High Blood Lactate - Not always due to hypoxia

The use of blood lactate measurement is commonplace throughout the world, primarily in the management of critically ill patients in ICUs and Emergency Departments. In Medical School, students are generally taught Lactate is the result of tissue hypoxia (low oxygen levels), leading to anaerobic respiration, but it turns out this is only part of the story. 

Despite the close association between high blood lactate and tissue hypoxia, lactate levels rarely correlate with traditional indicators of perfusion (such as heart rate and blood pressure), nor do they improve with increased oxygen delivery. Consequently, there must be alternative causes for raised lactate levels other than hypoxia. 

It is important to remember, Lactate is a by-product of the metabolism of Glucose, even in the presence of adequate oxygen levels. Lactate is a crucial metabolite in the two main energy-producing processes within the body: glycolysis and oxidative phosphorylation.

a) Glycolysis - the splitting of Glucose. This occurs in the cell cytoplasm and creates 2 molecules of pyruvate and energy in the form of 2 molecules of Adenosine Triphosphate (ATP).

In all physiological conditions, pyruvate, the product of glycolysis, is continually converted into Lactate in the cytoplasm. This occurs via a reversible oxido-reduction reaction catalyzed by the enzyme Lactate Dehydrogenase (LDH). This prevents pyruvate from accumulating in the cytoplasm, allowing the maintenance of a concentration gradient, and ensuring high levels of pyruvate do not inhibit glycolysis. Although this is a continual process, this is particularly important during times of cell stress, when the rate of glycolysis can increase rapidly. Lactate formed in the cytoplasm crosses the outer membrane of the mitochondria, entering the Intermembrane Space in a process known as the Cytosol-to-Mitochondria Lactate Shuttle. Here it is converted back into pyruvate, again under the action of LDH. The pyruvate molecule is then transported across the inner mitochondrial membrane via a protein known as the Mitochondrial Pyruvate Carrier (MPC).

b) Oxidative phosphorylation – Inside the mitochondrial matrix, pyruvate molecules undergo a series of chemical reactions (the Krebs Cycle). The energy stored in the chemical bonds of the Glucose molecule is released via the Krebs Cycle, producing carbon dioxide and electron donors, NADH and FADH. These, together with oxygen to produce much larger quantities of energy (an additional 34 molecules of ATP), which can be used throughout the cell in processes such as muscle contraction, nerve impulse propagation and protein synthesis.

Lactate is converted back into pyruvate during recovery, again using the LDH enzyme. However, Lactate is not only a temporary energy store. 75-80% of the Lactate produced is metabolized immediately within slow-twitch muscle, cardiac myocytes, and the liver. This role of Lactate as a fuel is facilitated by a family of membrane-bound proteins, the mono-carboxylate transporters (MCT). In addition to the local metabolism, lactate is cleared from circulation by the liver with a small amount of additional clearance by the kidneys. 

Studies in athletes have demonstrated that the body can clear large lactate loads quickly following exercise cessation, and similar responses are seen following the return of circulation after cardiac arrest. However, several clinical conditions have been associated with reduced clearance of Lactate. These include liver failure following cardiopulmonary bypass surgery and sepsis.

As mentioned previously, the metabolism of Glucose to Lactate under aerobic conditions allows the body to produce significant energy during times of cell stress. Therefore, stimulating increased glycolysis has been shown to increase lactate levels in the absence of tissue hypoxia. Most notably, this is seen following the administration of the common critical care drug epinephrine (adrenaline), which has long been shown to result in a dose-dependent increase in lactate levels in the absence of hypoxia. Other medications, such as the diabetic drug, Metformin, have also been shown to increase lactate production in the absence of tissue hypoxia. 

Although raised lactate levels may be seen in tissue hypoxia, they are often the result of increased high glycolytic activity at times of adequate tissue oxygenation, particularly under the influence of epinephrine.