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Reduction of estimated fluid volumes following initiation of empagliflozin in patients with type 2 diabetes and cardiovascular disease: a secondary analysis of the placebo-controlled, randomized EMBLEM trial.
Tanaka, A, Shimabukuro, M, Teragawa, H, Okada, Y, Takamura, T, Taguchi, I, Toyoda, S, Tomiyama, H, Ueda, S, Higashi, Y, et al
Cardiovascular diabetology. 2021;(1):105
Abstract
BACKGROUNDS/AIM: Sodium glucose co-transporter 2 inhibitors promote osmotic/natriuretic diuresis and reduce excess fluid volume, and this improves cardiovascular outcomes, including hospitalization for heart failure. We sought to assess the effect of empagliflozin on estimated fluid volumes in patients with type 2 diabetes and cardiovascular disease (CVD). METHODS The study was a post-hoc analysis of the EMBLEM trial (UMIN000024502), an investigator-initiated, multi-center, placebo-controlled, double-blinded, randomized-controlled trial designed primarily to evaluate the effect of 24 weeks of empagliflozin treatment on vascular endothelial function in patients with type 2 diabetes and established CVD. The analysis compared serial changes between empagliflozin (10 mg once daily, n = 52) and placebo (n = 53) in estimated plasma volume (ePV), calculated by the Straus formula and estimated the extracellular volume (eEV), determined by the body surface area, measured at baseline and 4, 12, and 24 weeks after initiation of treatment. Correlations were examined between the changes from baseline to week 24 in each estimated fluid volume parameter and several clinical variables of interest, including N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration. RESULTS In an analysis using mixed-effects models for repeated measures, relative to placebo empagliflozin reduced ePV by - 2.23% (95% CI - 5.72 to 1.25) at week 4, - 8.07% (- 12.76 to - 3.37) at week 12, and - 5.60% (- 9.87 to - 1.32) at week 24; eEV by - 70.3 mL (95% CI - 136.8 to - 3.8) at week 4, - 135.9 mL (- 209.6 to - 62.3) at week 12, and - 144.4 mL (- 226.3 to - 62.4) at week 24. The effect of empagliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in log-transformed NT-proBNP was positively correlated with change in ePV (r = 0.351, p = 0.015), but not with change in eEV. CONCLUSIONS Our data demonstrated that initiation of empagliflozin treatment substantially reduced estimated fluid volume parameters in patients with type 2 diabetes and CVD, and that this effect was maintained for 24 weeks. Given the early beneficial effect of empagliflozin on cardiovascular outcomes seen in similar patient populations, our findings provide an important insight into the key mechanisms underlying the clinical benefit of the drug. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502.
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Effects of the Dual Endothelin Receptor Antagonist Aprocitentan on Body Weight and Fluid Homeostasis in Healthy Subjects on a High Sodium Diet.
Gueneau de Mussy, P, Sidharta, PN, Wuerzner, G, Maillard, MP, Guérard, N, Iglarz, M, Flamion, B, Dingemanse, J, Burnier, M
Clinical pharmacology and therapeutics. 2021;(3):746-753
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Abstract
Aprocitentan is a novel, oral, dual endothelin receptor antagonist (ERA) in development in difficult-to-control hypertension. As fluid retention and edema are concerns with ERAs, we investigated whether aprocitentan causes weight gain in healthy subjects on a high sodium diet and explored potential mechanisms if occurring. This double-blind, randomized, placebo-controlled, crossover study enrolled 28 subjects. Three doses of aprocitentan (10, 25, or 50 mg/day for 9 days) were compared with placebo. Increases in body weight were observed with aprocitentan (placebo-corrected mean weight gains [90% confidence interval]) of 0.43 [0.05-0.80], 0.77 [0.03-1.51], and 0.83 [0.33-1.32] kg at 10 mg, 25 mg, and 50 mg, respectively. Decreases in hemoglobin and uric acid were observed. Plasma volume increased at most by 5.5% without dose-response relationship. Urinary sodium excretion decreased at 10 mg and 25 mg but not at 50 mg. Therefore, aprocitentan produced moderate weight increases in healthy subjects on high sodium diet, without obvious sodium retention.
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Impact of Nuun Electrolyte Tablets on Fluid Balance in Active Men and Women.
Pence, J, Bloomer, RJ
Nutrients. 2020;(10)
Abstract
BACKGROUND Maintaining adequate hydration is important for overall health and has major implications for athletes involved in physically demanding tasks. While water is viewed as an effective means to rehydrate, and is inexpensive and readily available, electrolyte beverages appear to be more beneficial, in particular for athletes who routinely lose electrolytes through sweating. Nuun tablets contain a mix of electrolytes and are quickly dissolved in water to create an electrolyte-rich beverage. We determined the impact of Nuun tablets on the fluid balance of healthy, exercise-trained men and women at rest. METHODS Eight men (25.9 ± 4.5 yrs) and 10 women (28.2 ± 9.4 yrs) ingested either water only or water with Nuun electrolyte tablets, at both a single and double strength concentration, in random order, on three separate occasions separated by approximately one week, in a fasted and euhydrated state. A total of 1 liter of fluid was ingested at each visit over a 30 minute period. Urine was collected from each subject at 0, 1, 2, 3, and 4 hours post-ingestion. Urine mass values were used to calculate fluid balance and the beverage hydration index (BHI; i.e., the volume of urine produced after drinking the Nuun beverages, relative to that of water only-control condition). Heart rate and blood pressure were measured throughout the four-hour period, while body weight was measured at the start and end of the experiment. RESULTS Neither heart rate nor blood pressure were impacted by beverage consumption. Nuun tablets resulted in a lower urine output compared to water, with fluid balances for both concentrations more favorable compared to water (p < 0.05), beginning at 2 h post-ingestion and continuing at the 3 h and 4 h times. Body weight loss was less with Nuun at the single dose (0.38 kg; p = 0.02) and double dose (0.43 kg; p = 0.08), compared to water (0.57 kg). The BHI was higher for Nuun (single dose in particular) compared to water at both 2 h (p = 0.05) and 4 h (p = 0.02). CONCLUSION The addition of Nuun electrolyte tablets to water improves the fluid balance and BHI in healthy men and women. Results were similar for both concentrations, suggesting that additional electrolytes are not necessary when in a rested state. Future studies should determine the impact of various concentrations of the Nuun beverage during physical exercise-in particular, exercise in the heat, when sweat loss may be highest.
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Efficacy of Ingesting an Oral Rehydration Solution after Exercise on Fluid Balance and Endurance Performance.
Fan, PW, Burns, SF, Lee, JKW
Nutrients. 2020;(12)
Abstract
This study investigated the efficacy of ingesting an oral rehydration solution (DD) that has a high electrolyte concentration after exercise on fluid balance and cycling performance in comparison with a sports drink (SD) and water (WA). Nine healthy males aged 24 ± 2 years (mean ± SD), with peak oxygen uptake (VO2 peak) 55 ± 6 mL·kg-1·min-1 completed three experimental trials in a randomised manner ingesting WA, SD (carbohydrates: 62 g·L-1, sodium: 31 ± 3 mmol·L-1) or DD (carbohydrates: 33 g·L-1, sodium: 60 ± 3 mmol·L-1). On all trials, fluid was ingested during 75 min cycling at 65% VO2 peak (temperature: 30.4 ± 0.3 °C, relative humidity: 76 ± 1%, simulated wind speed: 8.0 ± 0.6 m·s-1) and during 2 h of recovery (temperature: 23.0 ± 1.0 °C, relative humidity: 67 ± 2%), with the total volume equivalent to 150% of sweat loss during the ride. A 45 min pre-load cycling time trial at a 65% VO2 peak followed by a 20 km time trial was conducted after a further 3 h of recovery. Fluid retention was higher with DD (30 ± 15%) than WA (-4 ± 19%; p < 0.001) and SD (10 ± 15%; p = 0.002). Mean ratings of palatability were similar among drinks (WA: 4.25 ± 2.60; SD: 5.61 ± 1.79; DD: 5.40 ± 1.58; p = 0.33). Although time trial performance was similar across all three trials (WA: 2365 ± 321 s; SD: 2252 ± 174 s; DD: 2268 ± 184 s; p = 0.65), the completion time was faster in eight participants with SD and seven participants with DD than with WA. Comparing SD with DD, completion time was reduced in five participants and increased in four participants. DD was more effective at restoring the fluid deficit during recovery from exercise than SD and WA without compromising the drink's palatability with increased sodium concentration. Most individuals demonstrated better endurance exercise time trial performance with DD and SD than with WA.
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Feasibility of Assessing Sodium-Associated Body Fluid Composition in End-Stage Renal Disease.
Clark-Cutaia, MN, Reisinger, N, Anache, MR, Ramos, K, Sommers, MS, Townsend, RR, Yu, G, Fargo, J
Nursing research. 2019;(3):246-252
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Abstract
BACKGROUND Cardiovascular disease accounts for more than half of all deaths in the hemodialysis (HD) population. Although much of this mortality is associated with fluid overload (FO), FO is difficult to measure, and many HD patients have significant pulmonary congestion despite the absence of clinical presentation. Cohort studies have observed that FO, as measured by bioimpedance spectroscopy (BIS), correlates with mortality. Other studies have observed that lower sodium intake is associated with less fluid-related weight gain, improved hypertension, and survival. Whether sodium intake influences FO in HD patients as measured by BIS is not known. OBJECTIVE The aims of the study were to determine the feasibility of assessing the impact of sodium restriction on body fluid composition as measured by BIS among patients with three levels of sodium intake and to determine if there are statistical and/or clinical differences in BIS measures across sodium intake groups. METHODS We used a double-blinded randomized controlled trial design with three levels of sodium restriction, 2,400 mg per day, 1,500 mg per day, and unrestricted (control group), to test our aims. Forty-two HD patients from a tertiary acute care academic institution associated with three urban DaVita dialysis centers were enrolled. Participants remained in the inpatient center for 5 days and 4 nights and were randomly assigned to sodium intake groups. Body fluid composition was measured with BIS. RESULTS Recruitment, enrollment, and retention statistics supported the feasibility of the study design. Regression analyses showed that there were no statistically significant differences among sodium intake groups on any of the outcomes. DISCUSSION Our data suggest the need for additional research into the effects of sodium restriction on body fluid composition.
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The Effect of Hypo-Hydration on Mood and Cognition Is Influenced by Electrolyte in a Drink and Its Colour: A Randomised Trial.
Cousins, AL, Young, HA, Thomas, AG, Benton, D
Nutrients. 2019;(9)
Abstract
Traditionally, it has been thought necessary to lose 2% of body mass due to dehydration to disrupt functioning, although recently, adverse effects have been reported, with a loss of 0.5%-0.7%. It is, however, unclear whether the response to small reductions in mass reflects dehydration as homeostatic mechanisms are thought to be effective. As psychological responses are most commonly reported, it is strange that the possibility of a placebo response has not been considered. Individuals were therefore subject to a temperature of 30 °C for three hours, and mood and cognition were monitored. To consider changes in hydration status, drinks were compared, differing in their ability to rehydrate due to the presence or absence of electrolytes. The possibility of a placebo response was considered by comparing the response to plain or coloured water. Not drinking was disruptive, although a combination of plain water and electrolyte tended to be the most effective means of preventing a decline in mood, indicating a role for rehydration after a loss of 0.66% body mass. There was, however, also evidence of a placebo response: a combination of plain water and electrolyte tended to be better able to prevent a decline in mood than coloured water and electrolyte.
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An iso-osmolar oral supplement increases natriuresis and does not increase stomal output in patients with an ileostomy: A randomised, double-blinded, active comparator, crossover intervention study.
Rud, C, Pedersen, AKN, Wilkens, TL, Borre, M, Andersen, JR, Moeller, HB, Dahlerup, JF, Hvas, CL
Clinical nutrition (Edinburgh, Scotland). 2019;(5):2079-2086
Abstract
BACKGROUND Patients with an ileostomy often experience fluid and electrolyte depletion because of gastrointestinal loss. This study aimed to compare how an iso-osmolar and a hyperosmolar oral supplement affect ileostomy output, urine production, and natriuresis as proxy measurements of water-electrolyte balance. METHODS In a randomised, double-blinded, active comparator, crossover intervention study, we included eight adult ileostomy patients who were independent of parenteral support. We investigated how an iso-osmolar (279 mOsm/kg) and a hyperosmolar (681 mOsm/kg) oral supplement affected ileostomy output mass, urine volume, and natriuresis. In addition to their habitual diet, each participant ingested 800 mL/day of either the iso-osmolar or hyperosmolar supplement in each of two study periods. Each period started with 24-hour baseline measurements, and the supplements were ingested during the following 48 h. All measurements were repeated in the last 24 h. RESULTS No statistically significant changes in ileostomy output were detected following the intake of either oral supplement (median (range) 67 (-728 to 290) g/day, p = 0.25) despite increased fluid intake. Compared with the hyperosmolar supplement, the iso-osmolar supplement induced a statistically significant increase in urine volume (470 (0-780) mL/day, p = 0.02) and natriuresis (36 (0-66) mmol/day, p = 0.02). CONCLUSION Intake of the two oral supplements did not affect ileostomy output during this short intervention. Natriuresis increased following intake of the iso-osmolar supplement compared to that after ingesting the hyperosmolar supplement, indicating that patients with an ileostomy may benefit from increasing their ingestion of iso-osmolar fluids. ClinicalTrials.gov identifier:NCT03348709.
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Hypertonic saline-hydroxyethyl starch solution attenuates fluid accumulation in cardiac surgery patients: a randomized controlled double-blind trial.
Järvelä, K, Rantanen, M, Kööbi, T, Huhtala, H, Sisto, T
Anaesthesiology intensive therapy. 2018;(2):122-127
Abstract
BACKGROUND Significant fluid retention is common after cardiac surgery with the use of cardiopulmonary bypass (CPB). The aim of the study was to evaluate the effects of hypertonic saline-hydroxyethyl starch (HS-HES) solution on fluid accumulation in patients undergoing coronary artery bypass grafting surgery (CABG). METHODS Fifty adult male patients undergoing coronary bypass surgery were enrolled in this interventional, randomized, double-blinded study to compare HS-HES with saline solution. The study fluid (250 mL) was given into the venous reservoir of the CPB circuit at the time of aortic declamping. RESULTS Body mass change from the baseline to the first postoperative morning was significantly less in the HS-HES group compared with the control group (3.3 ± 1.5 kg vs. 4.4 ± 1.5 kg, P = 0.022). In the extracellular water (ECW) or ECW-balance, there were no significant differences between the groups. The need for fluids and diuretic medication did not differ between the groups during the perioperative period. CONCLUSIONS Our study shows that 250 mL of HS-HES solution can reduce perioperative fluid accumulation to some degree in patients undergoing CABG surgery with CPB.
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Efficacy of Glucose or Amino Acid-Based Commercial Beverages in Meeting Oral Rehydration Therapy Goals After Acute Hypertonic and Isotonic Dehydration.
Cheuvront, SN, Kenefick, RW, Charkoudian, N, Mitchell, KM, Luippold, AJ, Bradbury, KE, Vidyasagar, S
JPEN. Journal of parenteral and enteral nutrition. 2018;(7):1185-1193
Abstract
BACKGROUND The efficacy of different commercial beverage compositions for meeting oral rehydration therapy (ORT) goals in the treatment of acute dehydration in healthy humans has not been systematically tested. The objective of the study was to compare fluid retention, plasma volume (PV), and interstitial fluid (ISF) volume restoration when using 1 popular glucose-based and 1 novel amino acid-based (AA) commercial ORT beverage following experimental hypertonic or isotonic dehydration. METHODS Twenty-six healthy adults (21 males, 5 females) underwent either a controlled bout of hypertonic (n = 13) or isotonic (n = 13) dehydration (3%-4% body mass) via eccrine or renal body water and electrolyte losses induced using exercise-heat stress (EHS) or Lasix administration (LAS), respectively. Rehydration was achieved over 90 minutes by matching fluid intake to water losses (1:1) using a sports drink (SP) or AA commercial ORT beverage. Fluid retention (water and electrolytes), PV, and ISF volume changes were tracked for 180 minutes. RESULTS AA produced significantly (P <0.05) greater fluid retention (75% vs 57%), ISF volume restoration, and tended (P = 0.06) to produce greater PV restoration in trial EHS. In trial LAS, neither beverage exceeded 65% retention, but AA replaced electrolytes and preserved ISF volume better than SP (P <0.05). CONCLUSION The results of this study demonstrate superior rehydration when using AA compared with SP for both hypertonic and isotonic dehydration.
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The effect of low-dose furosemide in critically ill patients with early acute kidney injury: A pilot randomized blinded controlled trial (the SPARK study).
Bagshaw, SM, Gibney, RTN, Kruger, P, Hassan, I, McAlister, FA, Bellomo, R
Journal of critical care. 2017;:138-146
Abstract
PURPOSE Furosemide is commonly prescribed in acute kidney injury (AKI). Prior studies have found conflicting findings on whether furosemide modifies the course and outcome of AKI. METHODS Pilot multi-center randomized blinded placebo-controlled trial in adult patients with AKI admitted to three intensive care units. Participants were randomly allocated to furosemide bolus and infusion or 0.9% saline placebo. Primary endpoint was worsening AKI, defined by the RIFLE criteria. Secondary endpoints were kidney recovery, renal replacement therapy (RRT) and adverse events. RESULTS The trial was terminated after enrollment of 73 participants (37 to furosemide and 36 to placebo). Mean (SD) age was 61.7 (14.3), 79.5% were medical admissions, mean (SD) APACHE II score was 26.6 (7.8), 90.4% received mechanical ventilation and 61.6% received vasoactives. Groups were similar at baseline. No differences were found in the proportion with worsening AKI (43.2% vs. 37.1%, p=0.6), kidney recovery (29.7% vs. 42.9%, p=0.3), or RRT (27.0% s. 28.6%, p=0.8). Adverse events, mostly electrolyte abnormalities, were more common in furosemide-treated patients (p<0.001). Protocol deviations were common, due often to supplementary furosemide. CONCLUSIONS In this pilot trial, furosemide did not reduce the rate of worsening AKI, improve recovery or reduce RRT; however, was associated with greater electrolyte abnormalities. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00978354 registered September 9, 2014.