Hyperlactatemia in critical illness: time for reappraisal?

Lactic acidosis commonly occurs in the critically ill, especially among patients in shock of varying etiology. High lactate levels are uniformly associated with poor clinical outcomes, including mortality.1 However, there is considerable interest and conflict of opinion regarding the clinical value of using lactate levels to guide resuscitation in critically ill patients. Although generally considered to be a marker of tissue hypoxia, the etiology of hyperlactatemia in the critically ill may be multifactorial. 

Lactate production and metabolism 

Lactate is generated at the rate of 0.8 mmol/kg/hour (1300 mmol/day), and the normal plasma level is 0.3–1.3 mmol/l. Lactate production occurs in the skeletal muscle, intestines, brain, and erythrocytes. In the glycolytic pathway, glucose is oxidized to pyruvate with the generation of NADH from NAD. The pyruvate is metabolized in the mitochondria by the aerobic pathway through the Krebs cycle. The metabolism of each molecule of pyruvate results in the generation of 36 molecules of ATP. Under anaerobic conditions, the pyruvate does not enter the mitochondria; instead, it is converted to lactate by lactate dehydrogenase in the cytosol, with the regeneration of NAD from NADH (Figure 1).  The concentrations of lactate and pyruvate are maintained at a 10:1 equilibrium by lactate dehydrogenase. 

The lactate generated is transported to the liver, where it is oxidized to pyruvate. The pyruvate is converted back to glucose through gluconeogenesis and re-enters the glycolytic pathway (Figure 1). The liver clears 70% of the generated lactate, mainly through gluconeogenesis and partly by oxidation to carbon dioxide and water. Tissues rich in mitochondria, including skeletal and cardiac muscle, and the proximal tubular tubules of the kidney eliminate the remaining lactate by conversion to pyruvate. The kidneys excrete less than 5% of the lactate produced. 

Figure 1. Normal pathways of glycolysis and gluconeogenesis

Why do lactate levels rise in the critically ill? 

Being the predominant metabolic pathway of lactate, impairment of liver function results in raised lactate levels. Any increase in the rate of glycolysis results in the generation of high levels of pyruvate. The pyruvate dehydrogenase enzyme may be overwhelmed by excessive pyruvate levels; this results, in turn, to the conversion of pyruvate to lactate by the lactate dehydrogenase enzyme. Accelerated glycolysis occurs in hypermetabolic states, including fever, thyrotoxicosis, and the use of beta-agonist drugs such as adrenaline. This may be the mechanism of causation of lactic acidosis in patients with acute severe asthma who are treated with high-dose beta-adrenergic bronchodilators. Thus, lactate levels may continue to rise in a patient with severe asthma who is clinically improving with the alleviation of bronchospasm. Mitochondrial dysfunction leads to failure of the aerobic pathway of metabolism. Thiamine is a crucial cofactor in the conversion of pyruvate to acetyl CoA. Thiamine deficiency can inhibit this reaction and lead to the conversion of pyruvate to lactate. Ischemic tissues, including gut ischemia, may lead to the generation of high levels of lactate. Toxins that poison the mitochondria, including cyanide and carbon monoxide, can lead to failure of the aerobic pathway and result in lactic acidosis. Biguanides may also lead to excessive lactate levels through inhibition of hepatic gluconeogenesis. Respiratory alkalosis may lead to the movement of intracellular lactate to the extracellular fluid and lead to elevated lactate levels in the plasma.2

Does hyperlactatemia occur due to impaired oxygen delivery in sepsis?

In patients with various types of shock, elevated lactate levels were considered to be due to oxygen delivery failing to meet tissue demand, leading to anaerobic metabolism.3 The Surviving Sepsis Guidelines (2017) recommends resuscitation aimed to normalize lactate levels based on the hypothesis of oxygen debt.4 However, there is scant evidence to support oxygen debt in septic shock. 

In septic patients, the partial pressure of oxygen in the skeletal muscle was found to be higher than normal and increased with the severity of sepsis.5 In an animal model of sepsis, elevated plasma lactate levels were observed in spite of high POvalues in the intestinal and bladder mucosa. This suggests that lactate generation occurs through mechanisms unrelated to cellular hypoxia in sepsis.6,7

Mitochondrial dysfunction has long been considered to be the underlying mechanism for the failure of oxygen utilization leading to anaerobic metabolism and the generation of lactate in sepsis. Mitochondrial function is evaluated by measurement of the levels of high-energy phosphates, including ATP, phosphocreatine, and intracellular pH. Using this technique, no evidence of mitochondrial dysfunction was observed in animal experiments and studies on human subjects with sepsis.8,9

Is there a mismatch between oxygen consumption and delivery in sepsis?

Ronco et al. studied critical O2 delivery and O2 extraction ratio among septic and non-septic patients. Tissue oxygen delivery was unaffected in these patients, and the ability of tissues to extract oxygen remained unaffected. However, hyperlactatemia was observed, suggesting that tissue dysoxia was not the underlying mechanism.10 A recent randomized controlled trial evaluated the administration of esmolol infusion in patients with septic shock. Despite reduced oxygen delivery, a significant decrease in lactate levels was observed, suggesting that lactate levels were unrelated to oxygen delivery among these patients.11

What is the source of lactate in sepsis? 

If tissue hypoxia leading to anaerobic metabolism is not the primary source of raised lactate levels in sepsis, what may be the mechanisms of hyperlactatemia in septic shock?

There may be an inhibition of mitochondrial pyruvate dehydrogenase activity in sepsis, the enzyme that converts pyruvate to acetyl CoA prior to its entry into the Krebs cycle. This results in the selective conversion of pyruvate to lactate and hyperlactatemia. The administration of dichloroacetate, a drug that enhances pyruvate dehydrogenase activity, has been shown to reduce lactate levels in animal models and human studies.12 Besides, accelerated aerobic glycolysis occurs in sepsis, leading to the generation of excessive pyruvate. High pyruvate levels overwhelm the capability of the pyruvate dehydrogenase enzyme for the conversion to acetyl CoA. Hence, the alternate pathway may dominate, with the conversion of pyruvate to lactate by the lactate dehydrogenase enzyme.

Opdam et al. performed an observational study among patients who underwent cardiopulmonary bypass and in patients with septic shock. They measured pulmonary oxygen consumption and lactate release from the lung. In this study, a substantial release of lactate was observed from the lung related to inflammation associated with cardiopulmonary bypass and sepsis.13 Thus, the lung may be the source of hyperlactatemia in patients with severe sepsis. 

Endogenous release of excessive catecholamines or their administration for hemodynamic support may lead to hyperlactatemia through increased activity of the Na+/K+–ATPase pump due to β2-receptor stimulation. This results in cyclic AMP release, with stimulation of accelerated glycogenolysis and glycolysis, leading to excessive pyruvate generation. When pyruvate levels continue to rise, increased conversion to lactate occurs, leading to hyperlactatemia. A hypermetabolic state characterized by excessive release of catecholamines may be the trigger for hyperlactatemia in sepsis.14  

We often see lactate levels rise with the use of catecholamine support, particularly with epinephrine infusion. However, the hyperlactatemia induced by catecholamine support does appear to lead to worse outcomes. A retrospective analysis evaluated the survival of patients in shock in relation to the rise in lactate levels following commencement of epinephrine infusion.  Survivors had a greater increase in lactate levels following the initiation of epinephrine support compared to non-survivors. Thus, failure of lactate levels to rise significantly following epinephrine infusion may be associated with poor outcomes.15

Although not the sole reason for hyperlactatemia, tissue hypoxia may occur in sepsis leading to stimulation of anaerobic metabolism and rise in lactate levels. Besides, failure of microcirculatory flow may also occur in sepsis. Indeed, studies on animal models suggest that inhibition of oxygen transport in early sepsis may likely result from microcirculatory dysfunction.16

Lactate clearance: a misnomer in sepsis

Lactate “clearance” has been suggested as a target to guide resuscitation in septic patients. However, it is important to note that clearance of substance denotes the extent of its removal from a unit volume over unit time. Clearly, in severe sepsis, lactate levels may decrease through mechanisms unrelated to its removal, including decreased generation or dilution consequent to fluid resuscitation.


  • High lactate levels in critically ill patients correlate with the severity of illness and strongly predicts mortality 
  • However, contrary to popular belief, the main reason for lactate rise in patients with severe sepsis is not tissue dysoxia and stimulation of anaerobic metabolism. On the contrary, in most patients with sepsis, tissue dysoxia does not occur
  • The origin of hyperlactatemia in sepsis is multifactorial, including accelerated glycolysis, a hypermetabolic state, and impaired activity or relative deficiency of pyruvate dehydrogenase. The lung may also be a lactate generator in sepsis
  • Under situations of stress, lactate acts as metabolic fuel through oxidation and conversion to pyruvate and glucose in the liver
  • The use of serum lactate levels as an endpoint to guide resuscitation may not represent the ideal approach in septic patients 


1.         Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010;182(6):752-761. doi:10.1164/rccm.200912-1918OC

2.         Sandoval DM. Hyperlactatemia in hyperventilation and respiratory alkalosis: report of three cases and literature review. Med Crítica. 2016;30(3):204-208.

3.         Nguyen HB, Rivers EP, Knoblich BP, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med. 2004;32(8):1637-1642. doi:10.1097/01.ccm.0000132904.35713.a7

4.         Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-377. doi:10.1007/s00134-017-4683-6

5.         Boekstegers P, Weidenhöfer S, Kapsner T, Werdan K. Skeletal muscle partial pressure of oxygen in patients with sepsis. Crit Care Med. 1994;22(4):640-650. doi:10.1097/00003246-199404000-00021

6.         VanderMeer TJ, Wang H, Fink MP. Endotoxemia causes ileal mucosal acidosis in the absence of mucosal hypoxia in a normodynamic porcine model of septic shock. Crit Care Med. 1995;23(7):1217-1226. doi:10.1097/00003246-199507000-00011

7.         Rosser DM, Stidwill RP, Jacobson D, Singer M. Oxygen tension in the bladder epithelium rises in both high and low cardiac output endotoxemic sepsis. J Appl Physiol Bethesda Md 1985. 1995;79(6):1878-1882. doi:10.1152/jappl.1995.79.6.1878

8.         Alamdari N, Constantin-Teodosiu D, Murton AJ, et al. Temporal changes in the involvement of pyruvate dehydrogenase complex in muscle lactate accumulation during lipopolysaccharide infusion in rats. J Physiol. 2008;586(6):1767-1775. doi:10.1113/jphysiol.2007.149625

9.         Brealey D, Brand M, Hargreaves I, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet Lond Engl. 2002;360(9328):219-223. doi:10.1016/S0140-6736(02)09459-X

10.       Ronco JJ, Fenwick JC, Tweeddale MG, et al. Identification of the critical oxygen delivery for anaerobic metabolism in critically ill septic and nonseptic humans. JAMA. 1993;270(14):1724-1730.

11.       Morelli A, Ertmer C, Westphal M, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA. 2013;310(16):1683-1691. doi:10.1001/jama.2013.278477

12.       Stacpoole PW, Nagaraja NV, Hutson AD. Efficacy of dichloroacetate as a lactate-lowering drug. J Clin Pharmacol. 2003;43(7):683-691.

13.       Opdam H, Bellomo R. Oxygen consumption and lactate release by the lung after cardiopulmonary bypass and during septic shock. Crit Care Resusc J Australas Acad Crit Care Med. 2000;2(3):181-187.

14.       Revelly J-P, Tappy L, Martinez A, et al. Lactate and glucose metabolism in severe sepsis and cardiogenic shock. Crit Care Med. 2005;33(10):2235-2240. doi:10.1097/01.ccm.0000181525.99295.8f

15.       Wutrich Y, Barraud D, Conrad M, et al. Early increase in arterial lactate concentration under epinephrine infusion is associated with a better prognosis during shock. Shock Augusta Ga. 2010;34(1):4-9. doi:10.1097/SHK.0b013e3181ce2d23

16.       Ellis CG, Bateman RM, Sharpe MD, Sibbald WJ, Gill R. Effect of a maldistribution of microvascular blood flow on capillary O(2) extraction in sepsis. Am J Physiol Heart Circ Physiol. 2002;282(1):H156-164. doi:10.1152/ajpheart.2002.282.1.H156

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