Alcohol metabolite acetic acid activates BK channels in a pH-dependent manner and decreases calcium oscillations and exocytosis of secretory granules in rat pituitary GH3 cells.

Acetaldehyde and acetic acid/acetate, the active metabolites of alcohol (ethanol, EtOH), generate actions of their own ranging from behavioral, physiological, to pathological/cancerogenic effects. EtOH and acetaldehyde have been studied to some depth, whereas the effects of acetic acid have been less well explored. In this study, we investigated the effect of acetic acid on big conductance calcium-activated potassium (BK) channels present in GH3 rat pituitary tumor cells in more detail. In whole cell voltage clamp recordings, extracellular application of acetic acid increased total outward currents in a dose-dependent manner. This effect was prevented after the application of the specific BK channel blocker paxilline. Acetic acid action was pH-dependent-in whole cell current and single BK channel recordings, open probability (Po) was significantly increased by extracellular pH reduction and decreased by neutral or base pH. Acetic acid hyperpolarized the membrane potential, whereas acidic physiological solution had a depolarizing effect. Moreover, acetic acid reduced calcium (Ca2+) oscillations and exocytosis of growth hormone contained secretory granules from GH3 cells. These effects were partially prevented by BK inhibitors-tetraethylammonium or paxillin. In conclusion, our experiments indicate that acetic acid activates BK channels in GH3 cells which eventually contribute to acetic acid-induced membrane hyperpolarization, cessation of Ca2+ oscillations, and decrease of growth hormone release.

Effect of 0.9% NaCl compared to plasma-lyte on biomarkers of kidney injury, sodium excretion and tubular transport proteins in patients undergoing primary uncemented hip replacement - a randomized trial.

BACKGROUND: Isotonic saline (IS) is widely used to secure perioperative cardiovascular stability. However, the high amount of chloride in IS can induce hyperchloremic acidosis. Therefore, IS is suspected to increase the risk of acute kidney injury (AKI). Biomarkers may have potential as indicators. METHODS: In a double-blinded, placebo-controlled study, 38 patients undergoing primary uncemented hip replacement were randomized to IS or PlasmaLyte (PL). Infusion was given during surgery as 15 ml/kg the first hour and 5 ml/kg the following two hours. Urinary samples were collected upon admission and the day after surgery. As surgery was initiated, urine was collected over the course of 4 h. Hereafter, another urine collection proceeded until the morning. Urine was analyzed for markers of AKI neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Arterious and venous blood samples for measurements of pH and plasma electrolytes including chloride (p-Cl) were collected as surgery was initiated, at the end of surgery and the following morning. RESULTS: IS induced an increase in p-Cl (111 ± 2 mmol/L after IS and 108 ± 3 after PL, p = 0.004) and a decrease in pH (7.39 ± 0.02 after IS and 7.43 ± 0.03 after PL, p = 0.001). Urinary NGAL excretion increased in both groups (ΔNGAL: 5.5 [4.1; 11.7] µg/mmol creatinine p = 0.004 after IS vs. 5.5 [2.1;9.4] µg/mmol creatinine after PL, p < 0.001). No difference was found between the groups (p = 0.839). Similarly, urinary KIM-1 excretion increased in both groups (ΔKIM-1: IS 115.8 [74.1; 156.2] ng/mmol creatinine, p < 0.001 vs. PL 152.4 [120.1; 307.9] ng/mmol creatinine, p < 0.001). No difference between the groups (p = 0.064). FENa increased (1.08 ± 0.52% after IS and 1.66 ± 1.15% after PL, p = 0.032). ENaC excretion was different within groups (p = 0.019). CONCLUSION: A significantly higher plasma chloride and a lower pH was present in the group receiving isotonic saline. However, u-NGAL and u-KIM-1 increased significantly in both groups after surgery despite absence of changes in creatinine. These results indicate that surgery induced subclinical kidney injury. Also, the IS group had a delayed sodium excretion as compared to the PL group which may indicate that IS affects renal sodium excretion differently from PL. TRIAL REGISTRATION: ClinicalTrials.gov Identifier:  NCT02528448 , 19/08/2015.

Sodium acetate alleviated high-carbohydrate induced intestinal inflammation by suppressing MAPK and NF-κB signaling pathways in Nile tilapia (Oreochromis niloticus).

With the development of aquaculture industry, high-carbohydrate diet is used to stimulate protein-sparing effect and reduce feed cost. However, fish utilize carbohydrates poorly in general, and instead, high level of carbohydrates in the diet influence the growth condition of fish. How to alleviate the side effects of high carbohydrate diet on fish health has attracted more and more attentions. In the present study, Nile tilapia (Oreochromis niloticus) were fed with 25% and 45% of carbohydrate diet for eight weeks. Higher body weight but lower resistance to pathogen was found in 45% carbohydrate diet group. Higher expression level of inflammation cytokines, increased expression of total NF-κB protein and phosphorylated NF-κB protein (p-NF-κB) were detected in higher carbohydrate group. Concentration of short-chain fatty acids (SCFAs) was measured and the results indicated that high-carbohydrate diet decreased acetate content in the intestine. In order to detect the relationship between the decreased concentration of acetate and lower resistance to pathogen in high-carbohydrate group, 45% of carbohydrate diets (HC) supplemented with different concentrations of sodium acetate (HC + LA, 100 mmol/L; HC + MA, 200 mmol/L; HC + HA, 400 mmol/L) were used to raise Nile Tilapia for eight weeks. The results indicated that addition of 200 mmol/L sodium acetate (HC + MA) reduced the mortality when fish were challenged with Aeromonas hydrophila. Furthermore, we also found that addition of 200 mmol/L sodium acetate mainly inhibited p38 mitogen-activated protein kinase (p38MAPK) and NF-κB phosphorylation to decrease the expression level of inflammation cytokines (IL-8, IL-12, TNF-α and IL-1ß) in the intestine. The present study indicated that certain concentration of sodium acetate could alleviate high-carbohydrate induced intestinal inflammation mainly by suppressing MAPK activation and NF-κB phosphorylation.

Oral Methods of Urinary Alkalinization for High-dose Methotrexate Administration: Alternatives to Intravenous Sodium Bicarbonate During a Critical Drug Shortage.

A nationwide shortage of intravenous (IV) sodium bicarbonate required institutions to explore alternative options for urinary alkalinization for high-dose methotrexate (HDMTX). Children's Hospital Colorado implemented a protocol utilizing oral alkalinizing agents as alternatives to intravenous sodium bicarbonate during the shortage. The purpose of this study was to determine the safety and efficacy of oral alkalinization strategies for HDMTX administration. This retrospective study was conducted at a pediatric institution and evaluated cycles of HDMTX administered with at least one dose of oral sodium bicarbonate tablets or sodium citrate-citric acid oral solution. The time to achieve urine pH of ≥7 was 3.48 hours from the start of alkalinization. A median dose of 66.4 mEq/m/day of oral sodium bicarbonate was administered to maintain a urine pH of ≥7 until methotrexate was cleared. Gastrointestinal side effects occurred with 43% of HDMTX cycles and patients switched to IV sodium acetate in 25.5% of HDMTX cycles, primarily due to inadequate alkalinization or intolerance. During a shortage of IV sodium bicarbonate, oral alkalinization is an effective strategy for most patients to allow for administration of HDMTX.

Physico-chemical stability of Plasma-Lyte 148® and Plasma-Lyte 148® + 5% Glucose with eight common intravenous medications.

BACKGROUND: Plasma-Lyte 148® is a balanced, crystalloid intravenous (IV) fluid which is both calcium-free and isotonic. It prevents the hyperchloremic metabolic acidosis and iatrogenic hyponatremia seen with use of 0.9% sodium chloride and hypotonic solutions, respectively. However, data on compatibility with commonly used drugs are lacking. AIMS: To investigate the stability of Plasma-Lyte 148® and Plasma-Lyte 148® + 5% Glucose with eight commonly used therapeutic agents when compared with 5% glucose and 0.9% sodium chloride as diluents. We aimed to provide vital data which may facilitate the introduction of what appears to be a safer and more economic fluid. METHODS: Plasma-Lyte 148® and Plasma-Lyte 148® + 5% Glucose were mixed with morphine, midazolam, fentanyl, ketamine, clonidine, aminophylline, salbutamol, and furosemide at set concentrations. Comparisons were made to 0.9% sodium chloride and 5% glucose fluid controls. Six repeats of each IV fluid and drug admixture were analyzed through high-performance liquid chromatography at three time points: 0, 2, and 24 hours. A concentration change of <5% was defined as chemically stable. Physical stability was assessed by observation of precipitate formation or color change. pH changes were measured using a Fisherbrand Hydrus 300 pH meter. RESULTS: Relative to starting concentration, all drugs except midazolam were stable to ±3%. All examined therapeutic agents were chemically stable at 2 and 24 hours relative to control solutions. No precipitate formed in any of the samples. All Plasma-Lyte 148® and Plasma-Lyte 148® + 5% Glucose drug admixtures remained in a safe, peripheral administration pH range of 5-9 and were closer to the pH of blood than standard fluid-drug admixtures. CONCLUSION: Morphine, fentanyl, ketamine, salbutamol, aminophylline, and clonidine are stable for 24 hours when mixed with Plasma-Lyte 148® and Plasma-Lyte 148®+5% Glucose for administration at concentrations equivalent to those found at a typical Y-site with maintenance fluid. Furosemide is stable at lower concentrations than those seen at a Y-site, but midazolam displayed instability.

Chronically Elevated Levels of Short-Chain Fatty Acids Induce T Cell-Mediated Ureteritis and Hydronephrosis.

Short-chain fatty acids (SCFAs) are major products of gut microbial fermentation and profoundly affect host health and disease. SCFAs generate IL-10(+) regulatory T cells, which may promote immune tolerance. However, SCFAs can also induce Th1 and Th17 cells upon immunological challenges and, therefore, also have the potential to induce inflammatory responses. Because of the seemingly paradoxical SCFA activities in regulating T cells, we investigated, in depth, the impact of elevated SCFA levels on T cells and tissue inflammation in mice. Orally administered SCFAs induced effector (Th1 and Th17) and regulatory T cells in ureter and kidney tissues, and they induced T cell-mediated ureteritis, leading to kidney hydronephrosis (hereafter called acetate-induced renal disease, or C2RD). Kidney hydronephrosis in C2RD was caused by ureteral obstruction, which was, in turn, induced by SCFA-induced inflammation in the ureteropelvic junction and proximal ureter. Oral administration of all major SCFAs, such as acetate, propionate, and butyrate, induced the disease. We found that C2RD development is dependent on mammalian target of rapamycin activation, T cell-derived inflammatory cytokines such as IFN-γ and IL-17, and gut microbiota. Young or male animals were more susceptible than old or female animals, respectively. However, SCFA receptor (GPR41 or GPR43) deficiency did not affect C2RD development. Thus, SCFAs, when systemically administered at levels higher than physiological levels, cause dysregulated T cell responses and tissue inflammation in the renal system. The results provide insights into the immunological and pathological effects of chronically elevated SCFAs.

Effects of acetic acid or sodium acetate infused into the rumen or abomasum on feeding behavior and metabolic response of cows in the postpartum period.

Effects of continuous isomolar infusions of acetic acid (AcA) or sodium acetate (NAc) infused into the rumen (RU) or into the abomasum (AB) on feeding behavior, dry matter intake (DMI), and metabolic response of cows in the early postpartum period were evaluated. Six rumen-cannulated multiparous Holstein cows (11.8 ± 3.9 d in milk; mean ± SD) were utilized in a 6 × 6 Latin square design experiment balanced for carryover effects with a 2 × 3 factorial arrangement of treatments. Treatments were AcA and NAc, with sodium chloride (CON) as a control, infused at a rate of ˜0.75 mol/h (0.5 L/h) into the RU or AB for the first 8 h following feeding, with a rest day between infusion days. Treatment sequences were assigned randomly to cows. Feeding behavior was recorded by a computerized data acquisition system and blood was sampled at 0, 4, and 8 h relative to the start of infusion. We hypothesized that AcA is more hypophagic than NAc, and that infusion into the AB is more hypophagic than infusion into the RU. Dry matter intakes (DMI) for the CON treatments were similar at 6.2 kg/8 h for RU and 6.1 kg/8 h for AB, and the AcA and NAc treatments interacted with site of infusion to affect DMI. The NAc-RU treatment did not reduce DMI (7.0 kg/8 h), whereas AcA-RU (2.6 kg/8 h), AcA-AB (3.7 kg/8 h), and NAc-AB (4.0 kg/8 h) decreased DMI compared with CON. Following infusions of AcA compared with NAc, there was a residual effect on DMI for the remainder of the day, but treatments did not affect DMI during the rest day. Treatments increased plasma acetate and ß-hydroxybutyrate concentrations over time (interaction) and decreased plasma insulin concentration compared with CON. Plasma glucose concentration decreased over time after AcA-AB infusion compared with other treatments and CON. Plasma nonesterified fatty acid concentration increased over time for AcA compared with NAc and CON, suggesting an increase in lipolysis to compensate the decrease in DMI. In contrast to the other treatments, NAc-RU did not decrease DMI compared with control but we cannot determine the reason for this from the data available from the current study.

Sodium acetate inhibits Staphylococcus aureus internalization into bovine mammary epithelial cells by inhibiting NF-κB activation.

Bovine mastitis is one of the most costly and prevalent disease affecting dairy cows worldwide. It was reported that Staphylococcus aureus could internalize into bovine mammary epithelial cells (bMEC) and induce mastitis. Some short chain fatty acids (SCFA) have shown to suppress S. aureus invasion into bMEC and regulate antimicrobial peptides expression. But it has not been evaluated that sodium acetate has the similar effect. The aim of this study was to investigate the effect of sodium acetate on the invasion of bovine mammary epithelial cells (bMEC) by S. aureus. Gentamicin protection assay showed that the invasion of S. aureus into bMEC was inhibited by sodium acetate in a dose-dependent manner. Sodium acetate (0.25-5 mM) did not affect S. aureus growth and bMEC viability. The TAP gene level was decreased, while the BNBD5 mRNA level was enhanced in sodium acetate treated bMEC. In sodium acetate treated and S. aureus challenged bMEC, the TAP gene expression was increased and BNBD5 gene expression was not modified at low concentrations, but decreased at high concentrations. The Nitric oxide (NO) production of bMEC after S. aureus stimulation was decreased by sodium acetate treatment. Furthermore, sodium acetate treatment suppressed S. aureus-induced NF-κB activation in bMEC in a dose manner. In conclusion, our results suggested that sodium acetate exerts an inhibitory property on S. aureus internalization and modulates antimicrobial peptides gene expression.

Effect of 0.9% Saline or Plasma-Lyte 148 as Crystalloid Fluid Therapy in the Intensive Care Unit on Blood Product Use and Postoperative Bleeding After Cardiac Surgery.

OBJECTIVE: To evaluate the effect of Plasma-Lyte 148 (PL-148) compared with 0.9% saline (saline) on blood product use and postoperative bleeding in patients admitted to the intensive care unit (ICU) following cardiac surgery. DESIGN: A post hoc subgroup analysis conducted within a multicenter, double-blind, cluster-randomized, double-crossover study (study 1) and a prospective, single-center nested-cohort study (study 2). SETTING: Tertiary-care hospitals. PARTICIPANTS: Adults admitted to the ICU after cardiac surgery requiring crystalloid fluid therapy as part of the 0.9% saline vs. PL-148 for ICU fluid therapy (SPLIT) trial. INTERVENTIONS: Blinded saline or PL-148 for 4 alternating 7-week blocks. MEASUREMENTS AND MAIN RESULTS: 954 patients were included in study 1; 475 patients received PL-148, and 479 received saline. 128 of 475 patients (26.9%) in the PL-148 group received blood or a blood product compared with 94 of 479 patients (19.6%) in the saline group (OR [95% confidence interval], 1.51 [1.11-2.05]; p = 0.008). In study 2, 131 patients were allocated to PL-148 and 120 patients were allocated to saline. There were no differences between groups in chest drain output from the time of arrival in the ICU until 12 hours postoperatively (geometric mean, 566 mL for the PL-148 group v 547 mL in the saline group; p = 0.60). CONCLUSIONS: The findings did not support the hypothesis that using PL-148 for fluid therapy in ICU following cardiac surgery reduces transfusion requirements compared to saline. The significantly increased proportion of patients receiving blood or blood product with allocation to PL-148 compared to saline was unexpected and requires verification through further research.

In vivo monitoring of urea cycle activity with (13)C-acetate as a tracer of ureagenesis.

BACKGROUND: The hepatic urea cycle is the main metabolic pathway for detoxification of ammonia. Inborn errors of urea cycle function present with severe hyperammonemia and a high case fatality rate. Long-term prognosis depends on the residual activity of the defective enzyme. A reliable method to estimate urea cycle activity in-vivo does not exist yet. The aim of this study was to evaluate a practical method to quantify (13)C-urea production as a marker for urea cycle function in healthy subjects, patients with confirmed urea cycle defect (UCD) and asymptomatic carriers of UCD mutations. METHODS: (13)C-labeled sodium acetate was applied orally in a single dose to 47 subjects (10 healthy subjects, 28 symptomatic patients, 9 asymptomatic carriers). RESULTS: The oral (13)C-ureagenesis assay is a safe method. While healthy subjects and asymptomatic carriers did not differ with regards to kinetic variables for urea cycle flux, symptomatic patients had lower (13)C-plasma urea levels. Although the (13)C-ureagenesis assay revealed no significant differences between individual urea cycle enzyme defects, it reflected the heterogeneity between different clinical subgroups, including male neonatal onset ornithine carbamoyltransferase deficiency. Applying the (13)C-urea area under the curve can differentiate between severe from more mildly affected neonates. Late onset patients differ significantly from neonates, carriers and healthy subjects. CONCLUSION: This study evaluated the oral (13)C-ureagenesis assay as a sensitive in-vivo measure for ureagenesis capacity. The assay has the potential to become a reliable tool to differentiate UCD patient subgroups, follow changes in ureagenesis capacity and could be helpful in monitoring novel therapies of UCD.

A randomized-controlled trial of high- or low-volume intravenous Plasma-Lyte(®) to prevent hypotension during sedation for colonoscopy.

PURPOSE: The purpose of this study was to compare the incidence of hypotension during sedation in adults presenting for elective colonoscopy and randomized to intravenous Plasma-Lyte 148(®) at either 2 mL·kg(-1) (low volume) or 20 mL·kg(-1) (high volume). METHODS: Patients aged ≥ 18 yr presenting for elective colonoscopy, with or without gastroscopy, after oral bowel preparation were randomized to receive the intervention immediately before the start of the procedure. Hypotension was defined as a ≥ 25% decrease in systolic blood pressure (SBP) from baseline during the procedure. Secondary outcomes included SBP < 90 mmHg, lowest SBP during sedation, duration of hypotension, use of vasopressors, postoperative outcomes, and cost. RESULTS: Seventy-five patients were randomly allocated to either the low-volume or high-volume group, respectively (total n = 150). The incidence of hypotension was similar in the two groups (59% vs 56%, respectively; odds ratio, 0.90; 95% confidence interval, 0.47 to 1.71; P = 0.74). The incidence of SBP < 90 mmHg, the lowest SBP during sedation, the duration of hypotension, the use of vasopressors, and postoperative outcomes were also similar in the two groups. CONCLUSIONS: This study does not support the routine use of 20 mL·kg(-1) of intravenous Plasma-Lyte 148 to prevent hypotension and other complications during sedation for elective colonoscopy in adult patients. Clinical Trials Registry (ANZCTR 12615001288516).

Precursors of hexoneogenesis within the human mammary gland.

The human mammary gland is capable of de novo synthesis of glucose and galactose (hexoneogenesis); however, the carbon source is incompletely understood. In this study, we investigated the role of acetate, glutamine, lactate and glycerol as potential carbon sources for hexoneogenesis. Healthy breastfeeding women were studied following a 24-h fast on two occasions separated by 1-3 wk. Five women were infused with [U-¹³C]lactate or [1,2-¹³C2]glutamine and five women with [U-¹³C]glycerol or [1,2-¹³C2]acetate. Enrichments of ¹³C in plasma and milk substrates were analyzed using GC-MS. Infusion of labeled lactate, glycerol, glutamine, and acetate resulted in plasma glucose being 22.0±3.7, 11.2±1.0, 2.5±0.5, and 1.3±0.2% labeled, respectively. Lactate, glutamine, or acetate did not contribute to milk glucose or galactose (0-2%). In milk, ¹³C-free glycerol enrichment was one-fourth that in plasma but free glycerol concentration in milk was fourfold higher than in plasma. Using [U-¹³C]glycerol and by accounting for tracer dilution, glycerol alone contributed to 10±2 and 69±11% of the hexoneogenesis of milk glucose and galactose, respectively. During [U-¹³C]glycerol infusion, the ratio of M3 enrichment on 4-6 carbons/M3 on 1-3 carbons of galactose was higher (P<0.05, 1.22±0.05) than those of glucose in plasma (1.05±0.03) and milk (1.07±0.02). Reanalysis of samples from a previous study involving [U-¹³C]glucose infusion alone suggested labeling a portion of galactose consistent with pentose phosphate pathway (PPP) activity. We conclude that, although lactate contributed significantly to gluconeogenesis, glycerol alone provides the vast majority of substrate for hexoneogenesis. The relative contribution of the PPP vs. the reversal Embden-Meyerhof pathway to hexoneogenesis within the human mammary gland remains to be determined.

The effect of sodium acetate ingestion on the metabolic response to prolonged moderate-intensity exercise in humans.

At rest, administration of the short-chain fatty acid acetate suppresses fat oxidation without affecting carbohydrate utilization. The combined effect of increased acetate availability and exercise on substrate utilization is, however, unclear. With local ethics approval, we studied the effect of ingesting either sodium acetate (NaAc) or sodium bicarbonate (NaHCO3) at a dose of 4 mmol·kg-1 body mass 90 min before completing 120 min of exercise at 50% VO2peak. Six healthy young men completed the trials after an overnight fast and ingested the sodium salts in randomized order. As expected NaAc ingestion decreased resting fat oxidation (mean ± SD; 0.09 ± 0.02 vs. 0.07 ± 0.02 g·min-1 pre- and post-ingestion respectively, p < .05) with no effect upon carbohydrate utilization. In contrast, NaHCO3 ingestion had no effect on substrate utilization at rest. In response to exercise, fat and CHO oxidation increased in both trials, but fat oxidation was lower (0.16 ± 0.10 vs. 0.29 ± 0.11 g·min-1, p < .05) and carbohydrate oxidation higher (1.67 ± 0.35 vs. 1.44 ± 0.22 g·min-1, p < .05) in the NaAc trial compared with the NaHCO3 trial during the first 15 min of exercise. Over the final 75 min of exercise an increase in fat oxidation and decrease in carbohydrate oxidation was observed only in the NaAc trial. These results demonstrate that increasing plasma acetate concentration suppresses fat oxidation both at rest and at the onset of moderate-intensity exercise.

Galactomannan antigenemia after infusion of gluconate-containing Plasma-Lyte.

We demonstrated that sodium gluconate was the factor causing false-positive galactomannan (GM) antigenemia of Plasma-Lyte hydration solution. Infusion of sodium gluconate-containing solution but not gluconate-free Plasma-Lyte resulted in positive serum GM antigenemia. Serum GM concentrations also correlated with the volume and in vitro concentrations of GM within gluconate-containing solutions of infused Plasma-Lyte.

Continuous infusion of a standard combination solution in the management of hyperkalemia.

BACKGROUND: Hyperkalemia, due to its effect on cardiac conductivity, is a potentially life-threatening electrolyte abnormality. Multiple therapeutic agents may be used alone or in combination for its prompt management. METHODS: We report on the safety and efficacy of continuous infusion of a solution containing fixed concentrations of calcium gluconate, insulin, dextrose and sodium acetate (HyperK-Cocktail) for the treatment of hyperkalemia. This solution is prepared at our institution and is infused parenterally until the plasma potassium level stabilizes. Twenty-one consecutive hyperkalemic patients managed with HyperK-Cocktail on 23 occasions are reported. RESULTS: None of the subjects had intravenous extravasation injuries, hypernatremia, hypocalcemia, hypercalcemia or alkalosis during HyperK-Cocktail infusion. Transient hyperglycemia developed in nine subjects and hypoglycemia in one subject. The decrease in serum potassium was similar in the initial hour when compared to prior studies using a beta-agonist and/or insulin and glucose; a larger decrease was present from 2 to 8 h with the HyperK-Cocktail. The plasma potassium decreased by a mean of 1.0, 1.7, 2.1 and 2.1 mmol/L at 1, 2, 4 and 8 h, respectively. The mean serum potassium at hours 1-8 was significantly lower than the initial level. CONCLUSION: The results of our study demonstrated that HyperK-Cocktail is a safe and effective combination therapy for children with hyperkalemia.

Acute acetate administration increases endogenous opioid levels in the human brain: A [11C]carfentanil molecular imaging study.

INTRODUCTION: A recent study has shown that acetate administration leads to a fourfold increase in the transcription of proopiomelanocortin (POMC) mRNA in the hypothalamus. POMC is cleaved to peptides, including ß-endorphin, an endogenous opioid (EO) agonist that binds preferentially to the µ-opioid receptor (MOR). We hypothesised that an acetate challenge would increase the levels of EO in the human brain. We have previously demonstrated that increased EO release in the human brain can be detected using positron emission tomography (PET) with the selective MOR radioligand [11C]carfentanil. We used this approach to evaluate the effects of an acute acetate challenge on EO levels in the brain of healthy human volunteers. METHODS: Seven volunteers each completed a baseline [11C]carfentanil PET scan followed by an administration of sodium acetate before a second [11C]carfentanil PET scan. Dynamic PET data were acquired over 90 minutes, and corrected for attenuation, scatter and subject motion. Regional [11C] carfentanil BPND values were then calculated using the simplified reference tissue model (with the occipital grey matter as the reference region). Change in regional EO concentration was evaluated as the change in [11C]carfentanil BPND following acetate administration. RESULTS: Following sodium acetate administration, 2.5-6.5% reductions in [11C]carfentanil regional BPND were seen, with statistical significance reached in the cerebellum, temporal lobe, orbitofrontal cortex, striatum and thalamus. CONCLUSIONS: We have demonstrated that an acute acetate challenge has the potential to increase EO release in the human brain, providing a plausible mechanism of the central effects of acetate on appetite in humans.

The effects of 0.9% saline versus Plasma-Lyte 148 on renal function as assessed by creatinine concentration in patients undergoing major surgery: A single-centre double-blinded cluster crossover trial.

OBJECTIVES: Saline and Plasma-Lyte have different physiochemical contents; consequently, they may differently affect patients' renal function. We compared the effects of fluid therapy with 0.9% saline and with Plasma-Lyte 148 on renal function as assessed by creatinine concentration among patients undergoing major surgery. METHODS: We conducted a prospective, double-blinded cluster crossover trial comparing the effects of the two fluids on major surgery patients. The primary aim was to establish the pilot feasibility, safety and preliminary efficacy evidence base for a large interventional trial to establish whether saline or Plasma-Lyte is the preferred crystalloid fluid for managing major surgery patients. The primary efficacy outcome was the proportion of patients with changes in renal function as assessed by creatinine concentration during their index hospital admission. We used changes in creatinine to define acute kidney injury (AKI) according to the RIFLE criteria. RESULTS: The study was feasible with 100% patient and clinician acceptance. There were no deviations from the trial protocol. After screening, we allocated 602 patients to saline and 458 to Plasma-Lyte. The median (IQR) volume of intraoperative fluid received was 2000 mL (1000:2000) in both groups. Forty-nine saline patients (8.1%) and 49 Plasma-Lyte patients (10.7%) developed a postoperative AKI (adjusted incidence rate ratio [aIRR]: 1.34; 95% CI: 0.93-1.95; p = 0.120). No differences were observed in the development of postoperative complications (aIRR: 0.98; 95% CI: 0.89-1.08) or the severity of the worst complication (aIRR: 1.00; 95% CI: 0.78-1.30). The median (IQR) length of hospital stay was six days (3:11) for the saline group and five days (3:10) for the Plasma-Lyte group (aIRR: 0.85; 95% CI: 0.73-0.98). There were no serious adverse events relating to the trial fluids, nor were there fluid crossover or contamination events. CONCLUSIONS: The study design was feasible to support a future follow-up larger clinical trial. Patients treated with saline did not demonstrate an increased incidence of postoperative AKI (defined as changes in creatinine) compared to those treated with Plasma-Lyte. Our findings imply that clinicians can reasonably use either solution intraoperatively for adult patients undergoing major surgery. TRIAL REGISTRATION: Registry: Australian New Zealand Clinical Trials Registry; ACTRN12613001042730; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=364988.

Acute effects of intravenous and rectal acetate on glucagon-like peptide-1, peptide YY, ghrelin, adiponectin and tumour necrosis factor-alpha.

In animals, colonic infusion of SCFA does not affect glucagon-like peptide-1 (GLP-1) release whereas intravenous infusion does and SCFA may directly stimulate peptide YY (PYY) release. It is unknown whether SCFA and their route of administration affect human blood concentrations of GLP-1 and PYY. Our aim was to conduct a pilot study to determine the effects of intravenous and rectal acetate on blood concentrations of GLP-1, PYY, ghrelin, adiponectin and TNF-alpha in hyperinsulinaemic human subjects. Six hyperinsulinaemic female subjects were given 20 mmol sodium acetate intravenously, 60 mmol acetate rectally, or normal saline rectally or intravenously on four separate occasions in randomised order, with blood samples collected at 0, 10, 15, 30, 45 and 60 min. Change in plasma PYY was significantly higher after acetate and rectal infusions (9.69 and 13.78 pg/ml) compared with saline and intravenous (0.60 and - 3.1 pg/ml; P < 0.01), respectively. Change in plasma GLP-1 was increased by rectal and acetate infusions (0.25 and 0.23 mmol/l) v. intravenous and saline ( - 0.26 and - 0.19 mmol/l; P < 0.01). Acetate decreased TNF-alpha v. saline ( - 0.8 and 0.15 pg/ml; P < 0.05). Rectal infusions increased TNF-alpha and ghrelin (0.2 and 98.27 pg/ml) v. intravenous ( - 0.9 and - 40 pg/ml; P < 0.01). There was no effect of treatment on plasma adiponectin. These preliminary results suggest that acetate raises plasma PYY and GLP-1, and suppresses TNF-alpha. Also, distending the rectum increases PYY, GLP-1, TNF-alpha and ghrelin in hyperinsulinaemic females. Increasing colonic fermentation products, particularly acetate, could yield a new mechanism for modifying weight gain.

[Effect of sodium acetate Ringer injection on perioperative fluid therapy in children with cyanotic congenital heart disease].

OBJECTIVE: To evaluate the efficacy of volume therapy with sodium acetate Ringer solution during the perioperative period in children with cyanotic congenital heart disease (CHD). METHODS: The children who underwent elective surgery for cyanotic CHD admitted to Shanghai Children's Medical Center Affiliated to the Medical School of Shanghai Jiaotong University from September to December 2018 were divided into three groups according to random number table with the informed consent of their legal representatives. All of the children received volume therapy with infusion of sodium acetate Ringer solution intravenously upon anesthesia induction. The volume of infusion was calculated according to the "4-2-1" formula (group A, the rehydration volume was 4 mL×kg-1×h-1 for the first 10 kg body weight, 2 mL×kg-1×h-1 for the second 10 kg, and 1 mL×kg-1×h-1 for the third 10 kg and above), and the volume was increased by 50% or 100% in groups B and C, respectively. The intravenous infusion lasted for 30 minutes in all the three groups. Arterial blood gas analysis was performed before and 30 minutes after infusion to observe the acid-base status and electrolyte level. Pulse oxygen saturation (SpO2), heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) before and 10, 20, 30 minutes after infusion, central venous pressure (CVP) at 30 minutes after infusion were recorded, as well as adverse events occurred after infusion. RESULTS: Twenty-six children with cyanotic CHD, 17 male and 9 female, aged from 1 to 36 months, body weight 3.6 to 16.0 kg, and America Society of Anesthesiologists (ASA) level of III or IV, were enrolled in the study. The pH value in group B at 30 minutes after infusion was significantly higher than that before infusion (7.35±0.05 vs. 7.32±0.06, P < 0.05), while no significant changes were found before and after infusion in the other two groups. The hematocrits (Hct) after infusion in three groups were significantly lower than those before infusion (0.433±0.141 vs. 0.473±0.146 in group A, 0.324±0.054 vs. 0.372±0.063 in group B, 0.363±0.097 vs. 0.418±0.111 in group C, all P < 0.01), indicating that all the children in the three groups achieved effective hemodilution. However, there was no significant difference in blood gas analysis before and after infusion among the three groups. The level of blood lactic acid (Lac) in all CHD children was decreased from (1.33±0.63) mmol/L to (0.98±0.36) mmol/L after infusion of sodium acetate Ringer solution, the serum Ca2+ concentration was decreased from (1.22±0.06) mmol/L to (1.19±0.06) mmol/L, and the serum Cl- concentration was increased from (108.74±2.70) mmol/L to (109.77±2.54) mmol/L with the statistically significant differences (all P < 0.01). However, no significant difference was found in Lac or electrolyte levels before and after infusion among the three groups. There was no significant difference in vital signs before and after infusion among the three groups, but the period of infusion had an effect on SpO2 (F = 5.998, P < 0.01), HR (F = 34.279, P < 0.01) and SBP (F = 4.345, P < 0.05). HR in groups A and C were significantly lower than those before infusion, and SBP in group A was decreased gradually with the prolongation of infusion time. The CVP value at 30 minutes after infusion in group B was higher than that in group A. No adverse reactions such as rash or anaphylactic shock occurred after infusion of sodium acetate Ringer solution in all children. CONCLUSIONS: The perioperative volume therapy with sodium acetate Ringer solution in children with cyanotic CHD can effectively prevent the increase in Lac level and does not aggravate metabolic acidosis. The volume of infusion was well tolerated by all the children without disturbing the hemodynamic parameters.