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Strenuous physical training increases total blood volume (BV) through expansion of plasma volume (PV) and red cell volume (RCV). In contrast, exogenous erythropoietin (EPO) treatment increases RCV but decreases PV, rendering BV stable or slightly decreased. This study aimed to determine the combined effects of strenuous training and EPO treatment on BV and markers of systemic and muscle iron homeostasis. In this longitudinal study, eight healthy nonanemic males were treated with EPO (50 IU/kg body mass, three times per week, sc) across 28 days of strenuous training (4 days/wk, exercise energy expenditures of 1,334 ± 24 kcal/day) while consuming a controlled, energy-balanced diet providing 39 ± 4 mg/day iron. Before (PRE) and after (POST) intervention, BV compartments were measured using carbon monoxide rebreathing, and markers of iron homeostasis were assessed in blood and skeletal muscle (vastus lateralis). Training + EPO increased ( P < 0.01) RCV (13 ± 6%) and BV (5 ± 4%), whereas PV remained unchanged ( P = 0.86). The expansion of RCV was accompanied by a large decrease in whole body iron stores, as indicated by decreased ( P < 0.01) ferritin (-77 ± 10%) and hepcidin (-49 ± 23%) concentrations in plasma. Training + EPO decreased ( P < 0.01) muscle protein abundance of ferritin (-25 ± 20%) and increased ( P < 0.05) transferrin receptor (47 ± 56%). These novel findings illustrate that strenuous training combined with EPO results in both increased total oxygen-carrying capacity and hypervolemia in young healthy males. The decrease in plasma and muscle ferritin suggests that the marked upregulation of erythropoiesis alters systemic and tissue iron homeostasis, resulting in a decline in whole body and skeletal muscle iron stores. NEW & NOTEWORTHY Strenuous exercise training combined with erythropoietin (EPO) treatment increases blood volume, driven exclusively by red cell volume expansion. This hematological adaptation results in increased total oxygen-carrying capacity and hypervolemia. The marked upregulation of erythropoiesis with training + EPO reduces whole body iron stores and circulating hepcidin concentrations. The finding that the abundance of ferritin in muscle decreased after training + EPO suggests that muscle may release iron to support red blood cell production.

Intravenous volume loading is a common treatment when hypovolemia is a potential cause of oliguria. We studied whether the effectiveness of Ringer's solution and 20% albumin in inducing diuresis differs depending on the mean arterial pressure (MAP). For this purpose, volume kinetic analysis was performed based on urine output and hemoglobin-derived plasma dilution obtained during and after 136 infusions of Ringer and 85 infusions of 20% albumin. Covariance analysis quantified the diuretic response at different arterial pressures. The results show that the diuretic response to a known plasma volume expansion was greater for Ringer's solution above a MAP of 70 mmHg, while 20% albumin was significantly more effective at lower pressures (p < 0.03). Simulations of the urinary output in response to infusion of a predefined fluid volume yielded superior efficacy for 20% albumin when the MAP was low, while Ringer's was similarly effective when the MAP averaged 100 mmHg. In conclusion, urine output in response to plasma volume expansion with 20% albumin was similar to, or even stronger, than that of Ringer's solution when the MAP was below 70 mmHg., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

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.

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.

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 (ΔPV Hb , %) 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 ΔPV Hb 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). ΔPV Hb 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)., (© 2020 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

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., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

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 (Fi Xe ) for 20 min, 50% Fi Xe for 5 min, and 70% Fi Xe for 2 min. Erythropoietin (EPO) was measured at baseline, during, and after xenon inhalation. To determine the chronic effects, eight subjects breathed 70% Fi Xe 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. Fi Xe 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.

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 O 2 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 O 2 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., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

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.

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor γ (PPAR γ ) 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 PPAR γ expression in endothelial cells (ECs) in these side effects, EC-targeted PPAR γ knockout ( Pparg ΔEC ) mice were placed on a high-fat diet to promote PPAR γ 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 PPAR γ activation and point toward a critical role for PPAR γ in ECs during rosiglitazone-mediated plasma volume expansion., (U.S. Government work not protected by U.S. copyright.)

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., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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/m 2 ) 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.

Objective: Dobutamine is the currently recommended β-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.

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 (V̇o 2 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 (T es ) and forearm skin blood flow (plethysmography) during exercise at 60% pretraining V̇o 2 peak for 20 min in a warm environment. We found that the forearm skin vascular conductance response to increased T es 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., (Copyright © 2016 the American Physiological Society.)

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., (© 2016 by the Society for the Study of Reproduction, Inc.)

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.

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.

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., (© 2015 American Heart Association, Inc.)

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.

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.

Purpose: Similarly to a wrestling match, upper-body intermittent sprint performance (UBISP) test elicits severe acidosis. This study aimed to determine whether sodium citrate (CIT) ingestion would help to better maintain peak power (PP) and mean power (MP) output across four consecutive UBISP tests simulating wrestling matches of a competition-day., Methods: In a double-blind, counterbalanced, crossover manner, 11 trained wrestlers ingested either placebo (PLC) or CIT (900 mg kg(-1)) within a 17-h supplementation period. Thereafter they completed four (T1-T4) 6-min UBISP tests interspersed with 30-min recovery periods., Results: Compared with PLC, CIT supplementation resulted in a persistent increase (P < 0.05) in blood HCO3 (-) concentration and pH: pre-T1 25.6 % and 0.08 units, post-T4 39.1 % and 0.14 units, respectively. Post-T1 blood lactate concentration in CIT (16.1 ± 3.8 mmol L(-1)) was higher (P = 0.037) than that in PLC (13.7 ± 2.3 mmol L(-1)). Decrease in plasma volume across the supplementation period and UBISP tests was greater (P = 0.03) in PLC (-6.91 ± 4.37 %) than in CIT (-1.51 ± 4.34 %). There was an overall decrease (P = 0.028) in ratings of perceived exertion in CIT compared with PLC, but no between-trial difference (P > 0.05) in PP or MP in any UBISP test occurred., Conclusion: In trained wrestlers, CIT ingestion induces alkalosis, counteracts reduction in plasma volume, increases post-test blood lactate concentration and reduces perceived exertion, but does not improve PP or MP attained in consecutive UBISP tests simulating four wrestling matches of a competition-day.

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.

Background and Aims: L-glutamine is an efficacious glucagon-like peptide (GLP)-1 secretagogue in vitro. When administered with a meal, glutamine increases GLP-1 and insulin excursions and reduces postprandial glycaemia in type 2 diabetes patients. The aim of the study was to assess the efficacy and safety of daily glutamine supplementation with or without the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin in well-controlled type 2 diabetes patients., Methods: Type 2 diabetes patients treated with metformin (n = 13, 9 men) with baseline glycated hemoglobin (HbA1c) 7.1±0.3% (54±4 mmol/mol) received glutamine (15 g bd)+ sitagliptin (100 mg/d) or glutamine (15 g bd) + placebo for 4 weeks in a randomized crossover study., Results: HbA1c (P = 0.007) and fructosamine (P = 0.02) decreased modestly, without significant time-treatment interactions (both P = 0.4). Blood urea increased (P<0.001) without a significant time-treatment interaction (P = 0.8), but creatinine and estimated glomerular filtration rate (eGFR) were unchanged (P≥0.5). Red blood cells, hemoglobin, hematocrit, and albumin modestly decreased (P≤0.02), without significant time-treatment interactions (P≥0.4). Body weight and plasma electrolytes remained unchanged (P≥0.2)., Conclusions: Daily oral supplementation of glutamine with or without sitagliptin for 4 weeks decreased glycaemia in well-controlled type 2 diabetes patients, but was also associated with mild plasma volume expansion., Trial Registration: ClincalTrials.gov NCT00673894.

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., (© 2014 John Wiley & Sons Ltd.)

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., (© 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Glycerol is prohibited as a masking agent by the World Anti-Doping Agency and a urinary threshold has recently been recommended. However, little is known about urinary glycerol excretion after exercise, when (1) exogenous glycerol is metabolized increasingly and (2) endogenous glycerol levels are elevated. The purpose of the placebo-controlled cross-over study was to determine the effects of pre-exercise glycerol administration on glycerol metabolism, urinary excretion, and selected blood parameters. After administration of glycerol (G; 1.0 g/kg body weight (BW) + 25 ml fluid/kg BW) or placebo (P; 25 ml fluid/kg), 14 cyclists exercised 90 min at 60% VO2max . Samples were taken at 0 h (before administration), 2.5 h (before exercise), 4 h (after exercise) and 6.5 h and additional urine samples were collected until 24 h. Exercise increased endogenous plasma glycerol (0.51 ± 0.21 mmol/l) but peak concentrations were much higher in G (2.5 h: 15.6 ± 7.8 mmol/l). Urinary glycerol increased rapidly (58,428 ± 71,084 µg/ml after 2.5 h) and was significantly higher than in P until 13.6 ± 0.9 h (p < 0.01). In comparison with placebo administration, G caused significantly greater changes in plasma volume and haemoglobin concentrations after 2.5 h. BW and urine production were significantly different between P and G after 2.5 h and post-exercise. Despite exercise-induced increases in endogenous glycerol in the control group, urinary excretion remained well below the previously recommended threshold. In addition, exercise-related glycerol degradation did not appear to negatively affect the detection of exogenously administered glycerol., (Copyright © 2013 John Wiley & Sons, Ltd.)

Thiazolidinediones (TZDs), which are synthetic peroxisome proliferator-activated receptor subtype-γ (PPARγ), agonists are highly effective for treatment of type 2 diabetes. However, the side effect of fluid retention has significantly limited their application. Most of the previous studies addressing TZD-induced fluid retention employed healthy animals. The underlying mechanism of this phenomenon is still incompletely understood, particularly in the setting of disease state. The present study was undertaken to examine rosiglitazone (RGZ)-induced fluid retention in db/db mice and to further investigate the underlying mechanism. In response to RGZ treatment, db/db mice exhibited an accelerated plasma volume expansion as assessed by hematocrit (Hct) and fluorescent nanoparticles, in parallel with a greater increase in body weight, compared with lean controls. In response to RGZ-induced fluid retention, urinary Na(+) excretion and urine volume were significantly increased in lean mice. In contrast, the natriuretic and diuretic responses were significantly blunted in db/db mice. RGZ db/db mice exhibited a parallel decrease in plasma Na(+) concentration and plasma osmolality, contrasting to unchanged levels in lean controls. Imunoblotting analysis showed downregulation of renal aquaporin (AQP) 2 expression in response to RGZ treatment in lean mice but not in db/db mice. Renal AQP3 protein expression was unaffected by RGZ treatment in lean mice but was elevated in db/db mice. In contrast, the expression of Na(+)/H(+) exchanger-3 (NHE3) and NKCC2 was unchanged in either mouse strain. Together these results suggest that compared with the lean controls, db/db mice exhibited accelerated plasma volume expansion that was in part due to the inappropriate response of renal water transporters.

The use of glycerol in combination with excess fluid can be used to increase total body water. Because glycerol hyperhydration may also be misused to mask the effects of blood doping on doping-relevant parameters, namely haemoglobin and haematocrit, glycerol has been prohibited by the World Anti-Doping Agency since 2010. In order to test this rationale, the purpose of this meta-analysis was to quantify the effects of glycerol hyperhydration on plasma volume, haemoglobin, and haematocrit in comparison to administration of fluid only. Following a literature search, a total of seven studies was included and meta-analyses were performed separately for the effects on plasma volume (5 studies, total n = 54) and on haemoglobin (6 studies, n = 52) and haematocrit (6 studies, n = 52). The meta-analysis revealed that the increase in plasma volume was 3.3% larger (95%-CI: 1.1-5.5%) after glycerol administration when compared to fluid only. Reductions in haemoglobin were 0.2 g/dl (95%-CI: -0.3, 0.0) larger and there was no difference in the changes in haematocrit between glycerol and fluid administration (95%-CI: -0.7-0.8%). In comparison with other plasma-volume expanding agents, glycerol hyperhydration has a very limited potential in increasing plasma volume and altering doping-relevant blood parameters., (Copyright © 2013 John Wiley & Sons, Ltd.)

Background: Hyporesponders to erythropoietin-stimulating agents (ESAs) have been associated with an increased subsequent risk of death or cardiovascular events. We hypothesized that subjects who are hyporesponsive to erythropoietin alfa would have higher plasma volumes and lower red cell deficits than subjects who are responsive to therapy., Methods: As part of a prospective, single blind, randomized, placebo-controlled study comparing erythropoietin alfa with placebo in older adults (n = 56) with heart failure and a preserved ejection fraction (HFPEF), we performed blood volume analysis with the use of an indicator dilution technique with (131)iodine-labeled albumin. We evaluated differences in plasma volumes and red cell volumes in hyporesponders (eg, <1 g/dL increase in hemoglobin within the first 4 weeks of treatment with erythropoetin alfa) compared with subjects who were responders and controls., Results: Nine of 28 subjects (32%) assigned to ESA were hyporesponders. Hyporesponders did not differ from responders nor control subjects by any baseline demographic, clinical, or laboratory parameter, including hemoglobin. Hyporesponders had a greater total blood volume expansion (1,264.7 ± 387 vs 229 ± 206 mL; P = .02) but less of a red cell deficit (-96.2 ± 126 vs -402.5 ± 80.6 mL; P = .04) and a greater plasma volume expansion (+1,360.8 ± 264.5 vs +601.1 ± 165.5 mL; P = .01). Among responders, the increase in hemoglobin with erythropoietin alfa was associated primarily with increases in red cell volume (r = 0.91; P < .0001) as well as a decline in plasma volume (r = -0.55; P = .06)., Conclusions: Among older adults with HFPEF and anemia, hyporesponders to erythropoietin alfa had a hemodilutional basis of their anemia, suggesting that blood volume analysis can identify a cohort likely to respond to therapy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: A highly positive intraoperative fluid balance should be prevented as it negatively impacts patient outcome. Analysis of volume-kinetics has identified an increase in interstitial fluid volume after crystalloid fluid loading during isoflurane anesthesia. Isoflurane has also been associated with postoperative hypoxemia and may be associated with an increase in alveolar epithelial permeability, edema formation, and hindered oxygen exchange. In this article, the authors compare fluid extravasation rates before and during cardiopulmonary bypass (CPB) with isoflurane- versus propofol-based anesthesia., Methods: Fourteen pigs underwent 2 h of tepid CPB with propofol (P-group; n = 7) or isoflurane anesthesia (I-group; n = 7). Fluid requirements, plasma volume, colloid osmotic pressures in plasma and interstitial fluid, hematocrit levels, and total tissue water content were recorded, and fluid extravasation rates calculated., Results: Fluid extravasation rates increased in the I-group from the pre-CPB level of 0.27 (0.13) to 0.92 (0.36) ml·kg·min, but remained essentially unchanged in the P-group with significant between-group differences during CPB (pb = 0.002). The results are supported by corresponding changes in interstitial colloid osmotic pressure and total tissue water content., Conclusions: During CPB, isoflurane, in contrast to propofol, significantly contributes to a general increase in fluid shifts from the intravascular to the interstitial space with edema formation and a possible negative impact on postoperative organ function.

Objective: The objective of this study was to determine the degree of plasma volume expansion by 0.9% NaCl in relation to the infused volume, in sepsis/systemic inflammatory response syndrome (SIRS), after a standardized hemorrhage, and in a normal condition., Design: Prospective, randomized animal study., Setting: The study was performed at a university hospital laboratory., Subjects: Thirty anesthetized adult male rats were included in the study., Interventions: The study was performed in three groups: a sepsis/SIRS group (the S group), in which sepsis/SIRS was induced by cecal ligation and incision; a hemorrhage group (the H group), in which the rats were left without intervention for 4 h and bled 8 mL/kg thereafter; and a group that was left without intervention (the N group). Then, 4 h after baseline, all three groups were given an infusion of 0.9% NaCl (32 mL/kg) for 15 min. Baseline was defined as the time point when the surgical preparation was finished., Measurements and Main Results: Plasma volumes were measured using I-albumin dilution technique at baseline, after 4 h, and 20 min after the end of infusion. The plasma volume-expanding effect 20 min after end of infusion was 0.6% ± 2.9% in the S group, 20% ± 6.4% in the H group, and 12% ± 11% in the N group, compared with just before start of infusion., Conclusions: The present study in rats showed that the plasma volume-expanding effect after an infusion of 0.9% NaCl was smaller in a septic/SIRS state than after hemorrhage and in a normal state. This indicates that the plasma volume-expanding effect of a crystalloid is dependent on pathophysiologic changes in sepsis/SIRS.

Background: Increased vascular leakage leading to hypovolaemia and tissue oedema is common in severe sepsis. Hypovolaemia together with oedema formation may contribute to hypoxia and result in multiorgan failure and death. To improve treatment during sepsis, a potential therapeutic target may be to reduce the vascular leakage. Substances affecting the endothelial barrier are interesting in this respect, as it is suggested that increase in vascular leakage depends on reorganisation of the endothelial cells and breakdown of the endothelial barrier. The agonist of the bioactive lipid sphingosine-1-phosphate, FTY720, has been shown to modulate the integrity of the endothelium and reduce permeability both in vitro and in vivo. The aim of the present study was to determine if FTY720 could reduce the loss of plasma volume during experimental sepsis in rats., Methods: Sepsis was induced by ligation and incision of the caecum in the rat. Plasma volume was determined before and 4.5 h after induction of sepsis by a dilution technique using (125) I-labelled albumin., Results: FTY720 in a dose of 0.2 mg/kg reduced the loss of plasma during sepsis by approximately 30% compared with vehicle, without any adverse effects on haemodynamic and physiological parameters. The increase in hematocrit and haemoglobin concentration was also found to be higher in the vehicle group., Conclusion: FTY720 in a dose without haemodynamic side effects reduces loss of plasma volume during experimental sepsis most likely because of reduction in permeability and may therefore be beneficial in sepsis., (© 2013 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

The endothelial glycocalyx forms a hyaluronan-containing interface between the flowing blood and the endothelium throughout the body. By comparing the systemic distribution of a small glycocalyx-accessible tracer vs. a large circulating plasma tracer, the size-selective barrier properties of the glycocalyx have recently been utilized to estimate whole body glycocalyx volumes in humans and animals, but a comprehensive validation of this approach has been lacking at the moment. In the present study, we compared, in anesthetized, ventilated C57Bl/6 mice, the whole body distribution of small (40 kDa) dextrans (Texas Red labeled; Dex40) vs. that of intermediate (70 kDa) and large (500 kDa) dextrans (both FITC labeled; Dex70 and Dex500, respectively) using tracer dilution and vs. that of circulating plasma, as derived from the dilution of fluorescein-labeled red blood cells and large-vessel hematocrit. The contribution of the glycocalyx was evaluated by intravenous infusion of a bolus of the enzyme hyaluronidase. In saline-treated control mice, distribution volume (in ml) differed between tracers (P < 0.05; ANOVA) in the following order: Dex40 (0.97 ± 0.04) > Dex70 (0.90 ± 0.04) > Dex500 (0.81 ± 0.10) > plasma (0.71 ± 0.02), resulting in an inaccessible vascular volume, i.e., compared with the distribution volume of Dex40, of 0.03 ± 0.01, 0.15 ± 0.04, and 0.31 ± 0.05 ml for Dex70, Dex500, and plasma, respectively. In hyaluronidase-treated mice, Dex70 and Dex40 volumes were not different from each other, and inaccessible vascular volumes for Dex500 (0.03 ± 0.03) and plasma (0.14 ± 0.05) were smaller (P < 0.05) than those in control animals. Clearance of Dex70 and Dex500 from the circulation was enhanced (P < 0.05) in hyaluronidase-treated vs. control mice. These results indicate that the glycocalyx contributes to size-dependent differences in whole body vascular distribution of plasma solutes in mice. Whole body vascular volume measurements based on the differential distribution of glycocalyx-selective tracers appear appropriate for the detection of generalized glycocalyx degradation in experimental animals and humans.

Spaceflight-induced orthostatic intolerance has been studied for decades. Although ∼22% of the astronaut corps are women, most mechanistic studies use mostly male subjects, despite known sex differences in autonomic control and postflight orthostatic intolerance. We studied adrenergic, baroreflex, and autonomic indexes during continuous infusions of vasoactive drugs in men and women during a 60-day head-down bed rest. Volunteers were tested before bed rest (20 men and 10 women) and around day 30 (20 men and 10 women) and day 60 (16 men and 8 women) of bed rest. Three increasing doses of phenylephrine (PE) and sodium nitroprusside were infused for 10 min after an infusion of normal saline. A 20-min rest period separated the phenylephrine and sodium nitroprusside infusions. Autonomic activity was approximated by spectral indexes of heart rate and blood pressure variability, and baroreflex sensitivity was measured by the spontaneous baroreflex slope. Parasympathetic modulation and baroreflex sensitivity decreased with bed rest, with women experiencing a larger decrease in baroreflex sensitivity by day 30 than men. The sympathetic activation of men and parasympathetic responsiveness of women in blood pressure control during physiological stress were preserved throughout bed rest. During PE infusions, women experienced saturation of the R-R interval at high frequency, whereas men did not, revealing a sex difference in the parabolic relationship between high-frequency R-R interval, a measurement of respiratory sinus arrhythmia, and R-R interval. These sex differences in blood pressure control during simulated microgravity reveal the need to study sex differences in long-duration spaceflight to ensure the health and safety of the entire astronaut corps.

Aims: To investigate the reasonable dose of Voluven for rapid plasma volume expansion during the anaesthesia induction patients receiving gastrointestinal surgery., Methods: Sixty patients were randomly divided into three groups (n=20): Group A (5 ml/kg), Group B (7 ml/kg) and Group C (9 ml/kg). HES 130/0.4 was intravenously transfused at a rate of 0.3 ml/kg/min) at 30 min before anaesthesia induction. Besides standard haemodynamic monitoring, cardiac index (CI), systemic vascular resistance index (SVRI) and stroke volume variation (SVV) was continuously detected with the FloTrac/Vigileo system. Haemodynamic variables were recorded immediately before fluid transfusion (T0), immediately before induction (T1), immediately before intubation (T2), immediately after intubation (T3) and 5 min, 10 min, 20 min and 60 min after intubation (T4-T7). Arterial and venous blood was collected for blood gas analysis, Hb and Hct before volume expansion (t0), immediately after volume expansion (t1) and at 1 h after volume expansion (t2). Oxygen delivery (DO2), oxygen extraction ratio (ERO2) and volume expansion rate were calculated., Results: 1) MAP and CI decreased in Group A in T2~T7 and remained changed in Group B and C. 2) CVP increased in three groups after fluid infusion without significant difference. 3) The decrease in SVRI was more obvious in Group B and C than that in Group A after induction and more obvious in Group C than in Group B in T2-T4 and T6~T7. 4) SVV was lower in Group B and C than that in Group A after intubation, and lower in Group C than that in Group B in T3-T6. 5) Hb and Hct decreased after fluid infusion, and the decrease in Hb and Hct was in the order of C>B>A. 6) Volume expansion rate was in the order of C>B>A. 7) ScvO2, PaO2 and DO2 increased in three groups after fluid infusion and the increase in DO2 was in the order of C>B>A., Conclusions: Rapid plasma volume expansion with Voluven at 7-9 ml/kg can prevent haemodynamic fluctuation during anaesthesia induction, maintain the balance between oxygen supply and oxygen consumption during gastrointestinal surgery, and Voluven at 9 ml/kg can improve the oxygen delivery.

Background: There is evidence that suggests that early fluid resuscitation is beneficial in the treatment of sepsis. We previously demonstrated that hydroxyethyl starch (HES) 130/0.42 attenuated capillary leakage better than HES 200/0.5. Using a similar porcine fecal sepsis model, we tested the effects of two new synthetic high molecular weight (700 kDa) hydroxyethyl starches with the same molar substitution of 0.42 but with a different C2/C6 ratio compared to 6% HES 130/0.42 on plasma volume (PV), systemic and tissue oxygenation., Methods: This was a prospective, randomized, controlled animal study. Twenty-five anesthetized and mechanically ventilated pigs (28.4±2.3 kg) were observed over 8 h. Septic shock was induced with fecal peritonitis. Animals were randomized for volume-replacement therapy with HES 700/0.42 C2/C6/2.5:1 (N.=5), HES 700/0.42 C2/C6/6:1 (N.=5), HES 130/0.42 C2/C6/5:1 (N.=5) or Ringer’s Solution (RS, N.=5), and compared to non-septic controls receiving RS (N.=5). The albumin escape rate (AER) was calculated and plasma volume was determined at the end of the study. Tissue Oxygen Saturation was measured with the InSpectra™ Device (InSpectra Tissue Spectrometer, Hutchinson Technology Inc., Hutchinson, MN, USA)., Results: The AER increased in all groups compared to control. All colloids (HES 700/6:1 68±15; HES 130 67±4; HES 700/2.5:1 71±12; P<0.05) but not RS (44±7) stabilized PV (mL/kg BW) after eight hours of sepsis. Systemic oxygenation was significantly lower in the RS group (44±17%; P<0.05) compared to all other groups at study end (P<0.05)., Conclusion: In this porcine fecal peritonitis model, the high molecular weight artificial colloids HES 700/2.5:1 and HES 700/6:1 were not more effective in maintaining plasma volume and systemic and tissue oxygenation than HES 130. In comparison to crystalloid RS, all HES solutions were more effective at maintaining plasma volume, mean arterial pressure (MAP), and systemic and tissue oxygenation.

This study assessed the effects of dietary sodium citrate supplementation during a 16 h recovery from 5% rapid body mass loss (RBML) on physiological functions, affective state, and performance in trained wrestlers. Sixteen wrestlers performed an upper body intermittent sprint performance (UBISP) test under three conditions: before RBML, after RBML, and after a 16 h recovery from RBML. During recovery, the subjects ate a prescribed diet supplemented with sodium citrate (600 mg·kg(-1); CIT group, N = 8) or placebo (PLC group, N = 8) and drank water ad libitum. RBML reduced (p < 0.05) UBISP mean power and increased urine specific gravity (USG). Reduction in mean power was associated with changes in plasma volume (PV) (r = 0.649, p = 0.006) and USG (r = -0.553, p = 0.026). During the 16 h recovery, increases in body mass (BM) and PV were greater (p < 0.05) in the CIT group than in the PLC group. BM gain was associated with water retention in the CIT group (r = 0.899, p = 0.002) but not in the PLC group (r = 0.335, p = 0.417). Blood pH, HCO(3)(-) concentration, and base excess increased (p < 0.05) only in the CIT group. Changes in UBISP, general negative affect, and general positive affect did not differ in the two groups. In conclusion, ingestion of sodium citrate increases blood buffering capacity and PV and stimulates BM regain during a 16 h recovery from RBML in trained wrestlers. However, sodium citrate does not improve UBISP nor does it have an impact on the affective state.

Background: Trauma induces transcapillary leakage of fluid and proteins because of increased microvascular permeability. Based on studies showing that prostacyclin (PGI2) has permeability-reducing properties, in the present study, we investigated whether PGI2 reduces plasma volume (PV) loss after a nonhemorrhagic trauma., Methods: The study was performed on anesthetized Sprague-Dawley rats exposed to a controlled standardized blunt trauma to the abdominal rectus muscle. Thereafter, the animals were randomized to treatment with either PGI2 (2 ng/kg per minute) or 0.9% NaCl. PV was estimated before and 3 hours after the trauma using I-albumin as tracer. In separate experiments, the transcapillary escape rate of I-albumin was calculated and plasma concentrations of cytokines were measured after both treatments., Results: Average PV at baseline was 41.6 mL/kg ± 2.5 mL/kg and 42.3 mL/kg ± 1.7 mL/kg in the PGI2 and NaCl animals, respectively. PV was decreased by 22% ± 8% in the NaCl animals and by 11% ± 9% in the PGI2 animals 3 hours after the trauma (p < 0.05). Trauma induced a decrease in mean arterial blood pressure and an increase in hematocrit in both groups. There were no differences in urine production and mean arterial blood pressure between the PGI2 and NaCl animals. The transcapillary escape rate for albumin was calculated for one hour starting 30 minutes after the trauma and was 15.1% ± 2.4% per hour in the PGI2 animals and 17.4% ± 3.3% per hour in the NaCl animals (p = 0.09). Interleukin 6 concentration 3 hours after the trauma was lower in the PGI2 animals than in the NaCl animals (p < 0.05)., Conclusion: We conclude that PGI2 attenuates PV loss after blunt muscle trauma. The vascular effects of PGI2 are associated with a modulation of the trauma-induced inflammatory response.

Oral rehydration solutions (ORS) are a simple and cheap method to treat diarrheal dehydration and acidosis. To maintain the energy supply of diarrheic calves, it is necessary to continue milk feeding. Suckling of milk or milk-based or hypertonic water-based ORS produces a slower rate of abomasal emptying than suckling isotonic water-based ORS. The faster abomasal passage of isotonic water-based ORS implies that efficacious electrolytes reach the gut more quickly, possibly providing a faster rate of rehydration. The aim of the study was to verify when and to what extent milk and water- and milk-based ORS increase plasma volume and affect plasma osmolality and acid-base status in healthy suckling calves. Eleven calves were fed with milk and with an ORS that was prepared in water or milk. Moreover, for one experiment, the calves remained fasting without suckling milk or ORS. During the experimental phase, the calves were deprived of water, hay, and concentrates. Blood samples were taken before and at various time points after feeding. Total plasma protein, osmolality, [Na(+)], [K(+)], [Cl(-)], and albumin were determined. In 6 of 11 experiments, blood gas analysis was also performed. The calculated change in plasma volume after feeding was assessed from the plasma protein concentration before feeding (P(t=0)) and the plasma protein concentration after feeding (P(t=x)): (P(t=0)- P(t=x)) × 100/P(t=x). Water- and milk-based ORS produced equal rates of plasma expansion in healthy calves. After milk feeding, the change in plasma volume was decelerated. Because of water influx, we did not observe a significant effect of feeding regimen on plasma osmolality. Acid-base status was little affected by feeding regimen. Feeding of milk-based ORS increased plasma strong ion difference, an alkaline response, which could potentially also reduce acidosis in calves suffering from diarrhea., (Copyright © 2012 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

This study examined the effectiveness of a short-duration but high-intensity exercise countermeasure in combination with a novel oral volume load in preventing bed rest deconditioning and orthostatic intolerance. Bed rest reduces work capacity and orthostatic tolerance due in part to cardiac atrophy and decreased stroke volume. Twenty seven healthy subjects completed 5 wk of -6 degree head down bed rest. Eighteen were randomized to daily rowing ergometry and biweekly strength training while nine remained sedentary. Measurements included cardiac mass, invasive pressure-volume relations, maximal upright exercise capacity, and orthostatic tolerance. Before post-bed rest orthostatic tolerance and exercise testing, nine exercise subjects were given 2 days of fludrocortisone and increased salt. Sedentary bed rest led to cardiac atrophy (125 ± 23 vs. 115 ± 20 g; P < 0.001); however, exercise preserved cardiac mass (128 ± 38 vs. 137 ± 34 g; P = 0.002). Exercise training preserved left ventricular chamber compliance, whereas sedentary bed rest increased stiffness (180 ± 170%, P = 0.032). Orthostatic tolerance was preserved only when exercise was combined with volume loading (-10 ± 22%, P = 0.169) but not with exercise (-14 ± 43%, P = 0.047) or sedentary bed rest (-24 ± 26%, P = 0.035) alone. Rowing and supplemental strength training prevent cardiovascular deconditioning during prolonged bed rest. When combined with an oral volume load, orthostatic tolerance is also preserved. This combined countermeasure may be an ideal strategy for prolonged spaceflight, or patients with orthostatic intolerance.

Introduction: Third-generation hydroxyethyl starch (HES) is now approved also for the use in children, but safety studies including large numbers of pediatric patients are still missing. Therefore, we performed an European multicentric prospective observational postauthorization safety study (PASS) to evaluate the use of HES 130/0.42/6:1 in normal saline (ns-HES) or a balanced electrolyte solution (bal-HES) in children undergoing surgery., Methods: Children aged up to 12 years with ASA risk scores of I-III receiving ns-HES (Venofundin 6%; Braun) or bal-HES (Tetraspan 6%; Braun) were followed perioperatively. Demographic data, surgical procedures performed, anesthesia, hemodynamic and laboratory data, adverse events (AE), and adverse drug reactions (ADR) were documented using a standardized case report form., Results: Of 1130 children studied at 11 European pediatric centers from 2006 to 2009 (ns-HES, 629 children; bal-HES, 475 children; mean age, 3.6 ± 3.8 [range, day of birth-12 years]; and body weight, 15.4 ± 13 [0.9-90 kg]), 1104 were included for analysis. The mean infused HES volume was 10.6 ± 5.8 (0.83-50) ml·kg(-1). In the 399 (36.1%) cases with blood gas analysis before and after HES infusion, hemoglobin and strong ion difference decreased significantly in both groups, whereas bicarbonate and base excess (BE before infusion: ns-HES -1.8 ± 3.1, bal-HES -1.2 ± 3.3 mm; after infusion: ns-HES -2.5 ± 2.8; bal-HES -1.1 ± 3.2 mm, P < 0.05) decreased only with ns-HES but remained stable with bal-HES. Chloride concentrations increased in both groups and were significantly higher with ns-HES (Cl before infusion: ns-HES 105.5 ± 3.6, bal-HES 104.9 ± 2.9 mm; Cl after infusion: ns-HES 107.6 ± 3.4, bal-HES 106.3 ± 2.9 mm, P < 0.05). For the AE/ADR rates, dose-response but no age relationships could be demonstrated. No serious and no severe ADR directly related to HES (i.e. anaphylactoid reaction, clotting disorders, renal failure) were observed., Conclusion: Moderate doses of HES 130/0.42/6:1 for perioperative plasma volume replacement seem to be safe even in neonates and small infants. The probability of serious ADR is lower than 0.3%. Changes in acid-base balance may be decreased when HES is used in an acetate-containing balanced electrolyte solution instead of normal saline. Caution should be exercised in patients with renal function disturbances and those with an increased bleeding risk., (© 2011 Blackwell Publishing Ltd.)

We tested the hypothesis that inhibition of phosphodiesterase 4 (PDE4) with rolipram to increase vascular endothelial cAMP and stabilize the endothelial barrier would attenuate the action of endogenous atrial natriuretic peptide (ANP) to increase vascular permeability to the plasma protein albumin after an acute plasma volume expansion. After rolipram pretreatment (8 mg (kg body wt)(-1), intraperitoneal, 30 min) more than 95% of the peak increase in plasma volume after volume expansion (4.5% bovine serum albumin, 114 μl (g body wt)(-1) h(-1), 15 min) remained in the vascular space 75 min after the end of infusion, whereas only 67% of the fluid was retained in volume-expanded animals with no rolipram pretreatment. Rolipram significantly decreased 30 min fluorescently labelled albumin clearance (μl (g dry wt)(-1)) relative to untreated volume-expanded controls in skin (e.g. back, 10.4 ± 1.6 vs. 19.5 ± 3.6, P = 0.04), muscle (e.g. hamstring, 15.0 ± 1.9 vs. 20.8 ± 1.4, P = 0.04) and in colon, caecum, and rectum (average reduction close to 50%). The mass of muscle and skin tissue accounted for 70% of volume-expansion-dependent albumin shifts from plasma to interstitium. The results are consistent with observations that the PDE4 inhibitor rolipram attenuates ANP-induced increases in vascular permeability after infusion of exogenous ANP and observations of elevated central venous pressure after a similar volume expansion in mice with selective deletion of the endothelial ANP receptor. These observations may form the basis for new strategies to retain intravenous fluid containing macromolecules.

Isotonic sports drinks are often consumed to offset the effects of dehydration and improve endurance performance, but hypotonic drinks may be more advantageous. The purpose of the study was to compare absorption and effects on performance of a commercially available hypotonic sports drink (Mizone Rapid: 3.9% carbohydrate [CHO], 218 mOsmol/kg) with those of an isotonic drink (PowerAde: 7.6% CHO, 281 mOsmol/ kg), a hypertonic drink (Gatorade: 6% CHO, 327 mOsmol/kg), and a noncaloric placebo (8 mOsmol/kg). In a crossover, 11 cyclists consumed each drink on separate days at 250 ml/15 min during a 2-hr preload ride at 55% peak power followed by an incremental test to exhaustion. Small to moderate increases in deuterium oxide enrichment in the preload were observed with Mizone Rapid relative to PowerAde, Gatorade, and placebo (differences of 88, 45, and 42 parts per million, respectively; 90% confidence limits ±28). Serum osmolality was moderately lower with Mizone Rapid than with PowerAde and Gatorade (-1.9, -2.4; mOsmol/L; ±1.2 mOsmol/L) but not clearly different vs. placebo. Plasma volume reduction was small to moderate with Mizone Rapid, PowerAde, and Gatorade relative to placebo (-1.9%, -2.5%, -2.9%; ± 2.5%). Gut comfort was highest with Mizone Rapid but clearly different (8.4% ± 4.8%) only vs PowerAde. Peak power was highest with Mizone Rapid (380 W) vs. placebo and other drinks (1.2-3.0%; 99% confidence limits ±4.7%), but differences were inconclusive with reference to the smallest important effect (~1.2%). The outcomes are consistent with fastest fluid absorption with the hypotonic sports drink. Further research should determine whether the effect has a meaningful impact on performance.

In a prospective cross-over study, the duration and magnitude of effect on the electrolyte and plasma volume changes of intravenous (IV) hypertonic hydroxyethyl starch (hyperHES) (7.5%/6%) and mannitol (20%) were compared. Eight Beagle dogs received an IV infusion of 4mL/kg hyperHES (group H) and 4mL/kg mannitol 20% (group M) on separate occasions. Urine and blood samples were taken in the first (T(60)) and second (T(120)) hour after infusion. Significant increases in plasma volume at each time point in group H and M were noted when compared to baseline (start of infusion=T(0)) level. There was no significant difference between groups. Both fluids resulted in diuresis, although no significant difference between groups was noted. A significant increase in plasma sodium (Na) was demonstrated in group H between T(0) and T(60) with a significant increase in the Na and chloride (Cl) fractional excretion (FE) between T(0), T(60) and T(120). In group M no changes in plasma electrolyte concentrations were detected, although FE of Na, Cl and K was increased significantly between T(0) and T(60). In conclusion, hyperHES and mannitol appear to have a volume expanding effect lasting at least 120 min. The hypernatraemia induced by hyperHES was minimal compared to previous reports of hypertonic saline use, and no clinical side effects were noted. HyperHES showed comparable effects to mannitol in increasing plasma volume and diuresis and could be considered for these applications., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Hyperkalemia is a common complication in neonatal diarrheic dairy calves and is corrected by administration of glucose or sodium bicarbonate. Although the hypokalemic effect of glucose is well established in other species, controversial results are reported for sodium bicarbonate. Our objective was to study the effect and mechanism of action of glucose and sodium bicarbonate on the potassium homeostasis of healthy neonatal dairy calves. Nine healthy neonatal Holstein-Friesian calves underwent 3 oral treatments with 2L of NaHCO(3) (150 mmol/L), glucose (300 mmol/L), and glucose+NaHCO(3) solution (300 mmol/L+150 mmol/L) in randomized order. Blood was obtained before treatment (T(0)) and at 30-min intervals thereafter. Changes between each time point and T(0) were determined for all parameters. Urine was collected volumetrically to determine total renal potassium excretion over an 8-h posttreatment period. Plasma volume changes were extrapolated from changes in plasma protein concentration. Treatment and time effects were tested with repeated-measures ANOVA. Multivariate stepwise regression analysis using dummy variable coding was conducted to identify associations between changes in plasma potassium concentration ([K]) and changes in plasma glucose concentration ([glucose]), blood base excess, and plasma volume. Oral glucose and sodium bicarbonate treatments decreased [K] by 25 and 19%, respectively, whereas the combination of both compounds caused an intermediate [K] decline (22%). For the glucose treatment, the decline in [K] was only associated with changes in plasma [glucose] (partial R(2)=0.19). In NaHCO(3)-treated calves, [K] decline was associated with change of extracellular volume (partial R(2)=0.31) and blood base excess (partial R(2)=0.19). When glucose and NaHCO(3) were combined, [K] decline was associated with changes in plasma volume (partial R(2)=0.30), BE (R(2)=0.22), and [glucose] (partial R(2)=0.03). Our results indicate that glucose lowers plasma [K] mainly through an insulin-dependent intracellular translocation of K, whereas NaHCO(3) causes hypokalemia through hemodilution followed by intracellular translocation of K caused by the strong ion effect. The combination of glucose and NaHCO(3) at the dosage used in this study does not have an additive hypokalemic effect. When combined, hemodilution and strong ion effect have the strongest effect on plasma [K], whereas the insulin-dependent effect of glucose appears to be blunted., (Copyright © 2011 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

KEY POINTS AND PRACTICAL RECOMMENDATIONS: •  α Antagonists lower blood pressure by selectively blocking post-synaptic α(1) -adrenoreceptors, which antagonizes catecholamine-induced constriction of the arterial and venous vascular beds. •  α(1) -Adrenoreceptor antagonists are not indicated for initial, first-line antihypertensive therapy; however, they can be added to most other antihypertensive drug classes in--preferably diuretic-containing--drug regimens. •  When used over time, these agents cause expansion of the extracellular fluid and plasma volumes that typically manifests as weight gain and an attenuation of the blood pressure-lowering efficacy in persons who are consuming usual amounts of dietary sodium. •  Utilization of α(1) -adrenoreceptor antagonists with diuretics such as chlorthalidone or hydrochlorothiazide is beneficial because these agents minimize the α antagonist-induced expansion of the extracellular and plasma volumes while providing significant incremental reductions in blood pressure. •  α(1) -Adrenoreceptor antagonists are especially useful in men with benign prostatic hypertrophy because they increase mean and peak urinary flow rates as well as reduce lower urinary tract symptoms. •  α(1) -Adrenoreceptor antagonists are contraindicated in persons with heart failure because of their aforementioned ability to expand extracellular and plasma volumes., (© 2011 Wiley Periodicals, Inc.)

In low-flow states, such as circulatory shock, both fluids and catecholamines are often coadministered. We have previously found that adrenergic agents alter volume expansion after a fluid bolus. The present study tested the volume expansion properties of dobutamine and norepinephrine in sheep treated with (series 1) and without (series 2) a fluid bolus. Series 1 (n = 6 per group): no drug (control), dobutamine (10 μg x kg(-1) x min), or norepinephrine (1.0 μg x kg(-1) x min(-1)) was begun 30 min before a 24-mL x kg(-1), 20-min, 0.9% NaCl bolus. The effect of drug and fluid on plasma volume (ΔPV), urinary output (UOP), and extravascular volume (ΔEVV) was determined. Series 2: Identical protocol but no fluid bolus. Series 1: the fluid bolus resulted in a peak and sustained ΔPV expansion. Norepinephrine (7.5 ± 0.9 mL x kg(-1)) and dobutamine (9.5 ± 1.1 mL x kg(-1)) significantly increased ΔPV compared with control (3.8 ± 1.1 mL x kg(-1)). Cumulative UOP was reduced by dobutamine (3.8 ± 1.4 mL x kg) compared with norepinephrine (25.1 ± 3.9 mL x kg(-1)) and control (16.9 ± 4.0 mL x kg(-1)). Norepinephrine increased ΔPV, while reducing ΔEVV after bolus. Series 2: ΔPV was unchanged in the control group. Dobutamine and norepinephrine increased ΔPV over time, 5.1 ± 0.5 and 4.0 ± 0.5 mL x kg(-1), respectively. At study end, UOP was lowest in dobutamine. Norepinephrine resulted in loss of ΔEVV fluid. data suggest a novel role for adrenergic receptors in regulating vascular and EVV expansion. β-Adrenergic agonists enhance vascular volume expansion, whereas α-adrenergic agonists eliminate extravascular fluid.