**2. The physiology of lactate production**

Lactate is a glycolytic product that is either used within the cells or transported through the interstitium and vasculature to adjacent and anatomically distributed cells for utilization. As such, lactate is a quantitatively important oxidizable substrate and gluconeogenetic precursor, as well as a means by which metabolism in diverse tissues is coordinated (Brooks, 2002; Stacpoole et al., 1994). Furthermore, lactate measurement in critically ill animals is practical and can provide information on illness severity and prognosis, because a high lactate level is most frequently, but not always, interpreted as resulting from anaerobic metabolism, particularly when associated with metabolic acidosis (Handy, 2006).

Lactic acid is derived from the metabolism of pyruvic acid, a reaction that is catalyzed by lactate dehydrogenase and one that involves the conversion of NADH into NAD+ (reduced and oxidized nicotine adenine dinucleotide, respectively) (Phypers, 2006). Under aerobic conditions, pyruvate is converted to acetyl CoA to enter the Kreb's cycle. Under anaerobic conditions, pyruvate is converted by lactate dehydrogenase (LDH) to lactic acid. In aqueous solutions, lactic acid dissociates almost completely to lactate and H**+**þ (Phypers, 2006). Once having been believed to be the consequence of oxygen lack in contracting skeletal muscle, it is now known that lactate is also formed and utilized continuously under fully aerobic conditions (Brooks, 2002).

Normal plasma lactate concentration is 0.3–1.3 mmol/liter (3-12 mg/dL), and normal basal lactate production is 0.8 mmol/kg/hour (1300 mmol/day) (Phypers, 2006). Normal subjects produce between 15 to 20 mmol/kg of lactic acid/day, most of which is generated either from glucose via the glycolytic pathway or from the deamination of alanine (Huckabee, 1961). Its concentration can rise to over 20 mmol/L (180 mg/dL ) during intense exertion or severe illness (Mizock & Falk, 1992).

Lactate has two chemical isomers in nature. The first, D-lactate, is produced from nonabsorbed carbohydrates by colonic bacteria (which may also proliferate in the ileum). The D isomer is mostly exogenous from Ringer's lactate solution infusion, and its non-iatrogenic presence in humans is uncommon. In the blood, it is a reflection of bacterial overgrowth in the gastrointestinal tract. Its clearance is much slower than the other chemical isomer, Llactate, with the clearance mainly depending on liver function (Uribarri et al., 1998). Llactate is the product of anaerobic glycolysis in humans and has been used as a marker of cellular hypoxia and tissue malperfusion. It can only be produced or consumed from pyruvate via the enzyme LDH in the cytosol, by means of a process of fermentation during normal metabolism and exercise (Mizock, 1989). It does not increase in concentration until the rate of lactate production exceeds the rate of lactate removal, a process which is governed by a number of factors, including monocarboxylate transporters, concentration and isoform of LDH, and oxidative capacity of the tissues.

Both the production and the removal of lactate are active functions of every tissue of the body. Tissue sources of lactate production include erythrocytes, perivenous hepatocytes, skeletal myocytes and skin. The liver is the major organ of lactate utilization, followed by the kidneys (Huckabee, 1961; Mizock, 1989). The liver removes 70% of lactate and less than 5% of lactate is renally excreted. Liver uptake involves both a monocarboxylate transporter and the less efficient process of diffusion, while renal fraction may increase and become more clinically significant during hyperlactatemia. Following the liver, skeletal muscle, brain, erythrocytes, and the renal medulla are considered to be the most important sources of lactate in the body (Phypers, 2006).
