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The ten pitfalls of lactate clearance in sepsis

The problem with clearance

Clearance is the removal of a substance from blood, expressed as a volume (milliliters) over time (minutes). However, changes in lactate levels are the sum of ongoing production and removal from the blood by excretion (e.g., urine, sweat) and its metabolism (e.g., uptake by cells as a direct source of energy, conversion to glucose by the liver). To talk about “lactate clearance” [1] when actually describing a decrease in blood level is wrong and misleading. Following the review of 96 studies, Vincent et al. [1] concluded that given recent evidence, measurements every 1–2 h would give clinically relevant data about the decrease in lactate levels.

Lactate levels: production versus clearance

In clinical practice the change in lactate levels over time is thought to primarily reflect a change in production. As increased levels are generally associated with circulatory dysfunction, we often see a decrease in lactate levels as associated with an improvement in circulatory status and hypothesize (but cannot prove) decreased production. However, as true clearance in both stable septic patients and septic shock animals is significantly decreased in shock states, ongoing hyperlactatemia or even a rise in lactate levels may reflect decreased clearance rather than an increase in production of lactate [2, 3]. This is typically seen in the presence of shock with associated ischemic hepatitis. In addition, the complex inter- and intracellular metabolism of lactate makes our understanding of lactate physiology in shock extremely limited (see Sect. “Lactate as a substrate”).

Lactate and glucose metabolism

As lactate is a normal product of glucose and pyruvate metabolism, any increase in glucose metabolism or decrease in pyruvate metabolism will increase lactate generation and, in some cases, levels, even in the presence of adequate tissue oxygenation (as seen with epinephrine infusion). In sepsis, the inflammatory response appears associated with an increase in glycolysis and impaired pyruvate dehydrogenase (the enzyme critical for pyruvate entry into the Krebs cycle). Thus, cytoplasmic pyruvate increases with greater lactate formation but preserved pyruvate to lactate ratio, and lactate levels rise. In this way, the relationship of increased lactate production with tissue hypoxia as its possible source is confounded by the stress response that increases glucose metabolism and lactate generation [4]. In addition, although lactate levels can be significantly decreased by improving its metabolism by the administration of dichloroacetate, this will not result in improved survival as it does not address the root cause [5]. The same might apply to the correction of acidosis in the presence of increased lactate levels as the relationship between pH, anaerobic glycolysis, and lactate levels is not fully understood and is likely to be complex [6, 7].

Lactate as a substrate

Just like glucose, lactate may also serve as a substrate for metabolism. Especially in stress (such as sepsis), lactate, through several “shuttles”, provides a source of cellular energy. The first is the organ-to-organ lactate shuttle. Lactate released by muscle is taken up by the liver to enter the Cori cycle to generate glucose, which then through glycolysis may generate lactate depending on liver bioenergetics. In addition, lactate may be metabolized by the kidneys, accounting for up to 50% of total lactate metabolism. The second is the cell-to-cell lactate shuttle. This shuttle appears particularly important in the brain, where lactate can become a more important energy substrate than glucose [8]. Lactate is transported from astrocytes into neurons by dedicated transporters and then transformed into pyruvate by lactate dehydrogenase type 1. Pyruvate then enters the Krebs cycle to produce ATP. The third is the intracellular shuttle where lactate, generated by glycolysis in the cytoplasm, is used through mitochondrial membrane shuttles to increase the concentration of reduced NAD (NADH), which provides a proton gradient to generate energy by the electron transport chain.

Lactate and liver dysfunction

The liver, which is responsible for 60% of systemic lactate metabolism, is a vulnerable organ during sepsis-related acute circulatory dysfunction. The contribution of the liver to persistent hyperlactatemia might be much higher than previously thought, and the mechanisms are probably multifactorial. Without doubt, hepatosplanchnic ischemia could contribute in some cases especially in, but not limited to, severe septic shock [9]. On the other hand, early and severe impairment of exogenous lactate clearance not related to liver hypoperfusion has been shown in experimental conditions [3].

Lactate concentration in resuscitation fluids

Intravenous administration of lactated Ringer’s solution does not seem to increase circulating lactate concentrations in hemodynamically stable adults, nor worsen metabolic acidosis during an infusion of 1 L in 60 min [10]. Only when infusing large volumes (180 mL/kg/h) do lactate levels rise significantly [11]. On the contrary, the buffering effect of Ringer’s solution, with a more physiologic strong anion difference, might have a positive effect on blood pH.

Lactate and its confounders

As every increase in glucose metabolism may increase lactate levels, many elements confound the clinical use of lactate. Best known in clinical practice is the use of catecholamines in septic shock patients, alkalosis-induced increases in glucose metabolism, lactate buffered continuous hemofiltration, liver dysfunction, and lung lactate production. Also, the use of specific drugs has been associated with increased lactate levels (nucleoside reverse transcriptase inhibitors for treatment of HIV, metformin) as are some intoxications (ethylene glycol, methanol, and steroids) [4, 12].

Lactate with or without hypoperfusion vs tissue hypoxia

Persistent hyperlactatemia is particularly difficult to interpret. At least four possible pathogenic mechanisms might be involved: anaerobic glycolysis in hypoperfused territories, especially in the presence of severe microcirculatory abnormalities [13]; stress-related adrenergic-induced aerobic glycolysis; impaired hepatic lactate clearance; and mitochondrial dysfunction limiting pyruvate metabolism [14, 15]. Recognizing a clinical pattern of hypoperfusion-related hyperlactatemia is important since optimizing systemic blood flow in this setting could revert ongoing hypoperfusion and improve prognosis. In contrast, pursuing additional resuscitation in non-hypoperfusion-related cases might lead to the toxicity of over-resuscitation. We recently proposed that a simultaneous analysis of three flow-sensitive parameters such as central venous O2 saturation, central venous–arterial pCO2 gradient (Pcv-aCO2), and peripheral perfusion (capillary refill time, peripheral perfusion index, skin temperature, mottling) might be helpful in suggesting the presence of hypoperfusion in the context of hyperlactatemia [15, 16]. In addition to the Pcv-aCO2 one could use the Pcv-aCO2 to arterial–venous O2 content difference as a marker of tissue hypoperfusion as a cause of hyperlactatemia [17]. Persistent hyperlactatemia without a hypoperfusion context is associated with a better prognosis and might suggest non-hypoperfusion-related sources [15] (Fig. 1).

Fig. 1
figure 1

Flowchart on the clinical use of increased lactate levels. ScvO2 central venous hemoglobin oxygenation, dPCO2 central venous–arterial PCO2 difference

Lactate as a marker of severity

The evidence that lactate is a marker of illness severity in all situations of physiological stress is overwhelming. In sepsis it is a powerful predictor of mortality. In the recent ARISE trial, data were prospectively collected on lactate levels at randomization [18]. Approximately, one-third of patients were randomized because of isolated hyperlactatemia and compared with patients randomized because of isolated hypotension. Despite similar age and sources of infection, patients with isolated hyperlactatemia had 1.7 times the risk of 90-day mortality and were less likely to be discharged alive form ICU and hospital. This predictive value has been recognized by the SEPSIS-3 consensus definition of shock, which requires the presence of hyperlactatemia [19].

Lactate as a goal of what?

The complexity of lactate as a molecule, substrate, biomarker, energy source, component of some intravenous fluids, and major modulator of cellular bioenergetics during physiological stress is formidable [20]. Such complexity makes it impossible to define what goal it should be a marker or target of. Seeking to lower lactate levels (by whatever means given the multiple events that regulate its blood levels) has no credibility and no logic in terms of hemodynamics, bioenergetics, or tissue protection. In fact, it could make more biological sense to assist the natural process of lactate utilization and generation during sepsis or during other physiological stress situations by administering lactate. Until we are able to define the goals that we wish to achieve by manipulating lactate and have the means of measuring whether we have achieved such goals or not, the idea of seeking to lower lactate by increasing its “clearance” in sepsis is both an illusion and a folly.


  1. Vincent JL, Quintairos ESA, Couto L Jr, Taccone FS (2016) The value of blood lactate kinetics in critically ill patients: a systematic review. Crit Care 20:257

    Article  PubMed  PubMed Central  Google Scholar 

  2. Levraut J, Ciebiera JP, Chave S, Rabary O, Jambou P, Carles M, Grimaud D (1998) Mild hyperlactatemia in stable septic patients is due to impaired lactate clearance rather than overproduction. Am J Respir Crit Care Med 157:1021–1026

    Article  CAS  PubMed  Google Scholar 

  3. Tapia P, Soto D, Bruhn A, Alegria L, Jarufe N, Luengo C, Kattan E, Regueira T, Meissner A, Menchaca R, Vives MI, Echeverria N, Ospina-Tascon G, Bakker J, Hernandez G (2015) Impairment of exogenous lactate clearance in experimental hyperdynamic septic shock is not related to total liver hypoperfusion. Crit Care 19:188

    Article  PubMed  PubMed Central  Google Scholar 

  4. Garcia-Alvarez M, Marik P, Bellomo R (2014) Sepsis-associated hyperlactatemia. Crit Care 18:503

    Article  PubMed  PubMed Central  Google Scholar 

  5. Stacpoole PW, Wright EC, Baumgartner TG, Bersin RM, Buchalter S, Curry SH, Duncan CA, Harman EM, Henderson GN, Jenkinson S (1992) A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group. N Engl J Med 327:1564–1569

    Article  CAS  PubMed  Google Scholar 

  6. Figge J, Bellomo R, Egi M (2018) Quantitative relationships among plasma lactate, inorganic phosphorus, albumin, unmeasured anions and the anion gap in lactic acidosis. J Crit Care 44:101–110

    Article  CAS  PubMed  Google Scholar 

  7. Mohr NM, Vakkalanka JP, Faine BA, Skow B, Harland KK, Dick-Perez R, Fuller BM, Ahmed A, Simson SQ (2018) Serum anion gap predicts lactate poorly, but may be used to identify sepsis patients at risk for death: a cohort study. J Crit Care 44:223–228

    Article  CAS  PubMed  Google Scholar 

  8. Brooks GA (2009) Cell-cell and intracellular lactate shuttles. J Physiol 587:5591–5600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hernandez G, Regueira T, Bruhn A, Castro R, Rovegno M, Fuentealba A, Veas E, Berrutti D, Florez J, Kattan E, Martin C, Ince C (2012) Relationship of systemic, hepatosplanchnic, and microcirculatory perfusion parameters with 6-hour lactate clearance in hyperdynamic septic shock patients: an acute, clinical-physiological, pilot study. Ann Intensive Care 2:44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Didwania A, Miller J, Kassel D, Jackson EV Jr, Chernow B (1997) Effect of intravenous lactated Ringer’s solution infusion on the circulating lactate concentration: Part 3. Results of a prospective, randomized, double-blind, placebo-controlled trial. Crit Care Med 25:1851–1854

    Article  CAS  PubMed  Google Scholar 

  11. Boysen SR, Dorval P (2014) Effects of rapid intravenous 100% L-isomer lactated Ringer’s administration on plasma lactate concentrations in healthy dogs. J Vet Emerg Crit Care (San Antonio) 24:571–577

    Article  Google Scholar 

  12. Jansen TC, van Bommel J, Bakker J (2009) Blood lactate monitoring in critically ill patients: a systematic health technology assessment. Crit Care Med 37:2827–2839

    PubMed  Google Scholar 

  13. Hernandez G, Boerma EC, Dubin A, Bruhn A, Koopmans M, Edul VK, Ruiz C, Castro R, Pozo MO, Pedreros C, Veas E, Fuentealba A, Kattan E, Rovegno M, Ince C (2013) Severe abnormalities in microvascular perfused vessel density are associated to organ dysfunctions and mortality and can be predicted by hyperlactatemia and norepinephrine requirements in septic shock patients. J Crit Care 28:538-e9

    Article  CAS  Google Scholar 

  14. Hernandez G, Luengo C, Bruhn A, Kattan E, Friedman G, Ospina-Tascon GA, Fuentealba A, Castro R, Regueira T, Romero C, Ince C, Bakker J (2014) When to stop septic shock resuscitation: clues from a dynamic perfusion monitoring. Ann Intensive Care 4:30

    Google Scholar 

  15. Alegria L, Vera M, Dreyse J, Castro R, Carpio D, Henriquez C, Gajardo D, Bravo S, Araneda F, Kattan E, Torres P, Ospina-Tascon G, Teboul JL, Bakker J, Hernandez G (2017) A hypoperfusion context may aid to interpret hyperlactatemia in sepsis-3 septic shock patients: a proof-of-concept study. Ann Intensive Care 7:29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ait-Oufella H, Bakker J (2016) Understanding clinical signs of poor tissue perfusion during septic shock. Intensive Care Med 42:2070–2072

    Article  PubMed  Google Scholar 

  17. Ospina-Tascon GA, Umana M, Bermudez W, Bautista-Rincon DF, Hernandez G, Bruhn A, Granados M, Salazar B, Arango-Davila C, De Backer D (2015) Combination of arterial lactate levels and venous-arterial CO2 to arterial-venous O2 content difference ratio as markers of resuscitation in patients with septic shock. Intensive Care Med 41:796–805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gotmaker R, Peake SL, Forbes A, Bellomo R, ARISE Investigators (2017) Mortality is greater in septic patients with hyperlactatemia than with refractory hypotension. Shock 48:294–300

    Article  PubMed  Google Scholar 

  19. Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, Angus DC, Rubenfeld GD, Singer M, Sepsis Definitions Task Force (2016) Developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315:775–787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Garcia-Alvarez M, Marik P, Bellomo R (2014) Stress hyperlactataemia: present understanding and controversy. Lancet Diabetes Endocrinol 2:339–347

    Article  PubMed  Google Scholar 

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Correspondence to Jan Bakker.

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Hernandez, G., Bellomo, R. & Bakker, J. The ten pitfalls of lactate clearance in sepsis. Intensive Care Med 45, 82–85 (2019).

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  • Lactate Clearance
  • Persistent Hyperlactatemia
  • Peripheral Perfusion Index
  • Increased Lactate Levels
  • Septic Shock Animal