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Lactic acidosis can be defined as a state of metabolic acidosis wherein there are clinical
signs of acidosis, with a blood lactate concentration persistently above 5 mmol/litre and an arterial pH of 7.25 or less (Albert! and Nattrass, 1977). The normal range of blood lactate varies between o.4 to 1.3 mmol/litre (Alberti, et al, 1975). Lactic acid, the end product of the anaerobic metabolism of glucose is formed by the reduction of pyruvic acid. Pyruvate is an important cross road in the intermediary metabolism. It equilibrates with lactate with a ratio of 1:10 on molar basis. The reaction is catalysed by lactate dehydrogenase requiring. NAD. Lactate is therefore an end product in glycolysis. Lactate concentration is dependent on two variables namely the concentration of pyruvate and constancy of the fraction NADH; NAD (Reduced Nicotinamide adenine dinucleotide: Nicotinamide adenine nucleotide) which in turn is dependent on the relative state of oxidation of the tissue. If the NADH: NAD ratio is kept constant, any change in lactate concentration must be due to change in pyruvate concentration and further any change which occurs should be linear i.e. Lactate: Pyruvate ratio should remain the same. Conversely if the concentration of pyruvate remains stable any change in the concentration of lactate must reflect a change in the ratio of NADH: NAD.
An absolute increase of blood pyruvate occurs with intravenous infusion of sodium
bicarbonate and after oral or intravenous administration of glucose. Under these circumstances there is concomitant linear increase in blood lactate and thus no excess lactate is produced. Lactate: Pyruvate ratio remains constant.
The oxidation state of NAD is constantly in flux depending on the effective supply of
oxygen to the tissues. Hypoxia will result in increase in reduced form of NAD and a consequent accumulation of lactate which cannot be oxidised. Increased lactate concentrations under these conditions are not associated with proportional increase in pyruvate concentration. Thus, lactate, pyruvate ratio rises and Huckabee (1961) has termed the lactate so formed as "Excess Lactate". Lactate is eliminated partly by direct oxidation and partly by conversion to glucose. In anaerobic conditions lactate is oxidised by conversion to pyruvate and subsequent oxidative decarboxylation to acetyl co-enzyme. A which is further oxidised in Kreb's cycle. Lactate is taken up by liver and kidney where gluconeogenesis occurs (Pontremoli and Grazi, (1968). Major tissues producing lactate are skin, erythrocyte, skeletal muscle, while liver and kidney are the main tissues involved in lactate clearance and utilization.
Causes of lactic acidosis
(Classification adopted from Cohen and Woods, 1976)
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Type-A
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Type-Bl Associated with other disorders |
Type-132 Drugs and Toxins |
Type-133 Hereditary forms |
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1. Cardiogenic shock
2. Endotoxic shock
3. Severe anemia
4. Left Ventricular failure
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1. Diabetes mellitus
2. Renal failure
3. Liver disease
4. Infection
5. Leukaemia
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1. Biguanides
a. Phenformin
b. Buformin
c. Metformin 2.Parenteral nutrition agents
a. Fructose
b. Sorbitol
c. Xylitol.
3. Ethanol
4. Salicylates
5. Methanol.
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1. Tvpe I Glycogen storage disease.
2. Fructose 1,6
diphosphatase deficiency
3. Leigh's Syndrome
4. Methyl malonic
acidaemia.
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NOTE : In type A lactic acidosis there is hypotension clinically evident poor tissue perfusion, leading to tissue anoxia. In type B lactic acidosis no clear evidence of tissue anoxia is present.
Cardiovascular insufficiency - shock
The occurrence of lactic acidosis in cardiogenic, haemorrhagic and septic shock is widely
recognized. Lactic acidosis occurs early during shock and may actually precede other clinically recognizable signs of the shock syndrome. The degree of hyperlactataemia during shock has been used as a prognostic sign by some investigators.
Cardiopulmonary bypass
During cardiopulmonary bypass increased lactate concentration and a mild acidosis
frequently develop due to low pump perfusion rates. Hypothermia also contributes towards increased lactate level.
Hypoxaemia
Chronic hypoxia as seen in chronic pulmonary disease with or without cyanosis is not a
cause of lactic acidosis. This is because of compensatory polycythaemia and vasodilatation with an increase in perfusion at the capillary level. Significant accumulation of lactic acid occurs only during acute severe hypoxaemia such as encountered during status asthmaticus or acute exacerbation of chronic obstructive pulmonary disease.
Severe anaemia
Severe anaemia per se does not appear to be a clinical cause of lactic acidosis. With
hemoglobin less than 6 grm. per cent a minimal but significant increase in blood lactate concentration and change in L:P ratio occurs.
Leukaemia
In acute leukaemia increased lactate level has been found. It might be due to over
production of lactic acid by the large number of leukocytes consequent to stagnant hypoxia and infiltration of the liver by leukaemic process with impaired hepatic removal of circulating lactate.
Diabetes Mellitus: Occasional occurrence of metabolic acidosis without ketonuria has
been recognized. Often when it develops these patients are in shock. It appears that in diabetes there is an impaired ability to oxidise pyruvate. However, it is not certain if such interference with pyruvate oxidation results in an increased reduction of pyruvate to lactate. Administration of insulin to the hyperglycaemic diabetic patient accelerates rate of lactate formation because of the effect of insulin on the cell membrane which makes more glucose available for metabolism. Finally, fatty acids and ketone bodies appear to have an influence on lactate production. In the experimental model fatty acids and ketones inhibit pyruvate dehydrogenase and is accompanied by increased lactate formation (Alberti and Nattrass, 1977).
Ethanol
Intermediary metabolism of ethanol involves oxidation to acetaldehyde by alcohol
dehydrogenase according to reaction:
CH3CH2OH + NAD = CH3CHO + NADH Alcohol dehydrogenase
Acetaldehyde is then further oxidised to acetic acid. The latter being converted into acetyl
co-enzyme A which in part is metabolised via the tricarboxylic acid cycle and in part incorporated in lipids. The preceding reactions take place in the extra mitochondrial portion of the cytoplasm. The NADH formed must be reoxidised by the mitochondrial flavoprotein cytochrome system which is relatively impermeable to cytoplasmic NADH. The extramitochondrial pyruvate lactate system provides an alternate pathway for oxidation of NADH. This results in increased L: P ratio due to increase in lactate and decrease in pyruvate concentration. Lactic acidosis associated with ethanol intoxication is usually short lived. Bicarbonate therapy is generally unnecessary since the arterial pH usually remains above 7.25. Spontaneous recovery is expected as the alcohol level declines and the lactate is metabolised.
Phenformin therapy and lactic acidosis :
Biguanides exert hypoglycaemic effect by three main mechanisms. They inhibit absorption
of glucose (Hollobongh, et al, 1970), aminoacids and other nutrients by the gut. They may enhance anaerobic glycolysis (Moorhouse, et al, 1958) and they inhibit gluconeogenesis from lactate, pyruvate and alanine in the liver (Williams, et al, 1958) and kidney. Clinically, the effects upon absorption and gluconeogenesis are probably the most important. Thus the hypoglycaemic effect of biguanide and hyperlactataemia are two facets of a single mechanism of action.
Looked at from the point of view of the development of lactic acidosis the increased blood
lactic acid of patients on phenformin with no coexisting disease may be unimportant since it rarely exceeds 2 mmol/1 (Nattrass et al, 1977). However, such patients must be considered. in the high risk category in that further acute unpredictable insult may cause the already impaired hepatic capacity for lactate clearance to be decreased to dangerous levels.
Phenformin is metabolished partly by the liver, but 50 per cent is excreted unchanged by
the kidney with a clearance rate of 20 ml/min (Albert! and Nattrass, 1977). In contrast, metformin is excreted in toto by the kidney with a clearance approximately to the glomerular filtration rate. Thus renal disease would be expected to potentiate the action of both biguanides while liver disease should potentiate the action of phenformin. Phenformin decreases the rate of removal of exogenously administered lactate and perhaps increases hyperlactataemia occuring after exercise. Phenformin increases the serum lactate concentration and reduces the ability of the kidney to excrete an acid load by as much as 50 per cent after a therapeutic dose (Rooth and Bandman, 1973). Lactic acidosis after suicide attempts with over dosage of phenformin in the absence of other precipitating factors is known (Davidson, et al, 1966). Study Committee on Nonketotic metabolic acidosis in diabetes mellitus (1963) reported that:
1. Lactic acidosis with excess lactate occurs in non-diabetics as well as diabetics.
2. Lactic acidosis has been found in diabetics treated with insulin, diet or phenformin
especially in those with obvious circulatory collapse.
3. Large doses of phenformin in vitro accelerates anaerobic glycolysis and increase
lactic acid and pyruvic acid and production, although diabetic patients receiving phenformin in ordinary therapeutic amounts manifest only a slight increase of lactic acid. Principles of proper management of any severely ill diabetic patient especially those with cardiac, renal, or hepatic failure dictate substitution of insulin for any oral hypoglycaemic agent. It is recommended that serum creatinine be checked prior to therapy and biguanide be given only if the levels are below 1.2 mgm per cent. The creatinine level be checked once every six months (Albert! and Nattrass, 1977). In therapeutic use ordinarily biguanides are non toxic but in special circumstances when lactate metabolism is disturbed biguanides are potentially toxic drugs (Hermann, 1973; Marble et al, 1972).
Parenteral nutritional agents and lactic acidosis
Lactic acidosis is well recognised to occur after parenteral nutrition. Large amounts of
fructose, sorbitol and xylitol are used and all of these compounds stimulate lactate formation. The rational behind their use is (1) that patients requiring parenteral nutrition are often insulin resistant and these sugars can be metabolised without insulin. (2) that they are less irritant to veins than glucose. They all, however, lead to lactate accumulation. In normal man fructose infusion cause a sharp rise in lactate concentration (Sahebjami and Scalettar, 1971) and some 35 per cent of fructose load is converted very rapidly to lactate and pyruvate by the liver. Unlike glucose, fructose is metabolised more rapidly under anaerobic than aerobic conditions so that tissue anoxia will enhance lactate formation from frustose as well as hamper clearance of the lactate. Similarly, infusion of fructose can cause catastrophic lactic acidosis in a patient with liver disease (Woods and Alberti, 1972). Sorbitol is metabolised through fructose and probably carries the same risk. Xylitol carries similar if not greater risk.
Glycogen storage disease: Type I glycogen storage disease (Glucose-6-phosphatase
deficiency) is associated with elevated blood lactate and pyruvate levels due to the inability to form glucose from glycogen. Following fasting or glucagon administration further rise in blood lactate levels may occur. Liver glycogen stores rather than muscle appear to be the source of the additional lactate during hypoglycaemia and following glucagon administration. Marked increase in lactate and severe acidosis under these circumstances may occur.
Spontaneous lactic acidosis
The syndrome of spontaneous lactic acidosis has occurred in association with a variety of
underlying infections or inflammatory conditions including acute pyelonephritis, acute peritonitis, acute pancreatitis, subacute bacterial endocarditis and poliomyelitis. The syndrome has also been recognised in noninfectious conditions like gastrointestinal haemorrhage, myocardial infarction and postoperative states.
Hyperventilation, exercise and epinephrine injection can increase blood lactate. In the
treatment of bronchial asthma if multiple subcutaneous injections are given, blood lactate levels are increased so that these patients can develop metabolic acidosis in addition to respiratory acidosis. This is probably due to epinephrine induced lactic acidosis.
Clinical picture and diagnosis of lactic acidosis
Clinical picture is indistinguishable from other forms of acidosis. The patient may manifest
Kussmaul breathing and he often shows signs of dehydration. Patient may complain of vague gastrointestinal symptoms, marked weakness, fatigue, muscular pain, hyperpnoea, and tachypnoea, followed by changed in state of consciousness. Frank coma, or stupor is more frequent when the patient is first seen. B^ood pressure is normal and there are no signs of decreased peripheral perfusion in type B lactic acidosis, while in others, circulatory failure is seen. In the absence of kidney disease the urine is strongly acidic but there is no acetonuria. An important clue to the diagnosis is furnished by the appearance of an anion gap or 'unmeasured anion'. The concentration of unmeasured anions is arbitrarily defined as the concentration of the serum sodium plus potassium minus the sum of the concentration of chloride plus the total Co2. Normally the unmeasured anion is 10 to 12 mEq/L.
In the patient with metabolic acidosis the reduction in bicarbonate concentration can
clearly be attributed either to the accumulation of hydrogen with chloride or to a loss of bicarbonate. With spectrum thus narrowed, it should again be relatively easy to identify the underlying disorder. A history of diarrhoea or of the ingestion of an acidifying agent such as ammonium chloride or acetazolamide will often clarify the problem. The finding of a relatively alkaline urine and of nephrocalcinosis on roentgenographic examination of the abdomen will strongly suggest the diagnosis of renal tubular acidosis.
In some patients, of course, several causes of metabolic acidosis may be present
simultaneously and this possibility should not be overlooked. If, for example the disappearance of ketonaemia during treatment of diabetic acidosis is not accompanied by restoration of a normal plasma bicarbonate concentration, the presence of a co-existent disorder such as lactic acidosis should be suspected.
Causes of metabolic acidosis
With increase in unmeasured unions.
1. Diabetic ketoacidosis.
2. Salicylate poisoning.
3. Ethylene glycol poisoning.
4. Methyl alcohol poisoning.
5. Paradehyle (rarely).
6. Lactic acidosis.
7. Renal failure.
Without increase in unmeasured unions.
1. Diarrhoea.
2. Drainage of pancreatic juice.
3. Ureterosigmoidostomy.
4. Ammonium chloride.
5. Carbonic anhydrase inhibiior.
6. Renal tubular acidosis.
In great majority of cases of lactic acidosis(f3eeson and Me dermott, (1971), the level of
lactic acid in blood exceeds 7 mEq/L. Care should be taken during venous blood collection and blood to be drawn without excessive or prolonged tourniquest pressure and that the specimen be sent to the laboratory for prompt analysis.
Management of lactic acidosis
The basic therapeutic aims in lactic acidosis are to eliminate the source of lactate over
production, to correct the acidosis with alkalinizing solution and to remove the existing lactate by pharmacologic or mechanical means.
Maintaining an adequate cardiac output
In a severe lactic acidosis careful assessment of patient's :ardiovascular status is to be
made. Maintenance of an adequate cardiac output and peripheral perfusion is basic to the treatment of ictic acidosis of any cause. The cardiovascular effects of severe kidosis are two fold. Firstly the force of ventricular contraction is Impressed and also it decreases the responsiveness of peripheral /asculature and the heart to endogenously produced or exogenously administered catecholamines. In the clinical setting of irreversible shock in which a number of processes are operable, acidosis is an important contributing factor. Thus it is apparent that regardless whether shock precedes of follows acidosis, both must be treated to achieve a stable circulatory status. The proper use of volume replacement, vasopressor, central venous pressure monitoring and ionotropic agents in the treatment of shock is essential because of the vasoconsrictive and lactate stimulating properties of epinephrine and norepinephrine. These drugs might better be avoided in the subject with lactic acidosis. The use of isoproternol with its vasodilatory and positive ionotropic properties seems to be more suitable under these circumstances.
Alkalinizing Therapy: The administration of lactate solutions as an alkalinizing agent in
the therapy of lactic acidosis is contra-indicated. Alkalinizing effect of lactate depends upon its oxidation to carbondioxide and water and subsequent generation of bicarbonate. In lactic acidosis lactate oxidation is impaired and exogenously administered lactate is not metabolised. Sodium bicarbonate is the agent of choice in the treatment of lactic acidosis. The quantity necessary to correct the acidosis may be roughly calculated by multiplying the bicarbonate deficit in milliquivalent per litre by a factor of 50 per cent of total body weight in kilograms. (25 mEq per litre observed plasma bicarbonate concentration X 0.5 body weight in Kg = mEq of alkaline solution). This factor takes into account the well known shift or neutralization by intracellular buffers of approximately 1/4 to 1/3 of an administered bicarbonate load from the extracellular space during therapy.
Use of tham
Tris hydroxy methyl aminomethane (THAM) which is used in lactic acidosis although
effective, does not seem to have any advantage over sodium bicarbonate except perhaps in patients with congestive cardiac failure where sodium load cannot be tolerated. THAM has effective intracellular alkalinizing property than sodium bicarbonate.
Methylene blue
The redox dye methylene blue was initially considered for the treatment of lactic acidosis
because of its ability to function as hydrogen ion aceptor-donor. This might be of value, it was reasoned since the situation at least in theory in most forms of lactic acidosis is one of an increased NADH: NAD ratio due to an inability to forma exidized NAD. The addition of methylene blue allows following reaction to take place.
Methylene blue + NADH = Methylene blue H + NAD. The NAD so formed is then available
to oxidize lactate to pyruvate. Following a single intravenous injection of 1 to 5 mg. per kg. of methylene blue maximal effects are achieved within 2 to 6 hours with duration of action upto 14 hours.
Peritoneal and hemodialysis
Since standard peritoneal dialysis solution contains higher concentration of lactate (40
mEq per litre) than blood, in most patients with lactic acidosis, dialysis would not be expected to result in removal of lactate. Haemodialysis, however, has the potential to remove lactate.
Use of insulin and glucose in treatment of lactic acidosis
As lactic acid is a terminal product of glycolysis it is a "dead end metabolite" and can be
metabolised only by reconversion to pyruvate. The remarkable effect of insulin and glucose in the treatment of lactic acidosis was first described by Johnson and Waterhouse (1968). This treatment is supposed to relieve the blockade of pyruvic acid metabolism. Insulin activates pyruvate dehydrogenase and thus enhances lactate clearance (Dembo et al, 1975). Treatment with 50 ml. 50 per cent glucose and 15 to 201.U., soluble insulin every 4 hours should be attempted in every case of lactic acidosis. Concommitantly bicarbonate therapy should be administered. This treatment seems to correct the acidosis as well as to correct the abnormal glucose metabolism. The side effects like hypokalaemia and hypoglycaemia are easy to diagnose and control (Aernlund Jensen, 1973). Insulin and glucose are certainly reasonable if the patient is diabetic, particularly since the patients with phenoformin lactic acidosis nearly always have substantial ketone body contribution to their acidaemia (Fulop and Hoberman, cited by Alberti and Nattrass, 1977).
Dichloroacetate is an agent which specifically activates pyruvate dehydrogenase, it has mild hypoglycaemic effect and causes decrease in blood lactate concentration in normal and diabetic animal and man (Blackshear et al, 1975). Whether it will have beneficial effect on type B lactic acidosis in man remains to be seen.
Summary
A brief description of lactate metabolism alongwith conditions causing hyperiactataemia
and lactic acidosis are described. Relationship between diabetes, phenformin therapy and lactic acidosis is reviewed. Management of lactic acidosis is outlined.
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