Lactate has been viewed as a byproduct of anaerobic metabolism and an indicator of tissue hypoperfusion since the 1900s. This theory is still widely believed. Paul busts the myths surrounding lactic acidosis, anaerobic metabolism, tissue hypoxia and the role of lactate in sepsis. Key take-away facts include: - The production of lactate actually consumes hydrogen ions. Lactic acidosis is really lactic alkalosis. - Lactate is produced physiologically and is a precursor for gluconeogenesis. - During exercise, skeletal muscle exports lactate as the primary fuel for the heart and brain. - At VO2max, intracellular oxygen stays the same. Anaerobic metabolism in cells only occur as a pre-terminal event. The exception is in complete arterial occlusion. - Adrenaline promotes lactate production - Lactate infusion has been shown to increase cardiac output in septic and cardiogenic shock - Lactate is a survival advantage!

1. Paul Marik, MD,FCCM,FCCP
Humans are not yeast and rarely become anaerobic
Lactate is Good and not BAD

2. Anaerobic Fermentation

3. Humans drink alcohol
They cannot undergo anaerobic fermentation
and only undergo anaerobic
metabolism as a pre-terminal event

4. The Myths
 Lactate causes an acidosis
 Increased lactate is due to anaerobic metabolism and decreased
oxygen delivery
 Anaerobic production of lactate occurs during exercise
 A defining feature of “shock” is anaerobic metabolism
 The earth is round

5. Historical Perspective

6. J Physiol 1907;35:247-309

7. Circulation 2004;110:e27

8. Anaerobic/Lactate Threshold

9. Circulation 1970; 41:989

11. NEJM 2014;371:2309

12. Biochemistry

13. Glycolysis
Glucose + 2ADP + 2Pi 2 Lactate +2ATP +2 H2O

15. The reaction producing lactate
consumes a pair of free protons, thus retarding acidosis

16. Am. J.Physiol 2004;287;R502
Lactic acidosis is a condition that does NOT EXIST
 Lactate production retards, not causes, acidosis
 The lactic acidosis explanation of metabolic acidosis is not
supported by fundamental biochemistry and has no research
base of support
 Acidosis is caused by reactions other than lactate production.
Every time ATP is broken down to ADP and Pi, a proton is
released

17. Normal Lactate Metabolism
Serum Level< 2 mmol/l
Daily production ~ 1400 mmol/day
Metabolized in liver (70%) and
kidney (30%) via Cori cycle

18. Gluconeogenesis
Oxidation (50% rest; 80% exercise)

19. The Tissue Hypoxia Myth

20. Normal oxygen diffusion gradient

21. Normal oxygen diffusion gradient
Cytosolic PO2 =~5 mmHg
Mitochondrial critical
threshold =~1 mmHg

22. NEJM 2009;360:140

23. NEJM 2009;360:140

24. Richardson RS, J Appl Physiol 1998;85:627
0
2
4
6
8
10
12
14
16
Level 1 Level 2 Level 3 Level 4 Level 5
Leg VO2 Intra-cellular O2 Lactate efflux Art Lactate

25. Lactate “threshold”

26. StanleyWC. Med Sci Sports Exercise 1991;23:920

27. Cerebral lactate uptake
FASEB J 2008;22:3443

28. JAMA 1992;267:1503

29. Crit Care Med 1994;22:640
0
5
10
15
20
25
30
35
40
45
50
Severe Sepsis Limited infectionMuscle PO2 CI

30. Crit Care Med 2001;29:1343
0
5
10
15
20
25
30
35
Muscle PtO2
Control CPB Sepsis

31. Ronco JJ, et al. JAMA 1993;270:1724
4ml/kg/min

32. N Engl J Med 1994; 330:1717

33. Am Rev Resp Dis 1993 147:25
VO2

34. 200
300
400
500
600
BL 24 48 72 96
Esmolol Control 0
0.5
1
1.5
2
2.5
BL 24 48 72 96
Esmolol Control
MorelliA,JAMA 2013;310:1683
DO2I Lactate

35. 2
3
4
5
6
7
8
BL 6-hour
Alive
Dead
Lactate (meq/l)
Clearance 32%
Clearance 31%
p<0.0001

37. Increased lactate may simply occur
due to increased production of
pyruvate due to increased glycolysis

38. Intracellular Lactate Shuttle

39. Intracellular Lactate Shuttle

40. Intracellular Lactate Shuttle

41. Cell-to-cell lactate shuttle

42. Cell-to-cell lactate shuttle

43. Astrocyte-Neuron Lactate Shuttle

44. Lactate is Good and not BAD

45. Cell-to-cell lactate shuttle
 Brain and cardiac oxidation of lactate increase during
exercise and shock
 Lactate removal during stress associated with cardiovascular
collapse
 Infusion of lactate increases cardiac output in cardiogenic
and septic shock
 Infusion of lactate improves energy utilization and cognitive
function afterTBI

47. a
b
c
c
b
a
a=hypertonic lactate
b=hypertonic bicarbonate
c=normal saline

48. Brain research 2002;928:156

50. Clinical Plausibility
 Lactate increases in adrenergic states
 Lactate increases with epinephrine infusion
 Lactate increases with hyperdynamic sepsis
 All these states have high cardiac output, high
oxygen delivery and not a trace of “hypoxia”

51. Conclusions
 Lactate is not an accurate, reliable or robust marker of “hypoxia”
(whatever that is)
 Its link with “hypoxia” is biologically implausible
 It is experimentally flawed
 It is clinically implausible (except perhaps with complete
regional vessel occlusion)

52. Conclusions
 It is now clear that lactate is a major mitochondrial fuel
 It is rapidly utilized in cell to cell and intra-cell shuttles
 It is taken up by mitochondria to optimize bioenergetics
 It acts like a hormone with powerful effects on protein
synthesis

53. Conclusions
 Lactate is associated with increased mortality
 The association is related to the fact that lactate is a
biomarker of physiological stress
 The greater the physiological stress the greater the risk of
death!