Serum Bilirubin and Bilirubin/Albumin Ratio as...

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Serum Bilirubin and Bilirubin/Albumin Ratio as Predictors of Bilirubin Encephalopathy WHATS KNOWN ON THIS SUBJECT: Jaundiced newborns without additional risk factors rarely develop kernicterus if the total serum bilirubin is ,25 mg/dL. Measuring the bilirubin/albumin ratio might improve risk assessment, but the relationships of both indicators to advancing stages of neurotoxicity are poorly documented. WHAT THIS STUDY ADDS: Both total serum bilirubin and bilirubin/albumin ratio are strong predictors of advancing stages of 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. abstract BACKGROUND AND OBJECTIVE: Bilirubin/albumin ratio (B/A) may provide a better estimate of free bilirubin than total serum bilirubin (TSB), thus improving identi cation of newborns at risk for bilirubin encephalopathy. The objective of the study was to identify thresholds and compare specicities of TSB and B/A in detecting patients with acute and posttreatment auditory and neurologic impairment. METHODS: A total of 193 term/near-term infants, admitted for severe jaundice to Cairo University Childrens Hospital, were evaluated for neurologic status and auditory impairment (automated auditory brainstem response), both at admission and posttreatment by investigators blinded to laboratory results. The relationships of TSB and B/A to advancing stages of neurotoxicity were compared by 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 identied in 86 (49%) of 173 infants at admission and in 22 of 128 at follow-up. In the absence of clinical risk factors, no residual neurologic or hearing impairment occurred unless TSB exceeded 31 mg/dl. However, transient auditory impairment occurred at lower TSB and B/A (22.9 mg/dL and 5.7 mg/g, respectively). Intervention values of TSB and B/A set at high sensitivity to detect different stages of neurotoxicity had nearly the same specicity. CONCLUSIONS: Both TSB and B/A are strong predictors of neurotoxicity, but B/A does not improve prediction over TSB alone. Threshold values detecting all affected patients (100% sensitivity) increase with advancing severity 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 Iman Seoud, MD, a Nesrin El Gharbawi, MD, c Hazem Abou-Youssef, MD, c Aleksandr Aravkin, PhD, d and Richard P. Wennberg, MD e Departments of a Pediatrics, b Audiology, and c Clinical/Chemical Pathology, Cairo University, Cairo, Egypt; d IBM Thomas J. Watson Research Center, Yorktown Heights, New York; and e Department of Pediatrics, University of Washington, Seattle, Washington KEY WORDS hyperbilirubinemia, bilirubin/albumin ratio, kernicterus, auditory impairment, bilirubin-induced neurologic dysfunction, bind score, automated auditory brainstem response ABBREVIATIONS AABRautomated auditory brainstem response AAPAmerican Academy of Pediatrics ABEacute bilirubin encephalopathy B/Abilirubin to albumin ratio Bffree bilirubin BINDbilirubin-induced neurologic dysfunction GAgestational age G6PDglucose 6 phosphate dehydrogenase ROCreceiver operating characteristic RRbilateral refer response TSBtotal serum bilirubin Dr Iskander helped in designing the study, was responsible for training for bilirubin-induced neurologic dysfunction score examination, monitored cases while in hospital and coordinated follow-up after discharge, supervised research steps and data collection, and drafted, reviewed, and edited the manuscript until nal approval; Dr Gamaleldin coordinated and supervised data collection and completion for both inpatients and follow-up and reviewed the manuscript before submission; Dr El Houchi was responsible for clinical examination at follow-up for all patients; Dr El Shenawy was responsible for the auditory assessments for infants during admission and at follow-up, as well as the diagnostic auditory procedures; Dr El Gharbawy was responsible for the laboratory coordination during admission as well as glucose 6 phosphate dehydrogenase at follow-up; Dr Abou-Youssef was responsible for data analysis as well as review and editing of the manuscript until nal approval; Dr Seoud participated in study design and in designing data- collection instruments as well as supervising research till completion; Dr Aravkin carried out receiver operating characteristic analyses and edited the manuscript; and Dr Wennberg was principal investigator on the supporting National 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 nal manuscript. (Continued on last page) e1330 ISKANDER et al by guest on April 19, 2018 http://pediatrics.aappublications.org/ Downloaded from

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Serum Bilirubin and BilirubinAlbumin Ratio asPredictors of Bilirubin Encephalopathy

WHATrsquoS KNOWN ON THIS SUBJECT Jaundiced newborns withoutadditional risk factors rarely develop kernicterus if the totalserum bilirubin is 25 mgdL Measuring the bilirubinalbuminratio might improve risk assessment but the relationships ofboth indicators to advancing stages of neurotoxicity are poorlydocumented

WHAT THIS STUDY ADDS Both total serum bilirubin andbilirubinalbumin ratio are strong predictors of advancing stagesof acute and post-treatment auditory and neurologic impairmentHowever bilirubinalbumin ratio adjusted to the same sensitivitydoes not improve prediction over total serum bilirubin alone

abstractBACKGROUND AND OBJECTIVE Bilirubinalbumin ratio (BA) 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 BA in detecting patients withacute and posttreatment auditory and neurologic impairment

METHODS A total of 193 termnear-term infants admitted for severejaundice to Cairo University Childrenrsquos 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 BA to advancing stages of neurotoxicity were comparedby using receiver operating characteristic curves

RESULTS TSB and BA ranged from 17 to 61 mgdL and 54 to 210 mggrespectively 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 mgdl However transient auditory impairment occurred at lowerTSB and BA (229 mgdL and 57 mgg respectively) Interventionvalues of TSB and BA set at high sensitivity to detect differentstages of neurotoxicity had nearly the same specificity

CONCLUSIONS Both TSB and BA are strong predictors of neurotoxicitybut BA does not improve prediction over TSB alone Threshold valuesdetecting all affected patients (100 sensitivity) increase with advancingseverity of neurotoxicity Pediatrics 2014134e1330ndashe1339

AUTHORS Iman Iskander MDa Rasha Gamaleldin MDa

Salma El Houchi MDa Amira El Shenawy MDb ImanSeoud MDa Nesrin El Gharbawi MDc HazemAbou-Youssef MDc Aleksandr Aravkin PhDd andRichard P Wennberg MDe

Departments of aPediatrics bAudiology and cClinicalChemicalPathology Cairo University Cairo Egypt dIBM Thomas J WatsonResearch Center Yorktown Heights New York and eDepartmentof Pediatrics University of Washington Seattle Washington

KEY WORDShyperbilirubinemia bilirubinalbumin ratio kernicterus auditoryimpairment bilirubin-induced neurologic dysfunction bind scoreautomated auditory brainstem response

ABBREVIATIONSAABRmdashautomated auditory brainstem responseAAPmdashAmerican Academy of PediatricsABEmdashacute bilirubin encephalopathyBAmdashbilirubin to albumin ratioBfmdashfree bilirubinBINDmdashbilirubin-induced neurologic dysfunctionGAmdashgestational ageG6PDmdashglucose 6 phosphate dehydrogenaseROCmdashreceiver operating characteristicRRmdashbilateral refer responseTSBmdashtotal 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-upDr Abou-Youssef was responsible for data analysis as well asreview and editing of the manuscript until final approvalDr 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 grantconceptualized and designed the study and data-collection toolsdrafted the initial manuscript and edited and approved the finalmanuscript

(Continued on last page)

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The American Academy of Pediatrics(AAP) guidelines for treating neonataljaundice and preventing kernicterus intermnear-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 barrier23 In the absence ofan available assay for Bf the bilirubinalbumin ratio (BA) might provide abetter estimate of Bf because it con-tains 2 of the 3 factors determiningBf (TSB albumin and the albumin-binding affinity)23 The relationshipbetween Bf and BA has been studiedby titration of serum samples4 and bymeasuring Bf in serum of infants withvarying BA5 but clinical evidencecomparing the relationships of TSBand BA with outcome is sparse67 BAis 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-centration1

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

METHODS

General Study Design

This prospective longitudinal observa-tional study was performed at CairoUniversity Childrenrsquos 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$25mgdLpresence 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

Subjects

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 Childrenrsquos HospitalTSB 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 64 Ughemoglobin

Outcome Definitions

Overt acute bilirubin encephalopathy(ABE) is defined as a BIND score of 4 to 9The 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 death814ndash16

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 criteriadeath from severe ABE neurologicfindings of kernicterus at follow-upas described by Shapiro10 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 ldquorefer for further evalua-tionrdquo result (RR AABR) Bilateral passor unilateral pass was consideredldquonormalrdquo Admission AABRs were usu-ally unsuccessful in severely affectedinfants due to muscle activity If theBIND score was 6 to 9 and the infantdied of kernicterus or had RR AABR atdischarge the unsuccessful admissionAABR was considered to be RR forstatistical analysis

A diagnostic evaluation for auditoryneuropathy17ndash19 was performed if theAABR screen was RR at 3 to 5 monthsCompliance with follow-up appoint-ments was 745

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Definition of Clinical Risk Factors

Hemolysis was arbitrarily defined ashematocrit 35 with increasedreticulocytes ($6) in patients withpossible isoimmunization Suspectedsepsis was defined as clinical de-terioration in the presence of leuko-cytosis leucopenia shift to the left ofneutrophils and a positive C-reactiveprotein screen20 The accuracy of GAassessment11 was limited by the pa-tientrsquos postnatal age and occasional ill-ness at admission Birth weights wererarely available accuracy of GA waslimited by postnatal age at admissionand confounded by disease in someinfants Historically birth weights or 2500 g have been used to assessrisk due to maturity421 Because birthweights were unavailable and GA oftenuncertain we used admission weight( or 2500 g) the only objectivemeasure available to assign risk re-lated to maturity

Statistical Methods

The initial TSB and BA were used topredict admission BIND scores andAABR results Occasionally blood forexchange transfusion was delayedtherefore peak TSB and peak BAbefore exchange transfusion wereused to predict subsequent out-comes

Quantitative biochemical data werenot normally distributed Data weresummarized asmedians interquartile(25thndash75th percentile) and total rangesand compared by using Mann-WhitneyU and Kruskal-Wallis tests22 Qualita-tive data were presented as fre-quency and percentage Sensitivitiesand specificities associated with dif-ferent cutoff values for TSB and BAwere evaluated by using receiver op-erating characteristic (ROC) curves23

Calculations were performed by usingthe IBM SPSS (version 20) program(IBM SPSS Statistics IBM CorporationChicago IL) For some analyses sub-

jects were stratified by the presenceor absence of possible clinical riskfactors

RESULTS

Patient Characteristics

Although 87of infantswere deliveredat hospitals newborns were usuallydischarged several hours after birthwithout evaluation for jaundice orscheduled follow-up24 Birth weightGA and blood type incompatibilitieswere rarely documented at the birth-ing hospital The median age at ad-mission to the NICU was 45 daysAdmission TSB was250 mgdL in 41infants 251 to 350 mgdL in 117infants and350 mgdL in 35 infantsPatient characteristics are summa-rized in Table 1

Clinical Risk Factors

In this cohort 59 (306) newbornshad no risk factors other than severehyperbilirubinemia Possible clinicalrisk factors were present in 134 infants(694) but confidence in assigningrisk was often lacking Fifty-eight infantsweighed2500 g but it was sometimesunclear whether they were immatureor small for GA

A total of 103 infants had ABO in-compatibility but therewas no evident

relationship between incompatibilityhematocrit reticulocyte count directantiglobulin test and magnitude ofhyperbilirubinemia G6PD deficiencywas identified in 10 of 134 patientstested at follow-up but only 1 had evi-denceof a hemolytic crisis at admissionBlood cultures were positive in 4 of 12infants with suspected sepsis

Because clinical risk factors wereuncertain in a large fraction of sub-jects we used both nonstratified dataand data dichotomized for absence orpresence of possible risk factors foranalyses

Patient Management

All patients received phototherapy (ir-radiance 20 mWcm2nm) Exchangetransfusions were performed in 147patients (762) including all infantsadmitted with ABE (BIND scores 4ndash9)However 66 of infants with no ormild ABE received exchange transfusionbecause of TSB25 mgdL Median TSBand BA values in infants receiving ex-change transfusion were 322 mgdLand 97 mgg respectively comparedwith TSB 251 mgdL and BA 77 mggin those receiving only phototherapyBlood was not available for ex-change transfusion in 3 infants withTSBs 300 to 336 mgdL but they

TABLE 1 Patient Description (n = 193)

Characteristic n

BoysGirls 10093ABO incompatibility 103Rh incompatibility 22G6PD deficiency ( 64 Ug) 10134 testedSuspected sepsis 12 4 positive cultureExchange transfusion 147 (76)

Median 1stndash3rd Quartile Range

Age d 45 30ndash64 04ndash132Admission weight g 2830 2500ndash3200 1500ndash4500Admission TSB mgdL 285 259ndash332 170ndash610Admission BA mgg 86 74ndash102 54ndash210Albumin gdL 35 31ndash37 18ndash48Peak TSB mgdL 296 264ndash344 170ndash610Peak BA mgg 89 76ndash105 54ndash210

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had normal BIND scores and normalfollow-up

Most infants with mild or moderate ABEimproved neurologically after exchangetransfusion but 4 infantswithmaximumTSBs ranging from 35 to 47 mgdL andadmission BIND scores ranging from1 to 4 deteriorated to severe ABE andkernicterusduringorafter theprocedureCulture-proven sepsis was present post-exchange in 2 of these infants A thirdinfant had marked hemolysis from G6PDdeficiency and deteriorated during theexchange transfusion

Outcomes

At admission 25 infants suffered mod-erate ABE (BIND 4ndash6) Among 22 of those25 infants attending follow-up 13 werehealthy 5 had isolated auditory neu-ropathy and 4 had frank kernicterusSevere ABE (BIND score 7ndash9 at admis-sion) occurred in 33 infants Two in-fants with BIND score of 7 lost tofollow-up were neurologically healthyat discharge but had RR AABR Theremaining 31 infants (94) had ad-verse outcomes compared with only 9(41) of 22 infants with moderate en-cephalopathy

Kernicterus was diagnosed in 35 cases13 infants died with severe ABE inhospital 17 had frank kernicterus10 atfollow-up and 5 infants lost to follow-up had signs of persistent bilirubinencephalopathy at discharge All in-fants with kernicterus had BIND scoresof 5 to 9 while hospitalized and all re-ceived exchange transfusion (see Ap-pendix 2 for details)

At admission the AABR was RR in 86(50) of 173 tests performed A total of128 surviving infants were evaluated atfollow-up Sixty percent of infants withadmission RR AABR converted to bi-lateral pass whereas 22 infants hadpersistent RR AABR confirmed to beauditory neuropathy by diagnostic au-diology procedures17ndash19 All infantswithmaximum TSB 31 mgdL and BIND

score3 had normal auditory functionat follow-up

Relationships of TSB and BA toOutcomes

We found a clear stepwise relationshipbetween TSB and BA median andthreshold values and the progressionof acute neurotoxicity (Table 2) Therewas a large gap in thresholds sepa-ratingmild ABE (200mgdLTSB 55mggBA) and moderate ABE (271 mgdL71 mgg) A smaller increase wasnoted between thresholds for moder-ate and severe ABE Two of 4 infantsadmitted at 24 hours of age withrapidly rising TSB (187 and 240 mgdL)had refer AABRs and 1 had a BINDscore of 5 Because the response torapidly rising bilirubin was unique inthese infants infants admitted at 1day of age were excluded from groupanalyses

Subjects were not stratified for riskfactors so results in Table 2 includepatients at the highest clinical riskcategory defined in the AAP guide-lines1 At all stages of toxicity TSBsidentifying 100 of diseased infantswere higher than the recommendedintervention guideline for high-riskinfants38 weeksrsquo GA1 (TSB 190 mgdL)but BA thresholds for mild neurotoxic-ity (BIND scores 2ndash3) and AABR RR atadmission were lower than the AAPrecommendation (68 mgdL)1 When

subjects were dichotomized by thepresence or absence of suspectedrisk factors threshold and medianvalues for most outcomes were nearlyidentical The median and thresholdvalues for severe ABE and kernicteruswere lower in 30 patients with riskfactors present (threshold 289 mgdL)than in 5 infants without clinical riskfactors (threshold 31 mgdL) butthe difference was not statisticallysignificant

ROC Analysis

We compared sensitivities and spe-cificities of TSB and BA in identifyingacute and posttreatment outcomes byusing ROC curves (Fig 1) ROC curvesdescribe the specificity of a diagnostictest at any selected sensitivity (andvice versa) For all outcomes the areaunder the curve for TSB is slightlyhigher than for BA and significantlyhigher for auditory impairment atadmission There is almost no cross-over of ROC curves for TSB and BA inany outcome prediction (ie at anygiven sensitivity the specificity of TSBis equal to or slightly better than BA)Table 3 lists TSB and BA cutoff valuesyielding 100 sensitivity together withspecificities and confidence intervalsfor various stages of neurotoxicity inour study population Calculated cut-offs are consistent with thresholdvalues described in Table 2

TABLE 2 Relationships of TSB and BA to Progression of Neurotoxicity (n = 189)

Outcome n Median TSBa (Range) Median BAb (Range)

Admission AABR RR 83 334 (229cndash610) 100 (57cndash210)Residual Auditory neuropathy at 3 mo 22 371 (310cndash610) 114 (86cndash210)BIND 2ndash3 mild ABE 47 270 (200cndash377) 76 (55cndash144)BIND 4ndash6 moderate ABE 24 323 (271cndash436)d 101 (71cndash137)d

BIND 7ndash9 severe ABE 32 382 (289cndash610)de 113 (86cndash211)df

Kernicterus 35 387 (289cndash610) 115 (86cndash210)

Four patients on admission with hyperbilirubinemia at 24 h of age are excludeda Total serum bilirubin (mgdL) median (minndashmax)b BA (mgg) median (minndashmax)c Thresholdsd P 0005 versus mild ABEe P = 003 versus moderate ABEf P = 030 versus moderate ABE

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DISCUSSION

Any criterion for intervention in hy-perbilirubinemia must have a highsensitivity identifying all or nearly allinfantswithapossibility of permanentinjury In this study both TSB and BAwere strong predictors of acute andresidual encephalopathy but whenBA and TSB intervention levels were

selected to yield the same sensitivityBA did not improve discrimination ofpatients at risk as hypothesized Thisdoes not mean that measuring serumalbumin is unimportant Severe hemolyticdiseaseandcapillary leak fromavarietyofconditions can result in plasma albumindepletion In such infants the risk forkernicterus may occur at TSB levels well

below AAP-recommended interventionlevels for sick infants25 but the BA cutoffwould be breeched

Role of Risk Factors

Proposed clinical risk factors forbilirubin toxicity1 had surprisinglylittle influence on either thresholdor median values of TSB and BA

FIGURE 1ROC curves evaluating total serumbilirubin and bilirubinalbumin as predictors of different stages of bilirubin neurotoxicity Excludes 4 patients24 hours ofage TSB solid line BA dashed line AUC area under the curve and standard error (SE) shown

TABLE 3 Sensitivity and Specificity for Cutoffs Identifying All Subjects With Disease

Outcome TSB mgdL BA mgg

Cutoff Sensitivity (95 CIa) Specificity (95 CI) Cutoff Sensitivity (95 CI) Specificity (95 CI)

AABR RR at admission 227 100 (96ndash100) 93 (41ndash175) 56 100 (96ndash100) 35 (08ndash99)ABE maximum BIND 4ndash9 270 100 (94ndash100) 492 (4092ndash581) 68 100 (94ndash100) 265 (192ndash349)AABR RR at follow-up 307 100 (84ndash100) 689 (591ndash777) 85 100 (84ndash100) 485 (386ndash586)Kernicterus 286 100 (90ndash100) 495 (395ndash595) 85 100 (90ndash100) 485 (386ndash586)

CI confidence interval including those who dieda CI Excludes 4 patients admitted at 24 h of age

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associated with disease in this studyHowever Rh hemolytic disease repre-senting only 11 of the cohort was re-sponsible for 20 of kernicterus casesConsistent with our previous study ofa different cohort of 212 newborns withTSB 25 mgdL26 only infants withhemolytic disease due to Rh incom-patibility orwith sepsis developed severeABE below a TSB of 31 mgdL ABO in-compatibility and G6PD deficiency (in theabsence of hemolytic crisis) createdminimal if any additional risk comparedwith idiopathic jaundice Wolf et al27 andWeng et al28 reported similar resultsResistance to long-termconsequences ofsevere hyperbilirubinemia in otherwisehealthy term infants was also reportedby Newman and colleagues2930 Thiscumulative evidence strongly suggeststhat asymptomatic termnear-termnewborns without risk factors rarelydevelop kernicterus or auditory neu-ropathy at TSB 31 mg andor BA86 mgg Given the risks of exchangetransfusion31 intensive phototherapy andclose monitoring may be a safer treat-ment option for those infants

Why Did BA Not ImproveIdentification of Risk in ThisPopulation

One possible explanation is that thereare wide variations in Bf transport intothe brain andor in cellular defensemechanisms Two of 4 infants with he-molytic disease admitted on day 1 of lifehad rapidly rising TSB and low thresh-olds for toxicity Whether the lowerthresholds are due to rate of rise of TSBpooralbuminbinding or increasedbrainsusceptibility to Bf on day 1 of life isunknown

A second possibility is that BA is notabetterpredictorofBf thanTSBalone (ievariations in binding ability exceed var-iations in albumin concentration) Incontrast to premature infants who maydevelop ABE at BA molar ratios132ndash34

(where Bf is largely dependent on thequality of albumin binding) moderate to

severe bilirubin toxicity in our cohortoccurred only when the molar concen-tration of bilirubin approached or sur-passed the concentration of albuminBf increases dramatically as TSB ap-proaches or exceeds a BAmolar ratio of11 (BA = 88 mgdL) and limitations ofbilirubin solubility become a dominantissue Several infants with no signs oftoxicity hadBAmolar ratios approaching125 indicating that additional bilirubin-binding sites must exist in plasma3536

The high likelihood of wide variations inthis expanded buffering capacity re-inforce the need to measure Bf directlyto validate its value as a marker of in-fants at risk

A third option relates to experimentaldesign limitations In this study as inmost published outcome studies1537ndash38

there were no untreated controlsand no serial documentation of TSBas signs of encephalopathy pro-gressed Fourteen patients had verylow serum albumin levels rangingfrom 18 to 27 gdL and might havebenefited from considering BA Six ofthese infants had severe ABE whenfirst seen TSBs ranged from 32 to44 mgdL and BAs ranged from 14 to20 mgg preventing any inference aboutthe levels of TSB and BA at the onsetof disease

Relationship of Thresholds toProgression of Neurotoxicity

The opportunity to evaluate AABR atadmission as well as repeated BINDscores during the first hours of ad-mission provided unique serial ob-servations of auditory and neurologicevents before and after therapy This inturn allowed us to estimate thresholdvalues for outcomes ranging from re-versible neurotoxicity to irreversibleinjury We observed a rather largejump in threshold values at high sen-sitivity between mild (BIND score 2ndash3)and moderate ABE with smallerchange between moderate and severe

ABE This separation in thresholdscould provide guidance for interventiondecisions

Mindful that our analysis was not strati-fied for GA or risk factors thresholds at100 sensitivity included infants withhighest clinical risk conditions Cutoffsfor TSB identified in this study aresubstantially higher than recommendedintervention levels for low GA withrisk factors1 Our findings should beconfirmed because other studies havereported ABE and hearing loss at lowerlevels than documented here1537ndash38 mostoften associated with severe hemolysisespecially from Rh hemolytic diseasesepsis or prematurity

Strengths and Limitations

This study was conducted at a singlevenue where the quality of clinicalevaluation was carefully monitoredEven so we encountered uncertain-ties in assigning risk factors1 for ABEExchange transfusion was associatedwith worsening ABE and kernicterusin 4 infants potentially confoundingthe relationship between admissiontest values and long-term outcomeFinally the inability to administeroptimal intensive phototherapy andoccasional delays in receiving bloodfor exchange transfusion might haveinfluenced outcomes Notwithstand-ing these limitations the ability ofadmission serum chemistries to pre-dict thresholds for both acute andposttreatment outcomes was ratherremarkable

In 1988 Perlman and Frank39 proposeda hierarchy of neurophysiological andbehavioral signals leading ultimatelyto irreversible brain injury (kernicterushearing loss) but lamented that pro-spective cohort studies needed to de-termine the relative risks associatedwith various biochemical and clinicalpredictive criteria may not be availablefor many years This study conducted inan environment in which kernicterus is

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not a rare event provides a first step inachieving that goal

CONCLUSIONS

TSB and BA are both strong in-dicators of risk for acute and re-

sidual bilirubin neurotoxicity Whenintervention values are adjusted toprovide equal sensitivity the specif-icities of TSB and BA are nearly thesame and BA offers no additionaladvantage over TSB alone in most

clinical settings TSBandBA thresholdsfor disease increased with advan-cing severity of neurotoxicity thisshould be considered when deli-berating appropriate interventionguidelines

REFERENCES

1 American Academy of Pediatrics Subcom-mittee on Hyperbilirubinemia Management ofhyperbilirubinemia in the newborn infant 35or more weeks of gestation Pediatrics 2004114(1)297ndash316

2 Wennberg RP Ahlfors CE Bhutani VK JohnsonLH Shapiro SM Toward understandingkernicterus a challenge to improve the man-agement of jaundiced newborns Pediatrics2006117(2)474ndash485

3 Ahlfors CE Wennberg RP Ostrow JD TiribelliC Unbound (free) bilirubin improving theparadigm for evaluating neonatal jaundiceClin Chem 200955(7)1288ndash1299

4 Ahlfors CE Criteria for exchange trans-fusion in jaundiced newborns Pediatrics199493(3)488ndash494

5 Sato Y Morioka I Miwa A et al Is bilirubinalbumin ratio correlated with unboundbilirubin concentration Pediatr Int 201254(1)81ndash85

6 Ardakani SB Dana VG Ziaee V AshtianiM-TH Djavid GE Alijani M Bilirubinalbuminratio for predicting acute bilirubin-inducedneurologic dysfunction Iran J Pediatr 201121(1)28ndash32

7 Hulzebos CV Dijk PH van Imhoff DE et alBARTrial Study Group The bilirubin albu-min ratio in the management of hyper-bilirubinemia in preterm infants to improveneurodevelopmental outcome a randomizedcontrolled trialmdashBARTrial PLoS ONE 20149(6)e99466

8 Johnson L Brown AK Bhutani V BINDmdashAclinical score for bilirubin induced neuro-logic dysfunction in newborns Pediatrics1999104(suppl 4)746ndash747

9 van Straaten HL Automated auditory brain-stem response in neonatal hearing screen-ing Acta Paediatr Suppl 199988(432)76ndash79

10 Shapiro SM Definition of the clinical spec-trum of kernicterus and bilirubin-inducedneurologic dysfunction (BIND) J Perinatol200525(1)54ndash59

11 Ballard JL Khoury JC Wedig K Wang L Eilers-Walsman BL Lipp R New Ballard Score

expanded to include extremely prematureinfants J Pediatr 1991119(3)417ndash423

12 Doumas BT Wu TW Jendrzejczak B Deltabilirubin absorption spectra molar ab-sorptivity and reactivity in the diazo re-action Clin Chem 198733(6)769ndash774

13 Carter P Ultramicroestimation of humanserum albumin binding cationic dye559dibromo-o cresolsulfonphthalein Micro-chem J 197015531ndash539

14 Volpe JJ Bilirubin and brain injury In VolpeJJ ed Neurology of the Newborn 3rd edPhiladelphia PA WB Saunders 2001490ndash514

15 Johnson L Bhutani VK Karp K Sivieri EMShapiro SM Clinical report from the pilot USAKernicterus Registry (1992 to 2004) J Peri-natol 200929(suppl 1)S25ndashS45

16 Johnson L Bhutani VK The clinical syndromeof bilirubin-induced neurologic dysfunctionSemin Perinatol 201135(3)101ndash113

17 Berlin CI Hood LJ Morlet T et al Multi-sitediagnosis and management of 260 patientswith auditory neuropathydys-synchrony(auditory neuropathy spectrum disorder)Int J Audiol 201049(1)30ndash43

18 Saluja S Agarwal A Kler N Amin S Audi-tory neuropathy spectrum disorder in latepreterm and term infants with severejaundice Int J Pediatr Otorhinolaryngol201074(11)1292ndash1297

19 Shapiro SM Popelka GR Auditory impair-ment in infants at risk for bilirubin-inducedneurologic dysfunction Semin Perinatol201135(3)162ndash170

20 Makkar M Gupta C Pathak R Garg S MahajanNC Performance evaluation of hematologicscoring system in early diagnosis of neonatalsepsis J Clin Neonatol 20132(1)25ndash29

21 Pearlman MA Gartner LM Lee K Morecki RHoroupian DS Absence of kernicterus inlow-birth weight infants from 1971 through1976 comparison with findings in 1966 and1967 Pediatrics 197862(4)460ndash464

22 Durkalski VL Palesch YY Lipsitz SR Rust PFAnalysis of clustered matched-pair dataStat Med 200322(15)2417ndash2428

23 Pepe MS The Statistical Evaluation ofMedical Tests for Classification and Pre-diction Oxford UK Oxford University Press2003

24 Iskander I Gamaleldin R Kabbani M Rootcauses for late presentation of severeneonatal hyperbilirubinaemia in Egypt EastMediterr Health J 201218(8)882ndash887

25 Odutolu Y Emmerson AJ Low bilirubinkernicterus with sepsis and hypoalbuminaemiaBMJ Case Reports 2013 doi101136bcr-2012-008042

26 Gamaleldin R Iskander I Seoud I et al Riskfactors for neurotoxicity in newborns withsevere neonatal hyperbilirubinemia Pediat-rics 2011128(4) Available at wwwpediat-ricsorgcgicontentfull1284e925

27 Wolf MJ Wolf B Beunen G Casaer PNeurodevelopmental outcome at 1 yearin Zimbabwean neonates with extremehyperbilirubinaemia Eur J Pediatr 1999158(2)111ndash114

28 Weng YH Chiu YW Cheng SW Hsieh MY Riskassessment for adverse outcome in termand late preterm neonates with bilirubinvalues of 20 mgdL or more Am J Perinatol201128(5)405ndash412

29 Newman TB Liljestrand P Escobar GJInfants with bilirubin levels of 30 mgdL ormore in a large managed care organiza-tion Pediatrics 2003111(6 pt 1)1303ndash1311

30 Newman TB Liljestrand P Jeremy RJ et alJaundice and Infant Feeding Study TeamOutcomes among newborns with total se-rum bilirubin levels of 25 mg per deciliteror more N Engl J Med 2006354(18)1889ndash1900

31 Smits-Wintjens VE Rath ME van Zwet EWet al Neonatal morbidity after exchangetransfusion for red cell alloimmune he-molytic disease Neonatology 2013103(2)141ndash147

32 Hulzebos CV van Imhoff DE Bos AF Ahlfors CEVerkade HJ Dijk PH Usefulness of thebilirubinalbumin ratio for predicting bilirubin-

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induced neurotoxicity in premature infantsArch Dis Child Fetal Neonatal Ed 200893(5)F384ndashF388

33 Cashore WJ Oh W Unbound bilirubin andkernicterus in low-birth-weight infantsPediatrics 198269(4)481ndash485

34 Nakamura H Yonetani M Uetani Y Funato MLee Y Determination of serum unbound bil-irubin for prediction of kernicterus in lowbirthweight infants Acta Paediatr Jpn 199234(6)642ndash647

35 Jacobsen J Binding of bilirubin to humanserum albumin - determination of the disso-ciation constants FEBS Lett 19695(2)112ndash114

36 Goessling W Zucker SD Role of apolipopro-tein D in the transport of bilirubin in plasmaAm J Physiol Gastrointest Liver Physiol 2000279(2)G356ndashG365

37 Hsia DY Allen FH Jr Gellis SS Diamond LKErythroblastosis fetalis VIII Studies ofserum bilirubin in relation to kernicterusN Engl J Med 1952247(18)668ndash671

38 Ip S Chung M Kulig J et al AmericanAcademy of Pediatrics Subcommitteeon Hyperbilirubinemia An evidence-based review of important issues con-cerning neonatal hyperbilirubinemiaPediatrics 2004114(1) Available atwwwpediatricsorgcgicontentfull1141e130

39 Perlman M Frank JW Bilirubin beyond theblood-brain barrier Pediatrics 198881(2)304ndash315

(Continued from first page)

wwwpediatricsorgcgidoi101542peds2013-1764

doi101542peds2013-1764

Accepted for publication Aug 27 2014

Address correspondence to Iman F Iskander MD Department of Pediatrics Cairo University 8 Salah El Din St Zamalek Cairo 11211 Egypt E-mail imaniskhotmailcom

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2014 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE The authors have indicated they have no financial relationships relevant to this article to disclose

FUNDING This research was supported in part by National Institutes of HealthEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentAward R21HD060901 the American Recovery and Reinvestment Act of 2009 and UL1 RR025014 from National Center for Research ResourcesNational Institutes ofHealth The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health Funded by theNational Institutes of Health (NIH)

POTENTIAL CONFLICT OF INTEREST The authors have indicated they have no potential conflicts of interest to disclose

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APPENDIX 1 BIND Scorea

Clinical Sign (Score Most Severe Sign) Score Severity

Mental statusNormal ndash Awake alert 0 NoneSleepy but arousable 1 MildDecreased feeding 1 MildLethargy 2 ModeratePoor suck andor 2 ModerateIrritablejittery 2 ModerateUnable to feed 3 SevereApnea 3 SevereSeizures 3 SevereComa ndash not arousable 3 Severe

Muscle toneNormal flexed tone 0 NonePersistent mild hypotonia 1 MildHypotonia or hypertonia depending on arousal state 2 ModerateBicycling 2 ModerateBeginning nuchal rigidity and truncal arching 2 ModeratePersistent retrocollis 3 SevereOpisthotonos 3 SevereSevere hypo- or hypertonia 3 Severe

Cry patternNormal 0 NoneHigh-pitched 1 MildShrill 2 ModerateInconsolable crying or cry weak or absent 3 Severe

Total bind (ABE score)

Tick all that apply but total score is based on the highest in each category or 9Proposed interpretationTotal BIND score 1ndash3 mild ABE subtle signs reversible no apparent sequelaeTotalBIND score 4ndash6 moderate ABE signs largely reversible with aggressive treatmentTotalBIND score 7ndash9 severe ABE largely irreversible but signs may decrease with prompt treatmenta Modified from Johnson L Brown AK Bhutani V BINDmdashA clinical score for bilirubin induced neurologic dysfunction innewborns Pediatrics 1999104(suppl 4)746ndash747

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APPENDIX 2 Characteristics of Patients with Kernicterus

BA TSB MaxBIND

3 moAABR

Hct Cause of Jaundice Admweight g

AdmAge d

Comments

1 86 291 9 ND ND Unknown 2250 53 DIED pH 72 HCO3 15 Direct Bil 562 86 342 9 RR 337 Hemolysis O-A 2800 55 Dystonia at 3 mo3 90 37 7 ND 440 Rh incompatibility 2250 4 DIED Suspected sepsis4 91 31 8 RR 397 Rh incomp DAT neg 2800 58 Severe ABE at admission Klebsiella sepsis post-exchange5 96 412 9 ND 292 Hemolysisa 3100 38 DIED pH 697 apnea seizures6 96 376 8 ND 388 O-A incomp 2100 72 Suspected sepsis7 97 32 4 PR 537 Unknown 3000 76 Mild kernicterus 3 mo8 102 317 9 RR 370 G6PD deficient 3200 65 No hemolysis kernicterus at 3 mo9 103 289 9 ND 248 Hemolysis Rh 2250 4 DIED Suspected sepsis pH 717b

10 104 311 5 RR 473 O-A incomp 1840 3 345 wks SGA high reticulocyte count Mild kernicterus11 105 43 8 ND 350 Unknown 2750 38 DIED 2 exchange transfusions12 105 387 9 ND 294 Hemolysisa 2900 2 Suspected sepsis13 106 35 8 ND 340 Hemolysis O-A 2500 34 DIED Pseudomonas sepsis pH 710b

14 108 4002 8 ND 484 Rh moderate G6PD 2750 45 Direct bilirubin 108 with no hemolysis15 113 397 7 RR 419 G6PD amp O-A incomp 2030 13 Late admission kernicterus at 3 mo16 114 366 9 ND 454 Unknown 2250 81 pH 72317 115 425 9 ND 311 Hemolysis O-B 3200 38 DIED Suspected sepsis seizures18 115 367 6 RR 425 O-B incomp 2250 77 Kernicterus at 3 mo19 118 436 6 RR 370 O-A incomp 2970 59 Kernicterus at 3 mo20 121 352 9 ND 429 Unknown 2000 58 DIED rapid deterioration after second exchangeb

21 124 37 7 RR 300 Hemolysis O-B 2400 5 35 wk GA hypertonic with head lag 3 mo22 126 39 9 ND 372 O-A incomp 2300 47 Suspected sepsisb

23 126 442 8 RR 509 Unknown 2400 54 Suspected sepsis pH 733 kernicterus at 3 mo24 128 397 8 ND 314 Hemolysis O-A 2760 98 DIED Suspected sepsis respiratory acidosis apnea seizures25 128 385 8 RR 370 O-A incomp 3150 23 Sustained high TSB kernicterus at 3 mo26 137 479 7 RR 217 Hemolysis G6PD def 2800 49 Suspected sepsis pH 73027 140 365 7 RR 257 Hemolysis Rh 4000 42 Deterioration after second exchangeb

28 149 462 9 ND 490 Unknown 2140 62 RR AABR and abnormal neurologically at discharge no FU29 151 407 7 ND ND O-A incomp 3000 4 DIED classic kernicterus seizures30 151 483 8 RR 381 O-B incomp 2930 13 Late admission Na 157 kernicterus at 3 mo31 156 4201 8 RR 317 Hemolysis Rh 2450 22 Direct bilirubin 16 kernicterus at 3 mo32 178 32 9 ND 279 Hemolysis O-A 2440 43 DIED Suspected sepsis pH 71333 192 479 7 ND 415 O-B amp Rh incomp 2620 26 DIED deteriorated postexchangeb

34 200 441 9 ND 319 Hemolysisa 2850 41 DIED pH 722 respiratory acidosis35 210 6103 7 RR 274 Hemolysis O-A 2900 51 Direct bilirubin 277 kernicterus at 3 mo

Ranked by increasing BA ratio Adm admission Hct hematocrit DAT direct antiglobulin test incomp blood type incompatibility without evident hemolysis Max maximum ND not done PRPass refer FU follow upa Unknown cause for hemolysisb Onset of kernicterus or worsening postexchange transfusion

ARTICLE

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DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

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References

-1httppediatricsaappublicationsorgcontent1345e1330fullref-listThis article cites 36 articles 12 of which you can access for free at

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binemia_subhttpclassicpediatricsaappublicationsorgcgicollectionhyperbiliruHyperbilirubinemiafollowing collection(s) This article along with others on similar topics appears in the

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ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

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DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

httppediatricsaappublicationsorgcontent1345e1330located on the World Wide Web at

The online version of this article along with updated information and services is

ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

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Page 2: Serum Bilirubin and Bilirubin/Albumin Ratio as …pediatrics.aappublications.org/content/pediatrics/134/5/e1330.full.pdf · Serum Bilirubin and Bilirubin/Albumin Ratio as Predictors

The American Academy of Pediatrics(AAP) guidelines for treating neonataljaundice and preventing kernicterus intermnear-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 barrier23 In the absence ofan available assay for Bf the bilirubinalbumin ratio (BA) might provide abetter estimate of Bf because it con-tains 2 of the 3 factors determiningBf (TSB albumin and the albumin-binding affinity)23 The relationshipbetween Bf and BA has been studiedby titration of serum samples4 and bymeasuring Bf in serum of infants withvarying BA5 but clinical evidencecomparing the relationships of TSBand BA with outcome is sparse67 BAis 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-centration1

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

METHODS

General Study Design

This prospective longitudinal observa-tional study was performed at CairoUniversity Childrenrsquos 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$25mgdLpresence 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

Subjects

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 Childrenrsquos HospitalTSB 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 64 Ughemoglobin

Outcome Definitions

Overt acute bilirubin encephalopathy(ABE) is defined as a BIND score of 4 to 9The 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 death814ndash16

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 criteriadeath from severe ABE neurologicfindings of kernicterus at follow-upas described by Shapiro10 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 ldquorefer for further evalua-tionrdquo result (RR AABR) Bilateral passor unilateral pass was consideredldquonormalrdquo Admission AABRs were usu-ally unsuccessful in severely affectedinfants due to muscle activity If theBIND score was 6 to 9 and the infantdied of kernicterus or had RR AABR atdischarge the unsuccessful admissionAABR was considered to be RR forstatistical analysis

A diagnostic evaluation for auditoryneuropathy17ndash19 was performed if theAABR screen was RR at 3 to 5 monthsCompliance with follow-up appoint-ments was 745

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Definition of Clinical Risk Factors

Hemolysis was arbitrarily defined ashematocrit 35 with increasedreticulocytes ($6) in patients withpossible isoimmunization Suspectedsepsis was defined as clinical de-terioration in the presence of leuko-cytosis leucopenia shift to the left ofneutrophils and a positive C-reactiveprotein screen20 The accuracy of GAassessment11 was limited by the pa-tientrsquos postnatal age and occasional ill-ness at admission Birth weights wererarely available accuracy of GA waslimited by postnatal age at admissionand confounded by disease in someinfants Historically birth weights or 2500 g have been used to assessrisk due to maturity421 Because birthweights were unavailable and GA oftenuncertain we used admission weight( or 2500 g) the only objectivemeasure available to assign risk re-lated to maturity

Statistical Methods

The initial TSB and BA were used topredict admission BIND scores andAABR results Occasionally blood forexchange transfusion was delayedtherefore peak TSB and peak BAbefore exchange transfusion wereused to predict subsequent out-comes

Quantitative biochemical data werenot normally distributed Data weresummarized asmedians interquartile(25thndash75th percentile) and total rangesand compared by using Mann-WhitneyU and Kruskal-Wallis tests22 Qualita-tive data were presented as fre-quency and percentage Sensitivitiesand specificities associated with dif-ferent cutoff values for TSB and BAwere evaluated by using receiver op-erating characteristic (ROC) curves23

Calculations were performed by usingthe IBM SPSS (version 20) program(IBM SPSS Statistics IBM CorporationChicago IL) For some analyses sub-

jects were stratified by the presenceor absence of possible clinical riskfactors

RESULTS

Patient Characteristics

Although 87of infantswere deliveredat hospitals newborns were usuallydischarged several hours after birthwithout evaluation for jaundice orscheduled follow-up24 Birth weightGA and blood type incompatibilitieswere rarely documented at the birth-ing hospital The median age at ad-mission to the NICU was 45 daysAdmission TSB was250 mgdL in 41infants 251 to 350 mgdL in 117infants and350 mgdL in 35 infantsPatient characteristics are summa-rized in Table 1

Clinical Risk Factors

In this cohort 59 (306) newbornshad no risk factors other than severehyperbilirubinemia Possible clinicalrisk factors were present in 134 infants(694) but confidence in assigningrisk was often lacking Fifty-eight infantsweighed2500 g but it was sometimesunclear whether they were immatureor small for GA

A total of 103 infants had ABO in-compatibility but therewas no evident

relationship between incompatibilityhematocrit reticulocyte count directantiglobulin test and magnitude ofhyperbilirubinemia G6PD deficiencywas identified in 10 of 134 patientstested at follow-up but only 1 had evi-denceof a hemolytic crisis at admissionBlood cultures were positive in 4 of 12infants with suspected sepsis

Because clinical risk factors wereuncertain in a large fraction of sub-jects we used both nonstratified dataand data dichotomized for absence orpresence of possible risk factors foranalyses

Patient Management

All patients received phototherapy (ir-radiance 20 mWcm2nm) Exchangetransfusions were performed in 147patients (762) including all infantsadmitted with ABE (BIND scores 4ndash9)However 66 of infants with no ormild ABE received exchange transfusionbecause of TSB25 mgdL Median TSBand BA values in infants receiving ex-change transfusion were 322 mgdLand 97 mgg respectively comparedwith TSB 251 mgdL and BA 77 mggin those receiving only phototherapyBlood was not available for ex-change transfusion in 3 infants withTSBs 300 to 336 mgdL but they

TABLE 1 Patient Description (n = 193)

Characteristic n

BoysGirls 10093ABO incompatibility 103Rh incompatibility 22G6PD deficiency ( 64 Ug) 10134 testedSuspected sepsis 12 4 positive cultureExchange transfusion 147 (76)

Median 1stndash3rd Quartile Range

Age d 45 30ndash64 04ndash132Admission weight g 2830 2500ndash3200 1500ndash4500Admission TSB mgdL 285 259ndash332 170ndash610Admission BA mgg 86 74ndash102 54ndash210Albumin gdL 35 31ndash37 18ndash48Peak TSB mgdL 296 264ndash344 170ndash610Peak BA mgg 89 76ndash105 54ndash210

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had normal BIND scores and normalfollow-up

Most infants with mild or moderate ABEimproved neurologically after exchangetransfusion but 4 infantswithmaximumTSBs ranging from 35 to 47 mgdL andadmission BIND scores ranging from1 to 4 deteriorated to severe ABE andkernicterusduringorafter theprocedureCulture-proven sepsis was present post-exchange in 2 of these infants A thirdinfant had marked hemolysis from G6PDdeficiency and deteriorated during theexchange transfusion

Outcomes

At admission 25 infants suffered mod-erate ABE (BIND 4ndash6) Among 22 of those25 infants attending follow-up 13 werehealthy 5 had isolated auditory neu-ropathy and 4 had frank kernicterusSevere ABE (BIND score 7ndash9 at admis-sion) occurred in 33 infants Two in-fants with BIND score of 7 lost tofollow-up were neurologically healthyat discharge but had RR AABR Theremaining 31 infants (94) had ad-verse outcomes compared with only 9(41) of 22 infants with moderate en-cephalopathy

Kernicterus was diagnosed in 35 cases13 infants died with severe ABE inhospital 17 had frank kernicterus10 atfollow-up and 5 infants lost to follow-up had signs of persistent bilirubinencephalopathy at discharge All in-fants with kernicterus had BIND scoresof 5 to 9 while hospitalized and all re-ceived exchange transfusion (see Ap-pendix 2 for details)

At admission the AABR was RR in 86(50) of 173 tests performed A total of128 surviving infants were evaluated atfollow-up Sixty percent of infants withadmission RR AABR converted to bi-lateral pass whereas 22 infants hadpersistent RR AABR confirmed to beauditory neuropathy by diagnostic au-diology procedures17ndash19 All infantswithmaximum TSB 31 mgdL and BIND

score3 had normal auditory functionat follow-up

Relationships of TSB and BA toOutcomes

We found a clear stepwise relationshipbetween TSB and BA median andthreshold values and the progressionof acute neurotoxicity (Table 2) Therewas a large gap in thresholds sepa-ratingmild ABE (200mgdLTSB 55mggBA) and moderate ABE (271 mgdL71 mgg) A smaller increase wasnoted between thresholds for moder-ate and severe ABE Two of 4 infantsadmitted at 24 hours of age withrapidly rising TSB (187 and 240 mgdL)had refer AABRs and 1 had a BINDscore of 5 Because the response torapidly rising bilirubin was unique inthese infants infants admitted at 1day of age were excluded from groupanalyses

Subjects were not stratified for riskfactors so results in Table 2 includepatients at the highest clinical riskcategory defined in the AAP guide-lines1 At all stages of toxicity TSBsidentifying 100 of diseased infantswere higher than the recommendedintervention guideline for high-riskinfants38 weeksrsquo GA1 (TSB 190 mgdL)but BA thresholds for mild neurotoxic-ity (BIND scores 2ndash3) and AABR RR atadmission were lower than the AAPrecommendation (68 mgdL)1 When

subjects were dichotomized by thepresence or absence of suspectedrisk factors threshold and medianvalues for most outcomes were nearlyidentical The median and thresholdvalues for severe ABE and kernicteruswere lower in 30 patients with riskfactors present (threshold 289 mgdL)than in 5 infants without clinical riskfactors (threshold 31 mgdL) butthe difference was not statisticallysignificant

ROC Analysis

We compared sensitivities and spe-cificities of TSB and BA in identifyingacute and posttreatment outcomes byusing ROC curves (Fig 1) ROC curvesdescribe the specificity of a diagnostictest at any selected sensitivity (andvice versa) For all outcomes the areaunder the curve for TSB is slightlyhigher than for BA and significantlyhigher for auditory impairment atadmission There is almost no cross-over of ROC curves for TSB and BA inany outcome prediction (ie at anygiven sensitivity the specificity of TSBis equal to or slightly better than BA)Table 3 lists TSB and BA cutoff valuesyielding 100 sensitivity together withspecificities and confidence intervalsfor various stages of neurotoxicity inour study population Calculated cut-offs are consistent with thresholdvalues described in Table 2

TABLE 2 Relationships of TSB and BA to Progression of Neurotoxicity (n = 189)

Outcome n Median TSBa (Range) Median BAb (Range)

Admission AABR RR 83 334 (229cndash610) 100 (57cndash210)Residual Auditory neuropathy at 3 mo 22 371 (310cndash610) 114 (86cndash210)BIND 2ndash3 mild ABE 47 270 (200cndash377) 76 (55cndash144)BIND 4ndash6 moderate ABE 24 323 (271cndash436)d 101 (71cndash137)d

BIND 7ndash9 severe ABE 32 382 (289cndash610)de 113 (86cndash211)df

Kernicterus 35 387 (289cndash610) 115 (86cndash210)

Four patients on admission with hyperbilirubinemia at 24 h of age are excludeda Total serum bilirubin (mgdL) median (minndashmax)b BA (mgg) median (minndashmax)c Thresholdsd P 0005 versus mild ABEe P = 003 versus moderate ABEf P = 030 versus moderate ABE

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DISCUSSION

Any criterion for intervention in hy-perbilirubinemia must have a highsensitivity identifying all or nearly allinfantswithapossibility of permanentinjury In this study both TSB and BAwere strong predictors of acute andresidual encephalopathy but whenBA and TSB intervention levels were

selected to yield the same sensitivityBA did not improve discrimination ofpatients at risk as hypothesized Thisdoes not mean that measuring serumalbumin is unimportant Severe hemolyticdiseaseandcapillary leak fromavarietyofconditions can result in plasma albumindepletion In such infants the risk forkernicterus may occur at TSB levels well

below AAP-recommended interventionlevels for sick infants25 but the BA cutoffwould be breeched

Role of Risk Factors

Proposed clinical risk factors forbilirubin toxicity1 had surprisinglylittle influence on either thresholdor median values of TSB and BA

FIGURE 1ROC curves evaluating total serumbilirubin and bilirubinalbumin as predictors of different stages of bilirubin neurotoxicity Excludes 4 patients24 hours ofage TSB solid line BA dashed line AUC area under the curve and standard error (SE) shown

TABLE 3 Sensitivity and Specificity for Cutoffs Identifying All Subjects With Disease

Outcome TSB mgdL BA mgg

Cutoff Sensitivity (95 CIa) Specificity (95 CI) Cutoff Sensitivity (95 CI) Specificity (95 CI)

AABR RR at admission 227 100 (96ndash100) 93 (41ndash175) 56 100 (96ndash100) 35 (08ndash99)ABE maximum BIND 4ndash9 270 100 (94ndash100) 492 (4092ndash581) 68 100 (94ndash100) 265 (192ndash349)AABR RR at follow-up 307 100 (84ndash100) 689 (591ndash777) 85 100 (84ndash100) 485 (386ndash586)Kernicterus 286 100 (90ndash100) 495 (395ndash595) 85 100 (90ndash100) 485 (386ndash586)

CI confidence interval including those who dieda CI Excludes 4 patients admitted at 24 h of age

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associated with disease in this studyHowever Rh hemolytic disease repre-senting only 11 of the cohort was re-sponsible for 20 of kernicterus casesConsistent with our previous study ofa different cohort of 212 newborns withTSB 25 mgdL26 only infants withhemolytic disease due to Rh incom-patibility orwith sepsis developed severeABE below a TSB of 31 mgdL ABO in-compatibility and G6PD deficiency (in theabsence of hemolytic crisis) createdminimal if any additional risk comparedwith idiopathic jaundice Wolf et al27 andWeng et al28 reported similar resultsResistance to long-termconsequences ofsevere hyperbilirubinemia in otherwisehealthy term infants was also reportedby Newman and colleagues2930 Thiscumulative evidence strongly suggeststhat asymptomatic termnear-termnewborns without risk factors rarelydevelop kernicterus or auditory neu-ropathy at TSB 31 mg andor BA86 mgg Given the risks of exchangetransfusion31 intensive phototherapy andclose monitoring may be a safer treat-ment option for those infants

Why Did BA Not ImproveIdentification of Risk in ThisPopulation

One possible explanation is that thereare wide variations in Bf transport intothe brain andor in cellular defensemechanisms Two of 4 infants with he-molytic disease admitted on day 1 of lifehad rapidly rising TSB and low thresh-olds for toxicity Whether the lowerthresholds are due to rate of rise of TSBpooralbuminbinding or increasedbrainsusceptibility to Bf on day 1 of life isunknown

A second possibility is that BA is notabetterpredictorofBf thanTSBalone (ievariations in binding ability exceed var-iations in albumin concentration) Incontrast to premature infants who maydevelop ABE at BA molar ratios132ndash34

(where Bf is largely dependent on thequality of albumin binding) moderate to

severe bilirubin toxicity in our cohortoccurred only when the molar concen-tration of bilirubin approached or sur-passed the concentration of albuminBf increases dramatically as TSB ap-proaches or exceeds a BAmolar ratio of11 (BA = 88 mgdL) and limitations ofbilirubin solubility become a dominantissue Several infants with no signs oftoxicity hadBAmolar ratios approaching125 indicating that additional bilirubin-binding sites must exist in plasma3536

The high likelihood of wide variations inthis expanded buffering capacity re-inforce the need to measure Bf directlyto validate its value as a marker of in-fants at risk

A third option relates to experimentaldesign limitations In this study as inmost published outcome studies1537ndash38

there were no untreated controlsand no serial documentation of TSBas signs of encephalopathy pro-gressed Fourteen patients had verylow serum albumin levels rangingfrom 18 to 27 gdL and might havebenefited from considering BA Six ofthese infants had severe ABE whenfirst seen TSBs ranged from 32 to44 mgdL and BAs ranged from 14 to20 mgg preventing any inference aboutthe levels of TSB and BA at the onsetof disease

Relationship of Thresholds toProgression of Neurotoxicity

The opportunity to evaluate AABR atadmission as well as repeated BINDscores during the first hours of ad-mission provided unique serial ob-servations of auditory and neurologicevents before and after therapy This inturn allowed us to estimate thresholdvalues for outcomes ranging from re-versible neurotoxicity to irreversibleinjury We observed a rather largejump in threshold values at high sen-sitivity between mild (BIND score 2ndash3)and moderate ABE with smallerchange between moderate and severe

ABE This separation in thresholdscould provide guidance for interventiondecisions

Mindful that our analysis was not strati-fied for GA or risk factors thresholds at100 sensitivity included infants withhighest clinical risk conditions Cutoffsfor TSB identified in this study aresubstantially higher than recommendedintervention levels for low GA withrisk factors1 Our findings should beconfirmed because other studies havereported ABE and hearing loss at lowerlevels than documented here1537ndash38 mostoften associated with severe hemolysisespecially from Rh hemolytic diseasesepsis or prematurity

Strengths and Limitations

This study was conducted at a singlevenue where the quality of clinicalevaluation was carefully monitoredEven so we encountered uncertain-ties in assigning risk factors1 for ABEExchange transfusion was associatedwith worsening ABE and kernicterusin 4 infants potentially confoundingthe relationship between admissiontest values and long-term outcomeFinally the inability to administeroptimal intensive phototherapy andoccasional delays in receiving bloodfor exchange transfusion might haveinfluenced outcomes Notwithstand-ing these limitations the ability ofadmission serum chemistries to pre-dict thresholds for both acute andposttreatment outcomes was ratherremarkable

In 1988 Perlman and Frank39 proposeda hierarchy of neurophysiological andbehavioral signals leading ultimatelyto irreversible brain injury (kernicterushearing loss) but lamented that pro-spective cohort studies needed to de-termine the relative risks associatedwith various biochemical and clinicalpredictive criteria may not be availablefor many years This study conducted inan environment in which kernicterus is

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not a rare event provides a first step inachieving that goal

CONCLUSIONS

TSB and BA are both strong in-dicators of risk for acute and re-

sidual bilirubin neurotoxicity Whenintervention values are adjusted toprovide equal sensitivity the specif-icities of TSB and BA are nearly thesame and BA offers no additionaladvantage over TSB alone in most

clinical settings TSBandBA thresholdsfor disease increased with advan-cing severity of neurotoxicity thisshould be considered when deli-berating appropriate interventionguidelines

REFERENCES

1 American Academy of Pediatrics Subcom-mittee on Hyperbilirubinemia Management ofhyperbilirubinemia in the newborn infant 35or more weeks of gestation Pediatrics 2004114(1)297ndash316

2 Wennberg RP Ahlfors CE Bhutani VK JohnsonLH Shapiro SM Toward understandingkernicterus a challenge to improve the man-agement of jaundiced newborns Pediatrics2006117(2)474ndash485

3 Ahlfors CE Wennberg RP Ostrow JD TiribelliC Unbound (free) bilirubin improving theparadigm for evaluating neonatal jaundiceClin Chem 200955(7)1288ndash1299

4 Ahlfors CE Criteria for exchange trans-fusion in jaundiced newborns Pediatrics199493(3)488ndash494

5 Sato Y Morioka I Miwa A et al Is bilirubinalbumin ratio correlated with unboundbilirubin concentration Pediatr Int 201254(1)81ndash85

6 Ardakani SB Dana VG Ziaee V AshtianiM-TH Djavid GE Alijani M Bilirubinalbuminratio for predicting acute bilirubin-inducedneurologic dysfunction Iran J Pediatr 201121(1)28ndash32

7 Hulzebos CV Dijk PH van Imhoff DE et alBARTrial Study Group The bilirubin albu-min ratio in the management of hyper-bilirubinemia in preterm infants to improveneurodevelopmental outcome a randomizedcontrolled trialmdashBARTrial PLoS ONE 20149(6)e99466

8 Johnson L Brown AK Bhutani V BINDmdashAclinical score for bilirubin induced neuro-logic dysfunction in newborns Pediatrics1999104(suppl 4)746ndash747

9 van Straaten HL Automated auditory brain-stem response in neonatal hearing screen-ing Acta Paediatr Suppl 199988(432)76ndash79

10 Shapiro SM Definition of the clinical spec-trum of kernicterus and bilirubin-inducedneurologic dysfunction (BIND) J Perinatol200525(1)54ndash59

11 Ballard JL Khoury JC Wedig K Wang L Eilers-Walsman BL Lipp R New Ballard Score

expanded to include extremely prematureinfants J Pediatr 1991119(3)417ndash423

12 Doumas BT Wu TW Jendrzejczak B Deltabilirubin absorption spectra molar ab-sorptivity and reactivity in the diazo re-action Clin Chem 198733(6)769ndash774

13 Carter P Ultramicroestimation of humanserum albumin binding cationic dye559dibromo-o cresolsulfonphthalein Micro-chem J 197015531ndash539

14 Volpe JJ Bilirubin and brain injury In VolpeJJ ed Neurology of the Newborn 3rd edPhiladelphia PA WB Saunders 2001490ndash514

15 Johnson L Bhutani VK Karp K Sivieri EMShapiro SM Clinical report from the pilot USAKernicterus Registry (1992 to 2004) J Peri-natol 200929(suppl 1)S25ndashS45

16 Johnson L Bhutani VK The clinical syndromeof bilirubin-induced neurologic dysfunctionSemin Perinatol 201135(3)101ndash113

17 Berlin CI Hood LJ Morlet T et al Multi-sitediagnosis and management of 260 patientswith auditory neuropathydys-synchrony(auditory neuropathy spectrum disorder)Int J Audiol 201049(1)30ndash43

18 Saluja S Agarwal A Kler N Amin S Audi-tory neuropathy spectrum disorder in latepreterm and term infants with severejaundice Int J Pediatr Otorhinolaryngol201074(11)1292ndash1297

19 Shapiro SM Popelka GR Auditory impair-ment in infants at risk for bilirubin-inducedneurologic dysfunction Semin Perinatol201135(3)162ndash170

20 Makkar M Gupta C Pathak R Garg S MahajanNC Performance evaluation of hematologicscoring system in early diagnosis of neonatalsepsis J Clin Neonatol 20132(1)25ndash29

21 Pearlman MA Gartner LM Lee K Morecki RHoroupian DS Absence of kernicterus inlow-birth weight infants from 1971 through1976 comparison with findings in 1966 and1967 Pediatrics 197862(4)460ndash464

22 Durkalski VL Palesch YY Lipsitz SR Rust PFAnalysis of clustered matched-pair dataStat Med 200322(15)2417ndash2428

23 Pepe MS The Statistical Evaluation ofMedical Tests for Classification and Pre-diction Oxford UK Oxford University Press2003

24 Iskander I Gamaleldin R Kabbani M Rootcauses for late presentation of severeneonatal hyperbilirubinaemia in Egypt EastMediterr Health J 201218(8)882ndash887

25 Odutolu Y Emmerson AJ Low bilirubinkernicterus with sepsis and hypoalbuminaemiaBMJ Case Reports 2013 doi101136bcr-2012-008042

26 Gamaleldin R Iskander I Seoud I et al Riskfactors for neurotoxicity in newborns withsevere neonatal hyperbilirubinemia Pediat-rics 2011128(4) Available at wwwpediat-ricsorgcgicontentfull1284e925

27 Wolf MJ Wolf B Beunen G Casaer PNeurodevelopmental outcome at 1 yearin Zimbabwean neonates with extremehyperbilirubinaemia Eur J Pediatr 1999158(2)111ndash114

28 Weng YH Chiu YW Cheng SW Hsieh MY Riskassessment for adverse outcome in termand late preterm neonates with bilirubinvalues of 20 mgdL or more Am J Perinatol201128(5)405ndash412

29 Newman TB Liljestrand P Escobar GJInfants with bilirubin levels of 30 mgdL ormore in a large managed care organiza-tion Pediatrics 2003111(6 pt 1)1303ndash1311

30 Newman TB Liljestrand P Jeremy RJ et alJaundice and Infant Feeding Study TeamOutcomes among newborns with total se-rum bilirubin levels of 25 mg per deciliteror more N Engl J Med 2006354(18)1889ndash1900

31 Smits-Wintjens VE Rath ME van Zwet EWet al Neonatal morbidity after exchangetransfusion for red cell alloimmune he-molytic disease Neonatology 2013103(2)141ndash147

32 Hulzebos CV van Imhoff DE Bos AF Ahlfors CEVerkade HJ Dijk PH Usefulness of thebilirubinalbumin ratio for predicting bilirubin-

e1336 ISKANDER et al

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induced neurotoxicity in premature infantsArch Dis Child Fetal Neonatal Ed 200893(5)F384ndashF388

33 Cashore WJ Oh W Unbound bilirubin andkernicterus in low-birth-weight infantsPediatrics 198269(4)481ndash485

34 Nakamura H Yonetani M Uetani Y Funato MLee Y Determination of serum unbound bil-irubin for prediction of kernicterus in lowbirthweight infants Acta Paediatr Jpn 199234(6)642ndash647

35 Jacobsen J Binding of bilirubin to humanserum albumin - determination of the disso-ciation constants FEBS Lett 19695(2)112ndash114

36 Goessling W Zucker SD Role of apolipopro-tein D in the transport of bilirubin in plasmaAm J Physiol Gastrointest Liver Physiol 2000279(2)G356ndashG365

37 Hsia DY Allen FH Jr Gellis SS Diamond LKErythroblastosis fetalis VIII Studies ofserum bilirubin in relation to kernicterusN Engl J Med 1952247(18)668ndash671

38 Ip S Chung M Kulig J et al AmericanAcademy of Pediatrics Subcommitteeon Hyperbilirubinemia An evidence-based review of important issues con-cerning neonatal hyperbilirubinemiaPediatrics 2004114(1) Available atwwwpediatricsorgcgicontentfull1141e130

39 Perlman M Frank JW Bilirubin beyond theblood-brain barrier Pediatrics 198881(2)304ndash315

(Continued from first page)

wwwpediatricsorgcgidoi101542peds2013-1764

doi101542peds2013-1764

Accepted for publication Aug 27 2014

Address correspondence to Iman F Iskander MD Department of Pediatrics Cairo University 8 Salah El Din St Zamalek Cairo 11211 Egypt E-mail imaniskhotmailcom

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2014 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE The authors have indicated they have no financial relationships relevant to this article to disclose

FUNDING This research was supported in part by National Institutes of HealthEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentAward R21HD060901 the American Recovery and Reinvestment Act of 2009 and UL1 RR025014 from National Center for Research ResourcesNational Institutes ofHealth The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health Funded by theNational Institutes of Health (NIH)

POTENTIAL CONFLICT OF INTEREST The authors have indicated they have no potential conflicts of interest to disclose

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APPENDIX 1 BIND Scorea

Clinical Sign (Score Most Severe Sign) Score Severity

Mental statusNormal ndash Awake alert 0 NoneSleepy but arousable 1 MildDecreased feeding 1 MildLethargy 2 ModeratePoor suck andor 2 ModerateIrritablejittery 2 ModerateUnable to feed 3 SevereApnea 3 SevereSeizures 3 SevereComa ndash not arousable 3 Severe

Muscle toneNormal flexed tone 0 NonePersistent mild hypotonia 1 MildHypotonia or hypertonia depending on arousal state 2 ModerateBicycling 2 ModerateBeginning nuchal rigidity and truncal arching 2 ModeratePersistent retrocollis 3 SevereOpisthotonos 3 SevereSevere hypo- or hypertonia 3 Severe

Cry patternNormal 0 NoneHigh-pitched 1 MildShrill 2 ModerateInconsolable crying or cry weak or absent 3 Severe

Total bind (ABE score)

Tick all that apply but total score is based on the highest in each category or 9Proposed interpretationTotal BIND score 1ndash3 mild ABE subtle signs reversible no apparent sequelaeTotalBIND score 4ndash6 moderate ABE signs largely reversible with aggressive treatmentTotalBIND score 7ndash9 severe ABE largely irreversible but signs may decrease with prompt treatmenta Modified from Johnson L Brown AK Bhutani V BINDmdashA clinical score for bilirubin induced neurologic dysfunction innewborns Pediatrics 1999104(suppl 4)746ndash747

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APPENDIX 2 Characteristics of Patients with Kernicterus

BA TSB MaxBIND

3 moAABR

Hct Cause of Jaundice Admweight g

AdmAge d

Comments

1 86 291 9 ND ND Unknown 2250 53 DIED pH 72 HCO3 15 Direct Bil 562 86 342 9 RR 337 Hemolysis O-A 2800 55 Dystonia at 3 mo3 90 37 7 ND 440 Rh incompatibility 2250 4 DIED Suspected sepsis4 91 31 8 RR 397 Rh incomp DAT neg 2800 58 Severe ABE at admission Klebsiella sepsis post-exchange5 96 412 9 ND 292 Hemolysisa 3100 38 DIED pH 697 apnea seizures6 96 376 8 ND 388 O-A incomp 2100 72 Suspected sepsis7 97 32 4 PR 537 Unknown 3000 76 Mild kernicterus 3 mo8 102 317 9 RR 370 G6PD deficient 3200 65 No hemolysis kernicterus at 3 mo9 103 289 9 ND 248 Hemolysis Rh 2250 4 DIED Suspected sepsis pH 717b

10 104 311 5 RR 473 O-A incomp 1840 3 345 wks SGA high reticulocyte count Mild kernicterus11 105 43 8 ND 350 Unknown 2750 38 DIED 2 exchange transfusions12 105 387 9 ND 294 Hemolysisa 2900 2 Suspected sepsis13 106 35 8 ND 340 Hemolysis O-A 2500 34 DIED Pseudomonas sepsis pH 710b

14 108 4002 8 ND 484 Rh moderate G6PD 2750 45 Direct bilirubin 108 with no hemolysis15 113 397 7 RR 419 G6PD amp O-A incomp 2030 13 Late admission kernicterus at 3 mo16 114 366 9 ND 454 Unknown 2250 81 pH 72317 115 425 9 ND 311 Hemolysis O-B 3200 38 DIED Suspected sepsis seizures18 115 367 6 RR 425 O-B incomp 2250 77 Kernicterus at 3 mo19 118 436 6 RR 370 O-A incomp 2970 59 Kernicterus at 3 mo20 121 352 9 ND 429 Unknown 2000 58 DIED rapid deterioration after second exchangeb

21 124 37 7 RR 300 Hemolysis O-B 2400 5 35 wk GA hypertonic with head lag 3 mo22 126 39 9 ND 372 O-A incomp 2300 47 Suspected sepsisb

23 126 442 8 RR 509 Unknown 2400 54 Suspected sepsis pH 733 kernicterus at 3 mo24 128 397 8 ND 314 Hemolysis O-A 2760 98 DIED Suspected sepsis respiratory acidosis apnea seizures25 128 385 8 RR 370 O-A incomp 3150 23 Sustained high TSB kernicterus at 3 mo26 137 479 7 RR 217 Hemolysis G6PD def 2800 49 Suspected sepsis pH 73027 140 365 7 RR 257 Hemolysis Rh 4000 42 Deterioration after second exchangeb

28 149 462 9 ND 490 Unknown 2140 62 RR AABR and abnormal neurologically at discharge no FU29 151 407 7 ND ND O-A incomp 3000 4 DIED classic kernicterus seizures30 151 483 8 RR 381 O-B incomp 2930 13 Late admission Na 157 kernicterus at 3 mo31 156 4201 8 RR 317 Hemolysis Rh 2450 22 Direct bilirubin 16 kernicterus at 3 mo32 178 32 9 ND 279 Hemolysis O-A 2440 43 DIED Suspected sepsis pH 71333 192 479 7 ND 415 O-B amp Rh incomp 2620 26 DIED deteriorated postexchangeb

34 200 441 9 ND 319 Hemolysisa 2850 41 DIED pH 722 respiratory acidosis35 210 6103 7 RR 274 Hemolysis O-A 2900 51 Direct bilirubin 277 kernicterus at 3 mo

Ranked by increasing BA ratio Adm admission Hct hematocrit DAT direct antiglobulin test incomp blood type incompatibility without evident hemolysis Max maximum ND not done PRPass refer FU follow upa Unknown cause for hemolysisb Onset of kernicterus or worsening postexchange transfusion

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DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

ServicesUpdated Information amp

httppediatricsaappublicationsorgcontent1345e1330including high resolution figures can be found at

References

-1httppediatricsaappublicationsorgcontent1345e1330fullref-listThis article cites 36 articles 12 of which you can access for free at

Subspecialty Collections

binemia_subhttpclassicpediatricsaappublicationsorgcgicollectionhyperbiliruHyperbilirubinemiafollowing collection(s) This article along with others on similar topics appears in the

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ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

httppediatricsaappublicationsorgcontent1345e1330located on the World Wide Web at

The online version of this article along with updated information and services is

ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

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Definition of Clinical Risk Factors

Hemolysis was arbitrarily defined ashematocrit 35 with increasedreticulocytes ($6) in patients withpossible isoimmunization Suspectedsepsis was defined as clinical de-terioration in the presence of leuko-cytosis leucopenia shift to the left ofneutrophils and a positive C-reactiveprotein screen20 The accuracy of GAassessment11 was limited by the pa-tientrsquos postnatal age and occasional ill-ness at admission Birth weights wererarely available accuracy of GA waslimited by postnatal age at admissionand confounded by disease in someinfants Historically birth weights or 2500 g have been used to assessrisk due to maturity421 Because birthweights were unavailable and GA oftenuncertain we used admission weight( or 2500 g) the only objectivemeasure available to assign risk re-lated to maturity

Statistical Methods

The initial TSB and BA were used topredict admission BIND scores andAABR results Occasionally blood forexchange transfusion was delayedtherefore peak TSB and peak BAbefore exchange transfusion wereused to predict subsequent out-comes

Quantitative biochemical data werenot normally distributed Data weresummarized asmedians interquartile(25thndash75th percentile) and total rangesand compared by using Mann-WhitneyU and Kruskal-Wallis tests22 Qualita-tive data were presented as fre-quency and percentage Sensitivitiesand specificities associated with dif-ferent cutoff values for TSB and BAwere evaluated by using receiver op-erating characteristic (ROC) curves23

Calculations were performed by usingthe IBM SPSS (version 20) program(IBM SPSS Statistics IBM CorporationChicago IL) For some analyses sub-

jects were stratified by the presenceor absence of possible clinical riskfactors

RESULTS

Patient Characteristics

Although 87of infantswere deliveredat hospitals newborns were usuallydischarged several hours after birthwithout evaluation for jaundice orscheduled follow-up24 Birth weightGA and blood type incompatibilitieswere rarely documented at the birth-ing hospital The median age at ad-mission to the NICU was 45 daysAdmission TSB was250 mgdL in 41infants 251 to 350 mgdL in 117infants and350 mgdL in 35 infantsPatient characteristics are summa-rized in Table 1

Clinical Risk Factors

In this cohort 59 (306) newbornshad no risk factors other than severehyperbilirubinemia Possible clinicalrisk factors were present in 134 infants(694) but confidence in assigningrisk was often lacking Fifty-eight infantsweighed2500 g but it was sometimesunclear whether they were immatureor small for GA

A total of 103 infants had ABO in-compatibility but therewas no evident

relationship between incompatibilityhematocrit reticulocyte count directantiglobulin test and magnitude ofhyperbilirubinemia G6PD deficiencywas identified in 10 of 134 patientstested at follow-up but only 1 had evi-denceof a hemolytic crisis at admissionBlood cultures were positive in 4 of 12infants with suspected sepsis

Because clinical risk factors wereuncertain in a large fraction of sub-jects we used both nonstratified dataand data dichotomized for absence orpresence of possible risk factors foranalyses

Patient Management

All patients received phototherapy (ir-radiance 20 mWcm2nm) Exchangetransfusions were performed in 147patients (762) including all infantsadmitted with ABE (BIND scores 4ndash9)However 66 of infants with no ormild ABE received exchange transfusionbecause of TSB25 mgdL Median TSBand BA values in infants receiving ex-change transfusion were 322 mgdLand 97 mgg respectively comparedwith TSB 251 mgdL and BA 77 mggin those receiving only phototherapyBlood was not available for ex-change transfusion in 3 infants withTSBs 300 to 336 mgdL but they

TABLE 1 Patient Description (n = 193)

Characteristic n

BoysGirls 10093ABO incompatibility 103Rh incompatibility 22G6PD deficiency ( 64 Ug) 10134 testedSuspected sepsis 12 4 positive cultureExchange transfusion 147 (76)

Median 1stndash3rd Quartile Range

Age d 45 30ndash64 04ndash132Admission weight g 2830 2500ndash3200 1500ndash4500Admission TSB mgdL 285 259ndash332 170ndash610Admission BA mgg 86 74ndash102 54ndash210Albumin gdL 35 31ndash37 18ndash48Peak TSB mgdL 296 264ndash344 170ndash610Peak BA mgg 89 76ndash105 54ndash210

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had normal BIND scores and normalfollow-up

Most infants with mild or moderate ABEimproved neurologically after exchangetransfusion but 4 infantswithmaximumTSBs ranging from 35 to 47 mgdL andadmission BIND scores ranging from1 to 4 deteriorated to severe ABE andkernicterusduringorafter theprocedureCulture-proven sepsis was present post-exchange in 2 of these infants A thirdinfant had marked hemolysis from G6PDdeficiency and deteriorated during theexchange transfusion

Outcomes

At admission 25 infants suffered mod-erate ABE (BIND 4ndash6) Among 22 of those25 infants attending follow-up 13 werehealthy 5 had isolated auditory neu-ropathy and 4 had frank kernicterusSevere ABE (BIND score 7ndash9 at admis-sion) occurred in 33 infants Two in-fants with BIND score of 7 lost tofollow-up were neurologically healthyat discharge but had RR AABR Theremaining 31 infants (94) had ad-verse outcomes compared with only 9(41) of 22 infants with moderate en-cephalopathy

Kernicterus was diagnosed in 35 cases13 infants died with severe ABE inhospital 17 had frank kernicterus10 atfollow-up and 5 infants lost to follow-up had signs of persistent bilirubinencephalopathy at discharge All in-fants with kernicterus had BIND scoresof 5 to 9 while hospitalized and all re-ceived exchange transfusion (see Ap-pendix 2 for details)

At admission the AABR was RR in 86(50) of 173 tests performed A total of128 surviving infants were evaluated atfollow-up Sixty percent of infants withadmission RR AABR converted to bi-lateral pass whereas 22 infants hadpersistent RR AABR confirmed to beauditory neuropathy by diagnostic au-diology procedures17ndash19 All infantswithmaximum TSB 31 mgdL and BIND

score3 had normal auditory functionat follow-up

Relationships of TSB and BA toOutcomes

We found a clear stepwise relationshipbetween TSB and BA median andthreshold values and the progressionof acute neurotoxicity (Table 2) Therewas a large gap in thresholds sepa-ratingmild ABE (200mgdLTSB 55mggBA) and moderate ABE (271 mgdL71 mgg) A smaller increase wasnoted between thresholds for moder-ate and severe ABE Two of 4 infantsadmitted at 24 hours of age withrapidly rising TSB (187 and 240 mgdL)had refer AABRs and 1 had a BINDscore of 5 Because the response torapidly rising bilirubin was unique inthese infants infants admitted at 1day of age were excluded from groupanalyses

Subjects were not stratified for riskfactors so results in Table 2 includepatients at the highest clinical riskcategory defined in the AAP guide-lines1 At all stages of toxicity TSBsidentifying 100 of diseased infantswere higher than the recommendedintervention guideline for high-riskinfants38 weeksrsquo GA1 (TSB 190 mgdL)but BA thresholds for mild neurotoxic-ity (BIND scores 2ndash3) and AABR RR atadmission were lower than the AAPrecommendation (68 mgdL)1 When

subjects were dichotomized by thepresence or absence of suspectedrisk factors threshold and medianvalues for most outcomes were nearlyidentical The median and thresholdvalues for severe ABE and kernicteruswere lower in 30 patients with riskfactors present (threshold 289 mgdL)than in 5 infants without clinical riskfactors (threshold 31 mgdL) butthe difference was not statisticallysignificant

ROC Analysis

We compared sensitivities and spe-cificities of TSB and BA in identifyingacute and posttreatment outcomes byusing ROC curves (Fig 1) ROC curvesdescribe the specificity of a diagnostictest at any selected sensitivity (andvice versa) For all outcomes the areaunder the curve for TSB is slightlyhigher than for BA and significantlyhigher for auditory impairment atadmission There is almost no cross-over of ROC curves for TSB and BA inany outcome prediction (ie at anygiven sensitivity the specificity of TSBis equal to or slightly better than BA)Table 3 lists TSB and BA cutoff valuesyielding 100 sensitivity together withspecificities and confidence intervalsfor various stages of neurotoxicity inour study population Calculated cut-offs are consistent with thresholdvalues described in Table 2

TABLE 2 Relationships of TSB and BA to Progression of Neurotoxicity (n = 189)

Outcome n Median TSBa (Range) Median BAb (Range)

Admission AABR RR 83 334 (229cndash610) 100 (57cndash210)Residual Auditory neuropathy at 3 mo 22 371 (310cndash610) 114 (86cndash210)BIND 2ndash3 mild ABE 47 270 (200cndash377) 76 (55cndash144)BIND 4ndash6 moderate ABE 24 323 (271cndash436)d 101 (71cndash137)d

BIND 7ndash9 severe ABE 32 382 (289cndash610)de 113 (86cndash211)df

Kernicterus 35 387 (289cndash610) 115 (86cndash210)

Four patients on admission with hyperbilirubinemia at 24 h of age are excludeda Total serum bilirubin (mgdL) median (minndashmax)b BA (mgg) median (minndashmax)c Thresholdsd P 0005 versus mild ABEe P = 003 versus moderate ABEf P = 030 versus moderate ABE

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DISCUSSION

Any criterion for intervention in hy-perbilirubinemia must have a highsensitivity identifying all or nearly allinfantswithapossibility of permanentinjury In this study both TSB and BAwere strong predictors of acute andresidual encephalopathy but whenBA and TSB intervention levels were

selected to yield the same sensitivityBA did not improve discrimination ofpatients at risk as hypothesized Thisdoes not mean that measuring serumalbumin is unimportant Severe hemolyticdiseaseandcapillary leak fromavarietyofconditions can result in plasma albumindepletion In such infants the risk forkernicterus may occur at TSB levels well

below AAP-recommended interventionlevels for sick infants25 but the BA cutoffwould be breeched

Role of Risk Factors

Proposed clinical risk factors forbilirubin toxicity1 had surprisinglylittle influence on either thresholdor median values of TSB and BA

FIGURE 1ROC curves evaluating total serumbilirubin and bilirubinalbumin as predictors of different stages of bilirubin neurotoxicity Excludes 4 patients24 hours ofage TSB solid line BA dashed line AUC area under the curve and standard error (SE) shown

TABLE 3 Sensitivity and Specificity for Cutoffs Identifying All Subjects With Disease

Outcome TSB mgdL BA mgg

Cutoff Sensitivity (95 CIa) Specificity (95 CI) Cutoff Sensitivity (95 CI) Specificity (95 CI)

AABR RR at admission 227 100 (96ndash100) 93 (41ndash175) 56 100 (96ndash100) 35 (08ndash99)ABE maximum BIND 4ndash9 270 100 (94ndash100) 492 (4092ndash581) 68 100 (94ndash100) 265 (192ndash349)AABR RR at follow-up 307 100 (84ndash100) 689 (591ndash777) 85 100 (84ndash100) 485 (386ndash586)Kernicterus 286 100 (90ndash100) 495 (395ndash595) 85 100 (90ndash100) 485 (386ndash586)

CI confidence interval including those who dieda CI Excludes 4 patients admitted at 24 h of age

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associated with disease in this studyHowever Rh hemolytic disease repre-senting only 11 of the cohort was re-sponsible for 20 of kernicterus casesConsistent with our previous study ofa different cohort of 212 newborns withTSB 25 mgdL26 only infants withhemolytic disease due to Rh incom-patibility orwith sepsis developed severeABE below a TSB of 31 mgdL ABO in-compatibility and G6PD deficiency (in theabsence of hemolytic crisis) createdminimal if any additional risk comparedwith idiopathic jaundice Wolf et al27 andWeng et al28 reported similar resultsResistance to long-termconsequences ofsevere hyperbilirubinemia in otherwisehealthy term infants was also reportedby Newman and colleagues2930 Thiscumulative evidence strongly suggeststhat asymptomatic termnear-termnewborns without risk factors rarelydevelop kernicterus or auditory neu-ropathy at TSB 31 mg andor BA86 mgg Given the risks of exchangetransfusion31 intensive phototherapy andclose monitoring may be a safer treat-ment option for those infants

Why Did BA Not ImproveIdentification of Risk in ThisPopulation

One possible explanation is that thereare wide variations in Bf transport intothe brain andor in cellular defensemechanisms Two of 4 infants with he-molytic disease admitted on day 1 of lifehad rapidly rising TSB and low thresh-olds for toxicity Whether the lowerthresholds are due to rate of rise of TSBpooralbuminbinding or increasedbrainsusceptibility to Bf on day 1 of life isunknown

A second possibility is that BA is notabetterpredictorofBf thanTSBalone (ievariations in binding ability exceed var-iations in albumin concentration) Incontrast to premature infants who maydevelop ABE at BA molar ratios132ndash34

(where Bf is largely dependent on thequality of albumin binding) moderate to

severe bilirubin toxicity in our cohortoccurred only when the molar concen-tration of bilirubin approached or sur-passed the concentration of albuminBf increases dramatically as TSB ap-proaches or exceeds a BAmolar ratio of11 (BA = 88 mgdL) and limitations ofbilirubin solubility become a dominantissue Several infants with no signs oftoxicity hadBAmolar ratios approaching125 indicating that additional bilirubin-binding sites must exist in plasma3536

The high likelihood of wide variations inthis expanded buffering capacity re-inforce the need to measure Bf directlyto validate its value as a marker of in-fants at risk

A third option relates to experimentaldesign limitations In this study as inmost published outcome studies1537ndash38

there were no untreated controlsand no serial documentation of TSBas signs of encephalopathy pro-gressed Fourteen patients had verylow serum albumin levels rangingfrom 18 to 27 gdL and might havebenefited from considering BA Six ofthese infants had severe ABE whenfirst seen TSBs ranged from 32 to44 mgdL and BAs ranged from 14 to20 mgg preventing any inference aboutthe levels of TSB and BA at the onsetof disease

Relationship of Thresholds toProgression of Neurotoxicity

The opportunity to evaluate AABR atadmission as well as repeated BINDscores during the first hours of ad-mission provided unique serial ob-servations of auditory and neurologicevents before and after therapy This inturn allowed us to estimate thresholdvalues for outcomes ranging from re-versible neurotoxicity to irreversibleinjury We observed a rather largejump in threshold values at high sen-sitivity between mild (BIND score 2ndash3)and moderate ABE with smallerchange between moderate and severe

ABE This separation in thresholdscould provide guidance for interventiondecisions

Mindful that our analysis was not strati-fied for GA or risk factors thresholds at100 sensitivity included infants withhighest clinical risk conditions Cutoffsfor TSB identified in this study aresubstantially higher than recommendedintervention levels for low GA withrisk factors1 Our findings should beconfirmed because other studies havereported ABE and hearing loss at lowerlevels than documented here1537ndash38 mostoften associated with severe hemolysisespecially from Rh hemolytic diseasesepsis or prematurity

Strengths and Limitations

This study was conducted at a singlevenue where the quality of clinicalevaluation was carefully monitoredEven so we encountered uncertain-ties in assigning risk factors1 for ABEExchange transfusion was associatedwith worsening ABE and kernicterusin 4 infants potentially confoundingthe relationship between admissiontest values and long-term outcomeFinally the inability to administeroptimal intensive phototherapy andoccasional delays in receiving bloodfor exchange transfusion might haveinfluenced outcomes Notwithstand-ing these limitations the ability ofadmission serum chemistries to pre-dict thresholds for both acute andposttreatment outcomes was ratherremarkable

In 1988 Perlman and Frank39 proposeda hierarchy of neurophysiological andbehavioral signals leading ultimatelyto irreversible brain injury (kernicterushearing loss) but lamented that pro-spective cohort studies needed to de-termine the relative risks associatedwith various biochemical and clinicalpredictive criteria may not be availablefor many years This study conducted inan environment in which kernicterus is

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not a rare event provides a first step inachieving that goal

CONCLUSIONS

TSB and BA are both strong in-dicators of risk for acute and re-

sidual bilirubin neurotoxicity Whenintervention values are adjusted toprovide equal sensitivity the specif-icities of TSB and BA are nearly thesame and BA offers no additionaladvantage over TSB alone in most

clinical settings TSBandBA thresholdsfor disease increased with advan-cing severity of neurotoxicity thisshould be considered when deli-berating appropriate interventionguidelines

REFERENCES

1 American Academy of Pediatrics Subcom-mittee on Hyperbilirubinemia Management ofhyperbilirubinemia in the newborn infant 35or more weeks of gestation Pediatrics 2004114(1)297ndash316

2 Wennberg RP Ahlfors CE Bhutani VK JohnsonLH Shapiro SM Toward understandingkernicterus a challenge to improve the man-agement of jaundiced newborns Pediatrics2006117(2)474ndash485

3 Ahlfors CE Wennberg RP Ostrow JD TiribelliC Unbound (free) bilirubin improving theparadigm for evaluating neonatal jaundiceClin Chem 200955(7)1288ndash1299

4 Ahlfors CE Criteria for exchange trans-fusion in jaundiced newborns Pediatrics199493(3)488ndash494

5 Sato Y Morioka I Miwa A et al Is bilirubinalbumin ratio correlated with unboundbilirubin concentration Pediatr Int 201254(1)81ndash85

6 Ardakani SB Dana VG Ziaee V AshtianiM-TH Djavid GE Alijani M Bilirubinalbuminratio for predicting acute bilirubin-inducedneurologic dysfunction Iran J Pediatr 201121(1)28ndash32

7 Hulzebos CV Dijk PH van Imhoff DE et alBARTrial Study Group The bilirubin albu-min ratio in the management of hyper-bilirubinemia in preterm infants to improveneurodevelopmental outcome a randomizedcontrolled trialmdashBARTrial PLoS ONE 20149(6)e99466

8 Johnson L Brown AK Bhutani V BINDmdashAclinical score for bilirubin induced neuro-logic dysfunction in newborns Pediatrics1999104(suppl 4)746ndash747

9 van Straaten HL Automated auditory brain-stem response in neonatal hearing screen-ing Acta Paediatr Suppl 199988(432)76ndash79

10 Shapiro SM Definition of the clinical spec-trum of kernicterus and bilirubin-inducedneurologic dysfunction (BIND) J Perinatol200525(1)54ndash59

11 Ballard JL Khoury JC Wedig K Wang L Eilers-Walsman BL Lipp R New Ballard Score

expanded to include extremely prematureinfants J Pediatr 1991119(3)417ndash423

12 Doumas BT Wu TW Jendrzejczak B Deltabilirubin absorption spectra molar ab-sorptivity and reactivity in the diazo re-action Clin Chem 198733(6)769ndash774

13 Carter P Ultramicroestimation of humanserum albumin binding cationic dye559dibromo-o cresolsulfonphthalein Micro-chem J 197015531ndash539

14 Volpe JJ Bilirubin and brain injury In VolpeJJ ed Neurology of the Newborn 3rd edPhiladelphia PA WB Saunders 2001490ndash514

15 Johnson L Bhutani VK Karp K Sivieri EMShapiro SM Clinical report from the pilot USAKernicterus Registry (1992 to 2004) J Peri-natol 200929(suppl 1)S25ndashS45

16 Johnson L Bhutani VK The clinical syndromeof bilirubin-induced neurologic dysfunctionSemin Perinatol 201135(3)101ndash113

17 Berlin CI Hood LJ Morlet T et al Multi-sitediagnosis and management of 260 patientswith auditory neuropathydys-synchrony(auditory neuropathy spectrum disorder)Int J Audiol 201049(1)30ndash43

18 Saluja S Agarwal A Kler N Amin S Audi-tory neuropathy spectrum disorder in latepreterm and term infants with severejaundice Int J Pediatr Otorhinolaryngol201074(11)1292ndash1297

19 Shapiro SM Popelka GR Auditory impair-ment in infants at risk for bilirubin-inducedneurologic dysfunction Semin Perinatol201135(3)162ndash170

20 Makkar M Gupta C Pathak R Garg S MahajanNC Performance evaluation of hematologicscoring system in early diagnosis of neonatalsepsis J Clin Neonatol 20132(1)25ndash29

21 Pearlman MA Gartner LM Lee K Morecki RHoroupian DS Absence of kernicterus inlow-birth weight infants from 1971 through1976 comparison with findings in 1966 and1967 Pediatrics 197862(4)460ndash464

22 Durkalski VL Palesch YY Lipsitz SR Rust PFAnalysis of clustered matched-pair dataStat Med 200322(15)2417ndash2428

23 Pepe MS The Statistical Evaluation ofMedical Tests for Classification and Pre-diction Oxford UK Oxford University Press2003

24 Iskander I Gamaleldin R Kabbani M Rootcauses for late presentation of severeneonatal hyperbilirubinaemia in Egypt EastMediterr Health J 201218(8)882ndash887

25 Odutolu Y Emmerson AJ Low bilirubinkernicterus with sepsis and hypoalbuminaemiaBMJ Case Reports 2013 doi101136bcr-2012-008042

26 Gamaleldin R Iskander I Seoud I et al Riskfactors for neurotoxicity in newborns withsevere neonatal hyperbilirubinemia Pediat-rics 2011128(4) Available at wwwpediat-ricsorgcgicontentfull1284e925

27 Wolf MJ Wolf B Beunen G Casaer PNeurodevelopmental outcome at 1 yearin Zimbabwean neonates with extremehyperbilirubinaemia Eur J Pediatr 1999158(2)111ndash114

28 Weng YH Chiu YW Cheng SW Hsieh MY Riskassessment for adverse outcome in termand late preterm neonates with bilirubinvalues of 20 mgdL or more Am J Perinatol201128(5)405ndash412

29 Newman TB Liljestrand P Escobar GJInfants with bilirubin levels of 30 mgdL ormore in a large managed care organiza-tion Pediatrics 2003111(6 pt 1)1303ndash1311

30 Newman TB Liljestrand P Jeremy RJ et alJaundice and Infant Feeding Study TeamOutcomes among newborns with total se-rum bilirubin levels of 25 mg per deciliteror more N Engl J Med 2006354(18)1889ndash1900

31 Smits-Wintjens VE Rath ME van Zwet EWet al Neonatal morbidity after exchangetransfusion for red cell alloimmune he-molytic disease Neonatology 2013103(2)141ndash147

32 Hulzebos CV van Imhoff DE Bos AF Ahlfors CEVerkade HJ Dijk PH Usefulness of thebilirubinalbumin ratio for predicting bilirubin-

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induced neurotoxicity in premature infantsArch Dis Child Fetal Neonatal Ed 200893(5)F384ndashF388

33 Cashore WJ Oh W Unbound bilirubin andkernicterus in low-birth-weight infantsPediatrics 198269(4)481ndash485

34 Nakamura H Yonetani M Uetani Y Funato MLee Y Determination of serum unbound bil-irubin for prediction of kernicterus in lowbirthweight infants Acta Paediatr Jpn 199234(6)642ndash647

35 Jacobsen J Binding of bilirubin to humanserum albumin - determination of the disso-ciation constants FEBS Lett 19695(2)112ndash114

36 Goessling W Zucker SD Role of apolipopro-tein D in the transport of bilirubin in plasmaAm J Physiol Gastrointest Liver Physiol 2000279(2)G356ndashG365

37 Hsia DY Allen FH Jr Gellis SS Diamond LKErythroblastosis fetalis VIII Studies ofserum bilirubin in relation to kernicterusN Engl J Med 1952247(18)668ndash671

38 Ip S Chung M Kulig J et al AmericanAcademy of Pediatrics Subcommitteeon Hyperbilirubinemia An evidence-based review of important issues con-cerning neonatal hyperbilirubinemiaPediatrics 2004114(1) Available atwwwpediatricsorgcgicontentfull1141e130

39 Perlman M Frank JW Bilirubin beyond theblood-brain barrier Pediatrics 198881(2)304ndash315

(Continued from first page)

wwwpediatricsorgcgidoi101542peds2013-1764

doi101542peds2013-1764

Accepted for publication Aug 27 2014

Address correspondence to Iman F Iskander MD Department of Pediatrics Cairo University 8 Salah El Din St Zamalek Cairo 11211 Egypt E-mail imaniskhotmailcom

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2014 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE The authors have indicated they have no financial relationships relevant to this article to disclose

FUNDING This research was supported in part by National Institutes of HealthEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentAward R21HD060901 the American Recovery and Reinvestment Act of 2009 and UL1 RR025014 from National Center for Research ResourcesNational Institutes ofHealth The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health Funded by theNational Institutes of Health (NIH)

POTENTIAL CONFLICT OF INTEREST The authors have indicated they have no potential conflicts of interest to disclose

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APPENDIX 1 BIND Scorea

Clinical Sign (Score Most Severe Sign) Score Severity

Mental statusNormal ndash Awake alert 0 NoneSleepy but arousable 1 MildDecreased feeding 1 MildLethargy 2 ModeratePoor suck andor 2 ModerateIrritablejittery 2 ModerateUnable to feed 3 SevereApnea 3 SevereSeizures 3 SevereComa ndash not arousable 3 Severe

Muscle toneNormal flexed tone 0 NonePersistent mild hypotonia 1 MildHypotonia or hypertonia depending on arousal state 2 ModerateBicycling 2 ModerateBeginning nuchal rigidity and truncal arching 2 ModeratePersistent retrocollis 3 SevereOpisthotonos 3 SevereSevere hypo- or hypertonia 3 Severe

Cry patternNormal 0 NoneHigh-pitched 1 MildShrill 2 ModerateInconsolable crying or cry weak or absent 3 Severe

Total bind (ABE score)

Tick all that apply but total score is based on the highest in each category or 9Proposed interpretationTotal BIND score 1ndash3 mild ABE subtle signs reversible no apparent sequelaeTotalBIND score 4ndash6 moderate ABE signs largely reversible with aggressive treatmentTotalBIND score 7ndash9 severe ABE largely irreversible but signs may decrease with prompt treatmenta Modified from Johnson L Brown AK Bhutani V BINDmdashA clinical score for bilirubin induced neurologic dysfunction innewborns Pediatrics 1999104(suppl 4)746ndash747

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APPENDIX 2 Characteristics of Patients with Kernicterus

BA TSB MaxBIND

3 moAABR

Hct Cause of Jaundice Admweight g

AdmAge d

Comments

1 86 291 9 ND ND Unknown 2250 53 DIED pH 72 HCO3 15 Direct Bil 562 86 342 9 RR 337 Hemolysis O-A 2800 55 Dystonia at 3 mo3 90 37 7 ND 440 Rh incompatibility 2250 4 DIED Suspected sepsis4 91 31 8 RR 397 Rh incomp DAT neg 2800 58 Severe ABE at admission Klebsiella sepsis post-exchange5 96 412 9 ND 292 Hemolysisa 3100 38 DIED pH 697 apnea seizures6 96 376 8 ND 388 O-A incomp 2100 72 Suspected sepsis7 97 32 4 PR 537 Unknown 3000 76 Mild kernicterus 3 mo8 102 317 9 RR 370 G6PD deficient 3200 65 No hemolysis kernicterus at 3 mo9 103 289 9 ND 248 Hemolysis Rh 2250 4 DIED Suspected sepsis pH 717b

10 104 311 5 RR 473 O-A incomp 1840 3 345 wks SGA high reticulocyte count Mild kernicterus11 105 43 8 ND 350 Unknown 2750 38 DIED 2 exchange transfusions12 105 387 9 ND 294 Hemolysisa 2900 2 Suspected sepsis13 106 35 8 ND 340 Hemolysis O-A 2500 34 DIED Pseudomonas sepsis pH 710b

14 108 4002 8 ND 484 Rh moderate G6PD 2750 45 Direct bilirubin 108 with no hemolysis15 113 397 7 RR 419 G6PD amp O-A incomp 2030 13 Late admission kernicterus at 3 mo16 114 366 9 ND 454 Unknown 2250 81 pH 72317 115 425 9 ND 311 Hemolysis O-B 3200 38 DIED Suspected sepsis seizures18 115 367 6 RR 425 O-B incomp 2250 77 Kernicterus at 3 mo19 118 436 6 RR 370 O-A incomp 2970 59 Kernicterus at 3 mo20 121 352 9 ND 429 Unknown 2000 58 DIED rapid deterioration after second exchangeb

21 124 37 7 RR 300 Hemolysis O-B 2400 5 35 wk GA hypertonic with head lag 3 mo22 126 39 9 ND 372 O-A incomp 2300 47 Suspected sepsisb

23 126 442 8 RR 509 Unknown 2400 54 Suspected sepsis pH 733 kernicterus at 3 mo24 128 397 8 ND 314 Hemolysis O-A 2760 98 DIED Suspected sepsis respiratory acidosis apnea seizures25 128 385 8 RR 370 O-A incomp 3150 23 Sustained high TSB kernicterus at 3 mo26 137 479 7 RR 217 Hemolysis G6PD def 2800 49 Suspected sepsis pH 73027 140 365 7 RR 257 Hemolysis Rh 4000 42 Deterioration after second exchangeb

28 149 462 9 ND 490 Unknown 2140 62 RR AABR and abnormal neurologically at discharge no FU29 151 407 7 ND ND O-A incomp 3000 4 DIED classic kernicterus seizures30 151 483 8 RR 381 O-B incomp 2930 13 Late admission Na 157 kernicterus at 3 mo31 156 4201 8 RR 317 Hemolysis Rh 2450 22 Direct bilirubin 16 kernicterus at 3 mo32 178 32 9 ND 279 Hemolysis O-A 2440 43 DIED Suspected sepsis pH 71333 192 479 7 ND 415 O-B amp Rh incomp 2620 26 DIED deteriorated postexchangeb

34 200 441 9 ND 319 Hemolysisa 2850 41 DIED pH 722 respiratory acidosis35 210 6103 7 RR 274 Hemolysis O-A 2900 51 Direct bilirubin 277 kernicterus at 3 mo

Ranked by increasing BA ratio Adm admission Hct hematocrit DAT direct antiglobulin test incomp blood type incompatibility without evident hemolysis Max maximum ND not done PRPass refer FU follow upa Unknown cause for hemolysisb Onset of kernicterus or worsening postexchange transfusion

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DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

ServicesUpdated Information amp

httppediatricsaappublicationsorgcontent1345e1330including high resolution figures can be found at

References

-1httppediatricsaappublicationsorgcontent1345e1330fullref-listThis article cites 36 articles 12 of which you can access for free at

Subspecialty Collections

binemia_subhttpclassicpediatricsaappublicationsorgcgicollectionhyperbiliruHyperbilirubinemiafollowing collection(s) This article along with others on similar topics appears in the

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ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

httppediatricsaappublicationsorgcontent1345e1330located on the World Wide Web at

The online version of this article along with updated information and services is

ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

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had normal BIND scores and normalfollow-up

Most infants with mild or moderate ABEimproved neurologically after exchangetransfusion but 4 infantswithmaximumTSBs ranging from 35 to 47 mgdL andadmission BIND scores ranging from1 to 4 deteriorated to severe ABE andkernicterusduringorafter theprocedureCulture-proven sepsis was present post-exchange in 2 of these infants A thirdinfant had marked hemolysis from G6PDdeficiency and deteriorated during theexchange transfusion

Outcomes

At admission 25 infants suffered mod-erate ABE (BIND 4ndash6) Among 22 of those25 infants attending follow-up 13 werehealthy 5 had isolated auditory neu-ropathy and 4 had frank kernicterusSevere ABE (BIND score 7ndash9 at admis-sion) occurred in 33 infants Two in-fants with BIND score of 7 lost tofollow-up were neurologically healthyat discharge but had RR AABR Theremaining 31 infants (94) had ad-verse outcomes compared with only 9(41) of 22 infants with moderate en-cephalopathy

Kernicterus was diagnosed in 35 cases13 infants died with severe ABE inhospital 17 had frank kernicterus10 atfollow-up and 5 infants lost to follow-up had signs of persistent bilirubinencephalopathy at discharge All in-fants with kernicterus had BIND scoresof 5 to 9 while hospitalized and all re-ceived exchange transfusion (see Ap-pendix 2 for details)

At admission the AABR was RR in 86(50) of 173 tests performed A total of128 surviving infants were evaluated atfollow-up Sixty percent of infants withadmission RR AABR converted to bi-lateral pass whereas 22 infants hadpersistent RR AABR confirmed to beauditory neuropathy by diagnostic au-diology procedures17ndash19 All infantswithmaximum TSB 31 mgdL and BIND

score3 had normal auditory functionat follow-up

Relationships of TSB and BA toOutcomes

We found a clear stepwise relationshipbetween TSB and BA median andthreshold values and the progressionof acute neurotoxicity (Table 2) Therewas a large gap in thresholds sepa-ratingmild ABE (200mgdLTSB 55mggBA) and moderate ABE (271 mgdL71 mgg) A smaller increase wasnoted between thresholds for moder-ate and severe ABE Two of 4 infantsadmitted at 24 hours of age withrapidly rising TSB (187 and 240 mgdL)had refer AABRs and 1 had a BINDscore of 5 Because the response torapidly rising bilirubin was unique inthese infants infants admitted at 1day of age were excluded from groupanalyses

Subjects were not stratified for riskfactors so results in Table 2 includepatients at the highest clinical riskcategory defined in the AAP guide-lines1 At all stages of toxicity TSBsidentifying 100 of diseased infantswere higher than the recommendedintervention guideline for high-riskinfants38 weeksrsquo GA1 (TSB 190 mgdL)but BA thresholds for mild neurotoxic-ity (BIND scores 2ndash3) and AABR RR atadmission were lower than the AAPrecommendation (68 mgdL)1 When

subjects were dichotomized by thepresence or absence of suspectedrisk factors threshold and medianvalues for most outcomes were nearlyidentical The median and thresholdvalues for severe ABE and kernicteruswere lower in 30 patients with riskfactors present (threshold 289 mgdL)than in 5 infants without clinical riskfactors (threshold 31 mgdL) butthe difference was not statisticallysignificant

ROC Analysis

We compared sensitivities and spe-cificities of TSB and BA in identifyingacute and posttreatment outcomes byusing ROC curves (Fig 1) ROC curvesdescribe the specificity of a diagnostictest at any selected sensitivity (andvice versa) For all outcomes the areaunder the curve for TSB is slightlyhigher than for BA and significantlyhigher for auditory impairment atadmission There is almost no cross-over of ROC curves for TSB and BA inany outcome prediction (ie at anygiven sensitivity the specificity of TSBis equal to or slightly better than BA)Table 3 lists TSB and BA cutoff valuesyielding 100 sensitivity together withspecificities and confidence intervalsfor various stages of neurotoxicity inour study population Calculated cut-offs are consistent with thresholdvalues described in Table 2

TABLE 2 Relationships of TSB and BA to Progression of Neurotoxicity (n = 189)

Outcome n Median TSBa (Range) Median BAb (Range)

Admission AABR RR 83 334 (229cndash610) 100 (57cndash210)Residual Auditory neuropathy at 3 mo 22 371 (310cndash610) 114 (86cndash210)BIND 2ndash3 mild ABE 47 270 (200cndash377) 76 (55cndash144)BIND 4ndash6 moderate ABE 24 323 (271cndash436)d 101 (71cndash137)d

BIND 7ndash9 severe ABE 32 382 (289cndash610)de 113 (86cndash211)df

Kernicterus 35 387 (289cndash610) 115 (86cndash210)

Four patients on admission with hyperbilirubinemia at 24 h of age are excludeda Total serum bilirubin (mgdL) median (minndashmax)b BA (mgg) median (minndashmax)c Thresholdsd P 0005 versus mild ABEe P = 003 versus moderate ABEf P = 030 versus moderate ABE

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DISCUSSION

Any criterion for intervention in hy-perbilirubinemia must have a highsensitivity identifying all or nearly allinfantswithapossibility of permanentinjury In this study both TSB and BAwere strong predictors of acute andresidual encephalopathy but whenBA and TSB intervention levels were

selected to yield the same sensitivityBA did not improve discrimination ofpatients at risk as hypothesized Thisdoes not mean that measuring serumalbumin is unimportant Severe hemolyticdiseaseandcapillary leak fromavarietyofconditions can result in plasma albumindepletion In such infants the risk forkernicterus may occur at TSB levels well

below AAP-recommended interventionlevels for sick infants25 but the BA cutoffwould be breeched

Role of Risk Factors

Proposed clinical risk factors forbilirubin toxicity1 had surprisinglylittle influence on either thresholdor median values of TSB and BA

FIGURE 1ROC curves evaluating total serumbilirubin and bilirubinalbumin as predictors of different stages of bilirubin neurotoxicity Excludes 4 patients24 hours ofage TSB solid line BA dashed line AUC area under the curve and standard error (SE) shown

TABLE 3 Sensitivity and Specificity for Cutoffs Identifying All Subjects With Disease

Outcome TSB mgdL BA mgg

Cutoff Sensitivity (95 CIa) Specificity (95 CI) Cutoff Sensitivity (95 CI) Specificity (95 CI)

AABR RR at admission 227 100 (96ndash100) 93 (41ndash175) 56 100 (96ndash100) 35 (08ndash99)ABE maximum BIND 4ndash9 270 100 (94ndash100) 492 (4092ndash581) 68 100 (94ndash100) 265 (192ndash349)AABR RR at follow-up 307 100 (84ndash100) 689 (591ndash777) 85 100 (84ndash100) 485 (386ndash586)Kernicterus 286 100 (90ndash100) 495 (395ndash595) 85 100 (90ndash100) 485 (386ndash586)

CI confidence interval including those who dieda CI Excludes 4 patients admitted at 24 h of age

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associated with disease in this studyHowever Rh hemolytic disease repre-senting only 11 of the cohort was re-sponsible for 20 of kernicterus casesConsistent with our previous study ofa different cohort of 212 newborns withTSB 25 mgdL26 only infants withhemolytic disease due to Rh incom-patibility orwith sepsis developed severeABE below a TSB of 31 mgdL ABO in-compatibility and G6PD deficiency (in theabsence of hemolytic crisis) createdminimal if any additional risk comparedwith idiopathic jaundice Wolf et al27 andWeng et al28 reported similar resultsResistance to long-termconsequences ofsevere hyperbilirubinemia in otherwisehealthy term infants was also reportedby Newman and colleagues2930 Thiscumulative evidence strongly suggeststhat asymptomatic termnear-termnewborns without risk factors rarelydevelop kernicterus or auditory neu-ropathy at TSB 31 mg andor BA86 mgg Given the risks of exchangetransfusion31 intensive phototherapy andclose monitoring may be a safer treat-ment option for those infants

Why Did BA Not ImproveIdentification of Risk in ThisPopulation

One possible explanation is that thereare wide variations in Bf transport intothe brain andor in cellular defensemechanisms Two of 4 infants with he-molytic disease admitted on day 1 of lifehad rapidly rising TSB and low thresh-olds for toxicity Whether the lowerthresholds are due to rate of rise of TSBpooralbuminbinding or increasedbrainsusceptibility to Bf on day 1 of life isunknown

A second possibility is that BA is notabetterpredictorofBf thanTSBalone (ievariations in binding ability exceed var-iations in albumin concentration) Incontrast to premature infants who maydevelop ABE at BA molar ratios132ndash34

(where Bf is largely dependent on thequality of albumin binding) moderate to

severe bilirubin toxicity in our cohortoccurred only when the molar concen-tration of bilirubin approached or sur-passed the concentration of albuminBf increases dramatically as TSB ap-proaches or exceeds a BAmolar ratio of11 (BA = 88 mgdL) and limitations ofbilirubin solubility become a dominantissue Several infants with no signs oftoxicity hadBAmolar ratios approaching125 indicating that additional bilirubin-binding sites must exist in plasma3536

The high likelihood of wide variations inthis expanded buffering capacity re-inforce the need to measure Bf directlyto validate its value as a marker of in-fants at risk

A third option relates to experimentaldesign limitations In this study as inmost published outcome studies1537ndash38

there were no untreated controlsand no serial documentation of TSBas signs of encephalopathy pro-gressed Fourteen patients had verylow serum albumin levels rangingfrom 18 to 27 gdL and might havebenefited from considering BA Six ofthese infants had severe ABE whenfirst seen TSBs ranged from 32 to44 mgdL and BAs ranged from 14 to20 mgg preventing any inference aboutthe levels of TSB and BA at the onsetof disease

Relationship of Thresholds toProgression of Neurotoxicity

The opportunity to evaluate AABR atadmission as well as repeated BINDscores during the first hours of ad-mission provided unique serial ob-servations of auditory and neurologicevents before and after therapy This inturn allowed us to estimate thresholdvalues for outcomes ranging from re-versible neurotoxicity to irreversibleinjury We observed a rather largejump in threshold values at high sen-sitivity between mild (BIND score 2ndash3)and moderate ABE with smallerchange between moderate and severe

ABE This separation in thresholdscould provide guidance for interventiondecisions

Mindful that our analysis was not strati-fied for GA or risk factors thresholds at100 sensitivity included infants withhighest clinical risk conditions Cutoffsfor TSB identified in this study aresubstantially higher than recommendedintervention levels for low GA withrisk factors1 Our findings should beconfirmed because other studies havereported ABE and hearing loss at lowerlevels than documented here1537ndash38 mostoften associated with severe hemolysisespecially from Rh hemolytic diseasesepsis or prematurity

Strengths and Limitations

This study was conducted at a singlevenue where the quality of clinicalevaluation was carefully monitoredEven so we encountered uncertain-ties in assigning risk factors1 for ABEExchange transfusion was associatedwith worsening ABE and kernicterusin 4 infants potentially confoundingthe relationship between admissiontest values and long-term outcomeFinally the inability to administeroptimal intensive phototherapy andoccasional delays in receiving bloodfor exchange transfusion might haveinfluenced outcomes Notwithstand-ing these limitations the ability ofadmission serum chemistries to pre-dict thresholds for both acute andposttreatment outcomes was ratherremarkable

In 1988 Perlman and Frank39 proposeda hierarchy of neurophysiological andbehavioral signals leading ultimatelyto irreversible brain injury (kernicterushearing loss) but lamented that pro-spective cohort studies needed to de-termine the relative risks associatedwith various biochemical and clinicalpredictive criteria may not be availablefor many years This study conducted inan environment in which kernicterus is

ARTICLE

PEDIATRICS Volume 134 Number 5 November 2014 e1335

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not a rare event provides a first step inachieving that goal

CONCLUSIONS

TSB and BA are both strong in-dicators of risk for acute and re-

sidual bilirubin neurotoxicity Whenintervention values are adjusted toprovide equal sensitivity the specif-icities of TSB and BA are nearly thesame and BA offers no additionaladvantage over TSB alone in most

clinical settings TSBandBA thresholdsfor disease increased with advan-cing severity of neurotoxicity thisshould be considered when deli-berating appropriate interventionguidelines

REFERENCES

1 American Academy of Pediatrics Subcom-mittee on Hyperbilirubinemia Management ofhyperbilirubinemia in the newborn infant 35or more weeks of gestation Pediatrics 2004114(1)297ndash316

2 Wennberg RP Ahlfors CE Bhutani VK JohnsonLH Shapiro SM Toward understandingkernicterus a challenge to improve the man-agement of jaundiced newborns Pediatrics2006117(2)474ndash485

3 Ahlfors CE Wennberg RP Ostrow JD TiribelliC Unbound (free) bilirubin improving theparadigm for evaluating neonatal jaundiceClin Chem 200955(7)1288ndash1299

4 Ahlfors CE Criteria for exchange trans-fusion in jaundiced newborns Pediatrics199493(3)488ndash494

5 Sato Y Morioka I Miwa A et al Is bilirubinalbumin ratio correlated with unboundbilirubin concentration Pediatr Int 201254(1)81ndash85

6 Ardakani SB Dana VG Ziaee V AshtianiM-TH Djavid GE Alijani M Bilirubinalbuminratio for predicting acute bilirubin-inducedneurologic dysfunction Iran J Pediatr 201121(1)28ndash32

7 Hulzebos CV Dijk PH van Imhoff DE et alBARTrial Study Group The bilirubin albu-min ratio in the management of hyper-bilirubinemia in preterm infants to improveneurodevelopmental outcome a randomizedcontrolled trialmdashBARTrial PLoS ONE 20149(6)e99466

8 Johnson L Brown AK Bhutani V BINDmdashAclinical score for bilirubin induced neuro-logic dysfunction in newborns Pediatrics1999104(suppl 4)746ndash747

9 van Straaten HL Automated auditory brain-stem response in neonatal hearing screen-ing Acta Paediatr Suppl 199988(432)76ndash79

10 Shapiro SM Definition of the clinical spec-trum of kernicterus and bilirubin-inducedneurologic dysfunction (BIND) J Perinatol200525(1)54ndash59

11 Ballard JL Khoury JC Wedig K Wang L Eilers-Walsman BL Lipp R New Ballard Score

expanded to include extremely prematureinfants J Pediatr 1991119(3)417ndash423

12 Doumas BT Wu TW Jendrzejczak B Deltabilirubin absorption spectra molar ab-sorptivity and reactivity in the diazo re-action Clin Chem 198733(6)769ndash774

13 Carter P Ultramicroestimation of humanserum albumin binding cationic dye559dibromo-o cresolsulfonphthalein Micro-chem J 197015531ndash539

14 Volpe JJ Bilirubin and brain injury In VolpeJJ ed Neurology of the Newborn 3rd edPhiladelphia PA WB Saunders 2001490ndash514

15 Johnson L Bhutani VK Karp K Sivieri EMShapiro SM Clinical report from the pilot USAKernicterus Registry (1992 to 2004) J Peri-natol 200929(suppl 1)S25ndashS45

16 Johnson L Bhutani VK The clinical syndromeof bilirubin-induced neurologic dysfunctionSemin Perinatol 201135(3)101ndash113

17 Berlin CI Hood LJ Morlet T et al Multi-sitediagnosis and management of 260 patientswith auditory neuropathydys-synchrony(auditory neuropathy spectrum disorder)Int J Audiol 201049(1)30ndash43

18 Saluja S Agarwal A Kler N Amin S Audi-tory neuropathy spectrum disorder in latepreterm and term infants with severejaundice Int J Pediatr Otorhinolaryngol201074(11)1292ndash1297

19 Shapiro SM Popelka GR Auditory impair-ment in infants at risk for bilirubin-inducedneurologic dysfunction Semin Perinatol201135(3)162ndash170

20 Makkar M Gupta C Pathak R Garg S MahajanNC Performance evaluation of hematologicscoring system in early diagnosis of neonatalsepsis J Clin Neonatol 20132(1)25ndash29

21 Pearlman MA Gartner LM Lee K Morecki RHoroupian DS Absence of kernicterus inlow-birth weight infants from 1971 through1976 comparison with findings in 1966 and1967 Pediatrics 197862(4)460ndash464

22 Durkalski VL Palesch YY Lipsitz SR Rust PFAnalysis of clustered matched-pair dataStat Med 200322(15)2417ndash2428

23 Pepe MS The Statistical Evaluation ofMedical Tests for Classification and Pre-diction Oxford UK Oxford University Press2003

24 Iskander I Gamaleldin R Kabbani M Rootcauses for late presentation of severeneonatal hyperbilirubinaemia in Egypt EastMediterr Health J 201218(8)882ndash887

25 Odutolu Y Emmerson AJ Low bilirubinkernicterus with sepsis and hypoalbuminaemiaBMJ Case Reports 2013 doi101136bcr-2012-008042

26 Gamaleldin R Iskander I Seoud I et al Riskfactors for neurotoxicity in newborns withsevere neonatal hyperbilirubinemia Pediat-rics 2011128(4) Available at wwwpediat-ricsorgcgicontentfull1284e925

27 Wolf MJ Wolf B Beunen G Casaer PNeurodevelopmental outcome at 1 yearin Zimbabwean neonates with extremehyperbilirubinaemia Eur J Pediatr 1999158(2)111ndash114

28 Weng YH Chiu YW Cheng SW Hsieh MY Riskassessment for adverse outcome in termand late preterm neonates with bilirubinvalues of 20 mgdL or more Am J Perinatol201128(5)405ndash412

29 Newman TB Liljestrand P Escobar GJInfants with bilirubin levels of 30 mgdL ormore in a large managed care organiza-tion Pediatrics 2003111(6 pt 1)1303ndash1311

30 Newman TB Liljestrand P Jeremy RJ et alJaundice and Infant Feeding Study TeamOutcomes among newborns with total se-rum bilirubin levels of 25 mg per deciliteror more N Engl J Med 2006354(18)1889ndash1900

31 Smits-Wintjens VE Rath ME van Zwet EWet al Neonatal morbidity after exchangetransfusion for red cell alloimmune he-molytic disease Neonatology 2013103(2)141ndash147

32 Hulzebos CV van Imhoff DE Bos AF Ahlfors CEVerkade HJ Dijk PH Usefulness of thebilirubinalbumin ratio for predicting bilirubin-

e1336 ISKANDER et al

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

induced neurotoxicity in premature infantsArch Dis Child Fetal Neonatal Ed 200893(5)F384ndashF388

33 Cashore WJ Oh W Unbound bilirubin andkernicterus in low-birth-weight infantsPediatrics 198269(4)481ndash485

34 Nakamura H Yonetani M Uetani Y Funato MLee Y Determination of serum unbound bil-irubin for prediction of kernicterus in lowbirthweight infants Acta Paediatr Jpn 199234(6)642ndash647

35 Jacobsen J Binding of bilirubin to humanserum albumin - determination of the disso-ciation constants FEBS Lett 19695(2)112ndash114

36 Goessling W Zucker SD Role of apolipopro-tein D in the transport of bilirubin in plasmaAm J Physiol Gastrointest Liver Physiol 2000279(2)G356ndashG365

37 Hsia DY Allen FH Jr Gellis SS Diamond LKErythroblastosis fetalis VIII Studies ofserum bilirubin in relation to kernicterusN Engl J Med 1952247(18)668ndash671

38 Ip S Chung M Kulig J et al AmericanAcademy of Pediatrics Subcommitteeon Hyperbilirubinemia An evidence-based review of important issues con-cerning neonatal hyperbilirubinemiaPediatrics 2004114(1) Available atwwwpediatricsorgcgicontentfull1141e130

39 Perlman M Frank JW Bilirubin beyond theblood-brain barrier Pediatrics 198881(2)304ndash315

(Continued from first page)

wwwpediatricsorgcgidoi101542peds2013-1764

doi101542peds2013-1764

Accepted for publication Aug 27 2014

Address correspondence to Iman F Iskander MD Department of Pediatrics Cairo University 8 Salah El Din St Zamalek Cairo 11211 Egypt E-mail imaniskhotmailcom

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2014 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE The authors have indicated they have no financial relationships relevant to this article to disclose

FUNDING This research was supported in part by National Institutes of HealthEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentAward R21HD060901 the American Recovery and Reinvestment Act of 2009 and UL1 RR025014 from National Center for Research ResourcesNational Institutes ofHealth The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health Funded by theNational Institutes of Health (NIH)

POTENTIAL CONFLICT OF INTEREST The authors have indicated they have no potential conflicts of interest to disclose

ARTICLE

PEDIATRICS Volume 134 Number 5 November 2014 e1337

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

APPENDIX 1 BIND Scorea

Clinical Sign (Score Most Severe Sign) Score Severity

Mental statusNormal ndash Awake alert 0 NoneSleepy but arousable 1 MildDecreased feeding 1 MildLethargy 2 ModeratePoor suck andor 2 ModerateIrritablejittery 2 ModerateUnable to feed 3 SevereApnea 3 SevereSeizures 3 SevereComa ndash not arousable 3 Severe

Muscle toneNormal flexed tone 0 NonePersistent mild hypotonia 1 MildHypotonia or hypertonia depending on arousal state 2 ModerateBicycling 2 ModerateBeginning nuchal rigidity and truncal arching 2 ModeratePersistent retrocollis 3 SevereOpisthotonos 3 SevereSevere hypo- or hypertonia 3 Severe

Cry patternNormal 0 NoneHigh-pitched 1 MildShrill 2 ModerateInconsolable crying or cry weak or absent 3 Severe

Total bind (ABE score)

Tick all that apply but total score is based on the highest in each category or 9Proposed interpretationTotal BIND score 1ndash3 mild ABE subtle signs reversible no apparent sequelaeTotalBIND score 4ndash6 moderate ABE signs largely reversible with aggressive treatmentTotalBIND score 7ndash9 severe ABE largely irreversible but signs may decrease with prompt treatmenta Modified from Johnson L Brown AK Bhutani V BINDmdashA clinical score for bilirubin induced neurologic dysfunction innewborns Pediatrics 1999104(suppl 4)746ndash747

e1338 ISKANDER et al

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APPENDIX 2 Characteristics of Patients with Kernicterus

BA TSB MaxBIND

3 moAABR

Hct Cause of Jaundice Admweight g

AdmAge d

Comments

1 86 291 9 ND ND Unknown 2250 53 DIED pH 72 HCO3 15 Direct Bil 562 86 342 9 RR 337 Hemolysis O-A 2800 55 Dystonia at 3 mo3 90 37 7 ND 440 Rh incompatibility 2250 4 DIED Suspected sepsis4 91 31 8 RR 397 Rh incomp DAT neg 2800 58 Severe ABE at admission Klebsiella sepsis post-exchange5 96 412 9 ND 292 Hemolysisa 3100 38 DIED pH 697 apnea seizures6 96 376 8 ND 388 O-A incomp 2100 72 Suspected sepsis7 97 32 4 PR 537 Unknown 3000 76 Mild kernicterus 3 mo8 102 317 9 RR 370 G6PD deficient 3200 65 No hemolysis kernicterus at 3 mo9 103 289 9 ND 248 Hemolysis Rh 2250 4 DIED Suspected sepsis pH 717b

10 104 311 5 RR 473 O-A incomp 1840 3 345 wks SGA high reticulocyte count Mild kernicterus11 105 43 8 ND 350 Unknown 2750 38 DIED 2 exchange transfusions12 105 387 9 ND 294 Hemolysisa 2900 2 Suspected sepsis13 106 35 8 ND 340 Hemolysis O-A 2500 34 DIED Pseudomonas sepsis pH 710b

14 108 4002 8 ND 484 Rh moderate G6PD 2750 45 Direct bilirubin 108 with no hemolysis15 113 397 7 RR 419 G6PD amp O-A incomp 2030 13 Late admission kernicterus at 3 mo16 114 366 9 ND 454 Unknown 2250 81 pH 72317 115 425 9 ND 311 Hemolysis O-B 3200 38 DIED Suspected sepsis seizures18 115 367 6 RR 425 O-B incomp 2250 77 Kernicterus at 3 mo19 118 436 6 RR 370 O-A incomp 2970 59 Kernicterus at 3 mo20 121 352 9 ND 429 Unknown 2000 58 DIED rapid deterioration after second exchangeb

21 124 37 7 RR 300 Hemolysis O-B 2400 5 35 wk GA hypertonic with head lag 3 mo22 126 39 9 ND 372 O-A incomp 2300 47 Suspected sepsisb

23 126 442 8 RR 509 Unknown 2400 54 Suspected sepsis pH 733 kernicterus at 3 mo24 128 397 8 ND 314 Hemolysis O-A 2760 98 DIED Suspected sepsis respiratory acidosis apnea seizures25 128 385 8 RR 370 O-A incomp 3150 23 Sustained high TSB kernicterus at 3 mo26 137 479 7 RR 217 Hemolysis G6PD def 2800 49 Suspected sepsis pH 73027 140 365 7 RR 257 Hemolysis Rh 4000 42 Deterioration after second exchangeb

28 149 462 9 ND 490 Unknown 2140 62 RR AABR and abnormal neurologically at discharge no FU29 151 407 7 ND ND O-A incomp 3000 4 DIED classic kernicterus seizures30 151 483 8 RR 381 O-B incomp 2930 13 Late admission Na 157 kernicterus at 3 mo31 156 4201 8 RR 317 Hemolysis Rh 2450 22 Direct bilirubin 16 kernicterus at 3 mo32 178 32 9 ND 279 Hemolysis O-A 2440 43 DIED Suspected sepsis pH 71333 192 479 7 ND 415 O-B amp Rh incomp 2620 26 DIED deteriorated postexchangeb

34 200 441 9 ND 319 Hemolysisa 2850 41 DIED pH 722 respiratory acidosis35 210 6103 7 RR 274 Hemolysis O-A 2900 51 Direct bilirubin 277 kernicterus at 3 mo

Ranked by increasing BA ratio Adm admission Hct hematocrit DAT direct antiglobulin test incomp blood type incompatibility without evident hemolysis Max maximum ND not done PRPass refer FU follow upa Unknown cause for hemolysisb Onset of kernicterus or worsening postexchange transfusion

ARTICLE

PEDIATRICS Volume 134 Number 5 November 2014 e1339

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

ServicesUpdated Information amp

httppediatricsaappublicationsorgcontent1345e1330including high resolution figures can be found at

References

-1httppediatricsaappublicationsorgcontent1345e1330fullref-listThis article cites 36 articles 12 of which you can access for free at

Subspecialty Collections

binemia_subhttpclassicpediatricsaappublicationsorgcgicollectionhyperbiliruHyperbilirubinemiafollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpsshopaaporglicensing-permissionsin its entirety can be found online at Information about reproducing this article in parts (figures tables) or

ReprintshttpclassicpediatricsaappublicationsorgcontentreprintsInformation about ordering reprints can be found online

ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

httppediatricsaappublicationsorgcontent1345e1330located on the World Wide Web at

The online version of this article along with updated information and services is

ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

Page 5: Serum Bilirubin and Bilirubin/Albumin Ratio as …pediatrics.aappublications.org/content/pediatrics/134/5/e1330.full.pdf · Serum Bilirubin and Bilirubin/Albumin Ratio as Predictors

DISCUSSION

Any criterion for intervention in hy-perbilirubinemia must have a highsensitivity identifying all or nearly allinfantswithapossibility of permanentinjury In this study both TSB and BAwere strong predictors of acute andresidual encephalopathy but whenBA and TSB intervention levels were

selected to yield the same sensitivityBA did not improve discrimination ofpatients at risk as hypothesized Thisdoes not mean that measuring serumalbumin is unimportant Severe hemolyticdiseaseandcapillary leak fromavarietyofconditions can result in plasma albumindepletion In such infants the risk forkernicterus may occur at TSB levels well

below AAP-recommended interventionlevels for sick infants25 but the BA cutoffwould be breeched

Role of Risk Factors

Proposed clinical risk factors forbilirubin toxicity1 had surprisinglylittle influence on either thresholdor median values of TSB and BA

FIGURE 1ROC curves evaluating total serumbilirubin and bilirubinalbumin as predictors of different stages of bilirubin neurotoxicity Excludes 4 patients24 hours ofage TSB solid line BA dashed line AUC area under the curve and standard error (SE) shown

TABLE 3 Sensitivity and Specificity for Cutoffs Identifying All Subjects With Disease

Outcome TSB mgdL BA mgg

Cutoff Sensitivity (95 CIa) Specificity (95 CI) Cutoff Sensitivity (95 CI) Specificity (95 CI)

AABR RR at admission 227 100 (96ndash100) 93 (41ndash175) 56 100 (96ndash100) 35 (08ndash99)ABE maximum BIND 4ndash9 270 100 (94ndash100) 492 (4092ndash581) 68 100 (94ndash100) 265 (192ndash349)AABR RR at follow-up 307 100 (84ndash100) 689 (591ndash777) 85 100 (84ndash100) 485 (386ndash586)Kernicterus 286 100 (90ndash100) 495 (395ndash595) 85 100 (90ndash100) 485 (386ndash586)

CI confidence interval including those who dieda CI Excludes 4 patients admitted at 24 h of age

e1334 ISKANDER et al

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

associated with disease in this studyHowever Rh hemolytic disease repre-senting only 11 of the cohort was re-sponsible for 20 of kernicterus casesConsistent with our previous study ofa different cohort of 212 newborns withTSB 25 mgdL26 only infants withhemolytic disease due to Rh incom-patibility orwith sepsis developed severeABE below a TSB of 31 mgdL ABO in-compatibility and G6PD deficiency (in theabsence of hemolytic crisis) createdminimal if any additional risk comparedwith idiopathic jaundice Wolf et al27 andWeng et al28 reported similar resultsResistance to long-termconsequences ofsevere hyperbilirubinemia in otherwisehealthy term infants was also reportedby Newman and colleagues2930 Thiscumulative evidence strongly suggeststhat asymptomatic termnear-termnewborns without risk factors rarelydevelop kernicterus or auditory neu-ropathy at TSB 31 mg andor BA86 mgg Given the risks of exchangetransfusion31 intensive phototherapy andclose monitoring may be a safer treat-ment option for those infants

Why Did BA Not ImproveIdentification of Risk in ThisPopulation

One possible explanation is that thereare wide variations in Bf transport intothe brain andor in cellular defensemechanisms Two of 4 infants with he-molytic disease admitted on day 1 of lifehad rapidly rising TSB and low thresh-olds for toxicity Whether the lowerthresholds are due to rate of rise of TSBpooralbuminbinding or increasedbrainsusceptibility to Bf on day 1 of life isunknown

A second possibility is that BA is notabetterpredictorofBf thanTSBalone (ievariations in binding ability exceed var-iations in albumin concentration) Incontrast to premature infants who maydevelop ABE at BA molar ratios132ndash34

(where Bf is largely dependent on thequality of albumin binding) moderate to

severe bilirubin toxicity in our cohortoccurred only when the molar concen-tration of bilirubin approached or sur-passed the concentration of albuminBf increases dramatically as TSB ap-proaches or exceeds a BAmolar ratio of11 (BA = 88 mgdL) and limitations ofbilirubin solubility become a dominantissue Several infants with no signs oftoxicity hadBAmolar ratios approaching125 indicating that additional bilirubin-binding sites must exist in plasma3536

The high likelihood of wide variations inthis expanded buffering capacity re-inforce the need to measure Bf directlyto validate its value as a marker of in-fants at risk

A third option relates to experimentaldesign limitations In this study as inmost published outcome studies1537ndash38

there were no untreated controlsand no serial documentation of TSBas signs of encephalopathy pro-gressed Fourteen patients had verylow serum albumin levels rangingfrom 18 to 27 gdL and might havebenefited from considering BA Six ofthese infants had severe ABE whenfirst seen TSBs ranged from 32 to44 mgdL and BAs ranged from 14 to20 mgg preventing any inference aboutthe levels of TSB and BA at the onsetof disease

Relationship of Thresholds toProgression of Neurotoxicity

The opportunity to evaluate AABR atadmission as well as repeated BINDscores during the first hours of ad-mission provided unique serial ob-servations of auditory and neurologicevents before and after therapy This inturn allowed us to estimate thresholdvalues for outcomes ranging from re-versible neurotoxicity to irreversibleinjury We observed a rather largejump in threshold values at high sen-sitivity between mild (BIND score 2ndash3)and moderate ABE with smallerchange between moderate and severe

ABE This separation in thresholdscould provide guidance for interventiondecisions

Mindful that our analysis was not strati-fied for GA or risk factors thresholds at100 sensitivity included infants withhighest clinical risk conditions Cutoffsfor TSB identified in this study aresubstantially higher than recommendedintervention levels for low GA withrisk factors1 Our findings should beconfirmed because other studies havereported ABE and hearing loss at lowerlevels than documented here1537ndash38 mostoften associated with severe hemolysisespecially from Rh hemolytic diseasesepsis or prematurity

Strengths and Limitations

This study was conducted at a singlevenue where the quality of clinicalevaluation was carefully monitoredEven so we encountered uncertain-ties in assigning risk factors1 for ABEExchange transfusion was associatedwith worsening ABE and kernicterusin 4 infants potentially confoundingthe relationship between admissiontest values and long-term outcomeFinally the inability to administeroptimal intensive phototherapy andoccasional delays in receiving bloodfor exchange transfusion might haveinfluenced outcomes Notwithstand-ing these limitations the ability ofadmission serum chemistries to pre-dict thresholds for both acute andposttreatment outcomes was ratherremarkable

In 1988 Perlman and Frank39 proposeda hierarchy of neurophysiological andbehavioral signals leading ultimatelyto irreversible brain injury (kernicterushearing loss) but lamented that pro-spective cohort studies needed to de-termine the relative risks associatedwith various biochemical and clinicalpredictive criteria may not be availablefor many years This study conducted inan environment in which kernicterus is

ARTICLE

PEDIATRICS Volume 134 Number 5 November 2014 e1335

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

not a rare event provides a first step inachieving that goal

CONCLUSIONS

TSB and BA are both strong in-dicators of risk for acute and re-

sidual bilirubin neurotoxicity Whenintervention values are adjusted toprovide equal sensitivity the specif-icities of TSB and BA are nearly thesame and BA offers no additionaladvantage over TSB alone in most

clinical settings TSBandBA thresholdsfor disease increased with advan-cing severity of neurotoxicity thisshould be considered when deli-berating appropriate interventionguidelines

REFERENCES

1 American Academy of Pediatrics Subcom-mittee on Hyperbilirubinemia Management ofhyperbilirubinemia in the newborn infant 35or more weeks of gestation Pediatrics 2004114(1)297ndash316

2 Wennberg RP Ahlfors CE Bhutani VK JohnsonLH Shapiro SM Toward understandingkernicterus a challenge to improve the man-agement of jaundiced newborns Pediatrics2006117(2)474ndash485

3 Ahlfors CE Wennberg RP Ostrow JD TiribelliC Unbound (free) bilirubin improving theparadigm for evaluating neonatal jaundiceClin Chem 200955(7)1288ndash1299

4 Ahlfors CE Criteria for exchange trans-fusion in jaundiced newborns Pediatrics199493(3)488ndash494

5 Sato Y Morioka I Miwa A et al Is bilirubinalbumin ratio correlated with unboundbilirubin concentration Pediatr Int 201254(1)81ndash85

6 Ardakani SB Dana VG Ziaee V AshtianiM-TH Djavid GE Alijani M Bilirubinalbuminratio for predicting acute bilirubin-inducedneurologic dysfunction Iran J Pediatr 201121(1)28ndash32

7 Hulzebos CV Dijk PH van Imhoff DE et alBARTrial Study Group The bilirubin albu-min ratio in the management of hyper-bilirubinemia in preterm infants to improveneurodevelopmental outcome a randomizedcontrolled trialmdashBARTrial PLoS ONE 20149(6)e99466

8 Johnson L Brown AK Bhutani V BINDmdashAclinical score for bilirubin induced neuro-logic dysfunction in newborns Pediatrics1999104(suppl 4)746ndash747

9 van Straaten HL Automated auditory brain-stem response in neonatal hearing screen-ing Acta Paediatr Suppl 199988(432)76ndash79

10 Shapiro SM Definition of the clinical spec-trum of kernicterus and bilirubin-inducedneurologic dysfunction (BIND) J Perinatol200525(1)54ndash59

11 Ballard JL Khoury JC Wedig K Wang L Eilers-Walsman BL Lipp R New Ballard Score

expanded to include extremely prematureinfants J Pediatr 1991119(3)417ndash423

12 Doumas BT Wu TW Jendrzejczak B Deltabilirubin absorption spectra molar ab-sorptivity and reactivity in the diazo re-action Clin Chem 198733(6)769ndash774

13 Carter P Ultramicroestimation of humanserum albumin binding cationic dye559dibromo-o cresolsulfonphthalein Micro-chem J 197015531ndash539

14 Volpe JJ Bilirubin and brain injury In VolpeJJ ed Neurology of the Newborn 3rd edPhiladelphia PA WB Saunders 2001490ndash514

15 Johnson L Bhutani VK Karp K Sivieri EMShapiro SM Clinical report from the pilot USAKernicterus Registry (1992 to 2004) J Peri-natol 200929(suppl 1)S25ndashS45

16 Johnson L Bhutani VK The clinical syndromeof bilirubin-induced neurologic dysfunctionSemin Perinatol 201135(3)101ndash113

17 Berlin CI Hood LJ Morlet T et al Multi-sitediagnosis and management of 260 patientswith auditory neuropathydys-synchrony(auditory neuropathy spectrum disorder)Int J Audiol 201049(1)30ndash43

18 Saluja S Agarwal A Kler N Amin S Audi-tory neuropathy spectrum disorder in latepreterm and term infants with severejaundice Int J Pediatr Otorhinolaryngol201074(11)1292ndash1297

19 Shapiro SM Popelka GR Auditory impair-ment in infants at risk for bilirubin-inducedneurologic dysfunction Semin Perinatol201135(3)162ndash170

20 Makkar M Gupta C Pathak R Garg S MahajanNC Performance evaluation of hematologicscoring system in early diagnosis of neonatalsepsis J Clin Neonatol 20132(1)25ndash29

21 Pearlman MA Gartner LM Lee K Morecki RHoroupian DS Absence of kernicterus inlow-birth weight infants from 1971 through1976 comparison with findings in 1966 and1967 Pediatrics 197862(4)460ndash464

22 Durkalski VL Palesch YY Lipsitz SR Rust PFAnalysis of clustered matched-pair dataStat Med 200322(15)2417ndash2428

23 Pepe MS The Statistical Evaluation ofMedical Tests for Classification and Pre-diction Oxford UK Oxford University Press2003

24 Iskander I Gamaleldin R Kabbani M Rootcauses for late presentation of severeneonatal hyperbilirubinaemia in Egypt EastMediterr Health J 201218(8)882ndash887

25 Odutolu Y Emmerson AJ Low bilirubinkernicterus with sepsis and hypoalbuminaemiaBMJ Case Reports 2013 doi101136bcr-2012-008042

26 Gamaleldin R Iskander I Seoud I et al Riskfactors for neurotoxicity in newborns withsevere neonatal hyperbilirubinemia Pediat-rics 2011128(4) Available at wwwpediat-ricsorgcgicontentfull1284e925

27 Wolf MJ Wolf B Beunen G Casaer PNeurodevelopmental outcome at 1 yearin Zimbabwean neonates with extremehyperbilirubinaemia Eur J Pediatr 1999158(2)111ndash114

28 Weng YH Chiu YW Cheng SW Hsieh MY Riskassessment for adverse outcome in termand late preterm neonates with bilirubinvalues of 20 mgdL or more Am J Perinatol201128(5)405ndash412

29 Newman TB Liljestrand P Escobar GJInfants with bilirubin levels of 30 mgdL ormore in a large managed care organiza-tion Pediatrics 2003111(6 pt 1)1303ndash1311

30 Newman TB Liljestrand P Jeremy RJ et alJaundice and Infant Feeding Study TeamOutcomes among newborns with total se-rum bilirubin levels of 25 mg per deciliteror more N Engl J Med 2006354(18)1889ndash1900

31 Smits-Wintjens VE Rath ME van Zwet EWet al Neonatal morbidity after exchangetransfusion for red cell alloimmune he-molytic disease Neonatology 2013103(2)141ndash147

32 Hulzebos CV van Imhoff DE Bos AF Ahlfors CEVerkade HJ Dijk PH Usefulness of thebilirubinalbumin ratio for predicting bilirubin-

e1336 ISKANDER et al

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

induced neurotoxicity in premature infantsArch Dis Child Fetal Neonatal Ed 200893(5)F384ndashF388

33 Cashore WJ Oh W Unbound bilirubin andkernicterus in low-birth-weight infantsPediatrics 198269(4)481ndash485

34 Nakamura H Yonetani M Uetani Y Funato MLee Y Determination of serum unbound bil-irubin for prediction of kernicterus in lowbirthweight infants Acta Paediatr Jpn 199234(6)642ndash647

35 Jacobsen J Binding of bilirubin to humanserum albumin - determination of the disso-ciation constants FEBS Lett 19695(2)112ndash114

36 Goessling W Zucker SD Role of apolipopro-tein D in the transport of bilirubin in plasmaAm J Physiol Gastrointest Liver Physiol 2000279(2)G356ndashG365

37 Hsia DY Allen FH Jr Gellis SS Diamond LKErythroblastosis fetalis VIII Studies ofserum bilirubin in relation to kernicterusN Engl J Med 1952247(18)668ndash671

38 Ip S Chung M Kulig J et al AmericanAcademy of Pediatrics Subcommitteeon Hyperbilirubinemia An evidence-based review of important issues con-cerning neonatal hyperbilirubinemiaPediatrics 2004114(1) Available atwwwpediatricsorgcgicontentfull1141e130

39 Perlman M Frank JW Bilirubin beyond theblood-brain barrier Pediatrics 198881(2)304ndash315

(Continued from first page)

wwwpediatricsorgcgidoi101542peds2013-1764

doi101542peds2013-1764

Accepted for publication Aug 27 2014

Address correspondence to Iman F Iskander MD Department of Pediatrics Cairo University 8 Salah El Din St Zamalek Cairo 11211 Egypt E-mail imaniskhotmailcom

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2014 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE The authors have indicated they have no financial relationships relevant to this article to disclose

FUNDING This research was supported in part by National Institutes of HealthEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentAward R21HD060901 the American Recovery and Reinvestment Act of 2009 and UL1 RR025014 from National Center for Research ResourcesNational Institutes ofHealth The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health Funded by theNational Institutes of Health (NIH)

POTENTIAL CONFLICT OF INTEREST The authors have indicated they have no potential conflicts of interest to disclose

ARTICLE

PEDIATRICS Volume 134 Number 5 November 2014 e1337

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

APPENDIX 1 BIND Scorea

Clinical Sign (Score Most Severe Sign) Score Severity

Mental statusNormal ndash Awake alert 0 NoneSleepy but arousable 1 MildDecreased feeding 1 MildLethargy 2 ModeratePoor suck andor 2 ModerateIrritablejittery 2 ModerateUnable to feed 3 SevereApnea 3 SevereSeizures 3 SevereComa ndash not arousable 3 Severe

Muscle toneNormal flexed tone 0 NonePersistent mild hypotonia 1 MildHypotonia or hypertonia depending on arousal state 2 ModerateBicycling 2 ModerateBeginning nuchal rigidity and truncal arching 2 ModeratePersistent retrocollis 3 SevereOpisthotonos 3 SevereSevere hypo- or hypertonia 3 Severe

Cry patternNormal 0 NoneHigh-pitched 1 MildShrill 2 ModerateInconsolable crying or cry weak or absent 3 Severe

Total bind (ABE score)

Tick all that apply but total score is based on the highest in each category or 9Proposed interpretationTotal BIND score 1ndash3 mild ABE subtle signs reversible no apparent sequelaeTotalBIND score 4ndash6 moderate ABE signs largely reversible with aggressive treatmentTotalBIND score 7ndash9 severe ABE largely irreversible but signs may decrease with prompt treatmenta Modified from Johnson L Brown AK Bhutani V BINDmdashA clinical score for bilirubin induced neurologic dysfunction innewborns Pediatrics 1999104(suppl 4)746ndash747

e1338 ISKANDER et al

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

APPENDIX 2 Characteristics of Patients with Kernicterus

BA TSB MaxBIND

3 moAABR

Hct Cause of Jaundice Admweight g

AdmAge d

Comments

1 86 291 9 ND ND Unknown 2250 53 DIED pH 72 HCO3 15 Direct Bil 562 86 342 9 RR 337 Hemolysis O-A 2800 55 Dystonia at 3 mo3 90 37 7 ND 440 Rh incompatibility 2250 4 DIED Suspected sepsis4 91 31 8 RR 397 Rh incomp DAT neg 2800 58 Severe ABE at admission Klebsiella sepsis post-exchange5 96 412 9 ND 292 Hemolysisa 3100 38 DIED pH 697 apnea seizures6 96 376 8 ND 388 O-A incomp 2100 72 Suspected sepsis7 97 32 4 PR 537 Unknown 3000 76 Mild kernicterus 3 mo8 102 317 9 RR 370 G6PD deficient 3200 65 No hemolysis kernicterus at 3 mo9 103 289 9 ND 248 Hemolysis Rh 2250 4 DIED Suspected sepsis pH 717b

10 104 311 5 RR 473 O-A incomp 1840 3 345 wks SGA high reticulocyte count Mild kernicterus11 105 43 8 ND 350 Unknown 2750 38 DIED 2 exchange transfusions12 105 387 9 ND 294 Hemolysisa 2900 2 Suspected sepsis13 106 35 8 ND 340 Hemolysis O-A 2500 34 DIED Pseudomonas sepsis pH 710b

14 108 4002 8 ND 484 Rh moderate G6PD 2750 45 Direct bilirubin 108 with no hemolysis15 113 397 7 RR 419 G6PD amp O-A incomp 2030 13 Late admission kernicterus at 3 mo16 114 366 9 ND 454 Unknown 2250 81 pH 72317 115 425 9 ND 311 Hemolysis O-B 3200 38 DIED Suspected sepsis seizures18 115 367 6 RR 425 O-B incomp 2250 77 Kernicterus at 3 mo19 118 436 6 RR 370 O-A incomp 2970 59 Kernicterus at 3 mo20 121 352 9 ND 429 Unknown 2000 58 DIED rapid deterioration after second exchangeb

21 124 37 7 RR 300 Hemolysis O-B 2400 5 35 wk GA hypertonic with head lag 3 mo22 126 39 9 ND 372 O-A incomp 2300 47 Suspected sepsisb

23 126 442 8 RR 509 Unknown 2400 54 Suspected sepsis pH 733 kernicterus at 3 mo24 128 397 8 ND 314 Hemolysis O-A 2760 98 DIED Suspected sepsis respiratory acidosis apnea seizures25 128 385 8 RR 370 O-A incomp 3150 23 Sustained high TSB kernicterus at 3 mo26 137 479 7 RR 217 Hemolysis G6PD def 2800 49 Suspected sepsis pH 73027 140 365 7 RR 257 Hemolysis Rh 4000 42 Deterioration after second exchangeb

28 149 462 9 ND 490 Unknown 2140 62 RR AABR and abnormal neurologically at discharge no FU29 151 407 7 ND ND O-A incomp 3000 4 DIED classic kernicterus seizures30 151 483 8 RR 381 O-B incomp 2930 13 Late admission Na 157 kernicterus at 3 mo31 156 4201 8 RR 317 Hemolysis Rh 2450 22 Direct bilirubin 16 kernicterus at 3 mo32 178 32 9 ND 279 Hemolysis O-A 2440 43 DIED Suspected sepsis pH 71333 192 479 7 ND 415 O-B amp Rh incomp 2620 26 DIED deteriorated postexchangeb

34 200 441 9 ND 319 Hemolysisa 2850 41 DIED pH 722 respiratory acidosis35 210 6103 7 RR 274 Hemolysis O-A 2900 51 Direct bilirubin 277 kernicterus at 3 mo

Ranked by increasing BA ratio Adm admission Hct hematocrit DAT direct antiglobulin test incomp blood type incompatibility without evident hemolysis Max maximum ND not done PRPass refer FU follow upa Unknown cause for hemolysisb Onset of kernicterus or worsening postexchange transfusion

ARTICLE

PEDIATRICS Volume 134 Number 5 November 2014 e1339

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

ServicesUpdated Information amp

httppediatricsaappublicationsorgcontent1345e1330including high resolution figures can be found at

References

-1httppediatricsaappublicationsorgcontent1345e1330fullref-listThis article cites 36 articles 12 of which you can access for free at

Subspecialty Collections

binemia_subhttpclassicpediatricsaappublicationsorgcgicollectionhyperbiliruHyperbilirubinemiafollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpsshopaaporglicensing-permissionsin its entirety can be found online at Information about reproducing this article in parts (figures tables) or

ReprintshttpclassicpediatricsaappublicationsorgcontentreprintsInformation about ordering reprints can be found online

ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

httppediatricsaappublicationsorgcontent1345e1330located on the World Wide Web at

The online version of this article along with updated information and services is

ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

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associated with disease in this studyHowever Rh hemolytic disease repre-senting only 11 of the cohort was re-sponsible for 20 of kernicterus casesConsistent with our previous study ofa different cohort of 212 newborns withTSB 25 mgdL26 only infants withhemolytic disease due to Rh incom-patibility orwith sepsis developed severeABE below a TSB of 31 mgdL ABO in-compatibility and G6PD deficiency (in theabsence of hemolytic crisis) createdminimal if any additional risk comparedwith idiopathic jaundice Wolf et al27 andWeng et al28 reported similar resultsResistance to long-termconsequences ofsevere hyperbilirubinemia in otherwisehealthy term infants was also reportedby Newman and colleagues2930 Thiscumulative evidence strongly suggeststhat asymptomatic termnear-termnewborns without risk factors rarelydevelop kernicterus or auditory neu-ropathy at TSB 31 mg andor BA86 mgg Given the risks of exchangetransfusion31 intensive phototherapy andclose monitoring may be a safer treat-ment option for those infants

Why Did BA Not ImproveIdentification of Risk in ThisPopulation

One possible explanation is that thereare wide variations in Bf transport intothe brain andor in cellular defensemechanisms Two of 4 infants with he-molytic disease admitted on day 1 of lifehad rapidly rising TSB and low thresh-olds for toxicity Whether the lowerthresholds are due to rate of rise of TSBpooralbuminbinding or increasedbrainsusceptibility to Bf on day 1 of life isunknown

A second possibility is that BA is notabetterpredictorofBf thanTSBalone (ievariations in binding ability exceed var-iations in albumin concentration) Incontrast to premature infants who maydevelop ABE at BA molar ratios132ndash34

(where Bf is largely dependent on thequality of albumin binding) moderate to

severe bilirubin toxicity in our cohortoccurred only when the molar concen-tration of bilirubin approached or sur-passed the concentration of albuminBf increases dramatically as TSB ap-proaches or exceeds a BAmolar ratio of11 (BA = 88 mgdL) and limitations ofbilirubin solubility become a dominantissue Several infants with no signs oftoxicity hadBAmolar ratios approaching125 indicating that additional bilirubin-binding sites must exist in plasma3536

The high likelihood of wide variations inthis expanded buffering capacity re-inforce the need to measure Bf directlyto validate its value as a marker of in-fants at risk

A third option relates to experimentaldesign limitations In this study as inmost published outcome studies1537ndash38

there were no untreated controlsand no serial documentation of TSBas signs of encephalopathy pro-gressed Fourteen patients had verylow serum albumin levels rangingfrom 18 to 27 gdL and might havebenefited from considering BA Six ofthese infants had severe ABE whenfirst seen TSBs ranged from 32 to44 mgdL and BAs ranged from 14 to20 mgg preventing any inference aboutthe levels of TSB and BA at the onsetof disease

Relationship of Thresholds toProgression of Neurotoxicity

The opportunity to evaluate AABR atadmission as well as repeated BINDscores during the first hours of ad-mission provided unique serial ob-servations of auditory and neurologicevents before and after therapy This inturn allowed us to estimate thresholdvalues for outcomes ranging from re-versible neurotoxicity to irreversibleinjury We observed a rather largejump in threshold values at high sen-sitivity between mild (BIND score 2ndash3)and moderate ABE with smallerchange between moderate and severe

ABE This separation in thresholdscould provide guidance for interventiondecisions

Mindful that our analysis was not strati-fied for GA or risk factors thresholds at100 sensitivity included infants withhighest clinical risk conditions Cutoffsfor TSB identified in this study aresubstantially higher than recommendedintervention levels for low GA withrisk factors1 Our findings should beconfirmed because other studies havereported ABE and hearing loss at lowerlevels than documented here1537ndash38 mostoften associated with severe hemolysisespecially from Rh hemolytic diseasesepsis or prematurity

Strengths and Limitations

This study was conducted at a singlevenue where the quality of clinicalevaluation was carefully monitoredEven so we encountered uncertain-ties in assigning risk factors1 for ABEExchange transfusion was associatedwith worsening ABE and kernicterusin 4 infants potentially confoundingthe relationship between admissiontest values and long-term outcomeFinally the inability to administeroptimal intensive phototherapy andoccasional delays in receiving bloodfor exchange transfusion might haveinfluenced outcomes Notwithstand-ing these limitations the ability ofadmission serum chemistries to pre-dict thresholds for both acute andposttreatment outcomes was ratherremarkable

In 1988 Perlman and Frank39 proposeda hierarchy of neurophysiological andbehavioral signals leading ultimatelyto irreversible brain injury (kernicterushearing loss) but lamented that pro-spective cohort studies needed to de-termine the relative risks associatedwith various biochemical and clinicalpredictive criteria may not be availablefor many years This study conducted inan environment in which kernicterus is

ARTICLE

PEDIATRICS Volume 134 Number 5 November 2014 e1335

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

not a rare event provides a first step inachieving that goal

CONCLUSIONS

TSB and BA are both strong in-dicators of risk for acute and re-

sidual bilirubin neurotoxicity Whenintervention values are adjusted toprovide equal sensitivity the specif-icities of TSB and BA are nearly thesame and BA offers no additionaladvantage over TSB alone in most

clinical settings TSBandBA thresholdsfor disease increased with advan-cing severity of neurotoxicity thisshould be considered when deli-berating appropriate interventionguidelines

REFERENCES

1 American Academy of Pediatrics Subcom-mittee on Hyperbilirubinemia Management ofhyperbilirubinemia in the newborn infant 35or more weeks of gestation Pediatrics 2004114(1)297ndash316

2 Wennberg RP Ahlfors CE Bhutani VK JohnsonLH Shapiro SM Toward understandingkernicterus a challenge to improve the man-agement of jaundiced newborns Pediatrics2006117(2)474ndash485

3 Ahlfors CE Wennberg RP Ostrow JD TiribelliC Unbound (free) bilirubin improving theparadigm for evaluating neonatal jaundiceClin Chem 200955(7)1288ndash1299

4 Ahlfors CE Criteria for exchange trans-fusion in jaundiced newborns Pediatrics199493(3)488ndash494

5 Sato Y Morioka I Miwa A et al Is bilirubinalbumin ratio correlated with unboundbilirubin concentration Pediatr Int 201254(1)81ndash85

6 Ardakani SB Dana VG Ziaee V AshtianiM-TH Djavid GE Alijani M Bilirubinalbuminratio for predicting acute bilirubin-inducedneurologic dysfunction Iran J Pediatr 201121(1)28ndash32

7 Hulzebos CV Dijk PH van Imhoff DE et alBARTrial Study Group The bilirubin albu-min ratio in the management of hyper-bilirubinemia in preterm infants to improveneurodevelopmental outcome a randomizedcontrolled trialmdashBARTrial PLoS ONE 20149(6)e99466

8 Johnson L Brown AK Bhutani V BINDmdashAclinical score for bilirubin induced neuro-logic dysfunction in newborns Pediatrics1999104(suppl 4)746ndash747

9 van Straaten HL Automated auditory brain-stem response in neonatal hearing screen-ing Acta Paediatr Suppl 199988(432)76ndash79

10 Shapiro SM Definition of the clinical spec-trum of kernicterus and bilirubin-inducedneurologic dysfunction (BIND) J Perinatol200525(1)54ndash59

11 Ballard JL Khoury JC Wedig K Wang L Eilers-Walsman BL Lipp R New Ballard Score

expanded to include extremely prematureinfants J Pediatr 1991119(3)417ndash423

12 Doumas BT Wu TW Jendrzejczak B Deltabilirubin absorption spectra molar ab-sorptivity and reactivity in the diazo re-action Clin Chem 198733(6)769ndash774

13 Carter P Ultramicroestimation of humanserum albumin binding cationic dye559dibromo-o cresolsulfonphthalein Micro-chem J 197015531ndash539

14 Volpe JJ Bilirubin and brain injury In VolpeJJ ed Neurology of the Newborn 3rd edPhiladelphia PA WB Saunders 2001490ndash514

15 Johnson L Bhutani VK Karp K Sivieri EMShapiro SM Clinical report from the pilot USAKernicterus Registry (1992 to 2004) J Peri-natol 200929(suppl 1)S25ndashS45

16 Johnson L Bhutani VK The clinical syndromeof bilirubin-induced neurologic dysfunctionSemin Perinatol 201135(3)101ndash113

17 Berlin CI Hood LJ Morlet T et al Multi-sitediagnosis and management of 260 patientswith auditory neuropathydys-synchrony(auditory neuropathy spectrum disorder)Int J Audiol 201049(1)30ndash43

18 Saluja S Agarwal A Kler N Amin S Audi-tory neuropathy spectrum disorder in latepreterm and term infants with severejaundice Int J Pediatr Otorhinolaryngol201074(11)1292ndash1297

19 Shapiro SM Popelka GR Auditory impair-ment in infants at risk for bilirubin-inducedneurologic dysfunction Semin Perinatol201135(3)162ndash170

20 Makkar M Gupta C Pathak R Garg S MahajanNC Performance evaluation of hematologicscoring system in early diagnosis of neonatalsepsis J Clin Neonatol 20132(1)25ndash29

21 Pearlman MA Gartner LM Lee K Morecki RHoroupian DS Absence of kernicterus inlow-birth weight infants from 1971 through1976 comparison with findings in 1966 and1967 Pediatrics 197862(4)460ndash464

22 Durkalski VL Palesch YY Lipsitz SR Rust PFAnalysis of clustered matched-pair dataStat Med 200322(15)2417ndash2428

23 Pepe MS The Statistical Evaluation ofMedical Tests for Classification and Pre-diction Oxford UK Oxford University Press2003

24 Iskander I Gamaleldin R Kabbani M Rootcauses for late presentation of severeneonatal hyperbilirubinaemia in Egypt EastMediterr Health J 201218(8)882ndash887

25 Odutolu Y Emmerson AJ Low bilirubinkernicterus with sepsis and hypoalbuminaemiaBMJ Case Reports 2013 doi101136bcr-2012-008042

26 Gamaleldin R Iskander I Seoud I et al Riskfactors for neurotoxicity in newborns withsevere neonatal hyperbilirubinemia Pediat-rics 2011128(4) Available at wwwpediat-ricsorgcgicontentfull1284e925

27 Wolf MJ Wolf B Beunen G Casaer PNeurodevelopmental outcome at 1 yearin Zimbabwean neonates with extremehyperbilirubinaemia Eur J Pediatr 1999158(2)111ndash114

28 Weng YH Chiu YW Cheng SW Hsieh MY Riskassessment for adverse outcome in termand late preterm neonates with bilirubinvalues of 20 mgdL or more Am J Perinatol201128(5)405ndash412

29 Newman TB Liljestrand P Escobar GJInfants with bilirubin levels of 30 mgdL ormore in a large managed care organiza-tion Pediatrics 2003111(6 pt 1)1303ndash1311

30 Newman TB Liljestrand P Jeremy RJ et alJaundice and Infant Feeding Study TeamOutcomes among newborns with total se-rum bilirubin levels of 25 mg per deciliteror more N Engl J Med 2006354(18)1889ndash1900

31 Smits-Wintjens VE Rath ME van Zwet EWet al Neonatal morbidity after exchangetransfusion for red cell alloimmune he-molytic disease Neonatology 2013103(2)141ndash147

32 Hulzebos CV van Imhoff DE Bos AF Ahlfors CEVerkade HJ Dijk PH Usefulness of thebilirubinalbumin ratio for predicting bilirubin-

e1336 ISKANDER et al

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

induced neurotoxicity in premature infantsArch Dis Child Fetal Neonatal Ed 200893(5)F384ndashF388

33 Cashore WJ Oh W Unbound bilirubin andkernicterus in low-birth-weight infantsPediatrics 198269(4)481ndash485

34 Nakamura H Yonetani M Uetani Y Funato MLee Y Determination of serum unbound bil-irubin for prediction of kernicterus in lowbirthweight infants Acta Paediatr Jpn 199234(6)642ndash647

35 Jacobsen J Binding of bilirubin to humanserum albumin - determination of the disso-ciation constants FEBS Lett 19695(2)112ndash114

36 Goessling W Zucker SD Role of apolipopro-tein D in the transport of bilirubin in plasmaAm J Physiol Gastrointest Liver Physiol 2000279(2)G356ndashG365

37 Hsia DY Allen FH Jr Gellis SS Diamond LKErythroblastosis fetalis VIII Studies ofserum bilirubin in relation to kernicterusN Engl J Med 1952247(18)668ndash671

38 Ip S Chung M Kulig J et al AmericanAcademy of Pediatrics Subcommitteeon Hyperbilirubinemia An evidence-based review of important issues con-cerning neonatal hyperbilirubinemiaPediatrics 2004114(1) Available atwwwpediatricsorgcgicontentfull1141e130

39 Perlman M Frank JW Bilirubin beyond theblood-brain barrier Pediatrics 198881(2)304ndash315

(Continued from first page)

wwwpediatricsorgcgidoi101542peds2013-1764

doi101542peds2013-1764

Accepted for publication Aug 27 2014

Address correspondence to Iman F Iskander MD Department of Pediatrics Cairo University 8 Salah El Din St Zamalek Cairo 11211 Egypt E-mail imaniskhotmailcom

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2014 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE The authors have indicated they have no financial relationships relevant to this article to disclose

FUNDING This research was supported in part by National Institutes of HealthEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentAward R21HD060901 the American Recovery and Reinvestment Act of 2009 and UL1 RR025014 from National Center for Research ResourcesNational Institutes ofHealth The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health Funded by theNational Institutes of Health (NIH)

POTENTIAL CONFLICT OF INTEREST The authors have indicated they have no potential conflicts of interest to disclose

ARTICLE

PEDIATRICS Volume 134 Number 5 November 2014 e1337

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

APPENDIX 1 BIND Scorea

Clinical Sign (Score Most Severe Sign) Score Severity

Mental statusNormal ndash Awake alert 0 NoneSleepy but arousable 1 MildDecreased feeding 1 MildLethargy 2 ModeratePoor suck andor 2 ModerateIrritablejittery 2 ModerateUnable to feed 3 SevereApnea 3 SevereSeizures 3 SevereComa ndash not arousable 3 Severe

Muscle toneNormal flexed tone 0 NonePersistent mild hypotonia 1 MildHypotonia or hypertonia depending on arousal state 2 ModerateBicycling 2 ModerateBeginning nuchal rigidity and truncal arching 2 ModeratePersistent retrocollis 3 SevereOpisthotonos 3 SevereSevere hypo- or hypertonia 3 Severe

Cry patternNormal 0 NoneHigh-pitched 1 MildShrill 2 ModerateInconsolable crying or cry weak or absent 3 Severe

Total bind (ABE score)

Tick all that apply but total score is based on the highest in each category or 9Proposed interpretationTotal BIND score 1ndash3 mild ABE subtle signs reversible no apparent sequelaeTotalBIND score 4ndash6 moderate ABE signs largely reversible with aggressive treatmentTotalBIND score 7ndash9 severe ABE largely irreversible but signs may decrease with prompt treatmenta Modified from Johnson L Brown AK Bhutani V BINDmdashA clinical score for bilirubin induced neurologic dysfunction innewborns Pediatrics 1999104(suppl 4)746ndash747

e1338 ISKANDER et al

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

APPENDIX 2 Characteristics of Patients with Kernicterus

BA TSB MaxBIND

3 moAABR

Hct Cause of Jaundice Admweight g

AdmAge d

Comments

1 86 291 9 ND ND Unknown 2250 53 DIED pH 72 HCO3 15 Direct Bil 562 86 342 9 RR 337 Hemolysis O-A 2800 55 Dystonia at 3 mo3 90 37 7 ND 440 Rh incompatibility 2250 4 DIED Suspected sepsis4 91 31 8 RR 397 Rh incomp DAT neg 2800 58 Severe ABE at admission Klebsiella sepsis post-exchange5 96 412 9 ND 292 Hemolysisa 3100 38 DIED pH 697 apnea seizures6 96 376 8 ND 388 O-A incomp 2100 72 Suspected sepsis7 97 32 4 PR 537 Unknown 3000 76 Mild kernicterus 3 mo8 102 317 9 RR 370 G6PD deficient 3200 65 No hemolysis kernicterus at 3 mo9 103 289 9 ND 248 Hemolysis Rh 2250 4 DIED Suspected sepsis pH 717b

10 104 311 5 RR 473 O-A incomp 1840 3 345 wks SGA high reticulocyte count Mild kernicterus11 105 43 8 ND 350 Unknown 2750 38 DIED 2 exchange transfusions12 105 387 9 ND 294 Hemolysisa 2900 2 Suspected sepsis13 106 35 8 ND 340 Hemolysis O-A 2500 34 DIED Pseudomonas sepsis pH 710b

14 108 4002 8 ND 484 Rh moderate G6PD 2750 45 Direct bilirubin 108 with no hemolysis15 113 397 7 RR 419 G6PD amp O-A incomp 2030 13 Late admission kernicterus at 3 mo16 114 366 9 ND 454 Unknown 2250 81 pH 72317 115 425 9 ND 311 Hemolysis O-B 3200 38 DIED Suspected sepsis seizures18 115 367 6 RR 425 O-B incomp 2250 77 Kernicterus at 3 mo19 118 436 6 RR 370 O-A incomp 2970 59 Kernicterus at 3 mo20 121 352 9 ND 429 Unknown 2000 58 DIED rapid deterioration after second exchangeb

21 124 37 7 RR 300 Hemolysis O-B 2400 5 35 wk GA hypertonic with head lag 3 mo22 126 39 9 ND 372 O-A incomp 2300 47 Suspected sepsisb

23 126 442 8 RR 509 Unknown 2400 54 Suspected sepsis pH 733 kernicterus at 3 mo24 128 397 8 ND 314 Hemolysis O-A 2760 98 DIED Suspected sepsis respiratory acidosis apnea seizures25 128 385 8 RR 370 O-A incomp 3150 23 Sustained high TSB kernicterus at 3 mo26 137 479 7 RR 217 Hemolysis G6PD def 2800 49 Suspected sepsis pH 73027 140 365 7 RR 257 Hemolysis Rh 4000 42 Deterioration after second exchangeb

28 149 462 9 ND 490 Unknown 2140 62 RR AABR and abnormal neurologically at discharge no FU29 151 407 7 ND ND O-A incomp 3000 4 DIED classic kernicterus seizures30 151 483 8 RR 381 O-B incomp 2930 13 Late admission Na 157 kernicterus at 3 mo31 156 4201 8 RR 317 Hemolysis Rh 2450 22 Direct bilirubin 16 kernicterus at 3 mo32 178 32 9 ND 279 Hemolysis O-A 2440 43 DIED Suspected sepsis pH 71333 192 479 7 ND 415 O-B amp Rh incomp 2620 26 DIED deteriorated postexchangeb

34 200 441 9 ND 319 Hemolysisa 2850 41 DIED pH 722 respiratory acidosis35 210 6103 7 RR 274 Hemolysis O-A 2900 51 Direct bilirubin 277 kernicterus at 3 mo

Ranked by increasing BA ratio Adm admission Hct hematocrit DAT direct antiglobulin test incomp blood type incompatibility without evident hemolysis Max maximum ND not done PRPass refer FU follow upa Unknown cause for hemolysisb Onset of kernicterus or worsening postexchange transfusion

ARTICLE

PEDIATRICS Volume 134 Number 5 November 2014 e1339

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

ServicesUpdated Information amp

httppediatricsaappublicationsorgcontent1345e1330including high resolution figures can be found at

References

-1httppediatricsaappublicationsorgcontent1345e1330fullref-listThis article cites 36 articles 12 of which you can access for free at

Subspecialty Collections

binemia_subhttpclassicpediatricsaappublicationsorgcgicollectionhyperbiliruHyperbilirubinemiafollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpsshopaaporglicensing-permissionsin its entirety can be found online at Information about reproducing this article in parts (figures tables) or

ReprintshttpclassicpediatricsaappublicationsorgcontentreprintsInformation about ordering reprints can be found online

ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

httppediatricsaappublicationsorgcontent1345e1330located on the World Wide Web at

The online version of this article along with updated information and services is

ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

Page 7: Serum Bilirubin and Bilirubin/Albumin Ratio as …pediatrics.aappublications.org/content/pediatrics/134/5/e1330.full.pdf · Serum Bilirubin and Bilirubin/Albumin Ratio as Predictors

not a rare event provides a first step inachieving that goal

CONCLUSIONS

TSB and BA are both strong in-dicators of risk for acute and re-

sidual bilirubin neurotoxicity Whenintervention values are adjusted toprovide equal sensitivity the specif-icities of TSB and BA are nearly thesame and BA offers no additionaladvantage over TSB alone in most

clinical settings TSBandBA thresholdsfor disease increased with advan-cing severity of neurotoxicity thisshould be considered when deli-berating appropriate interventionguidelines

REFERENCES

1 American Academy of Pediatrics Subcom-mittee on Hyperbilirubinemia Management ofhyperbilirubinemia in the newborn infant 35or more weeks of gestation Pediatrics 2004114(1)297ndash316

2 Wennberg RP Ahlfors CE Bhutani VK JohnsonLH Shapiro SM Toward understandingkernicterus a challenge to improve the man-agement of jaundiced newborns Pediatrics2006117(2)474ndash485

3 Ahlfors CE Wennberg RP Ostrow JD TiribelliC Unbound (free) bilirubin improving theparadigm for evaluating neonatal jaundiceClin Chem 200955(7)1288ndash1299

4 Ahlfors CE Criteria for exchange trans-fusion in jaundiced newborns Pediatrics199493(3)488ndash494

5 Sato Y Morioka I Miwa A et al Is bilirubinalbumin ratio correlated with unboundbilirubin concentration Pediatr Int 201254(1)81ndash85

6 Ardakani SB Dana VG Ziaee V AshtianiM-TH Djavid GE Alijani M Bilirubinalbuminratio for predicting acute bilirubin-inducedneurologic dysfunction Iran J Pediatr 201121(1)28ndash32

7 Hulzebos CV Dijk PH van Imhoff DE et alBARTrial Study Group The bilirubin albu-min ratio in the management of hyper-bilirubinemia in preterm infants to improveneurodevelopmental outcome a randomizedcontrolled trialmdashBARTrial PLoS ONE 20149(6)e99466

8 Johnson L Brown AK Bhutani V BINDmdashAclinical score for bilirubin induced neuro-logic dysfunction in newborns Pediatrics1999104(suppl 4)746ndash747

9 van Straaten HL Automated auditory brain-stem response in neonatal hearing screen-ing Acta Paediatr Suppl 199988(432)76ndash79

10 Shapiro SM Definition of the clinical spec-trum of kernicterus and bilirubin-inducedneurologic dysfunction (BIND) J Perinatol200525(1)54ndash59

11 Ballard JL Khoury JC Wedig K Wang L Eilers-Walsman BL Lipp R New Ballard Score

expanded to include extremely prematureinfants J Pediatr 1991119(3)417ndash423

12 Doumas BT Wu TW Jendrzejczak B Deltabilirubin absorption spectra molar ab-sorptivity and reactivity in the diazo re-action Clin Chem 198733(6)769ndash774

13 Carter P Ultramicroestimation of humanserum albumin binding cationic dye559dibromo-o cresolsulfonphthalein Micro-chem J 197015531ndash539

14 Volpe JJ Bilirubin and brain injury In VolpeJJ ed Neurology of the Newborn 3rd edPhiladelphia PA WB Saunders 2001490ndash514

15 Johnson L Bhutani VK Karp K Sivieri EMShapiro SM Clinical report from the pilot USAKernicterus Registry (1992 to 2004) J Peri-natol 200929(suppl 1)S25ndashS45

16 Johnson L Bhutani VK The clinical syndromeof bilirubin-induced neurologic dysfunctionSemin Perinatol 201135(3)101ndash113

17 Berlin CI Hood LJ Morlet T et al Multi-sitediagnosis and management of 260 patientswith auditory neuropathydys-synchrony(auditory neuropathy spectrum disorder)Int J Audiol 201049(1)30ndash43

18 Saluja S Agarwal A Kler N Amin S Audi-tory neuropathy spectrum disorder in latepreterm and term infants with severejaundice Int J Pediatr Otorhinolaryngol201074(11)1292ndash1297

19 Shapiro SM Popelka GR Auditory impair-ment in infants at risk for bilirubin-inducedneurologic dysfunction Semin Perinatol201135(3)162ndash170

20 Makkar M Gupta C Pathak R Garg S MahajanNC Performance evaluation of hematologicscoring system in early diagnosis of neonatalsepsis J Clin Neonatol 20132(1)25ndash29

21 Pearlman MA Gartner LM Lee K Morecki RHoroupian DS Absence of kernicterus inlow-birth weight infants from 1971 through1976 comparison with findings in 1966 and1967 Pediatrics 197862(4)460ndash464

22 Durkalski VL Palesch YY Lipsitz SR Rust PFAnalysis of clustered matched-pair dataStat Med 200322(15)2417ndash2428

23 Pepe MS The Statistical Evaluation ofMedical Tests for Classification and Pre-diction Oxford UK Oxford University Press2003

24 Iskander I Gamaleldin R Kabbani M Rootcauses for late presentation of severeneonatal hyperbilirubinaemia in Egypt EastMediterr Health J 201218(8)882ndash887

25 Odutolu Y Emmerson AJ Low bilirubinkernicterus with sepsis and hypoalbuminaemiaBMJ Case Reports 2013 doi101136bcr-2012-008042

26 Gamaleldin R Iskander I Seoud I et al Riskfactors for neurotoxicity in newborns withsevere neonatal hyperbilirubinemia Pediat-rics 2011128(4) Available at wwwpediat-ricsorgcgicontentfull1284e925

27 Wolf MJ Wolf B Beunen G Casaer PNeurodevelopmental outcome at 1 yearin Zimbabwean neonates with extremehyperbilirubinaemia Eur J Pediatr 1999158(2)111ndash114

28 Weng YH Chiu YW Cheng SW Hsieh MY Riskassessment for adverse outcome in termand late preterm neonates with bilirubinvalues of 20 mgdL or more Am J Perinatol201128(5)405ndash412

29 Newman TB Liljestrand P Escobar GJInfants with bilirubin levels of 30 mgdL ormore in a large managed care organiza-tion Pediatrics 2003111(6 pt 1)1303ndash1311

30 Newman TB Liljestrand P Jeremy RJ et alJaundice and Infant Feeding Study TeamOutcomes among newborns with total se-rum bilirubin levels of 25 mg per deciliteror more N Engl J Med 2006354(18)1889ndash1900

31 Smits-Wintjens VE Rath ME van Zwet EWet al Neonatal morbidity after exchangetransfusion for red cell alloimmune he-molytic disease Neonatology 2013103(2)141ndash147

32 Hulzebos CV van Imhoff DE Bos AF Ahlfors CEVerkade HJ Dijk PH Usefulness of thebilirubinalbumin ratio for predicting bilirubin-

e1336 ISKANDER et al

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

induced neurotoxicity in premature infantsArch Dis Child Fetal Neonatal Ed 200893(5)F384ndashF388

33 Cashore WJ Oh W Unbound bilirubin andkernicterus in low-birth-weight infantsPediatrics 198269(4)481ndash485

34 Nakamura H Yonetani M Uetani Y Funato MLee Y Determination of serum unbound bil-irubin for prediction of kernicterus in lowbirthweight infants Acta Paediatr Jpn 199234(6)642ndash647

35 Jacobsen J Binding of bilirubin to humanserum albumin - determination of the disso-ciation constants FEBS Lett 19695(2)112ndash114

36 Goessling W Zucker SD Role of apolipopro-tein D in the transport of bilirubin in plasmaAm J Physiol Gastrointest Liver Physiol 2000279(2)G356ndashG365

37 Hsia DY Allen FH Jr Gellis SS Diamond LKErythroblastosis fetalis VIII Studies ofserum bilirubin in relation to kernicterusN Engl J Med 1952247(18)668ndash671

38 Ip S Chung M Kulig J et al AmericanAcademy of Pediatrics Subcommitteeon Hyperbilirubinemia An evidence-based review of important issues con-cerning neonatal hyperbilirubinemiaPediatrics 2004114(1) Available atwwwpediatricsorgcgicontentfull1141e130

39 Perlman M Frank JW Bilirubin beyond theblood-brain barrier Pediatrics 198881(2)304ndash315

(Continued from first page)

wwwpediatricsorgcgidoi101542peds2013-1764

doi101542peds2013-1764

Accepted for publication Aug 27 2014

Address correspondence to Iman F Iskander MD Department of Pediatrics Cairo University 8 Salah El Din St Zamalek Cairo 11211 Egypt E-mail imaniskhotmailcom

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2014 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE The authors have indicated they have no financial relationships relevant to this article to disclose

FUNDING This research was supported in part by National Institutes of HealthEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentAward R21HD060901 the American Recovery and Reinvestment Act of 2009 and UL1 RR025014 from National Center for Research ResourcesNational Institutes ofHealth The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health Funded by theNational Institutes of Health (NIH)

POTENTIAL CONFLICT OF INTEREST The authors have indicated they have no potential conflicts of interest to disclose

ARTICLE

PEDIATRICS Volume 134 Number 5 November 2014 e1337

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

APPENDIX 1 BIND Scorea

Clinical Sign (Score Most Severe Sign) Score Severity

Mental statusNormal ndash Awake alert 0 NoneSleepy but arousable 1 MildDecreased feeding 1 MildLethargy 2 ModeratePoor suck andor 2 ModerateIrritablejittery 2 ModerateUnable to feed 3 SevereApnea 3 SevereSeizures 3 SevereComa ndash not arousable 3 Severe

Muscle toneNormal flexed tone 0 NonePersistent mild hypotonia 1 MildHypotonia or hypertonia depending on arousal state 2 ModerateBicycling 2 ModerateBeginning nuchal rigidity and truncal arching 2 ModeratePersistent retrocollis 3 SevereOpisthotonos 3 SevereSevere hypo- or hypertonia 3 Severe

Cry patternNormal 0 NoneHigh-pitched 1 MildShrill 2 ModerateInconsolable crying or cry weak or absent 3 Severe

Total bind (ABE score)

Tick all that apply but total score is based on the highest in each category or 9Proposed interpretationTotal BIND score 1ndash3 mild ABE subtle signs reversible no apparent sequelaeTotalBIND score 4ndash6 moderate ABE signs largely reversible with aggressive treatmentTotalBIND score 7ndash9 severe ABE largely irreversible but signs may decrease with prompt treatmenta Modified from Johnson L Brown AK Bhutani V BINDmdashA clinical score for bilirubin induced neurologic dysfunction innewborns Pediatrics 1999104(suppl 4)746ndash747

e1338 ISKANDER et al

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

APPENDIX 2 Characteristics of Patients with Kernicterus

BA TSB MaxBIND

3 moAABR

Hct Cause of Jaundice Admweight g

AdmAge d

Comments

1 86 291 9 ND ND Unknown 2250 53 DIED pH 72 HCO3 15 Direct Bil 562 86 342 9 RR 337 Hemolysis O-A 2800 55 Dystonia at 3 mo3 90 37 7 ND 440 Rh incompatibility 2250 4 DIED Suspected sepsis4 91 31 8 RR 397 Rh incomp DAT neg 2800 58 Severe ABE at admission Klebsiella sepsis post-exchange5 96 412 9 ND 292 Hemolysisa 3100 38 DIED pH 697 apnea seizures6 96 376 8 ND 388 O-A incomp 2100 72 Suspected sepsis7 97 32 4 PR 537 Unknown 3000 76 Mild kernicterus 3 mo8 102 317 9 RR 370 G6PD deficient 3200 65 No hemolysis kernicterus at 3 mo9 103 289 9 ND 248 Hemolysis Rh 2250 4 DIED Suspected sepsis pH 717b

10 104 311 5 RR 473 O-A incomp 1840 3 345 wks SGA high reticulocyte count Mild kernicterus11 105 43 8 ND 350 Unknown 2750 38 DIED 2 exchange transfusions12 105 387 9 ND 294 Hemolysisa 2900 2 Suspected sepsis13 106 35 8 ND 340 Hemolysis O-A 2500 34 DIED Pseudomonas sepsis pH 710b

14 108 4002 8 ND 484 Rh moderate G6PD 2750 45 Direct bilirubin 108 with no hemolysis15 113 397 7 RR 419 G6PD amp O-A incomp 2030 13 Late admission kernicterus at 3 mo16 114 366 9 ND 454 Unknown 2250 81 pH 72317 115 425 9 ND 311 Hemolysis O-B 3200 38 DIED Suspected sepsis seizures18 115 367 6 RR 425 O-B incomp 2250 77 Kernicterus at 3 mo19 118 436 6 RR 370 O-A incomp 2970 59 Kernicterus at 3 mo20 121 352 9 ND 429 Unknown 2000 58 DIED rapid deterioration after second exchangeb

21 124 37 7 RR 300 Hemolysis O-B 2400 5 35 wk GA hypertonic with head lag 3 mo22 126 39 9 ND 372 O-A incomp 2300 47 Suspected sepsisb

23 126 442 8 RR 509 Unknown 2400 54 Suspected sepsis pH 733 kernicterus at 3 mo24 128 397 8 ND 314 Hemolysis O-A 2760 98 DIED Suspected sepsis respiratory acidosis apnea seizures25 128 385 8 RR 370 O-A incomp 3150 23 Sustained high TSB kernicterus at 3 mo26 137 479 7 RR 217 Hemolysis G6PD def 2800 49 Suspected sepsis pH 73027 140 365 7 RR 257 Hemolysis Rh 4000 42 Deterioration after second exchangeb

28 149 462 9 ND 490 Unknown 2140 62 RR AABR and abnormal neurologically at discharge no FU29 151 407 7 ND ND O-A incomp 3000 4 DIED classic kernicterus seizures30 151 483 8 RR 381 O-B incomp 2930 13 Late admission Na 157 kernicterus at 3 mo31 156 4201 8 RR 317 Hemolysis Rh 2450 22 Direct bilirubin 16 kernicterus at 3 mo32 178 32 9 ND 279 Hemolysis O-A 2440 43 DIED Suspected sepsis pH 71333 192 479 7 ND 415 O-B amp Rh incomp 2620 26 DIED deteriorated postexchangeb

34 200 441 9 ND 319 Hemolysisa 2850 41 DIED pH 722 respiratory acidosis35 210 6103 7 RR 274 Hemolysis O-A 2900 51 Direct bilirubin 277 kernicterus at 3 mo

Ranked by increasing BA ratio Adm admission Hct hematocrit DAT direct antiglobulin test incomp blood type incompatibility without evident hemolysis Max maximum ND not done PRPass refer FU follow upa Unknown cause for hemolysisb Onset of kernicterus or worsening postexchange transfusion

ARTICLE

PEDIATRICS Volume 134 Number 5 November 2014 e1339

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

ServicesUpdated Information amp

httppediatricsaappublicationsorgcontent1345e1330including high resolution figures can be found at

References

-1httppediatricsaappublicationsorgcontent1345e1330fullref-listThis article cites 36 articles 12 of which you can access for free at

Subspecialty Collections

binemia_subhttpclassicpediatricsaappublicationsorgcgicollectionhyperbiliruHyperbilirubinemiafollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpsshopaaporglicensing-permissionsin its entirety can be found online at Information about reproducing this article in parts (figures tables) or

ReprintshttpclassicpediatricsaappublicationsorgcontentreprintsInformation about ordering reprints can be found online

ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

httppediatricsaappublicationsorgcontent1345e1330located on the World Wide Web at

The online version of this article along with updated information and services is

ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

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induced neurotoxicity in premature infantsArch Dis Child Fetal Neonatal Ed 200893(5)F384ndashF388

33 Cashore WJ Oh W Unbound bilirubin andkernicterus in low-birth-weight infantsPediatrics 198269(4)481ndash485

34 Nakamura H Yonetani M Uetani Y Funato MLee Y Determination of serum unbound bil-irubin for prediction of kernicterus in lowbirthweight infants Acta Paediatr Jpn 199234(6)642ndash647

35 Jacobsen J Binding of bilirubin to humanserum albumin - determination of the disso-ciation constants FEBS Lett 19695(2)112ndash114

36 Goessling W Zucker SD Role of apolipopro-tein D in the transport of bilirubin in plasmaAm J Physiol Gastrointest Liver Physiol 2000279(2)G356ndashG365

37 Hsia DY Allen FH Jr Gellis SS Diamond LKErythroblastosis fetalis VIII Studies ofserum bilirubin in relation to kernicterusN Engl J Med 1952247(18)668ndash671

38 Ip S Chung M Kulig J et al AmericanAcademy of Pediatrics Subcommitteeon Hyperbilirubinemia An evidence-based review of important issues con-cerning neonatal hyperbilirubinemiaPediatrics 2004114(1) Available atwwwpediatricsorgcgicontentfull1141e130

39 Perlman M Frank JW Bilirubin beyond theblood-brain barrier Pediatrics 198881(2)304ndash315

(Continued from first page)

wwwpediatricsorgcgidoi101542peds2013-1764

doi101542peds2013-1764

Accepted for publication Aug 27 2014

Address correspondence to Iman F Iskander MD Department of Pediatrics Cairo University 8 Salah El Din St Zamalek Cairo 11211 Egypt E-mail imaniskhotmailcom

PEDIATRICS (ISSN Numbers Print 0031-4005 Online 1098-4275)

Copyright copy 2014 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE The authors have indicated they have no financial relationships relevant to this article to disclose

FUNDING This research was supported in part by National Institutes of HealthEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentAward R21HD060901 the American Recovery and Reinvestment Act of 2009 and UL1 RR025014 from National Center for Research ResourcesNational Institutes ofHealth The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health Funded by theNational Institutes of Health (NIH)

POTENTIAL CONFLICT OF INTEREST The authors have indicated they have no potential conflicts of interest to disclose

ARTICLE

PEDIATRICS Volume 134 Number 5 November 2014 e1337

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

APPENDIX 1 BIND Scorea

Clinical Sign (Score Most Severe Sign) Score Severity

Mental statusNormal ndash Awake alert 0 NoneSleepy but arousable 1 MildDecreased feeding 1 MildLethargy 2 ModeratePoor suck andor 2 ModerateIrritablejittery 2 ModerateUnable to feed 3 SevereApnea 3 SevereSeizures 3 SevereComa ndash not arousable 3 Severe

Muscle toneNormal flexed tone 0 NonePersistent mild hypotonia 1 MildHypotonia or hypertonia depending on arousal state 2 ModerateBicycling 2 ModerateBeginning nuchal rigidity and truncal arching 2 ModeratePersistent retrocollis 3 SevereOpisthotonos 3 SevereSevere hypo- or hypertonia 3 Severe

Cry patternNormal 0 NoneHigh-pitched 1 MildShrill 2 ModerateInconsolable crying or cry weak or absent 3 Severe

Total bind (ABE score)

Tick all that apply but total score is based on the highest in each category or 9Proposed interpretationTotal BIND score 1ndash3 mild ABE subtle signs reversible no apparent sequelaeTotalBIND score 4ndash6 moderate ABE signs largely reversible with aggressive treatmentTotalBIND score 7ndash9 severe ABE largely irreversible but signs may decrease with prompt treatmenta Modified from Johnson L Brown AK Bhutani V BINDmdashA clinical score for bilirubin induced neurologic dysfunction innewborns Pediatrics 1999104(suppl 4)746ndash747

e1338 ISKANDER et al

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

APPENDIX 2 Characteristics of Patients with Kernicterus

BA TSB MaxBIND

3 moAABR

Hct Cause of Jaundice Admweight g

AdmAge d

Comments

1 86 291 9 ND ND Unknown 2250 53 DIED pH 72 HCO3 15 Direct Bil 562 86 342 9 RR 337 Hemolysis O-A 2800 55 Dystonia at 3 mo3 90 37 7 ND 440 Rh incompatibility 2250 4 DIED Suspected sepsis4 91 31 8 RR 397 Rh incomp DAT neg 2800 58 Severe ABE at admission Klebsiella sepsis post-exchange5 96 412 9 ND 292 Hemolysisa 3100 38 DIED pH 697 apnea seizures6 96 376 8 ND 388 O-A incomp 2100 72 Suspected sepsis7 97 32 4 PR 537 Unknown 3000 76 Mild kernicterus 3 mo8 102 317 9 RR 370 G6PD deficient 3200 65 No hemolysis kernicterus at 3 mo9 103 289 9 ND 248 Hemolysis Rh 2250 4 DIED Suspected sepsis pH 717b

10 104 311 5 RR 473 O-A incomp 1840 3 345 wks SGA high reticulocyte count Mild kernicterus11 105 43 8 ND 350 Unknown 2750 38 DIED 2 exchange transfusions12 105 387 9 ND 294 Hemolysisa 2900 2 Suspected sepsis13 106 35 8 ND 340 Hemolysis O-A 2500 34 DIED Pseudomonas sepsis pH 710b

14 108 4002 8 ND 484 Rh moderate G6PD 2750 45 Direct bilirubin 108 with no hemolysis15 113 397 7 RR 419 G6PD amp O-A incomp 2030 13 Late admission kernicterus at 3 mo16 114 366 9 ND 454 Unknown 2250 81 pH 72317 115 425 9 ND 311 Hemolysis O-B 3200 38 DIED Suspected sepsis seizures18 115 367 6 RR 425 O-B incomp 2250 77 Kernicterus at 3 mo19 118 436 6 RR 370 O-A incomp 2970 59 Kernicterus at 3 mo20 121 352 9 ND 429 Unknown 2000 58 DIED rapid deterioration after second exchangeb

21 124 37 7 RR 300 Hemolysis O-B 2400 5 35 wk GA hypertonic with head lag 3 mo22 126 39 9 ND 372 O-A incomp 2300 47 Suspected sepsisb

23 126 442 8 RR 509 Unknown 2400 54 Suspected sepsis pH 733 kernicterus at 3 mo24 128 397 8 ND 314 Hemolysis O-A 2760 98 DIED Suspected sepsis respiratory acidosis apnea seizures25 128 385 8 RR 370 O-A incomp 3150 23 Sustained high TSB kernicterus at 3 mo26 137 479 7 RR 217 Hemolysis G6PD def 2800 49 Suspected sepsis pH 73027 140 365 7 RR 257 Hemolysis Rh 4000 42 Deterioration after second exchangeb

28 149 462 9 ND 490 Unknown 2140 62 RR AABR and abnormal neurologically at discharge no FU29 151 407 7 ND ND O-A incomp 3000 4 DIED classic kernicterus seizures30 151 483 8 RR 381 O-B incomp 2930 13 Late admission Na 157 kernicterus at 3 mo31 156 4201 8 RR 317 Hemolysis Rh 2450 22 Direct bilirubin 16 kernicterus at 3 mo32 178 32 9 ND 279 Hemolysis O-A 2440 43 DIED Suspected sepsis pH 71333 192 479 7 ND 415 O-B amp Rh incomp 2620 26 DIED deteriorated postexchangeb

34 200 441 9 ND 319 Hemolysisa 2850 41 DIED pH 722 respiratory acidosis35 210 6103 7 RR 274 Hemolysis O-A 2900 51 Direct bilirubin 277 kernicterus at 3 mo

Ranked by increasing BA ratio Adm admission Hct hematocrit DAT direct antiglobulin test incomp blood type incompatibility without evident hemolysis Max maximum ND not done PRPass refer FU follow upa Unknown cause for hemolysisb Onset of kernicterus or worsening postexchange transfusion

ARTICLE

PEDIATRICS Volume 134 Number 5 November 2014 e1339

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

ServicesUpdated Information amp

httppediatricsaappublicationsorgcontent1345e1330including high resolution figures can be found at

References

-1httppediatricsaappublicationsorgcontent1345e1330fullref-listThis article cites 36 articles 12 of which you can access for free at

Subspecialty Collections

binemia_subhttpclassicpediatricsaappublicationsorgcgicollectionhyperbiliruHyperbilirubinemiafollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpsshopaaporglicensing-permissionsin its entirety can be found online at Information about reproducing this article in parts (figures tables) or

ReprintshttpclassicpediatricsaappublicationsorgcontentreprintsInformation about ordering reprints can be found online

ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

httppediatricsaappublicationsorgcontent1345e1330located on the World Wide Web at

The online version of this article along with updated information and services is

ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

Page 9: Serum Bilirubin and Bilirubin/Albumin Ratio as …pediatrics.aappublications.org/content/pediatrics/134/5/e1330.full.pdf · Serum Bilirubin and Bilirubin/Albumin Ratio as Predictors

APPENDIX 1 BIND Scorea

Clinical Sign (Score Most Severe Sign) Score Severity

Mental statusNormal ndash Awake alert 0 NoneSleepy but arousable 1 MildDecreased feeding 1 MildLethargy 2 ModeratePoor suck andor 2 ModerateIrritablejittery 2 ModerateUnable to feed 3 SevereApnea 3 SevereSeizures 3 SevereComa ndash not arousable 3 Severe

Muscle toneNormal flexed tone 0 NonePersistent mild hypotonia 1 MildHypotonia or hypertonia depending on arousal state 2 ModerateBicycling 2 ModerateBeginning nuchal rigidity and truncal arching 2 ModeratePersistent retrocollis 3 SevereOpisthotonos 3 SevereSevere hypo- or hypertonia 3 Severe

Cry patternNormal 0 NoneHigh-pitched 1 MildShrill 2 ModerateInconsolable crying or cry weak or absent 3 Severe

Total bind (ABE score)

Tick all that apply but total score is based on the highest in each category or 9Proposed interpretationTotal BIND score 1ndash3 mild ABE subtle signs reversible no apparent sequelaeTotalBIND score 4ndash6 moderate ABE signs largely reversible with aggressive treatmentTotalBIND score 7ndash9 severe ABE largely irreversible but signs may decrease with prompt treatmenta Modified from Johnson L Brown AK Bhutani V BINDmdashA clinical score for bilirubin induced neurologic dysfunction innewborns Pediatrics 1999104(suppl 4)746ndash747

e1338 ISKANDER et al

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

APPENDIX 2 Characteristics of Patients with Kernicterus

BA TSB MaxBIND

3 moAABR

Hct Cause of Jaundice Admweight g

AdmAge d

Comments

1 86 291 9 ND ND Unknown 2250 53 DIED pH 72 HCO3 15 Direct Bil 562 86 342 9 RR 337 Hemolysis O-A 2800 55 Dystonia at 3 mo3 90 37 7 ND 440 Rh incompatibility 2250 4 DIED Suspected sepsis4 91 31 8 RR 397 Rh incomp DAT neg 2800 58 Severe ABE at admission Klebsiella sepsis post-exchange5 96 412 9 ND 292 Hemolysisa 3100 38 DIED pH 697 apnea seizures6 96 376 8 ND 388 O-A incomp 2100 72 Suspected sepsis7 97 32 4 PR 537 Unknown 3000 76 Mild kernicterus 3 mo8 102 317 9 RR 370 G6PD deficient 3200 65 No hemolysis kernicterus at 3 mo9 103 289 9 ND 248 Hemolysis Rh 2250 4 DIED Suspected sepsis pH 717b

10 104 311 5 RR 473 O-A incomp 1840 3 345 wks SGA high reticulocyte count Mild kernicterus11 105 43 8 ND 350 Unknown 2750 38 DIED 2 exchange transfusions12 105 387 9 ND 294 Hemolysisa 2900 2 Suspected sepsis13 106 35 8 ND 340 Hemolysis O-A 2500 34 DIED Pseudomonas sepsis pH 710b

14 108 4002 8 ND 484 Rh moderate G6PD 2750 45 Direct bilirubin 108 with no hemolysis15 113 397 7 RR 419 G6PD amp O-A incomp 2030 13 Late admission kernicterus at 3 mo16 114 366 9 ND 454 Unknown 2250 81 pH 72317 115 425 9 ND 311 Hemolysis O-B 3200 38 DIED Suspected sepsis seizures18 115 367 6 RR 425 O-B incomp 2250 77 Kernicterus at 3 mo19 118 436 6 RR 370 O-A incomp 2970 59 Kernicterus at 3 mo20 121 352 9 ND 429 Unknown 2000 58 DIED rapid deterioration after second exchangeb

21 124 37 7 RR 300 Hemolysis O-B 2400 5 35 wk GA hypertonic with head lag 3 mo22 126 39 9 ND 372 O-A incomp 2300 47 Suspected sepsisb

23 126 442 8 RR 509 Unknown 2400 54 Suspected sepsis pH 733 kernicterus at 3 mo24 128 397 8 ND 314 Hemolysis O-A 2760 98 DIED Suspected sepsis respiratory acidosis apnea seizures25 128 385 8 RR 370 O-A incomp 3150 23 Sustained high TSB kernicterus at 3 mo26 137 479 7 RR 217 Hemolysis G6PD def 2800 49 Suspected sepsis pH 73027 140 365 7 RR 257 Hemolysis Rh 4000 42 Deterioration after second exchangeb

28 149 462 9 ND 490 Unknown 2140 62 RR AABR and abnormal neurologically at discharge no FU29 151 407 7 ND ND O-A incomp 3000 4 DIED classic kernicterus seizures30 151 483 8 RR 381 O-B incomp 2930 13 Late admission Na 157 kernicterus at 3 mo31 156 4201 8 RR 317 Hemolysis Rh 2450 22 Direct bilirubin 16 kernicterus at 3 mo32 178 32 9 ND 279 Hemolysis O-A 2440 43 DIED Suspected sepsis pH 71333 192 479 7 ND 415 O-B amp Rh incomp 2620 26 DIED deteriorated postexchangeb

34 200 441 9 ND 319 Hemolysisa 2850 41 DIED pH 722 respiratory acidosis35 210 6103 7 RR 274 Hemolysis O-A 2900 51 Direct bilirubin 277 kernicterus at 3 mo

Ranked by increasing BA ratio Adm admission Hct hematocrit DAT direct antiglobulin test incomp blood type incompatibility without evident hemolysis Max maximum ND not done PRPass refer FU follow upa Unknown cause for hemolysisb Onset of kernicterus or worsening postexchange transfusion

ARTICLE

PEDIATRICS Volume 134 Number 5 November 2014 e1339

by guest on April 19 2018httppediatricsaappublicationsorgDownloaded from

DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

ServicesUpdated Information amp

httppediatricsaappublicationsorgcontent1345e1330including high resolution figures can be found at

References

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Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

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APPENDIX 2 Characteristics of Patients with Kernicterus

BA TSB MaxBIND

3 moAABR

Hct Cause of Jaundice Admweight g

AdmAge d

Comments

1 86 291 9 ND ND Unknown 2250 53 DIED pH 72 HCO3 15 Direct Bil 562 86 342 9 RR 337 Hemolysis O-A 2800 55 Dystonia at 3 mo3 90 37 7 ND 440 Rh incompatibility 2250 4 DIED Suspected sepsis4 91 31 8 RR 397 Rh incomp DAT neg 2800 58 Severe ABE at admission Klebsiella sepsis post-exchange5 96 412 9 ND 292 Hemolysisa 3100 38 DIED pH 697 apnea seizures6 96 376 8 ND 388 O-A incomp 2100 72 Suspected sepsis7 97 32 4 PR 537 Unknown 3000 76 Mild kernicterus 3 mo8 102 317 9 RR 370 G6PD deficient 3200 65 No hemolysis kernicterus at 3 mo9 103 289 9 ND 248 Hemolysis Rh 2250 4 DIED Suspected sepsis pH 717b

10 104 311 5 RR 473 O-A incomp 1840 3 345 wks SGA high reticulocyte count Mild kernicterus11 105 43 8 ND 350 Unknown 2750 38 DIED 2 exchange transfusions12 105 387 9 ND 294 Hemolysisa 2900 2 Suspected sepsis13 106 35 8 ND 340 Hemolysis O-A 2500 34 DIED Pseudomonas sepsis pH 710b

14 108 4002 8 ND 484 Rh moderate G6PD 2750 45 Direct bilirubin 108 with no hemolysis15 113 397 7 RR 419 G6PD amp O-A incomp 2030 13 Late admission kernicterus at 3 mo16 114 366 9 ND 454 Unknown 2250 81 pH 72317 115 425 9 ND 311 Hemolysis O-B 3200 38 DIED Suspected sepsis seizures18 115 367 6 RR 425 O-B incomp 2250 77 Kernicterus at 3 mo19 118 436 6 RR 370 O-A incomp 2970 59 Kernicterus at 3 mo20 121 352 9 ND 429 Unknown 2000 58 DIED rapid deterioration after second exchangeb

21 124 37 7 RR 300 Hemolysis O-B 2400 5 35 wk GA hypertonic with head lag 3 mo22 126 39 9 ND 372 O-A incomp 2300 47 Suspected sepsisb

23 126 442 8 RR 509 Unknown 2400 54 Suspected sepsis pH 733 kernicterus at 3 mo24 128 397 8 ND 314 Hemolysis O-A 2760 98 DIED Suspected sepsis respiratory acidosis apnea seizures25 128 385 8 RR 370 O-A incomp 3150 23 Sustained high TSB kernicterus at 3 mo26 137 479 7 RR 217 Hemolysis G6PD def 2800 49 Suspected sepsis pH 73027 140 365 7 RR 257 Hemolysis Rh 4000 42 Deterioration after second exchangeb

28 149 462 9 ND 490 Unknown 2140 62 RR AABR and abnormal neurologically at discharge no FU29 151 407 7 ND ND O-A incomp 3000 4 DIED classic kernicterus seizures30 151 483 8 RR 381 O-B incomp 2930 13 Late admission Na 157 kernicterus at 3 mo31 156 4201 8 RR 317 Hemolysis Rh 2450 22 Direct bilirubin 16 kernicterus at 3 mo32 178 32 9 ND 279 Hemolysis O-A 2440 43 DIED Suspected sepsis pH 71333 192 479 7 ND 415 O-B amp Rh incomp 2620 26 DIED deteriorated postexchangeb

34 200 441 9 ND 319 Hemolysisa 2850 41 DIED pH 722 respiratory acidosis35 210 6103 7 RR 274 Hemolysis O-A 2900 51 Direct bilirubin 277 kernicterus at 3 mo

Ranked by increasing BA ratio Adm admission Hct hematocrit DAT direct antiglobulin test incomp blood type incompatibility without evident hemolysis Max maximum ND not done PRPass refer FU follow upa Unknown cause for hemolysisb Onset of kernicterus or worsening postexchange transfusion

ARTICLE

PEDIATRICS Volume 134 Number 5 November 2014 e1339

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WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

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-1httppediatricsaappublicationsorgcontent1345e1330fullref-listThis article cites 36 articles 12 of which you can access for free at

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WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

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ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

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DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

ServicesUpdated Information amp

httppediatricsaappublicationsorgcontent1345e1330including high resolution figures can be found at

References

-1httppediatricsaappublicationsorgcontent1345e1330fullref-listThis article cites 36 articles 12 of which you can access for free at

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binemia_subhttpclassicpediatricsaappublicationsorgcgicollectionhyperbiliruHyperbilirubinemiafollowing collection(s) This article along with others on similar topics appears in the

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ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

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DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

httppediatricsaappublicationsorgcontent1345e1330located on the World Wide Web at

The online version of this article along with updated information and services is

ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

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DOI 101542peds2013-1764 originally published online October 20 2014 2014134e1330Pediatrics

WennbergNesrin El Gharbawi Hazem Abou-Youssef Aleksandr Aravkin and Richard P

Iman Iskander Rasha Gamaleldin Salma El Houchi Amira El Shenawy Iman SeoudEncephalopathy

Serum Bilirubin and BilirubinAlbumin Ratio as Predictors of Bilirubin

httppediatricsaappublicationsorgcontent1345e1330located on the World Wide Web at

The online version of this article along with updated information and services is

ISSN 60007 Copyright copy 2014 by the American Academy of Pediatrics All rights reserved Print American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village Illinoishas been published continuously since Pediatrics is owned published and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics A monthly publication it

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