approach to hyperbilirubinemia in preterm · the american ^approach aap committee on fetus and...
TRANSCRIPT
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Head, Dept of NeonatologyJubilee Mission Medical College
Thrissur, Kerala
DR V C MANOJ
Approach to Hyperbilirubinemia in Preterm
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Approach to Hyperbilirubinemia in Preterm
Dr V C Manoj
Head, Dept of Neonatology
Jubilee Mission Medical College
Thrissur, Kerala
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Bhutani and Wong: Bilirubin neurotoxicity in premies, Journal of Clinical Neonatology 2013
Extubated from ventilator support by day 14
Discharged subsequently
11 mg/dL
Neurologic examination: signs of
kernicterus
MRI: Increased signals in the globus
pallidus and signs of periventricular
leukomalacia.
ABR: SN hearing impairment
‘Low Bilirubin Kernicterus’
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Preterm Jaundice –When is bilirubin level safe?
The problem:80% of preterm babies in the first week of life !
10 and 12 mg/ dl on D – 5
May not reach normal levels until the end of the first month
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Why in preterms?
Erythrocyte, hepatic and gastrointestinal immaturity• Large amount of short-lived red blood cells,
• Deficient hepatic conjugation of bilirubin
• Increase in enterohepatic circulation of bilirubin
Delayed enteral nutrition –• restrict intestinal blood flow and enhance the enterohepatic
reuptake
Blood extravasation –• extensive hematomas in upper and lower limbs due to birth
trauma or by IVH
Risk factors for penetration of bilirubin into the brain:Hypoxemia, Acidosis, Hypothermia,Hypoalbuminemia,Hypercapnia, ….
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Some basic hard facts !
• Presence of early-onset of jaundice (age <24 hrs) - a medical emergency
• TSB levels at 24-60 hrs predicts severe hyperbilirubinemia and need for PT
• PT reduces the need and/or use of exchange transfusion
• Both PT and exchange transfusion can individually prevent kernicterus
• The persistence of jaundice beyond age 2 wks warrants further inquiry.
• Detection of jaundice or measurement of TSB has not been shown to prevent kernicterus in any randomized control trial !!
(This kind of a study cannot be done ethically and should not be done)
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The ultimate Weapon?
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When should you treat?
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Prophylactic or Therapeutic?
95 babies < 1500 g
Prophylactic PT (from 12 hrs) Vs Therapeutic PT (when TSB < 8.8 mg/dl)
87 survivors – neurological behaviour followed up
82 up to 12 m and
75 up to 18 m (of corrected gestational age)
Cerebral palsy and death were more frequent in the therapeutic PT group.
The authors conclusion: lower bilirubin levels - associated with a better prognosis
Jangaard, et al, Pediatr Res. 2004
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• 9 clinical trials - 3449 infants
• “Phototherapy initiated soon after birth (within 36 hours) for preterm or low birth weight infants may prevent the serum bilirubin from reaching a level that would require exchange transfusion and may reduce the risk of impairment of brain and central nervous system development”
• However, further well- designed studies are needed to evaluate the effects of prophylactic phototherapy on brain and central nervous system development and other long-term outcomes.
2013
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Should you be Aggressive?
Bilirubin – One of the antioxidants for the immune deficient preterm with under developed scavenger systems
So why not be gentle on jaundice?
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1974 ELBW babies randomly assigned to -- aggressive or conservative phototherapy at 12 to 36 hrs of age.
Primary outcome: composite of death or neurodevelopmental impairment (Determined by investigators who were unaware of the treatment assignments)
Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental
impairment.
But it did significantly reduce the rate of neurodevelopmental impairment alone.
This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth.
?
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1974 ELBW babies randomly assigned to -- aggressive or conservative phototherapy at 12 to 36 hrs of age.
Primary outcome: composite of death or neurodevelopmental impairment (Determined by investigators who were unaware of the treatment assignments)
Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental
impairment.
But it did significantly reduce the rate of neurodevelopmental impairment alone.
This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth.
?
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Modest Elevations in TSB is associated with Neurodevelopmental Impairment(Recent studies of large populations of ELBW infants) Mazeiras G, et al,. PLoS ONE 2012
Oh W, Tyson JE, Fanaroff AA, et al, Pediatrics 2003
Moderate hyperbilirubinemia in
LBW infants poses no risk of neurotoxicity. O’Shea TM, Dillard RG, et al, Pediatrics 1992
Yeo KL, Perlman M, et al,. Pediatrics 1998;.
Keenan WJ, et al. Pediatrics 1972
Lipsitz PJ, et al, Pediatrics 1985
Govaert P, et al, Pediatrics 2003
Moll M, et al, Neonatology 2011
Sugama S, et al, Pediatr Neurol
2001Mazeiras G, et al, PLoS ONE 2012
‘Low Bilirubin Kernicterus’
Low bilirubin levels may be associated with a better
prognosis in VLBW newborns
Jangaard A, et al, Pediatr Res. 2004
Number needed to harm: 10638 In Downs syndrome - 1285.
(5144849 infants born ≥35 wks POG in California hospitals --1998 – 2007)
Pediatrics, 2016
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Why should we be aggressive?
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Phototherapy in newborns, according to this review, may increase the odds of developing any cancer by 1.3 times, the odds of leukemia in general by 1.7 times, the odds of myelocytic leukemia by 2.9 times and the odds of kidney cancer by 2.5 times.
Number of studies: 10
Study design: 5 case control and 5 cohort
Total no. of children: 6637417
Five countries: Sweden , USA, UK ,Canada and Taiwan.
A SYSTEMATIC REVIEW AND META-ANALYSIS By Dr Mohammed Abdellatif
BEWARE !!!
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What are the Guidelines available?
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Comparison of TSB thresholds for the use of phototherapy in preterm infants
Guidelines (in the Management of Preterm Hyperbilirubinemia)
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The NICE guidelines
Recommendations for < 23 or POG
TSB based PT thresholds formula:
PT threshold bilirubin (μmol/L) = (gestational age × 10) − 100
Separate nomograms - for infants from 23 to 37 wks POG
The thresholds rise from 40 μmol/L at birth to a plateau TSB level after 72 hours.
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The American “Approach”
AAP Committee on Fetus and Newborn (2007) tasked a group of experts to develop guidelines for the Mgt of jaundice <35 weeks POG
High level of evidence in preterm infants is lacking, - The recommendations of Maisels et al. did not meet AAP requirements for guidelines (2012)
Hence called “approach”
TSB treatment thresholds are lower when compared to the NICE guideline, especially for infants of lower GA
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TSB treatment thresholds are lower when compared to the NICE guideline, especially for infants of lower GA
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Maisels MJ, Watchko JF, Bhutani VK, et al, J Perinatol 2012
Suggested use of phototherapy and exchange transfusion in preterm infants < 35 weeks GA
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Norwegian guidelines: Treatment - based on bilirubin levels and birth weight. (Postnatal age is also factored)
Following the introduction of these guidelines, fewer babies in Norway receive PT, and no cases of chronic kernicterus have been reported during this period.
Message
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Another Parameter: Bilirubin/Albumin (B/A) ratio
• High bilirubin/albumin (B/A) ratios increase the risk of bilirubin neurotoxicity.
• Is B/A ratio a valuable measure, in addition to the total serum bilirubin (TSB), in the management of hyperbilirubinemia?
Bilirubin Albumin Ratio (BAR) Trial
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The Bilirubin Albumin Ratio in the Management of Hyperbilirubinemia in Preterm Infants to Improve Neurodevelopmental Outcome:
A Randomized Controlled Trial – BAR Trial (Netherlands)
615 preterm infants < 32 weeks' gestation or less: Randomly assigned to treatment based on either B/A ratio and TSB thresholds (consensus-based), whichever threshold was crossed first, or on the TSB thresholds only.
The primary outcome: Neurodevelopment at 18 to 24 months' corrected age (Bayley Scales of ID III)
The additional use of B/A ratio in the management of hyperbilirubinemia in preterm infants did not improve their neurodevelopmental outcome.
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…. Apps in the Age of Smart Medicine !
Created to provide clinical decision support for treatment of indirect hyperbilirubinemia
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• Preterms (27 wks 0 days - 34 wks 6 days)
• PBR serves to operationalize the Maisels 2012 Approach
• As phototherapy and exchange transfusion thresholds are lower at early postnatal age, the tool is intended for use in infants greater than 48 hours of age only.
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14
28 6
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so finally………..
Newborn infants should have their bilirubin levels screened and assessment of risk factors done prior to hospital discharge
and again within 48 to 72 hours after discharge. (Maisels et al., 2012)
Systematic screening guidelines have been found to significantly decrease the incidence of kernicterus (Christensen et al., 2012).
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…… the final word ?
“There is no level, there probably never was a level, nor will there be a level” of bilirubin to exclude the disease.
Lucey 1982
Lucey JF. Bilirubin and brain damage: a real mess. Pediatrics. 1982;69:381-2.
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