Unlocking the metabolic and anti-inflammatory therapeutic potential of lactate in critically ill patients

Tchatat Wangueu et al. Critical Care (2025) 29:450 https://doi.org/10.1186/s13054-025-05665-4 Critical Care Open Access REVIEW Unlocking the metabolic and antiinflammatory therapeutic potential of lactate in critically ill patients Lionel Tchatat Wangueu1,2*, Eva Correia1, Fabienne Tamion1,3 and Emmanuel Besnier1,4 Abstract Background Lactate, traditionally viewed as a biomarker of hypoxia and severity in critical illness, has recently emerged as a potential therapeutic agent. Its roles extend beyond energy metabolism to include anti-inflammatory and signaling functions. This review explores the evolving evidence supporting lactates therapeutic application in critical care settings. Main body We synthesize current knowledge on lactate physiology, including its production, transport, and metabolism across organs. Experimental models and clinical studies data suggest that exogenous lactate, particularly in the form of hypertonic sodium lactate (HSL), improves hemodynamics, reduces inflammation, and enhances organ function in sepsis, acute heart failure, and brain injury. Lactate administration shows promise in restoring metabolic homeostasis, improving microcirculation, and supporting cardiac and cerebral recovery. However, clinical studies in critical care remain limited, largely because lactate is predominantly regarded as a marker of poor prognosis rather than as a potential energy substrate with therapeutic value. Conclusion Lactate-based therapy represents a paradigm shift in the management of critical illness. While preclinical data are promising, larger, well-designed randomized trials are needed to establish its safety, efficacy, and optimal indications. The therapeutic repositioning of lactate could complement or replace current resuscitation fluids and metabolic modulators in intensive care unit (ICU). Keywords Lactate infusion, Critical illness, Sepsis, Heart failure, Brain injury, Metabolism, Resuscitation fluids, Hypertonic sodium lactate *Correspondence: Lionel Tchatat Wangueu Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. Tchatat Wangueu et al. Critical Care (2025) 29:450 Page 2 of 14 Graphical Abstract Introduction In the dynamic landscape of intensive care medicine, researchers and clinicians are continually exploring novel approaches to optimize patient outcomes. Among the emerging therapeutic strategies, the use of lactate has garnered increasing attention for its multifaceted role in cellular metabolism and its potential to serve as a valuable tool in managing critically ill patients [1]. It has traditionally been viewed as a metabolic waste product associated with anaerobic metabolism, and circulating lactate is often a strong predictor of disease severity [2]. However, the production of lactate is not only confined to anaerobic conditions but it is recognized as an energy intermediate, produced in tissues with high glycolytic activity (during exercise for example), which can then be transported throughout the body to be oxidized in other tissues such as skeletal muscle, heart and brain [3–6]. This paradigm shift called “cell-to-cell lactate shuttle”, introduced by Brooks in 2007 [7], has led to a deeper understanding of lactate's therapeutic potential, prompting over the last two decades to both fundamental and clinical trials investigations into its targeted use to improve outcomes, particularly in the intensive care setting [8]. As a crucial component of the bodys energy metabolism, lactate serves not only as a substrate for energy production but also as a signaling molecule with diverse physiological effects such as volume-cell control or pathological effects such as its role in carcinogenesis [9–12]. In critically ill patients, modification in metabolism, including lactate production and utilization, often occurs in response to a variety of stressors, such as inflammation, sepsis, and shock, among others [13]. Both high plasma levels of lactate and poor lactate clearance are associated with prognosis [14], making the reduction of blood levels of lactate a potential therapeutic objective in Tchatat Wangueu et al. Critical Care (2025) 29:450 Page 3 of 14 Physiology Structure, production, transport, shuttle and metabolism Fig. 1 (A) Chemicals structures of lactic acid and lactate acid-base pair. (B) Chemicals structures of acid lactic enantiomere the management of critically ill patients. But beyond this pragmatic approach for monitoring patients, recent studies have highlighted a more nuanced role in the pathophysiology of critical illness [15]. This review reports the current knowledge about lactate as a potential therapeutic in intensive care, examining the underlying mechanisms, clinical evidence, and emerging strategies that harness lactate modulation to enhance the recovery of critically ill patients. Lactate/lactic acid was first isolated from sour milk by the Swedish chemist Carl Wilhelm Scheele, in 1780. It has secondly been described as involved in many biochemical pathways in living organisms, and notably in muscle functioning where accumulating lactate was described as early as in the early nineteenth century [16]. Lactate (C3H5O3−) and lactic acid (C3H5O3− + H+) constitute an acid–base pair with a pkA of 3.90, explaining why lactate constitutes the main form in Humans, under a physiological pH of 7.40. (Fig. 1A). It exists in the form of two enantiomers (Fig. 1B). The levorotatory form [L(+)La −] also call enantiomer S is predominantly produced during glycolysis [17] and is measured in clinical practice. The dextrorotatory form [L(+)La +] is primarily produced by gut bacteria and is found at very low concentrations in healthy and resting individuals (0.2 to less than 0.5 mmol/L) [18, 19], and its measurement has been explored as a marker for the early diagnosis of acute appendicitis or in the spinal fluid during meningitidis [18, 20]. Because the [L(+)La −] exerts (...truncated)