1. Neonatal Jaundice: Indirect Hyperbilirubinemia

2. 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

4. Epidemiology: Increased risk for neonatal jaundice
Infant Factors
Blood group incompatibilities: Rh, ABO, others
Hemolysis (non-isoimmune): infection, drugs, T-antigen exposure, coagulopathy, RBC enzyme deficiencies (G6PD, PK, HK), RBC structural defects (spherocytosis, elliptocytosis)
Hemorrhage: cephalohematomas, intracranial bleeding, bruising
Infection: sepsis, UTI
Endocrine: hypothyroidism, adrenal insufficiency

5. Epidemiology: Increased risk for neonatal jaundice
Infant Factors
Prematurity
Male
Polycythemia
Breast feeding vs. formula feeding
Caloric deprivation, postnatal weight loss
increased enterohepatic circulation
Delayed passage of meconium

6. Epidemiology: Increased risk for neonatal jaundice
Race:
Increased production: East Asian, Native American
G6PD: Greek, East Asian, African
Genetic:
History of sibling with jaundice
G6PD, hexokinase, pyruvate kinase deficiency
Gilbert’s syndrome, Crigler Najjar Syndrome
Spherocytosis, Elliptocytosis
G6PD prevents RBC oxidative damage.
Hexokinase and Pyruvate Kinase are essential for glycolysis in RBCs
Gilbert’s syndrome: AR, reduced activity of glucuronyltransferase to conjugate bilirubin
Crigler Najjar syndrome: AR, little to no glucuronyltransferase present to conjugate bilirubin, more severe than Gilbert’s

7. 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
Beta-glucuronidase converts conjugated bilirubin to the unconjugated form for reabsorption

8. Epidemiology: Increased risk for neonatal jaundice
Environmental factors:
Phenolic detergents
Naphthalene (moth balls)
Short hospital stay
Failure to detect significant jaundice
Failure to establish breastfeeding

9. 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 reach higher peaks

10. How should non-physiologic jaundice be defined?
Collaborative Perinatal Project ( ) and Maisels (1986): upper limit of physiologic jaundice (95%) 12.9 mg/dL
Kaiser (1997): 95% = 17.5 mg/dL
Multicentered international study (Natus, 1998): 95% = 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

11. JCAHO Sentinel Alert: April 2001 Root causes for re-admission for hyperbilirubinemia 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 <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

12. Strategies to prevent severe jaundice
Pre-discharge assessment (transcutaneous bilimeter or serum bilirubin) with use of Bhutani nomogram to predict risk
Standardized policies for screening
Follow-up of all newborns in hr
Informational materials for parents about jaundice
Lactation support
Optimal application of phototherapy

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

14. Predictive nomograms for severe hyperbilirubinemia: Bhutani 1991
What is the risk for subsequent “severe hyperbilirubinemia” (i.e. bilirubin level in the high risk zone, 95th%)?
> 95th %: 39.5%
75-95th %: 21.6%
40-75th %: 11.6%
< 40th %: virtually 0

15. Bilirubin follow-up policy
Compare serum bilirubin or transcutaneous bilirubin to Bhutani curves
> 95th%: repeat serum bilirubin in hours
75-95th%: repeat serum bilirubin in hours
40-75th%: if risk factors present, serum bilirubin in hours
< 40th%: no follow-up needed

16. Bilirubin injury to the brain
Bilirubin encephalopathy:
Acute reversible changes
Acute irreversible changes
Kernicterus (yellow staining of the brain)
Neurodevelopmental sequelae
Clinical correlations
Epidemiologic studies

17. Clinical features of acute bilirubin encephalopathy
Acute form:
Early Phase 1 (1-2 days): poor suck, stupor, hypotonia, seizures
Intermediate Phase 2 (mid 1st week): hypertonia of extensor muscles, irritability, retrocollis-opisthotonus, fever
Advanced Phase 3 (after 1st week): irreversible CNS damage, retrocollis-opisthotonus, hypertonia, shrill cry, seizures, coma, apnea, death

18. Clinical features of kernicterus
Chronic form:
First year: hypertonia, active DTRs, obligatory tonic neck reflexes, delayed motor skills
> 1 year: movement disorders (choreoathetosis, ballismus, tremor), paralysis of upward gaze, hearing loss, mental retardation

19. Pathology of kernicterus
Orth: described bilirubin pigmentation of the brain in 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
Death of neurons

20. Pathophysiology of bilirubin encephalopathy
Bilirubin monoanion binds to membrane
Causes changes in membrane characteristics
May affect membrane permeability
P-glycoprotein (PGP): ATP mediated transport of bilirubin across membranes and out of the cell
Activity low in immature animal
Can be inhibited by drugs: e.g., ceftriaxone
Membrane associated bilirubin oxidizing enzyme in the brain: activity low in immature animal

21. 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

22. Cellular mechanisms of bilirubin toxicity
Binding to cellular membranes
Decreased Na-K exchange
Cellular accumulation of water
Axonal swelling
Lowering of membrane potentials, decreased action potential
Decreased amplitude and longer intervals in auditory response

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

24. Astute Observation from a Nurse
Sister J. Ward, Charge Nurse Premature Baby Unit, Rochford Hospital, Essex England 1957
Skin of jaundiced infants bleached on exposure to sunlight, unexposed skin does not

25. The Science of Phototherapy
Bilirubin is a yellow pigment, absorbs blue light spectrum
Conversion of bilirubin into lumirubin, a water soluble compound
Elimination by the GI tract and kidney

26. Can You “Overdose” With Phototherapy?
“With existing equipment there is no such thing as an overdose of phototherapy” (Maisels2001)
The saturation point (where higher irradiance levels don’t matter) is not known

27. Phototherapy devices White fluorescent tubes Blue fluorescent tubes
Broad spectrum light exposure
Blue fluorescent tubes
Blue light is more effective
Blue LED lights (NeoBlue)
Halogen lamps
More compact, bulbs are hot and can burn if too close
Fiber optic blankets
small area of exposure

28. How Fast Can the Bilirubin Decline?
6-20% decrease in 24 hours-”standard phototherapy”
32% decrease in 18 hours- fiberoptic + bluelights
43% decrease in 24 hours- blue lights above and below

29. Fluorescent Phototherapy Lights
Fluorescent lights cover more skin surface
Deliver higher intensity without heating
White lights effective, blue lights most effective
Bulbs lose intensity long before they “burn out”

30. Fluorescent Bili Lights: 30-35 microwatts

31. LED Phototherapy: 25-50 microwatts

32. NeoBlue Mini: 30-40 microwatts

33. Halogen Spotlight Phototherapy
Halogen spotlights heat skin if closer than 55cm
Cannot deliver higher “doses” of phototherapy
Bulbs burn out
Preferred by staff
More compact, easier to use in NICUs

34. “Triple”Phototherapy: Halogen, Blanket

35. Halogen Photometer Reading
“Double” halogen lights
Only able to generate 10 microwatts/cm2/nm
Very low “dose” of phototherapy

36. Fiberoptic Phototherapy
Light from tungsten-halogen bulb through fiberoptic cable
Less effective than conventional phototherapy
Should not be used in VLBW infants, potential for skin injury

37. Skin Injury From Bili Blanket

38. Factors that determine dose and effectiveness of phototherapy
Spectrum of light (blue is best)
Irradiance of light source
power output of the lamp
Design of phototherapy device
does it expose the maximal amount of skin?
Surface area exposed to light
Distance of infant from light

39. Acute management of severe hyperbilirubinemia
Phototherapy with fluorescent or LED blue lights: maximal surface exposure and dose
Correct dehydration, 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
Reduce enterohepatic circulation of bilirubin: stop breast milk feedings, use formula feedings
PO charcoal and agar reported, but not commonly used

40. Acute management of severe hyperbilirubinemia
Avoid drugs which displace bilirubin from albumin or affect P glycoprotein
Avoid use of hyperosmolar drugs or infusions
Inhibitors of heme oxygenase (protoporphyrins):
Reduces bilirubin production
Sn and Zn protoporphyrins reported to be useful, but not yet FDA approved
Extra-corporeal removal of bilirubin:
theoretical possible
extracorporeal charcoal binding used in Russia

41. Recommendations for treatment of hyperbilirubinemia (AAP practice guideline)
Age Consider Exchange if Exchange*
(hr) phototherapy phototherapy photoRx fails# transfusion
25-48 > 12 > 15 > 20 > 25
48-72 > 15 > 18 > 25 > 30
>72 > 17 > 20 > 25 > 30
#Phototherapy should result in a decline 1-2 mg/dL of total bilirubin within 4-6 hour, should continue to fall and remain below exchange transfusion levels.
*Intensive phototherapy, prepare for exchange, exchange if bilirubin does not fall below exchange transfusion levels.
Adapted from Pediatrics 1994;94:558

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

43. Exchange Transfusion
ABO type-specific Rh negative blood in cases with Rh incompatibility
Type O Rh-specific cells in cases with cases with ABO incompatibility
Whole blood diluted with FFP to Hct of 50-55%.
Fresh blood < 24 hours old preferred.
Double volume exchange 160ml/kg

44. Technique for Exchange Transfusion
Withdrawal thru UA catheter with simultaneous infusion thru UVC catheter
5-to 20-ml increments of warmed blood
Agitate blood every minutes so cells don’t settle.
Initial sample sent for bilirubin, Hct, lytes, calcium, cultures

45. Things to Remember Monitor ECG, BP, and temperature during procedure
Measure ABG at beginning, middle, and end of procedure.
Measure glucose at 10, 30, 60 minutes post procedure.
Measure calcium after each 100 ml of blood.
Warming blood > 37 degrees causes hemolysis

46. Bilirubin After Double Volume Exchange
Serum bilirubin is 45% to 60% of preexchange level

47. Potential complications
Infant
Hypothermia
Hyperkalemia
Thrombocytopenia
Low Ca++ and Mg++
Reactive hypoglycemia
Action
Warm donor blood
Use fresh blood, monitor ECG
Transfuse platelets at end if < 75K
Give CaGluconate 100mg/kg/d
IV glucose 5mg/kg/min minutes after end of exchange

48. Followup issues for hyperbilirubinemia
Hearing screen
“Rebound” bilirubin
AAP guideline: repeat bilirubin level not indicated in healthy term infants
useful in premature infants, hemolysis (isoimmunization, G6PD)
Infants with bilirubin encephalopathy
neurodevelopmental followup
hearing screen