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INTRODUCTION: Bumetanide, a loop diuretic, was identified as a candidate drug for repurposing for Alzheimers disease (AD) based on its effects on transcriptomic apolipoprotein E signatures. Cross-sectional analyses of electronic health records suggest that bumetanide is associated with decreased prevalence of AD; however, temporality between bumetanide exposure and AD development has not been established. METHODS: We evaluated Medicare claims data using Cox proportional hazards regression to evaluate the association between time-dependent use of bumetanide and time to first AD diagnosis while controlling for patient characteristics. Multiple sensitivity analyses were conducted to test the robustness of the findings. RESULTS: We sampled 833,561 Medicare beneficiaries, 60.8% female, with mean (standard deviation) age of 70.4 (12). Bumetanide use was not significantly associated with AD risk (hazard ratio 1.05; 95% confidence interval, 0.99-1.10). DISCUSSION: Using a nationwide dataset and a retrospective cohort study design, we were not able to identify a time-dependent effect of bumetanide lowering AD risk. HIGHLIGHTS: Bumetanide was identified as a candidate for repurposing for Alzheimers disease (AD). We evaluated the association between bumetanide use and risk of AD. We used Medicare data and accounted for duration of bumetanide use. Bumetanide use was not significantly associated with risk of AD.

Heart failure is a common condition in the older population. As severity progresses, fluid accumulates resulting in congestive symptoms. Loop diuretics are the cornerstone of managing fluid overload and dosing should target euvolemia and congestive symptoms. Volume status is difficult to assess but signs and symptoms such as dyspnea, orthopnea, edema, and weight changes can be evaluated even without specialized equipment in the outpatient setting. Pharmacists are capable of assessing diuretic response and making recommendations for dosing changes in older heart failure patients. [ABSTRACT FROM AUTHOR]

Purpose: To study the association between the use of drugs for hypertension or heart failure, particularly diuretics, and risk of death in COVID-19. Methods: We conducted a cohort study, based on record linked individual-based data from national registers, of all Swedish inhabitants 50 years and older (n = 3,909,321) at the start of the first SARS-CoV-2 wave in Sweden. The association between use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), thiazides, loop diuretics, aldosterone antagonists, beta blocking agents and calcium channel blockers at the index date 6 March 2020, and death in COVID-19 during 7 March to 31 July 2020, was analysed using Cox-proportional hazards regression, adjusted for a wide range of possible confounders. Results: Use of loop diuretics was associated with higher risk [adjusted hazard ratio (HR) 1.26; 95% confidence interval (95% CI) 1.17–1.35] and thiazides with reduced risk (0.78; 0.69–0.88) of death in COVID-19. In addition, lower risk was observed for ACEI and higher risk for beta-blocking agents, although both associations were weak. For ARB, aldosterone antagonists and calcium channel blockers no significant associations were found. Conclusion: In this nationwide cohort of nearly 4 million persons 50 years and older, the use of loop diuretics was associated with increased risk of death in COVID-19 during the first SARS-CoV-2 wave in Sweden. This contrasted to the decreased risk observed for thiazides. As treatment with loop diuretics is common, particularly in the elderly, the group most affected by severe COVID-19, this finding merit further investigation. [ABSTRACT FROM AUTHOR]

Background: We examined whether denosumab-induced hypocalcaemia is evident in osteoporosis when given loop diuretics that promote urinary calcium excretion. Methods: Japanese Spontaneous Adverse Drug Event Reports was analyzed to examine signals for denosumab-induced hypocalcaemia co-administered loop diuretics. We retrospectively included osteoporotic patients to detect predictors for denosumab-induced hypocalcaemia (corrected calcium level < 8.5 mg/dL) using multivariate logistic regression analysis. We compared differences in corrected calcium levels (ΔCa = nadir-baseline). Results: A significant signal for hypocalcaemia was detected (Reporting odds ratio = 865.8, 95% confidence interval [95% CI]: 596.8 to 1255.9, p < 0.0001). Among 164 patients (hypocalcaemia, 12%), loop diuretics have a significant association with hypocalcaemia (odds ratio [OR] = 6.410, 95% CI: 1.005 to 40.90, p = 0.0494). However, hypocalcaemia was found to be lower in high corrected calcium levels at baseline (OR = 0.032, 95% CI: 0.005 to 0.209, p < 0.0001) and calcium and vitamin D supplementation (OR = 0.285, 95% CI: 0.094 to 0.868, p = 0.0270). In the non-hypocalcaemia, ΔCa decreased significantly in the denosumab plus loop diuretics than in the denosumab alone (-0.9 [-1.3 to -0.7] mg/dL vs. -0.5 [-0.8 to -0.3] mg/dL, p = 0.0156). However, ΔCa remained comparable in the hypocalcaemia despite loop diuretics co-administration (-1.0 [-1.2 to -0.8] mg/dL vs. -0.8 [-1.5 to -0.7] mg/dL, p = 0.7904). Conclusions: Loop diuretics may predispose to developing denosumab-induced hypocalcaemia. [ABSTRACT FROM AUTHOR]

Background and Aims In the STEP-HFpEF trial programme, treatment with semaglutide resulted in multiple beneficial effects in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Efficacy may vary according to baseline diuretic use, and semaglutide treatment could modify diuretic dose. Methods In this pre-specified analysis of pooled data from the STEP-HFpEF and STEP-HFpEF-DM trials (n = 1145), which randomized participants with HFpEF and body mass index ≥ 30 kg/m2 to once weekly semaglutide 2.4 mg or placebo for 52 weeks, we examined whether efficacy and safety endpoints differed by baseline diuretic use, as well as the effect of semaglutide on loop diuretic use and dose changes over the 52-week treatment period. Results At baseline, across no diuretic (n = 220), non-loop diuretic only (n = 223), and loop diuretic [<40 (n = 219), 40 (n = 309), and >40 (n = 174) mg/day furosemide equivalents] groups, there was progressively higher prevalence of hypertension and atrial fibrillation; and greater severity of obesity and heart failure. Over 52 weeks of treatment, semaglutide had a consistent beneficial effect on change in body weight across diuretic use categories (adjusted mean difference vs. placebo ranged from −8.8% [95% confidence interval (CI) −10.3, −6.3] to −6.9% [95% CI −9.1, −4.7] from no diuretics to the highest loop diuretic dose category; interaction P =.39). Kansas City Cardiomyopathy Questionnaire clinical summary score improvement was greater in patients on loop diuretics compared to those not on loop diuretics (adjusted mean difference vs. placebo: +9.3 [6.5; 12.1] vs. +4.7 points [1.3, 8.2]; P =.042). Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including 6 min walk distance) across diuretic subgroups (interaction P =.24–.92). Safety also favoured semaglutide vs. placebo across the diuretic subgroups. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (P <.0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67 [95% CI 1.70, 4.18]) and less likely dose increase (OR 0.35 [95% CI 0.23, 0.53]; P <.001 for both) from baseline to 52 weeks. Conclusions In patients with obesity-related HFpEF, semaglutide improved heart failure-related symptoms and physical limitations across diuretic use subgroups, with more pronounced benefits among patients receiving loop diuretics at baseline. Reductions in weight and improvements in exercise function with semaglutide vs. placebo were consistent in all diuretic use categories. Semaglutide also led to a reduction in loop diuretic use and dose between baseline and 52 weeks. Clinical Trial Registration NCT04788511 and NCT04916470. [ABSTRACT FROM AUTHOR]

• In patients with acute heart failure, it is recommended to add a second diuretic early if the patient has not responded adequately to the initial diuretic. • The combination of thiazide and loop diuretics at discharge was not associated with a risk of adverse clinical events. • The effect of a nephron blockade strategy using in the outpatient setting after a recent episode of AHF is sure. To investigate the association of the addition of thiazide diuretic on top of loop diuretic and standard of care with short-term outcomes of patients discharged after surviving an acute heart failure (AHF) episode. This is a secondary analysis of 14,403 patients from three independent cohorts representing the main departments involved in AHF treatment for whom treatment at discharge was recorded and included loop diuretics. Patients were divided according to whether treatment included or not thiazide diuretics. Short-term outcomes consisted of 30-day all-cause mortality, hospitalization (with a separate analysis for hospitalization due to AHF or to other causes) and the combination of death and hospitalization. The association between thiazide diuretics on short-term outcomes was explored by Cox regression and expressed as hazard ratios (HR) with 95 % confidence intervals, which were adjusted for 18 patient-related variables and 9 additional drugs (aside from loop and thiazide diuretics) prescribed at discharge. The median age was 81 (interquartile range=73–86) years, 53 % were women, and patients were mainly discharged from the cardiology (42 %), internal medicine or geriatric department (29 %) and emergency department (19 %). There were 1,367 patients (9.5 %) discharged with thiazide and loop diuretics, while the rest (13,036; 90.5 %) were discharged with only loop diuretics on top of the remaining standard of care treatments. The combination of thiazide and loop diuretics showed a neutral effect on all outcomes: death (adjusted HR 1.149, 0.850–1.552), hospitalization (0.898, 0.770–1.048; hospitalization due to AHF 0.799, 0.599–1.065; hospitalization due to other causes 1.136, 0.756–1.708) and combined event (0.934, 0.811–1.076). The combination of thiazide and loop diuretics was not associated with changes in risk of death, hospitalization or a combination of both. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is characterized by progressive cognitive decline, and behavioural and psychological symptoms of dementia are common. The APOE ε4 allele, a genetic risk factor, significantly increases susceptibility to the disease. Despite efforts to effectively treat the disease, only seven drugs are approved for its treatment, and only two of these prevent its progression. This highlights the need to identify new pharmacological options. This review focuses on mimetic peptides, small molecule correctors and HAE‐4 antibodies that target ApoE. These drugs reduce β‐amyloid‐induced neurodegeneration in preclinical models. In addition, loop diuretics such as bumetanide and furosemide show the potential to reduce the prevalence of Alzheimer's disease in humans, and antidepressants such as imipramine improve cognitive function in individuals diagnosed with Alzheimer's disease. Consistent with this, both classes of drugs have been shown to exert neuroprotective effects by inhibiting ApoE4‐catalysed Aβ aggregation in preclinical models. Moreover, peroxisome proliferator‐activated receptor ligands, particularly pioglitazone and rosiglitazone, reduce ApoE4‐induced neurodegeneration in animal models. However, they do not prevent the cognitive decline in APOE ε4 allele carriers. Finally, ApoE4 impairs the integrity of the blood–brain barrier and haemostasis. On this basis, ApoE4 modulation is a promising avenue for the treatment of late‐onset Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Abstract Background We examined whether denosumab-induced hypocalcaemia is evident in osteoporosis when given loop diuretics that promote urinary calcium excretion. Methods Japanese Spontaneous Adverse Drug Event Reports was analyzed to examine signals for denosumab-induced hypocalcaemia co-administered loop diuretics. We retrospectively included osteoporotic patients to detect predictors for denosumab-induced hypocalcaemia (corrected calcium level

Acute heart failure (AHF) is a serious condition with a high mortality rate. It is considered as the most common cause of unplanned hospitalizations in the elderly population. In 90% of all cases AHF presents with congestive symptoms, thus mostly treated with loop diuretics. However, in some cases resistance to loop diuretics develops, causing a major problem. In these cases, despite diuretic treatment, urinary output remains inadequate. Resistance, apart from leading to longer hospitalization and inadequate improvement of congestion, has been shown to be responsible for a worse prognosis compared to properly established diuretic response. Thus, managing resistance is important for which the addition of other diuretics (acting at other targets) may be a solution. The most widely studied of these are thiazide diuretics. Although, previous research suggests that thiazides may be effective in treating diuretic resistance, their early side effects can significantly affect patient survival, therefore their use in combination has not yet been widely adopted. However, the recent CLOROTIC trial has provided promising results on this issue. In our review, we are investigating the use of thiazides in the acute heart failure population in the presence of loop diuretic resistance in the light of these new results.

Abstract Background The efficacy of dapagliflozin in patients with acute heart failure remains unclear. Objective To investigate the impact of dapagliflozin (DAPA) on loop diuretics use and 90-day readmission in patients with acute heart failure. Methods In a retrospective cohort study, patients diagnosed with acute heart failure or chronic heart failure with acute exacerbation admitted to Fuyang People’s Hospital from January 2021 to April 2023, this study used DAPA (at a dose of 10 mg once daily) in combination with standard treatment. The patients were divided into DAPA group and DAPA-Free group based on whether they used DAPA in acute heart failure. To minimize the influence of confounding factors and ensure comparability between groups, we used propensity score matching (PSM). Results A total of 399 patients were included, with 206 patients (51.63%) in the DAPA group and 193 patients (48.37%) in the DAPA-Free group. PSM produced 160 pairs. After PSM, there were no statistically significant differences between the DAPA and DAPA-Free groups in terms of readmission of all causes (16.88% vs. 18.12%, OR 0.9141, 95% CI 0.5385–1.552, log rank P = 0.739) or readmission for heart failure (11.88% vs. 15.0%, OR 0.9077, 95% CI 0.4441–1.469, log rank P = 0.484) after 90-day follow-up. Patients in the DAPA group had a lower mean daily dose of intravenous loop diuretics compared to the DAPA-Free group (20 mg/d vs. 30.00 mg/d, P

Episodes of congestion characterize the disease course of patients with heart failure, resulting in a high morbidity with the need for urgent hospitalization. The main treatment goal is to alleviate signs and symptoms of congestion to reach euvolemia. Loop diuretics remain the cornerstone in the treatment, however diuretic response is unpredictable and therapy should be individualized. The neurohormonal activation result in an increased sodium reabsorption along the whole nephron. Each segment provides a different target site to increase diuretic and natriuretic response. This manuscript provides further insight in the pathophysiology behind the cardiorenal interactions, which lead to the increased sodium avidity in heart failure. In addition, the different therapeutic options to enhance diuretic response in patients with acute heart failure is discussed, as well as the assessment of the diuretic response based on the urinary sodium concentration.

Background: Normothermic machine perfusion (NMP) is a promising pretransplant kidney quality assessment platform, but it remains crucial to increase its diagnostic potential while ensuring minimal additional injury to the already damaged kidney. Interventions that alter tubular transport can influence renal function and injury during perfusion. This study aimed to determine whether furosemide and desmopressin affect renal function and injury during NMP. Methods: Eighteen porcine kidneys (n = 6 per group) were subjected to 30 min of warm ischemia and 4 h of oxygenated hypothermic perfusion before being subjected to 6 h of NMP. Each organ was randomized to receive no drug, furosemide (750 mg), or desmopressin (16 μg) during NMP. Results: Compared with the other groups, the addition of furosemide resulted in significantly increased urine output, fractional excretion of sodium and potassium, and urea clearance during NMP. Urinary neutrophil gelatinase‐associated lipocalin levels decreased significantly with furosemide supplementation compared with the other groups. The addition of desmopressin did not result in any significantly different outcome measurements compared with the control group. Conclusions: This study showed that the addition of furosemide affected renal function while attenuating tubulointerstitial injury during NMP. Therefore, furosemide supplementation may provide renal protection and serve as a functional test for pretransplant kidney viability assessment during NMP. [ABSTRACT FROM AUTHOR]

Background: The relationship between patterns of outpatient oral loop diuretic (LD) dose reduction and prognosis in patients with heart failure (HF) remains unclear. Methods: We evaluated 679 patients with HF-prescribed LDs at baseline between September 2015 and August 2019. Dose reduction was defined as a change to a lower LD dose than the previous outpatient dose. Dose intensification was defined as a change to a higher LD dose than the previous outpatient dose. Patients were classified into no-reduction (no LD dose reduction during follow-up) and reduction groups (categorized into successive-reduction [≥2 successive LD dose reductions without intervening LD dose intensification] and single-reduction [LD dose reduction without successive dose reduction] groups). The primary outcomes were all-cause death, HF hospitalization (HFH), and the composite of cardiovascular death (CVD) or HFH. Results: Within a median follow-up of 53.7 (range, 2.6–99.1) months, 156 deaths were recorded: 121 (29 %), 31 (15 %), and three (4 %) patients in the no-reduction (n = 411), single-reduction (n = 195), and successive-reduction (n = 73) groups, respectively. After adjusting for cofounders, the reduction group had a lower risk of primary outcomes than the no reduction group (all-cause death: hazard ratio (HR) = 0.65, 95 % confidence interval (CI) = 0.44–0.96; CVD or HFH: HR=0.69, 95 %CI=0.52–0.93; HFH: HR=0.69, 95 % CI=0.52–0.93). The successive-reduction group had a lower risk of the composite of CVD or HFH (HR=0.26, 95 % CI: 0.10–0.67) and HFH (HR=0.34, 95 % CI=0.13–0.86) than the single-reduction group. Conclusions: Outpatient LD dose reduction patterns can be indicators of good prognosis in HF patients.

Purpose Hypophosphatemia (serum phosphate < 0.80 mmol/L) leads to musculoskeletal complaints. The most common drugs linked to hypophosphatemia are thiazide and loop diuretics, but studies in the general population are lacking. Our aim was to study associations between diuretic use and serum phosphate in the Rotterdam Study (RS), a population-based cohort study, with replication in UK Biobank (UKBB). Methods Associations between thiazide and loop diuretic use and serum phosphate and odds of hypophosphatemia were analyzed with cross-sectional multivariate linear and logistic regression in participants without chronic kidney disease in the RS and UKBB. Analyses were adjusted for age, sex, and body mass index (BMI) and pooled in 3 RS cohorts with further adjustment for cohort and serum potassium, which was not available in UKBB. Results Thiazide diuretics were associated with lower serum phosphate in both sexes. This association lost significance in RS females after adjustment for BMI and in males after adjustment for serum potassium. Thiazide diuretics increased odds of hypophosphatemia in females in both cohorts and in males in UKBB only. Loop diuretics were associated with lower serum phosphate in females but not males. Adjustment for BMI attenuated these associations. Associations between loop diuretics and increased odds of hypophosphatemia in females lost significance after BMI adjustment. Conclusion Thiazides, but not loop diuretics, and increased BMI and decreased serum potassium should be considered as contributing factors in subjects with hypophosphatemia. Further studies are needed to replicate the findings and elucidate the potential role of hypokalemia as a mediator of this effect. [ABSTRACT FROM AUTHOR]

Objectives: The research aimed to study the following questions: (1) five well-known gout-related medications were selected to test the validity of the prescription symmetry sequence analysis in Taiwan; (2) four exploratory medications were selected to test their relation to gout flares. Methods: We utilized the 2003–2017 dataset of the Taiwan National Health Insurance Program containing all claims data with 2 million beneficiaries as a data source. In order to explore the temporal association, we designed a scenario of medication-induced gout flares. Nine medications were selected as the index agent, including aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol, pyrazinamide, metformin, pioglitazone, fenofibrate, and losartan. The gout flare was defined as subjects with use of the marker agent for treatment of gout flares. The observation-window period between initiation of the index agent and initiation of the marker agent was 1 year. Subjects who used an index agent and a marker agent on the same day were excluded. The prescription symmetry sequence analysis was carried out to compare the observed number of persons who took an index agent prior to starting a marker agent with the observed number of persons who took a marker agent before starting an index agent. The adjusted sequence ratio (adjusted SR) with 95% confidence interval was applied to estimate the relation between an index agent and the marker agent. Results: Among five medications including aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol, and pyrazinamide, the adjusted sequence ratio ranged from 1.15 to 3.35 and all reached statistical significance. Fenofibrate use and losartan use were associated with a lower probability of gout flares, with reaching statistical significance (adjusted SR = 0.60 for fenofibrate and adjusted SR = 0.92 for losartan). Metformin use was associated with a greater probability of gout flares, with reaching statistical significance (adjusted SR = 1.14). Pioglitazone use did not reach statistical significance. Conclusion: Based on the confirmatory analysis including five well-known gout-related medications, this study supports that the prescription symmetry sequence analysis can be used to detect an adverse drug event associated with one potential offending agent. The exposure to fenofibrate or losartan might be a protective factor against gout flares. Metformin use could be associated with a greater probability of gout flares, but this finding should be validated by other studies. Key Points: • What is already known about this subject? 1. The prescription symmetry sequence analysis is a useful method for detecting an adverse drug reaction associated with one potential offending drug. 2. Numerous medications are found to induce gout flares. • What does this study add? 1. The prescription symmetry sequence analysis supports the evidence that aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol and pyrazinamide are associated with a greater probability of gout flares. 2. The exposure to fenofibrate or losartan might be a protective factor against gout flares. 3. Metformin use could be associated with a greater probability of gout flares. • How might this impact on clinical practice or future developments? 1. Clinicians should always consider the possibility of medication-induced gout flares. If gout flares develop, discontinuation of risky medications is the first step. Then prescribing cascades can be eliminated. [ABSTRACT FROM AUTHOR]

Simple Summary: The most common heart disease in dogs is a leaky mitral valve. This disease is incurable and slowly progressive. However, with appropriate therapy, prolonged longevity and improved quality of life can be reached. International guidelines are available to help veterinarians treat these dogs according to the latest insights. However, these guidelines might become outdated because scientific evidence can only be reviewed until about a year before their publication. Moreover, disagreements among the panelists who prepare the guidelines, and newer study results challenging the guidelines can make it difficult for practicing veterinarians to choose the right treatment. Our study aimed to investigate, using a survey, how Dutch and Belgian veterinary practitioners treat dogs with a leaky mitral valve. From the 363 responses, we concluded that the more advanced the disease stage is, the more variation there is among the recommended drug regimes. The earliest asymptomatic stage of the disease was treated correctly by 93% of the respondents, whereas the more advanced asymptomatic stage was treated by 67% of the respondents correctly. For the treatment of the symptomatic stage of the disease, 16 various drug combinations were reported, of which only 2 are considered correct, recommended by 48%. No respondents recommended surgery. Background: Myxomatous mitral valve degeneration is the most common canine heart disease. Several clinical trials have investigated various treatments. The latest recommendations are published in the ACVIM consensus guidelines (2019). Our study aimed to investigate how closely veterinary practitioners apply the treatment recommendations of these guidelines and the latest clinical trials. Methods: An online survey was sent to Dutch and Belgian veterinary practices via digital channels. Results: The data from 363 fully completed surveys were analyzed. For stage B1 disease, 93% recommended, correctly, no treatment. For stage B2 disease, 67% of the respondents recommended starting pimobendan as monotherapy. For chronic treatment of stage C disease, 16 different drug combinations were mentioned, but nobody recommended surgery. Only 48% of the respondents recommended the only evidence-based drug combination: a loop diuretic with pimobendan. A concerning finding was the simultaneous prescription of two loop diuretics, by 19% of the respondents. Conclusions: Treatment recommendations showed an increasing variation with more advanced disease stages from B1 through B2 to C. This reflects the increasing disagreement among the panelists who prepared the ACVIM consensus guidelines. Practitioners of our study seem to practice more evidence-based medicine than veterinary cardiologists, as it was reported in a recent survey-based study. [ABSTRACT FROM AUTHOR]

Diuresis with loop diuretics is the mainstay treatment for volume optimization in patients with congestive heart failure, in which perfusion and volume expansion play a crucial role. There are robust guidelines with extensive evidence for the management of heart failure; however, clear guidance is needed for patients who do not respond to standard diuretic treatment. Diuretic resistance (DR) can be defined as an insufficient quantity of natriuresis with proper diuretic therapy. A combination of diuretic regimens is used to overcome DR and, more recently, SGLT2 inhibitors have been shown to improve diuresis. Despite DR being relatively common, it is challenging to treat and there remains a notable lack of substantial data guiding its management. Moreover, DR has been linked with poor prognosis. This review aims to expose the multiple approaches for treatment of patients with DR and the importance of intravascular volume expansion in the response to therapy.

Rationale & objectiveHeart failure treatment relies on loop diuretics to induce natriuresis and decongestion, but the therapy is often limited by diuretic resistance. We explored the association of renin-angiotensin-aldosterone system (RAAS) activation with diuretic response.Study designObservational cohort.Setting & populationEuvolemic ambulatory adults with chronic heart failure were administered torsemide in a monitored environment.PredictorsPlasma total renin, active renin, angiotensinogen, and aldosterone levels. Urine total renin and angiotensinogen levels.OutcomesSodium output per doubling of diuretic dose and fractional excretion of sodium per doubling of diuretic dose.Analytical approachRobust linear regression models estimated the associations of each RAAS intermediate with outcomes.ResultsThe analysis included 56 participants, and the median age was 65 years; 50% were women, and 41% were Black. The median home diuretic dose was 80-mg furosemide equivalents. In unadjusted and multivariable-adjusted models, higher levels of RAAS measures were generally associated with lower diuretic efficiency. Higher plasma total renin remained significantly associated with lower sodium output per doubling of diuretic dose (β = -0.41 [-0.76, -0.059] per SD change) with adjustment; higher plasma total and active renin were significantly associated with lower fractional excretion of sodium per doubling of diuretic dose (β = -0.48 [-0.83, -0.14] and β = -0.51 [-0.95, -0.08], respectively) in adjusted models. Stratification by RAAS inhibitor use did not substantially alter these associations.LimitationsSmall sample size; highly selected participants; associations may not be causal.ConclusionsAmong multiple measures of RAAS activation, higher plasma total and active renin levels were consistently associated with lower diuretic response. These findings highlight the potential drivers of diuretic resistance and underscore the need for high-quality trials of decongestive therapy enhanced by RAAS blockade.

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Purpose: Vancomycin (VAN) is widely used in neurosurgical patients for intracranial infections. We aimed to assess the incidence and risk factors for VAN-associated acute kidney injury (VA-AKI) in this population. Methods: A case–control study of patients who treated with vancomycin in neurosurgery from January 2020 to December 2022 was conducted. Demographics and potential risk factors were collected. Multivariate logistic regression analyses were performed to identify risk factors for VA-AKI. AKI was defined according to the Kidney Disease Improving Global Outcomes Guidelines (KDIGO). Results: A total of 345 patients participated with a VA-AKI incidence of 17.1% (59 cases). Among them, 15 patients had renal impairment (Stage 2 or higher), and 2 required dialysis. With univariate analysis and binary logistic regression analysis, we found that the use of mannitol (OR: 4.164; 95% CI: 1.606–10.792; P = 0.003), loop diuretics (OR: 3.371; 95% CI: 1.633–6.958; P = 0.001), three or more antimicrobial applications (OR: 3.623; 95% CI: 1.600–8.206; P = 0.002), diastolic blood pressure 80–89 mm Hg (OR: 5.532; 95% CI: 1.677–18.250; P = 0.005) and diastolic blood pressure ≥ 90 mm Hg (OR: 6.845; 95% CI: 1.518–30.866; P = 0.012) were independent risk factors for VA-AKI. In addition, according to the Youden Index, the trough concentration of vancomycin should not exceed 15.845 mg/L. Conclusion: The incidence of VA-AKI in neurosurgical patients was 17.1%. The concomitant use of mannitol and loop diuretics, along with higher diastolic blood pressure and the combined use of more than three antimicrobial agents, were associated with an increased risk of neurosurgical VA-AKI. [ABSTRACT FROM AUTHOR]

This review paper presents a review of the evolution of this disease throughout the centuries, describes and summarizes the pathophysiologic mechanisms, briefly discusses the mechanism of action of diuretics, presents their role in decongesting heart failure in patients, and reveals the data behind ultrafiltration in the management of acutely or chronically decompensated heart failure (ADHF), focusing on all the available data and advancements in this field. Acutely decompensated heart failure (ADHF) presents a critical clinical condition characterized by worsening symptoms and signs of heart failure, necessitating prompt intervention to alleviate congestion and improve cardiac function. Diuretics have traditionally been the mainstay for managing fluid overload in ADHF. Mounting evidence suggests that due to numerous causes, such as coexisting renal failure or chronic use of loop diuretics, an increasing rate of diuretic resistance is noticed and needs to be addressed. There has been a series of trials that combined diuretics of different categories without the expected results. Emerging evidence suggests that ultrafiltration may offer an alternative or adjunctive approach. [ABSTRACT FROM AUTHOR]

Background: Loop diuretics (LDs) are used to treat various health conditions including heart failure (HF), liver cirrhosis, and chronic kidney disease (CKD). Sarcopenia is a skeletal muscle health issue related to the depletion and decrease of muscle mass and strength, leading to adverse outcomes including frailty syndrome, functional decline, falls, hospitalizations, augmented length of hospital stay, and increased morbidity and mortality. Methods: This study investigated the probable association between LD use and sarcopenia via conducting a non-systematic review of the existing literature. Results: In subjects with non-dialysis-dependent chronic kidney disease (NDD-CKD), an augmented risk of sarcopenia is significantly associated with LD use. Interestingly, in patients with HF treated with LDs, thigh and arm circumferences were significantly small, which is indicative of skeletal muscle wasting. Additionally, in anorexic subjects who are more likely to be on diuretic medication, suffering also from cachexia, a higher prevalence of sarcopenia was demonstrated. In cirrhotic subjects, the treatment dosage of LDs was inversely correlated with the skeletal muscle area per year (ΔSMA). Nevertheless, in subjects with liver cirrhosis treated with LDs, who were divided into those with and those without muscle cramps, the presence of sarcopenia was similar. Conclusions: Further investigation is imperative to validate potential interplay between LDs and sarcopenia. [ABSTRACT FROM AUTHOR]

Background: Loop diuretics (LDs) are used to treat various health conditions including heart failure (HF), liver cirrhosis, and chronic kidney disease (CKD). Sarcopenia is a skeletal muscle health issue related to the depletion and decrease of muscle mass and strength, leading to adverse outcomes including frailty syndrome, functional decline, falls, hospitalizations, augmented length of hospital stay, and increased morbidity and mortality. Methods: This study investigated the probable association between LD use and sarcopenia via conducting a non-systematic review of the existing literature. Results: In subjects with non-dialysis-dependent chronic kidney disease (NDD-CKD), an augmented risk of sarcopenia is significantly associated with LD use. Interestingly, in patients with HF treated with LDs, thigh and arm circumferences were significantly small, which is indicative of skeletal muscle wasting. Additionally, in anorexic subjects who are more likely to be on diuretic medication, suffering also from cachexia, a higher prevalence of sarcopenia was demonstrated. In cirrhotic subjects, the treatment dosage of LDs was inversely correlated with the skeletal muscle area per year (ΔSMA). Nevertheless, in subjects with liver cirrhosis treated with LDs, who were divided into those with and those without muscle cramps, the presence of sarcopenia was similar. Conclusions: Further investigation is imperative to validate potential interplay between LDs and sarcopenia.

Abstract Furosemide, a loop diuretic, is commonly used to treat fluid overload symptoms and heart failure. Drug‐induced immune haemolytic anaemia is an unusual drug‐adverse event. Furosemide‐induced haemolysis is even rarer. This case report presents a 91‐year‐old male who developed acute haemolytic anaemia 3 days after initiating furosemide to treat myocardial infarction complicated with acute decompensated heart failure. He had increased lactate dehydrogenase and unconjugated bilirubin with undetectable haptoglobin, which indicated the destruction of red blood cells. Other causes for haemolytic anaemia, including hereditary, microangiopathic haemolytic anaemia, and paroxysmal nocturnal haemoglobinuria, were also excluded. He improved with drug cessation and a short course of glucocorticoids. This report aims to raise awareness of this rare complication caused by commonly prescribed drugs. Despite a negative result of a direct antiglobulin test, physicians must remain suspicious of drug‐induced immune haemolytic anaemia in unclear cases of haemolysis.

BackgroundLoop diuretics are essential for managing congestion in acute heart failure (AHF) patients, but concerns exist about their dosing and administration. This study aims to explore the relationship between aggressive diuretic treatment and clinical outcomes in AHF patients.MethodsWe randomly selected 370 AHF patients from admissions at Maastricht University Medical Center between January 2011 and March 2017. Patients were divided into four quartiles based on diuretic doses administrated during index hospitalization. The primary endpoint was a composite of cardiovascular (CV) rehospitalization or death at 1 year.Results42.4% of patients experimented the primary outcome The composite endpoint rates were 35.4%, 41.6%, 38.5%, and 54.9%, respectively, from lowest to highest dose quartiles (p = 0.033). In univariate analysis, the outcome was significantly lower in the first three quartiles as compared to the fourth quartile. One-year CV mortality was 9.1%, 10.1%, 20.9% and 27.2%, respectively (p = 0.002). After adjusting for confounders, the association between loop diuretic dosage disappeared for both the primary outcome and one-year CV mortality. Most secondary outcomes and endpoints at 3 months, including worsening renal function, showed no significant differences between groups, while hypokaliemia occurrence, length of hospital stay and weight loss at index admission were higher in the fourth quartile compared to the first one.ConclusionsHigh loop diuretic doses are associated with poor outcomes in AHF patients, reflecting disease severity rather than harm from aggressive diuretic use. Furthermore, high diuretic doses do not seem to negatively affect kidney function.

Aims: Diuretic response in heart failure is blunted when compared to healthy individuals, but the pathophysiology underlying this phenomenon is unclear. We aimed to investigate whether the diuretic resistance mechanism is related to insufficient furosemide tubular delivery or low tubular responsiveness. Methods and results: We conducted a prospective, observational study of 50 patients with acute heart failure patients divided into two groups based on previous furosemide use (furosemide naïve: n = 28 [56%] and chronic furosemide users: n = 22 [44%]). Each patient received a protocol‐derived, standardized furosemide dose based on body weight. We measured diuretic response and urine furosemide concentrations. The furosemide naïve group had significantly higher urine volumes and natriuresis when compared to chronic users at all timepoints (all p < 0.05). Urine furosemide delivery was similar in furosemide naïve versus chronic users after accounting for differences in estimated glomerular filtration rate (28.02 [21.03–35.89] vs. 29.70 [18.19–34.71] mg, p = 0.87). However, the tubular response to delivered diuretic was dramatically higher in naïve versus chronic users, that is the urine volume per 1 μg/ml of urine furosemide at 2 h was 148.6 ± 136.1 versus 50.6 ± 56.1 ml (p = 0.005). Conclusions: Patients naïve to furosemide have significantly better diuresis and natriuresis when compared to chronic furosemide users. The blunted diuretic response in patients with chronic loop diuretic exposure is driven by decreased tubular responsiveness rather than insufficient furosemide tubular delivery. [ABSTRACT FROM AUTHOR]

Medicinal plants received special attention due to their biological and medicinal activities, aspects of safety in their use, and low cost. This study aimed to prove gum Arabic (GA) extract’s preventive and therapeutic role against furosemide toxicity. Moreover, histological findings, renal functions, and the level of MDA and GSH in the serum and kidney tissues of newborn rats were assessed. Thirty pregnant rats were divided into six groups (n = 5 per group). The first group is the control group, with no treatment. The second is the GA group, administered 15% w/v GA in drinking water daily from conception day 0 until the end of pregnancy. The third group is the furosemide group; furosemide (20 mg/k, ip) was taken daily from conception day 0 until the end of pregnancy. The fourth group is the protective group (preventive group); GA was taken daily (15% w/v in drinking water) from conception day 0 to day 10, followed by furosemide (20 mg/kg, ip) daily until the end of pregnancy. The fifth group is the therapeutic group; furosemide (20 mg/kg, ip) was taken daily from conception day 0 to day 10, followed by GA (15% w/v in drinking water) daily until the end of pregnancy. The sixth group is the mixed group; GA and furosemide were administered together from conception day 0 until the end of pregnancy. [ABSTRACT FROM AUTHOR]

Evidence for modulating the sodium chloride (NaCl) intake of patients hospitalized with acute heart failure (AHF) is inconclusive. Salt restriction may not benefit; hypertonic saline may aid diuresis. To compare the safety and efficacy of oral NaCl during intravenous (IV) diuretic therapy in renal function and weight. Seventy hospitalized patients with AHF who were being treated with IV furosemide infusion consented to receive, randomly, 2 grams of oral NaCl or placebo 3 times a day in a double-blind manner during diuresis. Treatment efficacy (bivariate primary endpoints of change in serum creatinine levels and change in weight) was measured at 96 hours, and adverse safety events were tracked for 90 days. Sixty-five patients (34 NaCl, 31 placebo) were included for analysis after 5 withdrew. A median of 13 grams of NaCl was given compared to placebo. At 96 hours, there was no significant difference between treatment groups with respect to the primary endpoint (P = 0.33); however, the trial was underpowered, and there was greater than expected standard deviation in weight change. The mean change in creatinine levels and weight was 0.15 ± 0.44 mg/dL and 4.6 ± 4.2 kg in the placebo group compared with 0.04 ± 0.40 mg/dL and 4.0 ± 4.3 kg in the NaCl group (P = 0.30 and 0.57, respectively). Across efficacy and safety endpoints, we observed no significant difference between the 2 groups other than changes in serum sodium levels (-2.6 ± 2.7 in the placebo group and -0.3 ± 3.3 mEq/L in the NaCl group; P < 0.001) and in serum blood urea nitrogen levels (11 ± 15 in the placebo group; 3.1 ± 13 mEq/L in the NaCl group; P = 0.025). In this single-center study, liberal vs restrictive oral sodium chloride intake strategies did not impact the safety and efficacy of intravenous diuretic therapy in patients with AHF. (ClinicalTrials.gov registration NCT04334668.) [Display omitted] [ABSTRACT FROM AUTHOR]

Milk-alkali syndrome, which is characterized by hypercalcemia, metabolic alkalosis, and renal dysfunction, typically results from the ingestion of large amounts of calcium and absorbable alkaline products. However, these symptoms can also manifest when alkalosis and calcium loading occur simultaneously, owing to other factors. We report a case of milk-alkali syndrome caused by loop-diuretic-induced alkaline load and polypharmacy in an 85-year-old Japanese woman with multiple comorbidities, including osteoporosis, hypertension, type 2 diabetes, dyslipidemia, and Parkinson's disease. The patient regularly took 14 drugs, including calcium L-aspartate, eldecalcitol, celecoxib, and a fixed-dose combination of losartan and hydrochlorothiazide. Immediately before admission, furosemide was administered for the treatment of edema. The patient presented with chest discomfort, general malaise, and clinical signs of dehydration, hypercalcemia, hypophosphatemia, hypokalemia, and hypomagnesemia, accompanied by electrocardiogram abnormalities, renal dysfunction, and chloride-resistant metabolic alkalosis. The hypercalcemia was specifically induced by calcium L-aspartate and eldecalcitol. The hypomagnesaemia and hypophosphatemia were caused by diuretics and hypercalcemia. Thus, all the oral medications were discontinued, and rehydration and electrolyte correction therapy were administered. The final diagnosis was milk-alkali syndrome caused by the concomitant use of loop diuretics and other medications, without absorbable alkaline preparation use. This case underscores the importance of considering drug-related factors, checking concomitant medications, and being aware of the benefits, harmful effects, and side effects of polypharmacy in older adults with multimorbidity. [ABSTRACT FROM AUTHOR]

BackgroundHeart failure (HF) is a major source of morbidity and mortality. Fluid retention and shortness of breath are its cardinal manifestations for which loop diuretics are used. Although their usefulness is well accepted, less is known about their role in improving clinical outcomes.ObjectivesThe purpose of this study was to determine the relationship between loop diuretics and clinical outcomes in patients with HF.MethodsOf the 25,345 older patients hospitalized for HF in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 9,866 (39%) received no pre-admission diuretics. The study excluded 1,083 patients receiving dialysis and 847 discharged on thiazide diuretics. Of the remaining 7,936 patients, 5,568 (70%) were prescribed loop diuretics at discharge. Using propensity scores for receipt of loop diuretics estimated for each of the 7,936 patients, a matched cohort of 2,191 pairs of patients was assembled balanced on 74 baseline characteristics. Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes were estimated in the matched cohort.ResultsMatched patients (n = 4,382) had a mean age of 78 years, 54% were women, and 11% were African American. The 30-day all-cause mortality occurred in 4.9% (107 of 2,191) and 6.6% (144 of 2,191) of patients in the loop diuretic and no loop diuretic groups, respectively (HR when the use of loop diuretics was compared with nonuse: 0.73; 95% CI: 0.57 to 0.94; p = 0.016). Patients in the loop diuretic group had a significantly lower risk of 30-day HF readmission (HR: 0.79; 95% CI: 0.63 to 0.99; p = 0.037) but not of 30-day all-cause readmission (HR: 0.89; 95% CI: 0.79 to 1.01; p = 0.081). None of the associations was statistically significant during 60 days of follow-up.ConclusionsHospitalized older patients not taking diuretics prior to hospitalization for HF decompensation who received a discharge prescription for loop diuretics had significantly better 30-day clinical outcomes than those not discharged on loop diuretics. These findings provide new information about short-term clinical benefits associated with loop diuretic use in HF.

Loop diuretics and antibiotics are commonly co-prescribed across many clinical care settings. Loop diuretics may alter antibiotic pharmacokinetics (PK) via several potential drug interactions. A systematic review of the literature was performed to investigate the impact of loop diuretics on antibiotic PK. The primary outcome metric was the ratio of means (ROM) of antibiotic PK parameters such as area under the curve (AUC) and volume of distribution (Vd) on and off loop diuretics. Twelve crossover studies were amenable for metanalysis. Coadministration of diuretics was associated with a mean 17% increase in plasma antibiotic AUC (ROM 1.17, 95% CI 1.09–1.25, I2 = 0%) and a mean decrease in antibiotic Vd by 11% (ROM 0.89, 95% CI 0.81–0.97, I2 = 0%). However, the half-life was not significantly different (ROM 1.06, 95% CI 0.99–1.13, I2 = 26%). The remaining 13 observational and population PK studies were heterogeneous in design and population, as well as prone to bias. No large trends were collectively observed in these studies. There is currently not enough evidence to support antibiotic dosing changes based on the presence or absence of loop diuretics alone. Further studies designed and powered to detect the effect of loop diuretics on antibiotic PK are warranted in applicable patient populations. [ABSTRACT FROM AUTHOR]

Furosemide, a loop diuretic, is commonly used to treat fluid overload symptoms and heart failure. Drug‐induced immune haemolytic anaemia is an unusual drug‐adverse event. Furosemide‐induced haemolysis is even rarer. This case report presents a 91‐year‐old male who developed acute haemolytic anaemia 3 days after initiating furosemide to treat myocardial infarction complicated with acute decompensated heart failure. He had increased lactate dehydrogenase and unconjugated bilirubin with undetectable haptoglobin, which indicated the destruction of red blood cells. Other causes for haemolytic anaemia, including hereditary, microangiopathic haemolytic anaemia, and paroxysmal nocturnal haemoglobinuria, were also excluded. He improved with drug cessation and a short course of glucocorticoids. This report aims to raise awareness of this rare complication caused by commonly prescribed drugs. Despite a negative result of a direct antiglobulin test, physicians must remain suspicious of drug‐induced immune haemolytic anaemia in unclear cases of haemolysis. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated the prognostic value of spot urinary sodium (UNa+) in acutely decompensated chronic HF (ADCHF) patients. However, data on the prognostic role of UNa+ and spot urinary chloride (UCl−) in patients with advanced HF are limited. In the present prospective pilot study, we examined the predictive value of UNa+ and UCl− concentration at baseline, at 2 h and at 24 h after admission for all-cause mortality and HF rehospitalization up to 3 months post-discharge. Consecutive advanced HF patients (n = 30) admitted with ADCHF and aged > 18 years were included in the study. Loop diuretics were administered based on the natriuresis-guided algorithm recommended by the recent HF guidelines. Exclusion criteria were cardiogenic shock, acute coronary syndrome, estimated glomerular filtration rate < 15 mL/min/1.73 m2, severe hepatic dysfunction (Child–Pugh category C), and sepsis. UNa+ at baseline (Area Under the Curve (AUC) = 0.75, 95% Confidence Interval (CI) (0.58–0.93), p = 0.019) and at 2 h after admission (AUC = 0.80, 95% CI: 0.64–0.96, p = 0.005) showed good and excellent discrimination, respectively. UCl− at 2 h after admission (AUC = 0.75, 95%CI (0.57–0.93), p = 0.017) demonstrated good discrimination. In the multivariate logistic regression analysis, UNa+ at 2 h (p = 0.02) and dose of loop diuretics at admission (p = 0.03) were the only factors independently associated with the study outcome. In conclusion, UNa+ and UCl− may have a prognostic role in hospitalized advanced HF patients. [ABSTRACT FROM AUTHOR]

Background: For patients with heart failure, prescription of loop diuretics (LD) and of higher doses are associated with an adverse prognosis. We investigated LD dose trajectories and their associations with outcomes in patients with dilated cardiomyopathy (DCM). Methods: Associations between outcomes and both furosemide-equivalent dose (FED) at enrolment and change in FED in the subsequent 24 months were evaluated. According to FED trajectory, patients were classified as (i) dose↑ (FED increase by ≥ 50% or newly initiated); (ii) dose↓ (FED decrease by ≥ 50%); (iii) stable dose (change in FED by < 50%); and (iv) never-users. The primary outcome was all-cause-death/heart transplantation/ventricular-assist-device/heart failure hospitalization. The secondary outcome was all-cause-death/heart transplantation/ventricular-assist-device. Results: Of 1,131 patients enrolled, 738 (65%) were prescribed LD at baseline. Baseline FED was independently associated with outcome (HR per 20 mg increase: 1.12 [95% CI 1.04–1.22], p = 0.003). Of the 908 with information on FED within 24 months from enrolment, 31% were never-users; 29% were dose↓; 26% were stable dose and 14% were dose↑. In adjusted models, compared to never-users, stable dose had a higher risk of the primary outcome (HR 2.42 [95% CI 1.19–4.93], p = 0.015), while dose↑ had the worst prognosis (HR 2.76 [95% CI 1.27–6.03], p = 0.011). Results were similar for the secondary outcome. Compared to patients who remained on LD, discontinuation of LD (143, 24%) was associated with an improved outcome (HR 0.43 [95% CI 0.28–0.65], p < 0.001). Conclusions: In patients with DCM, LD use and increasing FED are powerful markers of adverse outcomes. Patients who never receive LD have an excellent prognosis. [ABSTRACT FROM AUTHOR]

Background: Myxomatous mitral valve degeneration is the most common canine heart disease. Several clinical trials have investigated various treatments. The latest recommendations are published in the ACVIM consensus guidelines (2019). Our study aimed to investigate how closely veterinary practitioners apply the treatment recommendations of these guidelines and the latest clinical trials. Methods: An online survey was sent to Dutch and Belgian veterinary practices via digital channels. Results: The data from 363 fully completed surveys were analyzed. For stage B1 disease, 93% recommended, correctly, no treatment. For stage B2 disease, 67% of the respondents recommended starting pimobendan as monotherapy. For chronic treatment of stage C disease, 16 different drug combinations were mentioned, but nobody recommended surgery. Only 48% of the respondents recommended the only evidence-based drug combination: a loop diuretic with pimobendan. A concerning finding was the simultaneous prescription of two loop diuretics, by 19% of the respondents. Conclusions: Treatment recommendations showed an increasing variation with more advanced disease stages from B1 through B2 to C. This reflects the increasing disagreement among the panelists who prepared the ACVIM consensus guidelines. Practitioners of our study seem to practice more evidence-based medicine than veterinary cardiologists, as it was reported in a recent survey-based study.

Abstract Background Fluid overload is a risk factor for organ dysfunction and death in intensive care unit (ICU) patients, but no guidelines exist for its management. We systematically reviewed benefits and harms of a single loop diuretic, the predominant treatment used for fluid overload in these patients. Methods We conducted a systematic review with meta-analysis and Trial Sequential Analysis (TSA) of a single loop diuretic vs. other interventions reported in randomised clinical trials, adhering to our published protocol, the Cochrane Handbook, and PRISMA statement. We assessed the risks of bias with the ROB2-tool and certainty of evidence with GRADE. This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42020184799). Results We included 10 trials (804 participants), all at overall high risk of bias. For loop diuretics vs. placebo/no intervention, we found no difference in all-cause mortality (relative risk (RR) 0.72, 95% confidence interval (CI) 0.49–1.06; 4 trials; 359 participants; I 2 = 0%; TSA-adjusted CI 0.15–3.48; very low certainty of evidence). Fewer serious adverse events were registered in the group treated with loop diuretics (RR 0.81, 95% CI 0.66–0.99; 6 trials; 476 participants; I 2 = 0%; very low certainty of evidence), though contested by TSA (TSA-adjusted CI 0.55–1.20). Conclusions The evidence is very uncertain about the effect of loop diuretics on mortality and serious adverse events in adult ICU patients with fluid overload. Loop diuretics may reduce the occurrence of these outcomes, but large randomised placebo-controlled trials at low risk of bias are needed.

Background: The use of a new medication (e.g., potassium supplementation) for managing a drug‐induced adverse event (e.g., loop diuretic‐induced hypokalemia) constitutes a prescribing cascade. However, loop diuretics are often stopped while potassium may be unnecessarily continued (i.e., relic). We aimed to quantify the occurrence of relics using older adults previously experiencing a loop diuretic‐potassium prescribing cascade as an example. Methods: We conducted a prescription sequence symmetry analysis using the population‐based Medicare Fee‐For‐Service data (2011–2018) and partitioned the 150 days following potassium initiation by day to assess the daily treatment scenarios (i.e., loop diuretics alone, potassium alone, combination of loop diuretics and potassium, or neither). We calculated the proportion of patients developing the relic, proportion of person‐days under potassium alone, the daily probability of the relic, and the proportion of patients filling potassium after loop diuretic discontinuation. We also identified the risk factors of the relic. Results: We identified 284,369 loop diuretic initiators who were 8 times more likely to receive potassium supplementation simultaneously or after (i.e., the prescribing cascade), rather than before, loop diuretic initiation (aSR 8.0, 95% CI 7.9–8.2). Among the 66,451 loop diuretic initiators who subsequently (≤30 days) initiated potassium, 20,445 (30.8%) patients remained on potassium after loop diuretic discontinuation, and 9365 (14.1%) patients subsequently filled another potassium supplementation. Following loop diuretic initiation, 4.0% of person‐days were for potassium alone, and daily probability of the relic was the highest after day 90 of loop diuretic initiation (5.6%). Older age, female sex, higher diuretic daily dose, and greater baseline comorbidities were risk factors for the relic, while patients having the same prescriber or pharmacy involved in the use of both medications were less likely to experience the relic. Conclusions: Our findings suggest the need for clinicians to be aware of the potential of relic to avoid unnecessary drug use. [ABSTRACT FROM AUTHOR]

Hyponatremia is commonly encountered in the setting of heart failure, especially in decompensated, fluid-overloaded patients. The pathophysiology of hyponatremia in patients with heart failure is complex, including numerous mechanisms: increased activity of the sympathetic nervous system and the renin–angiotensin–aldosterone system, high levels of arginine vasopressin and diuretic use. Symptoms are usually mild but hyponatremic encephalopathy can occur if there is an acute decrease in serum sodium levels. It is crucial to differentiate between dilutional hyponatremia, where free water excretion should be promoted, and depletional hyponatremia, where administration of saline is needed. An inappropriate correction of hyponatremia may lead to osmotic demyelination syndrome which can cause severe neurological symptoms. Treatment options for hyponatremia in heart failure, such as water restriction or the use of hypertonic saline with loop diuretics, have limited efficacy. The aim of this review is to summarize the principal mechanisms involved in the occurrence of hyponatremia, to present the main guidelines for the treatment of hyponatremia, and to collect and analyze data from studies which target new treatment options, such as vaptans. [ABSTRACT FROM AUTHOR]

• When patients are diagnosed with decompensated heart failure and signs or symptoms of hypervolemia, they require an intravenous bolus of a loop diuretic that should be equal to the total daily dose prescribed for home use and if not on a loop diuretic, 40 mg dose of furosemide or the equivalent dose of another loop diuretic agent. • In this study, emergency department providers under-dosed the initial loop diuretic administered, which could have increased the need for acute hospitalization. • Emergency department provider teams and leaders should develop algorithms and quality improvement metrics to enhance adherence to national guideline diuretic recommendations. Among patients with acute decompensated heart failure (HF), national and international loop diuretic therapy recommendations may not be followed in the emergency department (ED). To examine if loop diuretic treatment and patient disposition from the ED differed after implementing a clinical pathway based on national HF guidelines. Using an observational, pre- and post-intervention design, after clinical pathway implementation, loop diuretic medications and clinical outcomes were retrieved from medical records. Analyses included Pearson's Chi-square or Fisher's exact test, 2-sample T-test or Wilcoxon rank sum test. Of 182 pre- and 122 post-intervention patients, mean (SD) patient age was 67.9 (13.4) years and 44.2% were Caucasian. There were no between-group differences in pre-ED visit loop diuretic prescription or dosages. More post-intervention ED patients received at least one dose of loop diuretic (94.3% vs. 81.9%, p = 0.010); however, the overall dose (mg) across groups was lower than the home dose and was not based on national guideline expectations. Doses from home to ED decreased less in the post-intervention group for patients who received doses at both time points and for all patients: p = 0.047 and p = 0.048, respectively. There was no between-group differences in short-stay unit (SSU) admissions, p = 0.33. Post-intervention patients were hospitalized from the ED (p = 0.050) and SSU (p = 0.005) less often than pre-intervention patients. Discharge to home from the ED or SSU increased in the post-intervention period; 16.4% vs. 4.9%, p = 0.009. Among ED patients treated for HF, diuretic dosing was non-optimized. New interventions are needed to enhance adherence to national guidelines. [ABSTRACT FROM AUTHOR]

Aims: To assess the gabapentinoid–oedema–loop diuretic prescribing cascade in adults using large administrative health care databases from the USA and Denmark. Methods: This study used a sequence symmetry analysis to assess loop diuretic initiation before and after the initiation of gabapentinoids among patients aged 20 years or older without heart failure or chronic kidney disease. Data from MarketScan Commercial and Medicare Supplemental Claims databases (2005 to 2019) and Danish National Prescription Register (2005 to 2018) were analyzed. Use of loop diuretics associated with initiation of selective norepinephrine reuptake inhibitors (SNRI) was used as a negative control. We assessed the pooled temporality of loop diuretic initiation relative to gabapentinoid or SNRI initiation across the 2 countries. Secular trend‐adjusted sequence ratios (aSRs) with 95% confidence intervals (CIs) were calculated using data from 90 days before and after initiation of gabapentinoids. Pooled ratio of aSRs were calculated by comparing gabapentinoids to SNRIs. Results: Among the 1 511 493 gabapentinoid initiators (Denmark [n = 338 941]; USA [n = 1 172 552]), 20 139 patients had a new loop diuretic prescription 90 days before or after gabapentinoid initiation, resulting in a pooled aSR of 1.33 (95% CI 1.06–1.67). The pooled aSR for the negative control (i.e., SNRI) was 0.84 (95% CI 0.75–0.94), which resulted in a pooled ratio of aSRs of 1.58 (95% CI 1.23–2.04). Pooled estimated incidence of the gabapentinoid–loop diuretic prescribing cascade was 8.14 (95% CI, 1.92–34.49) events per 1000 patient‐years. Conclusion: We identified evidence of the gabapentinoid–oedema–loop diuretic prescribing cascade in 2 countries. [ABSTRACT FROM AUTHOR]

Background and Objectives: Albumin binding of the loop diuretic furosemide forms the basis for its transport to the kidney and subsequent tubular secretion, which is a prerequisite for its therapeutic effects. Accordingly, high albumin concentrations should result in higher efficacy of furosemide. However, study results on the combination of furosemide in conjunction with albumin, and on the efficacy of furosemide in hypoalbuminemia, did not confirm this hypothesis. The aim of this study was to determine the efficacy of furosemide not only in relation to albumin concentration, but also taking albumin function into account. Materials and Methods: In a prospective and non-interventional clinical observational trial, blood and urine samples from 50 intensive care patients receiving continuous intravenous furosemide therapy were evaluated. Albumin binding capacity (ABiC) determination allowed conclusions to be drawn about the binding site-specific loading state of albumin, by quantifying the unbound fraction of the fluorescent marker dansylsarcosine. In addition, assessment of the total concentration of furosemide in plasma and urine, as well as the concentration of free furosemide fraction in plasma, was performed by HPLC–MS. The efficacy of furosemide was evaluated by the ratio of urine excretion to fluid intake. Results: In patients with an ABiC ≥ 60% free furosemide fraction was significantly lower compared to patients with a lower ABiC (p < 0.001), urinary furosemide concentration was higher (p = 0.136), and a significantly higher proportion of infused furosemide was excreted renally (p = 0.010). ABiC was positively correlated (r = 0.908, p = 0.017) with increase in the urine excretion to fluid input ratio after initiation of furosemide therapy. Conclusions: ABiC could serve as a marker for individual response to furosemide and could be used to generate patient-specific therapeutic regimens. In view of the relatively low number of patients in this study, the relationship between furosemide efficacy and albumin function should be investigated in larger studies in the future. [ABSTRACT FROM AUTHOR]

Background: Severe renal dysfunction (SRD), an advanced stage of chronic kidney disease (CKD), can limit the treatment options for acute stroke (AS) patients. Therefore, it is important to investigate the associated factors of SRD in AS patients to inhibit CKD progression to SRD before AS. Sex differences exist in the renal function. Therefore, we investigated the frequency of SRD and its associated factors among AS patients by sex. Methods: Our cross-sectional study included patients admitted within 24 h of AS onset between 2013 and 2019 with available pre-stroke medication information. We used the Cockcroft–Gault equation for calculating the creatinine clearance (Ccr) and defined SRD as a Ccr < 30 mL/min. We performed multivariable logistic regression analysis to identify the independent factors associated with SRD. Results: Out of 4294 patients, 3472 matched our criteria. Of these, 1905 (54.9%) were male, with median ages of 75 and 81 years for males and females, respectively. The frequency of SRD was 9.7% in males and 18.7% in females. Loop diuretics and anemia were associated factors of SRD. Conclusions: Pre-stroke loop diuretics and anemia in elderly patients were associated factors of SRD in both sexes. Individualized drug therapy and anemia management are essential to prevent SRD.

Abstract Aims Control of pulmonary pressures monitored remotely reduced heart failure hospitalizations mainly by lowering filling pressures through the use of loop diuretics. Sacubitril/valsartan improves heart failure outcomes and increases the kidney sensitivity for diuretics. We explored whether sacubitril/valsartan is associated with less utilization of loop diuretics in patients guided with haemodynamic monitoring in the CardioMEMS European Monitoring Study for Heart Failure (MEMS‐HF). Methods and results The MEMS‐HF population (n = 239) was separated by the use of sacubitril/valsartan (n = 68) or no use of it (n = 164). Utilization of diuretics and their doses was prespecified in the protocol and was monitored in both groups. Multivariable regression, ANCOVA, and a generalized linear model were used to fit baseline covariates with furosemide equivalents and changes for 12 months. MEMS‐HF participants (n = 239) were grouped in sacubitril/valsartan users [n = 68, 64 ± 11 years, left ventricular ejection fraction (LVEF) 25 ± 9%, cardiac index (CI) 1.89 ± 0.4 L/min/m2] vs. non‐users (n = 164, 70 ± 10 years, LVEF 36 ± 16%, CI 2.11 ± 0.58 L/min/m2, P = 0.0002, P