Transcript
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
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