Metformin Intoxication Research Articles

Clinical and Laboratory Features of Metformin Intoxication in Suicidal Patients Attending an Intensive Care Unit.

This study has been performed for the purpose of researching the complications occurred at patients who took metformin overdose in an attempt to suicide. None of the patients has the diagnosis of diabetes mellitus and never used metformin. This retrospective cross-sectional study was carried out with 21 patients who has neither diagnosed diabetes mellitus nor taken metformin for suicide before. It was observed that there is a moderate, negative (r = -0.63) statistically significant correlation (P < 0.001) between the time of applying to the hospital and arterial blood pH at the arrival and a statistically significant positive mild correlation (P < 0.041) between applying and blood lactate level (r = 0.45), and a moderate positive (r = 0.63) and statistically significant correlation (P < 0.001) between the total metformin dose and blood lactate level at the arrival and a positive, moderate (r = 0.68) significant correlation (P < 0.001) between the creatinine and metformin dose at the arrival. Lactic acidosis has been detected at 8 of 21 patients, 6 patients were hemodialized, 2 patients needed mechanical ventilation, and 2 patients died. It is observed that there is no mortality for early hemodialized patients. The most important reason of the mortality in patients who has metformin intoxication is metformin-associated lactic acidosis (MALA). It was considered that hemodialysis therapy could be effective in MALA.

Treatment of Metformin Intoxication Complicated by Lactic Acidosis and Acute Kidney Injury: The Role of Prolonged Intermittent Hemodialysis

Metformin intoxication with lactic acidosis, a potentially lethal condition, may develop in diabetic patients when the drug dose is inappropriate and/or its clearance is reduced. Diagnosis and therapy may be delayed due to nonspecific symptoms at presentation, with severe anion gap metabolic acidosis and elevated serum creatinine values being the most prominent laboratory findings. Confirmation requires measurement of serum metformin by high-performance liquid chromatography-tandem mass spectrometry, but this technique is available only at specialized institutions and cannot be relied on as a guide to immediate treatment. Thus, based on strong clinical suspicion, renal replacement therapy must be started promptly to achieve efficient drug clearance and correct the metabolic acidosis. However, because metformin accumulates in the intracellular compartment with prolonged treatment, a rebound in serum concentrations due to redistribution is expected at the end of dialysis. We report a case of metformin intoxication, severe lactic acidosis, and acute kidney injury in a diabetic patient with pre-existing chronic kidney disease stage 3, treated effectively with sustained low-efficiency dialysis. We discuss the pathophysiology, differential diagnosis, and treatment options and highlight specific pharmacokinetic issues that should be considered in selecting the appropriate modality of renal replacement therapy.

A Rare Outcome Induced by Metformin Intoxication: Severe Lactic Acidosis and Hepatotoxicity

Abstract Metformin is a widely used oral anti-diabetic agent that decreases insulin resistance. Lactic acidosis rarely develops with this medication. Metformin-induced hepatotoxicity has been rarely reported in the literature. We describe a patient, who presented with lactic acidosis and hepatotoxicity after ingestion of 40 pills of metformin in order to commit suicide. The most important treatment step in patients with metformin-associated lactic acidosis (MALA) is high-volume hemodialysis and hemofiltration.

Skeletal muscle lactate overproduction during metformin intoxication: An animal study with reverse microdialysis.

Lactic acidosis during metformin intoxication is classically mainly attributed to diminished lactate clearance through liver gluconeogenesis. Here we studied 6 healthy, sedated and mechanically ventilated pigs to clarify whether high dose of metformin also increases skeletal muscle lactate production. Each animal had two microdialysis catheters inserted in gluteus muscles, one per side. One catheter was infused with saline (control) while the other one was infused with metformin diluted in saline (1M), both at a rate of 0.3μl/min. Dialysate lactate concentration and lactate-to-pyruvate ratio, a marker of the balance between anaerobic glycolysis and aerobic (mitochondrial) metabolism, were measured every 3h, for 12h. Continuous infusion of metformin caused a progressive rise in dialysate lactate level (p=0.007) and lactate-to-pyruvate ratio (p<0.001) compared to that of saline, as for mitochondrial "poisoning". These findings suggest that skeletal muscle lactate overproduction contributes to the development of metformin-induced lactic acidosis.

Pancreatitis and Metformin: Case-Report and Review of Literature

Metformin is the most used anti-hyperglycemic agent for the treatment of Type 2 Diabetes Mellitus. It is considered a very good drug, with low risk and high benefit. Metformin intoxication can be due to massive ingestion or to a progressive accumulation due to renal failure. Fatal cases due to metformin intoxication have been described. With regard to that we present a fatal case of a fifty-six-year-old patient with severe metformin intoxication (100 μg/ml) who presented kidney failure, lactic acidosis, hyperglycemia and pancreatitis. He received alkalinization and hemodialysis therapy, afterwards which shortly hereby improved his condition, but the patient deceased after 7 days for a nosocomial pneumonia. Pancreatitis was confirmed by the post-mortem histopathological analysis. Acute pancreatitis as side effect of metformin is very rare, either in overdose or therapeutic dosage, and it has been attributed to an intrinsic toxicity mechanism. With regard to that, we performed a review of the literature of all cases in which pancreatitis was referred to metformin use in order to evaluate if this complication usually develops in presence of specific predisposing factors, or if it is unpredictable. From our review, according to the literature, we confirm that acute pancreatitis represents a very rare side effect of metformin, either in therapeutic dosage or overdose. In metformin intoxication, polypharmacy and high doses might be possible risk factors in order to develop pancreatitis. There is not a specific association of metformin related pancreatitis and hyperglycemia, even if pancreatitis is generally linked to glucose homeostasis alterations. It is possible to assume that the presence of hyperglycemia depends on the extent of pancreatitis that if much extended could lead to a deficit of insulin release and to an increase of blood glucose levels.

Metformin in Chronic Kidney Disease: Time for a Rethink

Metformin has traditionally been regarded as contraindicated in chronic kidney disease (CKD), though guidelines in recent years have been relaxed to permit therapy if the glomerular filtration rate (GFR) is > 30 mL/min. The main problem is the perceived risk of lactic acidosis (LA). Epidemiological evidence suggests that this fear is disproportionate. Lactic acidosis is a rare complication to type 2 diabetes mellitus (T2DM), with an incidence of 6/100,000 patient-years. The risk is not increased in metformin-treated patients. Metformin possesses a number of clinical effects independent of glucose reduction, including weight loss, which are beneficial to patients. The risk of death and cardiovascular disease is reduced by about a third in non-CKD patients. Since metformin intoxication undoubtedly causes LA, and metformin is renally excreted, inappropriate dosage of metformin will increase the risk of LA. It is suggested that introduction of metformin therapy to more advanced stages of CKD may bring therapeutic benefits that outweigh the possible risks.

Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial complex I inhibition.

Metformin is a widely used antidiabetic drug associated with the rare side effect of lactic acidosis which has been proposed to be linked to drug-induced mitochondrial dysfunction. Using respirometry, the aim of this study was to evaluate mitochondrial toxicity of metformin to human blood cells in relation to that of phenformin, a biguanide analogue withdrawn in most countries due to a high incidence of lactic acidosis. Peripheral blood mononuclear cells and platelets were isolated from healthy volunteers, and integrated mitochondrial function was studied in permeabilized and intact cells using high-resolution respirometry. A wide concentration range of metformin (0.1-100mm) and phenformin (25-500μm) was investigated for dose- and time-dependent effects on respiratory capacities, lactate production and pH. Metformin induced respiratory inhibition at complex I in peripheral blood mononuclear cells and platelets (IC50 0.45mm and 1.2mm respectively). Phenformin was about 20-fold more potent in complex I inhibition of platelets than metformin. Metformin further demonstrated a dose- and time-dependent respiratory inhibition and augmented lactate release at a concentration of 1mm and higher. Respirometry of human peripheral blood cells readily detected respiratory inhibition by metformin and phenformin specific to complex I, providing a suitable model for probing drug toxicity. Lactate production was increased at concentrations relevant for clinical metformin intoxication, indicating mitochondrial inhibition as a direct causative pathophysiological mechanism. Relative to clinical dosing, phenformin displayed a more potent respiratory inhibition than metformin, possibly explaining the higher incidence of lactic acidosis in phenformin-treated patients.

ABSTRACT 652

Background and aims: Metformin is a biguanide anti-hyperglycemic agent used in type 2 diabetes to augment insulin sensitivity without lowering glucose concentration below normal. Aims: Metformin, a widely used and promising antidiabetic agent, became a new threat for childhood intoxication. Methods: In this report we present seven cases with metformin ingestion of doses ranging from 3.4 g to 85 g (Table). Results: We would like to emphasize two adolescent girls of 85 g and 70 g metformin intake, much higher than previous cases in literature. 85 g metformin combined with 10 g nateglinid lead to intractable MALA, multiorgan failure, and exitus. The patient with 70 g intake benefited from hemodialysis and hyperbaric oxygen treatment. Conclusions: Metformin intoxication associated lactic acidosis is a potentially fatal condition, which should be urgently treated with prolonged hemodialysis. The primary goal of hemodialysis is clearance of lactate. Hyperbaric oxygen therapy may be administered in selected patients to induce aerobic respiration. Organ failure and shock during MALA predict poor outcome.

Fatal metformin overdose: case report and postmortem biochemistry contribution

Metformin is an oral antihyperglycemic agent used in the management of type 2 diabetes mellitus. Lactic acidosis from metformin overdose is a rare complication of metformin therapy and occurs infrequently with therapeutic use. Fatal cases, both accidental and intentional, are extremely rare in clinical practice. Metformin is eliminated by the kidneys, and impaired renal function can result in an increased plasma concentration of the drug. In this report, we describe an autopsy case involving a 70-year-old woman suffering from diabetes mellitus and impaired renal function who received metformin treatment. Metformin concentrations in the peripheral blood collected during hospitalization and femoral blood collected during autopsy were 42 and 47.3 µg/ml, respectively. Lactic acidosis (29.10 mmol/l) was objectified during hospitalization. Furthermore, postmortem biochemistry allowed ketoacidosis to be diagnosed (blood β-hydroxybutyrate, 10,500 µmol/l). Death was attributed to lactic acidosis due to metformin intoxication. Increased plasma concentrations of the drug were attributed to severely impaired renal function. The case emphasizes the usefulness of performing exhaustive toxicology and postmortem biochemistry towards the more complete understanding of the pathophysiological mechanisms that may be involved in the death process.

Succinate ameliorates mitochondrial oxygen consumption of metformin-intoxicated human platelets

Metformin intoxication inhibits mitochondrial complex I and oxygen consumption (VO2). Succinate bypasses complex I by donating electrons to complex II. The aim of this study was to clarify whether succinate ameliorates mitochondrial VO2 of metformin-intoxicated human platelets.

Fatal Metformin Intoxication with Markedly Elevated Blood and Liver Concentrations

The highest postmortem metformin concentrations are recorded utilizing a sensitive and specific analytical procedure. The peripheral blood metformin concentration was 240 mg/L, the liver concentration was 240 mg/kg and the gastric concentration was 1,700 mg. Additionally, an antemortem blood sample collected shortly after admission revealed a metformin concentration of 210 mg/L. These data, revealing a liver to peripheral blood ratio of 1.0, provide additional support that metformin is not subject to postmortem redistribution. Intentional self-poisonings with metformin can result in death, despite multiple medical interventions.

Metformin overdose, but not lactic acidosis per se, inhibits oxygen consumption in pigs

IntroductionHepatic mitochondrial dysfunction may play a critical role in the pathogenesis of metformin-induced lactic acidosis. However, patients with severe metformin intoxication may have a 30 to 60% decrease in their global oxygen consumption, as for generalized inhibition of mitochondrial respiration. We developed a pig model of severe metformin intoxication to validate this clinical finding and assess mitochondrial function in liver and other tissues.MethodsTwenty healthy pigs were sedated and mechanically ventilated. Ten were infused with a large dose of metformin (4 to 8 g) and five were not (sham controls). Five others were infused with lactic acid to clarify whether lactic acidosis per se diminishes global oxygen use. Arterial pH, lactatemia, global oxygen consumption (VO2) (metabolic module) and delivery (DO2) (cardiac output by thermodilution) were monitored for nine hours. Oxygen extraction was computed as VO2/DO2. Activities of the main components of the mitochondrial respiratory chain (complex I, II and III, and IV) were measured with spectrophotometry (and expressed relative to citrate synthase activity) in heart, kidney, liver, skeletal muscle and platelets taken at the end of the study.ResultsPigs infused with metformin (6 ± 2 g; final serum drug level 77 ± 45 mg/L) progressively developed lactic acidosis (final arterial pH 6.93 ± 0.24 and lactate 18 ± 7 mmol/L, P < 0.001 for both). Their VO2 declined over time (from 115 ± 34 to 71 ± 30 ml/min, P < 0.001) despite grossly preserved DO2 (from 269 ± 68 to 239 ± 51 ml/min, P = 0.58). Oxygen extraction accordingly fell from 43 ± 10 to 30 ± 10% (P = 0.008). None of these changes occurred in either sham controls or pigs infused with lactic acid (final arterial pH 6.86 ± 0.16 and lactate 22 ± 3 mmol/L). Metformin intoxication was associated with inhibition of complex I in the liver (P < 0.001), heart (P < 0.001), kidney (P = 0.003), skeletal muscle (P = 0.012) and platelets (P = 0.053). The activity of complex II and III diminished in the liver (P < 0.001), heart (P < 0.001) and kidney (P < 0.005) while that of complex IV declined in the heart (P < 0.001).ConclusionsMetformin intoxication induces lactic acidosis, inhibits global oxygen consumption and causes mitochondrial dysfunction in liver and other tissues. Lactic acidosis per se does not decrease whole-body respiration.

İntihar Davranışı Olan İki Olguda Masif Metformin Aşırı Dozu: Kısa Bildiri

Lactic acidosis is a well-recognized side effect of metformin, especially in patients with renal failure. Only a few cases of deliberate self-poisoning with metformin have been described in the literature. The mechanism of metformin-associated lactic acidosis is complex. In the absence of acute overdose, metformin-associated lactic acidosis rarely develops in patients without comor - bidities such as renal or hepatic insufficiency or acute infection. We report two patients who had a large dose of metformin in an attempt to harm themselves and presented with lactic acidosis. In our experience, metformin intoxication may lead a high anion gap metabolic acidosis after a suicide attempt. Sodium bicarbonate infusion is able to correct the acid-base metabolism sufficiently in subjects with normal renal functions.

Metformin overdose causes platelet mitochondrial dysfunction in humans

IntroductionWe have recently demonstrated that metformin intoxication causes mitochondrial dysfunction in several porcine tissues, including platelets. The aim of the present work was to clarify whether it also causes mitochondrial dysfunction (and secondary lactate overproduction) in human platelets, in vitro and ex vivo.MethodsHuman platelets were incubated for 72 hours with saline or increasing doses of metformin (in vitro experiments). Lactate production, respiratory chain complex activities (spectrophotometry), mitochondrial membrane potential (flow-cytometry after staining with JC-1) and oxygen consumption (Clark-type electrode) were then measured. Platelets were also obtained from ten patients with lactic acidosis (arterial pH 6.97 ± 0.18 and lactate 16 ± 7 mmol/L) due to accidental metformin intoxication (serum drug level 32 ± 14 mg/L) and ten healthy volunteers of similar sex and age. Respiratory chain complex activities were measured as above (ex vivo experiments).ResultsIn vitro, metformin dose-dependently increased lactate production (P < 0.001), decreased respiratory chain complex I activity (P = 0.009), mitochondrial membrane potential (P = 0.003) and oxygen consumption (P < 0.001) of human platelets. Ex vivo, platelets taken from intoxicated patients had significantly lower complex I (P = 0.045) and complex IV (P < 0.001) activity compared to controls.ConclusionsDepending on dose, metformin can cause mitochondrial dysfunction and lactate overproduction in human platelets in vitro and, possibly, in vivo.Trial registrationNCT 00942123.

Dialysis therapy for lactic acidosis caused by metformin intoxication: presentation of two cases

Metformin is an oral antidiabetic, which is frequently used in the treatment of type II diabetes mellitus. Serious side effects may be seen during the administration of high doses of metformin. Two cases of lactic acidosis due to ingestion of high dose metformin for suicidal purposes have been presented here; in both cases, clinical improvement was seen with bicarbonate hemodialysis.

Metformin increases skeletal muscle lactate production in pigs: a microdialysis study

Lactic acidosis during metformin intoxication is mainly attributed to impaired hepatic lactate clearance [1]. The aim of this present work was to clarify whether metformin at high dose also increases skeletal muscle lactate production.

A Case of Fatal Metformin Overdose

Metformin is a widely used antidiabetic agent that is generally considered safe. Reported here is a fatal case of acute metformin overdose in a 73‐year‐old male patient. The rapid clinical deterioration is described to illustrate the possible severity of toxicity. It is followed by a literature review on the topics concerning acute metformin intoxication. Pathogenesis and clinical features on metformin‐associated lactic acidosis, as well as the current recommendations in management are discussed in details.

Successful Treatment of Severe Lactic Acidosis Caused by a Suicide Attempt with a Metformin Overdose

Metformin-associated lactic acidosis is a very rare but critical condition. It is seen in patients with type 2 diabetes mellitus who take metformin and attempt suicide with a metformin overdose. Here, we report a 43-year-old woman with type 2 diabetes mellitus and chronic renal insufficiency who developed hypoglycemia, hypothermia, tachycardia and lactic acidosis after a suicide attempt with a metformin overdose. She was successfully treated by continuous venovenous hemofiltration, and adequate hemodynamic and ventilatory support. Although metformin does not usually cause hypoglycemia when administered as monotherapy, hypoglycemia can occur in a condition coexistent with lactic acidosis secondary to metformin overdose. Metformin intoxication should be suspected when patients present with high anion gap metabolic acidosis after attempting suicide by ingesting drugs, particularly when comorbidities such as renal failure are present. Early diagnosis and rapid correction of the metabolic acidosis using hemodialysis or hemofiltration, together with concomitant cardiovascular support, and maintenance of blood glucose and core body temperature, provide the possibility of a positive outcome.

Severe metformin intoxication treated with prolonged haemodialyses and plasma exchange

Biguanides pose a significant risk of morbidity, mortality and permanent sequelae secondary to prolonged periods of hypoglycaemia. To investigate the treatment of massive metformin overdose associated with lactic acidosis. We present the case of a 30-year-old woman, who attempted to commit suicide by ingesting an 85-g massive metformin overdose associated with severe lactic acidosis, which we treated by performing prolonged haemodialysis with bicarbonate and plasma exchange. For the maximum elimination of metformin, extended haemodialysis is required and the treatment of the accompanying metabolic acidosis with bicarbonate is important for the effectiveness of the treatment. Patients benefit much more from the treatment of combined haemodialysis with plasma exchange.

Alterations of coagulation in metformin intoxication

It is widely known that metformin reduces the levels of circulating pro-coagulant factors and improve fibrinolytic activity in type 2 diabetes when used in therapeutic doses. Potential alterations of coagulation have not been reported in patients with metformin intoxication. We evaluated certain components of the coagulation system in a patient with metformin intoxication upon admission and after recovery. Our results indicate that both the levels of coagulation proteins synthesized by the liver and the anti-coagulant activity decrease temporarily in metformin intoxication. Nevertheless, no change in the coagulation factors secreted by the endothelium were observed.