B.I.N.D. Center at Pennsylvania Hospital (Bilirubin Induced Neurologic Dysfunction) University of Pennsylvania, Philadelphia Pre-discharge bilirubin screening to prevent adverse outcomes of neonatal hyperbilirubinemia Vinod K. Bhutani MD and Lois H. Johnson MD

Does hyperbilirubinemia damage the brain of healthy full term infants ?.………………. Newman and Maisels 1990 Clinics in Perinatology Evidence-based Question Raised in 1990

Potential Adverse Clinical Outcomes for Newborn Jaundice Death: respiratory failure (n = 6 in Pilot KI Registry) Acute bilirubin encephalopathy Post-icteric sequelae (neuromotor / auditory) Subtle manifestations (extra-pyramidal and central processing disorders) CLINICAL SPECTRUM Bilirubin Induced Neurologic Dysfunction (BIND) BIND CENTER - Pennsylvania Hospital

Adverse Outcomes and Concerns for Patient Safety with Newborn Jaundice Bilirubin levels in newborns discharged as healthy from well baby nursery: a)What is the evidence that the TSB level is high? b)What is the evidence that the TSB is harmful? c)What is the evidence that the TSB level is safe? d)How sure are we that these levels will be safe? e)Can we manage the hyperbilirubinemiac infant with a safer, kinder, gentler approach ?

Settling for a Reduced Occurrence of Extreme Hyperbilirubinemia TSB level >20 mg/dl 99 th percentile ( <72hrs) TSB level >25 mg/dl th percentile ( >72hrs) AHRQ: National Quality Forum A “NEVER EVENT” TSB level >30 mg/dl >99.99 th percentile Thresholds for timely and effective interventions in a safe setting

BIND CENTER - Pennsylvania Hospital “Vigintiphobia”: Pediatricians’ Fear of 20 Questioned for Lack of Evidence Before 1970: Exchange transfusion was the standard of care for TSB >20 mg /dl. After 1984: Treatment with phototherapy for a TSB of 15 mg/dl to prevent progression to 20mg/dl questioned as unnecessary.

BIND CENTER - Pennsylvania Hospital PILOT KERNICTERUS REGISTRY Confirmed Cases of Acute Kernictrerus (Voluntary Reporting) “Healthy” Term and Near Term Infants Born in 34 States PICK and Partners AAP updates guidelines New cases are still being reported

Sources of Data for Kernicterus Registry Papers and abstracts dated Medical-legal consultations Contributions from colleagues Detailed information available in 80 babies Only one case in babies born before 1984 Total of 106 cases in Registry as of December 2002

Matrix Used to Assess Cases Reported to Pilot Kernicterus Registry Patient Centeredness SafetyEffective CareTimeliness Experience of services Diagnosis of kernicterus Preventive care provided Access Patient-Provider Partnerships Treatment safety Acute care and chronic care effectiveness Getting the right care in a timely manner Trustworthy CareEnvironment and facilities Procedures usedContinuity of care Comprehensive review of care provided in US nurseries to 60 infants admitted by 7 days age with acute bilirubin encephalopathy: Johnson, Brown, Bhutani: Journal of Pediatrics April 2002

Preliminary Root Cause Analysis Loss of concern of neurotoxic potential of bilirubin Limitations on visual recognition of jaundice as index to initiate evaluation or estimate severity Failure to recognize severity of hyperbilirubinemia corrected for age in hours Failure to ensure follow-up 1-2 days after early discharge Delay in intensive or timely intervention pre- discharge or at readmission Johnson, Brown, Bhutani: Journal of Pediatrics April, 2002

Occurrence of Kernicterus In babies who are jaundiced In babies who have hyperbilirubinemia Increased in babies with co-morbidities: hemolysis, prematurity, hypoalbuminemia, asphyxia / blood-brain barrier disruption, infection, hypoglycemia, decreased binding affinity of albumin to bilirubin, etc There is no evidence for a specific bilirubin level that causes neuro-toxicity (likely to be influenced by postnatal age, duration, rate of rise and presence of co-morbidities).

Kernicteric Death End stage coma due to acute bilirubin encephalopathy Respiratory failure Intractable seizures Postmortem-global bilirubin staining of the brain and tissues Jones (1954), Van Pragh (1961), Volpe (2001).

Clinical Progression of Acute Bilirubin Encephalopathy Intermediate Lethargy + Irritability Semi-coma Seizures Late Sleepy + poor feed Early Mental Status Hyper or Hypotonia depending on arousal state Mild Nuchal / Truncal arching Markedly Increased or Decreased Opisthotonus Bicycling Muscle Tone ShrillInconsolableHi pitchedCry Clinical Evaluation Slight Decrease As proposed by Johnson, Brown et al. (abstract in Pediatrics, 1999)

Post-Kernicteric Sequelae in Infancy (Inclusion criteria: two or more signs) Extrapyramidal movement abnormalities –Athetosis, dystonia, muscle tone abnormalities Gaze abnormalities –Especially upward gaze Auditory disturbances –Neuropathy with central processing disorders Enamel dysplasia of deciduous teeth (Intellectual compromise is rare) Jones (1954), Van Pragh (1961), Volpe (2001).

Attitudes regarding the toxic potential of bilirubin “Jaundice does not cause brain damage in healthy babies” “Kinder and gentler approach to jaundice” “Do not worry all babies get jaundice” “You can easily get rid of jaundice with sunshine” “Bilirubin is an anti-oxidant” Data from Pilot Kernicterus Registry: Johnson, Brown and Bhutani

The Under-reporting of Occurrence of Kernicterus No national reporting system Lack of diagnosis on death certificate Lack of diagnosis on discharge diagnosis Limited and voluntary reporting to the Pilot Kernicterus Registry Delayed recognition of babies with signs of acute bilirubin encephalopathy who are admitted to emergency rooms Data from Pilot Kernicterus Registry: Johnson et al

What is the clinical evidence that this level of TSB is safe? Does hyperbilirubinemia damage the brain of healthy full term infants ?.………………. Newman and Maisels 1990

Incidence of Kernicterus Related to Total Serum Bilirubin Levels (Rh disease; n = 60) 0%02410 to 18 mg/dl 8%11319 to 24 mg/dl 35%41225 to 29 mg/dl 73%81130 to 40 mg/dl PercentageNumber with Kernicterus Number of Babies Maximum TSB level Mollison and Cutbush: 1954: Recent Advances in Pediatrics } 25%

Collaborative Perinatal Project to ,795 Total live births 41,324 Excluding multiple births, BW < 2500g, Unk BW, No SB levels, Died < 1 yr, Race not black or white, 41,324 90% 37 wks GA, 70% bottle fed, 96% Coombs negative, 48.5% black, 51.5% white 40,993 (99.2%) peak SB <20mg/dl 0.3% Rx ExTx 323 ( 0.8%) peak SB >20mg/dl 53.0% Rx Ex Tx 66 (0.16% ) peak SB >25mg/dl ± 85% Rx Ex Tx

Collaborative Perinatal Project (cont’d) Number of Infants by Bilirubin Category with Abnormal Seven Year Neurologic Exam * u M/L mg/dl Number % < 171< > 342 > P (trend, unadjusted) Adjusted odds ratio (OR) per bilirubin category % confidence interval , 1.23 * 1261 / (3.7%) of those examined

Collaborative Perinatal Project (cont’d) Number of Infants by Bilirubin Category with Abnormal or Suspicious 7 Year Neurologic * u M/L Mg/dl Number % < 171< > 342 > P (trend, unadjusted) <0.001 Adjusted odds ratio per bilirubin category % confidence limits , 1.20 * 5035 / (14.7%) of those examined

Collaborative Perinatal Project (cont’d) Association of abnormal or suspicious neurologic findings with stepwise increase in peak serum bilirubin levels Gait abnormalities Awkwardness Equivocal Babinski Failure at fine stereognosis Questionable hypotonia Gaze abnormalities Vasomotor abnormalities Abnormal abdominal reflexes Abnormal cremasteric reflexes < to to Probability

How sure are we, as pediatricians, that this level will be safe for an otherwise healthy newborn?

Are Moderate* Degrees of Hyperbilirubinemia in Healthy Term Neonates Really Safe for the Brain? Soorani-Lunsing et al: Pediatric Research 2001, 50: COMMENTARIES: Pediatric Research: 2001 (50): Neonatal Jaundice: Continuing Concern and Need for Research: Ohlsson, A (Editor) Just when you thought it was safe..Hintz, S & Stevenson, DK Bilirubin and Neurological Dysfunction- Do we need to change what we are doing? Maisels, MJ & Newman, TB Neonatal Hyperbilirubinemia and the Potential Risk for Subtle Neurologic Dysfunction. Bhutani, VK * “Moderate” is defined by bilirubin levels >17.5 mg/dl

(40)(17)(15)(8)Total (n = ) TSB Range Overall: 2.5 to 5 days Day 5 Day 4 Day 2.5 – 3 Readmit Age Pilot Kernicterus Registry (Johnson, Brown, Bhutani) Based on readmission data available in 102 Babies TSB rise/d TSB rise/hr At 95 th percentile (24 to 72 hrs age): TSB rise = 0.2 mg/hr

Unbound Bilirubin and Risk of BIND Unbound bilirubin levels (UB Analyzer) of 0.8 mcg/dl and above have been shown to predict the BAER abnormalities described for Stage IB or worse of the BIND Score by H. Nakamura and colleagues in Japan. B/A ratio may predict risk in healthy babies >72 hours age. It is less predictive of toxicity in infants with compromised albumin- bilirubin binding. These factors may not be evident clinically.

Defatted Human Albumin y = Ae Bx r = Unbound Bilirubin by the Peroxidase Technique Ahlfors, 1996

TSB Levels Associated with different B:A Ratios Risk of BIND 25 mg/dl 19 to 2519 mg/dl TSB to Serum Albumin of 3.6 g 30 mg/dl 23 to 3023 mg/dl TSB to Serum Albumin of 4.3 g 22 mg/dl 17 to 2217 mg/dl TSB to Serum Albumin of 3.2 g > 7.0 (molar: >0.80) 5.3 to ) B: A (mg/g) AdvancedProgressiveSubtleBIND Signs Adapted from Ahlfors C. Criteria for Exchange Transfusion. Pediatrics 1994;93:448

How does this affect my practice ?

Clinical Vectors –Visual Jaundice: poor vector of severity –Bruising: recurrent useful clinical risk factor –Risk Score for “Dangerous” levels ( Newman et al) TcB: M a isels et al, Bhutani et al, Rubaltelli et al TSB: Bhutani et al, Alpay et al, Kaplan et al TSB and ETCO : Stevenson, Fanaroff, Maisels et al (Multinational Jaundice Study Group) Others under study: unbound bilirubin Preventive Management: Pre-discharge Prediction for Severe Hyperbilirubinemia

Objective Assessment of Newborn Jaundice Use of jaundice as a clinical predictor to assess severity of bilirubinemia and predict subsequent hyperbilirubinemia is not evidence-based (AHRQ report). It is also impractical and unsafe Bilirubin (mg/dl serum) % of Observations

Prediction and Prevention of “Dangerous” Hyperbilirubinemia Predictors for TSB >25 mg/dl (73/51,387; 0.14%): –Early Jaundice…………………….Odds Ratio = 7.3 –Family history:…………………….Odds Ratio = 6.0 –Exclusive breast feeding………..Odds Ratio = 5.7 –Bruising……………………….……Odds Ratio = 4.0 –Asian race………………………….Odds Ratio = 3.5 –Cephalhematoma…………………Odds Ratio = 3.3 –Maternal age…………………….…Odds Ratio = 3.1 –Lower Gestation…………….…….Odds Ratio = 0.6/wk Conclusions: Prevention may require a closer follow-up than presently recommended by AAP Newman TB et al: Arch Pediatr Adolesc Med 2000; 154:

Clinical and Epidemiological-based Evidence of Risk Factors for “Dangerous” Hyperbilirubinemia Supposedly a baby who is not at (clinical or epidemiological) risk for hyperbilirubinemia is: A white, anglo-saxon, female neonate, who is exclusively formula-fed, who has no bruising, does not have a sibling with jaundice and in whom there is no ABO / Rh, minor blood group incompatibility or other evidence of hemolysis. Case report of Kernicterus in one such baby (Pilot Kernicterus Registry)

Objective Measurement by Total Serum Bilirubin Testing Based on Percentiles Based on Post-natal Age in hours Based on Accuracy and Precision

Hour-Specific Bilirubin Nomogram 95th %ile 75th %ile 40th %ile

Hour-Specific Bilirubin Nomogram High Risk Bilirubin Tract (age in hrs) Low Risk Bilirubin Tract (age in hrs) Rate of TSB rise = 0.2 mg/hr) Pediatrics: 1999

(40)(17)(15)(8)Total (n = 40 ) OverallDay Readmit Age Pilot Kernicterus Registry (Johnson, Brown, Bhutani) Based on readmission data available in 102 Babies TSB rise/hr At 95 th percentile (24 to 72 hrs age): TSB rise = 0.2 mg/hr TSB Range – to 5In Days

My bilirubin level is 9.2 mg and it is way too high because I am only ….17 hours old

Practical Strategy: Plot Bilirubin on Nomogram  9.2 mg/dl at 17 hrs age 17

Practical Strategy: Predict and Target Follow-up  32 mg/dl at 66 hrs age 9.2 mg/dl at 17 hrs age  Rate of TSB rise = 0.47 mg/dl  17

Dynamic Changes in Bilirubin Load Rapid Rate rise (>0.20 mg/dl/hr) by increase to >95 th percentile on the bilirubin nomogram Bilirubin ProductionBilirubin Elimination Bilirubin Load intravascular hemolysis: ETCO bruising / cephalhematoma: Visual Exam & ETCO enterohepatic circulation: Clinical Risk factors UGT1A1 polymorphisms: Ethnic Risk Factors

Outcome for Subsequent Severe Hyperbilirubinemia Increased Bilirubin Load Pediatrics: 1999

Outcome for Subsequent Severe Hyperbilirubinemia Pediatrics: 1999

Predictive Ability of a Predischarge Bilirubin Value Pediatrics: 1999

Incidence of “significant” hyperbilirubinemia: Well babies with TSB > 17 mg/dl or >95 th percentile (data not collected as formal investigation) Studies account for all cases followed prospectively

Incidence of “severe” hyperbilirubinemia: Well babies with TSB > 20 mg/dl (data not collected as formal investigation)

Incidence of “extreme” hyperbilirubinemia: Well babies with TSB > 25 mg/dl (data not collected as formal investigation)

Incidence of “severe” hyperbilirubinemia: Well babies with TSB > 30 mg/dl (data not collected as formal investigation)

Pooled comparison of incidences of extreme hyperbilirubinemia: Pre-discharge screening strategy Jaundice-based screening studies TSB-based screening studies Bhutani et al (Phila) CPP database: multi- center study (US centers) Stevenson et al: multi- national study Newman et al (HMO, North California) Martinez et al (Argentina) Meberg et al 1998: ( excluded) Alpay et al 2000: (excluded)

Pooled Analysis of incidence of extreme hyperbilirubinemia: Pre-discharge screening strategies Outcome of subsequent TSB level Jaundice-based screening studies TSB-based screening studies Mean95% CIMean95% CI TSB >20 mg/dl TSB >25 mg/dl TSB >30 mg/dl

Early-onset severe hyperbilirubinemia: TSB >75 th percentile at <72 hours age Clinical Management: –Clinical history for hemolytic disorders –Clinical evaluation (for acute bilirubin encephalopathy) –Serum Albumin: B:A ratio –End-tidal carbon monoxide testing (if available) –Evaluation for hemolysis (+Type and Coombs, G-6PD etc) –Rate of rise of bilirubin (“jumping tracks” on nomogram) –BAER by ALGO-2 screening technique (if feasible) –Intensive Phototherapy: clinical and objective evaluation –Exchange Transfusion: failure of Intensive phototherapy

Late-onset severe hyperbilirubinemia: TSB >95 th percentile at >72 hours age Clinical Management –Clinical history / counseling re feeding / stooling patterns –Clinical evaluation (for acute bilirubin encephalopathy) –Serum Albumin: to measure B:A ratio –Evaluation for hemolysis (including G-6PD) –BAER by ALGO-2 screening technique abnormal B:A (> 7.0 mg/g) ratio) abnormal clinical exam TSB >97th percentile (> mg/dl) –Intensive Phototherapy / Exchange transfusion consideration based on clinical and laboratory evaluation

Need for “Crash-Cart” Management of “Dangerous” Hyperbilirubinemia Assess for clinical signs of Acute Bilirubin Encephalopathy in a jaundiced newborn with any neurological symptoms Immediate transcutaneous measure of bilirubin and send a blood sample to laboratory for stat results If symptomatic, start intensive phototherapy (conduct procedures while baby is under lights) and admit directly intensive care nursery Arrange for an expeditious exchange transfusion for any signs of bilirubin encephalopathy and perform it promptly

System-based Policies and Procedures Hospital / Nursing policy and procedures Provide parental education materials Jaundice evaluation by nurses: a clinical vital sign checked periodically and corroborated by TcB /TSB –Assess and promote optimal lactational nutrition. –Track, evaluate for hemolysis and follow infants on bilirubin nomogram at high or intermediate risk (>75th percentile track). –Pre-discharge TcB or, TSB (at metabolic screen). –Risk-based post discharge bilirubin follow-up. –Prospectively manage parental education, expectations and inform of potential options / risk. –Peer-Review of babies with TSB >25 mg/dl

System-based Policies and Procedures Involves MDs, Parents, Nurses, Administrators Bilirubin measurement within 48 hours of birthing System-based program to ensure follow-up for those at risk for significant hyperbilirubinemia (>95 th percentile) Peer-review and surveillance for extreme hyperbilirubinemia (TSB levels > 20 to 25 mg/dl) Family education of potential risks of jaundice

95th %ile 75th %ile 40th %ile Bilirubin Care Map to Prevent Acute Bilirubin Encephalopathy (for professional use) 99th %ile Intensive Phototherapy for TSB rise >0.20 mg/dl/hr TSB Follow-up in 6-12 hrs TSB/TcB & MD Follow-up in 24 hrs TcB Follow-up in 48 hrs Check for Jaundice with TcB every 8 to 12 hours Clinical follow-up or Transcutaneous Bilirubin within 48 hrs of discharge at MD discretion “Crash-Cart” Interventions BIND CENTER - Pennsylvania Hospital

At Pennsylvania Hospital

PREVENTION OF KERNICTERUS TSB level >30 mg/dl: “never event” Kernicterus is a “Never Event” AHRQ: National Quality Forum List Universal bilirubin screening endorsed by CDC, NIHCHD, JCAHO, March of Dimes, NAAN, TSB level >25 mg/dl: is a “close call” and a threshold for intensive interventions Predictable by pre- discharge screening

PUBLIC HEALTH MESSAGES 1.“We” 1.“We” should “worry” about neonatal jaundice 2.Neurotoxicity of bilirubin is confounded by: a) early postnatal age ( 0.20 mg/dl/hr) 3.Kernicterus can occur in babies discharged as healthy (TSB levels >95 th percentile) 4.Unmonitored hyperbilirubinemia is UNSAFE

PUBLIC HEALTH GOALS…….. # 1: Clinical expectations: Prevention, Early Diagnosis, Effective and Safe Treatment # 2: Public Health expectations: Lowered incidence of “extreme” (TSB >25 mg/dl) hyperbilirubinemia # 3: Societal expectations: “Zero Tolerance” of kernicterus in otherwise healthy babies # 4: Family expectations: a SAFE experience with newborn jaundice