5Lactic acidosis: Current concepts

5Lactic acidosis: Current concepts

5 Lactic Acidosis: Current Concepts ROBERT PARK A L L E N I. A R I E F F Since Huckabee's description of lactic acidosis (1961), this entity has beco...

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5 Lactic Acidosis: Current Concepts ROBERT PARK A L L E N I. A R I E F F

Since Huckabee's description of lactic acidosis (1961), this entity has become widely recognized in a variety of clinical settings and now constitutes one of the more common causes of metabolic acidosis. In the past decade, a number of important developments have contributed to our present state o f knowledge with regard to its pathogenesis and treatment, especially in the area of Type A or hypoxic lactic acidosis. These advances have helped to explain certain enigmatic features of this disease such as its excessively high mortality. The purpose of this review is to update these important developments in particular areas of pathogenesis, pathophysiology and treatment. The reader is also referred to other recent reviews which may emphasize in more detail those areas not adequately covered by this monograph (Huckabee, 1961; Relman, 1978a; Park and Arieff, 1980). L A C T A T E HOMEOSTASIS A brief review of normal lactate homeostatis will help provide the reader with sufficient background to appreciate better the subsequent areas of discussion. The concentration o f lactate in the extracellular fluid is normally about 1 mM, and it is usually maintained at this level despite the relatively high rates of concomitant production and utilization by various tissues. The daily flux of lactate is estimated to be 18 -22 m M / k g / d a y , so that approximately 1200-1500 mmol of lactic acid are concomitantly produced and consumed each day by the average 70 kg man (Kreisberg, 1972). Lactic acid is formed from pyruvate as the end-product o f anaerobic glycolysis. Most tissues in the body are capable of producing lactate, but most of it comes from those tissues which are characterized by high rates of glycolysis (Figure 1), such as skeletal muscle, gut, brain, skin and red cells. The rates of lactate production by various tissues as shown in Figure 1 are an estimate under basal conditions. During certain situations (e.g. skeletal muscle during strenuous exercise) these rates may increase dramatically to levels perhaps tenfold greater than basal. Despite the relatively high rate at which lactate can be produced and secreted into the extracellular fluid, Clinics in Endocrinology and M e t a b o l i s m - Vol. 12, No. 2, July 1983 0300-595X/83/12.02/339 [email protected]. B. Saunders Company Ltd




blood levels normally remain fairly constant because of concomitant reutilization of lactate by gluconeogenic tissues such as the liver and kidney. Via the process of gluconeogenesis, more than half of the lactate taken up is resynthesized into glucose which provides a continuing source of this fuel to glycolytic tissues. Most of the remaining lactate is metabolized in the Krebs cycle to carbon dioxide and water. This cyclical pattern of normal lactate metabolism, or the Cori cycle, not only provides an ongoing source of glucose but also plays an important role in systemic acid-base balance by consuming the H + ion which was produced during lactic acid formation. Regardless of the metabolic fate o f lactate (i.e. gluconeogenesis or complete oxidation), protons are consumed with lactate in an equimolar fashion so that acid-base balance is achieved under normal circumstances. Thus the Cori cycle also produces and consumes on a daily basis about 1200-1500 mmol of H + in addition to lactate. Glucose


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Figure 1. The Cori cycle. Tissues with active glycolysis (skin, skeletal muscle, red cells, brain and intestine) metabolize glucose to lactic acid which is released into the extracellular fluid at the basal rate of about 1300 mmol/day in the average 70 kg man. The normal blood level of lactate (1 raM) is maintained by the concomitant metabolism of the daily lactate load to glucose via gluconeogenesis by the liver and kidney. From Park and Arieff (1980), with kind permission of the authors and the editor of Advances in Internal Medicine.

At a cellular level, the production of lactic acid from glucose occurs via anaerobic glycolysis. The activity of this pathway, which determines the rate at which glucose is metabolized to lactate, is regulated in three discrete enzymatic steps (Figure 2). Glycolytic tissues such as skeletal muscle, gut, etc. in general possess greater amounts of these enzymes, and this accounts for the net flux from glucose to lactate. In order to be reutilized as an endproduct of metabolism by gluconeogenic tissues, lactate must first be converted back to pyruvate. Unlike lactate, however, pyruvate is an important intermediate and has the availability of several important metabolic pathways including gluconeogenesis, oxidation and transamination with alanine (Figure 2). Since gluconeogenesis is the major route o f lactate metabolism by the liver and kidney, the regulation of gluconeo-



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I Oxidation ATP+CO2+H20 Figure 2. The Metabolic pathways available to lactate. Glycolytic tissues preferentially metabolize glucose by the pathways shown to pyruvate, lactate and alanine which are then released as precursors for gluconeogenesis. Gluconeogenic tissues (liver and kidney) preferentially metabolize lactate, pyruvate and alanine to glucose. Within the liver, about two-thirds of the lactate is converted to glucose, and about one-third is oxidized via the Krebs' cycle. The activity of gluconeogenesis is largely controlled at four key enzymatic steps: pyruvate carboxylase, phosphoeneolpyruvate carboxykinase, fructose diphosphatase and glucose-6-phosphatase (not shown). From Park and Arieff (1980), with kind permission of the editor of Advances in Internal Medicine.

genesis has a major impact on the overall control of lactate levels in blood. As will be discussed, recent experimental studies suggest that apparent defects in lactate disposal by the liver may play an important role in the pathogenesis of lactic acidosis. Gluconeogenesis is a metabolic pathway which is highly regulated at certain enzymatic control points. These key enzymes include pyruvate carboxylase, phosphenolpyruvate carboxykinase, fructose diphosphatase, and glucose-6-phosphatase. The rate at which lactate is metabolized to glucose by the gluconeogenic pathway is largely determined by the activities of these rate-limiting enzymes. The formation o f lactate from pyruvate is catalysed by the enzyme lactic dehydrogenase (LDH), as shown Pyruvate + NADH" + H +

LDH ~ lactate + NAD


This reaction is almost always at equilibrium so that in blood the concentration of lactate is usually about ten times greater than pyruvate. By rearranging equation 1 Lactate = pyruvate × Keq

(NADH) (H +) (NAD)


Expressed in this manner, it becomes easier to visualize that the concentration of lactate is dependent on the pyruvate concentration, the cytosolic



pyridine nucleotide redox state ( N A D H / N A D ) , and the intracellular concentration of H ÷, or pHi. Within cells, each of these variables modulate the concentration of lactate. To the extent that they influence the activation of glycolysis and gluconeogenesis, these variables may also influence the rate of lactate flux, and hence the respective rates of production (glycolysis) a n d / o r utilization (gluconeogenesis). C L I N I C A L FEATURES Because of the rapid expansion in the recognition o f lactic acidosis, Huckabee's original classification has been modified by Cohen and Woods (1976) into two basic types. Type A lactic acidosis refers to those cases which are clearly due to poor tissue perfusion or hypoxic states such as cardiogenic shock. This form probably occurs most often, and in several studies the mortality rate appears to be related directly to the severity of the hyperlactataemia (Peretz et al, 1965; Mattar et al, 1974). Type B is subdivided into three subtypes. Type B1 includes those cases which have been known to occur in association with other systemic disorders such as diabetes, liver and renal failure, pancreatitis, infection and leukaemia. Such disorders apparently predispose patients to the development of lactic acidosis, but in a manner which is unclear. Type B2 are cases secondary to drugs or toxins, such as phenformin and other biguanides, fructose and methanol. In the United States, phenformin was withdrawn from routine use in the treatment of diabetes because of the risk of developing lactic acidosis. This decision by the FDA was controversial (Kolata, 1979) but similar considerations have been entertained in the United Kingdom as well (Nattrass and Aberti, 1978). Of all the biguanides, phenformin has been the most commonly used, but other biguanide derivatives such as metformin and buformin are widely available in Europe. Data suggest that these other biguanides may not carry the same risk of developing lactic acidosis as phenformin, and this may warrant the continued use of metformin a n d possibly buformin in certain selected patients. Certain recognition of lactic acidosis is frequently made because of the classical hallmarks of metabolic acidosis. Kussmaul hyperventilation, an alteration in consciousness and rapid onset of acidosis in a predisposed patient should quickly alert the physician. The acidosis is of the anion gap variety, and most other causes of anion gap acidosis can be readily excluded, such as diabetic ketoacidosis, uraemic acidosis, and ingestion of methanol, ethylene glycol, or salicylates. Measurement of the lactate levels (usually greater than 5 mM in arterial blood) will confirm the diagnosis, and the lactate should account for most, but not all, o f the anion gap. The ratio of lactate/pyruvate is usually elevated in all forms of lactic acidosis, and the blood bicarbonate is variably titrated to levels of 10 mEq/1 or less. Other electrolyte abnormalities such as hyperkalaemia and hyperphosphataemia (Oliva, 1970; Park and Arieff, 1980) may be present with other laboratory abnormalities associated with concomitant predisposing illnesses. Initial evidence of tissue hypoxia or decreased perfusion characterizes the Type A variety, whereas these signs may occur later on in the various forms of Type B lactic acidosis.



PATHOPHYSIOLOGY Conceptually, lactic acidosis occurs from either excess lactate production (by glycolytic tissues), inadequate utilization (by gluconeogenic tissues), or varying combinations of the two processes. This rather simple concept has been substantiated by recent experimental evidence from several laboratories. Workers in this area have demonstrated that inadequate lactate utilization by peripheral gluconeogenic tissues, liver in particular, plays a much more contributory role in the development of lactic acidosis than previously appreciated. These important developments have therapeutic implications because current therapy in general is still supportive treatment with removal of known predisposing conditions. Identification of specific pathophysiological mechanisms can lead to more definitive forms of treatment for this generally fatal disorder.

Type A (Hypoxic) Lactic Acidosis There has been little research done on the pathogenesis of hypoxic (Type A) lactic acidosis. Preliminary observations from our laboratory in an animal model of hypoxic lactic acidosis (PO2 = 30 mmHg, lactate = 9 raM) suggest the heterogeneous nature of lactic acidosis (Arieff, Leach and Park, 1982a). Common clinical dogma suggests that most lactate is produced from skeletal muscle. However, while much lactate is produced by muscle, the bulk (over 50 per cent) is produced by the gut. The ability of the liver to extract lactate is markedly diminished, concomitant with a decrease in hepatocellular pH. Despite arterial pH of 7.10, cardiac output is actually increased by about 40 per cent, compared with a substantial decrement of cardiac output in other forms of experimental lactic acidosis (see Figure 6).

Type B2-Phenformin-Associated Lactic Acidosis Phenformin-associated lactic acidosis has been commonly reported (Misbin, 1977; Luft, Schmulling, and Eggstein, 1978). Several mechanisms have been proposed for the mechanism of biguanide-induced lactic acidosis, including impaired hepatic gluconeogenesis (Altschuld and Kruger, 1968; Lloyd et al, 1975) and inhibition of mitochondrial'respiration (Davidoff, 1968). Recent experimental studies in this area have advanced our understanding considerably. To place these developments in perspective, it should be emphasized that the liver normally ha's a large capacity to metabolize lactate. This capacity may exceed by two to four times the daily quantity of lactate produced by all tissues, and it has thus been suggested that there must be some degree of hepatic impairment in order to develop most forms of lactic acidosis (Berry and Scheuer, 1967). The role of inadequate liver blood flow or hepatic hypoxia impairing lactate utilization by the liver has been noted by previous workers (Berry and Scheuer, 1967; Tashkin, Goldstein, and Simmons, 1972). In addition to these factors, the role of decreased liver pHi as a result of phenformin therapy has been examined. Experimental studies by Lloyd and colleagues



(1975) have shown that phenformin lowers liver pHi to values less than 7.0, causing inhibition of gluconeogenesis from lactate. These workers suggested that reduction of liver pH~ probably lowers the activity of the ratelimiting enzyme, pyruvate carboxylase, the first enzyme in the pathway of lactate gluconeogenesis. In this manner, lactate consumption would be impaired leading to hyperlactataemia and acidosis. Data from our laboratory (Arieff et al, 1980) confirmed this effect of phenformin. In diabetic dogs with experimental phenformin-induced lactic acidosis there was a significant fall in liver pH~ to values of about 6.8. A substantial decrease in hepatic lactate extraction occurred, despite a significant increase in the lactate load actually presented to the liver (see Figure 5). Unlike Lloyd's studies, our animals did not demonstrate net hepatic lactate production during acidosis, but both studies suggest that decreased liver pH~ may be an important biochemical factor which serves to impair the normal function of the liver in the Cori cycle. Since the human liver normally removes approximately 30-35 mmol/h of lactate and H +, significant impairment of hepatic lactate uptake would lead quickly to the accumulation of lactic acid in the extracellular fluid. In addition to decreasing lactate utilization by the liver, phenformin can increase lactate production by gut tissue. In these same studies, there was almost a doubling of gut lactate production (Arieff et al, 1980; Figure 3) as a result of phenformin infusion. Other pathophysiological mechanisms which may have contributed to the development of lactic acidosis in these animals include an impairment in cardiac contractility and consequent decrease in systemic perfusion. LACTIC ACIDOSIS AND THE CARDIOVASCULAR SYSTEM In Type A lactic acidosis, there is evidence for tissue hypoxia or hypoperfusion, whereas in Type B lactic acidosis, there is no obvious evidence for tissue hypoxia or hypoperfusion. It is not generally appreciated, but a majority of patients with Type B lactic acidosis have clinical evidence of cardiovascular collapse, at the time treatment for lactic acidosis is begun. Among patients with phenformin-associated lactic acidosis, 66 per cent of 140 individuals evaluated had tachycardia, clinical evidence of peripheral vasoconstriction and systolic blood pressure below 100 mm Hg. In patients with other forms of Type B lactic acidosis, clinical shock is common (Peretz et al, 1965; Tranquada, Grant, and Peterson, 1966; Luft, Schmulling, and Eggstein, 1978) and may actually precede the onset of hyperlactataemia. Among patients with any form of lactic acidosis, recovery is uncommon when systolic blood pressure is below 100 mmHg at the time treatment is begun (Luft, Schmulling, and Eggstein, 1978). It is known that cardiovascular collapse can lead to Type A lactic acidosis, but it is not clear whether Type B lactic acidosis is associated with impaired cardiac performance (Assan et al, 1975). It is possible that in some forms of Type B lactic acidosis there are primary effects on the heart, and some of the commonly observed systemic manifestations, such as hyperlactataemia, metabolic acidosis and shock, are secondary.



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Figure 3. Extrahepatic splanchnic lactate production and liver lactate uptake are shown in four groups of dogs. In dogs with lactic acidosis, there were significant decrements of both lactate production and uptake of lactate by the liver (P < 0.01). Liver lactate uptake was unaffected by treatment with either NaC1 or NaHCO~. However, treatment with NaHCO~ resulted in a highly significant increase in both extrahepatic and net splanchnic lactate production (P < 0.01), whereas treatment with NaCI did not. Liver lactate uptake does not include contribution of hepatic artery. From Arieff et al (1982b), with kind permission of the authors and the editor of American Journal of Physiology.

Clinically, specific studies where cardiac function in patients with Type B lactic acidosis was evaluated are lacking. However, available evidence suggests that impairment of myocardial function may develop in patients with Type B lactic acidosis. Tranquada, Grant and Peterson (1966) described 46 diabetic patients with lactic acidosis of whom 25 were in shock: none of the 25 survived. Among 36 patients with phenformin-related lactic acidosis 21 were in "shock and 20 died (Assan et al, 1975; Fulop and Hoberma, 1976). Overall, it appears that about 90 per cent of the patients with phenformin-related lactic acidosis may present with shock. Thus, over 70 per cent of the patients with Type B lactic acidosis are in shock when initially diagnosed and their mortality exceeds 90 per cent. The available clinical evidence, therefore, supports the concept that the heart may be primarily affected in some forms of Type B lactic acidosis (Tranquada, Grant and Peterson, 1966; Fulop et al, 1973; Assan et al, 1975; Dembo, Marliss and Halperin, 1975).



In our laboratory, we have evaluated effects on cardiac function in three different animal models o f Type B acidosis. These models are phenformin lactic acidosis, hepatectomy lactic acidosis and lactic acid infusion. The techniques for producing the animal models have already been described (Arieff et al, 1980; Arieff et al, 1983). It was found that when dogs were infused with phenformin for 99 minutes, the mean arterial pressure was no different from control values, but there was significant deterioration o f cardiovascular function as shown in Figure 4. The cardiac output fell by 30 per cent, with a modest increase in heart rate and the peak positive d P / d t fell by 30 per cent. However, despite the marked deterioration of cardiac function after 99 minutes of phenformin infusion, mean systemic arterial pressure was unchanged and there was no biochemical evidence of lactic acidosis. The arterial p H was 7.31 (control = 7.35), bicarbonate was 17.2 mEq/1 (control = 19.6 mEq/1) and lactate was 2.5 mmol/1 (control = 2.0 mmol/1). In addition, there was no change in the arterial oxygen tension, but the myocardial extraction o f oxygen was reduced f r o m 72 to 58 per cent. Thus, even in the face o f normal arterial pH, bicarbonate, lactate concentration, and pO2, as well as a normal systemic arterial pressure, there was a significant decrement of both myocardial function and myocardial extraction of oxygen. Along with the








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Figure 4. The effects of 99 minutes of phenformin infusion on several indices of cardiac function and systemic acid-base balance. The arterial concentrations of bicarbonate, H + ion and lactate are normal, as are the heart rate and mean arterial pressure. At the same time, there are significant decrements in cardiac output, peak positive d P / d t and myocardial lactate extraction, and a 300 per cent increase in left ventricular end diastolic pressure (LVEDP). All values are shown as a per cent of the control value, with normal = 100%, *P < 0.01. The actual values for these indices are given in the text. From Arieff et al (1983), with kind • pei'mission of the authors and the editor of Clinical Science.



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Figure 5. The effect on cardiac output, glomerular filtration rate (GFR) and hepatic portal vein (HPV) blood flow of phenformin infusion for 99 minutes. There are significant (P < 0.01) decrements in all three indices, although systemicarterial pressure is normal. From Arieff et al (1983), with kind permission of the authors and the editor of Clinical Science.

decrease in cardiac output, there were also significant decrements in both GFR and hepatic portal vein (HPV) blood flow, as shown in Figure 5. There was also marked deterioration of the ECG (Arieff et al, 1983). To determine if the observed E C G changes and alterations in cardiac performance could be due to either metabolic acidosis per se or a direct effect of phenformin on the heart, studies were also carried out in two additional groups of dogs. In animals who had been subjected to functional hepatectomy, the blood lactate was 6.0 mmol/1 and arterial p H was 7.20 after two hours. In these dogs, the cardiac output was 20 per cent below the control value. After three hours of hepatectomy, blood lactate was 10.7 mmol/1 and arterial p H was 7.13. In these animals, cardiac output was reduced by over 50 per cent. Thus, when lactic acidosis was associated with hepatectomy, cardiac output was still significantly decreased when arterial pH and lactate were similar to those associated with phenformin infusion (Figure 6). In another study, dogs were infused with lactic acid for periods o f up to three hours. After two hours of infusion, arterial pH was 7.20, lactate was 6.8 mmol/1 and the cardiac output was normal. After three hours o f lactic acid infusion, arterial p H was 7.17 and blood lactate was 5.6 mmol/l. Cardiac output in these animals was still not different from control (Figure 6) and the ECG was unaltered. Thus, three hours of hyperlactataemia and metabolic acidosis had no effect on cardiac output, while Type B lactic acidosis, whether due to phenformin or hepatectomy, was associated with a decrease in cardiac output (Figure 6).



P r e l i m i n a r y studies h a v e also b e e n c a r r i e d o u t in dogs with T y p e A h y p o x i c lactic acidosis (arterial pO2 = 30 m m H g , arterial p H = 7.08, b l o o d l a c t a t e = 9 m M ) . In these studies, it was f o u n d t h a t despite the severe m e t a b o l i c acidosis, c a r d i a c o u t p u t a c t u a l l y rose to a b o u t 40 p e r cent a b o v e the c o n t r o l value ( A r i e f f , Leach, a n d P a r k , 1982a). T h e studies cited a b o v e serve to e m p h a s i z e the h e t e r o g e n e o u s n a t u r e o f lactic acidosis.

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Figure 6. Metabolic acidosis and hyperlactataemia were achieved by three different methods, and the effect on cardiac output was studied. The arterial pH and blood lactate levels were not significantly different among the three groups after both 100 and 180 minutes. Lactic acid infusion had no effect on cardiac output over three hours. With either hepatectomy or phenformin infusion, cardiac output progressively declines over three hours, and the values for hepatectomy versus phenformin infusion are not significantly different after 100 or 180 minutes. From Arieff et al (1983), with kind permission of the authors and the editor of Clinical Science.



T h e clinical s y n d r o m e o f lactic acidosis h a s been w e l l - k n o w n f o r at least 25 years (Oliva, 1970; R e l m a n , 1978) b u t t r e a t m e n t has always been largely e m p i r i c a l . T h e m o s t o b v i o u s b i o c h e m i c a l a b n o r m a l i t i e s in p a t i e n t s with lactic acidosis are h y p e r l a c t a t a e m i a a n d m e t a b o l i c acidosis. Because m e t a b o l i c acidosis s h o u l d t h e o r e t i c a l l y b e r e a d i l y t r e a t a b l e , a n d since t h e r e a r e a p p a r e n t l y w e l l - k n o w n d e t r i m e n t a l effects o f acidosis o n c a r d i o v a s c u l a r f u n c t i o n , the m e t a b o l i c acidosis has always been aggressively



treated. Although some patients have received either bicarbonate precursors (acetate, lactate, gluconate) or other H + ion acceptors (THAM), the mainstay of treatment in most patients has been intravenous NaHCO3. In fact, much of the time, the bicarbonate failed to accomplish its primary goal, i.e. t h e normalization of arterial pH (Waters, Hall, and Schwartz, 1963; Fraley et al, 1980; Fields, Wolman, and Halperin, 1981). Additionally, recent evidence suggests an even worse potential consequence of bicarbonate therapy. In many cells and tissues, NaHCO 3 infusion actually lowers intracellular pH (McGivan, 1979; Arieff et al, 1982b). In fact, in cardiac arrest, where NaHCO 3 has long been a mainstay, there is actually an increase in mixed venous pCO2, which probably lowers cardiac intracellular pH and may actually tend to decrease cardiac output (Arieff et al, 1982b). The other empirical mode of therapy in patients with lactic acidosis consists of manoeuvres designed to lower plasma lactate levels. However, none has been directed at the cause of the increased blood lactate. Such manipulations have consisted of dialysis, methylene blue and glucose plus insulin administration. A difficulty in assessing the effectiveness of any mode of therapy for lactic acidosis is that the only criterion commonly employed is the gross survival. This tends to group together all forms of lactic acidosis, despite vastly different pathogenesis, and also ignores the contribution to overall mortality of associated medical conditions. The overall mortality in patients with lactic acidosis exceeds 50 per cent. In most instances, the mainstay of therapy has been the administration of large quantities of intravenous NaHCO3. Other adjunctive forms of therapy have included insulin and glucose, methylene blue, dialysis and dichloroacetate. In addition, most patients have been treated with intensive supportive therapy, which has included (where appropriate) volume expansion, antibiotics, oxygen, vasopressors, vasodilators and cardiac glycosides (Tranquada, Grant, and Peterson, 1966; Taradash and Jacobson, 1975; Relman, 1978a). The only rationale for administration of NaHCO3 is the presence of metabolic acidosis. There are several theoretically harmful effects of metabolic acidosis, which include a decrease in cardiac output and impaired effectiveness of various pharmacological agents (digitalis preparations, antiarrhythmic agents, vasopressors). However, it has always been assumed that administration of NaHCO3 will actually increase extracellular (arterial) pH, and either increase or have no effect upon intracellular pH (pHi). However, recent work, both in patients and laboratory animals, suggests that bicarbonate may actually decrease PHi (Singer et al, 1955; Waters, Hall and Schwartz, 1963; Fraley et al, 1980; Fields, Wolman and Halperin, 1981). In normal animals (dogs) infusion of NaHCO3 results in a decrease of myocardial extraction of oxygen and lactate, with a 400 per cent increase in blood lactate. The arterial pCO2 increases by over 230 per cent (Scheuer, 1968). Although not specifically measured, the increase in p C O 2 probably leads to a decrement of myocardial intracellular pH (Steenbergen et al, 1977). The increase of pCO2 is also observed after NaHCO3 is added to an in vitro blood system (Ostrea and Odell, 1972). Furthermore, in patients with severe dehydration (due to cholera), administration of NaHCO3 actually leads to a decrement of cardiac output, whereas



NaC1 does not (Harvey et al, 1966). Thus in normal and dehydrated humans, N a H C O 3 may have several potentially adverse effects. In general, little is known about the systemic and metabolic effects o f bicarbonate in patients with lactic acidosis. There have been several studies on the effects o f NaHCO3 in several animal models with :lactic acidosis. In the first of these, Minot and associates (1934) developed an experimental model of lactic acidosis in the dog with guanidine injection (pH = 7.08, lactate = 13 mM). Administration o f NaHCO3 to such dogs induced muscle twitching, grand mal seizures, emesis and diarrhoea. Biochemically, there was a rise in blood lactate and no change in bicarbonate. Mortality was 100 per cent. In our laboratory, we have investigated effects o f NaHCO3 in dogs with either phenformin-lactic acidosis or hepatectomy-lactic acidosis. In animals with phenformin-lactic acidosis (pH = 7.15; lactate = 7 mM), serial measurements were made o f cardiac output, liver pHi, extrahepatic splanchnic (gut) lactate production, liver lactate uptake, arterial p H and concentrations in arterial blood o f lactate and bicarbonate. Animals were treated with either no therapy, N a H C O 3 (at a rate of 2.5 m m o l / k g / m i n ) , or NaC1 at the same volume (1 ml/min) and sodium concentration. When dogs with phenformin-lactic acidosis were treated with NaHCO3, the four hour mortality was 83 per cent. There was essentially no change in the arterial pH or bicarbonate, while blood lactate doubled (Arieff et al, 1982b). There was a significant decline in the pH~ of liver (Figure 7). The cardiac output, GFR and hepatic portal vein (HPV) blood flow declined significantly (Figure 5). Production o f lactate by the gut doubled, while liver extraction of lactate declined by 60 per cent. The overall effect was an

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Figure 7. Liver intracellular pH (pHi) is shown in four groups of dogs. In dogs with lactic acidosis, there was a significant'decrement (P < 0.01) in liver p h i compared with control diabetic animals. Liver p h i was unaffected by NaCI treatment, but decreased significantly (P < 0.01 versus dogs with lactic acidosis before treatment) after therapy with NaHCO~. From Park and Arieff (1982), with kind permission of the editor of Journal o f Clinical Investigation.



increase in net splanchnic lactate production to 42.2 mmol/h (control value showed no net increase). The rate of bicarbonate infusion was 60 retool/h, so that most (70 per cent) of infused bicarbonate was titrated with increased lactic acid production by the gut (Figure 3). In dogs with phenformin-lactic acidosis who were treated with NaCI, the four hour mortality was identical (83 per cent) to NaHCO 3 therapy. Values for arterial pH and bicarbonate were similar to those in NaHCO3 treated dogs, but lactate levels were unchanged. However, liver pHi was unaltered by NaC1 infusion, while cardiac output was also unchanged (Arieff et al, 1982b). Most important, NaC1 infusion did not augment the net splanchnic lactate production, which was 18.7 mmol/h versus 42.2 mmol/h in NaHCO3 treated dogs (Figure 3). No therapy resulted in similar changes to those reported with NaCI therapy. Thus, NaHCO 3 infusion in dogs with lactic acidosis increased extrahepatic splanchnic lactate production, which was significantly greater than with NaC1 infusion. The increased lactate production was manifested by both a doubling of blood lactate after NaHCO3 infusion and an unaltered blood bicarbonate level, despite continuous intravenous NaHCO3 infusion. These data show that in dogs with experimental (phenformin-induced) lactic acidosis, survival time is similar in NaHCO3 versus NaCl-treated animals. However, the metabolic parameters evaluated reveal that NaHCO3 treatment in dogs with lactic acidosis results in a decrement of cardiac output and intracellular pH in liver and erythrocytes, whereas treatment with NaC1 does not. Furthermore, despite continuous infusion of NaHCO3, blood bicarbonate and pH are unaltered. The detrimental effects of NaHCO3 infusion are not due to either volume expansion or sodium infusion, as they are not duplicated by NaC1 infusion at the same volume and sodium concentration. The observed effects of NaHCO3 therapy for experimental lactic acidosis parallel some commonly observed clinical observations in patients. Several investigators have observed that infusion of over 1000 mEq/day of NaCO3 did not alter blood pH or bicarbonate. Fraley et al (1980) have recently shown that in a patient with lactic acidosis and cancer, bicarbonate infusion resulted in an increase of lactate production that almost stoichiometrically paralleled the rate of bicarbonate infusion, results similar to those reported in experimental lactic acidosis (Figure 3). Glucose and insulin have been suggested as therapy for lactic acidosis. The rationale for such therapy is unclear, but several factors may be relevant. Insulin deficiency can lead to inhibition of pyruvate dehydrogenase, which is necessary for pyruvate to enter the citric acid cycle (Misbin, 1977). It has been shown that in dogs with experimental lactic acidosis, insulin therapy increases extrahepatic lactate removal (Alpert, 1965). Empirically, it has been suggested (Dembo, Marliss and Halperin, 1975) that since lactic acidosis is often associated with insulin deficiency and its sequelae, such as hyperglycaemia, hyperketonaemia and elevated plasma amino acids, insulin therapy may be of benefit. It has been observed in patients with lactic acidosis that insulin therapy may diminish blood lactate levels (Dembo, Marliss and Halperin, 1975; Misbin, 1977). In two large



reviews, combined survival in insulin treated subjects with lactic acidosis was 69 per cent versus 49 per cent in 'controls'. However, all patients received supportive care, most were given alkali and volume expansion, and many also received digoxin, diuretics and KC1. Thus, it is almost impossible to assess the efficacy of insulin and glucose. Peritoneal dialysis has been suggested as an adjunctive therapy for lactic acidosis, but experience is limited. The basis for dialytic therapy in patients with lactic acidosis is the ability to administer large quantities o f NaHCO~ into the circulation, but avoid hazards of sodium overload. This is accomplished by removal of excess sodium via dialysis. Theoretically, excess H + ions can be neutralized with NaHCO3, while both sodium and lactate ions are being removed. Such a strategy may occasionally be beneficial..However, dialysis does nothing to address the cause of the lactic acidosis. In published series of patients with lactic acidosis treated with dialysis, all patients also received intravenous bicarbonate, as well as antibiotics, vasopressors and volume expansion (Vaziri et al, 1979). The outcome in these studies appears to be related to the underlying disease state rather than the lactic acidosis per se. Thus, peritoneal dialysis must be regarded as of no proved benefit in patients with lactic acidosis. Vasodilators (nitroprusside) have been suggested as therapy for lactic acidosis (Taradash and Jacobson, 1975). The basis for such therapy was treatment of a patient with pulmonary oedema, whose blood lactate was 20 mM and bicarbonate 13 raM. These became normal after nitroprusside therapy. However, most patients with pulmonary oedema have elevated plasma lactate levels (Fulop et al, 1973) and these respond to treatment o f the pulmonary oedema. Thus, vasodilators must also be regarded as unproved therapy. Intravenous methylene blue is a hydrogen ion acceptor and thus might act, as does NAD, in the conversion of lactate to pyruvate. Although studies have been carried out in at least five patients, results remain inconclusive. Blood lactate levels were lowered, but survival was unaffected (mortality = 80 per cent) (Tranquada, Bernstein and Grant, 1964). Dichloroacetate (DCA) is a drug which acts primarily by activation of the pyruvate dehydrogenase complex in many different tissues (Crabb, Yount and Harris, 1981). In humans and laboratory animals, DCA lowers blood lactate in vivo (Stacpoole, Moore and Kornhauser, 1978; Crabb, Yount and Harris, 1981). It has been suggested as a treatment for lactic acidosis in patients (Relman, 1978b). To date, only a few sporadic studies have been carried out in patients, and the results are inconclusive (Irsigler, Kaspar and Kritz, 1977; Coude et al, 1978). However, there is some recent literature on the use of DCA in laboratory animals with lactic acidosis. Previous studies from this laboratory have shown that in dogs with phenformin-lactic acidosis, there is increased production of lactate by the extrahepatic splanchnic vascular bed (gut), in addition to impaired liver lactate uptake, low liver pHi, and decreased cardiac output (Arieff et al, 1980; Arieff et al, 1983). In hepatectomy-lactic acidosis, cardiac output was also decreased (Arieff et al, 1983). Thus, we evaluated the effects o f DCA on the abnormalities listed above.



Dogs with phenformin-lactic acidosis (pH = 7.15, lactate = 7 mM) were treated with either NaC1 or D C A for up to four hours. Cardiac indices in the two groups of animals are shown in Figure 8. During treatment with NaHCO3, mean cardiac index declined by 58per cent versus control values, whereas in DCA-treated animals, cardiac index steadily rose back to the control value (Park and Arieff, 1982).

Lactic Acidosis-Cardiac Index mllKg/min




t~ ¢..) 5(I


~ 1 ~


Time (Hours) Figure 8. The effects of NaHCO3 versus DCA treatment on cardiac index in dogs with phenformin-lactic acidosis. After four hours of intravenous DCA, cardiac index is not significantly different from the control value. During treatment with NaHCO3, cardiac index progressively diminished, leading to an eventual 91 per cent mortality versus a 22 per cent mortality in DCA-treated dogs. From Park and Arieff (1982), with kind permission of the authors and the editor of Journal of Clinical Investigation. As shown in Figure 9, the changes in cardiac index were accompanied by corresponding changes in arterial pH, bicarbonate and lactate. There was no change in arterial pH in bicarbonate-treated dogs, but a significant rise occurred in DCA-treated dogs. Similarly, blood bicarbonate was unaltered in bicarbonate-treated animals, but there was a significant increment in DCA-treated dogs. The arterial p C O 2 w a s 32 mm Hg and after D C A it was unaltered. However, in NaHCOa-treated animals, arterial p C O 2 r o s e from 30 to 35 m m Hg and the mixed venous (inferior vena cava) p C O 2 r o s e from 37 to 55 m m Hg. The most dramatic changes in arterial blood were seen in the lactate values. After N a H C O 3 therapy, blood lactate almost doubled. By contrast, D C A treatment resulted in a significant decrement o f lactate (Figure 9). The liver pHi, which was significantly decreased in dogs with lactic acidosis, fell still further following N a H C O 3 (Figure 7). However,





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Time, min. Figure 9. The effects of intravenous DCA versus NaHCO3 in dogs with phenformin-lactic acidosis are compared. Two groups of diabetic dogs were given intravenous phenformin for a mean of 210 minutes (groups 3 and 4), and then half received DCA (group 4) while the other half was given NaHCOs (group 3) for a maximum of 240 minutes. In the DCA-treated animals arterial lactate was significantly lower (P < 0.01) while arterial pH and bicarbonate (HCO~) were significantly higher (P < 0.01) despite the fact that the bicarbonate-treated dogs had received an average of 72 mEq of NaHCO3 versus none for the DCA-treated animals. From Park and Arieff (1982), with kind permission of the authors and the editor of Journal of

Clinical Investigation.



after DCA there was an increment of hepatocellular pH i such that the value was significantly greater than in NaHCO3-treated dogs (Figure 7). Thus, DCA therapy resulted in normalization of cardiac index, with. improvement in arterial pH, bicarbonate, lactate and liver pH i, whereas bicarbonate therapy was associated with a decrement of cardiac output and liver pHi, an increase in both arterial pCO2 and lactate, and venous pCO2, with no change in blood pH or bicarbonate. The mean survival time for DCA-treated animals was almost twice that observed in bicarbonate-treated dogs (Park and Arieff, 1982). Dogs were then pretreated with DCA (300 mg/kg i.v. sustained infusion), lactic acidosis was induced by functional hepatectomy and dogs were observed for up to four hours. After three hours, arterial lactate was 3.8 mM while bicarbonate and pH were 11.4 mM and 7.18 respectively. All of the values were significantly different from untreated dogs. All dogs treated with DCA survived four hours versus a 33 per cent mortality in untreated dogs. In a separate group of dogs with hepatectomy-lactic acidosis, effects of DCA versus NaHCO3 therapy were evaluated on cardiac index only. Among dogs treated with NaHCO3, the cardiac index fell by over 50 per cent during therapy, and only 33 per cent of bicarbonate-treated dogs survived four hours (Park and Arieff, 1982). Among dogs treated with DCA, 83 per cent survived four hours. However, in contrast to the results in bicarbonate-treated dogs, cardiac index did not decline during DCA therapy. These data demonstrate that in dogs with the two different types of Type B experimental lactic acidosis, treatment with DCA significantly improves survival when compared with conventional therapy with either NaC1 or NaHCO3. In addition to improved survival, therapy with DCA results in significant improvement of several biochemical and physiological entities. In particular, treatment with DCA results in either an increase (Figure 8) or stabilization of cardiac output; a decrement of blood lactate and an increase of blood pH and bicarbonate (Figure 9); and a rise in liver pHi (Figure 7). These effects of DCA may be unique to only these two forms of lactic acidosis, and it is possible that DCA would be ineffectual in other forms of lactic acidosis. Additionally, DCA may lower blood lactate in some forms of lactic acidosis, but have no effect on the course of the associated illness (Crabb, Yount and Harris, 1981). There are some toxic effects of DCA that have been described after chronic administration. These include limb paralysis, cataracts, increased urinary oxalate excretion, testicular degeneration, neuropathy, mutagenicity and changes in central nervous system's white matter (Crabb, Yount and Harris, 1981). Most such toxic effects result from long-term oral administration of DCA, with few if any side effects reported with shortterm intravenous use (Crabb, Yount and Harris, 1981). Short-term administration to human subjects orally or intravenously has not resulted in any serious side effects (Crabb, Yount and Harris, 1981). With the above reservations in mind, clinical trials of DCA as adjunctive therapy of lactic acidosis are probably indicated.



CONCLUSIONS 1. Inadequacy of hepatic lactate disposal appears to play a central pathophysiologic role in both experimental Type B (phenformin) and Type A (hypoxic) lactic acidosis. Decreased lactate delivery and biochemical alterations in intracellular pH of liver are important pathogenetic factors which contribute to the development of lactic acidosis. 2. Cardiovascular compromise may be present in many cases of Type B, as well as in all case of Type A, lactic acidosis. 3. Bicarbonate treatment of lactic acidosis may potentially worsen blood lactate levels, increase lactate production, and have little beneficial effects on overall survival. In experimental studies, dichloroacetate improves biochemical parameters, normalizes cardiac dysfunction, and improves survival in Type B lactic acidosis. SUMMARY

Lactic acidosis is now a widely recognized disorder in clinical medicine. Experimental studies during the past decade demonstrate an important role of lactate disposal mechanisms in the pathogenesis of lactic acidosis. Such factors as decreased cardiovascular reserve, inadequate liver perfusion and alterations in liver intracellular pH appear to limit the normally large capacity of the liver to dispose of lactic acid. The continued high mortality of this disorder has led to a re-examination of the conventional, empirical treatment of lactic acidosis with sodium bicarbonate. Available data suggest that alkali may cause or exacerbate the conditions of excessive lactate production, decreased cardiac reserve and inadequate hepatic lactate disposal which exist in this disorder. In contrast, dichloroacetate therapy shows strikingly beneficial results, at least in early experimental studies. REFERENCES Alpert, N. R. (1965) Lactate production and removal and the regulation of metabolism. Annals New York Academy of Science, 119, 995-1012. Altschuld, R. A. & Kruger, F. A. (1968) Inhibition of hepatic gluconeogenesis in guinea pig by phenformin. Annals New York Academy of Science, 148, 612. Arieff, A. I., Leach, W. & Park, R. (1982a) Production and recovery from type A hypoxic lactic acidosis: Studies on mechanisms. Clinical Research, 30, 522A. Arieff, A. I., Park, R., Leach, W. J. & Lazarowitz, V. C. (1980) Pathophysiology of experimental lactic acidosis in dogs. American Journal of Physiology, 239, F135-F142. Arieff, A. I., Park, R., Leach, W. & Lazarowitz, V. C. (1982b) Systemic effects of NaHCO3 in experimental lactic acidosis in dogs. American Journal of Physiology, 242, F586-F591. Arieff, A. I., Gertz, E. W., Park, R. et al (1983) Lactic acidosis and the cardiovascular system in the dog. Clinical Science, 63. Assan, R., Heuclin, C., Girard, J. R. et al (1975) Phenformin-induced lactic acidosis in diabetic patients. Diabetes, 24, 791-800. Berry, M. D. & Scheuer, J. (1967) Splanchnic lactic acid metabolism in hyperventilation, metabolic alkalosis and shock. Metabolism, 16, 537-547. Cohen, R. D., & Woods, H. F. (1976) The clinical presentations and classification of lactic acidosis. In Clinical and Biochemical Aspects of Lactic Acidosis, pp. 40-76. Oxford: Blackwell Scientific Publications. Coude, F. X., Saudubray, J. M., DeMaugre, F. et al (1978) Dichloroacetate as treatment for congenital lactic acidosis. New England Journal of Medicine, 299, 1365-1366.



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Relman, A. S. (1978b) Lactic acidosis and a possible new treatment. New England Journal of Medicine, 298, 564-566. Singer, R. B., Clark, J. K., Barker, E. S. et al (1955) The acute effects in man of rapid intravenous infusion of hypertonic sodium bicarbonate solution. Medicine, 34, 51-95. Scheuer, J. (1968) The effects of respiratory and metabolic alkalosis on coronary flow, hemodynamics and myocardial carbohydrate metabolism. Cardiologia, 52, 275-286. Stacpoole, P. W., Moore, G. W. & Kornhauser, D. M. (1978) Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia. New England Journal of Medicine, 298, 526-530. Steenbergen, C., Deleeuw, G., Rich, T. & Williamson, J. R. (1977) Effects of acidosis and ischemia on contractility and intracellular pH of rat heart. Circulation Research, 41, 849-858. Taradash, M. R. & Jacobson, L. B. (1975) Vasodilator therapy of idiopathic lactic acidosis. New England Journal of Medicine, 293, 468-471. Tashkin, D. P., Goldstein, P. J. & Simmons, D. H. (1972) Hepatic lactate uptake during decreased liver perfusion and hypoxemia. American Journal of Physiology, 223,968-974. Tranquada, R. E., Bernstein, S. & Grant, W. J. (1964) Intravenous methylene blue in the therapy of lactic acidosis. Archives of Internal Medicine, 114, 13-25. Tranquada, R. E., Grant, W. J. & Peterson, C. R. (1966) Lactic acidosis. Archives of Internal Medicine, 117, 192-202. Vazari, N. D., Ness, R., Wellikson, L. et al (1979) Bicarbonate-buffered peritoneal dialysis: An effective adjunct in the treatment of lactic acidosis. American Journal of Medicine, 67, 392-396. Waters, W. C. III, Hall, J. D. & Schwartz, W. B. (1963) Spontaneous lactic acidosis. American Journal of Medicine, 35, 781-793.