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Pediatric Nephrology (Berlin, Germany) Apr 2018D-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...
BACKGROUND
D-lactic acidosis is an uncommon and challenging form of metabolic acidosis that may develop in short bowel syndrome. It has been documented exclusively in case reports and small case series.
METHODS
We performed a review of the literature in the National Library of Medicine and Excerpta Medica databases.
RESULTS
We identified 84 original reports published between 1977 and 2017. D-lactic acidosis was observed in 98 individuals ranging in age from 7 months to 86 years with short bowel syndrome. The clinical presentation included Kussmaul breathing, confusion, slurred speech, and gait disturbances. Furthermore, among 99 consecutive patients with short bowel syndrome, 21 reported having episodes with symptoms consistent with D-lactic acidosis. In addition, D-lactic acid might also contribute to acidosis in diabetes mellitus. Finally, abnormally high D-lactic acid was documented after administration or ingestion of large amounts of propylene glycol, as paraneoplastic phenomenon and perhaps also in a so far poorly characterized inherited inborn error of metabolism.
CONCLUSIONS
In humans with short bowel syndrome (or carbohydrate malabsorption), D-lactic acidosis is likely rather common and under-recognized. This condition should be included in the differential diagnosis of unexplained high-gap metabolic acidosis where the anion causing the acidosis is not known. Furthermore, diabetic acidosis might be caused by accumulation of both ketone bodies and D-lactic acid. Finally, there are endogenous sources of D-lactic acid in subjects with propylene glycol intoxication.
Topics: Acidosis, Lactic; Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Female; Humans; Infant; Lactic Acid; Male; Middle Aged; Short Bowel Syndrome; Young Adult
PubMed: 29218437
DOI: 10.1007/s00467-017-3844-8 -
Pediatric Nephrology (Berlin, Germany) Jun 2023Valproic acid is prescribed for epilepsy and as prophylaxis for bipolar disorder and migraine headaches. It has also been implicated as a cause of a kidney tubular... (Review)
Review
BACKGROUND
Valproic acid is prescribed for epilepsy and as prophylaxis for bipolar disorder and migraine headaches. It has also been implicated as a cause of a kidney tubular injury.
METHODS
We undertook a review of the literature to characterize the biochemical and histopathological features of the overt kidney tubular injury and to evaluate the possible existence of a pauci-symptomatic injury. The pre-registered review (CRD42022360357) was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. Searches were conducted in Excerpta Medica, the National Library of Medicine, and Web of Science. The gray literature was also considered.
RESULTS
For the final analysis, we retained 36 articles: 28 case reports documented 48 individuals with epilepsy on valproic acid for 7 months or more and presenting with features consistent with an overt kidney tubular injury. The following disturbances were noted: hypophosphatemia (N = 46), normoglycemic glycosuria (N = 46), total proteinuria (N = 45), metabolic acidosis (N = 36), hypouricemia (N = 27), tubular proteinuria (N = 27), hypokalemia (N = 23), and hypocalcemia (N = 8). A biopsy, obtained in six cases, disclosed altered proximal tubular cells with giant and dysmorphic mitochondria. Eight case series addressed the existence of a pauci- or even asymptomatic kidney injury. In the reported 285 subjects on valproic acid for 7 months or more, an isolated tubular proteinuria, mostly N-acetyl-β-glucosaminidase, was often noted.
CONCLUSIONS
Valproic acid may induce an overt kidney tubular injury, which is associated with a proximal tubular mitochondrial toxicity. Treatment for 7 months or more is often associated with a pauci- or oligosymptomatic kidney tubular injury. A higher resolution version of the Graphical abstract is available as Supplementary information.
Topics: Humans; Valproic Acid; Kidney Tubules, Proximal; Kidney; Proteinuria; Epilepsy
PubMed: 36645492
DOI: 10.1007/s00467-022-05869-8 -
Journal of Pediatric Gastroenterology... Dec 2015Recent guidelines for preterm neonates recommend early initiation of parenteral nutrition (PN) with high protein and relatively high caloric intake. This review... (Review)
Review
OBJECTIVES
Recent guidelines for preterm neonates recommend early initiation of parenteral nutrition (PN) with high protein and relatively high caloric intake. This review considers whether these changes could influence homeostasis in very preterm infants during the first few postnatal weeks.
METHODS
This systematic review of relevant literature from searches of PubMed and recent guidelines was reviewed by investigators from several perinatal centers in France.
RESULTS
New recommendations for PN could be associated with metabolic acidosis via the increase in the amino acid ion gap, hyperchloremic acidosis, and ammonia acidosis. The introduction of high-intake amino acids soon after birth could induce hypophosphatemia and hypercalcemia, simulating a "repeat feeding-like syndrome" and could be prevented by the early intake of phosphorus, especially in preterm infants born after fetal growth restriction. Early high-dose amino acid infusions are relatively well tolerated in the preterm infant with regard to renal function. Additional studies, however, are warranted to determine markers of protein intolerance and to specify the optimal composition and amount of amino acid solutions.
CONCLUSIONS
Optimal PN following new guidelines in very preterm infants, despite their demonstrated benefits on growth, may induce adverse effects on ionic homeostasis. Clinicians should implement appropriate monitoring to prevent and/or correct them.
Topics: Acidosis; Amino Acids; Dietary Proteins; Homeostasis; Humans; Infant, Newborn; Infant, Premature; Parenteral Nutrition; Phosphorus
PubMed: 26147627
DOI: 10.1097/MPG.0000000000000898 -
Clinical Toxicology (Philadelphia, Pa.) Apr 2023Metformin-associated lactic acidosis is a well-described and commonly encountered condition associated with significant morbidity and mortality. Patients with...
INTRODUCTION
Metformin-associated lactic acidosis is a well-described and commonly encountered condition associated with significant morbidity and mortality. Patients with metformin-associated lactic acidosis are frequently managed in the intensive care unit with supportive care, including volume resuscitation and consideration of an extracorporeal treatment to correct metabolic acidemia and remove metformin and lactate.
EXTRACORPOREAL TREATMENTS IN POISONING WORKGROUP
The Extracorporeal Treatments in Poisoning Workgroup published evidence-based consensus recommendations in 2015 regarding the use of extracorporeal treatment in metformin toxicity. These recommendations list both clinical and biochemical indications, and they outline the rationale and evidence supporting each recommendation.
NEW RESEARCH SINCE RECOMMENDATIONS WERE PUBLISHED
Subsequent publications have provided new information regarding metformin-associated lactic acidosis and its treatment. A retrospective study showed that patients who did not meet the Extracorporeal Treatments in Poisoning Workgroup criteria for initiation of an extracorporeal treatment had a 100% survival. In patients who met the criteria, survival was approximately 75%; only 66% of these patients received an extracorporeal treatment, and this treatment did not appear to impact survival. Two other retrospective studies in patients diagnosed with metformin-associated lactic acidosis noted that extracorporeal treatments did not improve survival. However, those who received an extracorporeal treatment were more severely ill, potentially supporting a benefit from this intervention. A systematic review of patients receiving continuous kidney replacement therapy identified an overall survival that was higher than the overall survival in patients included in the Workgroup publication. This led the authors to suggest that intermittent hemodialysis may not be the preferred treatment for metformin toxicity. However, a closer look at the Workgroup data identified improved survival with each decade since the initial reports in the 1970s. Furthermore, there are multiple reports of persistent metformin-associated lactic acidosis that did not improve with standard continuous kidney replacement therapy, prompting an increase in the dosage of the extracorporeal treatment. The data supporting these observations are largely derived from retrospective studies, which have inherent biases, so prospective studies are required.
PRESCRIBING EXTRACORPOREAL TREATMENTS FOR PATIENTS WITH METFORMIN POISONING
Case-based decision-making is always necessary, but in general, we continue to follow the Extracorporeal Treatments in Poisoning Workgroup criteria because a convincing reason for changing these has not yet been presented. This includes the use of intermittent hemodialysis where possible, particularly in cases of severe poisoning. For patients with less severe poisoning or when intermittent hemodialysis is not readily available, it is reasonable to trial continuous modalities with careful observation for deterioration.
Topics: Humans; Retrospective Studies; Acidosis, Lactic; Metformin; Drug Overdose; Acidosis; Renal Dialysis; Poisoning; Hypoglycemic Agents
PubMed: 37129225
DOI: 10.1080/15563650.2023.2196372 -
Clinical Toxicology (Philadelphia, Pa.) Dec 2020Paracetamol (acetaminophen) remains a leading cause of poisoning in Europe, North America, and Australia. For over four decades, acetylcysteine has been the antidote of...
BACKGROUND
Paracetamol (acetaminophen) remains a leading cause of poisoning in Europe, North America, and Australia. For over four decades, acetylcysteine has been the antidote of choice. However, despite the use of acetylcysteine, some patients who ingest very large doses of paracetamol or who reach hospital late in the course of their poisoning, develop acute liver failure. Some will develop metabolic acidosis indicating mitochondrial toxicity.
OBJECTIVE
We review the experimental and clinical data reported with the use of cimetidine, fomepizole, and calmangafodipir in the treatment of paracetamol toxicity to determine if these treatments alone or in combination with acetylcysteine might be of benefit.
METHODS
We searched Ovid Medline 1946-2020, Embase 1947-2020, Scopus 2004-2020, Cochrane Databases of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov 1997-2020 for records including the concepts of paracetamol poisoning and cimetidine, fomepizole, calmangafodipir, and acetylcysteine. We included basic science studies in animals and all available study types in humans. We reviewed the reference lists of included articles to search for references missed in the original search. We registered the protocol in PROSPERO.
RESULTS
We completed all search strategies on 20 August 2019, 27 January 2020, and 15 June 2020. These produced 6,826 citations. We identified and deleted 2,843 duplicate resulting in a total of 3,856 unique citations. After applying inclusion and exclusion criteria, 89 studies remained. The largest numbers of studies described the past use of cimetidine, and the more recent use of fomepizole. There is good animal evidence that cimetidine blocks CYP 2E1 with the potential to inhibit the toxic metabolism of paracetamol. Early case reports were inconclusive regarding the benefit to humans in paracetamol poisoning. Two comparative trials found no benefit of cimetidine in paracetamol poisoning, but few patients had severe poisoning. There is good animal evidence that fomepizole blocks CYP 2E1 with the potential to inhibit the toxic metabolism of paracetamol. There are no comparative trials of fomepizole for acute paracetamol poisoning. Case reports are inconclusive due to multiple other interventions including the use of acetylcysteine in all cases. The benefit of fomepizole as adjunct treatment has not been demonstrated. Calmangafodipir, a drug mimicking superoxide dismutase, has emerged as a potential treatment for severe paracetamol toxicity because the formation of superoxide free radicals appears to explain part of the mitochondrial toxicity of extremely large paracetamol overdoses. Calmangafodipir has reached Phase I/II trial of safety in humans with acute paracetamol overdose. Planning for a Phase III study of efficacy is currently underway.
CONCLUSIONS
The vast majority of patients with acute paracetamol overdose enjoy excellent outcomes with acetylcysteine alone. Although cimetidine and fomepizole inhibit CYP 2E1 in animals, there is insufficient evidence to recommend their use either as a primary treatment or adjunct therapy in paracetamol poisoning. Calmangafodipir remains investigational.
Topics: Acetaminophen; Acetylcysteine; Acidosis; Animals; Antidotes; Cimetidine; Drug Overdose; Edetic Acid; Fomepizole; Humans; Mitochondria; Pyridoxal Phosphate
PubMed: 32762579
DOI: 10.1080/15563650.2020.1798979 -
Nutricion Hospitalaria Jun 2022In order to improve the recovery process in combat sports disciplines, ergo-nutritional strategies could be an effective option in training and competition. Some of...
In order to improve the recovery process in combat sports disciplines, ergo-nutritional strategies could be an effective option in training and competition. Some of these ergo-nutritional aids could improve performance but literature references are scarce, with controversial results regarding actual recovery effects. This systematic review aimed to examine which ergo-nutritional methods are most effective for assisting in the recovery process in combat sports, and to determine the appropriate training stimuli. This systematic review was carried out following the Preferred Reporting Items for Systematic Review (PRISMA) guidelines. A computerized search was performed in PubMed, Web of Science, the Cochrane Collaboration Database, Evidence Database, Evidence Based Medicine Search review, National Guidelines, EM-BASE, Scopus and Google Scholar system (from 1995 to April 30, 2021). The PICOS model was used to define inclusion and exclusion criteria. Out of 123 studies initially found, 18 met the eligibility criteria and were included in the review. Data from 367 athletes from different disciplines were examined. The evidence was grouped in 4 areas: oxidative stress, muscle and energy recovery, muscle repair, and metabolic acidosis. Evidence showed that vitamins, minerals, and some natural ergo-nutritional products are effective as antioxidants. Carbohydrates and protein determine the recovery effect. Sodium bicarbonate has a role as primary acidosis metabolic delayer. Accordingly, ergo-nutritional aids can help in the recovery process. Considering the effects outlined in the literature, more studies are needed to provide firm evidence.
Topics: Humans; Antioxidants; Athletes; Sports; Vitamins
PubMed: 35076252
DOI: 10.20960/nh.03886 -
Pharmacology 2023Metformin-treated patients may experience severe hyperlactatemia or lactic acidosis (LA). LA often requires intensive-care-unit (ICU) treatment, and mortality rates are...
INTRODUCTION
Metformin-treated patients may experience severe hyperlactatemia or lactic acidosis (LA). LA often requires intensive-care-unit (ICU) treatment, and mortality rates are high. Here, we investigate the impact of renal dysfunction and renal replacement therapy (RRT) on the outcomes of critically ill patients with metformin-associated LA (MALA). Furthermore, we assessed associations between mortality and metformin dose, metformin plasma/serum concentrations, lactate level, and arterial pH. Finally, we investigated whether the recommended classification in MALA, metformin-unrelated LA, metformin-induced LA, and LA in metformin therapy appears useful in this regard.
METHODS
We performed a retrospective analysis based on a systematic PubMed search for publications on hyperlactatemia/LA in metformin-treated ICU patients from January 1995 to February 2020. Case-level data including demographics and clinical conditions were extracted, and logistic regression analyses were performed.
RESULTS
A total of 92 ICU patients were reported. Two of these patients had no comorbidities interfering with lactate metabolism. In the overall group, arterial pH, lactate levels, and metformin plasma/serum concentrations were similar in survivors versus non-survivors. Ingested daily metformin doses and plasma/serum creatinine levels were significantly higher in survivors versus non-survivors (p = 0.007 vs. p = 0.024, respectively). Higher plasma/serum creatinine levels, higher lactate levels, and lower arterial pH were all associated with patients receiving RRT (all p < 0.05). Overall mortality was 22% (20 out of 92 patients) and did not differ between the RRT and non-RRT groups.
CONCLUSION
Mortality is high in ICU patients with metformin-associated hyperlactatemia/LA. Unexpectedly, higher ingested metformin dose and plasma/serum creatinine were associated with a better outcome. Survival was similar in patients with or without need for RRT.
Topics: Humans; Hyperlactatemia; Acidosis, Lactic; Retrospective Studies; Creatinine; Metformin; Intensive Care Units; Lactates; Hypoglycemic Agents
PubMed: 36652938
DOI: 10.1159/000528252 -
Drug Safety Dec 2019There is increasing evidence to suggest that therapeutic doses of metformin are unlikely to cause lactic acidosis. The aims of this research were (1) to formally...
INTRODUCTION AND OBJECTIVES
There is increasing evidence to suggest that therapeutic doses of metformin are unlikely to cause lactic acidosis. The aims of this research were (1) to formally evaluate the association between metformin therapy and lactic acidosis in published case reports using two causality scoring systems, (2) to determine the frequency of pre-existing independent risk factors in published metformin-associated lactic acidosis cases, (3) to investigate the association between risk factors and mortality in metformin-associated lactic acidosis cases, and (4) to explore the relationship between prescribed metformin doses, elevated metformin plasma concentrations and the development of lactic acidosis in cases with chronic renal impairment.
METHODS
A systematic review was conducted to identify metformin-associated lactic acidosis cases. Causality was assessed using the World Health Organisation-Uppsala Monitoring Centre system and the Naranjo adverse drug reaction probability scale. Compliance to dosing guidelines was investigated for cases with chronic renal impairment as well as the association between steady-state plasma metformin concentrations prior to admission.
RESULTS
We identified 559 metformin-associated lactic acidosis cases. Almost all cases reviewed (97%) presented with independent risk factors for lactic acidosis. The prescribed metformin dose exceeded published guidelines in 60% of cases in patients with impaired kidney function. Metformin steady-state plasma concentrations prior to admission were predicted to be below the proposed upper limit of the therapeutic range of 5 mg/L.
CONCLUSIONS
Almost all cases of metformin-associated lactic acidosis reviewed presented with independent risk factors for lactic acidosis, supporting the suggestion that metformin plays a contributory role. The prescribed metformin dose, on average, exceeded the dosing recommendations by 1000 mg/day in patients with varying degrees of renal impairment but the predicted pre-admission plasma concentrations did not exceed the therapeutic range.
Topics: Acidosis, Lactic; Causality; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Renal Insufficiency, Chronic; Risk Factors
PubMed: 31372935
DOI: 10.1007/s40264-019-00854-x -
Molecular Genetics and Metabolism Jul 2023Sengers syndrome (OMIM# 212350) is a rare autosomal recessive mitochondrial disease caused by biallelic pathogenic variants in the AGK gene, which encodes the... (Review)
Review
Sengers syndrome (OMIM# 212350) is a rare autosomal recessive mitochondrial disease caused by biallelic pathogenic variants in the AGK gene, which encodes the acylglycerol kinase enzyme. The syndrome was originally defined as a "triad" of hypertrophic cardiomyopathy, cataracts, and lactic acidosis, with or without skeletal myopathy. The clinical manifestation of Sengers Syndrome exhibits substantial heterogeneity, with mild and severe/infantile forms reported. Further, biallelic AGK pathogenic variants have also been identified in a familial case of non-syndromic isolated cataract (OMIM# 614691), expanding our understanding of the gene's influence beyond the originally defined syndrome. In this study, we provide a systematic review of molecularly confirmed cases with biallelic AGK pathogenic variants (Supplementary Table 1). Our analysis demonstrates the variable expressivity and penetrance of the central features of Sengers syndrome, as follows: cataracts (98%), cardiomyopathy (88%), lactic acidosis (adjusted 88%), and skeletal myopathy (adjusted 74%) (Table 1). Furthermore, we investigate the associations between genotype, biochemical profiles, and clinical outcomes, with a particular focus on infantile mortality. Our findings reveal that patients carrying homozygous nonsense variants have a higher incidence of infant mortality and a lower median age of death (p = 0.005 and p = 0.02, Table 2a). However, the location of pathogenic variants within the AGK domains was not significantly associated with infantile death (p = 0.62, Table 2b). Additionally, we observe a borderline association between the absence of lactic acidosis and longer survival (p = 0.053, Table 2c). Overall, our systematic review sheds light on the diverse clinical manifestations of AGK-related disorders and highlights potential factors that influence its prognosis. These provide important implications for the diagnosis, treatment, and counseling of affected individuals and families.
Topics: Infant; Humans; Acidosis, Lactic; Cardiomyopathies; Cataract; Muscular Diseases; Biological Variation, Population; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 37354892
DOI: 10.1016/j.ymgme.2023.107626 -
Pediatrics Sep 2014We sought to create and implement recommendations from an evidence-based pathway for hospital management of pediatric diabetic ketoacidosis (DKA) and to sustain... (Review)
Review
OBJECTIVE
We sought to create and implement recommendations from an evidence-based pathway for hospital management of pediatric diabetic ketoacidosis (DKA) and to sustain improvement. We hypothesized that development and utilization of standard work for inpatient care of DKA would lead to reduction in hypokalemia and improvement in outcome measures.
METHODS
Development involved systematic review of published literature by a multidisciplinary team. Implementation included multidisciplinary feedback, hospital-wide education, daily team huddles, and development of computer decision support and electronic order sets.
RESULTS
Pathway-based order sets forced clinical pathway adherence; yet, variations in care persisted, requiring ongoing iterative review and pathway tool adjustment. Quality improvement measures have identified barriers and informed subsequent adjustments to interventions. We compared 281 patients treated postimplementation with 172 treated preimplementation. Our most notable findings included the following: (1) monitoring of serum potassium concentrations identified unanticipated hypokalemia episodes, not recognized before standard work implementation, and earlier addition of potassium to fluids resulted in a notable reduction in hypokalemia; (2) improvements in insulin infusion management were associated with reduced duration of ICU stay; and (3) with overall improved DKA management and education, cerebral edema occurrence and bicarbonate use were reduced. We continue to convene quarterly meetings, review cases, and process ongoing issues with system-based elements of implementing the recommendations.
CONCLUSIONS
Our multidisciplinary development and implementation of an evidence-based pathway for DKA have led to overall improvements in care. We continue to monitor quality improvement metric measures to sustain clinical gains while continuing to identify iterative improvement opportunities.
Topics: Diabetic Ketoacidosis; Disease Management; Hospitalization; Humans; Patient Care
PubMed: 25092935
DOI: 10.1542/peds.2013-3764