Lactic acid isa strong acid which dissociates quantitatively and at physiological pH is almost completely ionised to lactate and hydrogen ions (H⁺). The increased concentration of lactate in the blood is called hyperlactataemia and it may indicate the presence of metabolic acidosis (pH inferior to 7.35). Acidosis does not occur when H⁺ions are buffered by the bases present in the blood, when compensation is able to correct the acid-base imbalance or when there is a simultaneous respiratory alkalosis (mixed disorder).
PATHOPHYSIOLOGY
The lactate ion, producedin large quantities during lactic acidosis, may result from anaerobic glycolysis (type A lactic acidosis) or from a biochemical alteration of glycolysis (type B lactic acidosis). The pathophysiology of type A and type B acidosis issimilar; in both cases the increase in blood lactate derives from a reduction of the redox potential (caused by a deficit of aerobic metabolism).
The causes of an hypoxic type A lactic acidosis are: a decrease in tissue perfusion, shock, gastric wall necrosis, abdominal visceral ischaemia, aortic thromboembolism, severe hypoxaemia, severe anaemia (haematocrit < 15%), intense muscle activity, seizures, tremors, cardiac arrest, reduction of cardiac contraction, acute pulmonary oedema, decreased partial pressure of arterial oxygen and hypoxaemia.
The causes of type B lactic acidosis are:
- B1-syndromes: diabetes mellitus, hepatic failure, renal failure, malignant tumours (e.g. lymphoma), sepsis, pheochromocytoma and thiamine deficiency;
- B2-intoxications: paracetamol, salicylates, cyanides, epinephrine, ethanol, ethylene glycol, insulin, methanol, morphine, nitroprusside and terbutaline
- B3-mitocondrial (congenital) myopathy: alkalosis, hyperventilation and hypocalcaemia.
The most frequent causes of hyperlactataemia in our patients are hypoperfusion and hypoxia. Liver and renal functionimpairment, which may occur in decompensated shock, reduces the capability of these organs to convert lactate into pyruvate, aggravating its already increased production. The administration of epinephrine and norepinephrine can increase lactic acidosis due to the stimulation of glycolysis and excessive vasoconstriction, which may exacerbate the already compromised perfusion. During sepsis and septic shock, in addition to an insufficient perfusion caused by excessive vasodilatation (hypovolaemia), there is also an increased energy demand by the body that can aggravate lactic acidosis due to an increase in anaerobic glycolysis. When sepsis occurs, type A and type B hyperlactataemia often coexist, even when oxygenation has returned to normal values; this phenomenon is due to an altered mitochondrial function, which limits the production of ATP and NADH favouring the production of NAD, and to an increased production of pyruvate. Sufficient amounts of NADH are only produced under aerobiotic conditions. NADH is necessary to convert pyruvate into lactate according to the following formula:
CH3COCOO- + NADH + H+ ↔ CH3CHOHCOO- + NAD++ H+ Formula No. 1
Pyruvate Lactate
The direction of theformula depends on the quantity of NADH available; the higher the quantity, the greater the production of pyruvate which enters the Krebs cycle producing energy. Pyruvate, unlike lactate, is able to enter the Krebs cycle, which allows it to generate a significantly greater quantity of adenosine triphosphate (ATP). Under conditions of aerobiosis, NADH is oxidised to NAD⁺at mitochondrial levelandlactate is converted into pyruvate; the latter is transported into the mitochondria, combined with acetyl coenzyme A (CoA) and it is used by the Krebs cycle to produce energy or it is converted into oxaloacetate and then used for gluconeogenesis in the liver and in the renal cortex.
Under anaerobic conditionsthe mitochondrial oxidative pathway is altered, producing an accumulation of NAD⁺andlactate in the cellular cytosol. The lactate produced by the anaerobic metabolism cannot be reoxidised to pyruvate, therefore, when there is a deficit of perfusion associated with a deficiency of oxygen the concentration of lactate increases compared to that of pyruvate.
An increase in cellular lactate causes an increase in the lactate present in the interstitial space and, therefore, in the blood lactate. The greater the quantity of lactate produced, the greater the quantity of H⁺ions present in the blood responsible for lactic acidosis. Lactate in itself is not responsible for acidosis, but is simply a marker of the increased H⁺ions.
The increase in lactate levels indicates the presence of a protective response by the organism, in the attempt to produce energy notwithstanding the oxygen demand is not being satisfied (Fig. 1). Anaerobic glycolysis is an alternative metabolic pathway to aerobic glycolysis and, even if it produces a reduced amount of energy, it is still able to produce ATP and is, therefore, a final attempt to preserve life in the presence of severe tissue hypoxia. Thecapabilities of the body to buffer lactic acidosis depend on the amount of available bases. Under normal conditions of perfusion and oxygenation, the lactate produced is converted into pyruvate, oxidised and then used in the liver and kidney gluconeogenesis by consuming H⁺ionsand by producing carbon dioxide which is buffered or eliminated through ventilation.
During aerobic glycolysis, from 1 mole of glucose 36 moles of ATP are produced, while anaerobic glycolysis produces only 2 moles of ATP (Fig. 1).
Under anaerobic conditions there is therefore a drastic reduction in the production of ATP, which, in turn, stimulates anaerobic glycolysis increasing the production of lactate. Generally, a blood lactate greater than 5 mmol/L is associated with acidaemia; in order to achieve acidosis and hyperlactataemia the production of lactates should exceed their clearance, thus determining an increased concentration of lactates in the blood.
The blood sample forthe measurement of lactate may be taken from a vein (peripheral or central) or from an artery; the lactate concentration in the samples taken from the cephalic vein is slightly greater than that coming from the jugular vein or the femoral artery. The measurement is carried out using instruments dedicated to the assessment of this parameter or with blood gas analysers equipped with the proper measurement tools. Normal values in adult dogs should not exceed 2.5 mmol/L. In paediatric patients the concentration of lactate is higher: 1.1-6.6 mmol/L; from the 10th to the 28th day of life values decrease gradually to 0.8-4.6 mmol/L, from the 70th day the concentration is similar to that of the adult animal. In the adult cat values are close to those of the dog. After a deficit inperfusion and oxygenation or after intense muscle work values ten times higher than the maximum can be found, without necessarily being indicative of a permanent injury.
The prognosis is adverse when lactate concentration, despite the therapies, is not restored within 1-3 hours; if in the following 24-48 hours values remain high, the prognosis is confirmed. The cause is usually attributed to insufficient oxygenation and perfusion, which inhibit the mitochondrial oxidative metabolism (reduction of the redox potential caused by decreased NADH).
Thelactate produced by viscera like the stomach and the intestine is discharged into the bloodstream, and when these organs are subjected to ischemia or to a lack of perfusion and oxygenation they can cause an increase in blood lactate. The severity of lesions is responsible for a proportional increase in the concentration of lactate; however, not always do severe lesions produce high lactataemia because the concentration of lactate in the blood is influenced by its clearance.
Atypical example of the use of blood lactate is provided bygastric dilatation and volvulus syndrome (GDV). In the course of this condition it is not uncommon to see blood lactate values higher than 6-9 mmol/L; such high values have a less favourable prognosis (due to necrosis of the gastric wall and to the deficit in organ perfusion). In veterinary medicine lactataemia has been used in critically ill patients as a prognostic factor and to estimate the degree of metabolic alterations during feline aortic thromboembolism, in intensive care and in horses with acute gastrointestinal syndromes. Also in human medicine serial measurements of blood lactate are used as a prognostic factor.
Skin, red blood cells, skeletal muscles, stomach and intestines are the greatest producers of lactate; clearance occurs mainly in the liver and the kidneys, which use lactates for gluconeogenesis or oxidation. Lactic acidosis occurs when the lactates produced by muscles, but especially by the viscera, such as the stomach and intestines, exceed liver and kidney metabolisation and are then discharged into the bloodstream. Severe lactatemia also damages and reduces the intake of lactates by the liver which, in severe forms, cannot metabolise lactate, but can manage to produce it. Nevertheless, the clinical use of blood lactate is controversial because in cases of mild hypoperfusion, the body, in any case, manages to compensate (e.g. increased capability to extract oxygen from the blood and vasoconstriction) and to satisfy oxygen demand without increasing lactataemia; only when the body is no longer able to compensate are high levels of lactate detected, which occurs in the presence of severe perfusion and oxygenation deficit.
TREATMENT
The most common forms of hyperlactataemia, being type A forms, can be treated by restoring oxygen delivery (DO₂). DO2 depends on cardiac output and on the total content of oxygen (CaO₂), as shown by the formula:
DO2 = CaO2 x CO Formula No. 2
The total content ofarterial oxygen depends mainly on the amount of oxygen bound to haemoglobin as indicated in formula No. 3.
CaO2 = (1.34 x Hb x SaO2) + (0.03 x PaO2) Formula No. 3
(Hb: haemoglobin; SaO2: saturation of haemoglobin; PaO2: partial pressure of arterial oxygen)
CaO2 measures all the oxygen available for the cell, not only the one dissolved in blood based on the pressure gradient. Observing formula No. 3 it is clear to which extent oxygen depends on the fraction bound to haemoglobin (about 90%). Although the oxygen dissolved in the blood by the pressure gradient (PaO₂) is only a small fraction of CaO₂, its reduction in a critically ill and anaemic or hypoxaemic patient can make the difference between life and death; for this reason, in critically ill patients, oxygen is administered in the attempt to increase PaO₂.
The second component ofDO2 (see formula No. 2) depends on CO, which is measured by multiplying the ventricular ejection volume (SV) by the heart rate (HR), as indicated in formula No. 4. In hypovolaemic patients SV is improved with an intravenous fluid resuscitation therapy; in fact, the measurement of CO is carried out using the following formula:
CO = SV x HR Formula No. 4
When the therapy is able to restore DO₂, lactataemia (if type A) returns to normal values within 1-3 hours. In our patients being DO₂ difficult to measure, as it requires the implant of a pulmonary catheter and to perform a thermodilution to calculate CO, blood lactate is used as a surrogate objective parameter of DO₂,and as an objective parameter of perfusion. The serial evaluation (every 1-3 hours) of blood lactate concentrations in critically ill patients is an easy method to perform, it requires small venous or arterial blood samples (10 microlitres), it is not an invasive assay, it is not expensive and it allows to quantify oxygenation and perfusion; it is also useful for evaluating the effectiveness of the adopted therapies and to obtain a prognostic indication.
Suggested readings
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