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Purpose: The aim of this study was to determine how sodium hydrogen carbonate (NaHCO 3 ) ingestion during a 1-h recovery period after a 200-m front-crawl swim affects blood-gas levels, acid-base balance, and performance during a successive trial., Methods: Fourteen national-level male swimmers (age: 21 ± 3 years, body mass (BM):77 ± 10 kg, stature: 181 ± 7 cm) performed four maximal 200-m front-crawl tests. On one of the two days, the swimmers swam two 200-m tests with a 1-h recovery break, during which they drank water (WATER); on the other day, they performed the same protocol but consumed 0.3 g min -1 NaHCO 3 solution during the recovery break (NaHCO 3 )., Results: The ingestion of NaHCO 3 before the second test had no effect on swim time despite a greater [ HCO 3 - ] (19.2 ± 2.3 mmol L -1 ) than that measured during the first test (NaHCO 3 ) (14.5 ± 1.1 mmol L -1 ) and the other two tests (WATER) (12.7 ± 2.4 and 14.8 ± 1.5 mmol L -1 ; F = 18.554; p = 0.000) and a higher blood pH (7.46 ± 0.03) than that measured during the first test (NaHCO 3 ) (7.39 ± 0.02) and the other two tests (WATER) (7.16 ± 0.04 and 7.20 ± 0.05); (F = 5.255; p = 0.004). An increase in blood pCO 2 (0.2 ± 0.3 kPa) between both tests (NaHCO 3 ) compared to unchanged pCO 2 values (- 0.1 ± 0.3 kPa) between the other two tests (WATER) (t = - 2.984; p = 0.011; power = 0.741) was confirmed., Conclusions: NaHCO 3 ingestion during the recovery period between two 200-m front-crawl time trials had a strong buffering effect that did not positively affect performance. An increase in pCO 2 may have counterbalanced this impact., (© 2024. The Author(s).)

While metabolic acidosis is one of the most common complications in patients with chronic kidney disease (CKD), there are several uncommon etiologies that are challenging to diagnose. Here, we describe a patient on peritoneal dialysis who developed high anion gap metabolic acidosis secondary to acquired 5-oxoprolinemia from acetaminophen use. While CKD is a known risk factor for developing this potentially serious complication, this case further highlights how 5-oxoproline accumulation can occur, even with therapeutic dosing of acetaminophen., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

This study investigated the effect of oral and topical sodium bicarbonate (SB) on soccer-specific performance during simulated soccer exercise. In a block randomized, double-blind, crossover design, 10 collegiate male soccer players (stature: 181.7 ± 3.2 cm, body mass: 81.7 ± 10.5 kg) performed soccer-specific performance tests (countermovement jumps, Illinois agility, 8 × 25 m repeated sprints) throughout a 90-min soccer-specific aerobic field test (SAFT90) following 0.3 g/kg body mass SB in capsules (SB-ORAL), 0.9036 g/kg body mass PR Lotion (SB-LOTION), or placebo capsules and lotion (PLA). Soccer-specific performance tests were conducted pre-SAFT90, during half-time and post-SAFT90. Blood samples were analyzed for acid-base balance (pH; bicarbonate, HCO3-) and strong ions (sodium, Na+; potassium, K+). Average sprint times were quicker for SB-ORAL than PLA during half-time (3.7%; p = .049; g = .57) and post-SAFT90 (4.9%; p = .041; g = .66). SB-ORAL increased pH and HCO3- prewarm-up and during half-time (p < .05), and lowered K+ during half-time (p = .035) compared with PLA. SB-LOTION increased pH (p = .019) and lowered K+ (p = .012) during half-time compared with PLA. SB-LOTION increased Na+ postexercise compared with PLA (p = .008). Repeated sprint times during simulated soccer exercise improved for SB-ORAL, which might have been mechanistically underpinned by elevated blood buffering capacity and greater regulation of strong ion concentration. Consuming SB in capsules is a more effective strategy than topical SB application for improving blood buffering capacity and repeated sprint performance throughout competitive soccer matches.

Muscle relaxants have broad application in anesthesiology. They can be used for safe intubation, preparing the patient for surgery, or improving mechanical ventilation. Muscle relaxants can be classified based on their mechanism of action into depolarizing and non-depolarizing muscle relaxants and centrally acting muscle relaxants. Non-depolarizing neuromuscular blocking drugs (NMBDs) (eg, tubocurarine, atracurium, pipecuronium, mivacurium, pancuronium, rocuronium, vecuronium) act as competitive antagonists of nicotine receptors. By doing so, these drugs hinder the depolarizing effect of acetylcholine, thereby eliminating the potential stimulation of muscle fibers. Depolarizing drugs like succinylcholine and decamethonium induce an initial activation (depolarization) of the receptor followed by a sustained and steady blockade. These drugs do not act as competitive antagonists; instead, they function as more enduring agonists compared to acetylcholine itself. Many factors can influence the duration of action of these drugs. Among them, electrolyte disturbances and disruptions in acid-base balance can have an impact. Acidosis increases the potency of non-depolarizing muscle relaxants, while alkalosis induces resistance to their effects. In depolarizing drugs, acidosis and alkalosis produce opposite effects. The results of studies on the impact of acid-base balance disturbances on non-depolarizing relaxants have been conflicting. This work is based on the available literature and the authors' experience. This article aimed to review the use of anesthetic muscle relaxants in patients with acid-base disturbances.

Background: The use of balanced crystalloids over normal saline for perioperative fluid management during kidney transplantation and its benefits on acid-base and electrolyte balance along with its influence on postoperative clinical outcomes remains a topic of controversy. Therefore, we conducted this review to assess the impact of balanced solutions compared to normal saline on outcomes for kidney transplant patients., Methods: We searched MEDLINE, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) comparing balanced lower-chloride solutions to normal saline in renal transplant patients. Our main outcome of interest was delayed graft function (DGF). Additionally, we examined acid-base and electrolyte measurements, along with postoperative renal function. We computed relative risk (RR) using the Mantel-Haenszel test for binary outcomes, and mean difference (MD) for continuous data, and applied DerSimonian and Laird random-effects models to address heterogeneity. Furthermore, we performed a trial sequential analysis (TSA) for all outcomes., Results: Twelve RCTs comprising a total of 1668 patients were included; 832 (49.9%) were assigned to receive balanced solutions. Balanced crystalloids reduced the occurrence of DGF compared to normal saline, with RR of 0.82 (95% confidence interval [CI], 0.71-0.94), P = .005; I² = 0%. The occurrence was 25% (194 of 787) in the balanced crystalloids group and 34% (240 of 701) in the normal saline group. Moreover, our TSA supported the primary outcome result and suggests that the sample size was sufficient for our conclusion. End-of-surgery chloride (MD, -8.80 mEq·L -1 ; 95% CI, -13.98 to -3.63 mEq.L -1 ; P < .001), bicarbonate (MD, 2.12 mEq·L -1 ; 95% CI, 1.02-3.21 mEq·L -1 ; P < .001), pH (MD, 0.06; 95% CI, 0.04-0.07; P < .001), and base excess (BE) (MD, 2.41 mEq·L -1 ; 95% CI, 0.88-3.95 mEq·L -1 ; P = .002) significantly favored the balanced crystalloids groups and the end of surgery potassium (MD, -0.17 mEq·L -1 ; 95% CI, -0.36 to 0.02 mEq·L -1 ; P = .07) did not differ between groups. However, creatinine did not differ in the first (MD, -0.06 mg·dL -1 ; 95% CI, -0.38 to 0.26 mg·dL -1 ; P = .71) and seventh (MD, -0.06 mg·dL -1 ; 95% CI, -0.18 to 0.06 mg·dL -1 ; P = .30) postoperative days nor urine output in the first (MD, -1.12 L; 95% CI, -3.67 to 1.43 L; P = .39) and seventh (MD, -0.01 L; 95% CI, -0.45 to 0.42 L; P = .95) postoperative days., Conclusions: Balanced lower-chloride solutions significantly reduce the occurrence of DGF and provide an improved acid-base and electrolyte control in patients undergoing kidney transplantation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 International Anesthesia Research Society.)

Background: Paediatric convulsive status epilepticus is the most common neurological emergency presenting to emergency departments. Risks of resultant neurological morbidity and mortality increase with seizure duration. If the seizure fails to stop within defined time-windows, standard care follows an algorithm of stepwise escalation to more intensive treatments, ultimately resorting to induction of general anaesthesia and ventilation. Additionally, ventilatory support may also be required to treat respiratory depression, a common unwanted effect of treatment. There is strong pre-clinical evidence that pH (acid-base balance) is an important determinant of seizure commencement and cessation, with seizures tending to start under alkaline conditions and terminate under acidic conditions. These mechanisms may be particularly important in febrile status epilepticus: prolonged fever-related seizures which predominantly affect very young children. This trial will assess whether imposition of mild respiratory acidosis by manipulation of inhaled medical gas improves response rates to first-line medical treatment., Methods: A double-blind, placebo-controlled trial of pH manipulation as an adjunct to standard medical treatment of convulsive status epilepticus in children. The control arm receives standard medical management whilst inhaling 100% oxygen; the active arm receives standard medical management whilst inhaling a commercially available mixture of 95% oxygen, 5% carbon dioxide known as 'carbogen'. Due to the urgent need to treat the seizure, deferred consent is used. The primary outcome is success of first-line treatment in seizure cessation. Planned subgroup analyses will be undertaken for febrile and non-febrile seizures. Secondary outcomes include rates of induction of general anaesthesia, admission to intensive care, adverse events, and 30-day mortality., Discussion: If safe and effective 95% oxygen, 5% carbon dioxide may be an important adjunct in the management of convulsive status epilepticus with potential for pre-hospital use by paramedics, families, and school staff., Trial Registration: EudraCT: 2021-005367-49. CTA: 17136/0300/001., Isrctn: 52731862. Registered on July 2022., (© 2024. The Author(s).)

This case describes a rare occurrence of high anion gap metabolic acidosis due to chronic acetaminophen (paracetamol) usage, which can be confirmed by measuring 5-oxoproline (pyroglutamate), an organic acid metabolite. As acetaminophen is an extremely common drug prescribed in both inpatient and outpatient settings, a high degree of clinical suspicion is required to isolate it as the aetiology for metabolic acidosis. Management includes discontinuation of acetaminophen use and at times the supplementation of oral bicarbonate. Metabolic acidosis due to a high anion gap is commonly described by the mnemonic 'MUDPILES' in daily practice. A newer mnemonic, 'GOLD MARK' is proposed to be a more inclusive tool to assist in determining the cause of high anion gap metabolic acidosis, especially with such cases being reported., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Short-term acid-base effects of 0.9% saline solution infusion are not well described. Aim of this study was to assess the effects of a fluid challenge with 0.9% saline in critically ill patients according to the Stewart's approach, which allows a precise determination of acid base equilibrium., Methods: In 40 mechanically ventilated critically ill patients, acid-base variables according to Stewart's approach were measured before and after 30 minutes from the infusion of 0.5L of 0.9% saline. Patients were divided in saline responder (fractional sodium excretion increase <0.5) and non-responders, and in patients with (estimated glomerular filtration rate >63 mL/min) and without renal impairment., Results: After saline infusion, plasma sodium concentration did not change (138 [135-141] vs. 138 [135-140] mEq/L, P=0.646), while chloride concentration significantly increased (102 [100-106] vs. 104 [191-106] mEq/L, P=0.003), reducing strong ion difference (37.0 [34.9-38.0] vs. 35.4 [32.7-37.5] mEq/L, P=0.004) without any impact on pH, due to the concomitant albumin dilution. In saline non-responders, the increase of plasma chloride concentration caused a reduction in strong ion difference, while in saline responders both plasma chloride concentration and strong ion difference remained similar. Patients with and without renal impairment presented a similar acid-base response., Conclusions: The infusion of 0.9% saline reduced strong ion difference by increasing plasma chloride concentration, with no effect on pH due to concomitant albumin dilution. Saline non-responders, characterized by the ability to excrete the sodium excess, were more likely to suffer the acidifying effects of saline infusion, while renal function did not affect the acid-base response to saline infusion.

Self-poisoning with organophosphorus (OP) insecticides is an important means of global self-harm. The insecticides are formulated with solvents that may also contribute to toxicity. We set up a study to detect changes in osmolal and anion gaps following ingestion of OP insecticides. We recruited consecutive patients admitted to a Teaching Hospital, Sri Lanka, with a history of OP self-poisoning. The osmolal and anion gaps were calculated on admission and at 4, 24 and 72 h post-ingestion together with ethanol concentration. Forty-nine patients were recruited (28 profenofos, 10 diazinon, one coumaphos, one chlorpyrifos, one phenthoate and eight unknown OP). Only modest increases in osmolal and anion gaps were noted. Small rises in osmolal gap above the upper limit of normal were noted in 16/49 (32.7%) of all cases, 9/28 (32.1%) profenofos cases and 4/10 (40.0%) diazinon cases. The anion gap was raised in 24/49 (49.0%) of all cases, 15/28 (53.6%) profenofos cases and 5/10 (50.0%) diazinon cases. We observed a trend for a fall in osmolal gap during the first 24 h, followed by an increase up to 72 h. There was no correlation between the anion gap and serum lactate concentration, indicating that a lactic acidosis was not responsible for the anion gap. Formate, which could have explained the increased gap, was not detected in any of the samples; ketoacids (beta-hydroxybutyrate and acetoacetate) were not measured. This pilot study found that profenofos and diazinon poisoning caused only modest increases in the osmolal and anion gaps in a minority of cases., (© 2021 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

We have previously reported that the long-term exposure of Isocarbophos, a kind of organophosphorus compounds, induces vascular dementia (VD) in rats. Studies have also shown that organophosphorus compounds have adverse effects on offsprings. Vitamin B6 is a coenzyme mainly involved in the regulation of metabolism and has been demonstrated to ameliorate VD. Sphingosine-1-phosphate (S1P), a biologically active lipid, plays a vital role in the cardiovascular system. However, whether S1P is involved in the therapeutic effects of Vitamin B6 on posterior cerebral artery injury has yet to be further answered. In the present study, we aimed to explore the potential influence of Vitamin B6 on Isocarbophos-induced posterior cerebral artery injury in offspring rats and the role of the S1P receptor in this process. We found that Vitamin B6 significantly improves the vasoconstriction function of the posterior cerebral artery in rats induced by Isocarbophos by the blood gas analysis and endothelium-dependent relaxation function assay. We further demonstrated that Vitamin B6 alleviates the Isocarbophos-induced elevation of ICAM-1, VCAM-1, IL-1, and IL-6 by using the enzyme-linked immunosorbent assay kits. By performing immunofluorescence and the western blot assay, we revealed that Vitamin B6 prevents the down-regulation of S1P in posterior cerebral artery injury. It is worth noting that Fingolimod, the S1P inhibitor, significantly inhibits the Vitamin B6-induced up-regulation of S1P in posterior cerebral artery injury. Collectively, our data indicate that Vitamin B6 may be a novel drug for the treatment of posterior cerebral artery injury and that S1P may be a drug target for its treatment., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The ongoing Covid-19 is a contagious disease, and it is characterised by different symptoms such as fever, cough, and shortness of breath. Rising concerns about Covid-19 have severely affected the healthcare system in all countries as the Covid-19 outbreak has developed at a rapid rate all around the globe. Intriguing, a clinically used drug, acetazolamide (a specific inhibitor of carbonic anhydrase, CA, EC 4.2.1.1), is used to treat high-altitude pulmonary oedema (HAPE), showing a high degree of clinical similarities with the pulmonary disease caused by Covid-19. In this context, this preliminary study aims to provide insights into some factors affecting the Covid-19 patients, such as hypoxaemia, hypoxia as well as the blood CA activity. We hypothesise that patients with Covid-19 problems could show a dysregulated acid-base status influenced by CA activity. These preliminary results suggest that the use of CA inhibitors as a pharmacological treatment for Covid-19 may be beneficial.

This study investigated the effect of post-exercise sodium bicarbonate (NaHCO 3 ) ingestion on acid-base balance recovery and time-to-exhaustion (TTE) running performance. Eleven male runners (stature, 1.80 ± 0.05 m; body mass, 74.4 ± 6.5 kg; maximal oxygen consumption, 51.7 ± 5.4 mL·kg -1 ·min -1 ) participated in this randomised, single-blind, counterbalanced and crossover design study. Maximal running velocity (v- V̇ O 2max ) was identified from a graded exercise test. During experimental trials, participants repeated 100% v- V̇ O 2max TTE protocols (TTE1, TTE2) separated by 40 min following the ingestion of either 0.3 g·kg -1 body mass NaHCO 3 (SB) or 0.03 g·kg -1 body mass sodium chloride (PLA) at the start of TTE1 recovery. Acid-base balance (blood pH and bicarbonate, HCO 3 - ) data were studied at baseline, post-TTE1, after 35 min recovery and post-TTE2. Blood pH and HCO 3 - concentration were unchanged at 35 min recovery ( p  > 0.05), but HCO 3 - concentration was elevated post-TTE2 for SB vs. PLA (+2.6 mmol·L -1 ; p  = 0.005; g  = 0.99). No significant differences were observed for TTE2 performance ( p  > 0.05), although a moderate effect size was present for SB vs. PLA (+14.3 s; g  = 0.56). Post-exercise NaHCO 3 ingestion is not an effective strategy for accelerating the restoration of acid-base balance or improving subsequent TTE performance when limited recovery is available. Novelty: Post-exercise sodium bicarbonate ingestion did not accelerate the restoration of blood pH or bicarbonate after 35 min. Performance enhancing effects of sodium bicarbonate ingestion may display a high degree of inter-individual variation. Small-to-moderate changes in performance were likely due to greater up-regulation of glycolytic activation during exercise.

In anaesthetic practice the risk of hypoxia and arterial blood gas disturbances is evident, as most anaesthetic regimens depress the respiratory function. Hypoxia may be extended during recovery, and for this reason we wished to investigate if oxygen supply during a one hour post-operative period reduced the development of hypoxia and respiratory acidosis in rats anaesthetized with fentanyl/fluanisone and midazolam. Twelve Sprague Dawley rats underwent surgery and were divided in two groups, breathing either 100% oxygen or atmospheric air during a post-operative period. The peripheral blood oxygen saturation and arterial acid-base status were analyzed for differences between the two groups. We found that oxygen supply after surgery prevented hypoxia but did not result in a significant difference in the blood acid-base status. All rats developed respiratory acidosis, which could not be reversed by supplemental oxygen supply. We concluded that oxygen supply improved oxygen saturation and avoided hypoxia but did not have an influence on the acid-base status., Competing Interests: The authors have declared that no competing interests exist.

Following the accidental feeding of a compound feed containing the coccidiostat nicarbacin in layer breeder flocks (Lohmann Brown Classic), the birds displayed distinct clinical signs within a few hours. Mortality increased during the following 5 days, whereas laying performance and hatching rate of eggs during this period decreased markedly. Egg shell discoloration was observed as early as during the first day. As a consequence, an association between feeding of the coccidiostat nicarbacin and the observed symptoms was assumed. Recent studies indicate that Nicarbacin reduces the activity of aminolevulinic acid synthase type 1 (ALAS 1), which is responsible for the synthesis of protoporphyrin IX in the shell gland as main compound of brown egg shells. Reduced laying performance and increased mortality was likely due to nicarbacin-induced deregulated body temperature homeostasis and concomitant imbalances in acid-base status of the animals. The case reveals that the accidental feeding of nicarbacin to non-target animals such as laying hens and their parents may result in acute clinical symptoms. This highlights the necessity of appropriate care in handling feed additives and their premixes for specific non-target animals and should sensitize farmers and veterinarians., Competing Interests: Die Autoren erklären, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Baking soda and vinegar have been used as home remedies for generations and today we are only a mouse-click away from claims that baking soda, lemon juice, and apple cider vinegar are miracles cures for everything from cancer to COVID-19. Despite these specious claims, the therapeutic value of controlling acid-base balance is indisputable and is the basis of Food and Drug Administration-approved treatments for constipation, epilepsy, metabolic acidosis, and peptic ulcers. In this narrative review, we present evidence in support of the current and potential therapeutic value of countering local and systemic acid-base imbalances, several of which do in fact involve the administration of baking soda (sodium bicarbonate). Furthermore, we discuss the side effects of pharmaceuticals on acid-base balance as well as the influence of acid-base status on the pharmacokinetic properties of drugs. Our review considers all major organ systems as well as information relevant to several clinical specialties such as anesthesiology, infectious disease, oncology, dentistry, and surgery., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Sodium-glucose transporter (SGLT)2 inhibitors increase plasma magnesium and plasma phosphate and may cause ketoacidosis, but the contribution of improved glycemic control to these observations as well as effects on other electrolytes and acid-base parameters remain unknown. Therefore, our objective was to compare the effects of SGLT2 inhibitors dapagliflozin and sulfonylurea gliclazide on plasma electrolytes, urinary electrolyte excretion, and acid-base balance in people with Type 2 diabetes (T2D). We assessed the effects of dapagliflozin and gliclazide treatment on plasma electrolytes and bicarbonate, 24-hour urinary pH and excretions of electrolytes, ammonium, citrate, and sulfate in 44 metformin-treated people with T2D and preserved kidney function. Compared with gliclazide, dapagliflozin increased plasma chloride by 1.4 mmol/l (95% CI 0.4-2.4), plasma magnesium by 0.03 mmol/l (95% CI 0.01-0.06), and plasma sulfate by 0.02 mmol/l (95% CI 0.01-0.04). Compared with baseline, dapagliflozin also significantly increased plasma phosphate, but the same trend was observed with gliclazide. From baseline to week 12, dapagliflozin increased the urinary excretion of citrate by 0.93 ± 1.72 mmol/day, acetoacetate by 48 μmol/day (IQR 17-138), and β-hydroxybutyrate by 59 μmol/day (IQR 0-336), without disturbing acid-base balance. In conclusion, dapagliflozin increases plasma magnesium, chloride, and sulfate compared with gliclazide, while reaching similar glucose-lowering in people with T2D. Dapagliflozin also increases urinary ketone excretion without changing acid-base balance. Therefore, the increase in urinary citrate excretion by dapagliflozin may reflect an effect on cellular metabolism including the tricarboxylic acid cycle. This potentially contributes to kidney protection., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Chronic metabolic acidosis leads to bone-remodelling disorders based on excessive mineral matrix resorption and inhibition of bone formation, but also affects the homeostasis of citrate, which is an essential player in maintaining the acid-base balance and in driving the mineralisation process. This study aimed to investigate the impact of acidosis on the osteogenic properties of bone-forming cells and the effects of citrate supplementation in restoring the osteogenic features impaired by the acidic milieu. For this purpose, human mesenchymal stromal cells were cultured in an osteogenic medium and the extracellular matrix mineralisation was analysed at the micro- and nano-level, both in neutral and acidic conditions and after treatment with calcium citrate and potassium citrate. The acidic milieu significantly decreased the citrate release and hindered the organisation of the extracellular matrix, but the citrate supplementation increased collagen production and, particularly calcium citrate, promoted the mineralisation process. Moreover, the positive effect of citrate supplementation was observed also in the physiological microenvironment. This in vitro study proves that the mineral matrix organisation is influenced by citrate availability in the microenvironment surrounding bone-forming cells, thus providing a biological basis for using citrate-based supplements in the management of bone-remodelling disorders related to chronic low-grade acidosis.

Sodium bicarbonate (NaHCO 3 ) has been recognized as a possible therapy to target chronic kidney disease (CKD) progression. Several small clinical trials have demonstrated that supplementation with NaHCO 3 or other alkalizing agents slows renal functional decline in patients with CKD. While the benefits of NaHCO 3 treatment have been thought to result from restoring pH homeostasis, a number of studies have now indicated that NaHCO 3 or other alkalis may provide benefit regardless of the presence of metabolic acidosis. These data have raised questions as to how NaHCO 3 protects the kidneys. To date, the physiological mechanism(s) that mediates the reported protective effect of NaHCO 3 in CKD remain unclear. In this review, we first examine the evidence from clinical trials in support of a beneficial effect of NaHCO 3 and other alkali in slowing kidney disease progression and their relationship to acid-base status. Then, we discuss the physiological pathways that have been proposed to underlie these renoprotective effects and highlight strengths and weaknesses in the data supporting each pathway. Finally, we discuss how answering key questions regarding the physiological mechanism(s) mediating the beneficial actions of NaHCO 3 therapy in CKD is likely to be important in the design of future clinical trials. We conclude that basic research in animal models is likely to be critical in identifying the physiological mechanisms underlying the benefits of NaHCO 3 treatment in CKD. Gaining an understanding of these pathways may lead to the improved implementation of NaHCO 3 as a therapy in CKD and perhaps other disease states.

Inhibitors of proximal tubular Na + -glucose cotransporter 2 (SGLT2) are natriuretic, and they lower blood pressure. There are reports that the activities of SGLT2 and Na + -H + exchanger 3 (NHE3) are coordinated. If so, then part of the natriuretic response to an SGLT2 inhibitor is mediated by suppressing NHE3. To examine this further, we compared the effects of an SGLT2 inhibitor, empagliflozin, on urine composition and systolic blood pressure (SBP) in nondiabetic mice with tubule-specific NHE3 knockdown (NHE3-ko) and wild-type (WT) littermates. A single dose of empagliflozin, titrated to cause minimal glucosuria, increased urinary excretion of Na + and bicarbonate and raised urine pH in WT mice but not in NHE3-ko mice. Chronic empagliflozin treatment tended to lower SBP despite higher renal renin mRNA expression and lowered the ratio of SBP to renin mRNA, indicating volume loss. This effect of empagliflozin depended on tubular NHE3. In diabetic Akita mice, chronic empagliflozin enhanced phosphorylation of NHE3 (S552/S605), changes previously linked to lesser NHE3-mediated reabsorption. Chronic empagliflozin also increased expression of genes involved with renal gluconeogenesis, bicarbonate regeneration, and ammonium formation. While this could reflect compensatory responses to acidification of proximal tubular cells resulting from reduced NHE3 activity, these effects were at least in part independent of tubular NHE3 and potentially indicated metabolic adaptations to urinary glucose loss. Moreover, empagliflozin increased luminal α-ketoglutarate, which may serve to stimulate compensatory distal NaCl reabsorption, while cogenerated and excreted ammonium balances urine losses of this "potential bicarbonate." The data implicate NHE3 as a determinant of the natriuretic effect of empagliflozin.

Carbonic anhydrase (CAII) binds to the electrogenic basolateral Na + -[Formula: see text] cotransporter (NBCe1) and facilitates [Formula: see text] reabsorption across the proximal tubule. However, whether the inhibition of CAII with acetazolamide (ACTZ) alters NBCe1 activity and interferes with the ammoniagenesis pathway remains elusive. To address this issue, we compared the renal adaptation of rats treated with ACTZ to NH 4 Cl loading for up to 2 wk. The results indicated that ACTZ-treated rats exhibited a sustained metabolic acidosis for up to 2 wk, whereas in NH 4 Cl-loaded rats, metabolic acidosis was corrected within 2 wk of treatment. [Formula: see text] excretion increased by 10-fold in NH 4 Cl-loaded rats but only slightly (1.7-fold) in ACTZ-treated rats during the first week despite a similar degree of acidosis. Immunoblot experiments showed that the protein abundance of glutaminase (4-fold), glutamate dehydrogenase (6-fold), and SN1 (8-fold) increased significantly in NH 4 Cl-loaded rats but remained unchanged in ACTZ-treated rats. Na + /H + exchanger 3 and NBCe1 proteins were upregulated in response to NH 4 Cl loading but not ACTZ treatment and were rather sharply downregulated after 2 wk of ACTZ treatment. ACTZ causes renal [Formula: see text] wasting and induces metabolic acidosis but inhibits the upregulation of glutamine transporter and ammoniagenic enzymes and thus suppresses ammonia synthesis and secretion in the proximal tubule, which prevented the correction of acidosis. This effect is likely mediated through the inhibition of the CA-NBCe1 metabolon complex, which results in cell alkalinization. During chronic ACTZ treatment, the downregulation of both NBCe1 and Na + /H + exchanger 3, along with the inhibition of ammoniagenesis and [Formula: see text] generation, contributes to the maintenance of metabolic acidosis.

Purpose: Enteric-coated sodium bicarbonate (NaHCO 3 ) can attenuate gastrointestinal (GI) symptoms following acute bicarbonate loading, although the subsequent effects on exercise performance have not been investigated. The purpose of this study was to examine the effects of enteric-coated NaHCO 3 supplementation on high-intensity exercise performance and GI symptoms., Methods: Eleven trained male cyclists completed three 4 km time trials after consuming; a placebo or 0.3 g∙kg -1 body mass NaHCO 3 in enteric-coated or gelatin capsules. Exercise trials were timed with individual peak blood bicarbonate ion concentration ([HCO 3 - ]). Blood acid-base balance was measured pre-ingestion, pre-exercise, and post-exercise, whereas GI symptoms were recorded pre-ingestion and immediately pre-exercise., Results: Pre-exercise blood [HCO3 - ] and potential hydrogen (pH) were greater for both NaHCO 3 conditions (P < 0.0005) when compared to placebo. Performance time was faster with enteric-coated (- 8.5 ± 9.6 s, P = 0.044) and gelatin (- 9.6 ± 7.2 s, P = 0.004) NaHCO 3 compared to placebo, with no significant difference between conditions (mean difference = 1.1 ± 5.3 s, P = 1.000). Physiological responses were similar between conditions, although blood lactate ion concentration was higher with gelatin NaHCO 3 (2.4 ± 1.7 mmol∙L -1 , P = 0.003) compared with placebo. Furthermore, fewer participants experienced GI symptoms with enteric-coated (n = 3) compared to gelatin (n = 7) NaHCO 3 ., Discussion: Acute enteric-coated NaHCO 3 consumption mitigates GI symptoms at the onset of exercise and improves subsequent 4 km cycling TT performance. Athletes who experience GI side-effects after acute bicarbonate loading may, therefore, benefit from enteric-coated NaHCO 3 supplementation prior to exercise performance.

Intercalated cells (ICs) are found in the connecting tubule and the collecting duct. Of the three IC subtypes identified, type B intercalated cells are one of the best characterized and known to mediate Cl - absorption and HCO 3 - secretion, largely through the anion exchanger pendrin. This exchanger is thought to act in tandem with the Na + -dependent Cl - /HCO 3 - exchanger, NDCBE, to mediate net NaCl absorption. Pendrin is stimulated by angiotensin II and aldosterone administration via the angiotensin type 1a and the mineralocorticoid receptors, respectively. It is also stimulated in models of metabolic alkalosis, such as with NaHCO 3 administration. In some rodent models, pendrin-mediated HCO 3 - secretion modulates acid-base balance. However, of probably more physiological or clinical significance is the role of these pendrin-positive ICs in blood pressure regulation, which occurs, at least in part, through pendrin-mediated renal Cl - absorption, as well as their effect on the epithelial Na + channel, ENaC. Aldosterone stimulates ENaC directly through principal cell mineralocorticoid hormone receptor (ligand) binding and also indirectly through its effect on pendrin expression and function. In so doing, pendrin contributes to the aldosterone pressor response. Pendrin may also modulate blood pressure in part through its action in the adrenal medulla, where it modulates the release of catecholamines, or through an indirect effect on vascular contractile force. In addition to its role in Na + and Cl - balance, pendrin affects the balance of other ions, such as K + and I - . This review describes how aldosterone and angiotensin II-induced signaling regulate pendrin and the contribution of pendrin-positive ICs in the kidney to distal nephron function and blood pressure.

Objectives: We sought to test the strength of correlation between predicted and observed systemic acid-base status based on the Stewart model equations during continuous infusion (CI) furosemide therapy., Design, Setting and Participants: This was a prospective, single-center, observational study conducted in the Surgical ICU of a large academic medical center. Ten critically ill patients who received CI furosemide were included., Main Outcomes and Measures: The primary purpose was to characterize the relationship between changes in serum electrolyte and acid-base status and the excretion of electrolytes in the urine during infusion of CI furosemide in critically ill patients. As a secondary endpoint, we sought to evaluate the predictive application of the Stewart model. Over 72-h, intake and output volumes, electrolyte content of fluids administered, plasma and urine electrolytes, urine pH, and venous blood gases were collected. Predicted and observed changes in acid-based status were compared for each day of diuretic therapy using Spearman's correlation coefficient., Results: The mean (SD) strong ion difference (SID) increased from 45.2 (3.2) at baseline to 49.6 (4.0) after 72 h of continuous infusion furosemide. At Day 1, the mean SID (observed) (SD) was 47.5 (3.5) and the predicted SID was 49.5 (5.8). Day 1 observed plasma SID was positively correlated with the predicted SID (r s  = 0.80, p = 0.01). By Days 2 and 3, the correlations of observed and predicted SID were no longer statistically significant., Conclusions and Relevance: Using the Stewart model, increases in SID as an indicator of metabolic alkalosis due to the chloruretic effects of furosemide were observed. Predicted and observed SID correlated well over the first 24 h of treatment.

Coral calcification is intricately linked to the chemical composition of the fluid in the extracellular calcifying medium (ECM), which is situated between the calcifying cells and the skeleton. Here we demonstrate that the acid-base sensing enzyme soluble adenylyl cyclase (sAC) is expressed in calcifying cells of the coral Stylophora pistillata. Furthermore, pharmacological inhibition of sAC in coral microcolonies resulted in acidification of the ECM as estimated by the pH-sensitive ratiometric indicator SNARF, and decreased calcification rates, as estimated by calcein labeling of crystal growth. These results indicate that sAC activity modulates some of the molecular machinery involved in producing the coral skeleton, which could include ion-transporting proteins and vesicular transport. To our knowledge this is the first study to directly demonstrate biological regulation of the alkaline pH of the coral ECM and its correlation with calcification., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The present study investigated the effects of chronic sodium bicarbonate (NaHCO 3 ) ingestion on a single bout of high-intensity exercise and on acid-base balance during 7-day high-altitude exposure., Methods: Ten recreationally active subjects participated in a pre-test at sea level and a 7-day hiking tour in the Swiss Alps up to 4554 m above sea level. Subjects received either a daily dose of 0.3 g/kg NaHCO 3 solution (n = 5) or water as a placebo (n = 5) for 7 days. Anaerobic high-intensity exercise performance was assessed using the portable tethered sprint running (PTSR) test under normoxic and hypoxic conditions (3585 m). PTSR tests assessed overall peak force, mean force, and fatigue index. Blood lactate levels and blood gas parameters were assessed pre- and post-PTSR. Urinary pH and blood gas parameters were further analyzed daily at rest in early morning samples under normoxic and hypoxic conditions., Results: There were no significant differences between the bicarbonate and control group in any of the PTSR-related parameters. However, urinary pH (p = 0.003, ηp 2  = 0.458), early morning blood bicarbonate concentration (p < 0.001, ηp 2  = 0.457) and base excess (p = 0.002, ηp 2  = 0.436) were significantly higher in the bicarbonate group compared with the control group under hypoxic conditions., Conclusions: These results indicate that oral NaHCO 3 ingestion does not ameliorate the hypoxia-induced impairment in anaerobic, high-intensity exercise performance, represented by PTSR-related test parameters, under hypobaric, hypoxic conditions, but the maximal performance measurements may have been negatively affected by other factors, such as poor implementation of PTSR test instructions, pre-acclimatization, the time course of hypoxia-induced renal [HCO 3 - ] compensation, changes in the concentrations of intra- and extracellular ions others than [H + ] and [HCO 3 - ], or gastrointestinal disturbances caused by NaHCO 3 ingestion. However, chronic NaHCO 3 ingestion improves blood bicarbonate concentration and base excess at altitude, which partially represent the blood buffering capacity.

Objectives: Metformin-associated lactic acidosis (MALA) may occur after acute metformin overdose, or from therapeutic use in patients with renal compromise. The mortality is high, historically 50% and more recently 25%. In many disease states, lactate concentration is strongly associated with mortality. The aim of this systematic review and meta-analysis is to investigate the utility of pH and lactate concentration in predicting mortality in patients with MALA., Methods: We searched PubMed, EMBASE, and Web of Science from their inception to April 2019 for case reports, case series, prospective, and retrospective studies investigating mortality in patients with MALA. Cases and studies were reviewed by all authors and included if they reported data on pH, lactate, and outcome. Where necessary, authors of studies were contacted for patient-level data. Receiver operating characteristic (ROC) curves were generated for pH and lactate for predicting mortality in patients with MALA., Results: Forty-four studies were included encompassing 170 cases of MALA with median age of 68.5 years old. Median pH and lactate were 7.02 mmol/L and 14.45 mmol/L, respectively. Overall mortality was 36.2% (95% CI 29.6-43.94). Neither lactate nor pH was a good predictor of mortality among patients with MALA. The area under the ROC curve for lactate and pH were 0.59 (0.51-0.68) and 0.43 (0.34-0.52), respectively., Conclusion: Our review found higher mortality from MALA than seen in recent studies. This may be due to variation in standard medical practice both geographically and across the study interval, sample size, misidentification of MALA for another disease process and vice versa, confounding by selection and reporting biases, and treatment intensity (e.g., hemodialysis) influenced by degree of pH and lactate derangement. The ROC curves showed poor predictive power of either lactate or pH for mortality in MALA. With the exception of patients with acute metformin overdose, patients with MALA usually have coexisting precipitating illnesses such as sepsis or renal failure, though lactate from MALA is generally higher than would be considered survivable for those disease states on their own. It is possible that mortality is more related to that coexisting illness than MALA itself, and many patients die with MALA rather than from MALA. Additional work looking solely at MALA in healthy patients with acute metformin overdose may show a closer relationship between lactate, pH, and mortality.

Retrospective analyses and single-center prospective studies identify chronic metabolic acidosis as an independent and modifiable risk factor for progression of CKD. In patients with CKD, untreated chronic metabolic acidosis often leads to an accelerated reduction in GFR. Mechanisms responsible for this reduction include adaptive responses that increase acid excretion but lead to a decline in kidney function. Metabolic acidosis in CKD stimulates production of intrakidney paracrine hormones including angiotensin II, aldosterone, and endothelin-1 (ET-1) that mediate the immediate benefit of increased kidney acid excretion, but their chronic upregulation promotes inflammation and fibrosis. Chronic metabolic acidosis also stimulates ammoniagenesis that increases acid excretion but also leads to ammonia-induced complement activation and deposition of C3 and C5b-9 that can cause tubule-interstitial damage, further worsening disease progression. These effects, along with acid accumulation in kidney tissue, combine to accelerate progression of kidney disease. Treatment of chronic metabolic acidosis attenuates these adaptive responses; reduces levels of angiotensin II, aldosterone, and ET-1; reduces ammoniagenesis; and diminishes inflammation and fibrosis that may lead to slowing of CKD progression., (Copyright © 2020 by the American Society of Nephrology.)

Background: Mammalian central neurons regulate their intracellular pH (pHi) strongly and even slight pHi-fluctuations can influence inter-/intracellular signaling, synaptic plasticity and excitability., Objective: For the first time, we investigated topiramate´s (TPM) influence on pHi-behavior of human central neurons representing a promising target for anticonvulsants and antimigraine drugs., Methods: In slice-preparations of tissue resected from the middle temporal gyrus of five adults with intractable temporal lobe epilepsy, BCECF-AM-loaded neocortical pyramidal-cells were investigated by fluorometry. The pHi-regulation was estimated by using the recovery-slope from intracellular acidification after an Ammonium-Prepulse (APP)., Results: Among 17 pyramidal neurons exposed to 50 μM TPM, seven (41.24%) responded with an altered resting-pHi (7.02±0.12), i.e., acidification of 0.01-0.03 pH-units. The more alkaline the neurons, the greater the TPM-related acidifications (r=0.7, p=0.001, n=17). The recovery from APPacidification was significantly slowed under TPM (p<0.001, n=5). Further experiments using nominal bicarbonate-free (n=2) and chloride-free (n=2) conditions pointed to a modulation of the HCO3 -- driven pHi-regulation by TPM, favoring a stimulation of the passive Cl-/HCO3 --antiporter (CBT) - an acid-loader predominantly in more alkaline neurons., Conclusion: TPM modulated the bicarbonate-driven pHi-regulation, just as previously described in adult guinea-pig hippocampal neurons. We discussed the significance of the resulting subtle acidifications for beneficial antiepileptic, antimigraine and neuroprotective effects as well as for unwanted cognitive deficits., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose of Review: We review mechanisms for chronic kidney disease (CKD) progression that might be addressed with nonpharmacologic and novel pharmacologic interventions as strategies by which to slow or even prevent CKD progression., Recent Findings: Evolving data support the contribution of the broad spectrum of disorders of acid (H) accumulation, which we refer to as 'H stress', to CKD progression. Recent studies support that amelioration of H stress, including spectra of H accumulation that are insufficient to cause metabolic acidosis, is kidney-protective. In addition, gut-derived toxins appear to contribute to CKD progression and to the well described increased cardiovascular disease (CVD) risk in patients with CKD. Dietary and novel pharmacologic interventions hold promise as strategies to slow CKD progression through reducing levels of these gut-derived toxins. In addition, oxidative stress appears to mediate CKD progression and contributing factors like diet and cigarette smoking can exacerbate oxidative stress. Dietary changes and smoking cessation hold promise to favorably affect CKD progression by reducing kidney oxidative stress., Summary: The urgent need to add to the traditional armamentarium of blood pressure control and antiangiotensin II pharmacologic therapy for kidney protection has led to investigations into additional kidney-protective strategies. Acid stress, a disordered gut microbiome, and oxidative stress each appear to contribute to CKD progression and can be potentially addressed by nonpharmacologic and novel pharmacologic interventions.

The present study was conducted to evaluate the effects of dietary garcinol supplementation during late gestation (from the 90th day of pregnancy; day 90) and lactation on the acid-base balance of the umbilical cord blood and performance of sows and piglets. Sixty sows (Duroc × Yorkshire × Landrace; second- or third-parity; n = 20) were randomly divided into 3 gestation (day 90 of pregnancy) or lactation treatments, control diet (CON; basal diet), basal diet with 200 mg garcinol, and basal diet with 600 mg garcinol per kg of feed. The body weight (BW); backfat thickness and litter size of the sows; and birth weight, weaning weight, and mortality of piglets were recorded. Sows' blood and piglets' umbilical cord blood were collected for the measurements of hematological parameters and antioxidative and immune indexes, and acid-base balance parameters, respectively. The colostrum and milk and fecal samples of the sows were also collected for analysis of milk composition and apparent total tract nutrient digestibility. Garcinol had no effect on the BW and backfat thickness of the sows but significantly increased the birth weight and weaning weight of piglets (P < 0.05) and decreased the mortality (P < 0.05). Moreover, the white blood cell counts and neutrophil count, mean cell hemoglobin, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activity in the plasma of the sows were increased more significantly (P < 0.05) in the garcinol groups than that in the CON group, whereas the malondialdehyde (MDA) content was decreased (P < 0.05). The garcinol treatment significantly increased the pH, HCO3- and base excess values (P < 0.05), whereas it decreased the pCO2 and lactate content (P < 0.05) in the umbilical blood. Dry matter (DM), ash, and ether extract in the colostrum were similar between groups (P > 0.05), whereas the garcinol significantly increased the crude protein (CP) in the milk. In addition, the content of immunoglobulin A (IgA) and immunoglobulin G (IgG) in the plasma of piglets and in colostrum and milk of sows were increased more significantly (P < 0.05) in the garcinol groups than that in the CON group. The apparent total tract nutrient digestibility was similar between treatments. Collectively, this study indicates that sows fed with garcinol in late gestation and lactation showed improved maternal health and antioxidative status, milk protein content, acid-base balance in the umbilical cord blood, and growth performance in piglets, showing promise in natural plant extract nutrition for sows., (© The Author(s) 2019. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aquatic CO 2 tensions may exceed 30-60 Torr (ca. 30,000-79,000 μatm, respectively; hypercarbia) in some environments inducing severe acid-base challenges in fish. Typically, during exposure to hypercarbia blood pH (pH e ) is initially reduced and then compensated in association with an increase in plasma HCO 3 - in exchange for Cl - . Typically, intracellular pH (pH i ) is reduced and recovery is to some degree coupled to pH e recovery (coupled pH regulation). However, during acute hypercarbia, pH e recovery has been proposed to be limited by an "apparent upper bicarbonate threshold", restricting complete pH e recovery to below 15 Torr PCO 2 . At PCO 2 values beyond that which fish can compensate pH e , some fish are able to fully protect pH i despite large sustained reductions in pH e (preferential pH i regulation) and can tolerate PCO 2  > 45 Torr. This review discusses pH e and pH i regulation during exposure to hypercarbia starting with modeling the capacity and theoretical limit to pH e compensation in 19 studies. Next, we discuss how fish compensate severe acute hypercarbia exposures beyond the putative limit of pH e compensation using preferential pH i regulation which has recently been observed to be common among fish subjected to severe hypercarbia. Finally, we consider the evolution of pH regulatory strategies in vertebrates, including how the presence of preferential pH i regulation in embryonic reptiles may indicate that it is an embryonic trait that is either lost or retained in adult vertebrates and may have served as an exaptation for key evolutionary transitions during vertebrate evolution., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

In this era of global climate change, ocean acidification is becoming a serious threat to the marine ecosystem. Despite this, it remains almost unknown how fish will respond to the co-occurrence of ocean acidification with other conventional environmental perturbations typically salinity fluctuation and high ammonia threat. Therefore, the present work evaluated the interactive effects of elevated pCO 2 , salinity reduction and high environmental ammonia (HEA) on the ecophysiological performance of European sea bass (Dicentrarchus labrax). Fish were progressively acclimated to seawater (32 ppt), to brackish water (10 ppt) and to hyposaline water (2.5 ppt). Following acclimation to different salinities for at least two weeks, fish were exposed to CO 2 -induced water acidification representing present-day (control pCO 2 , 400 μatm, LoCO 2 ) and future (high pCO 2 , 1000 μatm, HiCO 2 ) sea-surface CO 2 level for 3, 7 and 21 days. At the end of each exposure period, fish were challenged with HEA for 6 h (1.18 mM representing 50% of 96 h LC 50 ). Results show that, in response to the individual HiCO 2 exposure, fish within each salinity compensated for blood acidosis. Fish subjected to HiCO 2 were able to maintain ammonia excretion rate (J amm ) within control levels, suggesting that HiCO 2 exposure alone had no impact on J amm at any of the salinities. For 32 and 10 ppt fish, up-regulated expression of Na + /K + -ATPase was evident in all exposure groups (HEA, HiCO 2 and HEA/HiCO 2 co-exposed), whereas Na + /K + /2Cl - co-transporter was up-regulated mainly in HiCO 2 group. Plasma glucose and lactate content were augmented in all exposure conditions for all salinity regimes. During HEA and HEA/HiCO 2 , J amm was inhibited at different time points for all salinities, which resulted in a significant build-up of ammonia in plasma and muscle. Branchial expressions of Rhesus glycoproteins (Rhcg isoforms and Rhbg) were upregulated in response to HiCO 2 as well as HEA at 10 ppt, with a more moderate response in 32 ppt groups. Overall, our findings denote that the adverse effect of single exposures of ocean acidification or HEA is exacerbated when present together, and suggests that fish are more vulnerable to these environmental threats at low salinities., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been reported to cause euglycemic diabetic ketoacidosis (eDKA), a diagnosis that may be challenging to establish in the emergency department (ED)., Case Report: This is a case report of missed eDKA in a 47-year-old male taking empagliflozin (a SGLT2 inhibitor) that presented to the ED with generalized weakness. His past medical history included multiple sclerosis (MS) diagnosed 4 years ago and type 2 diabetes mellitus. The patient attributed his weakness to MS. His neurologist was consulted and agreed with the plan to discharge the patient with diagnoses of asthenia and dehydration and a prescription of prednisone. The patient returned to the ED the next day with similar symptoms and was admitted to the hospital for treatment of eDKA. He was eventually treated per the hospital diabetic ketoacidosis (DKA) protocol and discharged home with instructions to discontinue empagliflozin. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The increasing utilization of SGLT2 inhibitor in patients with type 2 diabetes mellitus will inevitably lead to more cases of eDKA seen in the ED. Emergency physicians need to consider this diagnosis in patients taking these medications that present with symptoms including weakness, nausea, vomiting, abdominal pain, and dehydration. Patients taking these medications should be warned about these symptoms, especially because they may be falsely reassured by relatively low plasma glucose levels on home glucometer readings., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This study investigated the effects of two separate doses of sodium bicarbonate (NaHCO 3 ) on 4 km time trial (TT) cycling performance and post-exercise acid base balance recovery in hypoxia. Fourteen club-level cyclists completed four cycling TT's, followed by a 40 min passive recovery in normobaric hypoxic conditions (FiO 2  = 14.5%) following one of either: two doses of NaHCO 3 (0.2 g.kg -1 BM; SBC2, or 0.3 g.kg -1 BM; SBC3), a taste-matched placebo (0.07 g.kg -1 BM sodium chloride; PLA), or a control trial in a double-blind, randomized, repeated-measures and crossover design study. Compared to PLA, TT performance was improved following SBC2 (p = 0.04, g = 0.16, very likely beneficial), but was improved to a greater extent following SBC3 (p = 0.01, g = 0.24, very likely beneficial). Furthermore, a likely benefit of ingesting SBC3 over SBC2 was observed (p = 0.13, g =  0.10), although there was a large inter-individual variation. Both SBC treatments achieved full recovery within 40 min, which was not observed in either PLA or CON following the TT. In conclusion, NaHCO 3 improves 4 km TT performance and acid base balance recovery in acute moderate hypoxic conditions, however the optimal dose warrants an individual approach.

Background: Antagonists of the V1a vasopressin receptor (V1aR) are emerging as a strategy for slowing progression of CKD. Physiologically, V1aR signaling has been linked with acid-base homeostasis, but more detailed information is needed about renal V1aR distribution and function., Methods: We used a new anti-V1aR antibody and high-resolution microscopy to investigate Va1R distribution in rodent and human kidneys. To investigate whether V1aR activation promotes urinary H + secretion, we used a V1aR agonist or antagonist to evaluate V1aR function in vasopressin-deficient Brattleboro rats, bladder-catheterized mice, isolated collecting ducts, and cultured inner medullary collecting duct (IMCD) cells., Results: Localization of V1aR in rodent and human kidneys produced a basolateral signal in type A intercalated cells (A-ICs) and a perinuclear to subapical signal in type B intercalated cells of connecting tubules and collecting ducts. Treating vasopressin-deficient Brattleboro rats with a V1aR agonist decreased urinary pH and tripled net acid excretion; we observed a similar response in C57BL/6J mice. In contrast, V1aR antagonist did not affect urinary pH in normal or acid-loaded mice. In ex vivo settings, basolateral treatment of isolated perfused medullary collecting ducts with the V1aR agonist or vasopressin increased intracellular calcium levels in ICs and decreased luminal pH, suggesting V1aR-dependent calcium release and stimulation of proton-secreting proteins. Basolateral treatment of IMCD cells with the V1aR agonist increased apical abundance of vacuolar H + -ATPase in A-ICs., Conclusions: Our results show that activation of V1aR contributes to urinary acidification via H + secretion by A-ICs, which may have clinical implications for pharmacologic targeting of V1aR., (Copyright © 2019 by the American Society of Nephrology.)

In response to rapid alkali delivery during hemodialysis, hydrogen ions (H + ) are mobilized from body buffers and from stimulation of organic acid production in amounts sufficient to convert most of the delivered bicarbonate to CO 2 and water. Release of H + from nonbicarbonate buffers serves to back-titrate them to a more alkaline state, readying them to buffer acids that accumulate in the interval between treatments. By contrast, stimulation of organic acid production only serves to remove added bicarbonate (HCO 3 - ) from the body; the organic anions produced by this process are lost into the dialysate, irreversibly acidifying the patient as well as diverting metabolic activity from normal homeostasis. We have developed an analytic tool to quantify these acid-base events, which has shown that almost two-thirds of the H + mobilized during hemodialysis comes from organic acid production when bath bicarbonate concentration ([HCO 3 - ]) is 32 mEq/L or higher. Using data from the hemodialysis patients we studied with our analytical model, we have simulated the effect of changing bath solute on estimated organic acid production. Our simulations demonstrate that reducing bath [HCO 3 - ] should decrease organic acid production, a change we propose as beneficial to the patient. They also highlight the differential effects of variations in bath acetate concentration, as compared to [HCO 3 - ], on the amount and rate of alkali delivery. Our results suggest that transferring HCO 3 - delivery from direct influx to acetate influx and metabolism provides a more stable and predictable rate of HCO 3 - addition to the patient receiving bicarbonate-based hemodialysis. Our simulations provide the groundwork for the clinical studies needed to verify these conclusions., (© 2019 Wiley Periodicals, Inc.)

Bupivacaine, a drug used in obstetric anesthesia and analgesia, is commercially available as a racemic mixture of the R-bupivacaine and S-bupivacaine enantiomers, which show differences in pharmacokinetics, efficacy and toxicity. Changes in bupivacaine plasma protein binding is of clinical relevance considering its high protein binding (approximately 95%) and its classification as an intermediate hepatic extraction ratio drug (E = 0.38). Furthermore, the plasma protein binding of bupivacaine is also of clinical relevance considering that pregnancy is a physiological condition associated with reduced plasma albumin concentration. Also, different pathological conditions, such as pre-eclampsia, can reduce the maternal plasma protein concentrations and consequently increase the bupivacaine placental transfer. This report describes the development and validation of analytical methods for the sequential analysis of the total and unbound concentrations of bupivacaine enantiomers in human plasma using liquid chromatography coupled to mass spectrometry (LC-MS/MS) with a sensitivity compatible with application in pharmacokinetic studies including placental transfer. Aliquots of 200 μL of plasma or plasma ultra-filtrate were extracted with n-hexane in alkaline medium after the deproteinization of the matrix with acetonitrile and water. The separation of bupivacaine enantiomers was obtained on a Chirex® 3020 chiral stationary phase column using as a mobile phase a mixture of 95% n-hexane:ethanol (80:20, v/v) at a flow rate of 0.8 mL/min. The lower limit of quantification was 0.25 ng of each enantiomer/mL of plasma as the total concentration and 0.125 ng of each enantiomer/mL of plasma as the unbound concentration. The methods were applied to study the pharmacokinetics of bupivacaine enantiomers after the administration of 2.5 mg of 0.5% racemic bupivacaine hydrochloride with 1:200,000 epinephrine via the epidural route to an HIV-positive parturient woman undergoing antiretroviral treatment. The parturient showed lower AUC 0-∞ (25.42 vs. 30.57 ng.h/mL) and higher volume of distribution (841.96 vs 655.05 L) and total clearance (98.34 vs 81.79 L/h) for the R-bupivacaine enantiomer. The pharmacokinetics of bupivacaine were enantioselective displaying a lower plasma proportion of the enantiomer R-bupivacaine (AUC (R)/(S) ratio equal to 0.83). The placental transfer was approximately 60% for both bupivacaine enantiomers. The unbound fraction (Fu) for the R-bupivacaine enantiomer was higher (10.84%) than the eutomer S-bupivacaine (6.29%)., (Copyright © 2018. Published by Elsevier B.V.)

Aims: Cardiovascular (CV) complications are common in chronic kidney disease (CKD). Numerous metabolic disturbances including hyperphosphatemia, high circulating calciprotein particles (CPP), hyperparathyroidism, metabolic acidosis, and magnesium deficiency are associated with, and likely pathogenic for CV complications in CKD. The goal of this feasibility study was to determine whether effervescent calcium magnesium citrate (EffCaMgCit) ameliorates the aforementioned pathogenic intermediates., Methods: Nine patients with Stage 3 and nine patients with Stage 5D CKD underwent a randomized crossover study, where they took EffCaMgCit three times daily for 7 days in one phase, and a conventional phosphorus binder calcium acetate (CaAc) three times daily for 7 days in the other phase. Two-hour postprandial blood samples were obtained on the day before and on the 7th day of treatment., Results: In Stage 5D CKD, EffCaMgCit significantly increased T50 (half time for conversion of primary to secondary CPP) from baseline by 63% (P = 0.013), coincident with statistically non-significant declines in serum phosphorus by 25% and in saturation of octacalcium phosphate by 35%; CaAc did not change T50. In Stage 3 CKD, neither EffCaMgCit nor CaAc altered T50. With EffCaMgCit, a significant increase in plasma citrate was accompanied by statistically non-significant increase in serum Mg and phosphate. CaAc was without effect in any of these parameters in Stage 3 CKD. In both Stages 3 and 5D, both drugs significantly reduced serum parathyroid hormone. Only EffCaMgCit significantly increased serum bicarbonate by 3 mM (P = 0.015) in Stage 5D., Conclusions: In Stage 5D, EffCaMgCit inhibited formation of CPP, suppressed PTH, and conferred magnesium and alkali loads. These effects were unique, since they were not observed with CaAc. In Stage 3 CKD, neither of the regimens have any effect. These metabolic changes suggest that EffCaMgCit might be useful in protecting against cardiovascular complications of CKD by ameliorating pathobiologic intermediates.

Objectives: Propofol-based sedation may increase hemodynamic instability by decreasing vascular tone and venous return. Incremental exogenous catecholamines doses may be required to counteract such effects, aggravating the deleterious effects of sympathetic overstimulation. α-2 adrenergic agonists have been reported to decrease norepinephrine requirements in experimental septic shock. The aim of the present study is to test the hypothesis that switching from sedation with propofol to the α-2 agonist dexmedetomidine may decrease norepinephrine doses in septic shock., Design: Prospective open-label crossover study., Settings: University hospital, ICU., Patients: Thirty-eight septic shock patients requiring norepinephrine to maintain adequate mean arterial pressure and needing deep sedation with propofol and remifentanil to maintain a Richmond Agitation-Sedation Scale score between -3 and -4., Interventions: An initial set of measurements including hemodynamics, norepinephrine doses, and depth of sedation were obtained during sedation with propofol. Propofol was then replaced by dexmedetomidine and a second set of data was obtained after 4 hours of dexmedetomidine infusion. Sedation was switched back to propofol, and a final set of measurements was obtained after 8 hours. A Richmond Agitation-Sedation Scale score between -3 and -4 was maintained during the study period., Measurements and Main Results: Norepinephrine requirements decreased from 0.69 ± 0.72 μg/kg/min before dexmedetomidine to 0.30 ± 0.25 μg/kg/min 4 hours after dexmedetomidine infusion, increasing again to 0.42 ± 0.36 μg/kg/min while on propofol 8 hours after stopping dexmedetomidine (p < 0.005). Dexmedetomidine dosage was 0.7 ± 0.2 μg/kg/hr. Before and after dexmedetomidine infusion, sedative doses remained unchanged (propofol 2.6 ± 1.2 vs 2.6 ± 1.2 mg/kg/hr; p = 0.23 and remifentanil 1.27 ± 0.17 vs 1.27 ± 0.16 μg/kg/hr; p = 0.52, respectively). Richmond Agitation-Sedation Scale was -4 (-4 to -3) before, -4 (-4 to -3) during, and -4 (-4 to -4) after dexmedetomidine (p = 0.07)., Conclusions: For a comparable level of sedation, switching from propofol to dexmedetomidine resulted in a reduction of catecholamine requirements in septic shock patients.

Background: Regional citrate anticoagulation (RCA) is a widely used strategy for continuous renal replacement therapy (CRRT). Most of the current guidelines recommend liver failure as one of the contraindications for citrate anticoagulation. However, some studies suggested that the use of citrate for CRRT in liver failure patients did not increase the risk of citrate-related complications. The purpose of this systematic review is to summarize the current evidences on the safety and efficacy of RCA for CRRT in liver failure patients., Methods: We performed a comprehensive search on PubMed, Embase, and the Cochrane Library databases from the inception to March 1, 2018. Studies enrolled adult (age > 18 years) patients with various levels of liver dysfunction underwent RCA-CRRT were included in this systematic review., Results: After the study screening, 10 observational studies with 1241 liver dysfunction patients were included in this systematic review. The pooled rate of citrate accumulation and bleeding was 12% [3%, 22%] and 5% [2%, 8%], respectively. Compared with the baseline data, the serum pH, bicarbonate, and base excess (BE), the rate of metabolic alkalosis, the serum ionized calcium (ionCa) and total calcium (totCa) level, and the ratio of total calcium/ionized calcium (totCa/ionCa) significantly increased at the end of observation. However, no significant increase was observed in serum citrate (MD - 65.82 [- 194.19, 62.55]), lactate (MD 0.49 [- 0.27, 1.26]) and total bilirubin concentration (MD 0.79 [- 0.70, 2.29]) at the end of CRRT. Compared with non-liver failure patients, the live failure patients showed no significant difference in the pH (MD - 0.04 [- 0.13, 0.05]), serum lactate level (MD 0.69 [- 0.26, 1.64]), and totCa/ionCa ratio (MD 0.03 [- 0.12, 0.18]) during CRRT. The median of mean filter lifespan was 55.9 h, with a range from 22.7 to 72 h., Conclusions: Regional citrate anticoagulation seems to be a safe anticoagulation method in liver failure patients underwent CRRT and could yield a favorable filter lifespan. Closely monitoring the acid base status and electrolyte balance may be more necessary during RCA-CRRT in patients with liver failure.

Objectives: Optimal care of potential donors can lead to successful transplantation. Hemodynamic instability is a common complication in deceased potential donors. The most common underlying causes are hormonal and electrolyte disturbances as well as a hyperinflammatory state, which is rooted in activation of the cytokine cascade. In this study, our aim was to evaluate the efficacy of methylprednisolone injection, an agent introduced for inflammation suppression to achieve more stability in cases of hemodynamic disturbances., Materials and Methods: This study covered the period from April 2016 to June 2017 and included 45 randomly selected hemodynamically unstable brain-dead cases (mean arterial pressure < 60 mm Hg). For these cases, primary management included trying to achieve stability; however, after many hours, we experienced hemodynamic instability again. Because of no other correctable methods, we decided to use methylprednisolone injection. The potential deceased donors received a total of 1 g methylprednisolone in two 500-mg divided doses after transfer to the organ procurement unit., Results: Of 45 patients, 26 were male (58%), and the mean age of patients was 33 years. The most common causes of brain death were trauma (33%) and cerebrovascular accident (22%). Systolic and diastolic blood pressures increased significantly after methylprednisolone use. We observed no significant dif ferences in pulse rate. In addition, methylprednisolone could correct pH from 7.33 ± 0.11 to 7.38 ± 0.12 (P = .007)., Conclusions: Use of methylprednisolone in hemodynamically unstable deceased donors could allow better management of these cases. Because there are various factors such as infusion of vasopressor drugs or fluid therapy that could affect the hemodynamic status of these cases, future studies with larger sample sizes are recommended to control these confounding factors.

Purpose: The objective of this study was to fabricate PLA-based porous scaffold by 3D printing technology and to evaluate their cytotoxicity and biocompatibility under in vitro conditions in respect to bone tissue engineering., Material and Methods: Pure PLA in filamentous form was processed via 3D printing technology of fused filament fabrication into porous scaffolds. The structure and porosity of scaffolds were measured by metrotomography. PLA scaffolds were pre-treated by human serum, foetal bovine serum and complete cell culture medium to enhance bio-attractivity of the scaffold's surface for the adherence of the cells. Cells were enzymatically isolated from the periosteum of the proximal tibia and then expanded in monolayer. Periosteum-derived osteoprogenitors (PDOs) were seeded on the pre-treated PLA scaffolds and subsequent cell proliferation was measured by commercially available cell proliferation assay. Adherence of PDOs on the PLA scaffold was confirmed by scanning electron microscopy (SEM)., Results: Prepared scaffolds had well-defined structure and were characterized by uniform distribution of pores. They were non-toxic and biocompatible with PDOs, however, PLA scaffold with the periosteum-derived progenitor cells was significantly better in the group of scaffolds pre-treated with normal human serum., Conclusions: The obtained PLA porous scaffolds favored attachment of periosteum derived progenitors and proliferation, furthermore, cells penetrated into the scaffold through the interstitial pores which was meaningful for cytocompatibility evaluation.

Members of TRP receptor family are involved in response to acidification. Here, we determined the effect of capsaicin, one of the TRP receptor activators, on hemolymph acid-base status in the American cockroach. Periplaneta americana adult individuals were injected with lactic acid (5% or 10%) and exposed to 100 µM capsaicin solution. Hemolymph pH was measured 15 min, 1, 4, 8 and 24 h after lactic acid and capsaicin application with a glass microelectrode. The results demonstrated that cockroaches recover from acidosis within 4 h from acid injection. Capsaicin impaired the buffering capacity of insects' hemolymph, resulting in significant drop of hemolymph pH observed even 24 h after application. Joint action of capsaicin and acidosis reveals new insight into possible mechanism of capsaicin action on TRP receptors in insects.

Background: To compare the effects of intraoperative infusions of balanced electrolyte solution (BES)-based hydroxyethyl starch (HES) and saline-based albumin on metabolic acidosis and acid/base changes during major abdominal surgery conducted using Stewart's approach., Methods: Forty patients, aged 20-65 years, undergoing major abdominal surgery, were randomly assigned to the HES group (n = 20; received 500 ml of BES-based 6% HES 130/0.4) or the albumin group (n = 20; received 500 ml of normal saline-based 5% albumin). Acid-base parameters were measured and calculated using results obtained from arterial blood samples taken after anesthesia induction (T1), 2 hours after surgery commencement (T2), immediately after surgery (T3), and 1 hour after arriving at a postanesthetic care unit (T4)., Results: Arterial pH in the HES group was significantly higher than that in the albumin group at T3 (7.40 ± 0.04 vs. 7.38 ± 0.04, P = 0.043), and pH values exhibited significant intergroup difference over time (P = 0.002). Arterial pH was significantly lower at T3 and T4 in the HES group and at T2, T3, and T4 in the albumin group than at T1. Apparent strong ion difference (SIDa) was significantly lower at T2, T3, and T4 than at T1 in both groups. Total plasma weak nonvolatile acid (ATOT) was significantly lower in the HES group than in the albumin group at T2, T3 and T4 and exhibited a significant intergroup difference over time (P < 0.001)., Conclusions: BES-based 6% HES infusion was associated with lower arterial pH values at the end of surgery than saline-based 5% albumin infusion, but neither colloid caused clinically significant metabolic acidosis (defined as an arterial pH < 7.35).

In teleost fishes, renal contributions to acid-base and ammonia regulation are often neglected compared with the gills. In goldfish, increased renal acid excretion in response to feeding was indicated by increased urine ammonia and inorganic phosphate concentrations and decreased urine pH. By microdissecting the kidney tubules and performing quantitative real-time PCR and/or immunohistochemistry, we profiled the section-specific expression of glutamate dehydrogenase (GDH), glutamine synthetase (GS), Na + /H + -exchanger 3 (NHE3), carbonic anhydrase II (CAIIa), V-H + -ATPase subunit 1b, Cl - / HCO 3 - -exchanger 1 (AE1), Na + / HCO 3 - -cotransporter 1 (NBC1), Na + /K + -ATPase subunit 1α, and Rhesus-proteins Rhbg, Rhcg1a, and Rhcg1b. Here, we show for the first time that 1) the proximal tubule appears to be the major site for ammoniagenesis, 2) epithelial transporters are differentially expressed along the renal tubule, and 3) a potential feeding-related "acidic tide" results in the differential regulation of epithelial transporters, resembling the mammalian renal response to a metabolic acidosis. Specifically, GDH and NHE3 mRNAs were upregulated and GS downregulated in the proximal tubule upon feeding, suggesting this section as a major site for ammoniagenesis and acid secretion. The distal tubule may play a major role in renal ammonia secretion, with feeding-induced upregulation of mRNA and protein for apical NHE3, cytoplasmic CAIIa, universal Rhcg1a and apical Rhcg1b, and downregulation of basolateral Rhbg and AE1. Changes in mRNA expression of the Wolffian ducts and bladder suggest supporting roles in fine-tuning urine composition. The present study verifies an important renal contribution to acid-base balance and emphasizes that studies looking at the whole kidney may overlook key section-specific responses.

Methanol mass poisoning is a global problem with high fatality rates and often severe sequelae in survivors. Patients typically present late to the hospital with severe metabolic acidosis followed by a rapid deterioration in their clinical status. The hypothesis 'Circulus hypoxicus' describes the metabolic acidosis following methanol poisoning as a self-enhancing hypoxic circle responsible for methanol toxicity. We wanted to test the validity of this hypothesis by an observational study based on 35 patients from the methanol outbreaks in Norway (2004) and the Czech Republic (2012). Comprehensive laboratory values, including S(serum)-methanol, S-formate, S-lactate, arterial blood gases, anion and osmolal gaps, were used in the calculations. Laboratory values and calculated gaps were compared to each other using linear regression. S-lactate and S-formate correlated better with the increased base deficit and anion gap than did S-formate alone. Base deficit rose to about 20 mmol/L and S-formate rose to 12 mmol/L prior to a significant rise in S-lactate - most likely caused by formate inhibition of mitochondrial respiration (type B lactacidosis). The further rise in S-lactate was not linear to S-formate most likely due to the self-enhancing pathophysiology, but may also be associated with hypotension in critically ill patients and variable ethanol drinking habits. Our study suggests that the primary metabolic acidosis leads to a secondary lactic acidosis mainly due to the toxic effects of formate. The following decline in pH will further increase this toxicity. As such, a vicious and self-enhancing acidotic circle may explain the pathophysiology in methanol poisoning, namely the 'Circulus hypoxicus'., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Hydration is one of the most significant issues for combat sports as athletes often use water restriction for quick weight loss before competition. It appears that alkaline water can be an effective alternative to sodium bicarbonate in preventing the effects of exercise-induced metabolic acidosis. Therefore, the main aim of the present study was to investigate, in a double blind, placebo controlled randomized study, the impact of mineral-based highly alkaline water on acid-base balance, hydration status, and anaerobic capacity. Sixteen well trained combat sport athletes (n = 16), were randomly divided into two groups; the experimental group (EG; n = 8), which ingested highly alkaline water for three weeks, and the control group (CG; n = 8), which received regular table water. Anaerobic performance was evaluated by two double 30 s Wingate tests for lower and upper limbs, respectively, with a passive rest interval of 3 minutes between the bouts of exercise. Fingertip capillary blood samples for the assessment of lactate concentration were drawn at rest and during the 3rd min of recovery. In addition, acid-base equilibrium and electrolyte status were evaluated. Urine samples were evaluated for specific gravity and pH. The results indicate that drinking alkalized water enhances hydration, improves acid-base balance and anaerobic exercise performance., Competing Interests: The authors have declared that no competing interests exist.