The Microcirculation as a Therapeutic Target in the Treatment of Sepsis and Shock

Vanina S. Kanoore Edul, M.D.; Arnaldo Dubin, M.D., Ph.D.; Can Ince, Ph.D.

Disclosures

Semin Respir Crit Care Med. 2011;32(5):558-568. 

In This Article

Therapeutics Strategies to Recruit the Microcirculation

The presence of microcirculatory distress despite resuscitation based on global hemodynamic variables strongly suggests that microcirculatory failure is a key factor in poor outcome. At this point, perhaps the more relevant clinical questions are the following: (1) can the microcirculation be recruited by therapeutic approaches; (2) if so, can the recruitment of the microcirculation be used as a therapeutic end point; and (3) are therapeutic improvements in the microcirculation associated with a decreased mortality rate? Although the available scientific evidence to answer these questions is scarce, several studies have investigated the response of the microcirculation to different therapeutic modalities. To date, however, most of the studies performed have been single-center observational studies.

Corticosteroids are very effective at inhibiting inducible nitric oxide synthase (iNOS) and improving hemodynamic compromise. High-dose steroids prevent endotoxin-induced hypotension in animal models of sepsis when administered before the lipopolysaccharide (LPS) challenge.[54] Late administration, however, had no beneficial effect.[55] The effects of low-dose hydrocortisone on sublingual microcirculation was studied in 20 patients with septic shock. There were subtle improvements in sublingual microvascular perfusion at 1 hour after the start of hydrocortisone administration.[56] The impact of this study is difficult to evaluate because such doses have been shown not to improve survival or reverse shock.[57]

The rationale for the use of vasodilators in sepsis is based on the experimental findings of pockets of ischemic areas lying close to well-perfused zones.[11] Vasodilators may increase the driving pressure of blood flow at the entrance of the microcirculation and perfuse hypoxic zones.[58] As previously mentioned, NO donors in combination with fluids improved microcirculatory oxygenation and corrected gastric pCO2 in a porcine model of sepsis. In a small series of septic patients, Spronk et al found an improvement in sublingual perfusion after a bolus of 0.5 mg followed by an infusion of 2 mg/h nitroglycerin in the pressure resuscitation of septic shock patients.[59] Recently, in contrast to this study, a prospective, single-center, randomized, placebo-controlled, double-blind clinical trial showed that nitroglycerin has no beneficial effects on improving sublingual microcirculatory perfusion.[60] Moreover, there was a trend of increased mortality, although the study was not powered for testing the outcome in patients treated with nitroglycerin. However, the organ function in the survivors of the nitroglycerine group was better than that of the survivors in the nonnitroglycerine group.[60]

When the mean arterial pressure (MAP) decreases below an autoregulatory threshold of ~60 to 65 mm Hg, organ perfusion becomes pressure dependent.[61] During sepsis, vascular reactivity can be shifted to an autoregulatory threshold with higher values,[62,63] and, consequently, the increase in MAP could improve tissue perfusion. However, vasopressors, although effective in increasing arterial pressure, may do so at the expense of decreased microcirculatory flow,[64,65] suggesting that, in some circumstances, excessive vasoconstriction could be deleterious to the microcirculation.

Jhanji et al recently demonstrated that increasing doses of norepinephrine, while successful in increasing the MAP from 60 to 90 mm Hg, resulted in an increase in global DO2 and caused no change in cutaneous microvascular flow and tissue pO2 or in sublingual microcirculation.[66] In a similar study, we evaluated the effects of titration of a norepinephrine infusion on the sublingual microcirculation to increase the MAP from 65 to 75 and then to 85 mm Hg. Our main finding was that increasing the MAP with norepinephrine failed to improve sublingual microcirculation or any other variable related to tissue oxygenation or perfusion such as arterial lactate, anion gap, ΔpCO2, and oxygen-derived parameters. Interestingly, there were considerable variations in the individual responses that were strongly dependent on the basal condition of the microcirculation.[67] An unexpected finding of this study was that the perfused capillary density improved in patients with an altered sublingual perfusion at baseline and decreased in patients with a preserved baseline microvascular perfusion (Fig. 3). These data suggest that the optimal MAP for the microcirculation should be selected on an individual basis whereby microcirculatory compromise should be taken into account.

Figure 3.

(A) Individual behavior of sublingual perfused capillary density. Results are shown as the mean arterial pressure (MAP) was increased from 65 mmHg to 85 mmHg with norepinephrine. (B) Relationship between the changes of perfused capillary density when mean arterial pressure was increased from the baseline to a MAP of 85 mmHg, with the basal perfused capillary density at a MAP of 65 mmHg. Reproduced with permission from Dubin et al.[67]

De Backer et al studied the effects of dobutamine (5 μg/kg/min for 2 hours) in 22 patients with septic shock.[68] Dobutamine significantly improved capillary perfusion, but the changes were independent of changes in systemic hemodynamic variables. In addition, it was found that a reduction in lactate levels was not associated with changes in the cardiac index or MAP but rather in improved microcirculatory perfusion.

Levosimendan is an inotropic and vasodilator drug that has been proven useful in cardiogenic shock. Also, retreatment with levosimendan in experimental hypodynamic septic shock in pigs has shown valuable effects on oxygen transport. We evaluated the effects of levosimendan in a normodynamic sheep model of endotoxemia. Levosimendan improved oxygen transport and prevented the development of intramucosal acidosis; however, systemic hypotension and lactic acidosis occurred.[69] Then we tested the hypothesis that levosimendan, at doses lower than those used in our previous study, had a beneficial effect during sepsis by avoiding elevations in intramucosal arterial pCO2 difference (ΔpCO2) through increases in systemic and intestinal oxygen transport without producing hypotension or elevations in lactate. We compared the oxygen transport and hemodynamic responses of an experimental model of septic shock infused with levosimendan or dobutamine. Levosimendan prevented the decreases in systemic and intestinal oxygen transport and diminished the development of intramucosal acidosis; it also corrected pulmonary hypertension.[70]

In patients with myocardial dysfunction related to sepsis, Morelli et al evaluated the infusion of levosimendan compared with dobutamine after 48 hours of persistent myocardial depression. The levosimendan group presented a better pCO2 intramucosal minus arterial gradient, better perfusion assessed by laser Doppler-measured gastric mucosal perfusion, and lower arterial lactate levels.[71] The same group of researchers recently performed a prospective, randomized, double-blind clinical trial to investigate microcirculatory blood flow in patients with septic shock treated with levosimendan compared with dobutamine. The primary end point was a difference of ≥20% in the microvascular flow index of small vessels (MFIs) among groups. Levosimendan improved sublingual microcirculatory blood flow, although the difference in MFI was very subtle.[72]

Fluid resuscitation is the first-line therapy for sepsis-induced hypoperfusion, but there are few data on the effects of fluid administration on microcirculatory alterations during sepsis. Ospina-Tascon et al studied the effects of early (within 24 hours) or late (more than 48 hours) volume expansion using 1000 mL Ringer's lactate or 400 mL 4% albumin solutions.[73] Sublingual microvascular perfusion increased in the early but not in the late phase of sepsis. The effect was independent of global hemodynamic effects and the type of solution used. However, we showed that the use of hydroxyethyl starch (HES) 130/0.4 allowed better resuscitation of the microcirculation.[74] In a randomized, controlled pilot study, we compared the effects of the EGDT using 6% HES 130/0.4 (n = 9) or saline solution (n = 11) on the sublingual microcirculation of septic shock patients. Despite the fact that similar goals of resuscitation, such as MAP, CVP (central venous pressure), ScvO2 (central venous oxygen saturation), and urine output, were achieved in both groups according to a modification of an algorithm proposed by Rivers et al,[75] the characteristics of the microcirculation were quite different. These results are in line with extensive experimental research that shows beneficial effects of starches on the microcirculation.[76,77] These findings justify a larger clinical trial to confirm the beneficial effects of 6% HES/0.4 on microvascular perfusion and to determine if these improved parameters are associated with an improved outcome.

Sakr et al studied 35 patients with severe sepsis who required RBC transfusions.[78] Microvascular perfusion was not significantly altered by transfusion, but there was considerable interindividual variation. The change in capillary perfusion after transfusion correlated with baseline capillary perfusion. Therefore, sublingual microcirculation can improve in patients with altered capillary perfusion at baseline. In addition, the type of storage process and time may affect the efficacy of RBC transfusions over tissue oxygenation. In a group of cardiac surgical patients, Yuruk et al recently showed that blood transfusion improved microcirculatory Hb availability and saturation, not by improved microcirculatory flow but rather by recruiting the microcirculation, as shown by enhanced functional capillary density associated with a reduction in diffusion distances.[79]

Alterations in coagulation and fibrinolysis may play a role in the microvascular disorders of sepsis. De Backer et al studied a series of patients with severe sepsis who received activated protein C with others who received a contraindication to the drug administration. The proportion of perfused capillaries increased in patients treated with activated protein C but not in the control group. In addition, microvascular perfusion decreased transiently at the end of activated protein C infusion.[80] Unfortunately, the scope of this study was limited because of the uncertainties of the use of activated protein C.[81]

In summary, the present review of the current literature shows persistent microcirculatory alterations in critically ill adult and pediatric patients. In addition, the literature shows that various therapeutic approaches are effective in recruiting the microcirculation. Nevertheless, it is unclear whether such a therapeutic approach aimed at recruiting the microcirculation contributes to an improved outcome. Controlled studies are now needed in a protocol-driven resuscitation strategy aimed at improving the microcirculation to investigate whether recruiting the microcirculation will improve the morbidity and mortality of critically ill patients.

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