Hypoxic ischaemic encephalopathy in low resource settings—time to stop cooling?
Authors: Satinder Aneja, Suvasini Sharma
Journal: The Lancet Global Health (2021)

Perinatal asphyxia is a notable cause of mortality in newborn babies and of neurodevelopmental disability in infancy and childhood, especially in low-income and middle-income countries (LMICs). Therapeutic hypothermia has profoundly changed the management of hypoxic ischaemic encephalopathy. This therapy is the standard of care for neonatal hypoxic ischaemic encephalopathy in high-income countries (HICs). Despite having a higher burden of this injury than HICs, LMICs have been slow to adopt therapeutic hypothermia for several reasons: the non-availability of expensive cooling equipment, need for well equipped neonatal intensive care units with trained staff, the high incidence of home deliveries, frequent comorbid sepsis, and delayed transport and referral. In the past decade, there have been advances in developing low-cost cooling equipment, and the increased awareness and implementation of therapeutic hypothermia in LMICs. In a survey across neonatal units in India in 2017, it was found that cooling was being offered for babies with neonatal encephalopathy in 40% of public and 51% of private neonatal units.1Chandrasekaran M Swamy R Ramji S Shankaran S Thayyil S Therapeutic hypothermia for neonatal encephalopathy in indian neonatal units: a survey of national practices.Indian Pediatr. 2017; 54: 969-970Crossref PubMed Scopus (17) Google Scholar Approximately half of these centres used locally improvised cooling methods and practices that differed from the protocols used in HICs. Although single-centre trials from LMICs have shown good outcomes with the use of therapeutic hypothermia,2Catherine RC Ballambattu VB Adhisivam B Bharadwaj SK Palanivel C Effect of therapeutic hypothermia on the outcome in term neonates with hypoxic ischemic encephalopathy-a randomized controlled trial.J Trop Pediatr. 2021; 67fmaa073Crossref PubMed Scopus (6) Google Scholar, 3Aker K Støen R Eikenes L et al.Therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy in India (THIN study): a randomised controlled trial.Arch Dis Child Fetal Neonatal Ed. 2020; 105: 405-411Crossref PubMed Scopus (12) Google Scholar a meta-analysis done in 2013 did not show any significant reduction in mortality.4Pauliah SS Shankaran S Wade A Cady EB Thayyil S Therapeutic hypothermia for neonatal encephalopathy in low- and middle-income countries: a systematic review and meta-analysis.PLoS One. 2013; 8e58834Crossref PubMed Scopus (104) Google Scholar In one meta-analysis of 28 studies (15 from HICs, four in upper middle-income countries, seven in low middle-income countries, and two in low-income countries) the pooled relative risk of mortality after the implementation of therapeutic hypothermia was 0·74 (95% CI 0·67–0·80).5Abate BB Bimerew M Gebremichael B et al.Effects of therapeutic hypothermia on death among asphyxiated neonates with hypoxic-ischemic encephalopathy: a systematic review and meta-analysis of randomized control trials.PLoS One. 2021; 16e0247229Crossref PubMed Scopus (14) Google Scholar The results of the hypothermia for neonatal encephalopathy in LMICs (HELIX) trial are therefore surprising and disappointing. In this multi-country, randomised controlled trial across centres in India, Sri Lanka, and Bangladesh, Thayyil and colleagues6Thayyil S Pant S Montaldo P et al.Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh.Lancet Glob Health. 2021; (published online Aug 3.)https://doi.org/10.1016/S2214-109X(21)00264-3Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar have shown that therapeutic hypothermia did not reduce the combined outcome of death or disability at 18 months after neonatal encephalopathy, but significantly increased mortality. The authors concluded that therapeutic hypothermia should not be offered as treatment for neonatal encephalopathy in LMICs, even when tertiary neonatal intensive care facilities are available. The strengths of this study included a large and well powered sample size, the use of a servocontrolled cooling device, the use of advanced imaging techniques, and adequate follow-up with neurodevelopment assessments. In addition to the overall higher mortality, the infants in the hypothermia group had higher proportions of adverse outcomes such as coagulopathy, a longer hospital stay, and a higher need for inotropic support. Possible reasons for worse outcomes with hypothermia as compared with HICs include the inclusion of a higher proportion of babies at a low birthweight or who were small for their gestational age, more babies born at locations outside the hospital, a high proportion of babies having clinical seizures at enrolment, and the longer duration of the hypoxic insult. The absence of seizures at enrolment is one of the predictors of better outcomes following hypothermia.7Wyatt JS Gluckman PD Liu PY et al.Determinants of outcomes after head cooling for neonatal encephalopathy.Pediatrics. 2007; 119: 912-921Crossref PubMed Scopus (261) Google Scholar In the HELIX study, MRI scans revealed white-matter injury in approximately 80% of the enrolled newborn babies, suggesting subacute hypoxia. This result possibly explains the absence of neuroprotection with cooling. Less than 13% of the babies in the HELIX trial had perinatal sentinel events, in either of the groups. Poor maternal nutrition, especially anaemia, which is prevalent in south Asia, might be a contributing factor for subacute hypoxia. The proportion of babies born at locations outside the hospital in the HELIX trial was high. Optimising post-resuscitation care and the early initiation of hypothermia is a key factor in improving outcomes,8Davies A Wassink G Bennet L Gunn AJ Davidson JO Can we further optimize therapeutic hypothermia for hypoxic-ischemic encephalopathy?.Neural Regen Res. 2019; 14: 1678-1683Crossref PubMed Scopus (19) Google Scholar and transport facilities in LMICs are inadequate. In a study of 303 extramural neonates admitted to a tertiary care hospital, only 11% were transported in ambulances.9Rathod D Adhisivam B Bhat BV Transport of sick neonates to a tertiary care hospital, South India: condition at arrival and outcome.Trop Doct. 2015; 45: 96-99Crossref PubMed Scopus (12) Google Scholar In a single-centre study in south India, in which only infants born within the hospital were enrolled, there were more healthy survivors at discharge in the hypothermia group compared with the controls.2Catherine RC Ballambattu VB Adhisivam B Bharadwaj SK Palanivel C Effect of therapeutic hypothermia on the outcome in term neonates with hypoxic ischemic encephalopathy-a randomized controlled trial.J Trop Pediatr. 2021; 67fmaa073Crossref PubMed Scopus (6) Google Scholar Is this study the last word on cooling babies with hypoxic ischaemic encephalopathy in LMICs? The HELIX trial was done in neonatal intensive care units in public-sector hospitals that cater to the population of those patients with a low income, and it is generalisable to a large proportion of the population that bears the highest burden of hypoxic ischaemic encephalopathy in LMICs. However, there is a small but notable number of patients in LMICs who are middle-income or high-income, who have access to optimum prenatal and intrapartum care and to well resourced and accredited private-sector hospitals with facilities similar to those in HICs. Therapeutic hypothermia might show a benefit in this subpopulation, especially in newborns whose birthweight is appropriate for their gestational age born in the hospital with the presence of a perinatal sentinel event. Hence, it might be premature to completely discourage the use of therapeutic hypothermia in LMICs. The current guidelines for neonatal life support in LMICs suggest that neonates with moderate to severe hypoxic ischaemic encephalopathy might be given therapeutic hypothermia in centres with the capacity to provide multidisciplinary care with adequate resources and using clearly defined standard protocols.10Wyckoff MH Wyllie J Aziz K et al.Neonatal life support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with treatment recommendations.Circulation. 2020; 142: S185-S221PubMed Google Scholar Until more data is available, therapeutic hypothermia cannot be considered a standard of care and should only be offered in carefully selected centres in these countries. Further studies are needed to identify alternative treatments that might reduce mortality and neuromorbidity because of hypoxic ischaemic encephalopathy in LMICs. Meanwhile, the universal coverage of high-quality antenatal and intrapartum care along with care of unwell newborn babies will be the best approach to reduce the burden of perinatal hypoxic ischaemic encephalopathy in LMICs. We declare no competing interests. Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and BangladeshTherapeutic hypothermia did not reduce the combined outcome of death or disability at 18 months after neonatal encephalopathy in low-income and middle-income countries, but significantly increased death alone. Therapeutic hypothermia should not be offered as treatment for neonatal encephalopathy in low-income and middle-income countries, even when tertiary neonatal intensive care facilities are available. Full-Text PDF Open Access