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      Intermittent furosemide administration in patients with or at risk for acute kidney injury: Meta-analysis of randomized trials

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          Abstract

          Background

          Furosemide is the most common loop diuretic used worldwide. The off-label administration of furosemide bolus(es) for the prevention or to reverse acute kidney injury (AKI) is widespread but not supported by available evidence. We conducted a meta-analysis of randomized trials (RCTs) to investigate whether bolus furosemide to prevent or treat AKI is detrimental on patients’ survival.

          Methods

          Electronic databases were searched through October 2017 for RCTs comparing bolus furosemide administration versus any comparator in patients with or at risk for AKI. The primary endpoint was all-cause longest follow-up mortality. Secondary endpoints included new or worsening AKI, receipt of renal replacement therapy, length of hospital stay, and peak serum creatinine after randomization.

          Results

          A total of 28 studies randomizing 3,228 patients were included in the analysis. We found no difference in mortality between the two groups (143/892 [16%] in the furosemide group versus 141/881 [16%] in the control group; odds ratio [OR], 0.84; 95% confidence interval [CI], 0.63 to 1.13; p = 0.25). No significant differences in secondary outcomes were found. A significant improvement in survival was found in the subgroup of patients receiving furosemide bolus(es) as a preventive measure (43/613 [7.0%] versus 67/619 [10.8%], OR 0.62; 95% CI, 0.41 to 0.94; p = 0.03)

          Conclusions

          Intermittent furosemide administration is not associated with an increased mortality in patients with or at risk for AKI, although it may reduce mortality when used as a preventive measure. Future high-quality RCTs are needed to define the role of loop diuretics in AKI prevention and management.

          Trial registration

          The study protocol was registered on PROSPERO database for systematic reviews (Registration no. CRD42017078607 – http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017078607).

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          Most cited references65

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          Diuretic strategies in patients with acute decompensated heart failure.

          Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use. In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient's previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours. In the comparison of bolus with continuous infusion, there was no significant difference in patients' global assessment of symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P=0.47) or in the mean change in the creatinine level (0.05±0.3 mg per deciliter [4.4±26.5 μmol per liter] and 0.07±0.3 mg per deciliter [6.2±26.5 μmol per liter], respectively; P=0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients' global assessment of symptoms in the high-dose group (mean AUC, 4430±1401 vs. 4171±1436; P=0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08±0.3 mg per deciliter [7.1±26.5 μmol per liter] with the high-dose strategy and 0.04±0.3 mg per deciliter [3.5±26.5 μmol per liter] with the low-dose strategy, P=0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function. Among patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00577135.).
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            Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial.

            Intravenous saline is recommended in clinical practice guidelines as the cornerstone for preventing contrast-induced nephropathy in patients with compromised renal function. However, clinical-effectiveness and cost-effectiveness of this prophylactic hydration treatment in protecting renal function has not been adequately studied in the population targeted by the guidelines, against a group receiving no prophylaxis. This was the aim of the AMACING trial.
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              Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents.

              Injections of radiocontrast agents are a frequent cause of acute decreases in renal function, occurring most often in patients with chronic renal insufficiency and diabetes mellitus. We prospectively studied 78 patients with chronic renal insufficiency (mean [+/- SD] serum creatinine concentration, 2.1 +/- 0.6 mg per deciliter [186 +/- 53 mumol per liter]) who underwent cardiac angiography. The patients were randomly assigned to receive 0.45 percent saline alone for 12 hours before and 12 hours after angiography, saline plus mannitol, or saline plus furosemide. The mannitol and furosemide were given just before angiography. Serum creatinine was measured before and for 48 hours after angiography, and urine was collected for 24 hours after angiography. An acute radiocontrast-induced decrease in renal function was defined as an increase in the base-line serum creatinine concentration of at least 0.5 mg per deciliter (44 mumol per liter) within 48 hours after the injection of radiocontrast agents. Twenty of the 78 patients (26 percent) had an increase in the serum creatinine concentration of at least 0.5 mg per deciliter after angiography. Among the 28 patients in the saline group, 3 (11 percent) had such an increase in serum creatinine, as compared with 7 of 25 in the mannitol group (28 percent) and 10 of 25 in the furosemide group (40 percent) (P = 0.05). The mean increase in serum creatinine 48 hours after angiography was significantly greater in the furosemide group (P = 0.01) than in the saline group. In patients with chronic renal insufficiency who are undergoing cardiac angiography, hydration with 0.45 percent saline provides better protection against acute decreases in renal function induced by radiocontrast agents than does hydration with 0.45 percent saline plus mannitol or furosemide.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: Data curationRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                24 April 2018
                2018
                : 13
                : 4
                : e0196088
                Affiliations
                [1 ] Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
                [2 ] Department of Cardiovascular Anesthesia and Intensive Care, Fondazione Cardiocentro Ticino, Lugano, Switzerland
                [3 ] Vita-Salute San Raffaele University, Milan, Italy
                [4 ] Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
                University of Sao Paulo Medical School, BRAZIL
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-8594-5980
                Article
                PONE-D-18-04807
                10.1371/journal.pone.0196088
                5915682
                29689116
                47e6009b-2930-4e72-97fb-9ad7bb29a8d1
                © 2018 Bove et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 13 February 2018
                : 5 April 2018
                Page count
                Figures: 4, Tables: 2, Pages: 18
                Funding
                Funded by: Agenzia Italiana del Farmaco, Ministero della Salute (IT)
                Award ID: FARM12JFX9
                Award Recipient :
                Supported by a grant from the Italian Medicines Agency (AIFA – Grant no. FARM12JFX9, http://www.agenziafarmaco.gov.it/) received by Prof. Tiziana Bove. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Diuretics
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Meta-Analysis
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Statistical Methods
                Meta-Analysis
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Medicine and Health Sciences
                Cardiology
                Heart Failure
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Health Care
                Health Care Facilities
                Hospitals
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Creatinine
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Cardiovascular Procedures
                Cardiac Surgery
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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                Uncategorized

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