Hyperbilirubenemai in preterm neonates

small matters in
hyperbilirubinaemia
AMANDLA ABANTWANA AMANCANE
Power to the small babies
1785
UNIVERSITY OF PARIS RESEARCH PRIZE
Traité de l'Ictère ou Jaunisse des Enfans des
Naissance
Jean Baptiste Thomasee Baumes
Hansen TWPioneers in the scientific study of neonatal jaundice and
kernicterus.Pediatrics.2000
• Bidault F. Essai sur l'Ictère des Nouveau-nés. Paris,
France: University of Paris; 1804. Doctoral thesis
• Vaillant L. Dissertation sur l'Ictère des Nouveau-nés.
Paris, France: University of Paris; 1816. Doctoral thesis
• Denis P-S. De l'Ictère et de l'Endurcissement du Tissu
Cellulaire des Enfans Nouveau-nés. Paris, France:
University of Paris; 1824. Doctoral thesis
• Bouton J-P. Thèse Pour le Doctorat en Médicine. Paris,
France: University of Paris; 1838. Doctoral thesis
• Billard C. Traité des Maladies des Enfans Nouveau-nés
et a la Mamelle. Paris, France: JB Baillière; 1828
Jacques François Édouard Hervieux
1847
De l'Ictère des
Nouveau-nés “
…. On the
Jaundice of
Newborns)
Hansen TWPioneers in the scientific study of neonatal jaundice and
kernicterus.Pediatrics.2000 Hervieus De l'Ictère des Nouveau-nés
(English translation: On the Jaundice of Newborns). Paris, France:
University of Paris; 1847. Doctoral thesis
Virchow discovers bilirubin crystals in
1847
• Suggests it is derived from blood
Orth 1875
Haemolytic anaemia
and jaundice
HansenPioneers in the scientific study of neonatal jaundice and kernicterus.Pediatrics
2000
Christian Schmorl coins
the term kernicterus
1903
HansenPioneers in the scientific study of neonatal jaundice and kernicterus.Pediatrics
2000
280 neonatal autopsies
120 with jaundice
114 yellow stained brains
6 intense staining of basal ganglia and medulla
oblongata
2 preserved in formaldehyde
HansenPioneers in the scientific study of neonatal jaundice and kernicterus.Pediatrics
2000
Kern= nucleus
Icterus = Jaundice
Illustrations from
Schmorls report
HansenPioneers in the scientific study of neonatal jaundice and kernicterus.Pediatrics
2000
Scotty, beam me up
McDonagh
A Plant Pigment
Strelitzia nicolai
New Scientist, 2010
HEAT SHOCK PROTEIN
Heme
oxygenase
Antioxidant
Burtis, C, Ashwood, E and Bruns, D. Tietzs Textbook of Clinical Chemistry
and Molecular Diagnostics, 4th Edition,
Tyson J Perinatology 2012 September)
Bilirubin might have a protective role in the
progression of type 1 diabetic nephropathy
NishimuraSerum bilirubin concentration is associated with eGFR
and urinary albumin excretion in patients with type 1 diabetes
mellitus. J Diabetes Complications. 2015
ToyaAssociation of serum bilirubin levels with development and
progression of albuminuria, and decline in estimated glomerular
filtration rate in patients with type 2 diabetes mellitusJ Diabetes
Investig 2014
Albumin level
Gestational age
Sepsis
Acidosis
Drugs
Unbound FFA
Bili- alb bindingκ
DIRECT BILIRUBIN
EPIDEMIOLOGY OF NEONATAL
JAUNDICE
e
The Young Infants Clinical Signs Study Group. (2008) Clinical signs that predict severe
illness in children under age 2 months: a multicentre study. Lancet 371
Newborn Jaundice in the USA
No
Jaundice
Jaundice
Severe
Jaundice
Bhutani Johnson,Kernicterus in the 21st century:
frequently asked questions, Journal of
Perinatology (2009)
Bolajoko O. Olusanya Risk Factors for Severe Neonatal Hyperbilirubinemia in Low and Middle-Income Countries: A
Systematic Review and Meta-Analysis PLOS One 2015Centre for Healthy Start Initiative
Kernicterus in Rh Disease
2,8/100000 births
NIGERIAN CONSENSUS STATEMENT ON NEWBORN JAUNDICE
Bolajoko O. Olusanya Risk Factors for Severe Neonatal Hyperbilirubinemia in Low and Middle-Income Countries: A
Systematic Review and Meta-Analysis PLOS One 2015Centre for Healthy Start Initiative
ETF
+PTT
+RhIg
VK Bhutani1 and L Johnson Kernicterus in the 21st century: frequently asked questions J Perinatology.
2009
Johnson, VK Bhutan Clinical report from the Pilot USA Kernicterus Registry (1992 to 2004) J Perinatology 2009
St Elsewhere
Watchko, Oski Pediatrics 1983
AAP 1994
1994
20
2004
A R Horn Neonatal academic hospitals’ consensus guidelines for South African hospitals and primary care facilities 2006
L Johnson VK Bhutani Clinical report from the Pilot USA
Kernicterus Registry (1992 to 2004) J Perinatology 2009
Clinical report from the Pilot USA Kernicterus Registry (1992 to 2004) J perinatology
2009L Johnson1, VK Bhutan
Pilot US Kernicterus registry 19922004
Kernicterus n= 122
25
Hemolysis
No hemolysis
97
Clinical report from the Pilot USA Kernicterus Registry (1992 to 2004) J perinatology L
Johnson1, VK Bhutan
So what about the babies < 35 weeks?
Kernicterus in Preterm Babies
EVIDENCE
AUTOPSY STUDIES
CASE STUDIES IN PREMS
SENSORIMOTOR HEARING
LOSS
CHOREOATHETOID CP
Moll M Are recommended phototherapy thresholds safe enough for(ELBW) infants? Neonatology 2011
Oh W Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight
infantsPediatrics.2003
BILI EFFECT IN PREMS
• Kernicterus in prems at low bili levels- 128-148
mmol/l
• Peak TSB in premature babies associated with
– Death/ disability
– Sensorineural hearing loss
– Low psychomotor development index
Moll M Are recommended phototherapy thresholds safe enough for(ELBW) infants? Neonatology 2011
Oh W Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth
weight infantsPediatrics.2003
↑TSB
↑ Cerebral palsy risk
in
hyperbilirubinaemia
↓Gestational
age
BhutaniBilirubin Neurotoxicity in Preterm Infants: Risk and PreventionJ Clin Neonatol2013
van de Bor. Hyperbilirubinemia in preterm infants and neurodevelopmental outcome at 2 years of age: results of
a national collaborative survey. Pediatrics. 1989
Airede AI. Relation of peak total serum bilirubin concentrations to neurodevelopmental outcome at 2 years of
age in premature African neonates. Ann Trop Paediatr. 1992
PROLEMS WITH PROGNOSTICATING
• Difficult to tease out from other
neurodevelopmental issues with extreme
preterm infants
• Definitely and issue with the late preterm
baby
REFERENCES FOR SLIDES 38-41
Treatment of jaundice in low birthweight infants
M J Maisels, J F Watchko 2003 Moll M, Goelz R, Naegele
T, Wilke M, Poets CF. Are recommended phototherapy thresholds safe
enough for extremely low birth weight (ELBW) infants? A report on 2
ELBW infants with kernicterus despite only moderate
hyperbilirubinemia. Neonatology 2011
Watchko Maisels The enigma of low bilirubin kernicterus in premature
infants: Why does it still occur, and is it preventable? S e m i n ars in p e r
inatology 3 8 (2014)397 – 4 0 6
Watchko Maisels Enduring controversies in the management of
hyperbilirubinemia
in preterm neonates Seminars in Fetal and Neonatal Medicine
Additional risks in preterm baby
Immature liver
Immature GI tract
Later feeding
Enhance
enterohepatic
circulation
J F WatchkoM J MaiselsJaundice in low birthweight infants: pathobiology and outcomeARCH DIS CHILD 2003
Risks of the preterm baby
•
•
•
•
•
•
Sepsis/ chorioamnionitis/ FIRS
Hypoalbuminaemia
Elevated FFA levels
Genetic conditions
Dehydration
Poor feeding
Watchko Maisels The enigma of low bilirubin kernicterus in premature infants: Why does it still occur, and is it
preventable? Seminars in Perinatology 3 8 (2014)397
Shapiro Kernicterus.In:StevensonDK,MaiselsMJ, Watchko JF,eds. Care of the Jaundiced Neonate. NewYork: McGraw
Hill;2012.229–242
The high risk baby
•
•
•
•
•
•
•
pH<7,15
Pressor dependant
Blood culture proven sepsis in last 24 hours
Lower gestational age
Mechanical ventilation at time of sample
Apnoea or bradycardias in prev 24 hours
Rapidly rising TSB
Watchko Maisels The enigma of low bilirubin kernicterus in premature infants:
Why does it still occur, and is it preventable? Seminars in Perinatology 3 8
(2014)397
Bilirubin
encephalopathy
Haemolysis -associated
hyperbilirubinaemia
Non-haemolysis
associated
hyperbilirubinaemia
Kaplan, Hyperbilirubinaemia, hemolysis and increased bilirubin
neurotoxicity, Seminars in Perinatology 2014
PVL
IVH
BILIRUBIN
ENCEPHALOPATHY
Shapiro Kernicterus.In:StevensonDK,MaiselsMJ, Watchko
JF,eds. Care of the Jaundiced Neonate. NewYork: McGraw
Hill;2012.229–242.
Watchko Maisels The enigma of low bilirubin kernicterus in
premature infants: Why does it still occur, and is it
preventable? Seminars in perinatology2014
How does Kernicterus
present in a premature
baby?
Signs may be so
subtle, that they
may be missed
Bilirubin
encephalopathy
premature baby
Abnormal ABER
Abnormal cry
Apnoea
Apnoea
Hyperbilirubinaemia
Especially high
unbound
bilirubin levels
Reversible
auditary
dysfunction
Amin, Apnoea in Acute bilirubin encephalopathy Seminars in
perinatology 2014
So it’s a problem? How do we screen?
Yaser Interscapular site for transcutaneous bilirubin measurement in preterm infants: a better and safer screening site. J
Perinatol. 2014.
Engle Transcutaneous bilirubinometry Seminars in perinatology 2014
Y
N
Bilirubin / albumin ratio
Need more evidence
Iskander I Serum bilirubin and bilirubin/albumin ratio as predictors of bilirubin encephalopathy.
Pediatrics 2014
Hulzebos Dijk van Imhoff The bilirubin albumin ratio in the management of hyperbilirubinemia in preterm infants to improve
neurodevelopmental outcome: a randomized controlled trial--BARTrial.PLoS One.2014
Watchko Maisels The enigma of low bilirubin kernicterus in premature infants: Why does it still occur, and is it preventable? S e m i n
ars in p e r inatology 3 8 (2014)
So what are guidelines for babies < 35
weeks?
bilirubin in micromol/litre =
(gestational age × 10) − 100
At 72 hours
NICE 2010
A R Horn Neonatal academic hospitals’ consensus guidelines for South African hospitals andprimary care facilities
2006
Watchko JF, Maisels MJ. Jaundice in low birthweightinfants: pathobiology and outcome. Arch Dis Child FetalNeonatal
Ed 2003Jon
Watchko Maisels Enduring controversies in the management of hyperbilirubinemiain preterm neonatesSeminars fetal
Neonatal med
UK 28
week
2010
NORWAY
1-1500G
2006
DUTCH 11250 g
2007
SA 28-29+
week
2006
AAP 28+
week
2012
UK 30+
week
2010
DUTCH
12501500 g
2007
NORWAY
1-1500G
2006
SA 30-31+
week
2006
AAP 30+
week
2012
Neonatal Research Network
• 2008
• Conservative vs Aggressive Phototherapy in
ELBW infants
• Phototherapy started at prescribed bilirubin
levels per gestational age
Brenda H. Morris Aggressive vs. Conservative Phototherapy for Infants
with Extremely Low Birth Weight. NEJM 2008
750-1000g
Exchange
Transfusion
255
SA=220
Conservative
171
Aggressive 85
Brenda H. Morris Aggressive vs. Conservative Phototherapy
for Infants with Extremely Low Birth Weight. NEJM
500-750g
Exchange
Transfusion
230
SA= 220
Conservative
120
Aggressive
85
Brenda H. Morris Aggressive vs. Conservative Phototherapy
for Infants with Extremely Low Birth Weight. NEJM
CONCLUSIONS
• Aggressive PTT decreases NDI
• Aggressive PTT increases death esp <750g
• Aggressive phototherapy has no effect on
death / NDI
Brenda H. Morris Aggressive vs. Conservative Phototherapy
for Infants with Extremely Low Birth Weight. NEJM
Lipsitz PJ, Gartner LM, Bryla DA. Neonatal
and infant mortality in relation to
phototherapy. Pediatrics 1985; 75
???? Light may penetrate deeper into
premature tissue because of immature skin
???? Direct oxidative effect of
phototherapy on tissues
???? Potential benefits of bilirubin negated
???? Potential effects of light on other
protective molecules
Watchko Maisels Enduring controversies in the management of hyperbilirubinemiain preterm neonatesSeminars
fetal Neonatal med
When to stop phototherapy?
TSB LEVEL
NICE- 34-51 mmol/l below PTT threshold
SA guidelines – 50 mmol/ l below threshold
AGE AT WHICH TO STOP?
Blood brain barrierPiglet model
Research in humans
Polin, Fetal and Neonatal Physiology Development of the blood brain barrier 2011
Lee, postnatal maturation of the blood brain barrier for unbound bilirubin in newborn piglets. Brain research Aug 1995
Brito The blood brain barrier and bilirubin Archives of medical research Nov 2014
“Our first attempts at phototherapy took place during the
summer of 1971, when MEHK was still well. At this time
it seemed impractical to restrict her activities sufficiently
to permit the prolonged exposure to phototherapy lamps
that would have been necessary for effective treatment(12 or more hours a
Accordingly, a simple compromise
was struck. The patient was sent to the
beach every day for 5 days, and spent 8
hours in the sun in a fashionably small twopiece bathing suit. The plasma bilirubin concentration was
day).
measured every morning on
the way to the beach and every afternoon on the way
home. However, it fell by an average of only 0.5 mg/100
ml during the day and had usually returned to the base line
level by the following morning so that we were not encouraged
to pursue the phototherapy, at least in the form
of heliotherapy”
BERK; JAMES F. MARTIN,Unconjugated Hyperbilirubinemia Physiologic Evaluation and
Experimental Approaches to Therapy Annals of Internal Medicine 82:552-570, 1975
Bilirubin in the adult brain
Bilirubin damage
Intracerebral haemorrhage
Lakovic K Bilirubin and its oxidation products damage brain white matter. J
Cereb Blood Flow Metab.2014 Nov;34(11):1837-47
The Bruised Premature Baby
• ?More prone to hyperbilirubinaemia?
• ? Will benefit from prophylactic
phototherapy?
“Certainly phototherapy, if used appropriately, is
capable of controlling the bilirubin levels in
almost all LBW infants, with the possible
exception of the occasional infant with severe
erythroblastosis fetalis or pronounced bruising”
Maisels WatchkoTreatment of jaundice in low birthweight infants ADC Fet &
Neo 2003
Prophylactic phototherapy
• Cochrane review
- less ETF in older trial with liberal ETF policy
-slightly less risk of neurodevelopmental
impairment in prophylactic group RR 0.85(0.740.99)
-All cause mortality similar between groups
• Possible benefits- but trials required that assess
safety of PTT
Okwundu Cochrane Review: Prophylactic phototherapy for preventing jaundice in
preterm or low birth weight infants Evid Based Child Health 2013
Type of lights
•
•
•
•
Conventional fluorescent tubes
Halogen
LED
Fibre-optic blanket
Mills Fibreoptic phototherapy for neonatal jaundice Cochrane Database Syst Rev 2001
Intravenous Immunoglobulin
in isoimmune hemolytic
disease
A
GUARDE
DYES
AAP 2004/2012
If TSB is rising and within 34-51 mml/l of ETF level
NICE 2010
TSB increase 51mmol/l in 6
hours
Cochrane review 2014
Maisels Watchko
An approach to the management of hyperbilirubinemia in the
preterm infant less than 35 weeks of gestation J Pernatology 2012
Vinod K. Bhutani Bilirubin Neurotoxicity in Preterm Infants: Risk and Prevention. J Clin Neonatol. 2013
Louis Intravenous immunoglobulin in isoimmune haemolytic disease of newborn: an updated systematic review and
meta-analysis. Arch Dis Child Fetal Neonatal Ed.2014
Cochrane review 2014
Rh incompatibility: no benefit shown in studies
with low risk of bias
Rh and ABO incompatibility : benefit shown in
studies with high risk of bias
Albumin infusion
no evidence
problems in prems
increased IV volume
alveolar leak
cardiopulmonary compromise
Bhutani Bilirubin Neurotoxicity in Preterm Infants: Risk and
Prevention J Clin Neonatol. 2013 Apr-Jun; 2(2): 61–69.
Phenobarbital
•
•
•
•
No clinical effect <32 weeks
Ineffective < 12hrs of age
Slow onset of action
Long duration of action- unwanted sedation
will persist
Bhutani Bilirubin Neurotoxicity in Preterm Infants: Risk and
Prevention J Clin Neonatol. 2013 Apr-Jun; 2(2): 61–69.
Future directions
• Tin mesoporphyrin
• Safety trials pending
• Not yet FDA approved
WatchkoTiribelliBilirubin-Induced Neurologic Damage — Mechanisms
and Management ApproachesN Engl J Med 2013
Future directions
• Decrease enterohepatic circulation and β
glucuronidase
Casein supplements
L Aspartic Acid
Watchko Tiribelli ilirubin-Induced Neurologic Damage — Mechanisms and
Management ApproachesN Engl J Med 2013; 369
Future directions
• Minocycline attenuated bilirubin induced
neurotoxicity in Gunn rats
Jon F. Watchko, M.D., and Claudio Tiribelli, M.D., Ph.D.
Bilirubin-Induced Neurologic Damage — Mechanisms and
Management ApproachesN Engl J Med2013
The Anatomy Lesson of Dr
Nichlaes Tulp, Rembrandt
St Elsewhere
• Bhutani:
• “detection of jaundice and measurement of
TSB does not prevent the complications of
kernicterus.
• It is the targeted treatment about which we
are discovering more and more.
• However the panacea still eludes us”
BhutaniBilirubin Neurotoxicity in Preterm Infants: Risk and
PreventionJ Clin Neonatol. 2013
Temper(r)
Preterm
Jaundice?
A conundrum for modern
neonatology
USANA 2017 guest list
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Maisels
Watchko
Bhutani
Johnson
Edit out
What about light intensity?
Hyperbilirubinaemia
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What is hyperbilirubinaemia
Why must we make special considerations in prem
Kernicterus in prems
BIND in prems
Signs in prems that hyperbilirubinaemia is reaching potentially toxic levels
What do we/ don’t we know about hyperbilirubinaemia in prems?
What is the potential benefit of bilirubin?
When must we start phototherapy- what is the evidence base?
Should we start photo prophylactically?
The sick/ septic/haemolysing acidotic/ hypercapnoiec prem and bili level
What are the dangers of phototherapy?
Which phototherapy?- what is intensive, what is single, what is double?
What about conventional photo, what about fibreoptic?
Do we know enough about hyperbilirubinaemia in prems
Measurements in prems
What measurements? TSB/ UCB/ Bili: alb ratio
TcB in prems, what site, in SA TcB in black population
Which nomogram- AAP/NICE/Dutch/ Norway
Use of ABR in prems to determine therapy
Other therapies: metalloporphyrins, phenobarbitone
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