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Randomized Phase II Study Comparing Mannitol with Furosemide for the Prevention of Renal Toxicity Induced by Cisplatin-based Chemotherapy with Short-term Low-volume Hydration in Advanced Non-small Cell Lung Cancer: The OLCSG1406 Study Protocol.
Makimoto, G, Ichihara, E, Hotta, K, Ninomiya, K, Oze, I, Minami, D, Ninomiya, T, Kubo, T, Ohashi, K, Tabata, M, et al
Acta medica Okayama. 2018;(3):319-323
Abstract
Although cisplatin-based chemotherapy shows a survival advantage compared to carboplatin for treating advanced non-small cell lung cancer, high-volume hydration and a long infusion time are necessary to avoid nephrotoxicity, and cisplatin-based chemotherapy has been difficult to administer in outpatient settings. A low-volume hydration method using mannitol or furosemide as forced diuresis was recently introduced, but there are no clear conclusions regarding which agent should be used. We describe our ongoing randomized phase II trial (the OLCSG1406 Study) evaluating the efficacy of forced diuresis. This study will clarify whether mannitol or furosemide is more suitable in cisplatin-based chemotherapy with low-volume hydration.
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Diuretic response in patients with acute decompensated heart failure: characteristics and clinical outcome--an analysis from RELAX-AHF.
Voors, AA, Davison, BA, Teerlink, JR, Felker, GM, Cotter, G, Filippatos, G, Greenberg, BH, Pang, PS, Levin, B, Hua, TA, et al
European journal of heart failure. 2014;(11):1230-40
Abstract
AIMS: We studied the characteristics and clinical outcome related to diuretic response and the effects of serelaxin in patients hospitalized for acute heart failure (AHF). METHODS AND RESULTS RELAX-AHF was a double-blind, placebo-controlled trial, enrolling 1161 patients admitted to hospital for AHF who were randomized to 48 h i.v infusions of placebo or serelaxin (30 µg/kg per day) within 16 h from presentation. Diuretic response was defined as Δ weight kg/[(total i.v. dose)/40 mg] + [(total oral dose)/80 mg)] furosemide (or equivalent loop diuretic dose) up to day 5. Median diuretic response was -0.42 (-1.00, -0.14) kg/40 mg. A poor diuretic response was independently associated with Western-like region (Western Europe, North America, Israel, and Poland), lower diastolic blood pressure, the absence of oedema, higher blood urea nitrogen, and lower levels of aspartate aminotransferase and potassium (all P < 0.01). Randomization to serelaxin was associated with lower doses of i.v. loop diuretics and slightly less weight loss, resulting in a neutral effect on diuretic response. Worse diuretic response was independently associated both with less relief of dyspnoea, measured with a visual analogue scale (VAS) at day 5 (primary endpoint; P = 0.0002), and with a higher risk of cardiovascular death or rehospitalization for heart failure or renal failure through day 60 (secondary endpoint, P < 0.0001), but not with increased 180-day cardiovascular mortality (P = 0.507). CONCLUSIONS In patients hospitalized for AHF, a poor diuretic response was associated with a poor in-hospital and early post-discharge clinical outcome. Serelaxin had a neutral effect on diuretic response. TRIAL REGISTRATION NCT00520806.
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Clinical features and outcome in hospitalized heart failure in Japan (from the ATTEND Registry).
Sato, N, Kajimoto, K, Keida, T, Mizuno, M, Minami, Y, Yumino, D, Asai, K, Murai, K, Muanakata, R, Aokage, T, et al
Circulation journal : official journal of the Japanese Circulation Society. 2013;(4):944-51
Abstract
BACKGROUND Hospitalized heart failure (HHF) is a critical issue in Japan. To improve its management and outcomes, the clinical features, in-hospital management, and outcomes should be analyzed to improve the guidelines for HHF. METHODS AND RESULTS The acute decompensated heart failure syndromes (ATTEND) registry is the largest study of HHF in Japan. The present report covers the clinical features and in-hospital management of HHF patients. The data from 4,842 enrolled patients have demonstrated that most Japanese HHF patients are elderly, with new onset, and a history of hypertension and orthopnea on admission. During hospitalization, furosemide and carperitide were commonly used and the length of stay was extremely long (mean 30 days), with 6.4% in-hospital mortality. CONCLUSIONS The findings of the present study suggest the following: (1) the focus for hypertensive elderly and diabetic patients should be on primary prevention of HHF,(2) more intensive management with noninvasive positive pressure ventilation should be performed at the urgent stage, (3) it is necessary to clarify the clinical benefit of carperitide and angiotensin-receptor blockers, because they are commonly used in Japan, and (4) it is necessary to clarify the relationship between in-hospital mortality and length of stay from the viewpoint of both outcome and cost of patient care.
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Whites excrete a water load more rapidly than blacks.
Weder, AB, Gleiberman, L, Sachdeva, A
Hypertension (Dallas, Tex. : 1979). 2009;(4):715-8
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Abstract
A recent report demonstrated a racial difference in response to furosemide compatible with increased ion reabsorption in the thick ascending limb of the loop of Henle in blacks. Urinary dilution is another function of the loop-diuretic-sensitive Na,K,2Cl cotransporter in the thick ascending limb, and racial differences in urinary diluting capacity have not been reported previously. We assessed diluting segment (cortical thick ascending limb and distal convoluted tubule) function in black and white normotensives in 2 studies using a water-loading approach. In both studies, we found that whites excreted a water load more rapidly than blacks. In the first study, the final free water clearance rates (mean+/-SD) were 7.3+/-4.7 mL/min in whites (n=17, 7 females and 10 males) and 3.8+/-3.6 mL/min in blacks (n=14, 9 females and 5 males; P<0.03). In the second study, final free water clearance rates were 8.3+/-2.6 mL/min in whites (n=17, 8 females and 9 males) and 6.4+/-1.8 mL/min in blacks (n=11, 8 females and 3 males; P<0.01). We found no evidence of a racial difference in renal proximal tubular fluid reabsorption as assessed by renal endogenous lithium clearance or in plasma vasopressin level that could explain the difference in free water excretion. We conclude that our observations are most consistent with a lower capacity of ion reabsorption in the renal diluting segment in blacks. Slower excretion of an acute water load may have been an advantage during natural selection of humans living in arid, hot climates.
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Treatment of severe edema in children with nephrotic syndrome with diuretics alone--a prospective study.
Kapur, G, Valentini, RP, Imam, AA, Mattoo, TK
Clinical journal of the American Society of Nephrology : CJASN. 2009;(5):907-13
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BACKGROUND AND OBJECTIVE Severe edema in children with nephrotic syndrome (NS) may be associated with volume contraction (VC) or volume expansion (VE). Usually, severe edema in children is treated with intravenous (IV) albumin and diuretics, which is appropriate for VC patients. However, in VE patients, this can precipitate fluid overload. The objective of this study was to evaluate treatment of severe edema in NS with diuretics alone. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Thirty NS patients with severe edema were enrolled in this prospective study in two phases. VC was diagnosed based on fractional excretion of sodium (FeNa) <1%. VC patients received IV albumin and furosemide. VE patients received IV furosemide and oral spironolactone. On the basis of phase 1 observations, FeNa <0.2% identified VC in 20 phase 2 patients. RESULTS All phase 1 patients had FeNa <1%. Phase 1 patients when reanalyzed based on a FeNa cutoff of 0.2%; it was noted that VC patients had higher BUN, BUN/creatinine ratio, urine osmolality, and lower FeNa and urine sodium compared with VE patients. Similar results were observed in phase 2. VC patients had significantly higher renin, aldosterone, and antidiuretic hormone levels. In phase 2, 11 VE patients received diuretics alone and 9 VC patients received albumin and furosemide. There was no difference in hospital stay and weight loss in VC and VE groups after treatment. CONCLUSIONS FeNa is useful in distinguishing VC versus VE in NS children with severe edema. The use of diuretics alone in VE patients is safe and effective.
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Changes in brain natriuretic peptide levels and bioelectrical impedance measurements after treatment with high-dose furosemide and hypertonic saline solution versus high-dose furosemide alone in refractory congestive heart failure: a double-blind study.
Paterna, S, Di Pasquale, P, Parrinello, G, Fornaciari, E, Di Gaudio, F, Fasullo, S, Giammanco, M, Sarullo, FM, Licata, G
Journal of the American College of Cardiology. 2005;(12):1997-2003
Abstract
OBJECTIVES The aim of this study was to evaluate the effect of a new treatment for refractory congestive heart failure (CHF) on brain natriuretic peptide (BNP) plasma levels and hydration station. BACKGROUND The study was aimed at evaluating the effects of the combination of high-dose furosemide and small-volume hypertonic saline solution (HSS) in refractory CHF patients. METHODS A total of 94 patients (34 women/60 men) with refractory CHF (age 55 to 80 years) were enrolled. They had to have an ejection fraction <35%, serum creatinine <2 mg/dl, blood urea nitrogen <60 mg/dl, a reduced urinary volume, and a low natriuresis (<500 ml/24 h and <60 mEq/24 h, respectively). Patients were divided (double-blind) into two groups: group 1 (18 women/30 men) received an intravenous furosemide (500 to 1,000 mg) plus HSS twice a day in 30 min. Group 2 (16 women/30 men) received an intravenous bolus of furosemide (500 to 1,000 mg/twice a day) alone, for four to six days. At entry, body weight, blood pressure, heart rate, and laboratory parameters were checked during hospitalization; BNP levels were measured on admission, 6 and 30 days after discharge, while on admission and 6 days after, impedance plethysmography was performed. The HSS group received 120 mmol of Na intake versus 80 mmol in non-HSS group. Fluid intake of 1,000 was given to both groups. RESULTS The groups were similar for clinical characteristics. A significant increase in daily diuresis and natriuresis was observed in HSS group, p < 0.05. The BNP values showed significant intragroup and intergroup differences, 6 and 30 days after treatment. The patients from the HSS group reached a better hydration state than the non-HSS group after six days. In addition, the HSS group showed a significant reduction in hospitalization time and readmission rate. CONCLUSIONS Our data show that the HSS group reached dry weight more rapidly, a significantly faster reduction in BNP levels, shorter hospitalization stay, and lower incidence in readmissions in the 30-day study period.
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Role of excess volume in the pathophysiology of hypertension in chronic kidney disease.
Vasavada, N, Agarwal, R
Kidney international. 2003;(5):1772-9
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BACKGROUND The pathophysiology of hypertension in patients with chronic kidney disease (CKD) is largely attributed to positive sodium balance. It is unclear how loop diuretics affect fluid volume compartments, especially with respect to their antihypertensive effect. METHODS Subjects with CKD were administered a single therapeutically equivalent dose of an oral loop diuretic (furosemide or torsemide in randomized crossover design). We measured acute volume changes over 12 hours using biophysical and hormonal biomarkers and then 24-hour ambulatory blood pressure after daily diuretic therapy for 3 weeks. RESULTS Single-dose administration of loop diuretic decreased extracellular water (ECW) by 1.7 L [95% confidence interval (95% CI) 1.2, 2.2, P < 0.001], total body water (TBW) by 1.2 L (95% CI 0.5, 1.9, P < 0.001), and increased natural log (ln) plasma renin activity (PRA) from -1.2 +/- 1.3 ng/mL/hour to -0.5 +/- 1.5 ng/mL/hour (P < 0.001). Daily loop diuretic administration resulted in reduced ECW from 24.2 +/- 6.4 L to 22.3 +/- 5.2 L (P = 0.02) and TBW from 54.3 +/- 12.7 L to 51.6 +/- 11.9 L (P < 0.001) in 1 week. After 3 weeks of diuretic therapy, whereas ECW reduction persisted at 22.8 +/- 5.1 L (P = 0.05), TBW trended toward baseline level at 52.7 +/- 11.8 L. A concomitant increase in ln PRA from -1.0 +/- 1.3 ng/mL/hour to 0.4 +/- 1.9 ng/mL/hour (P < 0.001) and ln plasma aldosterone (PA) from 2.0 +/- 0.8 ng/dL to 2.3 +/- 0.8 ng/dL (P < 0.005) and fall in ln brain natriuretic peptide (BNP) from 4.3 +/- 0.9 pg/mL to 3.7 +/- 1.0 pg/mL (P < 0.01) were seen at 1 week. Despite a trend toward restoration of TBW, changes in hormonal biomarkers were maintained at 3 weeks. Over these 3 weeks, furosemide reduced 24-hour ambulatory blood pressure from 147 +/- 17/78 +/- 11 mm Hg to 138 +/- 21/74 +/- 12 mm Hg (P = 0.021) and torsemide reduced it from 143 +/- 18/75 +/- 10 mm Hg to 133 +/- 19/71 +/- 10 mm Hg (P = 0.007). CONCLUSION Patients with CKD have elevated extracellular fluid volume that can be corrected acutely with loop diuretics. Persistent diuretic use results in dynamic changes in ECW and other body fluid compartments that translate into chronic blood pressure reduction.
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Role of diuretics in the preservation of residual renal function in patients on continuous ambulatory peritoneal dialysis.
Medcalf, JF, Harris, KP, Walls, J
Kidney international. 2001;(3):1128-33
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BACKGROUND Patients on continuous ambulatory peritoneal dialysis (CAPD) are dependent on residual renal function for solute and water clearances, and this declines with time on dialysis. Loop diuretics have been postulated to slow this decline. METHODS Sixty-one patients new to dialysis were randomly assigned to either furosemide 250 mg every day or no furosemide at the time of CAPD training and were followed prospectively. Urine volume (UV), urea clearance (C(Urea)), and creatinine clearance on cimetidine (C(Cr)) were measured at randomization at six months and at one year. Patients underwent a standard four-hour peritoneum equilibrium test, and total body water was measured by bioelectrical impedance. Results were expressed on an intention-to-treat basis. RESULTS UV, C(Cr), and C(Urea) were similar at randomization (1020 +/- 104 vs. 1040 +/- 130 mL/24 hours, 4.95 +/- 0.51 vs. 4.07 +/- 0.40 mL/min/1.73 m2, 0.91 +/- 0.09 vs. 0.84 +/- 0.08, diuretic vs. control). UV in the diuretic-treated group increased, whereas in the control group, it declined (+176 vs. -200 mL/24 hours at 6 months and +48.8 vs. -305 mL/24 hours at 1 year, P < 0.05). C(Cr) and C(Urea) declined at a constant rate and were unaffected by diuretic administration (0.12 +/- 0.05 vs. 0.071 +/- 0.04 mL/min/1.73 m2/month, 0.020 +/- 0.01 vs. 0.019 +/- 0.01 per month). Urinary sodium excretion increased in the diuretic group and declined in the control group (+0.72 +/- 0.85 vs. -2.56 +/- 1.31 mmol/24 hours/month, P = 0.04). Body weight rose in both groups (4.3 vs. 3.0 kg), but the percentage of total body weight rose in the control group and remained constant in the diuretic group (52 +/- 2.4 vs. 64 +/- 6.6%, P = 0.10). CONCLUSIONS Long-term furosemide produces a significant increase in UV over 12 months when on CAPD and may result in clinically significant improvement in fluid balance. However, furosemide has no effect on preserving residual renal function.
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Does albumin preinfusion potentiate diuretic action of furosemide in patients with nephrotic syndrome?
Na, KY, Han, JS, Kim, YS, Ahn, C, Kim, S, Lee, JS, Bae, KS, Jang, IJ, Shin, SG, Huh, W, et al
Journal of Korean medical science. 2001;(4):448-54
Abstract
The aim of this cross-over study was to investigate whether albumin infusion before furosemide administration could potentiate the diuretic action of furosemide. Seven patients with nephrotic syndrome were given the following infusions in random order on two separate days: 1) a sham solution followed by 160 mg of furosemide, 2) 100 ml of 20% human albumin followed by 160 mg of furosemide. Urine and serum furosemide concentrations were measured by high-performance liquid chromatography. The increment of urine volume was greater in albumin preinfusion than in furosemide alone. However, the increments of sodium and chloride excretions between furosemide alone and albumin preinfusion were not different. No significant differences in the pharmacokinetic parameters between the two treatments were observed: area under the concentration-time curve (AUC: 12.7+/-2.2 vs 15.1+/-4.4 g/ml hr), total plasma clearance (253+/-41 vs 256+/-54 ml/min), volume of distribution (341+/-34 vs 494+/-153 ml/kg), elimination half life (4.0+/-1.1 vs 4.6+/-0.8 hr), and urine furosemide excretion of the administered amount (16.5+/-7.3 vs 7.5+/-1.6%). In conclusion, these data show that albumin preinfusion potentiated diuresis, but not natriuresis, of furosemide without any change in the pharmacokinetics of the agent in patients with nephrotic syndrome.
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Effects of high-dose furosemide and small-volume hypertonic saline solution infusion in comparison with a high dose of furosemide as a bolus, in refractory congestive heart failure.
Paterna, S, Di Pasquale, P, Parrinello, G, Amato, P, Cardinale, A, Follone, G, Giubilato, A, Licata, G
European journal of heart failure. 2000;(3):305-13
Abstract
BACKGROUND Diuretics, have been accepted as first-line treatment in refractory heart failure, but a lack of response is a frequent event. A randomised single blind study was performed to evaluate the effects of the combination of high-dose furosemide and small-volume hypertonic saline solution (HSS) infusion in the treatment of refractory NYHA class IV congestive heart failure (CHF). MATERIALS AND METHODS Sixty patients (21 F/39 M) with refractory CHF (NYHA class IV) of different etiologies, unresponsive to high oral doses of furosemide, ACE-inhibitors, digitalis, and nitrates, aged 65-90 years, were enrolled. They had to have an ejection fraction (EF) <35%, serum creatinine <2 mg/dl, BUN ≤60 mg/dl, a reduced urinary volume and a low natriuresis. The patients were randomised in two groups (single blind): group 1 (11 F/19 M) received an i.v. infusion of furosemide (500-1000 mg) plus HSS (150 ml of 1.4-4.6% NaCl) b.i.d. in 30 min. Group 2 (10 F/20 M) received an i.v. bolus of furosemide (500-1000 mg) b.i.d., without HSS, during a period lasting 6-12 days. Both groups received KCl (20-40 mEq.) i.v. to prevent hypokalemia. All patients underwent at entry a physical examination, measurement of body weight (BW), blood pressure (BP), heart rate (HR), evaluation of signs of CHF, and controls of serum Na, K, Cl, bicarbonate, albumin, uric acid, creatinine, urea and glycemia and daily during hospitalization, as well as the daily output of urine for, Na, K and Cl measurements. Chest X-ray, ECG and echocardiogram were obtained at entry during and at the discharge. During the treatment and after discharge the daily dietary Na intake was 120 mmol with a drink fluid intake of 1000 ml daily. An assessment of BW and 24-h urinary volume, serum and urinary laboratory parameters, until reaching a compensated state, were performed daily, when i.v. furosemide was replaced with oral administration (250-500 mg/day). After discharge, patients were followed as outpatients weekly for the first 3 months and subsequently once per month. RESULTS The groups were similar for age, sex, EF, risk factors, treatment and etiology of CHF. All patients showed a clinical improvement. Six patients in both groups had hyponatremia (from 120 to 128 mEq./l) at entry. A significant increase in daily diuresis in both groups was observed (from 390+/-155 to 2100+/-626, and from 433+/-141 to 1650+/-537 ml/24 h, P<0.05). Natriuresis (from 49+/-15 to 198+/-28 mEq./24 h) was higher in group 1 vs. group 2 (from 53.83+/-12 to 129+/-39 mEq./24 h, P<0.05). Serum Na (from 135.9+/-6.8 to 142.2+/-3. 8 mEq./l, P<0.05) increased in the group 1 and decreased in the group 2 (from 134.7+/-7.9 to 130.1+/-4.3 mEq./l). Serum K was decreased (from 4.4+/-0.6 to 3.9+/-0.6, and 4.6+/-9 to 3.6+/-0.5 mEq. /l, P<0. 05) in both groups. BW was reduced (from 73.8+/-9.1 to 63. 8+/-8.8, and from 72.9+/-10.2 to 64.5+/-7.5 kg, P<0. 05) in both groups. Group 2 showed more patients in NYHA class III than group 1 (18 vs. 2 patients, P<0.05). Group 2 showed an increase of serum creatinine. Serum uric acid increased in both groups. BP values decreased, and HR was corrected to normal values in both groups. Group 2 showed a longer hospitalization time than group receiving HHS infusion (11.67+/-1.8 vs. 8.57+/-2.3 days, P<0.001). In the follow-up (6-12 months), none of the patients from group 1 were readmitted to the hospital and they maintained the NYHA class achieved at the discharge. Group 2 showed 12 patients readmitted to hospital and a higher class than at discharge. CONCLUSION Our data suggest that the combination of furosemide with HSS is feasible and it appears that this combination produces an improvement of hemodynamic and clinical parameters, reduces the hospitalization time and maintains the obtained results over time in comparison with those receiving high-dose furosemide as bolus.