Browsing by Author "Herberg, J.A."

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    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
    (Elsevier Ltd., 2021) Thayyil, S.; Pant, S.; Montaldo, P.; Shukla, D.; Oliveira, V.; Ivain, P.; Bassett, P.; Swamy, R.; Mendoza, J.; Moreno-Morales, M.; Lally, P.J.; Benakappa, N.; Bandiya, P.; Shivarudhrappa, I.; Somanna, J.; Kantharajanna, U.B.; Rajvanshi, A.; Krishnappa, S.; Joby, P.K.; Jayaraman, K.; Chandramohan, R.; Kamalarathnam, C.N.; Sebastian, M.; Tamilselvam, I.A.; Rajendran, U.D.; Soundrarajan, R.; Kumar, V.; Sudarsanan, H.; Vadakepat, P.; Gopalan, K.; Sundaram, M.; Seeralar, A.; Vinayagam, P.; Sajjid, M.; Baburaj, M.; Murugan, K.D.; Sathyanathan, B.P.; Kumaran, E.S.; Mondkar, J.; Manerkar, S.; Joshi, A.R.; Dewang, K.; Bhisikar, S.M.; Kalamdani, P.; Bichkar, V.; Patra, S.; Jiwnani, K.; Shahidullah, M.; Moni, S.C.; Jahan, I.; Mannan, M.A.; Dey, S.K.; Nahar, M.N.; Islam, M.N.; Shabuj, K.H.; Rodrigo, R.; Sumanasena, S.; Abayabandara-Herath, T.; Chathurangika, G.K.; Wanigasinghe, J.; Sujatha, R.; Saraswathy, S.; Rahul, A.; Radha, S.J.; Sarojam, M.K.; Krishnan, V.; Nair, M.K.; Devadas, S.; Chandriah, S.; Venkateswaran, H.; Burgod, C.; Chandrasekaran, M.; Atreja, G.; Muraleedharan, P.; Herberg, J.A.; Chong, W.K.K.; Sebire, N.J.; Pressler, R.; Ramji, S.; Shankaran, S.; HELIX consortium
    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.
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    Whole-Blood gene expression profile after hypoxic-ischemic encephalopathy
    (American Medical Association, 2024) Montaldo, P.; Burgod, C.; Herberg, J.A.; Kaforou, M.; Cunnington, A.J.; Mejias, A.; Cirillo, G.; Giudice, E.M.D.; Capristo, C.; Bandiya, P.; Kamalaratnam, C.N.; Chandramohan, R.; Manerkar, S.; Rodrigo, R.; Sumanasena, S.; Krishnan, V.; Pant, S.; Shankaran, S.; Thayyil, S.
    IMPORTANCE: Induced hypothermia, the standard treatment for hypoxic-ischemic encephalopathy (HIE) in high-income countries (HICs), is less effective in the low-income populations in South Asia, who have the highest disease burden. OBJECTIVE: To investigate the differences in blood genome expression profiles of neonates with HIE from an HIC vs neonates with HIE from South Asia. DESIGN, SETTING, AND PARTICIPANTS: This case-control study analyzed data from (1) a prospective observational study involving neonates with moderate or severe HIE who underwent whole-body hypothermia between January 2017 and June 2019 and age-matched term healthy controls in Italy and (2) a randomized clinical trial involving neonates with moderate or severe HIE in India, Sri Lanka, and Bangladesh recruited between August 2015 and February 2019. Data were analyzed between October 2020 and August 2023. EXPOSURE: Whole-blood RNA that underwent next-generation sequencing. MAIN OUTCOME AND MEASURES: The primary outcomes were whole-blood genome expression profile at birth associated with adverse outcome (death or disability at 18 months) after HIE in the HIC and South Asia cohorts and changes in whole-genome expression profile during the first 72 hours after birth in neonates with HIE and healthy controls from the HIC cohort. Blood samples for RNA extraction were collected before whole-body hypothermia at 4 time points (6, 24, 48, and 72 hours after birth) for the HIC cohort. Only 1 blood sample was drawn within 6 hours after birth for the South Asia cohort. RESULTS: The HIC cohort was composed of 35 neonates (21 females [60.0%]) with a median (IQR) birth weight of 3.3 (3.0-3.6) kg and gestational age of 40.0 (39.0-40.6) weeks. The South Asia cohort consisted of 99 neonates (57 males [57.6%]) with a median (IQR) birth weight of 2.9 (2.7-3.3) kg and gestational age of 39.0 (38.0-40.0) weeks. Healthy controls included 14 neonates (9 females [64.3%]) with a median (IQR) birth weight of 3.4 (3.2-3.7) kg and gestational age of 39.2 (38.9-40.4) weeks. A total of 1793 significant genes in the HIC cohort and 99 significant genes in the South Asia cohort were associated with adverse outcome (false discovery rate <0.05). Only 11 of these genes were in common, and all had opposite direction in fold change. The most significant pathways associated with adverse outcome were downregulation of eukaryotic translation initiation factor 2 signaling in the HIC cohort (z score = -4.56; P < .001) and aldosterone signaling in epithelial cells in the South Asia cohort (z score = null; P < .001). The genome expression profile of neonates with HIE (n = 35) at birth, 24 hours, 48 hours, and 72 hours remained significantly different from that of age-matched healthy controls in the HIC cohort (n = 14). CONCLUSIONS AND RELEVANCE: This case-control study found that disease mechanisms underlying HIE were primarily associated with acute hypoxia in the HIC cohort and nonacute hypoxia in the South Asia cohort. This finding might explain the lack of hypothermic neuroprotection.