Metformin and antihypertensive therapy with drugs blocking the renin angiotensin system, a cause of concern?

BACKGROUND: The burden of diabetes mellitus type 2 (DM2) is increasing worldwide. The combination of DM2 and hypertension (HT) is frequently encountered. Concurrent use of drugs blocking the renin angiotensin system (angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB)) and metformin have become frequent in this group of patients. That combination can become life-threatening under certain circumstances. METHOD: We present 5 patients with DM2 and HT who developed severe metformin-associated lactic acidosis in a setting with acute renal failure, precipitated by dehydration and aggravated by the use of ACEI or ARB. RESULTS: None of the patients had reduced renal function before the acute illness. They were admitted to the hospital in critical condition with severe metabolic acidosis (pH 6.60 6.94), high S-lactate (14 - 23 mmol/l) and S-creatinine 796 1,621 micromol/l. They were all hypothermic and 3 were hypoglycemic. All developed circulatory and respiratory collapse. They were treated with either intermittent bicarbonate hemodialysis (HD) or with continuous venovenous hemodiafiltration (CVVHDF) and bicarbonate buffering. All patients recovered without renal sequela. CONCLUSION: We believe that the incidence of metformin-associated lactic acidosis in Norway may become more frequent due to increased use of metformin and drugs blocking the renin angiotensin system. The awareness of lactic acidosis as a complication to the use ofmetformin in predisposed individuals is important. General advice should be given to patients regarding reduction of dosage or withdrawal of the drugs during acute intercurrent illness with dehydration. Early diagnosis and treatment of metformin-associated lactic acidosis are crucial for the patient outcome. Hemodialysis can be life-saving and should be started without delay.

Clinical vs. laboratory identification of drugs of abuse in patients admitted for acute poisoning.

OBJECTIVE: The extent of drug abuse in patients admitted for self-poisonings is uncertain. The aim of this study was to assess the pattern of drugs of abuse among patients admitted for acute poisoning according to age and gender, and to study the concordance between the clinical assessments by the physicians on duty and the drug analyses. METHODS: Prospective cross sectional study of all patients (n = 405, 52% males, median age 31 years) treated for acute poisoning in our department during one year (2001). The physician on-call classified type of drug of abuse by history and clinical assessment. This was later compared to urine and blood samples analysed for ethanol, benzodiazepines, opiates, cocaine, ecstasy, GHB, amphetamine and cannabis. RESULTS: In 320 admissions (79%), the comparison between clinical diagnosis and laboratory analyses could be performed. A total of 478 drugs were suspected and 621 were found. The main toxic agents found were benzodiazepines (49.7%), ethanol (40.3%), opiates (35.3%), cannabis (23.8%) and amphetamine (21.3%). Ninety-two had used drugs of abuse. The agreement between clinical assessments and laboratory findings was best for GHB and ethanol (kappa = 0.43), and for opiates (k = 0.38). For benzodiazepines and cannabis, the concordance was poor (k = 0.18 and 0.10, respectively). However, the correct clinical evaluation for these substances was 59% and 77%, respectively. CONCLUSIONS: Drugs of abuse were more frequently found than suspected clinically. Benzodiazepines, ethanol and opiates were most common. The agreement between clinical assessment and drug analyses was moderate to low. Physicians seem to underestimate the use of these drugs.

Fomepizole may change indication for hemodialysis in methanol poisoning: prospective study in seven cases.

BACKGROUND: Treatment of methanol poisoning includes administration of buffer, antidote and hemodialysis. The role of hemodialysis using the new antidote fomepizole has not been studied. We studied the kinetics of methanol and formate during hemodialysis, and the possibility for delayed hemodialysis in the methanol poisoned patients without severe metabolic acidosis or visual disturbances. PATIENTS AND METHODS: Prospective case series study on methanol, formate and dialysis kinetics in 7 cases of severe methanol poisoning treated with buffer, fomepizole and hemodialysis (average 7 hours, range 5 - 8). Four patients were dialyzed early after diagnosis was obtained, while three were dialyzed "electively" the next day. RESULTS: The median pH upon admission was 6.9 (range 6.6 - 7.5) and median base deficit 20.4 mmol/l (range 5.1 - 30.0). Their median S-methanol was 76.3 mmol/l (range 15.6 - 140.6) and S-formate 13.6 mmol/l (range 3.3 - 21). The median half-life of methanol during fomepizole treatment before dialysis was 71.2 hours (range 69.3 - 77); compared to 2.5 hours (range 1.7 - 3.3) during procedure. The median half-life of formate during dialysis was 1.7 hours (range 1.5 - 1.9). The median dialysis clearance of methanol was 222 ml/min (range 204 - 232) and for formate 225 ml/min (range 220 - 229) at a blood flow of 250 ml/min. One patient died and 2 were discharged with permanent visual and cerebral sequelae, whereas one died one year later. All three patients, in whom "elective" hemodialysis was performed, were discharged without sequelae. CONCLUSION: The efficacy and side effect profile of fomepizole may change the role of hemodialysis in methanol poisoning. More patients may be stabilized in local hospitals and transferred for "elective" dialysis, if methanol removal is still indicated after correction of metabolic acidosis.

Methanol outbreak in Norway 2002-2004: epidemiology, clinical features and prognostic signs.

OBJECTIVES: Knowledge on methanol poisoning does mainly come from clinical studies. We therefore report epidemiological, clinical and prognostic features from the large methanol outbreak in Norway in 2002-2004 where the new antidote fomepizole was the primary antidote in use. DESIGN AND SUBJECTS: Combined prospective and retrospective case series study of 51 hospitalized patients who were confirmed poisoned with methanol, of whom nine died. In addition, eight patients died outside hospital. Most patients were admitted in a late stage and because of symptoms. Treatment consisted of alkali, fomepizole (71%) and haemodialysis (73%). RESULTS: The median serum methanol was 25.0 mmol L-1 (80 mg dL-1) (range 3.1-147.0 mmol L-1), median pH was 7.20 (6.50-7.50), and median base deficit 22 mmol L-1 (range 0-31). The most frequent clinical features reported were visual disturbances (55%), dyspnoea (41%), and gastrointestinal symptoms (43%). Twenty-four per cent were comatose on admission, of whom 67% died. There was a trend towards decreasing pCO2 with decreasing pH amongst the patients surviving. The opposite trend was demonstrated in the dying; the difference was highly significant by linear regression analyses (P<0.001). CONCLUSIONS: Methanol poisoning still has a high morbidity and mortality, mainly because of late diagnosis and treatment. Respiratory arrest, coma and severe metabolic acidosis (pH<6.90, base deficit>28 mmol L-1) upon admission were strong predictors of poor outcome. Early admission and ability of respiratory compensation of metabolic acidosis was associated with survival.

A new isosorbide dinitrate extended-release formulation: pharmacokinetic and clinical parameters in patients with stable angina pectoris.

In a double-blind, cross-over study the acute clinical efficacy and pharmacokinetic profile of a newly developed isosorbide dinitrate extended-release (ISDN-ER) formulation (10 mg immediate release and 60 mg slow release) were examined in eight angina patients. Exercise tests were done 1 h before and 1, 6 and 10 h after acute ISDN or placebo; similar testing was repeated after 14 days of open-labelled treatment. At 1, 6 and 10 h after administration, ISDN-ER significantly reduced the mean ST depression at highest comparable workload (HCWL) by 0.8, 0.6, and 0.6 mm, respectively. Total exercise duration increased significantly by 46, 42 and 72 s. The rate-pressure product at HCWL was not reduced significantly at any time, while digital plethysmography demonstrated a significant effect on arterial pulse curves throughout the 10 h. After 14 days of once-daily treatment, similar or somewhat attenuated clinical effects were observed. Pharmacokinetic measurements showed a first peak of ISDN at 1-2 h and a second peak at 4-5 h. The 5-isosorbide mononitrate (5-ISMN) metabolite peaked at 5-8 h and remained high at 10 h. After 14 days of treatment, the mean plasma concentrations of ISDN and 5-ISMN before drug were 0 and 69 ng.ml-1, respectively. Thus, satisfactory acute clinical efficacy and low nitrate levels during the night were observed. However, long-term clinical efficacy needs to be established in larger, placebo-controlled trials.