Download
1 / 57
E N D
Bilirubin metabolism RBCs in newborn has the life span of 70-90 days compared with 120 days in adult. Hemoglobin is degraded to heme and globin after breakdown of RBCs in reticuloendothelial system. Heme is converted to biliverdin by heme oxygenase. biliverdin is converted to bilirubin by biliverdin reductase. Bilirubin is attached to albumin and is transferred to hepatic cells from sinusoids. Bilirubin is then conjugated to monoglucuronide and diglucuronidewhich are water solubleand can be excreted via renal and biliary systems.Approximately 25% of excreted bilirubin is deconjugated and reabsorbed by enterohepatic circulation, 10% is excreted in stool and the remaining part is converted to urobilinogen.
Four stages of bilirubin metabolism 1-transport 2-hepatic uptake 3-conjugation 4-excretion. in neonates uptake and conjugation are the more restrictive steps.
Different forms of bilirubin in serum Bilirubin exists in four different forms in serum: 1-unconjugated bilirubin 2-free bilirubin 3-conjugated bilirubin 4-δ bilirubin
Physiologic hyperbilirubinemia 1-never begins in the first 24 h 2-maximum bilirubin level of 12mg/dl in terms and 10-14 in preterms 3-returns to normal after 10 days in terms and 10-14 days in preterms 4- maximum rising rate is 5mg/dl/day 5-direct level is not more than 1mg/dl
Neonatal hyperbilirubinemia Term neonates: peaklevel of 5-6mg/dl in white and African American babies and 10-14mg/dl in Asian American babies between 72 and 120hr of age. Preterm neonates: peak level of 10-12mg/dl by the fifth day of life. Postterm neonates: nearlyall post mature neonates and approximately half of SGA term neonates may be expected to have little or no physiologic jaundice, with peak total serum bilirubin concentrations of less than 2.5mg/dl.
Nonphysiologic jaundice STB concentrations have been defined as nonphysiologic if the concentration exceeds 5 mg/ dL on the first day of life in a term neonate, 10 mg/ dL on the second day, or 12 to 13 mg/ dL thereafter, based on data from the national Collaborative Perinatal Project (Hardy et ai,1979).
Causes of unconjugated hyperbilirubinemia Isoimmune hemolytic disease (ABO- Rh incompatibility between mother and fetus). Erythrocyte enzymatic defects (G6PD & PK deficiency). Erythrocyte structural defects (spherocytosis, elliptocytosis, pyknocytosis). Infection Concealed hemorrhage Gillbert syndrome Crigler-Najjar syndrome type1&2 Transient familial neonatal hyperbilirubinemia (Lucey- Driscoll syndrome). Pyloric stenosis Hypothyroidism Breast feeding jaundice Breast milk jaundice
ABO & Rh incompatibility Mother O Infant A – B – AB Mother Rh negative Infant Rh positive
Lucey - Driscoll syndrome A rare disorder in which every neonate of certain mothers may be expected to develop severe unconjugated hyperbilirubinemia during the first 48 hrs of life with TSB concentration of usually 20 mg/dl or greater. Cause: high concentration of UGT inhibitor in maternal and neonatal serum
Pyloric stenosis three causes of hyperbilirubinemia are: 1- decrease UGT activity 2-decreased caloric supplement 3-enhanced enterohepatic circulation
Hypothyroidism UGT activity in congenital hypothyroidism is deficient and may remain suboptimal for weeks or months. Treatment with thyroid hormone promptly alleviates the hyperbilirubinemia.
Breast milk jaundice Significant elevationin unconjugated bilirubin develops inan estimated 2% of breast-fed term infants after the 7th day oflife, with maximal concentrations as high as 10-30 mg/dLreached during the 2nd-3rd week. If breast-feeding is continued,the bilirubin gradually decreases but may persist for 3-10 wk atlower levels. If nursing is discontinued, the serum bilirubin levelfalls rapidly, reaching normal levels within a few days. Withresumption of breast-feeding, bilirubin levels seldom return topreviously high levels. Phototherapy may be of benefit. Although uncommon, kernicterus can occur in patientswith breast-milk jaundice. The etiology of breast-milk jaundiceis not entirely clear, but may be attributed to the presence of glucuronidasein some breast milk.
Breast feeding jaundice occurs in the 1st week of life, inbreast-fed infants who normally have higher bilirubin levelsthan formula-fed infants. Hyperbilirubinemia(>12 mg/dL) develops in 13% of breast-fed infants in the 1st wkof life and may be due to decreased milk intake with dehydrationand/or reduced caloric intake. Giving supplements of glucosewater to breast-fed infants is associated with higher bilirubin levels, in part because of reduced intake of the higher caloricdensity of breast milk. Frequent breast-feeding (>10/24 hr),rooming-in with night feeding, discouraging 5% dextrose orwater supplementation, and ongoing lactation support mayreduce the incidence of early breast-feeding jaundice.
First day jaundice Neonatal jaundice in first 24hr of life is due to ABO or Rh incompatibility until proved otherwise.
Diagnostic work up Regardless of gestationor time of appearance of jaundice, patients with significanthyperbilirubinemia require acomplete diagnostic evaluation, which includes: 1-CBC+ reticulocyte count+ peripheral blood smear 2- blood group of mother and neonate 3- direct coombs test 4- G6PD
Hemolytic jaundice 1-reticulocytosis 2-smear with evidence of RBC destruction 3-drop in hemoglobin 4- direct coombs positive 5- mother/neonate blood group incompatibility 6-G6PD deficiency 7- daily increment > 5mg/dl
Visual estimation of jaundice Bilirubin is at least 5 mg/dl if the sclera and face is yellow. Chest yellow: about 10mg/dl Umbilicus: about 15mg/dl Knee: about 20mg/dl Ankle: about 25mg/dl Sole: more than 25mg/dl
Phototherapy & exchange level Exchange level may be estimated according to the premature infant chart or chart for premature infants more than 35wk. Phototherapy is started at 75% of the exchange level. Phototherapy is discontinued at 50% of the exchange level.
phototherapy guidline GA> 35wk Phototherapy guideline
Suggested Maximal Indirect Serum BilirubinConcentrations (mg/ dL) in Preterm Infants
Sequelae of unconjugated hyperbilirubinemia • Transient encephalopathy: early bilirubin toxicity is transient and reversible. this is suggested by clinical observations of increasing lethargy with rising TSB concentrations, which reverses after exchange transfusion. • Kernicterus: in term neonates several phases have been classically described. Phase1 is marked by poor sucking, hypotonia and depressed sensorium. Phase 2: fever, retrocollis and hypertonia that may progress to frank opisthotonus. Phase 3: hypertonia becomes less pronounced, but high pitched cry, hearing and visual abnormalities, poor feeding and athetosis are manifest.Seizures may also occur. The usual time course for progression of disease is approximately 24 hours. Long term survivors often demonstrate choreoathetoid cerebral palsy, upward gaze palsy, sensorineural hearing loss, and less often mental retardation and dental dysplasia during later infancy and childhood.
KERNICTERUS Kernicterus, or bilirubin encephalopathy, is a neurologic syndrome resulting from the deposition of unconjugated (indirect)bilirubin in the basal ganglia and brainstem nuclei.
KERNICTERUS The pathogenesisof kernicterus is multifactorial and involves an interactionbetween unconjugated bilirubin levels, albumin binding andunbound bilirubin levels, passage across the blood-brain barrier,and neuronal susceptibility to injury.
KERNICTERUS level of indirect bilirubin, duration ofexposure to elevated levels, the cause of jaundice, and the infant'swell-being.
KERNICTERUS The precise blood level above which indirect-reacting bilirubinor free bilirubin will be toxic for an individual infant is unpredictable,but kernicterus is rare in healthy term infants and in theabsence of hemolysis if the serum level is <25 mg/dL.
KERNICTERUS The risk in infantswith hemolytic disease is directly related to serum bilirubin levels. The duration of exposure needed to produce toxic effects isunknown.
NCIDENCEAND PROGNOSIS By pathologic criteria, Kernicteruswill develop in 1/3of infants (all gestational ages) with untreatedhemolytic disease and bilirubin levels >25-30 mg/dL. Reliable estimates of the frequency of the clinical syndrome are not available because of the wide spectrum of manifestations.
NCIDENCEAND PROGNOSIS Overt neurologic signs have a grave prognosis; Morethan 75% of such infants die, and 80% of affected survivors havebilateral choreoathetosis with involuntary muscle spasms. Mentalretardation, deafness, and spastic quadriplegia are common.
Factors affecting the risk of kernicterus Hypoproteinemia Drugs competing for binding to albumin Acidosis Increased free fatty acid levels Hypoglycemia Hypothermia Asphyxia Infection Prematurity Hyperosmolality IVH
Factors affecting the risk of kernicterus Delay in passage of meconium, which contains 1 mg bilirubin/dL, may contribute to jaundice by enterohepatic circulation after deconjugation by intestinal glucuronidase. Oxytocin Phenolic detergents Polycythemia IDM
Phototherapy three independent mechanisms have been proposed to explain the action of phototherapy in reducing serum bilirubin concentrations in neonates. Geometric photoisomerization Intramolecular cyclization Oxidation
Standard phototherapy -intensive phototherapy lamps are normally positioned within 40cm or in cases of intensive phototherapy within 15-20cm of the patient. The patient should be on an open warmer or in a crib as opposed to an incubator. A prolonged on-off schedule may not be as effective as continuous therapy , but an on-off cycle of less than 1hour is apparently as effective as continuous treatment. Complications: 1- retinal degeneration 2-increase in body and environmental temperature 3-loose stool 4-bronze baby syndrome 5-hypocalcemia 6-DNA damage 7-risk of PDA in VLBW.
Efficacy The use of phototherapy has decreased the need for exchangetransfusion in term and preterm infants with hemolytic and nonhemolyticjaundice. When indications for exchange transfusionare present, phototherapy should not be used as a substitute; however, phototherapy may reduce the need for repeatedexchange transfusions in infants with hemolysis.
The therapeutic effect of phototherapy depends on the: Lightenergy emitted in the effective range ofwavelengths, the distancebetween the lights and the infant, the surface area of exposedskin, the rate of hemolysis and in vivo metabolism andexcretion of bilirubin.
Frequency of bilirubin check Depends on the bilirubin level. In hemolytic disease and bilirubin level near exchange, sampling should be done q4-8h to ensure bilirubin has fallen to a nontoxic level, then the frequency of check may be decreased to q12h. Checking bilirubin level with a phototherapy duration less than 4hr is not useful, because there is no decrement with such a short duration.
When to subtract direct bilirubin from total? In making decision about exchange transfusion direct bilirubin should not be subtracted from total, unless the direct level is more than 50% of total. (f)
Complications Complications associated with phototherapy include • loosestools, • erythematous macular rash, • purpuric rash associated withtransient porphyrinemia, • dehydration (increasedinsensible water loss, diarrhea), • hypothermia from exposure, • overheating, • bronze baby syndrome. The term bronze baby syndrome refers to a sometimes-noteddark, grayish-brown skin discoloration in infants undergoingphototherapy. Almost all infants observed with this syndromehave had significant elevation of direct-reacting bilirubin andother evidence of obstructive liver disease. The discoloration maybe due to photo-induced modification of porphyrins, which areoften present during cholestatic jaundice and may last for manymonths. Despite the bronze baby syndrome, phototherapy cancontinue if needed.
Preparations- cautions • Before initiatingphototherapy, the infant's eyes should be closed and adequatelycovered to prevent light exposure and corneal damage. Eyeshields should be fitted properly to avoid pressure injury to theclosed eyes, corneal excoriation if the eyes can be opened underthe binding, and nasal occlusion. Body temperature should bemonitored, and the infant should be shielded from bulb breakage.Irradiance should be measured directly and details of theexposure recorded (type and age of the bulbs, duration of exposure,distance from the light source to the infant). • In infants withhemolytic disease, care must be taken to monitor for the developmentof anemia, which may require transfusion. • Anemia maydevelop despite lowering of bilirubin levels. • Clinical experiencesuggests that long-term adverse biologic effects of phototherapyare absent, minimal, or unrecognized.
Prophylactic phototherapy In premature infants less than 1500g phototherapy is usually started on admission to prevent bilirubin rising which may approach exchange levels during the hospital course.
Exchange transfusion it is the standard mode of therapy for immediate treatment of hyperbilirubinemia to prevent kernicterus. in this technique, the equivalent of two neonatal blood volumes (170cc/kg)is replaced in aliquots not more than 10% of total blood volume. The procedure usually takes 1-2hours. By the end of double volume exchange transfusion only about 15% of circulating erythrocytes remain, but the serum bilirubin is still 45-60% of the pre exchange level. Immediately after the exchange further equilibration takes place which is completed within 30 minutes and produces the early rebound of plasma bilirubin to 60% to 80% of the pre exchange level. Blood sugar, calcium, sodium, potassium, bilirubin, HCT, platelet count should be measured 4hr after exchange .
Potential complications of exchange transfusion • Thrombocytopenia • Portal vein thrombosis or other thromboembolic complications • Umbilical or portal vein perforation • Acute necrotizing enterocolitis (NEC) • Arrhythmia, cardiac arrest • Hypocalcemia, hypomagnesemia, hypoglycemia • Metabolic acidosis, rebound metabolic alkalosis • Graft versus host disease • HIV, HBV, HCV infections • All other potential complications of blood transfusion
