Following study enrolment, patients were randomised to receive either half-molar sodium lactate (Kalsolac; Aguettant Santé SA, Lyon, France), denominated the lactate group, or Hartmann’s solution (Compound Sodium Lactate Solution; Baxter Australia, Old Toongabbie NSW, Australia), classified as the control group. Randomisation was carried out in blocks of variable size in sequentially numbered, opaque, sealed envelopes provided by an independent statistician. After baseline parameters were recorded and transthoracic echocardiography (TTE) was performed, patients were given an intravenous bolus of 3 ml/kg actual body weight (ABW) of the assigned fluid according to randomisation over the course of 15 minutes. A continuous infusion of half-molar sodium lactate at 1 ml/kg/h ABW for 24 hours was then infused in the lactate group. To prevent potentially harmful fluid overload, no additional study fluid was infused in the control group. The Scientific Committee of the local Ethics Committee mandated this aspect of the protocol. Both groups received standard therapy for AHF according to best practice, which included a combination of inotropes, vasopressors, vasodilators, diuretics, intraaortic balloon counterpulsation and mechanical ventilation as required. Patients had TTE performed 24 and 48 hours after enrolment, except for those who died or were discharged from the ICU. Arterial blood gas analysis was performed at baseline, after the initial study fluid bolus and together with other laboratory and vital sign parameters at 6, 12, 24 and 48 hours after enrolment. These laboratory examinations included fluid balance, electrolytes, full blood count and renal and liver function tests. All patients were followed up for up to 90 days.

Qualified sonographers or clinicians performed TTE using ultrasound systems equipped with tissue Doppler (Vivid i, Vivid q or Vivid 7; GE Healthcare, Oslo, Norway). LVEF was estimated on the basis of apical two- and four-chamber views according to Simpson’s formula as recommended by the American Society of Echocardiography 19 . CO was obtained by multiplication of stroke volume (SV) by heart rate (HR) in the left ventricular outflow tract (LVOT) using the Doppler method. SV was determined as follows: π × (LVOT diameter ÷ 2)² × Velocity time integral (VTI) of the blood flow signal in the LVOT. The LVOT diameter was obtained from the parasternal long axis, and the LVOT VTI was determined from the apical five-chamber view using pulsed wave Doppler (PWD). Tricuspid annular plane systolic excursion (TAPSE) in the apical four-chamber view was recorded to assess right ventricular systolic function. Early mitral inflow velocity (E) was measured by PWD at the tip of the mitral valve during diastole, and tissue Doppler imaging–derived early diastolic motion velocity (E′) and systolic motion of the mitral annulus (averaged medial and lateral) by tissue Doppler imaging (SmTDI) were obtained by placing the sample gate at the level of the mitral annulus of the interventricular septum and lateral wall in the apical four-chamber view. E′ and SmTDI from both locations were averaged as recommended previously 20 . A qualified cardiologist and intensivist (RP), who was blinded to treatment assignment, reviewed and measured offline all TTE parameters as appropriate. Intra- and interobserver variability from a random sample of ten patients were calculated.

The primary study outcome was CO at 24 hours after study entry, which was measured by TTE as described above. Secondary outcome parameters included SmTDI, E/E′ ratio and TAPSE, overall fluid balance, blood pressure, acid-base status, electrolytes, renal and liver function tests, need for mechanical ventilation (including noninvasive), ICU and hospital lengths of stay and 28- and 90-day mortality.

Data are expressed as mean ± standard deviation (SD). Between-group and within-group differences due to treatment (lactate vs. control) were assessed by two-way repeated-measures analysis of variance and Fisher’s exact test for qualitative data (that is, number of additional treatments used). In cases where significant intra- or intergroup differences were present, pairwise post hoc analyses were performed by using Student’s t-test. The significance level was set at 0.05 and adjusted for multiple comparisons by the Bonferroni correction method. To adjust for baseline imbalances and the unequal amount of intravenous fluid in the study groups, the ‘regression to the mean’ effects and analysis of covariance (ANCOVA) were carried out using a linear model containing primary outcome as the dependent variable, with treatment as a dummy variable with baseline CO and 24-hour fluid balance used as the covariates. Time to events data were analysed using Kaplan-Meier statistics with survival compared using a logrank test. This trial was a pilot study, so no formal sample size calculation was possible. An arbitrary number of 40 patients was chosen.

The mean arterial blood pressure remained unchanged throughout the study period in both groups (Table 2). The mean CO was lower in the lactate group at baseline (4.05 ± 1.37 L/min vs. 4.72 ± 1.3 L/min), but this difference was not significant. There was no change in mean CO over time in the control group (4.96 ± 1.21 L/min at 24 hours and 4.76 ± 1.58 L/min at 48 hours). At the end of the 24-hour period, CO significantly increased in the lactate group (5.49 ± 1.9 L/min; P < 0.01) and remained higher than at baseline at 48 hours (4.87 ± 2.38 L/min; P = 0.026). The improvement in CO remained significant even after adjusting for the baseline imbalance by ANCOVA (Table 3). The temporal change in individual CO over time is presented in Figure 2. The intra- and interobserver variability of CO measurements were 5.9% and 7.2%, respectively. When the components of CO were analysed separately, SV changes, but not HR changes, were responsible for the increase in CO. Similarly, the right ventricular systolic function (TAPSE) was unchanged in the control group but improved in the lactate group (P = 0.02) (Table 2). The SmTDI and E′ values were not significantly different at any time point in either group, although there was a trend toward increased SmTDI in the lactate group at 24 hours. Although E/E′ was unchanged over 24 hours in the lactate group (14.4 ± 6.8 to 15.2 ± 7.6), it was reduced (17.3 ± 8.3 to 13.5 ± 4.7; P = 0.03) in the control group, suggesting reduction in left atrial pressure (Table 3). There were no significant intergroup differences in the concomitant use of vasoactive and inotropic therapy or in the use of intraaortic balloon counterpulsation, although fewer patients in the lactate group required vasopressor support at 24 hours. More patients were invasively ventilated in the lactate group than in the control group (Table 4).

^a E/E′ = Ratio of early peak diastolic transmitral Doppler flow velocity to early peak diastolic tissue Doppler velocity of the mitral annulus (averaged medial and lateral); HR = heart rate (beats/min); MAP = Mean arterial pressure (mmHg); SmTDI = Systolic motion of the mitral annulus (averaged medial and lateral) by tissue Doppler imaging (cm/s); SV = Stroke volume; TAPSE = Tricuspid annular plane systolic excursion (mm). ^b P < 0.05 and ^c P < 0.01 compared to baseline values. Data are expressed as mean ± SD.

^aβ: Regression coefficient; CI: Confidence interval; CO: Cardiac output. F-value for the model = 12.12. P < 0.001.

^aIABP = Intraaortic balloon counterpulsation device. Vasopressors are noradrenaline or adrenaline. Levosimendan (12.5 mg) was administered at 0.1 μg/kg/min over the course of 24 hours during the study period. Infusions were always started prior to study enrolment. All data are expressed as number of patients, except for vasopressor dose, for which data are expressed as mean ± SD.

There were no significant changes in any of the acid-base parameters in the control group apart from significant increases in bicarbonate levels and base excess (BE) at 48 hours. In the lactate group, pH increased from 7.4 ± 0.06 to 7.45 ± 0.05, bicarbonate from 23.3 ± 3.3 to 25.9 ± 4.1 mmol/L, BE from -0.3 ± 4.1 to 2.7 ± 4.2 mmol/L and lactate from 2.4 ± 2.3 to 4.8 ± 2.0 mmol/L (all P < 0.01) within 15 minutes of half-molar sodium lactate solution bolus. The pH, bicarbonate and BE continued to rise over the 24-hour period (all P < 0.01). Once the half-molar sodium lactate infusion ceased, pH, bicarbonate and BE declined, but they remained higher than either baseline or the control group at 48 hours. Plasma lactate remained elevated during the infusion; however, the mean lactate at 24 hours was similar to baseline and declined further, so that it was lower than in the control group at 48 hours (Table 5).

^aBE = Base excess (mmol/L); HCO₃ ^- = Bicarbonate (mmol/L); PaCO₂ = Partial pressure of carbon dioxide (mmHg); PaO₂ = Partial pressure of oxygen (mmHg). ^b P < 0.01 compared to baseline values and ^c P < 0.01 for intergroup comparison. Data are expressed as mean ± SD.

There were significant changes in electrolyte levels in the lactate group. The sodium level increased from 136 ± 4 mmol/L at baseline to 146 ± 6 mmol/L at 24 hours (P < 0.01). We also noted a significant decrease in levels of potassium (4.2 ± 0.7 to 3.3 ± 0.4 mmol/L; P < 0.01), chloride (104 ± 7 to 98 ± 9 mmol/L; P < 0.01) and phosphate (1.23 ± 0.46 to 0.98 ± 0.40 mmol/L; P = 0.04), despite clinically driven supplementation. There were no significant changes in electrolyte levels in the control group (Table 6).

^aCl - = Plasma chloride concentration (mmol/L), Crea = Plasma creatinine concentration (μmol/L), K⁺ = Plasma potassium concentration (mmol/L), Na⁺ = Plasma sodium concentration (mmol/L), P = Plasma phosphate concentration (mmol/L). ^b P < 0.01 compared to baseline, ^c P < 0.05, ^d P < 0.05, ^e P < 0.01 intergroup comparison. Data are expressed as mean ± SD.

The fluid balance in the first 24 hours was 1,296 ± 1,633 ml in the lactate group versus 845 ± 1,421 ml in the control group. The fluid balance was -339 ± 1,453 ml in the controls and 230 ± 991 ml in the lactate group from 24 to 48 hours. Once adjusted for the volume of study fluid, the mean fluid balance was 586 ml in the control group and -843 ml in the lactate group at 24 hours, and it was -598 ml and -1,909 ml in the control and lactate groups, respectively, at 48 hours. We found no correlation between fluid balance and the change in SV in the lactate group and a slightly negative correlation in the control group at 24 hours. After adjusting for fluid balance by ANCOVA, the results still showed strong support for a treatment effect of lactate, with the lactate group exhibiting an estimated CO of 0.91 L/min more, on average, than the control group (P = 0.011) (Table 3).

There were no significant differences in other organ functions between the groups, although serum creatinine (Table 4) tended to be lower in the lactate group. Likewise, there was no significant difference between the groups regarding the ICU and hospital length of stay or 28-day mortality (five in the lactate group vs. four in the control group) or 90-day mortality (five in each group).

We conducted a pilot, single-centre, open-label clinical trial. Despite the relatively small number of randomised patients, we demonstrate a significant effect of half-molar sodium lactate on cardiac function, a finding similar those reported by others 18 26 . We did not utilize continuous measurement of CO in our study, because this is not a universal practice in our ICU. Instead, we used comprehensive echocardiographic assessment by skilled operators, and a qualified reporter blinded to treatment group assignment measured the echocardiographic parameters. An important limitation of this study is the imbalance in the amount of fluid infusion between the two groups, resulting in possible confounding effects of positive fluid balance. However, the ANCOVA shows that, after adjusting for the nonsignificant baseline imbalance in CO and the fluid balance over the course of 24 hours, CO still significantly increased in the group that received lactate. Despite the increase in CO, there was no effect on length of ICU or hospital stay, mechanical ventilation or survival; however, the study was not sufficiently powered for those endpoints.