Abstract
SummaryBackgroundAlthough 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.MethodsWe 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.FindingsWe 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.InterpretationTherapeutic 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.FundingNational Institute for Health Research, Garfield Weston Foundation, and Bill & Melinda Gates Foundation.TranslationsFor the Hindi, Malayalam, Telugu, Kannada, Singhalese, Tamil, Marathi and Bangla translations of the abstract see Supplementary Materials section.
Highlights
Neonatal encephalopathy is the cause of 1 million deaths worldwide every year, of which 99% occur in low-income and middle-income countries (LMICs).[1]
We examined whether therapeutic hypothermia that is initiated within 6 h of birth and continued for 72 h reduces death or disability at 18–22 months when compared with usual care, in full-term babies with moderate or severe neonatal encephalopathy who have been admitted to tertiary neonatal units in LMICs
Evidence before this study One Cochrane review and three other systematic reviews have reported that therapeutic hypothermia reduces death or disability after neonatal encephalopathy, but these metaanalyses were primarily focused on clinical trials from highincome countries
Summary
Neonatal encephalopathy is the cause of 1 million deaths worldwide every year, of which 99% occur in low-income and middle-income countries (LMICs).[1] The pooled data from clinical trials in high-income countries suggest that death or disability is reduced at 18 months through use of induced hypothermia for moderate or severe neonatal encephalopathy.[2,3,4,5]. Hypothermia therapy has been extensively implemented in most LMICs as the standard care and adopted into their national guidelines.[9]. We examined whether therapeutic hypothermia that is initiated within 6 h of birth and continued for 72 h reduces death or disability at 18–22 months when compared with usual care, in full-term babies with moderate or severe neonatal encephalopathy who have been admitted to tertiary neonatal units in LMICs Several trials have suggested that there are beneficial effects of hypothermia in LMICs, these studies have been small or poorly designed, or both, and systematic reviews have reported conflicting results.[6,7] The International Liaison Committee Resuscitation guidelines in 2015 recommended therapeutic hypothermia as the standard of care in LMICs for neonatal encephalopathy, but acknowledged that the existing evidence was weak.[8]
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