemia,and diagnosis for bilirubin encephalopathy in early-stage and prevention from bilirubin encephalopathy sequelae.