Elsevier

The Lancet

Volume 354, Issue 9177, 7 August 1999, Pages 505-508
The Lancet

Hypothesis
Lactate is an unreliable indicator of tissue hypoxia in injury or sepsis

https://doi.org/10.1016/S0140-6736(98)91132-1Get rights and content

Summary

High blood lactate concentration (hyperlactacidaemia) in trauma or sepsis is thought to indicate tissue hypoxia and anaerobic glycolysis even when blood pressure, cardiac output, and urine output are within clinically acceptable ranges. However, mechanisms of lactate generation by well-oxygenated tissues have received little attention. Within cells, oxidative and glycolytic energy production can proceed in separate, independent compartments. In skeletal muscle and other tissues, aerobic glycolysis is linked to ATP provision for the Na+−K+ pump, the activity of which is stimulated by epinephrine. In injured patients, hypokalaemia may reflect increased Na+, K+-ATPase activity. We propose that increased blood lactate often reflects increased aerobic glycolysis in skeletal muscle secondary to epinephrine-stimulated Na+, K+-ATPase activity and not anaerobic glycolysis due to hypoperfusion. The hypothesis explains why hyperlactacidaemia often neither correlates with traditional indicators of perfusion nor diminishes with increased oxygen delivery. When other variables have returned to normal, continued attempts at resuscitation based on elevated blood lactate may lead to unnecessary use of blood transfusion and inotropic agents in an effort to increase oxygen delivery and lactate clearance.

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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