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CARDIOPULMONARY MONITORING Blood lactate levels in sepsis: in 8 questions Vincent, Jean-Louisa; Bakker, Janb,c,d,eAuthor Information Current Opinion in Critical Care: June 2021 - Volume 27 - Issue 3 - p 298-302 doi: 10.1097/MCC.0000000000000824 Abstract Purpose of review Blood lactate concentrations are frequently measured in critically ill patients and have important prognostic value. Here, we review some key questions related to their clinical use in sepsis. Recent findings Despite the metabolic hurdles, measuring lactate concentrations remains very informative in clinical practice. Although blood lactate levels change too slowly to represent the only guide to resuscitation, serial lactate levels can help to define the patient's trajectory and encourage a review of the therapeutic strategy if they remain stable or increase over time. Summary Lactate concentrations respond too slowly to be used to guide acute changes in therapy, but can help evaluate overall response. Hyperlactatemia should not be considered as a problem in itself, but as a warning of altered cell function（乳酸浓度反应太慢，无法用于指导治疗的急性变化，但可以帮助评估整体反应。高乳糖血症本身不应被视为一个问题，而应被视为细胞功能改变的警告）. 要点：
INTRODUCTION Measurement of blood lactate concentrations can be very useful in septic shock, as in other forms of shock, providing a marker of altered tissue perfusion, disease severity, and prognosis [1–4,5▪]. Moreover, the evaluation of serial lactate concentrations can help monitor a patient's response to treatment. The normal blood lactate concentration is about 1 mEq/l (or mMol/l), and an increase to 1.5 mEq/l (hyperlactatemia) or above is an important alarm signal [6]. Septic shock is associated with a lactate concentration above an arbitrary value of 2 mEq/L [7]. In this article, we will provide an up-to-date review on the role of blood lactate measurement in patients with sepsis by providing answers to eight important questions. Question 1: Does hyperlactatemia always reflect anaerobic metabolism in sepsis? Answer: No. 问题1：高乳酸血症能反映脓毒症的无氧代谢吗？ 回 答：No Under physiological conditions, lactate is a normal end-product of glucose metabolism via two main pathways: glycolysis and oxidative phosphorylation. Glycolysis is a process that generates small amounts of adenosine triphosphate (ATP), but because of its speed, can create significant energy. Oxidative phosphorylation is the process that involves the Krebs cycle. This is a slower process than glycolysis and requires oxygen to metabolize the pyruvate generated from glucose. In shock, including septic shock, lack of oxygen prohibits the metabolism of pyruvate in the Krebs cycle, and anaerobic metabolism converts it to lactate via the enzyme lactate dehydrogenase. Indeed, hypoxic states are characterized by inadequate oxygen supply to the cells such that supply is unable to match demand. Experimental studies, including models of endotoxin administration or bacterial sepsis, have clearly documented that an acute and profound reduction in global oxygen delivery (DO2) results in a decrease in oxygen uptake (VO2) and that the critical DO2 value at which this occurs is also the moment when lactate concentrations start to increase sharply. In sepsis, the altered microcirculation, with increased heterogeneity of flow, further limits tissue oxygenation [8]. In cardiac surgery patients, who have similar microcirculatory changes to those seen in sepsis, greater severity of microcirculatory impairment was associated with significantly higher blood lactate concentrations [9▪]. In patients with increased lactate production, liver dysfunction, frequently present in patients with sepsis, may reduce the capacity to clear lactate, thus contribute to raised blood lactate concentrations. However, liver failure alone cannot result in hyperlactatemia [10]. The kidneys also metabolize lactate but to a much lesser extent such that renal failure does not have a major impact on blood lactate concentrations. In addition metabolic changes in sepsis, such as inhibition of pyruvate dehydrogenase and increased Na/K pump activity, may result in increased lactate concentrations despite the presence of adequate tissue oxygen availability. Another possible reason for increased lactate in sepsis is increased glycolysis, a process that is stimulated by beta-adrenergic agents and alkalemia among other causes (Table 1). Other causes of hyperlactatemia, which are less relevant to our discussion in sepsis, also exist. For example, metformin use can cause hyperlactatemia by interfering with oxidative phosphorylation [11▪]. If there are associated metabolic alterations, the lactate/pyruvate (L/P) ratio will be increased above the normal value of around 10/1, whereas with increased glycolysis, it is the excess pyruvate that can lead to hyperlactatemia, with an unchanged L/P ratio. Separation of hyperlactatemia into hypoxic and nonhypoxic causes based on the L/P ratio has been attempted, but pyruvate measurements are difficult and prone to technical problems. Moreover, the two types (hypoxic and nonhypoxic) usually co-exist. Studies have shown that pyruvate concentrations and/or the L/P ratio have limited clinical use. Question 2: Does vasoactive drug therapy contribute to increased lactate concentrations? Answer: Yes and no. 问题2：血管活性药物能增加乳酸水平吗？ 回 答：似是而非. Catecholamines with strong beta-adrenergic activity can stimulate cellular metabolism and thereby increase lactate concentrations. This is particularly the case with administration of epinephrine, which is now relatively uncommon. Any changes in lactate concentration associated with vasoactive drug administration would, however, only amplify the alarm signal, because the sicker the patient, the greater the need for vasoactive agents and the higher the lactate concentrations. It would be a clinical error to overestimate this phenomenon and to assume that a patient's hyperlactatemia is solely the result of administration of adrenergic agents without an associated decrease in tissue perfusion（高估血管活性药物造成乳酸增加的情况，并认为患者的高乳酸血症仅仅是由肾上腺素给药造成而忽略组织灌注减少，这完全是一个错误）. Question 3: Can blood lactate concentrations be considered as markers of sepsis? Answer: No. 问题3：乳酸水平可视为脓毒症的标志物吗？ 回 答：No. Lactate concentrations are increased in all forms of shock [12], whether the main underlying pathophysiologic alteration is hypovolemic, cardiogenic, obstructive or distributive. The presence of hyperlactatemia does not provide any information about the cause or type of the underlying shock. Despite the contribution of cellular alterations to sepsis-related hyperlactatemia, few patients with sepsis will have elevated lactate concentrations if their tissue perfusion is normal, except perhaps if lactate concentrations remain above normal values in a patient who has been fully resuscitated, because they have not yet had time to return to normal [6,13]. Hyperlactatemia should not be considered as being due to cellular alterations alone; reduced tissue perfusion is an important factor. Question 4: Can lactate concentrations predict outcome? Answer: Yes, definitely. 问题4：乳酸水平能预测预后吗？ 回 答：Yes，必须滴 Numerous studies have shown that lactate concentrations are associated with patient survival and/or organ failure in both adult and pediatric sepsis [1,3,4,5▪]. Importantly, even early measurements are predictive of outcome [3]. Question 5: Should we combine lactate and SvO2 concentrations? Answer: Yes and no. 问题5：乳酸水平与 SvO2（混合静脉血氧饱和度）联用如何？ 回 答：似是而非. Patient management should never be based on one variable alone, and adding mixed (SvO2) or central (ScvO2) venous oxygen saturation values, a marker of inadequate oxygen delivery, to lactate concentrations can help identify tissue hypoperfusion and may lead to beneficial clinical interventions. However, one cannot expect lactate and S(c)vO2 to be correlated [14]. During resuscitation, changes in S(c)vO2 during an increase in DO2 (e.g., with fluids or dobutamine administration) are much faster than changes in lactate concentrations, so that the relationship between the two is difficult to interpret [15]; combining these two variables is therefore not straightforward. It may be attractive to consider that a high SvO2 (or ScvO2 when only a central venous catheter is available) in the presence of elevated lactate concentrations could reflect a severe alteration in cellular function, wherein the cells can no longer use oxygen (a process sometimes called 'cytopathic hypoxia’). Unfortunately, a high SvO2 can also be due to microvascular alterations. One may consider that an increase in DO2 will increase cellular metabolism in the presence of hemodynamic alterations and not in the presence of cellular alterations. The former is indeed what characterizes VO2/DO2 dependency in shock states. Unfortunately, these measurements are not easily applied at the bedside. Question 6: Is it valuable to repeat the measurement of blood lactate concentrations? Answer: Yes, definitely. 问题6：连续监测乳酸水平价值如何？ 回 答：Yes，必须滴 Following the time course of blood lactate concentrations can provide valuable information, especially when the evolution of the patient's condition is uncertain. Some people have used the term 'lactate clearance’ to describe the decrease in lactate concentrations over time, but this is inappropriate, because hyperlactatemia is determined more by increased production than by decreased elimination [16]. A recent study showed that increased production and decreased elimination can coexist also in malaria [17]. Reference to lactate clearance can also lead to confusion when a patient is receiving renal replacement therapy. Moreover, an increase in lactate concentrations over time would represent 'negative clearance’ [6]. To separate the effects of decreased lactate elimination from increased production would require infusion of a highly concentrated lactate solution or the administration of radiolabeled lactate [18▪], which, although potentially of interest to study the mechanisms of lactate kinetics, would be of little practical use in routine patient care. Lactate concentrations change relatively slowly, because lactate metabolism takes time. The first study on serial lactate concentrations in 1993 [13] showed that in the best case scenario of a rapid response to fluid therapy, lactate concentrations decreased by 10% in one hour; higher rates of decline are therefore unlikely. Therefore, measurement of lactate concentrations every one or two hours is recommended [6]. Some monitoring systems may allow more frequent assessment of blood lactate concentrations, but it is unclear whether this holds any advantage over hourly measurements. Importantly, because the majority of lactate is metabolized in the liver, evaluating the time course in patients with advanced liver dysfunction is more complex（乳酸浓度变化相对缓慢，因为乳酸代谢需要时间。1993年关于连环乳酸浓度的第一项研究[13]表明，在对液体治疗快速反应的最佳情况下，乳酸浓度在一小时内下降了10%：因此，不太可能有更高的下降速度。因此，建议每一两个小时测量一次乳酸酯浓度[6]。一些监测系统可能允许更频繁地评估血液乳酸浓度，但尚不清楚这是否比每小时测量有任何优势。重要的是，由于大多数乳酸酯在肝脏中代谢，评估晚期肝功能障碍患者的时间过程更为复杂）. Question 7: Can assessment of serial lactate concentrations be used to guide therapy? Answer: Yes and no. 问题7：连续监测乳酸水平能用于指导治疗吗？ 回 答：似是而非 Jansen et al.[19] showed that evaluating lactate kinetics over time could be used to influence therapy, but, as already stated, one should not focus on a single variable to guide therapy, and this applies to lactate as well as to other variables. Because changes in lactate concentrations over time are slow and variable, they are of little use alone to guide therapy in the critically ill patient in whom rapid therapeutic decisions are often needed as hemodynamic status alters quickly. In a post hoc analysis of the ANDROMEDA-SHOCK study, resuscitation guided by blood lactate levels in patients with normal capillary refill time, a much more rapid indicator of tissue perfusion than lactate, was associated with more organ dysfunction [20▪▪]. Nevertheless, trends in lactate concentrations in combination with other variables can help indicate response to treatment. A pragmatic approach to use of lactate concentrations to help guide therapy in critically ill patients is proposed in Fig. 1. Question 8: Is lactate toxic? Answer: Not really. 问题8：乳酸有毒性吗？ 回 答：非也！ Lactate in and of itself is not a toxic molecule and is used as a fuel for cells via the mono-carboxylate transporters; it may even have important beneficial regulatory properties [21▪]. When lactate concentrations increase in the blood, they increase also in the cells and influence their function. Lactate increases T helper 1 cell differentiation and the production of interferon-γ and modifies macrophage function. These effects may also have some immunosuppressive action [22], and may therefore contribute to the acquired immunosuppression (sometimes called 'immunoparalysis’) of sepsis, although the implications of this possible effect in patients with sepsis are not well-defined. It is unclear whether improving lactate metabolism can improve outcome. The administration of dichloroacetate can decrease lactate concentrations, but this was not associated with improved hemodynamics or survival [23]. There was no correlation between thiamine, a co-factor in aerobic metabolism, and lactate concentrations [24] and thiamine supplementation was not associated with improved outcomes in a small pilot study of patients with septic shock [25]. There has been some recent interest in the administration of hypertonic lactate. In experimental sepsis, it was suggested that hypertonic lactate infusion could improve the microcirculation [26], but in a larger animal model of hyperdynamic sepsis, Su et al.[27] observed harmful effects. The goal of therapy should not per se be to decrease lactate concentrations, but to intervene in the process that leads to increased lactate concentrations if this process is likely to be harmful to the patient, for example, tissue hypoxia. CONCLUSION Measuring lactate concentrations in sepsis provides important and useful information in terms of prognosis and a patient's response to treatment. Serial lactate concentrations may not help directly guide acute changes in therapy, but may help orient the overall therapeutic strategy. Hyperlactatemia should not be considered as a problem in itself but as a reflection of altered cell function where the cause of this alteration relates to the clinical actions needed to improve the patient's condition and outcome（脓毒症乳酸浓度为判断预后以及评价患者对治疗的反应方面提供了重要而有用的信息。连续乳酸浓度恐怕无助于直接指导治疗的快速调整，但可能有助于指导整体治疗策略。高乳糖血症本身不应被视为一个问题，而应被视为细胞功能的变化，这种变化是由改善患者病情和结局的临床行为造成）. REFERENCES（略）.
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