Questions about the HELIX trial
Authors: Supreet Khurana, Deepak Chawla, Suksham Jain
Journal: The Lancet Global Health (2021)

Despite 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.1Every NewbornAn action plan to end preventable deaths. World Health Organization, 2014https://apps.who.int/iris/handle/10665/127938Date accessed: August 10, 2021Google Scholar 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. 2Thayyil 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 However, we have several critical observations. First, most previous studies use the essential criteria for perinatal asphyxia as having a 10 min Apgar score and a cord pH or the presence of a sentinel event and a postnatal pH within 1 h of birth.3Azzopardi D Brocklehurst P Edwards D et al.The TOBY Study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial.BMC Pediatr. 2008; 8: 17Crossref PubMed Scopus (231) Google Scholar, 4Shankaran S Laptook AR Ehrenkranz RA et al.Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.N Engl J Med. 2005; 353: 1574-1584Crossref PubMed Scopus (2007) Google Scholar In the HELIX trial, perinatal sentinel event details were reported in 8% of neonates in the hypothermia group and 13% of neonates in the control group, while cord pH was reported in 11% of neonates in the hypothermia group and 12% of neonates in the control group. The low number of perinatal sentinel events and cord pH makes the acuteness of insult questionable. Second, the mean admission temperature in the therapeutic hypothermia group indicates that a large number of neonates were hypothermic at the time of admission, which could have contributed to higher mortality.5Aneja S Sharma S Hypoxic ischaemic encephalopathy in low resource settings—time to stop cooling?.Lancet Glob Health. 2021; 9: e1187-e1188Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar Third, although the authors mention that none of the deaths were related to withdrawal of life support, three neonates in the therapeutic hypothermia group and seven neonates in the control group who were discharged against medical advice must have had an unfavourable outcome and, on accounting for these, the 95% CI of the risk ratio for mortality crosses the line of no difference (0·9–1·7). Fourth, the article mentions that the investigators doing a Bayley Scales of Infant and Toddler Development assessment at 18 to 22 months were masked. However, on a closer look, the initials of the investigators doing neurological examination during the study intervention and outcome assessment overlap, indicating that the blinding of study investigators was compromised. Fifth, about 70% of neonates in the study had inadequate antenatal and peripartum monitoring and improper transport facilities, which was reflected in the subgroup analysis, whereby a single centre contributed towards most poor outcomes rather than being generalisable to all study sites. Sixth, most neonates had abnormal total leukocyte counts 24 h after study admission (77% in the hypothermia group and 82% in the control group); indicative of early onset sepsis. Therefore, despite having a large number of survivors, there was a 15% higher incidence of combined moderate and severe encephalopathy in the standard treatment group compared with the control group. Lastly, a similar study done by the same group of investigators reported a risk of higher mortality with therapeutic hypothermia. We were surprised to find that, despite this evidence, the authors did not plan an interim analysis to find harm while planning the HELIX trial. To summarise, the factors that could have led to poorer outcomes in the HELIX trial could have been any of the following: inadequate antenatal or intrapartum care, presence of perinatal sepsis, insufficient individualised supportive care, and improper masking of study personnel. In our view, the HELIX trial raises many questions that can only be answered by doing further research. We declare no competing interests. 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 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