hyperbilirubinemia in preterm neonates...ganglia, central and peripheral auditory pathways,...

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Hyperbilirubinemia in Preterm Neonates V INOD (V INNY ) K. B HUTANI , MD, FAAP

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Page 1: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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

Page 2: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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

Page 3: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor
Page 4: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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.

Page 5: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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

Page 6: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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.

Page 7: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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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Page 8: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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1979…….………………………………………………...…………

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Common Cause Variation ?

Page 9: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

0

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Special Cause Variation

Page 10: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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.

Page 11: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

Can we avoid the exchange transfusion And prevent “BIND”?

After birthing, and successful resuscitation, should we focus on a “Safer First Week”?

Page 12: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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).

Page 13: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor
Page 14: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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)

Page 15: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor
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Page 17: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor
Page 18: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

Brites and Bhutani. Chapter in Cerebral Palsy. 2014

Page 19: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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.

Page 20: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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.

Page 21: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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.

Page 22: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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.

Page 23: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor
Page 24: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

Damage

1. Astrocytes

2. Microglia

3. Oligodendroc

yte

Protection

Bilirubin oxidase

P450 enzymes

ABCB1/ABCC1

Page 25: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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)

Page 26: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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).

Page 27: Hyperbilirubinemia in Preterm Neonates...ganglia, central and peripheral auditory pathways, hippocampus, diencephalon, subthalamic nuclei, midbrain, pontine, brainstem nuclei for visuomotor

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.