MICROCIRCULATION IN SEPSIS - Semantic Scholar

MICROCIRCULATION IN SEPSIS: NEW PERSPECTIVES

Glenn Hernandez MD (1,2) Alejandro Bruhn MD PhD (2) Can Ince PhD (1)

(1)

Department of Translational Physiology, Academic Medical Center, University of Amsterdam, The Netherlands

(2)

Departamento de Medicina Intensiva, Pontificia Universidad Catolica de Chile, Chile

Corresponding Author

Can Ince PhD Department of Translational Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands +31653444684

ABSTRACT

Microcirculatory dysfunction has been recently recognized as a key pathophysiologic process in the evolution of sepsis. In the present review, we discuss fundamental aspects of microcirculatory abnormalities during septic shock, including pathogenic mechanisms, technological assessment, clinical correlates and potential therapies. The most important function of the microcirculation is the regulation and distribution of flow within the different organs. In septic shock, microcirculatory dysfunction may arise as a result of several factors such as endothelial dysfunction, leukocyte-endothelium interactions, coagulation and inflammatory disorders, hemorheologic abnormalities, and functional shunting. Severity and persistence of these microcirculatory abnormalities are associated with bad prognosis and are not necessarily predicted by systemic variables. The introduction of bedside techniques that allow evaluation of the microcirculation into clinical practice has opened up a new field of functional hemodynamic monitoring. Recent data suggest that microcirculatory abnormalities can be staged in severity. Some microcirculatory indices are more accurately related to morbidity and mortality, and thus a definition of clinically relevant microcirculatory abnormalities is feasible. On the other hand, although several systemic variables do not predict microcirculatory status, high norepinephrine (NE) requirements and hyperlactatemia are associated with a much higher prevalence of relevant microcirculatory derangements. Therefore, severe septic shock patients could represent a more precise target for interventions, particularly in microcirculation-oriented clinical trials. Clinical research has identified various therapeutic approaches that are successful in modifying the microcirculation. Future research must determine whether some of these approaches are successful in improving outcome of critically ill patients by recruiting the microcirculation.

Key Words Sepsis, septic shock, microcirculation, OPS SDF imaging , lactate, fluids, vasoactive drugs

Introduction

Microcirculatory dysfunction has been recently recognized as a key pathophysiologic process in the evolution of sepsis. In the present review, we discuss fundamental aspects of microcirculatory abnormalities during septic shock, including pathogenic mechanisms, technological assessment, clinical correlates and potential therapies.

I. Characteristics of normal microcirculation By microcirculation we refer to the network of small blood vessels (80% could be significantly related to survival in septic patients [8, 29, 30]. With regard to PVD, there are no clear normal reference values. Nevertheless, some studies have described basal pre-resuscitation PVD values of 12-13 n/mm that can improve with therapy [25, 27]. Thus, the cutoff value of 12 n/mm for PVD is also consistent with literature. The lack of predictive value for MFI in this study is intriguing since this parameter has been related to outcome in previous studies [7, 31]. Since MFI is inherently subjective, it is possible that intercenter differences in analysis may have compromised its prognostic value. Additionally, logistic regression analysis demonstrated that among systemic variables, only NE doses (OR 39 [4-341]) and lactate levels (OR 1.3 [1.1-1.6]) were significantly associated with the probability of finding a PPV 0.3 mcg/kg/min and hyperlactatemia > 4 mmol/l, more than doubled the probability of presenting clinically relevant microcirculatory abnormalities. These results tend to confirm that hyperlactatemia during septic shock effectively reflects a wide array of derangements among the determinants of tissue perfusion, including an 1

Hernandez G, Boerma EC, Dubin A, Pedreros C, Bruhn A, Koopmans M, Pozo M, Kanoore Edul V, Ruiz C, Kattan E, Castro R, Rovegno M, Ince C. The relationship between microcirculatory flow abnormalities and systemic hemodynamic variables in septic shock patients. A multi-centre crosssectional study. Intensive Care Med 2011; 37 (Suppl 1): 0341 (abstract)

abnormal microcirculatory flow. This could explain at least in part, the high mortality risk associated with hyperlactatemia. In contrast, a relatively better preserved microcirculation in patients with septic-related hypotension but without hyperlactatemia, could explain the better prognosis associated with this condition [32]. Nevertheless, the preceding studies do not clarify if hyperlactatemia in the setting of microcirculatory dysfunction may reflect hypoxia or simply a stagnant lactate accumulation. On the other hand, mean arterial pressure (MAP), cardiac index (CI), or central / mixed venous O2 saturation (SvO2) values, commonly used to assess response to septic resuscitation, failed to predict microcirculatory abnormalities. In the case of SvO2, it could be surprising since an impaired O2 extraction capacity has been attributed to potential microcirculatory abnormalities during septic shock [33, 34]. Even more, a normal SvO2 in the presence of hyperlactatemia has been advocated as an indication for the use of vasodilators to improve microcirculatory flow [35], and SvO2 is a commonly recommended resuscitation goal [36]. Thus, in contrast to common beliefs [37], microcirculatory status may not be predicted by any SvO2 value. In summary, recent data suggest that microcirculatory abnormalities can be staged in severity. Some microcirculatory indices are more accurately related to morbidity and mortality, and thus, a definition of clinically relevant microcirculatory abnormalities is feasible. On the other hand, although several systemic variables do not predict microcirculatory status, high NE requirements and hyperlactatemia are associated with a much higher prevalence of relevant microcirculatory derangements. Therefore, severe septic shock patients could represent a more precise target for interventions, particularly in microcirculation-oriented clinical trials. V. Therapeutic strategies Fluid resuscitation Fluid resuscitation is a fundamental therapy aimed at restoring circulating volume, and consequently increasing cardiac output and arterial blood pressure in septic shock patients. Fluid loading may improve microcirculatory blood flow through several mechanisms. Among them, volume resuscitation could increase perfusion pressure and/or CI, induce rheologic changes with decreased microvascular blood viscosity, trigger local vasodilation, or modulate interactions between the endothelium and circulating cells [26, 38]. Pottecher et al. showed that sublingual microcirculatory

perfusion in septic shock patients was significantly improved following fluid loading [26]. Interestingly, both passive leg raising maneuver and effective volume expansion simultaneously increased microcirculatory functional capillary density (FCD) and flow (MFI and PPV), and reduced microvascular heterogeneity. Since MFI is known to be sensitive to flow variations, while changes in FCD or PPV are more likely related to microcirculatory recruitment, these results reflect a global impact of fluid resuscitation over several determinants of microcirculatory perfusion. Another interesting aspect of the previous study [26] is that in contrast to other reports [38], changes in microcirculatory flow exhibited some correlation with improvement in global hemodynamics, particularly with CI. These results in preload-responsive patients confirm the findings of Trzeciak et al. showing correlations between macrocirculatory and microcirculatory variables in patients studied within 6 h of early goal-directed therapy [7]. Thus, it appears that during early resuscitation, microcirculatory flow can be improved with aggressive fluid resuscitation in parallel with changes in systemic hemodynamics. In fact, the very low values of MFI found by Trzeciak et al. early on after emergency room admission in pre-resuscitated patients have not been reproduced in the ICU arena. In the same line, Boerma et al. reported that MFI increased from 1.42 to 2.25, after only 2 hours of resuscitation in the placebo arm of their nitroglycerin trial [23]. These data taken together suggest that MFI values are very low in non-resuscitated patients but may improve rapidly after initial fluid expansion, resembling what happens with SvO2. In summary, fluid loading is an essential first step in the resuscitation of the microcirculation. Concerning the type of fluids, Dubin et al. demonstrated that a hydroxyethyl starch solution (HES) had superior microcirculatory recruitment power compared to a saline solution in early goal-directed therapy in septic patients [24]. The beneficial effects of HES on sublingual microcirculation seen in this study might be related to potential effects on several mechanisms involved in septic-related microcirculatory dysfunction, as has been suggested by several experimental studies. Infusion of HES could modulate the inflammatory response, including reductions in extravascular fluid losses, endothelial cell activation [39], neutrophil adhesion and transendothelial migration [40]. A HES solution could also reduce platelet aggregation [41], but the effect of different HES solutions on blood viscosity is variable and probably depends on molecular weight [42]. Finally, other explanations for the favorable effects of HES could be a better intravascular volume expansion and less edema formation [43].

Red blood cell transfusions RBC transfusions are commonly used in critically ill patients to restore oxygen carrying capacity and thus improve global oxygen transport (DO2). However, transfusion decisions are based on serum hemoglobin levels, and the final effect on microvascular flow is difficult to predict, especially since normal microvascular hematocrit is much lower than systemic values [44]. Additionally, several rheologic properties of transfused RBCs may be altered during storage, or secondary to sepsis, including a reduction in RBC deformability, and 2,3-diphosphoglycerate and ATP levels, thus compromising microcirculatory flow or oxygenating capacity [44]. Finally, vasoactive properties of stored RBCs are modified as their capacity to capture nitric oxide is enhanced. The resulting drop in nitric oxide bioavailability in small vessels may lead to worsening microcirculatory dysfunction [44]. Response to RBC transfusions may be quite variable. Sakr et al. studied the sublingual microcirculation in 35 septic patients. They performed the measurements just before RBC unit transfusion and one hour after transfusion of leuko-reduced RBC units with a mean age of 24 days. They found that although global hemodynamics increased following RBC transfusion, oxygen uptake and microcirculatory parameters did not. It must be noted, however, that there was interindividual variability with an increase in sublingual capillary perfusion in patients with depressed perfusion at baseline and a decrease in perfusion in patients with normal baseline perfusion [45]. These findings were confirmed by Creteur et al. in a study evaluating the impact of RBC transfusions on near-infrared spectroscopy

(NIRS)-derived oxygenation parameters [46]. The

authors reported a divergent response, with an improvement in microvascular reactivity in patients with altered microvascular reactivity at baseline, and deterioration in patients with preserved baseline microvascular reactivity. The complexity of this subject is highlighted by a recent pilot study, which failed to demonstrate any beneficial effect of RBC transfusions on sublingual microcirculatory density in adult septic patients 2. In contrast, several studies have demonstrated an increase in skin and sublingual functional capillary densities, or in NIRS-derived oxygenation parameters after RBC transfusions in other settings [4749]. These studies confirmed that RBC transfusions are effective in improving tissue oxygen transport by promoting RBC delivery to the microcirculation. Yuruk et al demonstrated in cardiac 2

Ayhan B, Yuruk K, Bakker J, de Mol BAJM, Ince C: Blood transfusions recruit the microcirculation in on-pump cardiac surgery patients, but not in septic patients. Intensive Care Med 2010; 36 (Suppl 2):0489 (abstract)

surgery patients that red blood cell transfusions were effective in increasing RBC availability and oxygenation at the microcirculatory level using respectively sublingual SDF imaging and fibre reflectance spectrophotometry (for measurement of microcirculatory Hb saturation) [43]. They identified in this interesting study the mechanism by which RBC transfusions cause an increase in microcirculatory RBC availability thereby improving tissue oxygenation. The mechanism of efficacy of RBC transfusions for improving tissue oxygenation was identified as RBC transfusion filling previously empty capillaries and thus reducing oxygen diffusion distances to cells and not by increasing RBC convective flow. Similar results were obtained in other non-septic patients such as anemic hemotological patients [44]. In summary, there are conflicting data concerning the effect of RBC transfusions over microcirculatory parameters in septic patients, although at least patients with more severe microvascular dysfunction at baseline may benefit. This fact highlights the relevance of monitoring sublingual microcirculation in critically ill septic patients to target therapies on an individual basis. Arterial pressure and vasopressors When MAP decreases below an autoregulatory threshold of 60 to 65 mm Hg, organ perfusion becomes pressure dependent and, consequently, the use of vasopressors to increase MAP could improve tissue perfusion in septic shock patients. Georger et al. evaluated the effects of increasing MAP on NIRS-derived thenar oxygenation parameters in 28 severely hypotensive septic shock patients [50]. Administration of NE in doses up to 0.7 mcg/kg/min was associated with significant increases on MAP from 54 ± 8 to 77 ± 9 mmHg, on CI from 3.14 ± 1.03 to 3.61 ± 1.28 L/min/m2, on thenar tissue oxygen saturation (StO2) from 75 ± 9 to 78 ± 9%, and on StO2 recovery slope from 1.0 ± 0.6 to 1.5 ± 0.7%/s. However, vasopressors, although effective in increasing blood pressure, may do so at the expense of microcirculatory flow suggesting that in some circumstances excessive vasoconstriction could be deleterious to the microcirculation [51]. Jhanji et al. recently demonstrated that increasing MAP from 60 to 90 mm Hg with NE resulted in an increase in global DO2, but caused no change in cutaneous microvascular flow and tissue pO2, or in sublingual microcirculation [52]. Dubin et al. titrated NE to increase MAP from 65 to 75 and then to 85 mm Hg to evaluate effects on sublingual microcirculation in septic patients [53]. Their main finding was that increasing MAP failed to improve sublingual microcirculation or any other variable related to tissue oxygenation or

perfusion such as arterial lactate, anion gap, pCO2 gradients, and oxygen-derived parameters. Interestingly, there was considerable variation in the individual responses that were strongly dependent on the basal condition of microcirculation. In fact, PVD improved in patients with an altered sublingual perfusion at baseline and decreased in patients with a preserved baseline microvascular perfusion. There are conflicting reports about the microcirculatory effects of other vasopressors such as phenylephrine or vasopressin analogues, but at least some studies have demonstrated detrimental effects, and thus should be used with caution in patients with suspected microcirculatory dysfunction [51]. In summary, there is no doubt that increasing MAP with NE in refractory hypotension improves microcirculatory flow, but the preceding data suggest that optimal MAP for microcirculatory perfusion is quite variable and should be selected on an individual basis. Vasodilators The rationale for the use of vasodilators in sepsis is based on experimental findings of pockets of ischemic areas lying close to well-perfused zones [54]. Vasodilators may increase the driving pressure of blood flow at the entrance of the microcirculation and perfuse hypoxic zones [5]. Nitroglycerin undergoes intracellular metabolism in order to produce NO-mediated vasodilatation. Despite the fact that excessive NO production is believed to play an important role in sepsis-induced hypotension, it has also been suggested as a therapeutic strategy to overcome heterogeneity in microcirculatory blood flow [55]. The general idea that increasing MAP results in a higher net microcirculatory perfusion pressure is not in line with physiological theory of the microcirculation as a low-pressure vascular compartment [51, 56]. In a small series of septic patients who fulfilled static systemic hemodynamic resuscitation endpoints, Spronk et al. found an improvement in sublingual perfusion despite a significant decrease in MAP, after a bolus of 0.5 mg followed by an infusion of 2 mg/h nitroglycerin (NTG) [57]. Of note, improvement of microcirculatory blood flow after the NTG bolus was instantaneous, indicating some NO-mediated endothelial ability for vasodilatation. However, it is important to consider that this study protocol included a large fluid challenge, and thus it is rather difficult to isolate the effects of concomitant fluids vs. NTG. Nevertheless, Spronk’s observations together

with the recent report of sublingual microcirculatory recruitment after topical acetylcholine in already

resuscitated

septic

patients

[29],

challenge

the

general

idea

of

endothelial

hyporesponsiveness in sepsis-induced hypotension. More recently Boerma et al, in a double-blind placebo-controlled study, demonstrated that sublingual microcrocirculatory perfusion improved significantly over time, but no effect of NTG in comparison to placebo could be shown [23]. Although other NO-donors or vasodilators have been tested in experimental or clinical settings, the role of vasodilators in sepsis as a therapeutic strategy to recruit “microcirculatory weak units” is yet to be elucidated [51]. Inodilators Dobutamine has both inotropic and vasodilatory effects. In an open label setting addition of dobutamine in septic patients was associated with improved OPS-measured sublingual microcirculatory perfusion over time, irrespective of changes in systemic hemodynamic variables [29]. However, this was an uncontrolled study and it is rather difficult to isolate net dobutamine effects from previous fluid loading or ongoing background resuscitation. In contrast, other controlled experimental and clinical studies in sepsis challenge the common view that dobutamine can improve regional or microcirculatory flow [25, 58, 59] 3 Levosimendan, a calcium-sensitizer drug with inotropic and vasodilator effects has been proven useful in cardiogenic shock. Some recent experimental and small clinical trials have shown favorable effects on regional and microcirculatory flow as compared to dobutamine, in septic shock [25, 58, 59]. The place of these inodilators in a microcirculation-oriented resuscitation strategy has yet to be defined in view of the discordant results cited above. Activated protein C Another agent potentially useful for improving microvascular function in critically ill patients is recombinant activated protein C (APC), which decreases the uncontrolled cascades of inflammation and coagulation and impaired fibrinolysis in sepsis [60, 61]. Several experimental studies with sepsis models showed beneficial effects of APC over different aspects of microcirculatory dysfunction, including a decrease in oxidative stress and glycocalyx destruction during 3

Hernandez G, Regueira T, Bruhn A, Pedreros C, Ruiz C, Veas E, Ramirez J, Martin C, Bugedo G, McNab P, Castro R, Zapata M, Ince C. Effects of dobutamine on microcirculation, regional and peripheral perfusion in septic shock patients: a randomized double-blind crossover study. Preliminary report. Intensive Care Med 2011; 37 (Suppl 1): 0346

endotoxemia [62-64]. Bernard et al. demonstrated that exogenous APC administration significantly reduced organ failure and improved survival in severely septic patients [65]. Later, De Backer et al. reported that severely septic patients had an increased proportion of perfused microvessels while receiving continuous infusion of APC [66]. Once APC infusion stopped, microvascular perfusion transiently decreased. Thus, APC appeared as an interesting drug for microcirculatory-oriented resuscitation. However the recent failure of several studies including the PROWESS Shock trial to demonstrate any outcome benefit, not only lead to withdrawal of the drug from the market, but also challenged the view that microcirculatory abnormalities in sepsis can be improved by a single drug approach. Steroids Despite conflicting studies, hydrocortisone is frequently used as an adjunctive therapy in patients with septic shock. The drug may have opposite effects over microcirculatory flow. It induces some degree of arterial vasoconstriction and thus could alter capillary perfusion. On the other hand, due to its anti-inflammatory effects, it could improve endothelial dysfunction and thereby ameliorate the distributive defect [67]. In a clinical observational study in 20 septic shock patients, Buchele et al. observed only mild effects of hydrocortisone over sublingual microvascular perfusion [68]. Clearly more studies are needed to establish the role of steroids in microcirculatory dysfunction in septic shock. High-volume hemofiltration High volume hemofiltration (HVHF) has been used as a rescue therapy to revert refractory hypotension in severe septic shock patients in a couple of small uncontrolled studies [69, 70]. In this setting, more than 50% of patients responded with an improvement in global hemodynamics and lactate clearance, and responders exhibited a much lower mortality than non-responders. The mechanism of HVHF potential favorable effects is still debated but includes removal of proinflammatory mediators and an improvement in immunological homeostasis [69]. Since HVHF may decrease NE requirements by increasing systemic vascular resistance, this effect could potentially have detrimental effects over microcirculatory flow. To address this subject, Ruiz et al. explored the effects of a 12-h course of HVHF over sublingual microcirculatory parameters in twelve severe septic shock patients [27]. Microcirculatory flow index increased after 12 hours of HVHF and this increase persisted 6 hours after stopping the procedure. A similar trend was observed for the proportion of perfused microvessels. The increase in microcirculatory blood flow

was inversely correlated with baseline levels, resembling what happens with MAP manipulation and RBC transfusions. The potential beneficial role of HVHF or other extracorporeal depurative therapies over septic microcirculation should be explored in future studies, especially since some recent large controlled studies have failed to show an impact of less intense hemofiltration rates on major clinical outcomes. Conclusion In conclusion the present review has covered the current state of knowledge concerning the effects on the microcirculation of disease and therapy in critically ill patients. These insights have been obtained by use of first and second generation OPS and SDF based devices. These types of measurements have allowed for the first time the direct observations of the cellular response to disease and therapy at the bed-side and has given much new insight into the nature of critical illness. The latest third generation computer controlled high resolution digital camera with short illumination time devices are expected to bring one step closer to instant analysis of the nature of microcirculatory dysfunction at the bedside and

provide more sensitive detail about the

(sub)cellular nature of disease and response to therapy at the bed-side to support clinical decision making. Competing interests CI is the inventor of SDF technology which is commercialized by MicroVision Medical. He has been a consultant for this company in the past, but he has broken all contact with this company for more than two years now, and he has no competing interests. CI has also no competing interests in Cytometrics, KK Technology or Braedius Scientific other than his commitment to promote the importance of the microcirculation in the care of critically ill patients.

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