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Hyperbili_Kravitz - Michelle B Kravitz MD Michelle Case 1...

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Unformatted text preview: Michelle B. Kravitz, MD Michelle June 29, 2006 Case 1 Case You are called by the nurse that a You newborn’s TcB is 11.1. newborn’s Is this concerning? What information do you need to answer What that question? that Case 2 Case You are called by the ER to see an infant You whose bili is 22. whose Must you admit? What information do you need to answer What this question? this Outline Outline Review of physiology Kernicterus Risk factors Assessing the risk Therapies BILIRUBIN BILIRUBIN Non-polar, water insoluble compound Non-polar, requiring conjugation with glucuronic acid to form a water soluble product that can be excreted. excreted. It circulates to the liver reversibly bound It to albumin to BILIRUBIN PHYSIOLOGY BILIRUBIN Increased production in neonate due to larger red Increased cell volume, which produces bilirubin as cells are broken down and shorter RBC life span, so broken down faster. broken Heme is catabolized within the Heme reticuloendothelial system by heme oxygenase to form biliverdin. form Biliverdin is metabolized to bilirubin in the Biliverdin presence of biliverdin reductase presence BILIRUBIN PHYSIOLOGY BILIRUBIN PHYSIOLOGY Heme Heme oxygenase Biliverdin Biliverdin reductase Bilirubin Bilirubin Physiology Bilirubin Ligandins responsible for transport from Ligandins plasma membrane to endoplasmic reticulum. reticulum. Bilirubin conjugated in presence of Bilirubin UDPGT (uridine diphosphate glucuronyl transferase) to mono and diglucoronides, which are then excreted into bile canaliculi. canaliculi. Enterohepatic Circulation Enterohepatic Meconium contains 100-200mg of conjugated Meconium bilirubin at birth. bilirubin Conjugated bilirubin is unstable and easily Conjugated hydrolyzed to unconjugated bilirubin. hydrolyzed This process occurs non-enzymatically in the This 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. milk. Conjugation Conjugation Since conjugated bilirubin crosses the placenta Since very little, conjugation is not active in the fetus with levels of UDPGT about 1% of adult levels at 30 - 40 weeks gestation at After birth, the levels of UDPGT rise rapidly but After do not reach adult levels until 4-6 weeks of age. do Ligandins, which are necessary for intracellular Ligandins, transport of bilirubin, are also low at birth and reach adult levels by 3-5 days. reach CONJUGATED VS UNCONJUNCATED HYPERBILI HYPERBILI Conjugated hyperbilirubinemia is always Conjugated pathologic pathologic When the total bili is quite high, the conjugated When fraction can rise to as high as 20% of the total, although it usually stays under 1.0. although Always check a total and direct, so that you can Always be sure you are excluding conjugated hyperbilirubinemia, which has totally different etiologies and treatments. etiologies KERNICTERUS KERNICTERUS Why we care about indirect hyperbilirubinemia Staining of the brain by bilirubin Early symptoms-acute bilirubin encephalopathypoor feeding, abnormal cry, hypotonia, poor Intermediate phase-stupor, irritability, hypertonia Late – shrill cry, no feeding, opisthotonus, Late apnea, seizures, coma, death apnea, KERNICTERUS KERNICTERUS Late sequelae can include gaze abnormalities feeding difficulties dystonia incoordination choreoathetosis sensorineural hearing loss painful muscle spasms KERNICTERUS KERNICTERUS Incidence of bilirubin levels>30 1/10,000 Over 120 cases kernicterus documented since Over 1990 1990 Overwhelming majority term, breastfed Majority of those had levels in high 30s to 40s. Lowest level recorded in case series of 111 from Lowest 1991-2002 was 20.7, but the mean was 38. 1991-2002 Many cases had no planned follow up and had Many been discharged early (<48 hours). been KERNICTERUS AND FREE BILIRUBIN BILIRUBIN An article published this year in Pediatrics An Pediatrics makes the case for establishing free bilirubin levels rather than total serum bilirubin levels to monitor jaundice and assess risk for kernicterus. monitor Since bilirubin travels bound to albumin Since predominantly, the free bilirubin is inversely proportional to the albumin concentration. proportional ALBUMIN ALBUMIN A low albumin level could possibly be the low reason behind kernicterus occurring in some infants at relatively low bilirubin levels. infants There was a report of a 29 week infant whose There peak bilirubin level was only 15.7 and yet developed classic kernicterus with spasticity, dystonia, ballismus, and gaze abnormalities. dystonia, Her bilirubin/albumin molar ratio was 0.67. It Her has been suggested that a ratio of >0.5 might be a threshold in sick preterm infants. threshold ALBUMIN ALBUMIN Wenneberg et. al. suggest that an infant with an Wenneberg 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. with We do not have data on albumin levels in We healthy term infants, but most likely, hypoalbuminemia is a concern in extremely preterm or otherwise sick infants. preterm RISK FACTORS FOR SIGNIFICANT JAUNDICE SIGNIFICANT Gestational Age Race Family history of jaundice requiring Family phototherapy phototherapy Hemolysis (ABO or other) Severe bruising Breastfeeding TIME COURSE OF JAUNDICE JAUNDICE Pathologic by definition if significant Pathologic in first 24 hours in Usually begins to peak by 48 hours Usually and continues until 96 hours and In Asian infants and preterm infants, In peak can continue out to 5-7 days. peak RISK FACTORS-RACE RISK Asians-highest risk 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. peak Black infants have a lower peak, rarely Black exceeding 12. (but they have a much higher incidence of G6PD deficiency) incidence Caucasians are in the middle. RISK FACTORSRISK GESTATIONAL AGE The younger the gestation, the higher the The risk of jaundice. risk 37 weeks more prone to jaundice than 40 37 weeker who is more prone than a 42 weeker. weeker. 35 and below is much more prone Extreme preemies also more prone to Extreme kernicterus and are treated at much lower levels. levels. RISK FACTORS-FAMILY HX HX A child whose sibling needed child phototherapy is 12 times more likely to also have significant jaundice. also Frequently peak bilirubin levels correlate Frequently between siblings. between RISK FACTORSRISK HEMOLYSIS ABO Incompatibility is the most common cause of ABO hemolysis causing jaundice. hemolysis Only 10-20% of infants with ABO mismatch develop Only significant jaundice. significant Some of these infants, however, develop very Some significant jaundice quickly. significant Coombs positive ABO is more likely to cause Coombs hemolysis, but many babies will be asymptomatic. Conversely, Coombs negative ABO mismatch does occasionally cause significant hemolysis, but this is rather rare. rather RISK FACTORSRISK PATHOLOGIC G6PD Deficiency Hereditary Spherocytosis Glucuronyl Transferase Deficiency Type 1 Glucuronyl (Crigler Najar Syndrome) (Crigler GT deficiency Type 2 (Arias Syndrome) Polycythemia BREASTMILK/BREASTFEEDING BREASTMILK/BREASTFEEDING JAUNDICE JAUNDICE Breastfeeding jaundice occurs early It is due to the lack of breast milk It is often associated with poor passage of It meconium. meconium. Treatment should be aimed at supporting Treatment breastfeeding while supplementing as needed to avoid extreme weight loss, dehydration, and worsening jaundice. dehydration, BREASTMILK/BREASTFEEDING JAUNDICE JAUNDICE Breast milk jaundice is a different, more benign entity, Breast which tends to occur late in the first week or afterwards. which It is actually due to something in the breast milk which It tends to prolong jaundice. tends Usually weight gain is good, and the baby is otherwise Usually well. well. Jaundice might persist as late as 3-4 weeks, but usually Jaundice will peak by 2 weeks. will Textbook treatment is to interrupt breastfeeding (I Textbook usually do not do this). usually ASSESSING THE RISK OF JAUNDICE BY THE NUMBERS JAUNDICE Bhutani curve ASSESSING THE RISK OF JAUNDICE BY THE NUMBERS JAUNDICE Maisels’ and Kring’s study showed that Maisels’ not all early higher TcB will continue going up. going They divided the rate of rise to be They concerned with into 6-24hr >0.22/hr 24-48 >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 JAUNDICE www.bilitool.org Palm downloadable! Palm THERAPIESTHERAPIESPHOTOTHERAPY Phototherapy has been the mainstay of treating Phototherapy hyperbilirubinemia since the 1960s. hyperbilirubinemia Phototherapy causes structural isomerization, Phototherapy forming lumirubin, which is then excreted in the bile and urine. bile Since photoisomers are water soluble, they Since 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. the THERAPIESTHERAPIESPHOTOTHERAPY Bilirubin absorbs light best at 450 nm, but Bilirubin longer wavelenths penetrate skin better. longer Make sure skin is as exposed as possible Make and that light is not too far from baby. and Fiberoptic light (bili blanket) is much less Fiberoptic efficacious on its own. THERAPIES-EXCHANGE TRANSFUSION TRANSFUSION Double volume exchange transfusion was Double a common procedure prior to advent of Rhogam and phototherapy. Rhogam Now fortunately a rare occurrence Used for bilirubin >25 in a term infant and Used not decreasing despite phototherapy not THERAPIES-Sn Mesoporphyrin Mesoporphyrin SnMP is a structural analog of heme It blocks the site on heme oxygenase where It conversion of heme to bilirubin occurs. conversion Still under investigation (why?) Administered parenterally in a small dose (6 Administered micromoles/kg) micromoles/kg) In term infants, obviated need for phototherapy Some preterm infants still needed phototherapy Some but none needed exchange transfusion but Virtually 100% efficacy THERAPIES-Sn Mesoporphyrin Mesoporphyrin Can also be used repeatedly for patients with Can Crigler-Najar (effects last several days). Crigler-Najar Stanate®-currently being patented Ongoing study at Children’s Hospital of Ongoing Columbus in newborns at risk of exchange transfusion transfusion Accepting patients until September, 2006 Richard McCleod, MD, Principal Investigator 614-722-2718 Review of Case 1 Review 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 Review 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 JAUNDICEMANAGING TAKE HOME POINTS Consider the risk factors, particularly Consider prematurity and hemolysis prematurity Follow up is key! Consider how well baby is feeding, parents’ Consider ability to return, reliability, etc ability The higher the number of risk factors, the lower The the level at which to intervene the Sometimes, you will be surprised. We can’t Sometimes, always prevent hyperbilirubinemia, but we should always prevent kernicterus. should REFERENCES REFERENCES Tate, M, Neonatal Hyperbilirubinemia, Revised, Tate, June 2001 in MICC Curriculum. Maisels MJ and E Kring, Transcutaneous Maisels bilirubin levels in the first 96 hours in a normal newborn population of >/= 35 weeks’ gestation. Pediatrics. 2006, 117(4):1169-73. Pediatrics. Wennberg et. al., Toward understanding Wennberg kernicterus: a challenge to improve the management of jaundiced newborns. Pediatrics. 2006, 117(2):474-485. 2006, Watchko JF, Vigintophobia revisited. Pediatrics, 2005, Watchko Pediatrics 2005, 115(6):1747-53. 115(6):1747-53. Gourley GR et. al., A controlled, randomized, double Gourley blind trial of prophylaxis against jaundice among breastfed newborns. Pediatrics, 2005, 116(2):385-91. Pediatrics Merhar SL and DL Gilbert, Clinical Findings and Merhar 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. Pediatrics, M Herschel et. al., Isoimmunization is unlikely Herschel to be the cause of hemolysis in ABOto incompatible but direct antiglobulin test-negative incompatible neonates. Pediatrics. 2002, 110(1):127-30. Pediatrics. LD Eggert et. al., The effect of instituting a LD prehospital-discharge newborn bilirubin screening program in an 18-hospital health system. Pediatrics. 2006, 117(5):e855-62. 2006, A Kappas, A method for interdicting the Kappas, development of severe jaundice in newborns by inhibiting the production of bilirubin. Pediatrics. Pediatrics 2004, 113(1)119-23. 2004, D Alexander, Commentary on “A method for Alexander, interdicting the development of severe jaundice in newborns by inhibiting the production of bilirubin. Pediatrics. 113(1):135. Pediatrics. J Grupp-Phelan et. Al., Early newborn hospital Grupp-Phelan discharge and readmission for mild and severe jaundice. Arch Pediatr Adolesc Med. 1999;153:1283-1288. Med. P Goevaert et. al. Changes in globus pallidus Goevaert with pre(term) kernicterus. Pediatrics. 2003, 112 (6): 1256-1263. (6): S Ip et. al. An evidence-based review of Ip important issues concerning neonatal hyperbilirubinemia. Pediatrics. 2004, Pediatrics. 114(1):e130-153. 114(1):e130-153. T WR Hansen, Neonatal Jaundice. WR eMedicine.com/ped/topic1061.htm, updated June 8, 2006. updated ...
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