A STUDY OF BRAINSTEM EVOKED RESPONSE

“A STUDY OF BRAINSTEM
EVOKED
RESPONSE
AUDIOMETRY CHANGES IN NEONATES WITH
UNCONJUGATED HYPERBILIRUBINEMIA BEFORE AND
AFTER THERAPY”
BY
Dr. NAYANA NAYAK,
M.B.B.S.
Dissertation submitted to the
Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore
In partial fulfillment of the requirements for the degree of
DOCTOR OF MEDICINE
IN
PAEDIATRICS
Under the Guidance of
Dr. D. NARAYANAPPA
M.D.
Professor and Head,
Department of Paediatrics
JAGADGURU SRI SHIVARATHREESHWARA MEDICAL COLLEGE,
SHIVARATHREESHWARA NAGAR, MYSORE- 570 015
APRIL - 2010
i
ii
iii
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v
vi
ACKNOWLEDGEMENT
It gives me great pleasure in preparing this dissertation and I take this
opportunity to thank everyone who has made this possible.
First, I would like to extend my sincere thanks and appreciation towards all
our patients for their willingness to cooperate with this study.
My inexpressible gratitude to my mentor, Dr. D. Narayanappa, M.D.,
Professor and Head, Department of Paediatrics, J.S.S. Medical College, Mysore., for
his constant encouragement and skillful guidance at each step of the preparation of
this work. His enthusiasm, zeal for perfection and eagerness for exploring the depth of
learning, helped me a lot to understand various aspects of the subject. It was only due
to his constant inspiration, efforts and guidance that this study was made possible.
My sincere regards to Dr. M. D. Ravi, M.D., DCH, Professor of Paediatrics,
for his timely advice and guidance.
I thank Dr. Jagadish Kumar, M.D., Professor, Department of Paediatrics,
J.S.S.Medical College, who whole heartedly supported and helped me in the
completion of this study.
I thank Dr. N.P Nataraj, Director JSS institute of Speech and Hearing and his
team members Ms.Shruti and Ms.Meryl, for their unconditional support.
I wish to express my sincere thanks to Dr. Lancy D’ Souza for helping with
Statistics.
vii
My sincere thanks to all my colleagues in the department for their
understanding and extension of help. I also thank all the nursing, and technical staff of
the institute who have helped with this study.
I am grateful to Dr.Sandesh Prabhu, my husband, for having shown moral
support throughout the study.
I am grateful to my parents who are always a constant source of affection,
moral support and encouragement.
I am grateful to the Management, Principal, Medical Superintendent and all
the office staff for permitting me to do this study and to use the facilities at the
institute for the study.
Place: Mysore
Dr. Nayana Nayak
Date:
viii
LIST OF ABBREVIATIONS
AAP
:
American Academy of Paediatrics
ABR
:
Auditory Brainstem Response
BBB
:
Blood Brain Barrier
BERA
:
Brainstem Evoked Response Audiometry
BH2
:
Bilirubin acid
BIND
:
Bilirubin induced Neurological Dysfunction
CB
:
Conjugated Bilirubin
CBFV
:
Cerebral Blood Flow Velocity
CHD
:
Congenital Heart Disease
CNS
:
Central Nervous System
CO
:
Carbon Monoxide
CPD
:
Citrate Phosphate dextrose
DCT
:
Direct Coomb’s test
EDD
:
Expected date of Delivery
ET
:
Exchange Transfusion
ETCOc
:
End Tidal Carbon Monoxide Corrected for ambient-Co
FFA
:
Free Fatty Acids
G-6-PD
:
Glucose-6-Phosphate Dehydrogenase
GVHD
:
Graft versus Host Disease
HBABA
:
2-4’ hydroxybenzene azo benzoic acid
HDN
:
Hemolytic Disease of the Newborn
IVH
:
Intra Ventricular Haemorrhage
ix
LFT
:
Liver Function Test
LSCS
:
Lower Segment Caeserean Section
MRI
:
Magnetic Resonance Imaging
NEC
:
Necrotising Enterocolitis
NICU
:
Neonatal Intensive Care Unit
PBS
:
Peripheral Blood Smear
PT
:
Phototherapy
RBC
:
Red Blood Cell
RES
:
Reticuloendothelial system
TSB
:
Total Serum Bilirubin
UCB
:
Unconjugated Bilirubin
UDPG-T :
Uridine Diphosphate Glucuronyl Transferase
x
ABSTRACT
Neonatal hyperbilirubinemia is a common problem in the neonates which can
cause significant morbidity and mortality. Auditory neuropathy is noted in one third
to one half of infants with significant hyperbilirubinemia. Brainstem Evoked
Response Audiometry (BERA) is an effective and non-invasive means of assessing the
functional status of the auditory nerve and brainstem auditory sensory pathway.
OBJECTIVES OF THE STUDY
1. To
study
the
BERA
changes
in
neonates
with
unconjugated
hyperbilirubinemia.
2. To compare the BERA changes in the neonates with unconjugated
hyperbilirubinemia before and after therapy.
METHODOLOGY
This study was conducted in the Department of Pediatrics of JSS Medical
College, Mysore. The study period was between November 2007- May 2009. Thirty
consecutive term AGA (Appropriate For Gestational Age) neonates presenting to the
NICU of J.S.S. Hospital, with total serum bilirubin requiring intervention (using the
American Academy of Pediatrics guidelines3) were included in the study as cases and
thirty normal term AGA neonates with uneventful peri-natal period and a maximum
measured serum bilirubin <12 mg/dl were included as controls after obtaining
informed consent. Initial BERA was done within 3-24 hours of hospitalization.
xi
Repeat BERA was done in all cases after therapy , at the time of discharge and after a
follow-up period of 3 months.
RESULTS
There were 34 cases and 30 controls in the study. Of the 34 cases, 28 cases
came for follow up after a period of 3 months, whereas 6 were lost for follow up. In
our study out of the 34 cases 12 (35.3 %) cases were found to have BERA changes.
Raised threshold was the most common BERA change observed in majority of the
patient 12(35.3%) cases, absent wave forms at 90 dBnHL was seen in 6(17.6%) cases.
Prolonged latency I, III, V, prolonged inter peak latency I-III and I-V were seen in
8.8%, 14.7%, 14.7%, 17.6% and 11.8% of cases respectively. Prolonged inter peak
III-V was not observed in any of the cases. Out of the 12 (35.3%) cases which had
BERA changes at peak level of bilirubin, 9 (26.4%) cases had persistent changes at
the time of discharge. Of these 9 cases, on follow up at 3 months 3 (8.8%) cases had
persistent changes and 2 were lost for follow up. All these 3 cases had bilirubin >
25mg/dl before therapy.
CONCLUSION
BERA can be used as an effective and non invasive means of assessing the
functional status of the auditory pathway in neonates with hyperbilirubinemia.
Neonates with BERA changes need to be followed up over a period, an essential aim
being the early identification of infants with impaired hearing so that rehabilitation
can be initiated at a time when brain is still sensitive to the development of speech and
language.
Keywords: Hyperbilirubinemia, auditory neuropathy, BERA.
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TABLE OF CONTENTS
Chapters
Page No.
1.
INTRODUCTION
1
2.
OBJECTIVES OF THE STUDY
3
3.
REVIEW OF LITERATURE
4
4.
METHODOLOGY
49
6.
RESULTS
55
7.
DISCUSSION
70
8.
SUMMARY
75
9.
CONCLUSION
77
10.
BIBLIOGRAPHY
78
11.
ANNEXURES
i.
PROFORMA
ii.
KEY
TO
84
MASTER
89
CHART
iii.
MASTER CHART
xiv
90
LIST OF TABLES
Sl. No.
1
Title
Page No.
Management of hyperbilirubinemia in the healthy term new
27
born
2
Normal BERA parameter at 90dBnHL
55
3
Mean age (in days) of cases and controls
56
4
Sex wise distribuition of cases and controls
57
5
Average birth weight in kgs of cases and controls
58
6
Distribution of cases in different bilirubin range
59
7
Number of cases with BERA changes
60
8
Number of cases with different BERA changes at peak level
61
of bilirubin
9
Comparison of latencies of I,III,V of cases at peak level of
63
bilirubin, at discharge and follow-up at 90 dBnHL
10
Comparison of inter peak latencies of cases at peak level of
63
bilirubin, at discharge and follow-up at 90 dBnHL
11
Comparison of BERA changes at peak level of bilirubin, at
64
discharge and follow-up at 90 dBnHL
12
Correlation of bilirubin level with BERA changes
65
13
Type of treatment given to cases
66
14
Comparison of various BERA changes in different studies
71
15
Comparison of BERA changes at peak level at discharge and
72
follow-up with other studies
xv
LIST OF GRAPHS
Sl.No.
Title
Page No.
1
Mean age (in days) of cases and controls
56
2
Sex wise distribuition of cases and controls
57
3
Average birth weight in kgs of cases and controls
58
4
Distribution of cases in different bilirubin range
59
5
Percentage of cases with BERA changes
60
6
Number of cases with different BERA changes at peak
62
level of bilirubin
7
Types of treatment given to cases
xvi
66
LIST OF FIGURES
Sl.No.
Title
Page No.
1
A Jaundiced baby under phototherapy
52
2
A Jaundiced baby undergoing BERA
52
3
A BERA report of a control showing normal BERA
67
waveforms
4
A BERA report showing absent waveforms at 90 dBnHL
67
5
A BERA report showing raised threshold i.e absent
68
waveform at 30dBnHL,but presence at 50dBnHL
6
A BERA report showing prolonged latency of 7.2 ms.
68
7
A BERA report showing prolonged interpeak interval I-V
69
of 5.4 ms
xvii
INTRODUCTION
Neonatal jaundice is a common problem seen in the newborn. It is observed
during the first week of life in approximately 60% of term and 80% of preterm2-6.
Although most jaundiced newborns are otherwise healthy, they make the
neonatologist anxious because bilirubin is potentially toxic to the central nervous
system5.
The terms bilirubin encephalopathy and kernicterus represent clinical and
pathological abnormalities resulting from bilirubin toxicity in the central nervous
system5.
Besides other sequelae, unconjugated hyperbilirubinemia is found to be
particularly toxic to the auditory pathway resulting in sensorineural hearing loss.
Auditory neuropathy is noted in one third to one half of infants with significant
hyperbilirubinemia5. Unbound bilirubin, because of its lipophilic nature can cross the
blood brain barrier and exert toxicity at cellular level. Interruption of normal
neurotransmission has been proposed to be one of the mechanisms of toxicity5.
There is no level of bilirubin that definitely predicts kernicterus and also, the
bilirubin levels that are toxic to one infant may not be toxic to another or even to the
same infant in different clinical circumstances34, 35. The duration of exposure needed
to produce toxic effects is also unknown. The imprecise relationship between total
serum bilirubin and adverse neurological outcome has encouraged research, seeking
more accurate markers of bilirubin toxicity.
1
Brainstem Evoked Response Audiometry (BERA) is an effective and noninvasive means of assessing the functional status of the auditory nerve and brainstem
auditory sensory pathway51. It is not significantly altered by the state of
consciousness, drugs and variety of environmental factors.
The BERA changes in response to hyperbilirubinemia include loss of one or
more peaks of waves I to V, raised threshold, increase in latency of waves I, III or V
or increased inter peak interval51.
BERA can detect subclinical bilirubin encephalopathy even before the
appearance of any signs or symptoms of kernicterus.
The present study was undertaken to evaluate the effect of hyperbilirubinemia
in term newborns on Brainstem evoked response audiometry (BERA) and change, if
any, in BERA after therapy.
2
OBJECTIVES OF THE STUDY
1. To
study
the
BERA
changes
in
neonates
with
unconjugated
hyperbilirubinemia.
2. To compare the BERA changes in the neonates with unconjugated
hyperbilirubinemia before and after therapy.
3
REVIEW OF LITERATURE
•
Neonatal hyperbilirubinemia is a common problem in the neonates which can
cause significant morbidity and mortality.
•
The normal adult serum bilirubin level is less than 1mg/dL. Adults appear
jaundiced when the serum bilirubin level is greater than 2mg/dL, and
newborns appear jaundiced when it is greater than 7mg/dL and by adult
standards, almost all newborn babies are jaundiced during early days of life2, 3.
What constitutes significant hyperbilirubinemia is the subject of continuing
controversy, as only limited information exists regarding the association between
specific levels of TSB during non hemolytic hyperbilirubinemia in term newborns and
subsequent adverse neurologic and cognitive outcome8-10.
BILIRUBIN METABOLISM2, 3, 7, 12, 13
Source
Bilirubin is derived from the breakdown of heme-containing proteins in the
reticuloendothelial system. The normal newborn produces 6 to 10 mg of bilirubin per
kg per day as opposed to the production of 3-4 mg per kg per day in the adult.
1. The major heme-containing protein is hemoglobin. Hemoglobin released from
senescent RBCs in the reticuloendothelial system (RES) is the source of 75% of
all bilirubin production. One gram of hemoglobin produces 34 mg of bilirubin.
4
2. The other 25% of bilirubin is called early labeled bilirubin. It is derived from
hemoglobin released by ineffective erythropoiesis in the bone marrow, from other
heme-containing proteins in tissues (eg. Myoglobin, cytochromes, catalase and
peroxidase) and from free heme.
Metabolism
The
heme
ring
from
heme
containing
proteins
is
oxidised
in
reticuloendothelial cells to biliverdin by the microsomal enzyme heme oxygenase.
This reaction releases carbon monoxide (CO) (excreted from the lung) and iron
(reutilized). Biliverdin is then reduced to bilirubin by the enzyme bilirubin reductase.
Catabolism of 1 mole of Hb produces 1 mole each of CO and bilirubin. Increased
bilirubin production as measured by CO excretion rates, accounts for the higher
bilirubin levels seen in Asian, Native American and Greek infants3.
Transport
Bilirubin is non polar and insoluble in water and is transported to liver cells
bound reversibly but tightly to serum albumin. It is believed that the neurotoxicity
associated with hyperbilirubinemia is primarily the result of unbound bilirubin, so the
amount of bilirubin available for binding is important.
Uptake
Uptake of bilirubin from bilirubin-albumin complex occurs on the surface of
liver parenchymal cells. Albumin bound bilirubin reaches the liver cell membrane
where bilirubin is released from albumin. Bilirubin and not albumin is transferred
across the cell membrane into the hepatocyte. The exact mechanism is not clear still.
Several cytoplasmic proteins such as ligandin, lipoprotein, and fatty acid binding
5
protein may be involved. Bilirubin is primarily bound to ligandin within the cell and
this binding prevents back flow into circulation. This bound intracellular bilirubin is
transferred to smooth endoplasmic reticulum for conjugation.
Conjugation
Unconjugated/indirect bilirubin is converted to water soluble conjugated/direct
bilirubin in the smooth endoplasmic reticulum by Uridine Diphosphate Glucuronyl
Transferase (UDPG-T). In the first 48 hours of life, only bilirubin monoglucuronide is
produced. After that, bilirubin diglucuronide is the main product. Both these products
are water soluble and are secreted into biliary canaliculi and excreted into intestines as
bile. This is an active energy dependent process as the conjugated bilirubin is excreted
against a large concentration gradient.
Excretion
Conjugated bilirubin (CB) in the biliary tree enters GIT and is then eliminated
from the body in stool, which contains large amounts of bilirubin. CB is not normally
re absorbed from the bowel unless it is converted back to UCB by the intestinal
enzyme beta-glucuronidase. The sterile intestine in the newborn is rich in βglucuronidase enzyme which splits bilirubin glucuronide into bilirubin and glucuronic
acid. Then unconjugated bilirubin (UCB) is reabsorbed and returned to circulation. It
has to be exported once again to liver for conjugation and excretion.
This re absorption of bilirubin from the gastrointestinal tract and delivery back
to the liver for reconjugation is called “entero hepatic circulation”.
Conjugated bilirubin is converted into urobilinogen / urobilinoids by bacterial
action of the gut and this prevents enterohepatic circulation as urobilinoids are not
6
substrates for β-glucuronidase. A part of urobilinogen is absorbed into portal
circulation and is mostly re-excreted by liver as bilirubin. A part of it reaches
systemic circulation and is excreted through kidneys.
Fetal bilirubin metabolism3
The UCB formed by the fetus is cleared by the placenta into the maternal
circulation. Formation of CB is limited in the fetus because of decreased hepatic
blood flow, hepatic ligandin and UDPG-T activity. The small amount of CB excreted
into the fetal gut is usually hydrolysed by beta glucuronidase and re absorbed.
Bilirubin is normally found in amniotic fluid by 12 weeks and is gone by 37 weeks
gestation. Increased amniotic fluid bilirubin is found in hemolytic disease of newborn
and in fetal intestinal obstruction below the bile ducts.
BILIRUBIN TURNOVER IN NEWBORN2, 3, 12
Several biophysiological handicaps lead to increase in frequency and severity
of jaundice among newborn babies.
•
Physiologic polycythemia and shorter life span of fetal red blood cells result in
release of 0.15 gm/Kg of hemoglobin every day because 1.0 ml/kg (≅1%) of blood
hemolyse everyday.
1gram of hemoglobin yields about 34 mg of bilirubin, so that in a 3kg infant,
about 15 mg of bilirubin is produced daily from hemoglobin sources i.e., 5mg/kg of
bilirubin is generated.
Additional 1mg/kg bilirubin is produced from non-hemoglobin sources, thus
resulting in net daily load of 18mg of bilirubin to the liver in a healthy term infant.
7
•
Hepatic uptake, conjugation and excretion of bilirubin are limited due to transient
deficiency of Y and Z acceptor proteins and UDPG-T enzyme in newborn babies.
Because of relative lack of hepatic conjugatory enzymes, hyperbilirubinemia
is mostly limited to unconjugated fraction of bilirubin during early days of life. On an
average, 100-200 mg of bilirubin is present in the gut in a concentration of 1.0 mg of
bilirubin per gram of meconium.
•
Due to paucity of bacterial flora in the gut of a newborn baby and over activity of
intestinal β-glucuronidase enzyme, the conjugated bilirubin entering the
duodenum is rapidly deconjugated and recirculated in the blood and delivered to
the liver for reconjugation through enterohepatic circulation.
Thus, increased production of bilirubin, reduced hepatic clearance, enhanced
enterohepatic circulation contribute to increased prevalence of jaundice among
newborn babies.
The rate of bilirubin production (6-8 mg/kg/24 hrs) is at least twice in
magnitude in the normal newborn population as compared to older children.
CAUSES OF JAUNDICE ON THE BASIS OF AGE OF ONSET1, 2, 3, 13
A. Within 24 hours of birth
1. Hemolytic disease of the newborn due to feto-maternal blood group
incompatibility in the rhesus, ABO and minor blood group systems,
2. Intrauterine infections such as, toxoplasmosis, cytomegalic inclusion disease,
syphilis, rubella, herpes simplex, bacterial infections,
8
3. Deficiency of red cell enzymes such as G-6-PD, pyruvate kinase, hexokinase,
phosphoglucose isomerase, and unstable Hb,
4. Administration of large amount of certain drugs such as vitamin-K, salicylates,
sulfisoxazole etc. to the mother,
5. Hereditary spherocytosis,
6. Crigler-Najjar syndrome,
7. Lucey-Driscoll syndrome,
8. Homozygous alpha-thalassemia.
B. Between 24-72 hours of age
Physiological jaundice appears during this period but can be aggravated and
prolonged by immaturity, birth asphyxia, acidosis, hypothermia, hypoglycemia, drugs,
cephalhematoma, concealed hemorrhage and bruising, polycythemia, high altitude,
cretinism, infections and mild hemolytic states due to fetomaternal blood group
incompatability, spherocytosis and deficiency of red cell enzymes.
C. After 72 hours of age (and within first 2 weeks)
1. Septicemia
2. Neonatal hepatitis including other causes of intrauterine infections.
3. Extrahepatic biliary atresia.
4. Breast milk jaundice
5. Metabolic disease such as galactosemia, tyrosinemia, hereditary fructosemia,
organic acidemia, cystic fibrosis, α-1-antitrypsin deficiency.
6. Hypertrophic pyloric stenosis and intestinal obstruction.
9
Intrauterine infections should be considered in the differential diagnosis of
jaundice having onset any time during the neonatal period. The age of onset of
jaundice gives an important clue to the possible etiology.
The common causes of jaundice in our country in order of their frequency include2:
•
Physiological jaundice
•
Immaturity
•
Blood group incompatibility between mother and fetus
•
Intrauterine and postnatal infections.
•
G-6-PD deficiency
•
Subcutaneous bruising and cephalohematoma
•
Drugs
•
Breast milk jaundice
Even after detailed investigations, the cause of neonatal hyperbilirubinemia
remains uncertain in over 1/3rd of cases2, 6.
CLINICAL ASSESSMENT OF SEVERITY OF JAUNDICE 2
Clinical judgment utilizes the principle that clinical jaundice first becomes
obvious in the face followed by a downward progression as it increases in intensity
(cephalo pedal progression) 2.
Assessment of jaundice is done in natural light and there should be no yellow
clothes or curtains in the background which can lead to an error of over estimation.
Yellow discoloration is first evident on the skin of face, naso labial folds and tip of
the nose. It is masked by physiological plethora of newborn. The pulp of finger or
10
thumb is pressed on the baby’s skin, preferably over a bony part, till it blanches. The
underlying skin is noted for yellow colour2.
11
Extent of jaundice thus detected gives a rough estimate of serum bilirubin1, 7, 13.
Area of body
Range of bilirubin (mg/100ml)
Face
4-8
Upper trunk
5-12
Lower trunk and thighs
8-16
Arms and lower legs
11-18
Palms and soles
>15
Criteria to estimate clinical jaundice
The yellow staining of sclera is difficult to evaluate because of physiological
photophobia. Eyes and sclera are best examined by holding the infant against diffuse
light and without trying to forcibly open the eyelids.
The cephalo pedal progression is apparently related to the relative thickness of
skin at various parts, skin being thinnest in the face and extremely thick over the
palms and soles. Cephalo pedal color difference may be related to differences in blood
flow or lipid content of skin and due to conformational changes in the newly formed
bilirubin albumin complexes2.
There is no difficulty in clinically recognizing jaundice among Indian babies
because increased skin pigmentation generally appears after 2 weeks of age2.
It is essential that all newborn babies must be clinically screened twice a day
in good day light to detect the onset and severity of jaundice.
12
PHYSIOLOGICAL JAUNDICE
60% of term and 70% of preterm babies develop visible jaundice due to
elevation of unconjugated bilirubin during their first week. This common condition is
called ‘Physiological Jaundice’2, 3, 12, 13.
It may provide useful protection to the baby against oxygen free radical
triggered neonatal disorders, because bilirubin is an antioxidant2, 6, 14, 15.
The pattern of hyperbilirubinemia has been classified into two functionally
distinct periods13:
Phase one: Lasts for 5 days in term infants and about 7 days in preterm infants, when
there is a rapid rise in serum bilirubin levels to 12 to 15 mg/dL respectively.
Phase two: There is decline in Total Serum Bilirubin (TSB) level to about 2mg/dL,
which lasts for 2 weeks after which adult values are attained. Levels under 2mg/dL
may not be seen until 1 month or more than a month in preterm infants and full term
infants on exclusive breast feeding.
Term babies: Jaundice appears between 30-72 hours of age. Maximum intensity is
seen on 4th day. (Serum bilirubin does not exceed 15mg/dL) and disappears by 10
days of life13.
Preterm babies: Jaundice appears earlier but not before 24 hours of age. Maximum
intensity is seen on 5th or 6th day (serum bilirubin may go up to 15 mg/dL) and may
persist upto 14 days13.
13
Etiology of physiological jaundice appears to be multifactorial.
Possible mechanisms involved in physiological jaundice1,2,3,13
1. Increased bilirubin load on liver cells
¾ Increased erythrocyte volume / kg body weight (polycythemia)
¾ Increased early labeled bilirubin, increased ineffective erythropoiesis and
increased turnover of non Hb heme proteins.
¾ Increased enterohepatic circulation of bilirubin. Caused by :
a. High levels of intestinal β-glucuronidase.
b. Decreased intestinal bacteria.
c. Decreased gut motility with poor evacuation of bilirubin laden meconium.
¾ Decreased erythrocyte survival / shorter life span (90 days Vs. 120 days in
adults).
2. Defective hepatic uptake of bilirubin from plasma
¾ Decreased ligandin (Y protein) in hepatocytes.
¾ Increased binding of Y protein by other anions.
3. Defective bilirubin conjugation
¾ Decreased UDPG activity.
4. Defective hepatic bilirubin excretion
PATHOLOGICAL JAUNDICE2, 3, 13
Definition
Presence of any of the following features characterizes pathological jaundice:
1. Onset of jaundice before 24 hours of age
2. Increase in level of total bilirubin by more than 0.5 mg/dL/hr or 5mg/dL
/24hrs.
14
3. Total bilirubin >12mg/dL in full term and > 10-14 mg/dL in preterm.
4. Direct bilirubin >2.0 mg/dL
5. Signs of underlying illness in any infant (vomiting, lethargy, poor feeding,
excessive weight loss, apnea, tachypnea, temperature instability).
6. Jaundice persisting after 10 days in a term infant or after 14 days in a
preterm infant.
DANGERS OF HYPERBILIRUBINEMIA
KERNICTERUS OR BILIRUBIN ENCEPHALOPATHY
It is a neurologic syndrome resulting from the deposition of unconjugated
bilirubin in the basal ganglia and brainstem nuclei3.
The word kernicterus originated as a description of yellow nuclear staining of
the brain, but has become synonymous with the acute and chronic bilirubin
encephalopathy1, 2.
The pathogenesis of kernicterus is multifactorial and involves an interaction
between1, 2, 3
1. Unconjugated bilirubin levels and factors that affect its level.
2. Albumin binding and unbound bilirubin levels.
3. Passage across the blood brain barrier and
4. Neuronal susceptibility to injury.
Factors that influence bilirubin toxicity to the brain cells of newborn are
complex and incompletely understood1, 2, 12.
15
PATHOGENESIS
Uncertainty remains regarding the exact mechanism of neurotoxicity observed
in association with hyperbilirubinemia1, 2.
For bilirubin to exert its toxic effect on the central nervous system (CNS), it
has to get into the brain. Albumin bound bilirubin is unable to cross intact blood brain
barrier (BBB). Once bilirubin sites on albumin are saturated, free bilirubin appears in
the serum and it is this free bilirubin that crosses the blood brain barrier and produce
brain damage1, 2, 7. In cases of existing insult to BBB, even albumin bound bilirubin
can get access to CNS. The ‘FREE BILIRUBIN THEORY’1 states that the risk of
bilirubin neurotoxicity increases with increasing non-albumin-bound bilirubin
concentration, which is a function of both albumin concentration and total bilirubin
concentration, increasing as the bilirubin to albumin ratio increases.
Albumin has 2 binding sites for bilirubin.1, 2
a) Primary/firm binding site/high affinity site which binds bilirubin in the molar
ratio of 1:1.
b) Secondary/loose binding site/low affinity sites, probably 2 on each albumin
molecule, bringing bilirubin to albumin molar ratio to 3:1.
One gram of albumin binds to 8.5mg of bilirubin2, 7.
Free fatty acids (FFA), hematin, low pH and drugs that compete for the
binding sites in albumin can easily displace bilirubin from these sites1.
16
The saturation of albumin with unbound bilirubin can be measured by
bilirubin binding capacity and it helps to predict neurotoxicity in susceptible
neonates1.
Anoxia, hypercarbia and hyperosmolarity increase the permeability of BBB
and increase deposition of bilirubin in the brain. Respiratory acidosis also increase
bilirubin brain deposition1, 2, 16.
Because of low solubility, bilirubin aggregates in the tissues and binds
opportunistically to membranes or membrane components on the cells1. Once in
contact with neurons, further damage to neurons depends on availability of Hydrogen
ion. Bilirubin normally exists as a bi-anion and combines with H+ ion to form
bilirubin acid (BH2) which precipitates on to neurons producing damage.
Other theory states that bilirubin combines with one H+ ion and this molecule
positions itself between lipid bilayer of the membranes. This moiety has surfactant
like property and changes membrane function of ion channel producing early
manifestation of encephalopathy7, 17.
BILIRUBIN TOXICITY AT CELLULAR LEVEL
Four possible mechanism have been proposed
1. Interruption of neurotransmission
By binding to the nerve terminals, it causes a reversible lowering of membrane
potential and a decrease in nerve conduction12, thus explaining the reversibility of
early bilirubin encephalopathy1. At higher concentration, the nerve terminals are
severely injured and bilirubin penetrates the axons with retrograde uptake into the cell
17
body and also, if acidosis persists, then BH2 is formed resulting in permanent
neuronal damage6.
18
2. Mitochondrial dysfunction
Some researchers have hypothesized that bilirubin acid precipitates in
phospolipid membranes resulting in mitochondrial dysfunction
3. Cellular or intracellular membrane impairment
This is due to bilirubin forming reversible complexes with various cellular
membranes.
4. Interference with enzyme activity
This theory holds that bilirubin acid is capable of binding receptor sites on
specific enzymes, rendering them inoperative or at least severely diminishing their
activities.
The precise blood level above which indirect-reacting bilirubin or free
bilirubin will be toxic for an individual infant is unpredictable. The duration of
exposure needed to produce toxic effects is also unknown.
19
PATHOLOGY
Kernicterus is a pathological diagnosis and refers to yellow staining of the
brain by bilirubin together with the evidence of neuronal injury. Grossly, bilirubin
staining is most commonly seen in basal ganglia, various cranial nerve nuclei, other
brainstem nuclei - inferior olivary nuclei, dentate nucleus subthalamic nuclei, nuclei
of the floor of 4th ventricle, cerebellar nuclei, hippocampus and anterior horn cells of
spinal cord1, 2, 3.
The classical neurological signs are not seen among preterm infants, as
bilirubin staining among them is limited to nuclei of cranial nerves subthalamus and
thalamus2.
Microscopically there is necrosis, neuronal loss and gliosis. Loss of neurons,
reactive gliosis, and atrophy of involved fiber systems are found in late disease2.
CLINICAL BILIRUBIN ENCEPHALOPATHY OR CLINICAL FEATURES1-4, 20
Signs and symptoms of kernicterus usually appear 2-5 days after birth in term
infants and as late as 7th day in premature ones, but hyperbilirubinemia may lead to
the syndrome at any time during the neonatal period.
The early signs may be subtle and indistinguishable from those of sepsis,
asphyxia, hypoglycemia, intracranial hemorrhage and other acute systemic illnesses in
a neonatal infant.
20
Acute form
Three clinical phases have been identified in acute bilirubin encephalopathy,
classically seen in term infants1-4, 20.
Phase 1: (1st 1-2 days):
Poor sucking, stupor, lethargy, vomiting high
pitched cry, decreased tone, and poor Moro’s
reflex.
Phase 2: (middle of 1st week): Hypertonia of extensor muscles → rigidity,
opisthotonus, retrocollis, oculogyric crisis, fever,
seizures, and paralysis of upward gaze.
Most infants die in this phase. Those infants,
who
survive,
develop
chronic
bilirubin
encephalopathy.
Phase 3: (after the 1st week):
Infant demonstrates hypertonia with marked
retrocollis and opisthotonos , stupor or coma and
a shrill cry.
Many infants who progress to phase 2 die; the survivors are usually seriously
damaged but may appear to recover and for 2-3mo show few abnormalities. Later in
the 1st year of life, opisthotonus, muscle rigidity, irregular movements and
convulsions tend to recur. In the 2nd year, the opisthotonus and seizures abate, but
irregular, involuntary movements, muscle rigidity or in some infants, hypotonia
increase steadily.
By 3rd year of age, the complete neurologic syndrome is often apparent and
consists of bilateral choreoathetosis with involuntary muscle spasms, extrapyramidal
21
signs, seizures, mental deficiency, dysarthric speech, high-frequency hearing loss,
squinting and defective upward movement of eyes. Pyramidal signs, hypotonia and
ataxia occur in a few infants1, 2, 19.
In mildly affected infants, the syndrome may be characterized only by mild to
moderate neuromuscular incoordination, partial deafness, or “minimal brain
dysfunction”, occurring singly or in combination; these problems may not be apparent
until the child enters school1, 2.
PREDICTORS OF BILIRUBIN TOXICITY 1, 2, 21
The imprecise relationship between total serum bilirubin and adverse
neurological outcome has encouraged research seeking more accurate markers of
bilirubin toxicity.
Assessment of free bilirubin, bilirubin-binding capacity, bilirubin to albumin
ratio, brainstem auditory evoked responses, magnetic resonance imaging of brain and
computer analysis of abnormality of jaundiced infant’s cry have been proposed:
Total Serum Bilirubin
The precise blood level above which indirect reacting or free bilirubin will be
toxic for an individual infant is unpredictable1, 2, 3, 34. As of now, there is no level of
bilirubin that definitely predicts kernicterus and also, the bilirubin levels that are toxic
to one infant may not be toxic to another or even to the same infant in different
clinical circumstances34, 35.
Bilirubin levels refer to total bilirubin. Direct bilirubin is not subtracted from
the total unless it constitutes more than 50% of total bilirubin. Currently major debate
22
surrounds the toxicity of bilirubin in otherwise healthy-term infants22-33. The AAP
recommends, that in term babies with non-hemolytic jaundice, serum bilirubin level
of 25-29mg/dL are safe and do not require exchange transfusion11. But Indian studies
suggest that kernicterus could occur in babies even when the serum bilirubin is <
25mg/dL34, 35.
Reserve Bilirubin Binding Capacity And Free Bilirubin2, 19
Î HBABA dye binding measures both reserve albumin binding capacity for
bilirubin and non-bilirubin binding sites on albumin.
HBABA dye binding capacity of <50% may be associated with bilirubin brain
damage.
Î SALICYLATE SATURATION INDEX – determines the extent to which albumin
is saturated with bilirubin by assessing its displacement on addition of salicylate in
vitro.
Salicylate saturation index of 8 or more is associated with bilirubin
encephalopathy.
Î SEPHADEX G-25 measures both free and loosely bound bilirubin to albumin.
Sephadex column consists of tiny beads of hydrated polymeric material
packed into a tube and it actively absorbs both free and loosely bound bilirubin. The
baby is not at risk to develop kernicterus if sephadex G-25 column is not yellow
stained and level of free and loosely bound bilirubin is less than 0.1mg/dL.
Î Red blood cell binding of bilirubin has also been utilized to assess the risk of
kernicterus.
23
Whenever bilirubin bound to RBC, exceed 4mg/dL, it is considered as unsafe.
Î A front face reflectance fluorometry or semi-automated technique for rapid
determination of albumin bound bilirubin, total bilirubin and reserve binding
capacity on a drop of blood has been evolved.
Bilirubin Protein Ratio
Adequate levels of serum protein are essential for effective binding of
bilirubin to prevent leakage into the interstitial tissue and intracellular compartment.
Bilirubin protein ratio of 3.5 or more may be associated with developmental
sequelae of bilirubin encephalopathy2.
The level of serum albumin may not provide a true estimate of the available
bilirubin binding capacity because binding sites in the albumin may also be blocked
by H+ ions and other organic anions such as salicylates, sulfonamides, FFA, hematin,
furosemide, sodium benzoate, indomethacin and certain antibiotics. In presence of
these anions, the bilirubin binding capacity is compromised and brain damage may
develop at lower serum bilirubin levels even in the presence of normal serum protein
concentration2.
Brainstem Evoked Response Audiometry (BERA)
The auditory pathway of the newborn is particularly vulnerable to insult from
bilirubin. Increased bilirubin concentrations have been correlated with changes in
amplitude and latency of BERA. BERA testing is accurate and non invasive and
assesses the functional status of the auditory nerve in the brainstem auditory
24
pathway1. This test could be used to screen hearing loss due to hyperbilirubinemia and
to predict need for exchange transfusion in jaundiced neonates.
Infant Cry Analysis
Analysis of characteristics of infant’s crying have shown that moderate
elevation in TSB could alter the neural conduction and have impact on the vocal cords
(increased tension or phonation) 1.
Magnetic Resonance Imaging (MRI)
MRI has been proposed as a rapid non invasive measurement of impending or
actual brain cell injury during periods of hyperbilirubinemia. Diffusion weighted
images may enable the diagnosis of reversible brain injury in sufficient time to
intervene and to determine what is irreversible for timely prognostication1. After
extreme hyperbilirubinemia, specific symmetric abnormalities are known to occur in
patients that are seen in autopsied kernicterus babies32.
MANAGEMENT OF HYPERBILIRUBINEMIA IN THE HEALTHY TERM
NEWBORN2-4, 9
Under certain circumstances, bilirubin may be toxic to the CNS and may cause
neurologic impairment even in healthy term newborns. Most studies, however, have
failed to substantiate significant associations between a specific level of total serum
bilirubin (TSB) during non hemolytic hyperbilirubinemia in term newborns and
subsequent IQ or serious neurologic abnormality (including hearing impairment).
Other studies have detected subtle differences in outcomes associated with TSB
levels, particularly when used in conjunction with albumin binding test, and/or
duration of exposure.
25
Continuing uncertainties about the relationship between serum bilirubin levels
and brain damage as well as differences in patient populations and practice settings
contribute to variations in the management of hyperbilirubinemia. Early postpartum
discharge from the hospital further complicates the management of jaundiced
newborns, because it places additional responsibilities on parents or guardians to
recognize and respond to developing jaundice or clinical symptoms.
MANAGEMENT OF HYPERBILIRUBINEMIA – AAP
RECOMMENDATIONS 2-4, 13
The following recommendations were developed by the AAP to aid in the
evaluation and treatment of the healthy term infant with hyperbilirubinemia.
Important in the development of these guidelines is the general belief that therapeutic
interventions for hyperbilirubinemia in the healthy term infant may carry significant
risk relative to the uncertain risk of hyperbilirubinemia in this population.
Evaluation
1. Maternal prenatal testing should include ABO + Rh (D) typing and a serum for
unusual iso immune antibodies.
2. A direct Coomb’s test, a blood type, and an Rh (D) type on the infant’s (Cord)
blood are recommended when the mother has not had prenatal blood grouping or
is Rh-negative.
3. Institutions are encouraged to save cord blood for future testing, particularly when
the mother’s blood group is O. Appropriate testing may then be performed as
needed.
4. When family history, ethnic or geographic origin, or the timing of the appearance
of jaundice suggests the possibility of G-6-D deficiency or some other cause of
26
hemolytic disease, appropriate laboratory assessment of the infant should be
performed.
5. A TSB level needs to be determined in infants noted to be jaundiced in the first 24
hours of life.
6. In newborn infants, jaundice can be detected by blanching the skin with digital
pressure, revealing the underlying color of the skin and subcutaneous tissue. The
clinical assessment of jaundice must be done in a well-lighted room. Dermal
icterus is seen first in the face and progresses caudally to the trunk and
extremities. As the TSB level rises, the extent of cephalocaudal progression may
be helpful in quantifying the degree of jaundice. Use of an icterometer or
transcutaneous bilirubinometer may also be helpful.
7. Evaluation of newborn infants who develop abnormal signs such as feeding
difficulty, behaviour changes, and apnea or temperature instability is
recommended – regardless of whether jaundice has been detected – to rule out
underlying illness.
Factors to be considered when assessing a jaundiced infant
1. Factors that suggest the possibility of hemolytic disease
•
Family history of significant hemolytic disease
•
Onset of jaundice before age 24 hours.
•
A rise in serum bilirubin levels of more than 0.5mg/dL/hr
•
Pallor, hepato splenomegaly
•
Rapid increase in the TSB level after 24-48 hours (consider G-6-PD
deficiency)
•
Ethnicity suggestive of inherited disease (G-6-PD deficiency etc.)
•
Failure of phototherapy to lower the TSB level
27
2. Clinical signs suggesting the possibility of other diseases such as sepsis or
galactosemia in which jaundice may be one manifestation of the disease.
•
Vomiting
•
Lethargy
•
Poor-feeding
•
Hepatosplenomegaly
•
Excessive weight loss
•
Apnea
•
Temperature instability
•
Tachypnea
3. Signs of cholestatic jaundice suggesting the need to rule out biliary atresia or other
causes of cholestasis
•
Dark urine or urine positive for bilirubin
•
High colored stools
•
Persistent jaundice > 3 week
4. Follow up should be provided to all neonates discharged less than 48 hours after
birth by a health care professional within 2 to 3 days of discharge.
5. Approximately 1/3rd of healthy breast-fed infants, have persistent jaundice after 2
weeks of age. A report of dark urine or light stools should prompt a measurement
of direct serum bilirubin. If the history (particularly the appearance of urine and
stool) and physical examination results are normal, continued observation is
appropriate. If jaundice persists beyond 3 weeks, a urine sample should be tested
for bilirubin and a measurement of total and direct serum bilirubin obtained.
28
TREATMENT
Table 1. Management of hyperbilirubinemia in the healthy term new born3, 4, 7, 11
*TSB level, mg/dL (μmol / L)
Exchange
Age
Exchange transfusion if
Consider
hours
transfusion and
Phototherapy
intensive phototherapy
phototherapy †
intensive
fails ‡
phototherapy
≤ 24§
-
-
-
-
25-48
≥ 12 (170)
≥15 (260)
≥20 (340)
≥25 (430)
49-72
≥ 15(260)
≥ 18 (310)
≥ 25(43)
≥ 30 (510)
> 72
≥ 17 (290)
≥ 20 (340)
≥ 25 (430)
≥30 (510)
*TSB indicates total serum bilirubin
†Phototherapy at these TSB levels is a clinical option, meaning that the intervention is
available and may be used on the basis of individual clinical judgment.
‡Intensive phototherapy should produce a decline of TSB of 1 to 2 mg/dL within 4 to
6 hours and the TSB level should continue to fall and remain below the threshold
level for exchange transfusion. If this does not occur, it is considered a failure of
phototherapy.
§Term infants who are clinically jaundiced at ≤ 24 hours old are not considered
healthy and require further evaluation.
29
PHOTOTHERAPY (PT)
Phototherapy is by far the most widely used treatment for hyperbilirubinemia,
and it is both safe and effective. Phototherapy has been found to be effective in
treating hyperbilirubinemia in hemolytic as well as in non-hemolytic settings. It has
dramatically reduced the need for exchange transfusion2, 3, 7, 12.
Factors that determine dose of phototherapy 12
•
Spectrum of light emitted
•
Irradiance of light source
•
Design of phototherapy unit
•
Surface area of infant exposed to the light
•
Distance of infant from light source
Light Spectrum 2, 3, 12, 13
Unconjugated
bilirubin
in
skin
gets
converted
into
water-soluble
photoproducts on exposure to light of a particular wavelength (425-475 nm). These
photoproducts are water soluble, nontoxic and excreted in intestine and urine.
For phototherapy to be effective, bilirubin needs to be present in skin so there
is no role for prophylactic phototherapy7.
Although bilirubin absorbs visible light with wavelength, about 400 to 500
nm, the most effective lights for phototherapy are those with high-energy output near
the maximum adsorption peak of bilirubin (450 to 460 nm). Special blue lamps with a
peak output at 425 to 475 nm are the most efficient for phototherapy.
30
MECHANISM OF ACTION
Photochemical reactions or mechanisms that lower serum bilirubin levels2, 3, 7, 12, 13
When bilirubin adsorbs light, 3 types of photochemical reactions occur:
1. Photoisomerisation / configurational isomerisation
-
Occurs in the extravascular space of the skin.
-
The natural isomers of unconjugated bilirubin (4Z, 15Z) are instantaneously
converted to a less toxic more polar water soluble diazo-negative compounds – E
isomers (4Z15E, 4E15E, 4E15Z), that diffuse into the blood and are excreted into
the bile without conjugation. However, excretion is slow, and configurational
isomers are not very stable and they revert back to Z-isomers, which is re
absorbed from the gut if the baby is not passing stools. Therefore, it is not a major
mechanism for decrease in TSB.
After about 12 hours of phototherapy, the photo isomers make up for about
20% of total bilirubin which is nontoxic.
Standard tests do not distinguish between naturally occuring bilirubin and the
photoisomer, so bilirubin levels may not change much even though the phototherapy
has made the bilirubin present less toxic.
2. Structural Isomerisation
It is the intramolecular cyclization of bilirubin to stable water soluble isomer –
LUMIRUBIN. Lumirubin makes upto 2-6% of serum concentration of bilirubin
31
during phototherapy and is rapidly excreted in the bile and urine, without conjugation.
Unlike photoisomerisation, the conversion of bilirubin to lumirubin is irreversible and
it cannot be reabsorbed.
It is the most important pathway for phototherapy induced decline in serum
bilirubin level and is strongly related to the dose of phototherapy used in the range of
6-12 μw/cm2/nm.
3. Photo-oxidation
This slow process converts bilirubin to small polar water soluble colorless
products that are excreted in urine. It is the least important reaction for reducing
serum bilirubin.
Phototherapy used for treating jaundice is like giving a drug. One is not
justified in using substandard light sources for treatment of neonatal jaundice. So it is
imperative that irradiance of phototherapy units must be checked periodically.
The infant is exposed under a portable or fixed light source kept at a distance
of about 45 cm from the skin2, 13. The distance between the baby and phototherapy
unit can be reduced to 15-20 cm to provide more effective or intensive phototherapy2.
Simple measures like lining the bassinet with white linen and putting a white curtain
around the phototherapy unit and bassinet have found to increase the efficiency of
phototherapy unit by several folds by reflecting light on to the baby’s skin
11, 38
.
During exposure to light, the eyes must be effectively shielded to prevent retinal
damage and a diaper may be kept on to cover the genitals.
During phototherapy, infant’s position should be changed off and on (every 2
hours) so that maximal areas of skin are exposed to light2.
32
For effective phototherapy, it is desirable that minimum spectral irradiance or
‘flux’ of 4-6 μw/cm2/nm is available and maintained at the level of infant’s skin2.
The flux must be checked after every 100-200 hours of use to ensure that
phototherapy lamps are effective2.
Double surface phototherapy is more effective than the single surface because
the average irradiance of the former is greater. Double surface phototherapy can be
provided either by double surface special blue lights or by conventional blue light and
undersurface fiberoptic phototherapy. This is a convenient way of delivering double
phototherapy when it is necessary to reduce the bilirubin level as rapidly as possible7.
Intensive PT should produce a decline in TSB of 1-2 mg/dL within 4-6 hours1, 7.
Intermittent versus continuous phototherapy11, 12
Clinical studies comparing these two methods have shown conflicting results.
If bilirubin levels are very high, intensive phototherapy should be administered
continuously until a satisfactory decline in the TSB level has occurred. On the other
hand, in most circumstances, phototherapy does not need to be continuous and it
should certainly be interrupted during feeding or parental visits.
Hydration11, 12
Because some of the lumirubin produced during phototherapy is excreted in
urine, maintaining adequate hydration and a good urine output does help to improve
the efficacy of phototherapy.
33
When to stop phototherapy11
A recent study found that, in infants who do not have hemolytic disease, the
average bilirubin rebound after phototherapy is less than 1mg/dL. Phototherapy may
be discontinued when the TSB level falls below 14 to 15 mg/dL. Discharge from the
hospital need not be delayed in order to observe the infant for rebound and, in most
cases, no further measurement of bilirubin is necessary.
Biological effects7, 10
Phototherapy is in use since last 50 years and has shown excellent track of
safety. There are more than 50 published controlled trials confirming the efficacy of
phototherapy7.
Recently, the effect of phototherapy on cerebral blood flow velocity (CBFV)
has been reported. Phototherapy increased mean CBFV in all preterm infants, which
returned to pre-therapy values after discontinuation of phototherapy only in nonventilated babies. Even in term babies, phototherapy increased CBFV, which returned
to pre-therapy level upon discontinuation of PT. PT has been shown to affect shortterm behavior of the term infant, which has been attributed to maternal separation39.
So mother should be encouraged to breast-feed and interact with her baby regularly.
In addition, phototherapy influences cytokine production by peripheral
mononuclear blood cells. Phototherapy has also photo-oxidative effects on
intravenous lipids, proteins and drugs like amphotericin B12.
34
Side effects2, 3, 12, 13
1. Insensible water loss is increased in infants undergoing phototherapy – leads to
hyperthermia, irritability and dehydration.
2. Passage of loose green stools and increased fecal water loss because of transient
lactose intolerance and irritant effect of photo-catabolites, increased bile salts and
unconjugated bilirubin in the bowel causes increased colonic secretory losses.
3. Increased risk of opening up of ductus arteriosus in preterm babies.
4. Hypocalcemia may occur due to secretion of melatonin from pineal gland –
Melatonin inhibits the action of cortisol, which causes Ca2+ uptake by bone.
5. Retinal damage has been described in animals. The eyes should be shielded with
eye patches.
6. Tanning of the skin of black infants. Erythema and increased skin blood flow may
be seen. Some infants may develop flea bite rash on trunk or extremities.
7. Infants with parenchymal liver disease with biliary obstruction may develop
peculiar bronze discoloration of skin – ‘BRONZE BABY’ SYNDROME – due to
excessive accumulation of one of the photoisomers designated as lumirubin which
is retained and polymerised to bilifuscin imparting brownish discolouration to the
skin. Therefore phototherapy is usually contraindicated in infants with direct
hyperbilirubinemia.
If both direct and indirect bilirubin are high, exchange
transfusion is probably safer than phototherapy because it is not known whether
the bronze pigment is toxic.
35
8. Mutations, sister chromatid exchange and DNA strand breaks have been described
in cell culture. Paradoxically, it has been shown that intermittent phototherapy
causes more damage to intracellular DNA as compared to continuous exposure to
light.
9. There is theoretical increased risk of developing malignancy of skin.
10. There is experimental evidence to suggest that exposure to light may disturb the
circadian rhythm of the sex hormones thus having potential implications regarding
onset of puberty and disturbances in future sex behaviour.
11. Photo-oxidant damage to RBCs may cause hemolysis.
12. Platelet turnover may be increased resulting in lower mean platelet counts but
bleeding does not occur.
•
Body weight and serum osmolality should be monitored.
•
Infants under phototherapy should receive additional feeds and fluid (2040 ml/kg/24 hrs) to safeguard against dehydration and haemoconcentration.
•
Term babies should be breast fed every 2nd hourly.
•
During exposure to light, infant skin gets, bleached and clinical evaluation
of severity of jaundice becomes unreliable in babies receiving
phototherapy and thus serum bilirubin levels should be monitored every 68 hrs.
36
•
Hct or Hb checked after every 48 hrs, because there is a greater need for
“top-up” blood transfusion since antibodies continue to cause hemolysis.
Sunlight is relatively ineffective because of low blue content of light. Besides,
hyperpyrexia and skin burns can occur in prolonged sunlight exposure. More data is
needed for recommendations for exposure to sunlight regarding duration of exposure,
time of the day and potential hazards7.
EXCHANGE BLOOD TRANSFUSION2, 21
It is the most effective and reliable method to reduce bilirubin levels.
It removes much of the circulating bilirubin and sensitized red cells, replacing
them with red cells compatible with mother’s antibody rich serum and providing fresh
albumin with binding sites for bilirubin.
Choice of blood2, 9, 21
Rh iso-immunisation : In emergency situation O Rh negative cells is used.
Ideal is to use O Rh Negative blood suspended in AB plasma. Cross matched Baby’s
blood group but Rh negative can also be used.
ABO incompatibility: Blood group O types (Rh compatible) compatible with baby.
Ideal is to use blood group O (Rh compatible) suspended in AB plasma.
Other situations: Cross-matched baby’s blood group.
Fresh citrate phosphate dextrose blood (not>3 days old) or heparinised blood
can be used for the procedure.
37
An effective exchange is achieved by performing the procedure with double
the blood volume of baby that is about 170 ml/kg. A double volume exchange
transfusion removes about 85% of the infant’s RBCs, but because most of the infant’s
bilirubin is in the extra-vascular compartment only 25% of the total body bilirubin is
removed. Post-exchange levels are about 60% of pre-exchange levels, and the reequilibration that occurs between the vascular and extra-vascular bilirubin
compartments produces a rapid rebound (within 30min) of serum bilirubin levels to
70% to 80% of pre-exchange levels12.
Administration of albumin half to one hour before the exchange, is associated
with more effective removal of bilirubin. Instead of albumin primed exchange
transfusion, some workers prefer addition of albumin into exchange blood itself2.
Before the procedure, blood sample should be collected for Hb, Hct, bilirubin,
glucose, potassium, and pH. Post Exchange, blood should be sent for Hb, Hct,
bilirubin, glucose, calcium, potassium, and pH. Umbilical swab for culture sensitivity
should be sent at the beginning and blood culture sensitivity at the end2.
The procedure is performed by passing a 5 or 6 F catheter in umbilical vein for
a distance where free flow of blood is obtained and blood is withdrawn with gentle
suction and donor’s blood is injected slowly in aliquots of 5-10 ml depending on the
size of baby. Heart rate, respiratory rate, SaO2 should be monitored throughout the
procedure. An assistant must maintain an accurate record of IN/OUT blood and
condition of the baby2.
After exchange transfusion, PT is continued.
38
Complications2, 21
1.
a.
ACD blood causes hypocalcemia, hyperkalemia, and acidosis
b.
Heparinised blood causes hypoglycemia, increase in FFA leading to
displacement of bilirubin from albumin binding sites.
c.
CPD blood is relatively safe but binds ionic calcium and magnesium
and leads to hypocalcemia and hypomagnesemia.
2.
Cardiovascular complications: Perforation of vessels, embolization, vasospasm,
thrombosis, infarction, arrhythmia, volume overload and cardiac arrest.
3.
Bleeding due to thrombocytopenia and deficient clotting factors.
4.
Infections: Bacteremia, hepatitis, CMV, HIV, Malaria.
5.
Hemolysis causing hemoglobinuria, hemoglobinemia, hyperkalemia.
6.
GVHD – can be prevented by using irradiated blood.
7.
Hypothermia hyperthermia
8.
NEC.
PHARMACOLOGICAL TREATMENT
Here, the objective is to accelerate normal metabolic pathways for bilirubin
clearance by using drugs:
Phenobarbitone1, 2, 7, 12
Has long been in use for prevention of jaundice. It induces glucuronyl
transferase enzyme thus improving conjugation as well as uptake and excretion of
bilirubin by liver cells.
Because of concerns about toxicity, it is rarely used, but there is increasing
evidence that it can be a useful preventive measure, especially in preterms, hemolytic
39
settings and in the event of extravasated blood. If used in doses of 5 to 10mg/kg/day,
it can have beneficial effect without significant adverse effects. A recent study by
Arya VB et al.,26 concluded that prophylactic phenobarbitone is not helpful in
reducing the incidence of hyperbilirubinemia in “at risk” term neonates.
Protoporphyrins2, 7, 12
Metalloporphyrins are competitive, inhibitors of heme oxygenase, a rate
limiting enzyme in heme catabolism, thus reducing the bilirubin production.
Clinical trials have demonstrated that tin mesoporphyrins (SnMP) suppress
bilirubin production. The drug has been found to be devoid of major adverse effects,
transient cutaneous rash being the only one.
SnMP at a single dose of 6μmol/kg proved more effective than phototherapy
in a group of term and near term infants without hemolytic disease. Recently, a
similar study on term breastfed infants without hemolytic disease also showed the
ability of SnMP to abolish the need for phototherapy. Till date, SnMP remains
experimental but it appears to hold a promise a future41-44.
High dose intravenous immunoglobulin
Recent
studies
have
demonstrated
that
high
dose
of
intravenous
immunoglobulin therapy is effective in modifying the hyperbilirubinemia in most
cases of Coomb’s positive hemolytic anemia. Intravenous immunoglobulin is given in
dose of 500-1000mg/kg as slow infusion over 2 hours2, 7, 12.
40
New approaches for prevention of bilirubin brain damage are on the horizon, but
phototherapy and exchange blood transfusion are still the most commonly used
effective modalities for lowering TSB levels.
41
BRAINSTEM EVOKED RESPONSE AUDIOMETRY (AUDITORY
BRAINSTEM RESPONSE)
DefinitionIt represents the bioelectrical responses from auditory nerve and various nuclei
in the brainstem in response to acoustic stimuli.
Auditory Brainstem Response Waveform55
It consists of 5-7 vertex positive peaks that normally occur within 10
milliseconds after the presentation of stimuli. Responses are usually displayed with
positive peaks reflecting activity toward vertex positive and these peaks are labeled
with Roman Numerals I through VII. The negative troughs following each positive
peak are labeled with Roman numerals and a prime (´) symbol such as wave I´.
The full complement of seven waves is not always present in the BERA
waveform, the most prominent vertex positive peaks being I, III and V.
Neural Generators of the BERA55
BERA is generated by the auditory nerve and subsequent structures within the
auditory brainstem pathways. Information regarding the origin of individual wave
components of BERA was provided by Moller and Janetta.
Wave I: It is the representation from the compound action potential in the distal
portion of cranial nerve VIII. The response is believed to originate from afferent
42
activity of cranial nerve VIII fibres as they leave cochlea and enter the internal
auditory canal.
Wave II: It is generated by the proximal VIII nerve as it enters the brainstem.
Wave III: Generated mainly in the cochlear nucleus (second order neuron).
Wave IV: It arises from pontine third order neuron. Mostly located in superior olivary
nucleus, but additional contributions may come from cochlear nucleus and nucleus of
lateral lemniscus.
Wave V: Generation of wave V reflects activity of multiple anatomic auditory
structures. Sharp positive peak of wave V arises mainly from the lateral lemniscus,
following slow negative wave represents dendritic potential in the inferior colliculus.
Wave V is the component analysed most often in the clinical application of the
BERA.
Wave VI and VII: These waves appear to be generated in the inferior colliculus,
perhaps in the medial geniculate body.
Characteristics of a normal BERA55
Several parameters can be examined to determine whether or not an BERA is
normal:
a. Absolute Latency –
The time interval between the stimulus onset and the peak of a waveform is referred
to as the latency of the response .The unit of measurement of latency is millisecond.
43
The latency of BERA waveforms is the most reliable and robust characteristic and
provides the core of BERA interpretation
44
b. Inter wave latency interval –
The time between peaks in the BERA is referred to as inter wave latency
interval / inter peak latency. The inter wave intervals used for clinical interpretation
are I-III, III-V, and I-V.
Wave I-III interval represents synchronous activity in 8th nerve and lower
brainstem. Wave III-V interval reflects activity primarily within brainstem. I-V
interval is considered a representation of overall activity from VIII nerve and nuclei
and tracts of the brainstem responsive to auditory stimuli.
c. Inter aural latency differences
Inter aural latency differences compare the absolute latencies of wave V
obtained from stimulation of the right versus left ear at equal intensity level. When
peripheral hearing sensitivity is similar in each ear, latency should not differ by more
than 0.2 -0.4ms.
d. Latency Intensity Functions
As the intensity of a stimulus decreases, the latencies of the peaks of BERA
increase and response amplitude decreases. Latency intensity functions differ
depending on the nature of a hearing disorder and differ for conductive, cochlear and
retro-cochlear lesions. Conductive hearing losses are characterized by longer than
normal latencies with latencies at all intensities being prolonged. Cochlear hearing
loss often show a steeper than normal latency intensity function with prolonged
latencies at low intensities. In retro cochlear auditory nerve/ brainstem disorder
45
latency of wave V is prolonged at all intensities but earlier peaks will be within
Normal limits.
e. Rate Changes
Increasing the rate at which stimuli are presented results in latency and
amplitude changes in BERA. When the stimulus rate is increased from about 10
stimuli per sec to 100 stimuli per sec., Wave V latency increases by approximately
0.5ms in normal individual. Increase in wave V latencies of more than 0.6-0.8 ms
from lower to higher rate is considered abnormal.
f. Amplitude
A normal BERA ranges in amplitude from 0.1-1 µV. As the stimulus intensity
decreases, response amplitude decreases. The lower amplitude earlier peak may
become obscure with wave V remaining visible at lowest intensities. Amplitude of
BERA is usually measured as peak to peak amplitude such as amplitude of a positive
peak to the following negative trough [eg. Wave V-V’]. A reduced Wave V/I
amplitude ratio may be diagnostically significant.
Recording Techniques55
•
Evoked potential should be acquired in a quiet test environment.
•
A sound treated room with appropriate acoustic and electrical isolation is
desirable
•
Recording of the early evoked potential are best obtained when the patient is
quiet and relaxed, sedation is often used in children
46
Stimulus types55
a. Clicks – An ideal stimulus for eliciting an BERA is a click, which is a brief
rectangular pulse of 50-200 µs duration with an instantaneous onset. The rapid
onset of click provides good neural synchrony, thereby eliciting a clearly
defined BERA
b. Brief tone bursts – These stimuli are very brief tones with rise - fall times of
only a few cycles and brief / no plateau duration, eg. 2-1-2 consists of 2 cycles
of tone in rise-fall and 1 cycle in plateau.
Electrodes55
BERA is recorded from electrodes attached to various positions on head;
BERA is generally plotted in the vertex positive direction with vertex upward.
2 methods1. Two channel recording
2. One channel recording
Two channels recording using a 4 electrode montage are recommended for
neurological applications in order to obtain ipsilateral and contralateral responses.
One channel recording is done using 3 electrodes with attachments at vertex
and one on each ear. Recordings are obtained between electrodes at the vertex and the
ear receiving the acoustic stimulus with other ear electrode as the ground.
Electrode application55
47
•
Skin must be thoroughly cleaned to remove excess oil, dead skin and dirt to
obtain a good contact between skin and electrode
•
Electrodes are filled with a conducting cream and taped into place
•
Once the electrodes have been applied, adequacy of contact with skin is
assessed by measuring electrical impedance between each electrode pair. For
high quality recording, inter electrode impedance ≤ 5kΩ is acceptable.
Processing of electrical activity55
Electrical activity picked up by the recording electrodes within the specified
time window must be processed through several stages to visualize the BERA
waveform. This is because the BERA peaks are of extremely small voltage (>1µV)
and are buried in a background of interference (termed ‘noise’), which includes
ongoing electroencephalogram (EEG) activity, muscle potentials caused by
movement or tension, and 50 Hz power-line radiation. The stages of processing
include amplification, filtering, and signal averaging.
Amplification and Filtering55
Because of small size of the BERA peaks, amplification is necessary to
increase the magnitude of the electrical activity picked up by the electrodes. An
amplifier gain of 105 is typically used.
The problem of interference obscuring the BERA can be diminished partially
by filtering the electrical activity coming from the electrodes. Bandpass filters are
used to accept energy only within the particular frequency band of interest and reject
48
energy in other frequency ranges. For BERA recording, A filter setting of 30-3000 Hz
is recommended to enhance the BERA when testing infants.
Filtering can only eliminate a portion of the interfering noise because of
overlap between the frequency content of the BERA and the frequency of the
interference. Therefore, another technique, called signal averaging, must be used to
further reduce unwanted interference.
Signal Averaging55
The BERA is very small, and even with filtering, it is buried with a
background of noise. Signal averaging helps to reduce this noise so that the signal, in
this case the BERA, can be detected. Signal averaging is possible because the BERA
is time-locked to stimulus onset, whereas the noise interference occurs randomly.
That is, the signal occurs at the same points in time following onset of the eliciting
stimulus, but the noise has no regular pattern. In signal averaging, a large number of
stimuli are presented, and the responses to each of the individual stimulus
presentations (termed ‘sweeps’) are averaged together to obtain a final averaged
waveform. By averaging, the random noise tends to cancel out, whereas the evoked
potential is retained because it is basically the same in each sweep. The greater the
number of stimulus presentations used, the greater the improvement in signal to noise
ratio, and the more clearly the BERA can be visualized in the final averaged
waveform.
49
ROLE OF BERA IN NEONATAL HYPERBILIRUBINEMIA
BERA is an effective and noninvasive means for the evaluation of auditory
functions in the neonate. It is not significantly altered by the state of consciousness,
drugs and variety of environmental factors51.
BERA changes in response to hyperbilirubinemia include loss of one or more
peaks of waves I to V, increase in latency of wave I, III or V or increased inter peak
interval or raised threshold51.
The acute changes seen in BERA can be reversed by early bilirubin lowering
interventions, thereby explaining the transient nature of bilirubin encephalopathy. But
persistent elevation of bilirubin can cause neuronal degeneration and thereby
persistent changes on BERA.
Some studies have found correlation between the bilirubin level and BERA
changes, whereas some have disproved it.
In a study done by Agrawal et al, it was found that 17 out of 30 (56.7%)
neonates with jaundice showed abnormalities in initial BERA. Commonest change
seen was raised threshold of wave V in 22 neonates (40%), absence of all waves at
90dBnHL (23.3%), prolongation of latencies of various waves (26.7%) and
prolongation of various interval (26.7%). After therapy, abnormalities reverted back
to normal in 10 cases & persisted in 7(41.7%). Development screening at l year was
abnormal in 3 infants, all of whom had persistent abnormalities in BERA51.
50
Abnormal BERA was recorded in 22 out of 30(73.3%) cases and the
abnormality persisted in the follow up tracings in 5 (16.6%) cases of the study group
in a study done by Sharma et al52.
In a study done by Gupta et al53, it was found that 56% of hyperbilirubinemic
neonates had some abnormalities in ABR (Auditory Brainstem Response) pattern.
ABR abnormalities were found with greater frequency in hyperbilirubinemic neonates
requiring a repeat exchange transfusion (mean serum bilirubin:30.8+/-2.4 mg %). On
follow-up retesting at 3 months, however all infants were found to have normal ABR
latencies and threshold, suggestive of transient toxic brainstem encephalopathy.
In a study done by Bhandari et al50, it was found that out of the 30 cases, 4
cases had absent ABR responses at the initial examination. After treatment, 3 babies
had persistent absent responses and 2 of these were clinically kernicteric. Total
plasma bilirubin level at the time of ABR examination had no correlation with the
incidence and degree of ABR abnormalities.
7 out of 18 neonates with hyperbilirubinemia that were studied by Deorari et
al54, had abnormal ABR. The abnormalities reversed to normal in all the seven cases
after exchange blood transfusion, indicating transient nature of bilirubin toxicity to
brain. All of these seven cases had normal hearing, development quotient and were
free of neurological sequelae on follow up for one year.
Thus serial BERA can be used as a tool to detect neuro developmental delay
secondary to neonatal hyperbilirubinemia.
51
52
METHODOLOGY
This study was conducted in the Department of Pediatrics of JSS Medical
College, Mysore. The study period was between November 2007- May 2009.
Study Design: CASE CONTROL STUDY
Inclusion Criteria: Thirty consecutive term AGA (Appropriate For Gestational Age)
neonates presenting to the NICU of J.S.S. Hospital, with total serum bilirubin
requiring intervention (using the American Academy of Pediatrics guidelines3,11) were
included in the study as cases and thirty normal term AGA neonates with uneventful
peri-natal period and a maximum measured serum bilirubin <12 mg/dl were included
as controls after obtaining informed consent.`
Exclusion criteria:
• Neonates born with birth asphyxia
• Intrauterine infections
• Sepsis
• Meningitis
• Amino glycoside administration
• Craniofacial malformation
• Preterm
• Conjugated hyperbilirubinemia
• Kernicterus
53
Mode of collection of data: All neonates presenting with icterus to the NICU of JSS
Hospital were subjected to total bilirubin estimation.
Total and direct bilirubin estimation was done by Jendrassik and Grof method.
Term neonates meeting the inclusion criteria were included as cases. Data
regarding the antenatal, birth history and detailed examination of the newborn were
collected in a predesigned proforma (Ref. Annexure i).
Weight was recorded using digital weighing scale.
Gestational age assessment was done by modified Ballard score.
Initial BERA was done within 3-24 hours of hospitalization after obtaining
informed consent from parents.
Procedure: BERA was performed in a dark quiet room. If the neonate was awake, it
was sedated by 20mg/kg of triclofos orally. Cup electrode was used and was applied
according to single channel, horizontal montage system of electrode placement. The
recordings were obtained through a computer based software, Intelligent hearing
system, version 3.3. Click acoustic stimuli with a click rate of 11.1/sec, rarefaction in
polarity was presented by insert ear phone to each ear at an intensity from 90-30
dBnHL. Time window was 15 milliseconds; with a filter setting of 30-3000Hz. The
presence of wave V at the Intensity of 30 dBnHL was taken as the normal threshold.
BERA measures considered for diagnosis were
• Loss of one or more peaks of I-V at 90 dBnHL.
• Raised threshold
54
• Absolute latencies of wave I, III, V peaks.
• Inter peak intervals of I - III, III - V and I – V.
Neonates were treated for hyperbilirubinemia according to the standard
treatment protocol (using the American Academy of Paediatrics guidelines) 3,11.
Repeat BERA was done in all cases after therapy
¾ At the time of discharge and
¾ After a follow-up period of 3 months
55
Fig 1- A jaundiced baby under phototherapy.
Fig 2. A jaundiced baby undergoing BERA
56
STATISTICAL METHODS APPLIED
Following statistical methods were employed in the present study
¾ Descriptive statistics
¾ Frequencies
¾ Cross tabs procedure
¾ Independent-Samples T Test
¾ Paired samples t test
¾ Chi-Square Test
Descriptive statistics
The Descriptive procedure displays univariate summary statistics for several
variables in a single table and calculates standardized values (z scores). Variables can
be ordered by the size of their means (in ascending or descending order),
alphabetically, or by the order in which one selects the variables (the default).
Frequencies
The Frequencies procedure provides statistics and graphical displays that are
useful for describing many types of variables. The Frequencies procedure is a good
place to start looking at one’s data.
Cross tabs procedure
57
The Crosstabs procedure forms two-way and multi-way tables and provides a
variety of tests and measures of association for two-way tables. The structure of the
table and whether categories are ordered determine what test or measure to use.
Independent-Samples T Test
The Independent-Samples T Test procedure compares means for two groups
of cases. Ideally, for this test, the subjects should be randomly assigned to two groups,
so that any difference in response is due to the treatment (or lack of treatment) and not
due to other factors.
Paired samples t test
The Paired-Samples T Test procedure compares the means of two variables
for a single group. It computes the differences between values of the two variables for
each case and tests whether the average differs from 0.
Chi- Square Test
It is a non-parametric test not based on any assumption or distribution of any
variable. It is used in testing hypotheses about nominal scale data. It is basically a test
of proportions.
All the statistical methods were carried out through the SPSS for Windows
(version 16.0)
58
RESULTS
This study was done in the Department of Pediatrics, JSS Medical College,
Mysore, over a period of 2 years from November 2007- May 2009.
There were 34 cases and 30 controls in the study.
BERA was done in both cases and controls. In the cases, BERA was done at
peak level of bilirubin, at the time of discharge and at follow up after 3 months. Of the
34 cases, 28 cases came for follow up after a period of 3 months, whereas 6 were lost
for follow up.
BERA was done only once for controls.
As there are no normative values of BERA parameter established for
newborns, controls were taken. The mean and SD was computed for each parameter.
The criterion for normality was considered to be within 2 SDs from the mean. The
following values were established as normal range for our study.
Table 2. Normal range of BERA parameter at 90 dBnHL
PARAMETER
NORMAL VALUE (Mean±2S.D.)
LATENCY OF V WAVE
5.96-6.5 (6.24±0.27)
LATENCY OF III WAVE
4-4.44 (4.22±0.22)
LATENCY OF I WAVE
1.53-1.87 (1.69±0.16)
LATENCY OF I-III
2.35-2.69 (2.52±0.17)
59
LATENCY OF III-V
1.67-2.03 (1.85±0.18)
LATENCY OF I-V
4.22-4.54 (4.38±0.15)
The following observation were made from the study and the study results
were analysed using appropriate statistical analysis and compared with other studies.
Table 3. Mean age (in days) of cases and controls
Number
Mean in days
Case
34
5
Control
30
4.7
The mean age of babies among the cases was 5 days and among the controls
was 4.7 days in our study.
Graph 1. Mean age (in days) of cases and controls
60
61
Table 4. Sex wise distribution of cases and controls
Case
Control
SEX
n=34
n=30
Male
22
15
Female
12
15
In our study among the cases M: F ratio was 1.8:1 and among the controls it
was 1:1
Graph 2. Sex distribution of cases and controls
62
Table 5. Average birth weight in kg of cases and control
N
Mean in kg
Case
34
2.8621
Control
30
2.8370
In our study the average birth weight of the cases was 2.86kg and that of
controls was 2.84kg
Graph 3. Average birth weight in kg of cases and control
63
Table 6. Distribution of cases in different bilirubin range
Maximum measured bilirubin in mg/dl
Case (n=34)
15-20
22(64.7%)
20-25
7(20.6%)
25-30
5(14.7%)
In our study it was found that majority of the cases 22 (64.7%) were having
bilirubin in the range of 15-20mg/dl, 7 (20.6%) cases between 20-25mg/dl and 5
cases(14.7%) between 25-30mg/dl.
Graph 4. Distribution of cases in different bilirubin range
64
65
Table 7. Number of cases with BERA changes
BERA changes
Cases (n=34)
Present
12(35.3%)
Absent
22(74.7%)
In our study out of the 34 cases 12 (35.3 %) cases were found to have BERA
changes in the form of absent wave forms, raised threshold, prolonged latencies or
prolonged inter peak latencies.
Graph 5. Percentage of cases with BERA changes
66
Table 8. Number of cases with different BERA changes at peak levels of bilirubin
BERA Changes
Cases*
Absent wave forms
6(17.6%)
Raised threshold
12(35.3%)
Prolonged latencies I
3(8.8%)
Prolonged latencies III
5(14.7%)
Prolonged latencies V
5(14.7%)
Prolonged Inter peak interval
6(17.6%)
I-III
Prolonged Inter peak interval
0
III-V
Prolonged Inter peak Interval
4(11.8%)
I-V
* No. of cases as percentage of the total sample size is shown along with the no.s
In our study, it was found that raised threshold was the most common BERA
change observed in majority of the patient 12(35.3%) cases, absent wave forms at 90
dB was seen in 6(17.6%) cases of which 3 had bilateral absent responses. Prolonged
latency I, III, V, prolonged inter peak latency I-III and I-V were seen in 8.8%, 14.7%,
67
14.7%, 17.6% and 11.8% of cases respectively. Prolonged inter peak III-V was not
observed in any of the cases.
Graph 6. Number of cases with different BERA changes at peak levels of
bilirubin
68
Table 9. Comparison of latencies of I, III, V of cases at peak level of bilirubin, at
the time of discharge and follow-up at 90 dBnHL
At peak
At discharge
At followup
p value
p value
p value
level(A) In msc
(B) In msc
(C)In msc
A Vs B
B Vs C
A Vs C
I
2.1088
1.7707
1.5814
0.041
0.098
0.017
III
4.5600
4.4813
4.1750
0.342
0.284
0.112
V
6.8250
6.6643
6.3521
0.545
0.107
0.145
Waves
p value was significant only for wave I when latency at peak level was
compared with that at discharge and follow-up
Table 10. Comparison of inter peak latencies of cases at peak level of bilirubin at
the time of discharge and follow-up at 90 dBnHL
At peak level
At discharge
At followup
p value
p value
p value
(A) In msc
(B) In msc
(C) In msc
A Vs. B
B Vs. C
A Vs. C
I –III
2.7592
2.5575
2.6067
0.201
0.816
0.475
III-V
2.0808
2.1133
2.2375
0.857
0.430
0.286
I-V
4.7567
4.6508
4.6567
0.679
0.685
0.801
Waves
69
p value was not significant for any of the inter peak intervals
Table 11. Comparison of BERA changes at peak level of bilirubin at the time of
discharge and follow-up
BERA Changes
Peak
At
Follow
level
discharge
up
Absent wave forms
6(17.6%)
3(8.8%)
1(2.9%)
Raised threshold
12(35.3%)
8(23.5%)
1(2.9%)
Prolonged latencies I
3(8.8%)
0
0
Prolonged latencies III
5(14.7%)
2(5.9%)
2(5.9%)
Prolonged latencies V
5(14.7%)
2(5.9%)
2(5.9%)
6(17.6%)
1(2.9%)
0
0
0
0
4(11.8%)
0
0
Prolonged Interpeak
Interval I-III
Prolonged Interpeak
Interval III-V
Prolonged Interpeak
Interval I-V
In our study, it was found that out of the 12 (35.3%) cases which had BERA
changes at peak level of bilirubin, 9 (26.4%) cases had persistent changes at the time
of discharge. Of these 9 cases, on follow up at 3 months 3 (8.8%) cases had persistent
70
changes and 2 were lost for follow up. Among the cases which had absent responses 3
cases continued to have absent responses bilaterally at the time of discharge. When
these cases were followed up, it was found that 1 case had persistent absent response,
1 was lost for follow up and in 1 case, wave forms appeared but with slightly
prolonged latency of V peak. All these 3 cases had bilirubin > 25mg/dl before
therapy.
Among the 12 cases with raised threshold it was found that 8(23.5%) cases
had raised threshold even at discharge but on follow up only 1(2.9%) case had
persistently raised threshold. Of the 3 cases with prolonged latencies of wave I on
follow up all were found to have improved latencies, Of the 5 cases with prolonged
latencies III and V, 2 had persistent changes at discharge ,as well as at follow up
whereas in 3 cases it was found that latencies improved. Similarly it was found that of
the 6 cases with prolonged I-III and 4 cases with prolonged I-V when followed up all
had normal latencies.
Table 12. Correlation of Bilirubin level with BERA changes
Maximum measured
No. of
Cases with
% of cases showing
bilirubin in mg/dl
Cases
BERA changes
BERA changes
15-20
22
4
18%
20-25
7
3
43%
25-30
5
5
100%
χ2=12.163 p value< .002
71
In our study, it was observed that there was statistically significant correlation
between increasing bilirubin level and BERA changes.
Table 13. Type of treatment given to cases
Type of treatment
Frequency
Percentage
Exchange transfusion + phototherapy
4
11.8
Phototherapy
29
85.3
Phototherapy + phenobarbitone
1
2.9
Total
34
100.0
In our study, majority of the cases 29 (85.3%) had received phototherapy, 4
underwent exchange transfusion and one child received phototherapy with
phenobarbitone in view of inability to perform exchange transfusion due to non
availability of a central or umbilical line.
Graph 7. Types of treatment given to the cases
72
BERA REPORTS
Fig 3. A BERA report of a control showing normal BERA waveforms.
Fig 4. A BERA report showing absent waveforms at 90 dBnHL
73
Fig 5 A BERA report showing raised threshold i.e absent waveforms at 30
dBnHL but presence at 50 dBnHL
Fig 6. A BERA report showing prolonged latency V of 7.2ms
74
Fig 7. A BERA report showing prolonged interpeak interval I-V of 5.4 ms
75
DISCUSSION
Neonatal unconjugated hyperbilirubinemia is neurotoxic. Besides other
sequelae, it is found to be particularly toxic to the auditory pathway and may result in
sensorineural hearing loss.
BERA provides an accurate and non invasive evaluation of the auditory
pathway. The BERA changes in response to hyperbilirubinemia includes loss of one
or more peaks of waves I-V, raised threshold, increase in latency of wave I, III or V or
increased inter peak interval. Some of the earlier observations of BERA have
demonstrated the reversible effects of bilirubin toxicity. This study was undertaken to
evaluate the effect of hyperbilirubinemia in term newborns on BERA and change if
any after therapy.
In our study, it was observed that 12 out of 34 cases had BERA changes at
peak level of bilirubin. Among the changes, most common abnormality was raised
threshold seen in all the 12 cases (35.3%).
76
Table . 14 Comparison of various BERA changes in different studies
Parameter
Cases with BERA
Our
Agrawal
Sharma
Gupta et
Study
et al
et al
al
et al
et al
n=34
n=30
n=30
n=25
n=18
n=30
12(48%)
7 (39%)
14
12(35.3%) 17(56.7%) 22(73.3%)
Deorari Bhandari
(46.6%)
Changes
Absent Wave form
6(17.6%)
7(23.3%)
-
5(16.5%)
5 (28%)
-
Raised Threshold
12 (35%)
22(73.3%)
-
12(48%)
-
-
Prolonged latency I
3(8.8%)
3(10%)
22(73.3%)
10(40%)
-
-
Prolonged latency III
5(14.7%)
7(23.3%)
-
-
-
Prolonged latency V
5(14.7%)
8(26.7%)
-
4(22%)
-
Prolonged latency
6(17.6%)
2(6.7%)
-
-
-
-
-
-
-
-
4(11.7%)
6(20%)
-
6(33.3%)
-
22(73.3%)
I-III
Prolonged latency
III-V
Prolonged latency
I-V
The frequency of BERA abnormalities noted in our study was slightly less
compared to other study.
The commonest abnormality observed in our study was raised threshold seen
in 12 (35.3%) cases which was comparable with other studies.
77
The other commonest abnormalities noted was prolonged latencies (14.7%)
and absent wave forms (17.6%) which were also comparable with other studies.
Prolonged latencies of waves and inter peak interval indicated prolongation of nerve
conduction at auditory nerve and brain stem level.
All cases were reviewed with a follow up BERA at the time of discharge and
after a period of 3 months in our study and in other studies by Sharma et al, Gupta et
al and Agrawal et al. Whereas Deorari et al followed up the cases till 1 year. Bhandari
et al did not follow up the cases.
Out of the 12 cases with significant BERA changes, it was found that 9 cases
had persisted abnormalities at the time of discharge and 3 cases were found to have
persistent abnormalities at the time of follow up after 3 months.
Table 15. Comparison of the BERA changes at peak level at discharge and follow
up with other studies
Study
n
At peak level
At discharge
At follow up
Our study
34
12 (35%)
9 (26%)
3(8.8%)
Agrawal et al
30
17 (56.7%)
7 (23.3%)
3 (10%)
Sharma et al
30
22(73.3%)
7 (23.3%)
5 (16.7%)
Bhandari et al
30
5 (16.7%)
2 (6.6%)
-
Deorari et al
18
7 (39%)
0
0
Gupta et al
25
12 (48%)
0
0
78
In the study done by Agrawal et al, it was found that 7 out of 17 (41.7%) had
persistent changes at discharge. Of these, 3 cases had persistent changes at follow up.
It was found that latency of different waves and interval decreased significantly after
therapy. Response remained absent in 2 of 7, raised threshold persisted in the rest 5.
At follow up after 3 months, 3 had persistent abnormalities51.
In the study by Sharma et al, it was found that 7 cases had persistent changes
among which latencies had normalized, but prolonged inter wave intervals persisted.
On follow up at 3 months, 5 cases continued to have changes52.
But studies by Deorari et al and Gupta et al showed normalization of BERA
changes at follow up, indicating transient nature of Bilirubin encephalopathy53,54.
By binding to the nerve terminals, bilirubin causes a reversible lowering of
membrane potential and a decrease in nerve conduction6, thus explaining the
reversibility of early bilirubin encephalopathy1. Improved brain functions may be due
to removal of bilirubin because of phototherapy or exchange transfusion. At higher
concentration, the nerve terminals are severely injured and bilirubin penetrates the
axons with retrograde uptake into the cell body and also, if acidosis persists, BH2 is
formed resulting in permanent neuronal damage6.
In our study, it was found that there was significant correlation between serum
bilirubin more than 25mg and presence of significant BERA changes.
The study by Bhandari et al found that mean maximum bilirubin level had no
correlation with the incidence and degree of BERA abnormalities. In their study, in 5
babies who had BERA changes, mean level of bilirubin was 17.82 +/- 3.87. This was
79
not significantly different from the value of 16.95 +/- 2.76mg/dl average value of
bilirubin of 30 babies50.
Whereas studies by Sharma et al, Agrawal et al, Deorari et al, Gupta et al, also
found statistically significant correlation of BERA changes with Serum Bilirubin
>25mg.
Indicating that higher the level of bilirubin there is increased risk of bilirubin
toxicity but with active intervention, it is possible to reverse the changes.
Correlation of the findings of this study with previous few studies indicates
that BERA can be used as a useful non invasive tool to determine auditory functions
in the neonate especially changes of early bilirubin toxicity.
80
SUMMARY
In the present study, there were 34 cases and 30 controls.
BERA was done in both cases and controls. In the cases, BERA was done at
peak level of bilirubin, at the time of discharge and at follow up after 3 months.
Of the 34 cases, 28 cases came for follow up after a period of 3 months,
whereas 6 were lost for follow up.
The mean age of the cases was 5 days and it was 4.7 days in controls.
The male to female ratio was 1.8:1 among cases while it was 1:1 among
controls.
Average birth weight of cases in our study was 2.8621kg and that of controls
was 2.8370kg.
Majority of the cases, 22 cases (64.3%) had maximum measured bilirubin
between 15-20 mg/dl, 7 cases (20.6%) between 20 to 25 mg/dl and 5 cases (14.7%)
with bilirubin between 25 to 30 mg/dl.
12 (35.3%) out of 34 cases in our study had BERA changes.
The most common BERA change noted in our study was raised threshold seen
in 12 cases (35.3%), absent wave form seen in 6(17.6% )of cases. Prolonged latencies
I was seen in 3(8.8% )of cases, prolonged latencies III and V were seen in5( 14.7%)
cases, prolonged I-III interpeak interval and prolonged I-V in 6(17.6%) and 4(11.8% )
cases, respectively. Prolonged III-V was not noted in our study.
81
BERA changes persisted in 9 cases at the time of discharge of which in 3
cases, changes persisted at follow up after 3 months. 2 out of the 12 cases with BERA
changes were lost for follow up.
Absent wave forms persisted in 3 cases at the time of discharge, of which in
one case, it persisted at follow up, in one case wave forms appeared with slightly
prolonged latencies and other child was lost for follow up.
Raised threshold persisted in 8 cases at discharge, of which in one case it
persisted even at follow up.
All the 3 cases with prolonged latency I when followed up had improved
latencies.
Prolonged latencies III and V persisted in 2 out of 5 cases at discharge, which
persisted even at follow up.
It was found that of the 6 cases with prolonged I-III and 4 cases with
prolonged I-V latencies on follow up all had improved latencies.
In our study, it was found that all the 5 cases with bilirubin >25mg/dl had
BERA changes and out of these 5, 3 cases had persistent BERA changes at follow up
thus there was significant correlation between BERA changes and maximum
measured bilirubin indicating that higher the level of bilirubin, higher the risk of
toxicity to auditory pathway.
However, this study should be validated with further larger study.
82
CONCLUSION
Hyperbilirubinemia is one of the common problems encountered in the
neonatal period.
Auditory neuropathy is noted in one third to half of infants with significant
hyperbilirubinemia and may result in sensori-neural hearing loss.
BERA can be used as an effective and non invasive means of assessing the
functional status of the auditory pathway.
Neonates with BERA changes need to be followed up over a period, an
essential aim being the early identification of infants with impaired hearing so that
rehabilitation can be initiated at a time when brain is still sensitive to the development
of speech and language.
83
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89
PROFORMA
(For Data Collection as part of the thesis being done by Dr.Nayana Nayak,
J.S.S.Medical College, Mysore)
1. Name
4. I.P. No.
2. Age in Days
5. DOA
3. Gender
6. DOD
7. Mother’s Name
9.
8. Occupation
10. Occupation
Father’s Name
11. Address
12. Phone No.
(Residence)
(Mobile)
13. Diagnosis
14. Day of life on which Bilirubin was in phototherapy range
90
15. Birth History
A. Type of
delivery
B. APGAR
C. Birth Weight
16. Mother’s History
A. Age
B. Married Life
C. Consanguinity
D. Gravida
17. Details of Present Pregnancy
91
18. Examination
Vitals
S/E
19. Investigations
Hb%
Mothers Blood
group
TC
Maximum measured
T.Bilirubin
DC
Bilirubin at the time
of Discharge
PBS
Additional
investigation if any
Reticulocyte
Count
DCT
Baby Blood
Group
92
20. Treatment
TypePhototherapy / Exchange
If phototherapy, then, How many days?
21. BERA
A. At Peak Level of Bilirubin
i.
Absolute Latencies
RIGHT EAR (msec)
INTENSITY/
LEFT EAR (msec)
RATE
I
ii.
III
V
I
III
V
Interpeak Intervals/Latencies (msec)
RIGHT EAR (msec)
I-III
III-V
LEFT EAR (msec)
I-V
I-III
93
III-V
I-V
B. At the time of discharge
i. Absolute Latencies
RIGHT EAR (msec)
INTENSITY/
LEFT EAR (msec)
RATE
I
III
V
I
III
V
ii. Interpeak Intervals/Latencies (msec)
RIGHT EAR (msec)
I-III
III-V
LEFT EAR (msec)
I-V
I-III
III-V
I-V
C. After 3 Months
iii. Absolute Latencies
RIGHT EAR (msec)
INTENSITY/
LEFT EAR (msec)
RATE
I
III
V
I
III
V
iv. Interpeak Intervals/Latencies (msec)
RIGHT EAR (msec)
I-III
III-V
LEFT EAR (msec)
I-V
I-III
Signature Of the Guide
94
III-V
I-V
95
KEY TO MASTER CHART
AWF
Absent wave forms
RT
Raised threshold
PL I
Prolonged latencies I
96
PL III
Prolonged latencies III
PL V
Prolonged latencies V
PIPI I-III
Prolonged Inter peak Interval I-III
PIPI III-V
Prolonged Inter peak Interval III-V
PIPI I-V
Prolonged Inter peak Interval I-V
Yes
With BERA changes
No
With no BERA changes
NS
No show (lost for follow-up)
ET
Exchange transfusion
97
98
Sl.
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
Name
B/O Hemalatha
B/O Rupa
B/O Mahadevamma
B/O Pushpa
B/O Ashakiran
B/O Rani
B/O Bindu
B/O Jyothi
B/O Lakshmamma
B/O Suma
B/O Bhavya
B/O Zobeda
B/O Sudha
B/O Geetha
B/O Roopa
B/O Leelavathi 1
B/O Leelavathi 2
B/O Sheena
B/O Anitha
B/O Shantala
B/O Saritha
B/O Umamaheshwari
B/O Thayaba Sultana
B/O Suma
B/O Shini
B/O Shamala
B/O Poornima
B/O Dharitri
B/O Shweta
B/O Sangitha
B/O Satvi
B/O Mahadevamma
B/O Saraswati
B/O Shilpa
Age
in
Days
10
8
5
4
5
2
3
4
4
5
5
4
5
3
4
6
8
5
5
4
4
4
6
3
5
4
4
5
5
6
6
6
6
5
Gender
Birth
Weight
in kg
Type of
Delivery
Baby's
Blood
Group
Male
Male
Male
Male
Male
Male
Female
Male
Male
Female
Female
Male
Male
Male
Male
Female
Female
Female
Female
Female
Male
Male
Male
Male
Male
Male
Female
Male
Male
Female
Female
Female
Male
Male
2.5
2.75
3.3
3.5
2.5
3
2.6
3
2.6
2.5
2.6
3.25
2.8
2.6
2.5
2.6
2.5
3
2.9
2.75
3.5
2.75
2.6
2.8
2.75
3.4
3.4
2.75
2.9
2.9
3
2.6
2.6
3.25
LSCS
Vaginal
Vaginal
Vaginal
Vaginal
Vaginal
Vaginal
Vaginal
LSCS
LSCS
Vaginal
LSCS
Vaginal
LSCS
LSCS
LSCS
LSCS
LSCS
Vaginal
Vaginal
LSCS
Vaginal
LSCS
Vaginal
LSCS
LSCS
Vaginal
Vaginal
LSCS
Vaginal
LSCS
LSCS
Vaginal
Vaginal
A+ve
O+ve
A+ve
A+ve
O+ve
O+ve
A+ve
O+ve
A+ve
O+ve
O+ve
B+ve
O+ve
O+ve
O+ve
O+ve
O+ve
O+ve
O+ve
O+ve
O+ve
O+ve
O+ve
B+ve
B+ve
A+ve
O+ve
O+ve
O+ve
A+ve
O+ve
O+ve
AB+ve
A+ve
MASTER CHART- Patient Details
Mother's
Date of
DCT
Blood
Admission
Group
A-ve
O+ve
O-ve
O+ve
B+ve
O+ve
A+ve
B+ve
A+ve
O+ve
O+ve
AB-ve
O+ve
O+ve
O+ve
O+ve
O+ve
O+ve
O+ve
O+ve
A-ve
B+ve
O+ve
O+ve
O+ve
A+ve
O+ve
O+ve
O+ve
O+ve
O+ve
O+ve
AB+ve
O+ve
Positive
Negative
Positive
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
99
9-Feb-08
12-Jan-08
24-Jan-08
18-Jan-08
18-Jan-09
15-Nov-08
18-Feb-09
16-Jan-09
7-Jan-09
4-Nov-08
11-Feb-08
25-Oct-08
18-Jun-08
3-Feb-09
10-Oct-08
12-Oct-08
14-Oct-08
27-Nov-08
29-Jan-09
25-Feb-08
10-Oct-08
22-Aug-08
8-Dec-07
6-Dec-07
10-Oct-08
2-Nov-08
16-Nov-08
10-Nov-08
2-May-08
16-Apr-08
20-Jan-09
4-Feb-08
29-Apr-09
4-Dec-08
Date of
Discharge
Max level
of Bilirubin
in mg/dl
Level of Bilirubin
at discharge
in mg/dl
15-Feb-08
22-Jan-08
30-Jan-08
24-Jan-08
21-Jan-09
20-Nov-08
22-Feb-09
19-Jan-09
16-Jan-09
8-Nov-08
14-Feb-08
4-Nov-08
22-Jun-08
9-Feb-09
21-Oct-08
22-Oct-08
23-Oct-08
2-Dec-08
3-Feb-09
1-Mar-08
14-Oct-08
27-Aug-08
12-Dec-07
10-Dec-07
17-Oct-08
11-Nov-08
21-Nov-08
15-Nov-08
8-May-08
22-Apr-08
25-Jan-09
6-Feb-08
3-May-09
10-Dec-08
30
19.9
28.19
25.46
26.55
15.42
15.6
23.8
20.02
16.01
24.8
26.9
18.4
18.22
15.08
20.7
19.84
15.26
24.96
23
19.26
17.6
16.28
17.46
17.61
17.01
17.62
17.32
19.24
18.26
19.22
17.96
20.2
18.26
14
8.74
14.02
13.25
11.2
14.96
12.38
10.55
12.3
11.12
13.96
11.15
11.2
12.38
11.76
10.12
9.62
13
12.36
12
7.98
11.5
12.91
13.48
11.76
9.19
11.48
10.26
13.2
12.48
12.24
10.4
15.6
11.24
Type of
Treatment
No.of days
of therapy
Phototherapy+
Phenobarbitone
Phototherapy
ET + Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
ET+Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
ET + Phototherapy
ET + Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
Phototherapy
4
6
6
5
3
2
3
2
2
3
2
5
3
2
4
3
3
5
4
5
3
3
3
3
2
2
2
4
3
4
3
2
4
4
MASTER CHART- Cases with different BERA changes at various levels
AT PEAK LEVELS
Sl. No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
AWF
Yes
Yes
No
No
No
No
Yes
No
Yes
No
Yes
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
RT
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
PL
I
No
No
Yes
No
No
No
No
Yes
No
No
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
PL
III
No
No
Yes
Yes
yes
No
No
Yes
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
PL
V
No
No
Yes
Yes
Yes
No
No
Yes
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
PIPI
I-III
No
No
No
Yes
Yes
Yes
No
Yes
Yes
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
AT DISCHARGE
PIPI
IIIV
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
PIPI
I-V
No
No
No
Yes
Yes
No
No
No
Yes
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
AWF
Yes
Yes
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
RT
Yes
Yes
Yes
No
Yes
No
Yes
No
No
Yes
Yes
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
PL I
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
PL
III
No
No
Yes
No
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
100
PL
V
No
No
Yes
No
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
AT FOLLOW UP
PIPI
I-III
No
No
No
No
No
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
PIPI
IIIV
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
PIPI
I-V
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
AWF
Yes
No
No
No
No
No
No
No
No
No
NS
NS
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
NS
NS
NS
NS
RT
Yes
No
No
No
No
No
No
No
No
No
NS
NS
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
NS
NS
NS
NS
PL I
No
No
No
No
No
No
No
No
No
No
NS
NS
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
NS
NS
NS
NS
PL
III
No
No
Yes
No
Yes
No
No
No
No
No
NS
NS
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
NS
NS
NS
NS
PL
V
No
No
Yes
No
Yes
No
No
No
No
No
NS
NS
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
NS
NS
NS
NS
PIPI
I-III
No
No
No
No
No
No
No
No
No
No
NS
NS
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
NS
NS
NS
NS
PIPI
IIIV
No
No
No
No
No
No
No
No
No
No
NS
NS
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
NS
NS
NS
NS
PIPI
I-V
No
No
No
No
No
No
No
No
No
No
NS
NS
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
NS
NS
NS
NS
101
102
`