Can an early diagnostic procedure of metformin-associated lactic acidosis in an emergency unit reduce mortality?

Sémely, Damien; Bennett, Emily; Vallejo, Christine; Saint-Marcoux, Franck; Merle, Louis; Nouaille, Y.; Lachâtre, Gérard; Laroche, Marie‐Laure

doi:10.1016/j.therap.2016.05.006

Cited by 6 publications

(6 citation statements)

References 17 publications

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“…As a result, the therapeutic effects of using thalidezine could be more specific than metformin. In addition, the use of metformin is associated with the side effect of lactic acidosis [60]. When compared, thalidezine is isolated from the natural medicinal plant Thalictrum glandulosissimum , which have long been used in traditional Chinese medicine therapy.…”

Section: Discussionmentioning

confidence: 99%

Thalidezine, a novel AMPK activator, eliminates apoptosis-resistant cancer cells through energy-mediated autophagic cell death

Law

Gordillo-Martnez

et al. 2017

Oncotarget

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Cancers illustrating resistance towards apoptosis is one of the main factors causing clinical failure of conventional chemotherapy. Innovative therapeutic methods which can overcome the non-apoptotic phenotype are needed. The AMP-activated protein kinase (AMPK) is the central regulator of cellular energy homeostasis, metabolism, and autophagy. Our previous study showed that the identified natural AMPK activator is able to overcome apoptosis-resistant cancer via autophagic cell death. Therefore, AMPK is an ideal pharmaceutical target for chemoresistant cancers. Here, we unravelled that the bisbenzylisoquinoline alkaloid thalidezine is a novel direct AMPK activator by using biolayer interferometry analysis and AMPK kinase assays. The quantification of autophagic EGFP-LC3 puncta demonstrated that thalidezine increased autophagic flux in HeLa cancer cells. In addition, metabolic stress assay confirmed that thalidezine altered the energy status of our cellular model. Remarkably, thalidezine-induced autophagic cell death in HeLa or apoptosis-resistant DLD-1 BAX-BAK DKO cancer cells was abolished by addition of autophagy inhibitor (3-MA) and AMPK inhibitor (compound C). The mechanistic role of autophagic cell death in resistant cancer cells was further supported through the genetic removal of autophagic gene7 (Atg7). Overall, thalidezine is a novel AMPK activator which has great potential to be further developed into a safe and effective intervention for apoptosis- or multidrug-resistant cancers.

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Section: Discussionmentioning

confidence: 99%

Thalidezine, a novel AMPK activator, eliminates apoptosis-resistant cancer cells through energy-mediated autophagic cell death

Law

Gordillo-Martnez

et al. 2017

Oncotarget

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“…To our knowledge, this is the first study comparing MALA and suspected sepsis induced lactic acidosis patients. Three related studies were found [7,10,22]. Semely et al [10] have shown that an early MALA diagnosis procedure in all patients with metformin admitted at the ED tends to decrease mortality, especially for serious MALA cases.…”

Section: Discussionmentioning

confidence: 99%

“…Three related studies were found [7,10,22]. Semely et al [10] have shown that an early MALA diagnosis procedure in all patients with metformin admitted at the ED tends to decrease mortality, especially for serious MALA cases. Friesecke et al [7] have compared MALA patients with patients with lactic acidosis of other origin (LAOO).…”

Section: Discussionmentioning

confidence: 99%

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Identifying patients with metformin associated lactic acidosis in the emergency department

et al. 2020

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Background Metformin associated lactic acidosis (MALA) is a serious adverse event with a high mortality rate of 30–50%. Early recognition of MALA and timely starting treatment may reduce its morbidity and mortality. Objective The aim of this study was to explore clinical parameters to identify patients with MALA in patients with suspected sepsis induced lactic acidosis in the emergency department ED. Setting A retrospective single centre study was conducted at the Deventer Teaching Hospital in the Netherlands. Method Patients with lactate concentration > 4.0 mmol/l admitted at the ED between 2010 and 2017 with suspected sepsis or confirmed MALA and referred to the Intensive Care Unit were included. Baseline characteristics (pH, lactate, creatinine and CRP) of MALA patients were compared with patients with suspected sepsis induced lactic acidosis. Creatinine and lactate concentration were selected as potential relevant parameters. Main outcome measure Sensitivity and specificity of the highest tertiles of the creatinine and the lactate concentrations separately, in combination, and both combined with metformin use, were calculated. Results Thirteen MALA and 90 suspected sepsis induced lactic acidosis patients were included. Lactate (14.7 vs 5.9 mmol/l, p < 0.01) and creatinine concentration (642 vs 174 μmol/l, p < 0.01) were significantly higher in the MALA group and arterial pH (7.04 vs 7.38, p < 0.01) and CRP (90 vs 185 mg/l, p < 0.01) were significantly lower. The combined parameters lactate ≥ 8.4 mmol/l, creatinine ≥ 256 μmol/l had a sensitivity of 85% and a specificity of 95% for identifying MALA in suspected sepsis induced lactic acidosis patients in the ED. When combined with metformin use the specificity increased to 99%. Conclusion When managing lactic acidosis in the ED the diagnosis MALA should be considered in patients with a creatinine concentration ≥ 256 μmol/l and lactate concentration ≥ 8.4 mmol/l.

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“…The incidence of MALA varies from 0 to 138 per 100.000 patient years and may increase in the coming years due to the increase in the number of type 2 diabetes mellitus patients and the use of metformin [4,6,8,9]. Several studies suggest that starting timely treatment might reduce MALA-related morbidity and mortality [8][9][10][11][12][13][14]. Extracorporeal treatments (ECTRs) may be necessary to remove metformin, clear lactate, and correct acid-base abnormalities [1,11].…”

Section: Introductionmentioning

confidence: 99%

Extracorporeal treatment of metforminassociated lactic acidosis in clinical practice: a retrospective cohort study

Laar

Vermeij

Elsen-Hutten

et al. 2020

Eur J Clin Pharmacol

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Purpose To assess whether extracorporeal treatment (ECTR) improves outcome of patients with metformin-associated lactic acidosis (MALA) and to evaluate the clinical applicability of the Extracorporeal Treatments in Poisoning Workgroup (EXTRIP) criteria for starting ECTR in metformin poisoning. Methods Patients with metformin serum concentrations above 2 mg/l who were admitted in the Deventer Teaching Hospital between January 2000 and July 2019 and complied with the definition of MALA (pH < 7.35 and lactate concentration > 5 mmol/ l) were included. Mortality and clinical parameters of patients treated with ECTR or not were compared. In addition, treatment of MALA in clinical practice was verified against the criteria of EXTRIP. Results Forty-two patients were included. Lactate (13.8 versus 10.5 mmol/l, p = 0.01), creatinine (575 versus 254 umol/l, p < 0.01)), metformin (29.4 versus 8.6 mg/l, p < 0.01) concentrations, and vasopressor requirement (72% versus 23%, p < 0.01) were significantly higher in the ECTR-group. Blood pH (7.05 versus 7.19, p = 0.03) and bicarbonate (6 versus 11 mmol/l, p < 0.01) were significantly lower. Mortality, length of hospital stay, and mechanical ventilation requirement were not statistically different. In 83% of patients, treatment of MALA was in accordance with the EXTRIP criteria. Conclusions Although there was no statistical benefit in mortality shown from ECTR, ECTR might be lifesaving in MALA, considering the ECTR-group was significantly sicker than the non-ECTR-group. The majority of patients were treated in line with the EXTRIP criteria. Severity of lactic acidosis and renal impairment were the main indications for initiating ECTR.

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Can an early diagnostic procedure of metformin-associated lactic acidosis in an emergency unit reduce mortality?

Cited by 6 publications

References 17 publications

Thalidezine, a novel AMPK activator, eliminates apoptosis-resistant cancer cells through energy-mediated autophagic cell death

Thalidezine, a novel AMPK activator, eliminates apoptosis-resistant cancer cells through energy-mediated autophagic cell death

Identifying patients with metformin associated lactic acidosis in the emergency department

Extracorporeal treatment of metforminassociated lactic acidosis in clinical practice: a retrospective cohort study

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