frequency that the patient is incapacitated socio- threatening metabolic acidosis is a very common economically; (2) intensive drug therapy has been event in patients who are in shock from a variety unsuccessful; (3) availability of facilities for de- of causes, including hemorrhage, myocardial in- tailed clinical and electrophysiological analysis farction and septicemia. A significant association essential for neurosurgical exploration. Surgical with gram-negative infection has been noted. A excision is of value in a limited number of patients few patients, however, have been demonstrated to with epilepsy and search must be continued for develop lactic acidosis apparently spontaneously, newer drugs, without serious toxicity, to reduce and in the absence of other recognizable disease. our current failures in drug therapy. It is noteworthy that among reported diabetic pa- ROBERT A. FISHMAN, M.D. tients who have developed "spontaneous" lactic Department of Neurology acidosis, in whom there was not identifiable addi- University of California San Prancisco Medical Center tional cause for lactic acidosis, all were receiving phenformin. The latter factor we believe to be of major sig- nificance, since virtually every other case of lactic acidosis in the diabetic has been preceded by an acute illness whose characteristics are such as to be related to lactic acidosis in the non-diabetic as Phenformin and Lactic Acidosis well. In other words, in at least ten diabetics who developed lactic acidosis there was no other identi- fiable cause than phenformin ingestion. One case SINCE THE EARLIEST days of its clinical use in the of attempted suicide by ingestion of 1,500 mg of treatment of diabetes, there has been published phenformin did not result in an elevation of blood concern about the possible role of phenformin in lactate5; while a second case of ingestion of 850 the causation of lactic acidosis.' Elsewhere in this mg resulted in an unidentified metabolic aci- issue of CALIFORNIA MEDICINE is tthe twenty-sev- dosis.6 Furthermore, it seems clear that many thou- enth published case report of lactic acidosis occur- sands of patients have taken phenformin as therapy ring in a diabetic known to have been treated with for diabetes mellitus and have not developed lactic phenformin. We are aware of reports of 63 dia- acidosis. betic with lactic acidosis, of which 54 patients of the confusion in our to a cases have been and the remaining nine Part ability assign published to an are known to us in our own direct relationship of phenformin ingestion cases unpublished,2'3'4 incidence of lactic acidosis lies in our incomplete experience. Of this number, 38 were receiving lactic knowledge of the mechanism of action of this drug. phenformin at the time they developed aci- is metab- were known to have been taking Recent evidence that phenformin rapidly dosis, five patients to two and six insulin. olized, probably by the liver, para-hydroxyphen- tolbutamide, chlorpropamide casts much doubt the results This incidence of use of ethylbiguanide upon very high phenformin in vitro examinations of mechanism of ac- among reported and known cases of lactic acidosis of the in the diabetic leads naturally to the question of tion of the drug.7 Furthermore, there is a significant relationship between the in vitro effects of phen- cause and effect. Since lactic acidosis is known to situa- have occurred both in diabetic patients who were formin and its concentration in experimental tions. Evidence exists which supports the idea that taking no drug therapy and in diabetics on therapy is not clear. normally achieved blood levels of phenformin are other than phenformin, the relationship the metabolic of the more ob- not capable of producing effects On the other hand one convincing associated with the in- servations is the fact that at least ten of the reported which have been directly cases of lactic acidosis in which phenformin was creased production of lactic acid by tissues exposed being taken occurred in patients who were taking to phenformin. These effects are, however, possible no other medication and who were previously in with higher concentrations of phenformin, and such metabolic balance and who had no other identifi- levels have only been demonstrated in diabetics able cause for the lactic acidosis. who develop lactic acidosis while taking phenfor- The subject of lactic acidosis has been reviewed min.8 in detail elsewhere.2 The accumulation of quanti- In the absence of definitive evidence, however, ties of lactic acid sufficient to create severe and life- it is essential to have a rational approach to the use

348 APRIL 1969 * 10 . 4 of this drug in the therapy of the diabetic. In this careful observation of the patient for metabolic context, we would point to the following informa- acidosis. tion: Therapy of lactic acidosis remains empirical. 1. Apparently spontaneous lactic acidosis, with Therapeutic modalities reported to date include frequent fatal termination, has occurred in diabetic the correction of the metabolic acidosis with the patients being treated with phenformin alone, in use of large amounts of sodium bicarbonate in- whom there was no evidence of other potential travenously, peritoneal dialysis, methylene blue, cause of lactic acidosis. glucose and insulin, and tromethamene 2. Among therapeutic agents being given to dia- (THAM®9). Additionally it is agreed that meas- betic patients who have developed a catastrophic ures designed to maintain intravascular volume, illness which led to lactic acidosis, there is a greater tissue oxygenation, cardiac function and control of association with the use of phenformin than with infection are important in the management of this any other therapeutic agent, by a very wide margin. condition. Experience indicates that correction of 3. In vivo human studies exist which validate the acidosis with intravenous sodium bicarbonate, the existence of elevated resting blood lactate in along with detailed attention to the correction of patients receiving phenformin and which indicate identifiable defects in hydration, hemoglobin levels, that lactic acid is produced in increased amounts cardiac function, tissue oxygenation and control by diabetic patients given phenformin acutely.8'9 of infection are the most significant contributors 4. Phenformin is metabolized by the liver and to survival of these patients. The other therapeutic excreted in the urine. Seventeen of 18 reported modalities (methylene blue, THAM, glucose and cases of lactic acidosis in patients taking phenfor- insulin) await further confirmation. min, in whom estimates of renal function are avail- able, show evidence of impaired renal function at REFERENCES 1. Walker, R. S., and Linton, A. L.: Phenethylbiguanide: Danger. the onset of their lactic acidosis. ous side-effect, Brit. Med. J., 2:1005, 1959. 2. Tranquada, R. E.: Lactic acidosis-A review, Calif. Med., 101: 5. Three patients with lactic acidosis, who had 450, 1964. 3. Johnson, H. K., and Waterhouse, C.: Lactic acidosis and phen. been receiving phenformin were shown to have formin, Arch. Int. Med., 122:367, 1968. elevated levels of blood phenformin in concentra- 4. Proctor, D. W., and Stowers, J. M.: Fatal lactic acidosis after an overdose of phenformin, Brit. Med. J., 4:216, 1967. tion capable of inducing increased lactate pro- 5. Dobson, H. L.: Attempted suicide with phenformin, Diabetes, 14:811, 1965. duction by tissues in in vitro experiments.8 6. Davidson, M. B., Bozarth W. R., Challoner, D. R., and Good- ner, C. J.: Phenformin, hypogiycemia and lactic acidosis-Report of For these reasons, and until unequivocal evi- attempted suicide, New Eng. J. Med., 275:886, 1966. 7. Beckmann, R.: The fate of biguanides in man, Ann. N.Y. Acad. dence can be presented to the contrary, we are of Sci., 148:820, 1968. the opinion that there is a relationship between the 8. Tranquada, R. E., Bernstein, S., and Martin, H. E.: Irreversible lactic acidosis associated with phenformin therapy, JAMA, 184:37, incidence of lactic acidosis and the use of phenfor- 1963. 9. Searle, G. L., Shilling, S., Porte, D., Barbaccia, J., DeGrazia, J., min in the treatment of diabetes mellitus. It would and Cavalieri, R. R.: Body glucose kinetics in non-diabetic human appear that the hazard is greatest among patients subjects after phenethylbiguanide, Diabetes, 15:173, 1966. who have impaired renal function and those who are subjected to other causes of lactic acidosis, such as severe gram-negative infection or acute myo- cardial infarction. We therefore recommend that reemphasis be given to the current instructions packaged with this drug to the effect that phenfor- mn is contraindicated in patients who have im- paired renal function, and in the presence of other A Physician Is significant acute illness, chronic infection, and acute or chronic heart disease. Worthy of His Hire It should be pointed out that a significant num- ber of patients who developed lactic acidosis while A WORKMAN IS worthy of his hire. This has long on phenformin had the onset of lactic acidosis been an important tenet of our national philoso- accompanied by nausea and vomiting and ab- phy. Our society today also holds that discrimina- dominal pain. The occurrence of these symptoms tion is an evil thing. Whenever discrimination is in any diabetic taking phenformin should lead to suspected or exposed, there is apt to be a great the immediate discontinuation of the drug and public outcry accompanied by demands that the

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