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Lactate infusion improves cardiac function in a porcine model of ischemic cardiogenic shock

Critical Care volume 29, Article number: 113 (2025) Cite this article

Abstract

Background

Cardiogenic shock (CS) is associated with high mortality and medical therapies have failed to improve survival. Treatment with lactate is associated with improved cardiac function which may benefit this condition. Comprehensive hemodynamic assessment of lactate administration in CS is lacking, and the mechanisms underlying the cardiovascular effects of lactate in CS have not yet been elucidated. In this study we aimed to study the cardiovascular and cardiometabolic effects of treatment with lactate in experimental ischemic CS.

Methods

In a randomized, blinded design, 20 female pigs (60 kg) were studied. Left main coronary artery microsphere injections were used to cause CS, defined as a 30% reduction in CO or mixed venous saturation (SvO2). Subjects were randomized to receive either intravenous exogenous lactate or euvolemic, equimolar saline (control) for 180 min. Positive inotropic control with dobutamine was administered on top of ongoing treatment after 180 min. Extensive hemodynamic measurements were obtained from pulmonary artery and left ventricular (LV) pressure–volume catheterization. Furthermore, endomyocardial biopsies were analyzed for mitochondrial function and arterial, renal vein, and coronary sinus blood samples were collected. The primary endpoint was change in CO during 180 min of treatment.

Results

Arterial lactate levels increased from 2.4 ± 1.1 to 7.7 ± 1.1 mmol/L (P < 0.001) during lactate infusion. CO increased by 0.7 L/min (P < 0.001) compared with control, due to increased stroke volume (P = 0.003). Notably, heart rate and mean arterial pressure did not differ significantly between treatments. End-systolic elastance (load independent contractility) was enhanced during lactate infusion (P = 0.048), together with LV ejection fraction (P = 0.009) and dP/dt(max) (P = 0.041). Arterial elastance (afterload) did not differ significantly (P = 0.12). This resulted in improved ventriculo-arterial coupling efficiency (P = 0.012). Cardiac mechanical efficiency (P = 0.003), diuresis (P = 0.016), and SvO2 (P = 0.018) were increased during lactate infusion. Myocardial mitochondrial complex I respiration was enhanced during lactate infusion compared with control (P = 0.04). Concomitant administration of dobutamine on top of lactate resulted in further hemodynamic improvements compared with control.

Conclusions

Lactate infusion improved cardiac function and myocardial mitochondrial respiration in a porcine model of CS. The hemodynamic effects included increased CO mediated through stroke volume increase. These favorable cardiovascular effects may benefit patients with CS.

Introduction

Cardiogenic shock (CS) is a complex and life-threatening clinical syndrome with an in-hospital mortality of 30–50% despite treatment [1]. CS is often caused by ischemia due to myocardial infarction and key pathophysiological features involve impaired cardiac output (CO) causing compromised end-organ perfusion and cardiovascular collapse [2]. Current treatment strategies focus on restoring the compromised hemodynamic condition using vasoactive agents such as inotropes and vasopressors are pivotal, along with mechanical circulatory support in selected patients [2, 3]. However, no medical intervention has improved the survival rate in patients with CS [2, 4]. Hence, an urgent need for new medical treatment options for CS remains.

In CS, circulating lactate often increases as a result of hypoperfusion and increased anaerobic metabolism and is a strong predictor of disease severity and worse clinical outcome in CS [5, 6]. However, the production of lactate is not confined to anaerobic conditions but occurs even in resting state with aerobic conditions, and lactate is metabolized in healthy heart, brain, liver, skeletal muscle, and kidney, though to a lesser degree than during hypoperfusion [7]. In experimental models of cardiac arrest, lactate infusion increases mean arterial blood pressure (MAP) and CO and protects against cardiac and cerebral damage [8]–10]. Similar hemodynamic effects have been demonstrated in studies of healthy animals [11], healthy adults [12], and in experimental models of septic shock [13]–15]. Furthermore, lactate infusion increases CO in patients with various cardiac pathologies such as acute heart failure and non-ischemic CS [16,17,18,19], while increased myocardial lactate oxidation improves cardiac mechanical efficiency in patients with chronic heart failure [20]. Despite these findings, the underlying cardiovascular and metabolic mechanisms by which lactate exerts its hemodynamic effects remain unclear. Notably, no studies have explored the effects of lactate infusion in ischemic CS, leaving a considerable gap in our understanding of its therapeutic potential in critical care. Therefore, the aim of this study was to investigate the cardiovascular and cardiometabolic effects of lactate infusion in an established model of ischemic CS in human-sized pigs [21, 22]. We hypothesized that infusion of lactate could increase CO during ischemic CS.

Methods

Study design

In this prospective experimental study, female Danish Landrace pigs with an approximate weight of 60 kg were studied. A well-established method was applied to cause CS through repeated slow injections of polyvinyl microspheres (Contour™, Boston Scientific, USA) into the left main coronary artery [22]. Hemodynamic parameters were allowed to stabilize for three minutes following each injection before additional injections of microspheres. Inclusion criteria were a 30% reduction in either CO or mixed venous saturation (SvO2) relative to measurements in healthy state. Injections of microspheres were repeated until the inclusion criteria were met. These prespecified cutoff values were based on a pilot study in our animal laboratory, demonstrating that further hemodynamic deterioration would require treatment escalation, thus remaining out of the scope of the current study. Pigs that died before study end were replaced. Upon reaching the CS criteria, pigs were subjected to a one-hour no-touch period before initiation of the study interventions.

The study was a randomized, controlled, assessor-blinded study (Fig. 1). The pigs were randomized into two groups (n = 10 per group) using computer-generated randomization. Randomization was performed during the one-hour no-touch period after instrumentation. Pigs received either 2.9 ml/kg/h of 1 molar sodium lactate infusion (lactate) or 2.9 ml/kg/h equimolar, euvolemic matched hypertonic saline (control) for 180 min. At the end of the treatment period, a 15-min infusion of 5 µg/kg/min of dobutamine (Dobutrex, STADA Nordic ApS, Denmark) was infused on top of ongoing infusion with lactate or control to confirm a contractile reserve despite CS. The primary endpoint was defined as; mean change in CO during the 180 min of lactate infusion as compared with control infusion. All hemodynamic parameters, mitochondrial function, metabolites, and other biochemistry were evaluated as mean change during the 180 min of lactate infusion as compared with control infusion.

Fig. 1
figure 1

Study design and animal catheterization. A After catheterization cardiogenic shock (CS) was induced with repeated injections of microspheres into the left main coronary artery. CS was considered evident with a 30% reduction in either cardiac output or mixed venous saturation. After onset of cardiogenic shock pigs underwent a one-hour no-touch period to ensure absence of significant worsening or recovery from disease. At baseline, pigs were randomized to receive either a sodium lactate infusion or a tonicity-matched control infusion at a rate of 2.9 ml/kg/h. The primary endpoint was assessed after 180 min of infusion. The study ended following additional 15 min of dobutamine infusion as a positive control. B Pigs were catheterized as illustrated. Upon arrival, pigs were intubated and admitted to a ventilator. A Foley catheter was inserted into the bladder before invasive instrumentation. A pulmonary artery (PA) catheter and a coronary sinus catheter were placed through the right jugular vein. A pressure–volume (PV) admittance catheter was inserted into the left ventricle (LV) through the right common carotid artery. A coronary guide catheter was placed into the left main coronary artery through the left carotid artery. An occluding ballon catheter was placed in the inferior cava vein at diaphragm level through a femoral vein. The right renal vein was identified using ultrasound doppler and was catheterized through a femoral vein using a coronary guide catheter. Continuous arterial blood pressure was measured in the left femoral artery. In healthy state, at baseline and after 180 min of treatment endomyocardial biopsies were taken using a biopsy forceps through the left common carotid artery

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Animals and ethics approval

The study applied a procedure to minimize stress and increase refinement in the care of the pigs. Initially, pigs received sedation on the farm via intramuscular injection of a commonly used anesthetic mix (Zoletil 50 Vet, Virbac, Denmark). The pigs were intubated and immediately placed under invasive positive-pressure ventilation. Anesthesia maintenance entailed a continuous infusion of propofol (3.5 mg/kg/h) and fentanyl (15 µg/kg/h). Ventilation parameters included a tidal volume of 8 ml/kg with respiratory rate adjustments to maintain end-tidal CO2 between 4.5–5.5 kPa. PEEP was set to 5.0 cmH2O. Prior to baseline measurements, fractional inspired oxygen was adjusted to the lowest level to maintain PaO2 within 11 to 13 kPa.

The study was conducted after obtaining the necessary authorization from the Danish National Animal Experiment Inspectorate. (Hemodynamic Optimization with Carbonates, Permit no: 2023–15–0201–01466, issued on 19/06–2023). The treatment administered and ethical oversight concerning the animals strictly adhered to established animal welfare protocols and regulatory standards mandated by both Danish and European legislation. The methodologies employed and the handling of animals conformed to the guidelines outlined in the EU Directive 2010/63/EU pertaining to animal experimentation. Animal use was supervised by veterinarians, and all facilities and transportation complied with current legal requirements and guidelines. Following the conclusion of the study, all animals were humanely euthanized with a lethal dose of pentobarbital (Euthanimal, Scanvet, Denmark). The study was conducted in accordance with the PREPARE guidelines for study planning and the ARRIVE 2.0 guidelines for comprehensive study reporting.

Preparation of infusion solutions

The one molar sodium-lactate infusion was made by mixing a two molar sodium lactate solution (SODIO LATTATO 2 mEq/ML, Monico, Italy) with isotonic saline (Natriumklorid “B. Braun”, B. Braun Medical, Denmark) at a 1:1 ratio producing a solution with 1 mol/L sodium lactate (24.7 g/L of sodium). The control solution was a hypertonic sodium chloride solution with the same amounts of sodium as the intervention solution (24.7 g/L).

Infusions were administered in a peripheral venous catheter using a controlled infusion system (GP Plus Volumetric Pump, BD Alaris, USA). Infusion rates were set to 2.9 ml/kg/h (2.9 mmol lactate/kg/h). This infusion rate was chosen based on pilot studies to decrease the sodium load compared with our previous study while still achieving sufficiently elevated lactate levels [11].

Hemodynamic monitoring

MAP was measured via a femoral artery catheter, and heart rate (HR) was monitored using a three-lead ECG. A pulmonary artery (PA) catheter (Swan Ganz, Edwards Lifesciences, USA) was inserted via the internal jugular vein under pressure guidance, with placement confirmed by fluoroscopy. CO was measured using the bolus thermodilution method with a Vigilance box (Edwards Vigilance VGS), averaged over three measurements with less than 10% variation. Right atrial pressure (RAP), mean PA pressure (mPAP), and PA wedge pressure (PAWP) were recorded hourly. Stroke volume (SV = CO/HR), systemic vascular resistance (SVR = 80 × (MAP-RAP)/CO), pulmonary vascular resistance (PVR = 80 × (mPAP-PAWP)/CO), cardiac power output (CPO = (MAP × CO)/451) [23], and PA pulsatility index (PaPi =  [PA pulse pressure]/RAP) were calculated [24]. SvO2 was measured from the distal PA catheter port using a blood gas analyzer (ABL90 Flex, Radiometer, Denmark). Rate-pressure-product (RPP =  [systolic blood pressure] × HR) and coronary perfusion pressure were calculated (CPP =  [diastolic blood pressure]–PAWP).

Left ventricular pressure–volume assessment

A pressure–volume (PV) admittance catheter (Transsonic, USA) was advanced into the left ventricle (LV) via the right carotid artery under fluoroscopic guidance and remained fixed throughout the study. PV recordings were pressure-calibrated, then volume-calibrated to SV from the PA catheter, and data were collected during apnea. Recordings were continuously captured in LabChart 8 Pro (AD Instruments, Australia) for blinded analysis. A transfemoral occlusion balloon (Edwards Lifesciences) was placed in the inferior vena cava, and baseline balloon occlusion was used to determine theoretical ventricular volume when no pressure is generated (V0) [25, 26]. Arterial elastance (Ea) was calculated as the slope between LV end-diastolic volume (LVEDV) and LV end-systolic pressure (LVESP). End-systolic elastance (Ees) was estimated as (Ees = LVESP/ [LVESV-V0])) and defined as the slope of the end-systolic PV relationship (ESPVR). Ventriculo-arterial coupling (VA coupling) was defined as Ea/Ees. Additional hemodynamic parameters were assessed, including LV end-systolic volume (LVESV), LV ejection fraction (LVEF), maximum rate of LV pressure rise and decay (dP/dt(max) and dP/dt(min), and LV diastolic time constant (tau).

Mechanical energy parameters were calculated as described previously [27]. Briefly, these included stroke work (SW), which was calculated by the LabChart software, potential energy (PE = LVESP × (LVESV-V0)/2), pressure volume area (PVA = SW + PE), cardiac mechanical efficiency (CE = SW/PVA), and cardiac work (CW = PVA × HR).

Left main coronary artery catheterization

The left main coronary artery was catheterized under fluoroscopic guidance using a JL 3.5 catheter (Launcher, Medtronic Inc., USA) via the left carotid artery. The left anterior descending and left circumflex arteries were identified following contrast injection. The catheter was then secured and utilized for the injection of microspheres into the left main coronary artery. It was removed upon meeting the predefined CS criteria.

Endomyocardial mitochondrial respirometry

A flexible biopsy forceps (JawzTM, Argon Medical Devices, USA) was inserted through the left carotid artery into the LV under fluoroscopic guidance to collect endomyocardial biopsies. Mitochondrial respiratory capacity was measured using the Oxygraph 2 K (Oroboros Instruments, Austria). The substrate protocol included glutamate and malate for complex I respiration, followed by ADP and succinate for maximal respiration through complexes I and II, respectively. Oligomycin was added to assess state 4o leak respiration, and rotenone and antimycin A were used to measure residual oxygen consumption. Our aim was to assess the intrinsic oxidative phosphorylation capacity of the mitochondria. Thus, by bypassing upstream metabolic steps by using this standard protocol for analysis of permeabilized fibers and focusing on complexes I and II, the maximum capacity of the electron transport system rather than the immediate effect of specific in vivo substrates is quantified. Chambers were hyperoxygenated, and measurements were done in duplicate. Detailed protocols are available in Supplemental Material S1.

Coronary sinus and renal vein catheterizations

The coronary sinus was catheterized through a jugular vein using a coronary guide catheter under fluoroscopic guidance. The right renal vein was identified using ultrasound doppler and was catheterized through a femoral vein using a coronary guide catheter under fluoroscopic guidance. Correct positioning of both catheters was ensured using flushes of contrast. The catheters were fixed and left untouched throughout the study.

Biochemistry and fluid balance

Arterial, mixed venous, renal vein, and coronary sinus blood samples were obtained simultaneously at baseline, following CS induction, and every hour during the entire study period. Lactate, glucose, electrolytes, and acid–base parameters (pH, PaCO2, HCO3−) were analyzed immediately after sampling (ABL Flex90, Radiometer, Denmark). Free fatty acid (FFA) levels were measured with an enzymatic colorimetric method assay kit (Wako NEFA-HR [2], Wako Chemicals GmbH, Germany). The venous-to-arterial CO2 tension difference (P(v-a)CO2) was calculated, with lower values indicating improved peripheral tissue perfusion [28]. Transcardiac and transrenal P(v-a)CO2 were also calculated. Coronary sinus and renal vein blood samples were also used to measure cardiac and renal venous oxygen saturation (SO2) and arterio-venous (A-V) differences of O2, CO2 and metabolites.

Statistical methods

The standard deviation of CO (primary endpoint), measured using thermodilution in untreated pigs with CS in this experimental model, is 0.4 L/min (unpublished data from our research facility). By enrolling 20 pigs (10 per group), an effect size of 0.6 L/min would be detected with a power of 80% and a two-sided significance level of 5%. Data was visually analyzed for normal distribution with qq-plots. Normally and non-normally distributed variables are presented as mean ± standard deviation (SD) and median with interquartile range (IQR), respectively. Baseline hemodynamic characteristics were compared with CS at timepoint 0 using a paired T-test for normally distributed data or Wilcoxon signed rank test for non-normally distributed data. Continuous data were analyzed using a linear mixed effects model to compare the effect of lactate with the control. Residuals were analyzed for normal distribution using visual evaluation with qq-plots and parameters were transformed using expanded Box-Cox (Yeo-Johnson) transformation formation if necessary. Treatment and time were defined as fixed effects, whereas animals were selected as random effects. The mean treatment effects of lactate infusion versus control through the 180-min infusion period are presented with 95% confidence intervals (CI). We calculated a two-tailed P-value. P-values < 0.05 were considered statistically significant. Statistical analyses were conducted in the R software (Version 4.2.1, Rstudio, PBC) and graphics were constructed using Prism (Version 8.4.2, GraphPad, San Diego, CA, USA) or R.

Results

Induction of cardiogenic shock

CS was achieved in a total of 26 pigs. Three pigs died during the no-touch period due to refractory cardiac arrest with ventricular fibrillation prior to randomization. Two pigs died before randomization due to procedure-related irreversible ventricular fibrillation during endomyocardial biopsy sampling. One pig was excluded because it by mistake received a double dose of lactate. All pigs were replaced 1:1 (Supplemental Figure S1). Hence, 20 animals with CS were included for the final analysis. After induction of CS, at the end of the one-hour no-touch period, CO was reduced from 4.2 ± 1.0 L/min at baseline to 2.6 ± 0.7 L/min (38% reduction, P < 0.001) and SvO2 decreased from 58 ± 9 to 34 ± 6% (41% reduction, P < 0.001) (Table 1). CPO and MAP were decreased in CS while LV filling pressures (LVEDP and PAWP) were increased, accompanied by decreased SV, LVEF, and CE. A non-significant increase in Ea was observed whereas Ees decreased, resulting in VA decoupling. Arterial levels of endogenous lactate increased from 1.4 ± 0.7 to 2.5 ± 1.0 mmol/L (P < 0.001).

Table 1 Baseline and cardiogenic shock characteristics
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Hemodynamic effects of lactate infusion

Mean lactate levels were 7.7 ± 1.1 mmol/L during lactate infusion compared with 1.7 ± 2.0 mmol/L during control infusion (between-treatment difference: 5.1 mmol/L; 95% CI: 4.4 to 5.8 mmol/L; P < 0.001; Fig. 2). Lactate infusion caused an increase in CO by 0.7 L/min (95% CI: 0.4 to 1.0 L/min; P < 0.001) compared with control (Table 2, Figs. 2, and 3). SV increased by 7 mL (95% CI: 3 to 11 mL; P = 0.003) whereas HR remained similar between treatments (P = 0.71). CPO was also increased. SvO2 increased by 7%-points (95% CI: 2 to 12%-points; P = 0.018), accompanied by decreased P(v-a)CO2 during lactate compared with control, consistent with the increase in O2 delivery and CO. Also, the accumulated diuresis during the 180-min treatment period was greater in the lactate group than the control group (176 ml [IQR 131–207 ml] vs 102 ml [IQR 97–135 ml]; P = 0.016) (Supplemental Figure S2). PVR was decreased (P = 0.031), with no significant difference in SVR (P = 0.28). No significant between-treatment differences in RPP, MAP, pulmonary pressures, CPP, and PaPi were detected.

Fig. 2
figure 2

Temporal changes in arterial A lactate, B cardiac output, C mixed venous oxygen saturation, D stroke volume, and E heart rate. Data are shown as mean ± SEM. Temporal evolution in cardiac output determinants and arterial lactate concentration from baseline and until 180 min after treatment initiation. P-values are derived from the pairwise comparisons assessed using a repeated measurements linear mixed model with time and treatment as fixed effects and each animal as random effects

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Table 2 Hemodynamic parameters during lactate and control infusions
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Fig. 3
figure 3

Relative and absolute changes in hemodynamic parameters during lactate versus control. Changes in endpoint parameters during 180 min of lactate infusion versus control compared with baseline. Bars represent mean relative change during lactate infusion compared with control infusion and error bars indicate SEM. Corresponding mean absolute changes ± SEM are listed above or below each bar. P-values are stated on all results. CO Cardiac output, CPO Cardiac power output, Ea Arterial elastance, Ees End-systolic elastance, LVEF Left ventricular ejection fraction, MAP Mean arterial blood pressure, PAWP Pulmonary artery wedge pressure, SvO2 Mixed venous oxygen saturation, VA Coupling  Ventriculo-arterial coupling (Ea/Ees)

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Impact of lactate infusion on pressure–volume parameters

The load independent contractility measure, Ees, was increased by 0.28 mmHg/mL (95% CI: 0.02 to 0.53 mmHg/mL; P = 0.048) with a concomitant increase in dP/dt(max) (P = 0.041) during lactate infusion compared with control infusion. Despite a trend the afterload measure, Ea, did not differ significantly between treatments (− 0.86 mmHg/mL (95% CI: − 1.89 to 0.02 mmHg/mL; P = 0.121). Thus, the Ea/Ees ratio decreased significantly by − 0.67 (95% CI: − 1.13 to − 0.21; P = 0.012) during lactate infusion compared with control, indicating improved VA coupling. LVEF was significantly improved during lactate infusion by 9%-points (95% CI: 3 to 14%-points; P = 0.009), paralleled by decreased LVESV (between-treatment difference: − 15 mL; 95% CI: − 27 to − 2 mL; P = 0.038) compared with control infusion. Furthermore, cardiac mechanical efficiency was significantly enhanced by 10%-points (95% CI 4 to 15%-points; P = 0.003) during lactate infusion compared with control. No significant changes regarding SW, PE, PVA and CW were observed. Diastolic parameters (dP/dt(min) and Tau) and preload parameters (LVEDP and LVEDV) were not significantly altered by lactate infusion compared with control.

Impact of lactate infusion on transorgan gradients and biochemical parameters

The transcardiac lactate gradient increased by 1.0 mmol/L (95% CI: 0.6 to 1.4 mmol/L; P < 0.001) during lactate infusion compared with control. Meanwhile, there were no differences in transcardiac gradients of other metabolites, though a trend towards decreased transcardiac gradient of FFAs (−0.13 mmol/L (95% CI: −0.26 to 0.00 mmol/L; P = 0.075) was observed. Also, there was a trend of increased arterial and coronary sinus SO2 during lactate compared with control, with no significant difference between treatments in transcardiac oxygen difference. Furthermore, the transcardiac P(v-a)CO2 difference was significantly decreased (P = 0.012). No difference in transrenal metabolites, SO2, or P(v-a)CO2 was detected.

Whereas arterial sodium levels increased during both treatments, the increase was greater during control infusion (Table 3). Arterial potassium levels were significantly decreased during lactate infusion compared with control while arterial pH and bicarbonate levels increased. Finally, arterial glucose was slightly higher during lactate compared with control infusion (Fig. 4).

Table 3 Biochemical parameters during lactate and control infusions
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Fig. 4
figure 4

Temporal evolution in hemodynamic parameters during lactate and control. Data are shown as mean ± SEM. Temporal evolution in  A mean arterial blood pressure, B cardiac power output, C mean pulmonary arterial pressure, D right atrial pressure, E pulmonary arterial wedge pressure, F veno-arterial carbon dioxide difference, G end-systolic elastance, H arterial elastance, I ventriculo-arterial coupling, J pressure-volume area, K cardiac mechanical efficiency, and L LV ejection fraction from baseline and until 180 min after treatment initiation. P-values are derived from the pairwise comparisons assessed using a repeated measurements linear mixed model with time and treatment as fixed effects and each animal as random effects. Ea arterial elastance, Ees end-systolic elastance, LVEF left ventricular ejection fraction, PVA Pressure–volume area, P(V-A)CO2  veno-arterial carbon dioxide difference, VA Coupling Ventriculo-arterial coupling (Ea/Ees)

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Impact of lactate infusion on myocardial mitochondrial function

Mitochondrial respiration linked to complex I, reflecting electron transport chain activity reliant on NADH as the reducing equivalent, was significantly elevated during lactate infusion compared with control (P = 0.040; Fig. 5 and Supplementary Table S1). In contrast, the increase in oxidative phosphorylation (OXPHOS) capacity, which measures fully coupled respiration through complexes I and II and involves reducing equivalents NADH and FADH2, did not reach statistical significance (P = 0.152). Additionally, there was no observed difference in state 4o leak respiration between interventions, which reflects proton leak across the mitochondrial membrane without ATP production (P = 0.822).

Fig. 5
figure 5

Temporal evolution in left ventricular myocardial mitochondrial function parameters A complex I respiration, B OXPHOS, and C state 4o leak respiration during lactate versus control. Difference in mitochondrial parameters in healthy state (baseline) and after 180 min of treatment compared with cardiogenic shock baseline (Time = 0). Data are shown as mean ± SEM. Each replicate is shown. P-values are derived from an unpaired t-test on the change from time 0 to time 180. OXPHOS oxidative phosphorylation

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Addition of dobutamine on top of intervention

The addition of 15-min dobutamine infusion after 180 min of intervention with lactate or control resulted in significant increases in CO, SV, HR, MAP, Ees, and SvO2 during both treatments (Supplementary Table S2). The dobutamine-dependent effects on CO (P = 0.112), HR (P = 0.83), MAP (P = 0.18), Ees (P = 0.37), and SvO2 (P = 0.564) were similar during both treatments, while SV increased more during control infusion (P = 0.008). The cumulative effects (from CS baseline) of dobutamine on top of lactate exhibited improved CO (P = 0.013), CPO (P = 0.013), SvO2 (P = 0.049), P(v-a)CO2 (P = 0.030), LVEF (P = 0.001), VA coupling (P = 0.022), cardiac mechanical efficiency (P < 0.001) and SW (P = 0.006) compared with dobutamine on-top-off control.

Safety

No animals suffered from ventricular arrhythmias during lactate infusion while two animals demonstrated short sequences of pulse bearing ventricular tachycardia during control infusion. Four animals experienced supraventricular arrhythmias with no effect on blood pressures, two during each intervention. Ventilation parameters did not differ between treatments (Supplementary Table S3).

Discussion

We investigated the acute cardiovascular and cardiometabolic effects of lactate infusion in an experimental model of ischemic CS. Lactate improved CO through increased SV in parallel with improved contractility. Several indices of peripheral tissue perfusion also increased wheras MAP remained stable. Notably, the administration of lactate improved VA coupling accommodated by enhanced mechano-energetic function as evidenced by enhanced cardiac mechanical efficiency. These favorable cardiovascular effects were accompanied by increased transcardiac lactate gradient and improved mitochondrial function, while no adverse increases in surrogate parameters of myocardial oxygen consumption (PVA, CW, and CPP) were observed.

Lactate infusion enhanced the hemodynamic status in CS

CS is characterized by impaired contractile function with reduced CO and organ perfusion [1, 2]. The resulting drop in MAP triggers vasoconstriction to preserve perfusion, but the increased afterload exceeds the capacity of the heart, causing VA decoupling. This intensifies ventricular strain, worsens ischemia, and disrupts cardiac metabolism, leading to progressive hemodynamic decline and circulatory collapse. Hence, the primary treatment goal in CS is to reestablish organ perfusion by restoring systemic blood pressure and CO [2, 3]. A previous study demonstrated that treatment with lactate infusion in patients with acute heart failure and reduced LVEF led to an increase in CO [18]. Similar hemodynamic improvements have been observed in patients with non-ischemia-related CS [19].

The findings of the present study extend the understanding of therapeutic exogenous lactate infusion to the domain of ischemic CS and provide insights into the cardiovascular effects of lactate treatment in this setting. Foremost, the primary endpoint, CO, increased by 26% during lactate infusion compared with control. This increase was predominantly mediated through increased SV while MAP was maintained stable. In this regard, the contractility measures Ees and dP/dt(max) were higher compared with control and we observed an increase in CPO which is associated with improved prognosis in patients with CS [23]. Thus, VA coupling and LVEF also improved, resulting in reduced LVESV. Other LV preload and afterload metrics did not differ significantly between the treatments. Notably, the observed lactate-induced CO increase is comparable to supportive doses of common pharmacologic agents such as milrinone, dobutamine, and levosimendan in patients with severe heart failure and CS [29,30,31]. However, in addition to inotropic effects, these agents carry potential deleterious side effects such as increased chronotropy with associated risk of arrhythmias and increased myocardial oxygen consumption [32]. In this context, the CO increase during lactate infusion was achieved without significantly affecting HR compared with control, and we observed no excess risk of arrhythmias compared with control.

A hallmark of CS is the inability of the heart to accommodate metabolic and oxygen demands of the organs [2]. Hence, it is intriguing that parameters such as SvO2 and P(v-a)CO2 improved during lactate infusion, as these changes indicate enhanced tissue oxygen delivery and improved microcirculatory function [33,34,35]. Additionally, lactate infusion was associated with increased diuresis which may also indicate improved end-organ perfusion.

In healthy pigs, lactate infusion reduces SVR and afterload, with an increase in CO driven primarily by elevated HR without significantly affecting contractility [11]. In contrast, in the present study, lactate infusion enhanced contractility (higher Ees) and SV compared with control. These pathophysiology-dependent effects suggest that in the setting of ischemic CS where compensatory sympathoadrenergic mechanism prevail [36], the inotropic benefits of lactate become more prominent. Also, in our previous study, lactate levels were elevated to a greater extent than in the current investigation, which may have contributed to the differing effects.

Metabolic aspects of lactate infusion in CS

The heart can metabolize various substrates, including FFAs, glucose, ketone bodies, and lactate, with a preference for FFAs under normal conditions [37]. Lactate enters cells insulin-independently, unlike glucose. Notably, increased lactate oxidation has been associated with increased cardiac mechanical efficiency in experimental models of hemorrhagic shock [38] and in patients with congestive heart failure [20]. Thus, lactate has been proposed as an alternative myocardial substrate during cardiac disarray. We demonstrated an increased A-V gradient of lactate across the heart, while the FFA gradient showed a declining trend, pointing to an increased myocardial uptake of lactate, decreased FFA uptake, and unchanged glucose uptake. Notably, lactate infusion led to preserved myocardial complex I mitochondrial respiratory function. As complex I is particularly susceptible to ischemic injury [39], our findings point to a potential mitochondrial-protective effect of lactate infusion during ischemic conditions. As the mitochondria were analyzed ex vivo in absence of substrates like lactate and FFAs these results points to a lasting preservation of mitochondrial function of lactate rather than a transient, substrate driven augmentation.

Several mechanisms may underlie the observed cardiometabolic effects. First, lactate may serve as a readily oxidizable substrate for the failing heart with a greater ATP per oxygen yield than FFAs [40, 41]. While lactate can be metabolized through the pyruvate pathway, lactate per se can also be oxidized [42, 43]. Second, lactate may stimulate the electron transport chain activating oxidative phosphorylation independently of its conversion to pyruvate and thereby improve hemodynamic function [44]. Third, other properties of lactate include alteration of gene expression through histone lactylation [45, 46], and finally, lactate may improve cardiovascular effects independently of energy production through pleiotropic effects such as HCA1-receptor activation [47, 48]. Future investigations comparing lactate infusions with pyruvate infusions, along with real-time metabolic flux assessments, would be valuable in further delineating their respective contributions to myocardial function in CS.

Cardiac mechanical efficiency was also enhanced during lactate infusion, demonstrating a more favorable balance between stroke work and the total cardiac energy demand [11, 20, 49]. Also, a trend toward elevated coronary sinus SO2 was noted, albeit with a similar trending increase in arterial SO2, leaving the transcardiac SO2 difference unchanged between treatments. Correspondingly, PVA, CW, and RPP, which are indicators of myocardial oxygen consumption [50, 51] did not differ between lactate and control treatment, reflecting that the increase in cardiovascular performance observed with lactate infusion was not accompanied by excess myocardial oxygen consumption.

Ultimately, these findings suggest that lactate infusion enhances mechanical efficiency and contractility without imposing additional metabolic demand on the heart. It remains to be determined whether the mitochondrial effects of lactate infusion provide a direct cardioprotective mechanism through advantageous metabolic properties, or if they represent an indirect benefit to mitochondria due to improved hemodynamic conditions (e.g. improved VA coupling and mechanical efficiency) which leads to adequate output with minimal energy expenditure.

Clinical perspectives

As expected, endogenous production of lactate increased during induction of CS. While lactate traditionally has been seen as a marker of disease severity, studies suggest that lactate per se is protective rather than harmful. Indeed, in experimental shock, systemic lactate deprivation is associated with compromised myocardial function and increased mortality [38, 52]. The present study demonstrated significant beneficial hemodynamic effects of exogenous lactate administration in CS, which appeared to plateau at plasma lactate concentrations above 5 mmol/L (Fig. 2A–B). This finding points to that increasing lactate levels beyond this threshold, which may occur in the most profound cases of CS [53], may not yield additional hemodynamic benefits. However, the most severe cases of CS are often accompanied by metabolic acidosis. In this context, the alkalizing effect of exogenous lactate infusion, as observed in the present study, could represent a relevant clinical effect. This, however, must be explored in future studies. Also notably, the concomitant administration of dobutamine on top of lactate infusion resulted in further hemodynamic improvements, indicating that lactate infusion could potentially be incorporated into contemporary management strategies for CS.

Limitations

First, extrapolation of findings in experimental studies requires caution. To enhance translatability and clinical relevance, we chose human-sized pigs as experimental animals, as they have close cardiothoracic anatomical and physiological similarities with humans. However, porcine and human metabolism cannot be interchanged which may limit the generalizability from pigs to humans. Still, similar hemodynamics effects of lactate infusions have been found in patients with acute heart failure and non-ischemic CS [18, 19]. Also, CS induced by coronary occlusion through microsphere injections may differ from the disease resulting from atherosclerotic disease with plaque rupture and myocardial infarction or acute decompensated heart failure. Nevertheless, the model is well validated, and the hemodynamic alterations observed were vastly similar to patients with ischemic CS [22].

The current study utilized an equimolar, euvolemic saline infusion as a control with the same tonicity as the lactate infusion. Hence, the observed between treatment hemodynamic effects are unlikely to be explained by the tonicity of the lactate infusion. Still, hypertonic fluids can cause hemodynamic alterations. Indeed, hypertonic fluids reduce SVR and elevate CO following cardiac surgery [54]. Importantly, dobutamine was administered as a positive control, to rule out any persistent detrimental effect of the control solution. These data showed a significant cardiovascular response and did not indicate any adverse cardiac effects from the hypertonic control solution. Also, no effect was seen on preload parameters such as RAP and LVEDV between the treatments.

Lactate infusion resulted in metabolic alkalosis which is also known to have hemodynamic impacts [55]. Notably, our previous study demonstrated that CO increased during lactate infusion in healthy pigs independently from pH and bicarbonate levels [11]. Furthermore, hemodynamic improvements are superior during lactate treatment when comparing lactate with bicarbonate [14, 15]. Thus, it appears unlikely that the hemodynamic and cardiometabolic findings in the present study could be explained by alkalosis. In fact, alkalosis may cause vasoconstriction potentially blunting the potential hemodynamic benefit from lactate infusion [56]. Nevertheless, as lactate was not compared to an alkalizing control in this study, it was not possible to distinguish between direct effects from lactate and its metabolism from effects of subsequent metabolic alkalosis as the latter follows the former.

We catheterized the coronary sinus and renal vein to measure metabolite and gas gradients across organs, though without direct assessment of coronary or renal flow. Consequently, observed differences may reflect differences in myocardial perfusion. In addition, gradients across the heart do not take myocardial production of lactate from e.g. glycogen into account [57].

Finally, while permeabilized fiber techniques are a well-validated approach for assessing mitochondrial respiratory capacity, they do not entirely replicate the natural physiological setting. This introduces some uncertainty regarding the direct application of these findings at the whole organ level. Furthermore, the small sample size raises the possibility of regression toward the mean, where extreme values might appear closer to the average with repeated measures, potentially obscuring true variability or change [58]. Therefore, these data should be interpreted with caution, acknowledging these limitations. Nevertheless, the findings appear to demonstrate preserved mitochondrial function during lactate infusion.

Conclusion

Lactate infusion enhanced cardiac output and peripheral perfusion in ischemic CS, primarily through increased stroke volume, improved contractility, and enhanced ventriculo-arterial coupling, without affecting heart rate or systemic blood pressure. These effects were accompanied by better mechano-energetic and mitochondrial function, suggesting lactate as a potential therapeutic approach for CS.

Clinical perspectives

Clinical competencies

Medical knowledge: For the first time, this study utilized excessive hemodynamic monitoring with state-of-the-art techniques including right-, and left heart catheterization for hemodynamic assessment, mitochondrial analysis, and across-organ catheterization for blood sampling. The study highly expands the knowledge regarding hemodynamic effects of lactate infusion in critical care disease, highlighting that lactate infusion in ischemic cardiogenic shock can improve cardiac output, contractility, and ventriculo-arterial coupling, while enhancing peripheral perfusion without increasing markers myocardial oxygen demand.

Translational outlook

This experimental work suggests that lactate infusion can enhance cardiac function and metabolic efficiency in ischemic cardiogenic shock. It is the most rigorously designed study in the field with state-of-the-art implementation of hemodynamic and cardiovascular monitoring and measurement. However, before implementation in clinical practice, several translational steps remain. Future research should investigate patient selection, optimal dosing, and safety parameters of lactate infusion, followed by rigorously designed clinical trials. Additionally, integrating lactate infusion into existing treatment pathways and ensuring broad practitioner acceptance will be crucial. By streamlining these steps, from preclinical validation to clinical application, this therapy could ultimately improve patient outcomes and potentially reshape the management of ischemic cardiogenic shock.

Availability of data and materials

The data analysed in the current study is available from the corresponding author upon reasonable request.

Abbreviations

A-V:

Arterio-venous

CI:

Confidence interval

CO:

Cardiac output

CPO:

Cardiac power output

CPP:

Coronary perfusion pressure

CS:

Cardiogenic shock

CW:

Cardiac work

dP/dt(max):

Maximum rate of left ventricular pressure rise

dP/dt(min):

Minimum rate of left ventricular pressure decay

Ea:

Arterial elastance

Ees:

End-systolic elastance

ESPVR:

End-systolic pressure–volume relationship

FFA:

Free fatty acid

HR:

Heart rate

IQR:

Interquartile range

LV:

Left ventricle/left ventricular

LVEDP:

Left ventricular end-diastolic pressure

LVEDV:

Left ventricular end-diastolic volume

LVEF:

Left ventricular ejection fraction

LVESP:

Left ventricular end-systolic pressure

LVESV:

Left ventricular end-systolic volume

MAP:

Mean arterial pressure

mPAP:

Mean pulmonary artery pressure

PaPi:

Pulmonary artery pulsatility index

PAWP:

Pulmonary artery wedge pressure

P(v-a)CO2 :

Venous-to-arterial CO2 tension difference

PVR:

Pulmonary vascular resistance

PVA:

Pressure–volume area

RAP:

Right atrial pressure

RPP:

Rate-pressure-product

SD:

Standard deviation

SO2 :

Oxygen saturation

SV:

Stroke volume

SVR:

Systemic vascular resistance

SW:

Stroke work

VA  Coupling:

Ventriculo-Arterial Coupling 

References

  1. Harjola V-P, Lassus J, Sionis A, et al. Clinical picture and risk prediction of short-term mortality in cardiogenic shock. Eur J Heart Fail. 2015;17(5):501–9. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/ejhf.260.

    Article  PubMed  Google Scholar 

  2. van Diepen S, Katz JN, Albert NM, et al. Contemporary management of cardiogenic shock: a scientific statement from the American heart association. Circulation. 2017. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/CIR.0000000000000525.

    Article  PubMed  Google Scholar 

  3. Møller JE, Engstrøm T, Jensen LO, et al. Microaxial flow pump or standard care in infarct-related cardiogenic shock. N Engl J Med. 2024;390(15):1382–93. https://doiorg.publicaciones.saludcastillayleon.es/10.1056/NEJMoa2312572.

    Article  PubMed  Google Scholar 

  4. Thiele H, Ohman EM, Desch S, Eitel I, de Waha S. Management of cardiogenic shock. Eur Heart J. 2015;36(20):1223–30. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/eurheartj/ehv051.

    Article  PubMed  Google Scholar 

  5. Jentzer JC, Schrage B, Patel PC, et al. Association between the acidemia, lactic acidosis, and shock severity with outcomes in patients with cardiogenic shock. J Am Heart Assoc. 2022. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/JAHA.121.024932.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Fuernau G, Desch S, de Waha-Thiele S, et al. Arterial lactate in cardiogenic shock: prognostic value of clearance versus single values. JACC Cardiovasc Interv. 2020;13(19):2208–16. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jcin.2020.06.037.

    Article  PubMed  Google Scholar 

  7. Brooks GA. The science and translation of lactate shuttle theory. Cell Metab. 2018;27(4):757–85. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.cmet.2018.03.008.

    Article  CAS  PubMed  Google Scholar 

  8. Annoni F, Su F, Peluso L, et al. Hypertonic sodium lactate infusion reduces vasopressor requirements and biomarkers of brain and cardiac injury after experimental cardiac arrest. Crit Care. 2023;27(1):161. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13054-023-04454-1.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Miclescu A, Basu S, Wiklund L. Cardio-cerebral and metabolic effects of methylene blue in hypertonic sodium lactate during experimental cardiopulmonary resuscitation. Resuscitation. 2007;75(1):88–97. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.resuscitation.2007.03.014.

    Article  CAS  PubMed  Google Scholar 

  10. Stevic N, Argaud L, Loufouat J, et al. Molar sodium lactate attenuates the severity of postcardiac arrest syndrome: a preclinical study. Crit Care Med. 2022;50(1):E71–9. https://doiorg.publicaciones.saludcastillayleon.es/10.1097/CCM.0000000000005233.

    Article  CAS  PubMed  Google Scholar 

  11. Hørsdal OK, Moeslund N, Berg-Hansen K, et al. 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):285. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12967-024-05064-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Berg-Hansen K., Gopalasingam N., Pedersen MGB., et al. Cardiovascular effects of lactate in healthy adults. Crit Care 2025;29(1): 30. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13054-025-05259-0.

  13. Duburcq T, Favory R, Mathieu D, et al. Hypertonic sodium lactate improves fluid balance and hemodynamics in porcine endotoxic shock. Crit Care. 2014;18(4):467. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13054-014-0467-3.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Besnier E, Coquerel D, Kouadri G, et al. Hypertonic sodium lactate improves microcirculation, cardiac function, and inflammation in a rat model of sepsis. Crit Care. 2020;24(1):354. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13054-020-03083-2.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Duburcq T, Durand A, Dessein A-F, 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. Crit Care. 2017;21(1):113. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13054-017-1694-1.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Boom CE, Herdono P, Koto CG, Hadi S, Permana IMA. Effect of hyperosmolar sodium lactate infusion on haemodynamic status and fluid balance compared with hydroxyethyl starch 6% during the cardiac surgery. Indian J Anaesth. 2013;57(6):576–82. https://doiorg.publicaciones.saludcastillayleon.es/10.4103/0019-5049.123330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Leverve X, Boon C, Hakim T. Half-molar sodium-lactate solution hasa beneficial effect in patients after coronaryartery bypass grafting. Intensive Care Med. 2008;34(10):1749–51. https://doiorg.publicaciones.saludcastillayleon.es/10.1007/s00134-008-1166-9.

    Article  Google Scholar 

  18. Nalos M, Leverve X, Huang S, et al. Half-molar sodium lactate infusion improves cardiac performance in acute heart failure: a pilot randomised controlled clinical trial. Crit Care. 2014;18(2):R48. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/cc13793.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Revelly J-P, Tappy L, Martinez A, et al. Lactate and glucose metabolism in severe sepsis and cardiogenic shock. Crit Care Med. 2005;33(10):2235–40. https://doiorg.publicaciones.saludcastillayleon.es/10.1097/01.ccm.0000181525.99295.8f.

    Article  CAS  PubMed  Google Scholar 

  20. Bersin RM, Wolfe C, Kwasman M, et al. Improved hemodynamic function and mechanical efficiency in congestive heart failure with sodium dichloroacetate. J Am Coll Cardiol. 1994;23(7):1617–24. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/0735-1097(94)90665-3.

    Article  CAS  PubMed  Google Scholar 

  21. Hevrøy O, Reikerås O, Grundnes O, Mjøs OD. Cardiovascular effects of positive end-expiratory pressure during acute left ventricular failure in dogs. Clin Physiol. 1988;8(3):287–301. https://doiorg.publicaciones.saludcastillayleon.es/10.1111/j.1475-097x.1988.tb00271.x.

    Article  PubMed  Google Scholar 

  22. Møller-Helgestad OK, Ravn HB, Møller JE. Large porcine model of profound acute ischemic cardiogenic shock. Methods Mol Biol. 2018;1816:343–52. https://doiorg.publicaciones.saludcastillayleon.es/10.1007/978-1-4939-8597-5_27.

    Article  CAS  PubMed  Google Scholar 

  23. Fincke R, Hochman JS, Lowe AM, et al. Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry. J Am Coll Cardiol. 2004;44(2):340–8. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jacc.2004.03.060.

    Article  PubMed  Google Scholar 

  24. Lim HS, Gustafsson F. Pulmonary artery pulsatility index: physiological basis and clinical application. Eur J Heart Fail. 2020;22(1):32–8. https://doiorg.publicaciones.saludcastillayleon.es/10.1002/ejhf.1679.

    Article  PubMed  Google Scholar 

  25. Sagawa K. The end-systolic pressure-volume relation of the ventricle: definition, modifications and clinical use. Circulation. 1981;63(6):1223–7. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.cir.63.6.1223.

    Article  CAS  PubMed  Google Scholar 

  26. Senzaki H, Chen CH, Kass DA. Single-beat estimation of end-systolic pressure-volume relation in humans. A new method with the potential for noninvasive application. Circulation. 1996;94(10):2497–506. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.cir.94.10.2497.

    Article  CAS  PubMed  Google Scholar 

  27. Hørsdal OK, Wethelund KL, Gopalasingam N, et al. Cardiovascular effects of increasing positive end-expiratory pressure in a model of left ventricular cardiogenic shock in female pigs. Anesthesiology. 2024. https://doiorg.publicaciones.saludcastillayleon.es/10.1097/ALN.0000000000005201.

    Article  PubMed  Google Scholar 

  28. Ltaief Z, Schneider AG, Liaudet L. Pathophysiology and clinical implications of the veno-arterial PCO2 gap. Crit Care. 2021;25(1):318. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13054-021-03671-w.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Francis GS, Sharma B, Hodges M. Comparative hemodynamic effects of dopamine and dobutamine in patients with acute cardiogenic circulatory collapse. Am Heart J. 1982;103(6):995–1000. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/0002-8703(82)90562-2.

    Article  CAS  PubMed  Google Scholar 

  30. Eichhorn EJ, Konstam MA, Weiland DS, et al. Differential effects of milrinone and dobutamine on right ventricular preload, afterload and systolic performance in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1987;60(16):1329–33. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/0002-9149(87)90616-3.

    Article  CAS  PubMed  Google Scholar 

  31. Anderson JL, Baim DS, Fein SA, Goldstein RA, LeJemtel TH, Likoff MJ. Efficacy and safety of sustained (48 hour) intravenous infusions of milrinone in patients with severe congestive heart failure: a multicenter study. J Am Coll Cardiol. 1987;9(4):711–22. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/S0735-1097(87)80223-1.

    Article  CAS  PubMed  Google Scholar 

  32. Maack C, Eschenhagen T, Hamdani N, et al. Treatments targeting inotropy. Eur Heart J. 2019;40(44):3626–44. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/eurheartj/ehy600.

    Article  CAS  PubMed  Google Scholar 

  33. Hasanin A, Mukhtar A, Nassar H. Perfusion indices revisited. J Intensive Care. 2017;5:24. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40560-017-0220-5.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Lim N, Dubois M-J, De Backer D, Vincent J-L. Do all nonsurvivors of cardiogenic shock die with a low cardiac index? *. Chest. 2003;124(5):1885–91. https://doiorg.publicaciones.saludcastillayleon.es/10.1378/chest.124.5.1885.

    Article  PubMed  Google Scholar 

  35. Merdji H, Levy B, Jung C, Ince C, Siegemund M, Meziani F. Microcirculatory dysfunction in cardiogenic shock. Ann Intensive Care. 2023;13(1):38. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13613-023-01130-z.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Schomig A, Haass M, Richardt G. Catecholamine release and arrhythmias in acute myocardial ischaemia. Eur Heart J. 1991;12(suppl F):38–47. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/eurheartj/12.suppl_F.38.

    Article  PubMed  Google Scholar 

  37. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005;85(3):1093–129. https://doiorg.publicaciones.saludcastillayleon.es/10.1152/physrev.00006.2004.

    Article  CAS  PubMed  Google Scholar 

  38. Barbee RW, Kline JA, Watts JA. Depletion of lactate by dichloroacetate reduces cardiac efficiency after hemorrhagic shock. Shock. 2000;14(2):208–14. https://doiorg.publicaciones.saludcastillayleon.es/10.1097/00024382-200014020-00022.

    Article  CAS  PubMed  Google Scholar 

  39. Paradies G, Petrosillo G, Pistolese M, Di Venosa N, Federici A, Ruggiero FM. Decrease in mitochondrial complex I activity in ischemic/reperfused rat heart. Circ Res. 2004;94(1):53–9. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.RES.0000109416.56608.64.

    Article  CAS  PubMed  Google Scholar 

  40. Murashige D, Jang C, Neinast M, et al. Comprehensive quantification of fuel use by the failing and nonfailing human heart. Science. 2020;370(6514):364–8. https://doiorg.publicaciones.saludcastillayleon.es/10.1126/science.abc8861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mookerjee SA, Gerencser AA, Nicholls DG, Brand MD. Quantifying intracellular rates of glycolytic and oxidative ATP production and consumption using extracellular flux measurements. J Biol Chem. 2017;292(17):7189–207. https://doiorg.publicaciones.saludcastillayleon.es/10.1074/jbc.M116.774471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Brooks GA, Curl CC, Leija RG, Osmond AD, Duong JJ, Arevalo JA. Tracing the lactate shuttle to the mitochondrial reticulum. Exp Mol Med. 2022;54(9):1332–47. https://doiorg.publicaciones.saludcastillayleon.es/10.1038/s12276-022-00802-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Young A, Oldford C, Mailloux RJ. Lactate dehydrogenase supports lactate oxidation in mitochondria isolated from different mouse tissues. Redox Biol. 2020;28: 101339. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.redox.2019.101339.

    Article  CAS  PubMed  Google Scholar 

  44. Cai X, Ng CP, Jones O, et al. Lactate activates the mitochondrial electron transport chain independently of its metabolism. Mol Cell. 2023;83(21):3904-3920.e7. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.molcel.2023.09.034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang N, Wang W, Wang X, et al. Histone lactylation boosts reparative gene activation post-myocardial infarction. Circ Res. 2022;131(11):893–908. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/CIRCRESAHA.122.320488.

    Article  CAS  PubMed  Google Scholar 

  46. Zhang D, Tang Z, Huang H, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574(7779):575–80. https://doiorg.publicaciones.saludcastillayleon.es/10.1038/s41586-019-1678-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Certo M, Llibre A, Lee W, Mauro C. Understanding lactate sensing and signalling. Trends Endocrinol Metab. 2022;33(10):722–35. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.tem.2022.07.004.

    Article  CAS  PubMed  Google Scholar 

  48. Mohammad Nezhady MA, Modaresinejad M, Zia A, Chemtob S. Versatile lactate signaling via HCAR1: a multifaceted GPCR involved in many biological processes. Am J Physiol Cell Physiol. 2023;325(6):C1502–15. https://doiorg.publicaciones.saludcastillayleon.es/10.1152/ajpcell.00346.2023.

    Article  CAS  PubMed  Google Scholar 

  49. Kline JA, Thornton LR, Lopaschuk GD, Barbee RW, Watts JA. Lactate improves cardiac efficiency after hemorrhagic shock. Shock. 2000;14(2):215–21. https://doiorg.publicaciones.saludcastillayleon.es/10.1097/00024382-200014020-00023.

    Article  CAS  PubMed  Google Scholar 

  50. Westerhof N. Cardiac work and efficiency. Cardiovasc Res. 2000;48(1):4–7. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/s0008-6363(00)00176-0.

    Article  CAS  PubMed  Google Scholar 

  51. Wilkinson PL, Moyers JR, Ports T, Chatterjee K, Ullyott D, Hamilton WK. Rate-pressure product and myocardial oxygen consumption during surgery for coronary artery bypass. Circulation. 1979;60(2):170–3. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.CIR.60.2.170.

    Article  CAS  PubMed  Google Scholar 

  52. Levy B, Mansart A, Montemont C, et al. Myocardial lactate deprivation is associated with decreased cardiovascular performance, decreased myocardial energetics, and early death in endotoxic shock. Intensive Care Med. 2007;33(3):495–502. https://doiorg.publicaciones.saludcastillayleon.es/10.1007/s00134-006-0523-9.

    Article  CAS  PubMed  Google Scholar 

  53. Kapur NK, Kanwar M, Sinha SS, et al. Criteria for defining stages of cardiogenic shock severity. J Am Coll Cardiol. 2022;80(3):185–98. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jacc.2022.04.049.

    Article  CAS  PubMed  Google Scholar 

  54. Schroth M, Plank C, Meiβner U, et al. Hypertonic-hyperoncotic solutions improve cardiac function in children after open-heart surgery. Pediatrics. 2006;118(1):e76-84. https://doiorg.publicaciones.saludcastillayleon.es/10.1542/peds.2005-2795.

    Article  PubMed  Google Scholar 

  55. Mayoux E, Coutry N, Lechêne P, Marotte F, Hoffmann C, Ventura-Clapier R. Effects of acidosis and alkalosis on mechanical properties of hypertrophied rat heart fiber bundles. Am J Physiol. 1994;266(5 Pt 2):H2051–60. https://doiorg.publicaciones.saludcastillayleon.es/10.1152/ajpheart.1994.266.5.H2051.

    Article  CAS  PubMed  Google Scholar 

  56. Aalkjær C, Poston L. Effects of pH on vascular tension; which are the important mechanisms? J Vasc Res. 1996;33(5):347–59. https://doiorg.publicaciones.saludcastillayleon.es/10.1159/000159163.

    Article  PubMed  Google Scholar 

  57. Wisneski JA, Gertz EW, Neese RA, Gruenke LD, Cymerman CJ. Dual carbon-labeled isotope experiments using D- [6-14C] glucose and L- [1,2,3–13C3] lactate: a new approach for investigating human myocardial metabolism during ischemia. J Am Coll Cardiol. 1985;5(5):1138–46. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/S0735-1097(85)80016-4.

    Article  CAS  PubMed  Google Scholar 

  58. Barnett AG. Regression to the mean: what it is and how to deal with it. Int J Epidemiol. 2004;34(1):215–20. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/ije/dyh299.

    Article  PubMed  Google Scholar 

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Acknowledgements

We express our deepest recognition towards Casper Elkjær (Department of Cardiology, Aarhus University Hospital) for his invaluable help with mitochondrial biopsy and biochemical analysis. We also acknowledge Professor Hans Erik Bøtker (Department of Cardiology, AUH) for expert advice and invaluable support. Finally, we thank Lasse Juul Christensen (Department of Cardiology, Aarhus University Hospital), Kasper Lykke Wethelund (Aarhus University), Buse Bor (Department of Anesthesiology and Intensive Care, AUH) and Selma Elisabeth Fogh Rubenius (Aarhus University) for their voluntary contribution with data acquisition.

Funding

The project has received funding from the Novo Nordisk Foundation (Hellerup, Denmark), the Novo Nordisk Steno Collaborative Grant (Hellerup, Denmark), Aase & Ejnar Danielsens Foundation (Kongens Lyngby, Denmark), the Graduate School of Health (Aarhus University, Aarhus, Denmark), the Independent Research Fund Denmark (Odense, Denmark), Korning Fonden (Aarhus, Denmark), and Snedkermester Sophus Jacobsen og hustru Astrid Jacobsens Fond (Copenhagen, Denmark).

Author information

Author notes

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

Authors and Affiliations

  1. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

    Oskar Kjærgaard Hørsdal, Mark Stoltenberg Ellegaard, Alexander Møller Larsen, Halvor Guldbrandsen, Niels Moeslund, Henrik Wiggers, Roni Nielsen, Nigopan Gopalasingam & Kristoffer Berg-Hansen

  2. Department of Cardiology, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, 8200, Aarhus, Denmark

    Oskar Kjærgaard Hørsdal, Alexander Møller Larsen, Halvor Guldbrandsen, Henrik Wiggers, Roni Nielsen, Nigopan Gopalasingam & Kristoffer Berg-Hansen

  3. Department of Anesthesiology and Intensive Care, Aarhus University Hospital, Aarhus, Denmark

    Mark Stoltenberg Ellegaard

  4. Department of Heart-, Lung-, and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark

    Niels Moeslund

  5. Heart Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Jacob Eifer Møller

  6. Department of Cardiology, Odense University Hospital, Odense, Denmark

    Jacob Eifer Møller & Ole Kristian Lerche Helgestad

  7. Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark

    Ole Kristian Lerche Helgestad

  8. Department of Anesthesiology and Intensive Care, Odense University Hospital, Odense, Denmark

    Hanne Berg Ravn

  9. Department of Clinical Research, University of Southern Denmark, Odense, Denmark

    Hanne Berg Ravn

  10. Department of Cardiology, Gødstrup Hospital, Gødstrup, Denmark

    Nigopan Gopalasingam

Authors
  1. Oskar Kjærgaard Hørsdal
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  2. Mark Stoltenberg Ellegaard
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  3. Alexander Møller Larsen
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  4. Halvor Guldbrandsen
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  5. Niels Moeslund
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  6. Jacob Eifer Møller
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  7. Ole Kristian Lerche Helgestad
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  8. Hanne Berg Ravn
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  9. Henrik Wiggers
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  10. Roni Nielsen
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  11. Nigopan Gopalasingam
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  12. Kristoffer Berg-Hansen
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Contributions

OKH was the first author and carried out the experiments underlying the presented data, performed the data analysis, wrote the primary draft of the manuscript and aquisited funding. MSE, AML and HG helped carrying out the experiments underlying the presented data, and contributed writing the final manuscript. NM was involved in the design of the experiments, supervised the project and contributed writing the final manuscript. JEM, OKLH, HBR developed the animal model and provided expert experimental advise and supervised the project and contributed writing the final manuscript. HW and RN provided expert supervision and were involved in the design of the experiments and contributed writing the final manuscript. NG and KBH are contributing lead investigators and were involved in funding aquisition, design, data analysis, primary draft and final manuscript.

Corresponding author

Correspondence to Oskar Kjærgaard Hørsdal.

Ethics declarations

Ethics Approval and consent to participate

The study was conducted after obtaining the necessary authorization from the Danish National Animal Experiment Inspectorate. (Hemodynamic Optimization with Carbonates, Permit no: 2023-15-0201-01466, issued on 19/06-2023). The treatment administered and ethical oversight concerning the animals strictly adhered to established animal welfare protocols and regulatory standards mandated by both Danish and European legislation. The methodologies employed and the handling of animals conformed to the guidelines outlined in the EU Directive 2010/63/EU pertaining to animal experimentation.

Consent for publication

Not applicable.

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 patentholderof 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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In this experimental study in ischemic cardiogenic shock in human-sized pigs by @OHorsdal et al, infusion with #lactate increased cardiac output due to increased stroke volume. Contractility was increased and mitochondrial function was enhanced during lactate infusion.

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Hørsdal, O.K., Ellegaard, M.S., Larsen, A.M. et al. Lactate infusion improves cardiac function in a porcine model of ischemic cardiogenic shock. Crit Care 29, 113 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13054-025-05346-2

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13054-025-05346-2

Keywords

Critical Care

ISSN: 1364-8535