Unformatted text preview: Michelle B. Kravitz, MD
June 29, 2006 Case 1
Case You are called by the nurse that a
newborn’s TcB is 11.1.
Is this concerning?
What information do you need to answer
that Case 2
Case You are called by the ER to see an infant
whose bili is 22.
Must you admit?
What information do you need to answer
Outline Review of physiology
Assessing the risk
BILIRUBIN Non-polar, water insoluble compound
requiring conjugation with glucuronic acid
to form a water soluble product that can be
It circulates to the liver reversibly bound
to BILIRUBIN PHYSIOLOGY
BILIRUBIN Increased production in neonate due to larger red
cell volume, which produces bilirubin as cells
are broken down and shorter RBC life span, so
broken down faster.
Heme is catabolized within the
reticuloendothelial system by heme oxygenase to
Biliverdin is metabolized to bilirubin in the
presence of biliverdin reductase
presence BILIRUBIN PHYSIOLOGY
Heme Heme oxygenase Biliverdin Biliverdin reductase Bilirubin Bilirubin Physiology
Bilirubin Ligandins responsible for transport from
plasma membrane to endoplasmic
Bilirubin conjugated in presence of
UDPGT (uridine diphosphate glucuronyl
transferase) to mono and diglucoronides,
which are then excreted into bile
canaliculi. Enterohepatic Circulation
Enterohepatic Meconium contains 100-200mg of conjugated
bilirubin at birth.
Conjugated bilirubin is unstable and easily
hydrolyzed to unconjugated bilirubin.
This process occurs non-enzymatically in the
duodenum and jejunum and also occurs in the
presence of beta-glucuronidase, an enteric
mucosal enzyme, which is found in high
concentration in newborn infants and in human
Conjugation Since conjugated bilirubin crosses the placenta
very little, conjugation is not active in the fetus
with levels of UDPGT about 1% of adult levels
at 30 - 40 weeks gestation
After birth, the levels of UDPGT rise rapidly but
do not reach adult levels until 4-6 weeks of age.
Ligandins, which are necessary for intracellular
transport of bilirubin, are also low at birth and
reach adult levels by 3-5 days.
reach CONJUGATED VS
HYPERBILI Conjugated hyperbilirubinemia is always
When the total bili is quite high, the conjugated
fraction can rise to as high as 20% of the total,
although it usually stays under 1.0.
Always check a total and direct, so that you can
be sure you are excluding conjugated
hyperbilirubinemia, which has totally different
etiologies and treatments.
KERNICTERUS Why we care about indirect hyperbilirubinemia
Staining of the brain by bilirubin
Early symptoms-acute bilirubin encephalopathypoor feeding, abnormal cry, hypotonia,
Intermediate phase-stupor, irritability, hypertonia
Late – shrill cry, no feeding, opisthotonus,
apnea, seizures, coma, death
KERNICTERUS Late sequelae can include
sensorineural hearing loss
painful muscle spasms KERNICTERUS
KERNICTERUS Incidence of bilirubin levels>30 1/10,000
Over 120 cases kernicterus documented since
Overwhelming majority term, breastfed
Majority of those had levels in high 30s to 40s.
Lowest level recorded in case series of 111 from
1991-2002 was 20.7, but the mean was 38.
Many cases had no planned follow up and had
been discharged early (<48 hours).
been KERNICTERUS AND FREE
An article published this year in Pediatrics
makes the case for establishing free bilirubin
levels rather than total serum bilirubin levels to
monitor jaundice and assess risk for kernicterus.
Since bilirubin travels bound to albumin
predominantly, the free bilirubin is inversely
proportional to the albumin concentration.
ALBUMIN A low albumin level could possibly be the
reason behind kernicterus occurring in some
infants at relatively low bilirubin levels.
There was a report of a 29 week infant whose
peak bilirubin level was only 15.7 and yet
developed classic kernicterus with spasticity,
dystonia, ballismus, and gaze abnormalities.
Her bilirubin/albumin molar ratio was 0.67. It
has been suggested that a ratio of >0.5 might be
a threshold in sick preterm infants.
ALBUMIN Wenneberg et. al. suggest that an infant with an
albumin level of 2 would be at the same risk for
kernicterus with a bilirubin of 15 as an infant
with a bilirubin of 30 and an albumin level of 4.
We do not have data on albumin levels in
healthy term infants, but most likely,
hypoalbuminemia is a concern in extremely
preterm or otherwise sick infants.
preterm RISK FACTORS FOR
Gestational Age Race Family history of jaundice requiring
phototherapy Hemolysis (ABO or other) Severe bruising Breastfeeding TIME COURSE OF
Pathologic by definition if significant
in first 24 hours
in Usually begins to peak by 48 hours
and continues until 96 hours
and In Asian infants and preterm infants,
peak can continue out to 5-7 days.
peak RISK FACTORS-RACE
RISK Asians-highest risk
Levels peak at 16-18 as opposed to average
Caucasian levels of 6-8. There is also a later
peak which can occur at 5-7 days.
peak Black infants have a lower peak, rarely
exceeding 12. (but they have a much higher
incidence of G6PD deficiency)
incidence Caucasians are in the middle. RISK FACTORSRISK
GESTATIONAL AGE The younger the gestation, the higher the
risk of jaundice.
37 weeks more prone to jaundice than 40
weeker who is more prone than a 42
35 and below is much more prone
Extreme preemies also more prone to
kernicterus and are treated at much lower
levels. RISK FACTORS-FAMILY
HX A child whose sibling needed
phototherapy is 12 times more likely to
also have significant jaundice.
also Frequently peak bilirubin levels correlate
between RISK FACTORSRISK
HEMOLYSIS ABO Incompatibility is the most common cause of
hemolysis causing jaundice.
Only 10-20% of infants with ABO mismatch develop
Some of these infants, however, develop very
significant jaundice quickly.
Coombs positive ABO is more likely to cause
hemolysis, but many babies will be asymptomatic.
Conversely, Coombs negative ABO mismatch does
occasionally cause significant hemolysis, but this is
rather RISK FACTORSRISK
PATHOLOGIC G6PD Deficiency
Glucuronyl Transferase Deficiency Type 1
(Crigler Najar Syndrome)
GT deficiency Type 2 (Arias Syndrome)
JAUNDICE Breastfeeding jaundice occurs early
It is due to the lack of breast milk
It is often associated with poor passage of
Treatment should be aimed at supporting
breastfeeding while supplementing as
needed to avoid extreme weight loss,
dehydration, and worsening jaundice.
dehydration, BREASTMILK/BREASTFEEDING JAUNDICE
JAUNDICE Breast milk jaundice is a different, more benign entity,
which tends to occur late in the first week or afterwards.
It is actually due to something in the breast milk which
tends to prolong jaundice.
Usually weight gain is good, and the baby is otherwise
Jaundice might persist as late as 3-4 weeks, but usually
will peak by 2 weeks.
Textbook treatment is to interrupt breastfeeding (I
usually do not do this).
usually ASSESSING THE RISK OF
JAUNDICE BY THE NUMBERS
Bhutani curve ASSESSING THE RISK OF
JAUNDICE BY THE NUMBERS
JAUNDICE Maisels’ and Kring’s study showed that
not all early higher TcB will continue
They divided the rate of rise to be
concerned with into
>0.06/hr Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 Copyright ©2004 American Academy of Pediatrics ASSESSING THE RISK OF
JAUNDICE BY THE NUMBERS
JAUNDICE www.bilitool.org Palm downloadable! Palm THERAPIESTHERAPIESPHOTOTHERAPY Phototherapy has been the mainstay of treating
hyperbilirubinemia since the 1960s.
Phototherapy causes structural isomerization,
forming lumirubin, which is then excreted in the
bile and urine.
Since photoisomers are water soluble, they
should not be able to cross the blood-brain
barrier, so starting phototherapy should decrease
the risk of kernicterus by turning 20-25% of
bilirubin into a form unable to cross, even before
the level has lowered significantly.
the THERAPIESTHERAPIESPHOTOTHERAPY Bilirubin absorbs light best at 450 nm, but
longer wavelenths penetrate skin better.
Make sure skin is as exposed as possible
and that light is not too far from baby.
Fiberoptic light (bili blanket) is much less
efficacious on its own. THERAPIES-EXCHANGE
TRANSFUSION Double volume exchange transfusion was
a common procedure prior to advent of
Rhogam and phototherapy.
Now fortunately a rare occurrence
Used for bilirubin >25 in a term infant and
not decreasing despite phototherapy
Mesoporphyrin SnMP is a structural analog of heme
It blocks the site on heme oxygenase where
conversion of heme to bilirubin occurs.
Still under investigation (why?)
Administered parenterally in a small dose (6
In term infants, obviated need for phototherapy
Some preterm infants still needed phototherapy
but none needed exchange transfusion
Virtually 100% efficacy THERAPIES-Sn
Mesoporphyrin Can also be used repeatedly for patients with
Crigler-Najar (effects last several days).
Stanate®-currently being patented
Ongoing study at Children’s Hospital of
Columbus in newborns at risk of exchange
Accepting patients until September, 2006
Richard McCleod, MD, Principal Investigator
614-722-2718 Review of Case 1
Review How old is the patient?
What is the gestational age?
What other risk factors are present?
– 12 hours old
ABO incompatible Review of Case 2
Review How old is the patient?
What is the fractionation?
Breast or bottle fed?
Other risk factors?
– 10 days
22 total / 0.8 direct
None MANAGING JAUNDICEMANAGING
TAKE HOME POINTS Consider the risk factors, particularly
prematurity and hemolysis
prematurity Follow up is key! Consider how well baby is feeding, parents’
ability to return, reliability, etc
The higher the number of risk factors, the lower
the level at which to intervene
Sometimes, you will be surprised. We can’t
always prevent hyperbilirubinemia, but we
should always prevent kernicterus.
REFERENCES Tate, M, Neonatal Hyperbilirubinemia, Revised,
June 2001 in MICC Curriculum.
Maisels MJ and E Kring, Transcutaneous
bilirubin levels in the first 96 hours in a normal
newborn population of >/= 35 weeks’ gestation.
Pediatrics. 2006, 117(4):1169-73.
Wennberg et. al., Toward understanding
kernicterus: a challenge to improve the
management of jaundiced newborns. Pediatrics.
2006, Watchko JF, Vigintophobia revisited. Pediatrics, 2005,
Gourley GR et. al., A controlled, randomized, double
blind trial of prophylaxis against jaundice among
breastfed newborns. Pediatrics, 2005, 116(2):385-91.
Merhar SL and DL Gilbert, Clinical Findings and
Cerebrospinal fluid neurotransmitters in 2 children with
severe chronic bilirubin encephalopathy, including a
former preterm infant without marked
hyperbilirubinemia. Pediatrics, 2005, 116(5):1226-30.
Pediatrics, M Herschel et. al., Isoimmunization is unlikely
to be the cause of hemolysis in ABOto
incompatible but direct antiglobulin test-negative
neonates. Pediatrics. 2002, 110(1):127-30.
LD Eggert et. al., The effect of instituting a
prehospital-discharge newborn bilirubin
screening program in an 18-hospital health
system. Pediatrics. 2006, 117(5):e855-62.
2006, A Kappas, A method for interdicting the
development of severe jaundice in newborns by
inhibiting the production of bilirubin. Pediatrics.
D Alexander, Commentary on “A method for
interdicting the development of severe jaundice
in newborns by inhibiting the production of
bilirubin. Pediatrics. 113(1):135.
Pediatrics. J Grupp-Phelan et. Al., Early newborn hospital
discharge and readmission for mild and severe
jaundice. Arch Pediatr Adolesc
P Goevaert et. al. Changes in globus pallidus
with pre(term) kernicterus. Pediatrics. 2003, 112
S Ip et. al. An evidence-based review of
important issues concerning neonatal
hyperbilirubinemia. Pediatrics. 2004,
114(1):e130-153. T WR Hansen, Neonatal Jaundice.
updated June 8, 2006.
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- Fall '11
- neonatal hyperbilirubinemia, bilirubin levels