Effects of dexmedetomidine and esmolol on systemic hemodynamics and exogenous lactate clearance in early experimental septic shock
The use of dexmedetomidine and esmolol was associated with lower arterial and portal lactate levels, and less impairment of exogenous lactate clearance in a model of septic shock. Both drugs were well tolerated when started very early after shock induction. DEX and ESM appear to be associated with beneficial effects on gut lactate generation and exogenous lactate clearance, and exhibit no negative impact on systemic hemodynamics.
Dexmedetomidine, an ?2-agonist, attenuates sympathetic response to stress, and lowers epinephrine levels without adverse consequences on tissue perfusion [27–34]. Several experimental studies have consistently found anti-inflammatory effects and improvement in microcirculatory flow [32–34]. The drug is relatively well tolerated in anesthetized or critically ill patients, and even a post hoc analysis of the MENDS trial suggests an impact on mortality in septic patients [31]. Therefore, it could be useful as an adrenergic modulator in this setting.
On the other hand, the supporting evidence for ?-blockers in sepsis is weak. Some small experimental and clinical studies have shown favorable effects on HR and hemodynamic or perfusion parameters, and also in inflammatory and metabolic parameters, particularly with nonselective blockers since most of these latter effects are ?2 mediated [35]. However, ?1 blockade could also exert anti-inflammatory effects, as was demonstrated by Hagiwara et al in a LPS rat model, on which an ultrashort-acting ?-blocker inhibited nuclear factor-kappa B activity and attenuated histological lung damage [42]. Recently, a growing interest in esmolol, a short-acting selective ?1-blocker has arisen mainly because of its pharmacokinetic characteristics [36–39]. An elegant experimental septic shock study found that ESM improves cardiac contractibility and vascular reactivity probably in relation to an anti-inflammatory effect [37]. In a randomized controlled study in stable septic shock patients, ESM reduced heart rate, decreased fluid requirements and lactate levels, and surprisingly showed a significant effect on mortality [38].
A disproportionate sympathetic response can be detrimental to critically ill patients as was demonstrated decades ago in another context such as chronic heart failure [22, 26]. Therefore, a growing interest in adrenergic modulation has arisen [22–26]. The big dilemma is to what extent can adrenergic modulation or blockade be accomplished without affecting basic survival responses especially in systemic hemodynamics. We found that both DEX and ESM appear to be well tolerated when started very early after shock onset, not only in terms of CO, MAP or NE requirements, but also from a metabolic point of view since both SvO2 and p(v-a)CO2 were comparable to LPS-controls. Furthermore, DEX and ESM were associated with favorable effects on both lactate generation and clearance as will be commented upon below. The few septic shock studies, in which ESM was assessed, started the drug hours after initial stabilization [38, 40]. In the case of DEX, this drug is not frequently used for primary sedation in septic shock patients due to the risk of inducing hemodynamic instability. DEX and clonidine might have opposite actions on vasomotor tone, a direct vasopressor, and indirect vasodilatory effects, with variable impact on MAP. When administered in healthy volunteers, DEX exerts a biphasic response, an initial increase in MAP due to stimulation of postsynaptic ?2b receptors followed by a long-lasting fall in MAP due to its central sympatholytic action with a decrease in epinephrine and NE blood levels [43]. Some investigators have tested the hypothesis that central sympaticolysis might help to restore adrenergic vasoconstrictor responsiveness in septic shock by reversing downregulation of alpha receptors secondary to high endogenous catecholamines, and some experimental data tend to support this as feasible [27, 44]. However, this effect might take longer time. In any case, the hemodynamic tolerance exhibited by both drugs in our study opens new opportunities for research in this relevant subject.
Septic shock triggers a strong compensatory sympathetic activation with a wide array of circulatory, metabolic and immune effects that could potentially impact lactate production or clearance [22, 26]. Among metabolic effects, epinephrine stimulates aerobic glycolysis in skeletal muscle cells through ?2 stimulation. This process generates and releases lactate into the systemic circulation as a metabolic fuel [10, 11]. A dysregulated sympathetic stress response or exogenous catecholamines could also impair hepatosplanchnic or microcirculatory flow at the gut or the liver through excessive vasoconstriction, triggering anaerobic lactate generation and potentially impairing hepatic lactate clearance [15–21]. We designed our study to address three potential sources for persistent hyperlactatemia on which an overactive sympathetic response could exert some influence. DEX induced a 37 % reduction in serum epinephrine levels, but noteworthy, this was not associated to any negative effect, neither on hemodynamics, nor in muscle lactate outflow. Muscle lactate production can be decreased experimentally by different approaches and inversely, exogenous ?2-adrenergic stimulation with epinephrine and other ?2-agonists increases aerobic lactate generation [10, 11]. In this latter case, the threshold over which epinephrine might hasten muscle lactate outflow is unknown but clearly DEX in relatively high doses did not affect this process.
The effects on the hepatosplanchnic region are of particular interest. We observed that LPS animals treated with ESM and DEX exhibited less increase in portal lactate levels as compared with LPS controls. Additionally, portal venous O2 saturation decreased over time only in controls, whereas total hepatic blood flow tended to decrease in all groups. Progressive gut hypoperfusion eventually ameliorated by adrenergic modulation or blockade could explain these findings. Unfortunately, the study design does not allow us to affirm this with certainty since we did not measure mesenteric or mucosal microcirculatory flow directly. Clinical and experimental studies have yielded conflicting results on splanchnic lactate balance in sepsis [45–54]. While some studies report anaerobic lactate generation by the gut as regional flow decreases, other have minimized the contribution of gut-generated lactate to systemic hyperlactatemia, since most of this lactate would be normally cleared by the liver [45–54]. Nonetheless, if hepatic lactate clearance is simultaneously impaired, the systemic impact of gut-generated lactate might be higher.
In a previous study using the same model, LPS induced an early and severe impairment in exogenous whole body net lactate clearance that was not related to total liver hypoperfusion or evident biochemical dysfunction [13]. Indeed, the very low porto-hepatic vein lactate differences suggested at least a liver metabolic inability to handle increased lactate loads. The decrease in lactate clearance reached a 10 % of sham values at the end of the experiments [13]. In the present study, exogenous lactate clearance fell to extremely low levels in LPS-controls similarly than in our previous study, but this decrease was significantly attenuated both in DEX and ESM groups. The combined effects on gut perfusion and lactate clearance might explain the impact of DEX and ESM on serum lactate levels.
How can DEX and ESM actions decrease gut lactate generation or influence exogenous lactate clearance? We did not design this study as a mechanistic one, and therefore we can only speculate about the mechanisms. ?2-agonists such as DEX can attenuate the sympathetic response to surgery, decreasing circulating catecholamine levels in at least 10 to 20 %, but in our LPS model it was almost 40 % [27, 28]. Interestingly, DEX might exert opposite actions on vasomotor tone, a direct vasopressor and indirect vasodilatory effects, with variable impact on MAP [27, 28]. However, some experimental studies have shown that ?2 agonists could have predominantly favorable effects over the gut microcirculation [33, 34], a particularly vulnerable territory [55]. Yeh et al found that DEX prevented gut microcirculatory abnormalities induced by sympathetic activation after surgical stress in rats [33]. Miranda et al found a significant attenuation of capillary perfusion deficits with DEX in a LPS model [34]. Thus, it is possible that the favorable effect of DEX on portal lactate levels might be consequence of an attenuated adrenergic vasoconstriction on mesenteric or gut microcirculatory flow. It is more difficult to explain the effects of ESM since no direct vascular effect can be postulated. However, some experimental studies have shown protective vascular or microcirculatory effects potentially related to immunomodulation, or increased release of endothelial nitric oxide among other actions, but this should be confirmed by further research [35–38]. It is also well known that LPS can induce acute portal hypertension resulting in gut mucosal hypoperfusion [56] and that nonselective ?-blockers might reduce portal hypertension, but this effect might not be extrapolated to ?1-selective blockers. The favorable impact of DEX and ESM on exogenous lactate clearance can be hardly explained by hemodynamic effects, since only a small difference in total hepatic blood flow compared to controls was observed at the end of the experiments. Potential liver microcirculatory or cellular effects of DEX and ESM should be explored in future studies.
We acknowledge several limitations of our study. First, we did not assess directly gut or liver microcirculation, thus this precludes us establishing any conclusion on the microvascular effects of both drugs. Second, we did not evaluate immunological aspects or biomarkers, eventually missing the exploration of the impact of adrenergic modulation at this level in our model. Third, small differences in portal and hepatic vein lactate levels between ESM and controls were observed at baseline and after shock induction. Biological variability in response to surgical stress or LPS could explain this finding, but the strong differences still observed at points C and D support our conclusions. Fourth, since our study was not aimed at comparing DEX with ESM, but rather both drugs against LPS controls, we cannot formulate any conclusion concerning eventual superiority of one over the other. Finally, our study can be considered only as hypothesis-generating and therefore these results should be confirmed and expanded in further research.