EFFECT OF BIRTH ASPHYXIA ON SERUM CALCIUM AND GLUCOSE LEVEL– TIRUNELVELI

EFFECT OF BIRTH ASPHYXIA ON SERUM CALCIUM AND GLUCOSE LEVEL– TIRUNELVELI

MEDICAL COLLEGE AND HOSPITAL

DISSERTATION SUBMITTED TO

In partial fulfillment of the requirement for the degree of (Branch VII) M. D. (PAEDIATRIC MEDICINE)

REGISRATION NUMBER: 201717357 of

THE TAMIL NADU DR. M. G. R MEDICAL UNIVERSITY CHENNAI- 600032

DEPARTMENT OF PAEDIATRIC MEDICINE TIRUNELVELI MEDICAL COLLEGE

TIRUNELVELI- 11 MAY 2020

BONAFIDE CERTIFICATE

This is to certify that the dissertation entitled “EFFECT OF BIRTH ASPHYXIA ON SERUM CALCIUM AND GLUCOSE LEVEL- TIRUNELVELI MEDICAL COLLEG HOSPITAL” submitted by Dr.B.SIVAKUMAR the Tamilnadu Dr. M.G.R Medical University, Chennai, in partial fulfillment of the requirement for the award of M.D. Degree Branch – VII (Pediatric Medicine) is a bonafide research work carried out by him under direct supervision & guidance.

Professor &Head of the Department,

Department of Pediatric Medicine Tirunelveli Medical College,

Tirunelveli.

Unit chief

Department of Pediatric Medicine Tirunelveli Medical College,

Tirunelveli.

CERTIFICATE

This is to certify that the Dissertation “EFFECT OF BIRTH ASPHYXIA ON SERUM CALCIUM AND GLUCOSE LEVEL -TIRUNELVELI MEDICAL COLLEGE AND HOSPITAL” presented herein by Dr.B.SIVAKUMAR an original work done in the Department of Pediatric Medicine, Tirunelveli Medical College Hospital, Tirunelveli for the award of Degree of M.D. (Branch VII) Pediatric Medicine Under my guidance and supervision during the academic period of 2017 -2020.

The DEAN

Tirunelveli Medical College, Tirunelveli - 627011.

DECLARATION

I solemnly declare that the dissertation titled “EFFECT OF BIRTH ASPHYXIA ON SERUM CALCIUM AND GLUCOSE LEVEL - TIRUNELVELI MEDICAL COLLEGE AND HOSPITAL

”

is done by me at Tirunelveli Medical College Hospital, Tirunelveli Under the guidance and supervision of Prof. Dr. C.BASKAR M.D,DCH., PEDIATRICS the dissertation is submitted to The Tamilnadu Dr. M.G.R. Medical University towards the partial fulfilment of requirements for the award of M.D., Degree (Branch VII) in Pediatric Medicine.

Place: Tirunelveli Date:

Dr.B.SIVAKUMAR Postgraduate Student, Registration Number: 201717357

M.D Pediatric Medicine, Department of Pediatric Medicine,

Tirunelveli Medical College Tirunelveli.

CERTIFICATE – II

This is to certify that this dissertation work title

“

EFFECT OF BIRTH ASPHYXIA ON SERUM CALCIUM AND GLUCOSE LEVEL – TIRUNELVELI MEDICAL COLLEGE AND HOSPITAL” of the candidate Dr. B.SIVAKUMAR with registration Number 201717357 for the award of M.D., Degree in the branch of PAEDIATRIC MEDICINE (VII). I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains from introduction to conclusion page and result shows 13% percentage of plagiarism in the dissertation.

Guide & Supervisor sign with Seal.

ACKNOWLEDGEMENT

I wish to express my heartfelt gratitude to our Dean Prof.Dr.S.M.Kannan M.S., M.Ch., Tirunelveli Medical College for allowing me to do the study in this institution.

I would like to express my humble thanks to our Professor & Head of the Department Prof.Dr. C. Krishnamurthy M.D., Department of paediatrics.

I express my sincere thanks to guide Dr.C. BASKAR M.D.,DCH., Associate Professor Department of Paediatrics, Tirunelveli Medical College for his able guidance, valuable suggestions and constant encouragement

throughout the study.

I express my sincere thanks my professors Dr. T.R.R.Ananthy ShriM.D., professors Dr. Rukmani. J MD., Dr.A.S. Babukandhakumar, MD.,DCH.,DNB.,M.N.A.M.S., Dr.R. Padmanabhan M.D., D.C.H., Dr. R. Venkatasubramaniyan M.D., for their constant support, encouragement and suggestions which helped me greatly to expedite this dissertation ..

I express my sincere thanks to my PG registrar Dr. B. Naresh M.D., department of Paediatrics.

I am greatly obliged to Dr.P.Suresh M.D., Dr.J.Denny Clarin M.D.,DCH., Dr.G. Vivek M.D., Assistant Professors, Dept.of paediatrics for their valuable suggestions in preparing this dissertation.

TABLEOFCONTENTS

Sl. No. Title Page. No.

1. INTRODUCTION 1

2. Study justification 3

3. AIMS AND OBJECTIVES 4

4. REVIEW OF LITERATURE 5

5. METHODOLOGY 55

6. RESULTS 59

7. DISCUSSION 72

8. CONCLUSION 75

9. BIBLIOGRAPHY

10. ANNEXURE



LIST OF TABLES

Sl. No. Titles Page No.

1 Distribution of Asphyxiated neonates according to HIE clinical staging cclinical

59 2. Association between Gravida and HIE 61 3. Association between Mode of Delivery and

HIE

62

4. Sex distribution among HIE 64

5. Association between Birth weight and HIE 65 6. Hypoglycemia among study population 66 7. Association between serum glucose levels

with different clinical stages of HIE

67 8. Hypocalcemia among study population 69 9. Association between Serum ionised calcium

levels with

different clinical stages of HIE

doff

70

LIST OF FIGURES

Sl. No. Titles Page No.

1. Hypoxic Ischemic Brain Injury-

Pathophysiology 7

2. Phases of HIE 48

3. Distribution of Asphyxiated neonates according to HIE clinical staging cclinical

59 4. Association between Gravida and HIE 61

5. Association between Mode of Delivery

and HIE 62

6. Sex distribution among HIE 64

7. Association between Birth weight and

HIE 65

8. Hypoglycemia among study population 66

9. Association between serum glucose levels

with different clinical stages of HIE 67 10. Hypocalcemia among study population 69 11. Association between Serum ionised

calcium levels with different clinical stages of HIE

doff

70

ABBREVIATIONS ATP Adenosine triphosphate

AKI Acute kidney injury

aEEG Amplitude integrated Electroencephalogram 2M Beta -2 Microglobulin

cTnI Cardiac Troponin I Ca²⁺ Calcium

CBF Cerebral blood flow CP Cerebral palsy

DWI Diffusion Weighted imaging EEG Electroencephalogram

ECG Electrocardiogram ECHO Echocardiogram

FENa Fractional Excretion of sodium GFR Glomerular Filtration Rate

HIE Hypoxic Ischemic encephalopathy IUGR Intra Uterine Growth Restriction MAS Meconium Aspiration Syndrome MRS Magnetic Resonance Spectroscopy NMDA N- Methyl D aspartate receptors NO Nitric oxide

NOS Nitric oxide synthase

PIH Pregnancy Induced Hypertension PROM Premature Rupture of Membranes PPHN Persistent pulmonary hypertension PVL Periventricular leukomalacia RFT Renal Function Test

RFI Renal Failure Index

SVR Systemic Vascular Resistance

SIADH Syndrome of inappropriate antidiuretic Harmone SNCU Sick New Born Care Unit

UTI Urinary Tract Infection

AA Amino Acids

AAP American Academy of Paediatrics

ACOG American College of Obstetrics and Gynecology CNS Central Nervous System

RDS Respiratory Distress Syndrome EFM Electronic Fetal Monitoring CTG CardioTocoGraphy

CUS Cranial UltraSound CT Computed Tomography MRI Magnetic Resonance Imaging

GFAP Glial Fibrillary Acid Protein

UCH-L1 Ubiquitin Carboxy terminal Hydrolase L1 cAMP Cyclic Adenosine MonoPhosphate

ATN Acute Tubular Necrosis PTH ParaThyroid Hormone SHC Selective Head Cooling EPO Erythropoietin

MNC MonoNuclear Cells UCB Umbilical Cord Blood CPK Creatine PhosphoKinase

INTRODUCTION

Birth asphyxia accounts for major cause of morbidity and mortality in Neonates. It is estimated that of the 136 million annual births, about (10 million )5%-10% respond to simple stimulation to initiate breathing effort,3% to 6%

require basic resuscitation with bag and mask (6 million), and only less than 1%

(<1 million) require advanced resuscitation (0.1% chest compression and 0.05%

require drugs)¹.

Central nervous system involvement occurred in 62% of infants. Indeed, in 16% of infants, involvement of only the nervous system was apparent. Central nervous system involvement without overt dysfunction of systemic organs is particularly likely after severe, acute, terminal intrapartum insults with resulting injury primarily to deep nuclear structures. Systemic organ involvement, without neurological disease, occurred in only 16% of infants. The order of frequency of systemic organ involvement in all birth asphyxia overall has been hepatic >

pulmonary > renal > cardiac. Birth asphyxia is associated frequently with metabolic changes like hypoglycemia, hypocalcemia, hyponatremia, hyperphosphatemia and metabolic acidosis. Hence this study was undertaken to detect hypocalcemia and hypoglycemia in asphyxiated baby so as to prevent the adverse effects of these biochemical abnormalities in the newborns.

STUDY JUSTIFICATION

Perinatal asphyxia is one of the leading cause of neonatal mortality and it is the most common and important cause of preventable cerebral injury occuring in the neonatal period. Perinatal asphyxia leading to HIE, also causes metabolic abnormalities like hypoglycaemia and hypocalcemia.

Various studies were done previously measuring the serum ionised calcium and glucose at 24 hours of life and its correlation with HIE.In this study, by estimating calcium and glucose levels in asphyxiated newborns, we can initiate appropriate treatment and prevent further complications.

AIMS & OBJECTIVES

• To study serum ionized calcium and glucose levels in term asphyxiated newborns at 24 hours of life.

• To correlate the serum ionized calcium and glucose level with clinical severity of HIE as per SARNAT & SARNAT staging.

REVIEW OF LITERATURE

PERINATAL ASPHYXIA

Definition

Perinatal asphyxia refers to the Condition during the first and second stage of labour in which impaired gas exchange leads to fetal acidosis, hypoxemia, and hypercarbia.

CLINICAL DIAGNOSIS

1) evidence of cardio-respiratory dysfunction

2) neurological depression, defined as

- an APGAR score < 7 at 5 minutes

- arterial blood pH of < 7 or base excess greater than 16mmol/L.⁵

PATHOPHYSIOLOGY

Healthy fetus, shows adaptive responses to hypoxia- redistribution of cardiac output to the vital organs including brain, increases myocardial contractility, accelerates anaerobic glycolysis etc. Cerebral auto-regulation of cerebral blood flow initially maintains brain perfusion within a range of range 60–100 mm of Hg. With prolonged asphyxia, the early compensatory adjustments fail and Cerebral Blood Flow may become dependent on systemic blood pressure

(pressure - passive) leading to Brain hypoxia & intracellular energy failure.

However, prolonged hypoxic-ischemic damage can cause neuronal death. The majority of injury leading to neuronal death occurs after recovery from the initial insult.

PRIMARY NEURONAL INJURY

Neuronal cell membranes get affected due to hypoxic-ischemic injury causing intracellular energy depletion, which leads to failure of ionic pump mechanism at the cell membrane level which leads to excess sodium, calcium and water entering the cell causing cytotoxic neuronal injury and death.

SECONDARY NEURONAL INJURY

Reperfusion of the affected neuronal tissues after a hypoxic-ischemic insult initiates a host of biochemical reactions at the cellular level.

Free Radical Injury

Reactive oxygen metabolites including oxygen and hydroxyl free radicals damage the arteriolar endothelium which stimulates xanthine oxidase production leading to generation of oxygen free radicals which overwhelm endogenous

scavenger mechanisms, damage cellular lipids, proteins and nucleic acids and thereby the blood brain barrier.

Excitotoxic Amino Acid Injury

Hypoxic-ischemic insult causes release of excessive amounts of glutamate which acts on the NMDA receptors (N methyl D aspartate receptors) which thereby allows sodium and calcium to enter the neuronal cells causing immediate neuronal death from the osmolar load. The basal ganglia and perirolandic cortex - particularly sensitive to hypoxic injury in neonates. Further, these excitotoxins, because of provoking excessive calcium influx causes delayed neuronal death by activation of undesirable enzymes and secondary messenger systems (e.g. Ca2+

dependent lipases and proteases).

Nitric Oxide

Nitric oxide is generated in the cell as a result of stimulation of Nitric Oxide Synthase [NOS]. This generates another reactive metabolite peroxynitrite, causing lipid peroxidation of intracellular membranes with consequent loss of cell function.

Apoptosis

Apoptosis is regulated by genetic factors with little loss of cellular membrane integrity leading to contraction of the cells, which are subsequently consumed by macrophages. Other triggers of apoptosis include cytokines (Tumour necrosis factor alpha), reactive oxygen metabolites and NO⁵.

Figure 1

HYPOXIC ISCHEMIC BRAIN INJURY-PATHOPHYSIOLOGY

Adaptive responses of the fetus or newborn to asphyxia.

In response to asphyxia, the mature fetus redistributes blood flow to vital organs - heart, brain and adrenals.

1. Impairment of cerebrovascular autoregulation. Results from direct cellular injury and cellular necrosis from prolonged acidosis and hypercarbia.

2. Majority of neuronal disintegration.Occurs after termination of the asphyxia insult because of persistence of abnormal energy metabolism and low adenosine triphosphate (ATP) levels (primary energy failure).

3. Major circulatory changes during asphyxia (reperfusion phase):

a. Loss of cerebrovascular autoregulation-cerebral blood flow (CBF) becomes

“pressure passive,” leading to cerebral ischemia with systemic hypotension and cerebral hemorrhage with systemic hypertension.

b. Increase in cerebral blood flow(occurs in phase ofsecondary energy failure) because of redistribution of cardiac output, initial systemic hypertension, loss of cerebrovascular autoregulation, and local accumulation of vasodilator factors (H+, K+, adenosine and prostaglandins).

c. In prolonged asphyxia,there is a decrease in cardiac output, hypotension and a corresponding fall in CBF.

d. The post asphyxia newbornis in a persistent state of vasoparalysis and cerebral hyperemia. Cerebrovascular hemorrhage may occur on reperfusion of the ischemic areas of the brain. In case of prolonged and severe asphyxia local tissue recirculation may not be restored due to collapsed capillaries (severe cytotoxic edema)⁽⁶⁾.

ETIOLOGY

The most common maternal risk factors for newborns requiring resuscitation was PIH followed by oligohydramnios, multiple gestation, PROM, diabetes mellitus and UTI. IUGR was the most common fetal risk factor followed by fetal distress, prematurity, MAS and malpresentations⁷.

Factors that increase the risk of perinatal asphyxia :

1.Impairment of maternal oxygenation

2.Decreased blood flow from mother to placenta

3.Decreased blood flow from placenta to fetus

4.Impaired gas exchange across the placenta or at the fetal tissue level

5.Increased fetal O2 requirement

Etiology

1. Maternal factors:

Hypertension (acute or chronic), hypotension, infection (including chorioamnionitis), hypoxia from pulmonary or cardiac disorders, diabetes, maternal vascular disease and in uteroexposure to cocaine.

Lack of antenatal care, poor nutritional status, antepartum hemorrhage and

maternal toxaemia were associated with higher incidence of asphyxia⁸

2.Placental factors:

Abnormal placentation, abruption, infarction, fibrosis, or hydrops

3.Uterine rupture

4.Umbilical cord accidents: prolapse, entanglement, true knot, compression

5.Abnormalities of umbilical vessels

6. Fetal factors: anemia (e.g., from fetal-maternal hemorrhage), infection, cardiomyopathy, hydrops, severe cardiac/circulatory insufficiency

7. Neonatal factors: cyanotic congenital heart disease, persistent pulmonary hypertension of the newborn (PPHN), cardiomyopathy, other forms of neonatal cardiogenic and / or septic shock, meconium aspiration syndrome, neonatal pneumonia, pneumothorax⁸.

CAUSES OF ACUTE HYPOXIA

Acute intrapartum hypoxia:

 prolapsed umbilical cord

 placenta previa, placental abruption

• Sudden onset of bradycardia during labour - often idiopathic¹⁰

DEFINITIONS

Perinatal hypoxia, ischemia, and asphyxia.decreased oxygen (O2), blood flow, and gas exchange to the fetus or newborn respectively.

B. Perinatal / neonatal depressionis a clinical term that describes the condition of the infant on physical examination in the first hour after birth. The clinical features include depressed mental status, muscle hypotonia, and / or disturbances in spontaneous respiration and cardiovascular function.

C. Neonatal encephalopathy is a clinical term that (after the first one hour of life) describes an abnormal neurobehavioral state consisting of an altered level of consciousness (including hyperalert state) with other signs of brainstem and / or motor dysfunction. It may be caused by such reversible conditions as maternal medications or hypoglycemia.

D. Hypoxic-ischemic encephalopathy (HIE) is a term that describes clinical evidence of encephalopathy & objective data to support a hypoxic-ischemic (HI) mechanism as the underlying cause for the encephalopathy.

E. Hypoxic-ischemic (HI) brain injuryrefers to neuropathology due to hypoxia and or ischemia as evidenced by neuroimaging or post-mortem abnormalities^11.

In order for an acute intrapartum hypoxic event as cause of cerebral palsy (CP), the American Academy of Pediatrics (AAP) and the American College of Obstetrics and Gynecology (ACOG) define 4 essential criteria .

1. Evidence of a metabolic acidosis in fetal umbilical cord arterial blood obtained at delivery (pH <7 and base deficit ≥12 mmol/L).

2. Early onset of severe or moderate neonatal encephalopathy in infants born at 34 or more weeks of gestation.

3. CP of the spastic quadriplegic or dyskinetic type.

4. Exclusion of other identifiable etiologies such as trauma, coagulation disorders, infectious conditions or genetic disorders.

D. Criteria that suggest an acute intrapartum hypoxic event

1. A sentinel hypoxic eventoccurring immediately before or during labour

2. A sudden and sustained fetal bradycardia or the absence of fetal heart rate variability in the presence of persistent, late, or variable decelerations, usually after a hypoxic sentinel event when the pattern was previously normal

3. Apgar scores of 0–3 beyond 5 minutes

4. Onset of multisystem involvementwithin 72 hours of birth

5. Early imagingshowing evidence of acute non focal cerebral abnormality¹²

CLINICAL PRESENTATION

Perinatal asphyxia can result in

CNS injury alone - 16%

CNS and other end-organ damage - 46%,

isolated non-CNS organ injury - 16%

or no end-organ damage - 22%

Clinical Features of Severe Hypoxic-Ischemic Encephalopathy: 12 to 24 Hours

Variable change in level of alertness

More seizures

Apneic spells

Jitteriness

Weakness- involving

-Proximal limbs: upper > lower (full term)

-Hemiparesis (full term)

-Lower limbs (premature)

Clinical Features of Severe Hypoxic-Ischemic Encephalopathy: 24 to 72 Hours

Stupor or coma

Respiratory arrest

Brain stem oculomotor and pupillary disturbances

Catastrophic deterioration with severe intraventricularhemorrhage

and periventricular hemorrhagic infarction (premature)

Clinical Features of Severe Hypoxic-Ischemic Encephalopathy: After 72 Hours

Persistent, yet diminishing stupor

Disturbed sucking, swallowing, gag, and tongue movements

Hypotonia> hypertonia

Weakness of

-Proximal limbs: upper > lower (full term)

-Hemiparesis (full term)

-Lower limbs or hemiparesis (premature)^13.

MULTIORGAN SYSTEMIC EFFECTS OF ASPHYXIA

CNS

HIE, infarction, intracranial hemorrhage, seizures, cerebral edema, hypotonia, hypertonia

CARDIOVASCULAR

Myocardial ischemia, poor contractility, tricuspid insufficiency, hypotension.

PULMONARY

Pulmonary hypertension, pulmonary haemorrhage , RDS.

RENAL

Acute tubular or cortical necrosis

ADRENAL

Adrenal hemorrhage

GIT

Gastrointestinal Perforation, ulceration with hemorrhage, necrosis

METABOLIC

Inappropriate secretion of antidiuretic hormone, hyponatremia, hypoglycemia, hypocalcemia, myoglobinuria and Subcutaneous fat necrosis

Hematology

Disseminated intravascular coagulation.

INTRA-PARTUM FETAL MONITORING

• Electronic fetal monitoring (EFM) and fetal scalp pH monitoring:

A Fetal scalp pH of less than 7.20 indicates that delivery should be carried out rapidly. The only benefit however, in neonatal outcome seen after electronic fetal monitoring was a reduction in the incidence of early neonatal seizures.

• Fetal ECG analysis: It appears that a normal heart rate pattern may be reassuring, but an abnormal fetal heart rate pattern is poorly predictive of fetal compromise.

Close CTG monitoring with additional ECG ST-waveform correlates significantly with lower rate of acidotic umbilical artery pH compared with standard CTG monitoring .

• Fetal pulse oximetry

Near-infrared Spectroscopy: During labour, an optical probe is kept on to the fetal head via cervix to assess the anterior cerebral artery flows and oxygen

before delivery and the umbilical arterial acid-base status immediately after birth¹⁴.

NEUROPATHOLOGIC FEATURES OF PERINATAL BRAIN INJURIES

 parasagittal brain injury

 periventricular leukomalacia

 selective neuronal necrosis

 focal or multifocal ischemic lesions

Parasagittal Brain Injury -Occurs in term neonates. It is classically bilateral, symmetric, and affects the parasagittal portions of the cerebral convexities(

“watershed” areas between the territories of the anterior, middle, and posterior cerebral arteries) results inprolonged partial asphyxia.This type of injury affects the motor cortex - the portion responsible for proximal extremity function results in seizures, hypotension or both. The upper extremities are often more severely affected. These patients present with spastic quadriplegia and seizure disorders later in life.

Periventricular Leukomalacia

PVL is the most common injury in preterm babies. Before 32 weeks of gestation, blood vessels penetrate the cortex from the pial surface. Fetuses of this age have short penetrators (which end in the subcortical white matter) and long penetrators (which extend deeper into the brain). This results in relatively poor vascularization of the periventricular white matter, which predisposes premature infants to ischemic injury. The areas that are most prone to damage are the centrum semiovale and the optic (trigone and occipital horns) and acoustic (temporal horn) radiations. Because of involvement of the lower extremity axons of the corticospinal tract, which are periventricular in location, these patients present later with spastic diplegia. Visual field disorders are also characteristic of PVL because of damage that occurs within the optic radiations.

Selective Neuronal Necrosis

Selective Neuronal Necrosis is the most common pattern. The sequelae include mental retardation, spastic quadriparesis and seizures. Choreoathetosis and dystonia occur if the thalamus and basal ganglia are involved. Bulbar and pseudobulbar palsy occur if the brainstem and tegmentum are affected.

Pathogenesis include Hypoperfusion with subsequent reperfusion injury and glutamate-induced injury.

Diffuse neuronal injury

Occurs after severe, very prolonged hypoxic–ischemic insults in both term and premature infants. It affects the cortex, hippocampus, cerebellum, and anterior horn cells of the spinal cord. Within the cortex, the injury is more marked in the depth of the sulci than in the gyri. With more severe injuries, the more differentiated visual (calcarine) cortex and the perirolandic cortex may be damaged¹⁵.

POSTNATAL INVESTIGATIONS

Cranial Ultrasound

A high proportion of encephalopathy infants had evidence of major recent and evolving brain injury on early CUS imaging, suggesting prolonged or severe acute exposure to hypoxia-ischemia (HI). Early abnormalities were a significant predictor of death^16.cerebral edema recognized by a generalized increase in echo- density, a loss of anatomical landmarks, indistinct sulci and compression of the ventricles.

‘Slit –like’ ventricles are seen normally in the first 24 hours in term infants, and are only abnormal if persisting for more than 36 hours. Later ultrasound scan findings associated with a poor neurodevelopmental outcome include bilateral,

uniformly echogenic injury, diffuse parenchymal echo densities (which represent neuronal necrosis); multi-focal cystic changes; periventricular echo densities; and ventriculomegaly with cortical atrophy.

CT Scan

CT scan-prognostic factor when done about 4-6 weeks after asphyxia. In acute stages, CT shows reversal sign - diffuse cerebral hypodensity with loss of gray white differentiation but with relatively increased density of deep nuclear structures. In chronic cases CT shows changes in basal ganglia and thalamus.

These areas express a featureless appearance, with loss of distinction of deep nuclear structures and usually clearly decreased attenuation of these structures, which gradually deteriorates over several months. Rarely the injury can develop calcification. Because of the relatively superficial nature of the parasagittal cerebral injury it is more difficult to appreciate it on CT scan unless it is very severe. Periventricular leukomalacia in preterm infants can be seen in CT scans as periventricular hypodensity with a propensity for involvement of anterior and posterior periventricular areas.

Magnetic Resonance Imaging (MRI)

MRI is the most sensitive and specific imaging modality for evaluating suspected neonatal HIE. Conventional MRI is less sensitive than newer imaging techniques like DWI and MRS in diagnosing acute brain injury; however, they can help to exclude other causes of encephalopathy such as congenital malformation, neoplasm, cerebral infarction and hemorrhage¹⁷.

DWI often can show abnormalities within the first few hours after the insult and is pragmatically useful. DWI reveals restricted water diffusion not apparent on conventional MRI by detecting differences in rates of diffusion of water protons.

Atrophy of thalamus, basal ganglia usually accompanied by increased signal on T2W images is prominent especially in children with extra-pyramidal involvement. The sequelae of PVL are distinct and consists of decreased periventricular white matter, especially in the peri-trigonal area, compensatory ventricular dilation and increased signals in periventricular white matter on T2W images. MRI is useful in establishing the clinical diagnosis, assessing the severity of injury and thereby prognosticating the outcome¹⁸.

Cerebral Blood Flow Velocities

Using pulsed wave duplex Doppler with real-time analysis of the Doppler signal from a major cerebral artery (often the anterior), the cerebral blood flow can be determined. The end tidal CO2 should be kept in the normal range because hypercapnia causes cerebral acidosis and may cause cerebral vasodilation which may cause more flow to uninjured areas with relative ischemia to damaged areas and extension of infarct size. Excessive hypocapnia may decrease CBF.

Hyperventilation is not recommended. The decreasing diastolic blood flow velocity in relation to the peak systolic blood flow velocity (Pourcelot’s resistivity index <0.55) is associated with a poor outcome in asphyxiated infants. The cerebral blood flow velocities can take 24 hours to become abnormal following hypoxia-ischemia, and have been found to be of little prognostic value if performed at 6 hours.

Magnetic Resonance Spectroscopy

Calculation of absolute metabolite concentrations and relaxation times measured within the first 4 days after birth would improve prognostic accuracy and enhance the understanding of underlying neurochemical changes in neonates with neonatal encephalopathy¹⁹.

Intra-cerebral energy states can be measuredin vivoby magnetic resonance spectroscopy (MRS) technique. Phosphocreatinine (PCr) and inorganic phosphate (Pi) can be measured from the phosphorus-31 spectra. The PCr/Pi ratio represents the phosphorylated energy status within the brain, and a low PCr/Pi ratio in asphyxiated neonates is associated with later neurodevelopmental impairment. Prolonged high levels of lactate peaks predict a bad outcome.

EEG and Amplitude Integrated EEG (aEEG)—

Cerebral Function Monitoring

The severity of EEG abnormalities and their duration are of prognostic importance. Recovery of normal EEG background by day 7 is associated with a normal outcome. In contrast a burst suppression pattern or isoelectric pattern on any day is invariably associated with a poor outcome. Amplitude-integrated EEG recordings (Cerebral function monitor) obtained continuously from bipolar electrodes have recently been advocated as an objective tool for early prediction of poor outcome.

Use of aEEG monitoring can predict outcome, with a high degree of accuracy, after birth asphyxia, within the first six hours after birth. The predictive value of a suppression-burst pattern was, however, somewhat lower than the other

background patterns. The aEEG seems to be a feasible technique for identifying infants at high risk of subsequent brain damage who might benefit from interventionist treatment after asphyxia²⁰.^.

The aEEG was predictive of an abnormal outcome with a sensitivity of 78% and specificity of 94%, positive predictive value of 85% and a negative predictive value of 92%.

LABORATORY INVESTIGATIONS

Neonatal asphyxia affects multiple organs, which needs to be evaluated as it affects the prognosis of HIE

AKI is common in perinatal asphyxia mostly in term babies. FENa and RFI are parameters used to assess the renal function and urinary β2M is a good biomarker for diagnosis and prognosis of acute tubular injury in babies with perinatal asphyxia²¹.

Evaluation of blood urea and serum creatinine levels are used to assess the

The proximal renal tubule is affected the most. Urinaryβ2microglobulin could be used as a recent marker of kidney injury which signifies tubular dysfunction. Serum Cystatin C is a more sensitive marker of glomerular filtration rate than Cr in the newborns²².

Markers of neuronal dysfunction are available to identify the CNS injury like Glial Fibrillary acid protein(GFAP) and ubiquitin carboxy terminal hydrolase L1(UCH-L1) expressed in neurons and astrocytes. Another marker S-100 β protein is found to be elevated in the first urine of HIE newborns²³.

Other markers associated with CNS injury are neuron specific enolase ,brain derived neurotropic factor, interleukin -6 and creatinine kinase BB.

Management

A. Supportive care

1. Resuscitation. The 2011 Neonatal Resuscitation Program guidelines recommend initiating resuscitation with room air or blended oxygen with a targeted preductal Spo2 of 60–65% by 1 minute of life and 80–85% by 5 minutes of life in all term and preterm infants. There are no current guidelines specific to

neonates with HIE. While resuscitation with 100% O2 more rapidly restores CBF and perfusion in animal studies, hyperoxia should be avoided, as oxidative damage from oxygen-free radicals can further exacerbate hypoxic ischemic brain injury.

2. Ventilation.Assisted ventilation may be required to maintain Pco2 within the physiologic range. While hypercarbia exacerbates cerebral intracellular acidosis and impairs cerebrovascular autoregulation, hypocarbia (Paco2 <20–25 mm Hg) decreases CBF and is associated with PVL in preterm infants and late-onset sensorineural hearing loss in full-term infants.

3. Perfusion. Arterial blood pressure should be maintained in the normotensive range for gestational age and weight. Due to the loss of cerebrovascular autoregulation, volume expanders and inotropic support should be used cautiously in order to avoid rapid shifts between systemic hypotension and hypertension.

Physiology of shock in perinatal asphyxia involves the release of endogenous catecholamines leading to normal or increased SVR clinically

dysfunction. The baby is likely to be euvolemic and may have associated pulmonary hypertension.

Cardiovascular stability and adequate mean systemic arterial blood pressure are important in order to maintain adequate cerebral perfusion pressure.

Fluids, inotropes, vasopressors, and hydrocortisone replacement are used to treat shock in the neonate. Mainstay of shock management includes inotropes and vasopressortherapy.

1) Inotropes are used to improve cardiac function :

Sympathomimetic amines are commonly used in infants which includes Dopamine, Dobutamine and Epinephrine.

i. Dopamine activates receptors in a dose-dependent manner. At low doses (0.5 to 2 μg/kg/minute), dopamine has little effect on cardiac output. In intermediate doses (5 to 9 μg/kg/minute), dopamine has positive inotropic and chronotropic effects. The increase in myocardial contractility depends in part on myocardial norepinephrine stores.

ii. Dobutamineis a synthetic catecholamine with relatively cardioselectiveinotropic effects. In doses of 5 to15 μg/kg/minute, dobutamine increases cardiac output with little effect on heart rate. Dobutamine can decrease SVR and its inotropic effects are independent of norepinephrine stores.

iii. Epinephrine has potent inotropic and chronotropic effects in the 0.05 to 0.3 μg/kg/minute doses. At these doses, it has greater β2-adrenergic effects in the peripheral vasculature with little α-adrenergic effect resulting in lower SVR.

Epinephrine is an effective adjunct therapy to dopamine because cardiac norepinephrine stores are readily depleted with prolonged and high-rate dopamine infusions.

b. Milrinone is a phosphodiesterase-III inhibitor that enhances intracellular cyclic adenosine monophosphate content preferentially in the myocardium leading to increase in cardiac contractility. It improves diastolic myocardial function more readily than dobutamine. Milrinone also lowers pulmonary vascular resistance and SVR by increasing cAMP levels in vascular smooth muscle.

2. Vasopressor therapy is used to increase SVR and improve BP which will restore perfusion to vital organs.

a. Dopamine in high doses (10to 20 μg/kg/minute) causes vasoconstriction by releasing norepinephrine from stores and directα-adrenergic receptors. Neonates have reduced releasable stores of norepinephrine.

4. Acid-base status.The base deficit is thought to increase in the first 30 minutes of life due to an initial washout effect secondary to improved perfusion and transient increase in lactic acid levels. Acidosis normalizes in the majority of infants by 4 hours of life, regardless of bicarbonate therapy. The rate of recovery from acidosis is reflective of HIE severity but not duration, and is not predictive of outcomes. Sodium bicarbonate therapy is not recommended as it causes a concomitant rise in intracellular Pco2 levels, negating any changes in pH, and is associated with increased rates of intraventricular rhemorrhage and mortality.

5. Fluid status. Initial fluid restriction is recommended as HIE infants are predisposed to a fluid overload state from renal failure secondary to acute tubular necrosis (ATN) and SIADH. The avoidance of volume overload helps avert cerebral edema. A single dose of theophylline (8 mg/kg) may be considered

within the first hour to increase glomerular filtration by blocking adenosine mediated renal vasoconstriction.

6. Seizures. Seizure activity is both a consequence and determinant of brain injury. A Cochrane review showed no reduction in death, neurodevelopmental disability, or combined outcome with the prophylactic use of anticonvulsant therapy. Phenobarbital therapy is recommended as the first-line agent for prolonged or frequent clinical seizures. The use of prophylactic phenobarbital in conjunction with hypothermia has shown a reduction in clinical seizures but not neurodevelopmental outcome. Phenobarbital levels in asphyxiated infants should be carefully monitored because hepatic and renal dysfunction, as well as hypothermia, can increase the drug’s half-life and plasma concentration.

7. Hypocalcemia.

Role of Calcium in Humans

Calcium is involved in many biochemical processes in the body, such as blood coagulation, intracellular signal transduction, neural transmission, muscle functions, cellular membrane integrity, and function, cellular enzymatic activities, cell differentiation, and bone mineralization. About 99% of body calcium resides in the bone tissue and the remaining is present in the extracellular

fluid. Almost half of the calcium found in the extracellular fluid is in the ionized active form, whereas 10% is complexed to anions such as phosphate, citrate, sulfate, and lactate, and 40% is bound to albumin Calcium homeostasis is maintained by hormones, such as PTH, calcitonin, vitamin D, and calcium- sensing receptors. PTH increases bone resorption and, consequently, the serum level of calcium. In the kidneys, PTH increases the activity of 1- -hydroxylase in the proximal tubules, increasing production of the active form1,25- dihydroxyvitamin D from 25- hydroxyl vitamin D. Furthermore, PTH increases phosphate excretion, calcium, and magnesium reabsorption in the distal tubules.

The active form of vitamin D acts on the bones, intestines, and parathyroid glands.

It increases osteoid mineralization in the bones and causes resorption at high doses. 1,25-Dihydroxyvitamin D also increases the intestinal absorption of calcium and phosphate ions and decreases the renal excretion of these ions.

Vitamin D inhibits PTH secretion by the parathyroid glands. Calcitonin primarily reduces bone resorption, promotes calcium deposition in the bone by mineralization, and, consequently, decreases the serum calcium level. Calcitonin also increases the renal excretion of calcium and phosphate ions and decreases the gastrointestinal absorption of these ions

Fetal and Neonatal Calcium Homeostasis

At birth, the umbilical cord serum calcium level is increased (10 to 11mg/dl). In healthy term babies, calcium concentration decreases for the first 24 to 48 hours,

the nadir is usually 7.5 to 8.5 mg/dl. After that calcium concentration progressively rise to the mean values seen in older children and adults. After the infant becomes detached from the placenta in the postpartum period, serum total and ionized calcium levels decrease, reaching a physiological nadir in a healthy 2-day term infant. By contrast, phosphate levels increase. The pace and amount of such decrease in calcium levels are inversely related to the gestational week . Such a decreased level of calcium is associated with hypoparathyroidism, non- responsiveness of target organs to PTH, vitamin D metabolism disorders, hyperphosphatemia, hypomagnesemia, and hypercalcitonemia in the first days of life . PTH secretion increases in the first 48 h of life and with the increased PTH secretion, the intestinal absorption of calcium and phosphate, the renal reabsorption of calcium, and the renal excretion of phosphate increase in the new born. Similarly, serum calcium levels start increasing and serum phosphate levels start decreasing. Within the first four weeks of birth, the intestinal absorption and renal reabsorption of calcium become mature.

Causes of hypocalcemia in infants with asphyxia:

 Increased phosphate load due to cellular damage.

 Increased calcitonin production.

 Renal failure.

 Decreased PTH secretion [24].

Treatment of Hypocalcemia in the New born Period and Infancy:

Hypocalcemia is a common metabolic alteration after neonatal asphyxia. It is important to maintain calcium in the normal range because hypocalcemia can compromise cardiac contractility and may cause or exacerbate seizures. The cornerstone of treatment of hypocalcaemia is calcium replacement and the treatment options may vary by symptoms and the extent of hypocalcemia. Early- onset hypocalcemiais usually asymptomatic and treatment is Recommended when the serum calcium level is <6mg/dL in preterm and 7mg/dL in term infants.

It is recommended administering 40 to 80mg/kg/d elemental calcium replacement for asymptomatic newborns.

For infants who require parenteral nutrition, calcium can be added as 10%calciumgluconate (500mg/kg/d, 50mg/kg/d of elemental calcium) and given in continuous infusion. If parenteral calcium is administered for >2 days, phosphorus should also be replaced based on serum phosphate levels. In newborns with symptoms such as tetany or convulsion, intravenous 10 to 20mg/kg of elemental calcium (1–2 mL/kg/dose 10% calciumgluconate) is administered by slow infusion for about 10min under cardiac monitoring for the

acute treatment of hypocalcemia. This treatment does not normalize the calcium level but it prevents the severe symptoms of hypocalcemia, such as convulsion.

Following the administration of calciumas a bolus, 50 to 75mg/kg/d or 1 to 3mg/kg/h elemental calcium infusion should be initiated [25]. Continuous Calcium gluconate infusion is preferred rather than 1 mL/kg/dose intravenous bolus doses every 6 h. The amount of calcium given should be adjusted by measuring calcium every 8 to 12 h until normal calcium values are achieved.

Severe tissue necrosis may occur due to extravasation of calcium in the intravenous calcium gluconate therapy. Therefore, appropriate vascular access should be ensured and the infusion rate should not exceed 1mg/min. Cardiac arrhythmias such as bradycardia may occur and even cardiac arrest may develop during calcium gluconate infusion; therefore, intravenous administration should be performed slowly for 10 to 30min under cardiac monitoring. If an umbilical venous catheter is used for calcium administration, then the catheter tip should be in the inferior vena cava; a catheter tip in the portal vein may cause hepatic necrosis.

In patients who are asymptomatic or have mild symptoms or who have achieved normocalcemia by intravenous calcium, oral calcium therapy can be administered. In such patients, calcium lactate, carbonate, or citrate may be used and 40 to 80mg/kg/d of elemental calcium can be administered in 3 to 4 doses.

creatinine should be evaluated at frequent intervals and the dose should be adjusted so that daily urinary calcium excretion will be <4mg/kg/d.

Complications such as iatrogenic hypercalcemia, nephrocalcinosis, and renal failure can thus be avoided.

Hypoglycemia and Hypoxemia

The vulnerability of the immature brain to hypoxemic injury is enhanced by concomitant hypoglycemia, an observation first made in 1942. Studies of cerebral carbohydrate metabolism during hypoxemia and hypoglycemia in newborn rats have provided further insight into the mechanism of this effect. Thus newborn rats subjected to hypoxemia by breathing 100% nitrogen exhibited greater mortality rates when they were also subjected to insulin-induced hypoglycemia.

Indeed, animals rendered hypoglycemic for 1 hour experienced a fivefold reduction in survival ability, and those hypoglycemic for 2 hours did even worse.

Supplementation of hypoglycemic animals with glucose before anoxia improved outcome .

Animals rendered hypoglycemic as well as hypoxemic exhibited less accumulation of lactate in the brain and a faster decline in cerebral energy reserves (ATP and phosphocreatine) than those rendered hypoxemic alone.

Moreover, glucose supplementation ameliorated the adverse metabolic effects.

The mechanism for the enhanced deleterious effect of hypoxemia when hypoglycemia was associated appeared to relate to a diminution in brain glucose

reserves and thus retarded glycolytic flux. The improvement with glucose supplementation supports this notion. Studies of cultured immature glial cells are relevant to the adverse effect of the combination of hypoxemia and hypoglycemia. Thus not only are immature astrocytes more vulnerable to glucose deprivation than are mature glial cells but also, of special interest in this context, glucose deprivation markedly accentuates the vulnerability of differentiating glial cells to oxygen deprivation . This effect of glucose deprivation on immature glial cells is apparent in both differentiating astrocytes and oligodendroglia.

Hypoglycemia and Asphyxia

Study of the newborn dog has demonstrated the deleterious effect of hypoglycemia when combined with asphyxia. Thus, to approximate clinical circumstances more closely (than the nitrogen breathing of the experiments just described), neonatal dogs were asphyxiated with and without prior induction of hypoglycemia to plasma glucose levels of approximately 20 mg/dL. The data showed striking worsening of the cerebral metabolic effects of asphyxia in animals rendered hypoglycemic versus those that were normoglycemic.

Thus, whereas in normoglycemic animals levels of glycolytic substrates subsequent to the phosphofructokinase step increased secondary to the expected acceleration of anaerobic glycolysis, in hypoglycemic animals no such increase

Moreover, whereas hypoglycemia alone resulted in little or no alteration in levels of high-energy phosphate compounds, when combined with asphyxia a drastic reduction in these compounds resulted. ATP levels declined with asphyxia by 61% in the hypoglycemic animals compared with only 13% in the normoglycemic animals. Thus the data extended the findings described earlier with the combination of hypoglycemia and hypoxemia and indicated that hypoglycemia combined with asphyxia leads to greater cerebral metabolic derangements than those observed with asphyxia alone.

A deleterious effect of hypoglycemia in the postasphyxial period was shown by studies of newborn lambs. Here cerebral fractional oxygen extraction remained depressed relative to values in control or hyperglycemic animals for as long as 4 hours following termination of asphyxia (the last time point studied).

A study of 185 term infants with severe fetal acidemia (umbilical arterial pH

<7.00) suggested an important role for postasphyxial postnatal hypoglycemia in the genesis of brain injury.

Brain Imaging in Neonatal Hypoglycemia

A series of reports have identified, by brain imaging, a specific pattern of cerebral abnormality involving principally the parietooccipital regions. Consistent with the reported neuropathology, the dominant finding has been abnormal signal

intensity by MRI in the parietooccipital region . The involved areas exhibit restricted diffusion on diffusion-weighted MRI (DWI).

The topography is seen better in the acute stage by DWI than by conventional MRI. Magnetic resonance spectroscopy shows no or mild elevations of lactate with advanced lesions. The findings of no or mild elevations of lactate indicate that the lesion is not ischemic in basic nature but rather is related to glucose deprivation. Although 10% to 15% of the lesions resolve, most are followed in subsequent weeks and months by loss of cerebral cortex and white matter, often with ventricular dilation. A more diffuse pattern of cerebral cortical injury may occur with very severe hypoglycemia.

In general the posterior cerebral involvement includes both cortex and underlying white matter, seen best acutely by DWI imaging . Conventional MRI sequences often show predominantly white matter involvement. Other lesions are seen in a minority of infants and are often related to associated insults.

Management

Management of the infant with neonatal hypoglycemia is considered best in terms ofprevention and therapy. Major advances in both these aspects of management have been made in the past 20 years.

Prevention

Prevention of neonatal hypoglycemia must involve factors related to pregnancy, labor, delivery, and the early neonatal period. During pregnancy, importance can be attributed to control of maternal diabetes, nutrition, intrauterine growth restriction, and other factors that cause prematurity. Prevention and control of perinatalasphyxiaare clearly of major significance. Of particular relevanceafter deliveryare

(1) identification of the high-risk infant,

(2) minimization of excessive caloric expenditures by maintenance of temperature in the normal range,

(3) implementation of oral feedings (breast-feeds when possible) as soon as possible after birth,

(4) careful surveillance for clinical symptoms, and

(5) determination of blood glucose level before the first feeding and subsequently according to the clinical setting.

Early discharge of preterm infants before the firm establishment of oral feedings should be avoided to prevent the post discharge evolution of hypoglycemia.

Simple preventive guidelines in asymptomatic infants can be summarized as follows. In the healthy appropriately grown term infant, facilitating normal

feeding is sufficient. Inpreterm infantsof less than 32 to 34 weeks’ GA or those with respiratory distress, establishment of enteral feedings is relatively slow and intravenous glucose, generally commencing at 4 to 6 mg glucose/kg per minute, is needed. Because breast-fed neonates do not receive full caloric intake for several days after birth, it has been suggested that they are able to compensate for low glucose by the generation of ketones as an alternative fuel for the brain.

However, ketones are low in breast-fed babies during the first 1 to 2 days after birth and then rise modestly over 2 to 3 days after birth (0.7 to 1.4 mmol/L) before falling to very low levels as breast milk production matures.

The low levels of ketones and free fatty acids appear to be explained by incomplete suppression of insulin release in the face of low plasma glucose concentrations. Importantly, without specific measurements of plasma ketone concentrations, it cannot be assumed that ketones are available as an alternative fuel to support brain metabolism when normal neonates develop hypoglycemia or that breast-fed babies are protected against potential adverse effects of hypoglycemia by ketones if their postnatal fasting period becomes too long. For clearly intrauterine growth–restricted infants, management depends in part on the initial glucose values but usually includes early introduction of enteral feedings plus or minus intravenous glucose infusions. Such infants may require from 6 to 8 mg/kg per minute and on occasions even higher glucose infusion rates

For infants of diabetic mothers, early glucose screening (highest incidence of hypoglycemia is at ~2 to 4 hours of age), early enteral feeding and regular prefeed glucose monitoring are crucial. Excessive rapid intravenous glucose infusion should be avoided to prevent overstimulation of the infant’s pancreas, already primed to produce hyperinsulinism.

Therapy

When to Treat. The major issues in therapy relate to when and how to treat.

Detection of hypoglycemia at the bedside, previously dependent on Dextrostix determinations, has been facilitated in many units by portable reflectance meters, electrochemical glucose meters, and related instruments.

Confirmation of low values with laboratory determinations is important. The difficult issue in this context, of course, is the definition of hypoglycemia.

Moreover, treatment depends on whether the infant is symptomatic or not.

The American Academy of Pediatrics (AAP) has recently published guidelines for screening and management of postnatal glucose homeostasis in late-preterm (34 to 36 6/7 weeks’ GA), term small-for-GA infants, and infants who were born to mothers with diabetes/ large-for-GA infants.

These guidelines suggest that late-preterm and small-for-GA infants be screened at 0 to 24 hours and infants of diabetic mothers and large-for-GA infants (i.e.,

≥34 weeks’ GA) at 0 to 12 hours. In the asymptomatic infant, the AAP suggests for values less than 25 mg/dL (birth to 4 hours), or less than 35 mg/dL (4 to 24 hours of age), that the infant be fed and rechecked in an hour; if the blood glucose remains below 25 mg/dL or below 35 mg/dL, intravenous glucose should be administered.

For symptomatic babies and a glucose level below 40 mg/dL, intravenous glucose is recommended.(26) However, we favor the following approach: intravenous glucose should be considered in any infant with a persistently low blood glucose level who is at risk for impaired metabolic adaptation (e.g., small-for-GA infant, infant of a diabetic mother, or the infant with concomitant hypoxic–ischemic insult), even with no abnormal clinical signs, or a single low blood glucose level in an infant presenting with abnormal clinical signs. We suggest this approach based on

(1) neurophysiological, epidemiological, and clinical observations that levels less than 50 mg/dL can be associated with evidence for neurophysiological or neurodevelopmental dysfunction;

(2) the PET observation that cerebral glucose utilization in the premature infant may be limited by glucose transport at levels of plasma glucose less

(3) the likelihood that degrees of hypoglycemia not sufficient to cause brain injury alone may do so when combined with other factors deleterious to the central nervous system;

(4) the lack of precise information regarding the level of blood glucose below which neuronal injury is likely to occur;

(5) the realization that the parieto-occipital region and higher visual functions are most sensitive to hypoglycemia and that such ortical functions have not been carefully studied in most previous follow-up reports; and

(6)the ample experimental evidence that blood glucose levels are not accurate predictors of brain glucose levels, particularly in states such as asphyxia or seizures.

It is essential that the physician consider the status of Both cerebral glucose delivery (i.e., CBF) as well as blood glucose content and cerebral glucose utilization.

How to Treat.

If a decision is made to treat an infant, the next issue is the manner of therapy. A small group of infants requires specific therapies for hormonal or enzymatic aberrations;

For the large group of infants in whom glucose alone is the mainstay of therapy, it is prudent to avoid the relatively large bolus infusion, particularly in the premature infant. Lilien and co-workers. demonstrated particular effectiveness and safety of a minibolus infusion of 200 mg/kg (2 mL of 10% glucose injected over 1 minute), immediately followed by a continuous glucose infusion of 5 to 8 mg/kg per minute. The mini bolus infusion results in rapid correction of blood glucose level (usually within 1 minute), and a relative stability of values between approximately 70 and 80 mg/dL occurs thereafter with the continuous infusion of 5 to 8 mg/kg per minute, approximately the maximum usable dose of glucose in the newborn . Careful assessment of the initial clinical response after the mini bolus infusion is essential, especially if the indication for the infusion was seizure, because of variability in the response to blood glucose level; a second mini bolus infusion may be necessary.Continued careful monitoring of clinical response and blood glucose level also is important because certain infants (e.g., those with hyperinsulinism) may require higher maintenance doses of glucose, whereas some infants require lower maintenance doses to avoid hyperglycemia.

In general, after blood glucose levels are stable at 70 to 100 mg/dL, the dextrose concentration in the infusion may be decreased by 1 to 2 mg/kg per minute every 6 to 12 hours. Glucose levels are monitored closely and should be maintained at more than 50 mg/dL.

It is important not only to correct hypoglycemia but also to avoid hyperglycemia.

For infants whose glucose levels do not increase adequately despite higher infusion rates of at least 10 to 12 mg/kg per minute or who require infusion rates of more than 12 mg/kg per minute or if hypoglycaemia recurs, hyperinsulinism should be considered. Treatment for the latter condition includes diazoxide or octreotide (both of which suppress insulin secretion) or pancreatic surgery.

Less likely causes include specific hormonal defects (e.g., hypopituitarism) or a metabolic disorder, each of which requires specific therapy. Hydrocortisone, previously used in this context at 5 mg/kg every 12 hours, has benefit by increasing gluconeogenesis (from protein sources) and decreasing peripheral glucose utilization. This agent has been used less in recent years; if administered, it should be discontinued as soon as feasible.

Recent findings indicate that the rate of glucose infusion to correct hypoglycemia is not clear cut. Thus, in a study of infants (≤35 weeks GA) with hypoglycemia treated to maintain a blood glucose concentration of at least 47 mg/dL (2.6 mmol/L), a surprising finding was the association of neurosensory impairment, especially cognitive delay, with higher glucose concentrations and less glucose stability, indicated by a larger proportion of time outside a central range of 54 to 72 mg/dL in the first 48 hours. Of concern is the observation that rapid correction

of hypoglycemia to higher blood glucose concentrations may be associated with an adverse outcome.

This unanticipated finding must be interpreted with caution, since the study was observational. Furthermore, the association was seen only in tests of general development and not intests of processing ability. Hyperglycemia blood glucose concentration of >180 mg/dL [10.0 mmol/L]) has been shown previously to be associated with increased mortality and neurodevelopmental impairment in very preterm infants, but an association has not previously been reported in more mature infants, especially at glucose concentrations typically regarded as being within the normal range.

PHASES OF HYPOXIC ISCHEMIC ENCEPHALOPATHY

NEUROPROTECTIVE STRATEGIES IN PRETERM

Antenatal steroids, magnesium sulphate, delayed cord clamping, caffeine eythropoietin and melatonin.

IN TERM

Therapeutic hypothermia, erythropoietin, xenon, argon, stem cell therapy(umbilical cord stem cells,mesenchymal stem cells,embryonic stem cellsinduced pluripotent Stem cells, neuronal/amniotic fluid stem ) n-acetyl cysteine / allopurinol, magnesium, calcium channel blockers and anticonvulsants.

THERAPEUTIC HYPOTHERMIA:

Therapeutic hypothermia attenuates secondary energy failure by decreasing cerebral metabolism, inflammation, excitotoxicity, oxidative damage and cellular apoptosis. Hypothermia is now emerging as standard of care for perinatal asphyxia. Early identification of neonates with perinatal asphyxia and their timely referral to tertiary care centers for hypothermia therapy is therefore crucial. Hypothermia protocols that recommend temperature regulation prior to admission (such as passive cooling or active cooling on transport) are institution

specific and must be clarified with the accepting facility at the time of referral.

To date, 3 large multicenter trials of cerebral hypothermia for HIE, initiated within 6 hours of birth and continued for 72 hours, have been completed²⁷.

METHOD

Mild hypothermia initiated within 6 hours with a 33.5 degrees with a target oesophageal temperature goal (32.5-34.5 degrees) for 72 hours followed by Slow rewarming of 0.5 degree/2hrs untill 36.5(10 hrs).

The Total Body Hypothermia for Neonatal Encephalopathy (TOBY) TRIAL

In this trial babies are cooled to a body temperate of 33.5°C but used aEEG entrance criteria. Cooling did not reduce the combined rate of death or severe disability, but improved neurodevelopmental outcomes were seen among survivors.

Selective head cooling (SHC)increases the temperature gradient across the brain from the central to peripheral regions. This is in contrast to whole body cooling, which maintains a uniform temperature gradient across the brain. In a systematic review of 13 studies, systemic hypothermia, but not SHC, was associated with a

The reduction in mortality or neurodevelopmental disability among survivors was similar between both modes of cooling. There are no clinically significant adverse effects from therapeutic hypothermia, and the mode of cooling does not have any differential impact on multiorgan system dysfunction in asphyxiated infants²⁸.

FREE RADICAL SCAVENGERS

Allopurinol, desferrioxamine, vitamin E , C and N-Acetyl cysteine.

NMDA RECEPTOR BLOCKER

Magnesium, xenon and ketamine.

ERYTHROPOITIN

Hypoxia would promote upregulation of EPO receptor.when EPO available, promotes cell survival,when EPO absent, it leads to programmed cell death,Early benefits of EPO -anti apoptotic/anti-inflammatory and Late benefits-neurogenesis, plasticity, remodeling.

MELATONIN

N-ACETYL 5 METHOXY TRYPTAMINE. It is an Endogenous indolamine which crosses BBB. It functions as Antioxidant/anti apoptotic / anti- inflammatory. The combination therapy with MELATONIN+TH-improves survival. This therapy shows better neurodevelopmental outcome at 6 months of age.

XENON

Xenon Crosses blood brain barrier and placenta and Binds to NMDA/GLUTAMATE receptors thereby Inhibiting excitatory function reduced lactate to N Acetyl aspartate ratio in MRSis a good predictive imaging marker of neurodevelopmental outcome.

UMBILICAL STEM CELLS

Contains mesenchymal stem cells/progenitor stem cells/UCB- MONONUCLEAR CELLS.UCB-MNC could differentiate into all type of mature celll-neural cells .umbilical stem cells have greater proliferative potential and Low antigenicity.

FUTURE OUTLOOK ON NEUROPROTECTION

1)Remote ischemic post conditioning

2)Targeting inflammation

3)Targeting autophagy

PREDICTORS OF LONG-TERM NEURODEVELOPMENTAL OUTCOME IN PERINATAL ASPHYXIA

Parameters outcome

1)Fetal acid base measurement - Umbilical artery pH < 7.1, Base deficit >

11 Major neurological deficits in 14%

2)Extended APGAR score - At 20 minutes < 3: CP in 57% survivors

3) Severity of the encephalopathy- Mild-no neurological sequelae

- Moderate-25% have neurological sequelae.

-Severe - 100% have neurological sequelae.

3) Seizures - Early onset and refractory seizures

4) Elevated CPK BB - > 5 IU

5)Oliguria - Persistently < 1 ml/kg/hr for the first 36

hours of life

6)Background EEG - Burst suppression pattern on any day.

Isoelectric pattern on that day

7) Brainstem auditory, Visual -Abnormal latencies and amplitude ratios

and Somatosensory evoked potentials.

8)Neurologic examination at -If abnormal, predicts long-term

At the end of first week abnormality

9)head growth -If slow in the first month, is a poor

Prognosis.

MARKERS OF HYPOXIC MYOCARDIAL INJURY - CARDIAC TROPONIN I

Cardiac biomarkers are used to identify cardiac dysfunction and failure in term and preterm infants. Cardiac troponins are used to assess cardio myocyte compromise. Affected cardio myocytes release troponin into the bloodstream, resulting in elevated levels. Cardiac troponins are suggested as potential biomarkers in the diagnosis and treatment of neonatal disease complicated by circulatory compromise²⁹.

MATERIALS AND METHODS:

SOURCE OF DATA:

Prospective cohort study conducted on 100 asphyxiated term neonates recruited from Neonatal Intensive Care Unit (NICU) in Tirunelveli Medical College and Hospital.

DURATION OF STUDY:

One year from May 2018 to April 2019.

SAMPLE SIZE:

100 asphyxiated term babies admitted in NICU of Tirunelveli Medical College Hospital

TYPE OF STUDY:

Prospective Cohort Study.

INCLUSION CRITERIA:

Term( 37-42 weeks GA) , asphyxiated babies with APGAR score of <7 at one minute of life as per WHO perinatal & neonatal database

EXCLUSION CRITERIA:

Preterm(<37weeks) and Postterm babies(>42weeks)

Babies with congenital malformation

Neonates born to mothers who had received Magnesium Sulphate within 4 hours prior to delivery

Those born to mothers having diabetes mellitus & toxemia of pregnancy

Severe maternal deficiency of vitamin D

Maternal hyperparathyroidism

Mothers using anti-convulsants (Phenobarbitone& Sodium valproate)

Maternal intake of high dose antacids

LABORATORY ASSESSMENT:

• Serum Ionised Calcium

<4mg/dL – Hypocalcimia

Method- Ion selective Electrode method

• Serum glucose

< 45 mg/dL – Hypoglycemia

Method – Glucose Oxidase Peroxidase method

The following parameters are included and monitored in the present study.

1) Gravida

2) Mode of delivery