EXPRESS: The microdialysis-derived lactate-pyruvate gradient indicates anaerobic activity after brain injury.

BACKGROUND: Cerebral microdialysis (CMD) after traumatic brain injury (TBI) has focused on lactate/pyruvate ratio (LPR), overlooking lactate-pyruvate gradient (LPG, the linear regression slope within a time segment of CMD datapoints) as a proxy for anaerobic activity. METHODS: We retrospectively applied changepoint detection to the linear lactate-pyruvate relationship (L = mP + b) over time within patients from two independent CMD-monitored TBI cohorts (Cambridge, n = 510; Uppsala, n = 81), estimating per-segment LPG (m) and intercept (b, capturing metabolic variance). In vitro, we tested whether rotenone-induced mitochondrial dysfunction increases LPG in hiPSC-derived neurons, as expected if LPG tracks anaerobic activity. RESULTS: In the Cambridge cohort, a median of two linear segments were identified per patient (median LPG = 19.83; median b = 0.54 mM). Between segments, LPR tracked LPG with heavy attenuation (β = 0.255). LPG was negatively associated with cerebral microdialysate glucose (p < 0.001) and 6-month GOSE (p = 0.039). Uppsala data confirmed pipeline robustness and replicated the LPG-glucose association (p = 0.022). LPG was higher in rotenone-treated neurons than controls (32.9 vs. 14.2, p < 0.001). CONCLUSION: LPG calculated per time segment provides a more accurate, outcome-associated proxy for anaerobic activity than datapoint-level LPR.