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      Lactate is THE target for early resuscitation in sepsis Translated title: Lactato é O alvo para ressuscitação precoce na sepse

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          Abstract

          INTRODUCTION The resuscitation of patients in sepsis is a challenge for many reasons. One of the important questions is: Who needs what kind of resuscitation? In the present guidelines, resuscitation is mostly directed at patients with a high risk of mortality. In this review, I will discuss the value of using lactate levels to identify patients who might benefit from treatment and how to use sequential lactate levels in the process. THE CLINICAL SCENARIO Although lactate has been advocated as a marker of tissue hypoperfusion by the Surviving Sepsis Campaign guidelines when it rises above 1.0mmol/L,(1) aggressive fluid resuscitation is only recommended for patients with a lactate level above 4.0mmol/L, due to its association with high mortality.(2) However, the origin of hyperlactatemia and its treatment might be more complex. First, it is important to realize that tissue hypoperfusion does not cause a rise in lactate until the decrease in oxygen delivery to the tissues (as an effect of hypoperfusion) reaches a critical point, where it is insufficient to meet the oxygen demand of the tissues, causing cellular dysoxia to occur and lactate levels to increase.(3) Second, as the clearance capacity of the liver almost disappears in sepsis,(4) persistently increased lactate levels may not be related to tissue dysoxia. Finally, other factors in sepsis might contribute to increased lactate levels in the presence of adequate tissue oxygen delivery.(5) Nevertheless, lactate is an important marker of the patient's response to the initiated therapy. In ALL forms of acute circulatory failure, a decrease in lactate levels is associated with a more favorable outcome.(6) Thus, from this we can form our first conclusion: If lactate levels DO NOT decrease following the initiation of treatment, something is wrong. Although there are many reasons why patients with sepsis might have increased lactate levels, in the early presentation of these patients, inadequate oxygen delivery is the most likely cause. It is also the only cause we can effectively treat when we exclude intoxications, inborn errors of metabolism and other metabolic causes of increased lactate levels.(5) The initial treatment of hyperlactatemia in patients with sepsis should be directed at improving tissue oxygen delivery. This is most effectively accomplished by improving global blood flow, which aims to improve microcirculatory perfusion. Other measures that could be used simultaneously are improving arterial oxygen saturation, improving hemoglobin levels and decreasing oxygen demand. When started immediately upon admission to the ICU, this package will not only effectively decrease lactate levels; it will also improve survival by 20%.(7) Although patients in afore mentioned study(7) had a lactate concentration at or above 3.0mmol/L, it is conceivable that patients with lower concentration levels might also benefit, as lactate levels between 2.0 - 3.9mmol/L in patients with suspected infection are associated with significant mortality, even in the absence of hypotension.(8) The concept of using the treatment package from the study by Jansen et al.(7) only in the early resuscitation period (first 8 hours of ICU admission) was recently confirmed in a study on septic shock survivors. Hernandez et al.(9) assessed the normalization ratio of lactate and showed that a biphasic curve existed. In the early hours (first 6 hours), lactate levels normalized rapidly following the initiation of therapy. In the second phase (up to 24 hours), the normalization was much slower. In the end, 50% of the patients (all survivors) had increased lactate levels at 24 hours after the initiation of treatment. The authors speculated that, early in the course of sepsis, the increased lactate levels quickly responded to improvements in tissue oxygen delivery (the main effect of increasing cardiac output by fluid resuscitation and improving perfusion pressure by using vasopressors). This phase might thus represent a flow-dependent phase of hyperlactatemia whereas, in the later phase, the increased lactate levels are probably more related to other factors. This allows a second conclusion on the use of lactate levels in patients with sepsis: Increased lactate levels should be seen as the consequence of inadequate tissue oxygenation for only a limited time in the early course of sepsis. In addition, driving the patient to normal lactate levels with the continued resuscitation of tissue perfusion/oxygenation might not be effective any longer. The ultimate goal of resuscitation is to restore microcirculatory perfusion, not macro hemodynamics.(10) However, current guidelines/protocols are still mostly directed towards macrocirculatory parameters, such as blood pressure, using aggressive fluid resuscitation. Although recent trials on the use of early goal directed therapy (EGDT) have shown no benefit over usual care,(11) we should recognize that the resuscitation of sepsis patients has already changed significantly. In the recent EGDT studies, fluid resuscitation was already done in the majority of patients. Even in the lactate study by Jansen et al.,(7) lactate levels had the exact same trajectory in the control group patients compared to the protocol patients, despite the fact that the treatment team was unaware of the actual levels. This brings up a relevant question: If the lactate levels were not different between the two groups, why did the patients in the lactate oriented group have better survival? There were few differences in the variables collected in the study that could explain this effect. On average, the patients in the protocol group were treated with approximately 500mL more fluids in the treatment period and over 1L less fluids in the observation period (8 - 72 hours after initiation of treatment). In addition, the use of nitroglycerin to improve microcirculatory perfusion (as demanded by protocol in the protocol group) was more present in the protocol group than the control group (43% versus 20% of the patients, respectively). Although this did not result in differences in lactate levels, this adjustment in therapy might have had a significant effect in the patients who really needed the extra fluids and vasodilators when their lactate levels did not decrease as projected (20% decrease per 2 hours in the protocol group). Second, the use of less fluids in the observation period might have resulted in less morbidity associated with fluid overload.(12-14) One aspect, related to a comment made earlier, was not captured in the study. The goal in the protocol group was to decrease lactate by at least 20% per 2 hours; upon failure to meet this goal, a reassessment of the current treatment was initiated and, in some patients, additional diagnostic procedures (CT-scan, echo, etc.) were initiated and therapy was adjusted (laparotomy, change of antibiotic regimen, etc.). Therefore, given the above arguments, we can conclude that, in patients with sepsis, early resuscitation of the circulation aimed to improve the balance between oxygen delivery and oxygen demand, thereby restoring tissue oxygenation using a multimodal approach that is effective in improving survival. Several important factors should be taken into account when using this approach. First, this approach should be used for a limited time (current evidence suggests 6 - 8 hours). Although the original study(7) used a lactate level above 3.0mmol/L, studies suggest that this regimen might be effective in all sepsis patients with increased lactate levels (above 2.0mmol/L). Following the start of resuscitation, lactate levels should decrease rapidly if the balance between oxygen demand and oxygen delivery indeed improves (Figure 1). Therefore, frequent measurements (at least every 2 hours) should be part of the resuscitation protocol. If the therapeutic measures do not result in a rapid decrease in lactate levels, then RETHINK, REASSESS and RESOLVE. Figure 1 How to use lactate in resuscitating sepsis associated circulatory dysfunction.

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          Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial.

          It is unknown whether lactate monitoring aimed to decrease levels during initial treatment in critically ill patients improves outcome. To assess the effect of lactate monitoring and resuscitation directed at decreasing lactate levels in intensive care unit (ICU) patients admitted with a lactate level of greater than or equal to 3.0 mEq/L. Patients were randomly allocated to two groups. In the lactate group, treatment was guided by lactate levels with the objective to decrease lactate by 20% or more per 2 hours for the initial 8 hours of ICU stay. In the control group, the treatment team had no knowledge of lactate levels (except for the admission value) during this period. The primary outcome measure was hospital mortality. The lactate group received more fluids and vasodilators. However, there were no significant differences in lactate levels between the groups. In the intention-to-treat population (348 patients), hospital mortality in the control group was 43.5% (77/177) compared with 33.9% (58/171) in the lactate group (P = 0.067). When adjusted for predefined risk factors, hospital mortality was lower in the lactate group (hazard ratio, 0.61; 95% confidence interval, 0.43-0.87; P = 0.006). In the lactate group, Sequential Organ Failure Assessment scores were lower between 9 and 72 hours, inotropes could be stopped earlier, and patients could be weaned from mechanical ventilation and discharged from the ICU earlier. In patients with hyperlactatemia on ICU admission, lactate-guided therapy significantly reduced hospital mortality when adjusting for predefined risk factors. As this was consistent with important secondary endpoints, this study suggests that initial lactate monitoring has clinical benefit. Clinical trial registered with www.clinicaltrials.gov (NCT00270673).
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            Association between systemic hemodynamics and septic acute kidney injury in critically ill patients: a retrospective observational study

            Introduction The role of systemic hemodynamics in the pathogenesis of septic acute kidney injury (AKI) has received little attention. The purpose of this study was to investigate the association between systemic hemodynamics and new or persistent of AKI in severe sepsis. Methods A retrospective study between 2006 and 2010 was performed in a surgical ICU in a teaching hospital. AKI was defined as development (new AKI) or persistent AKI during the five days following admission based on the Acute Kidney Injury Network (AKIN) criteria. We studied the association between the following hemodynamic targets within 24 hours of admission and AKI: central venous pressure (CVP), cardiac output (CO), mean arterial pressure (MAP), diastolic arterial pressure (DAP), central venous oxygen saturation (ScvO2) or mixed venous oxygen saturation (SvO2). Results This study included 137 ICU septic patients. Of these, 69 had new or persistent AKI. AKI patients had a higher Simplified Acute Physiology Score (SAPS II) (57 (46 to 67) vs. 45 (33 to 52), P < 0.001) and higher mortality (38% vs. 15%, P = 0.003) than those with no AKI or improving AKI. MAP, ScvO2 and CO were not significantly different between groups. Patients with AKI had lower DAP and higher CVP (P = 0.0003). The CVP value was associated with the risk of developing new or persistent AKI even after adjustment for fluid balance and positive end-expiratory pressure (PEEP) level (OR = 1.22 (1.08 to 1.39), P = 0.002). A linear relationship between CVP and the risk of new or persistent AKI was observed. Conclusions We observed no association between most systemic hemodynamic parameters and AKI in septic patients. Association between elevated CVP and AKI suggests a role of venous congestion in the development of AKI. The paradigm that targeting high CVP may reduce occurrence of AKI should probably be revised. Furthermore, DAP should be considered as a potential important hemodynamic target for the kidney.
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              Clinical use of lactate monitoring in critically ill patients

              Increased blood lactate levels (hyperlactataemia) are common in critically ill patients. Although frequently used to diagnose inadequate tissue oxygenation, other processes not related to tissue oxygenation may increase lactate levels. Especially in critically ill patients, increased glycolysis may be an important cause of hyperlactataemia. Nevertheless, the presence of increased lactate levels has important implications for the morbidity and mortality of the hyperlactataemic patients. Although the term lactic acidosis is frequently used, a significant relationship between lactate and pH only exists at higher lactate levels. The term lactate associated acidosis is therefore more appropriate. Two recent studies have underscored the importance of monitoring lactate levels and adjust treatment to the change in lactate levels in early resuscitation. As lactate levels can be measured rapidly at the bedside from various sources, structured lactate measurements should be incorporated in resuscitation protocols.
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                Author and article information

                Journal
                Rev Bras Ter Intensiva
                Rev Bras Ter Intensiva
                rbti
                Revista Brasileira de Terapia Intensiva
                Associação de Medicina Intensiva Brasileira - AMIB
                0103-507X
                1982-4335
                Apr-Jun 2017
                Apr-Jun 2017
                : 29
                : 2
                : 124-127
                Affiliations
                [1 ] Department of Intensive Care Adults, Erasmus MC University Medical Center - Rotterdam, Netherlands.
                [2 ] Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Medical Center - New York, United States.
                [3 ] Division of Pulmonary, Sleep Medicine and Critical Care, New York University - Langone Medical Center - New York, United States.
                [4 ] Department of Intensive Care, Pontificia Universidad Catolica de Chile, Santiago, Chile.
                Author notes
                Corresponding author: Jan Bakker, Department of Intensive Care Adults, Erasmus, MC University Medical Center, PO Box 2040, Room H625, Rotterdam 3000 CA, Netherlands. E-mail: jb3387@ 123456cumc.columbia.edu
                Article
                10.5935/0103-507X.20170021
                5496745
                76d9d3fe-8fc0-425f-a154-d2909f00c45d

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 October 2016
                : 05 January 2017
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