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Pharmacotherapy Sep 2019Hyperlactatemia and lactic acidosis are two syndromes that are associated with morbidity and mortality. Medication-induced hyperlactatemia and lactic acidosis are...
Hyperlactatemia and lactic acidosis are two syndromes that are associated with morbidity and mortality. Medication-induced hyperlactatemia and lactic acidosis are diagnoses of exclusion and have the potential to be overlooked. The purposes of this systematic review are to identify published reports of medication-induced lactate level elevations to aid clinicians in diagnosing and comprehending the underlying mechanism of this rare adverse drug effect and to provide management strategies. The PubMed database was searched for case reports, case series, retrospective studies, and prospective studies describing cases of medication-induced lactate level elevation, including lactic acidosis and hyperlactatemia, published between January 1950 and June 2017. A standardized search strategy was used, and the articles identified underwent two rounds of independent evaluation by two reviewers to assess for inclusion. Articles were included if they described at least one patient older than 12 years with hyperlactatemia or lactic acidosis caused by a medication with United States Food and Drug Administration (FDA) approval and if alternative etiologies for an elevated lactate level were ruled out. Metformin and nucleoside/nucleotide reverse transcriptase inhibitors were excluded since the pathophysiology and incidence of lactic acidosis have been well established for these agents. Overall, 1918 articles were identified, and 101 met inclusion criteria. A total of 286 patients experienced medication-induced lactate level elevations, from which 59 unique medications were identified. The most commonly identified agents were epinephrine and albuterol. Medication-induced lactate level elevation was classified as lactic acidosis (64.0%), hyperlactatemia (31.1%), or not specified (4.9%). The doses ingested included FDA-labeled doses (86%), intentional overdoses (10.8%), or prescribed doses exceeding the FDA-labeled dose (3.1%). Medications were continued without a change (40.8%), were permanently discontinued (34.4%), were continued with a dosage reduction (11.6%), or were initially withheld then resumed after lactate level normalized (2.9%); medication management for the remaining 10.0% was not reported. Forty-six patients died (16%). Six deaths were attributed by treating clinicians to be secondary to medication-induced lactic acidosis. Management strategies were heterogeneous, and treatment included supportive care, exogenous bicarbonate therapy, medication specific antidotes, and decontamination strategies. Unexplained lactate level elevations should prompt clinicians to assess for medication-induced lactate level elevations. Pharmacists are members of the health care team that are well positioned to serve as experts in the diagnosis and management of medication-induced lactate level elevations.
Topics: Acidosis, Lactic; Dose-Response Relationship, Drug; Drug Overdose; Humans; Hyperlactatemia; Prescription Drug Misuse; Prescription Drugs; United States
PubMed: 31361914
DOI: 10.1002/phar.2316 -
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 -
Lancet (London, England) Nov 2022Large trials have shown that sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Large trials have shown that sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure or chronic kidney disease, or with type 2 diabetes and high risk of atherosclerotic cardiovascular disease. None of the trials recruiting patients with and without diabetes were designed to assess outcomes separately in patients without diabetes.
METHODS
We did a systematic review and meta-analysis of SGLT2 inhibitor trials. We searched the MEDLINE and Embase databases for trials published from database inception to Sept 5, 2022. SGLT2 inhibitor trials that were double-blind, placebo-controlled, performed in adults (age ≥18 years), large (≥500 participants per group), and at least 6 months in duration were included. Summary-level data used for analysis were extracted from published reports or provided by trial investigators, and inverse-variance-weighted meta-analyses were conducted to estimate treatment effects. The main efficacy outcomes were kidney disease progression (standardised to a definition of a sustained ≥50% decrease in estimated glomerular filtration rate [eGFR] from randomisation, a sustained low eGFR, end-stage kidney disease, or death from kidney failure), acute kidney injury, and a composite of cardiovascular death or hospitalisation for heart failure. Other outcomes were death from cardiovascular and non-cardiovascular disease considered separately, and the main safety outcomes were ketoacidosis and lower limb amputation. This study is registered with PROSPERO, CRD42022351618.
FINDINGS
We identified 13 trials involving 90 413 participants. After exclusion of four participants with uncertain diabetes status, we analysed 90 409 participants (74 804 [82·7%] participants with diabetes [>99% with type 2 diabetes] and 15 605 [17·3%] without diabetes; trial-level mean baseline eGFR range 37-85 mL/min per 1·73 m). Compared with placebo, allocation to an SGLT2 inhibitor reduced the risk of kidney disease progression by 37% (relative risk [RR] 0·63, 95% CI 0·58-0·69) with similar RRs in patients with and without diabetes. In the four chronic kidney disease trials, RRs were similar irrespective of primary kidney diagnosis. SGLT2 inhibitors reduced the risk of acute kidney injury by 23% (0·77, 0·70-0·84) and the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77, 0·74-0·81), again with similar effects in those with and without diabetes. SGLT2 inhibitors also reduced the risk of cardiovascular death (0·86, 0·81-0·92) but did not significantly reduce the risk of non-cardiovascular death (0·94, 0·88-1·02). For these mortality outcomes, RRs were similar in patients with and without diabetes. For all outcomes, results were broadly similar irrespective of trial mean baseline eGFR. Based on estimates of absolute effects, the absolute benefits of SGLT2 inhibition outweighed any serious hazards of ketoacidosis or amputation.
INTERPRETATION
In addition to the established cardiovascular benefits of SGLT2 inhibitors, the randomised data support their use for modifying risk of kidney disease progression and acute kidney injury, not only in patients with type 2 diabetes at high cardiovascular risk, but also in patients with chronic kidney disease or heart failure irrespective of diabetes status, primary kidney disease, or kidney function.
FUNDING
UK Medical Research Council and Kidney Research UK.
Topics: Humans; Adult; Adolescent; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Sodium-Glucose Transporter 2; Kidney; Acute Kidney Injury; Renal Insufficiency, Chronic; Heart Failure; Ketosis; Disease Progression; Glucose; Sodium; Randomized Controlled Trials as Topic
PubMed: 36351458
DOI: 10.1016/S0140-6736(22)02074-8 -
Current Gastroenterology Reports Jun 2017This study aimed to systematically review small bowel obstruction (SBO), focusing on recent changes in diagnosis/therapy. (Review)
Review
PURPOSE OF REVIEW
This study aimed to systematically review small bowel obstruction (SBO), focusing on recent changes in diagnosis/therapy.
RECENT FINDINGS
SBO incidence is about 350,000/annum in the USA. Etiologies include adhesions (65%), hernias (10%), neoplasms (5%), Crohn's disease (5%), and other (15%). Bowel dilatation occurs proximal to obstruction primarily from swallowed air and secondarily from intraluminal fluid accumulation. Dilatation increases mural tension, decreases mucosal perfusion, causes bacterial proliferation, and decreases mural tensile strength that increases bowel perforation risks. Classical clinical tetrad is abdominal pain, nausea and emesis, abdominal distention, and constipation-to-obstipation. Physical exam may reveal restlessness, acute illness, and signs of dehydration and sepsis, including tachycardia, pyrexia, dry mucous membranes, hypotension/orthostasis, abdominal distention, and hypoactive bowel sounds. Severe direct tenderness, involuntary guarding, abdominal rigidity, and rebound tenderness suggest advanced SBO, as do marked leukocytosis, neutrophilia, bandemia, and lactic acidosis. Differential diagnosis includes postoperative ileus, narcotic bowel, colonic pseudo-obstruction, mesenteric ischemia, and large bowel obstruction. Medical resuscitation includes intravenous hydration, correcting electrolyte abnormalities, intravenous antibiotics, nil per os, and nasoenteral suction. Abdominal CT with oral and intravenous gastrografin contrast is highly sensitive and specific in detecting/characterizing SBO. SBO usually resolves with medical therapy but requires surgery, preferentially by laparoscopy, for unremitting total obstruction, bowel perforation, severe ischemia, or clinical deterioration with medical therapy. Overall mortality is 10% but increases to 30% with bowel necrosis/perforation. Key point in SBO is early diagnosis, emphasizing abdominal CT; aggressive medical therapy including rehydration, antibiotics, and nil per os; and surgery for failed medical therapy.
Topics: Abdominal Pain; Diagnosis, Differential; Dilatation, Pathologic; Humans; Ileus; Intestinal Obstruction; Intestine, Small; Laparoscopy; Nausea; Physical Examination; Postoperative Complications; Vomiting
PubMed: 28439845
DOI: 10.1007/s11894-017-0566-9 -
Journal of Medical Virology Nov 2022Viral infections may increase the risk of developing type 1 diabetes (T1D), and recent reports suggest that Coronavirus Disease 2019 (COVID-19) might have increased the... (Meta-Analysis)
Meta-Analysis Review
Viral infections may increase the risk of developing type 1 diabetes (T1D), and recent reports suggest that Coronavirus Disease 2019 (COVID-19) might have increased the incidence of pediatric T1D and/or diabetic ketoacidosis (DKA). Therefore, this meta-analysis aims to estimate the risk of global pediatric new-onset T1D, DKA, and severe DKA before and after the COVID-19 pandemic. A systematic search of MEDLINE/PubMed, CINAHL, Scopus, and EMBASE was conducted for articles published up to March 2022. A random-effects meta-analysis was performed to compare the relative risk of T1D and DKA among pediatric patients with T1D between the COVID-19 pre-pandemic and pandemic periods. We also compared glucose and HbA1c values in children who were newly diagnosed with T1D before and after the COVID-19 pandemic. The global incidence rate of T1D in the 2019 period was 19.73 per 100 000 children and 32.39 per 100 000 in the 2020 period. Compared with pre-COVID-19 pandemic, the number of worldwide pediatric new-onset T1D, DKA, and severe DKA during the first year of the COVID-19 pandemic increased by 9.5%, 25%, and 19.5%, respectively. Compared with pre-COVID-19 pandemic levels, the median glucose, and HbA1c values in newly diagnosed T1D children after the COVID-19 pandemic increased by 6.43% and 6.42%, respectively. The COVID-19 pandemic has significantly increased the risk of global pediatric new-onset T1D, DKA, and severe DKA. Moreover, higher glucose and HbA1c values in newly diagnosed T1D children after the COVID-19 pandemic mandates targeted measures to raise public and physician awareness.
Topics: COVID-19; Child; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Glucose; Glycated Hemoglobin; Humans; Incidence; Pandemics
PubMed: 35831242
DOI: 10.1002/jmv.27996 -
Pharmacotherapy Feb 2017Currently only minimal information is available regarding risk factors for the development of sodium glucose cotransporter-2 inhibitor (SGLT2i)-related diabetic... (Review)
Review
STUDY OBJECTIVE
Currently only minimal information is available regarding risk factors for the development of sodium glucose cotransporter-2 inhibitor (SGLT2i)-related diabetic ketoacidosis (DKA). We aim to identify individual patient characteristics associated with cases of SGLT2i-related DKA to better describe potential risk factors.
DESIGN
Systematic review of primary literature.
PATIENTS
Thirty-four case reports of patients with type 1 and type 2 diabetes mellitus who developed DKA while receiving an SGLT2i.
METHODS AND MAIN RESULTS
This systematic review investigated the relationship between SGLT2i and DKA in patients with diabetes. The existing literature was reviewed with a primary outcome to identify patient-specific factors contributing to the incidence of ketoacidosis in patients with diabetes who were treated with a SGLT2i. Numerous databases were searched to identify appropriate primary literature. Search terms included canagliflozin, dapagliflozin, empagliflozin, SGLT2, sodium glucose cotransporter-2 inhibitor, diabetic ketoacidosis, ketoacidosis, metabolic acidosis, and acidosis. Primary literature was analyzed via descriptive statistics. Thirty-four individual case reports were identified via the primary literature search. Two-thirds (25 cases) involved patients with a diagnosis of type 2 diabetes mellitus (T2DM). The average blood glucose on presentation for SGLT2i-induced DKA was 265.6 ± 140.7 mg/dl (14.7 ± 7.8 mmol/L), with common symptoms including nausea, vomiting, and abdominal pain. Common precipitating factors included patients who were diagnosed with T2DM and were subsequently found to have latent autoimmune diabetes of adulthood, patients who had recently undergone major surgery, or patients who had decreased or discontinued insulin. No cases were fatal.
CONCLUSION
In this review, episodes of DKA with SGLT2i use were characterized by lower blood glucose levels and were often caused by a precipitating factor. Understanding precipitating factors for SGLT2i-related DKA may help providers better identify patients at risk for development of DKA.
Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 27931088
DOI: 10.1002/phar.1881 -
Obesity Reviews : An Official Journal... Jan 2015Very-low-energy diets (VLEDs) and ketogenic low-carbohydrate diets (KLCDs) are two dietary strategies that have been associated with a suppression of appetite. However,... (Meta-Analysis)
Meta-Analysis Review
Very-low-energy diets (VLEDs) and ketogenic low-carbohydrate diets (KLCDs) are two dietary strategies that have been associated with a suppression of appetite. However, the results of clinical trials investigating the effect of ketogenic diets on appetite are inconsistent. To evaluate quantitatively the effect of ketogenic diets on subjective appetite ratings, we conducted a systematic literature search and meta-analysis of studies that assessed appetite with visual analogue scales before (in energy balance) and during (while in ketosis) adherence to VLED or KLCD. Individuals were less hungry and exhibited greater fullness/satiety while adhering to VLED, and individuals adhering to KLCD were less hungry and had a reduced desire to eat. Although these absolute changes in appetite were small, they occurred within the context of energy restriction, which is known to increase appetite in obese people. Thus, the clinical benefit of a ketogenic diet is in preventing an increase in appetite, despite weight loss, although individuals may indeed feel slightly less hungry (or more full or satisfied). Ketosis appears to provide a plausible explanation for this suppression of appetite. Future studies should investigate the minimum level of ketosis required to achieve appetite suppression during ketogenic weight loss diets, as this could enable inclusion of a greater variety of healthy carbohydrate-containing foods into the diet.
Topics: Appetite Regulation; Diet, Carbohydrate-Restricted; Diet, Ketogenic; Diet, Reducing; Energy Intake; Humans; Hunger; Ketosis; Obesity; Risk Factors; Treatment Outcome; Weight Loss
PubMed: 25402637
DOI: 10.1111/obr.12230 -
Diabetologia Dec 2022Cardiovascular outcome trials (CVOTs) have demonstrated the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i). However, serious adverse drug reactions have... (Meta-Analysis)
Meta-Analysis Review
AIMS/HYPOTHESIS
Cardiovascular outcome trials (CVOTs) have demonstrated the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i). However, serious adverse drug reactions have been reported. The risk/benefit ratio of SGLT2i remains unquantified. We aimed to provide an estimation of their risk/benefit ratio in individuals with type 2 diabetes.
METHODS
We conducted a systematic review (MEDLINE, up to 14 September 2021) and meta-analysis. We included randomised CVOTs assessing SGLT2i in individuals with type 2 diabetes with or without other diseases. We used the Cochrane 'Risk of bias' assessment tool. The primary outcomes were overall mortality, major adverse cardiovascular events (MACE), hospitalisation for heart failure (HHF), end-stage renal disease (ESRD), amputation, diabetic ketoacidosis (DKA) and reported genital infections. For each outcome, we estimated the incidence rate ratio (IRR) with a 95% CI; we then computed the number of events expected spontaneously and with SGLT2i.
RESULTS
A total of 46,969 participants from five double-blind, placebo-controlled international trials (weighted mean follow-up 3.5 years) were included. The prevalence of previous CVD ranged from 40.6% to 99.2%. The definition of reported genital infections ranged from 'genital mycotic infection' to 'genital infections that led to discontinuation of the trial regimen or were considered to be serious adverse events'. The number of included studies for each outcomes was five. The use of SGLT2i decreased the risk of all-cause death (IRR 0.86 [95% CI 0.78, 0.95]), MACE (IRR 0.91 [95% CI 0.86, 0.96]), HHF (IRR 0.69 [95% CI 0.62, 0.76]) and ESRD (IRR 0.67 [95% CI 0.53, 0.84]), and increased the risk of DKA (IRR 2.59 [95% CI 1.57, 4.27]) and genital infection (IRR 3.50 [95% CI 3.09, 3.95]) but not of amputation (IRR 1.23 [95% CI 1.00, 1.51]). For 1000 individuals treated over 3.5 years, SGLT2i are expected, on average, to decrease the number of deaths from 70 to 61, to prevent nine MACE, 11 HHF and two cases of ESRD, while inducing two DKA occurrences and 36 genital infections; 778 individuals are expected to avoid all the following outcomes: MACE, HHF, ESRD, amputation, DKA and genital infection.
CONCLUSIONS/INTERPRETATION
Our study is limited to aggregate data. In a population of individuals with type 2 diabetes and a high CVD risk, the cardiovascular and renal benefits of SGLT2i remain substantial despite the risk of DKA and even the hypothetical risk of amputation.
TRIAL REGISTRATION
OSF Registries: https://doi.org/10.17605/OSF.IO/J3R7Y FUNDING: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Heart Failure; Risk Assessment; Kidney Failure, Chronic; Cardiovascular Diseases; Randomized Controlled Trials as Topic
PubMed: 35925319
DOI: 10.1007/s00125-022-05773-8 -
Archives of Disease in Childhood Nov 2022Diabetic ketoacidosis (DKA) is a serious complication of type 1 diabetes mellitus, which may lead to significant morbidity and mortality. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Diabetic ketoacidosis (DKA) is a serious complication of type 1 diabetes mellitus, which may lead to significant morbidity and mortality.
OBJECTIVES
To compare the safety and efficacy of liberalised versus conservative intravenous fluid regimens in the management of DKA in children.
DATA SOURCE AND STUDY SELECTION
Databases from inception to January 2022: MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials were included. Only randomised controlled trials (RCTs) that included children aged under 18 years were assessed. Two reviewers performed data assessment and extraction.
DATA EXTRACTION AND SYNTHESIS
Three studies out of 1536 citations were included.
MAIN OUTCOMES
The time to the recovery from the DKA; the frequency of paeditric intensive care unit (PICU) admissions; development of brain oedema; reduction in Glasgow Coma Scale (GCS); development of acute kidney injury and all-cause mortality.
RESULTS
We included three RCTs (n=1457). No evidence of difference was noted in the GCS reduction (risk ratio (RR)=0.77, 95% CI 0.44 to 1.36) or development of brain oedema (RR=0.50, 95% CI 0.15 to 1.68). The time to recovery from DKA was longer in the conservative group (mean difference=1.42, 95% CI 0.28 to 2.56). Time to hospital discharge, adverse or serious adverse events were comparable in the two studied groups.
CONCLUSION
There is no evidence from this meta-analysis that rate of fluid administration has any effect on adverse neurological and other outcomes or length of hospital stay.
Topics: Child; Humans; Adolescent; Diabetic Ketoacidosis; Brain Edema; Length of Stay; Clinical Protocols; Glasgow Coma Scale; Diabetes Mellitus
PubMed: 35738870
DOI: 10.1136/archdischild-2022-324042 -
JAMAMetformin is widely viewed as the best initial pharmacological option to lower glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is... (Review)
Review
IMPORTANCE
Metformin is widely viewed as the best initial pharmacological option to lower glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is contraindicated in many individuals with impaired kidney function because of concerns of lactic acidosis.
OBJECTIVE
To assess the risk of lactic acidosis associated with metformin use in individuals with impaired kidney function.
EVIDENCE ACQUISITION
In July 2014, we searched the MEDLINE and Cochrane databases for English-language articles pertaining to metformin, kidney disease, and lactic acidosis in humans between 1950 and June 2014. We excluded reviews, letters, editorials, case reports, small case series, and manuscripts that did not directly pertain to the topic area or that met other exclusion criteria. Of an original 818 articles, 65 were included in this review, including pharmacokinetic/metabolic studies, large case series, retrospective studies, meta-analyses, and a clinical trial.
RESULTS
Although metformin is renally cleared, drug levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min per 1.73 m2). The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100,000 person-years to 10 per 100,000 person-years and is generally indistinguishable from the background rate in the overall population with diabetes. Data suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney disease are limited, and no randomized controlled trials have been conducted to test the safety of metformin in patients with significantly impaired kidney function. Population-based studies demonstrate that metformin may be prescribed counter to prevailing guidelines suggesting a renal risk in up to 1 in 4 patients with type 2 diabetes mellitus--use which, in most reports, has not been associated with increased rates of lactic acidosis. Observational studies suggest a potential benefit from metformin on macrovascular outcomes, even in patients with prevalent renal contraindications for its use.
CONCLUSIONS AND RELEVANCE
Available evidence supports cautious expansion of metformin use in patients with mild to moderate chronic kidney disease, as defined by estimated glomerular filtration rate, with appropriate dosage reductions and careful follow-up of kidney function.
Topics: Acidosis, Lactic; Contraindications; Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Humans; Hypoglycemic Agents; Metformin; Renal Insufficiency, Chronic; Risk
PubMed: 25536258
DOI: 10.1001/jama.2014.15298