Microcirculation First!—Esmolol, a Candidate for the Next Term of Office*

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During the last decade, awareness of the relevance of microcirculatory perfusion for pathophysiologic mechanisms and its importance for therapeutic success increased rapidly. However, individual effects of different hemodynamically active compounds on microvascular blood flow in sepsis have not been clarified completely (1–3). Capillary perfusion depends on the gradient between inflow pressure and outflow pressure. The inflow pressure is regulated by vasomotor tone of arterioles and precapillary sphincters and depends on the pressure gradient from mean arterial pressure (MAP) to the arterial critical closing pressure (Pcc, the pressure threshold that coincides with the stop of organ blood flow). The outflow pressure is the pressure gradient from the mean systemic filling pressure (Pmsf) to central venous pressure (CVP). Even if MAP drops to Pcc, a pressure gradient between Pcc and Pmsf (the vascular waterfall) is still preserved, maintaining capillary perfusion even during low-flow conditions. The vascular waterfall phenomenon even explains why changes in CVP minimally affect capillary flow (4). In this issue of Critical Care Medicine, Du et al (5) reported their remarkable findings of an experimental study investigating the effects of endotoxemia and several therapeutic approaches, such as volume expansion, norepinephrine, and the selective β1-blocker esmolol, on systemic hemodynamics and renal microcirculatory perfusion with a special focus on renal microvascular pressure gradients and vascular waterfall phenomenon.
First, the authors demonstrated that endotoxemia caused a massive loss of smooth muscle tone leading to a parallel decrease of both MAP and Pcc with a subsequent inactivation of vascular waterfall. Based on these results, such loss of vascular waterfall should be considered as a contributing mechanism involved in the septic microcirculatory derangement. Second, they confirmed that the restoration of adequate systemic hemodynamics or macrocirculation, respectively, does not always correspond to parallel improvement of microcirculatory perfusion (loss of hemodynamic coherence). Although volume resuscitation increased cardiac output and MAP, it did not increase Pcc as it depends on the tone of precapillary sphincters (4). As a consequence, vascular waterfall remained ineffective following volume administration. This finding is relevant for clinical practice because on this condition Pcc may become equal to Pmsf. Furthermore, excessive fluid administration and/or reduced right ventricular performance (i.e., backward failure) may increase outflow pressure further worsening capillary perfusion.
MAP-guided resuscitation with norepinephrine in septic shock did not restore microcirculatory alterations, previously (6). In the present study (5), norepinephrine increased MAP but not Pcc adding new insights on the effects of vasoconstrictors on the septic impaired microcirculation. Heterogeneity in adrenergic receptor distribution and desensitization as well as differences in vascular reactivity between distributing arteries, arterioles, and precapillary sphincters may account for this response. This hypothesis is partly supported by the fact that septic microcirculatory dysfunction is characterized by the simultaneous presence of stopped-, normal-, intermittent-, and high-flow perfused capillaries. Thus, contrary to larger vessels, the precapillary sphincters capability to respond to a supraphysiologic stimulation with norepinephrine may be profoundly altered by the septic insult. Nevertheless, this assumption remains speculative as the exact location of the vascular waterfall is unknown.
Sepsis and septic shock are typically characterized by a hyper adrenergic state which may lead to multiple adverse effects (7–9). Accordingly, there is growing interest in the use of β-adrenergic blockade in septic shock with the aim to mitigate the adverse effects caused by sympathetic overstimulation (10). Long-term administration of β-blockers and continuing chronic β-blockade in the acute phase of severe sepsis and septic shock may be associated with decreased mortality rates (11, 12). As tachycardia may be considered a clinical hallmark of adrenergic overstimulation and contributes to poor outcomes, heart rate has been chosen as a target for β-blocker titration in several studies.
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