Exogenous lactate supplementation to the injured brain: misleading conclusions with clinical implications

Nordström, Carl‐Henrik; Nielsen, Troels Halfeld

doi:10.1007/s00134-014-3297-5

Cited by 8 publications

(11 citation statements)

References 4 publications

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“…Magistretti, Oddo, Pellerin, and colleagues support the use of hypertonic sodium lactate flooding in brain‐injured patients, based on their claims of lactate as a neuronal fuel and improved glucose and lactate metabolism and neuroenergetics after lactate flooding (Oddo et al, ; Bouzat et al, ; Patet et al, ; Quintard et al, ). However, they never measured metabolism or energetics in patients given high‐dose Na + ‐lactate, and they mis‐ and overinterpreted changes in extracellular metabolite concentrations in microdialysates (Dienel, ; Nordström and Nielsen, ; Dienel et al, ). A critical aspect of use of hypertonic sodium lactate is to first establish that patients do not have mitochondrial deficits that would prevent lactate oxidation.…”

Section: Lactate and The Cellular Basis Of Brain Energy Metabolism Dumentioning

confidence: 99%

Lack of appropriate stoichiometry: Strong evidence against an energetically important astrocyte–neuron lactate shuttle in brain

Dienel

2017

J of Neuroscience Research

142

160

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Glutamate-stimulated aerobic glycolysis in astrocytes coupled with lactate shuttling to neurons where it can be oxidized was proposed as a mechanism to couple excitatory neuronal activity with glucose utilization (CMR glc ) during brain activation. From the outset, this model was not viable because it did not fulfill critical stoichiometric requirements: (i) Calculated glycolytic rates and measured lactate release rates were discordant in cultured astrocytes. (ii) Lactate oxidation requires oxygen consumption, but the oxygen-glucose index (OGI, calculated as CMR O2 /CMR glc ) fell during activation in human brain, and the small rise in CMR O2 could not fully support oxidation of lactate produced by disproportionate increases in CMR glc . (iii) Labeled products of glucose metabolism are not retained in activated rat brain, indicating rapid release of a highly labeled, diffusible metabolite identified as lactate, thereby explaining the CMR glc -CMR O2 mismatch. Additional independent lines of evidence against lactate shuttling include the following: astrocytic oxidation of glutamate after its uptake can help "pay" for its uptake without stimulating glycolysis; blockade of glutamate receptors during activation in vivo prevents upregulation of metabolism and lactate release without impairing glutamate uptake; blockade of b-adrenergic receptors prevents the fall in OGI in activated human and rat brain while allowing glutamate uptake; and neurons upregulate glucose utilization in vivo and in vitro under many stimulatory conditions. Studies in immature cultured cells are not appropriate models for lactate shuttling in adult brain because of their incomplete development of metabolic capability and astrocyte-neuron interactions. Astrocyte-neuron lactate shuttling does not make large, metabolically significant contributions to energetics of brain activation. V C 2017 Wiley Periodicals, Inc.

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Section: Lactate and The Cellular Basis Of Brain Energy Metabolism Dumentioning

confidence: 99%

Lack of appropriate stoichiometry: Strong evidence against an energetically important astrocyte–neuron lactate shuttle in brain

Dienel

2017

J of Neuroscience Research

142

160

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“…These complications, along with previous concerns, 12,46,94 need to be addressed before lactate supplementation is used clinically. …”

Section: Discussionmentioning

confidence: 99%

“…In other words, this glucose level should be able to support CMR glc in white matter where the probe was implanted. Based on analysis of the results in Tables 2 and 3, the percent changes in microdialysate lactate and glucose concentrations presented in Figure 5 of the Patet et al 16 46,94 including lack of assays of brain metabolism and blood pyruvate level; changes in extracellular glucose or lactate concentration do not provide sufficient information to evaluate metabolism and energetics. Also, it is likely that increased brain pyruvate was due, in part, to uptake of blood pyruvate after peripheral lactate metabolism, so the brain LP ratios and percent changes in brain pyruvate level presented in Table 2 and Figure 5 of Bouzat et al 42 have no interpretive value.…”

Section: Glucose Depletionmentioning

confidence: 99%

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

Dienel

Rothman

Nordstrom

2016

J Cereb Blood Flow Metab

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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.

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“…"flooding" of the brain may not only simulate metabolic profile improvements but also be deleterious to brain energy production (Nordstrom and Nielsen, 2014;Dienel et al, 2016). To date, there are no studies demonstrating improvements in clinically important outcomes of lactate supplementation following TBI.…”

Section: Cerebral Microdialysis (Cmd)mentioning

confidence: 99%

Nutrition Therapy, Glucose Control, and Brain Metabolism in Traumatic Brain Injury: A Multimodal Monitoring Approach

Kurtz

Rocha²

2020

Front. Neurosci.

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The goal of neurocritical care in patients with traumatic brain injury (TBI) is to prevent secondary brain damage. Pathophysiological mechanisms lead to loss of body mass, negative nitrogen balance, dysglycemia, and cerebral metabolic dysfunction. All of these complications have been shown to impact outcomes. Therapeutic options are available that prevent or mitigate their negative impact. Nutrition therapy, glucose control, and multimodality monitoring with cerebral microdialysis (CMD) can be applied as an integrated approach to optimize systemic immune and organ function as well as adequate substrate delivery to the brain. CMD allows real-time bedside monitoring of aspects of brain energy metabolism, by measuring specific metabolites in the extracellular fluid of brain tissue. Sequential monitoring of brain glucose and lactate/pyruvate ratio may reveal pathologic processes that lead to imbalances in supply and demand. Early recognition of these patterns may help individualize cerebral perfusion targets and systemic glucose control following TBI. In this direction, recent consensus statements have provided guidelines and recommendations for CMD applications in neurocritical care. In this review, we summarize data from clinical research on patients with severe TBI focused on a multimodal approach to evaluate aspects of nutrition therapy, such as timing and route; aspects of systemic glucose management, such as intensive vs. moderate control; and finally, aspects of cerebral metabolism. Research and clinical applications of CMD to better understand the interplay between substrate supply, glycemic variations, insulin therapy, and their effects on the brain metabolic profile were also reviewed. Novel mechanistic hypotheses in the interpretation of brain biomarkers were also discussed. Finally, we offer an integrated approach that includes nutritional and brain metabolic monitoring to manage severe TBI patients.

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Exogenous lactate supplementation to the injured brain: misleading conclusions with clinical implications

Cited by 8 publications

References 4 publications

Lack of appropriate stoichiometry: Strong evidence against an energetically important astrocyte–neuron lactate shuttle in brain

Lack of appropriate stoichiometry: Strong evidence against an energetically important astrocyte–neuron lactate shuttle in brain

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

Nutrition Therapy, Glucose Control, and Brain Metabolism in Traumatic Brain Injury: A Multimodal Monitoring Approach

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