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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 sodium-glucose co-transporter-2 inhibitor dapagliflozin on estimated plasma volume in patients with type 2 diabetes.
Dekkers, CCJ, Sjöström, CD, Greasley, PJ, Cain, V, Boulton, DW, Heerspink, HJL
Diabetes, obesity & metabolism. 2019;(12):2667-2673
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Abstract
AIMS: To compare the effects of the sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin on estimated (ePV) and measured plasma volume (mPV) and to characterize the effects of dapagliflozin on ePV in a broad population of patients with type 2 diabetes. MATERIALS AND METHODS The Strauss formula was used to calculate changes in ePV. Change in plasma volume measured with 125 I-human serum albumin (mPV) was compared with change in ePV in 10 patients with type 2 diabetes randomized to dapagliflozin 10 mg/d or placebo. Subsequently, changes in ePV were measured in a pooled database of 13 phase 2b/3 placebo-controlled clinical trials involving 4533 patients with type 2 diabetes who were randomized to dapagliflozin 10 mg daily or matched placebo. RESULTS The median change in ePV was similar to the median change in mPV (-9.4% and -9.0%) during dapagliflozin treatment. In the pooled analysis of clinical trials, dapagliflozin decreased ePV by 9.6% (95% confidence interval 9.0 to 10.2) compared to placebo after 24 weeks. This effect was consistent in various patient subgroups, including subgroups with or without diuretic use or established cardiovascular disease. CONCLUSIONS ePV may be used as a proxy to assess changes in plasma volume during dapagliflozin treatment. Dapagliflozin consistently decreased ePV compared to placebo in a broad population of patients with type 2 diabetes.
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Transcapillary Refilling Rate and Its Determinants during Haemodialysis with Standard and High Ultrafiltration Rates.
Mitsides, N, Pietribiasi, M, Waniewski, J, Brenchley, P, Mitra, S
American journal of nephrology. 2019;(2):133-143
Abstract
BACKGROUND Achieving euvolaemia using ultrafiltration (UF) during haemodialysis (HD) without inducing haemodynamic instability presents a major clinical challenge. Transcapillary refill is a key factor in sustaining the circulating blood volume (BV) during UF, which is in turn predicted by the rate of refilling. However, absolute plasma refilling rate (PRR), its determinants and variability with UF rate (UFR), have not been reported in the literature. METHOD We studied paired HD sessions (n = 48) in 24 patients over 2 consecutive mid-week HD treatments. Plasma refilling was measured using real-time, minute-by-minute relative BV changes obtained from the integrated BV monitoring device during UF. A fixed bolus dilution approach at the start of HD was used to calculate absolute BV. The first control HD session was undertaken with a standard UFR required to achieve the prescribed target weight, while during the second study session, a fixed (high) UFR (1 L/h) was applied, either in the first (n = 12 patients) or in the final hour (n = 12 patients) of the HD session. Participants' had their hydration status measured pre- and post-HD using multifrequency bioimpedance (BIS). Blood pressure was measured at 15-min intervals and blood samples were collected at 7 intervals during HD sessions. RESULTS The mean PRR during a standard 4-hr HD session was 4.3 ± 2.0 mL/kg/h and varied between 2 and 6 mL/kg/h. There was a mean time delay of 22 min (range 13.3-35.0 min) for onset of plasma refilling after the application of UF irrespective of standard or high UFRs. The maximum refilling occurred during the second hour of HD (mean max PRR 6.8 mL/kg/h). UFR (beta = 0.60, p < 0.01) and BIS derived pre-HD overhydration index (beta = 0.44, p = 0.01) were consistent, independent predictors of the mean PRR (R2 = 0.49) in all HD sessions. At high UFRs, PRR exceeded 10 mL/kg/h. The total overall plasma refill contribution to UF volume was not significantly different between standard and high UF. During interventions no significant haemodynamic instability was observed in the study. CONCLUSION We describe absolute transcapillary refilling rate and its profile during HD with UF. The findings provide the basis for the development of UF strategies to match varying PRRs during HD. An approach to fluid removal, which is tailored to patients' refilling rates and capacity, provides an opportunity for more precision in the practice of UF.
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Effects of hypervolemia by protein and glucose supplementation during aerobic training on thermal and arterial pressure regulations in hypertensive older men.
Kataoka, Y, Kamijo, YI, Ogawa, Y, Sumiyoshi, E, Nakae, M, Ikegawa, S, Manabe, K, Morikawa, M, Nagata, M, Takasugi, S, et al
Journal of applied physiology (Bethesda, Md. : 1985). 2016;(4):1021-1031
Abstract
In Japan, the incidence of heat illness in older people has rapidly increased during midsummer in the last decade, and we suggested that whey-protein+carbohydrate supplementation during aerobic training would increased plasma volume (PV) to enhance thermoregulatory adaptation in older men (J Appl Physiol 107: 725-733, 2009); however, >60% of people age 65 and older suffer from hypertension, and the symptoms may be worsened by hypervolemia. To examine this, we randomly divided 21 older men (∼69 yr) with ∼160 mmHg for systolic and ∼90 mmHg for diastolic blood pressure at rest into two groups: Glc (n = 11) consuming glucose alone (25 g) and Pro-Glc (n = 10) consuming whey protein (10 g) + glucose (15 g), immediately after cycling exercise at 60-75% of peak aerobic capacity (V̇o2 peak) for 60 min/day, 3 days/wk, for 8 wk. Before and after training, we measured PV (dye dilution), baroreflex sensitivity (BRS) of heart rate (Valsalva maneuver), and carotid arterial compliance (CAC) from carotid arterial diameter (ultrasound imaging) responses to pulsatile arterial pressure change (photoplethysmography) at rest. Additionally, we measured esophageal temperature (Tes) and forearm skin blood flow (plethysmography) during exercise at 60% pretraining V̇o2 peak for 20 min in a warm environment. We found that the forearm skin vascular conductance response to increased Tes was enhanced in Pro-Glc with increased PV, but this was not found in Glc; however, despite the increased PV, arterial blood pressures rather decreased with increased CAC and BRS in Pro-Glc. Thus, the prescription was applicable to older men with hypertension to prevent heat illness during exercise.
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Oligonol supplementation modulates plasma volume and osmolality and sweating after heat load in humans.
Lee, J, Shin, Y, Murota, H
Journal of medicinal food. 2015;(5):578-83
Abstract
Oligonol is a low-molecular-weight polyphenol that possesses antioxidant and anti-inflammatory properties. This study investigated the effects of Oligonol supplementation on sweating response, plasma volume (PV), and osmolality (Osm) after heat load in human volunteers. We conducted a placebo-controlled crossover trial. Participants took a daily dose of 200 mg Oligonol or placebo for 1 week. After a 2-week washout period, the subjects were switched to the other study arm. As a heat load, half-body immersion into hot water (42°C±0.5°C for 30 min) was performed in an automated climate chamber. Tympanic and mean body temperature (Tty, mTb) and whole-body sweat loss volume (WBSLV) were measured. Changes in PV, Osm, and serum levels of aldosterone and sodium were analyzed. Oligonol intake attenuated increases in Tty, mTb, and WBSLV after heat load compared with the placebo (P<.01, P<.05, and P<.01, respectively). In addition, serum aldosterone was maintained at a relatively low degree and serum sodium was maintained at a relatively high degree with Oligonol compared to the placebo (P<.01 and P<.05, respectively). However, PV decreased and Osm increased significantly with Oligonol compared to the placebo (P<.05 and P<.05, respectively). This study demonstrates that Oligonol supplementation for 1 week can attenuate elevation of body temperature and excessive sweating under heat load in healthy humans, but interpretation of the results requires caution due to the potent diuretic effect of Oligonol.
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Diuretic response to colloid and crystalloid fluid loading in critically ill patients.
Smorenberg, A, Groeneveld, AB
Journal of nephrology. 2015;(1):89-95
Abstract
AIMS: In the critically ill patient, fluid loading is commonly done to stabilise hemodynamics and increase diuresis, whereas the absence of diuresis may predispose to harmful overloading. The goal of the current study was to evaluate the diuretic response and determinants thereof upon crystalloid and colloid fluid loading. SUBJECTS AND METHODS This is a substudy on 42 clinically hypovolemic, septic or non-septic patients without acute kidney injury, who were randomly assigned, after stratification for sepsis, to a 90-min fluid loading protocol with either 0.9% saline or a colloid solution (gelatin, hydroxyethyl starch 200/0.5 or albumin). Hemodynamics, biochemical parameters and diuresis were recorded. A response was defined by an increase in diuresis of >10% during fluid loading. RESULTS Diuresis increased more during saline than colloid infusion, together with a decline in colloid osmotic pressure (COP) of plasma and less increase in plasma volume and global hemodynamics with saline, at similar fluid balance. Nine patients (82%) receiving saline had a diuretic response, compared to 13 patients (42%) receiving colloids (P = 0.04), and the response was not predicted by underlying condition, global hemodynamics, volume of fluid infused and COP. CONCLUSION In critically ill patients with clinical hypovolemia, diuresis increases more during saline than colloid fluid loading, only partly dependent of a fall in plasma COP.
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Ingestion of sodium plus water improves cardiovascular function and performance during dehydrating cycling in the heat.
Hamouti, N, Fernández-Elías, VE, Ortega, JF, Mora-Rodriguez, R
Scandinavian journal of medicine & science in sports. 2014;(3):507-18
Abstract
We studied if salt and water ingestion alleviates the physiological strain caused by dehydrating exercise in the heat. Ten trained male cyclists (VO2max : 60 ± 7 mL/kg/min) completed three randomized trials in a hot-dry environment (33 °C, 30% rh, 2.5 m/s airflow). Ninety minutes before the exercise, participants ingested 10 mL of water/kg body mass either alone (CON trial) or with salt to result in concentrations of 82 or 164 mM Na(+) (ModNa(+) or HighNa(+) trial, respectively). Then, participants cycled at 63% of VO2 m a x for 120 min immediately followed by a time-trial. After 120 min of exercise, the reduction in plasma volume was lessened with ModNa(+) and HighNa(+) trials (-11.9 ± 2.1 and -9.8 ± 4.2%) in comparison with CON (-16.4 ± 3.2%; P < 0.05). However, heat accumulation or dissipation (forearm skin blood flow and sweat rate) were not improved by salt ingestion. In contrast, both salt trials maintained cardiac output (∼ 1.3 ± 1.4 L/min; P < 0.05) and stroke volume (∼ 10 ± 11 mL/beat; P < 0.05) above CON after 120 min of exercise. Furthermore, the salt trials equally improved time-trial performance by 7.4% above CON (∼ 289 ± 42 vs 269 ± 50 W, respectively; P < 0.05). Our data suggest that pre-exercise ingestion of salt plus water maintains higher plasma volume during dehydrating exercise in the heat without thermoregulatory effects. However, it maintains cardiovascular function and improves cycling performance.
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Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus.
Sha, S, Polidori, D, Heise, T, Natarajan, J, Farrell, K, Wang, SS, Sica, D, Rothenberg, P, Plum-Mörschel, L
Diabetes, obesity & metabolism. 2014;(11):1087-95
Abstract
AIM: To evaluate the effects of canagliflozin on plasma volume, urinary glucose excretion (UGE), fasting plasma glucose (FPG), glycated haemoglobin (HbA1c) and additional measures of fluid/electrolyte balance in patients with type 2 diabetes on background therapy with metformin and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. METHODS Patients (N = 36) were randomized (1:1) to receive canagliflozin 300 mg or placebo for 12 weeks. Pharmacodynamic parameters were assessed at baseline and at weeks 1 and 12. RESULTS Increased 24-h UGE was seen in the canagliflozin group compared with a reduction in the placebo group at both week 1 (91.8 vs. -2.4 g) and week 12 (82.6 vs. -0.4 g). Canagliflozin also reduced both FPG and HbA1c. Reductions in body weight and blood pressure were observed at weeks 1 and 12. Canagliflozin decreased plasma volume compared with an increase with placebo at week 1 (-5.4 vs. 4.3%; p = 0.02), but this was largely attenuated at week 12 (4.6 vs. 5.8%; p = 0.76). A modest numerical increase in urine volume was observed with canagliflozin at week 1 that was attenuated at week 12; other measures of volume status (i.e. blood urea nitrogen, serum creatinine and haematocrit) remained modestly increased with canagliflozin at week 12. CONCLUSION Canagliflozin provided sustained effects on UGE and FPG over 12 weeks and a transient reduction in plasma volume that was largely attenuated by week 12.
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The underestimated compression effect of neoprene wetsuit on divers hydromineral homeostasis.
Castagna, O, Blatteau, JE, Vallee, N, Schmid, B, Regnard, J
International journal of sports medicine. 2013;(12):1043-50
Abstract
This study aimed at demonstrating that the neoprene wetsuit provides not only thermal protection. Compression it exerts on the diver's shell significantly impacts hydromineral homeostasis by restraining the systemic vascular capacity and secondarily increasing urine output on dry land and during scuba diving. 8 healthy divers underwent five 2-h sessions: sitting out of water in trunks (control situation), sitting out of water wearing a wetsuit, and 3 wetsuit scuba-immersed sessions at 1, 6 and 12 msw depth, respectively. Urine volumes and blood samples were collected. Hemoglobin (Hb), hematocrit (Ht) and plasma sodium concentration were measured. Interface pressure between the garment and the skin was measured at 17 sites of the body shell, with a pressure transducer. Mean interface pressures between wetsuit and skin amounted to: 25.8±2.8 mm Hg. Whatever the depth, elastic recoil tension of wetsuit material was unchanged by immersion. Weight loss was respectively 2 and 3 times greater when wetsuit was worn out of water (430 g) and during immersion (710 g) than when divers did not wear any wetsuit out of water (235 g; p<0.05). Urine volume accounted for 85% of weight loss in either session. Weight loss and urine volume were similar whatever immersion depth. The decrease in plasma volume amounted to 8% of urine volume when divers did not wear any wetsuit out of water, and to 30% when wetsuit was worn out of water or during immersion. Diving wetsuit develops a pressure effect that alters diver's hydromineral homeostasis. During immersion, the wetsuit pressure merges into the larger main effect of hydrostatic pressure to reduce water content of body fluids, unrelated to immersion depth.
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Maternal nutritional status in early pregnancy is associated with body water and plasma volume changes in a pregnancy cohort in rural Bangladesh.
Gernand, AD, Christian, P, Schulze, KJ, Shaikh, S, Labrique, AB, Shamim, AA, West, KP
The Journal of nutrition. 2012;(6):1109-15
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Abstract
Plasma volume expansion has been associated with fetal growth. Our objective was to examine the associations between maternal nutritional status in early pregnancy and extracellular water (ECW), total body water (TBW), and percentage plasma volume change across pregnancy. In a subsample of 377 pregnant women participating in a cluster-randomized trial of micronutrient supplementation, hemoglobin, hematocrit, and multi-frequency bioelectrical impedance were measured at ~10, 20, and 32 wk of gestation. In early pregnancy, women were short (mean ± SD, 148.9 ± 5.3 cm) and thin (19.5 ± 2.5 kg/m(2)). In mixed-effects multiple regression models, a 1-unit higher BMI at ~10 wk was associated with higher ECW and TBW (0.27 and 0.66 kg per kg/m(2), respectively; P < 0.01) at ~10, ~20, and ~32 wk. Height was also positively associated with ECW and TBW at each time point. Early pregnancy BMI was negatively associated with gains in ECW and TBW (-0.06 and -0.14 kg per kg/m(2), respectively; P < 0.01) from 10 to 20 wk, but not with 20- to 32-wk gains after accounting for weight gain. BMI was positively associated with percentage changes in plasma volume from 20 to 32 wk (0.57% per kg/m(2); P < 0.05). Height was not associated with changes in body water or plasma volume. Women with low BMI and height in early pregnancy have lower ECW and TBW in early, mid, and late pregnancy and lower late pregnancy plasma volume expansion, potentially increasing risk of fetal growth restriction.