What is the role of detecting lactate levels in patients with sepsis and septic shock?

Despite advances in understanding and treatment of sepsis, sepsis remains the leading cause of death worldwide
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As a result, experts have attempted to distill core principles of sepsis management into simple, generic bandles and management guidelines, and advocated for widespread implementation of many sepsis bandles and management guidelines.
A core component of many sepsis bandles and management guidelines is the measurement of lactate levels as an Severity, prognosis, and means of resuscitation success
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The steady rise in lactate detection rates over the past two decades reflects a growing focus on lactate measurement
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However, most clinicians do not have a detailed understanding of lactate physiology and the causes of increased or decreased lactate levels
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This can lead to the inadvertent use of antibiotics or fluids in patients with elevated lactate levels for reasons other than infection or inadequate resuscitation
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The increasingly prominent role of lactate monitoring in contemporary practice is therefore the subject of controversy
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In this article, we review lactate metabolism and illustrate how this contributes to a deeper understanding of patient physiology and how it can explain elevated lactate levels in patients with sepsis
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We then review the evidence behind the use of lactate monitoring, diagnosis, prognosis, and treatment, and place it in the context of evolving guidelines for the diagnosis and management of sepsis
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1.
Normal physiology of lactic acid 1.
Lactic acid production Lactic acid is mainly produced in skeletal muscle, intestine, brain, skin and red blood cells
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Glycolysis in the cytoplasm of cells converts glucose to pyruvate and produces energy in the form of adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NADH)
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Under aerobic conditions, pyruvate is converted to acetyl-CoA by pyruvate dehydrogenase (PDH) and then enters the mitochondrial-based citric acid (Krebs) cycle
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In the penultimate step of anaerobic glycolysis, cells that do not have enough oxygen (or lack mitochondria, such as red blood cells) convert pyruvate to lactate by lactate dehydrogenase (LDH)
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Anaerobic glycolysis produces only 2 ATP molecules, while 38 ATP molecules are produced when glucose is converted to carbon dioxide and water through the citric acid cycle and oxidative phosphorylation
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2.
Lactic acid clears lactate produced by various cells in the body and circulates to the liver and kidneys, where it is converted back into pyruvate and subsequently undergoes gluconeogenesis (known as the Cori cycle) or into acetyl-CoA, which is then passed through the citric acid cycle oxidative metabolism
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The liver is responsible for removing most of the lactate from the systemic circulation (70-80%), followed by the kidneys (20-30%)
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Notably, only a small fraction (2%) of lactic acid is excreted in urine
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At rest, approximately half of the lactic acid produced by the body ends up being oxidatively metabolized through the citric acid cycle
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3.
Maintain lactic acid homeostasis The human body usually produces 20 mmol/kg of lactic acid every day
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At homeostasis, blood lactate levels are maintained within a concentration range of 0.
5 to 1.
5 mmol/L by balancing the production, utilization, and excretion of lactate
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The human body's ability to process lactate under normal conditions far exceeds the amount produced, which can reach 500 mmol per hour under stress
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For example, during exercise, the utilization of lactate for aerobic metabolism in the myocardium and brain increases, and the proportion of lactate scavenged by oxidative increases from approximately 50% to 75%
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This suggests that lactate is not just a dormant terminal or waste product, but serves as a fuel and energy-rich intermediate, available during times of stress
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Lactic acid as an energy intermediate has been shown to have a coordinated and coupled distribution throughout body tissues and organs, serving as an energy source in the absence of localized glycolysis
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But the term is misleading
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In fact, what is being measured is the overall change in lactate concentration caused by changes in the balance of production, utilization and excretion
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II.
Causes of Hyperlactatemia in General Conditions and Sepsis The normal lactate physiology described earlier helps to highlight potential alterations and bottlenecks that can occur in cellular and tissue metabolism, especially during acute illness and sepsis (►Fig.
1)
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Below, we discuss these potential mechanisms of hyperlactatemia in sepsis
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Table 1 Causes of elevated lactate 1.
Theory of tissue hypoxia Lactic acidosis The results of tissue hypoxia are widely cited in the literature, and this theory is based on the pioneering work of Nobel Prize winner Otto and by Karlman Wasserman "Anaerobic Acidosis" Exercise physiology for the development of the "threshold" concept.
"Type A" lactic acidosis or "hypoperfusion" is synonymous with the theory of tissue hypoxia because they believe that insufficient oxygen (DO2) delivery to tissues must increase the "hypoxia" characteristic Refers to the insufficiency of DO2 in metabolically active tissues during sepsis
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In inadequately resuscitated septic shock with severe vasodilation, the effective circulating blood volume may be so low that the oxygen uptake limit is reached, and central output may be severely impaired in sepsis-induced myocardial depression
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Acute respiratory distress syndrome (ARDS), which is often accompanied by septic shock, can also lead to low arterial partial pressure of oxygen
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      Although these concepts are biologically plausible, the aforementioned limitations of oxygen delivery are unlikely to be the primary cause of lactate elevations, even after accounting for increased tissue metabolic activity
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In fact, over the past few decades, substantial evidence has shown that lactate can accumulate even under fully aerobic conditions, with mechanisms that do not rely on limited oxygen and oxidative phosphorylation in the citric acid cycle
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In septic patients, DO2 and central venous oxygen values ​​for elevated arterial lactate range widely and correlate poorly with these markers of oxygen delivery
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Several studies have evaluated the relationship between partial pressure of oxygen and lactate production in muscle under a range of physiological conditions; even in patients with sepsis or septic shock, partial pressure of oxygen is normal, or even high, in contrast to serum Lactate levels were not relevant
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Measures to increase oxygen delivery—whether by adding supplemental oxygen or blood transfusions—did not improve indicators of oxygen utilization, nor did they improve outcomes
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In addition, studies evaluating the hemodynamic effects of esmolol in patients with septic shock found that although esmolol decreased oxygen delivery, it actually resulted in a decrease in lactate concentrations
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      However, this does not mean that lactate production is independent of oxygen concentration
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Other parallel effects of hypoxia that increase the rate of glycolysis, such as increased catecholamine release or altered ADP/ATP ratios under metabolic stress, may lead to increased lactate production
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Only in the case of extreme hypoxia is there a true lack of oxygen to support aerobic metabolism, which should be considered the exception rather than the norm
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2.
Catecholamine-induced lactate production Under stress, circulating catecholamines bind to β-adrenergic receptors on muscle cells to stimulate glycogenolysis
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At the same time, glycogen synthesis decreases, gluconeogenesis increases, and peripheral glucose uptake increases
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Catecholamines also accelerate membrane-bound sodium/potassium ATPases through binding to beta-2 receptors, which are associated with increased rates of glycolysis
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In this way, the substrate for glycolysis increases and the rate of glycolysis increases
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As mentioned earlier, any increase in glycolytic production leads to an increase in lactate production, which then enters the systemic circulation as an energy intermediate
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In this way, the body's stress response results in the release of catecholamines, which in turn provide fuel at both local and systemic levels
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Skeletal muscle is rich in beta-2 receptors and is the largest source of lactate production in septic shock due to adrenaline-induced stimulation of sodium/potassium ATPases
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The body's ability to respond to catecholamine surges, either endogenous or exogenous, may be a marker of cellular reserves to produce energy and is associated with lower mortality
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Previous studies have shown that patients with septic shock who respond to dopamine or dobutamine infusions are more likely to survive than non-responders
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Further support for this theory is the finding that an early increase in lactate following epinephrine infusion is associated with a reduction in mortality, and previous studies have shown that esmolol reduces lactate levels in patients with septic shock
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3.
Mitochondrial dysfunction The final stage of the mitochondrial electron transport chain requires oxygen to function as an electron acceptor
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In the absence of adequate tissue delivery of oxygen, ATP production decreases and reactive oxygen species production increases, potentially activating cell death pathways
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Unrelated to this, increased production of intermediate reactive oxygen species in sepsis may directly inhibit mitochondrial energy production
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The systemic inflammatory response to sepsis may also alter thyroid hormone levels, through complex cellular signaling, resulting in changes in mitochondrial protein and lipid composition, downregulation of protein transcription, and reduced mitochondrial carcinogenesis
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      Despite these expected biochemical changes, the extent to which mitochondrial dysfunction results in increased lactate formation remains unclear and may vary by physiological state
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Mitochondrial oxygen supply is insufficient for oxidative metabolism only during the stage of severe tissue hypoxia, which is uncommon in sepsis
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In addition, studies assessed the presence of intracellular substrates and expected physiological conditions such as low levels of ATP and phosphocreatine and low cytosolic pH in the context of altered mitochondrial function; however, despite sepsis Lactate levels were elevated in patients, but ATP and phosphocreatine levels were similar in septic and non-septic patients
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On the other hand, other studies have shown that low levels of the mitochondrial electron transport chain complex are associated with higher mortality in patients with sepsis
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4.
Decreased utilization and excretion of lactic acid due to liver and kidney injury The kidneys and liver are the main users of lactic acid and are easily damaged in sepsis and septic shock
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Lactate is usually not elevated at baseline in either end-stage renal disease or cirrhosis
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However, in sepsis, the small rise in blood lactate concentration may be associated with a decrease in lactate utilization rather than an increase in production
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The clearance of lactate from the blood is affected in patients with hepatic dysfunction, and lactate levels are frequently elevated in patients with fulminant hepatic failure
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Recent data also suggest that acute kidney injury reduces the ability of the kidneys to metabolize lactate
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Acidosis also impairs the ability of the liver and kidneys to metabolize lactate
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5.
Decreased pyruvate dehydrogenase activity Pyruvate dehydrogenase (PDH) regulates the conversion of pyruvate into acetyl-CoA, and then enters the citric acid cycle
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Decreased PDH activity reduces oxidative capacity, resulting in increased pyruvate and lactate concentrations
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An animal model showed no changes in PDH function in early sepsis, but the PDH complex was inhibited after 24 hours
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Dichloroacetic acid, a stimulator of the PDH complex, reduces lactate levels in patients with sepsis
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In addition, PDH activity and number of peripheral blood mononuclear cells were reduced in sepsis patients compared with controls, and PDH activity was inversely correlated with baseline lactate levels and mortality
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In addition, PDH activity and number of peripheral blood mononuclear cells were reduced in sepsis patients compared with controls, and PDH activity was inversely correlated with baseline lactate levels and mortality
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Thiamine is an important factor in PDH activity, but so far there is no clear evidence of benefit
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6.
Drugs A variety of drugs commonly used in the treatment of patients with sepsis (and those at risk for sepsis) may also alter lactate metabolism
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These include propofol and metformin, which may interfere with oxidative phosphorylation, resulting in elevated pyruvate and lactate concentrations
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Inhaled albuterol is used for bronchospasm and is a beta-2 adrenergic receptor agonist that stimulates glycolysis and lactate production
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3.
Definition of sepsis and determination of lactate in guidelines 1.
Definition of sepsis Hyperlactatemia with suspected or confirmed infection has been an integral part of the definition of sepsis since the first consensus definition meeting in 1991
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Specifically, Sepsis-1 defines sepsis as a systemic response to infection and severe sepsis as sepsis associated with organ dysfunction, hypoperfusion, or hypotension
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Both Sepsis-1 and Sepsis-2 include lactic acidosis as a form of hypoperfusion, although no specific lactate threshold is provided
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The original early goal-directed therapy (EGDT) trial by Rivers et al enrolled patients with suspected infection and hypotension who were refractory to initial fluid resuscitation or had initial lactate ≥4.
0 mmol/L; this subsequently became the standard for septic shock, with In three multicenter EGDT trials and Centers For Medicare And Medicare
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Notably, SEP-1 includes lactate levels above 2.
0 mmol/L as a criterion for organ dysfunction in severe sepsis, although CMS did not provide a specific rationale for this threshold
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      In 2016, the Third International Consensus Definition of Sepsis and Septic Shock (Sepsis-3) updated the definition of sepsis to reflect a focus on organ dysfunction rather than systemic inflammatory responses
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Organ dysfunction was defined as a ≥2-point increase in the Sequential Organ Failure Assessment (SOFA) score in the presence of suspected infection
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Notably, the SOFA score does not include lactate levels
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However, lactate is also included in the Sepsis-3 criteria for septic shock, which is defined as serum lactate greater than 2 mmol/L (as a marker of cellular dysfunction) in the absence of hypovolemia and the need for vascular Compression medication to maintain mean arterial pressure of 65mmHg
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2.
Management policy and quality measures SSC guidelines recommend lactate measurement as a core component of sepsis care
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The SSC recommends the measurement of lactate levels as a marker of sepsis-induced hypoperfusion, thereby prompting fluid resuscitation
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It is also used as a marker to monitor perfusion adequacy in patients requiring vasopressors
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In later iterations of the guideline, lactate measurement has received increasing attention, including a series of measurements to measure the adequacy of resuscitation and to inform the need for more fluids
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As part of the 2018 SSC update, the "1-hour bandle" requires immediate and prompt measurement of lactate when sepsis is detected
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The guideline appropriately states that lactate concentrations are not a direct measure of tissue perfusion and that there are many potential causes of elevated lactate concentrations in sepsis
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      In 2015, CMS applied the SSC guidelines to SEP-1 measurements
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Lactate monitoring plays a prominent role in SEP-1, requiring patients to have their first lactate measurement within 3 hours of meeting criteria for severe sepsis, and repeat lactate levels within 6 hours for patients with initial levels above 2 mmol/L
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Preliminary data suggest that failure to measure lactate levels is a common cause of SEP-1 failure, although it has no apparent impact on patient outcomes
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4.
Controversy Despite the strong prognostic value of initial lactate concentration and continuous lactate concentration, the increasing emphasis on routine lactate concentration monitoring in sepsis guidelines and quality indicators has caused controversy and concern.
We The summary is as follows
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1.
Does lactate-guided therapy lead to excessive resuscitation? A common reaction to elevated lactate levels is fluid infusion
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This conclusion is supported by a series of lactate monitoring studies in an informal resuscitation trial, in which the main change in clinical response in patients undergoing lactate monitoring was the administration of more intravenous fluids
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However, based on our current knowledge of lactate metabolism, it is clear that hyperlactatemia does not always reflect tissue hypoxia and hypoperfusion, and more broadly, there is little evidence that progressively elevated lactate levels reflect a fluid responsive state
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      The recently published ANDROMEDA-Shock trial evaluated capillary recongestion time (CRT) as an surrogate target for lactate resuscitation, providing additional reason to focus on lactate-guided resuscitation
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Previous observational studies have shown that longer CRT is associated with greater organ dysfunction and mortality
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In this trial, patients had received an initial minimum of 20 mL/kg of fluid to meet entry criteria
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Each trial arm had protocolized stepwise management, including assessment of fluid responsiveness, vasopressor testing in chronic To expand the test
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Study sites were generally experienced in assessing fluid responsiveness, with more than 80% of enrolled patients having fluid responsiveness assessments
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Mortality was 8% lower in the CRT group
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In a Bayesian reanalysis of this trial, the CRT group had a beneficial effect on 28-day mortality, and in the post hoc analysis, the lactate group had higher 28-day mortality in the CRT-normal group
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Patients in the lactate group received more fluids during the first 8 hours and had more organ dysfunction at 72 hours
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      The ANDROMEDA-Shock trial study supports concerns about excessive fluid resuscitation due to elevated lactate in patients with sepsis
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Aggressive fluid resuscitation in the early stages of sepsis is not benign, and volume overload is associated with more severe organ dysfunction and increased mortality
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Indeed, there is growing evidence that fluid restriction strategies may be beneficial in some patients with sepsis
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The "LactoBolo reflex" proposed by Spiegel and colleagues, while ironic in nature, is a good reminder that when clinicians are confronted with elevated lactate, the usual response is to reflex fluid resuscitation This "reflex" is not a coincidence, but rather a reflection of sepsis guidelines overemphasizing the link between hypoperfusion and lactate
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2.
Does universal lactate screening lead to unnecessary antibiotic use? The use of lactate as a screening tool for sepsis has become routine in many hospitals around the world, and as mentioned earlier, when co-infection is suspected, it can be as a useful risk stratification tool
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However, elevated lactate levels are not specific to sepsis
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Numerous other disease processes can lead to hyperlactatemia, including cardiogenic, hypovolemic, or obstructive shock; pancreatitis and other nonseptic distributive shock; limb or tissue ischemia; fluid and malignancy; ingestion and inhalation of toxic substances; seizures; diabetic ketoacidosis (Table 1), just as excessive lactate has been attributed to hypoperfusion, so have been attributed to sepsis
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Thus, a high emphasis on lactate concentration measurement may lead not only to reflex infusion but also to reflex antibiotic use—perhaps a “lactate-bioreflex”
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A strict bandle, such as SEP-1, which emphasizes timeliness rather than accuracy, may lead to the overuse of lactate as a screening tool for sepsis, although it is less sensitive for this purpose
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Antibiotic overuse is potentially harmful, potentially leading to direct toxic effects of broad-spectrum antibiotics, increased antibiotic resistance, and C.
difficile colitis
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3.
Does lactate monitoring improve patient outcomes? Lactate monitoring is gaining traction in current sepsis guidelines and quality measures, despite the lack of evidence that checking lactate levels improves outcomes
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Han and colleagues retrospectively observed that, in patients with elevated initial lactate levels, delaying subsequent lactate testing was associated with increased mortality and longer duration of antibiotic use
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However, the present study and other retrospective studies have established bias, and lactate measurements increased the detection rate in cases of less clinical severity
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As previously described, lactate-guided therapy was associated with increased organ dysfunction and mortality compared with peripheral perfusion-guided therapy as assessed in a single large RCT
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A large observational study found that failure to measure lactate was the most common reason for noncompliance with SEP-1 bundles, but there was no associated increase in mortality in these patients
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V.
CONCLUSIONS The data clearly demonstrate that higher lactate levels and failure to reduce lactate levels over time are associated with increased mortality in patients with sepsis and septic shock
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It is unclear whether targeting lactate clearance improves patient outcomes compared with other perfusion measures, and whether lactate is the optimal target for this purpose
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There is currently a lack of high-quality evidence to support a clear beneficial effect of initial and continuous lactate monitoring on patient-centred outcomes
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Fundamental pathobiological studies of lactate metabolism and disturbances in sepsis highlight the need to dilute hypoxia and hypoperfusion as the only mechanism for lactate production
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Because elevated lactate does not always reflect fluid responsiveness, the use of lactate as a measure of hypoperfusion during ongoing resuscitation may lead to excessive fluid administration and its associated harms
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Unfortunately, current sepsis guidelines and mandatory bandle continue to emphasize lactate as a marker of hypoperfusion, and for many clinicians, elevated lactate has become almost synonymous with sepsis, facilitating reflex drug administration Infusions and antibiotics
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Better use of lactate monitoring will serve as a warning sign for clinical teams to reassess end-organ perfusion, fluid responsiveness, and search for alternative causes of elevated lactate
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Future guidelines will ideally take these factors into account and help facilitate a more nuanced approach to sepsis management and resuscitation, tailored to the specific physiological characteristics of each patient
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