Microdialysate concentration changes do not provide sufficient information to evaluate metabolic effects of lactate supplementation in brain-injured patients

Abstract

Cerebral microdialysis is a widely used clinical tool for monitoring extracellular concentrations of selected metabolites after brain injury and to guide neurocritical care. Extracellular glucose levels and lactate/pyruvate ratios have high diagnostic value because they can detect hypoglycemia and deficits in oxidative metabolism, respectively. In addition, patterns of metabolite concentrations can distinguish between ischemia and mitochondrial dysfunction, and are helpful to choose and evaluate therapy. Increased intracranial pressure can be life-threatening after brain injury, and hypertonic solutions are commonly used for pressure reduction. Recent reports have advocated use of hypertonic sodium lactate, based on claims that it is glucose sparing and provides an oxidative fuel for injured brain. However, changes in extracellular concentrations in microdialysate are not evidence that a rise in extracellular glucose level is beneficial or that lactate is metabolized and improves neuroenergetics. The increase in glucose concentration may reflect inhibition of glycolysis, glycogenolysis, and pentose phosphate shunt pathway fluxes by lactate flooding in patients with mitochondrial dysfunction. In such cases, lactate will not be metabolizable and lactate flooding may be harmful. More rigorous approaches are required to evaluate metabolic and physiological effects of administration of hypertonic sodium lactate to brain-injured patients.

Keywords: Cerebral microdialysis; brain metabolism; glucose; lactate supplementation; traumatic brain injury.

Figure 1.

Simplified diagram of cerebral intermediary metabolism with a focus on the glycolytic pathway and its relation to glycerol and glycerophospholipids and to the citric acid cycle. Glucose, lactate, and pyruvate are involved in major pathways of brain energy metabolism, and changes in their concentrations and lactate/pyruvate (Lac/Pyr) ratio can reflect disturbances in transport and metabolism, whereas increases in glutamate and glycerol levels reflect excitatory neurotoxicity and membrane damage, respectively. P: phosphate; α-KG: α-ketoglutarate; TCA: tricarboxylic acid. Underlined metabolites are analyzed during routine cerebral microdialysis assays and displayed at the bedside. Reference levels (means ± SD) of the various metabolites for normal human brain were obtained from Reinstrup et al. Modified from Nordström, Childs Nerv Syst 2010; 26:465–472, Copyright © 2009, Springer-Verlag, with permission.

Figure 2.

Schematic illustration of brain tissue oxygenation (P_btO₂) and changes in the levels of lactate (Lac), pyruvate (Pyr), and the lactate/pyruvate ratio in two conditions: ischemia and mitochondrial dysfunction. Note the differences in tissue oxygenation and extracellular pyruvate levels during ischemia and mitochondrial dysfunction. Modified from Nordström et al. J Rehabil Med 2013; 45: 710–717. Copyright © 2013, The Authors, with permission.

Figure 3.

Sampling of brain extracellular metabolite levels versus assays of metabolism. Glucose is taken up and metabolized by neurons and astrocytes via the glycolytic pathway (glucose to pyruvate), pentose phosphate shunt pathway (PPP), and tricarboxylic acid (TCA) cycle. Glutamine is synthesized in astrocytes via the pyruvate carboxylase reaction to generate a “new” molecule of oxaloacetate that condenses with acetyl CoA from a second pyruvate molecule to sequentially form α-ketoglutarate, glutamate, and glutamine. The glutamine is shuttled to neurons where it serves as precursor for the glutamate and GABA neurotransmitter pools. Glutamate released to interstitial fluid during excitatotory neurotransmission is avidly taken up into astrocytes, and converted (in part) to glutamine for transfer back to neurons. This process is called the glutamate-glutamine (Glu-Gln) cycle and the cycle rate is directly proportional to the rate of oxidative metabolism over a wide range of brain activity levels (reviewed by Rothman et al.). Cerebral metabolic rates (CMR) can be determined by assay of arteriovenous differences (A-V) and cerebral blood flow (CBF) rates to obtain global rates, use of [¹⁸F]fluorodeoxyglucose-positron emission tomography (FDG-PET) to assay the hexokinase (HK) step and obtain total glucose utilization, or assays of oxidation of ¹³C-labeled substates using MRS and metabolic modeling. Glycogen is contained predominantly in astrocytes and it is a dynamic participant in brain metabolism. Microdialysis samples the ECs of compounds in ECF. After entry into cells (IC: intracellular concentration), compounds are metabolized via different pathways to generate ATP that provides energy for the cells. Note that ECs are the net balance of influxes and effluxes to and from blood and brain cells, whereas intracellular concentrations are the net balance between transport and metabolism. Glc: glucose; Lac: lactate; Pyr: pyruvate; Glu: glutamate; Gln: glutamine. Modified from Figure 1 of Dienel GA and Cruz NF. Contributions of glycogen to astrocytic energetics during brain activation. Metab Brain Dis 2015; 30: 281–298. Copyright © 2014, Springer Science+Business Media New York, with permission.

Figure 4.

Fractional contribution of brain lactate to total oxidation as function of brain lactate concentration. Boumezbeur et al. infused [¹³C]lactate into human subjects and measured its oxidation rate in brain. The linear regressions from their Figure 6 were used to calculate brain lactate levels from arterial plasma lactate levels at 0.5 µmol/mL intervals using their equation [lactate]_brain = 0.63 [lactate]_plasma. These data were plotted against the corresponding calculated values for CMR_lactate, calculated with their equation, CMR_lac = 0.019[lac]_plasma – 0.007; CMR_lac is expressed as % V_TCA, where V_TCA = 0.65 µmol/g min and represents the total oxidation rate in neurons plus glia. The plotted points illustrate the approximate fractional rates of lactate oxidation at plasma and brain lactate levels arising from the modest lactate intravenous infusion schedule. Actual values measured by Boumezbeur et al. and plotted in their Figure 6(c) would be distributed around this regression line. These results demonstrate that within the range of brain lactate levels in normal resting and activated brain in sedentary subjects, lactate contributes ∼2–8% to total oxidation and glucose accounts for the remaining 92–98%. The green text indicates the range of brain lactate levels in normal activated brain in sedentary rodents that have lower arterial plasma lactate levels and an outward, brain-to-blood lactate gradient. The red text denotes the point above which arterial plasma levels rise during progressively increasing intensity of exercise or of higher lactate infusion schedules causing an inward, blood-to-brain lactate gradient. CMR_lac: cerebral metabolic rate for lactate; TCA: tricarboxylic acid; V_TCA: total oxidation rate in neurons and astrocytes. Modified from Figure 10(c) of Dienel GA, Fueling and imaging brain activation. ASN Neuro 2012; 4:267–321.Copyright © 2012, The Author, with permission.

Figure 5.

Metabolic pathways that may be affected by lactate flooding of brain after traumatic brain injury. Entry of large amounts of exogenous lactate into a brain cell drives the lactate dehydrogenase reaction (LDH) towards pyruvate and NADH production, and at the same time co-transports H⁺ and generates a second H⁺ that can acidify the cytoplasm. Phosphofructokinase (PFK), one of the major regulatory enzymes of the glycolytic pathway, is very sensitive to small decreases in pH that inhibit its activity. Increased levels of glucose-6-phosphate will enhance its regulation of hexokinase activity by feedback inhibition. (Brown lines with a ball at one end denote inhibition.) Reduction of the NAD⁺ availablity will also impair glycolytic flux. Lactate flooding-mediated lowering of pH and NADH generation has the potential to impair glycolytic, glycogenolytic, and pentose-phosphate (P) shunt pathway fluxes. Cytoplasmic NAD⁺ is regenerated from NADH by the action of LDH or the malate-aspartate shuttle (MAS). Note that lactate cannot be oxidized if the MAS is impaired or if there is mitochondrial dysfunction. HK: hexokinase; Glc: glucose; Glc-6-P: glucose-6-phosphate (P); Fru-6-P: fructose-6-P; Fru-1,6-P₂: fructose-1,6-P₂; Lac: lactate; PDH: pyruvate dehydrogenase; PC: pyruvate carboxylase; OAA: oxaloacetate; cit: citrate; αKG: α-ketoglutarate; MCT: monocarboxylic acid transporter; GLUT: glucose transporter; NE: norepinephrine; LC: locus coeruleus. Modified from Figure 1 of Dienel GA. Brain lactate metabolism: the discoveries and the controversies. J Cereb Blood Flow Metab 2012; 32: 1107–1138. Copyright © 2012, International Society for Cerebral Blood Flow and Metabolism, with permission.

Figure 6.

Influence of lactate flooding after traumatic brain injury on aspects of brain metabolism and signaling. Summary of potential consequences of elevated lactate on brain functions. Superscripts refer to the following references: 1,^,; 2,^–; 3,; 4,; 5,; 6,; 7,.