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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: 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.)

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.

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.

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.

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.

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.)

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.)

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: 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.)

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.

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.

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.

Marine crabs inhabit shallow coastal/estuarine habitats particularly sensitive to climate change, and yet we know very little about the diversity of their responses to environmental change. We report the effects of a rarely studied, but increasingly prevalent, combination of environmental factors, that of near-future pCO 2 (~1000 µatm) and a physiologically relevant 20% reduction in salinity. We focused on two crab species with differing abilities to cope with natural salinity change, and revealed via physiological and molecular studies that salinity had an overriding effect on ion exchange in the osmoregulating shore crab, Carcinus maenas. This species was unaffected by elevated CO 2 , and was able to hyper-osmoregulate and maintain haemolymph pH homeostasis for at least one year. By contrast, the commercially important edible crab, Cancer pagurus, an osmoconformer, had limited ion-transporting capacities, which were unresponsive to dilute seawater. Elevated CO 2 disrupted haemolymph pH homeostasis, but there was some respite in dilute seawater due to a salinity-induced metabolic alkalosis (increase in HCO 3 - at constant pCO 2 ). Ultimately, Cancer pagurus was poorly equipped to compensate for change, and exposures were limited to 9 months. Failure to understand the full spectrum of species-related vulnerabilities could lead to erroneous predictions of the impacts of a changing marine climate.

Background: Transformer oil is used in oil-filled transformers for its insulating as well as coolant properties. Transformer oil ingestion for attempted suicide is seldom heard of. Our patient's case presented us with a major diagnostic as well as treatment challenge because we encountered such a case for the first time and were totally unaware of the fact that methanol might make up the main component of an aged transformer oil., Case Presentation: A 19-year-old Pakistani/Asian man was brought to our hospital with altered sensorium. He was found to have elevated anion gap acidosis, increased osmolal gap, and acute kidney injury. He had no evidence of rhabdomyolysis or hemolysis. Computed tomography of his head showed cerebral edema. He was resuscitated with intravenous fluids and bicarbonate. Three days later, he confessed taking transformer oil with suicidal intention. His clinical picture mimicked acute methanol intoxication. With an initial improvement in his neurological status, he started complaining of constant headache with episodes of agitation and delirium. His renal function continued worsening despite an adequate urine output. He showed a remarkable improvement in his neurological state after just one session of hemodialysis., Conclusions: There is evidence that aged transformer oil contains methanol, and a patient who consumes it can present with features mimicking acute methanol intoxication.

The experiments conducted on non-linear mature laboratory albino rats determined that under conditions of subacute cadmium-nitrate intoxication the indices of proteinuria and acid-regulating renal function depend on acetylation phenotype. Unlike rapid acetylators considerable increase of protein concentration in urine (192,8%, р<0,05) and standardized by glomerular filtration protein excretion (141,7%, р<0,05) are indicative of higher susceptibility of rats with slow acetylation type to nephrotoxic action of cadmium chloride and sodium nitrate. Lack of protein loss with urine and adaptive-compensative character of acid-regulating renal function changes directed to elimination of hydrogen ions excess from the body give evidence concerning less intensive damage of the nephron tubular portion in rats with rapid acetylation type, and at the same time do not exclude development of nephropathy. In order to confirm the significance of acetylation phenotype for assessment of susceptibility and degree of cadmium-nitrate damage of the kidneys the condition of other renal functions should be examined with analysis of biochemical criteria of nephrotoxicity, which is of an important practical value for the selection of appropriate pharmacotherapy.

The relationship involving acid-base imbalance, mineral metabolism and bone health status has previously been reported but the efficacy of the alkalizing supplementation in targeting acid overload and preventing bone loss has not yet been fully elucidated. In this randomized, double-blind, placebo-controlled study, the hypothesis that potassium citrate (K citrate) modifies bone turnover in women with postmenopausal osteopenia was tested. Three hundred and ten women were screened; 40 women met the inclusion criteria and were randomly assigned to the treatment or the placebo group. They were treated with K citrate (30 mEq day -1 ) or a placebo in addition to calcium carbonate (500 mg day -1 ) and vitamin D (400 IU day -1 ). At baseline and time points of 3 and 6 months, serum indicators of renal function, electrolytes, calciotropic hormones, serum bone turnover markers (BTMs), tartrate-resistant acid phosphatase 5b (TRACP5b), carboxy-terminal telopeptide of type I collagen (CTX), bone alkaline phosphatase (BAP), procollagen type 1 N terminal propeptide (PINP)), and urine pH, electrolytes, and citrate were measured. The follow-up was completed by 17/20 patients in the "K citrate" group and 18/20 patients in the "placebo" group. At baseline, 90% of the patients exhibited low potassium excretion in 24 h urine samples, and 85% of cases had at least one urine parameter associated with low-grade acidosis (low pH, low citrate excretion). After treatment, CTX and BAP decreased significantly in both groups, but subjects with evidence of low-grade acidosis gained significant benefits from the treatment compared to the placebo. In patients with low 24h-citrate excretion at baseline, a 30% mean decrease in BAP and CTX was observed at 6 months. A significant reduction was also evident when low citrate (BAP: -25%; CTX: -35%) and a low pH (BAP: -25%; CTX: -30%) were found in fasting-morning urine. In conclusion, our results suggested that K citrate supplementation improved the beneficial effects of calcium and vitamin D in osteopenic women with a documented potassium and citrate deficit, and a metabolic profile consistent with low-grade acidosis.

Metabolic acidosis is the most common acid-base disorder in septic patients and is associated with increased mortality. Previously, we demonstrated that sepsis induced by cecal ligation and puncture (CLP) impairs [Formula: see text] absorption in the medullary thick ascending limb (MTAL) by 1) decreasing the intrinsic [Formula: see text] absorptive capacity and 2) enhancing inhibition of [Formula: see text] absorption by LPS through upregulation of Toll-like receptor (TLR) 4 signaling. Both effects depend on ERK activation. Monophosphoryl lipid A (MPLA) is a detoxified TLR4 agonist that enhances innate antimicrobial immunity and improves survival following sepsis. Pretreatment of MTALs with MPLA in vitro prevents LPS inhibition of [Formula: see text] absorption. Here we examined whether pretreatment with MPLA would protect the MTAL against sepsis. Vehicle or MPLA was administered to mice 48 h before sham or CLP surgery, and MTALs were studied in vitro 18 h postsurgery. Pretreatment with MPLA prevented the effects of sepsis to decrease the basal [Formula: see text] absorption rate and enhance inhibition by LPS. These protective effects were mediated through MPLA stimulation of a Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β-(TRIF)-dependent phosphatidylinositol 3-kinase-Akt pathway that prevents sepsis- and LPS-induced ERK activation. The effects of MPLA to improve MTAL [Formula: see text] absorption were associated with marked improvement in plasma [Formula: see text] concentration, supporting a role for the kidneys in the pathogenesis of sepsis-induced metabolic acidosis. These studies support detoxified TLR4-based immunomodulators, such as MPLA, that enhance antimicrobial responses as a safe and effective approach to prevent or treat sepsis-induced renal tubule dysfunction and identify cell signaling pathways that can be targeted to preserve MTAL [Formula: see text] absorption and attenuate metabolic acidosis during sepsis.

A 52-year-old type 2 diabetic man previously on canagliflozin developed severe anion gap metabolic acidosis and markedly elevated beta-hydroxybutyrate on postoperative day (POD) 2 status post laparoscopic Roux-en-Y gastric bypass. An insulin drip and aggressive intravenous fluid repletion were initiated, and electrolytes were monitored and repleted. His anion gap closed, and he was discharged on POD 4. This euglycaemic diabetic ketoacidosis prolonged his hospital stay by 2 days., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Multiple environmental stressors may interact in complex ways to exceed or diminish the impacts of individual stressors. In the present study, the interactive effects of two ecologically relevant stressors [increased temperature and partial pressure of carbon dioxide (Pco 2 )] were assessed for freshwater mussels, a group of organisms that are among the most sensitive and rapidly declining worldwide. The individual and combined effects of elevated temperature (22°C-34°C) and Pco 2 (~230, 58,000 µatm) on juvenile Lampsilis siliquoidea were quantified over a 5- or 14-day period, during which physiological and whole animal responses were measured. Exposure to elevated temperature induced a series of physiological responses, including an increase in oxygen consumption rates following 5 days of exposure at 31°C and an increase in carbonic anhydrase ( ca) and heat shock protein 70 mRNA levels following 14 days of exposure at 28°C and 34°C, respectively. Treatment with elevated Pco 2 activated acid-base regulatory responses including increases in CA and Na + -K + -ATPase activity and a novel mechanism for acid-base regulation during Pco 2 exposure in freshwater mussels was proposed. Thermal and CO 2 stressors also interacted such that responses to the thermal stressor were diminished in mussels exposed to elevated Pco 2 , resulting in the greatest level of mortality. Additionally, larger mussels were more likely to survive treatment with elevated Pco 2 and/or temperature. Together, exposure to elevated Pco 2 may compromise the ability of juvenile freshwater mussels to respond to additional stressors, such as increased temperatures, highlighting the importance of considering not only the individual but also the interactive effects of multiple environmental stressors.

Background: Commercially available crystalloid solutions used for volume replacement do not exactly match the balance of electrolytes found in plasma. Large volume administration may lead to electrolyte imbalance and potential harm. We hypothesised that haemodilution using solutions containing different anions would result in diverse biochemical effects, particularly on acid-base status, and different outcomes., Methods: Anaesthetised, fluid-resuscitated, male Wistar rats underwent isovolaemic haemodilution by removal of 10% blood volume every 15 min, followed by replacement with one of three crystalloid solutions based on acetate, lactate, or chloride. Fluids were administered in a protocolised manner to achieve euvolaemia based on echocardiography-derived left ventrical volumetric measures. Removed blood was sampled for plasma ions, acid-base status, haemoglobin, and glucose. This cycle was repeated at 15-min intervals until death. The primary endpoint was change in plasma bicarbonate within each fluid group. Secondary endpoints included time to death and cardiac function., Results: During haemodilution, chloride-treated rats showed significantly greater decreases in plasma bicarbonate and strong ion difference levels compared with acetate- and lactate-treated rats. Time to death, total volume of fluid administered: chloride group 56 (3) ml, lactate group 62 (3) ml, and acetate group 65 (3) ml; haemodynamic and tissue oxygenation changes were, however, similar between groups., Conclusions: With progressive haemodilution, resuscitation with a chloride-based solution induced more acidosis compared with lactate- and acetate-based solutions, but outcomes were similar. No short-term impact was seen from hyperchloraemia in this model., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Greater H + retention in animal models of chronic kidney disease (CKD) mediates faster glomerular filtration rate (GFR) decline and dietary H + reduction slows eGFR decline in CKD patients with reduced eGFR and H + retention due to the high acid (H + ) diets of developed societies. We examined if H + retention in CKD is inversely associated with estimated GFR (eGFR) using cross-sectional and longitudinal analysis of individuals with CKD stage 1 (>90 ml·min - 1 ·1.73 m -2 ), CKD stage 2 (60-89 ml/min per 1.73 m 2 ), and CKD stage 3 (30-59 ml·min - 1 ·1.73 m -2 ) eGFR. H + retention was assessed using the difference between observed and expected plasma total CO 2 2 h after 0.5 meq/kg body wt oral NaHCO 3 . H + retention was higher in CKD 2 vs. CKD 1 ( P < 0.01) and in CKD 3 vs. CKD 2 ( P < 0.02) at baseline and 5 yr, and was higher in CKD 2 vs. CKD 1 ( P < 0.01) at 10 yr. All groups had lower eGFR at subsequent time points ( P < 0.01) but H + retention was not different among the three time points for CKD 1. By contrast, eGFR decrease was associated with higher H + retention in CKD 2 at 5 yr ( P = 0.04) and 10 yr ( P < 0.01) and with higher H + retention in CKD 3 at 5 yr ( P < 0.01). Yearly eGFR decline rate was faster in CKD 2 vs. CKD 1 ( P < 0.01) and in CKD 3 vs. CKD 2 ( P < 0.01). The data show that H + retention is inversely associated with eGFR, with faster eGFR decline, and support the need for greater dietary H + reduction therapy for CKD individuals with lower eGFR.

Modern Western diets, with higher contents of animal compared to fruits and vegetable products, have a greater content of acid precursors vs. base precursors, which results in a net acid load to the body. To prevent inexorable accumulation of acid in the body and progressively increasing degrees of metabolic acidosis, the body has multiple systems to buffer and titrate acid, including bone which contains large quantities of alkaline salts of calcium. Both in vitro and in vivo studies in animals and humans suggest that bone base helps neutralize part of the dietary net acid load. This raises the question of whether decades of eating a high acid diet might contribute to the loss of bone mass in osteoporosis. If this idea is true, then additional alkali ingestion in the form of net base-producing foods or alkalinizing salts could potentially prevent this acid-related loss of bone. Presently, data exists that support both the proponents as well as the opponents of this hypothesis. Recent literature reviews have tended to support either one side or the other. Assuming that the data cited by both sides is correct, we suggest a way to reconcile the discordant findings. This overview will first discuss dietary acids and bases and the idea of changes in acid balance with increasing age, then review the evidence for and against the usefulness of alkali therapy as a treatment for osteoporosis, and finally suggest a way of reconciling these two opposing points of view.

Background: Tricyclic antidepressants (TCAs) are a major cause of fatal drug poisoning due to their cardiotoxicity. Alkalinization by sodium bicarbonate (NaHCO3) administration, the first-line therapy for TCA-induced cardiotoxicity, can occasionally yield insufficient efficacy in severe cases. Because most TCAs are highly lipophilic, lipid emulsion may be more effective than alkalinization. However, it remains to be determined whether lipid emulsion is more beneficial than alkalinization in reversing amitriptyline-induced cardiotoxicity., Methods: Hemodynamic variables were recorded from in vivo guinea pig models and Langendorff-perfused hearts. Whole-cell patch-clamp experiments were conducted on enzymatically isolated ventricular cardiomyocytes to record fast sodium currents (INa). Lipid solutions were prepared using 20% Intralipid. The pH of the alkaline solution was set at 7.55. We assessed the effect of lipid emulsion on reversing amitriptyline-induced cardiotoxicity, in vivo and in vitro, compared to alkalinization. The data were evaluated by Student t test, 1-way repeated-measures analysis of variance, or analysis of covariance (covariate = amitriptyline concentration); we considered data statistically significant when P < .05., Results: In the in vivo model, intervention with lipids significantly reversed the amitriptyline-induced depression of mean arterial pressure and prolongation of QRS duration on electrocardiogram more than alkalinization (mean arterial pressure, mean difference [95% confidence interval]: 19.0 mm Hg [8.5-29.4]; QRS duration, mean difference [95% confidence interval] -12.0 milliseconds [-16.1 to -7.8]). In the Langendorff experiments, perfusion with 1% and 2% lipid solutions demonstrated significant recovery in left ventricular developed pressure (LVdevP), maximum change rate of increase of LVdevP (dP/dtmax) and rate-pressure product compared with alkaline solution (LVdevP [mm Hg], alkaline 57 ± 35, 1% lipid 94 ± 12, 2% lipid 110 ± 14; dP/dtmax [mm Hg/s], alkaline 748 ± 441, 1% lipid 1502 ± 334, 2% lipid 1753 ± 389; rate-pressure product [mm Hg·beats·minute], alkaline 11,214 ± 8272, 1% lipid 19,025 ± 8427, 2% lipid 25,261 ± 4803 with analysis of covariance). Furthermore, lipid solutions (0.5%-4%) resulted in greater recovery of hemodynamic parameters at 3 μM amitriptyline. Amitriptyline inhibited INa in a dose-dependent manner: the half-maximal inhibitory concentration (IC50) was 0.39 μM. The IC50 increased to 0.75 μM in the alkaline solution, 3.2 μM in 1% lipid solution, and 6.1 μM in 2% lipid solution. Furthermore, the lipid solution attenuated the use-dependent block of sodium channels by amitriptyline more than alkaline solution. On 30 consecutive pulses at 1 Hz, the current decreased to 50.1 ± 2.1, 60.3 ± 1.9, and 90.4% ± 1.8% in standard, alkaline, and 1% lipid solution, respectively. Even 0.5% lipid solution showed greater effects than the alkaline solution in all experiments., Conclusions: Lipid emulsion significantly suppressed amitriptyline-induced INa, inhibition, which was likely related to the marked improvement in hemodynamic status observed in vivo and in isolated perfused hearts. These results suggest the superiority of lipid emulsion as the first-line therapy for TCA-induced cardiotoxicity compared to alkalinization therapy.

Context: Elevated urine net acid excretion (NAE), indicative of subclinical metabolic acidosis, has been associated with higher bone turnover. Urine citrate, which is a common clinical measure, changes in response to acid-base status but its association with bone turnover is uncertain., Objective: We evaluated the association between change in urine citrate and change in bone turnover and calcium excretion., Design, Intervention, and Participants: A total of 233 healthy men and women ≥60 years old were randomly assigned to 1.0 mmol/kg/d potassium bicarbonate (KHCO3), 1.5 mmol/kg/d KHCO3, or placebo for 84 days., Outcome Measures: Urine citrate, NAE, N-telopeptide of collagen type-I (NTX), calcium excretion, and serum amino-terminal propeptide of type 1 procollagen (P1NP) were measured before and after intervention., Results: Urine citrate increased dose dependently after KHCO3 supplementation (P trend < 0.001). The urine citrate change was significantly inversely associated with P1NP change (P = 0.021) but not with change in NTX (P = 0.051) or calcium excretion (P = 0.652). The NAE change was positively associated with change in NTX and calcium excretion (P ≤ 0.003) but not with change in P1NP (P = 0.051). When the urine citrate change and NAE change were included in the same model, the urine citrate change was not associated with change in NTX, calcium excretion, or serum P1NP (P ≥ 0.086), whereas change in NAE remained associated with change in NTX and calcium excretion (P ≤ 0.003)., Conclusion: Urine citrate may not be a suitable alternative to NAE when assessing acid-base status in relation to bone turnover in older adults., (Copyright © 2017 Endocrine Society)

Background and Objectives: Metabolic acidosis is common in patients with CKD and has significant adverse effects on kidney, muscle, and bone. We tested the efficacy and safety of TRC101, a novel, sodium-free, nonabsorbed hydrochloric acid binder, to increase serum bicarbonate in patients with CKD and metabolic acidosis., Design, Setting, Participants, & Measurements: One hundred thirty-five patients were enrolled in this randomized, double-blind, placebo-controlled, multicenter, in-unit study (designated the TRCA-101 Study). Patients had a mean baseline eGFR of 35 ml/min per 1.73 m 2 , a mean baseline serum bicarbonate of 17.7 mEq/L, and comorbidities, including hypertension (93%), diabetes (70%), and heart failure (21%). Patients ate a controlled diet and were treated for 14 days with placebo or one of four TRC101 dosing regimens (1.5, 3, or 4.5 g twice daily or 6 g once daily). After treatment, patients were discharged and followed for 7-14 days., Results: All TRC101 treatment groups had a mean within-group increase in serum bicarbonate of ≥1.3 mEq/L ( P <0.001) within 72 hours of the first dose and a mean increase in serum bicarbonate of 3.2-3.9 mEq/L ( P <0.001) at the end of treatment compared with placebo, in which serum bicarbonate did not change. In the combined TRC101 treatment group, serum bicarbonate was normalized (22-29 mEq/L) at the end of treatment in 35% of patients and increased by ≥4 mEq/L in 39% of patients. After discontinuation of TRC101, serum bicarbonate decreased nearly to baseline levels within 2 weeks. All adverse events were mild or moderate, with gastrointestinal events most common. All patients completed the study., Conclusions: TRC101 safely and significantly increased the level of serum bicarbonate in patients with metabolic acidosis and CKD., (Copyright © 2018 by the American Society of Nephrology.)

Intravenous fluid therapy can alter plasma acid-base balance. The Stewart approach to acid-base balance is uniquely suited to identify and quantify the effects of the cationic and anionic constituents of crystalloid solutions on plasma pH. The plasma strong ion difference (SID) and weak acid concentrations are similar to those of the administered fluid, more so at higher administration rates and with larger volumes. A crystalloid's in vivo effects on plasma pH are described by 3 general rules: SID > [HCO3-] increases plasma pH (alkalosis); SID < [HCO3-] decreases plasma pH (alkalosis); and SID = [HCO3-] yields no change in plasma pH. The in vitro pH of commercially prepared crystalloid solutions has little to no effect on plasma pH because of their low titratable acidity. Appreciation of IV fluid composition and an understanding of basic physicochemical principles provide therapeutically valuable insights about how and why fluid therapy can produce and correct alterations of plasma acid-base equilibrium. The ideal balanced crystalloid should (1) contain species-specific concentrations of key electrolytes (Na + , Cl - , K + , Ca ++ , Mg ++ ), particularly Na + and Cl - ; (2) maintain or normalize acid-base balance (provide an appropriate SID); and (3) be isosmotic and isotonic (not induce inappropriate fluid shifts) with normal plasma., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: In mammals, homeostasis and survival are dependent on effective trans-membrane movement of ions and enzyme function, which are labile to extreme acid-base changes, but operate efficiently within a narrow regulated pH range. Research in patients demonstrating a pH shifts outside the narrow regulated range decreased the cardiac output and systemic vascular resistance and altered the oxygen binding to haemoglobin. These cardiopulmonary observations may be applicable to the risks associated with anaesthesia and performance of wildlife ungulates on game farms. The aim of this study was to compare blood pH changes over time in impala immobilised and anaesthetised with two different drug protocols (P-TMP - immobilisation: thiafentanil-medetomidine; maintenance: propofol-ketamine-medetomidine; P-EME - immobilisation: etorphine-medetomidine; maintenance: etorphine-ketamine-medetomidine). Additionally, we discuss the resultant blood pH using both the Henderson-Hasselbalch and the Stewart approaches. Two data collection time points were defined, Time1 before maintenance of general anaesthesia and Time 2 at end of maintenance of general anaesthesia. We hypothesise that blood pH would not be different between drug protocols and would not change over time., Results: Significant differences were detected over time but not between the two drug protocols. Overall, the blood pH decreased over time from 7.37 ± 0.04 to 7.31 ± 0.05 (p = 0.001). Overall, over time arterial partial pressure of carbon dioxide changed from 51.3 ± 7.5 mmHg to 72.6 ± 12.4 mmHg (p < 0.001); strong ion difference from 44.6 ± 2.4 mEq/L to 46.9 ± 3.1 mEq/L (p < 0.001); anion gap from 15.0 ± 3.1 mEq/L to 10.9 ± 2.2 mEq/L (p < 0.001); and total weak acids from 16.1 ± 1.2 mmol/L to 14.0 ± 1.1 mmol/L (p < 0.001). The bicarbonate changed from 29.6 ± 2.7 mEq/L to 36.0 ± 4.1 mEq/L (p < 0.001); and lactate changed from 2.9 ± 1.5 mEq/L to 0.3 ± 0.03 mEq/L (p < 0.001) over time., Conclusions: The profound increase in the partial pressure of carbon dioxide that worsened during the total intravenous anaesthesia in both protocols initiated a substantial metabolic compensatory response to prevent severe acidaemia. This compensation resulted in a clinically acceptable mild acidaemic state, which worsened over time but not between the protocols, in healthy impala. However, these important compensatory mechanisms require normal physiological function and therefore when immobilising ill or anorexic wild ungulates their acid-base status should be carefully assessed.

Introduction: The diagnosis of ethylene glycol intoxication can be challenging. Definitive testing for ethylene glycol is not readily available and clinical decisions are often based on clinical suspicion and the results of more readily available tests. One of these findings is hypocalcemia, presumable through complexation with the ethylene glycol metabolite oxalate., Methods: We performed a retrospective review of all patients admitted to a tertiary care hospital between 2005 and 2013 with laboratory confirmed ethylene glycol intoxication. Serum calcium on presentation was compared to blood gas pH on presentation as well as presentation serum bicarbonate., Results: We did not find any relationship between calcium and serum pH either by linear regression or when dichotomized by pH ≥ or <7.3. We did observe an inverse relationship between serum calcium and bicarbonate., Conclusions: Hypocalcemia is not commonly observed following ethylene glycol poisoning, even in acidotic patients.

Background: Major acid-base variations during dialysis and the imbalances in serum calcium levels intensified by them play a role in cardiovascular damage of hemodialysis patients. Early vascular walls modifications can be objectified by determining the pulse wave velocity (PWV) - a marker of vascular stiffness that is associated with increased risk of cardiovascular events. Material and methods: This was a prospective study conducted on 63 chronic hemodialysis patients with diuresis above 500 mL/ 24 hours and predialysis blood pressure below 160 mmHg (treatment controlled) randomized in two groups for 12 months - the study group receiving interdialitic oral sodium bicarbonate doses and control group, without oral sodium bicarbonate supplementation, but receiving higher bicarbonate prescriptions in dialysis. All the patients were monthly evaluated by biochemical tests (serum calcium, phosphate, iPTH, bicarbonate), the assessment of prescribed doses of phosphate binders being undergone. Two PWV determinations and chest X-ray exams for coronary calcifications were done - at the beginning and end of the study for every patient. Results: In the study group (n = 29), the mean age was 56.48 ± 12.78 years and the average duration of dialysis was 55.51 ± 34.53 months, the mean dialysis bicarbonate was 29.81 ± 1.41 mEq/ L and 27 of them (subgroup 0) had alkaline reserve (AR) 20-22 mEq/ L. The control group (n = 34) had a mean age of 57.35 ± 15.32 years and the mean dialysis duration 59.67 ± 34.79 months, with an average level of dialysis bicarbonate of 33 ± 2.2 mEq/ L necessary to maintain AR within guidelines. Depending on the mean AR obtained, this group was divided into three subgroups (subgroup 1, subgroup 2, and subgroup 3). There were statistically significant differences regarding the necessary of dialysis bicarbonate (p < 0.001), average serum calcium levels (p < 0.001) and serum phosphorus (p < 0.001), as well as PWV mean values and the number of vascular calcifications (p = 0.036) between the study and the control group. The average dose of phosphate binders was significantly higher in the study group (p = 0.01). At the end of the study, the serum iPTH average levels were decreased in the study group (p < 0.001) and significantly increased in the control group (p < 0.001). Conclusions: Avoiding large variations in serum bicarbonate levels is an important step in hemodialysis patients' management because wide acidosis-alkalosis variation can increase cardiovascular risks in terms of altering the vessel walls elasticity and favoring their calcifications. Abbreviations : GFR = glomerular filtration rate,PWV = pulse wave velocity, iPTH = intact parathyroid hormone,AR = alkaline reserve, BP = blood pressure,mEq = milliequivalents,L = liter.

Competing Interests: The authors declare that they have no conflicts of interest. Sources of Funding No funding was required for this toxicology observation.

Background: Citrate, the currently preferred anticoagulant for continuous veno-venous hemofiltration (CVVH), may influence acid-base equilibrium., Methods: The effect of 2 different citrate solutions on acid-base status was assessed according to the Stewart-Figge approach in two consecutive cohorts of critically ill adult patients. The first group received Prismocitrate 10/2 (PC10/2; 10 mmol citrate/L). The next group was treated with Prismocitrate 18/0 (PC18; 18 mmol citrate/L). Both groups received bicarbonate-buffered fluids in post-dilution., Results: At similar citrate flow, the metabolic acidosis present at baseline in both groups was significantly attenuated in PC18 patients but persisted in PC10/2 patients after 24 h of treatment (median pH 7,42 vs 7,28; p = 0.0001). Acidosis in the PC10/2 group was associated with a decreased strong ion difference and an increased strong ion gap (respectively 43 vs. 51 mmol/L and 17 vs. 12 mmol/L, PC10/2 vs. PC18; both p = 0.001). Chloride flow was higher in PC10/2 than in PC18 subjects (25.9 vs 14.3 mmol/L blood; p < 0.05)., Conclusion: Correction of acidosis was blunted in patients who received 10 mmol citrate/L as regional anticoagulation during CVVH. This could be explained by differences in chloride flow between the applied citrate solutions inducing hyperchloremic acidosis.

Sarafotoxins (SRTX) are endothelin-like peptides extracted from the venom of snakes belonging to the Atractaspididae family. A recent in vivo study on anesthetized and ventilated animals showed that sarafotoxin-b (SRTX-b), extracted from the venom of Atractaspis engaddensis, decreases cardiac output by inducing left ventricular dysfunction while sarafotoxin-m (SRTX-m), extracted from the venom of Atractaspis microlepidota microlepidota, induces right ventricular dysfunction with increased airway pressure. The aim of the present experimental study was to compare the respiratory effects of SRTX-m and SRTX-b. Male Wistar rats were anesthetized, tracheotomized and mechanically ventilated. They received either a 1 LD50 IV bolus of SRTX-b (n = 5) or 1 LD50 of SRTX-m (n = 5). The low-frequency forced oscillation technique was used to measure respiratory impedance. Airway resistance (Raw), parenchymal damping (G) and elastance (H) were determined from impedance data, before and 5 min after SRTX injection. SRTX-m and SRTX-b injections induced acute hypoxia and metabolic acidosis with an increased anion gap. Both toxins markedly increased Raw, G and H, but with a much greater effect of SRTX-b on H, which may have been due to pulmonary edema in addition to bronchoconstriction. Therefore, despite their structural analogy, these two toxins exert different effects on respiratory function. These results emphasize the role of the C-terminal extension in the in vivo effect of these toxins.

Background: Frequent causes of high anion gap metabolic acidosis are well known: ethanol, methanol, and ethylene glycol intoxication; hyperglycemia; lactic or D-lactic acidosis; and impaired renal function. There are other causes, less frequent but also important. This report illustrates a rare case of a patient with increased anion gap metabolic acidosis due to a deficit of the γ-glutamyl cycle that led to 5-oxoproline (acid pyroglutamic) accumulation., Case Presentation: An 82-year-old white woman was admitted to our intensive care unit because of septic shock caused by right knee methicillin-sensitive Staphylococcus aureus-induced arthritis. She was treated for 10 days with flucloxacillin and rifampicin and developed metabolic acidosis with high anion gap. Her test results for methanol, ethanol, ethylene glycol, and acetylsalicylic acid were negative. Her glycemia, lactate level, and renal function were normal. However, the result of a urinary assay for pyroglutamate was positive. We concluded that the patient had metabolic acidosis induced by accumulation of 5-oxoproline. We modified her antibiotic treatment, administered acetylcysteine, and her acidosis resolved., Conclusions: 5-Oxoprolinuria (pyroglutamic acid accumulation) is a rare, probably underdiagnosed cause of transient metabolic acidosis with increased anion gap.

Metabolic acidosis is a common complication of chronic kidney disease; it is typically caused by the accumulation of sulfate, phosphorus, and organic anions. Metabolic acidosis is correlated with several adverse outcomes, such as morbidity, hospitalization, and mortality. Thus, correction of metabolic acidosis is fundamental for the adequate management of many systemic complications of chronic kidney disease. In patients undergoing hemodialysis, acid-base homeostasis depends on many factors including the following: net acid production, amount of alkali given by the dialysate bath, duration of the interdialytic period, and residual diuresis, if any. Recent literature data suggest that the development of metabolic alkalosis after dialysis may contribute to adverse clinical outcomes. Our review is focused on the potential effects of different dialysate bicarbonate concentrations on hard outcomes such as mortality. Unfortunately, no randomized studies exist about this issue. Acid-base equilibrium is a complex and vital system whose regulation is impaired in chronic kidney disease. We await further studies to assess the extent to which acid-base status is a major determinant of overall survival in patients undergoing hemodialysis. For the present, the clinician should understand that target values for predialysis serum bicarbonate concentration have been established primarily based on observational studies and expert opinion. Based on this, we should keep the predialysis serum bicarbonate level at least at 22 mmol/l. Furthermore, a specific focus should be addressed by the attending nephrologist to the clinical and nutritional status of the major outliers on both the acid and alkaline sides of the curve., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Previous studies have shown that chronic oral deoxynivalenol (DON) exposure modulated Escherichia coli lipopolysaccharide (LPS)-induced systemic inflammation, whereby the liver was suspected to play an important role. Thus, a total of 41 barrows was fed one of two maize-based diets, either a DON-diet (4.59 mg DON/kg feed, n = 19) or a control diet (CON, n = 22). Pigs were equipped with indwelling catheters for pre- or post-hepatic (portal vs. jugular catheter) infusion of either control (0.9% NaCl) or LPS (7.5 µg/kg BW) for 1h and frequent blood sampling. This design yielded six groups: CON&#95;CONjugular‑CONportal, CON&#95;CONjugular‑LPSportal, CON&#95;LPSjugular‑CONportal, DON&#95;CONjugular‑CONportal, DON&#95;CONjugular‑LPSportal and DON&#95;LPSjugular‑CONportal. Blood samples were analyzed for blood gases, electrolytes, glucose, pH, lactate and red hemogram. The red hemogram and electrolytes were not affected by DON and LPS. DON-feeding solely decreased portal glucose uptake (p < 0.05). LPS-decreased partial oxygen pressure (pO₂) overall (p < 0.05), but reduced pCO₂ only in arterial blood, and DON had no effect on either. Irrespective of catheter localization, LPS decreased pH and base-excess (p < 0.01), but increased lactate and anion-gap (p < 0.01), indicating an emerging lactic acidosis. Lactic acidosis was more pronounced in the group DON&#95;LPSjugular-CONportal than in CON-fed counterparts (p < 0.05). DON-feeding aggravated the porcine acid-base balance in response to a subsequent immunostimulus dependent on its exposure site (pre- or post-hepatic).

Introduction: Regional citrate anticoagulation (RCA) for continuous renal replacement therapy is widely used in intensive care units (ICUs). However, concern exists about the safety of citrate in patients with liver failure (LF). The aim of this study was to evaluate safety and efficacy of RCA in ICU patients with varying degrees of impaired liver function., Methods: In a multicenter, prospective, observational study, 133 patients who were treated with RCA and continuous venovenous hemodialysis (RCA-CVVHD) were included. Endpoints for safety were severe acidosis or alkalosis (pH ≤7.2 or ≥7.55, respectively) and severe hypo- or hypercalcemia (ionized calcium ≤0.9 or ≥1.5 mmol/L, respectively) of any cause. The endpoint for efficacy was filter lifetime. For analysis, patients were stratified into three predefined liver function or LF groups according to their baseline serum bilirubin level (normal liver function ≤2 mg/dl, mild LF >2 to ≤7 mg/dl, severe LF >7 mg/dl)., Results: We included 48 patients with normal liver function, 43 with mild LF, and 42 with severe LF. LF was predominantly due to ischemia (39 %) or multiple organ dysfunction syndrome (27 %). The frequency of safety endpoints in the three patient strata did not differ: severe alkalosis (normal liver function 2 %, mild LF 0 %, severe LF 5 %; p = 0.41), severe acidosis (normal liver function 13 %, mild LF 16 %, severe LF 14 %; p = 0.95), severe hypocalcemia (normal liver function 8 %, mild LF 14 %, severe LF 12 %; p = 0.70), and severe hypercalcemia (0 % in all strata). Only three patients showed signs of impaired citrate metabolism. Overall filter patency was 49 % at 72 h. After censoring for stop of the treatment due to non-clotting causes, estimated 72-h filter survival was 96 %., Conclusions: RCA-CVVHD can be safely used in patients with LF. The technique yields excellent filter patency and thus can be recommended as first-line anticoagulation for the majority of ICU patients., Trial Registration: ISRCTN Registry identifier: ISRCTN92716512 . Date assigned: 4 December 2008.

Objectives: To study the effect of two intravenous maintenance fluids on plasma sodium (Na), and acid-base balance in pediatric intensive care patients during the first 24h of hospitalization., Methods: A prospective randomized controlled study was performed, which allocated 233 patients to groups: (A) NaCl 0.9% or (B) NaCl 0.45%. Patients were aged 1 day to 18 years, had normal electrolyte concentrations, and suffered an acute insult (medical/surgical)., Main Outcome Measured: change in plasma sodium. Parametric tests: t-tests, ANOVA, X(2) statistical significance level was set at α=0.05., Results: Group A (n=130): serum Na increased by 2.91 (±3.9)mmol/L at 24h (p<0.01); 2% patients had Na higher than 150 mmol/L. Mean urinary Na: 106.6 (±56.8)mmol/L. No change in pH at 0 and 24h. Group B (n=103): serum Na did not display statistically significant changes. Fifteen percent of the patients had Na<135 mmol/L at 24h. The two fluids had different effects on respiratory and post-operative situations., Conclusions: The use of saline 0.9% was associated with a lower incidence of electrolyte disturbances., (Copyright © 2015 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)