- Email: [email protected]
PHENFORMIN AND METABOLIC ACIDOSIS
69
readings of serological
tests
were
done
by different
observers.
cell may well be vulnerable to one or factors in the adult environment. The other possibility-that the hepatic injury in l.c.c. itself results in reappearance of A.F.P. synthetic activity in the liver-seems less likely, since such resumption of embryonal function would be expected to be transient. In subacute and chronic diseases such as i.c.c. a large number of A.F.P.-positive cases at any given time would be unusual. Also, other hepatic disorders in children above 1 year of age do not lead to reappearance of A.F.P. in the serum. 100
developed "
more
Results
detected in nineteen children with i.c.c. (45%), most of them being above 1 year of age (table). Only two of these children were below 1 year of age (5 and 6 months), while in the remaining seventeen the mean age was 20-4 months, with a range of 12-42 A.F.P. was
A.F.P. IN THE SERA OF I.C.C. PATIENTS AND CONTROLS BY AGE
Requests for reprints should be addressed to N. C. N., Departof Pathology, All India Institute of Medical Sciences, New Delhi 16, India.
ment
REFERENCES
Nayak, N. C., Ramalingaswami, V. in Pædiatric Problems in Developing Countries (edited by P. Tirumala Rao); p. 229. Madras, 1970. 2. Ramalingaswami, V., Nayak, N. C. in Progress in Liver Disease (edited by H. Popper and F. Schaffner); vol. III, p. 222. New 1.
months. In contrast, only two out of twenty-eight controls (7%) had detectable A.F.P. in the serum. Both these children were less than 1 year of age (3 and 4.5 months); one was a sibling of a patient with i.c.c. and the other had neonatal hepatitis. The mean age of the remaining controls was 20 months, with a range between 9 and 36 months (excluding one child aged 9 years with liver disease).
3. 4. 5. 6. 7.
8. 9. 10.
Discussion
Less than half the children with i.c.c. had A.F.P. in the serum; however, had we used more sensitive techniques 6,7 the yield of positive cases might have been higher. As far as we know, detection of A.F.P. by the gel-diffusion technique in such a high proportion of cases is unknown for diseases other than hepatoma or teratocarcinoma.7 A.F.P. has been occasionally found in adults with cirrhosis and hepatitis by the geldiffusion method,8,9 but the total number of reported cases is very small.7 With the more sensitive radioautographic technique, however, A.F.P. has been detected in a relatively larger proportion of patients with acute hepatitis.’7 Masopust and colleagues 10 found A.F.P. in a few children with different types of hepatic disorder, but all these children were less than 1 year of age. In our control group both children with A.F.P. in the serum were less than 12 months old: one of them had an established liver disease, and the other, a sibling of a patient with i.c.c., may have had a hepatic abnormality not apparent by routine histology at the time of examination. Normally, A.F.P. is present in the serum during fetal life only; it becomes undetectable several days to a few weeks after birth, disappearing with a half-life of 3 days.11 Dallner and his colleagues have shown that several fine-structural and enzymatic alterations occur in the hepatocyte immediately before and after births This perinatal transformation of the liver cell from the fetal to the adult type is also associated with rapid suppression of A.F.P. synthesis and secretion. Is it possible that in infants later developing .c.c. the fetal hepatocyte fails to achieve the normal adult transformation, the defect being manifest in continuing synthesis and secretion of A.F.P.? Such an " un-
11. 12.
York, 1970. Singh, A., Jolly, S. S., Kumar, L. R. Lancet, 1961, i, 587. Abelev, G. I. Cancer Res. 1968, 28, 1344. Ouchterlony, Ö. Progr. Allergy, 1962, 6, 30. Alpert, E., Hershberg, R., Schur, P. H., Isselbacher, K. J. Gastroenterology, 1971, 61, 137. Abelev, G. I. in Cancer Research (edited by G. Klein, S. Weinhouse, and A. Haddow); p. 295. London, 1971. O’Conor, G. T., Tatarinov, J. U. S., Abelev, G. I., Uriel, J. Cancer, 1970, 25, 1091. Kresno, S. B., Gandasoebrata, R., Rümke, P. Lancet, 1970, i, 1178. Masopust, J., Kithier, K., Radl, J., Koutecky, J., Kotal, L. Int. J. Cancer, 1968, 3, 364. Gitlin, D., Boesman, M. J. clin. Invest. 1966, 45, 1826. Dallner, G., Siekevitz, P., Palade, G. E. J. Cell Biol. 1966, 30, 73, 97.
PHENFORMIN AND METABOLIC ACIDOSIS
G. A. MACGREGOR P. A. POOLE-WILSON N. F. JONES St. Thomas’s
Hospital, London S.E.1
patient with oliguric renal failure complicating accelerated hypertension was given phenformin and ethylœstrenol as fibrinolytic therapy. On the fifth day of this treatment a profound and fatal metabolic acidosis developed despite good control of uræmia by peritoneal dialysis. The acidosis was resistant to 2500 meq. sodium bicarbonate given over five hours. Two diabetic patients are also described in whom severe metabolic acidosis developed during phenformin therapy. The blood-lactate level was raised in the one patient in whom it was measured. The risk of severe acidosis should preclude administration of phenformin in patients with renal impairment. Awareness of this hazard is particularly pertinent in view of claims for this drug in the treatment of the hæmolytic-uræmic syndrome and pre-eclamptic Summary
A
toxæmia. Introduction
PHENFORMIN has been alleged to cause profound metabolic acidosis associated with elevated levels of blood-lactate, a state usually described as lactic acidosis. However, reported cases have usually had diabetes, circulatory failure, septicsemia, or tissue hypoxia
70 -conditions
which
may
themselves
cause
lactic
acidosis. 1,II Patients with lactic acidosis have commonly been found to have raised blood-urea levels, and it has been claimed that ursemia predisposes to lactic acidosis in patients receiving phenformin 1-an allegation that is especially important in view of the recent advocacy of treatment of the haemolytic-uraemic syndrome with phenformin and the anabolic steroid, ethyloestrenol.33 In this condition the deposition of fibrin in small vessels is thought to be an important factor, and the rationale for the use of phenformin and ethylrestrenol
depends on the ability of these drugs to increase fibrinolytic activity, to reduce plasma-fibrinogen levels,4to increase the level of plasminogen activator,6 and to reduce platelet stickiness.6 Similar reasoning has led to the use of phenformin in pre-eclamptic
blood
toxaemia. ? We describe here fatal metabolic acidosis occurring during therapy with phenformin and ethyloestrenol in a patient with malignant hypertension and acute oliguric renal failure. Two diabetic patients who developed severe metabolic acidosis while receiving phenformin are also described. Case-records FIRST CASE
A
admitted with a three-month 44-year-old history of headache and blurred vision. He had evidence of malignant hypertension with papilloedema, exudates, and flame-shaped haemorrhages on fundoscopy and a blood-pressure of 220/150 mm. Hg. Blood-Sim examination showed fragmented erythrocytes suggestive of a microangiopathic haemotytic anaemia, but the haemoglobin level and platelet-count were normal. Serum-fibrinogen was 0-69 g. per 100 ml.: serum titre of fibrin degradation products (F.D.P.) 1 in 128 (normal less than 1 in 4): plasmasodium 131 meq. per litre, plasma-potassium 2-6 meq. man was
per litre, plasma-bicarbonate 26 meq. per litre, blood-urea 124 mg. per 100 ml., plasma-creatinine 6-1 mg. per 100 ml. Liver-function tests were normal, and there was no history of alcoholism. High-dose intravenous pyelography showed kidneys of normal size without evidence of urinary-
obstruction. The blood-pressure was controlled with clonidine, but oliguria persisted and renal failure progressed. On the seventh day in hospital the blood-urea had risen to 350 mg. per 100 ml. and the plasma-creatinine to 12-0 mg. per 100 ml., with a plasma-bicarbonate of 25 meq. per litre. Peritoneal dialysis was started. The blood-pressure remained well controlled and the blood-urea and plasmacreatinine were satisfactorily lowered (see accompanying
tract
figure). After six days of peritoneal dialysis the patient remained This complication of accelerated hypertension has a very high mortality.8 There is evidence that intravascular fibrin deposition is important in this condition,9,10 and phenformin 50 mg. twice daily and ethylcestrenol 2 mg. twice daily were therefore given in view of their known fibrinolytic action. Five days after the start of phenformin and ethylcestrenol the patient complained of anxiety and breathlessness. The respiratory rate was increased but no other new abnormality was detected and, in particular, the blood-pressure was 140/90 mm. Hg and the peripheral circulation appeared normal. Arterial blood analysis showed a profound metabolic acidosis with a pH of 7’1 and Pcoof 20 mm. Hg, plasma-sodium 140 meq. per litre, plasma-potassium 6-9 meq. per litre, plasma-bicarbonate 12 meq. per litre, blood-urea 134 mg. per 100 ml. This compared with values on the previous day of plasmasodium 136, plasma-potassium 5-3, plasma-bicarbonate 23, and blood-urea 132 (see figure). The blood-sugar was 130 mg. per 100 ml. and the chest X-ray was clear. Within an hour the patient became acutely ill with a low blood-pressure and tachycardia. The arterial blood pH was 6-9 and lactic acidosis was provisionally diagnosed. Clearly its correction would require a large amount of sodium bicarbonate, and, in an attempt to mitigate sodium overload, the dialysate sodium concentration was reduced to 80 meq. per litre with dextrose. Over the next five hours a total of 2500 meq. of sodium bicarbonate (8-4% solution) was administered intravenously, but, despite this enormous quantity of alkali, the blood pH remained at 6-9. Plasma-sodium rose to 155 meq. per litre. The patient died within six hours of complaining of breathlessness. Unfortunately it was not feasible to measure lactate levels. Blood-cultures subsequently proved negative. Post-mortem examination did not reveal any unexpected cause for the sudden deterioration; in particular, the heart, whilst enlarged, showed no evidence of infarction. The liver was normal. There was no evidence of peritonitis. The kidneys were swollen with subcapsular and pelvic hxmorrhages. The glomeruli were essentially normal on light microscopy. The tubules were dilated with red-cell
oliguric.
The main abnormality was in the small arterioles, which showed concentric thickening, intimal proliferation, and fibrinoid change. casts.
This patient’s blood-pressure and uraemia were well controlled by peritoneal dialysis, and the plasmabicarbonate was normal when treatment was started with phenformin and ethyloestrenol. Five days later he developed a massive metabolic acidosis for which no precipitating cause other than phenformin therapy was found. SECOND CASE un
Case 1: biochemical data
z
illustrating sudden
terminal acidosis
Diabetes mellitus in 1967 and
woman
was was
diagnosed in treated with
a 63-year-old chlorpropamide
71 250 mg. thrice daily and phenformin 25 mg. thrice daily. At that time her plasma-electrolyte and blood-urea levels were normal. In May, 1968, she was admitted to hospital with mild dysuria, nocturia, abdominal pain, and general ill-health. There was evidence of urinary retention, but the patient was afebrile and did not appear particularly ill. Investigations showed haemoglobin 11-5 g. per 100 ml., white blood-cells 12,000 per c.mm., sodium 128 meq. per litre, potassium 4-1 meq. per litre, bicarbonate 24 meq. per litre, urea 45 mg. per 100 ml., and glucose 170 mg. per 100ml. Liver-function tests were normal. The urine-culture grew klebsiella. Treatment was begun with nalidixic acid 1 g. four times daily, and after a week in hospital the phenformin was increased to 50 mg. thrice daily. Two days later her blood-urea was 68 mg. per 100 ml., white bloodcells 25,000 per c.mm., and bicarbonate 13 meq. per litre. After a further thirty-six hours her blood-urea had risen to 100 mg. per 100 ml. and her bicarbonate had fallen to 8 meq. per litre; arterial blood pH 6-97 and PC02 29; bloodsugar 170 mg. per 100 ml., urinary ketones a trace only. The patient died soon afterwards. Blood-cultures subse-
quently proved negative. At necropsy the only abnormality
was acute
pyeloneph-
ritis.
A profound and fatal metabolic acidosis developed in diabetic patient during an attack of acute pyeloThe patient was nephritis without septicxmia. and receiving phenformin chlorpropamide, and the acidosis developed three days after the dose of phenformin was increased. a
THIRD CASE
Diabetes mellitus was first diagnosed in a 67-year-old in 1960. In 1969 treatment with phenformin 50 mg. twice daily was started. A urinary-tract infection was treated in January, 1971, at which time her blood-urea was 46 mg. per 100 ml. and bicarbonate 19 meq. per litre. In May, 1971, the patient was admitted to hospital in coma with a 48-hour history of right-loin pain and dysuria. The systolic blood-pressure was 90 mm. Hg, and there was marked peripheral vasoconstriction. Investigations revealed a haemoglobin of 8-9 g. per 100 ml., white bloodcells 28,000 per c.mm., sodium 124 meq. per litre, potassium 6-8 meq. per litre, bicarbonate 3 meq. per litre, urea 270 mg. per 100 ml., creatinine 2-4 mg. per 100 ml. Liverfunction tests normal. Blood-glucose 510 mg. per 100 ml., lactate 12-9 meq. per litre. Arterial blood pH 6-92 and PC02 18. Blood and urine cultures grew Escherichia coli. Treatment was initiated with insulin, fluids, ampicillin, and gentamicin, and 500 meq. of sodium bicarbonate was given intravenously. The patient made an uneventful recovery and was discharged with a blood-urea of 68 mg. per 100 ml. and plasma-creatinine of 1-4 mg. per 100 ml., woman
taking chlorpropamide
500 mg.
daily.
A diabetic
patient receiving phenformin developed a urinary-tract infection, septicaemia, and diabetic coma. Her renal function was impaired and she had a severe
lactic acidosis from which she recovered. Discussion
The first patient developed profound and fatal metabolic acidosis within five days of starting phenformin. At that time he did not have circulatory failure, anoxia, diabetes, septicaemia, myocardial infarction, or liver failure--conditions in which severe acidosis may develop.22 Moreover, his renal failure was well controlled by dialysis. Unfortunately, blood-
lactate levels could not be measured before he died. However, the magnitude of the acidosis and its resistance to the infusion of massive quantities of sodium bicarbonate is best explained by the development of the metabolic derangement usually associated with lactic acidosis. The time-course of his final illness (see figure) strongly suggests that this acidosis was precipitated by administration of phenformin. Cases 2 and 3 were diabetic and had complicating infections, one with septicaemia. It is, therefore, less easy to assess the role of phenformin in the development of the severe metabolic acidosis in these patients, but the increasing number of such cases in published reports suggests that phenformin may be a precipitating factor.1 The blood-urea has been elevated in the majority of reported cases of lactic acidosis associated with phenformin administration. Phenformin and its metabolites are mainly excreted in the urine, 11 and it seems probable that blood levels are raised in the presence of renal failure. There is evidence that in diabetics the fasting blood-lactate concentration is related to the daily dose of phenformin. 12 In uraemia the utilisation of lactate is usually normal and the acidosis of renal failure is corrected by peritoneal dialysis with lactatecontaining solutions. Moreover, the administration of sodium lactate would not be expected to increase hydrogen-ion concentration. For these reasons it is highly unlikely that the terminal acidosis in case 1 was due to the lactate administered in the dialysis fluid. Nevertheless, it would seem sensible to treat lactic acidosis with intravenous sodium bicarbonate and peritoneal dialysis using an acetate-containing solution. Hxmodialysis has been advocated 13 and may be preferable; but, as in case 1, the course of the illness may be so rapid that such therapy cannot be initiated in time. The possible role of phenformin as a precipitant of lactic acidosis in urasmia is especially significant in the light of reports of its use in conjunction with ethyloestrenol as fibrinolytic therapy in the hxmolyticurxmic syndrome and pre-eclamptic toxaemia.3,7 Similar reasoning led to the use of these drugs in case 1. The subsequent course in this patient, together with increasing reported evidence, leads us to suggest that phenformin should not be used in the presence of renal failure, and should be used with caution in diabetic patients who may develop renal involvement. We are grateful to Prof. W. manuscript.
I. Cranston for his criticism of the
REFERENCES 1. Oliva, P. B. Am. J. Med. 1970, 48, 209. 2. Woods, H. F. Br. J. Hosp. Med. 1971, 11, 668. 3. Mandal, B. K., McNulty, M. Lancet, 1971, ii, 1036. 4. Fearnley, G. R., Chakrabarti, R., Hocking, E. D. ibid. 1967, ii, 1008. 5. Fearnley, G. R., Chakrabarti, R., Evans, J. F. ibid. 1971, i, 723. 6. Chakrabarti, R., Fearnley, G. R. ibid. 1967, ii, 1012. 7. Goldsmith, H. J., Menzies, D. N., de Boer, C. H., Caplan, W., McCandless, A. ibid. 1971, ii, 738. 8. Sevitt, L. H., Wrong, O. M., Evans, D. J. Q. Jl Med. 1971, 40, 127. 9. Linton, A. L., Gavras, H., Gleadle, R. I., Hutchison, H. E., Lawson, D. H., Lever, A. F., Macadam, R. F., McNicol, G. P., Robertson, J. I. S. Lancet, 1969, i, 1277. 10. Kincaid-Smith, P. ibid. 1969, ii, 266. 11. Beckmann, R. Ann. N.Y. Acad. Sci. 1968, 148, 820. 12. Craig, J. W., Miller, M., Woodward, J., Merik, E. Diabetes, 1960, 9, 186. 13. Waters, W. C., Hall, J. D., Schwartz, W. B. Am. J. Med. 1963, 35, 781.
readings of serological
tests
were
done
by different
observers.
cell may well be vulnerable to one or factors in the adult environment. The other possibility-that the hepatic injury in l.c.c. itself results in reappearance of A.F.P. synthetic activity in the liver-seems less likely, since such resumption of embryonal function would be expected to be transient. In subacute and chronic diseases such as i.c.c. a large number of A.F.P.-positive cases at any given time would be unusual. Also, other hepatic disorders in children above 1 year of age do not lead to reappearance of A.F.P. in the serum. 100
developed "
more
Results
detected in nineteen children with i.c.c. (45%), most of them being above 1 year of age (table). Only two of these children were below 1 year of age (5 and 6 months), while in the remaining seventeen the mean age was 20-4 months, with a range of 12-42 A.F.P. was
A.F.P. IN THE SERA OF I.C.C. PATIENTS AND CONTROLS BY AGE
Requests for reprints should be addressed to N. C. N., Departof Pathology, All India Institute of Medical Sciences, New Delhi 16, India.
ment
REFERENCES
Nayak, N. C., Ramalingaswami, V. in Pædiatric Problems in Developing Countries (edited by P. Tirumala Rao); p. 229. Madras, 1970. 2. Ramalingaswami, V., Nayak, N. C. in Progress in Liver Disease (edited by H. Popper and F. Schaffner); vol. III, p. 222. New 1.
months. In contrast, only two out of twenty-eight controls (7%) had detectable A.F.P. in the serum. Both these children were less than 1 year of age (3 and 4.5 months); one was a sibling of a patient with i.c.c. and the other had neonatal hepatitis. The mean age of the remaining controls was 20 months, with a range between 9 and 36 months (excluding one child aged 9 years with liver disease).
3. 4. 5. 6. 7.
8. 9. 10.
Discussion
Less than half the children with i.c.c. had A.F.P. in the serum; however, had we used more sensitive techniques 6,7 the yield of positive cases might have been higher. As far as we know, detection of A.F.P. by the gel-diffusion technique in such a high proportion of cases is unknown for diseases other than hepatoma or teratocarcinoma.7 A.F.P. has been occasionally found in adults with cirrhosis and hepatitis by the geldiffusion method,8,9 but the total number of reported cases is very small.7 With the more sensitive radioautographic technique, however, A.F.P. has been detected in a relatively larger proportion of patients with acute hepatitis.’7 Masopust and colleagues 10 found A.F.P. in a few children with different types of hepatic disorder, but all these children were less than 1 year of age. In our control group both children with A.F.P. in the serum were less than 12 months old: one of them had an established liver disease, and the other, a sibling of a patient with i.c.c., may have had a hepatic abnormality not apparent by routine histology at the time of examination. Normally, A.F.P. is present in the serum during fetal life only; it becomes undetectable several days to a few weeks after birth, disappearing with a half-life of 3 days.11 Dallner and his colleagues have shown that several fine-structural and enzymatic alterations occur in the hepatocyte immediately before and after births This perinatal transformation of the liver cell from the fetal to the adult type is also associated with rapid suppression of A.F.P. synthesis and secretion. Is it possible that in infants later developing .c.c. the fetal hepatocyte fails to achieve the normal adult transformation, the defect being manifest in continuing synthesis and secretion of A.F.P.? Such an " un-
11. 12.
York, 1970. Singh, A., Jolly, S. S., Kumar, L. R. Lancet, 1961, i, 587. Abelev, G. I. Cancer Res. 1968, 28, 1344. Ouchterlony, Ö. Progr. Allergy, 1962, 6, 30. Alpert, E., Hershberg, R., Schur, P. H., Isselbacher, K. J. Gastroenterology, 1971, 61, 137. Abelev, G. I. in Cancer Research (edited by G. Klein, S. Weinhouse, and A. Haddow); p. 295. London, 1971. O’Conor, G. T., Tatarinov, J. U. S., Abelev, G. I., Uriel, J. Cancer, 1970, 25, 1091. Kresno, S. B., Gandasoebrata, R., Rümke, P. Lancet, 1970, i, 1178. Masopust, J., Kithier, K., Radl, J., Koutecky, J., Kotal, L. Int. J. Cancer, 1968, 3, 364. Gitlin, D., Boesman, M. J. clin. Invest. 1966, 45, 1826. Dallner, G., Siekevitz, P., Palade, G. E. J. Cell Biol. 1966, 30, 73, 97.
PHENFORMIN AND METABOLIC ACIDOSIS
G. A. MACGREGOR P. A. POOLE-WILSON N. F. JONES St. Thomas’s
Hospital, London S.E.1
patient with oliguric renal failure complicating accelerated hypertension was given phenformin and ethylœstrenol as fibrinolytic therapy. On the fifth day of this treatment a profound and fatal metabolic acidosis developed despite good control of uræmia by peritoneal dialysis. The acidosis was resistant to 2500 meq. sodium bicarbonate given over five hours. Two diabetic patients are also described in whom severe metabolic acidosis developed during phenformin therapy. The blood-lactate level was raised in the one patient in whom it was measured. The risk of severe acidosis should preclude administration of phenformin in patients with renal impairment. Awareness of this hazard is particularly pertinent in view of claims for this drug in the treatment of the hæmolytic-uræmic syndrome and pre-eclamptic Summary
A
toxæmia. Introduction
PHENFORMIN has been alleged to cause profound metabolic acidosis associated with elevated levels of blood-lactate, a state usually described as lactic acidosis. However, reported cases have usually had diabetes, circulatory failure, septicsemia, or tissue hypoxia
70 -conditions
which
may
themselves
cause
lactic
acidosis. 1,II Patients with lactic acidosis have commonly been found to have raised blood-urea levels, and it has been claimed that ursemia predisposes to lactic acidosis in patients receiving phenformin 1-an allegation that is especially important in view of the recent advocacy of treatment of the haemolytic-uraemic syndrome with phenformin and the anabolic steroid, ethyloestrenol.33 In this condition the deposition of fibrin in small vessels is thought to be an important factor, and the rationale for the use of phenformin and ethylrestrenol
depends on the ability of these drugs to increase fibrinolytic activity, to reduce plasma-fibrinogen levels,4to increase the level of plasminogen activator,6 and to reduce platelet stickiness.6 Similar reasoning has led to the use of phenformin in pre-eclamptic
blood
toxaemia. ? We describe here fatal metabolic acidosis occurring during therapy with phenformin and ethyloestrenol in a patient with malignant hypertension and acute oliguric renal failure. Two diabetic patients who developed severe metabolic acidosis while receiving phenformin are also described. Case-records FIRST CASE
A
admitted with a three-month 44-year-old history of headache and blurred vision. He had evidence of malignant hypertension with papilloedema, exudates, and flame-shaped haemorrhages on fundoscopy and a blood-pressure of 220/150 mm. Hg. Blood-Sim examination showed fragmented erythrocytes suggestive of a microangiopathic haemotytic anaemia, but the haemoglobin level and platelet-count were normal. Serum-fibrinogen was 0-69 g. per 100 ml.: serum titre of fibrin degradation products (F.D.P.) 1 in 128 (normal less than 1 in 4): plasmasodium 131 meq. per litre, plasma-potassium 2-6 meq. man was
per litre, plasma-bicarbonate 26 meq. per litre, blood-urea 124 mg. per 100 ml., plasma-creatinine 6-1 mg. per 100 ml. Liver-function tests were normal, and there was no history of alcoholism. High-dose intravenous pyelography showed kidneys of normal size without evidence of urinary-
obstruction. The blood-pressure was controlled with clonidine, but oliguria persisted and renal failure progressed. On the seventh day in hospital the blood-urea had risen to 350 mg. per 100 ml. and the plasma-creatinine to 12-0 mg. per 100 ml., with a plasma-bicarbonate of 25 meq. per litre. Peritoneal dialysis was started. The blood-pressure remained well controlled and the blood-urea and plasmacreatinine were satisfactorily lowered (see accompanying
tract
figure). After six days of peritoneal dialysis the patient remained This complication of accelerated hypertension has a very high mortality.8 There is evidence that intravascular fibrin deposition is important in this condition,9,10 and phenformin 50 mg. twice daily and ethylcestrenol 2 mg. twice daily were therefore given in view of their known fibrinolytic action. Five days after the start of phenformin and ethylcestrenol the patient complained of anxiety and breathlessness. The respiratory rate was increased but no other new abnormality was detected and, in particular, the blood-pressure was 140/90 mm. Hg and the peripheral circulation appeared normal. Arterial blood analysis showed a profound metabolic acidosis with a pH of 7’1 and Pcoof 20 mm. Hg, plasma-sodium 140 meq. per litre, plasma-potassium 6-9 meq. per litre, plasma-bicarbonate 12 meq. per litre, blood-urea 134 mg. per 100 ml. This compared with values on the previous day of plasmasodium 136, plasma-potassium 5-3, plasma-bicarbonate 23, and blood-urea 132 (see figure). The blood-sugar was 130 mg. per 100 ml. and the chest X-ray was clear. Within an hour the patient became acutely ill with a low blood-pressure and tachycardia. The arterial blood pH was 6-9 and lactic acidosis was provisionally diagnosed. Clearly its correction would require a large amount of sodium bicarbonate, and, in an attempt to mitigate sodium overload, the dialysate sodium concentration was reduced to 80 meq. per litre with dextrose. Over the next five hours a total of 2500 meq. of sodium bicarbonate (8-4% solution) was administered intravenously, but, despite this enormous quantity of alkali, the blood pH remained at 6-9. Plasma-sodium rose to 155 meq. per litre. The patient died within six hours of complaining of breathlessness. Unfortunately it was not feasible to measure lactate levels. Blood-cultures subsequently proved negative. Post-mortem examination did not reveal any unexpected cause for the sudden deterioration; in particular, the heart, whilst enlarged, showed no evidence of infarction. The liver was normal. There was no evidence of peritonitis. The kidneys were swollen with subcapsular and pelvic hxmorrhages. The glomeruli were essentially normal on light microscopy. The tubules were dilated with red-cell
oliguric.
The main abnormality was in the small arterioles, which showed concentric thickening, intimal proliferation, and fibrinoid change. casts.
This patient’s blood-pressure and uraemia were well controlled by peritoneal dialysis, and the plasmabicarbonate was normal when treatment was started with phenformin and ethyloestrenol. Five days later he developed a massive metabolic acidosis for which no precipitating cause other than phenformin therapy was found. SECOND CASE un
Case 1: biochemical data
z
illustrating sudden
terminal acidosis
Diabetes mellitus in 1967 and
woman
was was
diagnosed in treated with
a 63-year-old chlorpropamide
71 250 mg. thrice daily and phenformin 25 mg. thrice daily. At that time her plasma-electrolyte and blood-urea levels were normal. In May, 1968, she was admitted to hospital with mild dysuria, nocturia, abdominal pain, and general ill-health. There was evidence of urinary retention, but the patient was afebrile and did not appear particularly ill. Investigations showed haemoglobin 11-5 g. per 100 ml., white blood-cells 12,000 per c.mm., sodium 128 meq. per litre, potassium 4-1 meq. per litre, bicarbonate 24 meq. per litre, urea 45 mg. per 100 ml., and glucose 170 mg. per 100ml. Liver-function tests were normal. The urine-culture grew klebsiella. Treatment was begun with nalidixic acid 1 g. four times daily, and after a week in hospital the phenformin was increased to 50 mg. thrice daily. Two days later her blood-urea was 68 mg. per 100 ml., white bloodcells 25,000 per c.mm., and bicarbonate 13 meq. per litre. After a further thirty-six hours her blood-urea had risen to 100 mg. per 100 ml. and her bicarbonate had fallen to 8 meq. per litre; arterial blood pH 6-97 and PC02 29; bloodsugar 170 mg. per 100 ml., urinary ketones a trace only. The patient died soon afterwards. Blood-cultures subse-
quently proved negative. At necropsy the only abnormality
was acute
pyeloneph-
ritis.
A profound and fatal metabolic acidosis developed in diabetic patient during an attack of acute pyeloThe patient was nephritis without septicxmia. and receiving phenformin chlorpropamide, and the acidosis developed three days after the dose of phenformin was increased. a
THIRD CASE
Diabetes mellitus was first diagnosed in a 67-year-old in 1960. In 1969 treatment with phenformin 50 mg. twice daily was started. A urinary-tract infection was treated in January, 1971, at which time her blood-urea was 46 mg. per 100 ml. and bicarbonate 19 meq. per litre. In May, 1971, the patient was admitted to hospital in coma with a 48-hour history of right-loin pain and dysuria. The systolic blood-pressure was 90 mm. Hg, and there was marked peripheral vasoconstriction. Investigations revealed a haemoglobin of 8-9 g. per 100 ml., white bloodcells 28,000 per c.mm., sodium 124 meq. per litre, potassium 6-8 meq. per litre, bicarbonate 3 meq. per litre, urea 270 mg. per 100 ml., creatinine 2-4 mg. per 100 ml. Liverfunction tests normal. Blood-glucose 510 mg. per 100 ml., lactate 12-9 meq. per litre. Arterial blood pH 6-92 and PC02 18. Blood and urine cultures grew Escherichia coli. Treatment was initiated with insulin, fluids, ampicillin, and gentamicin, and 500 meq. of sodium bicarbonate was given intravenously. The patient made an uneventful recovery and was discharged with a blood-urea of 68 mg. per 100 ml. and plasma-creatinine of 1-4 mg. per 100 ml., woman
taking chlorpropamide
500 mg.
daily.
A diabetic
patient receiving phenformin developed a urinary-tract infection, septicaemia, and diabetic coma. Her renal function was impaired and she had a severe
lactic acidosis from which she recovered. Discussion
The first patient developed profound and fatal metabolic acidosis within five days of starting phenformin. At that time he did not have circulatory failure, anoxia, diabetes, septicaemia, myocardial infarction, or liver failure--conditions in which severe acidosis may develop.22 Moreover, his renal failure was well controlled by dialysis. Unfortunately, blood-
lactate levels could not be measured before he died. However, the magnitude of the acidosis and its resistance to the infusion of massive quantities of sodium bicarbonate is best explained by the development of the metabolic derangement usually associated with lactic acidosis. The time-course of his final illness (see figure) strongly suggests that this acidosis was precipitated by administration of phenformin. Cases 2 and 3 were diabetic and had complicating infections, one with septicaemia. It is, therefore, less easy to assess the role of phenformin in the development of the severe metabolic acidosis in these patients, but the increasing number of such cases in published reports suggests that phenformin may be a precipitating factor.1 The blood-urea has been elevated in the majority of reported cases of lactic acidosis associated with phenformin administration. Phenformin and its metabolites are mainly excreted in the urine, 11 and it seems probable that blood levels are raised in the presence of renal failure. There is evidence that in diabetics the fasting blood-lactate concentration is related to the daily dose of phenformin. 12 In uraemia the utilisation of lactate is usually normal and the acidosis of renal failure is corrected by peritoneal dialysis with lactatecontaining solutions. Moreover, the administration of sodium lactate would not be expected to increase hydrogen-ion concentration. For these reasons it is highly unlikely that the terminal acidosis in case 1 was due to the lactate administered in the dialysis fluid. Nevertheless, it would seem sensible to treat lactic acidosis with intravenous sodium bicarbonate and peritoneal dialysis using an acetate-containing solution. Hxmodialysis has been advocated 13 and may be preferable; but, as in case 1, the course of the illness may be so rapid that such therapy cannot be initiated in time. The possible role of phenformin as a precipitant of lactic acidosis in urasmia is especially significant in the light of reports of its use in conjunction with ethyloestrenol as fibrinolytic therapy in the hxmolyticurxmic syndrome and pre-eclamptic toxaemia.3,7 Similar reasoning led to the use of these drugs in case 1. The subsequent course in this patient, together with increasing reported evidence, leads us to suggest that phenformin should not be used in the presence of renal failure, and should be used with caution in diabetic patients who may develop renal involvement. We are grateful to Prof. W. manuscript.
I. Cranston for his criticism of the
REFERENCES 1. Oliva, P. B. Am. J. Med. 1970, 48, 209. 2. Woods, H. F. Br. J. Hosp. Med. 1971, 11, 668. 3. Mandal, B. K., McNulty, M. Lancet, 1971, ii, 1036. 4. Fearnley, G. R., Chakrabarti, R., Hocking, E. D. ibid. 1967, ii, 1008. 5. Fearnley, G. R., Chakrabarti, R., Evans, J. F. ibid. 1971, i, 723. 6. Chakrabarti, R., Fearnley, G. R. ibid. 1967, ii, 1012. 7. Goldsmith, H. J., Menzies, D. N., de Boer, C. H., Caplan, W., McCandless, A. ibid. 1971, ii, 738. 8. Sevitt, L. H., Wrong, O. M., Evans, D. J. Q. Jl Med. 1971, 40, 127. 9. Linton, A. L., Gavras, H., Gleadle, R. I., Hutchison, H. E., Lawson, D. H., Lever, A. F., Macadam, R. F., McNicol, G. P., Robertson, J. I. S. Lancet, 1969, i, 1277. 10. Kincaid-Smith, P. ibid. 1969, ii, 266. 11. Beckmann, R. Ann. N.Y. Acad. Sci. 1968, 148, 820. 12. Craig, J. W., Miller, M., Woodward, J., Merik, E. Diabetes, 1960, 9, 186. 13. Waters, W. C., Hall, J. D., Schwartz, W. B. Am. J. Med. 1963, 35, 781.