The Effects of a Ketogenic Diet on Patients with Dihydrolipoamide Dehydrogenase Deficiency.

BACKGROUND: Dihydrolipoamide dehydrogenase (DLD lipoamide dehydrogenase, the E3 subunit of the pyruvate dehydrogenase complex (PDHC)) is the third catalytic enzyme of the PDHC, which converts pyruvate to acetyl-CoA catalyzed with the introduction of acetyl-CoA to the tricyclic acid (TCA) cycle. In humans, PDHC plays an important role in maintaining glycose homeostasis in an aerobic, energy-generating process. Inherited DLD-E3 deficiency, caused by the pathogenic variants in DLD, leads to variable presentations and courses of illness, ranging from myopathy, recurrent episodes of liver disease and vomiting, to Leigh disease and early death. Currently, there is no consensus on treatment guidelines, although one suggested solution is a ketogenic diet (KD). OBJECTIVE: To describe the use and effects of KD in patients with DLD-E3 deficiency, compared to the standard treatment. RESULTS: Sixteen patients were included. Of these, eight were from a historical cohort, and of the other eight, four were on a partial KD. All patients were homozygous for the D479V (or D444V, which corresponds to the mutated mature protein without the mitochondrial targeting sequence) pathogenic variant in DLD. The treatment with partial KD was found to improve patient survival. However, compared to a historical cohort, the patients' quality of life (QOL) was not significantly improved. CONCLUSIONS: The use of KD offers an advantage regarding survival; however, there is no significant improvement in QOL.

A Study of Associations Between Plasma Metformin Concentration, Lactic Acidosis, and Mortality in an Emergency Hospitalization Context.

OBJECTIVES: To determine the plasma metformin concentration threshold associated with lactic acidosis and analyze the outcome in metformin-treated patients with lactic acidosis hospitalized in an emergency context. DESIGN: A retrospective, observational, single-center study. SETTING: Emergency department and ICUs at Amiens University Hospital (Amiens, France). PATIENTS: All consecutive patients with data on arterial lactate and pH up to 12 hours before or after a plasma metformin assay within 24 hours of admission, over a 9.7-year period. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The study population consisted of 194 metformin-treated diabetic patients (median age: 68.6; males: 113 [58.2%]); 163 (84%) had acute kidney injury, which was associated variously with dehydration (45.4%), sepsis (41.1%), cardiogenic shock (20.9%), and diabetic ketoacidosis (16%). Eighty-seven patients (44.8%) had lactic acidosis defined as an arterial blood pH less than 7.35 and a lactate concentration greater than or equal to 4 mM, and 38 of them (43.7%) died in the ICU. A receiver operating characteristic curve analysis showed that a metformin concentration threshold of 9.9 mg/L was significantly associated with the occurrence of lactic acidosis (specificity: 92.9%; sensitivity: 67.1%; area under the receiver operating characteristic curve: 0.83; p < 0.0001). Among lactic acidosis-positive patients, however, in-ICU death was less frequent when the metformin concentration was greater than or equal to 9.9 mg/L (33.9% vs 61.3% for < 9.9 mg/L; p = 0.0252). After adjustment for the Simplified Acute Physiology Score II, in-ICU death was positively associated with prothrombin activity less than 70% and negatively associated with the initiation of renal replacement therapy at admission. CONCLUSIONS: In metformin-treated patients admitted in an emergency context, a plasma metformin concentration greater than or equal to 9.9 mg/L was strongly associated with the presence of lactic acidosis. This threshold may assist with the delicate decision of whether or not to initiate renal replacement therapy. Indeed, the outcome of lactic acidosis might depend on the prompt initiation of renal replacement therapy-especially when liver failure reduces lactate elimination.

Causes of death in feedlot beef cattle and their control: a brief review / Causas de morte em bovinos de corte confinados e seu controle: uma breve revisão

This review reports the leading causes of death in feedlot beef cattle. It describes economic losses resulting from these deaths and suggests control alternatives. Diseases associated with the respiratory and digestive systems were the most frequently observed. In different geographical areas, the importance of each one might vary. Outbreaks of diseases such as botulism occur occasionally and can cause important economic losses. Cattle tick fever can cause significant losses in zones of enzootic tick instability. Technical assistance and sanitary and food management are critical for the best productivity in feedlot cattle.(AU)

Esta revisão discute as principais causas de morte em bovinos de corte em confinamento. Descreve as perdas econômicas resultantes dessas mortes e sugere alternativas de controle. As doenças associadas aos sistemas respiratório e digestivo foram as mais frequentemente observadas. Em diferentes áreas geográficas, a importância de cada uma pode variar. Surtos de doenças como o botulismo ocorrem ocasionalmente e podem causar importantes perdas econômicas. A tristeza parasitária bovina pode causar perdas significativas em zonas de instabilidade enzoótica do carrapato. A assistência técnica e um bom gerenciamento sanitário e alimentar são essenciais para a melhor produtividade em bovinos de corte confinados.(AU)

A MELAS Patient Developing Fatal Acute Renal Failure with Lactic Acidosis and Rhabdomyolysis.

We herein present a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), who developed serious acute renal failure with lactic acidosis, followed by rhabdomyolysis. Despite receiving intensive care, he suffered multiple cardiopulmonary arrests and died 10 days after presentation due to a sudden deterioration of his symptoms. Renal pathology revealed diffuse tubular necrosis with interstitial edema and tubular dilatation on light microscopy, and a severe degeneration of intracellular organelles on electron microscopy. These pathological findings could have resulted from multiple cardiopulmonary arrests; however, we must be aware of the extremely rare but sudden occurrence of these fatal conditions in MELAS patients.

Do Patients Die with or from Metformin-Associated Lactic Acidosis (MALA)? Systematic Review and Meta-analysis of pH and Lactate as Predictors of Mortality in MALA.

OBJECTIVES: Metformin-associated lactic acidosis (MALA) may occur after acute metformin overdose, or from therapeutic use in patients with renal compromise. The mortality is high, historically 50% and more recently 25%. In many disease states, lactate concentration is strongly associated with mortality. The aim of this systematic review and meta-analysis is to investigate the utility of pH and lactate concentration in predicting mortality in patients with MALA. METHODS: We searched PubMed, EMBASE, and Web of Science from their inception to April 2019 for case reports, case series, prospective, and retrospective studies investigating mortality in patients with MALA. Cases and studies were reviewed by all authors and included if they reported data on pH, lactate, and outcome. Where necessary, authors of studies were contacted for patient-level data. Receiver operating characteristic (ROC) curves were generated for pH and lactate for predicting mortality in patients with MALA. RESULTS: Forty-four studies were included encompassing 170 cases of MALA with median age of 68.5 years old. Median pH and lactate were 7.02 mmol/L and 14.45 mmol/L, respectively. Overall mortality was 36.2% (95% CI 29.6-43.94). Neither lactate nor pH was a good predictor of mortality among patients with MALA. The area under the ROC curve for lactate and pH were 0.59 (0.51-0.68) and 0.43 (0.34-0.52), respectively. CONCLUSION: Our review found higher mortality from MALA than seen in recent studies. This may be due to variation in standard medical practice both geographically and across the study interval, sample size, misidentification of MALA for another disease process and vice versa, confounding by selection and reporting biases, and treatment intensity (e.g., hemodialysis) influenced by degree of pH and lactate derangement. The ROC curves showed poor predictive power of either lactate or pH for mortality in MALA. With the exception of patients with acute metformin overdose, patients with MALA usually have coexisting precipitating illnesses such as sepsis or renal failure, though lactate from MALA is generally higher than would be considered survivable for those disease states on their own. It is possible that mortality is more related to that coexisting illness than MALA itself, and many patients die with MALA rather than from MALA. Additional work looking solely at MALA in healthy patients with acute metformin overdose may show a closer relationship between lactate, pH, and mortality.

L-lactic acidosis: pathophysiology, classification, and causes; emphasis on biochemical and metabolic basis.

L-lactic acidosis (L-LA) is the most common cause of metabolic acidosis in the critical care setting, which has been associated with a large increase in mortality. The purpose of this article is to provide clinicians with an overview of the biochemical and metabolic background required to understand the different pathophysiological mechanisms that may lead to the development of L-LA. We propose a classification based on whether the pathophysiology of L-LA is due predominantly to increased production or decreased removal of L-lactic acid. In this article, we provide an overview of the biochemical and metabolic aspects of glucose oxidation, the production and removal of L-lactic acid, and a discussion of the pathophysiology of the various causes of L-LA.

Incidencia, factores relacionados con la presentación, evolución y mortalidad de la acidosis láctica asociada a metformina en el área sanitaria de un hospital de tercer nivel / Incidence, factors related to presentation, course and mortality of metformin-associated lactic acidosis in the healthcare area of a tertiary hospital

Objetivos: Conocer la incidencia de casos de acidosis láctica por metformina durante el periodo enero de 2014 y marzo de 2017 en el Área Sanitaria III de Aragón. Analizar los factores clínicos y analíticos asociados y la mortalidad. Resultados: Treinta y un casos (61,3% varones). Incidencia: 79,76 casos/100000 pacientes-año; edad media 75,39 ± 9,34 años; 23 de ellos con niveles séricos de metformina (21,91 ± 15,52 mcg / mL); miligramos/día de metformina ingeridos: 1790,32 ± 499; 96,8% de casos en el contexto de fracaso renal agudo; 11 casos con antecedentes de enfermedad renal crónica (35,5%); 12 requirieron UCI (38,7%); 13 requirieron tratamiento depurador (41,9%; 3 hemodiafiltración, 10 hemodiálisis) Existió correlación significativa entre: miligramos diarios ingeridos de metformina y niveles del fármaco; niveles de metformina y: creatinina pico, pH y lactato. La mortalidad fue del 25,8%. Solo hubo diferencias significativas entre los fallecidos y los supervivientes respecto a la duración de la estancia y la creatinina final. La regresión logística multivariante no detectó ninguna variable del estudio asociada con la mortalidad. Conclusiones: La incidencia en nuestra área sanitaria es más elevada que en otras series, con 25,8% de mortalidad. Prácticamente todos los casos en el contexto de fracaso renal agudo de origen prerrenal. En un 29% de los casos hubo sobredosificación. Es necesario advertir a los pacientes de las situaciones más frecuentes potencialmente inductoras de acidosis láctica, especialmente la deshidratación, si siguen tomando el fármaco durante las mismas

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

Levetiracetam administration is correlated with lower mortality in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes: a retrospective study.

BACKGROUND: Studies on the relationship between antiepileptic drug (AED) administration and clinical outcomes in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) remain scarce. Levetiracetam (LEV) is an AED that is neuroprotective in various neurologic disorders. This study aimed to determine the impact of LEV on the outcome of MELAS. METHODS: A retrospective, single-center study was performed based on a large cohort of patients with MELAS with a history of seizures (n = 102). Decisions on antiepileptic therapies were made empirically. Patients were followed up for 1 to 8 years (median, 4 years) and divided into 2 groups based on whether LEV was administered (LEV or non-LEV). The modified Rankin scale (mRS) scores and mortality risks were analyzed in all patients. RESULTS: LEV, carbamazepine, benzodiazepines, topiramate, oxcarbazepine, valproate, and lamotrigine were administered in 48, 37, 18, 13, 11, 9, and 9 patients, singly or in combination, respectively. The mean mRS score of the LEV group (n = 48) was lower than that of the non-LEV group (n = 54; mean ±â€Šstandard deviation, 2.79 ±â€Š1.47 vs. 3.83 ±â€Š1.93, P = 0.006) up to the end of the study. Nevertheless, there was no difference in the proportion of subjects without disability (mRS ranging 0-1) between the groups (P = 0.37). The multivariate regressions revealed that LEV treatment was associated with lower mRS scores (odds ratio 0.32, 95% confidence interval [CI] 0.15-0.68, P = 0.003) and mortality rates (hazard ratio 0.24, 95% CI 0.08-0.74, P = 0.013). There was a significant difference in the Kaplan-Meier survival curves between the groups (χ = 4.29, P = 0.04). CONCLUSIONS: The LEV administration is associated with lower mortality in patients with MELAS in this retrospective study. Further laboratory research and prospective cohort studies are needed to confirm whether LEV has neuroprotective effects on patients with mitochondrial diseases.

Incidence, factors related to presentation, course and mortality of metformin-associated lactic acidosis in the healthcare area of a tertiary hospital. / Incidencia, factores relacionados con la presentación, evolución y mortalidad de la acidosis láctica asociada a metformina en el área sanitaria de un hospital de tercer nivel.

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.

Sustained low-efficiency dialysis for metformin-associated lactic acidosis in patients with acute kidney injury.

BACKGROUND: The choice of the specific modality and treatment duration of renal replacement therapy (RRT) to adopt in metformin-associated lactic acidosis (MALA) is still debated. We aimed to verify if sustained low-efficiency dialysis (SLED) is a rational choice in patients with MALA and acute kidney injury (AKI). METHODS: We collected serial serum metformin measurements, clinical parameters, and outcome data in ten consecutive patients (mean age 77 years [range 58-88], 5 males) admitted to our renal intensive care unit for suspected MALA associated with AKI and hemodynamic instability. Patients underwent a 16-h SLED session performed with either conventional dialysis machines or machines for continuous RRT (CRRT). A 2-compartment open-infusion pharmacokinetic model with first-order elimination was fitted to each subject's serum concentration-time data to model post-SLED rebound and predict the need for further treatments. RESULTS: Two patients died within 24 h after SLED start. Three patients needed one further dialysis session. Surviving patients (n = 8) were dialysis-free at discharge. Metformin levels were in the toxic range at baseline (median [range] 32.5 mg/l [13.6-75.6]) and decreased rapidly by the end of SLED (8.1 mg/l [4.5-15.8], p < 0.001 vs. baseline), without differences according to the dialysis machine used (p = 0.84). We observed a slight 4-h post-SLED rebound (9.7 mg/l [3.5-22.0]), which could be predicted by our pharmacokinetic model. Accordingly, we predicted that the majority of patients would need one additional dialysis session performed the following day to restore safe metformin levels. CONCLUSIONS: A 16-h SLED session, performed with either conventional dialysis machines or CRRT machines, allows effective metformin removal in patients with MALA and AKI. However, due to possible post-SLED rebound in serum metformin levels, one additional dialysis treatment is required the following day in the majority of patients.

The risk factors of linezolid-induced lactic acidosis: A case report and review.

BACKGROUND: In recent years, linezolid is increasingly used in multidrug-resistant bacteria therapy. At the same time, linezolid-induced lactic acidosis has been continually reported as a serious side effect. Notably, to our knowledge, there are limited available literatures that evaluate risk factors for linezolid-induced lactic acidosis, and there is no highly reliable study on the relationship between linezolid-induced lactic acidosis and age or gender. However, clinicians need relevant information to advice on the use of linezolid. Therefore, we report on a case of life-threatening lactic acidosis after 3 doses of linezolid exposure and evaluate the risk factors of linezolid-induced lactic acidosis. METHODS: Cases of linezolid-induced lactic acidosis reported in PubMed were searched. Several characteristics and data of case numbers and deaths were extracted for analysis. RESULTS: A total of 35 articles including 47 cases were included in this study. Twelve patients (25.5%) died due to linezolid-induced lactic acidosis. At the cut-offs of 7, 14, and 28 days, the mortalities were 27.3%, 20%, and 27.3%. No statistically significant difference was observed according to age and gender. However, the proportion (27.7% and 29.8%) and mortality (30.8% and 35.7%) of male patients were much higher than females in both ≥65 and <65 years old groups (proportion: 15.2% and 23.9%; mortality: 14.3% and 18.2%). CONCLUSION: The mortality of linezolid-induced lactic acidosis was relatively high. The duration of linezolid use and age might not be risk factors. Gender (specifically, male) might be related to the mortality of linezolid-induced lactic acidosis.

[Lactic acidosis - update 2018]. / Laktatazidose ­ Update 2018.

Severe hyperlactaemia in intensive care patients is most often due to underlying sepsis or septic, cardiogenic or haemorrhagic shock. Hyperlactaemia is an independent predictor of death in various groups of critically ill patients. With serum lactate values > 10 mmol/l 80 % of the patients die in intensive care, and if the severe lactic acidosis persists for 48 hours, all patients die. Increased lactate levels require immediate diagnostic work-up and classification. The new sepsis definition requires a serum lactate > 2 mmol/l for septic shock with adequate volume substitution and vasopressor administration in order to achieve a mean arterial pressure in persistent hypotension ≥ 65 mmHg. The 1-hour bundle of the Surviving Sepsis Campaign published in 2018 recommends as a first measure the determination of the lactate serum concentrations, and increased values should be closely monitored. In addition, blood culture sampling, broad-spectrum antibiotics, fluid resuscitation and vasopressor administration are recommended within the first hour. Large amounts of crystalloids should be given for increased lactate levels (≥ 4 mmol/l) and refractory hypotension, the administration of fluids can be adjusted according to lactate clearance. Lactate metabolism is prolonged in patients with liver function impairment. Lactate levels on admission to intensive care are significantly associated with the number of failing organs and mortality in patients with cirrhosis. 12-hour lactate clearance has a strong predictive prognosis for survival in patients with baseline lactate levels above 5 mmol/l, the latter remains an independent predictor for the severity of the underlying disease even after correction. The greater the decrease in lactate during the initial therapy, the better the outcome.

Pyruvate is a prospective alkalizer to correct hypoxic lactic acidosis.

Type A lactic acidosis resulted from hypoxic mitochondrial dysfunction is an independent predictor of mortality for critically ill patients. However, current therapeutic agents are still in shortage and can even be harmful. This paper reviewed data regarding lactic acidosis treatment and recommended that pyruvate might be a potential alkalizer to correct type A lactic acidosis in future clinical practice. Pyruvate is a key energy metabolic substrate and a pyruvate dehydrogenase (PDH) activator with several unique beneficial biological properties, including anti-oxidant and anti-inflammatory effects and the ability to activate the hypoxia-inducible factor-1 (HIF-1α) - erythropoietin (EPO) signal pathway. Pyruvate preserves glucose metabolism and cellular energetics better than bicarbonate, lactate, acetate and malate in the efficient correction of hypoxic lactic acidosis and shows few side effects. Therefore, application of pyruvate may be promising and safe as a novel therapeutic strategy in hypoxic lactic acidosis correction accompanied with multi-organ protection in critical care patients.

Pyruvate in reduced osmolarity oral rehydration salt corrected lactic acidosis in sever scald rats.

BACKGROUND: A novel pyruvate-based oral rehydration salt (Pyr-ORS) was demonstrated of superiority over bicarbonate- or citrate-based one to preserve organ function and correct lactic acidosis in rehydration of lethal shock in animals. This study further compared these effects between low-osmolar Pyr-ORS and equimolar citrate-based counterpart. METHODS: Eighty rats, using a fatal burn shock model, were randomized into four groups (two subgroups per group: n = 10): the sham group (group SR), Pyr-ORS group (group PR), WHO-ORS III group (group CR), and no rehydration group. ORS was delivered by manual gavage during 24 h following burns. Oral administration consisted of half of counted volume in the initial 8 h plus the rest in the later 16 h. Systemic hemodynamics, visceral organ surface blood flow, organ function, and metabolic acidosis were determined at 8 h and 24 h after burn. Another set of rats with identical surgical procedures without tests was observed for survival. RESULTS: Survival was markedly improved in the groups PR and CR; the former showed a higher survival rate than the latter at 24 h (40% versus 20%, P < 0.05). Systemic hemodynamics, visceral blood flow, and function of heart, liver, and kidney were greatly restored in group PR, compared with group CR (all P < 0.05). Hypoxic lactic acidosis was efficiently reversed in group PR, instead of group CR, (pH 7.36 versus 7.11, base excess 2.1 versus -9.1 mmol/L, lactate 4.28 versus 8.18 mmol/L; all P < 0.05) at 24 h after injury. CONCLUSIONS: Pyruvate was advantageous over citrate in low-osmolar ORS for protection of organs and survival; pyruvate, but not citrate, in the ORS corrected hypoxic lactic acidosis in rats subjected to lethal burn shock in 24 h.

Hypoglycemia and lactic acidosis outperform King's College criteria for predicting death or transplant in acetaminophen toxic patients.

IMPORTANCE: Acetaminophen toxicity is common and is characterized by hepatic failure. In cases that are not improving with standard medical therapy with N-acetylcysteine, some patients may require hepatic transplant. While there are various criteria to predict patients who might benefit from transplant, the King's College criteria remain one of the most widely used. However, the King's College criteria have several limitations and do not incorporate glucose, an important marker of hepatic function. OBJECTIVE: The primary objective of this study is to compare the presence of hypoglycemia, coagulopathy, and metabolic acidosis with the King's College criteria for predicting a composite endpoint of death or transplant. DESIGN: This study is a retrospective cohort study of adult patients admitted with a discharge diagnosis of acetaminophen-induced liver failure. SETTING: The patients were admitted at one of six university-affiliated teaching hospitals in the United States. RESULTS: A total of 334 subjects were identified who met inclusion criteria. Fifty-one subjects (15.3%) met the composite endpoint of death or transplant. Ninety-six (28.7%) subjects met the King's College criteria for transplant. The presence of hypoglycemia increased the odds of reaching the composite endpoint by 3.39-fold. This model performed better than the King's College criteria (pseudo R2 for the area under the curve of 0.93 vs. 0.20 for the King's College criteria). CONCLUSIONS: The combination of hypoglycemia, coagulopathy, and lactic acidosis performed better than the King's College criteria for predicting death or transplant.

Quantitative relationships among plasma lactate, inorganic phosphorus, albumin, unmeasured anions and the anion gap in lactic acidosis.

BACKGROUND: Quantitative relationships among plasma [Lactate], [Pi], [Albumin], unmeasured anions ([UA]) and the anion gap (AGK) in lactic acidosis (LA) are not well defined. METHODS: A mathematical model featuring compensatory potassium and chloride shifts and respiratory changes in LA demonstrated: (1) AGK=[Lactate]+Zp×[Pi]+2.4×[Albumin]+constant1+e, where Zp is a function of pH, and e reflects unmeasured anions and cations plus pH-related variations. Eq. (1) can be algebraically rearranged to incorporate the albumin-corrected anion gap, cAGK: (2) cAGK=[Lactate]+Zp×[Pi]+constant2+e. Eq. (1) was tested against 948 data sets from critically ill patients with [Lactate] 4.0mEq/L or greater. AGK and cAGK were evaluated against 12,341 data sets for their ability to detect [Lactate]>4.0mEq/L. RESULTS: Analysis of Eq. (1) revealed r2=0.5950, p<0.001. cAGk>15mEq/L exhibited a sensitivity of 93.0% [95% CI: 91.3-94.5] in detecting [Lactate]>4.0mEq/L, whereas AGK>15mEq/L exhibited a sensitivity of only 70.4% [67.5-73.2]. Additionally, [Lactate]>4.0mEq/L and cAGK>20mEq/L were each strongly associated with intensive care unit mortality (χ2>200, p<0.0001 for each). CONCLUSIONS: In LA, cAGK is more sensitive than AGK in predicting [Lactate]>4.0mEq/L.

Serum lactate level and mortality in metformin-associated lactic acidosis requiring renal replacement therapy: a systematic review of case reports and case series.

BACKGROUND: The current practice concerning timing, mode, and dose of renal replacement therapy (RRT) in patients with metformin-associated lactic acidosis (MALA) with renal failure remains unknown. To investigate whether serum lactate level and prescription pattern of RRT are associated with mortality in patients with MALA requiring RRT. METHODS: We searched PubMed/Medline and EMBASE from inception to Sep 2014 and applied predetermined exclusion criteria. Case-level data including case's demographics and clinical information related to MALA were abstracted. Multiple logistic regression modeling was used to examine the predictors of mortality. RESULTS: A total of 253 unique cases were identified with cumulative mortality of 17.2%. Eighty-seven percent of patients had acute kidney injury. Serum lactate level was significantly higher in non-survivors (median 22.5 mmol/L) than in survivors (17.0 mmol/L, p-value <0.01) and so did the median blood metformin concentrations (58.5 vs. 43.9 mg/L, p-value = 0.05). The survival advantage was not significantly different between the modalities of RRT. The adjusted odds ratio of mortality for every one mmol/L increase in serum lactate level was 1.09 (95% CI 1.02-1.17, p-value = 0.01). The dose-response curve indicated a lactate threshold greater than 20 mmol/L was significantly associated with mortality. CONCLUSIONS: Our study suggests that predialysis level of serum lactate level is an important marker of mortality in MALA patients requiring RRT with a linear dose-response relationship. To better evaluate the optimal prescription of RRT in MALA, we recommend fostering an international consortium to support prospective research and large-scale standardized case collection.

Risk of acute kidney injury and survival in patients treated with Metformin: an observational cohort study.

BACKGROUND: Whether metformin precipitates lactic acidosis in patients with chronic kidney disease (CKD) remains under debate. We examined whether metformin use was associated with an increased risk of acute kidney injury (AKI) as a proxy for lactic acidosis and whether survival among those with AKI varied by metformin exposure. METHODS: All individuals with type 2 diabetes and available prescribing data between 2004 and 2013 in Tayside, Scotland were included. The electronic health record for diabetes which includes issued prescriptions was linked to laboratory biochemistry, hospital admission, death register and Scottish Renal Registry data. AKI events were defined using the Kidney Disease Improving Global Outcomes criteria with a rise in serum creatinine of at least  26.5 µmol/l or a rise of greater than 150% from baseline for all hospital admissions. Cox Regression Analyses were used to examine whether person-time periods in which current metformin exposure occurred were associated with an increased rate of first AKI compared to unexposed periods. Cox regression was also used to compare 28 day survival rates following first AKI events in those exposed to metformin versus those not exposed. RESULTS: Twenty-five thousand one-hundred fourty-eight patients were included with a total person-time of 126,904 person years. 4944 (19.7%) people had at least one episode of AKI during the study period. There were 32.4 cases of first AKI/1000pyrs in current metformin exposed person-time periods compared to 44.9 cases/1000pyrs in unexposed periods. After adjustment for age, sex, diabetes duration, calendar time, number of diabetes drugs and baseline renal function, current metformin use was not associated with AKI incidence, HR 0.94 (95% CI 0.87, 1.02, p = 0.15). Among those with incident AKI, being on metformin at admission was associated with a higher rate of survival at 28 days (HR 0.81, 95% CI 0.69, 0.94, p = 0.006) even after adjustment for age, sex, pre-admission eGFR, HbA1c and diabetes duration. CONCLUSIONS: Contrary to common perceptions, we found no evidence that metformin increases incidence of AKI and was associated with higher 28 day survival following incident AKI.

A lethal neonatal phenotype of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency.

Short-chain enoyl-CoA hydratase (SCEH) is a mitochondrial enzyme involved in the oxidation of fatty acids and the catabolic pathway of valine and, to a lesser extent, isoleucine. Deficiency of this enzyme was recently shown to cause an early childhood Leigh syndrome phenotype. The few reported patients were compound heterozygotes for two missense or missense with truncating variants in ECHS1 that encodes SCEH. We describe two siblings with severe refractory lactic acidosis and death within the first 2 days of life. Following negative clinical whole-exome and whole-genome sequencing, we resorted to autozygome/exome analysis on research basis and identified a homozygous splice site mutation (c.88+5G>A) in the two cases. Analysis of cDNA confirmed complete replacement of the normal transcript with an aberrant transcript (r.88_89ins 88+1_88+11) predicting premature truncation of the protein [p.(Ala31Glufs*23)]. Furthermore, quantitative reverse transcriptase polymerase chain reaction (RTPCR) showed marked reduction in ECHS1, most likely nonsense-mediated decay (NMD)-mediated. This is the first report of homozygosity for a truncating mutation in ECHS1, which may explain the severe phenotype. Our report highlights the need to consider SCEH deficiency in patients with lethal neonatal lactic acidosis, and the potentially limited sensitivity of untargeted genomic sequencing towards non-canonical splicing mutations, which may explain at least some of the 'negative' cases on clinical exome/genome sequencing.