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Competency Based Training Module for Physicians
Neonatal Health Care Modules
Neonatal Hyperbilirubinemia
Jayashree Ramasethu, M.D.
Georgetown University Hospital
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Module Overview: Purpose
• To introduce to the participants the knowledge, competencies and skills required to identify the etiology, diagnose and manage both unconjugated and conjugated hyperbilirubinemia in full term and preterm infants.
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Module Overview: Story
• Neonatal hyperbilirubinemia is an elevated serum bilirubin level in the neonate.
• The most common type is unconjugated hyperbilirubinemia, which is visible as jaundice in the first week of life.
• Although 60% of babies will develop jaundice, and most jaundice is benign, severe hyperbilirubinemia can cause serious permanent brain damage.
• The goal of this module is to teach physicians to identify,
assess and manage neonatal hyperbilirubinemia.
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Module Overview: Learning ObjectivesBroad Outline
Physicians must:• Understand the physiology of bilirubin metabolism in the
neonate, and the difference between unconjugated and conjugated hyperbilirubinemia
• Identify neonatal hyperbilirubinemia and decide whether it is physiological or pathological.
• Obtain an accurate history and perform a physical examination in order to diagnose the etiology of hyperbilirubinemia.
• Identify laboratory tests needed for investigation.• Manage unconjugated hyperbilirubinemia• Diagnose conjugated hyperbilirubinemia.
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CLINICAL JAUNDICE
• 60% of newborn• Visible jaundice: serum bilirubin > 5 mg/ dl
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Neonatal Jaundice: WHY WE WORRY
bilirubin bilirubin encephalopathy
KernicterusStage 1: lethargy, hypotonia, poor suck
Stage 2: fever, hypertonia, opisthotonus
Stage 3: apparent improvement
Sequelae: Sensorineural hearing loss Choreoathetoid cerebral palsy
Gaze abnormalities
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Kernicterus Neuropathology
yellow staining and neuronal necrosis• basal ganglia:
globus pallidus subthalamic nucleus
• cranial nerve nuclei:
vestibulocochlear oculomotor facial
• cerebellar nuclei
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• 1970s - KERNICTERUS ELIMINATED • 1990s - 125 CASES OF KERNICTERUS in the United States
• 2000s - ? Cases of kernicterus in Indonesia
A preventable tragedy
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NEONATAL JAUNDICE
• Mechanism
Physiologic vs Pathologic
• Non- physiologic jaundice:
differential diagnosis
• Management
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Bilirubin metabolism
HEME + Globin
BILIVERDIN
BILIRUBIN
Alb
UCBLIVER
CO(Heme Oxygenase)
Conjugated bilirubin
Free unconjugatedbilirubin
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BILIRUBIN
UNCONJUGATED • Indirect bilirubin• Water- insoluble• Bound to albumin for
transport• Free component
fat - soluble• Free component
TOXIC to brain
CONJUGATED • Direct bilirubin• Water soluble
• Not fat soluble
• Not toxic to brain
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BILIRUBIN TOXICITY
Unconjugated bilirubin level > 20 mg/ dL? >25 mg/ dl? > 30 mg/ dL?
• Gestational age• Hemolysis• Other illness: asphyxia, hypoglycemia,
acidosis, sepsis• Drugs displacing bilirubin from albumin
binding sites
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CLINICAL JAUNDICE
• 60% of newborn• Visible jaundice: serum bilirubin > 5 mg/ dl
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Why do babies have jaundice in the
first week of life? • Increased bilirubin production
– Higher turnover of red blood cells– Decreased life span of red blood cells
• Decreased excretion of bilirubin– Decreased uptake in the liver– Decreased conjugation by the liver– Increased enterohepatic circulation of bilirubin
Bilirubin excretion improves after 1 week
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PHYSIOLOGICAL JAUNDICE
0
2
4
6
8
10
12
14
DAY 1 DAY 3 DAY 5 DAY 7
S.Bili mg/dl
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Physiological Jaundice
• Note the natural history of physiologic jaundice in the full term newborn- – onset after 24 hours– peaks at 3 to 5 days– decreases by 7 days.
• Average full term newborn has peak serum bilirubin level of 5 to 6 mg/ dl.
• Exaggerated physiologic jaundice- when peak serum bilirubin is 7 to 15 mg/ dl in full term neonates.
• Always consider age of the baby and bilirubin level
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Hour- specific bilirubin level
• Bilirubin level of 10 mg/ dl at 72 hours of age in a term newborn is probably physiological.
• Bilirubin level of 10 mg/ dl at 10 hours of age is NOT physiological, and needs immediate attention.
(see natural history of physiological jaundice)
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Serum Bilirubin levels
in term and preterm infants
0
2
4
6
8
10
12
14
16
day 1 day 2 day 3 day 4 day 5 day 6 day 7
Normal term
Preterm
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Jaundice in preterm neonates
• Onset earlier
• Peaks later
• Higher peak
• Takes longer to resolve- up to 2 weeks
• What level is physiologic?
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Physiologic vs Non- physiologic
hyperbilirubinemia
02468
101214161820
day 1 day 2 day 3 day 4 day 5 day 6 day 7
physiologic
non- physiologic
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NON- PHYSIOLOGIC JAUNDICE
• Onset before 24 hours of age• Rate of rise > 0.5 mg/ dl/ hour• Cutoff levels
> 15 mg/ dl in term infant?
> ? mg/ dl in preterm infant?
• Jaundice persisting
> 8 days in term infant
> 14 days in preterm infant
• Other signs of illness
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HYPERBILIRUBINEMIA - CAUSES OVERPRODUCTION ( HEMOLYSIS)
• Extravascular blood- hematomas, bruises• Feto- maternal blood group incompatibility
Rh- mom / baby Rh+
O group mom / baby A or B
• Intrinsic red cell defects
G-6-PD deficiency
hereditary spherocytosis
• Polycythemia
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NEONATAL JAUNDICE - case ( ref. MacDonald MG. Pediatrics 1995)
African- American male infant, birth weight 3.47kg
Normal delivery 39 w gestation
Discharged home at 24 hrs of age
Jaundice and lethargy noted at 5 days of age
LABS: Total serum bilirubin 37mg/ dL
Peripheral blood smear normal, retic count 3.6%
Mom O+, Baby O +, Coomb’s test negative
Seizures, apnea, opisthotonus during Exchange Tx
13 months of age: profound hearing loss and hypotonia
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G6PD DEFICIENCY
• X- Linked disorder (2- 6% carrier rate in Indonesia)• enzyme protects red cell from oxidative damage• >150 mutations• Onset of jaundice usually day 2- 3, peaks day 4 - 5• Hyperbilirubinemia may be out of proportion to
anemia• microspherocytes/ bite cells/ normal blood picture• Diagnosis- enzyme assay baby and mother• False negative test with reticulocytosis• DNA analysis
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HYPERBILIRUBINEMIA CAUSESUNDERSECRETION
• Prematurity• Hypothyroidism• Infants of diabetic mothers• Inherited deficiency of conjugating enzyme
uridine diphosphate glucuronyl transferase• Other metabolic disorders
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HYPERBILIRUBINEMIA CAUSESSecreted but reabsorbed from gut
ENTEROHEPATIC CIRCULATION
• Decreased enteral intake• Pyloric stenosis• Intestinal atresia/ stenosis• Meconium ileus• Meconium plug• Hirschsprung’s disease
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OBSTRUCTIVE DISORDERS - direct hyperbilirubinemia
• Cholestasis• Biliary atresia• Choledochal cyst
# Direct bilirubin > 2 mg/ dL# Time of appearance# Color of stools# Color of urine
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HYPERBILIRUBINEMIA CAUSESMIXED
• Bacterial sepsis• Intrauterine infections: TORCH• Asphyxia
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Hyperbilirubinemia- diagnosis
• History• Physical exam:
– gestational age– activity/ feeding– level of icterus– pallor– hepatosplenomegaly– bruising, cephalhematoma
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Rapidly developing jaundice on Day 1
Likely– Rhesus, ABO, or other hemolytic disease– Spherocytosis
Less likely– Congenital infection– G-6-P-D deficiency
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Rapid Onset jaundice after 48 hours of age
• Likely– Infection– G-6-P-D deficiency
• Unlikely
– Rh, ABO, spherocytosis
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Hyperbilirubinemia- diagnosis
• Laboratory tests– Bilirubin levels: total and direct– Mother’s blood group and Rh type– Baby’s blood group and Rh type– Direct Coomb’s test on baby– Hemoglobin– Blood smear– Reticulocyte count
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NEONATAL HYPERBILIRUBINEMIA MANAGEMENT
• HYDRATION - FEEDING
• PHOTOTHERAPY
• EXCHANGE TRANSFUSION
• Phenobarbital• Tin protoporphyrin
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American Academy of PediatricsSubcommittee on Hyperbilirubinemia
Clinical Practice Guideline
Management of Hyperbilirubinemia
in the Newborn Infant
35 or more weeks of gestation
Pediatrics July 2004
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Management of Hyperbilirubinemia in the Newborn Infant
35 or more weeks of gestation
• Promote and support successful breast-feeding• Perform a systematic assessment before discharge
for the risk of severe hyperbilirubinemia• Provide early and focussed follow-up based on risk
assessment• When indicated, treat newborns with phototherapy or
exchange transfusion to prevent the development of severe jaundice and possibly, kernicterus.
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Feeding to Prevent and Treat Neonatal Jaundice
Mothers should breast feed their babies
at least 8 to 12 times per day
for the first several days
caloric intake / dehydration Jaundice
• Supplementation with water or dextrose water will not prevent prevent or treat hyperbilirubinemia
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Systematic Assessment for Neonatal Jaundice
• Pregnant women - Blood group and Rh type • If mom is Rh negative or O group: Baby’s cord blood
group/ Rh type/ DAT• Monitor infant for jaundice at least every 8 to 12
hours• If level of jaundice appears excessive for age,
perform transcutaneous bilirubin or total serum bilirubin measurement
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Clinical assessmentof severity of jaundice
• Cephalocaudal progression– face 5 mg/ dl (approximately)– upper chest 10 mg/ dl (approx)– abdomen and upper thighs 15 mg/ dl ( approx)– soles of feet 20 mg/ dl ( approx)
• Visual inspection may be misleading
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Transcutaneous Bilirubinometers•Useful as screening device •TcB measurement fairly accurate in most infants with TSB< 15mg/ dL.•Independent of age, race and weight of newborn
•Not accurate after phototherapy
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Assess risk factors for significant jaundice
• Blood group incompatibility with positive DAT • Gestational age 35- 36 weeks• Exclusive breast feeding - first time mom• Cephalhematoma or significant bruising • Asian race • Previous sibling had significant jaundice • Jaundice in the first 24 hours of life• Predischarge bilirubin in the high risk zone
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Hour Specific Serum BilirubinBhutani et al, Pediatrics 1999
Predictive Ability of a Predischarge Hour Specific Serum Bilirubin for Subsequent Significant Hyperbilirubinemia in Healthy Term and Near - term Newborns.
Serum Bilirubin levels pre- discharge in 13,003 babies
Serum Bilirubin levels post- discharge in 2840 babies
Racially diverse - 5% Asian
Nomogram- 95th percentile for serum bilirubin level
24 hours: 8 mg/ dl (137 M/ L)
48 hours: 14 mg/ dl (239 M/ L)
72 hours: 16 mg/ dl ( M/ L)
84 hours: 17 mg/ dl (290 M/ L)
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Nomogram for designation of risk based on hour specific serum bilirubin levels at discharge
Bhutani et al., Pediatrics 1999
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Guidelines for phototherapy in infants 35 or more weeks gestationAmerican Academy of Pediatrics, July 2004
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PHOTOTHERAPY
NOT UV LIGHT @#$%*!
• Light wavelength 450 to 460 nm• Blue lamps: 425 to 475 nm• Cool white lamps: 380 to 700 nm
• Spectral irradiance: 30 W / cm2 / nm
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PHOTOTHERAPY
Natural unconjugated bilirubin isomer: ZZZZ ZE( toxic, no conjugation need)
ZZ lumibilirubin
ZZ photooxidation products
Photoisomerization
Structural isomerization
photooxidation
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Measuring Adequacy of Phototherapy
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Intensive Phototherapy
• Light source: daylight, cool white, blue, special blue fluorescent tubes,tungten halogen lamps, fiberoptic blanket, gallium nitride light emitting diode.
• Distance from light: florescent lights should be as close as possible ( up to 10 cms from baby), halogen lights can cause overheating
• Surface area: maximal, remove all clothes except diaper, may remove diaper too
• Intermittent versus Continuous• Hydration
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Complications of phototherapy
• Significant complications very rare– separation of mother and baby– increased insensible water loss and
dehydration in premature baby– Bronze- baby syndrome (in babies with
cholestatic jaundice)
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What decline in serum bilirubin can you expect with phototherapy?
• Rate of decline depends on effectiveness of phototherapy and underlying cause of jaundice.
• With intensive phototherapy, the initial decline can be 0.5 to 1.0 mg/ dl/ hour in the first 4 to 8 hours, then slower.
• With standard phototherapy, expect decrease of 6% to 20% of the initial bilirubin level in the first 24 hours.
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When should phototherapy be stopped?
• Depends on the age of the baby
• Cause of the hyperbilirubinemia
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Exchange Transfusion
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Guidelines for Exchange Transfusion in Infants 35 or more weeks gestation
American Academy of Pediatrics, July 2004
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Exchange Transfusion
waste
Partially packedRed Blood Cells
Double volume Exchange Transfusion2 X 85 mL/ kg
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EXCHANGE TRANSFUSION - COMPLICATIONS
• cardiac failure
• metabolic- hypoglycemia, hyperkalemia, hypocalcemia, citrate toxicity,
• air embolism
• thrombocytopenia
• bacterial sepsis
• transfusion transmitted viral disease
• necrotizing enterocolitis
• portal vein thrombosis
Mortality / permanent sequelae 1-12%
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Phototherapy and Exchange Transfusion in VLBW infants (Cashore WJ, Clin Pediatr 2000)
Weight (g) Start phototherapy(mg/ dl)
Consider exchangetransfusion (mg/ dl)
500 - 750 5- 8 12- 15
750 - 1000 6 - 10 > 15
1000 - 1250 8 - 10 15 - 18
1250 – 1500 10 - 12 17 - 20
???
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LAB REPORT
Baby Boy Mango
Total Bilirubin: 13.0 mg / dl
(36 hours age)
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Baby Boy Mango
• Mother O Rh positive • Baby A Rh positive• Total serum bilirubin 13 mg/ dl at 36 hours age• Direct serum bilirubin 0.7 mg/ dl• Hematocrit 38 %• Reticulocyte count: 8%• Blood picture: microspherocytes present
DIAGNOSIS?
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Laboratory ReportBaby Girl Lemon
• Total bilirubin 13 mg/ dL
• Direct bilirubin 0.3 mg/ dL
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Baby Girl Lemon
• Bilirubin 13 mg/ dL at 72 hours age
• Baby breast fed
• Mom A Rh positive
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BREAST MILK JAUNDICE
0
5
10
15
20
25
day 4 day 8 day 12 day 16 day 20 day 24
normalB.M. jaundiceBMJ- stop BM