Paul Marik, MD,FCCM,FCCP

Humans are not yeast and rarely become anaerobic

Lactate is Good and not BAD

Anaerobic Fermentation

Humans drink alcoholThey cannot undergo anaerobic fermentation

and only undergo anaerobicmetabolism as a pre-terminal event

The MythsLactate causes an acidosisIncreased lactate is due to anaerobic

metabolism and decreased oxygen deliveryAnaerobic production of lactate occurs during

exerciseA defining feature of “shock” is anaerobic

metabolismThe earth is round

Historical Perspective

J Physiol 1907;35:247-309

Circulation 2004;110:e27

Anaerobic/Lactate Threshold

Circulation 1970; 41:989

NEJM 2014;371:2309

Biochemistry

GlycolysisGlucose + 2 ADP + 2Pi 2 Lactate +2ATP +2 H2O

The reaction producing lactateconsumes a pair of free protons, thus retarding acidosis

Am. J.Physiol 2004;287;R502Lactic 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

Normal Lactate Metabolism

Serum Level< 2 mmol/lDaily production ~ 1400 mmol/day

Metabolized in liver (70%) and kidney (30%) via Cori cycle

GluconeogenesisOxidation (50% rest; 80% exercise)

The Tissue Hypoxia Myth

Normal oxygen diffusion gradient

Normal oxygen diffusion gradient

Cytosolic PO2 =~5 mmHg Mitochondrial criticalthreshold =~1 mmHg

NEJM 2009;360:140

NEJM 2009;360:140

Richardson RS, J Appl Physiol 1998;85:627

Level 1 Level 2 Level 3 Level 4 Level 50

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Leg VO2 Intra-cellular O2 Lactate efflux Art Lactate

Lactate “threshold”

Stanley WC. Med Sci Sports Exercise 1991;23:920

Cerebral lactate uptake

FASEB J 2008;22:3443

JAMA 1992;267:1503

Crit Care Med 1994;22:640

Severe Sepsis Limited infection05

101520253035404550

Muscle PO2 CI

Crit Care Med 2001;29:1343

Muscle PtO20

5

10

15

20

25

30

35

Control CPB Sepsis

Ronco JJ, et al. JAMA 1993;270:1724

4ml/kg/min

N Engl J Med 1994; 330:1717

Am Rev Resp Dis 1993 147:25

VO2

BL 24 48 72 96200250300350400450500550600

BL 24 48 72 960

0.51

1.52

2.5

Morelli A, JAMA 2013;310:1683

DO2I Lactate

BL 6-hour2345678

AliveDead

Lactate (meq/l)

Clearance 32%

Clearance 31%

p<0.0001

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

Intracellular Lactate Shuttle

Intracellular Lactate Shuttle

Intracellular Lactate Shuttle

Cell-to-cell lactate shuttle

Cell-to-cell lactate shuttle

Astrocyte-Neuron Lactate Shuttle

Lactate is Good and not BAD

Cell-to-cell lactate shuttleBrain and cardiac oxidation of lactate

increase during exercise and shockLactate removal during stress associated

with cardiovascular collapseInfusion of lactate increases cardiac output

in cardiogenic and septic shockInfusion of lactate improves energy

utilization and cognitive function after TBI

abc

cb

a

a=hypertonic lactateb=hypertonic bicarbonatec=normal saline

Brain research 2002;928:156

Clinical PlausibilityLactate increases in adrenergic statesLactate increases with epinephrine

infusionLactate increases with hyperdynamic

sepsisAll these states have high cardiac

output, high oxygen delivery and not a trace of “hypoxia”

ConclusionsLactate is not an accurate, reliable or robust

marker of “hypoxia” (whatever that is)Its link with “hypoxia” is biologically

implausibleIt is experimentally flawedIt is clinically implausible (except perhaps

with complete regional vessel occlusion)

ConclusionsIt is now clear that lactate is a major

mitochondrial fuelIt is rapidly utilized in cell to cell and intra-

cell shuttlesIt is taken up by mitochondria to optimize

bioenergeticsIt acts like a hormone with powerful

effects on protein synthesis

ConclusionsLactate is associated with increased

mortalityThe 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!