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Purpose: The standard of care for burned patients experiencing hyperglycemia associated with the hypermetabolic response is insulin therapy. Insulin treatment predisposes burn patients to hypoglycemia, which increases morbidity and mortality. Metformin has been suggested as an alternative to insulin therapy for glycemic control in burn patients given its safety profile, but further research is warranted. This study investigated whether metformin use in burn patients is associated with improved glycemic control and morbidity/mortality outcomes compared to insulin use alone., Materials and Methods: Using the TriNetX database, we conducted a retrospective study of burned patients who were administered insulin, metformin, or both within one week of injury. Demographic, comorbidity, and burn severity information were collected. Patients were categorized by treatment type, propensity score-matched, and compared for the following outcomes within 3 months: hyperglycemia, hypoglycemia, sepsis, lactic acidosis, and death. Statistical significance was set a priori at p ≤ 0.05., Results: The insulin cohort was at increased risk for all outcomes (all p < 0.0001) compared to the metformin cohort, and an increased risk for sepsis, lactic acidosis, and death (all p ≤ 0.0002) compared to the insulin/metformin combination cohort. When compared to the metformin cohort, the combination cohort was at increased risk for all outcomes (all p ≤ 0.0107) except death., Conclusions: Treatment with metformin after burn is associated with a reduced risk of morbidity and mortality compared to insulin. The combination of insulin and metformin is no more effective in reducing the risk of hyperglycemia and hypoglycemia than insulin alone but is less effective than metformin alone., Competing Interests: Declaration of Competing Interest The authors do not have any financial disclosures or other conflicts of interest to report other than that SEW is the editor of this journal., (Copyright © 2024 Elsevier Ltd and International Society of Burns Injuries. All rights reserved.)

Objective: The objective of this study was to investigate the correlation between metformin exposure and the incidence of lactic acidosis in critically ill patients., Methods: The patients with type 2 diabetes mellitus (T2DM) were included from Medical Information Mart for Intensive Care IV database (MIMIC-IV). The primary outcome was the incidence of lactic acidosis. The secondary outcomes were lactate level and in-hospital mortality. Propensity score matching (PSM) method was adopted to reduce bias of the confounders. The multivariate logistic regression was used to explore the correlation between metformin exposure and the incidence of lactic acidosis. Subgroup analysis and sensitivity analysis were used to test the stability of the conclusion., Results: We included 4939 patients. There were 2070 patients in the metformin group, and 2869 patients in the nonmetformin group. The frequency of lactic acidosis was 5.7% (118/2070) in the metformin group and it was 4.3% (122/2869) in the nonmetformin group. There was a statistically significant difference between the two groups ( P <  0.05). The lactate level in the metformin group was higher than in the nonmetformin group (2.78 ± 2.23 vs. 2.45 ± 2.24, P <  0.001). After PSM, the frequency of lactic acidosis (6.3% vs. 3.7%, P  < 0.001) and lactate level (2.85 ± 2.38 vs. 2.40 ± 2.14, P <  0.001) were significantly higher in the metformin group compared with the nonmetformin group. In multivariate logistic models, the frequency of lactic acidosis was obviously increased in metformin group, and the adjusted odds ratio ( OR ) of metformin exposure was 1.852 ( 95% confidence interval (CI) =  1.298-2.643, P  < 0.001). The results were consistent with subgroup analysis except for respiratory failure subgroup. Metformin exposure increased lactate level but did not affect the frequency of lactic acidosis in patients of respiratory failure with hypercapnia. However, the in-hospital mortality between metformin and nonmetformin group had no obvious difference ( P  = 0.215). In sensitivity analysis, metformin exposure showed similar effect as the original cohort., Conclusions: In critically ill patients with T2DM, metformin exposure elevated the incidence of lactic acidosis except for patients of respiratory failure with hypercapnia, but did not affect the in-hospital mortality., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The relationship between hyperlactatemia and prognosis after cardiopulmonary bypass (CPB) is controversial, and some studies ignore the presence of lactic acidosis in patients with severe hyperlactacemia. This study explored the association between lactic acidosis (LA) and the occurrence of multiple organ dysfunction syndrome (MODS) after cardiopulmonary bypass., Methods: This study was a post hoc analysis of patients who underwent cardiac surgery between February 2017 and August 2018 and participated in a prospective study at Taizhou Hospital. The data were collected at: ICU admission (H0), and 4, 8, 12, 24, and 48 h after admission. Blood lactate levels gradually increased after CPB, peaking at H8 and then gradually decreasing. The patients were grouped as LA, hyperlactatemia (HL), and normal control (NC) based on blood test results 8 h after ICU admission. Basic preoperative, perioperative, and postoperative conditions were compared between the three groups, as well as postoperative perfusion and oxygen metabolism indexes., Results: There were 22 (19%), 73 (64%), and 19 (17%) patients in the LA, HL, and NC groups, respectively. APACHE II (24h) and SOFA (24h) scores were the highest in the LA group ( P  < 0.05). ICU stay duration was the longest for the LA group (48.5 (42.5, 50) h), compared with the HL (27 (22, 48) h) and NC (27 (25, 46) h) groups ( P  = 0.012). The LA group had the highest incidence of MODS (36%), compared with the HL (14%) and NC (5%) groups ( P  = 0.015). In the LA group, the oxygen extraction ratio (O 2 ER) was lower (21.5 (17.05, 32.8)%) than in the HL (31.3 (24.8, 37.6)%) and the NC group (31.3 (29.0, 35.4) %) ( P  = 0.018). In the univariable analyses, patient age (OR = 1.054, 95% CI [1.003-1.109], P  = 0.038), the LA group ( vs. the NC group, (OR = 10.286, 95% CI [1.148-92.185], P  = 0.037), and ΔPCO2 at H8 (OR = 1.197, 95% CI [1.022-1.401], P  = 0.025) were risk factor of MODS after CPB., Conclusions: We speculated that there was correlation between lactic acidosis and MODS after CPB. In addition, LA should be monitored intensively after CPB., Competing Interests: The authors declare there are no competing interests., (©2024 Zheng et al.)

Objective: This study aimed to evaluate lactic acidosis (LA) risk when using metformin combined with histamine H2 receptor inhibitors (H2RI) in patients with renal failure (RF)., Research Design and Methods: This study analyzed FDA Adverse Event Reporting System data (2012Q4 to 2022Q4) to characterize reports of LA associated with metformin alone or combined with H2RI. Using a disproportionality approach, LA risk signal in the overall population and in patients with RF was assessed. A physiologically based pharmacokinetic (PBPK) model was developed to predict metformin and cimetidine pharmacokinetic changes following conventional doses of the combinations in patients with various degrees of RF. To explore its correlation with LA risk, a peak plasma metformin concentration of 3 mg/L was considered the threshold., Results: Following the 2016 U.S. Food and Drug Administration metformin approval for mild-to-moderate RF, the percentage of patients with RF reporting LA associated with metformin combined with H2RI increased. Disproportionality analysis showed reported LA risk signal associated with metformin and cimetidine in the overall population within the study timeframe only. Furthermore, with PBPK simulations, for metformin (1,000 mg b.i.d.) with cimetidine (300 mg q.i.d. or 400 mg b.i.d.) in stage 1 of chronic kidney disease, metformin (1,000 mg b.i.d.) with cimetidine (300 mg q.i.d. or 400 mg b.i.d. or 800 mg q.d.) in stage 2, and most combinations in stage 3, the peak plasma metformin concentrations exceeded the 3 mg/L threshold., Conclusions: Metformin combined with cimetidine at conventional doses may cause LA in patients with mild-to-moderate RF., (© 2023 by the American Diabetes Association.)

Introduction: Metformin toxicity is a rare but serious condition that carries with it a high rate of morbidity and mortality., Objective: This review highlights the pearls and pitfalls of metformin toxicity, including diagnosis, initial resuscitation, and management in the emergency department (ED) based on current evidence., Discussion: Metformin is a common medication used for treatment of diabetes mellitus. Metformin toxicity is a spectrum of conditions that may be differentiated into three subgroups: metformin-associated lactic acidosis (MALA), metformin-induced lactic acidosis (MILA), and metformin-unrelated lactic acidosis (MULA). MILA is a condition found predominantly in patients chronically taking metformin or those with large acute overdoses. Conversely, MULA occurs in patients on metformin but with a critical illness stemming from a separate cause. MALA is rare but the most severe form, with mortality rates that reach 50%. Differentiating these entities is difficult in the ED setting without obtaining metformin levels. Patients with metformin toxicity present with nonspecific gastrointestinal symptoms and vital sign abnormalities. Laboratory analysis will reveal a high lactate with anion gap metabolic acidosis. Patients presenting with elevated lactate levels in the setting of metformin use should be considered at risk for the most severe form, MALA. Patients with MALA require aggressive treatment with intravenous fluids, treatment of any concomitant condition, and early consideration of hemodialysis, along with specialist consultation such as nephrology and toxicology., Conclusions: An understanding of metformin toxicity can assist emergency clinicians in diagnosing and managing this potentially deadly disease., Competing Interests: Declaration of Competing Interest None., (Published by Elsevier Inc.)

Introduction: Metformin toxicity following therapeutic use or overdose may result in metabolic acidosis with hyperlactatemia. This study aims to assess the relationship between serum lactate concentration, arterial pH, and ingested dose with severity of poisoning, and to identify if serum lactate concentration is a useful marker of severity in metformin toxicity., Methods: A retrospective study of telephone enquiries relating to metformin exposures to the National Poisons Information Service between 2010 and 2019 from hospitals in the United Kingdom., Results: Six-hundred and thirty-seven cases were identified; 117 involved metformin only and 520 involved metformin with other drugs. The majority of cases involved acute (87%) and intentional (69%) exposures. There was a statistically significant difference in doses between the Poisoning Severity Scores, as well as between intentional and unintentional or therapeutic error doses ( P  < 0.0001). The distribution of cases for each Poisoning Severity Score differed between the metformin only and metformin with other drugs cases ( P  < 0.0001). Lactic acidosis was reported in 232 cases. Serum lactate concentration and arterial pH differed across Poisoning Severity Scores. Arterial pH inversely correlated with ingested dose (r=-0.3, P  = 0.003), and serum lactate concentration positively correlated with ingested dose ( r  = 0.37, P  < 0.0001). Serum lactate concentration and arterial pH did not correlate with each other. Twenty-five deaths were recorded, all following intentional overdoses., Discussion: The dataset focuses mostly on acute, intentional overdoses. Increasing ingested metformin dose, a higher serum lactate concentration and worsening arterial pH were all associated with an unfavourable Poisoning Severity Score in patients in both metformin only and metformin with other drugs groups. As serum lactate concentration did not correlate with arterial pH, it represents an independent marker of poisoning severity., Conclusions: Data from the present study suggest that serum lactate concentration can be used to assess severity of poisoning in patients who have reportedly ingested metformin.

Patient data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) are used to assess the effect of biguanide administration on rates of lactic acidosis (LA) in hospitalized diabetes mellitus (DM) patients. In this retrospective cohort study (from April 2013 to March 2016), we compare DM inpatients prescribed biguanides to DM inpatients who were not prescribed biguanides to quantify the association between biguanides and incidence of LA. In total, 8,111,848 DM patient records are retrieved from the NDB. Of the 528,768 inpatients prescribed biguanides, 782 develop LA. Of the 1,967,982 inpatients not prescribed biguanides, 1310 develop LA. The rate ratio of inpatients who develop LA and are administered biguanides to those who developed LA without receiving biguanides is 1.44 (95% CI, 1.32-1.58). Incidence rates and rate ratios for both sexes are elevated in the group prescribed biguanides for patients aged 70 years and older, markedly in those 80 years and older: 40.12 and 6.31 (95% CI, 4.75-8.39), respectively, for men and 34.96 and 5.40 (95% CI, 3.91-7.46), respectively, for women. Biguanides should be used conservatively in patients older than 70 years, particularly for those with comorbidities, and with caution in patients 80 years and older.

Objectives: The clinical significance of hypophosphatemia in cardiac surgery has not been investigated extensively. The aim of this study was to evaluate the association of postoperative hypophosphatemia and lactic acidosis in cardiac surgery patients at the time of intensive care unit (ICU) admission., Design: A retrospective cohort study., Setting: At a single academic center., Participants: Patients who underwent nontransplant cardiac surgery with cardiopulmonary bypass between August 2009 and December 2020., Interventions: None., Measurements and Main Results: Serum phosphate and lactate levels were measured upon ICU admission in patients undergoing nontransplant cardiac surgery with cardiopulmonary bypass. There were 681 patients in the low-phosphate (<2.5 mg/dL) group and 2,579 patients in the normal phosphate group (2.5-4.5 mg/dL). A higher proportion of patients in the low phosphate group (26%; 179 of 681; 95% CI: 23-30) had severe lactic acidosis compared to patients in the normal phosphate group (16%; 417 of 2,579; 95% CI: 15-18). In an unadjusted logistic regression model, patients in the low phosphate group had 1.9-times the odds of having severe lactic acidosis (serum lactate ≥4.0 mmol/L) when compared to patients in the normal phosphate group (95% CI: 1.5-2.3), and still 1.4-times the odds (95% CI: 1.1-1.7) after adjusting for several possible confounders., Conclusions: Hypophosphatemia is associated with lactic acidosis in the immediate postoperative period in cardiac surgery patients. Future studies will need to investigate it as a potential treatment target for lactic acidosis., Competing Interests: Conflict of Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Evidence of metformin-associated lactic acidosis (MALA) in advanced chronic kidney disease (CKD) has been limited due to high mortality rate but rare incidence rate. The mechanism of increased MALA in advanced CKD is mainly based on the hypothesis of decreased drug elimination, which might also be confounded by increased comorbidities as CKD progresses. The goal of the study is to analyze the incidence and associated factors of lactic acidosis between metformin user and non-user with advanced CKD., Methods: This study used a three million population-based, propensity score-matched cohort from 2008 to 2016. The primary outcome was laboratory-defined lactic acidosis. Relationships between the probability of lactic acidosis and various estimated glomerular filtration rate (eGFR) values in advanced CKD patients were also presented in regression analysis., Results: Adults with type 2 diabetes whose eGFR was <30 mL/min/1.73 m 2 were enrolled in this study. After the process of propensity score matching, 7707 patients were divided into metformin and non-metformin groups. In linear regression model, metformin significantly increased the risk of lactic acidosis (p=0.0204) as the eGFR declined in advanced CKD over a mean follow up of over 600 days even after confounder adjustment with age, sex and comorbidities., Conclusions: Metformin was associated with a significant increased risk of laboratory-defined lactic acidosis (p=0.0204) even after adjusting confounder such as age, sex and underlying comorbidities. This "REMIND" study reminds us that metformin-associated lactic acidosis is mainly caused by decreased drug renal elimination other than underlying comorbidities in advanced CKD patients., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest with respect to this manuscript., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: Substantial inconsistencies exist in current guidelines regarding recommendations of metformin usage with the administration of a contrast medium. We aimed to perform a meta-analysis to determine whether the risks of contrast-induced acute kidney injury (CI-AKI) and lactic acidosis increase with metformin use in diabetic patients receiving a contrast medium., Methods: Studies were retrieved from databases from inception to May 15, 2021. Studies that compared the outcomes of using metformin with not using metformin during contrast medium administration were included. The primary outcomes were incidence of CI-AKI and lactic acidosis. The secondary outcomes were renal function changes from baseline. Data analysis was using risk ratio (RR) for dichotomous outcomes and mean differences (MD) with 95% confidence intervals (CI) for continuous outcomes., Results: Analyses of two randomized controlled trials and four retrospective cohorts examining a total of 1459 patients revealed no significant differences in the incidence of CI-AKI (RR = 1.08; 95% CI, 0.72 to 1.63) and in changes in renal function measurements (serum creatinine: MD = 0.00 mg/dL, 95% CI, - 0.05 to 0.05; estimated glomerular filtration rate: MD = 0.22, 95% CI, - 2.47 to 2.91) after contrast medium administration between patients using and not using metformin., Conclusions: There is no evidence that continuing metformin during contrast medium administration is associated with a higher risk of CI-AKI, lactic acidosis, or renal function deterioration compared to patients who discontinued metformin or who were not metformin users. The limited quality of the included studies may compromise the strength of evidence provided in this meta-analysis., Key Points: There is no need to discontinue metformin either before or after intravenous contrast medium exposure in patients with eGFR > 30 mL/min/1.73 m 2 . In patients receiving intra-arterial contrast medium with first-pass renal exposure, there is no need to withhold metformin if eGFR is above 60 mL/min/1.73 m 2 . For patients who have an eGFR level between 30 and 60 mL/min/1.73 m 2 and are receiving intra-arterial contrast medium with first-pass renal exposure, no case of lactic acidosis was observed based on present data, but further evidence is needed to make a strong suggestion regarding its safety., (© 2021. The Author(s), under exclusive licence to European Society of Radiology.)

Patients with cerebral malaria with polymorphic Cytochrome P450 2C19 (CYP2C19) genotypes who receive concurrent treatment with quinine are at risk of inadequate or toxic therapeutic drug concentrations due to metabolic drug interactions. The study aimed to predict the potential dose regimens of quinine when coadministered with phenobarbital in adult patients with cerebral malaria and complications (e.g., lactic acidosis and acute renal failure) and concurrent with seizures and acute renal failure who carry wild-type and polymorphic CYP2C19. The whole-body physiologically based pharmacokinetic (PBPK) models for quinine, phenobarbital, and quinine-phenobarbital coadministration were constructed based on the previously published information using Simbiology®. Four published articles were used for model validation. A total of 100 virtual patients were simulated based on the 14-day and 3-day courses of treatment. using the drug-drug interaction approach. The predicted results were within 15% of the observed values. Standard phenobarbital dose, when administered with quinine, is suitable for all groups with single or continuous seizures regardless of CYP2C19 genotype, renal failure, and lactic acidosis. Dose adjustment based on area under the curve ratio provided inappropriate quinine concentrations. The recommended dose of quinine when coadministered with phenobarbital based on the PBPK model for all groups is a loading dose of 2000 mg intravenous (i.v.) infusion rate 250 mg/h followed by 1200 mg i.v. rate 150 mg/h. The developed PBPK models are credible for further simulations. Because the predicted quinine doses in all groups were similar regardless of the CYP2C19 genotype, genotyping may not be required., (© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Aims: The aim of this case report is to specify the frequency and mortality of Metformin-Associated Lactic Acidosis (MALA) in emergency medicine, as the diagnosis seems to occur more often than estimated., Methods: To identify the subjects, we developed screening criteria for MALA. We measured the serum metformin concentration to confirm the diagnosis in all patients fulfilling these criteria. Retrospectively the patients were grouped according to individual risk (according to a defined risk score) and the application of renal replacement therapy., Results: From 2013 until 2018 we were able to identify 11 MALA patients revealing a frequency of 1:4,000 emergency patients. Six patients survived and five died in the follow-up. All three patients in the high-risk group died although all of them received renal replacement therapy. In the low-risk group (three patients, one with renal replacement therapy), all patients survived, while in the intermediate-risk group (five patients, one with renal replacement therapy) three patients survived and two died. Additional severe comorbidities also contributed to mortality., Conclusions: Every patient matching the screening criteria of acute renal failure, lactic acidosis and continued intake of metformin can be considered a potential MALA case. A risk score assessment which includes severe comorbidities may help to identify high-risk individuals and should be evaluated in larger studies.To prevent MALA, patients should be trained to immediately interrupt their own metformin use when showing signs of volume depletion. Physicians should be aware of the additional risk factors such as co-medication with diuretics, ACE (angiotensin converting enzyme) ACE inhibitors and NSAIDs (non steroidal anti inflammatory drugs)., Competing Interests: Monika Kellerer has received honorarium for speaking bureau and scientific advice from Abbott, AstraZeneca, Böhringer Ingelheim, MSD, Lilly, Novo Nordisk and Sanofi., (Thieme. All rights reserved.)

Aims/hypothesis: The long-term effects of metformin in individuals with type 2 diabetes who are at increased risk of severe respiratory infections are unknown. This study aimed to evaluate the effects of metformin use on the risk of first pneumonia hospitalisation and pneumonia-related death in a cohort of Chinese individuals with type 2 diabetes., Methods: We performed a retrospective analysis of a consecutive cohort of 22,638 individuals with type 2 diabetes in the Hong Kong Diabetes Register enrolled between 2001 and 2018, with follow-up until 31 December 2019. Overlap propensity-score weighting was performed to balance baseline characteristics., Results: Of 22,638 individuals with type 2 diabetes, after excluding those who had not been prescribed any glucose-lowering drugs (GLDs) and/or with eGFR ≤30 ml min -1 [1.73 m] -2 or treated by dialysis and/or treated with insulin at baseline, we identified 15,784 either prevalent or incident metformin users and 917 users of other GLDs during a mean follow-up period of 7.5 years. Overlap-weighted analysis showed an HR of 0.63 (95% CI 0.52, 0.77) for first pneumonia hospitalisation and 0.49 (95% CI 0.33, 0.73) for pneumonia-related death in metformin users vs users of other GLDs; similar observations resulted following stratification by sex and kidney function. There was also a negative association between metformin exposure over time (proportion of duration of metformin prescriptions during the total follow-up time) and pneumonia events using the penalised spline analysis. Metformin users had a lower neutrophil/lymphocyte ratio at first pneumonia hospitalisation vs non-metformin users (mean [95% CI]: 12.8 [12.1, 13.5] vs 14.8 [12.3, 17.3], p = 0.032). The rate of metformin-associated lactic acidosis was 2.5 per 100,000 person-years. The lower risk of pneumonia events was also observed among incident metformin users vs other GLD users., Conclusions/interpretation: Long-term use of metformin was associated with reduced risk of pneumonia and pneumonia-related death among Chinese individuals with diabetes. The relevance of these results to other respiratory infections merits further investigation.

Abstract: Despite advances in treatments for diabetes mellitus (DM), severe acute glycemic crises still occur. In this study, the characteristics of patients who were transported to an emergency department due to acute glycemic crises were investigated.We enrolled patients who were transported to our hospital by ambulance due to hypoglycemia or hyperglycemia during the period from January 2015 to December 2019. Initial glucose levels below 70 mg/dL and above 250 mg/dL were defined as hypoglycemia and hyperglycemia, respectively.In the 5-year period, 16,910 patients were transported to our hospital by ambulance. Of those patients, 87 patients (0.51%) were diagnosed with hypoglycemia, 26 patients (0.15%) were diagnosed with hyperglycemia and 1 patient was diagnosed with lactic acidosis. Compared to patients with hypoglycemia, blood urea nitrogen, serum potassium and hemoglobin levels were higher in patients with hyperglycemia. Systolic blood pressure was lower and pulse rate was higher in patients with hyperglycemia, possibly reflecting dehydration in hyperglycemia. Patients with hyperglycemia were younger (63 vs 70 years old, median), more likely to be hospitalized (92.3% vs 23.0%) with poorer prognosis (23.1% vs 4.6%) than those with hypoglycemia. In 64 DM patients with hypoglycemia, 34 patients were treated with insulin and 24 patients were treated with sulfonylurea or glinide, and their medication was often inappropriate. Excessive alcohol intake and malnutrition were the main causes of hypoglycemia in 23 non-DM patients. The main reasons for hyperglycemia were interrupted treatment, forgetting insulin injection and infection.To avoid acute glycemic crises, optimization of anti-DM therapy and education of patients are needed., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Lactic acidosis is a common complication of status asthmaticus in adults. However, data is sparse in children. The aim of this study was to describe the prevalence and risk factors for lactic acidosis in children hospitalised for acute moderate or severe asthma. A total of 154 children 2-17 years of age were enrolled in a prospective observational study conducted in a tertiary hospital. All had capillary blood gas assessment 4 h after the first dose of salbutamol in hospital. The primary endpoint was the prevalence of lactic acidosis. Potential contributing factors such as age, sex, BMI, initial degree of asthma severity, type of salbutamol administration (nebuliser or inhaler), steroids, ipratropium bromide, and glucose-containing maintenance fluid represented secondary endpoints. All in all, 87% of patients had hyperlactatemia (lactate concentration > 2.2 mmol/l). Lactic acidosis (lactate concentration > 5 mmol/l and anion gap ≥ 16 mmol/l) was observed in 26%. In multivariate analysis, age more than 6 years (OR = 2.8, 95% CI 1.2-6.6), glycemia above 11 mmol/l (OR = 3.2 95% CI 1.4-7.4), and salbutamol administered by nebuliser (OR = 10, 95% CI 2.7-47) were identified as risk factors for lactic acidosis in children with moderate or severe asthma.Conclusion: Lactic acidosis is a frequent and early complication of acute moderate or severe asthma in children. What is Known: • Lactic acidosis during acute asthma is associated with b2-mimetics administration. • Salbutamol-related lactic acidosis is self-limited but important to recognise, as compensatory hyperventilation of lactic acidosis can be mistaken for respiratory worsening and lead to inappropriate supplemental bronchodilator administration. What is New: • Lactic acidosis is a frequent complication of acute asthma in the paediatric population. • Age older than 6 years, hyperglycaemia, and nebulised salbutamol are risk factors for lactic acidosis during asthma.

Importance: Conducted electrical weapons (CEWs) are used broadly as a less-lethal force option for police officers. However, there is no clear picture of the possible health risks in humans on the basis of rigorously assessed scientific evidence from the international peer-reviewed literature., Objective: To synthesize and systematically evaluate the strength of published evidence for an association between exposure to different models of CEWs and adverse acute as well as chronic conditions., Evidence Review: Following a preregistered review protocol, the literature search strategy was based on a search of reviews published between January 1, 2000, and April 24, 2020, of PubMed, MEDLINE, EMBASE, Web of Science, PsycINFO, and Cochrane Library, as well as relevant online databases and bibliographic sources, such as reference sections of recent publications. The identified studies were independently assessed in terms of scope, relevance, methodologic bias, and quality. Peer-reviewed publications of human studies were included, using original data and with a focus on the use of taser CEWs in the context of law enforcement. Eligible studies examined clearly defined health outcomes as dependent variables following exposure to a CEW. The review followed the relevant sections of the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. A meta-analysis could not be conducted., Findings: Of the 1081 unique records screened, 33 relevant studies were identified, all of them of experimental design and conducted in the US. Eleven studies had a low risk of bias and 22 had a higher bias risk. Studies focused on outcomes such as physiologic stress responses, heart rate, blood pressure, arrhythmias, or cognitive performance. Independently of bias risk, the studies reported few or no acute health problems, apart from the wounds caused by the darts. Furthermore, no long-term outcomes were studied. Most of the studies were performed on healthy, physically fit individuals (eg, police officers) in a controlled setting, with short exposure duration (5 seconds). Half of the studies, mainly those with a higher risk of bias, were at least partly funded by the manufacturer., Conclusions and Relevance: Based on the findings of the reviewed studies, the risk for adverse health outcomes due to CEW exposure can be currently estimated as low. However, most of the reviewed studies had methodologic limitations. Considering that recruited participants were not representative of the population that usually encounters a CEW deployment, it is not possible to draw conclusions regarding exposure outcomes in potentially vulnerable populations or high-risk groups, such as those under the influence of substances.

What Is Known and Objective: Lactic acidosis (LA) is a rare but potentially lethal side effect of linezolid (LZD). However, limited by the study population, the number of patients with LA is insufficient to summarize all the clinical characteristics and risk factors., Methods: We evaluated the association between LZD and LA using the reporting odd ratio (ROR) for mining the adverse event report signals in the FDA Adverse Event Reporting System database from January 2013 to December 2019., Results and Discussion: There were 6218 reports of LZD as the primary suspected drug or secondary suspected drug, of which 275 (4.42%) reports were of LA. The ROR of LA with the use of LZD was 39.976 (95% CI 35.365-45.189). In the age composition of patients, elderly individuals (aged ≥60 years) accounted for the higher proportion, 42.54% (n = 117). LA usually occurred two weeks after LZD administration (n = 33). LZD was the unique suspected drug, accounting for 37.45% (n = 103) of all reports of LA. The drug with the most frequent occurrence of combination with LZD was 'meropenem' and 'warfarin'., What Is New and Conclusions: The ROR of LA caused by LZD was very high, and the number of reports about LA caused by other antibiotics was significantly different from that of LA caused by LZD. The drug combined with LZD did not seem to affect the occurrence of LA, and the high occurrence of warfarin in the reports deserves the attention of doctors., (© 2020 John Wiley & Sons Ltd.)

Background: Elevated lactate levels may be caused by increased production suggestive of tissue ischemia; however, they may also occur without evidence of ischemia, by catecholamine activation of beta receptors. The purpose of this study was to determine the factors associated with increased lactate levels during and after lung transplantation and to evaluate whether lactate levels were associated with increased time to extubation and postoperative complications., Methods: This was a retrospective study of patients who underwent lung transplantation between January 2015 and May 2017 at the University of Michigan, Ann Arbor, MI. Multivariable linear regression was used to determine the factors associated with peak lactate levels and to find the associations between lactate levels and outcomes of nitric oxide time, intubation time, length of stay, and creatinine level. Logistic regression was used to determine the associations between lactate levels and acute kidney injury and atrial fibrillation., Results: A total of 86 patients underwent single-lung transplantation (n = 17; 20%) or double-lung transplantation (n = 69; 80%). All patients initially had normal lactate levels. On univariate analysis, lactate levels at several time points were correlated with subsequent acute kidney injury, increased time to extubation, and increased nitric oxide time. After adjustment, the study found that higher peak intensive care unit lactate levels (regression coefficient B = 0.046; interquartile range, 0.006, 0.086; P = .025) were associated with longer length of stay., Conclusions: Cardiopulmonary bypass time, total ischemic time, and catecholamine use were associated with higher lactate levels, whereas nitric oxide and higher pulmonary artery pressures were associated with lower levels. Increased lactate levels were independently associated with longer intubation times, postoperative acute kidney injury, and longer length of stay., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: To compare the risk of lactic acidosis hospitalization between patients treated with metformin versus sulfonylureas following development of reduced kidney function., Research Design and Methods: This retrospective cohort combined data from the National Veterans Health Administration, Medicare, Medicaid, and the National Death Index. New users of metformin or sulfonylureas were followed from development of reduced kidney function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m 2 or serum creatinine ≥1.4 mg/dL [female] or 1.5 mg/dL [male]) through hospitalization for lactic acidosis, death, loss to follow-up, or study end. Lactic acidosis hospitalization was defined as a composite of primary discharge diagnosis or laboratory-confirmed lactic acidosis (lactic acid ≥2.5 mmol/L and either arterial blood pH <7.35 or serum bicarbonate ≤19 mmol/L within 24 h of admission). We report the cause-specific hazard of lactic acidosis hospitalization between metformin and sulfonylureas from a propensity score-matched weighted cohort and conduct an additional competing risks analysis to account for treatment change and death., Results: The weighted cohort included 24,542 metformin users and 24,662 sulfonylurea users who developed reduced kidney function (median age 70 years, median eGFR 55.8 mL/min/1.73 m 2 ). There were 4.18 (95% CI 3.63, 4.81) vs. 3.69 (3.19, 4.27) lactic acidosis hospitalizations per 1,000 person-years among metformin and sulfonylurea users, respectively (adjusted hazard ratio [aHR] 1.21 [95% CI 0.99, 1.50]). Results were consistent for both primary discharge diagnosis (aHR 1.11 [0.87, 1.44]) and laboratory-confirmed lactic acidosis (1.25 [0.92, 1.70])., Conclusions: Among veterans with diabetes who developed reduced kidney function, occurrence of lactic acidosis hospitalization was uncommon and not statistically different between patients who continued metformin and those patients who continued sulfonylureas., (© 2020 by the American Diabetes Association.)

Diabetes is among the most frequently reported comorbidities in patients infected with COVID-19. According to current data, diabetic patients do not appear to be at increased risk of contracting SARS-CoV-2 compared to the general population. On the other hand, diabetes is a risk factor for developing severe and critical forms of COVID-19, the latter requiring admission to an intensive care unit and/or use of invasive mechanical ventilation, with high mortality rates. The characteristics of diabetic patients at risk for developing severe and critical forms of COVID-19, as well as the prognostic impact of diabetes on the course of COVID-19, are under current investigation. Obesity, the main risk factor for incident type 2 diabetes, is more common in patients with critical forms of COVID-19 requiring invasive mechanical ventilation. On the other hand, COVID-19 is usually associated with poor glycemic control and a higher risk of ketoacidosis in diabetic patients. There are currently no recommendations in favour of discontinuing antihypertensive medications that interact with the renin-angiotensin-aldosterone system. Metformin and SGLT2 inhibitors should be discontinued in patients with severe forms of COVID-19 owing to the risks of lactic acidosis and ketoacidosis. Finally, we advise for systematic screening for (pre)diabetes in patients with proven COVID-19 infection., (Copyright © 2020. Published by Elsevier Masson SAS.)

Objective: Metformin is the first pharmacological option for treating type 2 diabetes. However, the use of this drug is not recommended in individuals with impaired kidney function because of the perceived risk of lactic acidosis. We aimed to assess the efficacy and safety of metformin in patients with type 2 diabetic kidney disease (DKD)., Research Design and Methods: We conducted a retrospective observational cohort study of 10,426 patients with type 2 DKD from two tertiary hospitals. The primary outcomes were all-cause mortality and end-stage renal disease (ESRD) progression. The secondary outcome was metformin-associated lactic acidosis. Taking into account the possibility that patients with less severe disease were prescribed metformin, propensity score matching (PSM) was conducted., Results: All-cause mortality and incident ESRD were lower in the metformin group according to the multivariate Cox analysis. Because the two groups had significantly different baseline characteristics, PSM was performed. After matching, metformin usage was still associated with lower all-cause mortality (adjusted hazard ratio [aHR] 0.65; 95% CI 0.57-0.73; P < 0.001) and ESRD progression (aHR 0.67; 95% CI 0.58-0.77; P < 0.001). Only one event of metformin-associated lactic acidosis was recorded. In both the original and PSM groups, metformin usage did not increase the risk of lactic acidosis events from all causes (aHR 0.92; 95% CI 0.668-1.276; P = 0.629)., Conclusions: In the present retrospective study, metformin usage in advanced chronic kidney disease (CKD) patients, especially those with CKD 3B, decreased the risk of all-cause mortality and incident ESRD. Additionally, metformin did not increase the risk of lactic acidosis. However, considering the remaining biases even after PSM, further randomized controlled trials are needed to change real-world practice., (© 2020 by the American Diabetes Association.)

Background: The FDA approved 'label' for metformin lists hepatic insufficiency as a risk for lactic acidosis. Little evidence supports this warning., Aims: To investigate the safety and pharmacokinetics of metformin in patients with chronic liver disease (CLD)., Methods: Chronic liver disease patients with and without type 2 diabetes mellitus (T2DM) were studied by a cross-sectional survey of patients already prescribed metformin (n = 34), and by a prospective study where metformin (500 mg, immediate release, twice daily) for up to 6 weeks was prescribed (n = 24). Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were obtained and compared to previously published values from healthy and T2DM populations without CLD., Results: All plasma metformin and lactate concentrations remained below the putative safety thresholds (metformin, 5 mg/L; lactate, 5 mmol/L). Lactate concentrations were unrelated to average steady-state metformin concentrations. In patients with CLD, T2DM was associated with higher plasma lactate concentrations (48% higher than those without T2DM, P < 0.0001). CLD patients with cirrhosis had 23% higher lactate concentrations than those without cirrhosis (P = 0.01). The pharmacokinetics of metformin in CLD patients were similar to patients with T2DM and no liver disease. The ratio of apparent metformin clearance (CL Met /F) to creatinine clearance was marginally lower in CLD patients compared to healthy subjects (median, interquartile range; 12.6, 9.5-15.9 vs 14.9, 13.4-16.4; P = 0.03)., Conclusions: The pharmacokinetics of metformin are not altered sufficiently in CLD patients to raise concerns regarding unsafe concentrations of metformin. There were no unsafe plasma lactate concentrations observed in CLD patients receiving metformin (ACTRN12619001292167; ACTRN12619001348145)., (© 2020 John Wiley & Sons Ltd.)

Objectives: The objective of this study was to investigate the significance and prevalence of lactic acidosis in pediatric diabetic ketoacidosis (DKA) presenting to the emergency department., Methods: A retrospective cohort study of children (age ≤ 21 years) presenting to a tertiary care emergency department in DKA from December 1, 2015 to December 1, 2018. Patients needed to have DKA requiring admission to the pediatric intensive care unit and have had a lactate level collected while in the emergency department to be included., Results: 92 patients resulting in 113 encounters had DKA and a lactate level collected in the emergency department. The mean lactate level was 3.5 mmol/L (±SD 2.1). 72 (63.7%) encounters had lactic acidosis (p < 0.001). There was no significant association between the presence of lactic acidosis and pediatric intensive care unit length of stay (p = 0.321), hospital length of stay (p = 0.426), morbidity (p = 0.552) and mortality (p = 1.000). Initial glucose levels were significantly higher in the patients presenting with lactic acidosis (p = 0.001)., Conclusions: Lactic acidosis is a common finding in pediatric DKA patients presenting to the emergency department. Serum lactate alone should not be used as an outcome predictor in pediatric DKA., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: In 2016, the U.S. Food and Drug Administration (FDA) revised metformin's label to permit use in patients with mild-moderate chronic kidney disease. We sought to determine whether this change was associated with increased reports of metformin-associated lactic acidosis (MALA) to the FDA's Adverse Event Reporting System (FAERS)., Research Design and Methods: Publicly available FAERS reports were analyzed., Results: MALA reports increased from 521 in 2015 to 1,939 in 2018. After restriction to U.S. reports, absolute and relative increase in MALA reports was less, from 111 to 243. The proportionate reporting ratio (PRR), a measure adjusted for rates of other adverse event reports, was stable., Conclusions: The increased reports deserve attention, but the PRR's stability and FAERS's known limitations, including lack of a denominator or control group, do not permit the conclusion that U.S. MALA rates have increased. Further study with more robust data sources is needed., (© 2019 by the American Diabetes Association.)

Background: Immigrants crossing the Southern U.S. border are particularly susceptible to heat illness. We review 3 patients from a heat-related mass-casualty incident with variations in heat stroke presentation, course, and outcome., Case Report: On July 23, 2017, emergency medical services responded to a trafficking-related mass-casualty incident in San Antonio, Texas, involving 39 migrants found inside an abandoned tractor trailer without air conditioning who had been trafficked from Laredo, Texas. Three victims exhibiting heat stroke symptoms were taken to the ED of a large academic teaching hospital. Patient 1 was a 42-year-old man who presented with seizing, vomiting, and a core temperature of 38.8°C (101.8°F). His 54-day hospital course was notable for 2 cardiac arrests, disseminated intravascular coagulation, prolonged lactic acidosis, and residual kidney disease. Patient 2 was a 32-year-old man who presented to the emergency department intubated in the field with a core temperature of 40.7°C (105.3°F). His 60-day hospital course was notable for disseminated intravascular coagulation, severely elevated troponin, prolonged lactic acidosis, and stroke. Patient 3 was a 20-year-old man who presented with seizing and decorticate posturing, with a core temperature of 40.5°C (104.9°F). His 6-day hospital course was notable for rapid clinical improvement and full recovery. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians will encounter heat stroke victims. Our patients were exposed to an identical environment, and while each patient was otherwise healthy and differed significantly only in age, they exhibited a diversity of heat stroke presentations and sequelae. Treatment prioritizes cooling, but rapid deterioration requires intensive treatment of multiorgan failure., (Copyright © 2019. Published by Elsevier Inc.)

Introduction and Objectives: There is increasing evidence to suggest that therapeutic doses of metformin are unlikely to cause lactic acidosis. The aims of this research were (1) to formally evaluate the association between metformin therapy and lactic acidosis in published case reports using two causality scoring systems, (2) to determine the frequency of pre-existing independent risk factors in published metformin-associated lactic acidosis cases, (3) to investigate the association between risk factors and mortality in metformin-associated lactic acidosis cases, and (4) to explore the relationship between prescribed metformin doses, elevated metformin plasma concentrations and the development of lactic acidosis in cases with chronic renal impairment., Methods: A systematic review was conducted to identify metformin-associated lactic acidosis cases. Causality was assessed using the World Health Organisation-Uppsala Monitoring Centre system and the Naranjo adverse drug reaction probability scale. Compliance to dosing guidelines was investigated for cases with chronic renal impairment as well as the association between steady-state plasma metformin concentrations prior to admission., Results: We identified 559 metformin-associated lactic acidosis cases. Almost all cases reviewed (97%) presented with independent risk factors for lactic acidosis. The prescribed metformin dose exceeded published guidelines in 60% of cases in patients with impaired kidney function. Metformin steady-state plasma concentrations prior to admission were predicted to be below the proposed upper limit of the therapeutic range of 5 mg/L., Conclusions: Almost all cases of metformin-associated lactic acidosis reviewed presented with independent risk factors for lactic acidosis, supporting the suggestion that metformin plays a contributory role. The prescribed metformin dose, on average, exceeded the dosing recommendations by 1000 mg/day in patients with varying degrees of renal impairment but the predicted pre-admission plasma concentrations did not exceed the therapeutic range.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (© 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Introduction: Metabolic acidosis is a dangerous and potentially life-threatening condition encountered in the inpatient and emergency department setting. Metabolic acidoses due to renal failure, bicarbonate losses, or lactic acidosis are common conditions, and the appropriate medical management of each is relevant to any inpatient medical provider. Therefore, we created a learning activity that utilizes blackboard-style videos followed by an interactive case-based learning session to help the medical student recognize, diagnose, and manage common causes of metabolic acidosis., Methods: We organized this learning activity by assigning digital videos, followed by application in an interactive team-based format. We created electronic blackboard-style videos and a quiz to assess medical knowledge related to concepts discussed in the videos. Next, we created case resources that facilitate an interactive case-based teaching session so the learners could apply their knowledge and simulate the management of metabolic acidosis., Results: We implemented this activity for 34 medical students. All students viewed the videos prior to the in-class session. In a pre/post assessment of medical knowledge, we observed a significant improvement in quiz scores. Next, we successfully facilitated the case-based active learning session, allowing the assessment of higher-order cognitive skills related to management of patients with metabolic acidosis. Our medical students felt highly satisfied and competent at the completion of our course., Discussion: Our medical students rated this as an excellent learning activity. Others may find this activity useful within the context of any course or rotation related to patients with metabolic acidosis., Competing Interests: None to report., (Copyright © 2019 Berkoben and Roberts.)

Background: The use of metformin in patients with type 2 diabetes mellitus has been associated with lactic acidosis. However, the information available in patients with moderate-severe chronic kidney disease is scarce., Methods: The ALIMAR-C2 study is a case-control study to assess the association between metformin and lactic acidosis in patients with type 2 diabetes mellitus and moderate-severe chronic kidney disease. The study will be performed with computerized registered electronic health records from eight Spanish hospitals linked to their corresponding primary care health areas from 2010 to 2016, comprising approximately 22.1 million person-years of follow-up. Logistic regression will be used to assess the crude and adjusted risk of lactic acidosis associated with metformin use overall and stratifying by use and dose categories, and chronic kidney disease stage. The overall case fatality rate of lactic acidosis, as well as the case fatality rate stratified by chronic kidney disease stage, will be calculated., Discussion: The ALIMAR-C2 study will provide useful information about the risk of lactic acidosis in type 2 diabetes mellitus patients with renal impairment using metformin.

The prevalence of type 2 diabetes mellitus (T2D) has risen in the United States and worldwide, with an increase in global prevalence from 4.7% to 8.5% between 1980 and 2014. A variety of antidiabetic drugs are available with different mechanisms of action, and multiple drugs are often used concomitantly to improve glycemic control. One of the newest classes of oral antihyperglycemic agents is the sodium glucose cotransporter-2 (SGLT2) inhibitors or "flozins". Recent clinical guidelines have suggested the use of SGLT2 inhibitors as add-on therapy in patients for whom metformin alone does not achieve glycemic targets, or as initial dual therapy with metformin in patients who present with higher glycated hemoglobin (HbA1c) levels. The FDA has approved fixed-dose combination (FDC) tablets with each of the three available SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) and metformin. Both drug classes are associated with the rare but serious life-threatening complications that result from metabolic acidosis, including lactic acidosis (with metformin) and euglycemic diabetic ketoacidosis (with SGLT2 inhibitors). This review summarizes the current literature on the pharmacokinetics and the molecular targets of metformin and SGLT2 inhibitors. It also addresses the common adverse effects and highlights the molecular mechanisms by which this dual antihyperglycemic therapy contributes to high anion gap metabolic acidosis. In conclusion, while the combination of metformin and SGLT2 inhibitors would be a better option in improving glycemic control with a low risk of hypoglycemia, an increase in the risk of metabolic acidosis during combination therapy may be borne in mind., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: To determine the incidence of metformin-induced lactic acidosis during the period January 2014 to March 2017 in Aragon Healthcare Area III. To analyse the associated clinical and analytical factors and mortality., Results: A total of 31 cases (61.3% males). Incidence: 79.76 cases/100,000 patients-year; mean age 75.39±9.34 years; 23 of them with levels of serum metformin (21.91±15.52 mcg/ ml); milligrams/day of metformin ingested: 1790.32±499; 96.8% of cases in the context of acute kidney failure; 11 cases with a history of chronic kidney disease (35.5%); 12 required intensive care (38.7%); 13 required purification treatment (41.9%; 3 haemodiafiltration, 10 haemodialysis). There was a significant correlation between daily milligrams of metformin ingested and drug levels; levels of metformin; and peak creatinine, pH and lactate. Mortality was 25.8%. There were only significant differences between the deceased and survivors regarding the duration of stay and final creatinine. Multivariate logistic regression did not detect any study variables associated with mortality., Conclusions: The incidence in our healthcare area is higher than in other series, with a 25.8% mortality rate. Virtually all cases were in the context of prerenal acute kidney failure. In 29% of cases, there was an overdose. Patients must be warned about the most common lactic acidosis-inducing situations, especially dehydration, if they continue taking the drug at such times., (Copyright © 2018 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: Birth acidemia is associated with short- and long-term morbidity in the child. Optimal intrapartum surveillance and timely interventions may reduce the incidence of these outcomes. Knowledge about conditions which increase the risks might be beneficial for optimal care. The aim with this study was to identify factors which increased the risk for lactacidemia in fetal scalp blood., Materials and Methods: A secondary analysis of a cohort study performed at Karolinska University Hospital Stockholm Sweden between February 2009 and February 2011. The study population included 1070 women in labor where fetal scalp blood sampling (FBS) was performed., Results: In a univariate logistic regression analysis for lactate >4.8 mmol/L at FBS, minor language barriers (OR 2.54; 95%CI 1.26-5.11), active bearing down (OR 2.46; 95%CI 1.12-5.39) and maternal height <155 cm (OR 2.15; 95%CI 1.08-4.26) were found as risk factors. In a multivariate logistic regression analysis, minor language barriers (OR 2.21; 95%CI 1.05-4.67) and active pushing (OR 2.68; 95%CI 1.20-6.00) remained significant., Conclusions: Language barriers, active pushing and short stature were found to be significant risk factors for intrapartum lactacidemia. In the group with minor language problems better use of interpreters might be beneficial.

Background: Metformin constitutes first-line treatment of type 2 diabetes mellitus. It is presumed to have lactic acidosis as a dangerous, but rare, side effect., Objectives: To estimate the incidence rate of lactic acidosis in patients with type 2 diabetes mellitus as well as to estimate the relative risk of lactic acidosis associated with metformin treatment., Methods: This is a population-based combined cohort and case-control study among patients with type 2 diabetes mellitus who were acutely admitted with lactic acidosis at Odense University Hospital, Denmark; in the period from 1st June 2009 to 1st October 2013. The patients included as cases were all acutely hospitalized with lactic acidosis (pH <7.35 and lactate ≥2.0 mmol/l). For each case, we identified 24 age- and sex-matched controls sampled from the same cohort with type 2 diabetes mellitus. The use of metformin identified by using a prescription database. Analyses included multivariable logistic regression and adjusting for predefined confounding: renal function, HbA1c, comorbidity and diabetes duration., Results: Our cohort included 10,652 patients with type 2 diabetes mellitus with a median age of 74 years, and 51.5% were male. During follow-up, 163 individuals were hospitalized with lactic acidosis, corresponding to an incidence rate of 391/100,000 person years. Use of metformin was not associated with lactic acidosis: adjusted odds ratio was 0.79 (95%CI 0.54-1.17)., Conclusion: Among patients with type 2 diabetes mellitus, the incidence rate of acute hospitalization with lactic acidosis was 391/100,000 person years. Use of metformin did not increase the risk of lactic acidosis. However, comorbidity seems to be an important risk factor.

Background: Metformin associated lactic acidosis (MALA) is a well-known serious side effect of biguanides. However, the best treatment strategy remains a matter of debate. In the last 14 years, we observed a significant increase in hospitalizations for MALA to our Center. We report the outcomes of our clinical and therapeutic approach., Methods: This is a single-center case series. Twenty-eight patients affected with MALA and acute kidney failure admitted between January 2000 and September 2014 were included. We analyzed comorbidities, laboratory tests and clinical parameters at admission, at 36 h and at discharge. All patients were treated with sustained low-efficiency dialysis (SLED) until normalization of serum lactate (≤ 3 mmol/L), bicarbonate (between 20 and 25 mmol/L) and potassium (between 4.0 and 5.1 mmol/L)., Results: The mortality rate was 21.4%, with all of the events occurring within 24 h from admission, and before or during the first hemodialysis treatment. Precipitating causes included; acute dehydration (86.4%), systemic inflammatory response syndrome (SIRS) (57.1%), sepsis (10.7%), nephrolithiasis (14.6%) and exposure to iodinated contrast (7.1%). No further episodes of lactic acidosis were described after discontinuing the drug over a mean follow-up of 27.2 months. Furthermore, while in 2010, we had a peak incidence of MALA of 76.8 cases per 100,000 patients on metformin, this rate fell after an education campaign conducted by specialists on the proper usage of metformin in patients at risk of MALA. Although the fall in incidence after the educational program was not necessarily causal, in 2014 the incidence was 32.9/100,000., Conclusions: We report an improved mortality rate in patients affected with MALA and acute kidney injury treated with SLED compared with other series published in literature. Rapid introduction of effective hemodialysis is critical in improving outcomes.

Background: D-lactic acidosis is an uncommon and challenging form of metabolic acidosis that may develop in short bowel syndrome. It has been documented exclusively in case reports and small case series., Methods: We performed a review of the literature in the National Library of Medicine and Excerpta Medica databases., Results: We identified 84 original reports published between 1977 and 2017. D-lactic acidosis was observed in 98 individuals ranging in age from 7 months to 86 years with short bowel syndrome. The clinical presentation included Kussmaul breathing, confusion, slurred speech, and gait disturbances. Furthermore, among 99 consecutive patients with short bowel syndrome, 21 reported having episodes with symptoms consistent with D-lactic acidosis. In addition, D-lactic acid might also contribute to acidosis in diabetes mellitus. Finally, abnormally high D-lactic acid was documented after administration or ingestion of large amounts of propylene glycol, as paraneoplastic phenomenon and perhaps also in a so far poorly characterized inherited inborn error of metabolism., Conclusions: In humans with short bowel syndrome (or carbohydrate malabsorption), D-lactic acidosis is likely rather common and under-recognized. This condition should be included in the differential diagnosis of unexplained high-gap metabolic acidosis where the anion causing the acidosis is not known. Furthermore, diabetic acidosis might be caused by accumulation of both ketone bodies and D-lactic acid. Finally, there are endogenous sources of D-lactic acid in subjects with propylene glycol intoxication.

Purpose: Lactic acidosis is a rare complication of linezolid (LZD) therapy, and its incidence and risk factors remain unknown. This study aimed to compare the incidence of LZD-associated lactic acidosis (LALA) and vancomycin (VAN)-associated lactic acidosis (VALA) and investigate the risk factors for LALA., Methods: We performed a retrospective cohort study using propensity score-matched analyses comparing the incidence of lactic acidosis between LZD and VAN therapy. We included adult patients administered LZD or VAN between April 2014 and March 2016 and extracted patient baseline data. In a case-control study, we identified the risk factors of lactic acidosis in patients treated with LZD., Results: We identified 94 and 313 patients who were administered LZD and VAN, respectively. The incidence of lactic acidosis after LZD and VAN therapy was 10.6 and 0.3%, respectively. After propensity score-matched analyses, the incidence of lactic acidosis with LZD therapy was significantly higher than that with VAN therapy [10.0% (8/80) vs. 0% (0/80), respectively; risk difference, 0.1; 95% confidence interval (CI), 0.03-0.17; p = 0.004]. In a case-control study, 10 patients with LALA were matched to 20 non-lactic acidosis patients by age and sex. Patients with LALA were more likely to have renal insufficiency than non-lactic acidosis patients that were in the univariate analysis (odds ratio, 7.4; 95% CI, 1.0-84.4; p = 0.02)., Conclusions: This study indicates that LALA occurs more frequently than VALA does and is associated with renal insufficiency. Therefore, close monitoring of kidney function and serum lactate is recommended during LZD therapy.

Metformin has been associated with lactic acidosis. Lactate levels are not commonly tested in clinical practice, and it is unclear to what extent metformin would typically increase lactate levels with chronic use. The aim of this review was to determine whether regular monitoring of the plasma lactate level would be beneficial in avoiding lactate accumulation and, ultimately, minimising the incidence of lactic acidosis in metformin-treated patients.A comprehensive search of PubMed, Embase, Web of Science, Cochrane and International Pharmaceutical Abstracts databases covering the period up to 30 May 2017 was performed. Search terms included combinations of terms and keywords, including "metformin", "lactate", "lactic acid" and "lactic acidosis". Cases series of lactic acidosis or metformin-associated lactic acidosis were excluded.Of 1539 potentially relevant articles, a total of 52 reported lactate levels from routine/regular pathological tests in metformin users. The studies were subdivided into four themes, regarding metformin usage and the reported lactate levels in patients who: (1) did not have contraindications to the use of metformin; (2) had contraindications, or renal impairment but without other contraindications; (3) exercised; or (4) also received any nucleoside reverse transcriptase inhibitor. Studies have reported that metformin treatment could increase lactate level of users. However, most results showed that the lactate level remained in the normal range.No definitive conclusions on the benefits of regular lactate monitoring in patients taking metformin can be made. Future research on larger populations focusing on the measurement of lactate levels with continuous metformin use is warranted.

Aims: Metformin is renally excreted and has been associated with the development of lactic acidosis. Although current advice is to omit metformin during illnesses that may increase the risk of acute kidney injury (AKI), the evidence supporting this is lacking. We investigated the relationship between AKI, lactate concentrations and the risk of lactic acidosis in those exposed to metformin., Materials and Methods: We undertook a population-based case-control study of lactic acidosis in 1746 participants with Type 2 diabetes and 846 individuals without diabetes with clinically measured lactates with and without AKI between 1994 and 2014. AKI was stratified by severity according to "Kidney Disease: Improving Global Outcomes" guidelines. Mixed-effects logistic and linear regression were used to analyse lactic acidosis risk and lactate concentrations, respectively., Results: Eighty-two cases of lactic acidosis were identified. In Type 2 diabetes, those treated with metformin had a greater incidence of lactic acidosis [45.7 per 100 000 patient years; 95% confidence interval (CI) 35.9-58.3] compared to those not exposed to this drug (11.8 per 100 000 patient years; 95% CI 4.9-28.5). Lactate concentrations were 0.34 mmol/L higher in the metformin-exposed cohort (P < .001). The risk of lactic acidosis was higher in metformin users [odds ratio (OR) 2.3; P = .002] and increased with AKI severity (stage 1: OR 3.0, P = .002; stage 2: OR 9.4, P < .001; stage 3: OR 16.1, P < .001)., Conclusions: A clear association was found between metformin, lactate accumulation and the development of lactic acidosis. This relationship is strongest in those with AKI. These results provide robust evidence to support current recommendations to omit metformin in any illness that may precipitate AKI., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Although metformin has been used for over 60 years, the balance between the drug's beneficial and adverse effects is still subject to debate. Following an analysis of how cases of so-called "metformin-associated lactic acidosis" (MALA) are reported in the literature, the present article reviews the pitfalls to be avoided when assessing the purported association between metformin and lactic acidosis. By starting from pathophysiological considerations, we propose a new paradigm for lactic acidosis in metformin-treated patients. Metformin therapy does not necessarily induce metformin accumulation, just as metformin accumulation does not necessarily induce hyperlactatemia, and hyperlactatemia does not necessarily induce lactic acidosis. In contrast to the conventional view, MALA probably accounts for a smaller proportion of cases than either metformin-unrelated lactic acidosis or metformin-induced lactic acidosis. Lastly, this review highlights the need for substantial improvements in the reporting of cases of lactic acidosis in metformin-treated patients. Accordingly, we propose a check-list as a guide to clinical practice., (© 2017 John Wiley & Sons Ltd.)

Background: Metformin associated lactic acidosis (MALA) is a rare but lethal complication. There is no consensus regarding when to stop and resume metformin in patients who undergo coronary artery bypass grafting (CABG). This study aimed to determine if uninterrupted metformin administration in patients with diabetes undergoing CABG increases the risk of lactic acidosis., Methods: Over a span of 12 months (2015-2016), 127 patients with type 2 diabetes underwent isolated CABG. Of those, 41 patients (32%) continued taking metformin and 86 patients (68%) took other antidiabetic agents. Patients taking metformin took the drug until the day of surgery and resumed taking it 3 h after extubation., Results: There were no differences in clinical outcomes or complications between groups. Serial measurement of cardiac, liver, and kidney biomarkers were similar between groups. The mean peak lactic acid level was significantly higher in the non-metformin users (5.4 ± 2.6 vs. 7.4 ± 4.1 mmol/l; P = 0.001). Multivariable logistic regression analysis identified the need for vasopressor administration as an independent predictor of lactic acidosis (odds ratio: 7.3, 95% confidence interval: 2.5-20.6; P < 0.001)., Conclusion: In the absence of risk factors associated with persistent lactic acidosis, such as shock or acute kidney or liver injury, continued peri-operative metformin administration was not associated with the occurrence of lactic acidosis in patients undergoing CABG. Elevated lactic acid levels seem to be directly related to tissue anoxia caused by escalating vasopressor support after surgery.

Aims: To assess risk of lactic acidosis among metformin users compared with other glucose-lowering agent users, according to renal function., Methods: Using routine registries and databases, we conducted a cohort study. Of 43 580 metformin and 37 788 other glucose-lowering agent users in northern Denmark and 102 688 metformin and 28 788 other glucose-lowering agent users in the UK during 2001-2011, we identified lactic acidosis using diagnostic codes. We calculated the incidence rates of lactic acidosis in metformin and other glucose-lowering agent users overall and according to baseline estimated GFR (eGFR) levels., Results: In Denmark, the incidence rates of lactic acidosis were 11.6 (95% CI 7.0-18.1) and 1.8 (95% CI 0.4-5.4) per 100 000 person-years of metformin use and of other glucose-lowering agent use, respectively. In the UK, the corresponding lactic acidosis incidence rates were 6.8 (95% CI 4.6-9.6) and 1.0 (95% CI 0.01-5.7) per 100 000 person-years of metformin use and of other glucose-lowering agent use. The incidence rates increased with decreasing baseline eGFR in both countries. Of the metformin-exposed people with lactic acidosis, 37% in Denmark and 34% in the UK experienced a decline in renal function in the year before the diagnosis., Conclusions: Risk of lactic acidosis was higher in metformin users than in other glucose-lowering agent users, and increased with decreasing eGFR, although this could be attributable to surveillance bias; however, diagnosed lactic acidosis was rare and can occur regardless of renal function., (© 2016 Diabetes UK.)

Severe hyperlactatemia (SH)/lactic acidosis (LA) after laparoscopic resection of pheochromocytoma is an infrequently reported complication. The study aims to investigate the incidence of this complication and to determine the clinical risk factors. Patients who underwent laparoscopic resection for pheochromocytoma between 2011 and 2014 at Peking Union Medical College Hospital were enrolled. LA was defined as pH < 7.35, bicarbonate <20 mmol/L, and serum lactate ≥5 mmol/L; SH as lactate ≥5 mmol/L; and moderate hyperlactatemia (MH) as lactate 2.5-5.0 mmol/L without evidence of acidosis (pH > 7.35 and/or bicarbonate >20 mmol/L). Data concerning patient demographics, clinical history, and laboratory results were collected and statistical analyses were performed. Out of 145 patients, 59 (40.7%) developed post-operative hyperlactatemia. The incidences of MH and SH/LA were 25.5% and 15.2%, respectively. Multivariate analysis demonstrated that body mass index (BMI) (odds ratio [OR], 1.204; 95% confidence interval [CI], 1.016-1.426), 24-hour urine epinephrine concentration (OR, 1.012; 95% CI, 1.002-1.022), and tumor size (OR, 1.571; 95% CI, 1.102-2.240) were independent predictors of post-operative SH/LA. The data show that post-operative SH/LA is not a rare complication after pheochromocytoma resection and may be closely associated with higher BMI, larger tumor size, and higher levels of urine epinephrine.

Metformin is the mainstay of treatment of type 2 diabetes. However, there has been significant concern on prescribing metformin in patients with renal impairment as a result of metformin-associated lactic acidosis (MALA). Recent studies have cast doubt on the existence of MALA purely related to metformin use. Medsafe recently initiated changes to datasheet so lower doses of metformin could be used in patients with GFR down to 15ml/min. In this paper we outline the context and implications of this change., Competing Interests: Dr Jayathissa is a member of Medicine Adverse Reaction Committee (MARC), a ministerial advisory committee for Medsafe. MARC committee endorsed Medsafe changes to metformin data sheet. Associate Professor David Reith is chair of the MARC committee.

Purpose: Metformin can reduce diabetes-related complications and mortality. However, its use is limited because of potential lactic acidosis-associated adverse effects, particularly in renal impairment patients. We aimed to investigate the association of metformin use with lactic acidosis and hyperlactatemia in patients with type 2 diabetes., Materials and Methods: This was a cross-sectional study from a tertiary university-affiliated medical center. A total of 1954 type 2 diabetes patients were recruited in 2007-2011, and stratified according to the estimated glomerular filtration rate of 60 mL/min/1.73 m². Lactic acidosis was defined as plasma lactate levels >5 mmol/L and arterial pH <7.35., Results: Metformin was used in 61.4% of the patients with type 2 diabetes mellitus. Plasma lactate levels were not different in the patients with and without metformin use. There was no difference in prevalence of hyperlactatemia and lactic acidosis between the patients with and without metformin use (18.9% vs. 18.7%, p=0.905 for hyperlactatemia and 2.8% vs. 3.3%, p=0.544 for lactic acidosis). Similar results were observed in the patients with estimated glomerular filtration rate <60 mL/min/1.73 m². Most patients with lactic acidosis had at least one condition related to hypoxia or poor tissue perfusion. Multiple regression analysis indicated no association between metformin use and lactic acidosis, whereas tissue hypoxia was an independent risk factor for lactic acidosis [odds ratio 4.603 (95% confidence interval, 1.327-15.965)]., Conclusion: Metformin use was not associated with hyperlactatemia or lactic acidosis in patients with type 2 diabetes., Competing Interests: The authors have no financial conflicts of interest.

Objectives: Time to clearance of pathogens is probably critical to outcome in septic shock. Current guidelines recommend intervention for source control within 12 hours after diagnosis. We aimed to determine the epidemiology of source control in the management of sepsis and to analyze the impact of timing to source control on mortality., Design: Prospective observational analysis of the Antibiotic Intervention in Severe Sepsis study, a Spanish national multicenter educational intervention to improve antibiotherapy in sepsis., Setting: Ninety-nine medical-surgical ICUs in Spain., Patients: We enrolled 3,663 patients with severe sepsis or septic shock during three 4-month periods between 2011 and 2013., Interventions: Source control and hospital mortality., Measurements and Main Results: A total of 1,173 patients (32%) underwent source control, predominantly for abdominal, urinary, and soft-tissue infections. Compared with patients who did not require source control, patients who underwent source control were older, with a greater prevalence of shock, major organ dysfunction, bacteremia, inflammatory markers, and lactic acidemia. In addition, compliance with the resuscitation bundle was worse in those undergoing source control. In patients who underwent source control, crude ICU mortality was lower (21.2% vs 25.1%; p = 0.010); after adjustment for confounding factors, hospital mortality was also lower (odds ratio, 0.809 [95% CI, 0.658-0.994]; p = 0.044). In this observational database analysis, source control after 12 hours was not associated with higher mortality (27.6% vs 26.8%; p = 0.789)., Conclusions: Despite greater severity and worse compliance with resuscitation bundles, mortality was lower in septic patients who underwent source control than in those who did not. The time to source control could not be linked to survival in this observational database.

Background: Metformin-associated lactic acidosis (MALA) is a severe complication of drug administration with significant morbidity and mortality. So far no study in large population areas have examined the incidence, clinical profile and outcome of acute kidney injury (AKI)-MALA patients admitted in intensive care units (ICUs) and treated by renal replacement therapy (MALA-RRT)., Methods: Retrospective analysis over a 6-year period (2010-2015) in Piedmont and Aosta Valley regions (5,305,940 inhabitants, 141,174 diabetics treated with metformin) of all MALA-RRT cases., Results: One hundred and seventeen cases of AKI-MALA-RRT were observed (12.04/100,000 metformin treated diabetics, 1.45% of all RRT-ICU patients). Survival rate was 78.3%. The average duration of RRT was 4.0 days at mean dialysis effluent of 977 mL/kg/day. At admission most patients were dehydrated, and experienced shock and oliguria., Conclusion: Our data showed that MALA-RRT is a common complication, needing more prevention. Adopted policy of early, extended, continuous and high efficiency dialysis could contribute to an observed high survival rate. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=471917., (© 2017 S. Karger AG, Basel.)

Purpose: To estimate the incidence of lactic acidosis (LA) and role of metformin in Japanese patients with type 2 diabetes mellitus (T2DM) treated with anti-diabetes drugs., Methods: This retrospective propensity score matched cohort study was conducted using the Japanese Medical Data Vision claims database. T2DM patients aged 18 or above who received diabetes drugs during January 2010 through August 2014 were identified. Cases of LA were identified based on reimbursement codes and confirmed by lactic acid test and subsequent treatment by hemodialysis or intravenous sodium bicarbonate. Poisson regression and Cox proportional hazard models were used to estimate the incidence and assess if metformin use was associated with increased risk of LA., Results: Thirty cases of LA were identified among 283 491 treated T2DM patients with 504 169 patient-years of follow-up. Crude incidence of LA was 5.95 per 100 000 patient-years. T2DM patients with chronic kidney disease (CKD) were seven-fold more likely to develop LA than those without CKD (adjusted hazard ratio (aHR), 7.33, 95%CI, 3.17-16.96). Use of metformin was not associated with risk of LA in the study population (aHR, 0.92, 95%CI, 0.33-2.55), and in the propensity score matched cohort (aHR, 0.90, 95%CI, 0.26-3.11). Similar findings were observed among diabetes patients with chronic liver disease (CLD) and CKD. The age-sex adjusted incidence rates in metformin users and non-users were 5.80 and 5.78 per 100 000 person-years, respectively (Incidence rate ratio, 1.00, p = 0.99)., Conclusions: This study found that use of metformin was not associated with increased risk of LA in diabetic patients including those with CKD or CLD. © 2016 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd., (© 2016 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)