Severe lactic acidosis with euglycemic diabetic ketoacidosis due to metformin overdose.

Metformin-associated lactic acidosis is a well-known metformin treatment complication; however, the development of euglycemic diabetic ketoacidosis (euDKA) has rarely been reported. Here we report a case of lactic acidosis and euDKA after metformin overdose. A 57-year-old female patient was transferred to our hospital with severe metabolic acidosis and acute kidney injury. She had type 2 diabetes mellitus and was on oral antidiabetic therapy of vildagliptin metformin hydrochloride daily. On the admission day, she had committed suicide by overdosing 50 tablets of vildagliptin metformin hydrochloride, which was equivalent to 25,000 mg of metformin and 2500 mg of vildagliptin. She had severe lactic acidosis 5 h after overdosing. However, after 34 h of overdosing, serum lactate levels decreased while serum anion gap levels increased. She received single hemodialysis treatment. Serum total ketone bodies, ß-hydroxybutyrate acetoacetic acid, and acetone were increased even after hemodialysis treatment. Her blood glucose levels have never exceeded 250 mg/dL since admission. Therefore, we considered that the cause of metabolic acidosis in this patient was not only lactic acidosis but also euDKA. The causes of euDKA in our patient might be hepatic production of ketone bodies due to metformin overdose in addition to type 2 diabetes mellitus, starvation, infection, and stressful physical conditions such as vomiting and diarrhea. We propose that not only lactic acidosis but also ketoacidosis is one of the important pathological conditions in patients with metformin overdose.

Specific interpretation of hair concentrations in 2 fatal metformin intoxication cases.

Hair analysis is very useful for toxicological investigations since, by providing a wider detection window, it gives the possibility to perform a retrospective study on the historical consumption of a substance. Unfortunately, there are no data available for hair concentrations in metformin-related deaths. In this study, the authors present 2 cases of fatal metformin intoxication in which, for the first time, hair analysis was performed using a specific GC-MS/MS method. Metformin was tested positive in femoral blood (112.3 mg/L and 64.7 mg/L respectively) and cardiac blood (226.9 and 203.2 mg/L) of the two subjects. For case 1, other samples were also tested positive, including vitreous humor (31.1 mg/L) and gastric contents (773.5 mg/L). In case 2, metformin was measured at 844.9 mg/L in urine. Metformin hair concentrations were 28.3-44.8 and 22.5 ng/mg for both cases, respectively. The concentrations found in the 2 fatal cases are clearly higher than those obtained in a previous study with subjects under treatment (0.3-3.8 ng/mg) or those found in 3 post-mortem cases where metformin death was excluded (0.6-1.4 ng/mg). Excessive sweating during the agonal phase due to fatal hypoglycemia could explain these elevated concentrations as sweat can have contaminated the hair.

Metformin-associated lactic acidosis: reinforcing learning points.

Metformin-associated lactic acidosis (MALA) carries a high mortality rate. It is seen in patients with type 2 diabetes on metformin or patients who attempt suicide with metformin overdose. We present the case of a man in his early 20s with type 2 diabetes, hypertension and hypothyroidism who presented with agitation, abdominal pain and vomiting after ingesting 50-60 g of metformin; he developed severe lactic acidosis (blood pH 6.93, bicarbonate 7.8 mEq/L, lactate 28.0 mEq/L). He was managed with intravenous 8.4% bicarbonate infusion and continuous venovenous haemodiafiltration. He also developed acute renal failure (ARF) requiring intermittent haemodialysis and continuous haemodiafiltration. MALA is uncommon and causes changes in different vital organs and even death. The primary goals of therapy are restoration of acid-base status and removal of metformin. Early renal replacement therapy for ARF can result in rapid reversal of the acidosis and good recovery, even with levels of lactate normally considered to be incompatible with survival.

Successful Dialysis Treatment of Metformin Associated Lactic Acidosis, Report of Two Cases.

INTRODUCTION: Metformin-associated lactic acidosis is rare despite its widespread use. It is often associated with the use of metformin in the presence of chronic kidney disease, but it may also occur in people with normal renal function in the case of acute overdose. CASE REPORT: 20 years old (patient 1) and 37 years old (patient 2) women without any chronic disease took 40 gram (727 mg/ kg) and 60 gram (1200 mg/kg) metformin, respectively; for the suicidal attempt. Deep lactic acidosis was detected in patients. In patient 1, hemodialysis was performed for 4 hours. After the interruption, deep acidosis evolved again and another dialysis session was performed. In patient 2, hemodialysis was performed for 16 hours without any interruption and she did not need any other dialysis session. CONCLUSION: Metformin has a large distribution volume. It is not correct to make a final decision as to how long the dialysis will continue when dialysis begins. Dialysis should be continued without interruption until clinical and laboratory targets are achieved.

Time to development of metformin-associated lactic acidosis.

Objective: Metformin-associated lactic acidosis (MALA) is a complication of metformin overdose. Recommendations for observation time after an acute ingestion to monitor for MALA vary. The aim of this study was to characterize the time to development of MALA after an acute metformin overdose.Methods: Utilizing Crystal Reports (Version 11.0), all metformin cases reported to the Illinois Poison Center (IPC) with a National Poison Data System (NPDS) clinical effects code of "acidosis" or "anion gap" were retrospectively queried over a 14-year period (2001-2014). Demographic data, time to MALA, co-ingestants, therapeutic modality use, and case outcome were extracted. Interrater reliability was assessed using kappa analysis.Results: A total of 88 cases were identified of which 44 met criteria for MALA; 40 were acute, acute on chronic, or unknown ingestions. The remaining four were chronic ingestions which were excluded. The mean age was 41 years (range 19-79 years). Most were female (55.0%) and over half (62.5%) were acute on chronic ingestions. Hypoglycemia was seen in three ingestions of metformin only. Of the 40 MALA cases, 18 developed MALA less than or equal to 6 h after ingestion, 9 between 6-12 h, 3 after 12 h, and 10 patients had an unknown time to MALA. The only death in the cohort had MALA detected beyond the typical 6-h observation period. Of the exposures when time to MALA was known, 40% (12/30) developed MALA greater than 6 h post ingestion.Conclusion: A 6-h observation period after a single acute ingestion of metformin may be inadequate, as a significant portion of exposures developed MALA beyond this time. We recommend a minimum of 12 h of observation following an acute overdose. Further study defining prospectively the time to development of MALA may improve management of this population.

Metformin - Postmortem fatal and non-fatal reference concentrations in femoral blood and risk factors associated with fatal intoxications.

BACKGROUND & OBJECTIVES: To improve the interpretation of fatal intoxications by establishing fatal and non-fatal reference concentrations of metformin in postmortem femoral blood and to further evaluate risk factors associated with fatal metformin intoxication. METHODS: All forensic autopsies in Sweden where metformin was detected in femoral blood 2011-2016 were identified in the National Board of Forensic Medicine databases (NFMD). The cases were classified as single substance intoxications, A (n = 22), multiple substance intoxications, B (N = 7) and postmortem controls, C (N = 13). The control group consisted of cases where metformin was detected, but the cause of death excluded the incapacitation by metformin or other substances. Strict inclusion criteria were used, and all postmortem cases were assessed by two independent reviewers. All other cases where the inclusion criteria of groups A-C where not met formed group O (N = 78). The forensic findings logged in the NFMD where linked to national registers whereby information on comorbidities, dispensed drugs and clinical data could be obtained. RESULTS: The mean age was 66 ± 10 years in the total study population and did not differ between the groups. The proportion of men was 64% in group A, 71% in B, 77% in C and 74% in group O. The median values of metformin in group A (48.5 µg/g; range 13.0-210 µg/g) and B (21.0 µg/g; range 4.40-95.0 µg/g) were significantly (p < 0.001 and p = 0.015 respectively) higher than those of the control group C (2.30 µg/g ; range 0.70-21.0 µg/g). The median concentration of metformin in group A and B was also significantly higher than in group O (4.60 µg/g; range 0.64-54.0 µg/g) (p < 0.001 and p = 0.040 respectively). The results suggest that intoxication with metformin as a cause of death should be considered when the postmortem femoral blood level exceeds about 10 µg/g, although higher levels may be seen in postmortem in cases without incapacitation. The metformin intoxication was confirmed to be intentional in 23% (n = 5) of the single intoxications. Underlying factors identified as important for the remaining fatal metformin intoxications included living alone, any contraindication for the use of metformin, known alcohol abuse and a history of stroke or cardiovascular disease. CONCLUSIONS: The reported post mortem femoral blood concentrations of metformin can hopefully contribute to a better interpretation of results in suspected poisonings and obscure cases. Living in a single household, history of cardiovascular disease and contraindications, predominantly alcohol abuse, were associated with fatal metformin intoxication.

Metformin-associated lactic acidosis treated successfully by peritoneal dialysis in a resource limited setting: case report.

Metformin is a commonly used treatment modality in type 2 diabetes mellitus with lactic acidosis as a rare but life-threatening side effect. In this case report we highlight the importance of recognizing this uncommon side effect and the treatment options in a resource limited situation. We present a 14-year-old African girl who ingested an unknown amount of metformin intentionally after an argument with her mother. She was referred late to our institution in severe lactic acidosis. Lactic acidosis resolved with appropriate treatment including peritoneal dialysis. We conclude that in resource constrained settings, peritoneal dialysis may be used for metformin associated lactic acidosis with favourable outcome.

Metformin overdose: A serious iatrogenic complication-Western France Poison Control Centre Data Analysis.

INTRODUCTION: The prevalence of type 2 diabetes (T2D) continues to rise across the world. Metformin is still considered the "gold standard" and is, therefore, increasingly prescribed. Monitoring of metformin continues to be debated because of its association with lactic acidosis (MALA), a rare but life-threatening complication. The aim of this study was to identify the main individual characteristics associated with severe poisoning in self-poisonings and therapeutic accidents reported at the Western France Poison Control Centre (PCC). METHODS: Retrospective study of metformin poisoning from September 1999 to September 2016 at the Western France PCC recorded in the French PCC's database (SICAP). The end-point was clinically high severity (mortality and/or cardiovascular shock and/or GCS ≤ 7/15). RESULTS: Of the 382 cases included, 197 concerned acute accidental exposures, 127 self-poisonings and 58 therapeutic accidents. MALA concerned 63 patients: 44 therapeutic accidents and 19 self-poisonings. High severity concerned 59 patients: 47 therapeutic accidents and 12 self-poisonings. T2D and age > 60 significantly increase the risk of high severity (OR 7.7, CI [1.54-38.41]; P = 0.013; OR 3.5, CI [1.60-7.84]; P = 0.002, respectively). CONCLUSIONS: Metformin may lead to MALA and severe poisoning in therapeutic accidents but also in self-poisoning circumstances. Among reported cases, T2D history and age >60 increase the risk of serious poisoning. Monitoring of their treatment should be taken seriously especially in the event of digestive symptoms such as diarrhoea.

Incidence and risk factors for hyperlactatemia in ED patients with acute metformin overdose.

INTRODUCTION: The goals of this study are to describe clinical characteristics and risk factors for metabolic acidosis with hyperlactatemia in emergency department (ED) patients with acute metformin overdose. METHODS: This was a secondary analysis of data from a retrospective observational cohort of adult ED patients presenting with acute drug overdose at two tertiary care hospitals over 5 years. The primary outcomes were: (1) hyperlactatemia, defined as a lactate concentration ≥ 2 mmol/L at any point during hospital admission and, (2) metformin associated lactic acidosis (MALA), defined as a lactate concentration ≥ 5 mmol/L and pH <7.35 at any point during hospital admission. RESULTS: We screened 3739 acute overdoses; 2872 met eligibility, 56 self-reported metformin overdose (57% female, mean age 55.8). Of these, 39 had measured lactate values. There was a high incidence of hyperlactatemia (56.4%); MALA was less frequent (17.9%). There were no deaths. Low serum bicarbonate was an independent clinical risk factor for hyperlactatemia (adjusted p < 0.05). Acetaminophen co-exposure was an independent clinical risk factor for MALA (OR 24.40, 95% CI 1.6-376.4). CONCLUSIONS: In ED patients with acute metformin overdose, initial hyperlactatemia is common but MALA is unusual. Acetaminophen co-exposure is a novel independent risk factor for the occurrence of MALA that deserves further investigation.

Atypical presentation of Crimean-Congo haemorrhagic fever: Lessons learned.

An atypical case of Crimean-Congo haemorrhagic fever is presented. The diagnosis of the case in the presence of several comorbidities was complicated and illustrates the importance of maintaining a high index of suspicion for viral haemorrhagic fever in cases presenting with multisystem disease and an epidemiological history that could present opportunities for exposure to a haemorrhagic fever virus.

Hemodialysis in metformin-associated lactic acidosis due to acute overdose in a metformin-naïve patient.

Metformin is a common and generally well-tolerated medication in the treatment of diabetes but rarely has been implicated as the cause for metformin-associated lactate acidosis. This is usually caused by decreased elimination from renal dysfunction but is rarely described after an acute ingestion. We present a case of an acute intentional overdose of metformin in a metformin-naïve patient without renal dysfunction. The patient gradually developed altered mental status, tachypnea, hypotension, hyperglycemia, hypoglycemia, hypothermia, and vasoplegic shock unresponsive to vasopressor support. Despite attempts at alkalinization, the patient developed a lactic acidosis with a pH of 6.9 and lactate of 33 mmol/L. Hemodialysis was performed with rapid improvement of clinical status. This case provides a clinical context in the acute setting and illustrates the rare need for extracorporeal support in this setting, which may be lifesaving.

'Massive' metformin overdose.

Massive metformin overdose can cause metabolic acidosis with hyperlactatemia. A 55-year-old woman presented 5 h after multidrug overdose, including 132 g extended-release metformin. Continuous venovenous haemodiafiltration (CVVHDF) and noradrenaline were commenced due to metabolic acidosis (pH 7.0, lactate 17 mmol l-1 ) and shock. Despite 3 h of CVVHDF, her acidosis worsened (pH 6.83, lactate 24 mmol l-1 ). Intermittent haemodialysis (IHD) improved acidosis (pH 7.13, lactate 26 mmol l-1 ) but again worsened (pH 6.91, lactate 30 mmol l-1 ) with CVVHDF recommencement. IHD (12 h), CVVHDF (26 h) and vasopressor support for 7 days resulted in survival. Measured metformin concentrations were extremely high with a peak of 292 µg ml-1 at 8 h postingestion. IHD, but not CVVHDF in this case, was associated with improvement in metabolic acidosis and hyperlactataemia. Pharmacokinetic analysis of metformin concentrations found a reduced apparent oral clearance of 8.2 l h-1 and a half-life of approximately 30 h. During IHD, the apparent oral clearance increased to 22.2 l h-1 with an approximate half-life of 10 h. The impact of prolonged oral absorption from a pharmacobezoar and redistribution of metformin from peripheral sites (including erythrocytes) on the pharmacokinetic profile cannot be determined from the data available.

Metformin intoxication: Vasopressin's key role in the management of severe lactic acidosis.

Vasopressin is a potent vasopressor used for improving organ perfusion during cardiac arrest, septic and catecholamine-resistant shock; with reference to this, it is useful for the treatment of vasoplegic shock because, restoring organ perfusion pressure by contraction of vascular smooth muscle through a non-catecholamine receptor pathway, it can be employed when catecholamines are ineffective. A 49-yr-old woman was admitted to the Emergency Department after having intentionally taken 95.2g of metformin, 1.6g of pioglitazone and 40 UI of insulin glargine in a suicide attempt. Despite fluid resuscitation, CVVHDF (continuous veno-venous hemodiafiltration) treatment, norepinephrine and epinephrine infusion, she developed a severe lactic acidosis and a catecholamines-refractive vasodilatory shock. Only the vasopressin infusion, in association with catecholamines, gradually stabilized the patient's hemodynamic status.

High-volume continuous venovenous hemodiafiltration plus resin hemoperfusion improves severe metformin-associated toxicity.

We present the case of a 42-year-old female patient who attempted suicide by taking approximately 100 tablets of metformin (500 mg). Laboratory tests revealed severe lactic acidosis with lactate levels of 24 mmol/L and pH of 7.09. The patient was treated with high-volume continuous venovenous hemodiafiltration (CVVH) and resin-sorbent hemoperfusion. Metformin concentrations were measured by high-performance liquid chromatography during CVVH and hemoperfusion treatment. Before extracorporeal treatment, the plasma metformin concentration was 208.5 mg/L. After CVVH treatment for 24 h, the plasma metformin concentration had decreased to 13.9 mg/L. Resin-based sorbent hemoperfusion plus CVVH treatment had reduced the metformin plasma concentration by 61.8% after 3 h. After 7 days, the patient's laboratory tests and clinical syndrome were improved, and she was discharged from hospital. We provide evidence that CVVH plus hemoperfusion is effective in eliminating metformins and metabolic products.

Metabolic acidosis in a patient with metformin overdose.

We report a rare fatal case of acute metformin overdose in a 19-year-old woman.

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.

Management of Sitagliptin and Metformin Combination Toxic Overdose.

Metformin and Sitagliptin are often used in combination in the management of non-insulin dependent diabetes mellitus. Though toxicity is rare, but occurs more frequently in cases of intentional or unintentional overdose of these drugs. Here, we present a case of an intentional overdose of a metformin- sitagliptin combination (70g metformin and 3500mg sitagliptin) in a suicide attempt by a young non-diabetic female who presented with severe lactic acidosis and was successfully treated with prompt hemodialysis and bicarbonate therapy.

Post-mortem analysis of lactate concentration in diabetics and metformin poisonings.

Lactate is produced in carbohydrate metabolism under anaerobic conditions. Lactic acidosis occurs when the production of lactate exceeds its removal. In post-mortem (PM) context, the lactic acidosis is difficult to interpret due to unknown pathophysiological factors prior to death and PM changes that may affect the lactate levels. We evaluated 1865 medico-legal autopsy cases where the quantitation of glucose, lactate, and ketone bodies was performed as a part of the cause of death (CoD) investigation. Lactate was shown to ascend in a logarithmic manner as the PM interval increased until a plateau was achieved approximately after 8-10 days PM, and the elevation was caused mainly by PM changes. The lactate level was higher than the mean in cases where the CoD was diabetes mellitus type 2 (DM2) or metformin poisoning. Although there was a correlation between metformin and lactate levels, our findings suggest the DM2 and its complications were the cause for elevated lactate levels rather than metformin, since the lactate levels were similar in DM2-associated deaths where no metformin was detected. Elevated lactate levels in PM samples rather referred to metabolic disturbances often caused by DM2. An assay to detect D-lactate in PM samples was described.

Lacticemia After Acute Overdose of Metformin in an Adolescent Managed Without Intravenous Sodium Bicarbonate or Extracorporeal Therapy.

Metformin-associated lactic acidosis or lacticemia has been widely reported as an adverse drug effect in diabetic patients with other significant comorbidities and in acute overdose in adults. Lacticemia has been reported twice in a previously healthy pediatric population, both of which were suicide attempts and required hemodialysis. We report a case of a 17-year-old, nondiabetic, healthy adolescent girl with metformin-associated lacticemia who intentionally overdosed on metformin, had no coingestants, and was treated only with crystalloids. Furthermore, she did not require intravenous bicarbonate administration or extracorporeal removal.