Cardiovascular effects of lactate in healthy adults: D-lactate, the forgotten enantiomer

Abstract

To the Editor

We read with great interest the article by Berg-Hansen et al., which provides valuable insights into the cardiovascular effects of hypertonic sodium lactate (HSL) administration in healthy volunteers [1]. This well-designed crossover study comparing HSL with iso-osmolar hypertonic sodium chloride suggests a benefit of HSL in improving cardiac function. According to the authors, HSL may be an advantageous resuscitation fluid in critically ill patients. However, we would like to focus on one key aspect to better interpret the findings, which is the use of a racemic lactate solution.

When discussing lactate in critical care, reference is made to L-lactate, which is the sole form that is routinely measured (e.g., on arterial blood gases). However, lactate exists as two enantiomers (i.e., non-superimposable mirror images of molecules, Fig. 1.), L-lactate and D-lactate, which differ in their sources, metabolic pathways, and physiological effects [2]. This difference is of paramount importance for clinicians, as L-lactate is easily and rapidly metabolized by the human body, whereas D-lactate is very poorly metabolized and potentially toxic. The human body produces approximately 1500 mmol of L-lactate per day, primarily through glycolysis. The molecule is catabolized via the L-lactate dehydrogenase (L-LDH) enzyme to fuel the Krebs or Cori cycle, leading to glucogenesis, ATP synthesis, and bicarbonate production, leading to alkalinization [3, 4]. Alternatively, the alkalizing effect of HSL can also be explained by the sodium load according to the Stewart model [5]. In contrast, D-lactate is present in negligible amounts in the human body, with plasma concentrations typically within the nanomolar range. The three sources of plasmatic D-lactate are dietary intake, production by gut bacteria, and endogenous production via the methylglyoxal pathway [2]. Unlike L-lactate, D-lactate is poorly catabolized, relying on a non-specific dehydrogenase with variable efficiency across different organs; a fraction of D-lactate is eliminated unchanged in the urine [6]. In therapeutics, exogenous L-lactate administration is a promising treatment. Based on the rationale that L-lactate is an energetic cellular substrate of choice for both the brain and the heart, as it is readily oxidable (unlike glucose), the L-lactate enantiomer has been logically chosen in studies to demonstrate benefits of HSL in pathologies encountered in critical care [4, 7, 8]. In their study, Berg-Hansen et al. chose a racemic HSL solution, meaning that it contains 50% L-lactate and 50% D­lactate. Therefore, not only did healthy volunteers receive only half the dose of lactate that is expected to confer benefits on cardiovascular function but also received large amounts of D-lactate. Even though this study did not suggest any side effects related to the infusion of D-lactate, the administration of exogenous D-lactate should be cautious in critically ill patients [9]. Indeed, as D-lactate is catabolized in the liver and kidneys and excreted in the urine, patients with multiple organ failure could accumulate it significantly, increasing the risk of adverse effects, such as metabolic D-lactic acidosis and/or neurological, cardiac, and leukocyte toxicity [2, 10,11,12]. Even small amounts of exogenous D-lactate could be deleterious in critically ill patients. This has been highlighted by a large retrospective study comparing the outcomes of brain trauma patients based on whether they received Ringer’s DL-lactate, Ringer’s L-lactate, or other lactate-free solutions, which found a significant association between D-lactate administration and both mortality and the need for ventilation. Berg-Hansen et al. observed an alkalizing rather than an acidifying effect of HSL. The absence of acidosis despite the co-administration of D-lactate in the intervention group could mean that the D-lactate blood level did not increase enough to cause acidosis, and/or that the alkalinizing effect of L-lactate catabolism counteracted the acidifying effect of D-lactate accumulation (if any), or that D-lactate by itself is not sufficient to provoke acidosis [2]. This question could have been partially addressed by the blood dosage of D-lactate to determine the degree of accumulation of the latter. However, this result in healthy subjects would not predict D-lactatemia evolution in critically ill patients.

Fig. 1

Structural formula of sodium D and L-lactate. D and L-lactate molecules are enantiomers: their molecular structure are mirror images of each other and are non-superposable. The solid black triangle (D-lactate) means that the oxygen atom projects in front of the plane, while the dotted triangle (L-lactate) means that it projects behind the plane

Full size image

Another unanswered question of the Berg-Hansen’s study is whether HSL-induced improvement in left ventricular contractility is related to direct effects on the cardiomyocytes or to indirect mechanisms related systemic effects of HSL. To avoid such systemic effects, the most relevant experimental model may be the isolated-perfused heart, submitted or not to pathological conditions such as cardiac arrest [13, 14]. Chan et al. used this model to investigate whether cardiac toxicity of racemic HSL administration observed in healthy rats was related or independent to D-lactate induced neurotoxicity. Interestingly, the authors found no effects of racemic HSL on cardiac function in healthy isolated hearts [11]. This highlights the importance for future research of individualizing the systemic from the direct effects of exogenous lactate. It would be also interesting to decipher the respective effects of exogenous D and L-lactate on cardiovascular function.

In conclusion, while the findings of Berg et al. are promising, further investigation is warranted before considering the use of racemic HSL in critically ill patients, to confirm its safety and efficacy in this specific population.

No datasets were generated or analysed during the current study.

HSL:

Hypertonic sodium lactate

1. Berg-Hansen K, Gopalasingam N, Pedersen MGB, Nyvad JT, Rittig N, Søndergaard E, et al. Cardiovascular effects of lactate in healthy adults. Crit Care. 2025;29:30.

   Article PubMed PubMed Central Google Scholar

2. Levitt MD, Levitt DG. Quantitative evaluation of D-lactate pathophysiology: new insights into the mechanisms involved and the many areas in need of further investigation. Clin Exp Gastroenterol. 2020;13:321–37.

   Article CAS PubMed PubMed Central Google Scholar

3. Brooks GA, Arevalo JA, Osmond AD, Leija RG, Curl CC, Tovar AP. Lactate in contemporary biology: a phoenix risen. J Physiol. 2022;600:1229–51.

   Article CAS PubMed Google Scholar

4. Fontaine E, Orban J-C, Ichai C. Hyperosmolar sodium-lactate in the ICU: vascular filling and cellular feeding. Crit Care. 2014;18:599.

   Article PubMed PubMed Central Google Scholar

5. Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol. 1983;61:1444–61.

   Article CAS PubMed Google Scholar

6. Jin S, Chen X, Yang J, Ding J. Lactate dehydrogenase D is a general dehydrogenase for D-2-hydroxyacids and is associated with D-lactic acidosis. Nat Commun. 2023;14:6638.

   Article CAS PubMed PubMed Central Google Scholar

7. Stevic N, Argaud L, Loufouat J, Kreitmann L, Desmurs L, Ovize M, et al. Molar sodium lactate attenuates the severity of postcardiac arrest syndrome: a preclinical study. Crit Care Med. 2022;50:e71–9.

   Article CAS PubMed Google Scholar

8. Annoni F, Su F, Peluso L, Lisi I, Caruso E, Pischiutta F, et al. Hypertonic sodium lactate infusion reduces vasopressor requirements and biomarkers of brain and cardiac injury after experimental cardiac arrest. Crit Care. 2023;27:161.

   Article PubMed PubMed Central Google Scholar

9. Kuwabara K, Hagiwara A, Matsuda S, Fushimi K, Ishikawa KB, Horiguchi H, et al. A community-based comparison of trauma patient outcomes between D- and L-lactate fluids. Am J Emerg Med. 2013;31:206–14.

   Article PubMed Google Scholar

10. Oh MS, Phelps KR, Traube M, Barbosa-Saldivar JL, Boxhill C, Carroll HJ. D-lactic acidosis in a man with the short-bowel syndrome. N Engl J Med. 1979;301:249–52.

    Article CAS PubMed Google Scholar

11. Chan L, Slater J, Hasbargen J, Herndon DN, Veech RL, Wolf S. Neurocardiac toxicity of racemic D, L-lactate fluids. Integr Physiol Behav Sci. 1994;29:383–94.

    Article CAS PubMed Google Scholar

12. Koustova E, Stanton K, Gushchin V, Alam HB, Stegalkina S, Rhee PM. Effects of lactated Ringer’s solutions on human leukocytes. J Trauma. 2002;52:872–8.

    CAS PubMed Google Scholar

13. Bell RM, Mocanu MM, Yellon DM. Retrograde heart perfusion: the Langendorff technique of isolated heart perfusion. J Mol Cell Cardiol. 2011;50:940–50.

    Article CAS PubMed Google Scholar

14. Stevic N, Pinède A, Mewton N, Ovize M, Argaud L, Lecour S, et al. Effect of ventricular fibrillation on infarct size after myocardial infarction: a translational study. Basic Res Cardiol. 2024;119:911–21.

    Article CAS PubMed PubMed Central Google Scholar

Download references

Not applicable.

Not applicable.

Authors and Affiliations

1. Service de Médecine Intensive-Réanimation, Hospices Civils de Lyon, Hôpital Edouard Herriot, 5 Place d’Arsonval, 69437, Lyon Cedex 03, France

   Neven Stevic, Laurent Argaud & Martin Cour

2. Faculté de médecine Lyon-Est, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France

   Neven Stevic, Laurent Argaud & Martin Cour

3. INSERM UMR 1060, CarMeN, IRIS, Lyon, France

   Neven Stevic, Laurent Argaud & Martin Cour

Authors

1. Neven StevicView author publications

   You can also search for this author inPubMed Google Scholar

2. Laurent ArgaudView author publications

   You can also search for this author inPubMed Google Scholar

3. Martin CourView author publications

   You can also search for this author inPubMed Google Scholar

Contributions

N.S. wrote the first draft of the manuscript. L.A. and M.C. contributed to the final version of the manuscript. All the authors approved the final manuscript.

Corresponding author

Correspondence to Neven Stevic.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

Cite this article

Stevic, N., Argaud, L. & Cour, M. Cardiovascular effects of lactate in healthy adults: D-lactate, the forgotten enantiomer. Crit Care 29, 122 (2025). https://doi.org/10.1186/s13054-025-05358-y

Download citation

• Received: 03 March 2025

• Accepted: 06 March 2025

• Published: 19 March 2025

• DOI: https://doi.org/10.1186/s13054-025-05358-y

Share this article

Anyone you share the following link with will be able to read this content:

Get shareable link

Sorry, a shareable link is not currently available for this article.

Copy to clipboard

Provided by the Springer Nature SharedIt content-sharing initiative