Jean Daniel Lalau

Lactic Acidosis in Metformin-Treated Patients

ObjectiveThe antidiabetic drug metformin has been associated in a small number of patients with lactic acidosis, a serious condition with a poor prognosis. However, because of lack of data, the prognostic significance of hyperlactataemia in metformin-treated patients is not known.MethodsData were collected from 49 metformin-treated patients with lactic acidosis (arterial lactate level ≥5 mmol/L and blood pH ≤7.35) and available plasma metformin concentration data to investigate the association of arterial lactate levels and plasma metformin concentrations with mortality.ResultsThe overall mortality rate in this patient sample was 45% and the median arterial lactate level was 13.1 mmol/L. Median lactate levels were similar in patients who survived (13 mmol/L) and those who died (14.3 mmol/L), whereas the median plasma metformin concentration was 3 times higher in patients who survived (20.6 mg/L versus 6.3 mg/L).ConclusionIn this, the largest series of metformin-treated patients with lactic acidosis yet reported, 55% of patients survived and these patients had a median arterial lactate level of 13.1 mmol/L. Neither arterial lactate levels nor plasma metformin concentrations were of prognostic significance in relation to mortality in this sample of metformin-treated patients with lactic acidosis. Death in these patients appeared instead to be associated with other hypoxic disease or underlying ill health. These observations suggest that accumulation of metformin may not be as significant with respect to high arterial levels of lactate and their effects as has been traditionally thought.

Role of Metformin Accumulation in Metformin-Associated Lactic Acidosis

OBJECTIVE To investigate the role of metformin accumulation in the pathophysiology of metformin-associated lactic acidosis. RESEARCH DESIGN AND METHODS We used high-performance liquid chromatography to measure plasma metformin concentrations in 14 patients who experienced lactic acidosis (pH <7.35 and lactate concentration >5 mmol/l) while receiving chronic metformin treatment. Their treatment was generally based on alkalinization and dialysis therapy. RESULTS Clinical shock and/or evidence of tissue hypoxia was found in all patients with the exception of one who had a nonsteroidal anti-inflammatory drug-induced anuria. Ten patients had significant metformin accumulation (plasma metformin concentrations 4.1-84.9 mg/l, normal value 0.6 ± 0.5 mg/l before drug intake), generally because of failure to withdraw metformin despite intercurrent pathological conditions affecting its renal elimination (serum creatinine concentrations ranging from 269 to 1,091 μmol/l). There was no metformin accumulation (plasma metformin 0.03–0.7 mg/l) in the four other patients, who had less severe renal failure (serum creatinine 140–349 mumol/l). The severity of the patients general condition did not predict early hospital mortality (death before discharge from the intensive care unit) even in patients in shock. Whereas it was high in those without metformin accumulation (only 1 of 4 patients recovered), early hospital mortality was low in the 10 patients with metformin accumulation and was not related to its extent (3 patients died with end-stage hepatic failure or cardiac failure). Correlation studies showed a positive correlation between serum creatinine and plasma metformin and between plasma metformin and arterial lactate but, for the latter correlation, only in patients with metformin accumulation. CONCLUSION Metformin-associated lactic acidosis is not necessarily due to metformin accumulation; true type B (aerobic) lactic acidosis, i.e., without an apparent associated hypoxic factor, seems exceptional. Neither the severity of the clinical picture nor the degree of metformin accumulation predicted survival; rather, the prognosis was dependent upon the severity of the associated pathological conditions.

Pancreatitis related to severe acute hypertriglyceridemia during pregnancy : treatment with lipoprotein apheresis

We report a clinical observation of acute pancreatitis due to severe hypertriglyceridemia in a pregnant woman. In order to decrease the serum triglyceride level rapidly, two lipaphereses were undertaken using the double-filtration technique. This lipoprotein apheresis technique is briefly described and the efficacy in reducing rapidly hypertriglyceridemia is outlined. Like in 3 previously published reports, the patient had a rapid recovery, confirming that lipoprotein apheresis should be an adequate and a well-tolerated treatment in such a condition.

Lactic Acidosis in Metformin Therapy: Relationship between plasma metformin concentration and renal function

M I etformin belongs to a class of drugs known as the biguanides that are [widely used in the treatment of N1DDM. Its association with lactic acidosis is well established, although rare (1). Metformin undergoes rapid renal excretion (2-5). After oral administration of metformin, ~90% of the absorbed dose is rapidly excreted unchanged in the 12-h urine. Drug clearance is four to five times that of creatinine. According to these pharmacokinetic aspects, it is firmly established that occurrence of lactic acidosis linked to metformin necessitates, overdose excepted, metformin accumulation by renal failure (1). Indeed, close correlations between plasma metformin and creatinine clearance have been found in subjects with normal renal function, as well as in patients with moderate or severe renal failure (4,6). We report the case of a metformintreated patient with lactic acidosis and metformin accumulation that was an exception to the rule in that massive metformin accumulation contrasted with a mild increase in serum creatinine. A 65-year-old man with NIDDM of 10 years duration treated with metformin 850 mgb.i.d. was admitted with a 1-day history of abdominal pain predominant on the left side, vomiting, liquid stools, and tachypnoea. His medical history also revealed hypertension treated with diuretics (thiazide plus spironolactone), hepatitis B, and constipation. Physical examination revealed a distended abdomen with diminished bowel sounds. Vital signs included a rectal temperature of 36.3°C, a pulse rate of 110 beats/min, and a systolic blood pressure of 130 mmHg. Urine output was 0-20 ml/h. An abdominal X-ray showed a typical intestinal obstruction pattern. The peripheral arterial blood gas analysis performed on admission demonstrated lactic acidosis: pH 7.13, bicarbonate 5 mmol/1, and lactate 24.5 mmol/1. Dipstick urinalysis was positive for ketone bodies. Other laboratory findings included (serum): glucose 15 mmol/1, blood urea nitrogen 6 mmol/1, creatinine 129 umol/1, potassium 6 mmol/1, hematocrit 0.55, and proteins 80 g/l. The creatinine clearance, 400 600 800 Serum creatinine (p.mol/1) 100

Plasma atrial natriuretic factor and urinary excretion of a ouabain displacing factor and dopamine in normotensive pregnant women before and after delivery.

Estimation of urinary excretion of a ouabain displacing factor and dopamine was carried out immediately before delivery, and 7 days and 70 to 90 days after delivery in 12 normotensive pregnant women. Simultaneous estimation of plasma 99-126 atrial natriuretic factor, plasma renin activity, and plasma aldosterone were also undertaken. The data were compared with those obtained in a group of nonpregnant normotensive women (n = 14) and a group of pregnant normotensive women in the early phase of the third trimester (n = 14). Urinary ouabain displacing factor and dopamine levels were significantly higher in the early phase of the third trimester, as compared with nonpregnant women. But immediately before delivery, ouabain displacing factor excretion had fallen below nonpregnant values and dopamine excretion had dropped to control values. Both remained low after delivery. Plasma atrial natriuretic factor was higher in pregnant women, as compared with nonpregnant controls and remained high just before delivery and 7 and 70 to 90 days after delivery. Plasma renin activity and plasma aldosterone levels were higher during pregnancy and had fallen to nonpregnant values 7 days post partum. This drop in plasma renin activity and aldosterone by 7 days post partum, in contrast with the unchanged high values of atrial natriuretic factor, may contribute to negative sodium balance after delivery. It is concluded that there is considerable discrepancy in natriuretic and antinatriuretic factors before and after delivery.

L'enfant diabétique à l'exercice : étude multiparamétrique

Resume Introduction – Une etude multiparametrique a ete menee chez des enfants diabetiques insulinodependants en vue de caracteriser leur aptitude a lexercice. Methodes et resultas – Onze enfants DID et 24 enfants temoins ont effectue un test incremental lineaire de puissance sur ergocycle, normalise par rapport a la puissance maximale aerobie de chaque enfant. Les signaux electromyographiques de chaque chef musculaire du muscle quadriceps (energie totale et frequence moyenne du signal), et les variables cardiorespiratoires (consommation maximale doxygene, frequence cardiaque) et metaboliques (glycemie, lactatemie) ont ete quantifiees. Pour les enfants diabetiques, les evolutions des variables cardiorespiratoires ne sont pas significativement differentes de celles des temoins alors que les variables metaboliques evoluent differemment. Les variables electromyographiques montrent des profils devolution qui different selon les enfants mais pas selon les groupes. Lanalyse discriminante realisee sur lensemble des profils de la frequence moyenne a permis de differencier les enfants diabetiques des enfants temoins. Conclusion – Levolution du signal electromyographique permet de caracteriser laptitude a lexercice des enfants diabetiques.

Hypertriglycéridémie sévère associée à une pancréatite aiguë au cours de la grossesse. Traitement par aphérèse des lipoprotéines

The authors present a case of pancreatitis associated with hypertriglyceridemia during pregnancy. In order to reduce the TG level rapidly, two plasmaphereses were performed using a double filtration technique. As a result of the two plasma exchanges, TG level was acutely lowered by more than 70%. As in the single previously published report, the patient had a rapid recovery, confirming that LDL-apheresis is an adequate and well tolerated therapeutic in such a condition.

L'hypertension artérielle peut-elle être expliquée par une anomalie de sécrétion du facteur atrial natriurétique et de l'endothéline ?

Plasma ANF and endothelin levels were measured in normotensive and hypertensive pregnant women and in non-pregnant controls. If ANF levels were normal in pregnant women the results concerning endothelin may account for the prevention in hypertensive pregnancy of the vasodilatation occuring in normal pregnancy.