Fatal lactic acidosis after an overdose of phenformin.

The patient; a 64-year-old housewife, had been known to suffer from maturity-onset diabetes for four years. She was treated with chlorpropamide for 18 months, and then with a 1,000-calorie diet (130 g. of carbohydrate) alone for three months. She remained more than a stone (6.4 kg.) above the standard weight for her height and was therefore started on phenformin in May 1964 in order to treat her mild hyperglycaemia and to facilitate weight reduction. The dose of phenformin was gradually increased and for five months before admission to hospital, on 10 June 1965, she was taking 25 mg. q.i.d. She had been in good health until 24 hours before admission, when the sudden onset of generalized abdominal pain was closely followed by vomiting of watery material. Her bowels were regular and a normal motion was passed in the interval between the onset of symptoms and admission. She denied any dyspeptic history or symptoms referable to the renal tract or cardiovascular system. The pain remained generalized and did not radiate from the abdomen. Twelve hours before the onset of her symptoms (36 hours before admission) she had mistakenly ingested two 25-mg. phenformin tablets in excess of her normal dose-that is, a total of 150 mg. in divided dosage in 12 hours. On examination the patient, who lived in comfortable circumstances, was ill, pale, and obese and had acidotic respirations, but acetone could not be detected in the breath. She was moderately dehydrated. The rectal temperature was 88.2' F. (31.2' C.), she was orientated and examination of the peripheral nervous system showed no abnormality, though the plantar responses could not be elicited. Neither pupil reacted to light or to accommodation, and the left was larger than the right. The left fundus was normal and the right was obscured by cataract. Her chest was clinically and radiologically normal, and examination of the abdomen (including rectal investigation) showed no abnormality. The pulse was of poor volume, though regular at 100 per minute. No signs of cardiac failure were observed and the heart sounds were normal. Blood pressure was recordable at 96/60 mm. Hg only after 7 mg. of metaraminol (Aramine) had been given intravenously. The laboratory findings on admission were as follows: Hb 11.6 g./100 ml.; W.B.C. 20,600/cu. mm., differential normal; E.S.R. 11 mm. in the first hour. Urinalysis showed moderate proteinuria, no glycosuria, and only a trace of ketones to Acetest and negative ferric chloride reaction. There were no cells or casts in the urinary deposit. E.C.G. showed left ventricular hypertrophy and ischaemia; J waves were not present. Serum and electrolyte values (sodium, potassium, and chloride) were normal. Blood urea was 140 mg./100 ml., falling to 84 mg./100 ml. after rehydration. No salicylates were detected in the serum, and the values of serum transaminases (S.G.O.T., S.G.P.T.) and of serum amylase were normal. The plasma CO2 combining power was 5.8 mEq/l.Blood sugar was 140 mg./100 ml. and the serum lactic acid level was 240 mg./100 ml. (26.7 mM./l.) five hours after admission. Therapy was started with intravenous dextrose 5% and isotonic saline with added metaraminol and sodium bicarbonate. After 12 hours of such treatment her condition remained desperate. Despite giving 400 mEq of sodium bicarbonate and 120 mg. of metaraminol in a total of 2,700 ml. of intravenous fluid she remained oliguric and grossly acidotic. At this point, 12 hours after starting treatment, the C02 combining power was 4.9 mEq/l. and the arterial pH 6.92 (Pco2 less than 30 mm. and standard bicarbonates less than 6 mEq/l.). The rectal temperature had risen to 940 F. (34.50 C.). The patient's condition and blood pressure improved slightly after the infusion of 540 ml. of 10% dextrose in two hours, and 600 ml of urine was passed in the second 12 hours, the blood pressure being 90 to 110/50 to 60 mm. Hg. Twenty-eight hours after admission she had a cardiac arrest. Immediate resuscitation was unsuccessful. Post-mortem examination failed to reveal any significant disease apart from thrombosed splenic vein. Comment.-The only recognized factor which could contribute to the metabolic acidosis was the history of taking 50 mg. in excess of her usual 100 mg. daily of phenformin. She had no significant uraemia, salicylism, infection, or external cause for her acidosis and there was no preceding period of severe carbohydrate .deprivation.