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

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

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

4. History
Juncker – 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

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

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

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

8. 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)

9. 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

11. 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

12. 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

13. 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

14. 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

15. 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

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

17. 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

18. 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.

19. 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!!!

20. 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

21. 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.

22. 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 weeks
Jaundice PTD
Prior sibling with hyperbili
IDDM
Boys
Moms > 25yo

23. 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

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

25. 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)

26. 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

27. 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

28. Bhutani Curves

29. Phototherapy Guidelines

30. Exchange Transfusion Guidelines

31. 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 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

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

33. 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

34. 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

35. 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

36. Bili Blanket
Spectral irradiance:
Large 49
Small 70

37. Bili Blanket

38. Bili Bed
Irradiance: 66 microwatts/cm2/nm

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

40. 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 min to perform (slower removes more bilirubin)
Double volume exchange should reduce
the serum bilirubin by 50% (replaces
85% of infant’s blood)

41. 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%

42. 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

43. 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.

44. 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

45. Questions?

46. 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 hr follow-up after discharge
Home phototherapy is not as effective as hospital phototherapy