Lactate: biochemical and physiologic basis for clinical significance

In order for us to survive, our cells must produce adenosine triphosphate (ATP) energy by undergoing glycolysis which breaks down glucose to pyruvate. Ideally, pyruvate gets shuttled into aerobic metabolism for oxidative phosphorylation because this is the most efficient and abundant way to produce 32 ATP molecules (1). In oxygen-deprived anaerobic situations, glycolysis of glucose to pyruvate and then lactate can generate 2 ATP (2).

Lactate biochemical and physiologic role. Annotated from (5).

Lactate serves two main physiologic functions (3):
1. It is a carbon building base for gluconeogenesis. In high metabolic states, the brain and heart dramatically increase their reliance on lactate.
2. Pyruvate conversion to lactate in anaerobic glycolysis regenerates NAD+ which an essential oxidizing cofactor (electron acceptor) to maintain glycolysis.

Lactate quick facts (3):
>> Lactate ⇆ lactic acid = 3000:1 physiologically
>> Human lactate is exclusively L-lactate b/c mammalian cells have L-lactate dehydrogenase. D-lactate accumulates in some pathologic processes, but this is generally not clinically relevant and rarely measured
>> Lactate is metabolized mostly via gluconeogenesis: 75% liver, 25% renal (of which 10% is excreted)

The “oxygen debt model” is a now outdated framework of understanding lactate as primarily a byproduct of anaerobic respiration (3). This thinking is now known to be oversimplified and growing evidence is showing the importance of lactate even in aerobic settings.

What are some of the evidence and concepts that suggest lactate is not simply a marker of hypoxia or anaerobic respiration?

>> High metabolic or proinflammatory states naturally increase glycolysis and therefore the production of pyruvate. If pyruvate is produced faster than the Krebs cycle can process it, then the body’s equilibrium will shift pyruvate to lactate.
>> Lactate is produced by muscles in fully oxygenated periods
>> The heart and brain rely on lactate for energy production even at rest
>> Doctors who climbed Mt. Everest had PaO2 = 24 and normal lactate level
>> Some septic patients develop vasopressor-dependent hypotension (i.e. shock) without associated lactate elevation; conversely, some septic patients have hyperlactatemia without shock
>> The lungs (theoretically the most oxygen-rich tissue) are a major producer of lactate in sepsis

The mechanisms for lactate elevation are numerous. One study showed that lactate >4 was attributed to 20% infectious etiology, 20% seizures, and the remaining other/noninfectious. Unless you have a reason to suspect shock/tissue hypoxia, understand that the clinical significance of hyperlactatemia is nonspecific, and it has a broad differential.

Select mechanisms of hyperlactetemia. Annotated from (5).

Anything that causes an elevation of pyruvate levels can increase lactate – which means increased production (glycolysis) or reduced clearance (Krebs, oxidative phosphorylation).

Framework for sorting a differential for hyperlactatemia (3).

Lactate “fun facts”:
>> Use of a tourniquet does not significantly alter venous lactate level (perhaps arterial but only after ~1 hr)
>> Lactated ringers boluses do not contribute significantly: 1L has ~30 mmol whereas the adult metabolizes 20 mmol/kg daily

So, what to do with lactate in the ED?

1. Think before you order a lactate level.
2. If you have already ordered it, here is a framework for interpretation. There is evidence for lactate as a prognostic tool in sepsis, trauma, burns, inhalation injuries, liver failure, hemorrhage, shock, and cardiac arrest (3-5).