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...

List of abbreviations AFR. african region AMR. antimicrobial resistances BCG. bacillus calmette-guérin BUD. buruli ulcera disease CFU. colony forming units DHS. demographic health surveys DRDR. drug resistance determining regions DSJI. disposable-syringe jet injectors DST. drug susceptibility testing EID. early infant HIV diagnosis EMR. eastern mediterranean region EUR. european region G2D. grade-2 disabilities GLP. global leprosy programm GTB. global TB programme HBsAg. hepatitis B surface antigen HCWs. health care workers HICs. high income countries IRIS. immune reconstitution inflammatory syndrome IUATLD. international union against TB and lung disease JRF. WHO/UNICEF Joint Reporting LBW. low birth weight LICs. low income countries LMICs. lower-middle income countries MB. multi-bacillary MDGs. millennium development goals MDR-TB. multidrug-resistant TB MDT. multi-drug therapy, multidrug therapy MICs. middle income countries MICS. multiple indicator cluster surveys MOTT. mycobacteria other than tuberculosis NRA. national regulatory authority NS. needle and syringe NTM. non-tuberculous mycobacterial OPV. oral polio vaccine PB. pauci-bacillary PEP. post-exposure prophylaxis PMTCT. prevention of mother to child transmission POC. point-of-care PQ'd. prequalified PTB. pulmonary tuberculosis R&D. research and development SAGE. strategic advisory group of experts on immunization SDGs. sustainable development goals SEAR. south east asian region TB. tuberculosis UHC. universal health coverage VENICE. vaccine european new integrated collaboration effort WPR. western pacific region WUENIC. WHO/UNICEF estimates of national immunization Coverage XDR-TB. extensively drug-resistant TB

Although therapeutic hypothermia (TH) is the standard of care for hypoxic ischaemic encephalopathy in high-income countries, the safety and efficacy of this therapy in low-income and middle-income countries (LMICs) is unknown. We aimed to describe the feasibility of TH using a low-cost servo-controlled cooling device and the short-term outcomes of the cooled babies in LMIC.DesignWe recruited babies with moderate or severe hypoxic ischaemic encephalopathy (aged <6 hours) admitted to public sector tertiary neonatal units in India over a 28-month period. We administered whole-body cooling (set core temperature 33.5°C) using a servo-controlled device for 72 hours, followed by passive rewarming. We collected the data on short-term neonatal outcomes prior to hospital discharge.ResultsEighty-two babies were included—61 (74%) had moderate and 21 (26%) had severe encephalopathy. Mean (SD) hypothermia cooling induction time was 1.7 hour (1.5) and the effective cooling time 95% (0.08). The mean (SD) hypothermia induction time was 1.7 hour (1.5 hour), core temperature during cooling was 33.4°C (0.2), rewarming rate was 0.34°C (0.16°C) per hour and the effective cooling time was 95% (8%). Twenty-five (51%) babies had gastric bleeds, 6 (12%) had pulmonary bleeds and 21 (27%) had meconium on delivery. Fifteen (18%) babies died before discharge from hospital. Heart rate more than 120 bpm during cooling (P=0.01) and gastric bleeds (P<0.001) were associated with neonatal mortality.ConclusionsThe low-cost servo-controlled cooling device maintained the core temperature well within the target range. Adequately powered clinical trials are required to establish the safety and efficacy of TH in LMICs.Clinical trial registration number NCT01760629.