Hyperbilirubinemia What is all the fuss Stephen Messier MD FAAP Staff Neonatologist SD ACEP Conference March 6, 2015

DISCLOSURE No Relevant Financial Relationships Brief mention of metaloporphorin use (not FDA approved)

Objectives History Definitions Pathophysiology Physiologic / Pathologic causes Risk Factors Evaluation Treatment

History Juncker -1724 – Conspectus Medicnae Theorticopraticae – Newborn Jaundice 1875 – Orth – autopsy study - staining of basal ganglia in newborns with severe jaundice 1903 – Schmorl – Coined term Kernicterus to describe this 1958 – Noted that jaundice faded in sunlight

History 1950-70s – Aggressive treatment with exchange transfusion and then phototherapy Marked decline in kernicterus 1980-90s – Thought that therapy may be too aggressive. Infants started being discharged prior to peak in TSB concentration Resurgence of kernicterus

History 1994 – AAP establishes treatment guidelines 2002 – NQF – Kernicterus “never event” 2004 – Most recent treatment guidelines Update clarification in 2009

Hyperbilirubinemia: Definition 2/3 of all newborns will appear jaundiced soon after birth Total Serum Bilirubin (TSB) >95th percentile Pathologic Exaggerated neonatal jaundice

BIND - Bilirubin Induced Neurological Dysfunction Unclear at what TSB level this occurs Depends on cause Acute Phase 1: Sleepy, hypotonia, high-pitched cry (1-2 days) Phase 2: Hypertonia, retrocollis, opisthotonos (3-7 days) Phase 3: Hypertonia (>7 days)

Kernicterus – Chronic BIND Literal Meaning: Kern (Kernal) - Icterus (Yellow) Staining of the Brainstem Nuclei and cerebellum Current implications: Permanent BIND First year: Hypotonia, Active DTRs, Delayed motor skills Later: Choreoathetotic cerebral palsy, Ballismus, upward gaze, enamal dysplasia, sensory neuronal hearing loss

Bilirubin Metabolism Fetal RBC are more fragile than Adult Immune or Non immune hemolysis occurs Traumatic injury after birth (Bruising, cephalohematomas, etc) Increased production of Free hemoglobin

Bilirubin Metabolism RE system – degradation to Biliverdin and CO Biliverdin degrades to unconjugated bilirubin Transported by albumin to liver Conjugates in liver via UGT1A1 Excreted into bile and urine Enterohepatic recirculation via deconjugation from enteric bacteria

Newborns are at Greater Risk Newborns are at increased risk of Hemolysis Rh disease, hereditary spherocytosis, G-6-PD Newborns have low levels of UGT1A1 30 weeks gestation: 1% of adult activity Dramatic increase in 1st week of life At adult activity at 3 months Newborns can have low albumin levels Unbound Unconjugated bilirubin is dangerous

Bilirubin Becomes Unbound Albumin is saturated with bilirubin High bili level or low albumin level Displaced by certain medications Ibuprofen Ceftriaxone Cotimoxazole Streptomycin Chloramphenicol Unbound bilirubin crosses the BBB

Physiologic Causes “Breastfeeding Jaundice” “Breast milk Jaundice” First few days of life Decreased enteral intake Decreased stooling if breastfeeding is ineffective Increased enterohepatic circulation “Breast milk Jaundice” First 1-2 weeks Inhibition of enzymes that conjugate Resolves spontaneously or with temp. cessation of breastfeeding

Pathologic Causes Increased production Impaired conjugation Immune destruction Non immune destruction Increased load (Bleeding, polycythemia) Impaired conjugation Gilbert’s disease Crigler-Naijar Syndrome

Check a Direct Bili and Check the NMS Pathologic Causes Decreased excretion – usually with elevated direct (conjugated) Biliary atresia Choledochael cyst Sepsis UTI Galactosemia Hypothyroidism Check a Direct Bili and Check the NMS

Definition of Elevated Conjugated bilirubin (Cholestasis) > 1mg/dL when total bilirubin is < 5mg/dL >20% of total bilirubin when total > 5mg/dL Must be checked and investigated if present.

Risk Factors Johnson Study – J Peds 2002 Pilot Kernicterus Registry 59/61 Breastfed 44/61 No follow-up scheduled after hospital discharge 14/61 Visual check without TSB measured 7/61 TSB < 30 with signs of acute BIND 19/61 G-6-PD (31%) 20/61 No Specific Cause Found!!! (33%) Term Healthy Newborns are at risk!!!

Glucose-6-Phosphate Dehydrogenase Deficiency X-linked disorder Most common enzymatic deficiency of RBCs Widespread, under recognized Traditionally Middle Eastern , Mediterranean, SE Asia 11% of African Americans “global village” found in any community

Glucose-6-Phosphate Dehydrogenase Deficiency May present with hemolysis from oxidative stress of birth Consider in patients with unexplained, severe hyperbilirubinemia Testing may be normal at times of hemolysis, so repeat testing at 4 months may be warranted.

BIND - Risk Factors Major Risk factors Minor Risk Factors Predischarge bili in High Risk Zone Jaundice in 1st 24 hrs DAT (+); Evidence of Hemolysis GA < 36 weeks Prior sibling needing PTx Ineffective Breastfeeding East Asian Race Predischarge bili in High intermediate risk zone GA 37-38 weeks Jaundice PTD Prior sibling with hyperbili IDDM Boys Moms > 25yo

Challenge – Remember who is at risk MMWR 2001: Systematic Approach to Prevention J – Jaundice in first 24 hours A – A sibling who required phototherapy U – Unrecognized Hemolysis N – Near term infant / Non-optimal breastfeeding D – G6PD I – Infection C – Cephalohematoma or other bruising E – East Asian Race or Mediterranian

Protective factors TSB in “low risk” zone GA > 41 weeks Exclusive bottle feeding African American Hospital discharge after 72 hours of life

Evaluation Birth Hx (GA, DOB, Race, Mat labs, feeding plan) Family Hx Weight (% loss from birth) Output (Urine and Stooling pattern) PE (Jaundiced, fluid status) Prior Labs (TSB, NMS)

Lab Evaluation TSB, serum Chemistry Blood type DAT or Coombs test Serum Albumin CBC / Smear Reticulocyte count G6PD (if suggested by ethnicity or poor response to phototherapy) Urine for reducing substances Evaluation for Sepsis if suggested by Hx

Hour Specific Assessment Bilirubin level changes quickly in the first 4-5 days of life. Bhutani proposed assessing TSB based on hour of life. Studied 2840 infants 50% breastfed 43% Caucasian Published in 1999

Bhutani Curves

Phototherapy Guidelines

Exchange Transfusion Guidelines

Notes about the Bhutani Curves Divided into four zones based on likelihood to be > 95%tile on follow up Low risk - ~ 0% (Recheck 3-4 days) Low – intermediate risk – 12% (Recheck in 24-48hrs) High - intermediate risk – 46% (Recheck in 12-24 hrs) High Risk – 68% (Recheck in 4-8 hrs) If you are crossing into higher risk zones, good chance of ongoing hemolysis > 0.2 mg/dL/hr

Online Assessment Tools www.bilitool.org Neonatal Hyperbilirubinemia Assessment Up To Date® Medscape® There’s an app for that…

Treatment - Phototherapy Start Phototherapy Immediately if indicated. All institutions who deliver infants should have the ability to provide phototheapy Mechanism of Action - Changes bilirubin to lumirubin Photo isomer Lumirubin is water soluble Light waves in the 460nm spectra work best Not standardized Dosage also not standardized

Phototherapy Intensive phototherapy Home phototherapy is not intensive High irradiance 30uW/cm2 430 – 490 nm band “More surface area and more irradiance, better the response” Not ultraviolet 30-40% decrease in 24 hours if no hemolysis Maintaining hydration helps with adequate urine output. Home phototherapy is not intensive and probably not effective

Giraffe Phototherapy Photo of SCH phototherapy: Irradiance at 38 cm is 35 microwatts/cm2/nm Design incorporates ultraviolet and infrared filters Irradiance: Power per unit area measured at a surface

Bili Blanket Spectral irradiance: Large 49 Small 70

Bili Blanket

Bili Bed Irradiance: 66 microwatts/cm2/nm

Phototherapy Safe Complications Cholestatic Jaundice – Bronze infant syndrome (self limited) Congenital Porphyria – Photosensitivity and blistering. (Contraindicated with symptoms or Family Hx)

Exchange Transfusion Less frequent than in the past with effective phototherapy Must be done in Level 3 NICU with experienced staff (Docs, Nurses, Blood bank) Takes about 3-4hrs to set up. 60-90 min to perform (slower removes more bilirubin) Double volume exchange should reduce the serum bilirubin by 50% (replaces 85% of infant’s blood)

Exchange Transfusion 1-2 people exchanging, 1 person monitoring, one person recording Radiant warmer, ABG machine, UAC, UVC, blood warmer, etc. CMV neg, leukofiltered, irradiated, cross matched blood <72 hours old (K < 7) PRBC mixed with FFP to a Hct of 50%

Exchange Transfusion - Complications Infection Clots, air emboli Arrythmias (Ca++, K+, Temp) Bleeding, Coagulopathies Hypoglycemia Electrolyte abnormalities Metabolic Acidosis Necrotizing Enterocolitis Graft vs Host Apnea Bradycardia Feeding intolerance Sepsis

Other Treatments IVF (NS Bolus then maintenance fluids if suggestion of dehydration) Albumin: 1g of 25% over 2 hours to help bind bilirubin IVIG: 0.5 – 1 g/kg over 2 hours Useful for immune mediated hemolysis Phenobarbitol – increases hepatic enzymatic activity Metalloporphyrins – Not FDA approved Decreases bilirubin production by inhibiting heme oxygenase.

Take home points Newborn looks jaundiced – check Total serum bilirubin and a Direct bilirubin Compare with prior measurements Review risk factors – don’t forget G-6-PD Plot levels on an hour specific normogram Start phototherapy as soon as it is indicated Refer early to level 3 NICU if high risk, nearing ET levels, or evidence of hemolysis

Questions?

Recommendations Breastfeeding should be supported and encouraged Late Preterm Infants should be watched for 72 hrs. in hospital if possible All infants should have a 24-72 hr follow-up after discharge Home phototherapy is not as effective as hospital phototherapy