Elsevier

The Lancet

Volume 365, Issue 9462, 5–11 March 2005, Pages 871-875
The Lancet

Mechanisms of Disease
Relation between muscle Na+K+ ATPase activity and raised lactate concentrations in septic shock: a prospective study

https://doi.org/10.1016/S0140-6736(05)71045-XGet rights and content

Summary

Background

Hyperlactataemia during septic shock is often viewed as evidence of tissue hypoxia. However, this blood disorder is not usually correlated with indicators of perfusion or diminished with increased oxygen delivery. Muscles can generate lactate under aerobic conditions in a process linking glycolytic ATP supply to stimulation of Na+K+ ATPase. Using in-vivo microdialysis, we tested whether inhibition of Na+K+ ATPase can reduce muscle lactate.

Methods

In 14 patients with septic shock, two microdialysis probes were inserted into the quadriceps muscles and infused with lactate-free Ringer's solution in the absence or presence of 10−7 mol/L ouabain, a specific inhibitor of Na+K+ ATPase. We measured lactate and pyruvate concentrations in both the dialysate fluid and arterial blood samples.

Findings

All patients had increased blood lactate concentrations (mean 4·0 mmol/L; SD 2·1). Lactate and pyruvate concentrations were consistently higher in muscle than in arteries during the study period, with a mean positive gradient of 1·98 mmol/L (SD 0·2; p=0·001) and 230 μmol/L (30; p=0·01), respectively. Ouabain infusion stopped over production of muscle lactate and pyruvate (p=0·0001). Muscle lactate to pyruvate ratios remained unchanged during ouabain infusion with no differences between blood and muscle.

Interpretation

Skeletal muscle could be a leading source of lactate formation as a result of exaggerated aerobic glycolysis through Na+K+ ATPase stimulation during septic shock. Lactate clearance as an end-point of resuscitation could therefore prove useful.

Relevance to clinical practice

In patients with septic shock, a high lactate concentration should be interpreted as a marker of disease, portending a bad outcome. The presence of hyperlactataemia in resuscitated septic patients should not be taken as proof of oxygen debt needing increases in systemic or regional oxygen transport to supranormal values. Lactate, instead of being regarded only as a marker of hypoxia, might be an important metabolic signal.

Introduction

Raised blood lactate concentrations during shock states are often viewed as evidence of tissue hypoxia, with values being proportional to the defect in oxidative metabolism.1 However, many tissues generate pyruvate and lactate under aerobic conditions (aerobic glycolysis) in a process linking glycolytic ATP supply to the activity of membrane ion pumps such as Na+K+ ATPase.2 Indeed, aerobic glycolysis and glycogenolysis occur not only in resting, well oxygenated skeletal muscles, but also during experimental haemorrhagic shock and experimental sepsis, and are closely linked to stimulation of active sarcolemmal Na+K+ ATPase transport due to epinephrine release.3, 4, 5

Hyperlactataemia and lactic acidosis are not synonymous. Lactic acidosis refers to a cellular metabolic process characterised by rises in blood lactate (>5 mmol/L) and decreases in blood pH (<7·25). During cellular hypoxia, hydrolysis of ATP leads to accumulation of H+ ions in the cytosol and subsequent acidosis. On the other hand, under aerobic conditions the H+ ions produced by hydrolysis of ATP are recycled during metabolism of glucose and therefore the process is non-acidifying. During septic shock, the distinction between hypoxic or non-hypoxic production of lactate is critical for understanding cellular responses to injury and for interpretation of lactate concentration during resuscitation.6 This knowledge could lead to the abandonment of potentially harmful actions aimed at increasing oxygen delivery to the tissue.7

We propose that increased epinephrine release in septic shock stimulates sarcolemmal Na+K+ ATPase and greatly accelerates aerobic glycolysis and Na+K+ ATPase–coupled lactate production in skeletal muscle. Consequently, most of the increase in blood lactate would thus be unrelated to poor perfusion and unlikely to respond to a rise in oxygen delivery. To our knowledge, there is no human study that has addressed whether the reported increase in lactate concentrations in septic shock is associated with a rise in muscle Na+K+ ATPase activity. We used microdialysis technology to assess whether specific inhibition of Na+K+ ATPase by ouabain is able to prevent production of lactate in muscle in patients with septic shock.

Section snippets

Patients

Our institutional review board approved this study, and patients or their relatives provided written informed consent before enrolment. 14 consecutive patients with septic shock, defined according to the International Sepsis Definitions Conference,8 were prospectively enrolled within 12 h of the occurrence of shock. All patients were treated according to international recommendations with broad-spectrum antibiotics, low-dose hydrocortisone in case of non-response to a short corticotropin test,

Results

Of the 14 patients with septic shock, ten survived the septic episode. Mean age was 65 years (SD 12). All patients were mechanically ventilated and ten had bicarbonate haemofiltration. Eight were infused with epinephrine and six with norepinephrine. Since the same analyses were done for both groups, pooled data are presented. A hyperdynamic state, as shown by a high mean cardiac index of 4·0 L/min per m2 body-surface area (SD 0·4), was present in all patients at inclusion. Mean SvO2 was 76%

Discussion

All patients had increased blood lactate concentrations, and lactate and pyruvate concentrations were consistently higher in muscle than in arteries during the study period. Selective inhibition of Na+K+ ATPase with ouabain infusion stopped over-production of muscle lactate and pyruvate.

Hypoxic-anaerobic metabolic production of lactate can be global (eg, hypovolaemia, cardiac failure) or focal (eg, bowel ischaemia). A non-hypoxic increase in lactate concentration can result from impaired

Glossary

Lactate
Mainly derived from pyruvate through the action of the enzyme lactate dehydrogenase, located in the inner mitochondrial membrane, according to the following equation: Pyruvate + NADH +H+ ↔ lactate + NAD+
Glycolysis
Oxidation of glucose to either pyruvate or lactate. Glycolysis proper is completely anaerobic. The global reaction of glycolysis is: Glucose + 2 NAD+ + 2 ADP + 2 Pi → 2 NADH + 2 pyruvate + 2 ATP + 2 H2O + 4 H+
Na+K+ ATPase
Pump system located in the sarcolemma, which requires a

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