Diuretic responses to Ringer's solution and 20% albumin at different arterial pressures.

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.

Effect of maneuvers, diuresis, and fluid administration on ultrasound-measured liver stiffness after Fontan.

BACKGROUND: To determine the effect of stress maneuvers/interventions on ultrasound liver stiffness measurements (LSMs) in patients with Fontan circulation and healthy controls. METHODS: In this prospective, IRB-approved study of 10 patients after Fontan palliation and 10 healthy controls, ultrasound 2D shear-wave elastography LSMs were acquired at baseline and after maximum inspiration, expiration, standing, handgrip, aerobic exercise, i.v. fluid (500 mL normal saline) administration, and i.v. furosemide (20 mg) administration. Absolute and percent change in LSM were compared between baseline and each maneuver, and then from fluid infusion to after diuresis. RESULTS: Median ages were 25.5 and 26 years in the post-Fontan and control groups (p = 0.796). LSMs after Fontan were higher at baseline (2.6 vs. 1.3 m/s) and with all maneuvers compared to controls (all p < 0.001). Changes in LSM with maneuvers, exercise, fluid, or diuresis were not significant when compared to baseline in post-Fontan patients. LSM in controls increased with inspiration (+0.02 m/s, 1.6%, p = 0.03), standing (+0.07 m/s, 5.5%, p = 0.03), and fluid administration (+0.10 m/s, 7.8%, p = 0.002), and decreased 60 minutes after diuretic administration (-0.05 m/s, -3.9%, p = 0.01) compared to baseline. LSM after diuretic administration significantly decreased when compared to after i.v. fluid administration at 30 minutes (-0.79 m/s, -26.5%, p = 0.004) and 60 minutes (-0.78 m/s, -26.2%, p = 0.017) for patients after Fontan and controls at 15 minutes (-0.12 m/s, -8.70%, p = 0.002), 30 minutes (-0.15 m/s, -10.9%, p = 0.003), and 60 minutes (-0.1 m/s, -10.9%, p = 0.005). CONCLUSIONS: LSM after Fontan is higher with more variability compared to controls. Diuresis is associated with significantly decreased liver stiffness in both patients after Fontan and controls, with the suggestion of a greater effect in Fontan patients.

Torsemide as a Primary Choice in Edema Associated with Heart Failure.

Heart failure (HF) is the fastest-growing disease with a higher fatality rate. The most differentiating feature of HF is pulmonary or peripheral edema, which is characterized by a gradient between intravascular and extravascular pressure. Loop diuretics were chosen as the primary treatment for edema associated with HF due to their efficacy and early onset of action. If an oral dose had not been provided, intravenous (IV) administration of torsemide, or equal doses of furosemide and bumetanide, was preferred. However, the key variables for selecting and administering loop diuretics are their pharmacological qualities as well as their clinical efficacy. Torsemide has greater bioavailability, a higher rate of absorption, a longer duration of action, and lesser ototoxicity, making it the primary choice in the management of edematous HF.

Fixed-dose Combination of Torsemide and Mineralocorticoid Receptor Antagonists.

The combination of torsemide and spironolactone presents a promising approach to managing conditions such as edema and hypertension. Torsemide, a loop diuretic, enhances diuresis by inhibiting sodium reabsorption in the kidneys, while spironolactone, a potassium-sparing diuretic and mineralocorticoid receptor antagonist (MRA), complements this effect by preventing potassium loss and offering additional cardiovascular benefits. This review examines clinical evidence supporting their combined effectiveness in treating fluid retention and improving outcomes in conditions like heart failure (HF). Given the limited research available, it is essential to carefully evaluate patient-specific factors. However, several side effects necessitate careful patient selection and monitoring. Moreover, optimizing dosing regimens is crucial to ensure the safety and efficacy of torsemide and MRAs in clinical settings.

Glucocorticoid-induced acute diuresis in rats in relation to the reduced renal expression of sodium-dependent cotransporter genes.

Although several studies have shown that glucocorticoids exert diuretic effects in animals and humans, the underlying mechanism responsible for the acute diuretic effect remains obscure. Here we examined the mechanism in terms of gene-expression. We observed that glucocorticoids, including dexamethasone (Dex) and prednisolone (PSL), acutely induced diuresis in rats in a dose-dependent manner. Free water clearance values were negative after Dex or PSL treatment, similar to those observed after treatment with osmotic diuretics (furosemide and acetazolamide). Dex significantly increased the urinary excretion of sodium, potassium, chloride, glucose, and inorganic phosphorus. Renal microarray analysis revealed that Dex significantly altered the renal expression of genes related to transmembrane transport activity. The mRNA levels of sodium/phosphate (NaPi-2a/Slc34a1, NaPi-2b/Slc34a2, and NaPi-2c/Slc34a3) and sodium/glucose cotransporters (Sglt2/Slc5a2) were significantly reduced in the Dex-treated kidney, being negatively correlated with the urinary excretion of their corresponding solutes. Dex did not affect renal expression of the natriuretic peptide receptor 1 (Npr1) gene, or the expression, localization, and phosphorylation of aquaporin-2 (AQP2), a water channel protein. These findings suggest that the acute diuretic effects of glucocorticoids might be mediated by reduced expression of sodium-dependent cotransporter genes.

Drug Consumption and Hydration Status: Analysis of the Associations in an Elder Population.

Hydration status plays a key role in healthy ageing, and it is potentially affected by several factors, including drug consumption. However, research on this issue to date is scarce, especially in highly vulnerable groups, such as the elderly. We aimed to study the relationship linking hydration status, analysed by means of a validated questionnaire, 24 h urine analysis, body composition assessment, and drug consumption in a sample of old adults. A total of 144 elders were included in the study. Cardiovascular drug consumption was significantly associated with a lower water intake in men (ß = -0.282, p = 0.029). Moreover, urinary analysis revealed that total drug intake as well as the consumption of diuretics and cardiovascular drugs were associated with poorer hydration status, whereas genito-urinary drugs were associated with an opposite effect, and these results were confirmed in terms of body composition. Hence, total drug consumption (ß = -0.205), diuretic (ß = -0.408), cardiovascular (ß = -0.297), and genito-urinary drugs (ß = 0.298) were significantly associated (p < 0.05) with total body water. The obtained results confirmed the impact of chronic treatment with certain drugs on hydration status. Nutritional interventions may be of great interest in certain population groups in order to prevent complications due to altered hydration status.

Intravenous delivery of furosemide using lipid-based versus polymer-based nanocapsules: in vitro and in vivo studies.

OBJECTIVES: Furosemide (FSM), a potent loop diuretic, is used to treat edema due to hypertension, congestive heart failure, and liver and renal failures. FSM applications are limited by its low bioavailability. Our aim is to use different nanoencapsulation strategies to control the release of FSM and enhance its pharmacokinetic properties. METHODS: Two types of FSM-loaded nanocapsules, namely FSM-loaded lipid nanocapsules (LNCs) and polymeric nanocapsules (PNCs), were developed, physicochemically characterized, and subjected to pharmacokinetic and pharmacodynamic studies. Lipid nanocapsules were prepared by the simple phase inversion method using LabrafacTM lipid, while the polymeric nanocapsules were prepared by nanoprecipitation method using polycaprolactone polymer. RESULTS: Transmission electron microscopy ascertains spherical structures, corroborating the nanometric diameter of both types of nanocapsules. The particle size of the optimized FSM-loaded LNCs and FSM-loaded PNCs was 32.19 ± 0.72 nm and 230.7 ± 5.13 nm, respectively. The percent entrapment efficiency was 63.56 ± 1.40% of FSM for the optimized PNCs. The in vitro release study indicated prolonged drug release compared to drug solutions. The two loaded nanocapsules systems succeeded in enhancing the pharmacokinetic parameters in comparison to the marketed FSM solution with superior diuretic activity (p < 0.05). The results of the stability study and the terminal sterilization by autoclave indicated the superiority of LNCs over PNCs in maintaining the physical parameters under storage conditions and the drastic conditions of sterilization. CONCLUSIONS: LNCs and PNCs are considered promising nanosysems for improving the diuretic effect of FSM.

Metolazone Versus Chlorothiazide in Acute Heart Failure Patients With Diuretic Resistance and Renal Dysfunction: A Retrospective Cohort Study.

ABSTRACT: Guidelines recommend intravenous loop diuretics as first-line therapy for patients hospitalized with acute heart failure (AHF) and volume overload. Additional agents can be used for augmentation, but there is limited guidance on agent selection. The study objective was to determine if chlorothiazide or metolazone is associated with differences in diuretic efficacy or safety in loop diuretic-resistant patients with AHF and renal dysfunction (eGFR <45 mL/min/1.73 m²). We conducted a multicenter, retrospective cohort study of patients hospitalized with AHF and renal dysfunction who received metolazone or chlorothiazide in addition to intravenous loop diuretics. The primary end point was a comparison of 24-hour urine output (UOP) between the 24 hours before and after thiazide administration. Secondary and safety end points included weight change, requirement for vasopressors or inotropes, electrolyte abnormalities, and changes in renal function. A total of 221 patients were included. The mean daily diuretic doses were chlorothiazide 632 mg and metolazone 7 mg. The mean 24-hour UOP increased more among chlorothiazide-treated (from 1668 mL to 3826 mL) versus metolazone-treated patients (from 1672 mL to 2834 mL) ( P < 0.001) after the addition of the second diuretic. Statistically significant reductions in serum creatinine were observed in the chlorothiazide group following 72 hours of treatment ( P = 0.016). More hypomagnesemia was observed in the chlorothiazide group; no differences in other electrolytes or changes in weight were observed. Overall, chlorothiazide was associated with a greater increase in 24-hour UOP than metolazone without an excess of potassium or serum creatinine derangements. However, weight changes did not differ significantly between groups. Future prospective studies are needed to confirm potential differences in diuretic response and safety.

Reprint of: Effect of pregabalin initiation on diuretic requirements in patients with chronic heart failure.

BACKGROUND: Literature on pregabalin use in patients with heart failure is largely limited to patient case reports and cohort studies. OBJECTIVE: This study aimed to evaluate the effect of pregabalin initiation on diuretic requirements in patients with heart failure. METHODS: A retrospective analysis of patients with heart failure who were started on pregabalin between January 1, 2014, and September 1, 2021, at the Veterans Affairs North Texas Health Care System was used. The primary objective was to determine the median change in loop diuretic dose, in furosemide dose equivalents, 6 months after pregabalin initiation. RESULTS: Of 58 patients analyzed, there was no statistically significant difference in the primary outcome (P = 0.162). The secondary outcomes were found to be nonstatistically significant, and there was no correlation between pregabalin dose and outcomes. CONCLUSION: This represents the largest analysis of diuretic dose requirements in patients with heart failure after initiation of pregabalin. Although there was no difference in the median change of diuretic dose prescribed, pregabalin should still be used with caution.

The utility of urine sodium-guided diuresis during acute decompensated heart failure.

Diuresis to achieve decongestion is a central aim of therapy in patients hospitalized for acute decompensated heart failure (ADHF). While multiple approaches have been tried to achieve adequate decongestion rapidly while minimizing adverse effects, no single diuretic strategy has shown superiority, and there is a paucity of data and guidelines to utilize in making these decisions. Observational cohort studies have shown associations between urine sodium excretion and outcomes after hospitalization for ADHF. Urine chemistries (urine sodium ± urine creatinine) may guide diuretic titration during ADHF, and multiple randomized clinical trials have been designed to compare a strategy of urine chemistry-guided diuresis to usual care. This review will summarize current literature for diuretic monitoring and titration strategies, outline evidence gaps, and describe the recently completed and ongoing clinical trials to address these gaps in patients with ADHF with a particular focus on the utility of urine sodium-guided strategies.

Preferred diuretic therapy for primary hypertension: Chlorthalidone or hydrochlorothiazide?

ABSTRACT: Because of its greater reduction of major adverse cardiovascular events (MACE), chlorthalidone is recommended over hydrochlorothiazide as the preferred diuretic for patients with primary hypertension. However, hydrochlorothiazide is more commonly prescribed than chlorthalidone for this condition. This article reviews recent studies investigating the effectiveness of chlorthalidone and hydrochlorothiazide in reducing MACE, to help clinicians make an evidence-based informed decision on which diuretic to prescribe.

Cost-effectiveness of single-pill and separate-pill administration of antihypertensive triple combination therapy: a population-based microsimulation study.

BACKGROUND: Single-pill combination (SPC) of three antihypertensive drugs has been shown to improve adherence to therapy compared with free combinations, but little is known about its long-term costs and health consequences. This study aimed to evaluate the lifetime cost-effectiveness profile of a three-drug SPC of an angiotensin-converting enzyme inhibitor, a calcium-channel blocker, and a diuretic vs the corresponding two-pill administration (a two-drug SPC plus a third drug separately) from the Italian payer perspective. METHODS: A cost-effectiveness analysis was conducted using multi-state semi-Markov modeling and microsimulation. Using the healthcare utilization database of the Lombardy Region (Italy), 30,172 and 65,817 patients aged ≥ 40 years who initiated SPC and two-pill combination, respectively, between 2015 and 2018 were identified. The observation period extended from the date of the first drug dispensation until death, emigration, or December 31, 2019. Disease and cost models were parametrized using the study cohort, and a lifetime microsimulation was applied to project costs and life expectancy for the compared strategies, assigning each of them to each cohort member. Costs and life-years gained were discounted by 3%. Probabilistic sensitivity analysis with 1,000 samples was performed to address parameter uncertainty. RESULTS: Compared with the two-pill combination, the SPC increased life expectancy by 0.86 years (95% confidence interval [CI] 0.61-1.14), with a mean cost differential of -€12 (95% CI -9,719-8,131), making it the dominant strategy (ICER = -14, 95% CI -€15,871-€7,113). The cost reduction associated with the SPC was primarily driven by savings in hospitalization costs, amounting to €1,850 (95% CI 17-7,813) and €2,027 (95% CI 19-8,603) for patients treated with the SPC and two-pill combination, respectively. Conversely, drug costs were higher for the SPC (€3,848, 95% CI 574-10,640 vs. €3,710, 95% CI 263-11,955). The cost-effectiveness profile did not significantly change according to age, sex, and clinical status. CONCLUSIONS: The SPC was projected to be cost-effective compared with the two-pill combination at almost all reasonable willingness-to-pay thresholds. As it is currently prescribed to only a few patients, the widespread use of this strategy could result in benefits for both patients and the healthcare system.

Time series forecasting of weight for diuretic dose adjustment using bidirectional long short-term memory.

Loop diuretics are prevailing drugs to manage fluid overload in heart failure. However, adjusting to loop diuretic doses is strenuous due to the lack of a diuretic guideline. Accordingly, we developed a novel clinician decision support system for adjusting loop diuretics dosage with a Long Short-Term Memory (LSTM) algorithm using time-series EMRs. Weight measurements were used as the target to estimate fluid loss during diuretic therapy. We designed the TSFD-LSTM, a bi-directional LSTM model with an attention mechanism, to forecast weight change 48 h after heart failure patients were injected with loop diuretics. The model utilized 65 variables, including disease conditions, concurrent medications, laboratory results, vital signs, and physical measurements from EMRs. The framework processed four sequences simultaneously as inputs. An ablation study on attention mechanisms and a comparison with the transformer model as a baseline were conducted. The TSFD-LSTM outperformed the other models, achieving 85% predictive accuracy with MAE and MSE values of 0.56 and 1.45, respectively. Thus, the TSFD-LSTM model can aid in personalized loop diuretic treatment and prevent adverse drug events, contributing to improved healthcare efficacy for heart failure patients.

Diuretics use in the management of hypertension.

Diuretics have been used for decades in the treatment of hypertension. Its efficacy has been demonstrated in numerous clinical trials. It is well known that the reduction in cardiovascular risk is a consequence of the reduction in blood pressure levels regardless of the drug used, but thiazide diuretics continue to be first-line drugs, especially in low doses and combined with other drugs. The debate on the advantages of using chlorthalidone or hydrochlorothiazide continues, however hydrochlorothiazide is drug most used and for which there is greater availability. The association with potassium-sparing diuretics increases the effectiveness and reduces the adverse reactions of thiazides. A new group of drugs, close to potassium-sparing diuretics, that antagonise aldosterone synthase are showing promising results as antihypertensives. There are no significant differences between men and women regarding the antihypertensive effect of thiazide diuretics.

Spot urine sodium-to-creatinine ratio surpasses sodium in identifying poor diuretic response in acute heart failure.

AIMS: We aim to identify the most accurate marker for early prediction of poor diuretic response in acute heart failure (AHF) patients with signs of congestion requiring intravenous diuretic treatment. METHODS: In this single-centre, prospective observational study, AHF patients with signs of congestion received a standardized intravenous furosemide dose (1 mg/kg of body weight; 40 mg in bolus and remaining dose in 2 h continuous infusion). Subsequently, we assessed spot urine composition at 2 h post-administration, comparing it with total urine output at 6 h. Various potential urine markers were analysed for predicting urine output using receiver operating characteristic (ROC) curves and logistic regression models. We investigated guideline-recommended markers, including spot urine sodium (UNa+) and its cut-off, and introduced the UNa+/UCr (urine creatinine concentration) ratio adjusting UNa+ for urine dilution. RESULTS: Out of 111 patients (85% males, 66.4 ± 13.9 years old, NTproBNP 7290 [4493-14 582] pg/ml), there were 18 (16%) with a poor diuretic response (cumulative urine output <600 ml during the first 6 h). The mean 6 h cumulative diuresis in patients with poor and good diuretic response was 406 ± 142 and 2114 ± 1164 ml, respectively, P < 0.005. After an initial evaluation of several potential biomarkers, only UNa+, UCr and UNa+/UCr were selected as candidates with the highest predictive value. The cut-off for UNa+ adjusted for urine dilution: UNa+/UCr ratio <0.167 mmol/mg × 10-1 was determined by ROC analysis with the highest area under the curve (95% confidence interval): 0.956 (0.915-0.997), P < 0.001. When compared with the guideline-recommended cut-off (UNa+ <50 mmol/L as a reference, specificity-0.97; sensitivity-0.83), the odds ratio (OR) for UNa+/UCreat to identify a poor diuretic response was 2.5 times greater, regardless of kidney function (OR for estimated glomerular filtration rate in the logistic regression model was 0.978 [0.945-1.013, P = 0.222]). CONCLUSIONS: The UNa+/UCr ratio in a spot urine sample 2 h after intravenous diuretic administration is a simple, highly predictive marker for the identification of AHF patients with poor diuretic response, surpassing guidelines-recommended markers like UNa+.

Combining Loop and Thiazide Diuretics Across the Left Ventricular Ejection Fraction Spectrum: The CLOROTIC Trial.

BACKGROUND: The addition of hydrochlorothiazide (HCTZ) to furosemide in the CLOROTIC (Combining Loop with Thiazide Diuretics for Decompensated Heart Failure) trial improved the diuretic response in patients with acute heart failure (AHF). OBJECTIVES: This work aimed to evaluate if these results differ across the spectrum of left ventricular ejection fraction (LVEF). METHODS: This post hoc analysis of the randomized, double-blind, placebo-controlled CLOROTIC trial enrolled 230 patients with AHF to receive either HCTZ or a placebo in addition to an intravenous furosemide regimen. The influence of LVEF on primary and secondary outcomes was evaluated. RESULTS: The median LVEF was 55%: 166 (72%) patients had LVEF >40%, and 64 (28%) had LVEF ≤40%. Patients with a lower LVEF were younger, more likely to be male, had a higher prevalence of ischemic heart disease, and had higher natriuretic peptide levels. The addition of HCTZ to furosemide was associated with the greatest weight loss at 72 of 96 hours, better metrics of diuretic response, and greater 24-hour diuresis compared with placebo, with no significant differences according to the LVEF category (using 2 LVEF cutoff points: 40% and 50%) or LVEF as a continuous variable (all P values were insignificant). There were no significant differences observed with the addition of HCTZ in terms of mortality, rehospitalizations, or safety endpoints (impaired renal function, hyponatremia, and hypokalemia) among the 2 LVEF groups (all P values were insignificant). CONCLUSIONS: Adding HCTZ to intravenous furosemide seems to be effective strategy for improving diuretic response in AHF without treatment effect modification according to baseline LVEF. (Combining Loop with Thiazide Diuretics for Decompensated Heart Failure [CLOROTIC], NCT01647932; Randomized, double blinded, multicenter study, to asses Safety and Efficacy of the Combination of Loop With Thiazide-type Diuretics vs Loop diuretics with placebo in Patients With Decompensated, EudraCT Number 2013-001852-36).

Evaluation of renal sodium handling in heart failure with preserved ejection fraction: A pilot study.

The pathophysiology behind sodium retention in heart failure with preserved ejection fraction (HFpEF) remains poorly understood. We hypothesized that patients with HFpEF have impaired natriuresis and diuresis in response to volume expansion and diuretic challenge, which is associated with renal hypo-responsiveness to endogenous natriuretic peptides. Nine HFpEF patients and five controls received saline infusion (0.25 mL/kg/min for 60 min) followed by intravenous furosemide (20 mg or home dose) 2 h after the infusion. Blood and urine samples were collected at baseline, 2 h after saline infusion, and 2 h after furosemide administration; urinary volumes were recorded. The urinary cyclic guanosine monophosphate (ucGMP)/plasma B-type NP (BNP) ratio was calculated as a measure of renal response to endogenous BNP. Wilcoxon rank-sum test was used to compare the groups. Compared to controls, HFpEF patients had reduced urine output (2480 vs.3541 mL; p = 0.028), lower urinary sodium excretion over 2 h after saline infusion (the percentage of infused sodium excreted 12% vs. 47%; p = 0.003), and a lower baseline ucGMP/plasma BNP ratio (0.7 vs. 7.3 (pmol/mL)/(mg/dL)/(pg/mL); p = 0.014). Patients with HFpEF had impaired natriuretic response to intravenous saline and furosemide administration and lower baseline ucGMP/plasma BNP ratios indicating renal hypo-responsiveness to NPs.

Diuretic response after neonatal cardiac surgery: a report from the NEPHRON collaborative.

BACKGROUND: Multicenter early diuretic response (DR) analysis of single furosemide dosing following neonatal cardiac surgery is lacking to inform whether early DR predicts adverse clinical outcomes. METHODS: We performed a retrospective cohort study utilizing data from the NEPHRON registry. Random forest machine learning generated receiver operating characteristic-area under the curve (ROC-AUC) and odds ratios for mechanical ventilation (MV) and respiratory support (RS). Prolonged MV and RS were defined using ≥ 90th percentile of observed/expected ratios. Secondary outcomes were prolonged CICU and hospital length of stay (LOS) and kidney failure (stage III acute kidney injury (AKI), peritoneal dialysis, and/or continuous kidney replacement therapy on postoperative day three) assessed using covariate-adjusted ROC-AUC curves. RESULTS: A total of 782 children were included. Cumulative urine output (UOP) metrics were lower in prolonged MV and RS patients, but DR poorly predicted prolonged MV (highest AUC 0.611, OR 0.98, sensitivity 0.67, specificity 0.53, p = 0.006, 95% OR CI 0.96-0.99 for cumulative 6-h UOP) and RS (highest AUC 0.674, OR 0.94, sensitivity 0.75, specificity 0.54, p < 0.001, 95% CI 0.91-0.97 UOP between 3 and 6 h). Secondary outcome results were similar. DR had fair discrimination for kidney failure (AUC 0.703, OR 0.94, sensitivity 0.63, specificity 0.71, 95% OR CI 0.91-0.98, p < 0.001, cumulative 6-h UOP). CONCLUSIONS: Early DR poorly discriminated patients with prolonged MV, RS, and LOS in this cohort, though it may identify severe postoperative AKI phenotype. Future work is warranted to determine if early DR or late postoperative DR later, in combination with other AKI metrics, may identify a higher-risk phenotype.