hyperbilirubinemia in preterm neonates...ganglia, central and peripheral auditory pathways,...
TRANSCRIPT
Hyperbilirubinemia in Preterm Neonates
V I N O D ( V I N N Y ) K . B H U TA N I , M D , FA A P
Discussion points
Natural bilirubin profile
Prevalence and incidence
Bilirubin Burden
Low-bilirubin Kernicterus
Auditory sequelae
Visuo-cortical sequelae
Integrity of brainstem
Beneficial role of bilirubin
Bench evidence of BIND
Margins of safety
Neonatal mortality with kernicterus among admits to neonatal nursery (by BW and GA)
GA (wks) Survivors >48 h
/All NICU Admits
% Cases of
Kernicterus
≥30–<31 109/264 10.1%
31–32 282/356 5.7%
33–34 685/801 3.2%
35–36 749/792 1.1%
>36 356/365 0.8%
Total 2181/2608 (84%) 2.8%
Crosse VM, Meyer TC, Gerrard JW. Kernicterus and prematurity.
Arch Dis Child 1955;30:501-8.
Assumptions
NO SURVEILLANCE DATA FROM USA
(UNLIKE DENMARK, GERMANY, CANADA AND UNITED
KINGDOM).
ALL KERNICTERUS MORTALITY SHOULD INCLUDE:
Acute bilirubin encephalopathy
Death during an exchange transfusion
Infant mortality (often, before a diagnosis is made)
Those with childhood disabilities
Sudden deaths but had neonatal history of high
bilirubin loads
Crude KI
Mortality.
Per 100,000
live-births
Year Livebirths Crude Death Rate
per million for KI
(95%CI)
1979 3 494 398 0.57 (0.28–2.07) 1980 3 612 258 0.55 (0.27–2.00)
1981 3 629 238 0.28 (0.08–1.54)
1982 3 680 537 0.54 (0.26–1.96) 1983 3 638 933 0.27 (0.08–1.53)
1984 3 669 141 0.27 (0.08–1.52)
1985 3 760 561 0.27 (0.08–1.48)
1986 3 756 547 0.00 (0.00–0.98) 1987 3 809 394 0.00 (0.00–0.97)
1988 3 909 510 0.00 (0.00–0.94)
1989 4 040 958 0.00 (0.00–0.91) 1990 4 158 212 0.00 (0.00–0.89)
1991 4 110 907 0.00 (0.00–0.90)
1992 4 065 014 0.25 (0.07–1.37) 1993 4 000 240 0.50 (0.24–1.81)
1994 3 952 767 0.76 (0.44–2.22)
1995 3 899 589 0.00 (0.00–0.95)
1996 3 891 494 0.00 (0.00–0.95) 1997 3 880 894 0.26 (0.07–1.44)
1998 3 941 553 0.51 (0.24–1.83)
1999 3 795 762 0.53 (0.25–1.90) 2000 3 805 648 0.26 (0.08–1.46)
2001 4 033 748 0.50 (0.24–1.79)
2002 4 033 719 0.50 (0.24–1.79) 2003 4 003 606 0.50 (0.24–1.80)
2004 4 077 187 0.25 (0.07–1.37)
2005 4 106 627 0.49 (0.23–1.76)
2006 4 130 153 0.00 (0.00–0.89) 1979-2006 108 888 595 0.28 (0.25–0.40)
Data represent Table 3 of
the article based on their
survey of the CDC and
Prevention’s Wide-Ranging
Online Data for
Epidemiologic Research.
These data calculated
incidence of infant
mortality from kernicterus
in the United States from
1979 to 2006.
Brooks JC et al. Evidence
suggests there was not a
"resurgence" of
kernicterus in the 1990s.
Pediatrics 2011; 127: 672-
679.
0.28 (95th CI): 0.25-0.45
1979…….………………………………………………...…………
…….2006
Common Cause Variation
0.
8
0.
6
0.4
0.2
0
Crude KI
Mortality
per 100,000
live-births
Brooks JC et al. Evidence suggests there was not a
"resurgence" of kernicterus in the 1990s. Pediatrics
2011; 127: 672-679.
Live births = 108,888,595
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1979…….………………………………………………...…………
…….2006
Common Cause Variation ?
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0.1
0.2
0.3
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1986 1991 1995-6 2006
*
* 1994 AAP
*
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PhotoRx 2004 AAP
Special Cause Variation
Changes in incidence and prevalence
Bilirubin rises for first 96-120h age
Presence of early-onset hyperbilirubinemia (<24 h of
age) is a medical emergency
Dramatic improvements in the care of jaundiced
preterm infants
Overall data still illustrate vulnerability of preterms.
Reliance on systems-approach in NICU has led to
tangible reductions in the use of exchange
transfusions and of kernicterus in the US. outcomes.
Can we avoid the exchange transfusion And prevent “BIND”?
After birthing, and successful resuscitation, should we focus on a “Safer First Week”?
Bilirubin burden
Clinical burden of bilirubin neurotoxicity usually
manifests as irreversible post-icteric sequelae.
BIND occurs when the TB level exceeds an infant’s
neuroprotective defenses, primarily in the basal
ganglia, central and peripheral auditory pathways,
hippocampus, diencephalon, subthalamic nuclei,
midbrain, pontine, brainstem nuclei for visuomotor
function, respiratory, neurohumoral and electrolyte
control, cerebellum and the vermis.
Acute signs are progressive changes in an infant’s
cardiorespiratory status, mental (behavioral) status,
neuro-motor and cry,
Clinical signs are non-specific or absent; regardless,
any neurological signs needs to be investigated and
may herald manifestations of ABE (incl. apnea).
Model for reversible bilirubin neurotoxicity. G6PD, glucose-6-phosphate
dehydrogenase; GA, gestational age; BBC, bilirubin binding capacity.
(Bhutani VK, Johnson-Hamerman L.
Semi. Fetal Neonatal Med. 2015;20:6-13)
Brites and Bhutani. Chapter in Cerebral Palsy. 2014
Schematic for BIND and CNS Injury
Hazardous
Free bilirubin
UB Expsoure
Endoplasmic Reticulum
Plasma Membrane
Mitochondria
Watchko et al. Bilirubin-induced
neurotoxicity in the
Preterm neonate.
Clin. Perinatology 2016.
Schematic for BIND and CNS Injury
Endoplasmic Stress
Neuro-inflammation
Increased iCa
Oxidative Stress
Watchko et al. Bilirubin-induced
neurotoxicity in the
Preterm neonate.
Clin. Perinatology 2016.
Schematic for BIND and CNS Injury
Mitochondrial Energy Failure
Excitotoxicity
Increased
iCA
Oxidative Stress
Watchko et al. Bilirubin-induced
neurotoxicity in the
Preterm neonate.
Clin. Perinatology 2016.
Schematic for BIND and CNS Injury
Increased
iCA
Neuronal-damage
Apotopsis
Cycle cell progression and arrest
Watchko et al. Bilirubin-induced
neurotoxicity in the
Preterm neonate.
Clin. Perinatology 2016.
Damage
1. Astrocytes
2. Microglia
3. Oligodendroc
yte
Protection
Bilirubin oxidase
P450 enzymes
ABCB1/ABCC1
Seminars in Fetal and Neonatal Medicine 2015 20, 14-19DOI: (10.1016/j.siny.2014.12.002)
Humans (Pre-term):
- Demyelination and CP at lower TB levels
- Auditory-predominant kernicterus Humans (Post-natal):
- Demyelination and CP at higher TB levels
- Motor-predominant kernicterus
Chapter in Cerebral Palsy: Bhutani&Brites, 2015
Rodent and Human Models for BIND (Brites et al)
Bilirubin burden
Clinical burden of bilirubin neurotoxicity usually
manifests as irreversible post-icteric sequelae.
BIND occurs when the TB level exceeds an infant’s
neuroprotective defenses, primarily in the basal
ganglia, central and peripheral auditory pathways,
hippocampus, diencephalon, subthalamic nuclei,
midbrain, pontine, brainstem nuclei for visuomotor
function, respiratory, neurohumoral and electrolyte
control, cerebellum and the vermis.
Acute signs are progressive changes in an infant’s
cardiorespiratory status, mental (behavioral) status,
neuro-motor and cry,
Clinical signs are non-specific or absent; regardless,
any neurological signs needs to be investigated and
may herald manifestations of ABE (incl. apnea).
Historic clinical risk factors for bilirubin neurotoxicity in preterm neonates
1 Birth weight <1000 g
2 Apgar Score <3 at 5 min of age
3 Arterial oxygen tension <40 mmHg for over 2 h
4 Arterial pH <7.15 for over an hour
5 Core temperature <35°C for over 4 h
6 Serum albumin <2.5 g/dL
7 Sepsis
8 Clinical deterioration
Brown AK, Kim MH, Wu PY, et al. Efficacy of phototherapy in
prevention and management of neonatal hyperbilirubinemia.
Pediatrics 1985;75:393-400.