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Metabolism: Clinical and Experimental Feb 2016Although metformin has become a drug of choice for the treatment of type 2 diabetes mellitus, some patients may not receive it owing to the risk of lactic acidosis.... (Review)
Review
Although metformin has become a drug of choice for the treatment of type 2 diabetes mellitus, some patients may not receive it owing to the risk of lactic acidosis. Metformin, along with other drugs in the biguanide class, increases plasma lactate levels in a plasma concentration-dependent manner by inhibiting mitochondrial respiration predominantly in the liver. Elevated plasma metformin concentrations (as occur in individuals with renal impairment) and a secondary event or condition that further disrupts lactate production or clearance (e.g., cirrhosis, sepsis, or hypoperfusion), are typically necessary to cause metformin-associated lactic acidosis (MALA). As these secondary events may be unpredictable and the mortality rate for MALA approaches 50%, metformin has been contraindicated in moderate and severe renal impairment since its FDA approval in patients with normal renal function or mild renal insufficiency to minimize the potential for toxic metformin levels and MALA. However, the reported incidence of lactic acidosis in clinical practice has proved to be very low (<10 cases per 100,000 patient-years). Several groups have suggested that current renal function cutoffs for metformin are too conservative, thus depriving a substantial number of type 2 diabetes patients from the potential benefit of metformin therapy. On the other hand, the success of metformin as the first-line diabetes therapy may be a direct consequence of conservative labeling, the absence of which could have led to excess patient risk and eventual withdrawal from the market, as happened with earlier biguanide therapies. An investigational delayed-release metformin currently under development could potentially provide a treatment option for patients with renal impairment pending the results of future studies. This literature-based review provides an update on the impact of renal function and other conditions on metformin plasma levels and the risk of MALA in patients with type 2 diabetes.
Topics: Acidosis, Lactic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Risk Factors
PubMed: 26773926
DOI: 10.1016/j.metabol.2015.10.014 -
American Journal of Physiology.... Sep 2004The development of acidosis during intense exercise has traditionally been explained by the increased production of lactic acid, causing the release of a proton and the... (Review)
Review
The development of acidosis during intense exercise has traditionally been explained by the increased production of lactic acid, causing the release of a proton and the formation of the acid salt sodium lactate. On the basis of this explanation, if the rate of lactate production is high enough, the cellular proton buffering capacity can be exceeded, resulting in a decrease in cellular pH. These biochemical events have been termed lactic acidosis. The lactic acidosis of exercise has been a classic explanation of the biochemistry of acidosis for more than 80 years. This belief has led to the interpretation that lactate production causes acidosis and, in turn, that increased lactate production is one of the several causes of muscle fatigue during intense exercise. This review presents clear evidence that there is no biochemical support for lactate production causing acidosis. Lactate production retards, not causes, acidosis. Similarly, there is a wealth of research evidence to show that acidosis is caused by reactions other than lactate production. Every time ATP is broken down to ADP and P(i), a proton is released. When the ATP demand of muscle contraction is met by mitochondrial respiration, there is no proton accumulation in the cell, as protons are used by the mitochondria for oxidative phosphorylation and to maintain the proton gradient in the intermembranous space. It is only when the exercise intensity increases beyond steady state that there is a need for greater reliance on ATP regeneration from glycolysis and the phosphagen system. The ATP that is supplied from these nonmitochondrial sources and is eventually used to fuel muscle contraction increases proton release and causes the acidosis of intense exercise. Lactate production increases under these cellular conditions to prevent pyruvate accumulation and supply the NAD(+) needed for phase 2 of glycolysis. Thus increased lactate production coincides with cellular acidosis and remains a good indirect marker for cell metabolic conditions that induce metabolic acidosis. If muscle did not produce lactate, acidosis and muscle fatigue would occur more quickly and exercise performance would be severely impaired.
Topics: Acidosis; Acidosis, Lactic; Animals; Buffers; Exercise; History, 18th Century; History, 20th Century; Humans; Lactic Acid; Models, Biological; Protons
PubMed: 15308499
DOI: 10.1152/ajpregu.00114.2004 -
International Journal of Molecular... Jul 2022Metformin, a molecule belonging to the biguanide family, represents one of the most commonly prescribed medications for the treatment of diabetes mellitus in the world.... (Review)
Review
Metformin, a molecule belonging to the biguanide family, represents one of the most commonly prescribed medications for the treatment of diabetes mellitus in the world. Over the sixty years during which it has been used, many benefits have been described, which are not limited to the treatment of diabetes mellitus. However, since metformin is similar to other members of the same drug family, there is still much concern regarding the risk of lactic acidosis. This article aims to highlight the correlation between the use of metformin and the onset of renal damage or lactic acidosis. Metformin-associated lactic acidosis exists; however, it is rare. The appropriate use of the drug, under safe conditions, induces benefits without risks.
Topics: Acidosis, Lactic; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fear; Humans; Hypoglycemic Agents; Metformin
PubMed: 35955455
DOI: 10.3390/ijms23158320 -
Kidney International Jan 2020L-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... (Review)
Review
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.
Topics: Acidosis, Lactic; Anions; Bicarbonates; Citric Acid Cycle; Critical Illness; Electron Transport Chain Complex Proteins; Gluconeogenesis; Glucose; Glycolysis; Hospital Mortality; Humans; Hydrogen-Ion Concentration; Hypoxia; Intensive Care Units; Kidney; Lactic Acid; Liver; Muscle, Skeletal; Oxidation-Reduction; Oxidative Phosphorylation; Oxygen
PubMed: 31784049
DOI: 10.1016/j.kint.2019.08.023 -
Acta Medica Indonesiana 2007Acute metabolic acidosis is frequently encountered in critically ill patients. Metabolic acidosis can occur as a result of either the accumulation of endogenous acids... (Review)
Review
Acute metabolic acidosis is frequently encountered in critically ill patients. Metabolic acidosis can occur as a result of either the accumulation of endogenous acids that consumes bicarbonate (high anion gap metabolic acidosis) or loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic or normal anion gap metabolic acidosis). The cause of high anion gap metabolic acidosis includes lactic acidosis, ketoacidosis, renal failure and intoxication with ethylene glycol, methanol, salicylate and less commonly with pyroglutamic acid (5-oxoproline), propylene glycole or djenkol bean (gjenkolism). The most common causes of hyperchloremic metabolic acidosis are gastrointestinal bicarbonate loss, renal tubular acidosis, drugs-induced hyperkalemia, early renal failure and administration of acids. The appropriate treatment of acute metabolic acidosis, in particular organic form of acidosis such as lactic acidosis, has been very controversial. The only effective treatment for organic acidosis is cessation of acid production via improvement of tissue oxygenation. Treatment of acute organic acidosis with sodium bicarbonate failed to reduce the morbidity and mortality despite improvement in acid-base parameters. Further studies are required to determine the optimal treatment strategies for acute metabolic acidosis.
Topics: Acidosis; Acidosis, Lactic; Acidosis, Renal Tubular; Acute Disease; Bicarbonates; Diabetic Ketoacidosis; Humans; Risk Factors; Sodium Bicarbonate
PubMed: 17936961
DOI: No ID Found -
BMJ Case Reports Jul 2021A 58-year-old female with known type 2 diabetes mellitus continued to take her usual medications, including metformin, an ACE inhibitor and a non-steroidal...
A 58-year-old female with known type 2 diabetes mellitus continued to take her usual medications, including metformin, an ACE inhibitor and a non-steroidal anti-inflammatory drug, while suffering from diarrhoea and vomiting. On presentation to the emergency department, she was found to have a profound lactic acidosis, cardiovascular instability and acute kidney injury. Despite a pH of 6.6, lactate of 14 mmol/L and a brief asystolic cardiac arrest, supportive treatment and the use of renal replacement therapy resulted in rapid improvement in her acid-base abnormalities and haemodynamic parameters. Metformin-associated lactic acidosis is a rare but life-threatening complication of diabetes management. Patient education and awareness amongst clinicians are paramount in the prevention and treatment of this condition.
Topics: Acidosis, Lactic; Acute Kidney Injury; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Metformin; Middle Aged
PubMed: 34244196
DOI: 10.1136/bcr-2020-239154 -
Kidney & Blood Pressure Research 2020The etiology of acute metabolic acidosis (aMA) is heterogeneous, and the consequences are potentially life-threatening. The aim of this article was to summarize the...
BACKGROUND
The etiology of acute metabolic acidosis (aMA) is heterogeneous, and the consequences are potentially life-threatening. The aim of this article was to summarize the causes and management of aMA from a clinician's perspective.
SUMMARY
We performed a systematic search on PubMed, applying the following search terms: "acute metabolic acidosis," "lactic acidosis," "metformin" AND "acidosis," "unbalanced solutions" AND "acidosis," "bicarbonate" AND "acidosis" AND "outcome," "acute metabolic acidosis" AND "management," and "acute metabolic acidosis" AND "renal replacement therapy (RRT)/dialysis." The literature search did not consider diabetic ketoacidosis at all. Lactic acidosis evolves from various conditions, either with or without systemic hypoxia. The incidence of metformin-associated aMA is actually quite low. Unbalanced electrolyte preparations can induce hyperchloremic aMA. The latter potentially worsens kidney-related outcome parameters. Nevertheless, prospective and controlled data are missing at the moment. Recently, bicarbonate has been shown to improve clinically relevant endpoints in the critically ill, even if higher pH values (>7.3) are targeted. New therapeutics for aMA control are under development, since bicarbonate treatment can induce serious side effects. Key Messages: aMA is a frequent and potentially life-threatening complication of various conditions. Lactic acidosis might occur even in the absence of systemic hypoxia. The incidence of metformin-associated aMA is comparably low. Unbalanced electrolyte solutions induce hyperchloremic aMA, which most likely worsens the renal prognosis of critically ill patients. Bicarbonate, although potentially deleterious due to increased carbon dioxide production with subsequent intracellular acidosis, improves kidney-related endpoints in the critically ill.
Topics: Acidosis; Acidosis, Lactic; Acute Disease; Animals; Bicarbonates; Disease Management; Electrolytes; Humans; Hypoglycemic Agents; Metformin
PubMed: 32663831
DOI: 10.1159/000507813 -
The Journal of Emergency Medicine Aug 2023The use of sodium bicarbonate to treat metabolic acidosis is intuitive, yet data suggest that not all patients benefit from this therapy. (Review)
Review
BACKGROUND
The use of sodium bicarbonate to treat metabolic acidosis is intuitive, yet data suggest that not all patients benefit from this therapy.
OBJECTIVE
In this narrative review, we describe the physiology behind commonly encountered nontoxicologic causes of metabolic acidosis, highlight potential harm from the indiscriminate administration of sodium bicarbonate in certain scenarios, and provide evidence-based recommendations to assist emergency physicians in the rational use of sodium bicarbonate.
DISCUSSION
Sodium bicarbonate can be administered as a hypertonic push, as a resuscitation fluid, or as an infusion. Lactic acidosis and cardiac arrest are two common scenarios where there is limited benefit to routine use of sodium bicarbonate, although certain circumstances, such as patients with concomitant acute kidney injury and lactic acidosis may benefit from sodium bicarbonate. Patients with cardiac arrest secondary to sodium channel blockade or hyperkalemia also benefit from sodium bicarbonate therapy. Recent data suggest that the use of sodium bicarbonate in diabetic ketoacidosis does not confer improved patient outcomes and may cause harm in pediatric patients. Available evidence suggests that alkalinization of urine in rhabdomyolysis does not improve patient-centered outcomes. Finally, patients with a nongap acidosis benefit from sodium bicarbonate supplementation.
CONCLUSIONS
Empiric use of sodium bicarbonate in patients with nontoxicologic causes of metabolic acidosis is not warranted and likely does not improve patient-centered outcomes, except in select scenarios. Emergency physicians should reserve use of this medication to conditions with clear benefit to patients.
Topics: Humans; Child; Bicarbonates; Sodium Bicarbonate; Acidosis, Lactic; Acidosis; Heart Arrest
PubMed: 37442665
DOI: 10.1016/j.jemermed.2023.04.012 -
American Journal of Respiratory and... Sep 2019Hyperlactatemia in sepsis may derive from a prevalent impairment of oxygen supply/demand and/or oxygen use. Discriminating between these two mechanisms may be relevant... (Randomized Controlled Trial)
Randomized Controlled Trial
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. To understand the relationship among central venous oxygen saturation (Scv), lactate, and base excess to better determine the origin of lactate. This was a 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 Scv. We defined the "alactic base excess," as the sum of lactate and standard base excess. Organ dysfunction severity scores, physiologic variables of hepatic, metabolic, cardiac, and renal function, and 90-day mortality were measured. Scv was lower than 70% only in 35% of patients. Mortality, organ dysfunction scores, and lactate were highest in the first and sixth sextiles of Scv. 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. 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.
Topics: Acidosis, Lactic; Adult; Aged; Aged, 80 and over; Biomarkers; Female; Fluid Therapy; Humans; Italy; Male; Middle Aged; Oxygen Consumption; Sepsis
PubMed: 30985210
DOI: 10.1164/rccm.201812-2342OC -
Ugeskrift For Laeger Aug 2021It is a common but flawed presumption that blood lactate reflects the lactic acid production in the body's tissues. Lactate is formed directly from pyruvate and... (Review)
Review
It is a common but flawed presumption that blood lactate reflects the lactic acid production in the body's tissues. Lactate is formed directly from pyruvate and functions to dampen reductions in intracellular pH through lactate-H+ cotransport to the extracellular space. Though this may give rise to elevated blood lactate, increased lactate production is not the cause of metabolic acidosis in such instances. "Lactic acidosis" is thus an inappropriate term as it indicates causality and in this review, we suggest that in the future, the term "hyperlactataemia-associated metabolic acidosis" should be used instead.
Topics: Acidosis; Acidosis, Lactic; Humans; Lactic Acid
PubMed: 34477100
DOI: No ID Found