Indian J Pediatr DOI 10.1007/s12098-016-2266-0

REVIEW ARTICLE

Therapeutic Hypothermia for Birth Asphyxia in Neonates Vikram Datta 1

Received: 24 May 2016 / Accepted: 16 November 2016 # Dr. K C Chaudhuri Foundation 2016

Abstract India contributes to the highest neonatal mortality globally. Birth asphyxia is one of the leading causes of neonatal mortality in India. A large number of neonates who suffer from birth asphyxia progress to Hypoxic Ischemic Encephalopathy (HIE). The risk of a neonate progressing to severe form of HIE is many times higher in the low and middle income countries (LMICs) with ill developed health infrastructure. Till date LMICs have had a low institutional delivery rate, poor regionalization of care, lack of adequate transport facilities and ill equipped neonatal intensive care facilities. This has lead to a tremendous burden on the health care systems with a cohort of developmentally challenged neonates surviving into adulthood. Recently, Therapeutic Hypothermia (TH) has emerged as an evidence based intervention to reduce mortality and neurodevelopmental disability associated with asphyxia induced encephalopathy. TH has become the gold standard in the management of such cases in the western world. Extension of this knowledge to the LMICs and countries like India require a better understanding of the unique sociocultural issues associated with asphyxial brain injury in neonates. The high incidence of sepsis and presence of economic constraints make this problem more complex in such countries. The current review has tried to address these issues and looked at the basics of this complex topic from the perspective of a general pediatrician. Keywords Therapeutic hypothermia . Birth asphyxia . Neonate

* Vikram Datta [email protected] 1

Department of Neonatology, Lady Hardinge Medical College, New Delhi 110001, India

Introduction India contributes to the largest neonatal mortality in the world with over 27% of global neonatal mortality being attributed to India. Birth asphyxia complicated by hypoxic ischemic encephalopathy (HIE) occurs in approximately 1–3/1000 live births in the developed countries. The rate of HIE is nearly 20-folds higher in low and middle income group countries (LMICs) [1]. HIE kills nearly a quarter of those afflicted and leads to permanent neurodevelopment sequelae in another 25% [2]. Developing nations with still evolving healthcare systems face a tremendous challenge in managing these neonates. The economic burden of the disease leads to severe strain on the community as well as the health care systems. The current management of birth asphyxia and its sequlae focus on attenuating the multi organ dysfunction. In layman language the action starts when the damage has already been done. Therapeutic hypothermia (TH) which has been frequently used in adult cardiac and neurological disorders has been found to be useful in the management of birth asphyxia and resultant neonatal encephalopathy. This review will peruse and take the reader through the supportive management of an asphyxiated neonate, briefly discuss the science and process of therapeutic hypothermia (TH) for the asphyxiated neonate. A sub section on low cost TH devices and their relevance for the Indian subcontinent will also be discussed.

Definitions Therapeutic Hypothermia (TH) is a modality of reducing the core body temperature of the asphyxiated neonate (who

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suffers from moderate to severe hypoxic encephalopathy) to 33-34o Celsius for a period close to 72 h using external devices in a controlled environment under close monitoring followed by slow rewarming (0.2–0.5 °C/h) [3]. Neonatal Encephalopathy (NE) is an abnormal neurological status due to extensive CNS injury which occurs as a sequence of events (asphyxia being one of them) in a neonate. The neonate with encephalopathy can be categorized into mild, moderate or severe using the Sarnat and Sarnat classification [4].

Problem Statement Globally, nearly 23% [5] of neonatal deaths are attributed to birth asphyxia; it also leads to a large number of neurologically impaired children with neurodevelopmental disabilities. In India as per the National Neonatal Perinatal Database (NNPD 2002–03) the incidence of HIE was 1.4% [6], no similar data exists as of today in 2016. Birth asphyxia continues to be one of the largest killers of neonates in India with nearly 20% of all neonatal deaths being directly linked to it. The magnitude of infants surviving with neurodevelopment handicaps is close to 60% [7].

Pathogenesis of NE due to Hypoxic Injury to CNS The pathogenesis of hypoxic ischemic encephalopathy is complex and involves two interdependent processes [8, 9]. Primary Energy Failure: which is characterized by decrease in the levels of energy rich substrates like adenosine triphosphate (ATP) and phosphocreatine. There is resultant intracellular acidosis, activation of enzymes like lipases, proteases and elevation of intracellular calcium leading to loss of intracellular membrane homeostasis. This is followed by a Blatent period^ of 6 to 15 h after which secondary energy failure ensues. This is characterized by activation of an inflammatory response which triggers apoptosis (programmed cell death) and promotes accumulation of excitatory neurotransmitters in the cell. The secondary energy failure causes extensive neuronal injury and is responsible for major clinical manifestations of neonatal encephalopathy. The aim of any therapy is to prevent the onset of secondary energy failure. It is during the Btherapeutic window^ of 6 h (during the latent phase) between the primary and secondary energy failure that interventions should be directed to contain and reverse the damage caused due to hypoxia and ischemia.

How to Recognize a Neonate of Neonatal Encephalopathy (NE)? NE is often difficult to diagnose in absence of proper history and investigative backup. There are certain prerequisites which the clinician must bear in mind before diagnosing neonatal encephalopathy. The possibility of a neonate suffering from NE is high if it is born with a cord pH of <7 or a base deficit of at least >12 mEq/l, there is evidence of multi organ dysfunction (renal, cardiac, CNS etc.) and contributing causes like trauma, metabolic disorders and structural malformations have been excluded [10]. Neurological examination of the neonate is of prime importance in diagnosing the severity of neonatal encephalopathy (NE). The grading system suggested by Sarnat and Sarnat is shown in Table 1 and is used to grade the severity [4]. Appropriate investigations will confirm the occurrence of asphyxia and assess the severity of multi organ involvement.

How to Confirm Birth Asphyxia? A umbilical arterial blood pH < 7 at birth indicates asphyxia along with a history of failure to initiate spontaneous respiratory efforts at birth.

Investigations to Assess Multi System/Organ Involvement Abnormalities of the following investigations suggest multiorgan dysfunction. A. Brain: Cranial sonography, CT, MRI, EEG, aEEG B. Heart: Cardiac enzymes (Troponin T, CPK MB/ BB), Echocardiography, Chest X-ray, ECG C. Kidneys: Urine microscopy, Kidney function tests, Renal doppler D. Lungs: Chest X-ray, Arterial blood gases (ABG) E. GIT: X-ray abdomen F. Miscellaneous: Blood sugar, Serum calcium, Sepsis screen if needed.

Supportive Management of Neonates Presenting with Neonatal Encephalopathy &

All neonates who present with neonatal encephalopathy need primary supportive management while investigations are ordered and specific management (TH) is initiated.

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Original Sarnat staging of NE [4]

Level of consciousness

Stage 1 (Mild)

Stage 2 (Moderate)

Stage 3 (Severe)

Muscular tone

Normal

Mild hypotonia

Flaccid

Posture Stretch

Mild distal flexion Overactive

Strong distal flexion Overactive

Intermittent decerebration Decreased/Absent

Present

Present

Absent

Suck

Weak

Weak/Absent

Absent

Moro Oculovestibular

Strong Normal

Weak Overactive

Absent Weak

Slight

Strong

Absent

Neuromuscular Control

Segmental myoclonus Complex Reflexes

Tonic neck Autonomic Function Pupils

Mydriasis

Miosis

Variable

Heart rate Salivary secretions

Tachycardia Sparse

Bradycardia Profuse

Variable Variable

Gastrontestinal motility Seizures

Normal/Decreased None

Increased/Diarrhea Common/Focal or multifocal

Variable Uncommon

EEG

Normal

Duration

< 24 h

Early low voltage continuous delta and theta, later periodic, seizures focal 1–1.5 Hz spike wave. 2–14 d

Early periodic pattern with isopotential phases, later isopotential. Hours-Weeks

&

In facilities where TH is unavailable, the only treatment option available would be a supportive management.

Some components of supportive management are detailed in the subsequent section. A. Temperature Maintenance: Baby should be placed under a servo controlled radiant warmer. The temperature should be maintained in normal range of 36.5 °C– 37.5 °C. If facility of Btherapeutic hypothermia^ exists and the neonate is > 36 wk of gestation, brought to the hospital within 6 h of birth the same should be immediately initiated. B. Airway Maintenance: The airway and the breathing should be monitored and any secretions should be removed to ensure a patent airway. If the neonate is having gasping respiration or absence of respiration, immediate assisted ventilation should be provided. C. Circulation Maintenance: Efforts should be made to identify features of shock [capillary filling time (CFT) > 3 s, hypotension, collapsed inferior venacava (IVC) on functional echo] and promptly corrected. D. Fluids and Feeds: IV fluids can be started depending on the clinical condition of the baby. Efforts should be made to initiate enteral feeding as soon as possible in babies who are clinically stable without any evidence of major organ system involvement. Enteral feeding can be safely started with expressed breast

milk at rate of 10–30 ml/kg/d. This can be changed to schedule feedings (2–3 hourly) depending on acceptance by the new born. E. Medications: Vitamin K 1 mg IM along with IV 10% calcium gluconate should be administered at a rate of 5 ml/kg/d prophylactically to all neonates. Calcium should be administered under cardiac monitoring. A fall in heart rate of >20 bpm from base line should prompt a temporary cessation of the infusion. Care should be taken to prevent extravasations of IV calcium as it leads to extensive necrosis. Blood sugar should be maintained in the normal euglycemic range. If need arises a dextrose infusion should be initiated. Inotropes like dobutamine can be considered in case of poor organ perfusion. Drugs like phenobarbitone and phenytoin can be considered in case of seizures. It is important to remember that drugs like sodium bicarbonate, respiratory stimulants, atropine, and mannitol have no role in the acute management of birth asphyxia. Monitoring: The following monitoring needs to be done: &

Temperature: It should be monitored and maintained in the normal range of 36.5 degree to 37.5 degree Celsius. In cases where TH has been initiated, core body temperature of 33–34 degree Celsius is maintained for a period of 72 h.

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& & &

& & & &

CNS: The neurological status should be monitoring every 8 h. Respiratory: The status should be monitored every 2–3 h. CVS: The cardiovascular status assessment should include heart rate, color, capillary refill time (CRT), peripheral pulses, pulse oximetry and non-invasive blood pressure (NIBP). Kidney: Urine output should be measured daily (it should normally be >1 ml/kg/h after the first 24 h of life). Blood Sugar: Monitoring every 6–8 h during the first 24 h and later as required. Serum Calcium should be monitored. Feed intolerance: It should be detected/monitored (vomiting, increase in abdominal girth by >2 cm and increased pre feed aspirate indicates feed intolerance).

Specific Management Therapeutic Hypothermia A systematic review of 11 randomized controlled trials (1505 term and late preterm infants with moderate/severe encephalopathy and evidence of intrapartum asphyxia) was conducted in 2013 by the Cochrane Collaboration. It concluded that, TH resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability at 18 mo of age [typical RR 0.75 (95% CI 0.68 to 0.83); Number needed to treat for beneficial outcome (NNTB) = 7 (95% CI 5 to 10)]. There were statistically significant reductions in mortality [typical RR 0.75 (95% CI 0.64 to 0.88), NNTB =11 (95% CI 8 to 25)] and neurodevelopmental disability in survivors [typical RR 0.77 (95% CI 0.63 to 0.94), NNTB 8 (95% CI 5 to 14)] [11]. Studies conducted in the developed countries have revealed that therapeutic hypothermia (TH) is beneficial in reducing neonatal mortality by nearly 22%. It improves the neurological outcome secondary to hypoxic ischemic encephalopathy [12]. Currently, TH has become a standard of care in the management of NE in the western world. The use of TH in low and middle income countries (LMIC) is restricted to a few technologically advanced neonatal units which are centered along the metropolitan cities. Till date most of the neonates born at peripheral outreach birthing centers have limited access to this state of art technology. In 2013 a systematic review and meta-analysis was conducted to evaluate the role of therapeutic hypothermia for neonatal encephalopathy in low and middle income countries [1]. It evaluated a total of 567 babies who were managed using a variety of cooling devices, including ice, frozen gel packs, fans, water bottles, water circulating caps or phase changing

materials. No statistically significant reduction in mortality was observed in the cooled and standard care infants with a risk ratio (RR) of 0.74 (95% confidence interval 0.44 to 1.25). The study was not adequately powered to comment on other neonatal morbidities and long term neurological outcomes. The meta analysis concluded that cooling therapy should be considered experimental and should be offered only under strict supervision and monitoring as in case of a clinical trial. They further noted that TH should be offered in settings wherein good basic neonatal care is available. Currently a large trial BHELIX^ (Hypothermia for encephalopathy in low income countries) is underway and once its results are available it will help in resolving this controversial issue. Introducing TH as a routine therapy for all neonates in peripheral ill equipped NICUs and birthing facilities can in fact be very dangerous and can lead to a higher mortality. This was evident in a study conducted in Uganda in 2007 where a five-fold higher mortality was observed in cooled infants when compared to neonates with no cooling [13]. A recent clinical report from the American Academy of Pediatrics Committee of Fetus and Newborn [14] has stated that hospitals that provide therapeutic hypothermia should be able to provide comprehensive intensive care, targeted temperature monitoring and continued follow-up of cooled neonates. Neonatal Resuscitation Program (NRP) 2015 concludes that use of therapeutic hypothermia in resource-limited settings (i.e., lack of qualified staff, inadequate equipments, etc.) may be considered and offered under clearly defined protocols similar to those used in published clinical trials and in facilities with the capabilities for multidisciplinary care and longitudinal follow-up (Class IIb, LOE-B-R) [15]. Thus there is a need to exercise caution in the adoption of TH in Indian neonatal units until further adequately powered clinical trials have been performed [16].

Mechanism of Action of TH [2] Numerous mechanisms have been suggested which contribute to the beneficial effects of TH. Some of the major mechanisms are as follows: & & & & &

Decreased energy utilization Suppression of free radical induced injury Decreased severity of secondary energy failure Reduction in the extent of brain injury Inhibition of inflammation and resultant release of cytokines.

Indications of Use of TH [17] Therapeutic hypothermia should be considered as a treatment of choice for any neonate who fulfils the following criteria:

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& & &

Term gestation (>36 wk) Age < 6 h Absence of major congenital anomalies And Meeting the following criteria

&

& & &

Evidence of perinatal asphyxia: Umbilical cord pH or ABG in the first hour of life <7 or base excess (BE) 16 meq/L, or History of a perinatal acute event (Cord prolapse or placental abruption) or Apgar score < 5 at 10 min or Need for ventilation beyond the 10th min of life

And Evidence of moderate to severe encephalopathy before 6 h of life (as evidenced by seizures, altered level of consciousness, decreased spontaneous activity, tone abnormalities, abnormal neonatal reflexes and autonomic system abnormalities).

Equipment [6] Currently two types of equipment are available to administer therapeutic hypothermia.

Recommended TH Devices and Accessories & & &

Selective Head Cooling: Cool Cap (Rs. 35,00,000 approx.); Not recommended for LMICs [8] Whole Body Hypothermia: Cooling Mattress (Rs. 5,00,000 approx.) Rectal Probes (Rs. 1000/probe approx.)

Inexpensive Innovative Cooling Devices A number of innovative low cost devices have been used by units in LMIC’s to administer TH. Published randomized controlled trials (RCT’s) of these devices have revealed promising results [6]. The safety and efficacy of these devices cannot be established till validation and certification by licensing authorities. Some devices in use are as follows: Frozen Gel Packs (Used in immunization clinics) [6] Phase Changing Material (PCM) [18] Water Bottles Filled with Tap Water [13]

Technique of TH Target Temperature After initiation of cooling, the recommended rectal temperatures in selective head cooling is 34.5 °C whereas in whole body cooling the temperatures are lowered till 33.5 °C [12, 19]. Duration The target temperatures should be maintained for 72 h. Rewarming Rewarming should be slow over a 4 h period wherein the temperature is slowly increased at the rate of 0.5 °C per hour till it reaches 36.5 °C. Method Selective head cooling is administered by a helmet and total body cooling with a whole body mattress with servo control to adjust the neonate’s temperature according to his body temperature. During the process of TH, temperatures should be not be allowed to drop below 33°. Temperatures lower than this are less neuroprotective and extremely low temperatures are associated with increased incidence of mortality. Extending the duration of cooling to beyond 72 h with an aim of achieving better neuroprotection is futile, can be dangerous and is not recommended.

Management of Vital Functions during TH Respiratory System: Maintain normal blood gases, avoid hyperoxia, hypercarbia and hypocarbia. Maintain normocarbia. Hypothermia decreases the delivery of oxygen to the tissues, try to maintain normal PaO2 levels of 50– 100 mmHg. Levels above 200 mmHg should be avoided [18, 20, 21]. Low body temperatures may require higher tidal volume (if the neonate is on ventilator) due to chest stiffness. Close monitoring of lung compliance is desired during the initiation and rewarming phases of TH [22]. Circulatory System: TH leads to bradycardia and decreased cardiac output. Monitor the BP, CFT and urine output closely to detect signs of hypoperfusion early. If facilities exist, then functional echocardiography can be used to monitor superior venacava (SVC) flow as it reflects cerebral circulation. Adjustments in the dose of inotropes are needed during the rewarming phase when cardiac output and SVC flow increase.

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A high SVC flow indicates loss of cerebral autoregulation and is a bad prognostic factor [23]. Fluid and Electrolytes: Initial fluid should be 10% Dextrose followed by normal maintenance fluid. Close monitoring of the urine output and the weight of the neonate can give an idea of the fluid requirement during TH. Syndrome of inappropriate ADH (SIADH), if detected, needs to be managed. Monitoring of K, Ca, Mg and glucose is of prime importance during TH. Nutritional Management: Do not initiate enteral nutrition till the rewarming has been completed as TH can decrease the mesenteric circulation and there are chances of ischemia of the bowel. Alternatively minimal enteral nutrition can be initiated during the TH. Total parenteral nutrition (TPN) should be planned and initiated early to prevent calorie deficit. Renal System: Detection and management of Acute Kidney Injury is of prime importance. Hematological System: Address coagulation abnormalities with fresh frozen plasma (FFP) if required and thrombocytopenia with platelet transfusions, if indicated. Pain Management and Developmentally Supportive Care (DSC): Untreated pain has been shown to affect the neurobehavior of the neonate adversely [24]. Efforts should be initiated to control pain effectively using narcotic agents like morphine or fentanyl. Unit should practice developmentally supportive care (DSC) to optimize neurodevelopment outcomes.

Infrastructure TH requires a fully functional level II or III special newborn care unit (SNCU) with adequate staff and trained manpower with good experience in initiation and monitoring of TH. The equipments which should be available in a fully functional state at the facility are as follows: 1. 2. 3. 4. 5. 6. 7. 8. 9.

Radiant Warmer with Servo Controlled option Cooling Device (as mentioned above) Facility for rectal temperature monitoring Multipara monitors Facility for invasive ventilation ABG Blood glucose and electrolyte monitoring facilities Access to aEEG Access to MRI

Clinical and Laboratory Monitoring during TH [3] Careful monitoring is essential to ensure a favorable clinical outcome in neonates initiated on TH. At the outset, a vascular

access should be secured by inserting an umbilical venous and arterial line. Urine output can be monitored using a urinary catheter. & & & &

& &

Vital Signs: All vital signs like core body temperature, heart rate, respiratory rate, BP, CFT, BP, Urine output and SpO2. Neurological Examination: It can be carried out using the Dubowitz method and Sarnat staging should be done daily till 7 d after TH. Cardiovascular System: Daily echocardiography for evaluating cardiac functions is required. CNS: Daily cranial ultrasound for diagnosis of intracranial bleeds, cerebral doppler for cerebral blood flow measurements. aEEG can be used if available. MRI for neuroimaging. Skin: Skin lesions and evidence of subcutaneous fat necrosis should be monitored daily. Biochemistry: Complete blood count (CBC), liver function test (LFT), kidney function test (KFT), prothrombin time (PT), activated partial thromboplastin time (APTT), Cardiac enzymes [Troponin and brain natriuretic peptide (BNP)], electrolytes and plasma levels of drugs may be monitored daily.

Side Effects of TH [3] The common side effects observed with TH are as follows: hypotension, low platelets, clotting abnormalities [increased prothrombin time (PT) and activated partial thromboplastin time], electrolyte disturbances, skin burns and sclerema. Most of the side effects are seen when adherence to the TH protocol is not strictly enforced. Careful monitoring during TH can prevent the occurrence of major side effects.

Controversies Safety Issues Hypothermia is often a catalyst to poor outcome in neonates suffering from a variety of neonatal disorders (sepsis, hypotension). Therapeutic hypothermia has been shown to be very safe in controlled well monitored western NICUs where the incidence of neonatal sepsis is negligible. Whether the same safety profile can be achieved in understaffed Indian SNCUs is a matter of debate. The effect of therapeutic hypothermia on pre-existing neonatal morbidities like small for gestational age (SGA) status, sepsis etc. in these settings needs to be evaluated.

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Feasibility Issues In LMICs and especially India, transporting a neonate within 6 h of suffering an asphyxial insult from a peripheral birthing center to a state of art neonatal unit capable of delivering TH is questionable in the present scenario. Regionalisation of care and linkages with data sharing on online platform are being developed. Specific data pertaining to the availability of TH as an option for a neonate travelling from a remote rural birthing center is still a dream. Institution of TH at the birthing facility soon after birth or enroute via portable servo controlled devices is still experimental and results from large trials are awaited before this can be recommended. Till such time it seems TH would be an option for only few fortunate neonates born intramural in facilities having access to TH. Availability Issues TH is available in very few units of the country at this point of time. Few teaching institutions have used and published their experiences with low cost innovative cooling devices for providing TH in India. No major safety issues were reported with their use. However for a country like India with one of the highest birth rates and a high asphyxia related neonatal mortality (20%), the number of units providing this therapy is grossly inadequate. There is no system of information sharing /web based platform for informing clients of the availability of such devices. The cost of therapy in private units is prohibitively expensive and beyond the reach of the common man. In such a scenario, till such time that the state supported SNCUs at District hospital level and newborn stabilisation units (NBSUs) at community health center (CHC) level provide TH as a part of the ongoing BFacility Based Neonatal Care (FBNC)^ initiative, TH will be largely unavailable to the Indian neonates. A similar picture is anticipated in other LMICs as well. Effectiveness Issues Though TH has been shown to be highly effective in reducing mortality in the western world, the same cannot be said about its effectiveness in the LMIC region. As mentioned previously, in a study conducted at Uganda with lack of basic neonatal care facilities, cooling led to a five-fold higher mortality in the intervention group. In various studies conducted in India using low cost innovative devices to provide TH [7, 25, 26], the results have shown a better neurodevelopment outcome in the intervention group in few studies whereas in a study by Thayyil et al., no reduction in brain injury was observed when the authors used phase change material (PCM) as a cooling modality [27]. Likewise, neonatal mortality was not different across the two study groups in a study done at JIPMER, Pondicherry [7]. Certain other factors unique to the Indian

scenario may contribute to the reduced effectiveness viz. presence of co-existing unrecognized neonatal sepsis, suboptimal antenatal and obstetric care along with pre-existing brain damage. Ethical Issues Pending extensive research involving standardized TH devices in LMICs, the outcome measures cannot be accurately judged. Based on a small study from LMICs which indicated a potential for increased mortality in the neonates who were cooled in inadequately staffed facilities, it becomes ethically important to be extremely careful before any decision is taken on rolling out TH for LMICs on a nation wide basis. Other ethical issues could be denial of a therapy which has been proven to be extremely effective in other settings to countless neonates due to economic constraints. Continued enrolment of neonates in trials with control limbs having no intervention and intervention limbs having unlicensed cooling devices in LMICs is another ethical issue. Ethical committees of LMICs are approving clinical trials without any interim analysis or stopping rules (as was seen in the Uganda study where a five-fold mortality with intervention was observed) [13].

Conclusions and Key Messages There is no doubt that TH has shown extremely promising results as far as the combined outcomes of mortality and neurodevelopment intactness post asphyxial encephalopathy is concerned. The need of the hour is to focus on improving the existing SNCU network and work towards achieving a better regionalization of neonatal care in India. The need is to improve the quality of care in our SNCUs, provide adequate staff, infrastructure, transport linkages, monitoring facilities, on site and off site trainings. The use and development of various low cost and innovative TH devices should be encouraged. They should take part in adequately powered randomized controlled trials to demonstrate effectiveness. For a vast country like India with more than 20,000 birthing points, there is an urgent need to investigate the role of TH at birth or enroute to a facility during the critical window period of 6 h. The clinician at peripheral health facilities and the practitioners should not feel frustrated due to the lack of TH and should make all attempts to prevent HIE by institution of an accurate Neonatal resuscitation program (NRP) as per the standard guidelines. The clinician should make all attempts to transport the neonate to the nearest center having facilities for TH by the shortest route and the fastest mode of transport. Only providing TH does not end the job as a good follow up for identification of neurodevelopmental disabilities and institution of early stimulation program with a team of

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developmental specialists and pediatric neurologists is of prime importance. A multi-disciplinary team approach is needed to effectively manage such babies. The attendants need to be communicated about the prognosis, risk of neurodevelopment disability, duration of stay need for regular follow up etc. They can be referred to child support groups to combat psychological distress associated with this clinical condition. Compliance with Ethical Standards Conflict of Interest None. Source of Funding None.

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