Transcript Document

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 diglucuronide which are water
soluble and 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:
peak level 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:
nearly all 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 elevation in unconjugated bilirubin develops in an
estimated 2% of breast-fed term infants after the 7th day of life,
with maximal concentrations as high as 10-30 mg/dL reached
during the 2nd-3rd week. If breast-feeding is continued, the
bilirubin gradually decreases but may persist for 3-10 wk at
lower levels. If nursing is discontinued, the serum bilirubin
level falls rapidly, reaching normal levels within a few days.
With resumption of breast-feeding, bilirubin levels seldom
return to previously high levels. Phototherapy may be of
benefit. Although uncommon, kernicterus can occur in
patients with breast-milk jaundice. The etiology of breast-milk
jaundice is not entirely clear, but may be attributed to the
presence of glucuronidase in some breast milk.
Breast feeding jaundice
occurs in the 1st week of life, in breast-fed infants who normally have
higher bilirubin levels than formula-fed infants.
Hyperbilirubinemia (>12 mg/dL) develops in 13% of breast-fed infants in
the 1st wk of life and may be due to decreased milk intake with
dehydration and/or reduced caloric intake.
Giving supplements of glucose water to breast-fed infants is associated
with higher bilirubin levels, in part because of reduced intake of the
higher caloric density of breast milk.
Frequent breast-feeding (>10/24 hr), rooming-in with night feeding,
discouraging 5% dextrose or water supplementation, and ongoing
lactation support may reduce 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 gestation or time of appearance of jaundice,
patients with significant hyperbilirubinemia require a
complete 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
Exchange transfusion guideline GA>35wk
Suggested Maximal Indirect Serum Bilirubin
Concentrations (mg/ dL) in Preterm Infants
Birth weight
Uncomplicated
Complicated
< 1000g
12 - 13
10 - 12
1000 – 1250g
12 - 14
10 - 12
1250 – 1500g
14 - 16
12 - 14
1500 – 2000g
16 - 20
15 - 17
2000 – 2500g
20 - 22
18 - 20
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 pathogenesis of kernicterus is multifactorial and
involves an interaction between
•unconjugated bilirubin levels,
•albumin binding and unbound bilirubin levels,
•passage across the blood-brain barrier, and
• neuronal susceptibility to injury.
KERNICTERUS
•
•
•
•
level of indirect bilirubin,
duration of exposure to elevated levels,
the cause of jaundice, and
the infant's well-being.
KERNICTERUS
The precise blood level above which indirect-reacting
bilirubin or free bilirubin will be toxic for an individual
infant is unpredictable, but kernicterus is rare in healthy
term infants and in the absence of hemolysis if the serum
level is <25 mg/dL.
KERNICTERUS
The risk in infants with hemolytic disease is
directly related to serum bilirubin levels.
The duration of exposure needed to produce toxic effects
is unknown.
NCIDENCE AND PROGNOSIS
By pathologic criteria,
Kernicterus will develop in 1/3 of infants (all gestational ages)
with untreated hemolytic 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.
NCIDENCE AND PROGNOSIS
Overt neurologic signs have a grave prognosis;
More than 75% of such infants die,
and 80% of affected survivors have bilateral
choreoathetosis with involuntary muscle spasms.
Mental retardation, 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
Risk factors for development of severe hyperbilirubinemia
High risk zone - first 24hr - ABO . Rh incompatibility
G6PD - 35-36wk - previous sibling phototherapy cephalohematoma / significant bruising - exclusive
breast feeding – east Asian race
Intermediate risk zone – 37-38wk - Jaundice observed
before discharge – Previous sibling with jaundiceMacrosomic infant of diabetic mother- Maternal age
>25years- male sex
Male sex
low risk zone - Gestational age >41weeks
Exclusive bottle feeding
Black race
Discharge from hospital after 72 hours
Phototherapy
three independent mechanisms have been proposed to
explain the action of phototherapy in reducing serum
bilirubin concentrations in neonates.
1.
Geometric photoisomerization
2.
Intramolecular cyclization
3.
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 5hypocalcemia 6-DNA damage 7-risk of PDA in VLBW.
Efficacy
The use of phototherapy has decreased the need for
exchange transfusion in term and preterm infants
with hemolytic and nonhemolytic jaundice.
When indications for exchange transfusion are present,
phototherapy should not be used as a substitute;
however, phototherapy may reduce the need for repeated
exchange transfusions in infants with hemolysis.
The therapeutic effect of phototherapy depends
on the:
1.
2.
3.
4.
5.
Light energy emitted in the effective range of
wavelengths,
the distance between the lights and the infant,
the surface area of exposed skin,
the rate of hemolysis and
in vivo metabolism and excretion 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

loose stools,

erythematous macular rash,

purpuric rash associated with transient porphyrinemia,

dehydration (increased insensible water loss, diarrhea),

hypothermia from exposure,

overheating,

bronze baby syndrome.
The term bronze baby syndrome refers to a sometimes-noted dark,
grayish-brown skin discoloration in infants undergoing
phototherapy. Almost all infants observed with this syndrome have
had significant elevation of direct-reacting bilirubin and other
evidence of obstructive liver disease. The discoloration may be due
to photo-induced modification of porphyrins, which are often
present during cholestatic jaundice and may last for many months.
Despite the bronze baby syndrome, phototherapy can continue if
needed.
Preparations- cautions
 Before initiating phototherapy, the infant's eyes should be closed and
adequately covered to prevent light exposure and corneal damage. Eye
shields should be fitted properly to avoid pressure injury to the closed
eyes, corneal excoriation if the eyes can be opened under the binding,
and nasal occlusion. Body temperature should be monitored, and the
infant should be shielded from bulb breakage. Irradiance should be
measured directly and details of the exposure recorded (type and age of
the bulbs, duration of exposure, distance from the light source to the
infant).
 In infants with hemolytic disease, care must be taken to monitor for the
development of anemia, which may require transfusion.
 Anemia may develop despite lowering of bilirubin levels.
 Clinical experience suggests that long-term adverse biologic effects of
phototherapy are 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 .
Exchange set
Potential complications of exchange transfusion
• Thrombocytopenia
• Portal vein thrombosis or other thromboembolic
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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
LED
LED
Halogen lamps
Fiberoptic phototherapy
photoblanket
Rebound
Serum bilirubin may rise after discontinuation of
phototherapy, especially in the case of hemolytic
jaundice and in preterm infants.
Bilirubin measurement is recommended 24 hr after
phototherapy discontinuation if the cause of jaundice
is considered to be hemolytic or if the infant is
premature.
Follow up
All infants with hyperbilirubinemia at exchange level
should be referred for hearing screening after
discharge.
Infants suffering hemolytic jaundice due to ABO – Rh
incompatibility should be controlled for anemia after
discharge, and may be candidate for human
recombinant erythropoietin.
Home phototherapy
Because most of the devices commonly used for home
phototherapy do not provide the same degree of
irradiance or surface area exposure as those available in
the hospital, home phototherapy, of necessity, is used in
the prophylactic rather than in the therapeutic mode.
Hyperbilirubinemia
1- CBC – Retic – PBS – Coombs – G6PD – Blood group/ Rh –
Bilirubin total – direct
2- phototherapy: conventional – double – intensive ( better in
bassinet than incubator)
3- check bilirubin q4-6-8-12-24h
4- work up for sepsis if suspected
5- IVIG in ABO – Rh incompatibility
6- Albumin transfusion (not common practice)
7- Exchange transfusion: preparation with NPO 4h –
duration 45 – 60 min. followed with post exchange lab tests→
CBC – PLT – BS – Ca – Na – K – Bilirubin total – direct and
PO feeding started after 2 – 4 h.
8- D/C breast feeding for 48 h.
9- white sheet or foil coverage around incubator or bassinet
10- decrease distance between baby and lamps