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Focally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction.

cam.issuedOnline2021-09-08
dc.contributor.authorKhellaf, Abdelhakim
dc.contributor.authorGarcia, Nuria Marco
dc.contributor.authorTajsic, Tamara
dc.contributor.authorAlam, Aftab
dc.contributor.authorStovell, Matthew G
dc.contributor.authorKillen, Monica J
dc.contributor.authorHowe, Duncan J
dc.contributor.authorGuilfoyle, Mathew R
dc.contributor.authorJalloh, Ibrahim
dc.contributor.authorTimofeev, Ivan
dc.contributor.authorMurphy, Michael P
dc.contributor.authorCarpenter, T Adrian
dc.contributor.authorMenon, David K
dc.contributor.authorErcole, Ari
dc.contributor.authorHutchinson, Peter J
dc.contributor.authorCarpenter, Keri Lh
dc.contributor.authorThelin, Eric P
dc.contributor.authorHelmy, Adel
dc.contributor.orcidStovell, Matthew G [0000-0002-4172-4617]
dc.contributor.orcidErcole, Ari [0000-0001-8350-8093]
dc.contributor.orcidHelmy, Adel [0000-0002-0531-0556]
dc.date.accessioned2022-01-07T16:49:05Z
dc.date.available2022-01-07T16:49:05Z
dc.date.issued2022-01
dc.date.submitted2021-02-09
dc.date.updated2022-01-07T16:49:04Z
dc.description.abstractFollowing 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.
dc.description.sponsorshipThe 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.
dc.identifier.doi10.17863/CAM.79807
dc.identifier.eissn1559-7016
dc.identifier.issn0271-678X
dc.identifier.other10.1177_0271678x211042112
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332361
dc.languageen
dc.language.isoeng
dc.publisherSAGE Publications
dc.publisher.urlhttp://dx.doi.org/10.1177/0271678x211042112
dc.subjectCerebral metabolism
dc.subjectmicrodialysis
dc.subjectmitochondrial dysfunction
dc.subjectsuccinate
dc.subjecttraumatic brain injury (Human)
dc.subjectAdult
dc.subjectBrain
dc.subjectBrain Injuries, Traumatic
dc.subjectEnergy Metabolism
dc.subjectFemale
dc.subjectHumans
dc.subjectIntracranial Pressure
dc.subjectLactic Acid
dc.subjectMale
dc.subjectMicrodialysis
dc.subjectMiddle Aged
dc.subjectMitochondria
dc.subjectNuclear Magnetic Resonance, Biomolecular
dc.subjectPyruvic Acid
dc.subjectSuccinic Acid
dc.titleFocally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction.
dc.typeArticle
dcterms.dateAccepted2021-07-20
prism.endingPage55
prism.issueIdentifier1
prism.publicationNameJ Cereb Blood Flow Metab
prism.startingPage39
prism.volume42
pubs.funder-project-idMedical Research Council (G1002277)
pubs.funder-project-idRoyal College of Surgeons of England (2016/2017)
pubs.funder-project-idMedical Research Council (G0600986)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
pubs.funder-project-idMedical Research Council (G9439390)
pubs.funder-project-idMedical Research Council (G0802251)
pubs.funder-project-idTCC (None)
rioxxterms.freetoread.startdate2021-09-08
rioxxterms.licenseref.startdate2021-09-08
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1177/0271678X211042112

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