Explore the vast range of titles available.

When lactic acidosis accompanies low-flow states or sepsis, mortality rates increase sharply. This review summarizes our current understanding of the pathophysiological aspects of lactic acidosis, as well as the approaches to its diagnosis and management. Lactic acidosis results from the accumulation of lactate and protons in the body fluids and is often associated with poor clinical outcomes. The effect of lactic acidosis is governed by its severity and the clinical context. Mortality is increased by a factor of nearly three when lactic acidosis accompanies low-flow states or sepsis, 1 and the higher the lactate level, the worse the outcome. 2 Although hyperlactatemia is often attributed to tissue hypoxia, it can result from other mechanisms. Control of the triggering conditions is the only effective means of treatment. However, advances in understanding its pathophysiological features and the factors causing . . .

Abstract Rationale Hyperlactatemia in sepsis may derive from a prevalent impairment of oxygen supply/demand and/or oxygen use. Discriminating between these two mechanisms may be relevant for the early fluid resuscitation strategy. Objectives To understand the relationship among central venous oxygen saturation (ScvO2), lactate, and base excess to better determine the origin of lactate. Methods This was a post hoc analysis of baseline variables of 1,741 patients with sepsis enrolled in the multicenter trial ALBIOS (Albumin Italian Outcome Sepsis). Variables were analyzed as a function of sextiles of lactate concentration and sextiles of ScvO2. We defined the “alactic base excess,” as the sum of lactate and standard base excess. Measurements and Main Results Organ dysfunction severity scores, physiologic variables of hepatic, metabolic, cardiac, and renal function, and 90-day mortality were measured. ScvO2 was lower than 70% only in 35% of patients. Mortality, organ dysfunction scores, and lactate were highest in the first and sixth sextiles of ScvO2. Although lactate level related strongly to mortality, it was associated with acidemia only when kidney function was impaired (creatinine >2 mg/dl), as rapidly detected by a negative alactic base excess. In contrast, positive values of alactic base excess were associated with a relative reduction of fluid balance. Conclusions Hyperlactatemia is powerfully correlated with severity of sepsis and, in established sepsis, is caused more frequently by impaired tissue oxygen use, rather than by impaired oxygen transport. Concomitant acidemia was only observed in the presence of renal dysfunction, as rapidly detected by alactic base excess. The current strategy of fluid resuscitation could be modified according to the origin of excess lactate.

Lactic acidosis associated with metformin treatment is a rare but important adverse event, and unravelling the problem is critical. First, this potential event still influences treatment strategies in type 2 diabetes mellitus, particularly in the many patients at risk of kidney failure, in those presenting contraindications to metformin and in the elderly. Second, the relationship between metformin and lactic acidosis is complex, since use of the drug may be causal, co-responsible or coincidental. The present review is divided into three parts, dealing with the incidence, management and prevention of lactic acidosis occurring during metformin treatment. In terms of incidence, the objective of this article is to counter the conventional view of the link between metformin and lactic acidosis, according to which metformin-associated lactic acidosis is rare but is still associated with a high rate of mortality. In fact, the direct metformin-related mortality is close to zero and metformin may even be protective in cases of very severe lactic acidosis unrelated to the drug. Metformin has also inherited a negative class effect, since the early biguanide, phenformin, was associated with more frequent and sometimes fatal lactic acidosis. In the second part of this review, the objective is to identify the most efficient patient management methods based on our knowledge of how metformin acts on glucose/lactate metabolism and how lactic acidosis may occur (at the organ and cellular levels) during metformin treatment. The liver appears to be a key organ for both the antidiabetic effect of metformin and the development of lactic acidosis; the latter is attributed to mitochondrial impairment and subsequent adenosine triphosphate depletion, acceleration of the glycolytic flux, increased glucose uptake and the generation of lactate, which effluxes into the circulation rather than being oxidized further. Haemodialysis should systematically be performed in severe forms of lactic acidosis, since it provides both symptomatic and aetiological treatment (by eliminating lactate and metformin). In the third part of the review (prevention), the objective is to examine the list of contraindications to metformin (primarily related to renal and cardiovascular function). Diabetes is above all a vascular disease and metformin is a vascular drug with antidiabetic properties. Given the importance of the liver in lactate clearance, we suggest focusing on the severity of and prognosis for liver disease; renal dysfunction is only a prerequisite for metformin accumulation, which may only be dangerous per se when associated with liver failure. Lastly, in view of metformin’s impressive overall effectiveness profile, it would be paradoxical to deny the majority of patients with long-established diabetes access to metformin because of the high prevalence of contraindications. The implications of these contraindications are discussed.

Background Akt signalling regulates glycolysis and drives the Warburg effect in cancer, thus decreased glucose utilisation is a pharmacodynamic marker of Akt inhibition. However, cancer cells can utilise alternative nutrients to glucose for energy such as lactate, which is often elevated in tumours together with increased acidity. We therefore hypothesised that lactic acidosis may confer resistance to Akt inhibition. Methods The effect of the pan-Akt inhibitor uprosertib (GSK2141795), on HCT116 and LS174T colon cancer cells was evaluated in the presence and absence of lactic acid in vitro. Expression of downstream Akt signalling proteins was determined using a phosphokinase array and immunoblotting. Metabolism was assessed using 1 H nuclear magnetic resonance spectroscopy, stable isotope labelling and gas chromatography-mass spectrometry. Results Lactic acid-induced resistance to uprosertib was characterised by increased cell survival and reduced apoptosis. Uprosertib treatment reduced Akt signalling and glucose uptake irrespective of lactic acid supplementation. However, incorporation of lactate carbon and enhanced respiration was maintained in the presence of uprosertib and lactic acid. Inhibiting lactate transport or oxidative phosphorylation was sufficient to potentiate apoptosis in the presence of uprosertib. Conclusions Lactic acidosis confers resistance to uprosertib, which can be reversed by inhibiting lactate transport or oxidative metabolism.

Lactic acidosis is a very common biological issue for shock patients. Experimental data clearly demonstrate that metabolic acidosis, including lactic acidosis, participates in the reduction of cardiac contractility and in the vascular hyporesponsiveness to vasopressors through various mechanisms. However, the contributions of each mechanism responsible for these deleterious effects have not been fully determined and their respective consequences on organ failure are still poorly defined, particularly in humans. Despite some convincing experimental data, no clinical trial has established the level at which pH becomes deleterious for hemodynamics. Consequently, the essential treatment for lactic acidosis in shock patients is to correct the cause. It is unknown, however, whether symptomatic pH correction is beneficial in shock patients. The latest Surviving Sepsis Campaign guidelines recommend against the use of buffer therapy with pH ≥7.15 and issue no recommendation for pH levels <7.15. Furthermore, based on strong experimental and clinical evidence, sodium bicarbonate infusion alone is not recommended for restoring pH. Indeed, bicarbonate induces carbon dioxide generation and hypocalcemia, both cardiovascular depressant factors. This review addresses the principal hemodynamic consequences of shock-associated lactic acidosis. Despite the lack of formal evidence, this review also highlights the various adapted supportive therapy options that could be putatively added to causal treatment in attempting to reverse the hemodynamic consequences of shock-associated lactic acidosis.

Type B lactic acidosis (LA), a rare yet fatal complication of lymphoma with poor prognosis, remains poorly characterized due to reliance on isolated case reports. To systematically delineate clinical characteristics and prognostic determinants in newly diagnosed lymphoma patients presenting with LA as the initial presentation, we conducted an integrated analysis synthesizing unpublished institutional cases with systematically identified cases from PubMed, Web of Science, and hospital databases. Demographic, clinical, laboratory, imaging, histopathological, and therapeutic intervention data were extracted. Prognostic correlates were evaluated using univariate and multivariate logistic regression, with predictive accuracy validated through receiver operating characteristic (ROC) curves. Among the 53 patients analyzed, the predominant manifestations included general malaise and gastrointestinal symptoms (62.3% each), with infrequent superficial lymph node enlargement (15.1%). Key biochemical abnormalities included hyperlactatemia (peak lactate: 15.89 ± 7.82 mmol/L) and elevated lactate dehydrogenase (60.4%). Imaging revealed lymph node enlargement (41.5%) and hepatic abnormalities (39.6%). Non-survivors were significantly older ( P  = 0.007), had a higher incidence of B-symptoms ( P  = 0.032), and were less likely to receive chemotherapy ( P  < 0.001). Chemotherapy emerged as the sole independent predictor of survival (multivariate odds ratio [OR] = 0.020; 95% confidence interval [CI]: 0.002–0.211; P  = 0.001), validated by ROC curve analysis (sensitivity 92.0%, specificity 95.5%). This integrated analysis of a case and literature review underscores that LA signifies aggressive lymphoma with frequent advanced-stage disease. Although advanced age and B-symptoms predicted mortality, chemotherapy was the sole independent survival predictor in multivariate analysis.

Metformin toxicity is a rare but serious condition that carries with it a high rate of morbidity and mortality. 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. 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. An understanding of metformin toxicity can assist emergency clinicians in diagnosing and managing this potentially deadly disease.

Metformin constitutes first-line treatment of type 2 diabetes mellitus. It is presumed to have lactic acidosis as a dangerous, but rare, side effect. 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. 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. 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). 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.

BackgroundD-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.MethodsWe performed a review of the literature in the National Library of Medicine and Excerpta Medica databases.ResultsWe 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.ConclusionsIn 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.

Lactic acidosis represents one of the most common conditions that can compromise the health of intensive care unit (ICU) patients, increasing the mortality of patients with high levels of Lactate who do not receive a proper treatment within the first 6 h of hospitalization. There are two enantiomers of lactic acid: L-lactic acid (when the concentration increases, it can lead to a state of severe acidemia risking cardiovascular collapse, causing an increase in mortality in ICU patients) and D lactic acid (produced in the human organism by microbiota and its production increases during some pathological status). Generally, increased levels of serum lactic acid could be due to numerous factors, including hypoxia (caused for example by septic/cardiogenic/hypovolemic or obstructive shock), specific pathologies (e.g., liver disease), use of some drugs (e.g., metformin), presence of toxins, and trauma. Since the underlying cause could be fatal for the ICU patient, it is important to understand the root of this clinical status with a view to correct it and prevent the risk of a poor clinical outcome. Prevention and early treatment are the keys to control the negative clinical consequences. The aim of this review is to revise the scientific literature for further confirmation about the importance of early identification of acidotic statuses and to underline how an early diagnosis can prevent the worst clinical outcome, especially for ICU patients who are more fragile compared to the general population.