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

Summary 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. Interpretatio...

Evaluating Neuroprotective Effects of Uridine, Erythropoietin, and Therapeutic Hypothermia in a Ferret Model of Inflammation-Sensitized Hypoxic-Ischemic Encephalopathy

“…Additionally, the Ur animals (649. 5 P42, all Ur animals were significantly lighter than control animals. In the males, the other HIH animals were also lighter than the controls; however, the comparison between control males and Veh males was not significant.…”

“…By comparison, although we have not studied response to these therapies without the presensitizing effect of LPS in the model, it is likely that the inclusion of LPS is the primary reason for a lack of neuroprotective effect of TH [ 13 , 40 , 41 ]. However, as more definitive evidence is accumulating regarding the lack of TH neuroprotection in lower income settings [ 5 ], perhaps due to more protracted or chronic perinatal insults, the model as used here may be particularly useful for examining therapies for use in scenarios where TH is not beneficial.…”

“…TH has been shown to significantly improve the outcomes of term and near-term infants with HIE in high resource settings, with a number needed to treat of 7 [ 4 ]. TH has not been proven to be beneficial in term infants in lower resource settings [ 5 ], or in preterm infants, so new approaches to neuroprotection are needed for these populations.…”

Pediatric Hypothermia: An Ambiguous Issue

“…below), one may wonder whether neonatology will remain virtually the sole domain of therapeutic hypothermia. This notion has gained further support from a brand-new study suggesting that hypothermic treatment may even do more harm than good, at least under circumstances such as those prevailing in low- and middle-income countries [ 56 , 57 ]. In any case, additional or alternative therapies are currently being sought that modulate the “tertiary” phase of hypoxic–ischemic brain injury so as to promote regenerative (rather than scarring) processes in the damaged neonatal brain [ 58 , 59 , 60 ].…”

Therapeutic Hypothermia for Perinatal Asphyxia in Low-Resource Settings

“…It portrays scientific research in LMIC in poor light using inappropriate language. The HELIX (hypothermia for encephalopathy in low-and middle-income countries) study did not observe any difference in the primary outcome [3]. However, the study had 17 predefined secondary outcomes and the authors have presented only unadjusted analysis raising serious concerns about the statistical handling of multiple comparisons and presenting an exaggerated view based on inappropriate analyses [3,4].…”