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

Abstract

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.

Characterising the dynamics of cerebral metabolic dysfunction following traumatic brain injury: A microdialysis study in 619 patients

“…The weakness of the relationship between LPR and PbtO 2 concords with the growing evidence that LPR>25 is not only a marker of hypoxia / ischaemia (which are nowadays uncommon, with modern neurocritical care), but LPR can become elevated even when PbtO 2 levels are regarded as “adequate”–suggesting mitochondrial dysfunction. This concurs with our recent study [ 35 ] wherein application of a tiered protocol enabled the identification of neurometabolic states. Within that study, in those patients with LPR>25, mitochondrial dysfunction and neuroglycopaenia were most frequent.…”

Current state of high-fidelity multimodal monitoring in traumatic brain injury

“…Albeit not based on other than level 3 evidence, and not specifying what each added modality provides for additional monitoring or predictive capability, they do provide guidance for centers using these monitoring modalities in combination. Recently, the group published a paper where an LPR-driven algorithm (if LPR > 25) was used with a tiered therapy escalating from initially correcting ICP if above 20 mmHg (intracranial hypertension), then adjusting CPP if PbtO 2 was < 20 mmHg (oxygen delivery failure), followed by increasing serum glucose to 10 mmol/l if brain glucose < 1.0 mmol/l (neuroglycopenia) [ 23 ]. If nothing corrected the LPR, the patient was deemed to suffer from mitochondrial dysfunction.…”

“…They then mapped exactly which neurometabolic state (NMS) the patient was in the first 2 weeks following injury. Apart from a normal LPR, the two most common NMS were mitochondrial dysfunction and neuroglycopenia, while intracranial hypertension and PbtO 2 issues were rare [ 23 ]. By dividing patients in different NMS, it was also possible to specifically target the group with a mitochondrial dysfunction.…”

Cerebral metabolic derangements following traumatic brain injury

“…Other strategies to support mitochondrial function include substrates such as succinate that bypass complex 1 of the electron transport chain, which has been shown to be sensitive to damage following sepsis and TBI [ 33 ]. Experimental clinical TBI studies have used focally administered 13 C-labeled disodium succinate to demonstrate succinate metabolism plus a reduction in microdialysis LPR and glucose sparing, suggestive of improvements in energy metabolism [ 34 ▪ , 35 ]. However, evidence from the cardiac and stroke literature demonstrate that the driver of reperfusion injury is succinate accumulation within mitochondria during ischemia.…”