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

Abstract

Background: Although therapeutic hypothermia reduces death or disability after neonatal encephalopathy in high-income countries, its safety and efficacy in low-income and middle-income countries is unclear. We aimed to examine whether therapeutic hypothermia alongside optimal supportive intensive care reduces death or moderate or severe disability after neonatal encephalopathy in south Asia.

Methods: We did a multicountry open-label, randomised controlled trial in seven tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh. We enrolled infants born at or after 36 weeks of gestation with moderate or severe neonatal encephalopathy and a need for continued resuscitation at 5 min of age or an Apgar score of less than 6 at 5 min of age (for babies born in a hospital), or both, or an absence of crying by 5 min of age (for babies born at home). Using a web-based randomisation system, we allocated infants into a group receiving whole body hypothermia (33·5°C) for 72 h using a servo-controlled cooling device, or to usual care (control group), within 6 h of birth. All recruiting sites had facilities for invasive ventilation, cardiovascular support, and access to 3 Tesla MRI scanners and spectroscopy. Masking of the intervention was not possible, but those involved in the magnetic resonance biomarker analysis and neurodevelopmental outcome assessments were masked to the allocation. The primary outcome was a combined endpoint of death or moderate or severe disability at 18-22 months, assessed by the Bayley Scales of Infant and Toddler Development (third edition) and a detailed neurological examination. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02387385.

Findings: We screened 2296 infants between Aug 15, 2015, and Feb 15, 2019, of whom 576 infants were eligible for inclusion. After exclusions, we recruited 408 eligible infants and we assigned 202 to the hypothermia group and 206 to the control group. Primary outcome data were available for 195 (97%) of the 202 infants in the hypothermia group and 199 (97%) of the 206 control group infants. 98 (50%) infants in the hypothermia group and 94 (47%) infants in the control group died or had a moderate or severe disability (risk ratio 1·06; 95% CI 0·87-1·30; p=0·55). 84 infants (42%) in the hypothermia group and 63 (31%; p=0·022) infants in the control group died, of whom 72 (36%) and 49 (24%; p=0·0087) died during neonatal hospitalisation. Five serious adverse events were reported: three in the hypothermia group (one hospital readmission relating to pneumonia, one septic arthritis, and one suspected venous thrombosis), and two in the control group (one related to desaturations during MRI and other because of endotracheal tube displacement during transport for MRI). No adverse events were considered causally related to the study intervention.

Interpretation: Therapeutic 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.

Funding: National Institute for Health Research, Garfield Weston Foundation, and Bill & Melinda Gates Foundation.

Translations: For the Hindi, Malayalam, Telugu, Kannada, Singhalese, Tamil, Marathi and Bangla translations of the abstract see Supplementary Materials section.

Figure 1

Trial profile ASQ=Ages and Stages Questionnaire. *We used the ASQ data for the assessment of mortality only and not for the assessment of disability.

Figure 2

Changes in encephalopathy severity (A), temperature profile (B), and Kaplan-Meier estimates of survival until 18 months (C) Error bars indicate mean (SD) of hourly rectal temperatures in the hypothermia group and control group

Figure 3

Thalamic NAA concentrations, and metabolite peak area ratios (A–D) and tract-based spatial statistics of white matter fractional anisotropy (E) (A–D) Medians are indicated by horizontal lines, boxes outline the upper and lower quartiles, and the whiskers indicate 1·5 times the IQR from the upper and lower quartiles. Outliers are indicated with dots lying beyond the whiskers. (E) Green indicates the mean fractional anisotropy tract skeleton, with a threshold range of 0·15 (lower) and 1·0 (upper) over regions with no statistically significant (p<0·05) groupwise difference in fractional anisotropy between groups. Regions in red and yellow indicate regions of increasing statistical significance (p<0·05 in red, p<0·01 in yellow), corrected for multiple comparisons over whole brain analysis. There are no areas in red or yellow indicating that the whole brain white matter fractional anisotropy in infants in the hypothermia group is not significantly different to that of the control infants. NAA=N-acetyl aspartate.