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  • Serum Bilirubin and Bilirubin/Albumin Ratio asPredictors of Bilirubin Encephalopathy

    WHATS KNOWN ON THIS SUBJECT: Jaundiced newborns withoutadditional risk factors rarely develop kernicterus if the totalserum bilirubin is ,25 mg/dL. Measuring the bilirubin/albuminratio might improve risk assessment, but the relationships ofboth indicators to advancing stages of neurotoxicity are poorlydocumented.

    WHAT THIS STUDY ADDS: Both total serum bilirubin andbilirubin/albumin ratio are strong predictors of advancing stagesof acute and post-treatment auditory and neurologic impairment.However, bilirubin/albumin ratio, adjusted to the same sensitivity,does not improve prediction over total serum bilirubin alone.

    abstractBACKGROUND AND OBJECTIVE: Bilirubin/albumin ratio (B/A) mayprovide a better estimate of free bilirubin than total serum bilirubin(TSB), thus improving identification of newborns at risk for bilirubinencephalopathy. The objective of the study was to identify thresholdsand compare specificities of TSB and B/A in detecting patients withacute and posttreatment auditory and neurologic impairment.

    METHODS: A total of 193 term/near-term infants, admitted for severejaundice to Cairo University Childrens Hospital, were evaluated forneurologic status and auditory impairment (automated auditorybrainstem response), both at admission and posttreatment byinvestigators blinded to laboratory results. The relationships ofTSB and B/A to advancing stages of neurotoxicity were comparedby using receiver operating characteristic curves.

    RESULTS: TSB and B/A ranged from 17 to 61 mg/dL and 5.4 to 21.0 mg/g,respectively; 58 (30%) of 193 subjects developed acute bilirubin enceph-alopathy, leading to kernicterus in 35 infants (13 lethal). Auditory impair-ment was identified in 86 (49%) of 173 infants at admission and in 22 of128 at follow-up. In the absence of clinical risk factors, no residualneurologic or hearing impairment occurred unless TSB exceeded31 mg/dl. However, transient auditory impairment occurred at lowerTSB and B/A (22.9 mg/dL and 5.7 mg/g, respectively). Interventionvalues of TSB and B/A set at high sensitivity to detect differentstages of neurotoxicity had nearly the same specificity.

    CONCLUSIONS: Both TSB and B/A are strong predictors of neurotoxicity,but B/A does not improve prediction over TSB alone. Threshold valuesdetecting all affected patients (100% sensitivity) increase with advancingseverity of neurotoxicity. Pediatrics 2014;134:e1330e1339

    AUTHORS: Iman Iskander, MD,a Rasha Gamaleldin, MD,a

    Salma El Houchi, MD,a Amira El Shenawy, MD,b ImanSeoud, MD,a Nesrin El Gharbawi, MD,c HazemAbou-Youssef, MD,c Aleksandr Aravkin, PhD,d andRichard P. Wennberg, MDe

    Departments of aPediatrics, bAudiology, and cClinical/ChemicalPathology, Cairo University, Cairo, Egypt; dIBM Thomas J. WatsonResearch Center, Yorktown Heights, New York; and eDepartmentof Pediatrics, University of Washington, Seattle, Washington

    KEY WORDShyperbilirubinemia, bilirubin/albumin ratio, kernicterus, auditoryimpairment, bilirubin-induced neurologic dysfunction, bind score,automated auditory brainstem response

    ABBREVIATIONSAABRautomated auditory brainstem responseAAPAmerican Academy of PediatricsABEacute bilirubin encephalopathyB/Abilirubin to albumin ratioBffree bilirubinBINDbilirubin-induced neurologic dysfunctionGAgestational ageG6PDglucose 6 phosphate dehydrogenaseROCreceiver operating characteristicRRbilateral refer responseTSBtotal serum bilirubin

    Dr Iskander helped in designing the study, was responsible fortraining for bilirubin-induced neurologic dysfunction scoreexamination, monitored cases while in hospital and coordinatedfollow-up after discharge, supervised research steps and datacollection, and drafted, reviewed, and edited the manuscriptuntil final approval; Dr Gamaleldin coordinated and superviseddata collection and completion for both inpatients and follow-upand reviewed the manuscript before submission; Dr El Houchiwas responsible for clinical examination at follow-up for allpatients; Dr El Shenawy was responsible for the auditoryassessments for infants during admission and at follow-up, aswell as the diagnostic auditory procedures; Dr El Gharbawy wasresponsible for the laboratory coordination during admission aswell as glucose 6 phosphate dehydrogenase at follow-up;Dr Abou-Youssef was responsible for data analysis as well asreview and editing of the manuscript until final approval;Dr Seoud participated in study design and in designing data-collection instruments as well as supervising research tillcompletion; Dr Aravkin carried out receiver operatingcharacteristic analyses and edited the manuscript; andDr Wennberg was principal investigator on the supportingNational Institute of Child Health and Human Development grant,conceptualized and designed the study and data-collection tools,drafted the initial manuscript, and edited and approved the finalmanuscript.

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  • The American Academy of Pediatrics(AAP) guidelines for treating neonataljaundice and preventing kernicterus interm/near-term infants are based ontotal serum bilirubin (TSB) levels ad-justed for the absence or presence ofclinical risk factors (eg, low gestationalage [GA], sepsis, hemolytic disease).1

    Plasma free bilirubin (Bf) is thought tobe a better indicator of neurotoxicitythan TSB, because only Bf can cross theblood-brain barrier.2,3 In the absence ofan available assay for Bf, the bilirubin/albumin ratio (B/A) might provide abetter estimate of Bf because it con-tains 2 of the 3 factors determiningBf (TSB, albumin, and the albumin-binding affinity).2,3 The relationshipbetween Bf and B/A has been studiedby titration of serum samples4 and bymeasuring Bf in serum of infants withvarying B/A,5 but clinical evidencecomparing the relationships of TSBand B/A with outcome is sparse.6,7 B/Ais currently recommended as a safe-guard to identify the rare infant atrisk for neurotoxicity at low TSB be-cause of a low serum albumin con-centration.1

    This study evaluated TSB and B/A aspredictors of pretreatment and posttreat-ment auditory and neurologic impairmentin infants with severe hyperbilirubinemia.We hypothesize that B/A is a betterpredictor of bilirubin toxicity than TSB.A secondary hypothesis is that advanc-ing stages of bilirubin neurotoxicityhave increasing threshold values for TSBand B/A.


    General Study Design

    This prospective longitudinal observa-tional study was performed at CairoUniversity Childrens Hospital. Infantsadmitted with severe hyperbilirubinemiareceived serial neurologic evaluationsusing a standard examination forgrading the severity of bilirubin-induced neurologic dysfunction (BIND

    score; Appendix 1).8 Auditory functionwas assessed with the automated au-ditory brainstem response (AABR) de-vice (Algo3i; Natus Medical, Inc, SanCarlos, CA).9 AABRs were obtainedwithin 2 hours of admission and atdischarge in most patients. Follow-upevaluation at 3 to 5 months includedboth a neurologic examination10 andrepeat AABR.

    Treatment decisions were made by at-tending physicians blinded to AABR andBIND score data. Criteria for exchangetransfusionwerea TSB level$25mg/dL,presence of neurologic signs, or arapid rise of TSB on day 1. Investigatorscalculating BIND score, performingAABRs, and conducting follow-up assess-ments were blinded to laboratory dataand were not involved in patient man-agement.


    A total of 224newbornswere enrolled ina study evaluating risk factors for bil-irubin encephalopathy between June2009 and October 2010. Entry criteriaincluded infants #14 days old withsevere jaundice requiring intensivephototherapy or exchange transfusionand an estimated GA$34 weeks (usingthe New Ballard Score).11 We analyzeda subcohort of 193 infants after ex-cluding infants with missing albumindata (23 cases), inadequate outcomedocumentation (4 cases), or comorbidconditions unrelated to jaundice (4cases). The study was approved byinstitutional review boards at partici-pating universities, and parental in-formed consents were obtained for allinfants.

    Laboratory Analysis

    TSB and albumin levels were de-termined in the clinical laboratory atCairo University Childrens Hospital.TSB was measured by the Doumasmodification of the Jendrassik-Grof

    diazo method12 and albumin by thebromocresol purple method13 by using aDimension RxL analyzer (Siemens Health-care Diagnostics Inc, Tarrytown, NY).Quantitative glucose-6-phosphate dehy-drogenase (G6PD) assay was performedat 3 to 5 months by using a G6PDH kit(Trinity Biotech, Bray, Ireland). Deficiencywas defined as G6PD activity ,6.4 U/ghemoglobin.

    Outcome Definitions

    Overt acute bilirubin encephalopathy(ABE) is defined as a BIND score of 4 to 9.The BIND score7 describes the pro-gression of ABE. Scores of 4 to 6 repre-sent moderate ABE, and scores of 7 to 9indicate severe ABE that is highly asso-ciated with kernicterus or death.8,1416

    Infants with BIND scores of 1 to 3 arereferred to as having mild neurotoxicityor mild ABE that is likely to be reversiblewithout sequelae.

    Posttreatment diagnosis of kernicterusrequired 1 of the following criteria:death from severe ABE, neurologicfindings of kernicterus at follow-upas described by Shapiro,10 or per-sistent severe encephalopathy andbilateral refer (RR) AABR at hospitaldischarge for infants lost to follow-up. MRI examinations were not per-formed.

    Auditory impairment was defined asa bilateral refer for further evalua-tion result (RR AABR). Bilateral passor unilateral pass was considerednormal. Admission AABRs were usu-ally unsuccessful in severely affectedinfants due to muscle activity. If theBIND score was 6 to 9 and