Questions about the HELIX trial
Authors: Gugu T J Kali, Shakti Pillay, Michael S Pepper, Alan R Horn
Journal: The Lancet Global Health (2021)

In the HELIX study,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 (35) Google Scholar Sudhin Thayyil and colleagues suggested that all low-income and middle-income countries (LMICs) should immediately suspend use of cooling in neonates.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 (35) Google Scholar 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.2Kali GTJ Martinez-Biarge M Van Zyl J Smith J Rutherford M Therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy had favourable outcomes at a referral hospital in a middle-income country.Acta Paediatr Int J Paediatr. 2016; 105: 806-815Crossref PubMed Scopus (16) Google Scholar, 3Abate BB Bimerew M Gebremichae 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; (published online Feb 25.)https://doi.org/10.1371/journal.pone.0247229Crossref Scopus (16) Google Scholar We represent academic hospitals in South Africa who use therapeutic hypothermia to treat neonatal encephalopathy with suspected hypoxic ischaemic encephalopathy. We also study the role of genetic and environmental influences in the national Neonatal Encephalopathy with Suspected Hypoxic Ischaemic Encephalopathy (NESHIE) study. Several differences in the HELIX study preclude the generalisation of their findings to all LMICs. First, the HELIX cohort showed increased illness severity compared with a South African cohort; more infants required ventilation (60% vs 34%), inotropes (80% vs 17%), and treatment for coagulopathy (39% vs 14%) in the HELIX trial than in the South African cohort.2Kali GTJ Martinez-Biarge M Van Zyl J Smith J Rutherford M Therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy had favourable outcomes at a referral hospital in a middle-income country.Acta Paediatr Int J Paediatr. 2016; 105: 806-815Crossref PubMed Scopus (16) Google Scholar Second, intrapartum hypoxia was not adequately defined: 11% of neonates had cord pH measurements; 67% of neonates had 5 min Apgar scores; and fetal heart rate decelerations were documented in 6% of neonates. The low proportion of neonates with prolonged second stage (3%) and obstructed labour (1%) further calls into question the contribution of intrapartum hypoxia. Third, encephalopathy and seizures were not robustly defined. Seizure onset before cooling is associated with reduced treatment effect; 73% of infants in the HELIX study had seizures before recruitment. Seizures are underdiagnosed in the absence of amplitude integrated electroencephalography (aEEG). Although clinical scores can be used to define encephalopathy, they lack specificity compared with aEEG.4Horn AR Swingler GH Myer L et al.Early clinical signs in neonates with hypoxic ischemic encephalopathy predict an abnormal amplitude-integrated electroencephalogram at age 6 hours.BMC Pediatr. 2013; 13: 1-11Crossref PubMed Scopus (34) Google Scholar Fourth, the inclusion of infants with anthropometry 2 SD below the mean and the use of low temperature targets in the control group (36·0°C vs 36·5°C) might have mitigated the benefits of cooling. However, anthropometric data are difficult to interpret because WHO growth charts are not gestation-specific. Lastly, sepsis limits the benefit of cooling and might have had a role in increased mortality.5Martinello KA Meehan C Avdic-Belltheus A et al.Hypothermia is not therapeutic in a neonatal piglet model of inflammation-sensitized hypoxia–ischemia.Pediatr Res. 2021; (published online May 10.)https://doi.org/10.1038/s41390-021-01584-6Crossref Scopus (6) Google Scholar Increasing antibiotic usage from 88% at 24 h to 95% at 96 h suggests that acquired infection was under-reported. Although data for chorioamnionitis were absent, funisitis in 16% of neonates implies antenatal infection (which is common in LMICs) that could explain the predominant white-matter damage that was detected by MRI. Despite these limitations, the HELIX study found an important benefit of decreased disabling cerebral palsy in cooled infants (11% vs 21%; risk ratio 0·53 [95% CI 0·28–0·98]), which is particularly relevant in resource-constrained settings. For the reasons we outline, the HELIX study therefore does not provide sufficient evidence to recommend cessation of cooling in all LMICs. Their study highlights the need to review outcomes in relation to selection criteria before changing cooling practice. ARH reports a patent issued to himself and to the University of Cape Town, in 2008, for a fan-cooling system for inducing neuroprotective hypothermia in neonates (patent number, WO 2008 142650 A1). All other authors declare no competing interests. NESHIE study leaders include Gugu T J Kali, Shakti Pillay, Michael S Pepper, Alan R Horn, Daynia Ballot, Melantha Coetzee, Khomotso Masemola, Firdose Nakwa, Nicola Robertson, Cally Tann, Jeanne Van Rensburg, and Sithembiso Velaphi. Questions about the HELIX trialWe congratulate Sudhin Thayyil and colleagues1 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. Full-Text PDF Open AccessQuestions 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 Access