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Evidence is scarce on the efficacy of long-term human albumin (HA) administration in patients with decompensated cirrhosis. The human Albumin for the treatmeNt of aScites in patients With hEpatic ciRrhosis (ANSWER) study was designed to clarify this issue. We did an investigator-initiated multicentre randomised, parallel, open-label, pragmatic trial in 33 academic and non-academic Italian hospitals. We randomly assigned patients with cirrhosis and uncomplicated ascites who were treated with anti-aldosteronic drugs (≥200 mg/day) and furosemide (≥25 mg/day) to receive either standard medical treatment (SMT) or SMT plus HA (40 g twice weekly for 2 weeks, and then 40 g weekly) for up to 18 months. The primary endpoint was 18-month mortality, evaluated as difference of events and analysis of survival time in patients included in the modified intention-to-treat and per-protocol populations. This study is registered with EudraCT, number 2008–000625–19, and ClinicalTrials.gov, number NCT01288794. From April 2, 2011, to May 27, 2015, 440 patients were randomly assigned and 431 were included in the modified intention-to-treat analysis. 38 of 218 patients died in the SMT plus HA group and 46 of 213 in the SMT group. Overall 18-month survival was significantly higher in the SMT plus HA than in the SMT group (Kaplan-Meier estimates 77% vs 66%; p=0·028), resulting in a 38% reduction in the mortality hazard ratio (0·62 [95% CI 0·40–0·95]). 46 (22%) patients in the SMT group and 49 (22%) in the SMT plus HA group had grade 3–4 non-liver related adverse events. In this trial, long-term HA administration prolongs overall survival and might act as a disease modifying treatment in patients with decompensated cirrhosis. Italian Medicine Agency.

Patients with acute decompensated heart failure received intravenous furosemide at either a low or a high dose and either boluses every 12 hours or continuous infusion. At 72 hours, there was no significant difference in symptoms or in the change in creatinine level from baseline for either comparison. Acute decompensated heart failure is the most common cause of hospital admissions among patients older than 65 years of age and is responsible for more than 1 million hospitalizations annually in the United States. 1 Intravenous loop diuretics are an essential component of current treatment and are administered to approximately 90% of patients who are hospitalized with heart failure. 2 Despite decades of clinical experience with these agents, prospective data to guide the use of loop diuretics are sparse, and current guidelines are based primarily on expert opinion. 3 , 4 As a result, clinical practice varies widely with regard to both the mode . . .

Furosemide is the most commonly used diuretic in intensive care units (ICU). We aimed to evaluate the physiological effects of adjunctive acetazolamide with furosemide on diuresis and the prevention of potential furosemide-induced metabolic alkalosis. We performed a two-center, pilot, open-label, randomized trial. Where the treating physicians planned intravenous diuretic therapy, we randomized ICU patients to a bolus of furosemide (40 mg) plus acetazolamide (500 mg) (n = 15) or furosemide alone (40 mg) (n = 15). Urine output, additional furosemide use, acid-base parameters, and electrolytes were compared following a Bayesian framework. Adjunctive acetazolamide didn't increase urine output in the first six hours (mean difference: −112 ml, credible interval: [−742, 514]). However, compared with furosemide alone, it maintained a greater urine output response to furosemide over 24 h, with 100 % probability. Acetazolamide also acidified plasma (pH difference: −0.045, [−0.081, −0.008]) while alkalinizing urine (1.10, [0.04, 2.11]) at six hours, compared to furosemide alone with >95 % probability. Finally, we didn't observe severe acidosis or electrolyte disturbances over 24 h. Adjunctive acetazolamide may increase diuretic efficacy and counterbalance furosemide-induced metabolic alkalosis without safety concerns. Larger trials are warranted to verify these findings and assess their impacts on clinical outcomes. ACTRN12623000624684. A pilot trial of single versus dual diuretic therapy in the intensive care unit. •Pathophysiologic effects of adjunctive acetazolamide were assessed in this pilot RCT.•Acetazolamide may have preserved urine output response to furosemide.•Acetazolamide may have counterbalanced furosemide-induced metabolic alkalosis.•Adjunctive acetazolamide may not result in severe acidosis or electrolyte disturbance.•Larger trials to evaluate the effect of adjunctive acetazolamide appear justified.

Furosemide is commonly prescribed in acute kidney injury (AKI). Prior studies have found conflicting findings on whether furosemide modifies the course and outcome of AKI. Pilot multi-center randomized blinded placebo-controlled trial in adult patients with AKI admitted to three intensive care units. Participants were randomly allocated to furosemide bolus and infusion or 0.9% saline placebo. Primary endpoint was worsening AKI, defined by the RIFLE criteria. Secondary endpoints were kidney recovery, renal replacement therapy (RRT) and adverse events. The trial was terminated after enrollment of 73 participants (37 to furosemide and 36 to placebo). Mean (SD) age was 61.7 (14.3), 79.5% were medical admissions, mean (SD) APACHE II score was 26.6 (7.8), 90.4% received mechanical ventilation and 61.6% received vasoactives. Groups were similar at baseline. No differences were found in the proportion with worsening AKI (43.2% vs. 37.1%, p=0.6), kidney recovery (29.7% vs. 42.9%, p=0.3), or RRT (27.0% s. 28.6%, p=0.8). Adverse events, mostly electrolyte abnormalities, were more common in furosemide-treated patients (p<0.001). Protocol deviations were common, due often to supplementary furosemide. In this pilot trial, furosemide did not reduce the rate of worsening AKI, improve recovery or reduce RRT; however, was associated with greater electrolyte abnormalities. ClinicalTrials.gov Identifier: NCT00978354 registered September 9, 2014. •Furosemide is commonly prescribed to patients with AKI in ICU settings, despite a contradictory evidence on their effectiveness and safety.•This pilot RCT aimed to evaluate the impact of furosemide in early AKI on worsening AKI, kidney recovery, and RRT use.•This trial found no differences in the proportion with worsening AKI, kidney recovery, or RRT use.•Adverse events, driven largely by electrolyte abnormalities, more commonly occurred in furosemide treated patients..

Objective:The aim of the study was to compare sequential versus combined diuretic therapy in patients with cirrhosis, moderate ascites and without renal failure.Design:One hundred patients were randomly assigned to the two diuretic treatments. The sequential treatment provided potassium canrenoate at the initial dose of 200 mg/day, then increased to 400 mg/day. Non-responders were treated with 400 mg/day of potassium canrenoate and furosemide at an initial dose of 50 mg/day, then increased to 150 mg/day. The combined treatment provided the initial dose of 200 mg/day of potassium canrenoate and 50 mg/day of furosemide, then increased to 400 mg/day and 150 mg/day, respectively.Results:Most patients who received sequential treatment responded to potassium canrenoate alone (19% to 200 mg/day and 52.63% to 400 mg/day, respectively). Most patients who received the combined treatment responded to the first two steps (40% to the first step and 50% to the second, ie, 400 mg/day of potassium canrenoate plus 100 mg/day of furosemide). Adverse effects (38% vs 20%, p<0.05), in particular, hyperkalaemia (18% vs 4%, p<0.05), were more frequent in patients who received sequential therapy. As a consequence, the per cent of patients who resolved ascites without changing the effective diuretic step was higher in those who received the combined treatment (56% vs 76%, p<0.05).Conclusions:The combined diuretic treatment is preferable to the sequential one in the treatment of moderate ascites in patients with cirrhosis and without renal failure.NCT00741663. This work is an open randomised clinical trial.

BackgroundDiuretic resistance is a common issue in patients with acute decompensation of advanced chronic heart failure (ACHF). The aim of this trial was to compare boluses and continuous infusion of furosemide in a selected population of patients with ACHF and high risk for diuretic resistance.MethodsIn this single-centre, double-blind, double-dummy, randomized trial, we enrolled 80 patients admitted for acute decompensation of ACHF (NYHA IV, EF ≤ 30%) with criteria of high risk for diuretic resistance (SBP ≤ 110 mmHg, wet score ≥ 12/18, and sodium ≤ 135 mMol/L). Patients were assigned in a 1:1 ratio to receive furosemide by bolus every 12 h or by continuous infusion. Diuretic treatment and dummy treatment were prepared by a nurse unassigned to patients’ care. The study treatment was continued for up to 72 h. Coprimary endpoints were total urinary output and freedom from congestion at 72 h.Results80 patients were enrolled with 40 patients in each treatment arm. Mean daily furosemide was 216 mg in continuous-infusion arm and 195 mg in the bolus intermittent arm. Freedom from congestion (defined as jugular venous pressure of < 8 cm, with no orthopnea and with trace peripheral edema or no edema) occurred more in the continuous infusion than in the bolus arm (48% vs. 25%, p = 0.04), while total urinary output after 72 h was 8612 ± 2984 ml in the bolus arm and 10,020 ± 3032 ml in the continuous arm (p = 0.04). Treatment failure occurred less in the continuous-infusion group (15% vs. 38%, p = 0.02), while there was no significant difference between groups in the incidence of worsening of renal function.ConclusionAmong patients with acute decompensation of ACHF and high risk of diuretic resistance, continuous infusion of intravenous furosemide was associated with better decongestion.DRAIN trialClinicalTrials.gov number NCT03592836.Graphic abstract

Aim The main treatment strategy in type 1 cardiorenal syndrome (CRS1) is vascular decongestion. It is probable that sequential blockage of the renal tubule with combined diuretics (CD) will obtain similar benefits compared with stepped-dose furosemide (SF). Methods In a pilot double-blind randomized controlled trial of CRS1 patients were allocated in a 1:1 fashion to SF or CD. The SF group received a continuous infusion of furosemide 100 mg during the first day, with daily incremental doses to 200 mg, 300 mg and 400 mg. The CD group received a combination of diuretics, including 4 consecutive days of oral chlorthalidone 50 mg, spironolactone 50 mg and infusion of furosemide 100 mg. The objectives were to assess renal function recovery and variables associated with vascular decongestion. Results From July 2017 to February 2020, 80 patients were randomized, 40 to the SF and 40 to the CD group. Groups were similar at baseline and had several very high-risk features. Their mean age was 59 ± 14.5 years, there were 37 men (46.2%). The primary endpoint occurred in 20% of the SF group and 15.2% of the DC group ( p  = 0.49). All secondary and exploratory endpoints were similar between groups. Adverse events occurred frequently (85%) with no differences between groups ( p  = 0.53). Conclusion In patients with CRS1 and a high risk of resistance to diuretics, the use of CD compared to SF offers the same results in renal recovery, diuresis, vascular decongestion and adverse events, and it can be considered an alternative treatment. ClinicalTrials.gov with number NCT04393493 on 19/05/2020 retrospectively registered.

Background Mannitol is exclusively recommended in the National Comprehensive Cancer Network guidelines for diuresis in cisplatin (CDDP)‐based chemotherapy. The utility of furosemide, a widely used and convenient diuretic, thus requires clarification. Methods This is a prospective, single‐centered, open‐label, noninferiority phase II study. Patients with thoracic malignancies who planned to receive CDDP‐based chemotherapy were randomly assigned to receive either mannitol (arm A) or furosemide (arm B). The primary end point was set as the proportion of patients who experienced any grade of “creatinine (Cr) increased” based on the upper limit of the normal range (ULN) during the first cycle as assessed by Common Terminology Criteria for Adverse Events Version 4.0. Secondary end points were Cr increased based on the baseline value during the first cycle, Cr increased after the completion of CDDP, and the proportion of patients with phlebitis. Results Between April 2018 and March 2022, 115 patients were enrolled and 106 were analyzed. Any grade of Cr increased based on the ULN during the first cycle was 17.3% (arm A) and 24.1% (arm B), respectively (p = 0.34). Therefore, the primary end point was not met. After completion of chemotherapy, any grade of Cr increased was observed in 23.1% (arm A) and 31.5% (arm B), respectively. However, the actual serum Cr level and Cr clearance during the courses were not different between the arms. Phlebitis occurred more frequently in arm A (28.8%) than arm B (16.7%). Conclusions Mannitol should remain the standard diuresis in CDDP‐based chemotherapy assessed by conventional CTCAE grading, but furosemide can be room for consideration when assessed by actual serum Cr level and Cr clearance. This is the largest prospective study to compare furosemide with mannitol in the prevention of renal toxicity in CDDP‐based chemotherapy. The proportion of patients with any grade of creatinine increase during the first cycle was 17.3% in the mannitol arm and 24.1% in the furosemide arm (p = 0.34). Although noninferiority of furosemide to mannitol was unproven, serum creatinine levels and creatinine clearance during the courses were mostly identical.

Four vocally untrained healthy adults, 2 men and 2 women, completed the study. A double-blind placebo-controlled approach was used to administer three treatments to each participant on separate days. Drugs treatments involved a single 60-mg dose of a diuretic, Lasix (LA), on one day, and a single 50-mg dose of an oral antihistamine, diphenhydramine hydrochloride (DH), on another day. A third day involved the administration of a placebo, sugar pills (SP). Critical posttreatment measures were weight (kg), which estimated systemic dehydration, saliva viscosity (centipoise), which estimated secretion dehydration, and phona-tion threshold pressure (PTP, in cm H 2 O), at high pitches, which indicated pulmonary drive for phonation. The central experimental question was: Does systemic dehydration, or secretory dehydration, or both, mediate increases in PTP that are known to occur following dehydration treatments? The results showed that LA induced systemic dehydration, as shown by a decrease in total body mass of about 1%. Weight losses were seen during a 1- to 4-hour block following drug administration and persisted for at least 8 hours thereafter. PTPs also increased in that condition, about 23% relative to baseline, but only several hours after whole-body dehydration was initially seen (5–12 hours after drug administration). In contrast, no evidence was seen that DH accomplished either secretory dehydration or PTP shifts. The results indicate that systemic dehydration can mediate PTP increases. The influence of secretory dehydration on PTP is unclear.

IntroductionIntradialytic hypotension (IDH) is a frequent and serious complication of maintaining haemodialysis (HD) patients and associated with subsequent cardiovascular events and higher mortality. Furosemide is commonly used in non-dialysis chronic kidney disease patients and can effectively manage the volume and blood pressure. However, these agents are often discontinued on initiation of dialysis. Two large observational studies have demonstrated that furosemide can lower the rate of IDH episodes. However, there is still no randomised controlled trial (RCT) to investigate the efficacy and safety of furosemide for prevention of IDH in HD patients. The purpose of this study was to assess the efficacy of furosemide in reducing IDH in HD patients with residual renal function.Methods and analysisA two-arm, parallel, multicente RCT will be conducted at 12 hospitals in China. An estimated sample of 560 HD patients will be recruited. Eligible patients will be randomly assigned to treatment group (patients receive oral furosemide 80 mg/day; after a 2-week treatment, if their urine volume is less than 400 mL/day, the dose of furosemide is adjusted to 160 mg/day) and blank control group via a central randomisation system using 1:1 ratio. The primary outcome is the occurrence of IDH. Outcome assessors and data analysts will be blinded and participants will be asked not to reveal their allocation to assessors. The outcome analyses will be performed both on the intention-to-treat, which includes all patients randomised, and per-protocol population, which includes eligible patients who adhere to the planned treatment and follow-ups.Ethics and disseminationThe trial protocol has been approved by the Biomedical Research Ethics Committee of West China Hospital of Sichuan University (2019.385)Results will be presented at national and international conferences and published in peer-reviewed journals.Trial registration numberChiCTR2000039724.