Metformin-associated lactic acidosis: A mini review of pathophysiology, diagnosis and management in critically ill patients.

Metformin is a common diabetes drug that may reduce lactate clearance by inhibiting mitochondrial oxidative phosphorylation, leading to metformin-associated lactic acidosis (MALA). As diabetes mellitus is a common chronic metabolic condition found in critically ill patients, pre-existing metformin use can often be found in critically ill patients admitted to the intensive care unit or the high dependency unit. The aim of this narrative mini review is therefore to update clinicians about MALA, and to provide a practical approach to its diagnosis and treatment. MALA in critically ill patients may be suspected in a patient who has received metformin and who has a high anion gap metabolic acidosis, and confirmed when lactate exceeds 5 mmol/L. Risk factors include those that reduce renal elimination of metformin (renal impairment from any cause, histamine-2 receptor antagonists, ribociclib) and excessive alcohol consumption (as ethanol oxidation consumes nicotinamide adenine dinucleotides that are also required for lactate metabolism). Treatment of MALA involves immediate cessation of metformin, supportive management, treating other concurrent causes of lactic acidosis like sepsis, and treating any coexisting diabetic ketoacidosis. Severe MALA requires extracorporeal removal of metformin with either intermittent hemodialysis or continuous kidney replacement therapy. The optimal time to restart metformin has not been well-studied. It is nonetheless reasonable to first ensure that lactic acidosis has resolved, and then recheck the kidney function post-recovery from critical illness, ensuring that the estimated glomerular filtration rate is 30 mL/min/1.73 m2 or better before restarting metformin.

The significance of metabolic alkalosis on acute decompensated heart failure: the ALCALOTIC study.

AIMS: To determine the prevalence and the impact on prognosis of metabolic alkalosis (MA) in patients admitted for acute heart failure (AHF). METHODS AND RESULTS: The ALCALOTIC is a multicenter, observational cohort study that prospectively included patients admitted for AHF. Patients were classified into four groups according to their acid-base status on admission: acidosis, MA, respiratory alkalosis, and normal pH (reference group for comparison). Primary endpoint was all-cause in-hospital mortality, and secondary endpoints included 30/90-day all-cause mortality, all-cause readmission, and readmission for HF. Associations between endpoints and acid-base alterations were estimated in a multivariate Cox regression model including sex, age, comorbidities, and Barthel index and expressed as hazard ratio (HR) with 95% confidence interval (95% CI). Six hundred sixty-five patients were included (84 years and 57% women), and 40% had acid-base alterations on admission: 188 (28%) acidosis and 78 (12%) alkalosis. The prevalence (95% CI) of MA was 9% (6.8-11.2%). Patients with MA were more women; had fewer comorbidities, better renal function, and higher left ventricle ejection fraction values; and received more treatment with oral acetazolamide during hospitalization and at discharge. MA was not associated with a higher risk of in-hospital mortality and 30/90-day all-cause mortality or readmissions but was associated with a significant increase in readmissions for HF at 30 and 90 days (adjusted HR [95% CI] 3.294 [1.397-7.767], p = 0.006 and 2.314 [1.075-4.978], p = 0.032). CONCLUSION: The prevalence of MA in patients admitted for AHF was 9%, and its presence was associated with more readmissions for HF but not with all-cause mortality.

Citrate-based dietary alkali supplements available in Germany: an overview.

BACKGROUND: Fruits and vegetables are abundant in alkali precursors and effectively reduce the Potential Renal Acid Load (PRAL) from diet. Oral alkali supplements are supposed to exert comparable alkalizing effects on the human body, and have been shown to beneficially affect bone and kidney health. A comparative analysis of the available dietary alkali supplements in Germany was performed, contrasting their potential PRAL-lowering potential. METHODS: We reviewed the currently available dietary citrate-based alkali supplements sold in Germany with a special focus on their mineral content, their PRAL-lowering potential and other characteristics inherent to each product. Supplements containing either potassium-, calcium- or magnesium citrate or any combination of these organic salts were reviewed. The total alkali load (TAL) was calculated based on the recommended daily dosage (RDD). RESULTS: Sixteen supplements with a mean alkali powder content of 220.69 ± 111.02 g were identified. The mean magnesium content per RDD was 239.93 ± 109.16 mg. The mean potassium and median calcium content were 550 ± 325.58 mg and 280 (240) mg, respectively. Median TAL was 1220 (328.75) mg. The PRAL-lowering potential from a single RDD ranged from - 51.65 mEq to -8.32 mEq. Substantial price differences were found, and the mean price of the examined supplements was 16.67 ± 5.77 Euros. The median price for a 1 mEq PRAL-reduction was 3.01 (3.14) cents, and ranged from 0.77 cents to 10.82 cents. CONCLUSIONS: Noticeable differences between the identified alkali supplements were encountered, warranting an individual and context-specific approach in daily clinical practice.

Hyperlacticaemia in children with status asthmaticus. The Stewart approach.

BACKGROUND: Patients with status asthmaticus (SA) frequently present with lactic acidosis (LA). Our goal is to identify the nature of this LA using the Stewart physicochemical model and to identify the independent factors associated with LA in children with SA. METHODS: Analytical study of a retrospective cohort using a nested case-control design. Twenty-eight episodes of SA in 24 children were included. Patients admitted to a paediatric intensive care unit (PICU) for SA over a 9-year period were recruited consecutively. Data were analysed using the Stewart model and the Strong Ion Calculator. Data were analysed using descriptive statistics and regression models were fitted within the general linear model. RESULTS: Hyperlacticaemia (Lact[mM/L] = 3.905 [95% CI = 3.018-4.792]) and acidosis (pH = 7.294 [95% CI = 7.241-7.339]) were observed in 18 episodes (15 patients; 62.5%). According to the Stewart model, acidosis was caused by a decrease in strong ion difference. Initially, pCO2 was high (pCO2[mmHg] = 45.806 [95% CI = 37.314-54.298]) but the net unmeasured ion (NUI) component was normal (NUI = -4,461 [95% CI = -3.51 to -5.412]), and neither changed significantly over the clinical course. There was no need to determine pyruvate, as the NUI was normal and the LA was type B (non-hypoxic, lactate/pyruvate < 25). We observed a correlation (P = .023) between LA and intramuscular epinephrine administered on arrival at hospital, but not between LA and the cumulative dose of nebulized salbutamol. CONCLUSIONS: Most patients with SA presented LA. The Stewart model confirmed that LA is not hypoxic, probably due to sympathomimetic-related glycolysis.

Bicarbonate ringer's solution could improve the intraoperative acid-base equilibrium and reduce hepatocellular enzyme levels after deceased donor liver transplantation: a randomized controlled study.

BACKGROUND: Bicarbonate Ringer's (BR) solution is a direct liver and kidney metabolism-independent HCO3- buffering system. We hypothesized that BR solution would be more effective in improving acid-base equilibrium and more conducive to better liver function than Acetate Ringer's (AR) solution in conventional orthotopic liver transplantation (OLT) patients. METHODS: Sixty-nine adult patients underwent OLT. Patients in the bicarbonate and acetate groups received BR solution or AR solution as infused crystalloids and graft washing solution, respectively. The primary outcome was the effect on pH and base excess (BE) levels. The secondary outcome measures were the incidence and volume of intraoperative 5% sodium bicarbonate infusion and laboratory indicates of liver and kidney function. RESULTS: The pH and absolute BE values changed significantly during the anhepatic phase and immediately after transplanted liver reperfusion in the bicarbonate group compared with the acetate group (all P < 0.05). The incidence and volume of 5% sodium bicarbonate infusion were lower in the bicarbonate group than in the acetate group (all P < 0.05). The aspartate transaminase (AST) level at 7 postoperative days and the creatine level at 30 postoperative days were significantly higher in the acetate group than in the bicarbonate group (all P < 0.05). CONCLUSION: Compared with AR solution, BR solution was associated with improved intraoperative acid-base balance and potentially protected early postoperative liver graft function and reduced late-postoperative renal injury.

Chloride Reduction Therapy with Furosemide: Short-Term Effects in Children with Acute Respiratory Failure.

From the perspective of the Stewart approach, it is known that expansion of the sodium chloride ion difference (SCD) induces alkalosis. We investigated the role of SCD expansion by furosemide-induced chloride reduction in pediatric patients with acute respiratory failure. We included patients admitted to our pediatric intensive care unit intubated for acute respiratory failure without underlying diseases, and excluded patients receiving extracorporeal circulation therapy (extracorporeal membrane oxygenation and/or renal replacement therapy). We classified eligible patients into the following two groups: case-those intubated who received furosemide within 24 hours, and control-those intubated who did not receive furosemide within 48 hours. Primary outcomes included SCD, partial pressure of carbon dioxide (PaCO 2 ), and pH results from arterial blood gas samples obtained over 48 hours following intubation. Multiple regression analysis was also performed to evaluate the effects of SCD and PaCO 2 changes on pH. Twenty-six patients were included of which 13 patients were assigned to each of the two groups. A total of 215 gas samples were analyzed. SCD (median [mEq/L] [interquartile range]) 48 hours after intubation significantly increased in the case group compared with the control group (37 [33-38] vs. 31 [30-34]; p = 0.005). Although hypercapnia persisted in the case group, the pH (median [interquartile range]) remained unchanged in both groups (7.454 [7.420-7.467] vs. 7.425 [7.421-7.436]; p = 0.089). SCD and PaCO 2 were independently associated with pH ( p < 0.001 for each regression coefficient). As a result, we provide evidence that SCD expansion with furosemide may be useful in maintaining pH within the normal range in pediatric patients with acute respiratory failure complicated by concurrent metabolic acidosis.

Acid/Base-Triggered Photophysical and Chiroptical Switching in a Series of Helicenoid Compounds.

A series of molecules that possess two quinolines, benzoquinolines, or phenanthrolines connected in a chiral fashion by a biaryl junction along with their water-soluble derivatives was developed and characterized. The influence of the structure on the basicity of the nitrogen atoms in two heterocycles was examined and the photophysical and chiroptical switching activity of the compounds upon protonation was studied both experimentally and computationally. The results demonstrated that changes in the electronic structure of the protonated vs. neutral species, promoting a bathochromic shift of dominant electronic transitions and alternation of their character from π-to-π* to charge-transfer-type, when additionally accompanied by the high structural flexibility of a system, leading to changes in conformational preferences upon proton binding, produce particularly pronounced modifications of the spectral properties in acidic medium. The latter combined with reversibility of the read-out make some of the molecules in this series very promising multifunctional pH probes.

Association between obstructive sleep apnea and 24-h urine chemistry risk factors for urinary stone disease.

The effect of obstructive sleep apnea (OSA) on 24-h urine parameters and resultant kidney stone risk is unknown. We sought to compare urinary lithogenic risk factors among patients with kidney stone disease with and without OSA. We performed a retrospective cohort study of adult patients with nephrolithiasis undergoing both polysomnography and 24-h urine analysis. Measures of acid load including gastrointestinal alkali absorption, urinary titratable acid, and net acid excretion were calculated from 24-h urine. We performed univariable comparisons of 24-h urine parameters between those with and without OSA and fit a multivariable linear regression model adjusting for age, sex, and BMI. Overall, there were 127 patients who underwent both polysomnography and a 24-h urine analysis from 2006 to 2018. There were 109 (86%) patients with OSA and 18 (14%) without. Patients with OSA were more commonly male, had greater BMI and had higher rates of hypertension. Patients with OSA had significantly higher levels of 24-h urinary oxalate, uric acid, sodium, potassium, phosphorous, chloride, and sulfate; higher supersaturation of uric acid; higher titratable acid, and net acid excretion; and lower urinary pH and supersaturation of calcium phosphate (p < 0.05). The difference in urinary pH and titratable acid, but not net acid excretion, remained significant when adjusting for BMI, age, and gender (both p = 0.02). OSA is associated with changes in urinary analytes that promote kidney stone formation, similar to those observed with obesity. After accounting for BMI, OSA is independently associated with lower urine pH and increased urinary titratable acid.

Sulfate and acid-base balance.

It has been acknowledged for years that compounds containing sulfur (S) are an important source of endogenous acid production. In the metabolism, S is oxidized to sulfate, and therefore the mEq sulfate excreted in the urine is counted as acid retained in the body. In this study we show that pH in fluids with constant [Na] and [HEPES] declines as sulfate ions are added, and we show that titratable acidity increases exactly with the equivalents of sulfate. Therefore, sulfate excretion in urine is also acid excretion per se. This is in accordance with the down-regulation of proximal sulfate reabsorption under acidosis and the observation that children with distal renal tubular acidosis may be sulfate depleted. These results are well explained using charge-balance modeling, which is based only on the three fundamental principles of electroneutrality, conservation of mass, and rules of dissociation as devised from physical chemistry. In contrast, the findings are in contrast to expectations from conventional narratives. These are unable to understand the decreasing pH as sulfate is added since no conventional acid is present. The results may undermine the traditional notion of endogenous acid production since in the case of sulfur balance, S oxidation and its excretion as sulfate exactly balance each other. Possible clinical correlates with these findings are discussed.

Molecular Characteristics of Water-Insoluble Tin-Porphyrins for Designing the One-Photon-Induced Two-Electron Oxidation of Water in Artificial Photosynthesis.

Faced with the new stage of water oxidation by molecular catalysts (MCs) in artificial photosynthesis to overcome the bottle neck issue, the "Photon-flux density problem of sunlight," a two-electron oxidation process forming H2O2 in place of the conventional four-electron oxidation evolving O2 has attracted much attention. The molecular characteristics of tin(IV)-tetrapyridylporphyrin (SnTPyP), as one of the most promising MCs for the two-electron water oxidation, has been studied in detail. The protolytic equilibria among nine species of SnTPyP, with eight pKa values on the axial ligands' water molecules and peripheral pyridyl nitrogen atoms in both the ground and excited states, have been clarified through the measurements of UV-vis, fluorescence, 1H NMR, and dynamic fluorescence decay behaviour. The oxidation potentials in the Pourbaix diagram and spin densities by DFT calculation of the one-electron oxidized form of each nine species have predicted that the fully deprotonated species ([SnTPyP(O-)2]2-) and the singly deprotonated one ([SnTPyP(OH)(O-)]-) serve as the most favourable MCs for visible light-induced two-electron water oxidation when they are adsorbed on TiO2 for H2 formation or SnO2 for Z-scheme CO2 reduction in the molecular catalyst sensitized system of artificial photosynthesis.

Strong ions and charge-balance.

It has been shown that the ability to predict the pH in any chemically characterized fluid, together with its buffer-capacity and acid content can be based on the requirement of electroneutrality, conservation of mass, and rules of dissociation as provided by physical chemistry. More is not required, and less is not enough. The charge in most biological fluids is dominated by the constant charge on the completely dissociated strong ions but, nonetheless, a persistent narrative in physiology has problematized the notion that these have any role at all in acid-base homeostasis. While skepticism is always to be welcomed, some common arguments against the importance of strong ions are examined and refuted here. We find that the rejection of the importance of strong ions comes with the prize that even very simple systems such as fluids containing nothing else, or solutions of sodium bicarbonate in equilibrium with known tensions of CO2 become incomprehensible. Importantly, there is nothing fundamentally wrong with the Henderson-Hasselbalch equation but the idea that it is sufficient to understand even simple systems is unfounded. What it lacks for a complete description is a statement of charge-balance including strong ions, total buffer concentrations, and water dissociation.

Assessment of Oxidative Stress Indices and Total Phenolics Concentrations in Obese Adult Women-The Effect of Training with Supplemental Oxygen: A Randomized Controlled Trial.

Background: The aim of this study was to determine the effect of using an oxygen-enriched breathing mixture during controlled physical training on blood oxidative stress parameters and total phenolics (TP) concentrations in obese adult women. Methods: A prospective randomized controlled trial study included 60 women aged 19−68 with BMIs greater than 30 kg/m2. Patients were randomly assigned to the study group (n = 30), which received additional intervention in supplementing the breathing mixture with oxygen at the flow of 6 L/min during training sessions, and the control group (n = 30). At the beginning and at the end of the study, anthropometric assessments (height and weight and BMI) and blood tests (CRP, FRAP, TBARS, TP, BAC, and La) were performed. For each patient, an individual endurance training plan was established on a cycloergometer, including 12 training units, based on a cardiopulmonary exercise test (CPET). Results: A decrease in blood TBARS concentration was observed in each study group. For the control group, the change was more remarkable, and the difference between the groups was significant at (p < 0.05; ES: 0.583). Training with the oxygen breathing mixture increased blood concentrations of TP, while a decrease in TP in blood was observed in the group without oxygen supplementation during physical training. The difference in the responses between the groups was significant at (p < 0.05; ES: 0.657) Conclusions: Increasing the concentration of oxygen in the respiratory mixture under conditions of increased exercise was shown to be safe because it did not exacerbate oxidative stress in the obese group.

Associations of Metabolic Syndrome and Abdominal Obesity with Anion Gap Metabolic Acidosis among US Adults.

Background: Obesity is a recently identified risk factor for metabolic acidosis and anion gap elevations in the absence of CKD. Metabolic acidosis is a treatable condition with substantial adverse effects on human health. Additional investigations are needed to characterize at-risk populations and explore potential mechanisms. We hypothesized metabolic syndrome (MetS) and waist circumference (WC) would be closely associated with this pathology. Methods: Adult participants from NHANES 1999-2018 meeting study criteria were compiled as main (n=31,163) and fasting (n=12,860) cohorts. Regression models adjusted for dietary acid, eGFR, and other factors examined associations of WC and MetS features with anion gap metabolic acidosis and its components (serum bicarbonate ≤23 mEq/L and anion gap >95th percentile). Results: Greater WC and MetS features were associated with progressively lower bicarbonate, higher anion gap, and greater odds ratios (OR) of metabolic acidosis (MA) and anion gap metabolic acidosis (AGMA). Compared with the reference, participants with the highest WC had ORs for MA and AGMA of 2.26; 95% CI, 1.96 to 2.62 and 2.89; 95% CI, 1.97 to 4.21; those with three and four versus zero MetS features had ORs for AGMA of 2.52; 95% CI, 1.95 to 2.94 and 3.05; 95% CI, 2.16 to 3.82. Associations of body mass index with outcomes were attenuated or absent after adjustment for WC or MetS. Findings were preserved after excluding eGFR <90 ml/min per 1.73 m2 and albuminuria. A lower MA cutoff (<22 mEq/L) raised the estimate of association between MetS and MA (OR for three and four vs zero features: 3.56; 95% CI, 2.53 to 5.02 and 5.44; 95% CI, 3.66 to 8.08). Conclusions: Metabolic diseases are characterized by metabolic acidosis and anion gap elevations. Metabolic dysfunction may predispose patients without CKD to systemic acidosis from endogenous sources. Comprehensive acid-base analyses may be informative in patients with metabolic diseases.

Lactic Acidosis Related to Pharmacotherapy and Human Diseases.

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.

Effects of Plasma-Lyte® and 0. 9% saline in renal function after deceased-donor kidney transplant: a randomized controlled trial

Abstract Background The influence of different crystalloid solutions infused during deceased-donor kidney transplant on the incidence of delayed graft function remains unclear. We investigated the influence of Plasma-Lyte® vs. 0.9% saline on the incidence of delayed graft function in deceased-donor kidney transplant recipients. Methods We conducted a single-blind randomized controlled trial of 104 patients aged 18 to 65 years who underwent deceased-donor kidney transplant under general anesthesia. Patients were randomly assigned to receive either Plasma-Lyte® (n = 52) or 0.9% saline (n = 52), at the same infusion volume, for intraoperative fluid replacement. The primary outcome was the occurrence of delayed graft function. Secondary outcomes included metabolic and electrolytic changes at the end of surgery. Results Two patients in the Plasma-Lyte® group and one in the 0.9% saline group died postoperatively and were not included for analysis. The incidence of delayed graft function in Plasma-Lyte® and 0.9% saline groups were 60.0% (95% Confidence Interval [95% CI 46.2-72.4]) and 74.5% (95% CI 61.1-84.4), respectively (p= 0.140). Mean (standard deviation) values of immediate postoperative pH and serum chloride levels in Plasma-Lyte® and 0.9% saline groups were 7.306 (0.071) and 7.273 (0.061) (p= 0.013), and 99.6 (4.2) mEq.L-1 and 103.3 (5.6) mEq.L-1, respectively (p< 0.001). All other postoperative metabolic and electrolyte variables were not statistically different at the immediate postoperative period (p> 0.05). Conclusion In deceased-donor kidney transplant recipients, the incidence of delayed graft function is not influenced by Plasma-Lyte® or 0.9% saline used for intraoperative fluid replacement.

Control de la ventilación y regulación del estado ácido-base del pez al hombre / Control of ventilation and regulation of acid-base status from fish to man

RESUMEN Este artículo analiza ciertos aspectos evolutivos en el intercambio gaseoso, el desa rrollo pulmonar, la bomba respiratoria, el estado ácido-base y el control de la ventila ción en relación con un evento trascendente: el pasaje de la vida acuática a la terres tre. Su estudio puede permitir comprender ciertos aspectos con los que lidiamos en la práctica clínica: ¿Por qué las personas con debilidad muscular respiratoria extrema respiran como ranas (respiración frog)?, ¿Por qué los recién nacidos con dificultad respiratoria tienen aleteo nasal y quejido espiratorio?, ¿cómo es posible que los mús culos abdominales, típicamente espiratorios, asistan a la inspiración en casos de la parálisis diafragmática?, ¿por qué en la insuficiencia respiratoria el patrón respiratorio tiene menos variabilidad y se torna más rígido? y, por último, ¿es posible imaginar un pH neutro que no tenga el valor de 7,0, para qué sirve este conocimiento y como se deben interpretar los gases en hipotermia? La transición del agua a la tierra es una de las más importantes e inspiradoras de las grandes transiciones en la evolución de los vertebrados. Ante la sorprendente diversi dad de organismos vivos, es tentador imaginar una cantidad enorme de adaptaciones evolutivas para resolver los diferentes desafíos que cada especie tiene para la vida en la tierra. Hay desarrollos tempranos que comparten algunos factores cruciales y algunas de las redes genéticas regulatorias cercanas y lejanas están conservadas. Somos testigos de hallazgos clínicos que son el testimonio de especies que han vivido en épocas remotas y nos han legado su historia evolutiva.

ABSTRACT This article analyzes certain evolutionary aspects of gas exchange, lung development, the respiratory pump, the acid-base status and control of ventilation in relation to a significant event: the passing from aquatic to terrestrial life. By studying this, we can understand certain aspects that are present in the clinical practice: Why do people with extreme respiratory muscle weakness breathe as frogs? (frog breathing); why do newborns with breathing difficulties have nasal flaring and expiratory grunting?; how is it possible that abdominal muscles, which are typically expiratory, assist with inspira tion in cases of diaphragmatic paralysis?; why does the breathing pattern of respiratory failure has less variability and becomes more rigid? and, finally, is it possible to imagine a neutral pH that doesn't have the 7.0 value?; what's the use of this knowledge, and how should gases in hypothermia be interpreted? Water-to-land transition is one of the most important and inspiring major transitions of vertebrate evolution. Given the amazing diversity of living organisms, it is tempting to imagine an enormous amount of evolutionary adaptation processes to solve the different challenges of living on earth faced by each species. There are certain early development processes that share some crucial factors, and some of the close and distant gene regulatory networks are conserved. We are witnesses of clinical findings that serve as testimony of the species that lived in remote times and left us their evo lutionary history.