Michelle B.

Kravitz, MD June 29, 2006

Case 1


 

You are called by the nurse that a newborns TcB is 11.1. Is this concerning? What information do you need to answer that question?

Case 2


 

You are called by the ER to see an infant whose bili is 22. Must you admit? What information do you need to answer this question?

Outline
    

Review of physiology Kernicterus Risk factors Assessing the risk Therapies

BILIRUBIN


NonNon-polar, water insoluble compound requiring conjugation with glucuronic acid to form a water soluble product that can be excreted. It circulates to the liver reversibly bound to albumin

BILIRUBIN PHYSIOLOGY


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 form biliverdin. Biliverdin is metabolized to bilirubin in the presence of biliverdin reductase

BILIRUBIN PHYSIOLOGY
Heme Heme oxygenase Biliverdin

Biliverdin reductase

Bilirubin

Bilirubin Physiology


Ligandins responsible for transport from plasma membrane to endoplasmic reticulum. Bilirubin conjugated in presence of UDPGT (uridine diphosphate glucuronyl transferase) to mono and diglucoronides, which are then excreted into bile canaliculi.

Enterohepatic Circulation
  

Meconium contains 100-200mg of conjugated 100bilirubin at birth. Conjugated bilirubin is unstable and easily hydrolyzed to unconjugated bilirubin. This process occurs non-enzymatically in the nonduodenum and jejunum and also occurs in the presence of beta-glucuronidase, an enteric betamucosal enzyme, which is found in high concentration in newborn infants and in human milk.

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. 4Ligandins, which are necessary for intracellular transport of bilirubin, are also low at birth and reach adult levels by 3-5 days. 3-

CONJUGATED VS UNCONJUNCATED HYPERBILI

 

Conjugated hyperbilirubinemia is always pathologic 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 encephalopathysymptomsencephalopathypoor feeding, abnormal cry, hypotonia, Intermediate phase-stupor, irritability, hypertonia phaseLate shrill cry, no feeding, opisthotonus, apnea, seizures, coma, death

KERNICTERUS


Late sequelae can include gaze abnormalities feeding difficulties dystonia incoordination choreoathetosis sensorineural hearing loss painful muscle spasms

KERNICTERUS
     

Incidence of bilirubin levels>30 1/10,000 Over 120 cases kernicterus documented since 1990 Overwhelming majority term, breastfed Majority of those had levels in high 30s to 40s. Lowest level recorded in case series of 111 from 19911991-2002 was 20.7, but the mean was 38. Many cases had no planned follow up and had been discharged early (<48 hours).

KERNICTERUS AND FREE BILIRUBIN



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.

RISK FACTORS FOR SIGNIFICANT JAUNDICE

Gestational Age  Race  Family history of jaundice requiring phototherapy  Hemolysis (ABO or other)  Severe bruising  Breastfeeding


TIME COURSE OF JAUNDICE

Pathologic by definition if significant in first 24 hours  Usually begins to peak by 48 hours and continues until 96 hours  In Asian infants and preterm infants, peak can continue out to 5-7 days. 5

RISK FACTORS-RACE FACTORS

AsiansAsians-highest risk Levels peak at 16-18 as opposed to average 16Caucasian levels of 6-8. There is also a later 6peak which can occur at 5-7 days. 5Black infants have a lower peak, rarely exceeding 12. (but they have a much higher incidence of G6PD deficiency) Caucasians are in the middle.

RISK FACTORSFACTORSGESTATIONAL 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 weeker. 35 and below is much more prone Extreme preemies also more prone to kernicterus and are treated at much lower levels.

RISK FACTORS-FAMILY FACTORSHX



A child whose sibling needed phototherapy is 12 times more likely to also have significant jaundice. Frequently peak bilirubin levels correlate between siblings.

RISK FACTORSFACTORSHEMOLYSIS
   

ABO Incompatibility is the most common cause of hemolysis causing jaundice. Only 10-20% of infants with ABO mismatch develop 10significant jaundice. 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 rare.

RISK FACTORSFACTORSPATHOLOGIC
  

 

G6PD Deficiency Hereditary Spherocytosis Glucuronyl Transferase Deficiency Type 1 (Crigler Najar Syndrome) GT deficiency Type 2 (Arias Syndrome) Polycythemia

BREASTMILK/BREASTFEEDING

JAUNDICE
  

Breastfeeding jaundice occurs early It is due to the lack of breast milk It is often associated with poor passage of meconium. Treatment should be aimed at supporting breastfeeding while supplementing as needed to avoid extreme weight loss, dehydration, and worsening jaundice.

BREASTMILK/BREASTFEEDING

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 well. Jaundice might persist as late as 3-4 weeks, but usually 3will peak by 2 weeks. Textbook treatment is to interrupt breastfeeding (I usually do not do this).

ASSESSING THE RISK OF JAUNDICE BY THE NUMBERS

Bhutani

curve

ASSESSING THE RISK OF JAUNDICE BY THE NUMBERS



   

Maisels and Krings study showed that not all early higher TcB will continue going up. They divided the rate of rise to be concerned with into 6-24hr >0.22/hr 2424-48 >0.15/hr 48+ >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

www.bilitool.org


Palm downloadable!

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 bloodbarrier, so starting phototherapy should decrease the risk of kernicterus by turning 20-25% of 20bilirubin into a form unable to cross, even before the level has lowered significantly.

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 THERAPIESTRANSFUSION


 

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

THERAPIES-Sn THERAPIESMesoporphyrin
      

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 micromoles/kg) In term infants, obviated need for phototherapy Some preterm infants still needed phototherapy but none needed exchange transfusion Virtually 100% efficacy

THERAPIES-Sn THERAPIESMesoporphyrin
  

  

Can also be used repeatedly for patients with CriglerCrigler-Najar (effects last several days). Stanate-currently being patented Ongoing study at Childrens Hospital of Columbus in newborns at risk of exchange transfusion Accepting patients until September, 2006 Richard McCleod, MD, Principal Investigator 614-722614-722-2718

Review of Case 1
  

How old is the patient? What is the gestational age? What other risk factors are present?
12 hours old Full term ABO incompatible

Review of Case 2
   

How old is the patient? What is the fractionation? Breast or bottle fed? Other risk factors?
10 days 22 total / 0.8 direct Breast fed None

MANAGING JAUNDICEJAUNDICETAKE HOME POINTS



Consider the risk factors, particularly prematurity and hemolysis

 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 cant 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. 117(4):1169Wennberg et. al., Toward understanding kernicterus: a challenge to improve the management of jaundiced newborns. Pediatrics. 2006, 117(2):474-485. 117(2):474-

 

Watchko JF, Vigintophobia revisited. Pediatrics, 2005, Pediatrics, 115(6):1747115(6):1747-53. Gourley GR et. al., A controlled, randomized, double blind trial of prophylaxis against jaundice among breastfed newborns. Pediatrics, 2005, 116(2):385-91. Pediatrics, 116(2):385Merhar 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. 116(5):1226-

M Herschel et. al., Isoimmunization is unlikely to be the cause of hemolysis in ABOABOincompatible but direct antiglobulin test-negative testneonates. Pediatrics. 2002, 110(1):127-30. 110(1):127LD Eggert et. al., The effect of instituting a prehospitalprehospital-discharge newborn bilirubin screening program in an 18-hospital health 18system. Pediatrics. 2006, 117(5):e855-62. 117(5):e855-

A Kappas, A method for interdicting the development of severe jaundice in newborns by inhibiting the production of bilirubin. Pediatrics. Pediatrics. 2004, 113(1)119-23. 113(1)119D Alexander, Commentary on A method for interdicting the development of severe jaundice in newborns by inhibiting the production of bilirubin. Pediatrics. 113(1):135.

J Grupp-Phelan et. Al., Early newborn hospital Gruppdischarge and readmission for mild and severe jaundice. Arch Pediatr Adolesc Med. 1999;153:1283-1288. 1999;153:1283P Goevaert et. al. Changes in globus pallidus with pre(term) kernicterus. Pediatrics. 2003, 112 (6): 1256-1263. 1256S Ip et. al. An evidence-based review of evidenceimportant issues concerning neonatal hyperbilirubinemia. Pediatrics. 2004, 114(1):e130114(1):e130-153.

T WR Hansen, Neonatal Jaundice. eMedicine.com/ped/topic1061.htm, updated June 8, 2006.