Tranexamic acid for reducing blood loss following vaginal delivery: a double-blind randomized controlled trial.

BACKGROUND: Postpartum haemorrhage (PPH) is a major cause of maternal morbidity and mortality worldwide. Tranexamic acid (TXA) is a useful drug for prevention of PPH and merits evaluation in Nigeria, where PPH is the leading cause of maternal death (25%) and severe maternal morbidity. This study evaluates the efficacy of TXA in reducing blood loss following vaginal delivery. METHODS: This was a double-blind randomized placebo-controlled study on the efficacy and safety of intravenous TXA in reducing blood loss in women undergoing vaginal delivery in a tertiary hospital. Data analysis was conducted with IBM SPSS software (version 20, Chicago II, USA). P-value < 0.05 was considered statistically significant. RESULTS: The mean estimated blood loss was lower in TXA compared with the placebo group. (174.87 ± 119.83 ml versus 341.07 ± 67.97 ml respectively; P < 0.0001). PPH (blood loss > 500 ml) was 5.13% in the study arm compared to the control arm 7.14%- risk ratio (RR) 0.71; 95% CI: 0.38-1.79, p = 0.5956]. Additional uterotonics was required more in the control group compared to the treatment group 14(16.67%) versus 3(3.85%), p-value= 0.007. There were no major complications noticed in the treatment group. CONCLUSION: This study demonstrated that intravenous administration of TXA reduced blood loss following vaginal delivery. It also reduced the need for additional uterotonics. However, blood loss greater than 500 was not significantly reduced. TRIAL REGISTRATION: This trial was registered retrospectively. Pan African Clinical Trial Registry: PACTR202010828881019 on 12/10/2020.

Insulin-mediated muscle microvascular perfusion and its phenotypic predictors in humans.

Insulin increases muscle microvascular perfusion and enhances tissue insulin and nutrient delivery. Our aim was to determine phenotypic traits that foretell human muscle microvascular insulin responses. Hyperinsulinemic euglycemic clamps were performed in 97 adult humans who were lean and healthy, had class 1 obesity without comorbidities, or controlled type 1 diabetes without complications. Insulin-mediated whole-body glucose disposal rates (M-value) and insulin-induced changes in muscle microvascular blood volume (ΔMBV) were determined. Univariate and multivariate analyses were conducted to examine bivariate and multivariate relationships between outcomes, ΔMBV and M-value, and predictor variables, body mass index (BMI), total body weight (WT), percent body fat (BF), lean body mass, blood pressure, maximum consumption of oxygen (VO2max), plasma LDL (LDL-C) and HDL cholesterol, triglycerides (TG), and fasting insulin (INS) levels. Among all factors, only M-value (r = 0.23, p = 0.02) and VO2max (r = 0.20, p = 0.047) correlated with ΔMBV. Conversely, INS (r = - 0.48, p ≤ 0.0001), BF (r = - 0.54, p ≤ 0.001), VO2max (r = 0.5, p ≤ 0.001), BMI (r = - 0.40, p < 0.001), WT (r = - 0.33, p = 0.001), LDL-C (r = - 0.26, p = 0.009), TG (r = - 0.25, p = 0.012) correlated with M-value. While both ΔMBV (p = 0.045) and TG (p = 0.03) provided significant predictive information about M-value in the multivariate regression model, only M-value was uniquely predictive of ΔMBV (p = 0.045). Thus, both M-value and VO2max correlated with ΔMBV but only M-value provided unique predictive information about ΔMBV. This suggests that metabolic and microvascular insulin responses are important predictors of one another, but most metabolic insulin resistance predictors do not predict microvascular insulin responses.

Opposed hemodynamic responses following increased excitation and parvalbumin-based inhibition.

Understanding cellular contributions to hemodynamic activity is essential for interpreting blood-based brain mapping signals. Optogenetic studies examining cell-specific influences on local hemodynamics have reported that excitatory activity results in cerebral perfusion and blood volume increase, while inhibitory activity contributes to both vasodilation and vasoconstriction. How specific subpopulations of interneurons regulate the brain's blood supply is less examined. Parvalbumin interneurons are the largest subpopulation of GABAergic neurons in the brain, critical for brain development, plasticity, and long-distance excitatory neurotransmission. Despite their essential role in brain function, the contribution of parvalbumin neurons to neurovascular coupling has been relatively unexamined. Using optical intrinsic signal imaging and laser speckle contrast imaging, we photostimulated awake and anesthetized transgenic mice expressing channelrhodopsin under a parvalbumin promoter. Increased parvalbumin activity reduced local oxygenation, cerebral blood volume, and cerebral blood flow. These "negative" hemodynamic responses were consistent within and across mice and reproducible across a broad range of photostimulus parameters. However, the sign and magnitude of the hemodynamic response resulting from increased parvalbumin activity depended on the type and level of anesthesia used. Opposed hemodynamic responses following increased excitation or parvalbumin-based inhibition suggest unique contributions from different cell populations to neurovascular coupling.

Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial.

BACKGROUND: Investigators have hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert diuretic effects that contribute to their ability to reduce serious heart failure events, and this action is particularly important in patients with fluid retention. OBJECTIVES: This study sought to evaluate the effects of the SGLT2 inhibitor empagliflozin on symptoms, health status, and major heart failure outcomes in patients with and without recent volume overload. METHODS: This double-blind randomized trial compared the effects of empagliflozin and placebo in 3,730 patients with heart failure and a reduced ejection fraction, with or without diabetes. Approximately 40% of the patients had volume overload in the 4 weeks before study enrollment. RESULTS: Patients with recent volume overload were more likely to have been hospitalized for heart failure and to have received an intravenous diuretic agent in an outpatient setting in the previous 12 months, and to experience a heart failure event following randomization, even though they were more likely to be treated with high doses of a loop diuretic agent as an outpatient (all p < 0.001). When compared with placebo, empagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure, decreased total hospitalizations for heart failure, and improved health status and functional class. Yet despite the predisposition of patients with recent volume overload to fluid retention, the magnitude of these benefits (even after 1 month of treatment) was not more marked in patients with recent volume overload (interaction p values > 0.05). Changes in body weight, hematocrit, and natriuretic peptides (each potentially indicative of a diuretic action of SGLT2 inhibitors) did not track each other closely in their time course or in individual patients. CONCLUSIONS: Taken together, study findings do not support a dominant role of diuresis in mediating the physiological changes or clinical benefits of SGLT2 inhibitors on the course of heart failure in patients with a reduced ejection fraction. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

In a cohort of individuals with type 2 diabetes using the drug sulfasalazine, HbA1c lowering is associated with haematological changes.

OBJECTIVES: Several small studies indicate the sulphonamide component of the drug sulfasalazine lowers HbA1c. We investigated reduction of HbA1c following incident prescription of sulfasalazine and related aminosalicylates, lacking the sulphonamide group, in an observational cohort. RESEARCH DESIGN AND METHODS: Individuals in the Scottish Care Information Diabetes Collaboration (SCI-Diabetes) with type 2 diabetes and incident prescription for an aminosalicylate drug (sulfasalazine, mesalazine, olsalazine or balsalazide) were identified. Baseline and 6-month HbA1c were required for eligibility, to calculate HbA1c response. To investigate association with haemolysis, change in components of full blood count was assessed. Paired t-tests compared difference in baseline and treatment HbA1c measures and other clinical variables. RESULTS: In all, 113 individuals treated with sulfasalazine and 103 with mesalazine (lacking the sulphonamide group) were eligible, with no eligible individuals treated with olsalazine or balsalazide. Baseline characteristics were similar. Mean (SD) HbA1c reduction at 6 months was -9 ± 16 mmol/mol (-0.9 ± 1.4%) (p < 0.0001) in those taking sulfasalazine with no reduction in those taking mesalazine (2 ± 16 mmol/mol (0.2 ± 1.4%). Sulfasalazine but not mesalazine was associated with a mean (SD) increase in mean cell volume of 3.7 ± 5.6 fl (p < 0.0001) and decrease in red cell count of -0.2 ± 0.4 × 10-12 /L (p < 0.0001). CONCLUSIONS: In this observational, population-based study, sulfasalazine initiation was associated with a 6-month reduction in HbA1c . This correlated with haematological changes suggesting haemolytic effects of sulfasalazine. Haemolysis is proposed to contribute to HbA1c lowering through the sulphonamide pharmacophore. This suggests that HbA1c is not a reliable measure of glycaemia in individuals prescribed sulfasalazine.

Predicted Cardiac Hemodynamic Consequences of the Renal Actions of SGLT2i in the DAPA-HF Study Population: A Mathematical Modeling Analysis.

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study demonstrated that dapagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), reduced heart failure hospitalization and cardiovascular death in patients with heart failure with reduced ejection fraction (HF-rEF), with and without type 2 diabetes mellitus. Multiple potential mechanisms have been proposed to explain this benefit, which may be multifactorial. This study aimed to quantify the contribution of the known natriuretic/diuretic effects of SGLT2is to changes in cardiac hemodynamics, remodeling, and fluid homeostasis in the setting of HF-rEF. An integrated cardiorenal mathematical model was used to simulate inhibition of SGLT2 and its consequences on cardiac hemodynamics in a virtual population of HF-rEF patients generated by varying model parameters over physiologically plausible ranges and matching to baseline characteristics of individual DAPA-HF trial patients. Cardiovascular responses to placebo and SGLT2i over time were then simulated. The baseline characteristics of the HF-rEF virtual population and DAPA-HF were in good agreement. SGLT2i-induced diuresis and natriuresis that reduced blood volume and interstitial fluid volume, relative to placebo within 14 days. This resulted in decreased left ventricular end-diastolic volume and pressure, indicating reduced cardiac preload. Thereafter, blood volume and interstitial fluid volume again began to accumulate, but pressures and volumes remained shifted lower relative to placebo. After 1 year, left ventricle mass was lower and ejection fraction was higher than placebo. These simulations considered only hemodynamic consequences of the natriuretic/diuretic effects of SGLT2i, as other mechanisms may contribute additional benefits besides those predictions.

Chronic intermittent hypoxia impairs diuretic and natriuretic responses to volume expansion in rats with preserved low-pressure baroreflex control of the kidney.

We examined the effects of exposure to chronic intermittent hypoxia (CIH) on baroreflex control of renal sympathetic nerve activity (RSNA) and renal excretory responses to volume expansion (VE) before and after intrarenal transient receptor potential vanilloid 1 (TRPV1) blockade by capsaizepine (CPZ). Male Wistar rats were exposed to 96 cycles of hypoxia per day for 14 days (CIH) or normoxia. Urine flow and absolute Na+ excretion during VE were less in CIH-exposed rats, but the progressive decrease in RSNA during VE was preserved. Assessment of the high-pressure baroreflex revealed an increase in the operating and response range of RSNA and decreased slope in CIH-exposed rats with substantial hypertension [+19 mmHg basal mean arterial pressure (MAP)] but not in a second cohort with modest hypertension (+12 mmHg). Intrarenal CPZ caused diuresis, natriuresis, and a reduction in MAP in sham-exposed (sham) and CIH-exposed rats. After intrarenal CPZ, diuretic and natriuretic responses to VE in CIH-exposed rats were equivalent to those of sham rats. TRPV1 expression in the renal pelvic wall was similar in both experimental groups. Exposure to CIH did not elicit glomerular hypertrophy, renal inflammation, or oxidative stress. We conclude that exposure to CIH 1) does not impair the low-pressure baroreflex control of RSNA; 2) has modest effects on the high-pressure baroreflex control of RSNA, most likely indirectly due to hypertension; 3) can elicit hypertension in the absence of kidney injury; and 4) impairs diuretic and natriuretic responses to fluid overload. Our results suggest that exposure to CIH causes renal dysfunction, which may be relevant to obstructive sleep apnea.

Hydroxyethyl starch for perioperative goal-directed fluid therapy in 2020: a narrative review.

BACKGROUND: Perioperative fluid management - including the type, dose, and timing of administration -directly affects patient outcome after major surgery. The objective of fluid administration is to optimize intravascular fluid status to maintain adequate tissue perfusion. There is continuing controversy around the perioperative use of crystalloid versus colloid fluids. Unfortunately, the importance of fluid volume, which significantly influences the benefit-to-risk ratio of each chosen solution, has often been overlooked in this debate. MAIN TEXT: The volume of fluid administered during the perioperative period can influence the incidence and severity of postoperative complications. Regrettably, there is still huge variability in fluid administration practices, both intra-and inter-individual, among clinicians. Goal-directed fluid therapy (GDFT), aimed at optimizing flow-related variables, has been demonstrated to have some clinical benefit and has been recommended by multiple professional societies. However, this approach has failed to achieve widespread adoption. A closed-loop fluid administration system designed to assist anesthesia providers in consistently applying GDFT strategies has recently been developed and tested. Such an approach may change the crystalloid versus colloid debate. Because colloid solutions have a more profound effect on intravascular volume and longer plasma persistence, their use in this more "controlled" context could be associated with a lower fluid balance, and potentially improved patient outcome. Additionally, most studies that have assessed the impact of a GDFT strategy on the outcome of high-risk surgical patients have used hydroxyethyl starch (HES) solutions in their protocols. Some of these studies have demonstrated beneficial effects, while none of them has reported severe complications. CONCLUSIONS: The type and volume of fluid used for perioperative management need to be individualized according to the patient's hemodynamic status and clinical condition. The amount of fluid given should be guided by well-defined physiologic targets. Compliance with a predefined hemodynamic protocol may be optimized by using a computerized system. The type of fluid should also be individualized, as should any drug therapy, with careful consideration of timing and dose. It is our perspective that HES solutions remain a valid option for fluid therapy in the perioperative context because of their effects on blood volume and their reasonable benefit/risk profile.

Cardiovascular Volume Reserve in Patients with Heart Failure and Reduced Ejection Fraction.

This study aimed to investigate the relationship between intravascular volume and intracardiac filling pressures in stable HF patients with reduced ejection fraction (HFrEF). A total of 40 HFrEF patients (LVEF 36 ± 10%) (10 subjects with a pulmonary artery catheter) underwent intravascular volume expansion with 1 L hydroxyl-ethyl-starch over 3 h with coinciding intravascular volume measurements (technetium (99 tc)-labeled red blood cell technique). Intravascular blood volume increased from 5.0 ± 1.0 L to 5.7 ± 1.0 L (p < 0.0001). No change in clinical status, echocardiographic indices, or cardiac filling pressures was noticed. Invasively measured right atrial pressure and pulmonary arterial wedge pressure increased significantly immediately after start of infusion (4 ± 2 mmHg to 8 ± 4 mmHg; p = 0.01 and 10 ± 3 mmHg to 15 ± 6 mmHg; p = 0.01, respectively), decreased afterwards, and remained stable for 3 h (6 ± 2 mmHg and 14 ± 4 mmHg, respectively). The accuracy of cardiac filling pressure estimates to predict intravascular volume expansion was low (all AUC < 0.65).

Management of perioperative volume therapy - monitoring and pitfalls.

Over 300 million surgical procedures are performed every year worldwide. Anesthesiologists play an important role in the perioperative process by assessing the overall risk of surgery and aim to reduce the risk of complications. Perioperative hemodynamic and volume management can help to improve outcomes in perioperative patients. There has been ongoing discussion about goal-directed therapy. However, there is a consensus that fluid overload and severe fluid depletion in the perioperative period are harmful and can lead to adverse outcomes. This article provides an overview of how to evaluate the fluid responsiveness of patients, details which parameters could be used, and what limitations should be noted.

A randomized, controlled, double-blind crossover study on the effects of isoeffective and isovolumetric intravenous crystalloid and gelatin on blood volume, and renal and cardiac hemodynamics.

BACKGROUND & AIMS: Blood volume expanding properties of colloids are superior to crystalloids. In addition to oncotic/osmotic properties, the electrolyte composition of infusions may have important effects on visceral perfusion, with infusions containing supraphysiological chloride causing hyperchloremic acidosis and decreased renal blood flow. In this non-inferiority study, a validated healthy human subject model was used to compare effects of colloid (4% succinylated gelatin) and crystalloid fluid regimens on blood volume, renal function, and cardiac output. METHODS: Healthy male participants were given infusions over 60 min > 7 days apart in a randomized, crossover manner. Reference arm (A): 1.5 L of Sterofundin ISO, isoeffective arm (B): 0.5 L of 4% Gelaspan®, isovolumetric arm (C): 0.5 L of 4% Gelaspan® and 1 L of Sterofundin ISO (all B. Braun, Melsungen, Germany). Participants were studied over 240 min. Changes in blood volume were calculated from changes in weight and hematocrit. Renal volume, renal artery blood flow (RABF), renal cortex perfusion and diffusion, and cardiac index were measured with magnetic resonance imaging. RESULTS: Ten of 12 males [mean (SE) age 23.9 (0.8) years] recruited, completed the study. Increase in body weight and extracellular fluid volume were significantly less after infusion B than infusions A and C, but changes in blood volume did not significantly differ between infusions. All infusions increased renal volume, with no significant differences between infusions. There was no significant difference in RABF across the infusion time course or between infusion types. Renal cortex perfusion decreased during the infusion (mean 18% decrease from baseline), with no significant difference between infusions. There was a trend for increased renal cortex diffusion (4.2% increase from baseline) for the crystalloid infusion. All infusions led to significant increases in cardiac index. CONCLUSIONS: A smaller volume of colloid (4% succinylated gelatin) was as effective as a larger volume of crystalloid at expanding blood volume, increasing cardiac output and changing renal function. Significantly less interstitial space expansion occurred with the colloid. TRIAL REGISTRATION: The protocol was registered with the European Union Drug Regulating Authorities Clinical Trials Database (https://eudract.ema.europa.eu) (EudraCT No. 2013-003260-32).

Effect of low-dose dexamethasone on extra vascular lung water in patients following on-pump elective primary coronary artery bypass graft surgery.

Background: The primary objective was to compare the effect of a low-dose dexamethasone as against a saline placebo on extravascular lung water index (EVLWI) in patients undergoing elective primary coronary artery bypass surgery. The secondary endpoints were to assess the effect of dexamethasone on other volumetric parameters (pulmonary vascular permeability index, global end diastolic volume index, and intrathoracic blood volume index), Vasoactive Inotrope Scores, hemodynamic parameters and serum osmolality in both groups. Settings and Design: Prospective observational study performed at a single tertiary cardiac care center. Materials and Methods: Twenty patients were randomized to receive either dexamethasone (steroid group, n = 10) or placebo (nonsteroid group, n = 10) twice before the institution of cardiopulmonary bypass (CPB). EVLWI and other volumetric parameters were obtained with the help of VolumeView™ Combo Kit connected to EV 1000 clinical platform at predetermined intervals. Hemodynamic parameters, vasoactive-inotropic Scores, hematocrit values were recorded at the predetermined time intervals. Baseline and 1st postoperative day serum osmolality values were also obtained. Results: The two groups were evenly matched in terms of demographic and CPB data. Intra- and inter-group comparison of the baseline EVLWI including other volumetric and hemodynamic parameters with those recorded at subsequent intervals revealed no statistical difference and was similar. Generalized estimating equation model was obtained to compare the changes between the groups over the entire study period which showed that on an average the changes between the steroid and nonsteroid group in terms of all volumetric parameters were not statistically significant. Conclusions: There were no beneficial effects of low-dose dexamethasone on EVLWI or other volumetric parameters in patients subjected to on-pump primary coronary bypass surgery. Hemodynamic parameters were also not affected. Probably, the advanced hemodynamic monitoring aided in optimal fluid management in the nonsteroidal group impacting EVLW accumulation.

The effect of dopamine on pulmonary diffusing capacity and capillary blood volume responses to exercise in young healthy humans.

NEW FINDINGS: What is the Central question? Does dopamine, a pulmonary vascular vasodilator, contribute to the regulation of pulmonary diffusing capacity and capillary blood volume responses to exercise and exercise tolerance? What are the main findings and their importance? Dopamine appears not to be important for regulating pulmonary diffusing capacity or pulmonary capillary blood volume during exercise in healthy participants. Dopamine blockade trials demonstrated that endogenous dopamine is important for maintaining exercise tolerance; however, exogenous dopamine does not improve exercise tolerance. ABSTRACT: Pulmonary capillary blood volume (Vc ) and diffusing membrane capacity (Dm ) expansion are important contributors to the increased pulmonary diffusing capacity (DLCO ) observed during upright exercise. Dopamine is a pulmonary vascular vasodilator, and recent studies suggest that it may play a role in Vc regulation through changes in pulmonary vascular tone. The purpose of this study was to examine the effect of exogenous dopamine and dopamine receptor-2 (D2 -receptor) blockade on DLCO , Vc and Dm at baseline and during cycle exercise, as well as time-to-exhaustion at 85% of V̇O2peak . We hypothesized that dopamine would increase DLCO , Vc , Dm and time-to-exhaustion, while D2 -receptor blockade would have the opposite effect. We recruited 14 young, healthy, recreationally active subjects ( V̇O2peak 45.8 ± 6.6 ml kg-1  min-1 ). DLCO , Vc and Dm were determined at baseline and during exercise at 60% and 85% of V̇O2peak under the following randomly assigned and double blinded conditions: (1) intravenous saline and placebo pill, (2) intravenous dopamine (2 µg kg-1  min-1 ) and placebo pill, and (3) intravenous saline and D2 -receptor antagonist (20 mg oral metoclopramide). Exogenous dopamine and dopamine blockade had no effect on DLCO , Vc and Dm responses at baseline or during exercise. Dopamine blockade reduced time-to-exhaustion by 47% (P = 0.04), but intravenous dopamine did not improve time-to-exhaustion. While dopamine modulation did not affect DLCO , Vc or Dm , the reduction in time-to-exhaustion with D2 -receptor blockade suggests that endogenous dopamine is important for exercise tolerance.

Modification of the CO-rebreathing method to determine haemoglobin mass and blood volume in patients suffering from chronic mountain sickness.

NEW FINDINGS: What is the central question of this study? Is it necessary to modify the CO-rebreathing method to acquire reliable measurements of haemoglobin mass in patients with chronic mountain sickness? What is the main finding and its importance? The CO-rebreathing method must be modified because of the prolonged CO-mixing time in patients with chronic mountain sickness. After adaptation of the blood sampling method, reliable and valid results were attained. With this modification, it is possible to quantify the extent of polycythaemia and to distinguish between a haemoconcentration and an exclusive enhancement of erythrocyte volume. ABSTRACT: Patients suffering from chronic mountain sickness (CMS) exhibit extremely high haemoglobin concentrations. Their haemoglobin mass (Hbmass), however, has rarely been investigated. The CO-rebreathing protocol for Hbmass determination in those patients might need to be modified because of restricted peripheral perfusion. The aim of this study was to evaluate the CO uptake and carboxyhaemoglobin-mixing time in the blood of CMS patients and to adapt the CO-rebreathing method for this group. Twenty-five male CMS patients living at elevations between 3600 and 4100 m above sea level were compared with ethnically matched healthy control subjects from identical elevations (n = 11) and near sea level (n = 9) and with a Caucasian group from sea level (n = 6). CO rebreathing was performed for 2 min, and blood samples were taken for the subsequent 30 min. After the method was modified, its reliability was evaluated in test-retest experiments (n = 28), and validity was investigated by measuring the Hbmass before and after the phlebotomy of 500 ml (n = 4). CO uptake was not affected by CMS. The carboxyhaemoglobin mixing was completed after 8 min in the Caucasian group but after 14 min in the groups living at altitude. When blood was sampled 14-20 min after inhalation, the typical error of the method was 1.6% (confidence limits 1.2-2.5%). After phlebotomy, Hbmass decreased from 1779 ± 123 to 1650 ± 129 g, and no difference was found between the measured and calculated Hbmass (1666 ± 122 g). When the time of blood sampling was adapted to accommodate a prolonged carboxyhaemoglobin-mixing time, the CO-rebreathing method became a reliable and valid tool to determine Hbmass in CMS patients.

Iloprost infusion prevents the insulin-induced reduction in skeletal muscle microvascular blood volume but does not enhance peripheral glucose uptake in type 2 diabetic patients.

AIMS: In type 2 diabetes impaired insulin-induced muscle perfusion is thought to contribute to reduced whole-body glucose uptake. In this study, we examined the effects of iloprost, a stable prostacyclin analogue, on insulin-induced muscle capillary recruitment and whole-body glucose uptake. MATERIALS AND METHODS: In a randomized cross-over design, 12 type 2 diabetes patients (age, 55 [46-69] years; BMI, 33.1 [31.0-39] kg/m2 ) underwent two hyperinsulinaemic-euglycaemic clamps, one with and one without simultaneous low-dose iloprost infusion. Contrast-enhanced ultrasonography of the vastus lateralis muscle was performed before and during the clamp. Muscle capillary recruitment was calculated as percentage change in microvascular blood volume (MBV) before and during the clamp. RESULTS: Insulin infusion reduced skeletal muscle MBV by ~50% compared to the fasting state (fasting, 1.77·10-4 [1.54·10-5 -2.44·10-3 ] arbitrary units (AU); hyperinsulinaemia, 6.69·10-5 [2.68·10-6 -5.72·10-4 ] AU; P = 0.050). Infusion of iloprost prevented this insulin-induced skeletal muscle capillary derecruitment, from (-49.5 [-89.5 to 55.3] %) to (8.0 [-68.8 to 306.6] %), for conditions without and with iloprost, respectively. The rate of glucose disappearance (Rd ) did not change significantly during iloprost infusion (17.3 [10.0-40.8] µmol/kg/min) compared with insulin infusion alone (17.6 [9.9-68.7] µmol/kg/min). CONCLUSIONS: Our data suggest that acute improvement in insulin-stimulated muscle perfusion is not an attractive therapeutic approach to bypass cellular resistance to glucose uptake in type 2 diabetes. Whether long-term improvements in insulin-induced muscle perfusion may prove beneficial for glucose disposal remains to be determined.

Longitudinal Volume Quantification of Deep Medullary Veins in Patients with Cerebral Venous Sinus Thrombosis : Venous Volume Assessment in Cerebral Venous Sinus Thrombosis Using SWI.

PURPOSE: Susceptibility-weighted imaging (SWI) visualizes small cerebral veins with high sensitivity and could, thus, enable quantification of hemodynamics of deep medullary veins. We aimed to evaluate volume changes of deep medullary veins in patients with acute cerebral venous sinus thrombosis (CVST) over time in comparison to healthy controls. METHODS: All magnetic resonance imaging (MRI) experiments were executed at 3 T using a 32-channel head coil. Based on SWI and semiautomatic postprocessing (statistical parametric mapping [SPM8] and ANTs), the volume of deep medullary veins was quantified in 14 patients with acute CVST at baseline and the 6­month follow-up, as well as in 13 healthy controls undergoing repeated MRI examination with an interscan interval of at least 1 month. RESULTS: Deep medullary venous volume change over time was significantly different between healthy controls and patient groups (p < 0.001). Patients with superior sagittal sinus thrombosis (SSST) showed a significant decline from baseline to follow-up measurements (9.8 ± 4.9 ml versus 7.5 ± 4.2 ml; p = 0.02), whereas in patients with transverse sinus thrombosis (TST) and healthy controls no significant volume changes were observable. CONCLUSIONS: Venous volume quantification was feasible and reproducible both in healthy volunteers and in patients. The decrease of venous volume in patients over time represents improvement of venous drainage, reduction of congestion, and normalization of microcirculation due to treatment. Thus, quantification of venous microcirculation could be valuable for estimation of prognosis and guidance of CVST therapy in the future.

Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis.

The effect of a sodium glucose cotransporter 2 inhibitor (SGLT2i) in reducing heart failure hospitalization in the EMPA-REG OUTCOMES trial has raised the possibility of using these agents to treat established heart failure. We hypothesize that osmotic diuresis induced by SGLT2 inhibition, a distinctly different diuretic mechanism than that of other diuretic classes, results in greater electrolyte-free water clearance and, ultimately, in greater fluid clearance from the interstitial fluid (IF) space than from the circulation, potentially resulting in congestion relief with minimal impact on blood volume, arterial filling and organ perfusion. We utilize a mathematical model to illustrate that electrolyte-free water clearance results in a greater reduction in IF volume compared to blood volume, and that this difference may be mediated by peripheral sequestration of osmotically inactive sodium. By coupling the model with data on plasma and urinary sodium and water in healthy subjects who received either the SGLT2i dapagliflozin or loop diuretic bumetanide, we predict that dapagliflozin produces a 2-fold greater reduction in IF volume compared to blood volume, while the reduction in IF volume with bumetanide is only 78% of the reduction in blood volume. Heart failure is characterized by excess fluid accumulation, in both the vascular compartment and interstitial space, yet many heart failure patients have arterial underfilling because of low cardiac output, which may be aggravated by conventional diuretic treatment. Thus, we hypothesize that, by reducing IF volume to a greater extent than blood volume, SGLT2 inhibitors might provide better control of congestion without reducing arterial filling and perfusion.

Influence of Inhaled Amiloride on Lung Fluid Clearance in Response to Normobaric Hypoxia in Healthy Individuals.

Wheatley, Courtney M., Sarah E. Baker, Bryan J. Taylor, Manda L. Keller-Ross, Steven C. Chase, Alex R. Carlson, Robert J. Wentz, Eric M. Snyder, and Bruce D. Johnson. Influence of inhaled amiloride on lung fluid clearance in response to normobaric hypoxia in healthy individuals. High Alt Med Biol 18:343-354, 2017. AIM: To investigate the role of epithelial sodium channels (ENaC) on lung fluid clearance in response to normobaric hypoxia, 20 healthy subjects were exposed to 15 hours of hypoxia (fraction of inspired oxygen [FiO2] = 12.5%) on two randomized occasions: (1) inhaled amiloride (A) (1.5 mg/5 mL saline); and (2) inhaled saline placebo (P). Changes in lung fluid were assessed through chest computed tomography (CT) for lung tissue volume (TV), and the diffusion capacity of the lungs for carbon monoxide (DLCO) and nitric oxide (DLNO) for pulmonary capillary blood volume (VC). Extravascular lung water (EVLW) was derived as TV-VC and changes in the CT attenuation distribution histograms were reviewed. RESULTS: Normobaric hypoxia caused (1) a reduction in EVLW (change from baseline for A vs. P, -8.5% ± 3.8% vs. -7.9% ± 5.2%, p < 0.05), (2) an increase in VC (53.6% ± 28.9% vs. 53.9% ± 52.3%, p < 0.05), (3) a small increase in DLCO (9.6% ± 29.3% vs. 9.9% ± 23.9%, p > 0.05), and (4) CT attenuation distribution became more negative, leftward skewed, and kurtotic (p < 0.05). CONCLUSION: Acute normobaric hypoxia caused a reduction in lung fluid that was unaffected by ENaC inhibition through inhaled amiloride. Although possible amiloride-sensitive ENaC may not be necessary to maintain lung fluid balance in response to hypoxia, it is more probable that normobaric hypoxia promotes lung fluid clearance rather than accumulation for the majority of healthy individuals. The observed reduction in interstitial lung fluid means alveolar fluid clearance may not have been challenged.

Renal response to intravascular volume expansion in euvolemic heart failure patients with reduced ejection fraction: Mechanistic insights and clinical implications.

BACKGROUND: Untreated and preclinical heart failure patients with reduced ejection fraction (HFrEF) have an impaired ability to alleviate excess intravascular volume. OBJECTIVES: To investigate 1) the renal response to intravascular volume expansion in euvolemic and optimally treated HFrEF patients and 2) loop diuretic efficiency. METHODS: 14 healthy and 28 HFrEF patients underwent intravascular volume expansion with 1l hydroxyl ethyl starch 6% during 3h after which a loop diuretic was administered. Clinical parameters, neurohormones and urine were hourly measured. RESULTS: In response to intravascular volume expansion (+0.6±0.2L; p<0.001 vs baseline) HFrEF patients demonstrated significantly lower natriuresis compared to healthy subjects (0.9±0.5 versus 1.7±0.6g/3h; p<0.001). However, natriuresis varied substantially with half of HFrEF patients exhibiting a response within the range of healthy and the other half demonstrating a significantly decreased response (1.4±0.4 vs 0.5±0.2g/3h; p<0.001). Natriuresis was associated with glomerular filtration function (eGFR), NT-proBNP and tubular fractional sodium excretion (FENa). Loop diuretic efficiency was significantly lower in HFrEF patients compared to healthy subjects (3.4±0.7 vs 2.6±1.1g/2h; p=0.044) but was only related to eGFR (R2=0.47; p<0.001) and independent of FENa (R2=0.07; p=0.20). Loop diuretics increased FENa similarly in healthy subjects and HFrEF patients (9.1±2.4 vs 9.3±3.3%; p=0.64). CONCLUSION: The ability of the kidneys to remove excess intravascular volume is decreased in a substantial amount of euvolemic and optimally treated HFrEF patients. Renal response relates to filtration function and tubular sodium handling. In contrast, loop diuretics can surmount decreased renal tubular sodium excretion but remain dependent on eGFR.