Lactic Acidosis

Metabolic acidosis characterized by the accumulation of lactate in the body. It is caused by tissue hypoxia.

To clheck this impression, onie of otir fouirtlh year students, 1\Jr. Kai Lau, and I reviewed all the cases of lactic acidosis seeni within the p)ast few years at the Hospital of the University of Pennsylvania, and we also carefully surveyed the available literature. 'AWe selected for study only those cases in which simultaneous determiniations of arterial pH and pCO2 and HCO3 were available prior to the start of any therapy and in which the diagnosis of lactic acidosis was confirmed by seruin lactate levels of at least 7 mEq/L,, without evidence of any other cause of acidosis.
For comparison with these cases of lactic acidosis, we selected from the literature patients with acute, untreated diabetic ketoacidosis, in whoin the same arterial acid-base data had been obtained prior to therapy. Figure 1 shows the data from these two groups. On the ordinate is the arterial CO2 tension, a measure of the degree of hyperventilation. On the abscissa is the plasma bicarbonate, and in the background of the figure are the faint diagonal lines indicating the pH.
The heavy diagonal line represents the calculated regression line for 32 cases of acute untreated diabetic ketoacidosis, and the shaded area dep)icts the 95% confidence band for this regression line. The regression line is a statistical expression of the extent to which pCO2 would be expected to fall with progressive acute ketoacidosis. Virtually identical data have been reported by other workers who have studied the degree of compensatory hyperventilation in patients with metabolic acidosis due to diabetes, renal failure, ammonium chloride ingestion and cholera.
In contrast to the data from the diabetics, are the nineteen solid dots on the graph, which represent arterial acid-base observations on patients with untreated lactic acidosis. Although some of these dots fall well within the 95% confidence band for the diabetics, you will note that all the CO2 tensions in the lactic acidosis patients fall below the regression line and 12 of the 19 are at or below the lower limit of the confidence band. Statistical analysis of the lactic acidosis data supports this visual impression. At any given bicarbonate level, the average pCO2 is nearly 8 mm Hg lower in lactic acidosis than in diabetic ketoacidosis, and this difference is highly significant. In several cases of lactic acidosis there is a striking disparity between the pCO2 and the pH. Thus for example, there are patients who were hyperventilating despite the fact that their blood pH was normal, or even slightly elevated. 1Iost of the patients had a pH of 7.2 or higher, and the patient who demonstrated the most profound hyperventilation had only a slight degree of acidemia, with a blood pH of 7.3.
We conclude from this analysis that in most patients with lactic acidosis there is a stimulus to respiration which seems excessiv-e in relation to the pH of their blood. What could explain this phenomenon? I hasten to admit that I am not at all sure. However, I shall assume that I am among friends and that a modicum of speculation at this point would not be viewed too harshly.
The hypothesis that I wish to propose is that lactic acidosis may differ from the usual causes of acute metabolic acidosis in that the disturbance leading to the acidosis probably occurs within the cells of the brain and the respiratory center, as well as in other tissues capable of producing lactic acid. In diabetic acidosis, in cholera and in ammonium chloride poisoning, the acid is generated ottside the brain and stimulates the cells of the respiratory center only after penetrating the blood-brain barrier. We do not yet know the exact nature of the metabolic disturbance in idiopathic lactic acidosis, but whatever it is, if it results in the accumulation of lactic acid inside the cells of the respiratory center, it is easy to imagine how respiration might be stimulated without regard to the extracellular pH. A similar kind of situation probably exists in certain cases of encephalitis, where an intracellular metabolic disturbance stimulates the cells of the respiratory center to inappropriate activity and therefore a respiratory alkalosis may develop.
Regardless of its ultimate explanation, the relatively excessive hypocapnea in lactic acidosis may well play a critical role in the maintenance of the syndrome. To make clear why I think this may be so, I must make a brief digression to summarize a few facts about the control of glycolysis by pH and the effect of hypocapnea on intracellular pH. I would begin by reminding you that the glycolytic pathway is very sensitive to pH over the range of acidity likely to be found in vivo. A few years ago, in collaboration with Drs. Manfred Karnovsky and Mitchell Halperin, I had an opportunity to study this phenomenon in guinea pig leukocytes.2 We found that glycolysis in this system is drastically inhibited by lowering pH and stimulated by raising it, between pH 6.5 and 7.5. Similar results have been obtained by other workers in a great variety of other tissues.
This effect of pH appears to be due largely to the pH sensitivity of the phosphofructokinase reaction, which is one of the rate-limiting steps early in the Embden-Meyerhof glycolytic pathway. In our studies on leukocytes, we were able to show that the mechanism probably involves a direct effect of pH on the structure of the enzyme. The other powerful physiological stimulant of glycolysis is, of course, hypoxia. Hypoxia, like pH, appears to have its major influence on the phosphofructokinase reaction, but the mechanism is quite different. Whereas the hydrogen ion reacts directly with the enzyme, hypoxia appears to act by changing the cytoplasmic concentration of certain co-factors (like ATP, inorganic phosphate, and citrate) which have an allosteric effect on the enzyme. Therefore, it is possible for hypoxia and changes in pH to have independeint, non-conll)etitive effects oin the rate of glycolysis.
Turning now, for a moment, to the effect of hypocapnea on intracellular pH, I would remiiinid you that much evidence supports the view that CO2 tension is a inore imliortant determinant of intracellular acidity than is the extracellular concentration of bicarbonate. This is illustrated by the results of some experiments that Adler, Roy and I carried out a few years ago.3 Using DMIO as an index of intracellular pH, we studied the effects of various combinations of CO2 tension and extracellular bicarbonate concentration on the internal pH of rat diaplhragm muscle in vitro. We found that a low pCO2 can counteract the effect of a low extracellular pH on the pH inside the miuscle. Thus, for example, at a pCO2 of 20 mm Hg and an extracellular bicarbonate concentration of 6 to 7 mEq/L, we found that the muscle cell pH was actually slightly higher than normal, despite the fact that the extracellular pH was 7.10. Now, if we assume that the behavior of this in vitro rat diaphragm system is relevant to what happens in vivo, one could predict that hyperventilation to the degree manifested by patients with lactic acidosis might well keep the pH of their cells normal or even slightly alkaline, despite the fact that their blood pH is low.
Putting all these ideas together, one could suggest that the initial event in idiopathic lactic acidosis is the development of some sort of metabolic defect which, like hypoxia, reduces the availability of oxidized pyridine nucleotide in the cell cytoplasm and thereby stimulates glycolysis and the accumulation of intracellular lactic acid. This phenomenon occurs inside the cells of the respiratory center, as well as in all other glycolyzing cells of the body, and this stimulates the respiratory center to an excessive degree of hyperventilation. Ordinarily, a marked increase in intracellular lactic acid accumulation would tend to lower intracellular pH and thereby inhibit further production of lactic acid. However, with involvement of the respiratory center and a resultant excessive respiratory drive, the CO2 tension in peripheral tissues tends to be lower, and intracellular pH does not fall as much as it otherwise would. This tends to minimize the feedback inhibition of lactic acid production by intracellular hydrogen ion, and so lactic acid continues to accuinulate at a rapid rate.
In summary, I would propose that hyperventilation in patients with lactic acidosis, while it prevents a significant fall in blood pH, probably adds to the severity of the underlying metabolic disturbance by favoring continued accumulation of intracellular lactic acid. In this sense the hyperventilation is not only out of proportion to the severity of the extracellular acidosis but may actually be contributing to the maintenance of the patient's primary difficulty. for some time that people with gram negative septicemia may have marked hyperpnea. Dr. Norman Hollenberg before he came to us studied prospectively people with gram negative septicemia. He found that during the period before they develop so-called irreversible shock, that is when they actually had a high cardiac output with vasodilation but did have positive blood cultures, they had an increasing concentration of lactic acid in their blood. He wondered whether this might have been the thing that precipitated the so-called irreversible shock. Would you comment on that, please? DR. RELMAN: Sepsis of course is one of the common clinical causes of primary hyperventilation, and I believe that if you look at any circumstance in which there is marked hyperventilation, there is some increase in blood lactate. If you hyperventilate a healthy man you get a very small increase in blood lactate. The lower you make the pC02 the more the lactate rises. If now you combine hyperventilation with some metabolic defect that impairs oxidative processes, such as the effect produced by endotoxin, then I think you really do have a pernicious combination. DR. A. MURRAY FISHER (Baltimore): Do patients with cholera have findings of this sort? DR. RELMAN: Dr. Fisher, I do not know. I have not seen good data on the lactic acid levels in patients with cholera prior to the time they go into shock. The problem with cholera, of course, is that you get catastrophic hypovolemia and you may be dealing with frank shock. In diabetic ketoacidosis, even in patients who are not in shock, and are well oxygenated on admission, it is common to have slight to modest increases in blood lactate and some patients with diabetic ketoacidosis have fairly impressive levels of blood lactate. DR. WOODWARD: In patients with extreme dehydration such as those with Asiatic cholera the depth of respirations may increase after rehydration. This results from lubrication of muscle which permits better respiratory excursion.
DR. BELTON A. BURROWS (Boston): Would there be any rationale in giving them C02? DR. RELMAN: I was sure some one would ask that question. Yes, if the blood pH is not too low, and certainly if one has a respiratory alkalosis, I think that there would be some rationale in having them breathe C02. The only published data of which I am aware are the two or three case reports by Dr. Dossetor at the Royal Victoria in Montreal,4 who did observe rather interesting significant reductions in blood lactate in patients to whom he gave C02 to breathe. The trouble is that when you see these patients they are usually desperately ill and it is not often possible to carry out wellcontrolled clinical observations of this sort. Although I have tried this approach a few times, I do not yet have any data worthy of discussion.
DR. E. D. PELLEGRINO (New York): I wonder if you would comment on the relationship of the mechanism you propose to the hyperventilation that occurs so readily and quickly in exercise. Here, in a sense, you have the reverse, explosive development of lactic acid in the periphery and very quickly. Even in the exercise of a localized muscle group, hyperventilation can occur within 30 to 45 seconds after initiation of exercise. How does this fit into your formulation? DR. RELMAN: I am not sure, Ed. I believe there is evidence that in the hyperventilation of exercise there are several types of stimuli for respiration. If you have a relatively anaerobic tissue, like muscle, producing lactate at a great rate, and if you also have an independent non-pH-oriented stimulus for respiration, you may well have the same sort of mechanism that I am suggesting here for these patients with idiopathic lactic acidosis. You could use other models. For example, you could study the effects of hyperventilation when y3ou poison oxidative phosphorylation with phenformin or with other drugs and I think you would show that the hyperventilated animal develops a higher lactate level than the non-hyperventilated animal.
DR. JAMES F. TOOLE (Winston Salem): What was the state of consciousness of the patients that you were discussing?
DR. RELMAN: I cannot really give you a satisfactory answer to that question. I can only give you anecdotal information about those patients I have personally seen. You should understand that most of the 19 dots in the figure that I showed you are from patients reported in the literature, and the clinical data were sometimes reported so sketchily that I really cannot answer your question. My impression from those patients I have seen personally is that they are all obtunded. DR. TOOLE: I would then ask you why you reject the usual explanation for hyperventilation in obtunded patients, which is a removal of cortical control. You suggest, I think, that the lactic acidosis causes a stimulation of the respiratory center but removal of cortical control would produce the same effect.
DR. RELMAN: I would yield to your more expert knowledge in this area, Dr. Toole. I was only intending to suggest that in this disease there is reason to believe that, unlike certain other types of metabolic acidosis, the stimulus originates within the head and not from without.