A middle aged man presented with urosepsis after several days antibiotic therapy in the community. He was in septic shock, with tachypnoea, tachycardia and hypotension. He had raised inflammatory markers and acute kidney injury. His initial lactate level was 14mmol/L with a significant metabolic acidosis (base deficit 21). He was commenced on iv antibiotics, noradrenaline and renal replacement therapy. Lactate levels cleared to less than 2mmol/L over the next 24hrs. He weaned off noradrenaline in 72 hours and CVVHDF over the next 5 days.

How is lactate produced and what is its significance in predicting the severity of critical illness?

Tahir Ali
Several variables are measured in critically ill patients in order to estimate disease severity, prognosticate morbidity and mortality, and monitor adequacy of treatment. Although no single test will be able to achieve all these goals, there has been a recent trend towards measurement of serial lactate levels to demonstrate these. The purpose of this review is to gain a better understanding of the literature related to lactate and its ability to assess disease severity, prognosticate and monitor treatment.
Lactate production
During aerobic respiration one glycogen molecule undergoes metabolism, as illustrated above, to yield 39 mols of ATP. Pyruvate enters the Krebs cycle in the presence of oxygen. In the absence of oxygen the alternative means of ATP production comes into play via the enzyme lactate dehydrogenase to yield Lactate. This produces an inefficient 3 mols of ATP per molecule of glycogen.(1) Metabolism of lactate is mainly via the liver (70%) where it undergoes gluconeogenesis, and, to a lesser extent, oxidation to CO2 and water. The rest of the lactate is removed by conversion to pyruvate in mitochondria-rich tissue such as skeletal myocytes, cardiac myocytes, and proximal tubule cells. Less than 5% is excreted renally.(2)

Hyperlactataemia can be divided into Type A, in which tissue hypoxia results in faster production than removal, and Type B, in which overt tissue hypoxia does not play a role. Type B can be further subdivided into B1 (due to underlying disease), B2 (drugs and toxins), and B3 (inborn errors of metabolism). (2)

The following mechanisms also explain various causes of hyperlactataemia:

Inadequate oxygen delivery (3)

• Volume depletion or profound dehydration
• Significant blood loss
• Septic shock
• Profound anaemia
• Severe hypoxaemia
• Prolonged carbon monoxide exposure
• Trauma

Disproportionate oxygen demands (3)

• Hyperthermia
• Shivering
• Seizures
• Strenuous exercise

Inadequate oxygen utilisation (3)

• Systemic inflammatory response syndrome
• Diabetes mellitus
• Total parenteral nutrition
• Thiamine deficiency
• HIV infection
• Drugs such as metformin, salicylate, antiretroviral agents, Isoniazid, Propofol, cyanide

Hyperlactataemia in critical illness (SIRS, Sepsis) is due to a combination of factors including tissue hypoxia and impaired lactate clearance.

Correlation between arterial, venous and capillary lactate.

Lavery et al confirmed good correlation in 375 patients between arterial and venous lactate levels(5). Arterial blood sampling is both more painful for patients and associated with higher rates of complications such as bleeding, haematoma, and arterio-venous fistulas. This correlation of 0.94 between arterial and venous lactate indicates no requirement for regular arterial sampling.

Lactate as a predictor of morbidity and mortality

In trauma
Abramson et al. looked at 76 consecutive poly-trauma patients admitted to ICU. Serial lactate levels were measured and lactate clearance over 48 hours recorded. Twenty seven patients in whom lactate normalised to < 2mmol/L within 24 hours all survived. If lactate levels cleared to normal between 24 and 48 hours, the survival rate was 75% (21 out of 27 patients). Only 3 patients out of the remainding 22 patients (13.6%) in whom lactate levels did not normalise by 48 hours survived.(6) Blow et al. went past the ‘golden hour’ and described a ‘silver day’ period. They prospectively studied 85 patients who presented to a Level 1 trauma center who had an Injury Severity Score (ISS) greater than 20 and underwent aggressive resuscitation to clear lactate levels to <2.5mmol/L. They found that all the patients who had their lactate levels corrected within 24 hours survived whilst 43% died if it took longer than 24 hours. The longer it took for lactate to clear, the higher the mortality and multi-system failure. (7)

In sepsis
Sharpiro et al. demonstrated that increasing lactate levels were associated with increased mortality. In 1,278 patients, lactate levels less than 2.5 mmol/L were associated with a 4.9% mortality compared to patients with lactate levels ≥ 4 mmol/L, who had a mortality of 28.4%. (8) Serial lactate measurement provides an additional guide to treatment and morbidity/mortality. Bakker et al. found that falling serial lactate levels (lower “lactimes”) were associated with improved survival.(9) Nguyen et al. looked at lactate clearance as a predictor of mortality. They demonstrated that in 111 critically ill patients, mortality was reduced by 11% for every 10% increase in lactate clearance.(10)

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Learning points

Lactate is a good screen for severe sepsis (the cause here) since it is increased by several mechanisms. Increased glycolysis but inhibition of pyruvate kinase prevents entry into Krebs cycle so production increased. Reduced hepatic blood flow limits clearance, and microvascular failure limits O2 delivery at the tissue level. Lactate levels are a simple test to measure, often available as a bedside test in most Emergency Medical departments and Intensive Care Units. There is ample evidence of its ability to predict mortality even in the normotensive and haemodynamically stable patients.

Venous lactate levels are sufficient to guide therapy and associated with less complications and discomfort in patients.

As with more tests and monitoring serial levels provide useful information rather than a single measurement. It is therefore imperative that patients admitted with high lactate levels are aggressively, and appropriately, resuscitated within the “silver day” (first 24 hours) and guide therapy using serial lactate measurements. Critical care involvement may be required as these patients may require more invasive monitoring, goal directed fluid therapy and vasopressor therapy.

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References
1. Burton DA., Stokes K., Hall GH. Physiological effects of exercise. CEACCP (2004). 4(6): 185-188.
2. Phypers B., Pierce JMT. Lactate physiology in health and disease. CEACCP (2006). 6(3): 128-132.
3. Blomkalns, Andra L. “Lactate-a marker for sepsis and trauma.” Emergency Medicine Cardiac Research and Education Group 2 (2006).
5. Lavery RF., Livingston DH., Tortella BJ., Sambol JT., Slomovitz BM., Seigel JH: The utility if venous lactate to triage injured patients in the trauma center. Journal of the American College of Surgeons (2000). 16(6):655-64.
6. Abramson D, Scalea TM, Hitchcock R, Trooskin SZ, Henry SM, Greenspan J. Lactate clearance and survival following injury. J Trauma. (1993). 35(4):584-589.
7. Blow O, Magliore L, Claridge JA, Butler K, Young JS. The golden hour and the silver day: detection and correction of occult hypoperfusion within 24 hours improves outcomes from major trauma. J Trauma. (1999). 47(5) 964-969).
8. Shapiro NI, Howell MD, Talmor D, Nathanson LA, Lisbon A, Wolfe RE, Weiss JW. Serum Lactate as a Predictor of Mortality in Emergency Department Patients with Infection. Annals of Emergency Medicine. (2005). 45(5): 524 – 528.
9. Bakker J, Gris P, Coffernils M, Kahn RJ, Vincent JL. Serial blood lactate levels can predict the development of multiple organ failure following septic shock. American Journal of Surgery. (1996). 171(2):221-226.
10.Nguyen HB1, Rivers EP, Knoblich BP, Jacobsen G, Muzzin A, Ressler JA, Tomlanovich MC. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Critical Care Medicine. (2004). 32(8):1637-42.

Editor’s note (PS): This article contained a reference from J Boldt et al which has now been retracted. The passage referring to the reference has been removed from the main text.