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Original research
Therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy in India (THIN study): a randomised controlled trial
  1. Karoline Aker1,2,
  2. Ragnhild Støen1,2,
  3. Live Eikenes3,
  4. Miriam Martinez-Biarge4,
  5. Ingeborg Nakken5,
  6. Asta Kristine Håberg5,6,
  7. Sridhar Gibikote7,
  8. Niranjan Thomas8
  1. 1 Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
  2. 2 Department of Paediatrics, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
  3. 3 Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
  4. 4 Department of Paediatrics, Imperial College London, London, UK
  5. 5 Norwegian Advisory Unit for Functional MRI, Department of Radiology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
  6. 6 Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway
  7. 7 Department of Radiology, Christian Medical College and Hospital Vellore, Vellore, Tamil Nadu, India
  8. 8 Department of Neonatology, Christian Medical College and Hospital Vellore, Vellore, Tamil Nadu, India
  1. Correspondence to Dr Karoline Aker, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology Faculty of Medicine and Health Sciences, PO Box 8905, 7491 Trondheim, Norway; karoline.aker{at}ntnu.no

Abstract

Objective To evaluate the neuroprotective effect of therapeutic hypothermia (TH) induced by phase changing material (PCM) on MRI biomarkers in infants with hypoxic-ischaemic encephalopathy (HIE) in a low-resource setting.

Design Open-label randomised controlled trial.

Setting One neonatal intensive care unit in a tertiary care centre in India.

Patients 50 term/near-term infants admitted within 5 hours after birth with predefined physiological criteria and signs of moderate/severe HIE.

Interventions Standard care (n=25) or standard care plus 72 hours of hypothermia (33.5°C±0.5°C, n=25) induced by PCM.

Main outcome measures Primary outcome was fractional anisotropy (FA) in the posterior limb of the internal capsule (PLIC) on neonatal diffusion tensor imaging analysed according to intention to treat.

Results Primary outcome was available for 22 infants (44%, 11 in each group). Diffusion tensor imaging showed significantly higher FA in the cooled than the non-cooled infants in left PLIC and several white matter tracts. After adjusting for sex, birth weight and gestational age, the mean difference in PLIC FA between groups was 0.026 (95% CI 0.004 to 0.048, p=0.023). Conventional MRI was available for 46 infants and demonstrated significantly less moderate/severe abnormalities in the cooled (n=2, 9%) than in the non-cooled (n=10, 43%) infants. There was no difference in adverse events between groups.

Conclusions This study confirmed that TH induced by PCM reduced brain injury detected on MRI in infants with moderate HIE in a neonatal intensive care unit in India. Future research should focus on optimal supportive treatment during hypothermia rather than looking at efficacy of TH in low-resource settings.

Trial registration number CTRI/2013/05/003693.

  • neonatology
  • imaging
  • neuropathology
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/archdischild-2019-317311

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    Footnotes

    • Contributors NT was the PI of the study. KA did the literature search, conceptualised and designed the study, drafted the initial manuscript, analysed and interpreted the data, and reviewed and revised the manuscript. RS did the literature search, conceptualised and designed the study, analysed and interpreted the data, and reviewed and revised the manuscript. LE made the MRI protocol, did the DTI analysis, interpreted the data, and reviewed and revised the manuscript. MMB did the conventional MRI analysis, and reviewed and revised the manuscript. IN made the MRI protocol, implemented and adapted the protocol on the local scanner, interpreted the data, and reviewed and revised the manuscript. AKH made the MRI protocol, interpreted the data, and reviewed and revised the manuscript. SG was responsible for the MRI acquisition, and reviewed and revised the manuscript. NT did the literature search, conceptualised and designed the study, enrolled the patients, collected clinical data, analysed and interpreted the data, and reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. KA and NT contributed equally to this work.

    • Funding The trial was funded by the Liaison Committee for Education, Research and Innovation in Central Norway, and the Joint Research Committee between St Olavs Hospital, Trondheim University Hospital, and the Faculty of Medicine, NTNU, Trondheim, Norway.

    • Disclaimer The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; or decision to submit the manuscript for publication.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval The study was approved by the Institutional Review Board at the CMC (number 2013/8223) and the Regional Committee for Medical and Health Research Ethics in central Norway (number 2013/2167).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon reasonable request.