Neonatal Hyperbilirubinemia CHO NICU Lecture Prepared by A D’Harlingue MD 12-13-10

Objectives Identify risk factors for severe hyperbilirubinemia Understand the relationship between hyperbilirubinemia and the risk for neurologic or developmental injury Discuss ways to screen for infants who might develop severe hyperbilirubinemia Discuss guidelines for treatment Identify common pitfalls and best practices in bilirubin management

Bilirubin production Heme is released from hemoglobin with RBC breakdown Heme is converted to bilirubin by the action of heme oxygenase Hyperbilirubinemia results from excessive production or decreased elimination of bilirubin

Epidemiology: increased risk for neonatal jaundice Race/gender: Increased risk in males Increased bilirubin production: East Asian, Native American G6PD: Greek, East Asian, African Genetic: history of sibling with jaundice G6PD deficiency gene for Gilbert’s syndrome Spherocytosis, hexokinase, pyruvate kinase

Epidemiology: increased risk for neonatal jaundice Maternal: diabetes mellitus Increased bilirubin production rate Correlation with macrosomia and polycythemia Elevated beta-glucuronidase in breastmilk Maternal drugs: epidural anesthesia (bupivacaine), oxytocin Delayed cord clamping (polycythemia)

Epidemiology: increased risk for neonatal jaundice: infant factors Prematurity Near term infant particularly at risk Polycythemia Breast feeding Caloric deprivation, postnatal weight loss increased enterohepatic circulation Delayed passage of meconium

Epidemiology: increased risk for neonatal jaundice: infant factors Isoimmune hemolysis: Rh ,ABO, others Non-isoimmune hemolysis: infection, drugs, T-antigen exposure, coagulopathy, RBC enzyme deficiencies (G6PD, PK, HK) Hemorrhage: cephalohematomas, intracranial bleeding, bruising Infection: sepsis, UTI Endocrine: hypothyroidism, hypopituitarism, adrenal insufficiency

Epidemiology: increased risk for neonatal jaundice Environmental factors: Phenolic detergents Naphthaline (moth balls) Short hospital stay Failure to detect significant jaundice Failure to establish breastfeeding

What is a normal physiologic serum bilirubin? Dennery et al. NEJM 2001: average peak bilirubin in term newborn, 5-6 mg/dL Breast fed infants are on average about 2 mg/dL higher than bottle fed infants in the first days of life. Racial differences Greek, Asian, Navajo at higher risk

How should non-physiologic jaundice be defined? Collaborative Perinatal Project (1955-61) and Maisels (1986): upper limit of physiologic jaundice (95%) 12.9 mg/dL Kaiser (1997): 95%-ile 17.5 mg/dL Multicentered international study (Natus, 1998): 95%-ile 15.5 mg/dL, 2 SD 17 mg/dL at 96 hours Bhutani. Pediatrics 1999; 103:6 Post discharge: 95th percentile 17.5 mg/dL predictive curves for severe hyperbilirubinemia

Why worry about bilirubin? Vast majority of patients are asymptomatic except for jaundice Classic kernicterus is relatively infrequent Aggressive approach to bilirubin management in the 1970s was followed by a less aggressive approach in the 1980s Bilirubin 20 mg/dL = Vigintiphobia Watchko JF, Oski FA. Pediatrics 1983;71:660

Why the increase in kernicterus in the late 80s-90s? Increase in breastfeeding Trend towards earlier discharge of mothers and newborns Less aggressive approach to jaundice led to an increase in severe hyperbilirubinemia Increase in bilirubin encephalopathy and kernicterus

Bilirubin injury to the brain Bilirubin encephalopathy: Acute reversible changes Acute irreversible changes Kernicterus (yellow staining of the brain) Neurodevelopmental sequelae

Clinical features of kernicterus Acute form: Phase 1 (first 1-2 days): poor suck, stupor, hypotonia, seizures Phase 2 (mid 1st week): hypertonia of extensor muscles, opisthotonus, retrocollis, fever Phase 3 (after 1st week): hypertonia Chronic form: First year: hypertonia, active DTRs, obligatory tonic neck reflexes, delayed motor skills After first year: movement disorders (choreoathetosis, ballismus, tremor), upward gaze, sensorineural hearing loss Adapted from Dennery, et al. NEJM 2001;344:584

Pathology of kernicterus Orth: described bilirubin pigmentation of the brain of infants with severe jaundice in 1875 Kernicterus: German word meaning jaundice of the nuclei Term was coined by Christian Schmorl in 1904 Yellow staining of the brain (basal ganglia) Neuronal swelling Programmed death of neurons Gliosis

Pathophysiology of bilirubin encephalopathy Blood brain barrier Hyperosmolarity opens the barrier Hypercarbia increases bilirubin deposition in the brain Bilirubin binding to albumin: 1:1 at the first binding site Displacement of bilirubin from albumin: sulfa drugs, benzyl alcohol, FFA, ceftriaxone Free bilirubin hypothesis

Cellular mechanisms of bilirubin toxicity Formation of bilirubin crystals in cells binding to cellular membranes Decreased Na-K exchange Cellular accumulation of water Axonal swelling Lowers membrane potentials, decreased action potential Decreased amplitude and longer intervals in auditory response Decreased phosphorylation of protein kinase

Cellular mechanisms of bilirubin toxicity Decreased phosphorylation of synapsone 1 Decreased tyrosine uptake and dopamine synthesis in dopaminergic striatal synaptosomes Bilirubin induced changes in energy metabolism: 31P nuclear magnetic resonance

Clinical factors which increase the risk for kernicterus or bilirubin encephalopathy Displacement of bilirubin from albumin Duration of severe hyperbilirubinemia Hemolysis Prematurity Hyperosmolarity Hypoxemia, hyperoxemia Hypercarbia Acidosis Sepsis

What is a safe bilirubin level? 1 g/100 ml of albumin binds 8.3 mg /100 ml of bilirubin Free bilirubin increases when the binding capacity to albumin is exceeded Safe free bilirubin level (Alfors): 1.3 mcg/dL to a max of 4 mcg/dL. This test generally not available for clinical use

Recent clinical reports of bilirubin encephalopathy Penn, Stevenson, 1994: TB 50 mg/dL, E. coli sepsis, abnormal neuro exam (acutely and 4 mo), EEG and MRI. Maisels, 1995: 6 “healthy infants” with bilirubin injury; range peak bilirubin 39.0-49.7 mg/dL MacDonald, 1995: 4 term infants with G6PD, TB 37-49 mg/dL, abnormal neuro exam and seizures Johnson, 1999: kernicterus registry (125 cases reported) Estimated incidence of kernicterus in USA: 1:27,000-55,000 Unknown incidence of mild injury

Recent clinical reports of bilirubin encephalopathy Ebbesen, 2000: 6 cases of kernicterus in Denmark. Peak TB 531-745 micromole/L (31-44 mg/dL) 1 spherocytosis, 1 galactosemia, 2 ABO incompatibility Harris, 2001: 6 term and near term infants, TB 26.4-36.9 mg/dL (5/6 >30). 5/6 presented with abnormal neuro exam. 3/4 had abnormal MRI (increase T1 signal in basal ganglia). 5/6 had normal neurodevelopmental followup. One infant had CP, MR, encephalomalacia. Ahlfors, 2003: term, TB 31.7 at 4 days, unbound bili 7.7 mcg/dL, seizures, G6PD deficiency, kernicterus at autopsy

Outcome of severe hyperbilirubinemia Newman, 2003: Kaiser, Northern CA 11 newborns (1:10,000 incidence) of TB > 30 mg/dL (mean 34.9, range 30.7-45.5). All treated with phototherapy; 5 XTX. Normal neurologic outcome in all infants. One infant died of SIDS, no evidence of kernicterus on autopsy. Newman, 2006: 130 newborns: TB 25-29.9; 10 newborns TB >= 30 mg/dL Outcome at >= 2 yr in 132 bili patients compared to 419 controls 17% vs. 29% questionable or abnormal neuro findings in hyperbilirubinemia vs. control, P = 0.04 Lower cognitive scores for hyperbili pts, if direct Coombs +

JCAHO Sentinel Alert: April 2001 Risk factors for severe hyperbilirubinemia Jaundice in the first 24 hours Inadequate PO intake due to suboptimal breastfeeding Mild prematurity: 35-37 weeks Bruising and cephalohematomas Unrecognized hemolysis: ABO G6PD deficiency Genetic/ethnic factors: siblings with jaundice, East-Asian or Mediterranean descent

JCAHO Sentinel Alert: April 2001 Root causes identified: Unreliability of visual assessment of jaundice Failure to measure bilirubin before discharge or in an infant with visible jaundice in the first 24 hours Early discharge: especially in <38 weeks GA infant Failure to provide early f/u assessment post discharge Failure to provide lactation support, information to parents about jaundice or poor feeding Failure to treat appropriately

AAP clinical practice guideline Management of hyperbilirubinemia in the newborn infant 35 or more weeks gestation Pediatrics 2004;114:297 Committee consensus revision of 1994 CPG Evidence based recommendations

AAP 2004 CPG: Summary recommendations Promote breastfeeding Nursery protocols to identify/evaluate jaundice Jaundice in 1st 24 hr: serum or transcutaneous bilirubin Recognize inaccuracy of visual bilirubin assessment Interpret bilirubin based on infant age (hr)

AAP 2004 CPG: Summary recommendations Higher risk: < 38 weeks and breastfed Assessment of risk for severe hyperbilirubinemia at discharge Parental education Appropriate follow up based on age at discharge and risk assessment Appropriate treatment

Strategies to diagnose severe hyperbilirubinemia Predischarge assessment (bilirubinometer, serum bilirubin) with use of nomogram to predict risk Identify risk factors: breastfeeding, <38 weeks, h/o jaundice in sib, jaundice prior to discharge home Standardized hospital policies for screening Procedures for followup of all newborns 24-48 hr Informational materials for parents about jaundice Lactation support

Algorithm for the management of jaundice in the newborn nursery Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 Copyright ©2004 American Academy of Pediatrics

Common pitfalls in recognition of at risk infants Treating the near term infant (35-37 wk) like a full term infant Poor feeding Failure to establish breast feeding Risk for dehydration More prolonged jaundice with higher peak in the preterm infant

Best practices Promotion of breast feeding Lactation support Weight checks Parental education re: expected feeding, voiding, stooling patterns

Bilirubin measurement and interpretation: common pitfalls Failure to measure bilirubin in a jaundiced patient, especially in the 1st 24 hr Cephalad to caudad progression of skin color used alone to assess jaundice Failure to interpret the bilirubin level with respect to age in hours

Transcutaneous bilirubin meter to screen for jaundice

Bhutani: hour specific serum bilirubin. Pediatrics 1999;103:6-14

Predictive nomograms for severe hyperbilirubinemia: Bhutani 1999 Risk for severe hyperbilirubinemia? (any subsequent bilirubin in the high risk zone, 95%) Above 95%: 39.5% 75-95%: 21.6% 40-75%: 11.6% Below 40%: very low (0)

Use of Bhutani curves to determine timing of follow up visit and/or bilirubin test (one approach) Compare serum bilirubin or transcutaneous photometer to Bhutani curves Above 95%: bilirubin within 24 hours 75-95%: bilirubin within 48 hours 40-75%: if risk factors present, bilirubin within 48 hours Below 40%: usually no followup bili needed

Risk factors for severe hyperbilirubinemia for consideration with hour specific bilirubin Exclusive breastfeeding: poor feeding, weight loss Isoimmune or other hemolytic disease Previous sibling with jaundice Cephalohematomas or bruising East Asian race Lower gestational age

An approach to time follow-up for repeat jaundice and bilirubin evaluation based on pre-discharge bilirubin testing. Bhutani & Johnson. Journal of Perinatology (2009) 29, S61–S67

Laboratory evaluation of hyperbilirubinemia Blood type and Coombs CBC and smear, reticulocyte count Direct bilirubin Albumin level G6PD Blood culture UA and urine culture Check results of state screen Thyroid studies

Acute management of severe hyperbilirubinemia Phototherapy with fluorescent blue lights: maximal surface exposure and dose Correct dehydration: no need to give extra fluids if hydration is normal Correct acidosis (respiratory and metabolic), and hypotension Correct hypoalbuminemia (1 g/dL of albumin binds 8.3 mg/dL bilirubin) Augments removal of bilirubin with exchange transfusion

Acute management of severe hyperbilirubinemia Avoid drugs which displace bilirubin from albumin Sulfa drugs, ceftriaxone IVIG for Rh or ABO isoimmunization Reduces need for exchange transfusion by blocking Fc receptor of the hemolytic antibody Dose: 0.5-1 g/kg, repeat q 12-24 hr as needed May increase risk of NEC Reduce enterohepatic circulation of bilirubin: limited restriction of breast milk feedings use formula feedings Stimulate stooling: frequent feeds, glycerin suppositories Agar, charcoal use has been reported

Phototherapy: pitfalls in its use Inadequate light source White vs. blue light Inadequate output Non-optimal use of lights Amount of skin exposure Distance of the light from the patient Delays in starting treatment Referral to ED vs. direct admission

Factors that Determine “Dose” of Phototherapy Spectrum of light Irradiance of light source Design of phototherapy device Surface area exposed to light Distance of infant from light Maisels: N Engl J Med 2008;358:920-8

Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 Effect of light source and distance from the light source to the infant on average spectral irradiance Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 Copyright ©2004 American Academy of Pediatrics

Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 Relationship between average spectral irradiance and decrease in serum bilirubin concentration Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 Copyright ©2004 American Academy of Pediatrics

Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 Copyright ©2004 American Academy of Pediatrics

Risk factors for neurotoxicity affecting bilirubin level to start phototherapy Immune hemolytic disease G6PD deficiency Asphyxia Sepsis Acidosis Albumin < 3.0

Light emitting diode phototherapy

When to stop phototherapy? Term and near term infants: TB < 13-14 mg/dL Lower levels if high risk or early severe jaundice Premature infants <35 weeks: TB <6-10 mg/dL Cholestasis: elevated direct bilirubin Most infants need not remain in hospital for measurement of “rebound” bilirubin High risk infants may need f/u outpatient testing

Complications of phototherapy Increase in stool water loss Change in skin water loss is minimal Thermal burns with inappropriate use of halogen lamps Abrasive injuries with bili blankets in premature infants Rare skin eruptions Bronze baby syndrome

Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 Guidelines for exchange transfusion in infants 35 or more weeks' gestation Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 Copyright ©2004 American Academy of Pediatrics

Prematures: observation studies, bilirubin encephalopathy or kernicterus Study bilirubin, mg/dL Crosse, 1955 >18 Meyer, 1956 >18 Crosse, 1958 >22 Crosse, 1961 >22 Koch, 1959 >20 Hugh-Jones, 1960 >30 adapted from Watchko, Pediatrics 1992;90:707

Randomized study of exchange transfusion for hyperbilirubinemia, prematures Patients with indirect bilirubin >18 mg/dL at >36 hours of age were randomized to exchange transfusion or observation. Study group #kernicterus/total Exchange, bilirubin >18 mg/dL 0/50 No exchange, bilirubin >18 mg/dL 1*/50 Not randomized, bilirubin <15 mg/dL 0/87 *peak indirect bilirubin 27.6, clinical symptoms noted at 17.7, seizures at 22.8, kernicterus noted at autopsy Wishingrad, Pediatrics 1965;36:162

Exchange transfusion: criteria Term: >= 25 mg/dL >= 20 mg/dL, Rh disease 35-36 weeks: > 25 mg/dL 30-34 weeks: > 20 mg/dL < 30 weeks: 15-20 mg/dL Reduce exchange level 3-5 mg/dL for seriously ill infants: sepsis, acidosis, respiratory failure Acute symptoms of bilirubin encephalopathy

Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 Fig 4. Guidelines for exchange transfusion in infants 35 or more weeks' gestation Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 Copyright ©2004 American Academy of Pediatrics

Exchange transfusion (XTX): criteria Immediate XTX for patients with acute bilirubin encephalopathy or TB >= 5 mg/dL above exchange level Hospitalized patients on intensive phototherapy who cross XTX threshold Readmitted patients who remain above XTX threshold despite 6 hours of phototherapy

Pitfalls with respect to patients near or above exchange level Failure to provide intensive phototherapy Exchange transfusion performed by inexperienced personnel Failure to recognize the risks and complications of exchange transfusion

Complications of exchange transfusion Vascular: thrombi, air embolism Metabolic: hypocalcemia, hypoglycemia Hematologic: hemolysis, thrombocytopenia, anemia, coagulopathy Infectious: blood exposure and vascular device related Mortality: <= 1% Other: NEC

Patients who might need XTX: Best Practices Prompt recognition of severe hyperbilirubinemia Intensive phototherapy Expanded laboratory evaluation: serum albumin, G6PD, blood gas Blood bank sets up blood for exchange transfusion Vascular access Timely referral to a NICU with experienced staff in XTX

Discharge and follow up issues “Rebound” bilirubin testing Hearing testing

Final take home messages Screen all newborns prior to discharge Bilirubin photometer vs. measured bilirubin in lab Risk assessment Appropriate outpatient bilirubin assessment of at risk infants Beware of the mildly premature infant (35-37 wk) Use effective (intensive) phototherapy (blue light) Parental education about bilirubin Lactation support