Septic shock is a life-threatening condition in both medical patients admitted to the intensive care unit (ICU) and surgical patients during the perioperative phase. Septic shock is associated with inadequate tissue perfusion in end organs and development of impaired organ function or even multiple organ dysfunction syndrome. Various technologies for the assessment of both the macrocirculation and the microcirculation are available.
However, the hemodynamic management of patients with septic shock remains to be a challenge. In the hemodynamic management of septic shock patients, there is still uncertainty how therapeutic treatment goals should be defined and implemented in clinical care. Are we ready to specifically target the microcirculation in septic shock patients as part of a hemodynamic management approach?
The aims of this review are to describe pathophysiologic changes in the macrocirculation and the microcirculation in septic shock and to critically review current diagnostic and therapeutic approaches for the assessment and optimization of both the macrocirculation and the microcirculation. We describe the concept of “individualized goal-directed hemodynamic therapy” and discuss if monitoring and targeting the microcirculation in parallel with the macrocirculation in the hemodynamic management of septic shock might be a promising future approach.
Pathophysiology—macrocirculatory and microcirculatory alterations in septic shock
In septic shock, specific alterations in systemic cardiovascular dynamics (i.e., macrocirculation) (1, 2) and in the microcirculatory blood vessel network (i.e., microcirculation) have been described (3, 4).
While non–infection-induced shock in the context of hypovolemic, cardiogenic, or obstructive shock (pericardial tamponade, pulmonary embolism, pneumothorax) is characterized by decreased cardiac output (CO) because of either decreased cardiac preload, decreased myocardial contractility, or increased cardiac afterload, respectively (2), the characteristic macrocirculatory hemodynamic state in septic shock, i.e., in distributive shock, is usually described as a decrease in systemic vascular resistance induced by various mediators with normal or even supranormal CO/cardiac index (1). It has to be emphasized that this characteristic “hyperdynamic circulatory state” can only be observed in septic shock patients without marked intravascular hypovolemia and in the absence of preexisting or sepsis-induced myocardial dysfunction. In patients with septic shock, however, marked intravascular fluid depletion resulting in reduced cardiac preload is a frequent finding. One main pathophysiological mechanism resulting in this hypovolemic intravascular fluid status is a mediator-induced (among others tumor necrosis factor α, interleukin 1, nitric oxide) increase in capillary permeability resulting in a shift of intravascular fluid to the interstitial compartment and the pleural and abdominal cavity (1). In addition, left and right ventricular myocardial dysfunction often complicates septic shock (1).
In parallel with the macrocirculatory alterations described above, characteristic microcirculatory alterations have been described in sepsis (3) and systemic inflammatory response syndrome (SIRS) due to noninfectious conditions such as heart failure and cardiogenic shock (5, 6), hemorrhage (7), and major surgery (8, 9). It has to be emphasized that studies describing microcirculatory alterations in noninfectious SIRS are rare and that the majority of studies evaluated impaired microcirculation in sepsis. In this context, a decrease in the density of microvessels accompanied by heterogeneous perfusion of capillaries is a characteristic finding in microcirculatory failure (3, 4). The presence of these alterations has been described in both experimental animal models and clinical studies (3). To explain these microcirculatory alterations, several potential sepsis-induced pathophysiological mechanisms need to be taken into account. In sepsis, a variety of inflammatory mediators are released that can decrease the vascular tone and increase capillary permeability. Underlying mechanisms include a mediator-induced impairment of the endothelium with abnormal interaction between the endothelial cells and a disturbed balance between vasoconstrictive and vasodilatory mediators (3, 4). In addition, alterations in the composition or even a destruction of the layer located on the surface of the endothelium, the so-called glycocalyx, can be observed (3, 4, 10). Furthermore, in sepsis, deformation of erythrocytes, adhesion of erythrocytes to the endothelium, formation of plugs of platelets, leukocytes, and erythrocytes, and activation of procoagulatory cascades can further contribute to the impairment of blood flow in the microcirculatory vasculature (3, 4).
Means for the assessment of the macrocirculation and the microcirculation
Assessment of the macrocirculation
Physical examination continues to be a significant part in determining a patient’s hemodynamic state. However, previous studies revealed limited capacity of the generally applied clinical signs to reliably evaluate hemodynamic (in)stability (11, 12).
A variety of different technologies are available for the assessment of hemodynamic variables reflecting the macrocirculation, i.e., blood flow, myocardial contractility, cardiac preload, and cardiac afterload. Hemodynamic monitoring devices should enable the physician to reliably identify and adequately manage hemodynamic alterations that require differentiated therapeutic modifications.
Different techniques provide estimates of CO. Among the indicator dilution techniques for intermittent CO measurement, the pulmonary artery catheter (pulmonary artery thermodilution) still remains the criterion standard method next to less invasive approaches (e.g., transpulmonary dye dilution methods and transpulmonary thermodilution methods) (13). Less invasive, continuous CO monitoring is possible by calibrated or uncalibrated pulse contour analysis (14). In addition, technologies allowing the noninvasive estimation of CO have been proposed during the last years (15). These technologies include thoracic electrical bioimpedance, thoracic bioreactance, the vascular unloading technique, pulse-wave transit time, and radial artery applanation tonometry (15).
Cardiac preload can be assessed by determination of cardiac filling pressures, volumetric preload parameters, or functional preload parameters. Physicians still frequently use the central venous pressure as a hemodynamic parameter for cardiac preload assessment (16). As cardiac filling pressures are incapable of adequately estimating fluid responsiveness (17), there was a search for alternative cardiac preload measurements, e.g., global end-diastolic volume as a static transpulmonary thermodilution parameter (18). Furthermore, the continuous pulse contour analysis provides dynamic functional parameters of cardiac preload, i.e., pulse pressure variation and stroke volume variation (19). In addition, functional tests may also help the intensivist to evaluate a patient’s fluid responsiveness. In the passive leg raising test, the patient’s legs are elevated to about 45 degrees to determine whether the shift of blood from the lower extremities to the central circulation results in changes in mean arterial pressure, CO, pulse pressure variation, or stroke volume variation (20). A fluid challenge maneuver can evaluate the direct hemodynamic response to fluid loading, and it is seen as the criterion standard method for the evaluation of fluid responsiveness (21).
Another important approach in the care of hemodynamic instable patients is the assessment of global oxygen transport/consumption and tissue oxygenation. This involves measurements of central venous oxygen saturation; mixed venous oxygen saturation, which can be measured continuously with a pulmonary artery catheter; and blood lactate. Abnormal central venous oxygen saturation and mixed venous oxygen saturation are unspecific indicators for tissue hypoxia, however, and cannot be used to draw conclusions regarding underlying pathophysiological processes. A detection of increased blood lactate also indicates inadequate tissue oxygenation, and the current sepsis guidelines recommend normalizing lactate as a target of early resuscitation therapy. Again, this parameter is an unspecific marker for tissue damage due to hypoperfusion and is therefore not useful for the prevention of tissue and subsequently organ impairment.
Assessment of the microcirculation
Different methods for monitoring the microvascular perfusion have been proposed. The existing technologies can either measure tissue oxygenation indirectly or allow direct assessment of the tissue perfusion (22). Indirect tissue oxygenation measurement techniques allow drawing conclusions about the quality of tissue oxygenation without directly measuring blood oxygen. More specifically, these methods include tissue carbon dioxide measurements and microdialysis (22, 23). When measuring tissue carbon dioxide, sublingual and buccal electrode sensors or capnometry at the earlobe can be used (24–26).
Different technologies have been introduced for direct visualization of microvascular perfusion including videomicroscopy (orthogonal polarization spectral [OPS] imaging and side-stream dark field [SDF] imaging) and near-infrared spectroscopy (NIRS) (27–29). Orthogonal polarization spectral imaging works on the following principle: the tissue embedding the microcirculation is illuminated by polarized green light. Using a second (orthogonal) polarizer and the absorption effects of hemoglobin on the green light, the microcirculation is visualized on a screen (27). A further development of the OPS method is the SDF imaging technique that also uses the absorption effects of hemoglobin on green light. Here, the lens system is optically isolated from light emitting diodes (28). With the help of handheld devices, a sublingual application of SDF imaging at the bedside in the ICU became possible (30).
Another method for noninvasive bedside monitoring of blood flow and hemoglobin oxygenation is NIRS, a technique applied on muscle or brain using the principles of light transmission and absorption to measure oxyhemoglobin and deoxyhemoglobin (31). In contrast to deoxyhemoglobin, oxyhemoglobin allows less red light and more infrared absorption (32). This method is particularly useful to evaluate the response of the microvascular bed to a decrease in oxygenation (occlusion test) (22), another point of interest when assessing the microcirculation. An upper arm cuff to cause an artificial temporary ischemia and a NIRS device to measure microvascular blood flow are applied. The test is based on the consideration that a reduced ability to restore the preexisting oxygen saturation reflects an impaired microcirculation (22, 33).
It has to be mentioned that all direct visualization techniques investigate microcirculatory blood flow only in a local area, and therefore results might not automatically represent microcirculatory changes at other sites (22, 34).
Therapeutic hemodynamic approaches to target the macrocirculation and the microcirculation
Targeting the macrocirculation
In general, the timely optimization of the macrocirculation in terms of optimizing intravascular fluid status, systemic vascular resistance, and myocardial contractility has become a cornerstone in intensive care and perioperative management. Advanced hemodynamic monitoring parameters can facilitate differential diagnosis of different types of circulatory shock (35–37). In addition, advanced hemodynamic monitoring can help to select the appropriate therapeutic interventions (fluid administration, vasoactive agents, inotropes) and to reassess the patient’s hemodynamic state after the intervention to evaluate the patient’s response to therapy (37). When performing functional tests for the assessment of a patient’s fluid responsiveness (fluid challenge test or passive leg raising), monitoring parameters reflecting the macrocirculation (stroke volume, CO, arterial pressure, heart rate) is fundamental to discriminate responders from nonresponders (21, 38).
In their landmark study published in 2001, Rivers and colleagues (39) demonstrated an improvement of clinical outcome by using an “early goal-directed therapy” algorithm based on the hemodynamic variables central venous pressure, mean arterial pressure, and central venous oxygen saturation in a specific group of patients with severe sepsis or septic shock admitted to the emergency department. Rivers and colleagues’ study essentially contributed to the understanding that goal-directed therapy applied early in the clinical course of sepsis can improve patient outcome, and the concept became part of clinical sepsis guidelines for the treatment of critically ill septic patients (16).
In a position paper, Rivers and colleagues (40) in 2012 provided evidence that protocol-based goal-directed care (resuscitation bundle) “modulates inflammation, decreases organ failure progression, and conserves health care resource consumption” and state that “this approach consistently saves one out of every six lives for patients presenting with severe sepsis and septic shock.” In accordance, the results of a present meta-analysis suggested that goal-directed hemodynamic therapy in septic patients statistically significantly reduces overall mortality (41).
However, although it is generally accepted that administration of fluids is beneficial in the early course of severe sepsis or septic shock, the hemodynamic treatment goals used in Rivers and colleagues’ study were repeatedly questioned. Central venous pressure has been demonstrated to be a poor marker of cardiac preload and fluid responsiveness (42, 43), and its use in early goal-directed therapy as a goal to “optimize” cardiac preload might lead to fluid overload (44, 45). In addition to central venous pressure, a mean arterial pressure target was proposed in the study of Rivers et al. (39) and is recommended in current guidelines (16). However, evidence regarding a definite optimal mean arterial pressure target is still missing (46) and is probably dependent on a patient’s individual normal arterial pressure. Central venous oxygen saturation is an unspecific global parameter of tissue oxygenation and needs to be interpreted in the context of a patient’s cardiocirculatory state.
Two large multicenter randomized controlled trials, the ProCESS trial (47) and the ARISE trial (48), recently challenged the concept of early goal-directed therapy as proposed by Rivers et al. (39). These two studies were not able to demonstrate an outcome benefit for patients treated according to the concept of early goal-directed therapy based on the treatment goals of the study of Rivers et al. in comparison with a “standard care” group. However, these results should not lead to the conclusion that the cornerstones of early goal-directed therapy—fluid administration and antibiotic therapy—should generally not be applied in patients with sepsis. One should rather consider that there is evidence that the outcome of patients with severe sepsis has dramatically improved over the last decade (49). This is probably due to a generally improved care for severe septic patients including early antibiotic therapy and fluid administration.
In addition, it needs to be emphasized that the ProCESS study and the ARISE study evaluated the Rivers protocol based on central venous pressure, mean arterial pressure, and central venous oxygen saturation in the very early course of severe sepsis. Because the study of Rivers et al. dramatically increased the awareness for early antibiotic therapy and fluid administration in sepsis, the patients randomized to the control groups in the ProCESS and ARISE trials were probably also treated in the sense of early goal-directed therapy. These studies must therefore not be interpreted as evidence that monitoring and optimization of advanced global hemodynamic variables reflecting cardiac preload and blood flow have no benefit in septic patients.
The potential outcome benefit of early goal-directed therapy based on advanced hemodynamic variables needs to be evaluated in future clinical trials.
Based on the described evidence, in clinical practice, the optimization of macrocirculatory parameters in septic patients is mainly based on the following mainstays of therapy. The initial resuscitation of patients with septic shock includes administration of crystalloids to maintain adequate mean arterial pressure and prevent or restore organ failure due to reduced perfusion pressure (16). To assess a patient’s fluid responsiveness the use of a fluid challenge technique based on static preload parameters (i.e., cardiac filling pressures or volumetric cardiac preload parameters) or dynamic preload parameters (i.e., functional cardiac preload parameters such as pulse pressure variation or stroke volume variation) is recommended (16). Hydroxyethyl starches should be avoided in sepsis (50). Whether the use of hydroxyethyl starches is beneficial in certain subgroups of surgical patients is beyond the scope of the present article. According to a subgroup analysis of a recently published randomized controlled trial in patients with severe sepsis, the use of albumin in addition to crystalloids might reduce mortality in patients with severe sepsis with septic shock (51).
In addition to optimization of intravascular volume status by fluid administration, vasopressors (norepinephrine, epinephrine, vasopressin) and inotropes (dobutamine) are used to optimize cardiac afterload and myocardial contractility in patients with sepsis (16, 52).
Adjunctive agents such as hydrocortisone can help to restore circulatory failure in patients with very severe sepsis-associated circulatory shock (16).
The transfusion of red blood cell concentrates can improve oxygen delivery by an increase in arterial oxygen content (53). A recent multicenter randomized parallel-group trial in septic shock patients found no difference in the primary end point (90-day mortality) or in secondary outcome end points when comparing a hemoglobin transfusion threshold of 7 g/dL with one of 9 g/dL (54). In general, with the exception of patients with acute complications of ischemic coronary artery disease, a restrictive red blood cell transfusion strategy should be applied in critically ill patients (55, 56). It has been demonstrated that prolonged storage of red blood cell concentrates influences transfusion-induced microcirculatory changes (57). In addition, residual leukocyte-derived inflammatory mediators may deteriorate microvessel perfusion. Whether leukodepleted red blood cells should therefore be used in critically ill patients remains a matter of debate (58).
The concept of “individualized goal-directed hemodynamic therapy”
As described in the previous paragraph, there are contradicting data regarding early goal-directed therapy based on basic hemodynamic variables such as central venous pressure and mean arterial pressure. Despite some evidence for its beneficial impact on patient outcome (41), there is no proof that the use of goal-directed hemodynamic therapy improves morbidity or survival in septic shock.
In contrast, the pathophysiologic rationale suggests that the optimization of advanced global hemodynamic variables reflecting blood flow, cardiac preload, and cardiac afterload is a crucial component in the treatment of septic shock. In this context, it will be a major challenge to evaluate what “normal values” and “optimization” of hemodynamic variables mean for the individual patient. While the pioneer of goal-directed therapy, William C. Shoemaker (59), proposed to target “supranormal” hemodynamic goals in high-risk surgical patients, the usefulness of this concept was questioned in critically ill septic patients (60, 61). In addition, recent data from an experimental animal study using a model for acute severe pancreatitis demonstrate that “maximization” of hemodynamic variables might not be “optimization” (62). In general, optimization of cardiac preload and blood flow by fluid administration bears the risk to induce fluid overload associated with detrimental effects on cardiocirculatory and pulmonary function (63).
When using advanced hemodynamic monitoring for guidance of hemodynamic therapy, we always have to keep in mind that it is a too simplistic approach to use the same normal values and treatment goal for every patient. Advanced hemodynamic variables are dependent on a variety of different biometric and pathophysiologic factors, and reference ranges can therefore not be applied to all groups of patients (64–67). The same holds true for uniform target values used in algorithms for goal-directed hemodynamic therapy.
In perioperative care, individualized goal-directed hemodynamic therapy approaches have been proposed (68, 69). These studies used dynamic cardiac preload parameters (stroke volume variation or pulse pressure variation) assessed under stable preoperative or intraoperative conditions (controlled mechanical ventilation and sinus rhythm) to define a patient’s individual optimal static cardiac preload parameter global end-diastolic volume or a patient’s individual optimal cardiac index. Following surgery, these individual optimal hemodynamic variables were used to guide therapy with fluids and vasoactive agents in the ICU. Comparable data on individualized goal-directed therapy in critically ill septic patients are missing. However, considering that our current understanding of normal values of hemodynamic variables (64–67) as well as the pathophysiologic rationale suggests that a “one-size-fits-all” approach cannot be appropriate for a complex disease state such as severe sepsis or septic shock, developing and evaluating algorithms for “individualized goal-directed hemodynamic therapy” must be the consequent next step in research aiming to demonstrate an improvement in patient outcome by optimization of hemodynamic variables.
Therapeutic hemodynamic approaches targeting the microcirculation—where are we today?
Because there is evidence from several experimental and clinical studies that an impairment of microcirculatory perfusion is a hallmark in the development of organ dysfunction and is associated with mortality (3, 4, 70–73), considering potential diagnostic and therapeutic approaches to target microcirculatory perfusion in septic shock is a challenge of outstanding importance. However, to further complicate matters in the clinical setting, alterations in the microcirculation in sepsis are in part independent from macrocirculatory parameters such as blood flow or cardiac afterload. This is reflected by the fact that a marked and unpredictable interindividual variability regarding the association between microcirculatory and macrocirculatory parameters has been demonstrated in clinical studies (3, 74–76). To put it another way, in early sepsis, relevant alterations in microcirculatory perfusion might already contribute to the development of organ failure and deterioration of the patient’s clinical state, although systemic hemodynamic parameters are still “normal.” On the other hand, in the course of sepsis, microcirculatory perfusion can still be markedly impaired despite a resuscitation of systemic hemodynamics, i.e., after normalization of blood flow and global oxygen delivery.
A variety of different means of resuscitation of the impaired microcirculation has been evaluated in both experimental and clinical studies. Some of these interventions are also used to resuscitate the macrocirculation in septic patients.
In an observational study by Ospina-Tascon et al. (77), fluid therapy using crystalloids or albumin resulted in an improvement of microvessel perfusion in the early phase of sepsis. Interestingly, this improvement of the microcirculation observed using SDF imaging was independent from the systemic hemodynamic parameters CO and mean arterial pressure (77). In line with these findings, Pottecher and colleagues (78) demonstrated that fluid challenge or passive leg raising maneuvers can improve the sublingual microcirculation in patients with severe sepsis or septic shock. Pranskunas et al. (79) showed that a fluid challenge significantly increased microvascular blood flow irrespective of changes in stroke volume in hemodynamically instable ICU patients with impaired organ perfusion and decreased baseline microvascular blood flow.
The effect of vasoactive or inotropic agents on microcirculatory perfusion has been evaluated in several clinical trials with—in part—contradicting results. By assessing the microcirculation in muscle tissue using the NIRS method, Georger and colleagues (80) demonstrated that increasing mean arterial pressure above 65 mmHg using norepinephrine improves the microcirculation in severely septic patients with hypotension. In another study, Dubin et al. (75) failed to show beneficial effects on the microcirculation when using norepinephrine to further increase mean arterial pressure (>65 mmHg). In addition, this study revealed a marked interindividual variability regarding the norepinephrine-induced microcirculatory changes with beneficial norepinephrine effects in some patients with markedly impaired baseline microcirculatory perfusion and even harmful effects in other patients. There are data showing an improvement in the microcirculation following administration of the inotropic agent dobutamine in patients with septic shock (74). Again, these beneficial dobutamine effects were not associated with effects on hemodynamic parameters reflecting the macrocirculation. In contrast, a small randomized controlled double-blind trial in 20 patients with septic shock failed to demonstrate a dobutamine-induced improvement of the sublingual microcirculation despite an increase in macrocirculatory hemodynamic variables such as cardiac index (81).
Morelli et al. (82) described an improvement of the sublingual microcirculatory blood flow in septic patients treated with the inotropic calcium sensitizer levosimendan in a prospective, randomized, double-blind clinical trial comparing levosimendan to dobutamine.
Although clinical data on red blood cell transfusion–induced changes in macrocirculatory parameters are available (53, 83), the effect of red blood cell transfusion on microcirculatory perfusion still needs to be further elucidated. According to available data from two small clinical studies in patients with severe sepsis, the microcirculation is globally not altered by transfusion of red blood cell concentrates (84, 85).
In addition to fluid administration and therapy with vasopressors or inotropes, several alternative interventions for resuscitation of the microcirculation have been investigated in experimental studies.
From a theoretical point of view, vasodilating substances could potentially improve microcirculatory perfusion in patients with impaired microvessel blood flow. In this context, there is evidence that topical administration of acetylcholine in high doses has beneficial effects on the microcirculation in patients with severe sepsis (72). Although Spronk and colleagues (86) demonstrated that the intravenous infusion of the vasodilator nitroglycerin in septic shock patients resulted in an increase in microvascular blood flow determined by OPS imaging, a more recent double-blind, randomized placebo-controlled trial in 70 septic shock patients failed to demonstrate a nitroglycerin-induced improvement of the microcirculation (34).
Hydrocortisone is recommended as an adjunctive therapeutic agent in patients with septic shock (16). Büchele and colleagues (87) observed an improvement in sublingual capillary perfusion measured by the OPS technique after infusion of a moderate dose (50 mg/6 h) of hydrocortisone.
In addition, agents with anticoagulatory properties could theoretically have beneficial effects on the microcirculation by improving blood flow through microvessels in SIRS. As shown by de Backer et al. (88), activated protein C (drotrecogin alfa activated) is capable of improving OPS-derived sublingual microperfusion in patients with severe sepsis. In addition, in an animal study, antithrombin has been demonstrated to attenuate microcirculatory failure probably by interactions with endothelial glycosaminoglycans (89).
Despite the variety of different therapeutic interventions that might improve microcirculatory perfusion in experimental and clinical studies, specific therapeutic approaches to prevent or restore an impairment of the microcirculation are today not part of routine clinical practice. Specific goals for the treatment of microcirculatory alterations are still a matter of debate and need to be defined in the treatment of patients with septic shock. As emphasized also in a recent consensus statement, further large-scale clinical studies are needed to assess whether “microcirculation-oriented or microcirculation-guided” therapeutic approaches can improve patient outcome in shock (37). Today, technologies for the monitoring of the microcirculation cannot be recommended for the clinical use outside of clinical studies (37). However, based on a pathophysiologic rationale, it might be an intriguing approach to assess and treat microcirculatory failure in septic shock in parallel to macrohemodynamic resuscitation.
Concept for a future integrative approach for hemodynamic management of the macrocirculation and the microcirculation in septic shock
Macrohemodynamic management in septic shock includes a rational differential diagnostic approach in parallel to the initial stabilization of the patient (Fig. 1). Furthermore, hemodynamic monitoring can be applied in terms of goal-directed optimization of the macrocirculation, i.e., blood flow, cardiac preload, fluid responsiveness, cardiac afterload, and pulmonary hydration.
In parallel, the early assessment of microcirculatory alterations might play a key role in the future treatment for patients with septic shock as microcirculatory failure is clearly associated with the development of organ dysfunction and clinical outcome. However, the presence and degree of microcirculatory failure is partly independent from systemic macrohemodynamic parameters such as blood flow. In other words, septic patients might present with markedly impaired microcirculatory perfusion and might be at risk for development of (multiple) organ dysfunction despite globally unimpaired or restored macrocirculation. Identifying these patients early in the course of sepsis by assessing microcirculatory perfusion and trying to specifically treat and optimize the microcirculation might constitute a huge opportunity to define additional resuscitation end points. Therefore, an integrative diagnostic and therapeutic approach with the goal of early assessment and individualized optimization of both the macrocirculation and the microcirculation in parallel might be an intriguing future concept to improve clinical outcome in patients with septic shock. Diagnostic and therapeutic approaches reflecting that microcirculatory and macrocirculatory failure can be present either simultaneously or independently from each other might provide the treating physician with more differentiated information about the patient’s risk for development of organ failure and allow more specific therapeutic interventions to optimize microcirculatory perfusion in parallel to macrocirculatory hemodynamic optimization. Future research should therefore try to identify concepts for the optimization of the microcirculation that are applicable in clinical practice (37).
In septic shock, both impaired macrocirculation and microcirculation can induce organ dysfunction. With regard to clinical outcome, the prevention or restoration of organ dysfunction is the major goal in the treatment of septic shock patients. In this context, the preservation of tissue perfusion and oxygenation is of crucial importance. Macrocirculatory failure and impaired microcirculation can independently induce organ dysfunction. Although there is some evidence that resuscitation of the macrocirculation should be performed using goal-directed treatment algorithms, adequate resuscitation goals for the optimization of the microcirculation still need to be evaluated. In addition, the link between microcirculatory impairment and macrocirculatory failure still needs to be elucidated. Future concepts for an integrative approach for hemodynamic management of the macrocirculation and the microcirculation might constitute a huge opportunity to define additional resuscitation end points in septic shock. Specific goals for the treatment of microcirculatory alterations still need to be defined. Therefore, more data on mechanisms leading to microcirculatory failure and its association with macrohemodynamics are eagerly longed for in patients with different forms of circulatory failure (hypovolemic, cardiogenic, obstructive, and distributive). Future studies should furthermore focus on improving bedside monitoring technologies for assessment of microcirculatory perfusion and on specific therapeutic interventions able to prevent or attenuate microcirculatory failure.
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