Hyperbilirubinemia and Effective Phototherapy Treatment Judy Moore MSc. MCGI. ANNP April 2014 Ekaterinburg, Russia. 1 PN 013352A Learning Objectives • • • • • • • • 2 Understand the physiology of bilirubin production Differentiate between physiologic and pathologic hyperbilirubinemia Describe risk factors associated with hyperbilirubinemia Understand the prevalence and danger of severe hyperbilirubinemia (kernicterus) Identify assessment techniques for monitoring hyperbilirubinemia Describe key elements of the 2004 AAP Clinical Practice Guideline for the Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation Identify prevention strategies Discuss LED Phototherapy options and benefits PN 013352Ab Basic Facts • • • • • • • 3 Each year, approximately 60 – 70% of term and near-term infants will become visibly jaundiced (TSB will be > 5-7 mg/dl or 85-120 micrommols/L)) Bilirubin generally peaks in 3-5 days of life Usually benign, self-limiting, and usually resolves on its own by the end of the first week of life Usually requires no treatment HOWEVER… 8 – 10% will go on to develop hyperbilirubinemia requiring some type of intervention One of the leading causes for hospital readmission during the first two weeks of life One of the major reasons for prolonged hospitalization in an otherwise healthy term newborn http://pediatry.0catch.com/pediatrypart1/id28 .htm PN 013352A Bilirubin Production http://anabolicminds.com/forum/steroids/125767-trauma1s-basic-interpretation.html 4 PN 013352A Bilirubin Transport and Conjugation • • • 5 Unconjucated Bilirubin Unconjugated (indirect) bilirubin is fat-soluble and is transported in the circulation tightly bound to albumin Unconjugated bilirubin can move into tissue and is seen as jaundice Unconjugated bilirubin can also cross the blood-brain barrier and cause neuronal injury PN 013352A Albumin Binding • • • • • • • • 6 Unconjugated bilirubin is transported to the liver bound to albumin Bilirubin that is not bound, is referred to as free bilirubin CAPACITY: the number of binding sites available on the albumin molecule AFFINITY: the tightness with which the bilirubin is bound to the available sites. Other substances can compete for binding sites Hypothermia and acidosis may interfere with albumin binding Free fatty acids may compete for sites such as those found in lipid solutions Hypothermia may also increase free fatty acid production http://flipper.diff.org/app/items/379 PN 013352A Bilirubin Transport and Conjugation • • • 7 Conjugated Bilirubin Once in the liver, bilirubin is conjugated by the enzyme uridine diphosphoglucuronosyl transferase (UDP-GT) Conjugation also requires glucose and oxygen Conjugated (direct) bilirubin is water-soluble and non-toxic PN 013352A Bilirubin Excretion • • Once conjugated in the liver, bilirubin is released into the bile duct and delivered to the intestinal tract for elimination (mostly in the stool) Conjugated bilirubin is unstable and can be easily converted back to it’s unconjugated form which can lead to increased enterohepatic uptake via: − − − − 8 Spontaneous unconjugation ß-glucuronidase (10 times greater concentration in newborns) Decreased intestinal motility Delayed passage of meconium/delayed stooling PN 013352A Physiologic Jaundice versus Pathologic Jaundice Why is this baby yellow? 9 PN 013352A HYPERBILIRUBINEMIA • Common in Term and Preterm infants http://www.ohmybaby.com.au/Jaundice.php 10 PN 013352A Physiologic Jaundice: Factors to Consider • • Fetal red blood cells have a lifespan of 80-90 days (120 days in adults) Norman newborns produce ~6-12 mg/dl/day of bilirubin − • • • • • 11 twice that of adults Infants have limited hepatic bilirubin clearance capability Infants also have immature enzyme systems Ineffective feeding/breastfeeding can lead to dehydration Decreased gut motility -> delayed elimination -> increased enterohepatic circulation http://www.youtube.com/watch?v=iBSTk5M6i7c …and the process begins again PN 013352A Pathologic Jaundice: Factors to Consider • • Jaundice that appears in the first 24-36 hour usually results from an underlying disease process Increased Production − • Decreased Elimination − • 12 Rh, ABO Incompatibility, G6PD deficiency, septicemia, extravascular blood (cephalhematoma), polycythemia Bowel obstruction, Crigler Najjar, Lucey Driscoll, medications/intralipids, hypothyroidism, hypopituitarism, hypoalbuminemia Combinations of Both PN 013352A The Final Factor… Urban Myth…or Truth? • • • • • All babies get jaundiced, what’s the big deal. If the baby looks yellow, … tell Mom to put her in the sun… Just give the baby some water, that will help with elimination… and the bilirubin will go down… Tell the parents if the baby’s eyes become yellow to call the Pediatrician… Have the baby’s follow-up scheduled for 2 weeks… The jaundice didn’t start until the 4th day…he’ll be fine, no need to worry… http://www.zipheal.com/gestational-diabetes/gestational-diabetes-complications/4299 A general lack of concern… 13 PN 013352A When Does Hyperbilirubinemia Become A Concern? • Regardless of whether the hyperbilirubinemia is caused by physiologic or pathologic factors: − − − 14 When plasma bilirubin levels exceed the binding sites on albumin, free unconjugated bilirubin binds to the phospholipids on the plasma membrane of the neuron, saturating the membrane A major site of neuronal injury is in the basal ganglia and the brainstem nuclei Acute bilirubin encephalopathy (ABE) and kernicterus are terms used to define neurological damage associated with severe or extreme hyperbilirubinemia PN 013352A When Does Bilirubin Cross the Blood Brain Barrier? • Extreme hyperbilirubinemia refers to a TSB greater than 25 mg/dl / 425 Micromoles/L and generally requires intensive phototherapy and/or exchange transfusion − − • 15 Double volume exchange transfusions remove ~85% of the RBC’s, however since most of the bilirubin is extravascular, only ~25% of the total bilirubin is removed Overall mortality from exchange transfusion is: 3:1,000 Are there milder forms of brain injury at high levels of bilirubin that are not identified as Kernicterus? PN 013352A Clinical Progression of ABE 16 Clinical Evaluation Non-specific, Subtle Changes Progressive Toxicity Advanced Toxicity Mental Status Sleepy + Poor Feed Lethargy + Irritability Semi-Coma Seizures Muscle Tone Slight Decrease Hyper or Hypotonia Depending on arousal state Mild Nuchal/Trunc al arching Markedly Increased or Decreased Opisthotonus Bicycling Cry Hi Pitched Shrill Inconsolable PN 013352A Clinical Progression of ABE - cont’d • • Death from acute kernicterus(ABE) is usually from respiratory failure and progressive coma, or intractable seizures Chronic, irreversible bilirubin encephalopathy, may include: − − − − 17 Extrapyramidal movement disorders (dystonia and athetosis) Gaze abnormalities (usually upward gaze) Auditory disturbances (especially sensory/neural hearing loss with central processing disorders or auditory neuropathy) Enamel dysplasia of the deciduous teeth http://shockerdaily.com/2013/07/26/11-year-old-girl-in-a-wheelchair-turned-awayfrom-a-museum-because-her-wheels-would-ruin-the-carpet/ PN 013352A Factors Contributing to the Re-Emergence of Kernicterus • • • • • 18 Early hospital discharge – shorter hospital stays without early or adequate follow-up (bilirubin peaks on 3rd – 5th day of life…when do most babies go home?) Lack of recognition and concern Bilirubin screening considered an extra healthcare cost (…the healthcare cost for each child with chronic kernicterus is ~$25 million) Over-reliance on visual assessment to detect hyperbilirubinemia Clinicians not following the AAP Guidelines for Jaundice Management http://www.lookfordiagnosis.com/mesh_info.php?term=Kernicterus&lang=2 PN 013352A Assessment Techniques • Visual Assessment (Cephalocaudal Progression) − Most widely used method – not reliable/not accurate http://www.nursestopic.com/2011/07/hemolytic-jaundice.html 19 PN 013352A Assessment Techniques • Total Serum Bilirubin Level (TSB) − • Transcutaneous Bilirubin Measurement (TcB) − − 20 Interpretation based on infant’s age in hours Non-invasive – more accurate than visual assessment Facilitates home and clinic follow-up PN 013352A Assessment Techniques • Risk Factor Assessment − − − − − − − − Jaundice in the first 24 hours of life Visible jaundice before discharge Previously jaundiced sibling Gestational age < 38 weeks East Asian Race Bruising, cephalhematoma (as seen with LGA/IDM infants) Exclusive breast feeding Male sex http://www.pediatricsconsultant360.com/lumps-bumps-cause-concern http://newborns.stanford.edu/PhotoGallery/Bruising2.html 21 PN 013352A Breast Feeding and Jaundice Two forms: Early onset and Late onset • Early onset is usually seen 2-4 days postnatally • Thought to be related to feeding practices and occasionally under hydration • Breast fed infants take longer to produce gut flora • Late onset occurs 4-7 days after birth • Thought to be due to attributes of breast milk • Levels gradually decrease to normal value by 3-12 weeks • Occurs in 1:100 – 200 breast fed infants. Breast milk contains Beta-Glucuronidase which further increases hepatic shunting One of the most effective interventions is early initiation of feeding Frequent feeding to stimulate gastric motility and reduce shunting. http://www.theboobgroup.com/tag/supplementation/ 22 PN 013352A American Academy of Pediatrics • Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation - July 2004 1. 2. 3. 4. 5. 23 Promote and support successful breastfeeding Establish nursery protocols for the identification and evaluation of hyperbilirubinemia Measure the TSB or TcB on infants jaundiced in the first 24 hours Recognize that visual estimation of the degree of jaundice can lead to errors, particularly in darkly pigmented infants Interpret all bilirubin levels according to the infant’s age in hours¹ PN 013352A Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation - July 2004 - continued 6. Recognize that infants at less than 38 weeks’ gestation, particularly those who are breastfed, are at higher risk of developing hyperbilirubinemia and require closer surveillance and monitoring 7. Perform a systematic assessment on all infants before discharge for the risk of severe hyperbilirubinemia 8. Provide parents with written and verbal information about newborn jaundice 9. Provide appropriate follow-up based on the time of discharge and risk assessment 10. Treat newborns, when indicated, with phototherapy or exchange transfusion¹ 24 PN 013352A JCAHO • Sentinel Event Alert – July, 2004 − Revised Guidance to Help Prevent Kernicterus • • • • • 25 Follow AAP Guidelines Assess all babies for risk prior to discharge Newborn follow-up scheduled within three to five days of age when the bilirubin level is highest Educated parents regarding newborn jaundice Support breastfeeding with education (feed 8-12 times/day)² PN 013352A AAP Clinical Practice Guideline and Phototherapy • “All nurseries and services treating infants should have the necessary equipment to provide intensive phototherapy.” − • 26 “Intensive Phototherapy implies the use of high levels of irradiance in the 430 to 490 nm band (usually 30 µW/cm²/nm or higher) delivered to as much of the infant’s surface area as possible.” “Because the devices available for home phototherapy may not provide the same degree of irradiance or surface-area exposure as those available in the hospital, home phototherapy should be used only in infants whose bilirubin levels are in the “optional phototherapy” range; it is not appropriate for infants with higher bilirubin concentrations.”¹ PN 013352A An approach to the management of hyperbilirubinaemia in the preterm infant less than 35 weeks gestation: Recommendations: • Increase irradiance by bringing lamp closer to baby • Increase surface area coverage by placing light source underneath infant • Use the radiometer recommended by the manufacturer • In infants <1000g, start PT at lower irradiance levels – additional PT should be provided by increasing surface area exposed. • Halogen and Tungsten lamps should be avoided as they cannot be placed closer to the infant 27 Journal of Perinatology (2012) 32, 660–664 PN 013352A Early Readmission of Newborns in a Large Healthcare System  35.3% of admissions were for jaundice treatment  90% of infants admitted for jaundice are within first 7 days of life  Average cost of $4500 per admission  From the perspectives of parents, physicians, and payers, an unplanned, unexpected readmission within a few weeks after discharge of an ostensibly healthy Newborn from a WBN is an undesirable event. This Demonstrates: • Need for Phototherapy in ER and Paediatric units • Need for community based phototherapy programmes Phototherapy is NOT just for the NICU http://pediatrics.aappublications.org/content/early/2013/04/03/peds.2012-2634 28 PN 013352A Are we meeting the Standards of Care? • • • • • 29 Is jaundice routinely assessed and documented as a vital sign in my hospital? Are risk factors for jaundice routinely assessed? Do nurses/bedside caregivers have the ability to order a TSB or TcB when visual jaundice is noted? Are TSB/TcB results interpreted based on the infant’s age in hours? Is there a procedure in place to notify Healthcare Professionals of results? http://pediatrics.aappublications.org/content/114/1/297/F2.full PN 013352A Are We Meeting the Standards of Care? • • • • • 30 Are infants discharged before 72 hours of age seen for followup within 24 to 48 hours? Is there an evidence based protocol for treatment and followup in place? Does my hospital or community setting have the necessary therapeutic equipment available to provide intensive phototherapy and monitor progress? Are parents educated about jaundice beginning with pre-natal classes, during hospitalization, and with written materials upon discharge? Are we following the AAP Clinical Practice Guidelines? PN 013352A Parent Education - What is Jaundice? • • • • • • 31 What is jaundice? How will I know if my baby has jaundice? Can jaundice hurt my baby? How is jaundice treated? Is my baby in pain during phototherapy? Why are my baby’s eyes covered? PN 013352A Clinical Role of Phototherapy • • • • 32 Standard of care for the treatment of neonatal hyperbilirubinemia Accepted technology, widely used in the hospital and in the home Considered a relatively benign therapy Eyes are covered to protect the retina PN 013352A Factors Affecting Efficacy of Phototherapy • Intensity – Brightness of the light − − • Spectrum (wavelength) – Color of the light − − • 33 Measured in units of µW/cm2/nm Varies inversely with distance from the patient Measured in units of nanometers Peak bilirubin absorption at 458 nm Treatment Area – Surface area of the baby’s body being treated PN 013352A AAP Guidelines - July 2004 • “Intensive phototherapy implies the use of high levels of irradiance in the 430-to 490-nm band (usually 30 µW/cm2/nm or higher) delivered to as much of the infant’s surface area as possible. • The most effective light sources currently commercially available for phototherapy are those that use special blue fluorescent tubes7 or a specially designed light-emitting diode light (Natus Inc, San Carlos, CA).” AMERICAN ACADEMY OF PEDIATRICS CLINICAL PRACTICE GUIDELINE 2004 Subcommittee on Hyperbilirubinemia Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation 34 PN 013352A Intensity Light Intensity vs Distance (1) 80 70 Intensity 60 50 40 30 20 10 0 0 20 40 60 80 Inches • Inverse relationship between intensity and distance As distance increases ↑, intensity decreases ↓ • Halogen spotlights emit heat • cannot be placed close to the baby without incurring the risk of burns or insensible water loss • The neoBLUE does not emit significant heat and can be placed closer to the baby, resulting in higher intensity 35 PN 013352A Spectrum AAP Guidelines recommend the use of light in the blue-green spectrum Blue light most closely corresponds to the peak absorption wavelength at which bilirubin is broken down 36 PN 013352A Spectrum – White Lights • • • 37 White light includes many colors across many wavelengths The color BLUE spans over 450-475 nm BLUE light does not contain – infrared (IR) light - heat – ultraviolet (UV) light – skin damage – Decreasing the potential for insensible water loss and skin damage PN 013352A Surface Area AAP Guidelines cite IEC 60601-2-50 (’00) standards for phototherapy relating to uniform treatment area: Define Effective Treatment Area  Even distribution of light as defined by 40% intensity ratio Note: “Light Emitted Area” is not the same as “Effective Treatment Area” 38 PN 013352A Why are blue LEDs the best technology? • Emits a narrow band of blue light, considered to be the most effective in the degradation of bilirubin – Narrow-band spectral emission peak around 450-470 nm (blue spectrum) – Clinically, this could mean shorter treatment times and/or a more rapid reduction in bilirubin levels • Does not radiate heat (IR) and UV light – Minimizes potential risk of insensible fluid loss and skin damage during routine use – Light can be positioned close to the baby • Operating Life is considerably longer – Saves time and money of frequent bulb replacements 39 PN 013352A Review TEWL Study • The Effect of Light Emitting Diode (LED) Phototherapy on Transepidermal Water Loss (TEWL) in Premature and Term Infants − • Conclusion: LED phototherapy does not increase TEWL in premature and term infants − 40 Carolyn H. Lund, Joanne M. Kuller, David J. Durand, Gay Gayle and Arthur E. D’Harlingue. Intensive Care Nursery, Children’s Hospital and Research Center of Oakland, Oakland, CA This suggests there is no need to increase fluid intake during the first weeks of life when using blue LED phototherapy lights. PN 013352A Hyperbilirubinemia Clinical Scenarios 41 PN 013352A Case #1: • • • • • 42 Full term baby girl born at 40 weeks to G1P0 mother BW 3200 g; Apgars 9,9 Pregnancy and delivery without complications Currently DOL #2 (48hrs of life) Nurses noted that she looks like this and call you to the Well-Baby Nursery to evaluate her: Case #1: • What else would you want to know? − − − − − − − 43 How is she feeding? How is it going? Is she stooling and voiding? How often? What is her current weight? How is she doing otherwise? Does she have any risk factors? Has she had her TcB checked? Has she had blood bilirubin levels checked? Case #1: • • • • • • 44 Her mother is breastfeeding her. She thinks it is going well but this is her first baby and she is not sure if her milk is in yet. She is feeding for 20 minutes every 4 hours. Voided urine once and stooled several times since birth. Current weight is 2850 g (about 11% less than BW). She seems less active and is sleeping more today. No known risk factors. Mother and baby are both B positive. Total/direct bilirubin is 18/1 mg/dL. Case #1: • What is your working diagnosis? – BREASTFEEDING JAUNDICE 45 Case #1: • What would you do next? − − − − 46 Initiate phototherapy Monitor serial bilirubin levels Encourage increased frequency of feedings (q 2-3h ATC) and consider supplementation prn Request lactation consult Bhutani Curve: Phototherapy Indication Case #2: • • • • • 47 Late pre-term baby boy born at 35 weeks BW 2500g; Apgars 8,9 Pregnancy and delivery without complications Currently DOL #1 (12 h of life) Nurses noted that he looks like this and called you into Room 1 to evaluate him: Case #2: • What else would you want to know? − − − − − − − 48 How is he feeding? How is it going? Is he stooling and voiding? How often? What is his current weight? How is he doing otherwise? Does he have any risk factors? Has he had his TcB checked? Has he had blood bilirubin levels checked? Case #2: • • • • • • • 49 He is taking preterm formula 2 ounces / 6oml q 2-3 hours. Voided twice and stooled several times since birth. Current weight is 2500 g (same as BW). He is less active and sleeping more today. Mother is O positive and baby is A positive. Total/direct bilirubin is 18.1 mg/dL. Coombs positive. Case #2: • What is your working diagnosis? – ABO INCOMPATIBILITY 50 Case #2: • What would you do next? – Intensive Phototherapy – enhance surface area coverage – Exchange transfusion Bhutani Curve: Phototherapy Indication Exchange Transfusion Indication 51 Case #3: • • • • • 52 Pre-term baby boy born at 28 weeks Currently DOL 21 BW 900 g; Apgars 5,8 Noted to have scleral icterus Bilirubin levels 7.2/3.4 mg/dL Case #3: • What else would you want to know? – Does he have any risk factors? – How has he been acting clinically? – Has he been receiving TPN? Any enteral feeds? – Has he had any signs of infection? – Does he have any syndromic features? – What were his newborn screen results? 53 Case #3: • No known risk factors. • He has been acting well without infectious symptoms. • He had NEC on DOL #4 and has an ostomy and mucous fistula. He has been on TPN since then. • No features concerning for syndromes. • Newborn screening results were normal. 54 Case #3: • What is your working diagnosis? – TPN-ASSOCIATED CHOLESTASIS 55 Case #3: • What would you do next? – Try to advance enteral feeds and reduce TPN as soon as clinically possible – Monitor bilirubin levels with LFTs every 2 weeks – Consider further work-up if bilirubin levels do not improve over time once off TPN 56 Matching the Product to the Need • • • 57 Where is the product being used? − NICU with or without incubator or warmer − Mom’s room or home − Well baby nursery − Emergency room What is the use case? − In bassinet or in mom’s arms What is the urgency of treatment? − Full surface area coverage vs. spot − “Double” Phototherapy PN 013352A neoBLUE® LED Phototherapy Products neoBLUE mini neoBLUE cozy LED Phototherapy System neoBLUE Radiometer LED Phototherapy System neoBLUE LED Phototherapy System 58 neoBLUE blanket LED Phototherapy System PN 013352A Summary • • • • • • • • Understand the physiology of bilirubin production Differentiate between physiologic and pathologic hyperbilirubinemia Describe risk factors associated with hyperbilirubinemia Understand the prevalence and danger of severe hyperbilirubinemia (kernicterus) Identify assessment techniques for monitoring hyperbilirubinemia Describe key elements of the 2004 AAP Clinical Practice Guideline for the Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation Identify prevention strategies Discuss LED Phototherapy options and benefits Natus Medical Incorporated 1501 Industrial Road San Carlos, CA 94070 USA 1-800-303-0306 +1-650-802-0400 www.natus.com 59 PN 013352A References/Further Reading: • • • • • • 60 Yale-NHH NBSCU Guidelines: “Indications for phototherapy and exchange transfusion” Lange: “Neonatology: Management, Procedures, On-Call Problems, Diseases and Drugs” Fanaroff and Martin chapters on hyperbilirubinemia Keren R et al. Visual assessment of jaundice in term and late preterm infants. Arch Dis Child Fetal Neonatal Ed. 2009 Sep;94(5):F317- 22. Epub 2009 Mar 22. Mishra S et al. Transcutaneous bilirubinometry reduces the need for blood sampling in neonates with visible jaundice. Acta Paediatr. 2009 Dec;98(12):1916-9. Epub 2009 Oct 7. All images found on google images