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Therapeutic Hypothermia in Moderate and Severe Hypoxic-Ischemic Encephalopathy: Use of Low- Cost vs High Technology Cooling Technique

Birth asphyxia leading to hypoxic-ischemic encephalopathy is one of the commonest cause of mortality and neuro-morbidity in infants in India. Acute perinatal insult to the brain is not a single event, it is an evolving process of cell death.1 In the immediate period following insult primary energy failure(first 6 hrs after birth) occurs where there is depletion of oxidative metabolites leading to neuronal cell injury and toxic oedema. A large number of neurons die but many survive only to enter into the process of re-deterioration after a latent period.2 This period during which secondary energy failure occurs is more severe and prolonged causing . ABSTRACT


INTRODUCTION
Birth asphyxia leading to hypoxic-ischemic encephalopathy is one of the commonest cause of mortality and neuro-morbidity in infants in India. Acute perinatal insult to the brain is not a single event, it is an evolving process of cell death. 1 In the immediate period following insult primary energy failure(first 6 hrs after birth) occurs where there is depletion of oxidative metabolites leading to neuronal cell injury and toxic oedema. A large number of neurons die but many survive only to enter into the process of re-deterioration after a latent period. 2 This period during which secondary energy failure occurs is more severe and prolonged causing . ABSTRACT permanent damage. 3 The latent period so-called window of opportunity is the only period during which if proper action is taken the process of permanent damage can be partially halted with better survival and long term outcome. 4,5 Therapeutic hypothermia has been proved to be effective at least partially during this period. The cooling process is effective if started immediately (at least within 6 hours after birth ) after the insult. Therapeutic hypothermia has been found to be useful in moderate and severe HIE secondary to perinatal asphyxia. 4 It reduces mortality as well as long term neuro-morbidity. The high technology cooling may not be affordable for all patients and may not be available in all the hospitals. This study will compare outcome in patients with moderate to severe HIE using low-cost cooling technique and state of art high technology cooling apparatus. The patient selection criteria will be the same in both groups. The low-cost technique will be used in NICU of Department of Pediatrics, JNMC Sawangi (M) Wardha whereas high technology cooling will be used use in NICU of the department of Pediatrics of Shree B. M. Patil Medical College Bijapur (Karnataka).
Patient selection criteria for both the groups will be the same and information gathered in the format also will be the same. Investigators from both institutes will share the data to make it collaborative study. A MOU will be made between both the institutes for the same.
Aim -To compare the outcome of moderate and severe HIE treated by low cost versus high technology cooling apparatus. Inclusion/exclusion criteria:

Primary Objectives
The first step will be ascertained criteria A and B. Second step is to confirm birth asphyxia (C)and then finally to confirm the severity of encephalopathy (D).

B. Age at presentation: For both inborn and Out-born neonates
i. 6 hours since birth C. Evidence of birth asphyxia: Inborn neonates: Any one of the following: 1. Apgar score at 5 minutes < 5 2. Need for Intermittent positive-pressure ventilation (IPPV) till 5 minutes of birth 3. Cord arterial blood or blood obtained within 1h of birth pH <7.0 4. Cord arterial blood or blood obtained within 1 h of birth base deficit > 16.0 Out-born neonates: Any one of the following: 1. Absence of cry at 5 minutes of age 2. Need for IPPV till 5 minutes of birth. 10,11

D. Staging of encephalopathy -For both inborn and outborn neonates
1. Anyone of the following: i Clinical seizures ii. An altered state of consciousness (lethargy, stupor or coma) AND any one of the following: a. Hypotonia b. Abnormal reflexes including oculomotor or papillary abnormalities c. Absent or weak suck We will perform neurological examination hourly until 6 hours of age to ascertain if baby fulfils the eligibility criteria.

Exclusion criteria:
1) Babies with syndromes or anomalies including anorectal anomalies. 2) Babies with Major intracranial haemorrhage.
3) Denial of consent by parents.
Target cooling point will be 33 o to 34.5 o C and the total duration of cooling will be set at 72 hours. A patient fulfilling selection criteria will be recruited in the study within 6 to 12 of birth.
In NICU of Sawangi (M) Wardha, the patients will be managed as follows: Patient will be randomised for low cost or high-cost cooling technique.
Step I: The warmer will be put off and the rectal temperature of the baby will be taken every 30 minutes.
Step II: a) In babies randomised for low technique-If it has not reached the targeted temperature, cool packs will be introduced wrapped in cloth one by one every 15 minutes till target temperature is reached with due precautions that none of the packs is frozen. After this temperature will be recorded at the 1 hour and if temperature maintained, the recording will be done every 2 hours. Always rectal temperature will be recorded and the target temperature will be maintained for 72 hrs.
b) In babies randomised for high-cost technique(Mera cradle). Baby will be managed in Mera cradle as per company instructions.
Step III: After 72hrs gradual rewarming of 0.5 o C /hour will be done by removal of packs one by one. All patients will be monitored as per the following table 1. Rest of management will be as per NICU protocol. Details of baby, mother, resuscitation, examination findings, cooling procedure, rewarming procedure, investigation, morbidities till discharge will be entered in a pre-validated proforma.

Follow up
These patients will be followed up in the high-risk clinic. First, follow-up will be after 1 week and subsequent visits will be monthly till one year of age. Any mortality if occurs will be entered including the cause of death and age of the baby at death. The neurodevelopment of the baby will be closely monitored till one year of age. The outcome will be noted at the end of the year concerning development, neuro deficit, vision and hearing.

Statistical Analysis:
The outcome of babies will be compared by clubbing the data both the institutes. The results will be expressed as numbers and percentages or on average. Statistical analysis will be carried by. The difference between the two groups will be studied either by non-parametric Mann Whitney test for quantitative variables or by Chi-square test or Fischer extract for qualitative variables. Statistical difference of < 0.05 will be considered significant.
Outcome measures-

DISCUSSION
Several studies showed the benefit of controlled hypothermia in infants with perinatal asphyxia of acute onset. Its effect has not been proved in chronic hypoxia. Initiation of cooling before 6 hours of life for 72 hours has been found useful and adequate as longer duration is known to cause more harm and mortality. Effect of longer duration of cooling needs to be studied further. 6,7 Most investigators used a target temperature between 32 o C to 34.5 o C. In India the most important problem faced was, asphyxia being more common in rural and remote areas. These are the areas with more mortality and poor long term outcome but these mother find it difficult to reach a facility with the provision of therapeutic hypothermia. Transport facilities are poor and have no means of therapeutic hypothermia. Quality of transport will be a big issue in rural India. The key to therapeutic hypothermia remains the start of therapy within 6 hours of birth. 5 Controlled therapeutic hypothermia reduced immediate mortality as well as long term neurological outcome 6 . Selective head cooling and total body cooling both are useful. 7,8 Predictors of outcome also have been identified. Baby having severe encephalopathy at <6 hours, severe neuro deficit at 72 hours of hypothermia has poor prognosis. 9,10 This indicates the importance of stage of encephalopathy while recruiting the cases. Though the therapy has to start before 6 hours of life, time to initiate cooling below 6 hours should not change at the cost of stabilization of neonate. 9,11 Birth weight of baby also has some relation to cooling, lower weight babies respond better but need better blood pressure support. 11,12 There are not much safety issues with hypothermia, some coagulopathy may occur as hypothermia slows down the enzymatic activity of coagulation cascade and blood pressure support may be needed. 13 Seizures may occur during rewarming. No other side effect has been noticed. 9 Some adjuvants like Xenon gas and erythropoietin are under study.
Better results after cooling therapy as compared to control has been shown in Neuroimaging also. 14