Unbound Bilirubin Levels Research Articles

Fluctuations in unbound bilirubin levels during acetaminophen therapy for patent ductus arteriosus.

Fluctuations in unbound bilirubin levels during acetaminophen therapy for patent ductus arteriosus.

Serum TGF-β1 and VEGF Levels Reflect the Liver Hardness and Function in Children with Biliary Atresia.

Objective This study further explored the wind direction correlation analysis between serum levels of TGF-β1 and VEGF and liver function assessment in children with biliary atresia. Methods A total of 62 children with biliary atresia (BA) who received surgical treatment in our hospital from October 2020 to October 2021 were selected as the research objects (BA group), and 50 normal healthy children who received routine physical examination in our hospital during the same period were selected as blank control group. Outcome measures included postoperative total bilirubin levels and conjugality of enrolled patients. Bilirubin level, unbound bilirubin level, serum transforming growth factor-beta-1 (TGF-β1), vascular endothelial growth factor (VEGF), liver function indicators albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and other observation indicators were included. All data in this study were collected and analyzed by SPSS 23.0 software, and t-test was performed. Results The serum levels of TGF-β1, VEGF, ALT, AST, GGT, and liver hardness were significantly higher in children with jaundice than those without jaundice, and the serum ALB level was significantly lower than that in children without jaundice (P < 0.05). The levels of TGF-β1 and VEGF in BA group were positively correlated with the levels of ALT, AST, GGT, and liver hardness (P < 0.05) but negatively correlated with the level of ALB (P < 0.05). Conclusion The levels of serum TGF-β1 and VEGF in children with biliary atresia have a certain risk correlation with liver function damage, which will become a research focus on the mechanism of liver fibrosis in the diagnosis and treatment of biliary atresia in children.

Time-Fixed Glucose Oxidase-Peroxidase Method for Measurement of Serum Unbound Bilirubin Levels.

In the original glucose oxidase-peroxidase (GOD-POD) protocol, the time required to decrease the initial total bilirubin (TB) level by 20% is used for unbound bilirubin (UB) calculation. However, it needs to continuously monitor the TB levels by spectrometry. Here, we hypothesized that the TB decrease during fixed time periods can also be used to extrapolate UB values (fixed-time protocol). Serum UB levels measured by the different protocols were compared using 10 newborn serum samples. Serum UB levels determined using the fixed-time protocol, especially using periods of 10 - 40 seconds, were strongly correlated with those determined using the original protocol (coefficient of determination > 0.9). The fixed-time protocol, using periods of 20 - 60 seconds, showed the high measurement precision (coefficient of variation < 5%). The fixed-time protocol, using periods of 20 - 40 seconds, can help determine serum UB levels as effectively as the original protocol.

High levels of unbound bilirubin are associated with acute bilirubin encephalopathy in post-exchange transfusion neonates

BackgroundAlthough it is known that unbound bilirubin can enter the brain, there is little evidence of its association with the development of acute bilirubin encephalopathy. Here, we investigated this potential relationship in neonates who had undergone exchange transfusion.MethodsData from 46 newborns who underwent exchange transfusion between 2016 and 1-1 to 2018-12-31 at the First People’s Hospital of Changde City in China were analyzed. The unbound bilirubin level was taken as the independent variable and the development of the acute bilirubin encephalopathy as the dependent variable. The covariates were age, birth weight, sex, red blood cell count, blood glucose, hemolytic disease, and whether the infant had received phototherapy.ResultsThe mean age and gestational age of the neonates were 146.5 ± 86.9 h and 38.6 ± 1.3 weeks [38.7(34.6–41.1) weeks] old, respectively; 52.17% were male. Binary logistic regression analysis after adjustment for covariates showed a positive association between the levels of unbound bilirubin and the development of acute bilirubin encephalopathy (odds ratio = 1.41, 95% confidence intervals 1.05–1.91, P = < 0.05).ConclusionThere is a significant association between unbound bilirubin levels and the development of acute bilirubin encephalopathy in neonates. Further investigations are required to explore the mechanisms.

Acetaminophen elevates unbound bilirubin levels by the glucose oxidase-peroxidase method.

Acetaminophen is widely administered to neonates but its effect on unbound bilirubin (UB) levels remains unclear. The aim of this study was to clarify whether administration of acetaminophen is related to an elevation of UB levels. Infants with a birthweight of ˂1,500g admitted to our neonatal intensive care unit between January 2017 and April 2020 were retrospectively reviewed. Seventy-one infants were enrolled, five of whom had received acetaminophen. Clinical data were analyzed when the highest UB value (UB peak) in each infant was recorded. Demographic data and information on treatment within the 24h before the UB peak were also collected. UB was determined by the glucose oxidase-peroxidase (GOD-POD) method. Infants were categorized according to the presence or absence of acetaminophen administration (acetaminophen and no acetaminophen groups) within 24h of the UB peak. The relationship between UB values and various clinical variables was then compared. Both the peak UB value and the ratio of gastrointestinal disease were higher in the acetaminophen group than in the no acetaminophen group. Univariate analysis revealed that a total of seven variables were potentially correlated with UB peak values (P<0.10). Multivariate analysis showed that acetaminophen and direct bilirubin were independently associated with UB peak values. Our study suggests that administration of acetaminophen is related to higher UB levels by the GOD-POD method. UB values measured by the GOD-POD method should not be used in infants treated with acetaminophen for evaluation of bilirubin neurotoxicity avoidance.

Neonatal Jaundice in Preterm Infants with Bilirubin Encephalopathy

Introduction: The aim of this study is to clarify bilirubin parameters and its treatment in preterm infants with bilirubin encephalopathy (pBE). Methods: We asked the responders to an earlier nationwide Japanese survey on pBE to provide additional information. pBE was diagnosed based on the criteria used in the nationwide survey. We collected data on serum total bilirubin (TB), direct bilirubin (DB), albumin, and unbound bilirubin (UB) levels during the first 8 weeks of life, and on phototherapy and exchange transfusion treatments. Results: We obtained clinical data from 75 patients with pBE from 58 hospitals (response rate of 59%), who were born between 2002 and 2016. The average peak TB level was 12.6 mg/dL (215 μmol/L), and the average age at peak attainment was 19.7 days after birth. Albumin level was <2.5 g/dL in 44 patients, and the peak DB level was ≥2 mg/dL (34.2 μmol/L) in 20 patients. The average peak bilirubin/albumin (B/A) (mg/g) ratio was 3.8 (molar ratio of 0.475), and the average age at peak attainment was 18.6 days. The average peak UB level was 0.67 μg/dL (11.5 nmol/L). The median duration of phototherapy was 6 days, and the median day of the last session was 12. The peak TB level occurred after the last day of phototherapy in 30 of the 61 patients available for comparison. Conclusions: Most patients with pBE lacked marked elevations in serum TB levels and the B/A ratio, the peaks of which were sometimes delayed to >4 weeks after birth.

Bilirubin/albumin (B/A) ratios correlate with unbound bilirubin levels in preterm infants.

A strong correlation between the bilirubin/albumin (B/A) ratio and unbound bilirubin (UB) levels in newborns ≥35 weeks of gestation has been reported. However, in preterm infants, the usefulness of B/A ratios remains unclear. We obtained serum from 381 newborns <35 weeks of gestation. UB levels were measured using the glucose oxidase-peroxidase method. Total serum bilirubin (TB) and albumin (Alb) concentrations were measured spectrophotometrically. Samples were then stratified into two groups based on the infant's phototherapy use. B/A ratios were calculated and correlated with UB levels. Samples taken from infants prior to or never receiving phototherapy (No PTx) were then stratified by gestational age (GA) epochs: 22-27, 28-29, 30-31, and 32-34 weeks and B/A ratios correlated with UB levels. B/A ratios significantly correlated with UB levels in samples from the No PTx cohort (n = 1250; y = 1.83x - 0.15, r2 = 0.93) when compared with samples from infants post-phototherapy (Post-PTx, n = 2039; y = 1.05x + 0.09, r2 = 0.69). Even when stratified by GA, the correlation remained. In preterm infants <35 weeks of gestation, B/A ratios correlated with UB levels better in infants prior to or never receiving phototherapy than in those infants receiving phototherapy. The bilirubin/albumin (B/A) ratio significantly correlates with unbound bilirubin (UB) levels in preterm infants <35 weeks of gestation. The B/A ratio can be used as an index of UB levels in preterm infants <35 weeks of gestation. The B/A ratio is useful, especially when UB measurements are not available, for managing hyperbilirubinemia in preterm infants.

Unbound bilirubin levels in phototherapy-treated preterm infants receiving soy-based lipid emulsion.

Phototherapy is an effective treatment for neonatal jaundice. Treatment indication uses total serum bilirubin (TSB), although unbound bilirubin (Bf) more accurately predicts disability risk. The goals of this investigation were to examine the response of Bf and TSB to phototherapy in preterm infants, and we hypothesized that (i) TSB and Bf respond differently; (ii) the relationship between TSB and Bf is altered; and (iii) unexpected Bf elevations are found. One hundred and seventeen preterm infants <2kg at birth and receiving (IL) were enrolled; and measurements of TSB and Bf were obtained. TSB was measured by the diazo method and Bf with a fluorescent Bf sensor BL22P1B11-Rh. Initial mean (± SD) TSB and Bf levels (41.4±6.9h) were 8.0±9.0mg/dL and 16.9±12.4nmol/L (P<0.05). The rates of rise (ROR) were 0.21±0.10mg/dL/h for TSB and 0.38±0.33nmol/L/h for Bf. Phototherapy reduced TSB from 8.0±9.0 to 5.8±9.4mg/dL (P=0.068) but Bf did not change (16.9±12.4 to 14.1±9.4nmol/L P=n.s.). Bf levels were >11nmol/L in 64, >17nmol/L in 18, and >22nmol/L in 7 infants. Bf and TSB responded differently. While TSB and Bf correlated well before phototherapy, they did not correlate during phototherapy. TSB showed a trend toward a reduction with treatment, Bf did not. While TSB ROR information is not helpful, ROR Bf data can be utilized to anticipate treatment. Potentially high Bf levels existed before and after phototherapy and the mean Bf level at phototherapy termination remained elevated in a significant proportion of infants.

Unbound bilirubin measurements by a novel probe in preterm infants

Background: Hyperbilirubinemia occurs in over 80% of newborns and severe bilirubin toxicity can lead to neurological dysfunction and death, especially in preterm infants. Currently, the risk of bilirubin toxicity is assessed by measuring the levels of total serum bilirubin (TSB), which are used to direct treatments including immunoglobulin administration, phototherapy, and exchange transfusion. However, free, unbound bilirubin levels (Bf) predict the risk of bilirubin neurotoxicity more accurately than TSB.Objective: To examine Bf levels in preterm infants and determine the frequency with which they exceed reported neurotoxic thresholds.Methods: One hundred thirty preterm infants (BW 500–2000 g; GA 23–34 weeks) were enrolled and Bf levels measured during the first week of life by the fluorescent Bf sensor BL22P1B11-Rh. TSB and plasma albumin were measured by standard techniques. Bilirubin-albumin dissociation constants (Kd) were calculated based on Bf and plasma albumin.Results: Five hundred eighty samples were measured during the first week of life, with an overall mean Bf of 13.6 ± 9.0 nM. A substantial number of measurements exceeded potential toxic thresholds levels as reported in the literature. The correlation between Bf and TSB was statistically significant (r2 0.17), but this weak relationship was lost at high Bf levels. Infants <28-week gestations had more hearing screening failures than infants ≥28-week gestation.Conclusions: Unbound (free) bilirubin values are extremely variable during the first week of life in preterm infants. A significant proportion of these values exceeded reported neurotoxic thresholds.

Neonatal Hyperbilirubinemia and Chronic Auditory Toxicity

Research Article| January 01 2018 Neonatal Hyperbilirubinemia and Chronic Auditory Toxicity AAP Grand Rounds (2018) 39 (1): 4. https://doi.org/10.1542/gr.39-1-4 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Neonatal Hyperbilirubinemia and Chronic Auditory Toxicity. AAP Grand Rounds January 2018; 39 (1): 4. https://doi.org/10.1542/gr.39-1-4 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search toolbar search search input Search input auto suggest filter your search All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: neonatal jaundice, toxic effect, hyperbilirubinemia Source: Amin SB, Saluja S, Saili A, et al. Chronic auditory toxicity in late preterm and term infants with significant hyperbilirubinemia. Pediatrics. 2017; 140(4): e20164009; doi: https://doi.org/10.1542/peds.2016-4009Google Scholar Investigators from multiple institutions in the United States and India conducted a prospective study to assess the association of chronic auditory toxicity and total serum bilirubin (TSB), unbound bilirubin (UB), and bilirubin albumin molar ratio (BAMR) in infants with significant neonatal hyperbilirubinemia. Study participants were infants born at ≥34 weeks’ gestation who were admitted to one of two NICUs in India with TSB levels ≥20 mg/dL or with TSB levels above the recommended threshold for exchange transfusion. In addition to TSB, both albumin levels (used to compute BAMR) and UB were measured. When study participants were 2–3 months old, they had auditory brainstem response and otoacoustic emission testing performed, along with tympanometry to detect auditory neuropathy spectrum disorder (ANSD). When the infants were 9–12 months old, they had formal auditory testing to detect sensorineural hearing loss (SNHL). Infants with either ANSD or SNHL with normal tympanometry were classified as having chronic auditory toxicity (CAT). After correcting for risk factors for bilirubin neurotoxicity (eg, perinatal asphyxia, sepsis, hypoxia, acidosis, hypoalbuminemia, and hemolysis), the association between TSB, BAMR, and UB and CAT were assessed using regression analysis. In addition, covariate-adjusted receiver operating characteristic curves were constructed using each of these markers as a predictor of CAT; the area under the curve (AUC) for each was compared. A total of 100 infants were enrolled in the study, and auditory testing was completed in 93. Overall, 12 infants (13%) were classified as having CAT, including 3 with ANSD, 4 with SNHL, and 5 with both; 4 children had profound SNHL (threshold >70 dB). Clinical characteristics were similar in infants with and without CAT. Mean peak TSB levels were 29.0 mg/dL among those with CAT and 23.6 mg/dL in infants without CAT (P = .14 after adjusting for covariates). Similarly, there was no statistically significant association between BAMR and CAT. However, UB levels were significantly higher in infants with CAT than in those without CAT (P = .001, adjusted odds ratio 2.41; 95% CI 1.43–4.07). The AUC for UB as a predictor of CAT was significantly higher than for TSB and BAMR (0.866, 0.775, and 0.724, respectively, P = .03). Among 63 study infants with a peak TSB <25 mg/dL, 5 (8%) were diagnosed with CAT. UB, but not TSB or BAMR, was significantly associated with CAT in this group of infants. The authors conclude that unconjugated bilirubin (ie, UB) is associated with CAT among infants born at ≥34 weeks’ gestation with significant hyperbilirubinemia. Dr Mintzer has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. Based on AAP guidelines, routine screening of bilirubin levels has become standard practice for the prevention of acute bilirubin encephalopathy among all newborn infants.1... You do not currently have access to this content.

The first 24-hour bilirubin level as a predictor of hyperbilirubinemia in healthy term newborns

Background Early discharging healthy term newborns results ina difficulty to recognize hyperbilirubinemia.Objective The aim of this study was to determine the value of thefirst 24-hour total and unbound bilirubin levels in predicting hyper-bilirubinemia in healthy term newborns.Methods The first 24-hour and the 5 th day total and unboundbilirubin levels were measured in 84 healthy term newborns. Thetotal bilirubin level was measured spectrophotometrically, whereasunbound bilirubin level was determined by peroxidase-oxidationmethod. Hyperbilirubinemia was defined as serum total bilirubin of&gt;12.9 mg/dL or serum unbound bilirubin of &gt;0.5 mg/dL after 24hours of life.Results A correlation between the first 24-hour and the 5 th daytotal bilirubin levels was found (r= 0.53) with a regression equa-tion: Y (total bilirubin on day 5) = 4.69 + 1.15X (total bilirubin in thefirst 24 hours). In unbound bilirubin (r=0.31), the regression equa-tion was Y (unbound bilirubin on day 5) = 0.13 + 0.95X (unboundbilirubin in the first 24-hours). The relative risk for developing hy-perbilirubinemia in newborns whose TB 1 was &gt;4.5 mg/dL was 12(95% CI 2.9;48.4), whereas newborns whose UB 1 was &gt;0.09 mg/dL was 9.5 (95% CI 1.2;77.4).Conclusion Total bilirubin level of &gt;4.5 mg/dL in the first 24 hourscan predict the development of hyperbilirubinemia in term new-borns in the first week of life. Newborns with such level of totalbilirubin need a longer stay or should visit the hospital on day 5-7

Serum unbound bilirubin as a predictor for clinical kernicterus in extremely low birth weight infants at a late age in the neonatal intensive care unit.

This study aimed to evaluate peak serum total bilirubin (TB) and unbound bilirubin (UB) levels in preterm infants with clinical kernicterus (KI) who were diagnosed by clinical findings during infancy. For this multicenter retrospective study, 18 Japanese extremely low birth weight (ELBW) infants with clinical KI were included. Clinical KI was diagnosed based on the presence of motor developmental impairment with/without athetosis, and abnormal magnetic resonance imaging or brainstem auditory evoked potential findings during infancy. High and low TB or UB levels were defined as serum TB levels ⩾ and <15 mg/dL or serum UB levels ⩾ and <0.8 μg/dL, respectively. The clinical characteristics of KI preterm infants were analyzed. The proportion of infants with high or low serum TB levels and with high or low serum UB levels was then investigated. Sensitivity and specificity were calculated. In 18 KI infants, the median age when serum TB levels peaked was 28 days after birth. In eight KI infants with low serum TB levels, 88% of them had high serum UB levels. For comparison of the number of infants who had high or low serum TB and UB levels, the sensitivity was 90% and specificity was 13%. Serum TB and UB levels peak at a later age than expected. Chronic serum UB monitoring may be helpful for identifying ELBW infants at risk for developing KI, even when they do not have high serum TB levels.

Unbound Unconjugated Hyperbilirubinemia Is Associated with Central Apnea in Premature Infants

To evaluate whether jaundice, indexed by unbound bilirubin (UB), is associated with central apnea in premature infants. A prospective observational study was performed with 27-33 weeks' gestational age infants who were not requiring either mechanical ventilation or noninvasive ventilation with continuous positive airway pressure beyond 24 hours after birth. Infants with congenital infections, chromosomal disorders, craniofacial anomalies, and/or family history of hearing loss were excluded. Total serum bilirubin and UB were measured twice daily during the first postnatal week and then when clinically indicated. Central apnea was evaluated by visual inspection of continuous, electronic cardiorespiratory recordings until 2 weeks of age. One hundred infants were subdivided into 2 groups via median peak UB level: the high UB group (greater than median) and low UB group (less than median). The high UB group had an increased frequency of apnea events during the first 2 weeks compared with infants in the low UB group. After we controlled for confounders, the high UB group had more events of apnea during the first 2 postnatal weeks compared with the low UB group (incidence rate ratio: 1.9, 95% CI 1.2-3.2). Our findings suggest that jaundice, as indexed by UB, is associated with central apnea in premature infants.

Severely high serum unbound bilirubin level after abdominal surgery in a newborn

We report a newborn with intestinal malrotation who developed a severely high serum unbound bilirubin level and a low serum albumin level without a marked increase in serum total bilirubin level after abdominal surgery, which required exchange transfusion and albumin supplementation. The serum unbound bilirubin level may be highly relative to the serum total bilirubin level in newborns who have undergone abdominal surgery soon after birth and are hypoalbuminemic after surgery.

The significance of measurement of serum unbound bilirubin concentrations in high‐risk infants

In the management of neonatal hyperbilirubinemia, total bilirubin (TB) concentration is not specific enough to predict the brain damage caused by bilirubin toxicity. Unbound bilirubin (UB) easily passes the blood-brain barrier and causes neurotoxicity. We aimed to evaluate whether serum UB concentration would be a useful predictor of bilirubin encephalopathy in high-risk infants. We measured the serum TB and UB concentrations of 388 newborn infants treated with phototherapy or exchange transfusion for their hyperbilirubinemia at Takatsuki General Hospital between January 2002 and October 2003. Peak serum TB and UB levels and UB/TB ratios were studied on each birthweight group: below 1500 g (very low birthweight), 1500 g-2499 g (low birthweight), above 2500 g (normal birthweight); and several clinical factors influencing hyperbilirubinemia were also studied. Peak serum TB and UB levels increased with increasing birthweight, while UB/TB ratios decreased. The very low birthweight group showed higher UB levels and UB/TB ratios despite lower TB levels in intraventricular hemorrhage or severe infection compared to those in the others. The low birthweight and normal birthweight groups showed higher TB and UB levels in cases of hemolytic disease of the newborn compared to non-hemolytic disease of the newborn cases. Eight of 44 cases showed high UB levels accompanied by abnormal auditory brainstem responses, one of whom subsequently developed ataxic cerebral palsy with hearing loss, whereas the other seven showed transient abnormalities of auditory brainstem responses by the treatment of exchange transfusion or phototherapy. The UB measurement was considered to be significant for the assessment of the risk of bilirubin neurotoxicity and the appropriate intervention for hyperbilirubinemia in high-risk infants.

Ontogeny of Bilirubin-Binding Capacity and the Effect of Clinical Status in Premature Infants Born at Less Than 1300 Grams

Bilirubin is toxic to the brain and enters the brain in unbound form. Serum unconjugated, unbound bilirubin may be a good predictor of bilirubin encephalopathy. Unbound bilirubin levels may depend on the bilirubin-binding capacity of albumin, which has not been described for neonates of <28 weeks' gestation. The purpose of this work was to determine the ontogeny of bilirubin-binding capacity and the effect of clinical status in very preterm neonates. A total of 152 neonates (23-31 weeks' gestational age; 440-1300 g) were enrolled prospectively. At 5 days of age, total serum bilirubin and unbound bilirubin were measured with the unbound bilirubin-A1 analyzer (Arrows Co, Osaka, Japan) and albumin with the Bromocresol-purple method. Scatchard plots were used to estimate bilirubin-binding affinity and capacity. Clinical status for each infant was rated as high, moderate, or low risk by using a modified Score for Neonatal Acute Physiology model. Low risk was considered clinically stable. Unbound bilirubin has a significant, direct correlation to total bilirubin and is greater in unstable than in stable neonates. For the entire cohort, bilirubin-binding capacity had a direct relationship to gestational age. The bilirubin-binding capacities of infants in the low- and high-risk groups also had a direct relationship to gestational age. Bilirubin-binding capacity was greater in the low-risk group (20.8 +/- 4.6 mg/dL; 356 +/- 79 micromol/L) than in the moderate- (17.8 +/- 3.5 mg/dL; 304 +/- 60 micromol/L) or high- (17.3 +/- 3.4 mg/dL; 296 +/- 58 micromol/L) risk groups. Bilirubin-binding affinity did not differ by clinical risk status or gestational age. In very preterm, very low birth weight infants, bilirubin-binding capacity is directly proportional to gestational age. Bilirubin-binding capacity is lower and unbound bilirubin higher in unstable than in stable neonates. These data may be useful in guiding the management of hyperbilirubinemia in very low birth weight infants.

Kernicterus: Past, Present, and Future

The concept of a relationship between severe neonatal hyperbilirubinemia and kernicterus evolved slowly. Jaundice was recognized in ancient as well as biblical times as a manifestation of disease. However, according to Louis K. Diamond (Fig. 1), who reviewed the history of neonatal jaundice, (1) the first record concerning jaundice of the newborn appears to be by Barthomomaeus Metlinger in 1473 in his book Ein Regiment der Jungen Kinder . The occurrence of jaundice shortly after birth as well as some suggestions for homeopathic treatment were mentioned by Michael Ettmuller in his 1708 treatise “De Infantum Morbis.” (1) An early description of icterus neonatorum was published in 1742 in London by John Burton in his treatise “A Full View of All the Diseases Incident to Children.” He suggested that “jaundice generally yields to any gentle purgative.” (1) This same approach was used by Condie in 1853 in Philadelphia. (2) At that time, he wrote that icterus neonatorum seemed to be “connected with the want of a free evacuation of meconium.” He suggested the use of castor oil or a small measure of calomel or rhubarb. It is interesting that he noted that the jaundice was known at times to be accompanied by a “good deal of drowsiness.” There were several publications in France concerning neonatal jaundice in the late eighteenth and early nineteenth centuries, the most significant of which, according to Thor Hansen, (3) was the thesis submitted by Jacques Francois Hervieux and defended by him for his M.D. degree at the University of Paris in 1847. The thesis was entitled “De l’ictere des nouveau-nes” (On the jaundice of newborns). Thor Hansen, to whom we are grateful for having reviewed the original French thesis, pointed out that the introductory section of the Hervieux thesis contains a valuable review of works by …

Bilirubin and serial auditory brainstem responses in premature infants.

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.

Brainstem bilirubin toxicity in the newborn primate may be promoted and reversed by modulating PCO2.

The auditory brainstem response (ABR) was monitored during infusion of bilirubin in six ventilated newborn rhesus monkeys (138-145 d gestation) while acute changes in pH were produced by varying inspired CO2. Prolonged respiratory acidosis without bilirubin infusion produced minimal changes in the ABR (one animal). CO2 exposure, usually initiated when the bilirubin level reached approximately 20 mg/dL, decreased arterial pH to values ranging from 6.85 to 7.10. ABR changes, including prolongation of the wave II-IV peak to peak intervals and decreased wave amplitudes, first developed 2-4 h after initial exposure to CO2. Total and unbound bilirubin levels at this time ranged from 376 to 564 mumol/L (22-33 mg/dL) and 38 to 65 nmol/L (2.5-3.8 micrograms/dL), respectively. Correction of respiratory acidosis produced partial to complete reversal of ABR changes within 3 to 20 min. Reexposure to CO2 immediately reproduced the ABR abnormality. Production and reversal of the abnormal ABR was obtained through two to three cycles in three animals. Thus, when the brainstem bilirubin level was near the threshold for toxicity, the effect of changes in PCO2 on the ABR were immediate, suggesting that auditory pathway toxicity is initially mediated by a reversible pH-dependent bilirubin-membrane complex. In contrast to humans, in monkeys auditory toxicity appeared to be a late manifestation of bilirubin toxicity, inasmuch as all monkeys were obtunded and apneic 30-70 min before ABR abnormalities appeared. Notwithstanding these limitations, the results support the hypothesis that bilirubin toxicity can be both promoted and reversed by modulating brain pH.

Stage-Specific Relationship between Plasma Total and Cerebellar Bilirubin Levels during Early Postnatal Period in Jaundiced Gunn Rats

Abstract Relationships between plasma total or unbound bilirubin level and cerebellar bilirubin level were examined during the first 14 days after birth in homozygous Gunn rats with hyperbilirubinemia. Correlation coefficients between plasma total and cerebellar bilirubin levels were 0.63, 0.74, 0.48 and 0.60 at days 3, 7, 9 and 11, respectively, and were all significant, whereas the coefficient at day 14 (0.10) was not significant. The correlation coefficients between plasma unbound and cerebellar bilirubin levels were 0.40, 0.09, and 0.12 at days 7, 11 and 14, respectively, and were not significant. Thus, the cerebellar bilirubin level is suggested to depend on the plasma total bilirubin level from day 3 to 11.