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
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
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
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
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
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
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
How should non-physiologic jaundice be defined?
• Collaborative Perinatal Project (1955-61) 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
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
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 24-48 hr• Informational materials for parents about jaundice• Lactation support• Optimal application of phototherapy
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
Bilirubin follow-up policy
• Compare serum bilirubin or transcutaneous bilirubin to Bhutani curves– > 95th%: repeat serum bilirubin in 24-48 hours– 75-95th%: repeat serum bilirubin in 24-48 hours– 40-75th%: if risk factors present, serum bilirubin
in 24-48 hours– < 40th%: no follow-up needed
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
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
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
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
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
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
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
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
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
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
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
Phototherapy devices
• White 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
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
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”
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
Halogen Photometer Reading
•“Double” halogen lights
•Only able to generate 10 microwatts/cm2/nm
•Very low “dose” of phototherapy
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
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
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
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
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
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: 15-20 mg/dL• Reduce exchange level 3-5 mg/dL for seriously ill
infants: sepsis, acidosis, respiratory failure• Acute symptoms of bilirubin encephalopathy
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
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 10-15 minutes so
cells don’t settle.• Initial sample sent for bilirubin, Hct,
lytes, calcium, cultures
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
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 10-30 minutes after end of exchange
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