Focally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction.
Garcia, Nuria Marco
Killen, Monica J
Howe, Duncan J
Guilfoyle, Mathew R
Menon, David K
J Cereb Blood Flow Metab
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Khellaf, A., Garcia, N. M., Tajsic, T., Alam, A., Stovell, M., Killen, M. J., Howe, D. J., et al. (2022). Focally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction.. J Cereb Blood Flow Metab, 42 (1), 39-55. https://doi.org/10.1177/0271678X211042112
Following traumatic brain injury (TBI), raised cerebral lactate/pyruvate ratio (LPR) reflects impaired energy metabolism. Raised LPR correlates with poor outcome and mortality following TBI. We prospectively recruited patients with TBI requiring neurocritical care and multimodal monitoring, and utilised a tiered management protocol targeting LPR. We identified patients with persistent raised LPR despite adequate cerebral glucose and oxygen provision, which we clinically classified as cerebral 'mitochondrial dysfunction' (MD). In patients with TBI and MD, we administered disodium 2,3-13C2 succinate (12 mmol/L) by retrodialysis into the monitored region of the brain. We recovered 13C-labelled metabolites by microdialysis and utilised nuclear magnetic resonance spectroscopy (NMR) for identification and quantification.Of 33 patients with complete monitoring, 73% had MD at some point during monitoring. In 5 patients with multimodality-defined MD, succinate administration resulted in reduced LPR(-12%) and raised brain glucose(+17%). NMR of microdialysates demonstrated that the exogenous 13C-labelled succinate was metabolised intracellularly via the tricarboxylic acid cycle. By targeting LPR using a tiered clinical algorithm incorporating intracranial pressure, brain tissue oxygenation and microdialysis parameters, we identified MD in TBI patients requiring neurointensive care. In these, focal succinate administration improved energy metabolism, evidenced by reduction in LPR. Succinate merits further investigation for TBI therapy.
Original Articles, Cerebral metabolism, microdialysis, mitochondrial dysfunction, succinate, traumatic brain injury (Human)
The authors disclose receipt of the following financial support for the research, authorship, and/or publication of this article: Medical Research Council (Grant no.G1002277 ID98489) and National Institute for Health Research Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). Authors’ support: NMG–National Institute for Health Research; AA–Academy of Medical Sciences Newton Fellowship; MGS–National Institute for Health Research Biomedical Research Centre, Cambridge; IJ–Medical Research Council (Grant no.G1002277 ID 98489) and National Institute for Health Research Biomedical Research Centre, Cambridge; DKM–National Institute for Health Research Senior Investigator Awards; MJK–Cambridge Australia Oliphant Scholarship in partnership with the Cambridge Trust; PJH–National Institute for Health Research (Professorship, Biomedical Research Centre, Brain Injury MedTech Co-operative, Senior Investigator Award and the Royal College of Surgeons of England; KLHC–National Institute for Health Research Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme); EPT–Swedish Brain Foundation (Hjärnfonden), Swedish Medical Society (SLS) and Swedish Society for Medical Research (SSMF); AH–Medical Research Council/Royal College of Surgeons of England Clinical Research Training Fellowship (Grant no.G0802251), the NIHR Biomedical Research Centre and the NIHR Brain Injury MedTech Co-operative.
Medical Research Council (G1002277)
Royal College of Surgeons of England (2016/2017)
Medical Research Council (G0600986)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Medical Research Council (G9439390)
External DOI: https://doi.org/10.1177/0271678X211042112
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332361