HypothesisLactate is an unreliable indicator of tissue hypoxia in injury or sepsis
Section snippets
Previous evidence linking hyperlactacidaemia and epinephrine in shock
Nearly 30 years ago, several studies made the existence of an unqualified link between hyperlactacidaemia and tissue hypoxia doubtful. These studies showed that hyperlactacidaemia accompanying haemorrhage could be largely prevented by pretreatment with combined α and β-adrenergic receptor blockade.6 Similarly, adrenergic blockade abolished lactic acidosis induced by infusion of epinephrine.7 In dogs with haemorrhagic shock, plasma lactate correlated well with plasma catecholamines.
Skeletal muscle as primary source of lactate in shock
In shocked dogs, the primary source of lactate was identified as skeletal muscle, in which lactate concentrations exceeded those in other tissues.10 When radiolabelled glucose was infused, the specific activity of lactate in arterial blood was similar to that in organs other than skeletal muscle, but lower in skeletal muscle itself.10 This result indicates that, in shock, skeletal muscle generates lactate more readily from its glycogen stores than from circulating glucose. Because skeletal
Epinephrine and hyperlactacidaemia
In healthy individuals at rest, the plasma epinephrine threshold for producing an increase in circulating lactate is between 150 and 300 pg/mL, or about three to six times the normal concentration.11, 12 In exercising individuals, increases in plasma lactate can be detected when the epinephrine concentration reaches about 200 pg/mL.13 As we shall discuss, epinephrine concentrations in sepsis or after injury frequently exceed these thresholds.
During exercise of increasing intensity, plasma
Epinephrine stimulates Na+, K+-ATPase activity in skeletal muscle
Epinephrine has acute effects on muscle physiology. Muscle's ability to conduct an action potential and contract depends on the membrane potential and concentration gradients across the membrane for sodium and potassium. These ion gradients are maintained by the Na+, K+-ATPase, which consumes one molecule of ATP to transport three sodium ions out of the cell and two potassium ions into the cell. At rest, muscle uses less than 10% of its total Na+, K+-ATPase activity to maintain sodium and
Aerobic glycolysis and the Na+, K+-ATPase
Increased activity of the Na+, K+-ATPase leads to increased lactate production under well-oxygenated conditions in various cells, including erythrocytes, vascular smooth muscle, neurons, glia, and skeletal muscle.33, 34, 35, 36 Conversely, inhibition of the Na+, K+ pump with ouabain reduces lactate production. To explain this feature, it has been proposed that clusters of enzymes consisting of the complete glycolytic cascade may be associated with membranes in proximity to ion transporters.33,
Hypokalaemia after injury indicates increased Na+, K+-ATPase activity
Muscle potassium uptake is stimulated by epinephrine or other β2 agonists, and that stimulation is inhibited by ouabain, indicating involvement of the Na+-K+ pump.31, 39 Administration of β2 agonists results in a prompt decrease in circulating potassium.32, 40 More than half of randomly selected trauma patients present with hypokalaemia, the degree of which is associated with the severity of trauma and with subsequent mortality.41 An acute, transient reduction in plasma potassium also occurs
Hypothesis
After injury and/or haemorrhage and during sepsis, neuroendocrine and cardiovascular stimuli combine to trigger and sustain release of epinephrine. High epinephrine concentrations stimulate adrenergic receptors in skeletal-muscle cell membranes and, among other effects, increase cyclic AMP production. This increase leads to the coordinated stimulation both of Na+, K+-ATPase activity and of glycogenolysis. Increased Na+-K+ pump activity results in accelerated aerobic glycolysis that is sustained
Testing the hypothesis
The hypothesis predicts that epinephrine is a primary stimulus to lactate production through stimulation of Na+, K+ pump activity in skeletal muscle. These predictions can be tested in healthy individuals by an assessment of the net flux of lactate and potassium across a limb. If this hypothesis is correct, we would expect to find the following associations over a range of epinephrine concentrations: (i) lactate flux should be positively correlated with epinephrine concentration; (ii) potassium
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