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Cardiovascular effects of lactate in healthy adults

Critical Care volume 29, Article number: 30 (2025) Cite this article

Matters Arising to this article was published on 23 April 2025

Abstract

Background

Low-volume hypertonic solutions, such as half-molar lactate (LAC), may be a potential treatment used for fluid resuscitation. This study aimed to evaluate the underlying cardiovascular effects and mechanisms of LAC infusion compared to sodium-matched hypertonic sodium chloride (SAL).

Methods

Eight healthy male participants were randomized in a controlled, single-blinded, crossover study. Each participant received a four-hour infusion of LAC and SAL in a randomized order. Assessor-blinded echocardiography and blood samples were performed. The primary endpoint was cardiac output (CO) measured by echocardiography.

Results

During LAC infusion, circulating lactate levels increased by 1.9 mmol/L (95% CI 1.8–2.0 mmol/L, P < 0.001) compared with SAL. CO increased by 1.0 L/min (95% CI 0.5–1.4 L/min, P < 0.001), driven primarily by a significant increase in stroke volume of 11 mL (95% CI 4–17 mL, P = 0.002), with no significant change in heart rate. Additionally, left ventricular ejection fraction improved by 5 percentage points (P < 0.001) and global longitudinal strain by 1.5 percentage points (P < 0.001). Preload indicators were elevated during SAL infusion compared with LAC infusion. Concomitantly, afterload parameters, including systemic vascular resistance and effective arterial elastance, were significantly decreased with LAC infusion compared with SAL, while mean arterial pressure remained similar. Indicators of contractility improved during LAC infusion.

Conclusions

In healthy participants, LAC infusion enhanced cardiac function, evidenced by increases in CO, stroke volume, and left ventricular ejection fraction compared with SAL. Indicators of contractility improved, afterload decreased, and preload remained stable. Therefore, LAC infusion may be an advantageous resuscitation fluid, particularly in patients with cardiac dysfunction.

Clinical trial registrations

https://clinicaltrials.gov/ct2/show/NCT04710875. Registered 1 December 2020.

Introduction

Hospitalized patients with low blood pressure often receive large amounts of intravenous fluids to enhance cardiac output (CO) and improve end-organ perfusion [1]. It remains a clinical challenge to balance hypo- and hypervolemia which both can increase mortality and no consensus exists on the optimal type of intravenous fluid for resuscitation [2, 3]. To minimize fluid overload, the concept of small-volume resuscitation with hypertonic saline has been employed. Low volumes of hypertonic saline can improve CO, vascular tone, and microcirculation [4,5,6] but may also induce hyperchloremia and metabolic acidosis, and thereby renal vasoconstriction and lower glomerular filtration rate [7]. Therefore, the use of other hypertonic crystalloid solutions for fluid resuscitation offers potential advantages, as improved hemodynamic effects are achieved without co-administration of chloride. In this context, hyperosmolar sodium-lactate has emerged as a promising infusion therapy. Studies have demonstrated enhanced end-organ perfusion and CO in acute heart failure and after coronary artery bypass grafting [5, 8, 9]. Despite these promising effects of hyperosmolar sodium-lactate, the physiological basis of the hemodynamic and cardiac effects have not been thoroughly investigated. In the present study, we aimed to investigate the hemodynamic effects and underlying mechanisms of a four-hour half-molar sodium lactate (LAC) infusion compared with hypertonic sodium chloride (SAL) in healthy participants.

Methods

Study design

Eight healthy participants were enrolled in a randomized, controlled, single-blind, crossover study (Fig. 1). This study served as a pre-planned sub-study of a clinical trial aiming to assess the metabolic effects of LAC infusion, with detailed methods and results previously published [10]. Each participant received a four-hour infusion of LAC and SAL in random order on two separate study days, with a minimum interval of 14 days between the sessions. Apart from the interventions, both study days followed identical protocols.

Fig. 1
figure 1

Study design. A randomized, double-blind, controlled cross-over trial in eight participants investigated at two study visits separated by ≥ 14 days washout period. At the first visit, participants were randomized to receive an intravenous infusion of either weight-adjusted half-molar sodium lactate (LAC) infusion or hypertonic sodium chloride (SAL). At the second visit, participants received the opposite treatment compared with the first visit. Serial echocardiographic evaluation and blood samples were collected before the infusion and at 60, 120, and 240 min during infusion

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Participants were instructed to avoid strenuous physical activity, alcohol, and maintain a regular diet for 48 h before each study day. They also fasted for 10 h prior to the study and arrived at the research lab by bus, car, or taxi to minimize physical exertion. Upon arrival, participants rested in bed throughout the study day. A peripheral venous catheter was inserted into the cubital vein for blood sampling. All participants were positioned in the supine position for a minimum of 10 min prior to each measurement. Echocardiography and blood samples were collected at baseline and 60, 120, and 240 min during both LAC and SAL infusions. The main study utilized a hyperinsulinemic-euglycemic clamp (HEC) to study the insulin sensitivity during LAC compared with SAL; these results have been reported [10]. The HEC was initiated at 180 min during each treatment [10]. Thus, measurements at 240 min in the present study were performed during the HEC. Specifically, 0.6 mU/kg/min insulin (Actrapid, Novo Nordisk, Denmark) was continuously infused in parallel with 20% glucose which was titrated to maintain a constant glucose level of 5 mmol/L. Fluid intake and urine output were recorded throughout the study visits.

The study was conducted at Aarhus University Hospital, Aarhus, Denmark, between March and June 2021, and was approved by the Ethics Committee of the Central Denmark Region. The study adhered to the CONSORT reporting guidelines.

Participants

Eight healthy participants were included in the study. The inclusion criteria were male sex, age ≥ 18 years, and body mass index between 18 and 30 kg/m2. Exclusion criteria included the daily use of medication, any abnormalities in routine screening blood tests, or the presence of acute or chronic diseases, including known heart disease.

Interventions

The LAC infusion consisted of a racemic sodium lactate mixture (Monico, S.P.A, Italy) containing 45 g of lactate per liter, equivalent to 0.5 mol/L (Supplementary file). During the initial 30 min, a bolus was administered at a rate of 50 μmol/kg/minute, followed by a continuous infusion of 25 μmol/kg /minute for the remaining 210 min. Dosing was based on actual body weight. The control was a sodium-matched hypertonic sodium chloride solution (SAL), infused at the same volumes as the LAC infusion.

Endpoints

The pre-planned primary endpoint was mean change in CO during the four-hour LAC infusion and SAL infusion. The secondary endpoints included SV, LVEF, global longitudinal strain (GLS), effective arterial elastance (Ea), and systemic vascular resistance (SVR).

Transthoracic echocardiography

Blood pressure (BP) and heart rate (HR) were measured non-invasively. All transthoracic echocardiographic data were acquired by an experienced echocardiographer using a 3.5-MHz transducer on a GE Vivid E95 system (GE Healthcare, USA) and analyzed with EchoPAC software (version 206, GE-Vingmed Ultrasound, Norway). The analysis was performed by another assessor who was blinded to the order of randomization. All parameters were calculated as the mean of three cardiac cycles. CO was estimated as the LV outflow tract (LVOT) area multiplied by the LVOT velocity time integral and HR. The LVOT area was derived from the LVOT diameter in the parasternal long-axis view during the first exam. The LVOT velocity time integral was measured using pulsed wave Doppler from the LVOT in the apical five-chamber view. Right atrial pressure was estimated based on inferior vena cava diameter and the respiratory variability [11]. Mean arterial blood pressure (MAP), systemic vascular resistance (SVR = [MAP-right atrial pressure]/CO), and effective arterial elastance (Ea = 0.9 × [systolic BP]/SV) were calculated [12]. End-systolic elastance (Ees) was estimated using the modified single-beat method [13]. Also, preload-independent measures of LV contractility were estimated, including LV stroke work normalized to LVEDV (LVSW/EDV) and preload recruitable stroke work (PRSW) [14, 15]. Systolic pulmonary artery pressure was estimated from the peak systolic velocity of tricuspid regurgitation using continuous-wave Doppler and applying the modified Bernoulli equation, with the addition of the estimated right atrial pressure. [16]

LV end-diastolic (LVEDV) and end-systolic (LVESV) volumes and LVEF were assessed using the Simpson biplane method from apical views, and GLS was obtained from the three apical views: four-chamber, two-chamber, and apical long-axis projections [17]. LV myocardial work parameters, including global wasted and constructive work, as well as global work efficiency and index, were calculated from the three apical views as previously described [18]. Early (E) and late (A) diastolic mitral inflow velocities were measured, and tissue Doppler imaging from the apical view was used to obtain septal and lateral early diastolic mitral plane tissue velocity (e') and peak systolic velocity (s'). Left atrial volume was calculated using the Simpson biplane method, and left atrial (LA) reservoir, conduit, and contractile strain was assessed from the two apical views (four-chamber and two-chamber projections) [19]. Right ventricular (RV) free wall longitudinal strain, tricuspid annular peak systolic velocity (RV S’), and tricuspid annular plane systolic excursion (TAPSE) were measured from an RV-focused apical view. [20]

Blood samples

Venous pH, potassium, sodium, chloride, glucose, hematocrit, bicarbonate, pCO2, and lactate were analyzed immediately following venous blood gas sampling (ABL90 FLEX PLUS, Radiometer, Denmark).

Statistical methods

Participant characteristics are presented as medians with interquartile ranges. A linear mixed model was employed to compare the effects of LAC infusion with SAL infusion. Treatment and treatment-by-time interaction were defined as fixed effects, while participants were treated as random effects. P-values were derived from least-squares means analysis of the linear mixed models. Residuals were assessed for normality and homoscedasticity, with log-transformations applied if necessary. The effect size of LAC compared to SAL is reported as the pairwise mean difference with a 95% confidence interval. Statistical significance was defined as P < 0.05. All data analyses, tables, and figures were generated using R software (version 2022.02.3, Build 492; R Core Team (2022); R Foundation for Statistical Computing, Vienna, Austria). The first authors had full access to all study data and are responsible for its integrity and analysis. Data supporting the study findings are available from the corresponding author upon reasonable request.

Results

Eight participants completed the study. The median age was 26 years (interquartile range 23–29 years), the median body weight was 78 kg (interquartile range 72–88 kg), and the median body mass index was 23.0 kg/m2 (interquartile range 20.6–26.7 kg/m2). All participants were white.

Hemodynamic effects of LAC infusion

LAC infusion increased circulating lactate from 0.9 ± 0.3 to 2.5 ± 0.8 mmol/L during the four-hour treatment period (SAL-adjusted difference: 1.9 mmol/L, 95% CI 1.8–2.0 mmol/L, P < 0.001; Table 1 and Fig. 2), as previously reported [10]. This was associated with a significant increase in CO, with a SAL-adjusted difference of 1.0 L/min (95% CI 0.5–1.4 L/min, P < 0.001). The increase in CO was largely driven by an increased SV (SAL-adjusted difference: 11 mL, 95% CI 4–17 mL, P = 0.002), while HR did not differ significantly between treatments. MAP remained similar between the treatments. The CO and SV responses to the HEC were more pronounced during SAL infusion compared with LAC (Fig. 2).

Table 1 Hemodynamic parameters
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Fig. 2
figure 2

Effect of each treatment on circulating lactate and hemodynamic parameters. Measurements during infusion with half-molar sodium lactate (LAC) infusion and hypertonic sodium chloride (SAL). Time = 0 indicates baseline before infusion. A Treatment with LAC significantly increased circulating lactate through the four-hour study period. This was associated with B a significant increase in cardiac output (CO) and C stroke volume. Meanwhile, D heart rate did not differ significantly. E Left ventricular ejection fraction (LVEF) and F left ventricular global longitudinal strain (LV-GLS) improved. Data are shown as mean, with bars indicating SEM. † indicates P < 0.05 between treatments at a given time point

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Preload parameters were generally elevated during SAL infusion compared with LAC. LA volume was significantly higher during SAL infusion and a similar trend was apparent for LVEDV (Table 2 and Fig. 3). This corroborated with increasing E/e´ during SAL infusion, with significantly higher levels at 240 min. Furthermore, systolic BP and estimated sPAP were significantly elevated during treatment with SAL compared with LAC. Meanwhile, the afterload parameters SVR and Ea were reduced during LAC treatment compared with SAL. Finally, treatment with LAC significantly increased the contractility measures LVSW/EDV (P = 0.005) and PRSW (P = 0.031) compared with SAL, while Ees remained similar between treatments (P = 0.234). Overall fluid intake was similar during both treatments (Table 3). Also, there was no between-treatment difference in urine output.

Table 2 Echocardiographic parameters
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Fig. 3
figure 3

Effect of each treatment on cardiac parameters. Measurements during infusion with half-molar sodium lactate (LAC) infusion and hypertonic sodium chloride (SAL). Time = 0 indicates baseline before infusion. A–C Preload parameters left ventricular end-diastolic volume (LVEDV), left atrial (LA) volume, and ratio of early (E) diastolic mitral inflow velocity and early diastolic mitral plane tissue velocity (e’) remained lower during LAC compared with SAL infusion. D–F Systolic blood pressure (sBP) remained lower during LAC compared with SAL infusion and systemic vascular resistance (SVR) and arterial elastance (Ea) were significantly reduced during LAC infusion. G–I Contractility measures preload recruitable stroke work (PRSW) and left ventricular stroke work normalized to end-diastolic volume (LVSW/EDV) were increased during LAC infusion, while end-systolic elastance (Ees) did not differ significantly. Data are shown as mean, with bars indicating SEM. † indicates P < 0.05 between treatments at a given time point

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Table 3 Fluid intake and output
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Effects of LAC infusion on cardiac function

LAC infusion increased LVEF by 5 percentage points (95% CI: 3 to 8 percentage points, P < 0.001) and GLS by 1.5 percentage points (95% CI 0.7–2.2 percentage points, P < 0.001) compared with SAL (Table 2 and Fig. 3). Thus, LVESV was reduced by 10 mL (95% CI − 17 to − 4 mL, P = 0.002). LV S’max was also increased during LAC infusion (P = 0.002). There was no difference in LV myocardial work parameters. In terms of diastolic function, the E/A-ratio was lower during LAC treatment compared with SAL. LA strain parameters remained similar between treatments. TAPSE was increased during LAC infusion, while RV S’max and free wall LS did not differ between treatments (Table 4).

Table 4 Biomarkers
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Changes in acid–base parameters and electrolytes

Treatment with LAC increased pH and bicarbonate compared with SAL. The pCO2 did not differ between treatments. Both treatments increased sodium levels; however, SAL treatment increased sodium levels more than LAC. SAL also caused a significant increase in chloride levels compared with LAC. Calcium and potassium levels were reduced during LAC treatment compared with SAL.

Discussion

The main finding of this study was that infusion with LAC infusion increased cardiac function compared to the sodium-matched SAL through a four-hour period. LAC improved CO by 20% (i.e., 1.0 L/min) and LVEF by 5 percentage points. A higher SV rather than HR was primarily responsible for the increase in CO. MAP remained constant while other indices of afterload were reduced, and indices of contractility were improved. LAC infusion did not increase measures of preload compared to saline. Therefore, LAC infusion provides potential beneficial hemodynamic effects beyond mere volume expansion.

Increasing circulating lactate presents a promising therapeutic option for cardiovascular distress [21]. Lactate is a metabolite that serves as a fuel source for myocardial energy production. In the healthy, resting heart, the contribution of lactate to myocardial ATP production is limited, with the main fuel source being fatty acids [22]. However, myocardial lactate oxidation can increase significantly with elevated supply [23], and lactate consumption correlates with circulating levels [24, 25]. As an oxidative fuel source, lactate infusion offers a potential means to optimize cardiac energy metabolism during cardiovascular distress [26]. This corroborates with beneficial hemodynamic effects of lactate in patients with acute decompensated heart failure and in the post-operative period after cardiac surgery [5, 9]. Additionally, lactate treatment has demonstrated beneficial cardiovascular effects in animal models of cardiovascular disarray, supporting its potential as an effective resuscitation fluid with favorable hemodynamic properties [27,28,29,30,31]. The cardiovascular effects of SAL and LAC infusions have been compared in healthy volunteers, where both infusions equally improved CO and LVEF by increasing preload [32]. However, hemodynamic assessments in that study were conducted after only 30 min of infusion, potentially limiting the ability to fully capture the beneficial effects of LAC infusion.

In this study, LAC infusion significantly enhanced CO and LV systolic function compared to a sodium-matched control solution. Importantly, these improvements were not attributed to increased preload, as LVEDV, LA volume, and E/e´ remained unchanged, and both treatments involved similar volumes of intravenous fluid. During SAL infusion a rise in preload parameters was recorded, particularly at the 240-min mark (during HEC) when additional intravenous fluid was given, though in similar amounts to the LAC infusion. This likely explains the modest SAL-induced increase in CO through Frank-Starling mechanisms, along with Bainbridge reflex activation during hypertonic fluid administration, as evidenced by a similar increase in HR between LAC and SAL. Additionally, the 60-min HEC clamp could influence cardiovascular function under fasting conditions, particularly during SAL infusion, by providing additional myocardial substrate via insulin-driven glycolysis [33]. This enhanced glycolysis may increase pyruvate availability in the SAL group, although in the LAC group, pyruvate production was already elevated due to lactate metabolism, potentially explaining the more pronounced cardiovascular response to the HEC observed with SAL. Interestingly, while lactate may cause arterial vasorelaxation and venoconstriction in isolated vessels [34,35,36], it may also enhance contractility [9, 31]. This aligns with the physiological role of lactate in promoting forward flow to support organ perfusion during distress. The combination of stable preload, decreased afterload, and indices of increased contractility suggests an efficient cardiovascular adaptation with a resultant improvement in CO. These findings all highlight the potential therapeutic value of LAC in optimizing cardiac performance.

Hypertonic solutions can raise systolic blood pressure by increasing intravascular volume through osmotic shifts [4,5,6], enhancing preload and stroke volume. The Bainbridge effect further elevates HR in response to increased venous return. While these effects may improve perfusion pressure, they also raise the cardiac rate-pressure product, thereby increasing energy demands, which could impair cardiac function during periods of distress. Indeed, SAL infusion raised systolic blood pressure and estimated sPAP, increasing biventricular afterload. In contrast, LAC infusion maintained stable systolic pressure while lowering sPAP. Additionally, SVR and Ea were significantly reduced during LAC treatment, reflecting a beneficial decrease in afterload despite equivalent fluid administration in both groups. This fits with unaltered measures of myocardial work despite an increase in CO, indicating no adverse increase in myocardial energy metabolism [18]. These findings support previous data demonstrating a vasodilatory effect of lactate [36]. Finally, treatment with LAC may exert direct cardiac effects to improve contractile function, as evident by improvement in the less load-independent measures of contractility. As such, the underlying mechanisms driving CO enhancement are multifaceted and intricately interconnected within the complex constraints of the cardiovascular system.

Safety issues

LAC infusion caused no adverse events in the present study. Previous studies have investigated lactate administration above 10 mmol/L without causing adverse effects [37, 38]. Others have demonstrated safety of 24 h of administration in patients with decompensated heart failure [5]. Future studies with prolonged treatment are required to further investigate the safety profile of LAC treatment.

Limitations

This study included only healthy, lean men, which limits its generalizability of our findings to women and populations with altered substrate metabolism. The crossover design minimized interindividual variation but posed a potential for carryover effects, which we addressed by implementing a significant washout period between visits. Moreover, the linear mixed model adjusted for treatment order and period effects and revealed no significant interactions. We used sodium-matched saline as a control to avoid confounding due to osmolality. Although hypertonic sodium chloride and sodium-lactate solutions have similar osmolarity, their effect on tonicity may differ due to lactate metabolism. This difference in tonicity can influence physiological responses beyond lactate oxidation through chloride-related mechanisms. SAL may increase extracellular tonicity and volume, potentially mitigating the relative LAC-induced cardiovascular effects in our study [39, 40]. Furthermore, SAL infusion may cause hyperchloremic acidosis, which we, however, did not observe, whereas LAC infusion induces mild metabolic alkalosis [5, 32, 36], similar to the effects of other monocarboxylates [41,42,43]. Nonetheless, studies comparing LAC to bicarbonate have shown superior improvements in CO during LAC infusion [27], and the vasodilatory effect of LAC seems to be independent of intracellular pH [44]. Thus, pH alterations are unlikely to account for the prominent cardiovascular effects observed in our study. While we did not measure levels of circulating catecholamines, previous studies did not demonstrate any effect of lactate on metanephrine levels [45, 46]. Also, we did not measure cardiac biomarkers, although these markers are expected to be normal in this cohort.

Conclusion

LAC infusion demonstrated significant cardiovascular benefits, enhancing CO and SV, improving systolic function, and reducing afterload, while maintaining stable preload parameters. These findings suggest that LAC may be a superior resuscitation fluid, particularly in patients with impaired cardiac function.

Data availability

Data supporting this work will be shared upon reasonable request to the corresponding author.

Abbreviations

BP:

Blood pressure

CO:

Cardiac output

E/A:

Ratio of early (E) and late (A) diastolic mitral in-flow velocity

Ea:

Arterial elastance

Ees:

End-systolic elastance

e':

Early diastolic mitral plane tissue velocity

GLS:

Global longitudinal strain

LAC:

Half-molar sodium lactate

LA:

Left atrial

LV:

Left ventricle

LVEDP:

Left ventricular end-diastolic pressure

LVEDV:

Left ventricular end-diastolic volume

LVOT:

Left ventricular outflow tract

LVSW:

Left ventricular stroke work

PRSW:

Preload recruitable stroke work

SAL:

Hypertonic sodium chloride

S’max:

Peak systolic velocity

sPAP:

Systolic pulmonary artery pressure

SV:

Stroke volume

SVR:

Systemic vascular resistance

TAPSE:

Tricuspid annular plane systolic excursion

References

  1. Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, Mcintyre L, Ostermann M, Prescott HC, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47:1181–247. https://doiorg.publicaciones.saludcastillayleon.es/10.1007/s00134-021-06506-y.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Acheampong A, Vincent JL. A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit Care. 2015;19:1–7. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13054-015-0970-1.

    Article  Google Scholar 

  3. Boyd JH, Forbes J, Nakada T, Walley KR, Russell JA. Fluid resuscitation in septic shock: A positive fluid balance and elevated central venous pressure are associated with increased mortality*. Crit Care Med. 2011;39:259.

    Article  PubMed  Google Scholar 

  4. Belba MK, Petrela EY, Belba GP. Comparison of hypertonic vs isotonic fluids during resuscitation of severely burned patients. Am J Emerg Med. 2009;27:1091–6. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.ajem.2008.08.008.

    Article  PubMed  Google Scholar 

  5. Nalos M, Leverve XM, Huang SJ, Weisbrodt L, Parkin R, Seppelt IM, Ting I, Mclean AS. Half-molar sodium lactate infusion improves cardiac performance in acute heart failure: A pilot randomised controlled clinical trial. Crit Care. 2014;18:1–9. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/cc13793.

    Article  Google Scholar 

  6. van Haren FMP, Sleigh J, Boerma EC, La Pine M, Bahr M, Pickkers P, van der Hoeven JG. Hypertonic fluid administration in patients with septic shock: a prospective randomized controlled pilot study. Shock. 2012;37:268–75. https://doiorg.publicaciones.saludcastillayleon.es/10.1097/SHK.0b013e31823f152f.

    Article  CAS  PubMed  Google Scholar 

  7. N.M. Y, R. B, D. S, J. K. Bench-to-bedside review: Chloride in critical illness. Crit Care 2010;14:1–10.

  8. Leverve XM, Mustafa I. Lactate: a key metabolite in the intercellular metabolic interplay. 2002;6:17–9.

    Google Scholar 

  9. Leverve XM, Boon C, Hakim T, Anwar M, Siregar E, Mustafa I. Half-molar sodium-lactate solution has a beneficial effect in patients after coronary artery bypass grafting. Intensive Care Med. 2008;34:1796–803. https://doiorg.publicaciones.saludcastillayleon.es/10.1007/s00134-008-1165-x.

    Article  CAS  PubMed  Google Scholar 

  10. Pedersen MGB, Rittig N, Bangshaab M, Berg-Hansen K, Gopalasingam N, Gormsen LC, Søndergaard E, Møller N. Effects of exogenous lactate on lipid, protein, and glucose metabolism—A randomized crossover trial in healthy males. Am J Physiol Endocrinol Metab. 2024;326:E443–53. https://doiorg.publicaciones.saludcastillayleon.es/10.1152/ajpendo.00301.2023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, Solomon SD, Louie EK, Schiller NB. Guidelines for the Echocardiographic Assessment of the Right Heart in Adults: A Report from the American Society of Echocardiography. Endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and. J Am Soc Echocardiogr 2010;23:685–713. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.echo.2010.05.010.

  12. Lam CSP, Roger VL, Rodeheffer RJ, Bursi F, Borlaug BA, Ommen SR, Kass DA, Redfield MM. Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation. 2007;115:1982–90. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/CIRCULATIONAHA.106.659763.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Chen CH, Fetics B, Nevo E, Rochitte CE, Chiou KR, Ding PYA, Kawaguchi M, Kass DA. Noninvasive single-beat determination of left ventricular end-systolic elastance in humans. J Am Coll Cardiol. 2001;38:2028–34. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/S0735-1097(01)01651-5.

    Article  CAS  PubMed  Google Scholar 

  14. Borlaug BA, Koepp KE, Melenovsky V. Sodium nitrite improves exercise hemodynamics and ventricular performance in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2015;66:1672–82. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jacc.2015.07.067.

    Article  CAS  PubMed  Google Scholar 

  15. Lee WS, Huang WP, Yu WC, Chiou KR, Yu-An Ding P, Chen CH. Estimation of preload recruitable stroke work relationship by a single-beat technique in humans. Am J Physiol - Hear Circ Physiol. 2003;284:744–50. https://doiorg.publicaciones.saludcastillayleon.es/10.1152/ajpheart.00455.2002.

    Article  Google Scholar 

  16. Currie PJ, Seward JB, Chan KL, Fyfe DA, Hagler DJ, Mair DD, Reeder GS, Nishimura RA, Tajik AJ. Continuous wave Doppler determination of right ventricular pressure: a simultaneous Doppler-catheterization study in 127 patients. J Am Coll Cardiol. 1985;6:750–6. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/s0735-1097(85)80477-0.

    Article  CAS  PubMed  Google Scholar 

  17. Lang RM, Badano LP, Victor MA, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28:1-39.e14. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.echo.2014.10.003.

    Article  PubMed  Google Scholar 

  18. Russell K, Eriksen M, Aaberge L, Wilhelmsen N, Skulstad H, Remme EW, Haugaa KH, Opdahl A, Fjeld JG, Gjesdal O, et al. A novel clinical method for quantification of regional left ventricular pressurestrain loop area: a non-invasive index of myocardial work. Eur Heart J. 2012;33:724–33. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/eurheartj/ehs016.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Pathan F, Elia ND, Nolan MT, Marwick TH. Normal ranges of left atrial strain by speckle-tracking echocardiography: a systematic review and meta-analysis. J Am Soc Echocardiogr. 2022;30:59-70.e8. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.echo.2016.09.007.

    Article  Google Scholar 

  20. Mitchell C, Rahko PS, Blauwet LA, Canaday B, Finstuen JA, Foster MC, Horton K, Ogunyankin KO, Palma RA, Velazquez EJ. Guidelines for performing a comprehensive transthoracic echocardiographic examination in adults: recommendations from the American Society of Echocardiography. J Am Soc Echocardiogr. 2019;32:1–64. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.echo.2018.06.004.

    Article  PubMed  Google Scholar 

  21. Brooks GA, Arevalo JA, Osmond AD, Leija RG, Curl CC, Tovar AP. Lactate in contemporary biology: a phoenix risen 1. J Physiol. 2021. https://doiorg.publicaciones.saludcastillayleon.es/10.1113/jp280955.

    Article  PubMed  Google Scholar 

  22. Murashige D, Jang C, Neinast M, Edwards JJ, Cowan A, Hyman MC, Rabinowitz JD, Frankel DS, Arany Z. Comprehensive quantification of fuel use by the failing and nonfailing human heart. Science (80-). 2020;370:364–8. https://doiorg.publicaciones.saludcastillayleon.es/10.1126/science.abc8861.

    Article  CAS  Google Scholar 

  23. Stanley WC. Myocardial lactate metabolism during exercise. Med Sci Sports Exerc. 1991;23:920–4.

    Article  CAS  PubMed  Google Scholar 

  24. Gertz EW, Wisneski JA, Neese R, Bristow JD, Searle GL, Hanlon JT. Myocardial lactate metabolism: evidence of lactate release during net chemical extraction in man. Circulation. 1981;63:1273–9. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.cir.63.6.1273.

    Article  CAS  PubMed  Google Scholar 

  25. Gertz EW, Wisneski JA, Stanley WC, Neese RA. Myocardial substrate utilization during exercise in humans. Dual carbon-labeled carbohydrate isotope experiments. J Clin Invest. 1988;82:2017–25. https://doiorg.publicaciones.saludcastillayleon.es/10.1172/JCI113822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lopaschuk GD, Karwi QG, Tian R, Wende AR, Abel ED. Cardiac energy metabolism in heart failure. Circ Res. 2021;128:1487–513. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/CIRCRESAHA.121.318241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Duburcq T, Favory R, Mathieu D, Hubert T, Mangalaboyi J, Gmyr V, Quintane L, Maboudou P, Pattou F, Jourdain M. Hypertonic sodium lactate improves fluid balance and hemodynamics in porcine endotoxic shock. 2014;18:1–11. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13054-014-0467-3.

    Article  Google Scholar 

  28. Duburcq T, Durand A, Dessein A, Vamecq J, Vienne J, Dobbelaere D, Mention K, Douillard C, Maboudou P, Gmyr V, et al. Comparison of fluid balance and hemodynamic and metabolic effects of sodium lactate versus sodium bicarbonate versus 0 . 9 % NaCl in porcine endotoxic shock: a randomized, open-label, controlled study 2017:1–9. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13054-017-1694-1.

  29. Kline JA, Thornton LR, Lopaschuk GD, Barbee RW, Watts JA. Lactate improves cardiac efficiency after hemorrhagic shock. Shock. 2000;14:215–21. https://doiorg.publicaciones.saludcastillayleon.es/10.1097/00024382-200014020-00023.

    Article  CAS  PubMed  Google Scholar 

  30. Besnier E, Coquerel D, Kouadri G, Clavier T, Favory R, Duburcq T, Lesur O, Bekri S, Richard V, Mulder P, et al. Hypertonic sodium lactate improves microcirculation, cardiac function, and inflammation in a rat model of sepsis. Crit Care. 2020;24:1–11. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13054-020-03083-2.

    Article  Google Scholar 

  31. Stevic N, Argaud L, Loufouat J, Kreitmann L, Desmurs L, Ovize M, Bidaux G, Cour M. Molar sodium lactate attenuates the severity of postcardiac arrest syndrome: a preclinical study. Crit Care Med. 2022;50.

  32. Nalos M, Kholodniak E, Smith L, Orde S, Ting I, Slama M, Seppelt I, McLean AS, Huang S. The comparative effects of 3% saline and 0.5M sodium lactate on cardiac function: a randomised, crossover study in volunteers. Crit Care Resusc. 2018;20:124–30.

    PubMed  Google Scholar 

  33. Sasso FC, Carbonara O, Cozzolino D, Rambaldi P, Mansi L, Torella D, Gentile S, Turco S, Torella R, Salvatore T. Effects of insulin-glucose infusion of left ventricular function at rest and during dynamic exercise in healthy subjects and noninsulin dependent diabetic patients. J Am Coll Cardiol. 2000;36:219–26. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/S0735-1097(00)00717-8.

    Article  CAS  PubMed  Google Scholar 

  34. Montoya JJ, Fernández N, Monge L, Diéguez G, Villalón ALG. Nitric oxide-mediated relaxation to lactate of coronary circulation in the isolated perfused rat heart. J Cardiovasc Pharmacol. 2011;58:392–8. https://doiorg.publicaciones.saludcastillayleon.es/10.1097/FJC.0b013e318226bcf7.

    Article  CAS  PubMed  Google Scholar 

  35. McKinnon W, Aaronson PI, Knock G, Graves J, Poston L. Mechanism of lactate-induced relaxation of isolated rat mesenteric resistance arteries. J Physiol. 1996;490(Pt 3):783–92. https://doiorg.publicaciones.saludcastillayleon.es/10.1113/jphysiol.1996.sp021186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hørsdal OK, Moeslund N, Berg-Hansen K, Nielsen R, Møller N, Eiskjær H, Wiggers H, Gopalasingam N. Lactate infusion elevates cardiac output through increased heart rate and decreased vascular resistance: a randomised, blinded, crossover trial in a healthy porcine model. J Transl Med. 2024;22:1–14. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12967-024-05064-3.

    Article  CAS  Google Scholar 

  37. Mustafa I, Leverve XM. Metabolic and hemodynamic effects of hypertonic solutions: Sodium-lactate versus sodium chloride infusion in postoperative patients. Shock. 2002;18:306–10. https://doiorg.publicaciones.saludcastillayleon.es/10.1097/00024382-200210000-00003.

    Article  PubMed  Google Scholar 

  38. Dager SR, Marro KI, Richards TL, Metzger GD. Localized magnetic resonance spectroscopy measurement of brain lactate during intravenous lactate infusion in healthy volunteers. Life Sci. 1992;51:973–85. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/0024-3205(92)90404-d.

    Article  CAS  PubMed  Google Scholar 

  39. Mouren S, Delayance S, Mion G, Souktani R, Fellahi JL, Arthaud M, Baron JF, Viars P. Mechanisms of increased myocardial contractility with hypertonic saline solutions in isolated blood-perfused rabbit hearts. Anesth Analg. 1995;81:777–82. https://doiorg.publicaciones.saludcastillayleon.es/10.1097/00000539-199510000-00021.

    Article  CAS  PubMed  Google Scholar 

  40. Pfortmueller CA, Schefold JC. Hypertonic saline in critical illness - A systematic review. J Crit Care. 2017;42:168–77. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jcrc.2017.06.019.

    Article  CAS  PubMed  Google Scholar 

  41. Gopalasingam N, Christensen KH, Berg Hansen K, Nielsen R, Johannsen M, Gormsen LC, Boedtkjer E, Nørregaard R, Møller N, Wiggers H. Stimulation of the hydroxycarboxylic acid receptor 2 with the ketone body 3-hydroxybutyrate and niacin in patients with chronic heart failure: hemodynamic and metabolic effects. J Am Heart Assoc. 2023;12:1–13. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/jaha.123.029849.

    Article  CAS  Google Scholar 

  42. Berg-Hansen K, Christensen KH, Gopalasingam N, Nielsen R, Eiskjær H, Møller N, Birkelund T, Christensen S, Wiggers H. Beneficial effects of ketone ester in patients with cardiogenic shock: a randomized, controlled, double-blind trial. JACC Hear Fail. 2023;11:1337–47. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jchf.2023.05.029.

    Article  CAS  Google Scholar 

  43. Gopalasingam N, Moeslund N, Christensen KH, Berg-Hansen K, Seefeldt J, Homilius C, Nielsen EN, Dollerup MR, Alstrup Olsen AK, Johannsen M, et al. Enantiomer-specific cardiovascular effects of the ketone body 3-hydroxybutyrate. J Am Heart Assoc. 2024;13: e033628. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/JAHA.123.033628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Smith GL, Austin C, Crichton C, Wray S. A review of the actions and control of intracellular pH in vascular smooth muscle. Cardiovasc Res. 1998;38:316–31. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/S0008-6363(98)00020-0.

    Article  CAS  PubMed  Google Scholar 

  45. Richter J, Rabe D, Duysen K, Melchert UH, Oltmanns KM. Lactate infusion increases brain energy content during euglycemia but not hypoglycemia in healthy men. NMR Biomed. 2019;32: e4167. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/nbm.4167.

    Article  PubMed  Google Scholar 

  46. Maran A, Crepaldi C, Trupiani S, Lucca T, Jori E, Macdonald IA, Tiengo A, Avogaro A, Del Prato S. Brain function rescue effect of lactate following hypoglycaemia is not an adaptation process in both normal and type I diabetic subjects. Diabetologia. 2000;43:733–41. https://doiorg.publicaciones.saludcastillayleon.es/10.1007/s001250051371.

    Article  CAS  PubMed  Google Scholar 

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Funding

Novo Nordisk Foundation—Tandem (NNF19OC0055002). The study was also supported by Aarhus University, the Independent Research Fund Denmark (Grant no. 8020-00120A, 0134-00043B), the Novo Nordisk Foundation (Grant no. NNF17OC0028230), the Lundbeck Foundation (Grant no. R231-2016-2716) and the Danish Heart Foundation (19-R135-A9280-22126).

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Author notes

  1. Kristoffer Berg-Hansen and Nigopan Gopalasingam contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark

    Kristoffer Berg-Hansen, Nigopan Gopalasingam, Henrik Wiggers & Roni Nielsen

  2. Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark

    Kristoffer Berg-Hansen, Nigopan Gopalasingam, Mette Glavind Bülow Pedersen, Nikolaj Rittig, Esben Søndergaard, Henrik Wiggers, Niels Møller & Roni Nielsen

  3. Department of Cardiology, Gødstrup Hospital, Herning, Denmark

    Nigopan Gopalasingam & Jakob Tobias Nyvad

  4. Department of Endocrinology and Metabolism, Aarhus University Hospital, Aarhus, Denmark

    Mette Glavind Bülow Pedersen, Nikolaj Rittig, Esben Søndergaard & Niels Møller

  5. Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark

    Mette Glavind Bülow Pedersen, Nikolaj Rittig & Esben Søndergaard

Authors
  1. Kristoffer Berg-Hansen
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Contributions

KBH, NG, MGBP, NR, ES, NM drafted the protocol. KBH, NG, and RN drafted the manuscript. MGBP recruited patients and MGBP, KBH, and NG performed the investigations. JTN, KBH, and NG analyzed the data. KBH, NG, MGBP, NR, JTN, ES, NM, HW, RN contributed to designing the study, interpreting the data, and writing the manuscript. All authors contributed considerable in revising the manuscript and approved the final version.

Corresponding author

Correspondence to Kristoffer Berg-Hansen.

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Competing interests

Roni Nielsen has collaboration with the pharceutical companies Imbria, Medtrace, Resother as an investigation and has received lectural fee from Astrazeneca. Roni Nielsen is a patentholder of 20205938.2 A Lactate/Ketone Body ester, 5-11-2020. Henrik Wiggers has been the principal or a sub-investigator in studies involving the following pharmaceutical companies: MSD, Bayer, Daiichi-Sankyo, Novartis, Novo Nordisk, Sanofi-Aventis, and Pfizer.

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Berg-Hansen, K., Gopalasingam, N., Pedersen, M.G.B. et al. Cardiovascular effects of lactate in healthy adults. Crit Care 29, 30 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13054-025-05259-0

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Keywords

Critical Care

ISSN: 1364-8535