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

Sepsis, considered today as a syndrome of physiologic, pathologic, and biochemical abnormalities induced by infection [1], is a major public health concern responsible for considerable morbidity and mortality [2]. Sepsis is frequently associated with a deficit in effective blood volume. Large amounts of intravenous fluid are commonly used to increase cardiac output and improve peripheral blood flow [3]. However, the clinical determination of intravascular volume can be extremely difficult, and dosing intravenous fluid during resuscitation of shock remains largely empirical [4]. In daily practice, the assessment of individual thresholds in order to avoid hypovolemia or deleterious fluid overload remains a challenge. Whereas under-resuscitation results in inadequate organ perfusion, accumulating data suggest a relationship between over-resuscitation with positive fluid balance and mortality [5‐8], but whether this represents a simple association or a cause-and-effect relationship remains unclear [9]. Liberal versus restrictive fluid management has been challenged by recent evidence, and the ideal approach appears to be an adequate initial resuscitation of patients in shock followed by a later more conservative fluid management [10]. This current strategy is often difficult to achieve with standard crystalloid solutions. In order to avoid excessive fluid, the concept of small volume resuscitation with hypertonic solutions has been developed. Low volumes of hypertonic saline fluids may have beneficial effects on the global circulation and the cardiac function that exceed simple intravascular volume expansion [11]. However, the presence of supraphysiological concentrations of chloride may increase the incidence of acute kidney injury and the use of renal replacement therapy [12]. Hence, in an attempt to avoid the detrimental effects of chloride anion, the use of metabolized anions such as lactate could be more suitable. The use of lactate as a resuscitation fluid-based energetic substrate is an interesting alternative because this anion is well metabolized [13] even in poor hemodynamic conditions [14]. Moreover, in several conditions, sodium lactate improves hemodynamics and, simultaneously, avoids fluid overload [15‐18]. We previously observed a better macrocirculatory and microcirculatory preservation together with a more negative fluid balance in a swine endotoxic model [19]. To date, three theoretical hypotheses may explain the preservation of a fluid balance with sodium lactate: first, an improvement in organ function by caloric intake; second, an improvement in organ function by a specific metabolic pathway; and third, a chloride balance with subsequent water movements.

Thus, we decided to conduct new experiments to confirm a beneficial effect on fluid balance and to determine what mechanism would be predominant in inflammatory conditions. As suggested by Fontaine et al. [20] in an editorial, we gave similar amounts of caloric intake to test the hypothesis of caloric effect in our previous control groups. Moreover, we decided to take urinary samples (with chloride dosage) at each timing of the experiment scheme to better investigate the evolution of the chloride balance between groups throughout the experiment.

We performed a randomized, open-label, controlled experimental study approved by the Institutional Review Board for Animal Research (protocol CEEA n°132012). Care and handling of the animals were in accordance with National Institutes of Health guidelines. We used here the same model already described in our previous work [19]. Detailed methods are available in Additional file 1.

Median weight was similar in the three groups of animals: 22.5 (18.25–23.75) kg in the NC group, 23 (21.75–23.5) kg in the SB group, and 23 (20.5–24) kg in the SL group. No animals died during the 5-h experiments.

In this study, we report that the infusion of sodium lactate enhances fluid balance, hemodynamics, oxygenation markers, and microcirculatory parameters. Hence, we confirm our previous results [19]; however, this time all the animals received the same amount of calories and we investigated the evolution of the chloride balance between groups throughout the experiment.

The advantage of lactate does not seem to be simply explained by its energy load. In fact, in the present study, all animals received the same caloric load. As a marker of shock severity, only the NC group developed insulin resistance (reflected by the increase in glycemia and insulinemia levels) and inhibition of gluconeogenesis (reflected by the increase in glycerol levels). Otherwise, the present study demonstrates that lactate, if used as an energy substrate, can help to avoid hyperglycemia under conditions of septic shock.

The advantage of lactate could not be explained by the chloride balance. As already described [19], we observed a negative chloride balance following SL infusion, which supported chloride urine excretion coupled to the high sodium urine excretion. In fact, the important amount of urinary sodium excretion creates an imbalance between positive and negative charges. As the urine is poor in protein (positive charges could be neutralized by the increase of negative charges on protein), a net anion efflux must therefore compensate the excess of positive charges in order to maintain electroneutrality. This is achieved in a substantial part by an increase in urinary chloride excretion [16, 25]. Chloride, the principal intracellular inorganic anion, is responsible for intracellular tonicity. In fact, recent data on Na+, K+, and Cl^– co-exchange support a significant role of chloride balance on cell volume regulation [26, 27]. Hence, the net efflux of chloride could be accompanied by a net flux of water and could participate in the larger urine output with SL infusion compared to the NC group. However, we observed the same chloride balance in the SL and SB groups. Thus, the hypertonic beneficial effect with sodium/chloride imbalance that may induce a negative fluid balance equivalent in the SL and SB groups could not explain the difference in fluid balance between the hypertonic groups.

The lactate-specific metabolic pathway may have contributed to improve hemodynamics and fluid balance. In fact, the induction of metabolic alkalosis by SL infusion could reflect the lactate oxidation. Moreover, the rapid increase in pyruvate after sodium lactate infusion strongly suggested a conversion of lactate to pyruvate. To our knowledge, this is the first time this last point has been highly suggested by in vivo data. This metabolic support could explain the better cardiac efficiency in the SL group. Indeed, evidence is now accumulating that sodium lactate may serve as a resuscitation fluid-based energetic substrate that is readily oxidizable and provides an important fuel for tissue energetics under stress or energy crisis conditions [28, 29]. It is known that lactate may improve myocardial function during shock [30, 31] and it has been shown that lactate deprivation during shock impairs heart metabolism [32].

In our model, as already described [19], the hemodynamic effects of lactate infusion seem well related to an improvement in cardiac function rather than to changes in vascular tone. SVR was not significantly modified by lactate administration, whereas CI and systolic index were higher. The rectal microcirculation was significantly enhanced in the SL group compared to both control groups. Consequently, the Pv-aCO₂ gradient remained low in the SL group while it increased significantly in the NC and SB groups. This last parameter argues for a better macro- and microcirculatory status with sodium lactate perfusion. Finally, fluid balance was significantly lower in the SL group compared to the NC and SB groups. The higher volume of urine output in the SL group could be easily explained by better macro- and microcirculatory status compared to the NC group. Nevertheless, a better hemodynamic status could not explain the large difference in fluid balance between the SL and SB groups. In fact, MAP and CI in the SB group were less decreased than in the NC group.

Another explanation for the prevention of fluid overload with sodium lactate could be an improvement in endothelial barrier function, as recently described in pediatric severe Dengue infection [17]. Although the pathogenesis of endotoxic shock is different from septic shock, endothelial cell dysfunction is common in both situations. In fact, porcine endotoxic shock is characterized by a severe vascular systemic capillary leak syndrome, and histologic findings supported the development of a respiratory distress syndrome with marked pulmonary leukocyte sequestration and interstitial edema [33]. In our model, sodium lactate infusion appeared to reduce capillary leakage, particularly in the lung. In fact, sodium lactate infusion preserved the PaO₂/FiO₂ ratio compared to the control groups, and the SL group seemed to develop a less-pronounced hypovolemia as reflected by lower tachycardia. As suggested by Somasetia et al. in dengue shock syndrome [17], we hypothesized that endotoxin challenge leads to endothelial cell swelling, which in turn increases endothelium permeability because of changes in the cell shape. We propose that lactate may lead to chloride egress from endothelial cells [34], causing the cell volume to revert back to normal, thus correcting capillary leakage. Finally, it was recently shown that lactate by itself has important anti-inflammatory properties through the activation of a specific membrane receptor that may lead to a reduced inflammatory response and endothelial activation [35].

A recently published study [36] may be viewed as challenging our results. Su et al., in an ovine model of septic shock, have shown that administration of half-molar sodium lactate resulted in an earlier onset of impaired tissue perfusion and a shorter survival time than similar infusions of 3% hypertonic saline. In our view, two main explanations can be drawn. 1) An insufficient dose of lactate; the total amount of lactate infused was only 200 mEq for a 15-h period whereas we perfused 450 mEq for a 4.5-h period (more than seven times more); hence lactate represents less than 10% of the total infused volume. 2) An under-resuscitated group; the only hemodynamic target was to maintain the pulmonary artery occlusion pressure (PAOP) at baseline levels. Consequently, the hypertonic sodium lactate group received 30% less total fluid intake than the hypertonic saline group. Thereby, the smaller fluid intake could explain the earlier impairment of tissue perfusion in this model of distributive shock.

The authors hypothesized that hypertonic sodium lactate-induced metabolic alkalosis is the most likely reason for the early decrease in tissue perfusion. Unfortunately, a control group with the same alkalinizing effect as sodium lactate was not performed to confirm this hypothesis.

Our model presents some limitations. The length of evaluation is short at only 5 h, and the endotoxic model is not a model of hyperdynamic septic shock. However, it reproduces some of the main alterations of inflammatory states, e.g., macrocirculatory and microcirculatory dysfunctions, insulin resistance, and capillary leakage, etc. We chose a MAP target of 65 mmHg, as in humans, which may be criticized. Yet, in a preclinical model of septic shock it seemed pragmatic to us to use a widely accepted MAP target in clinical practice. There were a limited number of animals per group; thus, a limited power in our statistical analyses. However, as in our previous work, we were able to detect statistical differences between groups. Finally, infusion of such a large amount of lactate will modify the serum lactate level and kinetics, and will have to be taken into account in interpreting lactate monitoring during the initial resuscitation.

In conclusion, sodium lactate infusion improves fluid balance, hemodynamics, oxygenation markers, and microcirculatory parameters in our model of endotoxic shock. The effects of sodium lactate do not seem to be explained by its energy load or its effect on the chloride balance with subsequent water movements. Two mechanisms may be advanced: first, lactate infusion is beneficial as a metabolic supplier better metabolized in poor hemodynamic conditions than glucose; and second, lactate could reduce the inflammatory response and endothelial activation attenuating capillary leakage. Further investigations are warranted to explain the underlying mechanisms and to assess the potential clinical benefits of sodium lactate resuscitation in sepsis.