Sepsis is a clinical syndrome that represents a systemic inflammatory response syndrome to infection. In 2001, an International Sepsis Definition Conference established that the definition of severe sepsis refers to an infection complicated by organ dysfunction, and septic shock is defined as severe sepsis with sustained hypotension (systolic blood pressure, <90 mmHg; or mean arterial pressure, <65 mmHg) despite adequate fluid resuscitation (1).
Although advances have been made in the knowledge of sepsis in the last decades and the establishment of an international campaign for the improvement of care of patients with this disorder (2), it is still one of the most important causes of death in intensive care units (3). In Brazil, there has been an estimate of 400,000 new cases of sepsis every year (4), and the mortality rates for septic shock are still as high as 56% (5).
Sepsis is the culmination of complex interactions between the infecting organisms and the host immune, inflammatory, and coagulation responses. Vascular endothelium plays an important role in these responses. Endothelial dysfunction with consequent impaired microvascular function is increasingly recognized as a key factor contributing to organ failure and death (6). The early stages of sepsis are characterized by a variety of hemodynamic derangements that induce a systemic imbalance between tissue oxygen supply and demand, leading to global tissue hypoxia. Global tissue hypoxia may be present in patients with normal vital signs; however, these individuals are certainly at high risk for multiple organ dysfunction syndrome (7-11).
The hemodynamic profile of septic shock is influenced by multiple sepsis-induced pathophysiological changes (12). These alterations can range from a hypodynamic state of oxygen delivery dependence to the more recognized hyperdynamic state where oxygen consumption (VO2) is independent of oxygen delivery (DO2), depending on the stage of disease presentation and hemodynamic optimization. After adequate fluid restoration, the initial hypodynamic and hypovolemic state with high or normal systemic vascular resistance is normally substituted by a vasodilatory profile with low vascular resistance (12). In all of these scenarios, even if macrovascular parameters have been normalized, microcirculation abnormalities can persist and play a pivotal role in organ dysfunction development. The prompt management of microcirculatory dysfunction with adequate resuscitation may mitigate global tissue hypoxia and modulate inflammatory and coagulation parameters, therefore reducing the incidence of multiple organ dysfunction syndrome (Fig. 1).
The best evidence for treatment of patients with sepsis has been synthesized in the Surviving Sepsis Campaign (SSC) guidelines (2). Early recognition and evidenced-based protocolized care are the cornerstones to reduce sepsis morbidity and mortality. Briefly, the actual management of severe sepsis and septic shock includes prompt fluid resuscitation based on central venous oxygen saturation (early goal-directed therapy [EGDT]), adequate diagnosis, collection of appropriate cultures, and early antibiotic therapy. Other suggested beneficial interventions are supraphysiological doses of corticosteroids, glycemic control, recombinant human activated protein C, and protective lung ventilation (2).
The end points to guide volemic resuscitation during severe sepsis and septic shock are still subject to some controversy in the literature. The purpose of this article was to review the most commonly used hemodynamic and perfusion parameters for hemodynamic optimization during sepsis, emphasizing the physiological background for their use, as well as the studies that demonstrated (or not) the efficacy of these parameters in guiding volemic replacement.
Mean arterial pressure
The autoregulation of mean arterial pressure (MAP) is a key feature of the cardiovascular system. An acute decrease in MAP promotes a prompt compensatory response from the autonomous nervous system. However, in critically ill patients, especially in septic ones, this response can become inadequate because of sepsis-induced derangements in vascular reactivity and in these compensatory mechanisms. The MAP is considered the driving pressure for perfusion of most vital organs, and when it declines below the lower limit of autoregulation, regional blood flow becomes linearly dependent on MAP (13).
Several guidelines for the management of sepsis patients recommend a goal of 65 to 90 mmHg for MAP (2, 14). According to some clinical data (15, 16), a minimum MAP of 65 mmHg would be adequate to preserve tissue perfusion, therefore being a safe value to be used as a guide in septic shock patients. However, when comorbidities such as severe arterial hypertension are present, a shift of autoregulation curve may occur and this threshold may not be adequate. A recent study demonstrated that the administration of escalating doses of norepinephrine targeting a higher MAP can improve global hemodynamics and tissue perfusion without exacerbating microcirculatory flow abnormalities (17). Trzeciak et al. (18) studied the relationship of EGDT and microcirculation and found a good correlation between MAP and microcirculatory flow. The EGDT study also aimed a MAP of 65 to 90 mmHg during the first 6 h of resuscitation and demonstrated a benefit of this approach, as will be described later (8). An interesting concept that evolved mainly after the EGDT study is the theory of cryptic shock, a condition where despite adequate MAP, patients may persist with tissue hypoxia as evaluated by lactate levels and thus have an increased mortality (60.9%). In the EGDT study, patients that presented with elevated MAP (>90 mmHg) were treated with vasodilators to maintain pressure levels among previously described limits (8).
The initial therapy to restore MAP should be intravenous fluid, but in extreme situations, vasopressor therapy should be initiated to sustain life and maintain perfusion, even if hypovolemia is not totally corrected (2). All efforts should be done to correct MAP earlier as possible because there are evidences correlating low MAP with poor outcome (16).
Central venous pressure
The hemodynamic goal of fluid resuscitation in septic shock is the restoration of tissue perfusion and not a predetermined and fixed value of hemodynamic data. An increase in cardiac output is dependent on expansion of blood volume when the ventricles work in the ascendant portion of the Frank-Starling curve. In theory, if one optimizes cardiac filling pressures, the cardiac output will be optimized, as well as oxygen delivery. However, there are recognized limitations on the use of filling pressures as indicators of volemia (19, 20) because several variables may interfere with this parameters, such as diastolic dysfunction, decreased ventricular compliance, previous pulmonary hypertension, high intra-abdominal pressure, and elevated positive end-expiratory pressures. Despite these important limitations, it has been recognized that there are situations where central venous pressure (CVP) may be useful, such as in patients with spontaneous breathing activity (CVP variation >1 mmHg during the respiratory cycle) (21).
Central venous pressure is one of the most used hemodynamic parameters because of the promptness of the measurement and the possibility to perform it in any hospital facility. On the EGDT study, CVP was measured in the emergency department and maintained between 8 and 12 mmHg during the first 6 h (8). The clinical caveat in using an algorithmic approach to CVP is that a value less than 8 mmHg always triggers the need for additional volume, which sometimes may induce a deleterious hypervolemic state (8, 9). The SSC guidelines recommend that fluid resuscitation should target a CVP of 8 to 12 mmHg in spontaneously breathing patients and 12 to 15 mmHg in mechanically ventilated individuals (2).
Pulse pressure variation
Because some studies have evidenced that static data are poorly correlated with fluid responsiveness or even hemodynamic status (22, 23), an increased interest on dynamic parameters has been noted. These dynamic parameters such as pulse pressure variation and stroke volume variation are related to heart-lung interactions in mechanically ventilated patients and can be used to access fluid responsiveness. Briefly, intermittent positive-pressure ventilation decreases right ventricular preload and increases right ventricular afterload. On the other hand, during the inspiratory phase, intermittent positive-pressure increases left ventricular preload and decreases afterload. All these alterations occur because of respiratory-induced cyclic changes in loading conditions of both ventricles (22).
Michard et al. (23) investigated the value of respiratory changes in pulse pressure to predict fluid responsiveness in mechanically ventilated sepsis patients. In this study, a cutoff of 13% for pulse pressure variation could discriminate between responders and nonresponders with great sensitivity and specificity. Albeit this variable may be useful to predict fluid responsiveness, no clinical relevant study using functional hemodynamic data as end points of resuscitation in sepsis patients has been published so far. Moreover, there are several limitations of these methods, and to date, they are indicated only in specific situations. Dynamic parameters are validated only for sedated mechanically ventilated patients with a tidal volume of 8 to 10 mL kg−1 and without spontaneous breathing movements. These characteristics are in disagreement with other routinely applied strategies such as protective ventilation for acute respiratory distress syndrome (2) and a recent tendency to use less sedation in intensive care unit patients (24). In studies evaluating different tidal volumes, pulse pressure variation did not obtain the same good results (25, 26). Dynamic parameters are not cited in SSC guidelines (2) as options to guide resuscitation during sepsis.
In previous studies, Shoemaker et al. (27) observed that survivors of critical illness had supranormal levels of oxygen delivery as compared with nonsurvivors. Trials testing this approach were applied in high-risk surgical patients with goal-directed therapy based on supranormal hemodynamic optimization, and improvements on outcomes have been obtained (28). The same approach was tested in general critically ill patients with disappointing results. Hayes et al. (29) studied a heterogeneous group of critically ill patients and used extremely elevated doses of dobutamine (up to 200 μg kg−1min−1) to achieve supranormal goals of cardiac index, VO2, and DO2. In this trial, there was an increase in the mortality of the study group compared with controls. Gattinoni et al. (30) similarly studied a heterogeneous population of critically ill patients using optimization goals of cardiac index and mixed venous saturation (SvO2) and did not find any benefit of this intervention. Velmahos et al. (31) evaluated the effect of early optimization in the survival of severely injured patients and again found no differences in mortality between the optimization group and the control group. An interesting finding of this study, however, was a reduced mortality in patients who could achieve optimal hemodynamics as compared with those who could not. This fact may represent a physiological reserve in survivors of severe injuries.
Several reasons may explain why these resuscitation trials failed, but two points deserve additional considerations. First, in most of the studies, a considerable number of patients did not achieve the predetermined end points (30). Second and more important: the time of intervention. A significant difference between the previously cited studies and the EGDT trial was that in EGDT, the treatment was initiated and the goals were obtained a few hours after hospital arrival, whereas in the other studies, the hemodynamic attempts of optimization occurred later when organ dysfunctions were already established. Other studies also demonstrated that hemodynamic optimization should be performed as early as possible during severe illness (9, 32). Thus, there is no recommendation to attempt late supranormal hemodynamic optimization in the approach of sepsis patients.
Lactate is a by-product of glycolysis. In the cytoplasm, glucose is converted into pyruvate by a reaction that does not require oxygen. After this step, pyruvate can be transformed into lactate (producing two molecules of adenosine triphosphate [ATP]) or enter the mitochondria, and after a sequence of oxygen-dependent reactions generate 36 molecules of ATP. Lactate balance depends on its production and consumption, being essentially metabolized by the liver and kidneys. During hypoxic situations, pyruvate cannot enter the mitochondria, and more lactate is produced (33). In the same extent, situations where lactate clearance is impaired, such as liver diseases, may cause hyperlactatemia even in the absence of hypoperfusion.
Lactate has traditionally been used as a marker of perfusion in intensive care. In sepsis, early hyperlactatemia may represent an imbalance between DO2 and VO2. However, other mechanisms such as accelerated aerobic glycolysis (34) and regional production of lactate shall not be forgotten (35, 36). Valenza et al. (37) hypothesized that hyperlactatemia could be a marker of energy failure in critical illness, thus representing the presence of functioning metabolic pathways and a potentially reversible condition despite the presence of an oxygen supply-dependent state. It has been also suggested that lactate is not only a marker of hypoperfusion. A cell-to-cell lactate shuttle has been proposed as an important intermediary in numerous metabolic processes and pathways, and lactate has been considered as a particularly mobile fuel for aerobic metabolism (38). In addition, recent experimental (38) and clinical evidence (39) has hypothesized that hyperlactatemia during sepsis may be the result of exaggerated aerobic glycolysis through Na+K+ ATPase stimulation during septic shock. Therefore, the role of lactate as only a marker of tissue dysoxia has been revisited.
Several studies demonstrated that lactate is an important diagnostic and prognostic marker of injury severity in critically ill and high-risk surgical patients (38, 40). Rivers et al. (8) used lactate as marker of high-risk patients with systemic inflammation in the EGDT study. Nguyen et al. (41) demonstrated that sepsis patients who presented an early lactate clearance greater than 10% had reduced mortality as compared with those who could not clear lactate. Arnold et al. (42) evaluated the relation between early lactate clearance and central venous oxygen saturation (ScvO2) in emergency department patients with severe sepsis who received early resuscitation. In this study, interestingly, patients who could not clear lactate during early resuscitation carried a high risk of death despite ScvO2 optimization.
Although this parameter has been recognized as an important prognostic marker, no study has been published that demonstrated that hemodynamic interventions aiming at lactate reduction are associated with survival improvement during sepsis. The SSC recommends an early lactate measurement for patients with sepsis and suggests that those with hypotension or lactate levels equal to or greater than 4 mmol L−1 should initiate EGDT (2).
Base deficit (BD) is defined as the amount of base required to increase 1 L of whole blood to the predicted pH based on the PacO2. Base deficit is usually viewed as a surrogate marker of lactic acidosis. However, it is important to remind that other metabolic conditions such as renal failure and hyperchloremic acidosis may produce a metabolic acidosis unrelated to tissue ischemia (43). Davis et al. (44) classified BD into mild (−2 to −5 mmol L−1), moderate (−6 to −14 mmol L−1), and severe (>−15 mmol L−1). Failure to normalize BD is directly correlated with mortality in trauma patients, and BD is regarded as an effective end point of resuscitation in this group (45). Park et al. (46) studied the evolution of BD in a group of severe sepsis and septic shock patients treated with EGDT and concluded that faster improvement of BD occurred in the survivors. Nevertheless, as described for lactate, no study aiming at BD as an end point of resuscitation during sepsis has been published.
Venous oxygen saturation
Venous oxygen saturation is commonly used to monitor the balance between VO2 and DO2. Usually VO2 is independent of DO2 because the tissues can maintain their oxygen needs by increasing oxygen extraction when DO2 decreases. Conversely, below a critical DO2, this compensatory mechanism is inefficient and VO2 becomes dependent on DO2, thus supervening tissue hypoxia. Low values of ScvO2 and SvO2 may represent a mismatch between oxygen delivery and tissue oxygen needs (47).
Mixed venous oxygen saturation is collected from a distal portion of the pulmonary artery catheter and represents venous oxygenation of the whole organism. The ScvO2, on the other hand, is collected from a central venous catheter generally located in the superior vena cava and mainly represents venous oxygen saturation from the brain and upper parts of the body. This may be a limitation regarding the use of ScvO2 as a surrogate for SvO2 (48, 49), but although there are differences on their absolutes values, changes in both parameters occur mostly in parallel (49). In healthy individuals, the ScvO2 is lower than SvO2 about 2% to 3%, although in sepsis and shock states, the ScvO2 may exceed SvO2 by about 8% because of a decrease in mesenteric and renal flows with a consequent increase in oxygen extraction (47).
The most important study in sepsis resuscitation used ScvO2 as a primary end point of resuscitation. In an emergency department, Rivers et al. (8) demonstrated a significant mortality reduction of 16.5% in patients treated with an algorithm combining CVP, MAP, diuresis, and ScvO2. Patients with systemic inflammatory response syndrome criteria associated with hypotension or hyperlactatemia were randomized to EGDT or control group. The control group was treated aiming a CVP between 8 and 12 mmHg, a MAP between 65 and 90 mmHg, and a urinary output up to 0.5 mL kg−1 h−1, whereas the EGDT group used the same parameters previously cited, plus a ScvO2 greater than 70% in the first 6 h. Strategies to achieve and maintain these goals included an early and more aggressive fluid resuscitation, blood transfusion, and inotropic therapy with dobutamine up to 20 μg kg−1 min−1.
Several lessons about the management of sepsis were learned with the EGDT trial, despite the considerable amount of controversies that this study generated. Since its publication, the need for prompt recognition of high-risk patients and institution of goal-directed therapy has been increasingly recognized. The relationship of EGDT and survival improvement is not totally understood because the mechanisms of action are partially unclear. It seems reasonable to suggest, however, that early hemodynamic optimization is related with less organ dysfunction. Varpula et al. (16) evaluated hemodynamic variables related to outcome in septic shock and found that SvO2 less than 70% in 48 h of admission was an independent variable of mortality in 30 days. In addition, Park et al. (46) demonstrated that EGDT-treated survivors had increased ScvO2 as compared with nonsurvivors, again evidencing an increased cardiovascular reserve in this group.
To summarize, ScvO2 has been proposed as an alternative to SvO2, and the SSC guidelines (2) recommend that it should be used to guide resuscitation during the first 6 h of hyperlactatemic severe sepsis or septic shock patients.
Sepsis is a complex syndrome still associated with increased morbidity and mortality. The transition of sepsis to severe sepsis or septic shock may occur in a few hours despite apparent normalization of routinely obtained vital signals. For this reason, it is vital to identify high-risk patients through perfusion markers such as lactate and venous oxygen saturation to promptly initiate early goal-directed therapy. This is definitely an important therapeutic strategy that may reduce organ dysfunction and consequently the morbidity and mortality of the syndrome.
NOTE ADDED IN PROOF
After this review was sent for publication, two studies were published regarding lactate resuscitation in critically ill patients. The first one demonstrated that an algorithm aiming at lactate clearance >10% was non-inferior to central venous oxygen resuscitation in septic patients (50). The second one showed that in critically ill (not only septic) patients, an approach aiming at lactate decrease >20% was associated to reduced SOFA scores and length of stay in the ICU (51).
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