resting electrocardiographic pattern of term …

1

RESTING ELECTROCARDIOGRAPHIC PATTERN OF TERM

NEONATES WITH MODERATE TO SEVERE UNCONJUGATED

HYPERBILIRUBINAEMIA SEEN AT THE UNIVERSITY OF ILORIN

TEACHING HOSPITAL, ILORIN.

A DISSERTATION SUBMITTED IN PART FULFILMENT OF THE

REQUIREMENTS FOR THE AWARD OF THE FELLOWSHIP OF THE

NATIONAL POST GRADUATE MEDICAL COLLEGE OF NIGERIA IN

THE FACULTY OF PAEDIATRICS

BY

DR ADEBAYO GANIYU YUSUF OLOKO

MBBS (ILORIN), 2001

DATE OF EXAMINATION: MAY, 2014

2

DECLARATION

I, DR. ADEBAYO GANIYU YUSUF OLOKO hereby declare that this dissertation

is original unless otherwise acknowledged. The dissertation has not been presented to

any College for Fellowship examination nor has it been submitted elsewhere for

publication.

Dr. Adebayo G Y Oloko ------------------------------------------------------

Signature/Date

3

CERTIFICATION

We hereby certify that Dr. Adebayo GY Oloko of the Department of Paediatrics and

Child Health, University of Ilorin Teaching Hospital, Ilorin, prepared this dissertation

under our close supervision.

Name of supervisors:

Professor OA Mokuolu …...…………………………………………………

Signature/Date

Prof IA Katibi ……………………………………………..………

Signature/Date

Prof. A Ojuawo ……………………………….……………………

Signature/Date

4

DEDICATION

This dissertation is dedicated to Almighty God, the all knowing and to millions of

children in the world struggling to survive neonatal jaundice and heart diseases.

5

ACKNOWLEDGEMENTS

I am sincerely grateful to Almighty God for the successful completion of this project.

I am also very grateful to my teachers and supervisors; Professor OA. Mokuolu,

Professor IA Katibi and Professor A Ojuawo, who did not only supervise this project

work but also ensured that I had a sound and firm training as a Resident Doctor in

Paediatrics. I appreciate your mentorship and critical review of this project. Thank

you all and may God bless and reward you abundantly.

I wish to wholeheartedly show my profound gratitude to Professor Emeritus Adeoye

Adeniyi (Baba) for his advice and encouragement at every stage of my residency

training and for being there always as a good model.

I am grateful to all Consultants in the Department of Paediatrics; Professor WBR`

Johnson, Professor OT Adedoyin, Dr SK Ernest, Dr M. Adegboye, Dr A Abdulkarim,

Dr O Adesiyun, Dr MAN Adeboye, Dr JK Afolabi, Dr R Olaosebikan, Dr AO Saka,

Dr MB Abdulkadir, Dr TO Obasa Dr OS Katibi and Dr RI Bidmus. I appreciate you

all. Many thanks to my other colleagues, the nursing and all staff in the Department

of Paediatrics and Child Health, UITH Ilorin. Thank you all for your support.

I am grateful to the authorities of University of Ilorin teaching Hospital (UITH) Ilorin

for the opportunity of the residency training and the present study. Thanks to all staff

of Cardiopulmonary Assessment Unit and Chemical Pathology laboratory of UITH

6

Ilorin. Thanks to the authority of University College Hospital (UCH) Ibadan for the

opportunity of further training in Paediatric Cardiology. Thanks to Dr A Ogunmodede

of UITH Ilorin, Professor Brune of University of Ilorin, Professor NMA Jiya of

UDUTH Sokoto, Professor Taofeeq of UDUTH, Professor SI. Omokhodion of UCH

Ibadan and Dr OO Ogunkunle for their assistance.

Special thanks and regards to my wife, Barr. Mrs AB Olokonla who has displayed

real friendship, sacrifice and support in ensuring that I attain a comfortable height

academically. May the good Lord bless and reward you. To my children; Awalulahi-

Mustapha, Nana-Hauwau and Baba-Abdulsalam, my mother, Nana-Hauwau and

BABANPAKATA, thank you all for your prayers and enormous support. I thank you

all.

TABLE OF CONTENTS

7

Title i

Declaration ii

Certification iii

Dedication iv

Acknowledgements v

Table of Contents vii

List of Abbreviations viii

List of Tables x

List of Figures xi

Appendices xii

Summary xiii

Introduction 1

Literature Review 4

Justification 35

Aims and Objectives 36

Materials and Methods 37

Results 53

Discussion 67

Conclusion 72

Recommendations 73

Limitations of the study 74

References 75

Appendix I 84

ABBREVIATIONS

8

BBB Bundle branch block

CAD Coronary artery disease

CFR Coronary flow reserve

CB Conjugated bilirubin.

DMSO Dimethyl sulfoxide

DNA Deoxyribonucleic acid.

ECG Electrocardiogram or Electrocardiograph

EDTA Ethylene diamine tetra acetate

EPU Emergency Paediatric Unit

FBC Full blood count

FEV Forced expiratory volume.

Hb Haemoglobin

HPLC High-pressure Liquid Chromatography

IHD Ischemic heart disease

LVEF left ventricular ejection fraction

LVH Left ventricular hypertrophy.

LQTS Long QT syndrome

NICU Neonatal Intensive Care Unit

NNJ Neonatal Jaundice

OFC Occipitofrontal circumference

9

PCV Packed cell volume

RAD Right axis deviation

RBC Red blood cell

RVH Right ventricular hypertrophy.

SIDS Sudden infant dead syndrome

TSB Total serum bilirubin

UITH University of Ilorin Teaching Hospital

UDPGT Uridine diphospho-glucuronyl transferase.

UCB Unconjugated bilirubin.

VSD Ventricular septal defect.

UCH University College Hospital.

WBC White blood cell.

WPWS Wolff –Parkinson-White Syndrome.

LIST OF TABLES

10

Table I: Socio-demographic characteristics of the subjects and controls -------53

Table II: Clinical and anthropometrics of the subjects and controls---------------54

Table III: Laboratory parameter of the studied group--------------------------------56

Table IV Electrocardiographic findings in the subject and controls---------------57

Table V Electrocardiographic abnormality in the subjects and controls---------59

Table VI Correlation between bilirubin concentration and ECG findings--------61

Table VII Correlation between ECG abnormalities and bilirubin levels-----------62

LIST OF FIGURES

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Figure 1: Normal neonatal electrocardiogram picture-------------------------------14

Figure 2: Electrocardiographic tracing of a normal neonate------------------------15

Figure 3: Normal pathway of bilirubin production-----------------------------------18

Figure 4: Normal pathway of bilirubin metabolism----------------------------------19

Figure 5: Some neonatal abnormal electrocardiogram-------------------------------33

Figure 6: Standard 12-lead Electrocardiographic lead placement------------------45

Figure 7: Pie chart showing distribution of causes of NNJ in subjects------------55

Figure 8: Normal ECG tracing in one of the control---------------------------------58

Figure 9: Electrocardiogram of a jaundiced neonate showing LQTS--------------60

Figure 10 Scatter plot of heart rate and bilirubin concentration---------------------63

Figure 11 Scatter plot of PR interval and bilirubin concentration------------------64

Figure 12 Scatter plot of QRS axis and bilirubin concentration---------------------65

Figure 13 Scatter plot of QTc and bilirubin concentration---------------------------66

Appendices

12

I Ethical approval, UITH, Ilorin-----------------------------------------------------84

II National Postgraduate Medical College approval-------------------------------85

III Information sheet and informed consent form---------------------------------86

IV Study proforma-----------------------------------------------------------------------88

V Socio economic classification scheme--------------------------------------------92

SUMMARY

13

Neonatal jaundice (NNJ) is highly prevalent in Nigeria and the world at large. It is

known that unconjugated hyperbilirubinaemia is toxic to all tissues of the body. It is

therefore postulated that bilirubin toxicity on the neonatal heart should be detectable

on the electrocardiogram (ECG).

This is a comparative cross sectional study comparing resting ECG of term neonates

with moderate to severe unconjugated hyperbilirubinaemia and matched controls.

Fifty neonates with moderate to severe NNJ served as subjects while 50 age and sex-

matched healthy neonates without jaundice served as controls. Subjects were

recruited using clinical grading of severity of hyperbilirubinaemia by Kramer.

Controls were recruited from post natal ward and postnatal clinic. Bilirubin was

estimated using modified Jendrassik Groff method. Resting 12-lead ECGs were

obtained from the two groups of patients using a heat writing Atria 6100

electrocardiograph®. Data were analysed using SPSS 18 computer software.

Age, gender, anthropometric indices and vital signs were comparable in the two

groups (p=0.10). The mean unconjugated bilirubin was significantly higher in the

subjects than controls (p<0.05). Patients in both groups were in sinus rhythm. The

mean heart rate in the groups was comparable with no statistically significant

difference. There was no statistically significant difference in the amplitude, duration

and frontal plane axis of P wave, QRS complex and T wave. The mean QTc intervals

in the groups were comparable with no statistically significant difference. Only 2 of

14

the subjects (4%) compared to 1 of the controls (2%) had tachycardia. Three of the

subjects (6%) compared to 2 of the controls (4%) had P wave abnormalities. The

mean PR interval was significantly shorter in subjects compared to the controls

(p=0.022). Three of the subjects (6%) compared to 2 of the controls (4%) had

prolonged PR interval. Only 1 of the controls (2%) had a superior axis. Compared to

5 of the subject (10%), 3 of the controls (6%) had rSr in lead I and II. Compared to

10 (20%) of the subjects, 8 of the controls (16%) had QTc prolongation. ST segment

abnormalities were seen in 5 of subjects (10%) and this was not significantly different

compared with 4 (8%) in the controls. T wave abnormalities seen in 3 (6%) of the

subject is comparable 5 (10%) seen in controls. Overall, ECG abnormalities were

observed in 64% of the subjects and are comparable to 54% in the controls. There was

no significant correlation between bilirubin level, electrocardiographic parameters

and ECG abnormalities seen in this study. In conclusion, there was no statistically

significant difference in the ECG of jaundiced neonates compared to that of normal

controls. However, more robust studies preferably large scale, multicentre,

longitudinal cohort studies are required to draw strong conclusion on the cardiac

effect of unconjugated hyperbilirubinaemia. Within the limits of the present study, it

appears that screening for ECG abnormality may not necessarily be a priority in the

management of neonates with NNJ.

15

INTRODUCTION

The electrocardiogram (ECG) is a recording of the electrical activity generated by the

heart on the body surface. It is an invaluable, cheap and non-invasive method of

assessing either the primary diseases of the heart or cardiovascular effects of other

systemic diseases.1-3

In neonatal period, ECG abnormalities are common and some of them are fatal

thereby contributing to neonatal mortality. The incidence of heart diseases in neonates

detectable by routine clinical examination is estimated to be about 7.5 per 1,000 live

births. This incidence increases by four to ten times when ECG and detailed

echocardiographic examinations are included. Mortality rate from cardiac anomalies

is 2.5 to 3 infants per 1,000 births. Almost half of these can be diagnosed during the

first week of life.4,5 Early identification of life-threatening arrhythmogenic disorders

which often manifest in infancy or later in life as complication may allow initiation

of effective preventive therapy.6,7

A large prospective study has indicated that some infants with prolonged QT interval

in the first week of life had sudden death, and was labelled as sudden infant death

syndrome (SIDS). This has necessitated the performance of ECG during the first

16

month of life in all newborns, as part of neonatal screening program in some centres.7-

9 Causes of abnormal ECG in neonatal period include asphyxia, drugs, electrolyte

abnormalities, myocardial ischaemic, inborn errors of metabolism, congenital heart

disease among several others.10-13

Neonatal jaundice (NNJ) is the clinical manifestation of hyperbilirubinaemia. This is

defined as serum bilirubin greater than 5 mg/dl in neonates and 2 mg/dl in the adult.14-

16 It is the commonest disease affecting newborns worldwide as 50-60% of normal

term neonates have clinically noticeable jaundice and about 5-10% of them will

require intervention. All preterm neonates by their immature physiology are expected

to have significant jaundice16. The commonest cause of NNJ and kernicterus is

Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency singly or in combination

with other disease conditions. With advancements in treatment, complication from

NNJ is now only common in middle and low income countries of the world.17-19

Bilirubin has both toxic and tissue-protective effects and its cardiac involvement has

long been recognized.20 Early complication of NNJ manifests as acute bilirubin

encephalopathy which can result in mortality while late complications are mental

retardation, enamel dysplasia, athetoid chorea and gaze palsy.21-23 At serum

unconjugated bilirubin level of 20 mg/dl and above, autopsy revealed bilirubin

staining and necrotic damage in the brain, gut, heart, liver, kidney, spleen, pancreas,

17

lung, gonads, adrenals and other body tissues necessitating the term vigintophobia in

earlier published literature.22 In studies reported in adults, abnormal ECGs are

commonly found in diseases associated with jaundice, such as epidemic viral

hepatitis,24-25 obstructive jaundice,26 leptospirosis27 and drug-induced jaundice.28

These abnormal ECGs in disease associated with jaundice are attributed to either

toxic effect of hyperbilirubinaemia or to the background pathology.24 Toxicity of

bilirubin is pan-systemic21-22, it is therefore hypothesized that hyperbilirubinaemia

that is causing systemic toxicity in neonates is likely to cause neonatal cardiac toxicity

which should be demonstrable on the ECG. The effects of neonatal conditions like

perinatal asphyxia, electrolyte imbalance and hypoglycaemia on the ECG of neonates

are well documented.10,28 However, there is paucity of literature on the effect of

hyperbilirubinaemia on the neonatal heart. This is coupled with the growing

knowledge of the effects of bilirubin on the cardiovascular system and the importance

of the ECG as a cheap and non-invasive tool for detecting and defining cardiac disease

especially cardiac rhythm abnormalities. These constitute the rationale for this study.

Also, finding from the present study will contribute to the efforts aimed at

understanding the effect of unconjugated hyperbilirubinaemia on the cardiovascular

system of the newborn. With such knowledge, early intervention can be sought for if

needed.

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Relevance of the Study to the Practice of Paediatrics

The outcome of this study within its limits provides baseline information on the

pattern of the ECG in neonates with jaundice. Correlates of clinical findings, ECG

parameters to the level of hyperbilirubinaemia provide information for cardiac

pathology secondary to hyperbilirubinaemia so that early identification and treatment

would be instituted. This would go a long way towards decreasing the morbidity and

mortality from cardiac involvement in hyperbilirubinaemia.

LITERATURE REVIEW

Definitions

Electrocardiography (ECG) is the recording of the electrical activity generated by the

heart on the body surface during heart beat. It is an invaluable cheap and non-invasive

method of assessing either the primary diseases of the heart or cardiovascular effects

of systemic diseases.1,3 The electrocardiograph is the machine while

electrocardiogram is the tracing of electrical activities generated by the machine. The

electrode is the sensor that has direct contact with the skin, each recording the same

cardiac electric signal from its vantage position.1-3

Jaundice is the clinical description of the yellowish discoloration of the skin, sclera

and mucous membrane. It is the peripheral clinical manifestation of

19

hyperbilirubinaemia.14 It was derived from the French word “jaune” which means

yellow. In normal cord and adult blood, serum bilirubin is about 1-2 mg/dl, mostly

conjugated. Hyperbilirubinaemia is defined as serum bilirubin greater than 2 mg/dL

in the older child and adults and 5 mg/dl in term neonates.14-16 When serum bilirubin

exceeds 6 mg/dl in term neonates, it manifests clinically as NNJ. Bilirubin

concentration of 12 mg/dl in term neonates is classified as mild; between 12.10 mg/dl

- 19.90 mg/dl is moderate while a serum level of 20 mg/dl and above is categorised

as severe neonatal hyperbilirubinaemia.29-30 In a normal term neonates, mild levels of

jaundice is usually due to normal physiology of newborn and it causes no harm,

whereas moderate to severe levels do have pathological basis and are injurious to the

body.14, 30

ECG as a Diagnostic Modality for Cardiac Diseases

Historical perspective

Scientists have long noticed that the relation between lightning, lodestone, amber,

gymnotus, malapterurus, trichiurus tetraodon and the torpedo fish is electricity.

Bancraft31, in 1763, demonstrated that the torpedo fish was capable of delivering a

shock of electricity. Galvani32 was the first to demonstrate electromotor activity in the

leg muscle of frogs in 1791. In 1856, Kolliker and Muller33 discovered the electrical

20

activity of the heart when a frog sciatic nerve-gastrocenemius preparation fell onto an

isolated frog heart and both muscles contracted synchronously. Lippmann and

Marey34 invented the capillary electrometer in 1872 which could demonstrate cardiac

electrical activity without exposing the heart. The first direct recording of human

cardiac electrical potentials was by Augustus Waller35 in 1887. Einthoven,36 in 1901,

invented a string galvanometer for recording cardiac electrical activity from the body

surface. He identified the major waveforms of the ECG as P, Q, R, S, T and U.

Goldberger37 introduced the three augmented (aV) leads. These are aVR which fills

the gap between leads I and II, aVF is located between leads II and III and aVL fills

the gap between leads III and I. The addition of the three augmented (aV) leads to the

triaxial reference system produces the hexaxial system at 30 degrees to each other.

Wilson et al38 introduced precordial leads. The six common precordial leads used to

produce the standard 12-lead ECG is labelled V1 to V6 as demonstrated in Figure-6.

Modification of these leads includes V3R or V4R as in Paediatrics to accommodate

certain peculiarities like right ventricular predominance. In 1913, Ziegler3 published

a comprehensive study evaluating the three standard bipolar leads I, II and III in ECG

tracings from premature infants, term infants and children with normal and abnormal

hearts. The other advancement made include automated recording and interpretation.

Interpretation of the ECG depends on previous knowledge about diseases and their

ECG manifestation.

21

Modalities of electrocardiography (ECG)

There are various ways by which electrocardiogram are obtained in human subject,

these includes:

(a) Resting ECG: Resting ECG is administered when the patient is at rest. It is used

to determine the health of the heart and circulatory system at rest. The patient’s resting

ECG is of interest because it helps to define the default heart activity and capability.

It may be normal in some disease conditions thereby necessitating further evaluation

by other type of ECG such as exercise ECG or Holter monitoring.39

(b) Exercise ECG: In Exercise ECG, electrodes are placed as in resting ECG albeit

with some modifications such as applying tension tape, but the patient exercises on a

treadmill or stationary bicycle during the test. This is also referred to as cardiac stress

test. It is used to determine the amount of work the heart of the patient can tolerate

while also determining stress-related cardiac abnormalities like arrhythmia. The

patient may decompensate in the process, hence, the system must have capacity for

resuscitation.39

(c) Ambulatory/Holter ECG: This is named after Dr. NJ Holter.40 The ambulatory

is used in the diagnosis of transient cardiac events such as paroxysmal

supraventricular tachycardia and other conduction disorders. It is used to detect

http://www.wisegeek.com/what-is-a-treadmill.htm

22

irregularities in the heart rhythms of patients during their daily activity. The ECG uses

electrodes that are applied to the skin with adhesive and then connected to ambulatory

ECG monitor which is usually clipped onto the belt or worn in a pouch. Certain types

of long term ambulatory ECG devices can be surgically implanted in the chest and

remain there for longer time. The two types of ambulatory ECG are the continuous

and the intermittent recorders.

Continuous recorder ECG devices monitor the patient's heart activity over a period of

24-72 hours or longer continuously. Intermittent recorder ambulatory ECG devices

are used when patients have infrequent heart arrhythmia. In the loop type of

intermittent recorder, the patient presses a button on the recording device when he or

she experiences heart symptoms while in the event monitor type, the electrodes are

not attached to the patient’s body with adhesive but can be worn like a watch or carried

in a purse or pocket. When patient experiences symptoms of heart arrhythmia, the

button is pressed to activate the device. The patient then places the electrodes of the

device on the skin for recording.40

(d) Wireless ECG: In wireless ECG, electrodes are covered in conductive gel and

placed on the patient's chest. The wireless units on the back of the electrodes relay

data to a base unit. The patient can wear or carry the base unit without having to worry

about managing leads. The electrodes can communicate directly with a computer or

23

telemetry station such that the health care provider is alerted or set to provide

emergency care.39

(e) Electrophysiology: Electrophysiology (EP) is an invasive procedure that is used

in evaluating heart rhythm disturbances. During EP study, thin wire electrodes are

inserted through a vein in the groin or neck. The wire electrodes are threaded into the

heart using fluoroscopy. Spread of electrical impulses can be mapped out to locate the

source of arrhythmia for which an ablation surgery may be done. Electrical signals

can also be sent through the catheter to initiate the heart rhythm disturbances for

evaluation. The abnormal heart rhythm may also be stimulated to evaluate the

effectiveness of a drug. The results of the study may also help in determining further

therapeutic measures, such as inserting a pacemaker, defibrillator, adding or changing

medications or performing additional ablation procedures. 39

(f) Oesophageal ECG: The oesophagus is behind the left atrium in close proximity

and when the electrode is placed in the esophagus it will record atrial activity more

locally than the standard ECG leads. This is useful in evaluating cardiac rhythm

disturbances, especially P wave in atrial flutter with 2:1 atrioventricular (AV)

conduction. Oesophageal ECG records atrial wave that may be larger than the

simultaneously recorded ventricular wave.41

24

Other investigative procedures for cardiovascular evaluation include cardiac

catheterization, chest X-ray, computed tomography (CT scan) of the chest,

echocardiography, magnetic resonance imaging (MRI) of the heart, myocardial

perfusion scans and radionuclide angiography among several others.

Recording the Neonatal ECG

Recording and interpretation of the ECG in the neonatal period is more difficult than

at any other age because of the rapid perinatal haemodynamic changes and the wide

overlap of normal and abnormal findings. Normal standards reported for this age

group also vary because they are based on data obtained with different types of

recorders like photographic, direct- writer and jet-writer.5 In evaluating the ECG,

there is no general agreement on how to take into consideration various age and

growth factors like chronologic age, gestational age, weight, state of nutrition,

anaemia and perinatal factors that affect the circulation like placental transfusion,

persistent arteriovenous shunt through the ductus arteriosus and hypoxia. There are

however, some obvious deviations from normal in some disease conditions.

The current recommendation by American Heart Association (AHA) for recording

paediatric ECGs is 150 Hz as a minimum bandwidth and 500 Hz as a minimum

sampling rate. A more recent systematic investigation by Canadian Cardiac Society

25

suggested a minimum bandwidth of 250 Hz and a minimum sampling rate of 1000

Hz.8

The procedure for ECG recording in neonates is the same as in adults except for some

adjustments. The limb leads and colour codes are the same; six precordial leads, V1-

V6 are also applicable but with occasional addition of V4R and V7 to have a better

view of both right and left ventricles. The same electrocardiograph that has potential

for the above adjustment can be used in adults and neonates.2 Different types of

electrodes are used in neonates but the most common are the disposable gel electrode

with adhesive properties. Artefacts in newborn ECGs are due to interference from

bedside electrical equipment and patient movement. There could be a fine irregular

undulation of the baseline due to muscle tremors, respiration, jitteriness or crying, but

normal complexes are seen along with the artefacts and the intrinsic cardiac rhythm

of the patient is usually not affected. The use of drugs like chloral hydrate to sedate

the patient for ECG especially neonate is not generally acceptable.5 ECG machine

with minimal Holter memory that allow evaluation of the record before printing is

invaluable in Paediatrics.8

Normal Neonatal Electrocardiographic Pattern

1) Heart rate: This is the number of heart beat per minutes. At birth the average rate

is 140 beats per minute at rest. If agitated or crying, it could be as high as 230 beats

26

per minute. It drops to less than 120 during the first several hours and then rises to

attain a maximum average rate of 160 at one to two months of age.1-3,8

2) The rhythm: Sinus rhythm is more common in neonate. Sinus arrhythmia is less

common at fast heart rate and thus neonates show a more regular rhythm than young

children and adolescents particularly in the first week of life.3,5,6,8

3) P wave: At birth P wave duration ranges from 60 to 85 msec, there after it declines

to about 50 msec through the first month of life. P wave amplitude in lead II range

between 0.5 - 2.5 mV at birth, it decreases to a low point of about 1mV at about second

days of life and later gradually rise to a maximum 2.5 mV at about five months of

age. P-wave axis ranges between 0 and 90 degrees. 3,5,42

(4) PR interval: The average PR interval at birth is 96 msec, it increases to 100 msec

after several minutes to hours and then declines to as low as 90 msec at approximately

one to three weeks of age. It gradually increases to reach 110 msec at the end of the

first year and 120mse in adult life. The normal neonatal PR interval ranges from a

minimum of 70 msec. to a maximum of 140 msec, with a mean of 100msec.8, 42

(5)The QRS complex: QRS patterns in the chest leads are classified into: (1) The

adult R/S pattern where the S wave is larger than the R wave in the right chest leads

and smaller than the R wave in the left chest leads. (2)The infantile R/S pattern in

which the R-wave amplitude is higher than that of the S wave in both right and left

27

chest leads and (3) The neonatal R/S progression where there is complete reversal of

R/S progression in which the R wave is larger than the S wave in the right and smaller

than the S wave in the left chest leads.1, 5

(6) QRS axis: The mean frontal plane QRS axis during the first day of life is about

+I300 with a range of -10 to +1350. At the end of the first week, the mean is 1300. By

the end of the 3rd week, it reduces further to 1050 and by the 5th week, it is 900. By

the end of the second month, it reduces to about 750. The range is between 600 and

1800 in the immediate post neonatal period. In premature infants the mean frontal

QRS axis has a significantly lower value than in full-term infants until the end of the

second week. 3,5,8

(7) Q-wave amplitude (frontal plane): There is an increase in the depth of the Q

wave in all leads except aVL from birth. The normal Q wave amplitude in the neonate

is 0.1-0.3mV. It reaches a maximum value at 6 months of age and then gradually

declines in amplitude to adult value by 1 year of age.5,8

(8) T-waves: At birth the incidence of upright T waves in lead V1 is about 70%. There

is a gradual decline so that by the fifth day, the average incidence is zero. At birth,

over 60% of the T waves in V6 are upright; it reduced to10% during the first day, then

rise to about 50% by the end of the second day and to 100% by the fourth day. This

28

same phenomenon is reflected in the amplitude of the T wave in leads V1 and V6. T-

wave axis is +7 degrees from 1 to 5 minutes after birth. The axis shifts to +115 degrees

by 2 to 4 hours after birth. It then reduces to +10 degrees during the ensuing 2 to 7

days. From the First week to the beginning of the third month of life, the frontal T-

wave axis gradually increases to approximate the adult value which is about 600. The

P amplitude wave range between 0-3mV.42,43

(9) QT interval: At birth the QT interval is about 295msec, the lowest value of 240

msec is reached at about 3 weeks. It then increases to 260- 270msec at one year and

370msec in early adulthood. The average corrected QT interval (QTc) is 400msec at

birth; it then risen to a peak of 420msec during the first 24hours and declines rapidly

to between 405-410msec at the end of the second day and to lowest value of 380msec

at one month. The stable adult value is reached at the end of the second month. 42, 44

ST segment: The ST segment should ideally be on isoelectric line. ST segment

abnormalities are not uncommon in neonates. ST elevation or depression of 0.5-1mm

had been reported in 20-50% of normal neonates.11, 42, 45

30

Figure 1: Normal Neonatal Electrocardiographic drawing2

31

Figure 2 Normal Neonatal ECG Tracing2

32

Pathogenesis of Cardiac Dysfunction in Hyperbilirubinaemia

Bilirubin metabolism

Bilirubin is the end product of haem (ferriprotoporphyrin-IX) catabolism.

Approximately 75% of haem is derived from haemoglobin while the remainder is

derived from ineffective or failed erythropoiesis, nonhaemoglobin haemoproteins like

myoglobin, catalase, nitric oxide synthase, peroxidases and cytochromes.14, 46,47 The

catabolism takes place in reticuloendothelial system (RES) which includes the spleen,

liver, lymph nodes and the bone marrows. Haem-oxygenase (HO) enzyme initiates

the first of the two steps, converting haem to biliverdin, Fe and carbon-monoxide

using nicotinamide adenosine dinucleotide (NADPH). In the second step, biliverdin

is reduced to bilirubin and catalyzed by the enzyme biliverdin reductase using NADP.

One gram of haemoglobin produces 35mg of bilirubin. Unconjugated bilirubin is

33

transported in the plasma tightly bounded to albumin, other proteins and the

erythrocytes. Bilirubin-albumin complex reaches the plasma membrane of the

hepatocytes. Bilirubin is transferred across the hepatic cell membrane. In the

hepatocytes, bilirubin bounds principally to ligandin protein X, Y, Z and other

cytosolic-binding proteins. While in the hepatocytes, unconjugated bilirubin is

enzymatically combined with glucuronic acid, producing bilirubin monoglucoronide

and diglucoronide in the presence of uridine glucuronyl transferase (UDPGT).

Free unconjugated bilirubin in the plasma readily crosses lipid containing membranes

and will concentrate in the tissue leading to toxicity. The bound conjugated and

unconjugated bilirubin are responsible for antinflamatory, antioxidant and anti

apoptotic property of bilirubin, hence the dual role of bilirubin.14,46,47

Conjugated bilirubin is more water soluble and is sufficiently polar to be filtered

through the kidney or excreted into the bile and then into the gut. In the gut, some are

hydrolyzed back to unconjugated bilirubin by beta-glucuronidase on the brush border

and is absorbed to enter the enterohepatic circulation. Some are reduced by gut flora

to urobilinogen which is absorbed and excreted in the urine while some are reduced

to stercobilinogen which is responsible for yellow colour of the faeces.16,46,47 (Figures

3 and 4)

35

Figure 3: Bilirubin biosynthesis16

36

Figure 4: Bilirubin metabolism16

37

Bilirubin as a Cardio-protective Antioxidant

Lower animals eliminate their haem as biliverdin which is non-toxic. The reason the

human body has to proceed from non toxic biliverdin to a toxic bilirubin in the process

of haem elimination was not clear until antioxidant property of bilirubin was

discovered.20, 48 The serum bilirubin concentration is now known to have a U- shaped

relationship with risk of tissue damage. That is, the concentration that is too low

predisposes to high oxidative stress, cardiovascular and other tissue injury. Moderate

level protects against cellular and tissue injury by exerting antioxidant, anti-apoptotic

and anti-inflammatory effects while higher levels are cytotoxic causing cell death,

tissue and organ damage.16, 20, 49-50

Breimer et al,49 in their prospective study of 7,685 patients demonstrated that Serum

bilirubin concentrations in the range of normal protect against coronary artery disease

(CAD). However, concentrations too low or too high increase atherogenicity and thus

ischaemic heart disease (IHD). Serum bilirubin thus has a U-shaped relationship with

the events of IHD. This may be due to the confounder as it was also noted that low

serum bilirubin strongly correlated with several cardiovascular risk factors like age,

38

cigarette smoking, social class, diabetes, serum cholesterol and lower serum albumin.

The serum bilirubin concentration of 4-5 mg/dl considered to be toxic in the quoted

adult studies is lower than 20mg/dl and above usually seen in severe NNJ, thus more

toxicity is anticipated. Under physiologic conditions,

bilirubin provides more potent protection against lipid peroxidation than α-

tocopherol, formerly known to be the most effective in preventing lipid

peroxidation.50-51 One molecule of glutathione can consume one oxidant molecule,

whereas one molecule of bilirubin can consume up to 10,000. At concentrations as

low as 10 nmol, bilirubin can protect against 10,000-fold greater concentrations of

H2O2. This demonstrates bilirubin to be the most potent physiological antioxidant.

Under normal conditions, bilirubin accounts for 2% of plasma antioxidant activity.

However, in injury, bilirubin production is up- regulated accounting for more than

70% of antioxidant activities.51-52 The mechanism is that peroxyl free radicals is said

to have a very high affinity for free or albumin- bounded bilirubin than for fatty acid

or any other substrate and thus were usually preferentially oxidized to produce non

toxic biliverdin, which, in the presence of biliverdin reductase, is reduced back to

bilirubin and the cycle continues. In the absence of bilirubin, free radicals cause

oxidative damage to all tissues of the body. It oxidises fatty acid to produce various

forms of lipids that are ingested by macrophages to produce foam cells. These are

deposited in the blood vessels to cause atheroma, atherosclerosis, coronary and carotid

39

artery disease and IHD.53-54 Studies have reported a strong inverse association

between serum bilirubin and severity of (CAD),55 peripheral and carotid vascular

disease, stroke, carotid intima media thickness,56,57 familial hypercholesterolaemia,

early familial coronary artery disease,58 IHD,59,60 and coronary blood flow reserve

(CFR). 61

The involvement of bilirubin in immune reactions and inflammatory processes has

important cardio protective effect. Oral or intravenous administration of biliverdin or

bilirubin has been demonstrated to inhibit Forssmann anaphylaxis, reduce vascular

leakage, inhibit inflammation and immunological responses, hence faster resolution

of inflammation.62,63

Haem oxygenase is the rate limiting step in catalytic conversion of haem to bilirubin,

carbon monoxide (CO) and iron. Studies have shown that Haem oxygenase

production is always induced or up-regulated in stress conditions like shock, hypoxia,

ischemia reperfusion and inflammations as a coping mechanism against oxidative

injury.63, 64 Benaron and Bowen,63 in their study, demonstrated that the mean increases in

serum bilirubin of infants with circulatory failure, prenatal asphyxia, aspiration

syndromes and proven sepsis were significantly lower than in controls matched for

gestational age and birth weight. These findings are consistent with the hypothesis

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Benaron%20DA%22%5BAuthor%5D

40

that bilirubin is consumed in vivo as an antioxidant in distress conditions such that

severely asphyxiated neonates rather appear cyanosed or dusky, but not jaundiced.

Experimental studies that knock-out haem-oxygenase genes are associated with

rapidly increasing tissue oxidative damage and cell death.50,62,65,66 Induction and up-

regulation of haem oxygenase-1 with resultant higher level of biliverdin, bilirubin, Fe

and CO was successfully used to prevent xenograft cardiac transplant rejection,

improved post-infarction survival50 and to prevent toxic effect of anticancer agents,

especially doxorubicin.67 Various control studies have demonstrated that the

mechanism of action of Simvastatin is induction of haem oxydenase-1.The drug is

used in the control of hyperlipidemia and heart diseases.68-70

Bilirubin as a Cardio-toxic Pro-oxidant

Oxidative stress is behind almost all cellular damage and death, from inflammation to

heart attack and stroke. Bilirubin is known to have antioxidant effects in moderate

concentration but is toxic at high concentrations.20 The polar group of the bilirubin

molecules are involved in intramolecular hydrogen bonding. This restricts solvation

and therefore renders the pigment nearly insoluble in water but lipophilic at pH 7.4.

At this PH, saturated bilirubin gradually aggregates and precipitates from plasma

forming crystals. Being lipophilic, bilirubin is preferentially sequestrated and

41

concentrated more in fatty tissue. This low water solubility of bilirubin and its

tendency to aggregate and precipitate at physiologic pH is the factor responsible for

its toxicity.14,46,47 Autopsies on kernicteric infants revealed bilirubin staining of all

body tissues and organs including the heart, kidney, adrenals, gonads, lungs, gut and

others.22 At cellular levels, the mechanism of bilirubin toxicity in high concentration

includes:22, 46,47

1) Uncoupling of oxidative phosphorylation,

2) Inhibition of cellular respiration and protein phosphorylation,

3) Inhibition of mitochondrial enzymes,

4) Interference with deoxyribonucleic acid (DNA) and protein synthesis,

5) Alteration of glucose metabolism,

6) Initiation of mitochondrial pathway of apoptosis,

7) Inhibition of the function of N-methyl-aspartate ion channels receptor thus

altering the function and makes cell membranes more permeable. This results in

cell leakages and therefore cell death both in vivo and in vitro in a concentration

dependent manner.

These processes occur in all cells and are responsible for the toxicity of bilirubin.

42

Various experimental studies have demonstrated that morphological changes occur

with incubation of cells in different molar ratios of unconjugated bilirubin. Cell death

increases directly with bilirubin concentration, temperature and inversely with PH and

albumin content in all cell lines cultured. These include microglia, cardiomyocites,

erythrocytes and others, leading to the loss of soluble proteins from cells. Bilirubin

closely resembles agents such as deoxycholate that affects cell membranes by

bringing about the loss of cellular proteins due to alteration of membrane lipids.71-73

Bernstein and Landing,22 in their review of sixty-nine cases of kernicterus,

demonstrated that at unconjugated bilirubin levels of 20 mg/dl and above, necrotic

damage occurred in tissues and organs. In all cases, there were necrobiosis with

pyknosis, karyorrhexism with leukocytic infiltration and nuclear fragmentation. The

degree of necrosis strongly correlated with the unconjugated serum bilirubin

concentration.21-22

Pathophysiologic Effects of Hyperbilirubinaemia on the Heart

Toxicity of bilirubin is pan-systemic and the degree of affectation depends on its

concentration in the tissue. The occurrence of necrobiosis in all tissues at toxic level

is responsible for various degrees of aberration in cardiovascular, renal and nervous

system physiology of jaundiced patients.21-22

43

In pathologic range, studies have shown bilirubin to be a functional antagonist of

isoprenaline by forming a monolayer mechanical barrier on the surface of the cell

membrane. This may explain the dose dependent association of jaundice with sinus

node dysfunction and bradycardia,26 vasodilatations and reduced blood pressure

(BP),74 negative chronotropic and inotropic effects.75-77 This finding was however at

variance with other studies that found no effect of bilirubin on cardiovascular

function.78-80

Green et al 81 in their study has demonstrated that the response of the left ventricle to

dobutamine was strikingly blunted in jaundiced patients as compared to that seen in

the normal controls. This may contribute to the susceptibility of jaundiced patients to

postoperative shock and acute renal failure. These is at variance with another study

which suggested that high incidence of endotoxemia in liver disease and jaundice

trigger the induction of vascular nitric oxide synthesis and is responsible for cardiac

suppression and systemic hypotension.82

Meakin83 noted that in a patient who had suffered from essential hypertension, BP

became normalized when the patient developed jaundice but hypertension returned

long after the successful treatment of the jaundice. He also found that in all cases of

obstructive jaundice, the systolic, diastolic and pulse pressure were lower than those

observed in the normal population. This was attributed to bradycardia and the

vasodilatory effect of bilirubin.

44

In an experimental study, Williams et al 84 has demonstrated that haemorrhage in

jaundiced animals led to a disproportionate fall in BP and a higher mortality compared

to the normal control group.

ECG Changes in Hyperbilirubinaemia

Diseases associated with jaundice are usually accompanied by abnormal ECG.

Various studies23-27 have demonstrated bradycardia, sinus arrest, hypotension and

arrhythmia in patients with jaundice due to viral hepatitis. These abnormalities had

been attributed to either the disease causing the jaundice, the toxic effect of bilirubin

on the heart or the complications like ischaemia and electrolyte disturbance that

usually accompany the disease. These abnormalities subside with resolution of the

jaundice. However, known cardiovascular complications of viral hepatitis like,

myocarditis and cardiomyopathy may also be responsible for the abnormal ECG.85

The toxic effect of bilirubin on the sinoatrial node (SA node) was also implicated in

bradycardia and sinus node dysfunction observed in obstructive jaundice caused by

liver pathologies and bile duct abnormalities. Talib et al26 demonstrated that

hyperbilirubinaemia could be responsible for various forms of arrhythmia commonly

seen in patients with biliary obstruction because these findings resolve completely

after the surgical removal of the obstruction and resolution of jaundice. These are in

45

contrast to the observation by Song et al, 80 who found no correlation in individual

patients between total serum bile acid concentration and arrhythmia.

Parshu and Michael,27 demonstrated unusual ECG abnormalities including marked

ST segment elevation in leads V1 to V3 in four cases of severe icteric leptospirosis.

These changes normalized with initiation of therapy and recovery from jaundice. The

ECGs abnormalities were attributed to hyperbilirubinaemia, although electrolyte

deragment and carditis that usually complicate leptospirosis could also be responsible.

The manifestations of hypothyroidism include chronic jaundice, reduced capacity and

thickness of the left ventricle, lower heart rate, reduced cardiac output, and

prolongation of the pre-ejection period of the left ventricle. In hypothyroidism, ECG

shows QTc prolongation and pericardial effusion which results in low voltage for P,

QRS and T waves. There is atrioventricular, intraventricular and bundle branch block

(BBB). These ECG abnormalities are ascribed to either hypothyroidism and/or toxic

effect of hyperbilirubinaemia.86-87

Ligen and Hassaini88 observed that of 661 patients referred with jaundice, only 8 had

a primary cardiac cause for their jaundice and this was attributed to passive congestion

of the liver or acute ischaemic hepatitis. All the patients had abnormal

electrocardiograms and echocardiograms suggesting the possible effect of

46

hyperbilirubinaemia on the heart,88 although the electrolyte abnormalities that usually

accompany diseases associated with jaundice could also be responsible.

ECG Abnormalities in the Newborn and Disease Conditions

Many disease conditions are associated with abnormal ECG in the newborns.4-6, 10

These include congenital abnormalities, inborn errors of metabolism, electrolyte

derangement, drugs, asphyxia, hypoglycaemia, infections, trauma, hypothermia and

others. Electrocardiographic abnormalities can be seen in primary cardiac and non

cardiac diseases.10 Also abnormality of the ECG may not necessarily imply the

presence of a disease. Common ECG abnormalities in the new born include;10

(1) Sinus arrhythmia: Sinus arrhythmia is of sinus origin but with irregular RR

interval. It is less pronounced at fast heart rate and thus neonates show a more regular

rhythm than young children and adolescents, particularly in the first week of life.4-5

Sinus arrhythmia represents normal physiologic variability with respiratory phase and

also due to immaturity of the SA node. In sinus arrhythmia, the P wave morphology

and axis do not change. Sinus arrhythmia differs from wandering pacemaker which

manifests as gradual change of P wave axis and morphology due to a shift of the

pacemaker from the sinus node to the atrium and the atrio ventricular (AV) junction.

It is usually a normal variant.3,5,8

47

(2) Sinus tachycardia: This is sinus rhythm with a heart rate above the normal limit

for age. In the newborn period, the upper normal limit is 166 beats/min in the first

week and 179 beats/min in the first month. Causes in the neonatal period include

fever, infection, anaemia, pain, carditis, dehydration, agitations, hyperthyroidism,

beta adrenergic agonists and theophyllin.4,89,90

(3) Sinus bradycardia: This is sinus rhythm with heart rate below the normal limit.

In the neonatal period the lower normal limit is 91 beats/min during the first week and

107 beats/min in the first month of life. Causes include gastro- oesophageal reflux,

hypothermia, hypopituarism, hypothyroidism, increased intracranial pressure,

meningitis, beta-adrenergic blockers, obstructive jaundice, conduction block and

congenital long QT syndrome.3,4, 90

(4) Premature atrial depolarizations: The diagnosis is assigned when there is an

identifiable early non sinus P wave. Atrial premature depolarizations occur in up to

30% of newborns. Causes include central venous catheters, myocarditis, cardiac

tumors, electrolyte abnormalities, drugs like dopamine, dobutamine, isoproterenol,

epinephrine, caffeine, theophyllin, and aminophylline.4 In an healthy infants, it

usually resolve over few months without any serious consequence.90

48

(5) Ventricular premature depolarizations: These are early QRS complexes with

morphology different from sinus beats and without an identifiable preceding P-wave.

It occurs in less than 1% of healthy newborns. Causes include hypokalaemia,

hyperkalaemia and hypocalcaemia, hypoglycaemia, hypoxaemias, congenital long-

QT syndrome, adrenergic drugs and anti-arrhythmic medications. It resolves with

successful management of the causes.90

(6) Junctional ectopic tachycardia: This is a tachyarrhythmia due to enhanced

automaticity in the A-V node and/or bundle of His. There is a normal QRS

morphology with variable ventricular rates. Some patients later develop complete

heart block. Causes include cardiac surgery and it could be familial.5, 90

(7) Ventricular tachycardia: This presents as a wide complex tachyarrhythmia.

There is a dissociation of the ventricles from the atria with more ventricular beats. It

occurs in SVT with aberrant conduction, atrioventricular reciprocating tachycardia in

WPW syndrome, tachycardia in the presence of bundle branch or intraventricular

conduction block, post cardiac surgery and hyperkalaemia.89, 90

(8) P wave abnormality: This may be seen in infants with atrial enlargement or non-

sinus origin of the P wave especially in congenital heart diseases presenting as tall or

wide dented P-wave. 4,5, 90

49

(9) Heart block

(i) First degree Heart block: First degree A-V block is characterized by an

abnormally prolonged P-R interval for age and heart rate. Causes include digoxin,

hypothermia, hypothyroidism, hypo or hyperkalaemia, hypo or hypercalcaemia,

hypoglycaemia and hypomagnesaemia. First-degree AV block is generally well

tolerated and requires no specific therapy, but should be followed up.4,12,90

(ii) Second-degree AV block: This is defined as intermittent failure of conduction of

some atrial depolarization to the ventricles. In Mobitz type I (Wenckebach) AV block,

there is progressive delay in conduction before a single atrial beat fails to conduct.

Mobitz type I AV block is generally caused by factors similar to those causing first

degree and is usually well tolerated. Mobitz Type II AV block is recognized by the

intermittent failure of atrioventricular conduction without an associated increasing

prolongation of the P-R interval. Causes include use of agents such as diphemanil or

doxapram in premature infants. 12, 90

(iii) Third-degree AV block: This present with the absence of conduction of atrial

impulses to the ventricles. The ventricular rhythm may arise from the AV node, His

bundle or ventricles. Congenital complete heart block occurs in 1 per 2000 live

births,90 most of which are associated with cardiovascular malformation such as

50

transposition of great artery (TGA), heterotaxy syndrome, endocardial cushion defect,

Ebstein’s anomaly, atrio-ventricular canal defects, tricuspid atresia and fibrosis of the

AV node or His bundle. Other causes include complication of cardiac surgery,

maternal auto antibodies, as it can occur in maternal connective tissue disease

particularly lupus erythematosis and Sjogren,s syndrome.91

(10) Wolff–Parkinson–White Syndrome (WPWS): In WPWS, conduction through

the atrio ventricular node and the accessory pathway results in collision of two

electrical wave fronts at the ventricular level causing a delta wave and a fusion QRS

complex and it presents with preexcitation syndrome. 8,90

(11) Increased QRS axis and amplitude: Features of RVH include RV1 greater

than 26 mm in 1st week, 21mm in 2nd to 4th week, presence of Q wave and or

persistence of upright T waves beyond age 1week. Features of LVH include elevated

RV6 greater than 12mm in 1st week, 16mm in 2nd to 4th week and deep Q wave

greater than 4mm, T wave flattening or inversion. Biventricular hypertrophy is seen

in left to right shunt lesions. RVH is seen in TOF while LVH is seen in aortic

stenosis4,8,90,92

(12) QT interval prolongation: This is clinical prolongation of the QT interval.

Causes include long QT syndrome, hypocalcaemia, Nervous system abnormalities,

51

drugs (trimethoprim, cisapride, spyramycin, erythromycin and larithromycin).5,92

Long QT syndrome is a genetic disease due to mutations of the genes coding ionic

potassium or sodium currents which is involved in the control of ventricular

repolarization. It presents with syncopal attack episodes due to torsades de pointes

and ventricular tachycardia (VT), it has a high risk for SIDS.5,8,9

(13) ST segment elevation: ST segment that are 1 mm above isoelectric line. Causes

include pericarditis, myocarditis, hyperkalaemia, hypoxaemias, head injury,

pneumothorax, pneumopericardium and subepicardial injury.4, 8,90

52

QT prolongation

A B C

(A) first degree (B) second degree and (C) Third degree Heart block

A B

(A) Sinus tachycardia (B) Atrial tachycardia

Wolff–Parkinson–White syndrome

53

Torsade De pointes

Figure 5 Some abnormal neonatal ECGs

Common Disease conditions and ECG abnormalities

Common ECG abnormalities in disease conditions includes:

AV canal defect: Superior axis in frontal plane, RAE and prolonged PR interval.

Ebstein's anomaly: low voltage QRS and right bundle branch block.1,92

Patent ductus arteriosus: There is left ventricular hypertrophy (LVH) left atrial

enlargement (LAE) and ST and T wave changes.92

Ventricular septal defect (VSD): LVH and RVH in complicated cases.92

Tetralogy of Fallot (TOF): ECG shows right axis deviation, right ventricular

hypertrophy which may be difficult to differentiate from normal in neonate.92

Hypoglycaemia: In this, there is bradycardia and junctional rhythm.95

http://www.google.com.ng/imgres?imgurl=http://www.mmh.org.tw/taitam/csc/doc/ekg/torsa.JPG&imgrefurl=http://www.mmh.org.tw/taitam/csc/doc/ekglib.htm&h=202&w=533&tbnid=YHStnxRA5V099M:&zoom=1&docid=CcizZuv3yKOY-M&hl=en&ei=KCjEU7zDO5KI7AbAr4CABw&tbm=isch&ved=0CD0QMygUMBQ&iact=rc&uact=3&dur=849&page=3&start=18&ndsp=13

54

Asphyxia: lower heart rate, fixed heart rate phenomenon and low voltage.10,11,93

Hyperkalaemia: Start with peaked, narrow T waves and a shortened QT followed by

QRS complex merger with T wave, then ventricular fibrillation or asystole.10,12

Hypokalaemia: ST-segment depression, decreased amplitude or inversion of the T

wave and increased U wave prominence. Increase in amplitude of the P wave,

widening of the QRS complex, PR and QT interval prolongation if severe.10,12

Hypercalcaemia: QRS complex and PR intervals are prolonged, there could be AV

block and Osborn wave, a hump like deflection between QRS and T wave10

Hypothermia: Osborn wave (J wave) is the pathognomonic ECG feature. 10, 96

Septic shock: ECG shows decreased QRS amplitudes, increased QRS duration with

or without BBB100

JUSTIFICATION FOR THE STUDY

Prevalence of NNJ is still high in Nigeria and the world at large. The negative impact

of NNJ on the child is pan systemic, but most studies have focused on the acute and

long term neurological complications excluding other systems. Adults with jaundice

associated diseases like leptospirosis, hepatitis, and hypothyroidism have abnormal

ECGs and hyperbilirubinaemia has been implicated. Generally, there is paucity of

literature on the cardiovascular abnormalities in NNJ while ECG had been adopted as

55

part of routine neonatal screening and management for some conditions. The role of

the ECG as a cheap and non-invasive means of evaluating both anatomical and

physiological involvement of the heart in disease conditions and the need to evaluate

the toxic effect of bilirubin on the neonatal heart form the rationale for this work. The

majority of the studies carried out on jaundice and its cardiovascular effects were done

several decades ago and were in the adults. Such studies were not in Sub-Saharan

Africa, thus there is paucity of data on this subject and hence the need for this study.

The present study will enable physicians to predict the status of the cardiovascular

system in this already compromised group of children. This would in turn reduce

childhood mortality and further enhance child survival in this part of the world, there

by bringing Nigeria closer to achieving the Millennium Development Goals (MDG).

AIMS AND OBJECTIVES

AIM

The aim of this study is to describe the resting ECG pattern in term neonates with

unconjugated hyperbilirubinaemia seen at the University of Ilorin Teaching Hospital.

SPECIFIC OBJECTIVES

56

The specific objectives of this study are to:

(1) Determine the concentration of serum total, conjugated and unconjugated bilirubin

levels in term neonates with jaundice in UITH Ilorin;

(2) Determine the ECG pattern: rhythm and values of heart rate, interval (PR, QT)

and ST segment, axis (P, QRS and T) voltages (R, S and T) in newborns with

hyperbilirubinaemia and controls.

(3) Compare ECG pattern in subjects and the controls.

(4) Estimate the proportion of ECG abnormalities present in the subjects and controls.

(5) Determine the association between the serum bilirubin concentration and

the ECG variables.

MATERIALS AND METHODS

57

Study Location

The study was conducted in the Neonatal Intensive Care Unit (NICU) of UITH, Ilorin,

in Ilorin East Local Government Area of Kwara State. Ilorin is the capital of Kwara

State. It is located in the North Central geopolitical zone of Nigeria and is situated

between latitude 8-8.50N, and 4.550- 4.58 E. The town is located 303 metres above

the sea level with the temperature range of 19.5-37.5oC, humidity of 42-45% and peak

annual rainfall of 200 cm.101 The vegetation is mainly Guinea savannah. Kwara State

has a population of 2.37 million. Ilorin has a population of 777,667from the 2009

census update and an annual growth rate of 2.3%. The predominant ethnic groups are

Yoruba, Hausa, Nupe, Fulani, Ibo and Baruba. The inhabitants are majorly farmers,

artisans, civil servants, Islamic scholars and clerics. University of Ilorin Teaching

Hospital is a tertiary institution serving most of the middle belt of Nigeria and

receiving referrals from Kwara, Kogi, Oyo, Niger and other states. The NICU of

UITH has an average yearly admission of 2000 about 20% of which is due to NNJ.102

Study population

Subjects were term neonates aged less than 2 weeks with moderate to severe NNJ

admitted into the NICU, UITH, Ilorin, while the controls were normal term neonates

without jaundice attending post natal clinic or in the post natal ward. Mild NNJ is

58

usually physiologic and is known not to be harmful in neonate. The study was done

in those with moderate to severe levels of unconjugated hyperbilirubinaemia where

the toxic effect if any is likely to be apparent. 0-12 mg/dl is mild, up to 19mg/dl is

moderate while greater than 20 mg/dl is severe hyperbilirubinaemia.

Inclusion criteria for subjects

Subjects were term neonates aged one to fourteen days, presenting with moderate to

severe icterus to the NICU, UITH, Ilorin, whose parents or care givers agreed to

participate. Neonatal jaundice was detected by yellowish discoloration of the sclera

and skin when it was blanched.

Exclusion criteria for subjects

(1) Clinical evidence of congenital heart disease.

(2) Clinical features suggestive of dehydration, anaemia, asphyxia or sepsis.

(3) Clinical feature suggestive of hypoglycaemia or electrolyte derangement

Selection of controls:

59

Controls were apparently healthy term neonates without jaundice in the postnatal

ward and post postnatal clinic. For each neonate with jaundice recruited, an age and

sex-matched control was recruited.

Study design:

This was a cross sectional study of term neonates with NNJ and those without but

apparently normal.

Sampling technique

Consecutive term neonates admitted into NICU with NNJ and meeting the inclusion

criteria were recruited until the sample size was attained.

Sample size determination:

No study has demonstrated the ECG abnormality in term neonates with

hyperbilirubinaemia to the best of researcher’s knowledge based on extensive

literature search hence the prevalence is not known. To compare ECG parameters in

neonates with and those without jaundice, the method of sample size calculation for

comparing means in study where prevalence were not known as advised by Cochran

was used.103

60

Formula: 𝑛 = 1 + 2𝐶(𝑠𝑑⁄ )2 Where 𝐶 = (𝑍1−𝛼

2⁄ + 𝑍1−𝛽)2

s = the standard deviation of parameter value,

d = the difference set to be detected, and

C = is a constant dependent on the value of power selected.

Z = is the confidence interval, which when set at 95% level, α = 0.05,

At a power of 90 % = 1- β = 0.9, 𝐶 = (1.96 + 1.28) 2 = 10.51

𝑛 = 1 + 2 𝑋 10.51(𝑠𝑑⁄ )2

Heart rate which is the most accessible of all the ECG parameters was used. The

mean heart rate is 133 beat/minute with standard deviation of 22.35 and and the

magnitude of the difference (d) or the effect to be detected is 30.

Sample size is given by 𝑛 = 1 + 2 𝑋 10.51(22.330⁄ )2 = 46

Allowing for possible incomplete documentation, a rate of 10% of the minimum

sample was added, thus providing a safe margin for statistical analysis. Hence a total

of 50 term neonates with NNJ and 50 term neonates without jaundice serving as

controls were recruited.

61

Training experience:

The investigator received training at the Paediatric Cardiology Unit of UCH Ibadan

for a period of six months under the supervision of Professor SI Omokhodion and Dr

OO Ogunkunle. He had been involved in ECG recording and interpretation under a

Consultant Paediatric Cardiologist at UITH, Ilorin over the past three years. He has

had five years of experience in newborn care as Resident in NICU, UITH, Ilorin under

the supervision of consultant neonatologists.

Ethical issues

Ethical clearance was obtained from the Ethical Review Committee of UITH Ilorin

(Appendix i) and also from the National Postgraduate Medical College of Nigeria

(Appendix ii). The aim and the procedures of the study were explained to the parent

or the guardians in the language they understood, after which the informed consent

(Appendix iii) was obtained. An interviewer-administered semi-structured

questionnaire (Appendix iv) was used to obtain socio demographic information.

Confidentiality was maintained throughout the study.

Patient Handling and Procedure

62

Consecutive neonates admitted into NICU with NNJ that met the inclusion criteria

were recruited. The entry point was the moderate to severe level of clinical jaundice

in a term neonate. The dermal staining of bilirubin as a clinical guide to the severity

of jaundice as described by Kramer 104 was used to recruit subjects before Serum

Bilirubin (SB) is available. The categorization is as follow; Jaundice at the level of

the face to the chin is 6mg/dl, Jaundice at the level of the breast nipple is 9 mg/dl,

Jaundice to the level of the umbilicus is 12mg/dl, Jaundice to the level of the thigh is

15 mg/dl, Jaundice to the level of ankle is 18 mg/dl and Jaundice at the level of sole

of the foot and palm of the hand is equal to or greater than 20 mg/dl. The researcher

was assisted by Senior Registrar in NICU and Paediatric Cardiology Unit and a

trained ECG technician assisted to perform the ECG recording.

Laboratory Procedure

Blood Collection

Neonates with jaundice who met other inclusion criteria had 2 ml of blood taken from

a peripheral vein using a 23 gauge needle after disinfecting the skin with 70% alcohol.

The blood collected was then emptied into a lithium heparin bottle. The blood samples

were prevented from exposure to light by wrapping it in aluminium foil and taken to

the laboratory where analysis was done by an assigned laboratory scientist. The blood

63

samples were centrifuged to separate the plasma. Using modified Jendrassik Groff105

method, 250 micro-litre of plasma were added to 1ml of diazotized P-nitrobenzoic

acid to form ruby-coloured azo-bilirubin. These were incubated for five minutes

before reading in a colorimeter at a wave length of 450 nanometres to read for the

amount of conjugated fraction. An accelerator, dimethyl sulfoxide (DMSO) or

caffeine was then added to the sample and then incubated for another five minutes.

This enabled the unconjugated fraction to react and form a yellow-red coloured

compound which was read in a colorimeter for estimation of total bilirubin. The value

of the unconjugated fraction was determined by subtracting the conjugated value from

the total bilirubin. Samples were also taken for full blood count (FBC), blood culture

and blood group (Appendix II)

Electrocardiography

ECG Machine

A portable and rechargeable Atria 6100® direct heat writing electrocardiograph by

Cardiovault with University of Glasgow analysis program was used to collect data. It

is a WHO approved ECG machine for routine use and for research purposes.

Standardization and Measurement

64

The machine was used to record ECG in adult and paediatric patients. The results

were found to be comparable to that of a Schiller ECG machine in use by UITH

cardiopulmonary unit. The machine also has capacity to record up to 15 sec which are

read before the sections required are printed out. This is of a great advantage in

neonatal ECG recording where patients easily get agitated. The 12-lead ECG was

recorded at calibration of 10 mm/mV vertical and paper speed of 25 mm/sec on the

horizontal axis. In line with paediatric practice, V3 of the conventional lead was

replaced by V3R on the right. A total of 5-10 cardiac cycles were recorded on each

patient. Lead II, at paper speed of 25 mm/sec was recorded to serve as rhythm strip.

In case of overlapping, calibrations were reduced to 5 mm/mV. The ECG technician

of UITH and rotating senior registrar were available to assist in the ECG recording.

Procedure for ECG Recording:

After stabilising the patient and general examination done, each infant had a standard

12 lead ECG recorded on admission at the time samples were being taken for bilirubin

assay. Using newborn disposable electrodes and with the subject in the supine position

on the couch, the chest was cleaned and dried. Electrodes were positioned as

recommended by the American Heart Association106

The Lead Placement for ECG Recording

65

Each electrode presents a view of the same cardiac activity from its vantage position

(Figure 6). The bipolar are leads are I, II and III. In lead I, electrodes are on the right

and left arm with the left arm being positive relative to the right. In lead II, the

electrodes are on the right arm and the left leg with the leg being positive. In lead III,

the electrodes are on the left arm and the left leg with the leg being positive. The six

unipolar chest leads (precordial leads) designated V1-V6 and three unipolar limb leads:

VR (right arm), VL (left arm), and VF (left foot). There are augmented limb leads,

designated by the letter aVR, aVL, aVF which record potential between one limb and

the other two limbs. These were used to increase the size of the potentials by 50%

without any change in configuration from the non-augmented records. The six

precordial leads “view” the heart in the horizontal plane while the six limb leads (I,

II, III, aVR, aVL and aVF) view the heart in the vertical plane. The information from

these 12 leads was combined to form a standard electrocardiogram.1-3, 8

• V1: 4th right intercostal space, parasternal

• V2: 4th left intercostal space parasternal

• V3: exactly mid way between V2 and V4

• V4: 5th left intercostal space, mid clavicular line

• V5: same transverse level as V4, anterior axillary line

• V6: same transverse line level as V4, mid axillary line

66

• V3R: corresponds to V3 on the right side

• V4R: corresponds to V4 on the right side

• V1,V2, V3R and V4R record best the right ventricular activity

• V3,V4 (transitional) record best the septal activity

• V5,V6: record best the left ventricular activity

67

Figure 6: Electrocardiographic 12-lead placement1

68

ECG Interpretation and Definition of Terms

Electrocardiographic measurements and interpretation were done manually by the

investigator. Amplitudes were measured in millimetres and time in millisecond. Both

upward and downward deflections were measured from the isoelectric line. A single

P-QRS-T in lead II that was representative of the majority type was used for the

reading. In case of poor quality printouts, the recordings were repeated. (see Appendix

iii: study proforma).

(1) Heart Rate: This is the number for heart beat per minute. This was calculated by

dividing 1500 by the number of small square between RR. Where RR intervals were

not regular, the count was made over 10 beats, then the average taken as the heart rate.

The range for 1-14 days is 91-166 mean 133. Value below 90 is bradycardia and

values above170 beat/minute is tachycardia for that age.8

(2) Rhythm: This defined the origin of the heart or the pace maker. This could be

sinus , atrial, junctional, or ventricular. Lead II printed as rhythm strip was used to

determine the rhythm using nature of PQRS and RR interval.

69

(3) P-wave: This is the first deflection of ECG tracing. It is due to atrial

depolarization. Morphology in lead II was screened for being too tall (Right atrial

enlargement, too wide (Left atrial enlargement) or tall M shaped P mitralis (Bia atrial

enlargement). Amplitude was read on the vertical axis from the isoelectric line to

peak in mVolt, duration was read on the horizontal line from beginning to the end of

P wave in lead II and P wave axis was read on the frontal plane using leads I, II, III,

avF, avR and avL. The axis was taken to be perpendicular to the least or the most

equiphasic lead in voltage deflection. Normal amplitude ranged 1.5-2.9 mV mean of

2 mV. The range for duration is 45-85 msec and means of 70 msec for age 1-14 days.

(4) PR interval: This is the time taken for electrical impulse to be conducted form

SA node to AV node plus the delay in AV node. This was read using lead II from the

beginning of P-wave to the beginning of QRS complex. The range for age 1-14 days

is 80-150msec, average 110 msec.

(5) QRS: This is the second deflection on ECG. It represents ventricular

depolarization. The duration range for age 1-14 days is 20 to 80 msec averages 65

msec. The axis is -10 to180 degrees, average 120 degree. It was examined for

morphology, amplitude, duration and frontal plane axis. QRS wave morphology in

lead II was screened for been being too tall or too wide. Amplitude was read on the

vertical axis from isoelectric line to the peak in mVolt; duration was read on the

70

horizontal line from the end of Q wave to the end of S in lead II and QRS axis was

read on the frontal plane using leads I, II, III, avF, avR and avL. The axis was

perpendicular to the least or the most equiphasic in voltage deflection.

(7) QT interval: This is the ventricular depolarization plus the repolarization time.

Because the value changes with heart rate, QT was corrected for heart rate (QTc)

using the Bazett’s formula: QTc = QT/√RR interval. This was read in lead II from

the beginning of QRS to the end of the T wave. The range for age 1-14 days is 250-

400 msec(average 300 msec). Values above 440msec are considered prolonged.

(10) ST-segment: This is the time between the end of QRS complex and the

beginning of the T wave. It represents the initial part of ventricular repolarization. It

should be isoelectric normally. Elevation or depression was measured from the

isoelectric line in lead II. A value greater than 1mm above or below the isoelectric

line was considered abnormal.11,42

(6) T-wave: This is the deflection after QRS complex and it follows the ST segment.

It represents the later part of ventricular repolarization. It was examined for

morphology, amplitude, duration and axis. P-wave morphology in lead V1 was

screened for being too tall, inverted or flat. Amplitude was read on the vertical axis

from the isoelectric line to peak in mVolt; duration was read on the horizontal line

71

from the end of the ST segment to the end of the T wave in lead V6. The T wave axis

was read on the frontal plane using leads I, II, III, avF, avR and avL. The axis was

perpendicular to the least or the most equiphasic in voltage deflection. The amplitude

range between 0-3 mV, average 1.5 mV. It may be everted in precordial leads. The T-

wave axis is -60 to 130 degrees, averaging 70 degrees. The duration of T wave is 40-

80 msec with an average of 65 msec. 5

(11) RS progression: The adult R/S progression, S>R in V1 and S<R in V6. The

Infantile R/S progression, R>S in V1and V6 (3) The Neonatal R/S progression, R>S

in V1 and S>R inV6.4, 5

Quality Control Assurance Measures

Measure for intra observer error/concordance with Consultant

Strict guidelines were followed in recording and interpreting the ECG. Randomly

selected one out of every ten strips was interpreted by the supervising Consultant. The

results were compared with those of the investigator. The degree of concordance was

expressed as a percentage.

The standard laboratory quality control was applied for the bilirubin analysis. Every

kit of the diluents had sample diluents with known concentration for quality

72

assurance. The laboratory technologist handling the samples also tested the diluents.

One laboratory technologist under the supervision of a Consultant Chemical

Pathologist did all the analysis. For every 10 samples analyzed, an independent

technologist analyzed one sample and compared the findings.105

Other Measurements and Documentations

Infantometer, tape rule, thermometer and weighing machine were used to collect data.

All subjects were recruited personally by the investigator assisted by a trained ECG

technician and a trained Senior Registrar rotating in the NICU. The procedures and

the aim of the study were explained to the parents or the guardians in the language

they understood after which the informed consent form was administered. Semi-

structured questionnaire was used to obtain information on;

A Socio demographic characteristics,

B Clinical signs and symptoms,

C Anthropometric measurements,

D Laboratory parameters.

A) Socio-demographic Characteristic,

73

Socio-economic index scores were awarded to the occupation and educational

attainments of their parents using the Oyedeji107 Socio–economic Classification

Scheme (Appendix v). The mean of four scores (two for the father and two for the

mother) approximated to the nearest whole number was the social class assigned to

the child as proposed by Oyedeji.107 For example, if the mother was a junior school

teacher (score = 3) and father a senior teacher (score = 2) and the educational

attainment of the mother was primary six (score = 4), and the father was a senior

secondary school certificate holder(score = 2), the socio-economic index score for

this child was; 3+2+4+2/4=3 to the nearest whole number. Socio economic classes I

and II are the upper class, III is the middle class while socio economic class IV and V

are the lower socio-economic class.

(B) Clinical Signs and Symptoms

(1) Respiratory rate: With the right hand on the abdomen, the respiratory rate was

counted for one minute three consecutive times and the average taken as respiratory

rate.

(2) The heart rate: This was also counted for 1 minute with a stethoscope on the

precordium and recorded immediately in the questionnaire.

74

(3) Temperature: After cleaning with methylated spirit and the mercury returned to

the base, axillary temperature was taken after three minutes. The mercury level was

read at the level of the eye and recorded immediately.

(4) The dermal staining of bilirubin as a clinical guide to the severity of jaundice as

described by Kramer104 was use to recruit patients before SB was available.

(C) Anthropometric Measurements.

(1) Weight: Babies were weighed using a digital weighing scale graduated in five

gram units with precision of one decimal place. Before weighing each baby, a metal

of known weight of 1-2 KG was always used to test run the accuracy status of the

machine.

(2) Occipitofrontal circumference (OFC): Measurement was done across the widest

part of the skull. The land marks used were at a point 1cm above the glabella anteriorly

and the occiput prominence posteriorly. A non-expandable flexible tape rule with

centimetre marking clearly inscribed across one end was used. The accuracy of the

metre tape reads in 0.1cm units.

(3) Length: Length was measured using an infantometer. It consists of a board, made

of light wood onto which a non-flexible tape, such as described above has been

75

attached. It has a stationary end where the infants’ feet are placed and the opposite

end was adjusted to touch the head of the baby. The 0.0 cm mark is at the stationary

end and the measurement was taken at the adjustable end where it touches the infants’

head.

Funding

The funding of the research was borne by the investigator assisted by the supervising

consultants.

Data analysis

Data were analyzed using SPSS 18 computer software package.108 The data was

entered for the socio demographic, anthropometry, physical findings and laboratory

for both subjects and controls. Categorical variables were compared using Chi-square

test while continuous variables were analyzed using the Student’s t test or analysis of

variance ANOVA.108 Continuous variables were expressed as mean (±SD) while

categorical variables were expressed in proportions, ratios and percentages.

Associations between subjects’ ECG parameters and bilirubin concentration were

examined using the Pearson’s rank correlation. For all statistical analysis P-values

less than 0.05 were considered significant at confidence level of 95%.108, 109

76

RESULTS

General characteristics of the study population

Table I shows that the age, sex and socio demographic characteristics of the two

groups were comparable (p=0.38). Parents of the controls had significantly higher

level of education compared to controls (p= 0.04)

Table I: Socio-demographic characteristics of subjects and controls

Variables Subjects

n=50

Controls n=50 χ2 p

Sex Male

Female

29 (58%)

21 (42%)

26 (52%)

24 (48%)

1.33

0.53

77

Maternal Education

None 21(42%) 6(12%) 1.18 0.012

Primary 13(26%) 8(16%) 1.05 0.045

Secondary 9(18%) 19(38) 1.12 0.038

Post secondary 7(14%) 17(34%) 1.02 0.041

Socio-economic class

I 6 (12%) 7(14%) 0.95 0.75

II 13 (26%) 9(18%) 1.12 0.53

III 11 (22%) 12(24%) 1.22 0.38

IV 8 (16%) 9(18%) 1.31 0.42

V 12 (24%) 13 (26%) 1.03 0.041

t p

Age (days) 5.0+1.3 5.2 +1.8 0.70 0.49

Clinical and Anthropometrics Characteristics of the Subjects and Controls

Table II shows that the respiratory rate, pulse rate and body temperature were

comparable in the subjects and controls (p = 0.21). The mean weight of the subject

was comparable to that of controls ( p = 0.31). The mean length and the head

circumferences were comparable in the two groups (p = 0.103).

Table II: Clinical and anthropometric characteristic of the subjects and controls

Variable Subject

n= 50

Controls

n=50

t p

78

Anthropometry

Weight (kg) 2.99 + 0.3 3.04+ 0.35 1.03 0.31

Length (cm) 50.09±1.56 50.73 + 0.99 2.12 0.10

Head circumference (cm) 35.4 ±1.2 35.5+- 0.91 1.63 0.12

Clinical

Respiratory rate (minute) 36 ± 4 37 ± 5 0.90 0.32

Pulse rate beat (minute) 133 ± 20 128 ± 25 1.03 0.31

Temperature (degree) 37.1 ± 0.4 36.9 ± 0.6 1.27 0.21

79

Figure 7: The distribution of subjects according to suspected cause of

hyperbilirubinaemia.

ABO set up 36%

Rhesus4%

? G6PD 60%

ABO Set up

Rhesus isomunization 2

?G6PD Deficient

80

Serum Bilirubin in the Subjects and Controls

The mean total serum bilirubin, conjugated and unconjugated bilirubin fraction was

significantly higher in the subjects compared to controls (p<0.05).

Table III: Serum bilirubin in the subjects and controls

Variable Subject

n= 50

Controls

n=50

t p

Mean total bilirubin mg/dl

23.4 ± 7.3 2.8 1.10 0.03

Mean unconjugated bilirubin

mg/dl

18.9 ± 6.6 1.2 2.87 0.02

Mean conjugated bilirubin mg/dl 4.5 ± 2.5 1.6 1.23 0.01

81

Electrocardiographic Parameters of the Subjects and Controls

Table IV shows that the mean PR interval in the subjects was significantly shorter

than in controls (p=0.022), otherwise the two groups did not differ significantly in

their ECG parameters.

TABLE IV: Electrocardiographic findings in the subjects and controls

Variable Subjects n=50 Controls n=50 t p

Heart rate (beat/min)

133+ 19 127 ± 26 1.04 0.12

P-wave duration(msec) 76.5 ± 8.6 74.12 ± 6.5 1.56 0.19

P-wave amplitude(mV) 2 .4+ 1.0 1.5+ 0.9 0.97 0.131

82

P-wave axis 55 + 7.5 60 + 8 1.54 0.16

PR interval (msec) 119 + 15.9 126.74+ 17.9 2.36 0.022

QRS duration (msec)

69.1 + 9.6

70.2 ± 10.1

0.51 0.568

QRS axis (degree) 111.2 + 41

127.4+ 40 1.14 0.259

QTc (msec) 431 + 31.9 439 + 32.7 1.27 0.207

T-wave axis (degree) 65 ±8.5 75 ± 11 1.15 0.18

RV1 (mv) 8.5 + 3.5 8.4 + 5.2 0.173 0.852

SV (mv)

3.52 + 3.5

3.3 + 3.3

0.08 0.761

RV6 (mv)

4.35 + 3.5

5.1 ± 3.9

1.74 0.539

SV6 (mv) 4.56 ± 3.5

5.1 ± 3.9

0.62 0.539

RS PROGRESSION

χ2

p

Neonatal (RS)

29(58%)

26(52%)

1.08 0.10

Infantile (RR) 15(30)

16(32%)

1.12 0.31

Adult (SR) 6(12%)

9(18%)

1.29

0.07

83

Figure 8 Electrocardiogram of a normal 4 day old term neonate showing a

84

normal electrocardiographic tracing

Table V shows that there is no significant difference in the prevalence of

ECG abnormalities in the (subjects 64% compared to 54% in the controls),

(χ2=2.07, p= 0.15

Table V: ECG abnormalities in Subjects and Controls.

Variable Subjects n= 50 Controls n=50 χ2

p

Heart rate : tachycardia

bradycardia

2 (4%)

1 (2%)

1 (2%)

-

1.5 0.55

Rhythm: Sinus arrhythmia - 2 (4) - -

P-wave : variation in shape

Lead II

3 (6%)

2 (2%) 1.18 0.10

PR interval: prolonged 3 (6%) 1 (4%) 1.4 0.07

QRS: rSr

RVH

Superior axis

5 (10%)

-

1 (2%)

3 (6%)

1 (2%)

-

1.20

-

-

0.21

-

-

QTc prolongation 10 (20%) 8 (16%) 1.12 0.10

ST segment: elevation 5 (10%) 3 (6%) 0.93 0.08

85

depression 1 (2%) 1 (2%)

T wave V1-V2 : flat

Tall

2 (4%)

1

3 (6%)

2 (4%)

1.30 0.52

Total - 31 (64%) 27 (54%) 2.07 0.15

86

Figure 9: Electrocardiographic tracing of a 5 day old term kernicteric neonate

showing QTc prolongation and infantile pattern of RS progression.

Table VI shows that there is no significant correlation between bilirubin

concentration and ECG parameters.

Table VI: The Correlation between Bilirubin Concentration and ECG

Parameters.

Bilirubin mg/dl

Variables

10-14.9 mg/dl

(n=10)

15-20 mg/dl

(n=8)

>20 mg/dl

(n=22)

r

p

Heart Rate (beat/mn) 143.28±19.24 134.33±17.19 128.95±22.02 -0.089 0.25

P-wave (msec) 74.62±11.51 78.38±9.33 76.43±6.93 0.075 0.24

P-wave amp (mv) 0.182±0.101 0.15±0.13 0.138±0.087 -0.156 0.60

PR interval (msec) 116.30±13.22 119.32±13.35 119.81±19.18 0.232 0.13

QRS axis (degree) 100.28±41.66 102.78±41.84 129.62±39.57 0.256 0.23

QRS duration (msec) 65.86±6.90 71.973±10.29 68.14±9.65 -0.052 0.56

87

QTc (msec) 446.22±51.90 424±14.44 431.05±28.72 0.113 0.20

St segment (mv) 0.10±0.06 0.08±0.06 0.08±0.07 0.278 0.10

T wave amp (mv) 0.14±0.13 0.17±0.16

0.19±0.08 0.136 0.60

RV1 (mv) 7.97±2.52 7.79±3.73 9.47±3.68 0.153 0.67

SV1 (mv) 3.252±3.58 3.63±4.63 3.42±4.69 0.013 0.70

RV6 (mv) 4.14±3.15 4.248±3.74 4.47±3.61 -0.025 0.34

SV6 (mv) 3.41±2.38 3.94±3.21 4.48±3.61 0.230 0.32

Multivariate tests F(39, 249) =1.20, p=0.565, Wilks' Lambda. 1.97

Table VII shows that there is no significant correlation between bilirubin

concentration and ECG abnormality in subject.

Table VII: Correlation between ECG abnormalities and bilirubin concentration

in the subjects

ECG abnormalities n= 10 n=18 n=22 t

p

Bilirubin mg/dl 10-14.9mg/dl 15-20mg/dl >20mg/dl 1

Heart rate beat/min 2 (4%) 1 (2%) 1 (2%) 0.03 0.45

P wave (msec) 1 (2%) 2(4%) 0 0.02 0.30

PR interval: prolong 0 1 (2%) 2 (4%) 0.012 0.25

88

QRS: rSr

Superior axis

2 (4%)

1 (2%)

1 (2%)

-

2 (4%)

-

0.02

-

0.41

QTc prolongation msec 3 (6%) 5 (10%) 2 (4%) 0.04 0.51

ST segment: (mV) 3 (6%) 2 (4%) 1 (2%) -0.07 0.36

T wave amplitude (mV) 0 2 (4%) 1 (2%) 0.04 0.32

Total - 12(24%) 14 (28%) 9 (18%) 2.07 0.15

Figure 10 shows that the heart rates positively correlates with unconjugated

bilirubin though not statistically significant (r=0.003)

89

Figure 10: Correlate between heart rate and unconjugated bilirubin in the

subjects (Scatter plot).

90

Figure 11 shows that the PR interval correlates positively with unconjugated bilirubin

though not statistically significant (r=0.107)

Figure 11: Correlation between PR interval and unconjugated bilirubin.

(Scatter plot)

91

Figure 12 shows that the QRS axis correlates positively with unconjugated bilirubin

though not statistically significant (r=0.034)

92

Figure 12: Correlation between QRS axis and unconjugated bilirubin.

(Scatter plots)

93

Figure 10 shows that the QTc correlates negatively with unconjugated bilirubin

though not statistically significant (r=0.009).

94

Figure 13: Correlation between QTc and unconjugated bilirubin (Scatter plots)

95

DISCUSSION

In this study, there were no significant differences in electrocardiographic parameters

of subjects compared with controls as regards the mean heart rate. Though there is no

electrocardiographic finding in neonates with jaundice to compare with, the values in

controls are comparable to those of normal neonates in various studies.3-5 Only one of

the subjects had bradycardia. This is unlike the findings in adults with jaundice who

almost always have severe bradycardia and some time sinus arrest.26 The reason for

this may not be unconnected with the shorter duration of exposure to

hyperbilirubinaemia in the neonates. Two of the subjects and one control had

tachycardia for age, heart rate 170-190 beat/minute. This is within limit established

by Davignon et al.5 It has been noted that some newborn infants may transiently reach

a heart rate up to 200 beats/min especially when agitated.89

All the subjects were in sinus rhythm; only two of the controls (4%) had sinus

arrhythmia. This finding is in conformity with other studies in which sinus arrhythmia

96

is not a common feature in neonates.3-7, 11 This was attributed to their fast heart rate.

The finding in the subjects may not be unconnected with short time of exposure to

hyperbilirubinaemia.

The mean P-wave amplitude, duration and axis were similar in the subjects and

controls and within the established limits. Compared to two in the subjects, three of

the controls had P-wave amplititudes that were greater than 3 mv, three of the controls

had zero amplititude. This prevalence is within the limits of P-wave findings in the

normal term neonates in other studies,3,5,6 unlike in adults with jaundice that have 30-

40% P-wave abnormalities.25,26

The mean QRS axis was normal in both subjects and controls. Only one of the subjects

had a superior axis. Compared to five of the subjects, three of the controls had rSr in

Lead I and V1 suggestive of RBBB, though not statistically significant. These

findings had been reported to be normal variant in various studies45,90

This study shows a significantly shortened mean PR interval in the neonates with

hyperbilirubinaemia compared to controls. Although the value for the controls and

the subjects were still within an acceptable range, the reason for this is not clearly

apparent from this study. Prolonged PR abnormality was seen in 6% of the subjects

compared to 4% in the controls, though not significant is at variance with other studies

97

that found normal PR in normal term neonate.4,5 It is said that isolated PR abnormality

is uncommon in new born.11 It is much less than prolonged PR interval abnormalities

in the adults with jaundice associated disease which can be up to 50 %.26,27

ST segment abnormality was seen in 12 % of the subjects compared to 8 % in the

controls, the difference was not statistically significant. Other studies had reported

higher value of ST segment abnormality in normal black neonates. Omokhodion et

al11 reported 50% while Furman and Haloran45 reported 57%. ST segment

abnormality had been described as normal variant in African children.110-111 Findings

in the subjects is unlike ST segment abnormalities in the adult with jaundice

associated disease and Paediatric hypothyroidism which can have abnormality of up

to 50-60 %.25,27

The mean QTc in the subject was not significantly different from that of the control

and is comparable to standard established by other studies.3-4,5 Prolong QTc longer

than 440 mill sec was found in 20% of the subject and 16% of control in this study.

The finding though at variance with 2.5-5 % established by some studies,5,8 it is in

agreement with some that find higher value of 15-18% in normal term neonate.3,4,6

Finding of 20% QTc abnormality in the subject is unlike QTc prolongation

abnormalities in the adult with jaundice associated disease and Paediatrics

hypothyroidism which can be up to 60 %.24-27

98

T wave amplitude, duration and axis are comparable in the subjects and controls. The

values for the controls are comparable with the standard established by studies.5,8 The

age specific variability in T wave precludes comparing with other studies. T-wave

abnormality were more prevalent in the controls (10%) than for the subjects (6%) in

this study, the difference though not significant, the finding is at variance with

Omokhodion et al11 who reported 39% in asphyxiated and 25% in normal term

neonate.45 This may be due to more sensitive Holter ECG used in their study.

There was a paucity of published literature documenting the relationship between

neonatal electrocardiogram and serum level of bilirubin for comparison, however the

values for the controls are comparable with standards established by Davignon et al 5

and other previous studies.3,6,8 The findings in the subject are unlike the

electrocardiogram in adults with jaundice associated diseases like viral hepatitis;

leptospirosis and heart failure which shows almost 100% ECG abnormality like

bradycardia, sinus arrest, QRS abnormalities, QTc prolongations and ST segment

abnormalities.22-27 The possible reason for these may not be unrelated to a wide range

of values acceptable as normal in neonatal electrocardiogram. Normal QRS axis for

instance is between -100 to 1800.4-5 This may also be due to short time of bilirubin

exposure in the subjects, though this time was enough to cause kernicterus in some

subjects. This may also be due to the level of sensitivity of the equipment used. A

99

more advanced cardiac investigation such as Holter monitoring, Doppler and

echocardiography may be able to discern the differences between the subjects and the

controls ECG parameters. Omokhodion et al11found almost a normal ECG comparing

asphyxiated babies with normal using resting 12 lead ECG but found a significant

difference when Holter monitor ECG was used.

Although there is paucity of published data on the effect of hyperbilirubinaemia on

the electrocardiogram of term neonate with jaundice to compare with, in this study,

there is no significant correlation between bilirubin concentrations and ECG

parameters and ECG abnormalities, the finding that is similar to some studies in adult

that found no strong relationship between bilirubin level and cardiac abnormality.79,80

Mittelstadt et al,79 in an experimental study observed no significant change in the

activity of the heart under the influence of high bilirubin concentrations. They

attributed the finding to non-susceptibility of the heart muscle to bilirubin, the short

duration of exposure, and or the different behaviour of newborn and adult organs.

In a similar study, Song et al80 found no correlation between total serum bile acid

concentration, sinus rate and Q-Tc interval. Reasons given for this finding were that

the conjugated hyperbilirubinaemia may not be as toxic as unconjugated bilirubin

though the concentration was not as high as those found in kernicteric neonates. The

absence of significant difference in the anthropometric parameters of the studied

100

group shows the appropriateness of the choice of controls and the comparability of

the variables and the cofounding variables in the groups.

The cause for the NNJ was 2% rhesus iso-immunization, 36% ABO set up and 62%

probably due to G6PD deficiency. Three that had culture positive was replaced from

the study. Studies have shown that G6PD deficiency either singly or in combination

with other condition is the highest cause of neonatal jaundice.17-19, 23 The observation

of lower educational status in mothers of the subjects is in keeping with finding in

other neonatal and paediatric conditions such as severe perinatal asphyxia and

malnutrition.107 Maternal education is known to be a major determinant of the healthy

development of children. The health seeking behaviour as well as clear understanding

of preventive and likelihood to consult orthodox medicine is more in educated than

an illiterate mother.107,112

CONCLUSIONS

It can be concluded from this study that

(1) About two thirds of the neonates with moderate to severe NNJ have abnormal

electrocardiographic abnormalities, the prevalence of which is slightly higher

than that of normal controls but not significantly so.

(2) The commonest ECG abnormality in both subjects and the controls is the QTc

prolongation and they need to be followed up for risk of SIDS.

101

(3) Mean PR interval is significantly shorter in NNJ than in age and sex-matched

controls and also need to be followed up.

(4) Correlation between ECG variables and serum bilirubin in NNJ is rather weak.

RECOMMENDATIONS

1. It is recommended that electrocardiographic evaluation for cardiovascular

involvement and abnormalities may not be a priority in babies with NNJ.

2. Further studies are required to study the effect of hyperbilirubinaemia on the

heart such as 24hour Holter monitoring, echocardiography, dynamarps and

others.

102

3. Further prospective longitudinal studies are also needed to study the long- term

effect of hyperbilirubinaemia on the heart.

4. All the babies with prolonged QTc and shorter PR interval should be followed

up.

LIMITATIONS

1 The use of the resting standard 12 lead ECG limits the details that may have

been observed were the recording done with a 24 hour Holter ECG.

103

2 Echocardiographic study would have added value to both physiologic and

anatomic findings in the subjects.

3 Short time study limits some details that may have been observed if the study

was longitudinal rather than cross sectional as many rhythm and functional

cardiovascular abnormalities evolve over time

4 Limited capacity to do the actual G6PD screening and evaluation.

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114

APPENDIX III

INFORMATION SHEETAND INFORMED CONSENT FORM

What is the study about?

My name is Dr. Adebayo Ganiyu Yusuf Oloko, a senior registrar in the Department

of Paediatrics of this hospital. I wish to carry out a study on Electrocardiogram (ECG)

in babies that have neonatal jaundice. I wish to compare those with jaundice with

those that do not have jaundice. Neonatal Jaundice could cause problems in many

parts of the body, including the heart, brain and others. This study intends to determine

the pattern of function of the heart in neonates with jaundice using a device called

Electrocardiographic (ECG) machine to see the effect of bilirubin on the function of

the heart. The information and the test will be helpful Doctors in make better decisions

on treatment of newborns that have jaundice. I am therefore asking for your

permission to allow your baby partake in the test. I will be very appreciative of your

cooperation.

Potential risk(s) of participation

115

There are no additional anticipated risks from participation in this study. The usual

blood sample taken for all babies with NNJ causes little pain.

Benefit from participation

Your child will benefit from partaking in the test as any occult heart diseases are likely

to be identified and thus treatment instituted early. In case of severe abnormality,

adequate referral shall be done.

Confidentiality

The information obtained from you and other findings during the study will be treated

with strict confidentiality and will be used only for the purpose of study and your

child treatment.

What is expected of you if you agree to participate

You will be expected to provide answers to questions concerning your baby like any

other baby with jaundice. There will be a need for a brief assessment of your baby

and to have ECG done in addition to blood taken for bilirubin level estimation like

any other baby with jaundice at no cost.

Your participation is voluntary

116

Your participation is voluntary. You may withdraw your child from the study at any

time and this will not, in any way, affect the quality of management.

In case of any concerns, you may contact:

The researcher………..DR ADEBAYO GANIYU YUSUF OLOKO

Contact address…….…c/o PAEDIATRICS DEPARTMENT, UNIVERSITY OF

ILORIN TEACHING HOSPITAL, ILORIN.

Email: [email protected] GSM: 08056364473

Ethical Committee Secretary. 08036846045.

I, Alhaji/Hajia/Dr/Mr/Mrs ………………………………………………….

of…………………………………………………………hereby give consent for my

child to participate in a study/research as explained in the above “Information sheet

for Parents” to me verbally and as contained by DR Adebayo G Y OLOKO. All the

117

terms of this consent including what it takes to participate have been fully explained

to me in a language that I understand. I am also aware that strict confidentiality will

be maintained in the study.

Parent……………………….. Sign/thumb print …………………..

Date……………………………. Time…………………………….

Interviewer………………………. Sign……………………………..

Date…………………………. Time………………………….

Witness……………………….. Sign…………………………..

Date………………………….. Time…………………………

In case of any need to ask question/complain, contact Dr Adebayo GY Oloko

08056364473, Mr Razaq Lawal, Secretary, Ethical Committee, UITH, Ilorin.

08036846045.

118

APPENDIX I V

STUDY PROFORMA

RESTING ELECTROCARDIOGRAPHIC PATTERN OF TERM

NEONATES WITH MODERATE TO SEVERE UNCONJUGATED

HYPERBILIRUBINAEMIA AT THE UNIVERSITY OF ILORIN

TEACHING HOSPITAL, ILORIN

(A) Socio-demographic characteristic.

Hospital number……………………... Serial number ……………...…….………

Child: Name…………………………..Tribe…………………..…………………

Age………………………….days. Sex………………………...…………M/F

Maternal age……………………………Parity…….………………..….…………

Occupation……………………………...Education…………………...…………..

Paternal age…….……………………..…Parity………………….…….…………

Occupation……………………….……...Education…………...………………..

119

Type of family……………………………………………………………………...

(B) Anthropometric measurements.

Weight……………………………… ...Kg., Length…….……………..…... cm.

Head circumference………………..(cm)

(C) Clinical sign and symptoms.

Temperature……………………….0C Pale……………………………….(+/++)

Icteric………………………….+/++ Pulse Rate……………...………………..

Heart rate…………………………… Respiratory rate………………………...

BIND Score…………………………

(D) Laboratory parameters

Bilirubin values

Serum bilirubin level total……….…mg/dl, Unconjugated..……………mg/dl,

120

Conjugated……..…..………..…mg/dl. FBC: Haematocrit ………….……… %,

Lymphocytes…….....Neutrophils……………Blood group………...……………

Electrocardiographic parameters

Heart Rate…………….....(beat/mnt), Arrhythmias………….…………………

P- wave Axis……………..(degree), P - wave duration………...……..(msec)

P- wave amplitude……………...(mm), PR interval…...……………...…..(msec)

Q- wave…………………………(mm), QRS axis…….………………(degree)

QT duration……………….(msec), QTc....................……........…………(msec)

ST–segment...........................(msec), T – wave amplititude.............................mm

T wave duration...............................(msec)

R-wave amplitude(mm)

V1………..............V2………........…V3……........................…4…...……........….

V5…………............V6….............………1………............……..11……........……

111……………..…aVL……………….aVR……......……..…aVR........................

121

S-wave amplitude of (mm)

V1……………........V2……..…………. V3…………………V4…...……………

V5………………….V6………………1……………...…11……….…......………

111……………….aVL……………….aVF………………..aVR……….…..........

QRS morphology…….….……………RS progression…..……………..…………

Conduction defects ………….....………………………………………………….

APPENDIX V

Socio-Economic Classification Scheme By Oyedeji

For Occupation

122

Class Occupation

I Senior Public Servants, Professionals, Managers, large scale traders,

businessmen and contractors.

II Intermediate grade public servants and senior school teachers.

III Junior school teachers, drivers, artisans.

IV Petty traders, laborers, messengers .

V Unemployed, full-time housewife, students, subsistence farmers.

For Educational Status

Class Educational Attainment

I University graduates or equivalents

II School certificate holders ordinary level (GCE/SCE)

III School certificate or grade II teachers’ certificate holders

IV Modern three and primary six certificate holders.

V Those who could either just read and write or were illiterate.

resting electrocardiographic pattern of term …

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