This document provides an overview of lactate physiology from a critical care perspective. It discusses: 1) Lactate production through anaerobic glycolysis when oxygen demands outpace supply, its role in energy production and transport between tissues. 2) Lactate metabolism primarily in the liver and kidneys which remove over half of circulating lactate daily through oxidation or gluconeogenesis. 3) Factors influencing lactate levels like perfusion adequacy, oxygenation status, substrate availability, and acid-base balance. Elevated lactate reflects a mismatch between tissue oxygen needs and delivery and serves as a marker of illness severity and resuscitation endpoints.

1. Lactate Physiology
Everything you need to know
Critical care perspective

7. • Malabsorbed carbohydrate is fermented
by Lactobacillus, Bifidobacterium,
Eubacterium and Streptococcus bovis in the
colon, producing an excess of D-lactate
Humans have a great capacity to metabolise
D-lactate (the hepatic metabolism of lactate
does not discriminate between isoforms)

9. • Lactate, the anion that results from dissociation of
lactic acid
• The final step of anaerobic glycolysis is conversion of
pyruvate to lactate by the enzyme lactate
dehydrogenase. This last reaction provides a source of
NAD+ essential for anaerobic glycolysis to proceed.
• Production of lactate is the only means for glucose
utilization and ATP production in erythrocytes (which
have no mitochondrion) and in exercising muscle cells
(which have an oxygen debt)

10. 2 ATP vs 38 ATP

11. • Although lactate can be produced in all
tissues, skeletal muscle, erythrocytes, brain
and renal medulla tissues are the principal
production sites in health

12. metabolism and shuttles

13. • Metabolism or clearance in Liver is 60 % of
circulating lactate, kidneys 25-30 %
• 1500mmol per day normal
• Can handle 500 mmol per hour
• Lactate produced within erythrocytes cannot be
metabolized further and is released to the
circulation.
• In some tissues (e.g. skeletal muscle) lactate may
be produced at a faster rate than it can be
metabolized and in these circumstances lactate
would also be released to circulation

14. • H+ are a product of ATP hydrolysis to ADP. In
the presence of oxygen, H+ produced during
ATP hydrolysis are utilized in the
mitochondrial process of oxidative
phosphorylation, but this is often not possible
in the context of anaerobic glycolysis
associated with hyperlactate production.

15. • From a biochemical viewpoint the central
problem is usually decreased utilization of
pyruvate in oxidative or gluconeogenic
pathways. Under these circumstances
pyruvate can only be converted to lactate. For
example, since oxygen is essential for pyruvate
oxidation, any condition that deprives tissues
of oxygen can lead to increased production of
lactate, which then accumulates

16. • in blood at a faster rate than it can be removed by liver and
kidneys.
• The problem is compounded by acidosis because the
capacity of the liver to remove lactate from the circulation
is pH dependent and severely impaired by reduced blood
pH. In fact, experimental evidence suggests that at blood
pH of 7.0 or less, lactate uptake is so impaired that the liver
produces more lactate than it consumes
• There is some renal compensation because acidosis
enhances kidney uptake of lactate.
However, this can only compensate for around 50 % of the
hepatic loss and acidosis, whatever its cause, can be a major
contributory factor in the pathogenesis of hyperlactatemia

17. • In practice, anemia and hypoxemia are rarely
the sole causes of Type A lactic acidosis. More
commonly they are contributory factors in the
development of Type A lactic acidosis among
patients already predisposed because of
inadequate perfusion

18. • Metabolism of ethanol is associated with
increased NADH/NAD+ ratio favoring
conversion of pyruvate to lactate

19. • Prognostication
• Trend
• Fall in the first 6-8 hours EGDT
• Mortality

21. • Major energy source;
• Major gluconeogenic precursor;
• Signaling molecule with autocrine-, paracrine- and endocrine-like
effects; and has been called a ‘‘lactormone.’’
• ‘‘Cell-cell’’ and ‘‘intracellular lactate shuttle’’ concepts describe the
roles of lactate in delivery of oxidative and gluconeogenic
substrates as well as in cell signaling.
– Cell-cell lactate shuttles: lactate exchanges between white-glycolytic
and red-oxidative fibers within a working muscle bed and between
working skeletal muscle and heart, brain, liver, and kidneys.
– Intracellular lactate shuttles: cytosol-mitochondrial and cytosol-
peroxisome exchanges
– Lactate shuttles are driven by a concentration or pH gradient or by
redox state

23. • ‘‘Pasteur effect’’: stimulation in glucose use
due to a limitation in O2 supply_ Warburg
• ‘‘lactate paradox’’ at altitude_ effects of
epinephrine on lactate production (blood Ra)

24. • In heart and red skeletal muscle, lactate disposal
is by mitochondrial respiration.
• In the liver and kidneys, mitochondria play roles
in oxidizing lactate to pyruvate and then in the
conversion to oxaloacetate (gluconeogenic
substrate) & PEP via Pcarboxylase and
PEPcarboxykinase.
• In the liver and kidneys, the oxidation of lactate
and other fuel sources provides energy
gluconeogenesis and glycogen synthesis

25. • By changes in cell redox, allosteric binding to
GPR81, lactate affects numerous processes.
• Intracellular, cellcell, and organ-organ ‘‘lactate
shuttles’’_interactive effects between
producer and consumer cells

26. • TBI
• Heart failure
• Dengue
• Hepatitis
• Pancreatitis
• Sepsis

27. • Increased Na +k+ ATPase pump activity results
in accelerated aerobic glycolysis_ sustained by
glucose-6-phosphate.
• Rapid ATP production fuelled by glycogen
causes hyperlactacidaemia and muscle
glycogen depletion, and intracellular
accumulation of potassium in muscle
_hypokalaemia.

28. SAHL
• Organ to organ shuttle
– Lactate released by muscle is taken up by the liver to
enter the Cori cycle to generate glucose_ glycolysis_
lactate depending on liver bioenergetics
• Cell to cell shuttle
– Brain
• Intracellular shuttle
– lactate, generated in the cytoplasm, is used through
mitochondrial membrane shuttles to increase NADH,
which provides a proton gradient to generate energy by
the electron transport chain.

29. Intracellular shuttle

31. Lactate vs resuscitaion fluids
• Lactated Ringer’s solution does not increase
circulating lactate concentrations in
hemodynamically stable, nor worsen metabolic
acidosis during an infusion of 1 L in 60 min.
(Only with large volumes (180 mL/kg/h) lactate
levels rise)
• The bufering effect of Ringer’s solution, with a
more physiologic SID, might have a positive effect
on blood pH

32. Confounders
• Catecholamines in septic shock patients,
alkalosis
• Induced increases in glucose metabolism,
lactate buffered continuous hemofltration,
liver dysfunction, and lung lactate production.
• Drugs associated with increased lactate levels
(NRTI,metformin), intoxications (ethylene
glycol, methanol, and steroids)

33. Krebs ceases, pyurvate cant enter
mitochondria, LP ratio elvevated, more H+

34. LP ratio normal
glycolytic flux>krebs flux, proton neutral

36. Aerobic portion of critical curve
• VCO2/VO2 <1.0
• Fick : VCO2/VO2=Venoarterial co2 content
difference /arterial venus O2 content
difference
• O2 consumption is equals to CO2 production

37. Anaerobic conditions
• The consumption falls hence the venous oxygen is high
hence the arterial venous O2 content
difference(consumption) narrows
• The CO2 production rises leading to elevated venous
CO2 content hence the venoarterial content
difference(production) in CO2 content rises
• Hence the Vco2/Vo2 ratio is >1(The predictive power is
excellent [AUC 0.962] for a ratio of 1.7 mmHg/mL)
• These patients were defined as having an increase in
VO2 by at least 15% following a volume challenge
(raise their VO2 in response to an increase in DO2)

38. Normal or increased SCVo2 but
compromised tissue oxygenation
• Admixture
• Maldistribution
• Histotoxic hypoxia