Hyperbilirubinemia What is all the fuss

Stephen Messier MD FAAPStaff 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 occursDepends on cause

AcutePhase 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 BINDFirst 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”– 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– Immune destruction– Non immune destruction– Increased load (Bleeding, polycythemia)

• Impaired conjugation– Gilbert’s disease– Crigler-Naijar Syndrome

Pathologic Causes

• Decreased excretion – usually with elevated direct (conjugated)– Biliary atresia– Choledochael cyst– Sepsis– UTI– Galactosemia– Hypothyroidism

Check a Direct Bili andCheck 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• 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

Minor Risk Factors• 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– 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

Bili Blanket

Bili Blanket

Bili Bed

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