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Abstract Rationale Difficult weaning from mechanical ventilation is often associated with fluid overload. B-type natriuretic peptide (BNP) has been proposed as a tool for predicting and detecting weaning failure of cardiovascular origin. Objectives To investigate whether fluid management guided by daily BNP plasma concentrations improves weaning outcomes compared with empirical therapy dictated by clinical acumen. Methods In a randomized controlled multicenter study, we allocated 304 patients to either a BNP-driven or physician-driven strategy of fluid management during ventilator weaning. To standardize the weaning process, patients in both groups were ventilated with an automatic computer-driven weaning system. The primary end point was time to successful extubation. Measurements and Main Results In the BNP-driven group, furosemide and acetazolamide were given more often and in higher doses than in the control group, resulting in a more negative median (interquartile range) fluid balance during weaning (–2,320 [–4,735, 738] vs. -180 [–2,556, 2,832] ml; P < 0.0001). Time to successful extubation was significantly shorter with the BNP-driven strategy (58.6 [23.3, 139.8] vs. 42.4 [20.8, 107.5] h; P = 0.034). The BNP-driven strategy increased the number of ventilator-free days but did not change length of stay or mortality. The effect on weaning time was strongest in patients with left ventricular systolic dysfunction. The two strategies did not differ significantly regarding electrolyte imbalance, renal failure, or shock. Conclusions Our results suggest that a BNP-driven fluid management strategy decreases the duration of weaning without increasing adverse events, especially in patients with left ventricular systolic dysfunction. Clinical trial registered with www.clinicaltrials.gov (NCT00473148).

Background Sodium-glucose cotransport-2 inhibitors (SGLT2i) have established benefits in diabetes mellitus, heart failure, and chronic kidney disease, but their physiological effects during critical illness remain unclear. We explored whether dapagliflozin affected urinary output, fluid balance, and other physiological parameters in critically ill patients with acute organ dysfunction. Methods This secondary analysis of the DEFENDER trial included 401 critically ill patients with acute organ dysfunction randomized to receive dapagliflozin 10 mg daily or standard care. We analyzed urinary output, fluid balance, electrolytes, acid–base status, glycemia, and vasopressor requirements over the first five days using Bayesian models. Results Dapagliflozin progressively increased urinary output (day 5: + 157 mL/day, 95% CrI -90 to 386, probability 90%) and decreased fluid balance (day 5: -290 mL/day, 95% CrI -564 to -27, probability 98%). Furosemide use was lower in the dapagliflozin group (overall -3%, 95% CrI -7% to 1%, probability 90%). Dapagliflozin had minimal effects on creatinine and electrolytes but was associated with progressive small decreases in pH (day 5: -0.02, probability 96%). Maximum glucose levels were consistently lower with dapagliflozin (-9 mg/dL overall, probability 83%). Norepinephrine requirements showed a time-dependent increase in the dapagliflozin group, with the expected dose difference reaching 0.034 mcg/kg/min by day 5 (probability 94%), and heterogeneity analysis revealed larger effects in patients with sepsis or on mechanical ventilation. Conclusion This exploratory analysis suggests dapagliflozin may enhance diuresis and reduce loop diuretic requirements in critically ill patients, potentially at the cost of increased vasopressor needs. Glucose levels were likely slightly lower with dapagliflozin. Given the study's limitations and heterogeneous treatment effects, these findings should be considered hypothesis-generating pending confirmation in prospective trials.

Balanced fluid replacement solutions can possibly reduce the risks for electrolyte imbalances, for acid-base imbalances, and thus for renal failure. To assess the intraoperative change of base excess (BE) and chloride in serum after treatment with either a balanced gelatine/electrolyte solution or a non-balanced gelatine/electrolyte solution, a prospective, controlled, randomized, double-blind, dual centre phase III study was conducted in two tertiary care university hospitals in Germany. 40 patients of both sexes, aged 18 to 90 years, who were scheduled to undergo elective abdominal surgery with assumed intraoperative volume requirement of at least 15 mL/kg body weight gelatine solution were included. Administration of study drug was performed intravenously according to patients need. The trigger for volume replacement was a central venous pressure (CVP) minus positive end-expiratory pressure (PEEP) <10 mmHg (CVP <10 mmHg). The crystalloid:colloid ratio was 1:1 intra- and postoperatively. The targets for volume replacement were a CVP between 10 and 14 mmHg minus PEEP after treatment with vasoactive agent and mean arterial pressure (MAP) > 65 mmHg. The primary endpoints, intraoperative changes of base excess -2.59 ± 2.25 (median: -2.65) mmol/L (balanced group) and -4.79 ± 2.38 (median: -4.70) mmol/L (non-balanced group)) or serum chloride 2.4 ± 1.9 (median: 3.0) mmol/L and 5.2 ± 3.1 (median: 5.0) mmol/L were significantly different (p = 0.0117 and p = 0.0045, respectively). In both groups (each n = 20) the investigational product administration in terms of volume and infusion rate was comparable throughout the course of the study, i.e. before, during and after surgery. Balanced gelatine solution 4% combined with a balanced electrolyte solution demonstrated significant smaller impact on blood gas analytic parameters in the primary endpoints BE and serum chloride when compared to a non-balanced gelatine solution 4% combined with NaCl 0.9%. No marked treatment differences were observed with respect to haemodynamics, coagulation and renal function. ClinicalTrials.gov (NCT01515397) and clinicaltrialsregister.eu, EudraCT number 2010-018524-58.

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

ObjectivesMedical history, physical examination and laboratory testing are not optimal for the assessment of volume status in heart failure (HF) patients. We aimed to study the clinical influence of focused ultrasound of the pleural cavities and inferior vena cava (IVC) performed by specialised nurses to assess volume status in HF patients at an outpatient clinic.MethodsHF outpatients were prospectively included and underwent laboratory testing, history recording and clinical examination by two nurses with and without an ultrasound examination of the pleural cavities and IVC using a pocket-size imaging device, in random order. Each nurse worked in a team with a cardiologist. The influence of the different diagnostic tests on diuretic dosing was assessed descriptively and in linear regression analyses.ResultsSixty-two patients were included and 119 examinations were performed. Mean±SD age was 74±12 years, EF was 34±14%, and N-terminal pro-brain natriuretic peptide (NT-proBNP) value was 3761±3072 ng/L. Dosing of diuretics differed between the teams in 31 out of 119 consultations. Weight change and volume status assessed clinically with and without ultrasound predicted dose adjustment of diuretics at follow-up (p<0.05). Change of oedema, NT-proBNP, creatinine, and symptoms did not (p≥0.10). In adjusted analyses, only volume status based on ultrasound predicted dose adjustments of diuretics at first visit and follow-up (all ultrasound p≤0.01, all other p≥0.2).ConclusionsUltrasound examinations of the pleural cavities and IVC by nurses may improve diagnostics and patient care in HF patients at an outpatient clinic, but more studies are needed to determine whether these examinations have an impact on clinical outcomes.Trial registration numberNCT01794715.

Background: Maintaining adequate hydration is critical to optimal health, well-being, and performance. Those who are physically active in stressful environments, such as warm and/or humid scenarios, may be at particular risk for dehydration with ensuing loss of electrolytes, leading to sluggishness and impaired physical performance. Methods: We evaluated an electrolyte and amino acid product containing L-alanine and L-glutamine, as well as select vitamins [B3 (niacin), B5 (pantothenic acid), B6 (pyridoxine), B12 (cobalamin), and vitamin C (ascorbic acid)]. Subjects (n = 40; four groups, n = 10) were randomized to consume either a placebo packet or one, two, or three packets daily of the test product for 4 weeks with site visits at 0, 2, and 4 weeks. We tested safety and tolerability by analyzing hematological parameters (complete blood counts), metabolic parameters (hepatic, renal, acid–base balance), urinalysis end products, thyroid status [T3 (triiodothyronine), T4 (thyroxine), TSH (thyroid-stimulating hormone)], tolerability (via questionnaire), vital signs, and dietary intake. Results: Statistical analyses displayed ten significant main effects (p < 0.05) with white blood cells, lymphocytes, neutrophils, urinary pH, thyroxine, urination frequency, calcium, calories, fat, and cholesterol. Interactions for time and group (p < 0.05) were observed for MCV, eGFR, potassium, overall tolerability, bloating, and cramping—demonstrating mild GA disturbances. Little to no change of physiological relevance was noted for any outcome variable, regardless of dosing level. Conclusions: Our results indicate the product was well-tolerated at all dosing levels and no significant adverse changes occurred in any of the test parameters compared to the placebo group, indicating relative safety of ingestion over a 4-week treatment period, at the volumes used, and outside the context of physical stress.

This study investigated the efficacy of ingesting an oral rehydration solution (DD) that has a high electrolyte concentration after exercise on fluid balance and cycling performance in comparison with a sports drink (SD) and water (WA). Nine healthy males aged 24 ± 2 years (mean ± SD), with peak oxygen uptake (VO2 peak) 55 ± 6 mL·kg−1·min−1 completed three experimental trials in a randomised manner ingesting WA, SD (carbohydrates: 62 g·L−1, sodium: 31 ± 3 mmol·L−1) or DD (carbohydrates: 33 g·L−1, sodium: 60 ± 3 mmol·L−1). On all trials, fluid was ingested during 75 min cycling at 65% VO2 peak (temperature: 30.4 ± 0.3 °C, relative humidity: 76 ± 1%, simulated wind speed: 8.0 ± 0.6 m·s−1) and during 2 h of recovery (temperature: 23.0 ± 1.0 °C, relative humidity: 67 ± 2%), with the total volume equivalent to 150% of sweat loss during the ride. A 45 min pre-load cycling time trial at a 65% VO2 peak followed by a 20 km time trial was conducted after a further 3 h of recovery. Fluid retention was higher with DD (30 ± 15%) than WA (−4 ± 19%; p < 0.001) and SD (10 ± 15%; p = 0.002). Mean ratings of palatability were similar among drinks (WA: 4.25 ± 2.60; SD: 5.61 ± 1.79; DD: 5.40 ± 1.58; p = 0.33). Although time trial performance was similar across all three trials (WA: 2365 ± 321 s; SD: 2252 ± 174 s; DD: 2268 ± 184 s; p = 0.65), the completion time was faster in eight participants with SD and seven participants with DD than with WA. Comparing SD with DD, completion time was reduced in five participants and increased in four participants. DD was more effective at restoring the fluid deficit during recovery from exercise than SD and WA without compromising the drink’s palatability with increased sodium concentration. Most individuals demonstrated better endurance exercise time trial performance with DD and SD than with WA.

Background In cardiac surgery with cardiopulmonary bypass (CPB), large amounts of fluids are administered. CPB priming with crystalloid solution causes marked hemodilution and fluid extravasation. Colloid solutions may reduce fluid overload because they have a better volume expansion effect than crystalloids. The European Medicines Agency does not recommend the use of hydroxyethyl starch solutions (HES) due to harmful renal effects. Albumin solution does not impair blood coagulation but the findings on kidney function are conflicting. On the other hand, albumin may reduce endothelial glycocalyx destruction and decrease platelet count during CPB. No large randomized, double-blind, clinical trials have compared albumin solution to crystalloid solution in cardiac surgery. Methods/design In this single-center, double-blind, randomized controlled trial comprising 1386 adult cardiac surgery patients, 4% albumin solution will be compared to Ringer’s acetate solution in CPB priming and volume replacement up to 3200 mL during surgery and the first 24 h of intensive care unit stay. The primary efficacy outcome is the number of patients with at least one major adverse event (MAE) during 90 postoperative days (all-cause death, acute myocardial injury, acute heart failure or low output syndrome, resternotomy, stroke, major arrhythmia, major bleeding, infection compromising post-procedural rehabilitation, acute kidney injury). Secondary outcomes are total number of MAEs, incidence of major adverse cardiac events (MACE; cardiac death, acute myocardial injury, acute heart failure, arrhythmia), amount of each type of blood product transfused (red blood cells, fresh frozen plasma, platelets), total fluid balance at the end of the intervention period, total measured blood loss, development of acute kidney injury, days alive without mechanical ventilation in 90 days, days alive outside intensive care unit at 90 days, days alive at home at 90 days, and 90-day mortality. Discussion The findings of this study will provide new evidence regarding efficacy and safety of albumin solution in adult patients undergoing cardiac surgery with CPB. Trial registration EudraCT (clinicaltrialsregister.eu) 2015–002556-27 Registered 11 Nov 2016 and ClinicalTrials.gov NCT02560519 . Registered 25 Sept 2015.

Background Investigations of the effect of beverages containing carbohydrates, only, on the sodium and fluid balance during intermittent exercise of high intensity are rare. Therefore, we compared the effects of water and carbohydrate supplementation on plasma, blood volume, and electrolyte shifts during intermittent exercise. Methods Ten male subjects performed an intermittent exercise test twice. In one trial, tap water (4 ml/kg/15 min) was consumed (Plac trial). In the other trial, the same amount of water supplemented with maltodextrin to achieve a 9.1 % carbohydrate solution (CHO trial) was ingested. Training schedule: warm-up at 50 % for 15 min. Afterwards, power changed between 100 % of the maximum power from a previous incremental test minus 10 and 10 W for each 30 s. Venous blood was sampled to measure electrolytes, osmolality, [protein], hct, [Lactate], [glucose], [Hb] and catecholamines. Hydration status was evaluated by BIA before and after exercise. Results After beverage ingestion [glucose] was significantly higher in CHO until the end of the trial. Starting with similar resting values, osmolality increased significantly more during CHO ( p  = 0.002). PV decreased by 5 % under both conditions, but recovered partly during exercise under Plac ( p  = 0.002). [Na+] and [Cl − ] decreased with Plac during exercise (both p  < 0.001) but remained constant during exercise with CHO. Conclusions Sole carbohydrate supplementation seems to stabilise plasma [Na+]. This cannot be explained simply by a cotransport of glucose and [Na+], because that should lead to a recovery of the blood and plasma volume under CHO. In contrast, this was found during exercise with Plac.

Traditionally, it has been thought necessary to lose 2% of body mass due to dehydration to disrupt functioning, although recently, adverse effects have been reported, with a loss of 0.5%–0.7%. It is, however, unclear whether the response to small reductions in mass reflects dehydration as homeostatic mechanisms are thought to be effective. As psychological responses are most commonly reported, it is strange that the possibility of a placebo response has not been considered. Individuals were therefore subject to a temperature of 30 °C for three hours, and mood and cognition were monitored. To consider changes in hydration status, drinks were compared, differing in their ability to rehydrate due to the presence or absence of electrolytes. The possibility of a placebo response was considered by comparing the response to plain or coloured water. Not drinking was disruptive, although a combination of plain water and electrolyte tended to be the most effective means of preventing a decline in mood, indicating a role for rehydration after a loss of 0.66% body mass. There was, however, also evidence of a placebo response: a combination of plain water and electrolyte tended to be better able to prevent a decline in mood than coloured water and electrolyte.