Therapeutic hypothermia (TH) is the standard of care for treating newborns with moderate to severe hypoxic-ischemic encephalopathy (HIE) in high-income countries. However, a recent trial in low and middle-income countries found no benefit of TH. This document provides guidelines on the use of TH for HIE in India based on a review of evidence. It finds TH may reduce death or disability, but the evidence is less clear for mortality before discharge in LMICs. Factors like cord pH, outborn status, admission temperature and illness severity can impact outcomes. TH should only be provided in facilities with intensive care capabilities and to newborns meeting specific criteria for moderate-severe H

1. NNF position statement and guidelines for
use of therapeutic hypothermia to treat HIE
in India

2. Background
• Therapeutic hypothermia (TH) is now offered as standard of care for the treatment of newborn
with moderate-severe HIE in High- Income countries.
• Based on the results of studies in HICs, TH has been offered as a treatment option by several
health facilities in LMIC using a variety of cooling methods.
• The recently published HELIX trial from LMIC had enrolled 408 subjects - reported that among
neonates with HIE, TH has no effect on the primary outcome of death and/or moderate/severe
disability at 18-24 months (RR: 1·06; 0·87–1·30).
• The debate on the appropriateness of TH as a treatment modality for neonates with moderate-
severe HIE in LMIC consequent to the HELIX trial publication warranted a balanced reappraisal of
this treatment modality in the Indian context

3. What could affect the outcomes of TH in neonates with HIE in LMIC?
Prior to embarking on guidelines for practice on the use of TH in neonates
with HIE, it was felt necessary to address the following questions in the
context of India
1. What is the impact of TH on in-hospital mortality in neonates with moderate- severe HIE?
2. What is the effect on death and/or disability at 18-24 months of age (or later)?
3. What factors modify the efficacy of TH?
4. Are there any specific groups of neonates and/or conditions in which TH will be effective
and safe?

4. What is the evidence?
To address this issue a search was made in PubMed for published RCTs that
• had enrolled neonates with HIE (P)
• have investigated the efficacy of therapeutic hypothermia (I) versus standard care (C)
• in reducing the incidence of death and/or disability (O).
• A total of 24 RCTs were found- 7 in HIC and 17 in LMIC.
• The following information was extracted from primary publications of the RCTs: inclusion
and exclusion criteria, method of hypothermia and target temperature, rate of
rewarming, baseline variables, illness severity indicators (proportion with severe HIE, on
ventilator support or on inotropic support) and main outcomes of interest (death till
discharge, death or severe neurosensory disability at 18-24 months of age, and cerebral
palsy).

5. 1. Death before discharge
• 6/7studies from HIC and 15/17 studies from LMIC have reported this outcome.
• The pooled risk of death before discharge was observed to be significantly low in the
treatment group.(pooled RR: 0.76; 95% CI: 0.62 to 0.93 )
• Subgroup analysis based on site of study showed that the beneficial effect was
significant in HICs (RR: 0.77; 062 to 0.94; I2: 0%) but not in LMIC (RR: 0.74; 0.53 to 1.02;
I2: 47.7%).
• No heterogeneity was observed in trials from HIC, substantial heterogeneity was
observed in trials from LMIC.
Cord pH
Proportion of outborn neonates
Proportion of neonates with severe HIE
Admission temperature
Illness severity

6. 2. Cord pH
Effect of cord pH on the outcome(death before discharge) was investigated
using the mean cord pH reported in the studies
1. Studies with mean cord pH <7.0: If the analysis is restricted to studies which reported mean
cord pH<7.0, it showed a similar pooled risk ratio in studies from LMIC and HIC with a
significant reduction in the incidence of death before discharge
2. Studies with mean cord pH >7.0: Three studies, all from LMIC included neonates with mean
cord pH 7.0 or more. Due to the small sample size and low event rate (probably because babies
were less severely asphyxiated), the pooled effect size showed wide CI

9. 3. Outborn (extramural births) neonates
• Studies with no outborn neonates: 6 studies were conducted exclusively on inborn
neonates. Pooled effect size showed significant reduction in death before discharge.
• Studies with outborn neonates:
4 studies from HIC included outborn neonates and the pooled effect size is similar to that
observed with overall analysis.
4 studies from LMIC enrolled outborn neonates. The outcome showed significant
heterogeneity and a non-significant pooled effect size.

10. 4. Temperature at admission
Effect of mean admission temperature on outcome of death before
discharge
• Mean admission temperature <36C: In four studies, all from LMIC, admission temperature
in the intervention group was <36C. Pooled estimate showed a significant increase in the
risk of death before discharge.
• Mean admission temperature >36C: In five studies, four from HIC and one from LMIC,
admission temperature in the intervention group was >36 C. Pooled estimate showed a
significant decrease in the risk of death before discharge

12. 5. Severe HIE

13. 6. Death or severe disability
• The pooled risk was observed to be significantly decreased in the treatment
group (pooled RR: 0.67; 95% CI: 0.58 to 0.78, I2: 64.1%)
• Subgroup analysis based on site of study showed that the beneficial effect was
significant in both HIC (RR: 0.76; 068 to 0.84; I2: 0%) and LMIC (RR: 0.57; 0.43
to 0.76; I2: 74.2%).
Outcome of death or severe disability was significantly low in those who received
TH in both HIC and LMIC.

14. 7. Cerebral palsy
• A total of six trials, 4 from HIC and 2 from LMIC, reported the effect of
therapeutic hypothermia on cerebral palsy at 18-24 months of age.
• Pooled risk and subgroup analysis based on site of study showed
significant beneficial effect of TH in both HIC and LMIC

15. What can we conclude?
• Therapeutic hypothermia is likely to decrease death or severe disability and cerebral
palsy at 18-24 months even in LMICs as compared to HICs.
• Significant heterogeneity in the studies from LMICs compared to HICs which reported
mortality prior to discharge following TH in neonates with HIE.
• The pooled estimates for mortality prior to discharge showed a significant benefit in favour
of TH, but there was uncertainty in studies from LMICs.
• Mortality before discharge when analyzed for infants with moderate-severe HIE with cord
pH<7.0 showed significant benefit in favour of TH in both subsets

16. • In neonates with hypothermia at admission and unclear evidence of
severe intrapartum asphyxia, there is uncertainty of the benefit from TH
• As the risk of death increases with severe encephalopathy, need for
invasive ventilation, and inotropic support, availability of optimum neonatal
intensive care facilities is essential if TH is to be offered at a health facility.

17. Where should TH be offered?
• Health facilities proposing to offer hypothermia must have high
quality intensive care facility and practices in existence before
embarking on TH.
• Must be Level III or Level IV – with expertise and competence to treat
complications of both HIE and TH.
• Must have access to bedside USG,CT,MRI and EEG.
• Neonatologist both on call and on-site 24*7

18. • Nursing staff trained in neonatal advanced care (nurse:patient ratio-
1:1 or 1:2)
• Access to multi-disciplinary team for acute care and follow up
• NICU should be capable of follow up at least 18 months.

19. Which neonates should be offered TH?
It is recommended that TH should be offered to neonates with HIE with GA> 36 weeks, <6 hrs of life and
with admission temperature 36-37.4C, IF they fulfil all of the following criteria:
• 1. pH <7 or BE >-16 on cord or arterial blood gas done within 1 h of life
AND
(i) Apgar score<5 at 10 minutes or at least 10 min of positive pressure ventilation
AND
(ii) history of acute perinatal event (such as but not limited to placental abruption, uterine rupture, cord
prolapse)
• 2. Evidence of moderate or severe encephalopathy

20. • During preparation for cooling, if encephalopathy improves, TH may
be deferred
• Parents should be provided sufficient information about benefits and
harm of cooling
• Written consent must be obtained
• Cooling is initiated as early as possible, and definitely prior to 6h of
life.

21. Which neonates should not receive TH?
1. Who are moribund
2. Major congenital or genetic abnormalities
3. Neonates with severe intrauterine growth restriction
4. Evidence of severe coagulopathy
5. Evidence of severe head trauma or intracranial hemorrhage

22. Which method is to be used for providing TH?
• Servo controlled device – preferred
• Non- servo controlled – ice/gel packs, phase changing material
A recent systematic review observed that death prior to discharge was lower in the
hypothermia group compared to the control group across all types of devices.
If non servo controlled devices are used – 1:1 nurse: patient deployment to
monitor maintenance of temperature and take immediate corrective steps.

23. Thank you