Lactate is oxidized by the human brain following traumatic brain injury

Background and Aims: We have previously shown in patients with traumatic brain injury (TBI) that the brain takes up rather than releases lactate (Glenn, 2003). However, the metabolic fate of lactate entering the brain in these patients has not been determined. Therefore, we infused the stable isotope tracer [3-13C]lactate into three severely injured TBI patients, and measured cerebral 13CO2 production to determine the extent to which consumed lactate is oxidized by the injured brain. As well, we infused [6,6-2H2]glucose simultaneously, and in separate experiments infused [1-13C]- and [6,6-2H2]glucose to facilitate comparison of cerebral lactate and glucose metabolism following TBI. Methods: Three severely injured TBI patients (age 58 +/-15 years, all male) were consented for the study. A primed continuous infusion of [3-13C]lactate and [6,6-2H2]glucose, or [1-13C]- and [6,6-2H2]glucose, was administered intravenously for 120 minutes, with arterial and jugular bulb venous blood samples collected at time 0 and every 30 minutes thereafter. Experiments were performed within 24 hours of each other. Blood samples were analyzed for isotope enrichments (IRMS or GCMS) and concentrations of CO2, lactate and glucose. Cerebral flux and oxidation rates were calculated using the combination of blood flow (133Xenon clearance technique), isotope and mass balance measurements. Absolute and relative flux or oxidation rates are presented. Results: Patients exhibited a small net cerebral lactate release during the [3-13C]lactate infusion trial (0.15±0.07 mg/100g tissue/min), but considerable tracer-measured lactate uptake was observed (1.84±0.64 mg/100g/min). Thus, total lactate production (net release + tracer-measured uptake) was far greater than net release alone (1.99±0.70 mg/100g/min). Lactate uptake exceeded net glucose uptake (1.39±0.30 mg/100g/min) in this trial. When [3-13C] lactate was infused, lactate oxidation was calculated to be 0.16±0.06 mg/100g/min which represents 15±4 % of arterial lactate extracted. This accounted for up to 16±8 % (range 4-32%) of cerebral oxidative CO2 production. Extra-cerebral [3-13C] lactate incorporation into glucose, and thus glucose contribution to cerebral 13CO2 production was considered neglible as judged by minimal arterial 13C glucose enrichment (0.006% vs. 1.373% for arterial lactate). Data for 2 patients is presented for the [1-13C]glucose infusion trial, during which net glucose uptake was also observed (3.45±0.48 mg/100g/min). Cerebral glucose oxidation was calculated to be 1.27±0.44 mg/100g/min, which accounted for 62±20% of cerebral oxidative CO2 production assuming no astrocyte-neuron lactate shuttling. Conclusions: This study is the first of its kind to show that, in addition to glucose, energy production from arterial lactate can be an important contributor to oxidative metabolism in the injured human brain. As well, the occurrence of a small net cerebral lactate release during substantial cerebral lactate uptake indicates, for the first time, dynamic cerebral lactate turnover in the injured brain (i.e. simultaneous lactate uptake and production). While inter-patient variability was high, due in part to the time after injury that the study was conducted and the differences in injury severity, the novel application of these techniques and the preliminary findings observed may have important implications for understanding both the metabolic consequences of TBI and directing future metabolically based therapies.