Cardiovascular effects of hypertonic lactate solutions: acid-base or metabolic cause, or both? Authors’ reply

Critical Care Berg-Hansen et al. Critical Care (2025) 29:447 https://doi.org/10.1186/s13054-025-05728-6 Open Access M AT T E R S A R I S I N G Cardiovascular effects of hypertonic lactate solutions: acid-base or metabolic cause, or both? Authors’ reply Kristoffer Berg-Hansen1,2*, Mette Glavind Bülow Pedersen3,5,6, Nigopan Gopalasingam1,3,4, Oskar Kjærgaard Hørsdal1,3, Niels Møller3,5,6, Henrik Wiggers1,3 and Roni Nielsen1,3 To the Editor, We read with great interest the recent comment on our publication regarding the cardiovascular effects of lactate [1]. Dr. Jorge and colleagues raise two important concerns about the mechanisms by which hypertonic sodium lactate (HSL) versus hypertonic sodium chloride (SAL) improves hemodynamic function: (1) whether the observed effects primarily reflect acid-base changes, and (2) whether the use of a racemic mixture of D/L-lactate confounds interpretation [2]. These are valid points, and we appreciate the opportunity to clarify the hemodynamic effects associated with HSL. In their commentary, the authors apply Stewart’s physicochemical framework, which describes how changes in the strong ion difference (SID) influence acid-base homeostasis. Dr. Jorge et al. note that the between-group differences in standard base excess reflect an increased SID from lactate metabolism. They therefore propose that the cardiovascular effects we observed stem from acid-base changes rather than lactate itself. In this view, any hypertonic solution expands intravascular volume and increases preload; however, when SID falls, as with This comment refers to the article available online at https://doi.org/ 10.1186/s13054-025-05259-0. This reply refers to the comment available online at https://doi.org/1 0.1186/s13054-025-05463-y. *Correspondence: Kristoffer Berg-Hansen 1 Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N DK-8200, Denmark SAL infusion, hyperchloremic acidosis develops and depresses contractility. By contrast, HSL raises SID, preventing acidosis and supporting cardiac performance during volume expansion. While we acknowledge this reasoning, several points merit clarification. In our study [1], pH was higher during HSL than SAL, but unchanged before versus after SAL infusion, arguing against pH-induced depression of contractility as the explanation for the lower cardiac output with SAL. Reference is made to studies with supraphysiological pH shifts indicating that only extreme alkalosis (pH ≈ 8.0) meaningfully increases contractility, with minimal effects observed at pH ≥ 7.2 [3, 4]. Thus, the between-treatment 0.1-unit pH difference is unlikely to account for the marked cardiovascular differences we observed. Second, direct cardiovascular effects of lactate have been demonstrated under fixed acid-base conditions [5]. In isolated perfused rat hearts, increasing extracellular lactate at constant pH (7.4) significantly enhanced contractility and induced arterial relaxation with venoconstriction. These findings support a direct, physiologically relevant role of lactate, independent 2 Department of Anesthesiology, Horsens Regional Hospital, Horsens, Denmark 3 Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark 4 Department of Cardiology, Gødstrup Hospital, Herning, Denmark 5 Department of Endocrinology and Metabolism, Aarhus University Hospital, Aarhus, Denmark 6 Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark © The Author(s) 2025. 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To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. Berg-Hansen et al. Critical Care (2025) 29:447 of acid-base shifts. Third, our recent porcine crossover study further supports this view, demonstrating increased cardiac output with HSL compared to SAL [6]. During washout, lactate concentrations normalized rapidly, whereas pH and SID showed carryover effects, resulting in persistent hypochloremic metabolic alkalosis despite lactate washout. Importantly, these acid-base changes did not influence cardiac function (Supplemental Material), despite theoretical predictions of a positive inotropic effect [2]. Conversely, hyperchloremic acidosis did not depress myocardial function. In fact, cardiac output consistently paralleled circulating lactate levels, not SID or pH variables. Finally, Dr. Jorge et al. suggest that sodium bicarbonate should serve as a comparator to match both osmolarity and SID. Indeed, a prior study comparing HSL with sodium bicarbonate found similar increases in pH and SID in both groups, yet only HSL improved hemodynamics [7]. In a rodent model of sepsis, HSL was associated with improved hemodynamics, whereas bicarbonate increased mortality [8]. These data again point to lactate itself - whether as an energetic substrate or through pleiotropic signaling - as the principal driver of cardiovascular improvement. Dr. Jorge et al. also note that our racemic HSL formulation does not distinguish the contributions of each isomer, a limitation we acknowledge [9]. Nevertheless, the same racemic solution has consistently produced hemodynamic benefits across animal and human studies [6, 10–12]. While D-lactate may compete with L-lactate for cellular transport and limit its full energetic potential, cardiac performance is unlikely to depend solely on substrate oxidation. Indeed, lactate contributes minimally to total cardiac metabolism [13]. Against this background, enantiomer-specific actions may help explain why racemic HSL remains physiologically relevant. D-lactate may slow L-lactate uptake [14], prolonging its plasma exposure and amplifying the vascular effects of elevated L-lactate, which are stronger than those of D-lactate at fixed pH [5]. Thus, the beneficial effects of HSL likely reflect a combination of mechanisms: the metabolic contribution of L-lactate as an oxidizable substrate together with broader nonmetabolic cardiovascular actions. We concur that future studies using pure L-lactate and matched comparators are warranted. Yet, cur (...truncated)