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

Matters Arising to this article was published on 23 April 2025

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
figure 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

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.

Availability of data and materials

No datasets were generated or analysed during the current study.

Abbreviations

HSL:

Hypertonic sodium lactate

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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.

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Correspondence to Neven Stevic.

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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

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