Questions about the HELIX trial
Authors: Karoline Aker, Ragnhild Støen, Miriam Martinez-Biarge, Niranjan Thomas
Journal: The Lancet Global Health (2021)

We congratulate Sudhin Thayyil and colleagues1Thayyil 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; 9: e1273-e1285Summary Full Text Full Text PDF PubMed Scopus (34) Google Scholar on publishing the HELIX trial in The Lancet Global Health. Based on their results, which showed increased mortality in the hypothermia group compared with the standard care group, they recommended that cooling for neonatal encephalopathy should not be offered in low-income and middle-income countries (LMICs).However, we feel that their results cannot be generalised. Thayyil and colleagues argue that all infants in the HELIX trial received optimal intensive care.1Thayyil 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; 9: e1273-e1285Summary Full Text Full Text PDF PubMed Scopus (34) Google Scholar Babies were cared for in public sector government hospitals (which were mostly in India) with one nurse per two to four babies. Blood pressure was measured non-invasively every 4 h. We feel that these measures do not constitute optimal intensive care, regardless of country or setting. The high occurrence of early seizures and the low incidence of sentinel events could be explained by more frequent prelabour injury, but could also be a marker of less rigorous monitoring during labour or poor initial resuscitation and stabilisation, especially given the fact that 70% of babies in their study were outborn. No data are presented on outcomes in relation to severity of encephalopathy or start of cooling (median age 4·30 h [IQR 1·09–6·00]). Increased mortality before hospital discharge is the greatest concern after this trial. Yet, no details are provided about the largest category of deaths—asphyxial brain injury-related complications—which could also be related to suboptimal intensive care. Differences in patterns of brain injury, with more white-matter and less basal ganglia and thalami (BGT) injury, is suggested as an explanation for the absence of a neuroprotective effect of cooling in the HELIX trial.1Thayyil 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; 9: e1273-e1285Summary Full Text Full Text PDF PubMed Scopus (34) Google Scholar However, there is a notable selection bias in the reported MRI data that is not discussed in the study; 28% of deaths occurred before MRI could be done, and 74% of babies with available MRI data survived with no or mild disability. By contrast, the therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy in India (THIN) study, with data for conventional MRI available in 92% of infants, found that only 35% of infants had normal BGT and the distribution of white-matter injury was similar to the TOBY trial.2Rutherford M Ramenghi LA Edwards AD et al.Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial.Lancet Neurol. 2010; 9: 39-45Summary Full Text Full Text PDF PubMed Scopus (385) 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 (15) Google Scholar We argue that a non-biased description of the setting is pivotal. Antenatal care, intrapartum monitoring, resources for timely caesarean section, resuscitation facilities and neonatal transport services, and detailed evaluation of supportive care should be considered when determining whether cooling should be provided and how the resources should be invested to improve outcomes. LMICs are home to 84% of the world's population and comprise countries and areas with huge socioeconomic and cultural diversity, as well as differences in infrastructure and delivery of health services.4The World BankThe World Bank country classification.https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groupsDate: 2021Date accessed: August 6, 2021Google Scholar To extrapolate the results from the HELIX trial to all babies born in LMICs discounts this diversity. NT reports a patent issued to himself for a cooling system for inducing hypothermia in neonates (patent number, 1796/DEL/2013). All other authors declare no competing interests. Questions about the HELIX trial – Authors' replyWe appreciate the clinician's dilemma when existing practice is challenged by evidence, and have provided a combined response.1 Full-Text PDF Open AccessQuestions about the HELIX trialDespite more than half a decade since the launch of the Every Newborn Action Plan, perinatal asphyxia remains one of the most important causes of perinatal mortality and morbidity in neonates in developing countries.1 Hence, the HELIX trial holds paramount importance. The study reports that therapeutic hypothermia was associated with increased mortality and therefore should not be offered in low-income and middle-income countries. 2 However, we have several critical observations. Full-Text PDF Open AccessHypothermia 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 AccessQuestions about the HELIX trialIn the HELIX trial, Sudhin Thayyil and colleagues1 found no benefit in risk of mortality or severe disability following therapeutic hypothermia in neonates with asphyxia in low-income and middle-income countries (LMICs). The authors made firm conclusions on the use of therapeutic hypothermia in LMICs that warrant careful consideration. Full-Text PDF Open AccessQuestions about the HELIX trialIn the HELIX study,1 Sudhin Thayyil and colleagues suggested that all low-income and middle-income countries (LMICs) should immediately suspend use of cooling in neonates.1 The reported absence of benefit and increased mortality in neonates who were cooled are in contrast to our experience and the findings in meta-analyses in LMICs.2,3 Full-Text PDF Open Access