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.

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.

Effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate in patients with heart failure (Empire HF Renal): a prespecified substudy of a double-blind, randomised, placebo-controlled trial.

BACKGROUND: SGLT2 inhibitors are a promising treatment option in patients with heart failure and reduced ejection fraction. We aimed to investigate the effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate (GFR) in patients with heart failure and reduced ejection fraction. METHODS: Empire HF Renal was a prespecified substudy of the investigator-initiated, double-blind, randomised, placebo-controlled Empire HF trial. The study was done at Herlev and Gentofte University Hospital (Herlev, Denmark), with patients recruited from four Danish heart failure outpatient clinics. Patients with New York Heart Association class I-III symptoms, with a left ventricular ejection fraction of 40% or lower, and on guideline-directed heart failure therapy were randomly assigned (1:1) to receive either oral empagliflozin 10 mg or matched placebo once daily for 12 weeks. The allocation sequence was computer-generated. Patients and study investigators were masked to treatment allocation. The coprimary prespecified renal outcomes were the between-group difference in the changes in estimated extracellular volume, estimated plasma volume, and measured GFR from baseline to 12 weeks. All analyses were done in the intention-to-treat population (apart from safety analyses, which were done in patients who received at least one dose of study drug), with no interim analyses done during the trial. The Empire HF trial is registered with ClinicalTrials.gov, NCT03198585, and EudraCT, 2017-001341-27. FINDINGS: Between June 29, 2017, and July 15, 2019, we assessed 391 patients for eligibility, of whom 120 (31%) were randomly assigned to empagliflozin or placebo, including 105 (88%) without diabetes. In intention-to-treat analyses, 60 (100%) patients in the empagliflozin group and 59 (98%) patients in the placebo group were included for estimated extracellular volume and estimated plasma volume, and 59 (98%) patients in the empagliflozin group and 58 (97%) patients in the placebo group were included for measured GFR. Empagliflozin treatment resulted in reductions in estimated extracellular volume (adjusted mean difference -0·12 L, 95% CI -0·18 to -0·05; p=0·00056), estimated plasma volume (-7·3%, -10·3 to -4·3; p<0·0001), and measured GFR (-7·5 mL/min, -11·2 to -3·8; p=0·00010) compared with placebo. Five (8%) of 60 patients in the empagliflozin group and three (5%) of 60 patients in the placebo group had one or more serious adverse events. INTERPRETATION: In patients with heart failure and reduced ejection fraction, empagliflozin reduced estimated extracellular volume, estimated plasma volume, and measured GFR after 12 weeks. Fluid volume changes might be an important mechanism underlying the beneficial clinical effects of SGLT2 inhibitors. FUNDING: Research Council at Herlev and Gentofte University Hospital, Research and Innovation Foundation of the Department of Cardiology at Herlev and Gentofte University Hospital, Capital Region of Denmark, Danish Heart Foundation, and AP Møller Foundation for the Advancement of Medical Science.

Plasma volume expansion and capillary leakage of 20% albumin in burned patients and volunteers.

BACKGROUND: Burn injury is associated with a long-standing inflammatory reaction. The use of albumin solutions for plasma volume support is controversial because of concerns of increased capillary leakage, which could aggravate the commonly seen interstitial oedema. METHODS: In the present open controlled clinical trial, an intravenous infusion of 20% albumin at 3 mL/kg was given over 30 min to 15 burn patients and 15 healthy volunteers. Blood samples and urine were collected for 5 h. Plasma dilution, plasma albumin and colloid osmotic pressure were compared. Mass balance calculations were used to estimate plasma volume expansion and capillary leakage of fluid and albumin. RESULTS: The patients were studied between 4 and 14 (median, 7) days after the burn injury, which spread over 7-48% (median, 15%) of the total body surface area. The albumin solution expanded the plasma volume by almost 15%, equivalent to twice the infused volume, in both groups. The urinary excretion exceeded the infused volume by a factor of 2.5. Capillary leakage of albumin occurred at a rate of 3.4 ± 1.5 g/h in burn patients and 3.7 ± 1.6 g/h in the volunteers (P = 0.61), which corresponded to 2.4 ± 1.0% and 2.5 ± 1.2% per hour of the intravascular pool (P = 0.85). The median half-life of the plasma volume expansion was 5.9 (25th-75th percentiles 2.7-11.7) h in the burn patients and 6.9 (3.4-8.5) h in the volunteers (P = 0.56). CONCLUSIONS: Albumin 20% was an effective volume expander in patients at 1 week post-burn. No relevant differences were found between burn patients and healthy volunteers. TRIAL REGISTRATION: EudraCT 2016-000996-26 on May 31, 2016.

Effects of anaesthesia-induced hypotension and phenylephrine on plasma volume expansion by hydroxyethyl starch: A randomised controlled study.

BACKGROUND: Changes in blood haemoglobin concentration indicate plasma volume expansion following hydroxyethyl starch (HES) infusion, but may be affected by vascular tone and HES-induced shedding of the endothelial surface layer (ESL). We hypothesised that anaesthesia-induced hypotension enhances changes in plasma volume as assessed by blood haemoglobin concentration (ΔPVHb , %) following HES infusion. METHODS: Fifty-two patients undergoing abdominal surgery were randomised to receive a continuous infusion of saline (S group) or phenylephrine to restore vascular tone (P group) (n = 26 each). Both groups received an infusion of 8 mL/kg 6% HES solution after induction of general anaesthesia. We compared ΔPVHb at the end of fluid infusion (15 minutes) and 15 minutes later (30 minutes) between the two groups. We assessed changes in ESL structure by measuring plasma concentrations of hyaluronate and syndecan-1. P < .05 was considered statistically significant. RESULTS: Mean arterial blood pressure was lower in the S group approximately by 30-40% compared to the P group (P < .001). ΔPVHb was larger in the S group compared to the P group at 15 minutes (24.9 [5.2] % vs 19.0 [5.2] %; P < .001) and 30 minutes (26.5 [5.9] % vs 16.9 [6.6] %; P < .001). There were no clinically significant differences in plasma concentrations of hyaluronate and syndecan-1 with time and between the groups. CONCLUSIONS: Increased volume expansion of circulating plasma following HES infusion in anaesthesia-induced hypotension compared to when blood pressure is restored by phenylephrine may result from an attenuation of transcapillary fluid filtration, rather than ESL shedding. UMIN Clinical Trial Registration Number: UMIN000017394 (http://www.umin.ac.jp/ctr/index.htm).

Effects of the sodium-glucose co-transporter-2 inhibitor dapagliflozin on estimated plasma volume in patients with type 2 diabetes.

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.

Effect of acute and chronic xenon inhalation on erythropoietin, hematological parameters, and athletic performance.

This study aimed to assess the efficacy of acute subanesthetic dosages of xenon inhalation to cause erythropoiesis and determine the effect of chronic xenon dosing on hematological parameters and athletic performance. To assess the acute effects, seven subjects breathed three subanesthetic concentrations of xenon: 30% fraction of inspired xenon (FiXe) for 20 min, 50% FiXe for 5 min, and 70% FiXe for 2 min. Erythropoietin (EPO) was measured at baseline, during, and after xenon inhalation. To determine the chronic effects, eight subjects breathed 70% FiXe for 2 min on 7 consecutive days, and EPO, total blood, and plasma volume were measured. Phase II involved assessment of 12 subjects for EPO, total blood volume, maximal oxygen uptake, and 3-km time before and after random assignment to 4 wk of xenon or sham gas inhalation. FiXe 50% and 70% stimulated an increase in EPO at 6 h [+2.3 mIU/mL; 95% confidence interval (CI) 0.1-4.5; P = 0.038] and at 192 h postinhalation (+2.9 mIU/mL; 95% CI 0.6-5.1; P = 0.017), respectively. Seven consecutive days of dosing significantly elevated plasma volume (+491 mL; 95% CI 194-789; P = 0.002). Phase II showed no significant effect on EPO, hemoglobin mass, plasma volume, maximal oxygen uptake, or 3-km time. Acute exposure to subanesthetic doses of xenon caused a consistent increase in EPO, and 7 consecutive days of xenon inhalation significantly expanded plasma volume. However, this physiological response appeared to be transient, and 4 wk of xenon inhalation did not stimulate increases in plasma volume or erythropoiesis, leaving cardiorespiratory fitness and athletic performance unchanged.NEW & NOTEWORTHY This is the first study to examine each element of the cascade by which xenon inhalation is purported to take effect, starting with measurement of the hypoxia-inducible factor effector, erythropoietin, to hemoglobin mass and blood volume and athletic performance. We found that acute exposure to xenon increased serum erythropoietin concentration, although major markers of erythropoiesis remained unchanged. While daily dosing significantly expanded plasma volume, no physiological or performance benefits were apparent following 4 wk of dosing.

Extracorporeal rewarming from experimental hypothermia: Effects of hydroxyethyl starch versus saline priming on fluid balance and blood flow distribution.

NEW FINDINGS: What is the central question of this study? Mortality in accidental hypothermia patients rewarmed by extracorporeal circulation remains high. Knowledge concerning optimal fluid additions for extracorporeal rewarming is lacking, with no apparent consensus. Does colloid versus crystalloid priming have different effects on fluid balance and blood flow distribution during extracorporeal rewarming? What is the main finding and its importance? In our rat model of extracorporeal rewarming from hypothermic cardiac arrest, hydroxyethyl starch generates less tissue oedema and increases circulating blood volume and organ blood flow, compared with saline. The composition of fluid additions appears to be important during extracorporeal rewarming from hypothermia. ABSTRACT: Rewarming by extracorporeal circulation (ECC) is the recommended treatment for accidental hypothermia patients with cardiac instability. Hypothermia, along with initiation of ECC, introduces major changes in fluid homeostasis and blood flow. Scientific data to recommend best practice use of ECC for rewarming these patients is lacking, and no current guidelines exist concerning the choice of priming fluid for the extracorporeal circuit. The primary aim of this study was to compare the effects of different fluid protocols on fluid balance and blood flow distribution during rewarming from deep hypothermic cardiac arrest. Sixteen anaesthetized rats were cooled to deep hypothermic cardiac arrest and rewarmed by ECC. During cooling, rats were equally randomized into two groups: an extracorporeal circuit primed with saline or primed with hydroxyethyl starch (HES). Calculations of plasma volume (PV), circulating blood volume (CBV), organ blood flow, total tissue water content, global O2 delivery and consumption were made. During and after rewarming, the pump flow rate, mean arterial pressure, PV and CBV were significantly higher in HES-treated compared with saline-treated rats. After rewarming, the HES group had significantly increased global O2 delivery and blood flow to the brain and kidneys compared with the saline group. Rats in the saline group demonstrated a significantly higher total tissue water content in the kidneys, skeletal muscle and lung. Compared with crystalloid priming, the use of an iso-oncotic colloid prime generates less tissue oedema and increases PV, CBV and organ blood flow during ECC rewarming. The composition of fluid additions appears to be an important factor during ECC rewarming from hypothermia.

Albumin infusion rate and plasma volume expansion: a randomized clinical trial in postoperative patients after major surgery.

BACKGROUND: Optimal infusion rate of colloids in patients with suspected hypovolemia is unknown, and the primary objective of the present study was to test if plasma volume expansion by 5% albumin is greater if fluid is administered slowly rather than rapidly. METHODS: Patients with signs of hypoperfusion after major abdominal surgery were randomized to intravenous infusion of 5% albumin at a dose of 10 ml/kg (ideal body weight) either rapidly (30 min) or slowly (180 min). Plasma volume was measured using radiolabeled albumin at baseline, at 30 min, and at 180 min after the start of infusion. Primary outcome was change in plasma volume from the start of infusion to 180 min after the start of infusion. Secondary outcomes included the change in the area under the plasma volume curve and transcapillary escape rate (TER) for albumin from 180 to 240 min after the start of albumin infusion. RESULTS: A total of 33 and 31 patients were included in the analysis in the slow and rapid groups, respectively. The change in plasma volume from the start of infusion to 180 min did not differ between the slow and rapid infusion groups (7.4 ± 2.6 vs. 6.5 ± 4.1 ml/kg; absolute difference, 0.9 ml/kg [95%CI, - 0.8 to 2.6], P = 0.301). Change in the area under the plasma volume curve was smaller in the slow than in the rapid infusion group and was 866 ± 341 and 1226 ± 419 min ml/kg, respectively, P < 0.001. TER for albumin did not differ and was 5.3 ± 3.1%/h and 5.4 ± 3%/h in the slow and in the rapid infusion groups, respectively, P = 0.931. CONCLUSIONS: This study does not support our hypothesis that a slow infusion of colloid results in a greater plasma volume expansion than a rapid infusion. Instead, our result of a smaller change in the area under the plasma volume curve indicates that a slow infusion results in a less efficient plasma volume expansion, but further studies are required to confirm this finding. A rapid infusion has no effect on vascular leak as measured after completion of the infusion. TRIAL REGISTRATION: EudraCT2013-004446-42 registered December 23, 2014.

Endothelial Cell-Targeted Deletion of PPARγ Blocks Rosiglitazone-Induced Plasma Volume Expansion and Vascular Remodeling in Adipose Tissue.

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor γ (PPARγ) agonists that represent an effective class of insulin-sensitizing agents; however, clinical use is associated with weight gain and peripheral edema. To elucidate the role of PPARγ expression in endothelial cells (ECs) in these side effects, EC-targeted PPARγ knockout (Pparg ΔEC) mice were placed on a high-fat diet to promote PPARγ agonist-induced plasma volume expansion, and then treated with the TZD rosiglitazone. Compared with Pparg-floxed wild-type control (Pparg f/f) mice, Pparg ΔEC treated with rosiglitazone are resistant to an increase in extracellular fluid, water content in epididymal and inguinal white adipose tissue, and plasma volume expansion. Interestingly, histologic assessment confirmed significant rosiglitazone-mediated capillary dilation within white adipose tissue of Pparg f/f mice, but not Pparg ΔEC mice. Analysis of ECs isolated from untreated mice in both strains suggested the involvement of changes in endothelial junction formation. Specifically, compared with cells from Pparg f/f mice, Pparg ΔEC cells had a 15-fold increase in focal adhesion kinase, critically important in EC focal adhesions, and >3-fold significant increase in vascular endothelial cadherin, the main component of focal adhesions. Together, these results indicate that rosiglitazone has direct effects on the endothelium via PPARγ activation and point toward a critical role for PPARγ in ECs during rosiglitazone-mediated plasma volume expansion.

Biochemical Determinants of Changes in Plasma Volume After Decongestion Therapy for Worsening Heart Failure.

BACKGROUND: Optimal vascular volume is required to avoid organ dysfunction during decongestive therapy for worsening heart failure (HF). This study investigated the relation between changes in serum substance(s) and the vascular volume after diuresis in HF patients. METHODS AND RESULTS: Data from 47 patients with HF undergoing conventional diuretic therapy were analyzed. Blood tests included measurements of hemoglobin, hematocrit, and serum albumin/solutes. The relative changes in the plasma volume (%PV) from worsening HF to recovery were determined with the use of the Strauss formula. When divided into 2 groups based on the median %PV, the group with preserved volume (%PV ≥ -10%, range -10% to 21%; n = 23) exhibited a smaller decrease in body weight (-2.50 ± 1.98 vs -4.29 ± 2.60 kg; P = .012) and serum sodium (Na) (-1.57 ± 3.29 vs -4.13 ± 4.96 mEq/L; P = .04) and chloride (Cl) (-2.0 ± 4.06 vs -6.79 ± 5.21 mEq/L; P = .001) concentrations and a smaller increase in albumin (0.20 ± 0.28 vs 0.41 ± 0.24g/dL; P = .009) compared with the group with nonpreserved volume (%PV < -11%, range -33% to -11%; n = 24) after decongestive therapy. Changes in %PV were positively correlated with changes in body weight (r = 0.406; P = .0047) and serum Na (r = 0.433; P = .0024) and Cl (r = 0.408; P = .0044) concentrations and negatively correlated with changes in albumin (r = -0.492; P = .0004), blood urea nitrogen (r = -0.306; P = .037), and creatinine (r = -0.306; P = .036). Multivariate logistic regression analysis demonstrated an independent association between preserved %PV and an increased or preserved serum Cl concentration after decongestive therapy (odds ratio 8.71, 95% confidence interval 1.20-63.0; P = .032). CONCLUSIONS: Positive and independent association exists between change in the vascular volume and the serum Cl concentration under decongestive HF therapy.

Efficacy of fluid loading as a countermeasure to the hemodynamic and hormonal changes of 28-h head-down bed rest.

After exposure to microgravity, or head-down bed rest (HDBR), fluid loading is often used with the intent of increasing plasma volume and maintaining mean arterial pressure during orthostatic stress. Nine men (aged 18-32 years) underwent three randomized trials with lower body negative pressure (LBNP) before and after: (1) 4-h of sitting with fluid loading (1 g sodium chloride/125 mL of water starting 2.5-h before LBNP), (2) 28-h of 6-degree HDBR without fluid loading, and (3) 28-h of 6-degree HDBR with fluid loading. LBNP was progressive from 0 to -40 mmHg. After 28-h HDBR, fluid loading did not protect against the loss of plasma volume (-280 ± 64 mL without fluid loading, -207 ± 86 with fluid loading, P = 0.472) nor did it protect against a drop of mean arterial pressure (P = 0.017) during LBNP (Post-28 h HDBR response from 0 to -40 mmHg LBNP: 88 ± 4 to 85 ± 4 mmHg without fluid loading and 93 ± 4 to 88 ± 5 mmHg with fluid loading, P = 0.557 between trials). However, fluid loading did protect against the loss of stroke volume index and central venous pressure observed after 28-h HDBR. Fluid loading also attenuated the increase of angiotensin II seen after 28-h HDBR and throughout the LBNP protocol (Post-28 h HDBR response from 0 to -40 mmHg LBNP: 16.6 ± 3.4 to 23.7 ± 5.0 pg/mL without fluid loading and 6.1 ± 0.8 to 12.2 ± 2.3 pg/mL with fluid loading, P < 0.001 between trials). Our results indicate that fluid loading did not protect against plasma volume loss due to HDBR or change blood pressure responses to LBNP. However, changes in central venous pressure, stroke volume and fluid regulatory hormones could potentially influence longer duration studies and those with more severe orthostatic stress.

In-human subject-specific evaluation of a control-theoretic plasma volume regulation model.

The goal of this study was to conduct a subject-specific evaluation of a control-theoretic plasma volume regulation model in humans. We employed a set of clinical data collected from nine human subjects receiving fluid bolus with and without co-administration of an inotrope agent, including fluid infusion rate, plasma volume, and urine output. Once fitted to the data associated with each subject, the model accurately reproduced the fractional plasma volume change responses in all subjects: the error between actual versus model-reproduced fractional plasma volume change responses was only 1.4 ± 1.6% and 1.2 ± 0.3% of the average fractional plasma volume change responses in the absence and presence of inotrope co-administration. In addition, the model parameters determined by the subject-specific fitting assumed physiologically plausible values: (i) initial plasma volume was estimated to be 36 ± 11 mL/kg and 37 ± 10 mL/kg in the absence and presence of inotrope infusion, respectively, which was comparable to its actual counterpart of 37 ± 4 mL/kg and 43 ± 6 mL/kg; (ii) volume distribution ratio, specifying the ratio with which the inputted fluid is distributed in the intra- and extra-vascular spaces, was estimated to be 3.5 ± 2.4 and 1.9 ± 0.5 in the absence and presence of inotrope infusion, respectively, which accorded with the experimental observation that inotrope could enhance plasma volume expansion in response to fluid infusion. We concluded that the model was equipped with the ability to reproduce plasma volume response to fluid infusion in humans with physiologically plausible model parameters, and its validity may persist even under co-administration of inotropic agents.

Mechanism of the blood pressure-lowering effect of sodium-glucose cotransporter 2 inhibitors in obese patients with type 2 diabetes.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are reported to have BP-lowering effect in addition to blood glucose-lowering effect, however, its mechanism is still unknown. This study aimed to investigate the mechanism of blood pressure (BP) lowering effects of SGLT2 inhibitors using 24-h urinary collection in obese type 2 diabetes patients. METHODS: Twenty patients with type 2 diabetes (age 48.2 ± 10.7 years, BMI 33.0 ± 4.9 kg/m2) were enrolled. Urine volume, 24-h urinary glucose and sodium excretion, and BP at baseline and 2 weeks and 6 months after administration were measured. Body weight, glycosylated hemoglobin, and BP were evaluated before and 1, 3, and 6 months after SGLT2 inhibitor administration. We evaluated the changes in urine volume and urinary excretion of glucose and sodium as well as correlations among urine volume and urinary sodium glucose excretion at 2 weeks and 6 months after administration of the SGLT2 inhibitors. Furthermore, we investigated the correlations between changes in BP and urinary excretion of sodium and glucose at the same time. RESULTS: Two weeks after administration, systolic BP (SBP) significantly decreased (128.5 ± 11.0 to 123.2 ± 9.8 mmHg, P = 0.0314), but diastolic BP (DBP) did not (74.4 ± 10.4 to 73.4 ± 8.5 mmHg, P = 0.5821). The decreased SBP significantly correlated with increased urinary glucose excretion (R = -0.62, P = 0.0073), but not increased urinary sodium excretion. At 6 months, SBP (118.6 ± 11.0 mmHg, P = 0.0041) and DBP (68.4 mmHg, P = 0.0363) significantly decreased. The decreased SBP significantly correlated with increased urinary sodium excretion (R = -0.60, P = 0.0014), but not increased urinary glucose excretion. CONCLUSIONS: SGLT2 inhibitors significantly decreased SBP after 1 month and DBP after 6 months in obese patients with type 2 diabetes. The main mechanism of the BP-lowering effect may be plasma volume reduction by osmotic diuresis at 2 weeks and by natriuresis at 6 months after SGLT2 inhibitor administration.

Apelin Compared With Dobutamine Exerts Cardioprotection and Extends Survival in a Rat Model of Endotoxin-Induced Myocardial Dysfunction.

OBJECTIVE: Dobutamine is the currently recommended ß-adrenergic inotropic drug for supporting sepsis-induced myocardial dysfunction when cardiac output index remains low after preload correction. Better and safer therapies are nonetheless mandatory because responsiveness to dobutamine is limited with numerous side effects. Apelin-13 is a powerful inotropic candidate that could be considered as an alternative noncatecholaminergic support in the setting of inflammatory cardiovascular dysfunction. DESIGN: Interventional controlled experimental animal study. SETTING: Tertiary care university-based research institute. SUBJECTS: One hundred ninety-eight adult male rats. INTERVENTIONS: Using a rat model of "systemic inflammation-induced cardiac dysfunction" induced by intraperitoneal lipopolysaccharide injection (10 mg/kg), hemodynamic efficacy, cardioprotection, and biomechanics were assessed under IV osmotic pump infusions of apelin-13 (0.25 µg/kg/min) or dobutamine (7.5 µg/kg/min). MEASUREMENTS AND MAIN RESULTS: In this model and in both in vivo and ex vivo studies, apelin-13 compared with dobutamine provoked distinctive effects on cardiac function: 1) optimized cardiac energy-dependent workload with improved cardiac index and lower vascular resistance, 2) upgraded hearts' apelinergic responsiveness, and 3) consecutive downstream advantages, including increased urine output, enhanced plasma volume, reduced weight loss, and substantially improved overall outcomes. In vitro studies confirmed that these apelin-13-driven processes encompassed a significant and rapid reduction in systemic cytokine release with dampening of myocardial inflammation, injury, and apoptosis and resolution of associated molecular pathways. CONCLUSIONS: In this inflammatory cardiovascular dysfunction, apelin-13 infusion delivers distinct and optimized hemodynamic support (including positive fluid balance), along with cardioprotective effects, modulation of circulatory inflammation and extended survival.

Prenatal Testosterone Exposure Decreases Aldosterone Production but Maintains Normal Plasma Volume and Increases Blood Pressure in Adult Female Rats.

Plasma testosterone levels are elevated in pregnant women with preeclampsia and polycystic ovaries; their offspring are at increased risk for hypertension during adult life. We tested the hypothesis that prenatal testosterone exposure induces dysregulation of the renin-angiotensin-aldosterone system, which is known to play an important role in water and electrolyte balance and blood pressure regulation. Female rats (6 mo old) prenatally exposed to testosterone were examined for adrenal expression of steroidogenic genes, telemetric blood pressure, blood volume and Na(+) and K(+) levels, plasma aldosterone, angiotensin II and vasopressin levels, and vascular responses to angiotensin II and arg(8)-vasopressin. The levels of Cyp11b2 (aldosterone synthase), but not the other adrenal steroidogenic genes, were decreased in testosterone females. Accordingly, plasma aldosterone levels were lower in testosterone females. Plasma volume and serum and urine Na(+) and K(+) levels were not significantly different between control and testosterone females; however, prenatal testosterone exposure significantly increased plasma vasopressin and angiotensin II levels and arterial pressure in adult females. In testosterone females, mesenteric artery contractile responses to angiotensin II were significantly greater, while contractile responses to vasopressin were unaffected. Angiotensin II type-1 receptor expression was increased, while angiotensin II type-2 receptor was decreased in testosterone arteries. These results suggest that prenatal testosterone exposure downregulates adrenal Cyp11b2 expression, leading to decreased plasma aldosterone levels. Elevated angiotensin II and vasopressin levels along with enhanced vascular responsiveness to angiotensin II may serve as an underlying mechanism to maintain plasma volume and Na(+) and K(+) levels and mediate hypertension in adult testosterone females.

Effects of hypervolemia by protein and glucose supplementation during aerobic training on thermal and arterial pressure regulations in hypertensive older men.

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.

Acute Mountain Sickness Symptom Severity at the South Pole: The Influence of Self-Selected Prophylaxis with Acetazolamide.

INTRODUCTION: Acetazolamide, a carbonic anhydrase inhibitor, remains the only FDA approved pharmaceutical prophylaxis for acute mountain sickness (AMS) though its effectiveness after rapid transport in real world conditions is less clear. METHODS: Over 2 years, 248 healthy adults traveled by airplane from sea level (SL) to the South Pole (ALT, ~3200m) and 226 participants provided Lake Louise Symptom Scores (LLSS) on a daily basis for 1 week; vital signs, blood samples, and urine samples were collected at SL and at ALT. Acetazolamide was available to any participant desiring prophylaxis. Comparisons were made between the acetazolamide with AMS (ACZ/AMS) (n = 42), acetazolamide without AMS (ACZ/No AMS)(n = 49), no acetazolamide with AMS (No ACZ/AMS) (n = 56), and the no acetazolamide without AMS (No ACZ/No AMS) (n = 79) groups. Statistical analysis included Chi-squared and one-way ANOVA with Bonferroni post-hoc tests. Significance was p≤0.05. RESULTS: No significant differences were found for between-group characteristics or incidence of AMS between ACZ and No ACZ groups. ACZ/AMS reported greater LLSS, BMI, and red cell distribution width. ACZ/No AMS had the highest oxygen saturation (O2Sat) at ALT. No significant differences were found in serum electrolyte concentrations or PFT results. DISCUSSION: Acetazolamide during rapid ascent provided no apparent protection from AMS based on LLSS. However, it is unclear if this lack of effect was directly associated with the drug or if perhaps there was some selection bias with individuals taking ACZ more likely to have symptoms or if there may have been more of perceptual phenomenon related to a constellation of side effects.

RhEPO improves time to exhaustion by non-hematopoietic factors in humans.

PURPOSE: Erythropoietin (EPO) controls red cell volume (RCV) and plasma volume (PV). Therefore, injecting recombinant human EPO (rhEPO) increases RCV and most likely reduces PV. RhEPO-induced endurance improvements are explained by an increase in blood oxygen (O2) transport capacity, which increases maximum O2 uptake ([Formula: see text]O2max). However, it is debatable whether increased RCV or [Formula: see text]O2max are the main reasons for the prolongation of the time to exhaustion (t lim) at submaximal intensity. We hypothesized that high rhEPO doses in particular contracts PV such that the improvement in t lim is not as strong as at lower doses while [Formula: see text]O2max increases in a dose-dependent manner. METHODS: We investigated the effects of different doses of rhEPO given during 4 weeks [placebo (P), low (L), medium (M), and high (H) dosage] on RCV, PV, [Formula: see text]O2max and t lim in 40 subjects. RESULTS: While RCV increased in a dose-dependent manner, PV decreased independent of the rhEPO dose. The improvements in t lim (P +21.4 ± 23.8%; L +16.7 ± 29.8%; M +44.8 ± 62.7%; H +69.7 ± 73.4%) depended on the applied doses (R (2) = 0.89) and clearly exceeded the dose-independent [Formula: see text]O2max increases (P -1.7 ± 3.2%; L +2.6 ± 6.8%; M +5.7 ± 5.1 %; H +5.6 ± 4.3 %) after 4 weeks of rhEPO administration. Furthermore, the absolute t lim was not related (R (2) ≈ 0) to RCV or to [Formula: see text]O2max. CONCLUSIONS: We conclude that a contraction in PV does not negatively affect t lim and that rhEPO improves t lim by additional, non-hematopoietic factors.

Effect of estimated plasma volume reduction on renal function for acute heart failure differs between patients with preserved and reduced ejection fraction.

BACKGROUND: The prognostic relevance of plasma volume reduction (PVR) in acute heart failure patients remains unclear because of the confounding hemodynamic effect of left ventricular ejection fraction impairment on kidney function. METHODS AND RESULTS: Subjects enrolled in the West Tokyo Heart Failure Registry were examined. The PV at admission and discharge was estimated from the subjects' body weight and its deviation from the ideal body weight. Patients in the top tertile of estimated PVR were classified as PVR+. Of the 381 patients with acute heart failure, 181 (47.5%) had heart failure with preserved ejection fraction (HFpEF). Estimated PVR was associated with worsening renal function in the HFpEF (odds ratio, 3.28; 95% confidence interval, 1.55-6.96; P=0.002) but not in the heart failure with reduced ejection fraction cohort (odds ratio, 1.22; 95% confidence interval, 0.61-2.42; P=0.57). This association in the HFpEF cohort remained significant after adjusting for a history of hypertension and diabetes mellitus and the estimated glomerular filtration rate (odds ratio, 3.34; 95% confidence interval, 1.52-7.33; P=0.003). The use of intravenous diuretics was a significant predictor of PVR in the HFpEF and heart failure with reduced ejection fraction groups. CONCLUSIONS: The effect of estimated PVR differs by HF type, and the estimated PVR during hospitalization is a predictor of worsening renal function in patients with HFpEF but not in heart failure with reduced ejection fraction. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/index-j.html. Unique identifier: UMIN000001549.

Plasma and electrolyte changes in exercising humans after ingestion of multiple boluses of pickle juice.

CONTEXT: Twenty-five percent of athletic trainers administer pickle juice (PJ) to treat cramping. Anecdotally, some clinicians provide multiple boluses of PJ during exercise but warn that repeated ingestion of PJ may cause hyperkalemia. To our knowledge, no researchers have examined the effect of ingesting multiple boluses of PJ on the same day or the effect of ingestion during exercise. OBJECTIVE: To determine the short-term effects of ingesting a single bolus or multiple boluses of PJ on plasma variables and to characterize changes in plasma variables when individuals ingest PJ and resume exercise. DESIGN: Crossover study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Nine euhydrated men (age = 23 ± 4 years, height = 180.9 ± 5.8 cm, mass = 80.7 ± 13.8 kg, urine specific gravity = 1.009 ± 0.005). INTERVENTION(S): On 3 days, participants rested for 30 minutes, and then a blood sample was collected. Participants ingested 0 or 1 bolus (1 mL · kg(-1) body weight) of PJ, donned sweat suits, biked vigorously for 30 minutes (approximate temperature = 37 °C, relative humidity = 18%), and had a blood sample collected. They either rested for 60 seconds (0- and 1-bolus conditions) or ingested a second 1 mL · kg(-1) body weight bolus of PJ (2-bolus condition). They resumed exercise for another 35 minutes. A third blood sample was collected, and they exited the environmental chamber and rested for 60 minutes (approximate temperature = 21 °C, relative humidity = 18%). Blood samples were collected at 30 and 60 minutes postexercise. MAIN OUTCOME MEASURE(S): Plasma sodium concentration, plasma potassium concentration, plasma osmolality, and changes in plasma volume. RESULTS: The number of PJ boluses ingested did not affect plasma sodium concentration, plasma potassium concentration, plasma osmolality, or changes in plasma volume over time. The plasma sodium concentration, plasma potassium concentration, and plasma osmolality did not exceed 144.6 mEq · L(-1) (144.6 mmol · L(-1)), 4.98 mEq · L(-1) (4.98 mmol · L(-1)), and 289.5 mOsm · kg(-1)H2O, respectively, in any condition at any time. CONCLUSIONS: Ingesting up to 2 boluses of PJ and resuming exercise caused negligible changes in blood variables. Ingesting up to 2 boluses of PJ did not increase plasma sodium concentration or cause hyperkalemia.