Intensive Care Med

https://doi.org/10.1007/s00134-018-5213-x

WHAT’S NEW IN INTENSIVE CARE

The ten pitfalls of lactate clearance

in sepsis
Glenn Hernandez1, Rinaldo Bellomo2,3,4,5 and Jan Bakker1,6,7,8* 

© 2018 The Author(s)

The problem with clearance Lactate and glucose metabolism

Clearance is the removal of a substance from blood, As lactate is a normal product of glucose and pyru-
expressed as a volume (milliliters) over time (minutes). vate metabolism, any increase in glucose metabolism or
However, changes in lactate levels are the sum of ongo- decrease in pyruvate metabolism will increase lactate
ing production and removal from the blood by excretion generation and, in some cases, levels, even in the pres-
(e.g., urine, sweat) and its metabolism (e.g., uptake by ence of adequate tissue oxygenation (as seen with epi-
cells as a direct source of energy, conversion to glucose nephrine infusion). In sepsis, the inflammatory response
by the liver). To talk about “lactate clearance” [1] when appears associated with an increase in glycolysis and
actually describing a decrease in blood level is wrong and impaired pyruvate dehydrogenase (the enzyme critical
misleading. Following the review of 96 studies, Vincent for pyruvate entry into the Krebs cycle). Thus, cytoplas-
et al. [1] concluded that given recent evidence, measure- mic pyruvate increases with greater lactate formation
ments every 1–2  h would give clinically relevant data but preserved pyruvate to lactate ratio, and lactate lev-
about the decrease in lactate levels. els rise. In this way, the relationship of increased lac-
tate production with tissue hypoxia as its possible source
Lactate levels: production versus clearance is confounded by the stress response that increases glu-
In clinical practice the change in lactate levels over time cose metabolism and lactate generation [4]. In addition,
is thought to primarily reflect a change in production. As although lactate levels can be significantly decreased
increased levels are generally associated with circulatory by improving its metabolism by the administration of
dysfunction, we often see a decrease in lactate levels as dichloroacetate, this will not result in improved survival
associated with an improvement in circulatory status and as it does not address the root cause [5]. The same might
hypothesize (but cannot prove) decreased production. apply to the correction of acidosis in the presence of
However, as true clearance in both stable septic patients increased lactate levels as the relationship between pH,
and septic shock animals is significantly decreased in anaerobic glycolysis, and lactate levels is not fully under-
shock states, ongoing hyperlactatemia or even a rise in stood and is likely to be complex [6, 7].
lactate levels may reflect decreased clearance rather than
an increase in production of lactate [2, 3]. This is typically Lactate as a substrate
seen in the presence of shock with associated ischemic Just like glucose, lactate may also serve as a substrate for
hepatitis. In addition, the complex inter- and intracellular metabolism. Especially in stress (such as sepsis), lactate,
metabolism of lactate makes our understanding of lactate through several “shuttles”, provides a source of cellu-
physiology in shock extremely limited (see Sect. “Lactate lar energy. The first is the organ-to-organ lactate shut-
as a substrate”). tle. 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
*Correspondence: [email protected] liver bioenergetics. In addition, lactate may be metabo-
6
Department of Intensive Care, Erasmus MC University Medical Center, lized by the kidneys, accounting for up to 50% of total
Rotterdam, Netherlands
Full author information is available at the end of the article lactate metabolism. The second is the cell-to-cell lactate
shuttle. This shuttle appears particularly important in
 Fig. 1  Flowchart on the clinical use of increased lactate levels. ScvO2 central venous hemoglobin oxygenation, dPCO2 central venous–arterial P
­ CO2
difference

the brain, where lactate can become a more important not limited to, severe septic shock [9]. On the other hand,
energy substrate than glucose [8]. Lactate is transported early and severe impairment of exogenous lactate clear-
from astrocytes into neurons by dedicated transporters ance not related to liver hypoperfusion has been shown
and then transformed into pyruvate by lactate dehydro- in experimental conditions [3].
genase type  1. Pyruvate then enters the Krebs cycle to
produce ATP. The third is the intracellular shuttle where Lactate concentration in resuscitation fluids
lactate, generated by glycolysis in the cytoplasm, is used Intravenous administration of lactated Ringer’s solution
through mitochondrial membrane shuttles to increase does not seem to increase circulating lactate concen-
the concentration of reduced NAD (NADH), which pro- trations in hemodynamically stable adults, nor worsen
vides a proton gradient to generate energy by the electron metabolic acidosis during an infusion of 1  L in 60  min
transport chain. [10]. Only when infusing large volumes (180 mL/kg/h) do
lactate levels rise significantly [11]. On the contrary, the
Lactate and liver dysfunction buffering effect of Ringer’s solution, with a more physio-
The liver, which is responsible for 60% of systemic lactate logic strong anion difference, might have a positive effect
metabolism, is a vulnerable organ during sepsis-related on blood pH.
acute circulatory dysfunction. The contribution of the
liver to persistent hyperlactatemia might be much higher Lactate and its confounders
than previously thought, and the mechanisms are prob- As every increase in glucose metabolism may increase
ably multifactorial. Without doubt, hepatosplanchnic lactate  levels, many elements confound the clinical
ischemia could contribute in some cases especially in, but use of lactate. Best known in clinical practice is the use
of catecholamines in septic shock patients, alkalosis- Lactate as a goal of what?
induced increases in glucose metabolism, lactate buff- The complexity of lactate as a molecule, substrate, bio-
ered continuous hemofiltration, liver dysfunction, and marker, energy source, component of some intravenous
lung lactate production. Also, the use of specific drugs fluids, and major modulator of cellular bioenergetics dur-
has been associated with increased lactate levels (nucleo- ing physiological stress is formidable [20]. Such complex-
side reverse transcriptase inhibitors for treatment of HIV, ity makes it impossible to define what goal it should be
metformin) as are some intoxications (ethylene glycol, a marker or target of. Seeking to lower lactate levels (by
methanol, and steroids) [4, 12]. whatever means given the multiple events that regulate
its blood levels) has no credibility and no logic in terms
Lactate with or without hypoperfusion vs tissue of hemodynamics, bioenergetics, or tissue protection.
hypoxia In fact, it could make more biological sense to assist the
Persistent hyperlactatemia is particularly difficult to natural process of lactate utilization and generation dur-
interpret. At least four possible pathogenic mechanisms ing sepsis or during other physiological stress situations
might be involved: anaerobic glycolysis in hypoperfused by administering lactate. Until we are able to define the
territories, especially in the presence of severe micro- goals that we wish to achieve by manipulating lactate and
circulatory abnormalities [13]; stress-related adrener- have the means of measuring whether we have achieved
gic-induced aerobic glycolysis; impaired hepatic lactate such goals or not, the idea of seeking to lower lactate by
clearance; and mitochondrial dysfunction limiting pyru- increasing its “clearance” in sepsis is both an illusion and
vate metabolism [14, 15]. Recognizing a clinical pattern a folly.
of hypoperfusion-related hyperlactatemia is important
since optimizing systemic blood flow in this setting could
Author details
revert ongoing hypoperfusion and improve prognosis. In 1
 Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia
contrast, pursuing additional resuscitation in non-hypop- Universidad Católica de Chile, Santiago, Chile. 2 Department of Intensive Care,
erfusion-related cases might lead to the toxicity of over- Austin Hospital, Melbourne, Australia. 3 Department of Intensive Care, Royal
Melbourne Hospital, Melbourne, Australia. 4 Australian and New Zealand
resuscitation. We recently proposed that a simultaneous Intensive Care Research Centre, Monash University School of Public Health
analysis of three flow-sensitive parameters such as cen- and Preventive Medicine, Melbourne, Australia. 5 School of Medicine, The
tral venous O ­ 2 saturation, central venous–arterial ­pCO2 University of Melbourne, Melbourne, Australia. 6 Department of Intensive Care,
Erasmus MC University Medical Center, Rotterdam, Netherlands. 7 Department
gradient (Pcv-aCO2), and peripheral perfusion (capillary of Pulmonology and Critical Care, Columbia University Medical Center, New
refill time, peripheral perfusion index, skin temperature, York, USA. 8 Department of Pulmonology and Critical Care, New York Univer-
mottling) might be helpful in suggesting the presence of sity Medical Center – Langone, New York, USA.
hypoperfusion in the context of hyperlactatemia [15, 16]. Compliance with ethical standards
In addition to the Pcv-aCO2 one could use the Pcv-aCO2
to arterial–venous ­O2 content difference as a marker of Conflicts of interest
The authors have no conflict of interest to declare.
tissue hypoperfusion as a cause of hyperlactatemia [17]. Open Access
Persistent hyperlactatemia without a hypoperfusion con- This article is distributed under the terms of the Creative Commons Attribu-
text is associated with a better prognosis and might sug- tion-NonCommercial 4.0 International License (http://creativecommons.org/
licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and
gest non-hypoperfusion-related sources [15] (Fig. 1). reproduction in any medium, provided you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons
Lactate as a marker of severity license, and indicate if changes were made.
The evidence that lactate is a marker of illness severity in
all situations of physiological stress is overwhelming. In Received: 2 February 2018 Accepted: 5 May 2018
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 hyperlac- References
tatemia and compared with patients randomized because 1. Vincent JL, Quintairos ESA, Couto L Jr, Taccone FS (2016) The value of
of isolated hypotension. Despite similar age and sources blood lactate kinetics in critically ill patients: a systematic review. Crit Care
20:257
of infection, patients with isolated hyperlactatemia had 2. Levraut J, Ciebiera JP, Chave S, Rabary O, Jambou P, Carles M, Grimaud D
1.7 times the risk of 90-day mortality and were less likely (1998) Mild hyperlactatemia in stable septic patients is due to impaired
to be discharged alive form ICU and hospital. This pre- lactate clearance rather than overproduction. Am J Respir Crit Care Med
157:1021–1026
dictive value has been recognized by the SEPSIS-3 con- 3. Tapia P, Soto D, Bruhn A, Alegria L, Jarufe N, Luengo C, Kattan E, Regueira
sensus definition of shock, which requires the presence of T, Meissner A, Menchaca R, Vives MI, Echeverria N, Ospina-Tascon G,
hyperlactatemia [19]. Bakker J, Hernandez G (2015) Impairment of exogenous lactate clearance
 in experimental hyperdynamic septic shock is not related to total liver 13. Hernandez G, Boerma EC, Dubin A, Bruhn A, Koopmans M, Edul VK, Ruiz
hypoperfusion. Crit Care 19:188 C, Castro R, Pozo MO, Pedreros C, Veas E, Fuentealba A, Kattan E, Rovegno
4. Garcia-Alvarez M, Marik P, Bellomo R (2014) Sepsis-associated hyperlac- M, Ince C (2013) Severe abnormalities in microvascular perfused vessel
tatemia. Crit Care 18:503 density are associated to organ dysfunctions and mortality and can be
5. Stacpoole PW, Wright EC, Baumgartner TG, Bersin RM, Buchalter S, predicted by hyperlactatemia and norepinephrine requirements in septic
Curry SH, Duncan CA, Harman EM, Henderson GN, Jenkinson S (1992) A shock patients. J Crit Care 28:538-e9
controlled clinical trial of dichloroacetate for treatment of lactic acidosis 14. Hernandez G, Luengo C, Bruhn A, Kattan E, Friedman G, Ospina-Tascon
in adults. The Dichloroacetate-Lactic Acidosis Study Group. N Engl J Med GA, Fuentealba A, Castro R, Regueira T, Romero C, Ince C, Bakker J (2014)
327:1564–1569 When to stop septic shock resuscitation: clues from a dynamic perfusion
6. Figge J, Bellomo R, Egi M (2018) Quantitative relationships among plasma monitoring. Ann Intensive Care 4:30
lactate, inorganic phosphorus, albumin, unmeasured anions and the 15. Alegria L, Vera M, Dreyse J, Castro R, Carpio D, Henriquez C, Gajardo D,
anion gap in lactic acidosis. J Crit Care 44:101–110 Bravo S, Araneda F, Kattan E, Torres P, Ospina-Tascon G, Teboul JL, Bakker
7. Mohr NM, Vakkalanka JP, Faine BA, Skow B, Harland KK, Dick-Perez R, Fuller J, Hernandez G (2017) A hypoperfusion context may aid to interpret
BM, Ahmed A, Simson SQ (2018) Serum anion gap predicts lactate poorly, hyperlactatemia in sepsis-3 septic shock patients: a proof-of-concept
but may be used to identify sepsis patients at risk for death: a cohort study. Ann Intensive Care 7:29
study. J Crit Care 44:223–228 16. Ait-Oufella H, Bakker J (2016) Understanding clinical signs of poor tissue
8. Brooks GA (2009) Cell-cell and intracellular lactate shuttles. J Physiol perfusion during septic shock. Intensive Care Med 42:2070–2072
587:5591–5600 17. Ospina-Tascon GA, Umana M, Bermudez W, Bautista-Rincon DF, Hernan-
9. Hernandez G, Regueira T, Bruhn A, Castro R, Rovegno M, Fuentealba A, dez G, Bruhn A, Granados M, Salazar B, Arango-Davila C, De Backer D
Veas E, Berrutti D, Florez J, Kattan E, Martin C, Ince C (2012) Relationship of (2015) Combination of arterial lactate levels and venous-arterial C­ O2 to
systemic, hepatosplanchnic, and microcirculatory perfusion parameters arterial-venous ­O2 content difference ratio as markers of resuscitation in
with 6-hour lactate clearance in hyperdynamic septic shock patients: an patients with septic shock. Intensive Care Med 41:796–805
acute, clinical-physiological, pilot study. Ann Intensive Care 2:44 18. Gotmaker R, Peake SL, Forbes A, Bellomo R, ARISE Investigators (2017)
10. Didwania A, Miller J, Kassel D, Jackson EV Jr, Chernow B (1997) Effect of Mortality is greater in septic patients with hyperlactatemia than with
intravenous lactated Ringer’s solution infusion on the circulating lactate refractory hypotension. Shock 48:294–300
concentration: Part 3. Results of a prospective, randomized, double-blind, 19. Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman
placebo-controlled trial. Crit Care Med 25:1851–1854 CS, Angus DC, Rubenfeld GD, Singer M, Sepsis Definitions Task Force
11. Boysen SR, Dorval P (2014) Effects of rapid intravenous 100% L-isomer (2016) Developing a new definition and assessing new clinical criteria for
lactated Ringer’s administration on plasma lactate concentrations in septic shock: for the third international consensus definitions for sepsis
healthy dogs. J Vet Emerg Crit Care (San Antonio) 24:571–577 and septic shock (sepsis-3). JAMA 315:775–787
12. Jansen TC, van Bommel J, Bakker J (2009) Blood lactate monitoring in 20. Garcia-Alvarez M, Marik P, Bellomo R (2014) Stress hyperlactataemia:
critically ill patients: a systematic health technology assessment. Crit Care present understanding and controversy. Lancet Diabetes Endocrinol
Med 37:2827–2839 2:339–347