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Focally perfused succinate potentiates brain metabolism in head injury patients.

ABSTRACT: Following traumatic brain injury, complex cerebral energy perturbations occur. Correlating with unfavourable outcome, high brain extracellular lactate/pyruvate ratio suggests hypoxic metabolism and/or mitochondrial dysfunction. We investigated whether focal administration of succinate, a tricarboxylic acid cycle intermediate interacting directly with the mitochondrial electron transport chain, could improve cerebral metabolism. Microdialysis perfused disodium 2,3-¹³C₂ succinate (12 mmol/L) for 24 h into nine sedated traumatic brain injury patients' brains, with simultaneous microdialysate collection for ISCUS analysis of energy metabolism biomarkers (nine patients) and nuclear magnetic resonance of ¹³C-labelled metabolites (six patients). Metabolites 2,3-¹³C₂ malate and 2,3-¹³C₂ glutamine indicated tricarboxylic acid cycle metabolism, and 2,3-¹³C₂ lactate suggested tricarboxylic acid cycle spinout of pyruvate (by malic enzyme or phosphoenolpyruvate carboxykinase and pyruvate kinase), then lactate dehydrogenase-mediated conversion to lactate. Versus baseline, succinate perfusion significantly decreased lactate/pyruvate ratio (p = 0.015), mean difference -12%, due to increased pyruvate concentration (+17%); lactate changed little (-3%); concentrations decreased for glutamate (-43%) (p = 0.018) and glucose (-15%) (p = 0.038). Lower lactate/pyruvate ratio suggests better redox status: cytosolic NADH recycled to NAD⁺ by mitochondrial shuttles (malate-aspartate and/or glycerol 3-phosphate), diminishing lactate dehydrogenase-mediated pyruvate-to-lactate conversion, and lowering glutamate. Glucose decrease suggests improved utilisation. Direct tricarboxylic acid cycle supplementation with 2,3-¹³C₂ succinate improved human traumatic brain injury brain chemistry, indicated by biomarkers and ¹³C-labelling patterns in metabolites.

SUBMITTER: Jalloh I

PROVIDER: S-EPMC5482384 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTherapeutic head positioning plays a role in the management of patients with acute brain injury. Although intracranial pressure (ICP) is typically lower in an upright posture than in a flat position, limited data exist concerning the effect of upright positioning on brain oxygenation and circulation. We sought to determine the impact of supine (0°) and semirecumbent (15° and 30°) postures on ICP, brain oxygenation, and brain circulation.MethodsAn observational cohort study was conducted between February 2012 and September 2015. Twenty-three patients with severe acute brain injury were successively observed at head elevations of 30°, 15°, and 0°. Postural-induced changes in ICP, cerebral perfusion pressure, brain tissue oxygenation pressure, and transcranial Doppler findings were simultaneously measured during three repeated experiments: 24 h after admission to the intensive care unit (exp1), 24 h later (exp2), and 96 h later (exp3). Cerebral perfusion pressure, arterial blood gases, hemoglobin content, and body temperature remained unchanged during the three experiments.ResultsUsing linear random-slope mixed models, we found that during the early phase of acute brain injury (exp1), lowering the head posture from 30° to 15°, and then to 0°, was associated with a gradual mean ICP increase of 2.6 mm Hg (1.4-3.7 mm Hg; P < 0.001); and from 30° to 0°, an increase of 7.4 mm Hg (6.3-8.6 mm Hg; P < 0.001). Furthermore, brain tissue oxygenation pressure and mean blood flow velocity improved when the head posture was lowered from 30° to 0° by 1.2 mm Hg (0.2-2.3 mm Hg) and 4.1 cm/s (0.0-8.2 cm/s), respectively (both P < 0.05).ConclusionsChanging the positioning of stable patients with acute brain injury resulted in opposite changes of ICP versus brain oxygenation and circulation. This information supports the concept of an individualized approach to head positioning that is based on the multimodal monitoring of brain parameters.

Project description:BACKGROUND:Hyperventilation-induced hypocapnia (HV) reduces elevated intracranial pressure (ICP), a dangerous and potentially fatal complication of traumatic brain injury (TBI). HV decreases the arteriolar diameter of intracranial vessels, raising the risk of cerebral ischemia. The aim of this study was to characterize the effects of moderate short-term HV in patients with severe TBI by using concomitant monitoring of cerebral metabolism, brain tissue oxygen tension (PbrO2), and cerebral hemodynamics with transcranial color-coded duplex sonography (TCCD). METHODS:This prospective trial was conducted between May 2014 and May 2017 in the surgical intensive care unit (ICU) at the University Hospital of Zurich. Patients with nonpenetrating TBI older than 18 years of age with a Glasgow Coma Scale (GCS) score?<?9 at presentation and with ICP monitoring, PbrO2, and/or microdialysis (MD) probes during ICU admission within 36?h after injury were included in our study. Data collection and TCCD measurements were performed at baseline (A), at the beginning of moderate HV (C), after 50?min of moderate HV (D), and after return to baseline (E). Moderate HV was defined as arterial partial pressure of carbon dioxide 4-4.7?kPa. Repeated measures analysis of variance was used to compare variables at the different time points, followed by post hoc analysis with Bonferroni adjustment as appropriate. RESULTS:Eleven patients (64% males, mean age 36?±?14?years) with an initial median GCS score of 7 (IQR 3-8) were enrolled. During HV, ICP and mean flow velocity (CBFV) in the middle cerebral artery decreased significantly. Glucose, lactate, and pyruvate in the brain extracellular fluid did not change significantly, whereas PbrO2 showed a statistically significant reduction but remained within the normal range. CONCLUSION:Moderate short-term hyperventilation has a potent effect on the cerebral blood flow, as shown by TCCD, with a concomitant ICP reduction. Under the specific conditions of this study, this degree of hyperventilation did not induce pathological alterations of brain metabolites and oxygenation. TRIAL REGISTRATION:NCT03822026 . Registered on 30 January 2019.

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Focally perfused succinate potentiates brain metabolism in head injury patients.

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