Lactate in Sepsis: Much Maligned, but Not Quite the Evil Devil!

In the 2018 iteration of the Surviving Sepsis Guidelines, a 1-h bundle is recommended for expeditious resuscitation and management of severe sepsis. Serial lactate measurements are advocated to guide resuscitation with the aim to normalize levels. High lactate levels are considered to indicate tissue hypoperfusion in sepsis.¹

Glucose metabolism

Aerobic pathway

Let us consider how lactate is generated. In the presence of an adequate supply of oxygen, aerobic metabolism occurs. Glucose is first converted to pyruvate, yielding two molecules of ATP. The pyruvate is then converted by pyruvate dehydrogenase to acetyl CoA (Fig. 1, red arrow). The acetyl CoA enters the tricarboxylic acid cycle (TCA) resulting in the formation of 36 molecules of ATP. If there is a lack of oxygen, the anaerobic pathway takes over. In this pathway, the first step, namely, the conversion of glucose to pyruvate occurs as previously, because oxygen is not required for this process. However, the next step, namely, the conversion of pyruvate to acetyl CoA, and subsequent entry into the TCA cannot happen in the absence of oxygen.

Fig. 1 Glucose metabolism. Red arrow: aerobic pathway through the TCA cycle. Green arrow: Due to enhanced aerobic glycolysis,  pyruvate accumulation occurs as the TCA pathway becomes saturated. The pyruvate is converted to lactate by lactate dehydrogenase 

Anaerobic pathway

What happens to the pyruvate that accumulates consequent to the failure of its conversion to acetyl CoA due to a lack of oxygen? Another enzyme, lactate dehydrogenase, takes over and converts the pyruvate to lactate (Fig. 1, green arrow). The lactate is then transported to the liver, where it is utilized in three different ways (Fig. 2): (1) Conversion to pyruvate by the same enzyme, lactate dehydrogenase, by a reverse process. The pyruvate generated by this process is converted to glucose by gluconeogenesis. The glucose thus produced goes back into circulation. The conversion of two molecules of pyruvate to one molecule of glucose consumes six molecules of ATP and hence is an energy expending process. (2) Conversion to glycogen, which may be converted to glucose for later use, and (3) Conversion to pyruvate, which re-enters the TCA under aerobic conditions to generate ATP. The excess lactate is also transported to the myocardium, where it is converted to pyruvate and enters the TCA cycle to yield ATP for the myocardial cells. Metabolism in the myocardial cells is always aerobic.

Fig. 2 The lactate generated from pyruvate (green arrow, Fig. 1) is transported to the liver. It may be converted to glucose (gluconeogenesis),  to glycogen, or to pyruvate in the liver  

Lactate levels in sepsis

Why do lactate levels rise in sepsis? Is it because of reduced tissue oxygen delivery, and anaerobic metabolism of glucose? Tissue hypoxia due to impaired oxygen delivery is highly unlikely is sepsis. In most cases, there is preserved or increased cardiac output with adequate oxygen delivery. Lactate levels rise in sepsis, through entirely different mechanisms that are unrelated to tissue hypoxia. In sepsis, there is excessive stimulation of beta-2 receptors. This leads to accelerated aerobic metabolism of glucose. Increased aerobic metabolism of glucose leads to high levels of pyruvate. However, the pyruvate dehydrogenase pathway through to the TCA cycle gets overwhelmed due to the excessively high pyruvate levels. Consequently, the excess pyruvate gets converted to lactate by the lactate dehydrogenase enzyme. Hence, with an increase in aerobic metabolism of glucose, the lactate levels rise hand in hand. However, lactate production through this mechanism is not due to tissue hypoxia; it is entirely due to excessive aerobic metabolism of glucose, stimulated by beta 2 receptor-mediated release of epinephrine, a characteristic feature of sepsis. In fact, failure of lactate levels to rise in response to epinephrine infusion in shocked patients has been associated with increased mortality.² Other mechanisms of lactate generation are also seen in sepsis, including excessive production in the lung due to ARDS and hepatic dysfunction leading to reduced utilization of lactate.

It has been clearly established that high lactate levels indicate more severe illness. Furthermore, increased lactate levels predict mortality.³ Hyperlactatemia without hypotension has been associated with significantly higher mortality compared to patients with hypotension and normal lactate levels.⁴ Be that as it may, will targeting resuscitative interventions with the lactate level as a therapeutic goal be appropriate? First, if the rise in lactate levels is unlikely to be due to oxygen debt, it would seem illogical to attempt to increase oxygen delivery with an eye on the lactate level. If a patient has improving blood pressures, urine output, and acid-base status, it defies logic to assume that continued measures aimed specifically at lactate levels would be beneficial.

The use of the term “lactate clearance” may also be flawed. Clearance is the volume of plasma from which a substance is completely removed per unit time. In a shocked patient, the lactate levels are more likely to fall due to reduced production; not from removal by metabolism. A falling lactate level is definitely more likely to be associated with survival; however, the rate of fall in lactate levels that may be associated with a better outcome is hard to define.⁵

The bottom line

• Lactate levels rise in sepsis mainly because of catecholamine-mediated enhanced aerobic glycolysis.
• Oxygen debt is uncommon in septic shock; hence “bundles” that target increased oxygen delivery are unlikely to help.
• Lactate is an important metabolic fuel in shock. It is a substrate for the production of glucose and glycogen in the liver, and a source of aerobic generation of ATP for the myocardium.
• A high lactate level is a strong predictor of mortality.
• A fall in lactate levels carries a good prognosis; however, resuscitative interventions that target lactate levels are unlikely to be beneficial.
• It is important not to view lactate levels in isolation; a holistic approach that addresses all the vital parameters that govern the circulatory status is essential.

 

References:

1. Levy, M. M., Evans, L. E. & Rhodes, A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med.44, 925–928 (2018).
2. Wutrich, Y. et al.Early increase in arterial lactate concentration under epinephrine infusion is associated with a better prognosis during shock. Shock Augusta Ga34, 4–9 (2010).
3. Serum lactate as a predictor of mortality in patients with infection. – PubMed – NCBI. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17431582. (Accessed: 12th December 2018)
4. Mortality is Greater in Septic Patients With Hyperlactatemia Than With Refractory Hypotension. – PubMed – NCBI. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28248722. (Accessed: 11th December 2018)
5. Vincent, J.-L., Quintairos e Silva, A., Couto, L. & Taccone, F. S. The value of blood lactate kinetics in critically ill patients: a systematic review. Crit. Care20, (2016).