Will the real

please step forward?

Dr. Andrew FergusonDr. Andrew FergusonMEd FRCA DIBICM FCCPMEd FRCA DIBICM FCCPAttending IntensivistAttending Intensivist

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

Useless end-productUseless end-product

or or

essential fuel?essential fuel?

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

So doesn’t that mean So doesn’t that mean that…?that…?

High LACTATE is BADBAD NEWS

High LACTATE means hypoxia/anoxia

High LACTATE means anaerobic metabolism

High LACTATE = WORSEWORSE outcome

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

Basal lactate productionBasal lactate production

Total = 1290 mmol / 24 hours for 70 kg

How is lactate How is lactate produced?produced?

If pyruvate production > oxidation in CAC then lactate formation increases

PDHPDH

SO…SO…

AnythingAnything that increases glycolysis can increase

lactataemia once once pyruvate oxidation is pyruvate oxidation is

overwhelmedoverwhelmed

NOT just anaerobic NOT just anaerobic metabolism!metabolism!

In the anaerobic In the anaerobic state…state…

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

Lactate/pyruvate ratioLactate/pyruvate ratio

Hypoxia blocks oxidative phosphorylationprevents NADH re-oxidation to NAD increases the NADH/NAD ratio increases the lactate/pyruvate ratioincreases the lactate/pyruvate ratioNormal 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 40:1Consistent with hypoxiaConsistent with hypoxia

Resuscitated septic shockResuscitated septic shock

L/P ratio 14:1L/P ratio 14:1Not consistent with hypoxiaNot consistent with hypoxia

When lactate When lactate hypoperfusionhypoperfusion Cardiogenic shock Haemorrhagic shock Septic shock if

Catecholamine resistant + depressed CIUnresuscitated (see Rivers)

Accelerated aerobic glycolysisAccelerated aerobic glycolysisCarbohydrate metabolism > mitochondrial

oxidative capacityStimulated 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 When lactate hypoperfusionhypoperfusion

Epinephrine and lactate Epinephrine and lactate productionproduction

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 ATPAdrenaline activates Na/K-ATPase using ATPIncreased glycolysis increases lactateLactate Lactate notnot produced if Na/K-ATPase blocked produced if Na/K-ATPase blockedIndependentIndependent of tissue hypoxia of tissue hypoxiaLactate overproduction blocked by Lactate overproduction blocked by 2 blockade2 blockade

Epinephrine and lactate Epinephrine and lactate productionproduction

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 When lactate hypoperfusionhypoperfusion

Lactate Lactate MetabolismMetabolism

LIVER60%

KIDNEYS30%

Excretion renal threshold = 5-6 mmol/L

MUSCLE10%

What happens to the What happens to the lactate?lactate?

Gluconeogenesis 20% – Cori cycle in liver

○ 2 CH3 CHOH COO- + 2H+ = C6H12O6

○ 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%○ CH3 CHOH COO- + H+ + 3 O2 = 3 CO2 + 3 H2O

Classification of lactic Classification of lactic acidosisacidosis

Type A Lactic AcidosisAssociated with malperfusion / dysoxia

Type B Lactic AcidosisIn the absence of malperfusion / dysoxia

B1B1 – Disease states e.g. DKA, leukaemia, lymphoma, thiamine deficiencyB2B2 – Drugs e.g. metformin, cyanide, b agonists, HAART

B3B3 – Inborn errors of metabolism

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

So what do we do about So what do we do about it?it? Look for evidence of malperfusion If present augment CO & O2 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!

ReferencesReferencesLevy 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