Hyperbili kravitz


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Hyperbili kravitz

  1. 1. Michelle B. Kravitz, MD June 29, 2006 NEONATAL HYPERBILIRUBINEMIA
  2. 2. Case 1 <ul><li>You are called by the nurse that a newborn’s TcB is 11.1. </li></ul><ul><li>Is this concerning? </li></ul><ul><li>What information do you need to answer that question? </li></ul>
  3. 3. Case 2 <ul><li>You are called by the ER to see an infant whose bili is 22. </li></ul><ul><li>Must you admit? </li></ul><ul><li>What information do you need to answer this question? </li></ul>
  4. 4. Outline <ul><li>Review of physiology </li></ul><ul><li>Kernicterus </li></ul><ul><li>Risk factors </li></ul><ul><li>Assessing the risk </li></ul><ul><li>Therapies </li></ul>
  5. 5. BILIRUBIN <ul><li>Non-polar, water insoluble compound requiring conjugation with glucuronic acid to form a water soluble product that can be excreted. </li></ul><ul><li>It circulates to the liver reversibly bound to albumin </li></ul>
  6. 6. BILIRUBIN PHYSIOLOGY <ul><li>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. </li></ul><ul><li>Heme is catabolized within the reticuloendothelial system by heme oxygenase to form biliverdin. </li></ul><ul><li>Biliverdin is metabolized to bilirubin in the presence of biliverdin reductase </li></ul>
  7. 7. BILIRUBIN PHYSIOLOGY Heme Biliverdin Heme oxygenase Bilirubin Biliverdin reductase
  8. 8. Bilirubin Physiology <ul><li>Ligandins responsible for transport from plasma membrane to endoplasmic reticulum. </li></ul><ul><li>Bilirubin conjugated in presence of UDPGT (uridine diphosphate glucuronyl transferase) to mono and diglucoronides, which are then excreted into bile canaliculi. </li></ul>
  9. 9. Enterohepatic Circulation <ul><li>Meconium contains 100-200mg of conjugated bilirubin at birth. </li></ul><ul><li>Conjugated bilirubin is unstable and easily hydrolyzed to unconjugated bilirubin. </li></ul><ul><li>This process occurs non-enzymatically in the duodenum and jejunum and also occurs in the presence of beta-glucuronidase, an enteric mucosal enzyme, which is found in high concentration in newborn infants and in human milk. </li></ul>
  10. 10. Conjugation <ul><li>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 </li></ul><ul><li>After birth, the levels of UDPGT rise rapidly but do not reach adult levels until 4-6 weeks of age. </li></ul><ul><li>Ligandins, which are necessary for intracellular transport of bilirubin, are also low at birth and reach adult levels by 3-5 days. </li></ul>
  11. 11. CONJUGATED VS UNCONJUNCATED HYPERBILI <ul><li>Conjugated hyperbilirubinemia is always pathologic </li></ul><ul><li>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. </li></ul><ul><li>Always check a total and direct, so that you can be sure you are excluding conjugated hyperbilirubinemia, which has totally different etiologies and treatments. </li></ul>
  12. 12. KERNICTERUS <ul><li>Why we care about indirect hyperbilirubinemia </li></ul><ul><li>Staining of the brain by bilirubin </li></ul><ul><li>Early symptoms-acute bilirubin encephalopathy-poor feeding, abnormal cry, hypotonia, </li></ul><ul><li>Intermediate phase-stupor, irritability, hypertonia </li></ul><ul><li>Late – shrill cry, no feeding, opisthotonus, apnea, seizures, coma, death </li></ul>
  13. 13. KERNICTERUS <ul><li>Late sequelae can include </li></ul><ul><li>gaze abnormalities </li></ul><ul><li>feeding difficulties </li></ul><ul><li>dystonia </li></ul><ul><li>incoordination </li></ul><ul><li>choreoathetosis </li></ul><ul><li>sensorineural hearing loss </li></ul><ul><li>painful muscle spasms </li></ul>
  14. 14. KERNICTERUS <ul><li>Incidence of bilirubin levels>30 1/10,000 </li></ul><ul><li>Over 120 cases kernicterus documented since 1990 </li></ul><ul><li>Overwhelming majority term, breastfed </li></ul><ul><li>Majority of those had levels in high 30s to 40s. </li></ul><ul><li>Lowest level recorded in case series of 111 from 1991-2002 was 20.7, but the mean was 38. </li></ul><ul><li>Many cases had no planned follow up and had been discharged early (<48 hours). </li></ul>
  15. 16. KERNICTERUS AND FREE BILIRUBIN <ul><li>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. </li></ul><ul><li>Since bilirubin travels bound to albumin predominantly, the free bilirubin is inversely proportional to the albumin concentration. </li></ul>
  16. 17. ALBUMIN <ul><li>A low albumin level could possibly be the reason behind kernicterus occurring in some infants at relatively low bilirubin levels. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul>
  17. 18. ALBUMIN <ul><li>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. </li></ul><ul><li>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. </li></ul>
  18. 19. RISK FACTORS FOR SIGNIFICANT JAUNDICE <ul><li>Gestational Age </li></ul><ul><li>Race </li></ul><ul><li>Family history of jaundice requiring phototherapy </li></ul><ul><li>Hemolysis (ABO or other) </li></ul><ul><li>Severe bruising </li></ul><ul><li>Breastfeeding </li></ul>
  19. 20. TIME COURSE OF JAUNDICE <ul><li>Pathologic by definition if significant in first 24 hours </li></ul><ul><li>Usually begins to peak by 48 hours and continues until 96 hours </li></ul><ul><li>In Asian infants and preterm infants, peak can continue out to 5-7 days. </li></ul>
  20. 21. RISK FACTORS-RACE <ul><li>Asians-highest risk </li></ul><ul><li>Levels peak at 16-18 as opposed to average Caucasian levels of 6-8. There is also a later peak which can occur at 5-7 days. </li></ul><ul><li>Black infants have a lower peak, rarely exceeding 12. (but they have a much higher incidence of G6PD deficiency) </li></ul><ul><li>Caucasians are in the middle. </li></ul>
  21. 23. RISK FACTORS-GESTATIONAL AGE <ul><li>The younger the gestation, the higher the risk of jaundice. </li></ul><ul><li>37 weeks more prone to jaundice than 40 weeker who is more prone than a 42 weeker. </li></ul><ul><li>35 and below is much more prone </li></ul><ul><li>Extreme preemies also more prone to kernicterus and are treated at much lower levels. </li></ul>
  22. 24. RISK FACTORS-FAMILY HX <ul><li>A child whose sibling needed phototherapy is 12 times more likely to also have significant jaundice. </li></ul><ul><li>Frequently peak bilirubin levels correlate between siblings. </li></ul>
  23. 25. RISK FACTORS-HEMOLYSIS <ul><li>ABO Incompatibility is the most common cause of hemolysis causing jaundice. </li></ul><ul><li>Only 10-20% of infants with ABO mismatch develop significant jaundice. </li></ul><ul><li>Some of these infants, however, develop very significant jaundice quickly. </li></ul><ul><li>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. </li></ul>
  24. 26. RISK FACTORS-PATHOLOGIC <ul><li>G6PD Deficiency </li></ul><ul><li>Hereditary Spherocytosis </li></ul><ul><li>Glucuronyl Transferase Deficiency Type 1 (Crigler Najar Syndrome) </li></ul><ul><li>GT deficiency Type 2 (Arias Syndrome) </li></ul><ul><li>Polycythemia </li></ul>
  25. 27. BREASTMILK/BREASTFEEDING JAUNDICE <ul><li>Breastfeeding jaundice occurs early </li></ul><ul><li>It is due to the lack of breast milk </li></ul><ul><li>It is often associated with poor passage of meconium. </li></ul><ul><li>Treatment should be aimed at supporting breastfeeding while supplementing as needed to avoid extreme weight loss, dehydration, and worsening jaundice. </li></ul>
  26. 28. BREASTMILK/BREASTFEEDING JAUNDICE <ul><li>Breast milk jaundice is a different, more benign entity, which tends to occur late in the first week or afterwards. </li></ul><ul><li>It is actually due to something in the breast milk which tends to prolong jaundice. </li></ul><ul><li>Usually weight gain is good, and the baby is otherwise well. </li></ul><ul><li>Jaundice might persist as late as 3-4 weeks, but usually will peak by 2 weeks. </li></ul><ul><li>Textbook treatment is to interrupt breastfeeding (I usually do not do this). </li></ul>
  27. 29. ASSESSING THE RISK OF JAUNDICE BY THE NUMBERS <ul><li>Bhutani curve </li></ul>
  28. 31. ASSESSING THE RISK OF JAUNDICE BY THE NUMBERS <ul><li>Maisels’ and Kring’s study showed that not all early higher TcB will continue going up. </li></ul><ul><li>They divided the rate of rise to be concerned with into </li></ul><ul><li>6-24hr >0.22/hr </li></ul><ul><li>24-48 >0.15/hr </li></ul><ul><li>48+ >0.06/hr </li></ul>
  29. 32. Copyright ©2004 American Academy of Pediatrics Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation
  30. 33. ASSESSING THE RISK OF JAUNDICE BY THE NUMBERS <ul><li>www.bilitool.org </li></ul><ul><li>Palm downloadable!  </li></ul>
  31. 34. THERAPIES-PHOTOTHERAPY <ul><li>Phototherapy has been the mainstay of treating hyperbilirubinemia since the 1960s. </li></ul><ul><li>Phototherapy causes structural isomerization, forming lumirubin, which is then excreted in the bile and urine. </li></ul><ul><li>Since photoisomers are water soluble, they should not be able to cross the blood-brain barrier, so starting phototherapy should decrease the risk of kernicterus by turning 20-25% of bilirubin into a form unable to cross, even before the level has lowered significantly. </li></ul>
  32. 35. THERAPIES-PHOTOTHERAPY <ul><li>Bilirubin absorbs light best at 450 nm, but longer wavelenths penetrate skin better. </li></ul><ul><li>Make sure skin is as exposed as possible and that light is not too far from baby. </li></ul><ul><li>Fiberoptic light (bili blanket) is much less efficacious on its own. </li></ul>
  33. 36. THERAPIES-EXCHANGE TRANSFUSION <ul><li>Double volume exchange transfusion was a common procedure prior to advent of Rhogam and phototherapy. </li></ul><ul><li>Now fortunately a rare occurrence </li></ul><ul><li>Used for bilirubin >25 in a term infant and not decreasing despite phototherapy </li></ul>
  34. 37. THERAPIES-Sn Mesoporphyrin <ul><li>SnMP is a structural analog of heme </li></ul><ul><li>It blocks the site on heme oxygenase where conversion of heme to bilirubin occurs. </li></ul><ul><li>Still under investigation (why?) </li></ul><ul><li>Administered parenterally in a small dose (6 micromoles/kg) </li></ul><ul><li>In term infants, obviated need for phototherapy </li></ul><ul><li>Some preterm infants still needed phototherapy but none needed exchange transfusion </li></ul><ul><li>Virtually 100% efficacy </li></ul>
  35. 38. THERAPIES-Sn Mesoporphyrin <ul><li>Can also be used repeatedly for patients with Crigler-Najar (effects last several days). </li></ul><ul><li>Stanate ® -currently being patented </li></ul><ul><li>Ongoing study at Children’s Hospital of Columbus in newborns at risk of exchange transfusion </li></ul><ul><li>Accepting patients until September, 2006 </li></ul><ul><li>Richard McCleod, MD, Principal Investigator </li></ul><ul><li>614-722-2718 </li></ul>
  36. 39. Review of Case 1 <ul><li>How old is the patient? </li></ul><ul><li>What is the gestational age? </li></ul><ul><li>What other risk factors are present? </li></ul><ul><ul><li>12 hours old </li></ul></ul><ul><ul><li>Full term </li></ul></ul><ul><ul><li>ABO incompatible </li></ul></ul>
  37. 40. Review of Case 2 <ul><li>How old is the patient? </li></ul><ul><li>What is the fractionation? </li></ul><ul><li>Breast or bottle fed? </li></ul><ul><li>Other risk factors? </li></ul><ul><ul><li>10 days </li></ul></ul><ul><ul><li>22 total / 0.8 direct </li></ul></ul><ul><ul><li>Breast fed </li></ul></ul><ul><ul><li>None </li></ul></ul>
  38. 41. MANAGING JAUNDICE-TAKE HOME POINTS <ul><li>Consider the risk factors, particularly prematurity and hemolysis </li></ul><ul><li>Follow up is key! </li></ul><ul><li>Consider how well baby is feeding, parents’ ability to return, reliability, etc </li></ul><ul><li>The higher the number of risk factors, the lower the level at which to intervene </li></ul><ul><li>Sometimes, you will be surprised. We can’t always prevent hyperbilirubinemia, but we should always prevent kernicterus. </li></ul>
  39. 43. REFERENCES <ul><li>Tate, M, Neonatal Hyperbilirubinemia, Revised, June 2001 in MICC Curriculum. </li></ul><ul><li>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. </li></ul><ul><li>Wennberg et. al., Toward understanding kernicterus: a challenge to improve the management of jaundiced newborns. Pediatrics. 2006, 117(2):474-485. </li></ul>
  40. 44. <ul><li>Watchko JF, Vigintophobia revisited. Pediatrics , 2005, 115(6):1747-53. </li></ul><ul><li>Gourley GR et. al., A controlled, randomized, double blind trial of prophylaxis against jaundice among breastfed newborns. Pediatrics , 2005, 116(2):385-91. </li></ul><ul><li>Merhar 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. </li></ul>
  41. 45. <ul><li>M Herschel et. al., Isoimmunization is unlikely to be the cause of hemolysis in ABO-incompatible but direct antiglobulin test-negative neonates. Pediatrics. 2002, 110(1):127-30. </li></ul><ul><li>LD Eggert et. al., The effect of instituting a prehospital-discharge newborn bilirubin screening program in an 18-hospital health system. Pediatrics. 2006, 117(5):e855-62. </li></ul>
  42. 46. <ul><li>A Kappas, A method for interdicting the development of severe jaundice in newborns by inhibiting the production of bilirubin. Pediatrics . 2004, 113(1)119-23. </li></ul><ul><li>D Alexander, Commentary on “A method for interdicting the development of severe jaundice in newborns by inhibiting the production of bilirubin. Pediatrics. 113(1):135. </li></ul>
  43. 47. <ul><li>J Grupp-Phelan et. Al., Early newborn hospital discharge and readmission for mild and severe jaundice. Arch Pediatr Adolesc Med.  1999;153:1283-1288. </li></ul><ul><li>P Goevaert et. al. Changes in globus pallidus with pre(term) kernicterus. Pediatrics. 2003, 112 (6): 1256-1263. </li></ul><ul><li>S Ip et. al. An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics. 2004, 114(1):e130-153. </li></ul>
  44. 48. <ul><li>T WR Hansen, Neonatal Jaundice. eMedicine.com/ped/topic1061.htm, updated June 8, 2006. </li></ul>