Lactate Overview

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

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

Useless end-product or essential fuel?

The traditional view…
Hypoxia/anoxia leads to anaerobic metabolism
Anaerobic metabolism produces lactate
Anaerobic metabolism is BAD NEWS
Hypoxia/anoxia is BAD 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

So doesn’t that mean that…?
High LACTATE is BAD NEWS
High LACTATE means hypoxia/anoxia
High LACTATE means anaerobic metabolism
High LACTATE = WORSE outcome

Hyperlactataemia (> 2mmol/L)

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

How is lactate produced? If pyruvate production > oxidation in CAC then lactate formation increases PDH

SO… Anything that increases glycolysis can increase lactataemia once pyruvate oxidation is overwhelmed NOT just anaerobic metabolism!

In the anaerobic state…

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

Lactate/pyruvate ratio
Hypoxia blocks oxidative phosphorylation
prevents NADH re-oxidation to NAD
increases the NADH/NAD ratio
increases the lactate/pyruvate ratio
Normal ratio around 10:1
Lactate/pyruvate = K x (NADH/NAD) x H + Cardiogenic shock L/P ratio 40:1 Consistent with hypoxia Resuscitated septic shock L/P ratio 14:1 Not consistent with hypoxia

When lactate hypoperfusion
Cardiogenic shock
Haemorrhagic shock
Septic shock if
Catecholamine resistant + depressed CI
Unresuscitated (see Rivers)

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

Epinephrine and lactate production

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 not produced if Na/K-ATPase blocked
Independent of tissue hypoxia
Lactate overproduction blocked by  2 blockade
Epinephrine and lactate production

Reduced 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 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 catabolism
AA’s converted to pyruvate then lactate
Inhibition of mitochondrial respiration
Sepsis, drugs e.g. metformin (rare), cyanide, antiretrovirals

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

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 ATP from  oxidation of fatty acids
LACTATE 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 shock
Oxidation 80%
CH 3 CHOH COO - + H + + 3 O 2 = 3 CO 2 + 3 H 2 O

Classification of lactic acidosis Type A Lactic Acidosis Associated with malperfusion / dysoxia Type B Lactic Acidosis In the absence of malperfusion / dysoxia B1 – Disease states e.g. DKA, leukaemia, lymphoma, thiamine deficiency B2 – Drugs e.g. metformin, cyanide, b agonists, HAART B3 – Inborn errors of metabolism

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

So what do we do about it?
Look for evidence of malperfusion
If present augment CO & O 2 delivery
BUT 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!

References
Levy B. Lactate 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

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Lactate Overview

by Andrew Ferguson on Feb 06, 2008

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Lactate Overview — Presentation Transcript