Lactate Overview

1. Will the real
please step forward?
Dr. Andrew FergusonDr. Andrew Ferguson
MEd FRCA DIBICM FCCPMEd FRCA DIBICM FCCP
Attending IntensivistAttending Intensivist

2. Dogma….Dogma….
A concept or principle accepted as absolute truth on theA concept or principle accepted as absolute truth on the
basis of unquestioned acceptance of an authority's basis of unquestioned acceptance of an authority's
statement to that effect rather than on the basis of statement to that effect rather than on the basis of
logical reasoning or demonstrated prooflogical reasoning or demonstrated proof
A blind belief in things often without a material baseA blind belief in things often without a material base

3. Useless end-productUseless end-product
or or
essential fuel?essential fuel?

4. The traditional view…The traditional view…
Hypoxia/anoxia leads to anaerobic metabolism
Anaerobic metabolism produces lactate
Anaerobic metabolism is BADBAD NEWS
Hypoxia/anoxia is BADBAD NEWS
“ current thinking continues to interpret
hyperlactacidemia as hypoxia and to support
stimulation of cardiac output and enhancement of
oxygen delivery as therapy”
James JH, Luchette FA, McCarter F, Fischer JE. Lactate is an unreliable indicator of tissue hypoxia in
injury or sepsis. Lancet 1999; 354: 505-508

5. So doesn’t that mean that…?So doesn’t that mean that…?
High LACTATE is BADBAD NEWS
High LACTATE means hypoxia/anoxia
High LACTATE means anaerobic metabolism
High LACTATE = WORSEWORSE outcome

6. Hyperlactataemia (> 2mmol/L)Hyperlactataemia (> 2mmol/L)

7. Basal lactate productionBasal lactate production
Total = 1290 mmol / 24 hours for 70 kg

8. How is lactate produced?How is lactate produced?
If pyruvate production > oxidation in CAC then lactate formation increases
PDHPDH

9. SO…SO…
AnythingAnything that increases
glycolysis can increase
lactataemia once pyruvate once pyruvate
oxidation is overwhelmedoxidation is overwhelmed
NOT just anaerobic metabolism!NOT just anaerobic metabolism!

10. In the anaerobic state…In the anaerobic state…

11. Another way to look at it…Another way to look at it…
Schurr A. Lactate: the ultimate cerebral oxidative energy substrate? Journal of Cerebral Blood Flow & Metabolism 2006; 26: 142-152

12. Lactate/pyruvate ratioLactate/pyruvate ratio
Hypoxia blocks oxidative phosphorylation
prevents NADH re-oxidation to NAD
increases the NADH/NAD ratio
increases the lactate/pyruvate ratioincreases the lactate/pyruvate ratio
Normal ratio around 10:1
Lactate/pyruvate = K Lactate/pyruvate = K xx (NADH/NAD) (NADH/NAD) xx H H
++
Cardiogenic shockCardiogenic shock
L/P ratio 40:1L/P ratio 40:1
Consistent with hypoxiaConsistent with hypoxia
Resuscitated septic shockResuscitated septic shock
L/P ratio 14:1L/P ratio 14:1
Not consistent with hypoxiaNot consistent with hypoxia

13. When lactate hypoperfusionWhen lactate hypoperfusion
Cardiogenic shock
Haemorrhagic shock
Septic shock if
Catecholamine resistant + depressed CI
Unresuscitated (see Rivers)

14. Accelerated aerobic glycolysisAccelerated aerobic glycolysis
Carbohydrate metabolism > mitochondrial
oxidative capacity
Stimulated by catecholamines / cytokinesStimulated by catecholamines / cytokines
○e.g. leukocyte lactate in blood / e.g. leukocyte lactate in blood / lung (ARDS)lung (ARDS)
Pyruvate build-up is the main issue
Aggravated in sepsis by pyruvate
dehydrogenase dysfunction
When lactate hypoperfusionWhen lactate hypoperfusion

15. Epinephrine and lactate productionEpinephrine and lactate production

16. Muscle tissue central to this
○40% of total cell mass of body
○2 receptors 99% of muscle adrenergic receptors
In stress and resuscitated sepsis:
Adrenaline activates glycolysis producing ATP
Adrenaline activates Na/K-ATPase using ATP
Increased glycolysis increases lactate
Lactate Lactate notnot produced if Na/K-ATPase blocked produced if Na/K-ATPase blocked
IndependentIndependent of tissue hypoxia of tissue hypoxia
Lactate overproduction blocked by Lactate overproduction blocked by 2 blockade2 blockade
Epinephrine and lactate productionEpinephrine and lactate production

17. Reduced lactate clearanceReduced lactate clearance
○Conflicting data depending on technique and initial lactate
○Possibly contributes to mild hyperlactataemia
○Unlikely to play major role in cases where production is near normal
Pyruvate dehydrogenase dysfunctionPyruvate dehydrogenase dysfunction
○PDH shifts pyruvate to Kreb’s cycle not to lactate
○Sub-normal levels in muscle in sepsis
○Function restored by dichloroacetate which also reduces lactate level
Protein catabolismProtein catabolism
○AA’s converted to pyruvate then lactate
Inhibition of mitochondrial respirationInhibition of mitochondrial respiration
○Sepsis, drugs e.g. metformin (rare), cyanide, antiretroviralsSepsis, drugs e.g. metformin (rare), cyanide, antiretrovirals
When lactate hypoperfusionWhen lactate hypoperfusion

18. Lactate MetabolismLactate Metabolism
LIVER
60%
KIDNEYS
30%
Excretion renal
threshold = 5-6 mmol/L
MUSCLE
10%

19. What happens to the lactate?What happens to the lactate?
Gluconeogenesis 20% – Cori cycle in liver
○2 CH
3
CHOH COO
-
+ 2H
+
= C
6
H
12
O
6
○Glucose production uses 6 ATPuses 6 ATP from  oxidation of fatty acids
○LACTATE SHUTTLELACTATE SHUTTLE: aerobic lactate used to move carbons for
oxidation/gluconeogenesis at critical time
○Hyperlactataemia = adaptive response
○Lactate is a “stress fuel” used by heart and brain
○Reduced lactate in heart reduces cardiac function in shockReduced lactate in heart reduces cardiac function in shock
Oxidation 80%
○CH
3
CHOH COO
-
+ H
+
+ 3 O
2
= 3 CO
2
+ 3 H
2
O

20. Classification of lactic acidosisClassification of lactic acidosis
Type A Lactic Acidosis
Associated with malperfusion / dysoxia
Type B Lactic Acidosis
In the absence of malperfusion / dysoxia
B1B1 – Disease states e.g. DKA, leukaemia, lymphoma, thiamine deficiency
B2B2 – Drugs e.g. metformin, cyanide, b agonists, HAART
B3B3 – Inborn errors of metabolism

21. Prognostic valuePrognostic value
Source doesn’t matter
High lactate still a marker of still a marker of
severe physiological stress severe physiological stress
and risk of deathand risk of death
High lactate often not hypoxia
related but represents metabolic
changes of severe stress

22. So what do we do about it?So what do we do about it?
Look for evidence of malperfusion
If present augment CO & O
2 delivery
BUTBUT don’t do this just for the lactate level
TREAT the malperfusion not the lactate
Consider the other reasons for high lactate
Lactate is the messenger…don’t shoot it!

23. ReferencesReferences
Levy B. Lactate and shock state: the metabolic viewLactate and shock state: the metabolic view. Curr Opin Crit Care 2006; 12: 315-321
Cohen RD, Simpson R. Lactate metabolism. Anesthesiology 1975; 43: 661-673
De Backer D. Lactic acidosis. Intensive care Med 2003; 29: 699-702
Levy B, Gibot S, Franck P, Cravoisy A, Bollaert P-E. Relation between muscle Na+K+
ATPase activity and raised lactate concentration in septic shock: a prospective study.
Lancet 2005; 365:871-875
Trzeciak S, Dellinger RP, Chansky ME, Arnold RC, Schorr C, Milcarek B, Hollenberg SM,
Parrillo JE. Serum lactate as a predictor of mortality in patients with infection. Intensive
Care Med 2007; 33: 970-977
James JH, Luchette FA, McCarter F, Fischer JE. Lactate is an unreliable indicator of
tissue hypoxia in injury or sepsis. Lancet 1999; 354: 505-508
Matejovic M, Radermacher P, Fontaine E. Lactate in shock: a high-octane fuel for the
heart? Intensive Care Med 2007; 33: 406-408
Schurr A. Lactate: the ultimate cerebral oxidative energy substrate? Journal of Cerebral
Blood Flow & Metabolism 2006; 26: 142-152