Effects of vasopressinergic receptor agonists on sublingual microcirculation in norepinephrine-dependent septic shock

The current guidelines on the management of patients with septic shock recommend the use of vasopressor agents, such as norepinephrine (NE) or dopamine, to increase peripheral vascular resistance and preserve organ perfusion following adequate volume therapy [1]. Since microvascular dysfunction plays a crucial role in the pathophysiology of septic shock and organ dysfunction [2, 3], special attention should be paid to the effects of vasopressor agents on tissue perfusion and microcirculatory blood flow [4, 5]. In this regard, recent studies have demonstrated that the administration of NE to achieve a target MAP between 60 and 90 mmHg does not worsen microcirculatory perfusion [6, 7]. Whether the vasopressor per se, rather than other factors (for example, volume status, timing, hemodynamics and progression of the disease), plays a role in preserving or deteriorating capillary perfusion in septic shock is still not fully understood.

Despite their efficacy in reducing catecholamine requirements and stabilizing hemodynamics in patients with vasodilatory shock, there are concerns that the addition of vasopressinergic agents may further impair microcirculation because of their pronounced vasoconstrictive potency. Although V₁ receptor agonism may cause excessive vasoconstriction, concomitant stimulation of vasodilatory V₂ receptors may potentially improve microcirculatory blood flow. Whether the reduction of catecholamine requirements following hemodynamic support with vasopressors has a positive effect on the microcirculation is likewise unknown. Despite these relevant open questions, the available data on the effects of vasopressinergic agonists on the microcirculation in human septic shock are scarce and remain to be determined.

The objective of the present randomized, controlled, double-blind clinical study was therefore to compare, for a predefined goal MAP in patients with septic shock treated with NE, the effects of adding continuously infused low-dose terlipressin (TP), arginine vasopressin (AVP) or placebo on microcirculatory perfusion as judged by modifications of sublingual microvascular blood flow using sidestream dark-field (SDF) imaging [8].

The major finding of the present study is that in fluid-resuscitated septic shock patients treated with NE to maintain a MAP between 65 and 75 mmHg, the addition of continuously infused low-dose TP and AVP does not affect sublingual microcirculatory blood flow compared with placebo. Although TP and AVP were effective in reducing NE requirements, there were no clinically relevant effects on the microcirculation.

The current guidelines for the treatment of septic shock recommend the use of vasopressor agents to achieve a MAP ≥ 65 mmHg [1]. While pressure-guided resuscitation is usually effective in restoring MAP, microcirculatory blood flow may not be linearly improved [4, 5, 11]. This assumption is supported by studies demonstrating that although the administration of NE to achieve incremental targets for MAP between 60 and 90 mmHg does not negatively affect the microcirculation, it does not correct preexisting microcirculatory flow abnormalities [6, 7]. Conversely, in the presence of normovolemia, an improvement of microcirculatory perfusion can theoretically be obtained by vasodilator agents, because it dilates afferent arterioles while reducing efferent venous pressure [11, 12]. From a physiological perspective, AVP and (to a lesser extent) TP may exert beneficial effects on the microcirculation compared to NE, because they also exert some vasodilatory effects by nitric oxide (NO) release secondary to V₂ receptor stimulation [13‐15].

Despite the different actions of these agents on V_1a and V₂ receptors, the present study failed to demonstrate differences between the combinational therapies with TP plus NE, AVP plus NE and sole NE infusion in terms of microcirculatory variables. This finding may imply either that TP and AVP have similar intrinsic activity on V_1a and V₂ receptors or that V₂-mediated vasorelaxant effects [13‐15] are attenuated and not hemodynamically relevant. The latter assumption is supported by the fact that the study drugs were administered in the setting of progressed septic shock, where V₂-mediated vasodilation may be impaired as a result of overproduction of NO. On the other hand, the tendency toward lower NE requirements in the TP group may be explained by different intrinsic activities of the respective AVP and TP concentrations at the V_1a receptor site.

Recently, the safety of supplemental AVP has been demonstrated in the Vasopressin and Septic Shock Trial (VASST), with a potential survival benefit in patients with less severe septic shock that may support administration of the drug in the early phase of the disease [16]. Moreover, experimental studies [17, 18] and clinical studies [19] have provided evidence of a superiority of first-line TP over AVP or sole NE in stabilizing cardiovascular hemodynamics in septic shock. In addition, it has been reported that selective V₂ receptor antagonism rather than V₂ receptor stimulation stabilized cardiopulmonary hemodynamics while attenuating metabolic acidosis and tissue injury, thereby limiting organ dysfunction in early experimental septic shock [20]. A review of the results of the present study and the available literature appears to show that there are not only advantages of selective [21] or relatively selective V_1a receptor agonists, such as TP over mixed vasopressinergic agonists like AVP, but also, more importantly, that the relationship between vasopressinergic receptor agonists and the timing of administration (early vs. late) may be crucial in preserving or deteriorating organ function.

In line with the above-referenced studies [16‐21], and supported by the results of our present study, it appears that delayed administration of TP or AVP may not translate into microcirculatory advantages over sole NE, although TP and AVP are still effective in reducing catecholamine requirements. The right timing of administering vasopressinergic agents, however, is still debated. In this context, Kampmeier et al. [22] recently reported that early TP infusion reduced catecholamine and fluid requirements compared with delayed TP therapy and placebo in ovine septic shock.

In harmony with the effects on the microcirculation, and in line with previous experimental and clinical studies [17‐19, 23], we did not notice differences in arterial pH or in lactate concentrations following TP or AVP administration, suggesting a lack of drug-related impairment of cellular oxygenation as well as the absence of differences in resuscitation quality between groups. In this context, it is also important to note that the multicenter VASST study [16] demonstrated no differences between AVP and sole NE in the rate of overall adverse events.

Interestingly, we observed a time-dependent improvement in some microcirculatory variables in all study groups. The beneficial evolution in the NE group over time is in agreement with a recent study by Boerma et al. [24], who reported an increase in MFIs even in the placebo group. In this regard, it may be possible that some patients experienced a beneficial evolution with respect to their course of disease during the study period. Another possible explanation is that fluid therapy administered over a short observational period, such as in our protocol, resulted in further recruitment of the microcirculation in some of the patients [25, 26]. However, it is important to note that only limited amounts of fluids were given (see Table 2) and that changes were similar between groups.

In the present study, we did not find differences between the study drugs when vasopressor support was titrated to maintain MAP between 65 and 75 mmHg. Nonetheless, we cannot exclude the possibility that a lower threshold MAP would have generated different results, thereby further reducing excessive NE requirements. It also cannot be excluded that the involvement of inflammatory mechanisms mediated by leukocyte activation and cytokine release, as well as hemorheological factors related to the progression of the disease, affected the microcirculatory blood flow more than the choice of vasopressor. Evaluation of these factors, however, was beyond the scope of the present study.

Our study has some limitations that we must acknowledge. First, our protocol did not allow us to draw conclusions regarding whether the observed findings were related mainly to a direct effect of vasopressinergic agents on microcirculation or to a concomitant reduction of NE dosage per se. However, we chose this protocol to mimic the clinical scenario, in which AVP and TP are currently used as adjuvant vasopressor support in established, NE-dependent septic shock. Since there are no equivalent doses of AVP and TP for continuous infusion, we decided to evaluate the effects of fixed doses of the study drugs on microcirculatory blood flow while maintaining the threshold MAP with titrated NE infusion. In this regard, it might be argued that a weight-adjusted TP dose was compared with a fixed AVP dose, and thus the chosen doses might not have been pharmacologically equivalent. Therefore, it is possible that the TP dose was relatively higher than the AVP dose. Second, we chose changes in MFIs as the primary end point of this study. Since we investigated only a small number of septic shock patients treated over a brief period, the risk of false-negative or false-positive results in a study with numerous microcirculatory variables has to be taken into account. Moreover, the marginally significant difference in PVD at baseline (P = 0.04) represents a limitation of the present study. However, the fact that > 20 variables were compared with a significance threshold of 5% indicates a high probability of significant differences in the absence of true clinical relevance. Since the difference in PVD was the only one observed at baseline, it probably had no major impact on the quality of the present data. However, it cannot be definitively excluded that the opposite is the case. In addition, we cannot rule out the possibility of divergent microcirculatory effects in response to more prolonged administration of the study drugs. When looking at the technique adopted in the present study, we have to acknowledge that whereas SDF imaging allows real-time imaging of the intact microcirculation in the clinical setting, the assessment of some microcirculatory variables that result from this technique remain semiquantitative and the data reliability may be affected by level of technical expertise and interobserver bias. Furthermore, we investigated the changes in microvascular perfusion of the sublingual mucosa, which may not necessarily be representative of alterations in other tissues [2, 27, 28]. Whether applying a different method to determine fluid responsiveness would have generated different results cannot be answered by the present study.