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Doi:10.1053/j.ajkd.2004.05.02Pathogenesis and Treatment of Kidney Disease and Hypertension
High-Dose Furosemide for Established ARF: A Prospective,
Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial
Félix Cantarovich, MD, Badrudin Rangoonwala, PhD, Horst Lorenz, DiplMath, Matti Verho, MD, and Vincent L.M. Esnault, MD, PhD, for the High-Dose Furosemide in Acute Renal Failure Study Group Background: The effect of furosemide on the survival and renal recovery of patients presenting with acute renal
failure (ARF) is still debated. Methods: Three hundred thirty-eight patients with ARF requiring dialysis therapy were
randomly assigned to the administration of either furosemide (25 mg/kg/d intravenously or 35 mg/kg/d orally) or
matched placebo, with stratification according to severity at presentation. The primary end point was survival. The
secondary end point was number of dialysis sessions. Tertiary end points included time on dialysis therapy, time to
achieve a serum creatinine level less than 2.26 mg/dL (<200 mol/L), and time to reach a 2-L/d diuresis. Results:
There were no differences in survival and renal recovery rates between the 2 groups. Time to achieve a 2-L/d
diuresis was shorter with furosemide (5.7 ⴞ 5.8 days) than placebo (7.8 ⴞ 6.8 days; P ⴝ 0.004). Overall, 148 patients
achieved a urine output of at least 2 L/d during the study period (94 of 166 patients; 57%) with furosemide versus 54
of 164 patients (33%) with placebo (P < 0.001). However, there were no significant differences in number of dialysis
sessions and time on dialysis therapy between the furosemide and placebo groups, even in the subgroup of
patients reaching a 2-L/d diuresis. Conclusion: High-dose furosemide helps maintain urinary output, but does not
have an impact on the survival and renal recovery rate of patients with established ARF. Am J Kidney Dis 44:
2004 by the National Kidney Foundation, Inc.
INDEX WORDS: Loop diuretics; acute renal failure (ARF); Simplified Acute Physiology Scores (SAPS); furosemide;
randomized placebo-controlled trial.
SEVERAL STRATEGIES aim to prevent the renal Endothelin or adenosine re-
onset of acute renal failure (ARF). Initiating ceptor antagonists and prostaglandin E have little conventional hemodialysis therapy may worsen effect (seefor review). Furosemide and dopamine renal failure in patients with ARF and modest infusion are inefor even in residual renal and cal- preventing the onset of ARF.
cium channel may prevent radiocon- After the onset of ARF, no drug proved effec- trast nephropathy. Calcium channel antagonists also tive in improving the renal recovery rate. The may decrease the need for dialysis therapy after effect of anaritideand furosemidein pa-tients with established ARF remains controver-sial. A recent cohort analysis suggested that di-uretics may increase death and delay renal From the Department of Transplantation and Intensive Care, Necker Hospital, Paris, France; Department of Phar- function recovery in critically ill patients with macology, Ulm University, Ulm, Germany; Bûro für Biomet- established ARFOnly 6 controlled trials of rie und Statistik, Neuberg, Germany; Mitsubishi Pharma, diuretics in patients with established ARF have London, England; and Nephrology and Clinical Immunol- been published to date; 5 of these trials were ogy Department, Nantes University Hospital, Nantes, France. Received January 5, 2004; accepted in revised form May including only 1 placebo- controlled trial.They were all negative. How- Supported in part by an unrestricted grant from Aventis ever, none of these studies can rule out a possible Pharmaceuticals. B.R. and M.V. were employees of Aventis beneficial effect of furosemide because of the Pharmaceuticals at the time of study initiation. small numbers of patients involved. Further- Address reprint requests to Félix Cantarovich, MD, Ser- vice de Transplantation et Réanimation, Hôpital Necker, 161 more, use of different furosemide dose regimens rue de Sèvres, 75743 Paris, France.E-mail: fscantarovich@ makes comparison between trials difficult and does not allow meta-analysis.
2004 by the National Kidney Foundation, Inc. Experimental data provide the rationale for the use of high-dose furosemide in patients with American Journal of Kidney Diseases, Vol 44, No 3 (September), 2004: pp 402-409 FUROSEMIDE FOR ACUTE RENAL FAILURE established ARFFurosemide inhibits so- screening period and were administered a 15-mg/kg intrave- dium transport, reducing energy requirements of nous (IV) infusion of furosemide over 4 hours, following the cells in the medullary thick ascending limb of recommendation of Brown et Illness severity wasdetermined using Simplified Acute Physiology Scores Henle, producing a "resting state" that may offer On day 1, if serum creatinine levels increased protection during It reduces tubu- further, patients were randomly assigned to the administra- lar-glomerular feedback to prevent a decrease in tion of either furosemide, 25 mg/kg/d IV (maximum, 2 g/d, glomerular filtration It may flush out in the upper range of previously used doses in controlled intratubular casts, reducing tubular obstruc- trials), or matched placebo. SAPS (ⱕ15 or ⬎15) were usedarbitrarily as a stratification factor in the randomization However, results obtained using furo- procedure. In practice, 2 sequences of patient numbers were semide in ARF-induced animal models are incon- assigned to each study center (1 sequence for patients with and depend on the nature of the initial SAPS ⱕ 15, 1 sequence for patients with SAPS ⬎ 15). The renal insult, type of animal used, and concomi- study drug was assigned to patients according to the random tant use of other drugs (mannitol, dopamine).
plan. Aventis Pharmaceuticals (Frankfurt, Germany) pro-vided the double-blinded medications (randomization on a Therefore, we set up a prospective, double- 1:1 basis between furosemide and placebo).
blind, randomized, placebo-controlled trial to After randomization, patients could enter an optional test the effect of high-dose furosemide on sur- predialysis period (phase I) for a maximum of 48 hours vival and renal recovery in patients with ARF (days 1 and 2). During phase I, 8 patients (2 patients requiring renal replacement therapy (RRT).
assigned to furosemide, 6 patients assigned to placebo)showed recovery in renal function, defined as a spontaneousdecrease in blood urea and serum creatinine levels on 2 consecutive days without RRT. Therefore, intention-to-treat analysis was performed on 330 patients (164 patients, furo-semide; 166 patients, placebo) who required RRT.
Three hundred thirty-eight consecutive patients with ARF The dialysis period (phase II) began either immediately requiring RRT were included in this prospective, random- after the screening period or after phase I, according to the ized, double-blind, placebo-controlled, multicenter trial. RRT urgency of dialysis requirements. Intermittent or continuous requirement was defined according to French practice guide- RRT could be performed. RRT modalities differed between lines available at the time, including a progressive increase intensive care units and nephrology wards and included in plasma urea levels greater than 180 mg/dL (⬎30 mmol/ continuous hemofiltration or hemodiafiltration, when pos- L), oligoanuria for 48 hours, or uremic syndrome.
sible, as well as hemodialysis daily or on alternate days. To Twenty-three French reference departments, including 13 take into account this possible confounding factor, random- intensive care units and 10 nephrology wards, participated in ization was equilibrated by centers, and the ratio of daily or continuous RRT to conventional alternate-day hemodialysis Exclusion criteria were: (1) preexisting advanced chronic was compared between the furosemide and placebo groups.
renal failure (serum creatinine level ⬎ 1.7 mg/dL [⬎150 Patients were administered either 25 mg/kg/d of IV furo- mol/L] or renal atrophy), (2) dehydration and prerenal semide infusion (maximum, 2 g/d) or the matched placebo failure (with a urine-plasma osmolality ratio ⬎ 1.1 and over 6 hours once daily after intermittent RRT. When toler- natriuresis ⬍ 20 mmol/L of sodium, as well as response to ated, IV infusions were replaced by oral administration of 35 filling experiment when clinically required), (3) obstructive mg/kg/d of furosemide (maximum, 2.5 g/d) or the matched uropathy, (4) glomerulonephritis (significant proteinuria or placebo once a day after RRT.
hematuria) or systemic disease involving the kidney (includ- As soon as the renal function of patients showed a ing diabetic and human immunodeficiency virus nephropa- recovery, they entered a 3-day postdialysis period (phase thy; however, renal biopsy was not a prerequisite to enter III). To help define renal function recovery, blood was drawn this study), (5) malignant disease with a life expectancy less before and after each intermittent RRT session. Continuous than 6 months, (6) known auditory defect or history of RRT was interrupted when a sustained decrease in serum hypersensitivity to the study drug, (7) pregnancy or lack of creatinine levels was observed. Recovery of renal function adequate contraception, and (8) inability to obtain written was confirmed if patients showed a spontaneous decrease in informed consent. A member of the family was asked to give blood urea and serum creatinine levels on 2 consecutive informed consent when a patient was unable to do so, days after stopping RRT. During phase III, the dose of according to French legislation.
furosemide was tapered as follows: 20 mg/kg/d orally or 15 The protocol was approved by local ethics committees mg/kg/d IV on day 1, 10 mg/kg/d orally or IV on day 2, and and conducted according to good clinical practice.
5 mg/kg/d orally or IV on day 3, before discontinuation.
Study Design Study Measures On day 0, after excluding patients with dehydration and The primary end point was survival at the end of the prerenal failure (urine-plasma osmolality ratio ⬎ 1.1, natri- 1-month phase II period for patients not showing a recovery uresis ⬍ 20 mmol/L of sodium, and those responding to in renal function or 7 days after RRT discontinuation for volume filling experiment), the remaining patients entered a patients showing a recovery in renal function. The main CANTAROVICH ET AL Flow-chart of pa-
tient randomization and fol-
secondary end point was number of RRT sessions (number ables by means of stratified Wilcoxon's 2-sample tests.
of intermittent RRT sessions or days on continuous RRT) Mortality was investigated using the Mantel-Haenszel test because it better reflects the total dose of RRT than time on with the same stratification factor. An interim analysis was dialysis therapy. Tertiary end points included time on dialy- planned after the treatment of 100 patients in each group. To sis therapy (days from start to end of RRT), time to achieve a achieve an overall significance level of 0.05, the interim serum creatinine level less than 2.26 mg/dL (⬍200 mol/L), analysis used the level of 0.026 and the final analysis was time to reach a 2-L/d diuresis for 2 consecutive days, and performed at the level of This report only presents tolerability. Side effects were systematically looked for by the final data analysis. Continuous baseline variables were daily questioning of conscious patients, physical examina- analyzed using Wilcoxon's 2-sample test, whereas categori- tion (including body weight, heart rate, blood pressure, and cal data were evaluated using Fisher's exact test.
Glasgow coma score), and laboratory tests (including bloodurea nitrogen [BUN], serum creatinine, sodium, potassium, and glucose levels and blood cell counts). At inclusion and Three hundred thirty-eight patients with ARF before discharge, conscious patients were systematically were randomly assigned between November 1992 questioned for hearing loss, and hearing tests were per-formed when necessary.
and December 1998, with stratification accord-ing to SAPS Eight patients, 2 patients in Sample Size Calculation the furosemide group and 6 patients in the pla- The primary efficacy variable was tested with a type I cebo group, showed a spontaneous recovery in ⫽ 0.034 to achieve a global error rate of ␣ renal function during predialysis phase I and ⫽ 0.05 (1 interim Sample size calculations were therefore were excluded. Of the remaining 330 performed for the primary variable of survival, assuming a45% baseline value, 15% difference between treatment patients assessable for efficacy because they re- groups, and 80% test power (2-sided test; ␣ quired at least 1 dialysis session, 166 patients which led to a required sample of 122 patients per treatment were allocated to the furosemide group, and 164 patients to the placebo group. Cause of renal failure was at least 1 of the following clinicalconditions: sepsis (n ⫽ 126; 38%), shock of all Statistical analysis was performed using SAS software causes (n ⫽ 156; 47%), toxic (n ⫽ 37; 11%), and (SAS Institute, Cary, NC). Because of stratified randomiza-tion (SAPS ⱕ15 or ⬎15), comparisons between treatment surgery (n ⫽ 68; 21%). Several patients mani- groups were performed for the primary and secondary vari- fested more than 1 of these clinical conditions FUROSEMIDE FOR ACUTE RENAL FAILURE Baseline Characteristics of Patients and Dialysis Procedures in the Population Assessable for Efficacy
Serum creatinine (mg/dL) Before 1st dialysis BUN at randomization (mg/dL) Bilirubin (mol/L) Dialysis procedure NOTE. N ⫽ 330. To convert creatinine in mg/dL to mol/L, multiply by 88.4; BUN in mg/dL to mmol/L, multiply by 0.357; bilirubin in mol/L to mg/dL, divide by 17.1.
*Wilcoxon's 2-sample test and Fisher's exact test, respectively.
simultaneously. There were no significant differ- (P ⫽ 0.055) and more sepsis with shock (P ⫽ ences between the furosemide and placebo groups 0.008) in the furosemide group compared with in terms of sex, age, severity of illness (SAPS), the placebo group.
initial urinary output, serum bilirubin concentra- Statistical analysis of efficacy end points, with tions, need for assisted ventilation, use of dopa- SAPS as the stratification factor, did not show mine or dobutamine, or dialysis procedure (daily significant differences between the 2 groups re- and/or continuous or intermittent; Pa- garding overall mortality (P ⫽ 0.36), number of tients in the furosemide group had greater renal dialysis sessions (P ⫽ 0.37), time on dialysis impairment at randomization, with greater serum therapy (P ⫽ 0.21), and time to achieve a serum creatinine (P ⫽ 0.013) and BUN levels (P ⬍ creatinine level less than 2.26 mg/dL (⬍200 0.001). However, this difference in serum creati- mol/L; P ⫽ 0.99; Assessment of a nine levels between groups was no longer present posteriori test power led to a value of approxi- at the time of RRT initiation although mately 70% for the primary end point (mortal- the length of the predialysis phase was not signifi- ity). Time to achieve urine output of at least 2 L/d cantly different between groups (P ⫽ 0.08).
was shorter with furosemide (5.7 ⫾ 5.8 days) Furthermore, there were more patients with dia- than placebo (7.8 ⫾ 6.8 days; P ⫽ 0.004; 95% betes (P ⫽ 0.002) and a trend toward more sepsis confidence interval for the difference, 1 to 5; CANTAROVICH ET AL Study End Points in the Population Assessable for Efficacy With Stratification According to SAPS
Patients alive at the end of the study (n ⫽ 221) Deaths (n ⫽ 109) No. of RRT sessions Time to achieve a serum creatinine level ⬍2.26 mg/dL without RRT (d) Time to achieve a 2-L/d diuresis (d) NOTE. N ⫽ 330. Values expressed as mean ⫾ SD. To convert creatinine in mg/dL to mol/L, multiply by 88.4.
*Mantel-Haenszel test with stratification according to SAPS (ⱕ15, ⬎15).
†Wilcoxon's 2-sample test with stratification according to SAPS (ⱕ15, ⬎15).
Overall, 148 patients achieved a urine were significantly greater in the furosemide group output of at least 2 L/d during the study period than control group, whereas mean serum creati- (94 of 166 patients [57%] with furosemide ver- nine levels differed between the 2 treatment sus 54 of 164 patients [33%] with placebo; P ⬍ groups with only borderline significance, suggest- 0.001). However, there were no significant differ- ing a degree of prerenal failure in the furosemide- ences in number of dialysis sessions and time on treated group (BUN, 36.4 versus 25.8 mg/dL dialysis therapy between the furosemide-treated [13.0 versus 9.2 mmol/L]; P ⬍ 0.001; serum and placebo-treated patients reaching a 2-L/d creatinine, 2.16 versus 1.89 mg/dL [191 versus 167 mol/L]; P ⫽ 0.056).
The death rate was greater with continuous or daily RRT (53 of 95 patients; 56%) than intermit-tent hemodialysis (61 of 235 patients; 26%; P ⬍0.001), but patients with more severe clinical Side Effects
conditions were more likely to be referred to intensive care units and receive continuous or daily RRT. Some patients were switched from IV to oral administration in the furosemide (54 of 166 patients; 33%) and placebo groups (51 of 164 patients; 31%; P ⫽ 0.78), and 38 of 54 patients (70%) administered furosemide orally Allergic reaction reached a 2-L/d diuresis.
There was no significant difference in terms of side effects between groups The only exception was an increase in the incidence of polyuria in the furosemide group (P ⫽ 0.015). In patients who showed recovery in renal function, diuresis during the 3-day postdialysis period was significantly greater with furosemide (11.5 ver- NOTE. Either specific side effects or those reaching P ⬍ sus 6.7 L/3 d; P ⬍ 0.001). One week after 0.20 are included.
discontinuing dialysis therapy, mean BUN levels Abbreviation: NS; not significant.
FUROSEMIDE FOR ACUTE RENAL FAILURE ototoxicity or hypotension. Nevertheless, cau- This randomized, double-blind, placebo-con- tion should be exercised before furosemide is trolled study testing high-dose furosemide in administered to patients with ARF. In this study, patients with established ARF is the first ad- dehydration and prerenal failure were carefully equately powered trial investigating whether fu- eliminated by determination of urine-plasma os- rosemide improves the survival rate in these molality ratio, natriuresis measurements, and vol- patients. Results show no significant impact of ume filling experiments, when clinically re- high-dose furosemide on either patient early sur- vival or renal recovery rate.
Two of the previous controlled studies found a Despite major technical advances during the trend toward improvement in rate of renal func- past 2 decades, the mortality rate of critically ill tion recovery.Conversely, 1 cohort analysis patients with ARF requiring RRT remains very suggested that diuretics may delay renal recov- This might be caused by the increased eryHowever, in the latter study, prerenal fail- prevalence of comorbid conditions, such as ad- ure was not eliminated by appropriate biological vanced age and multiple organ failure syndrome.
tests, although more than 40% of patients had Biocompatibility of the dialysis membrane has a ischemic nephropathyIn our study, renal recov- modest beneficial efand conventional ery rates were not different between the furo- intermittent hemodialysis might even negatively semide and placebo groups. However, several impact on survival.An increase in diuresis confounding factors have to be emphasized. First, might be beneficial because it would permit the furosemide test dose may have contributed to adequate parenteral nutrition. One previous pla- relaunch diuresis in some patients randomly as- cebo-controlled study suggested that nonoliguric signed to placebo. Furthermore, the beneficial patients treated with furosemide may have a effect of furosemide may have been underesti- lower mortalityand, conversely, 1 cohort anal- mated because baseline differences were ob- ysis found that diuretic use was associated with served despite a stratified randomization proce- decreased In our study, furosemide dure, with more severe renal impairment, did not have a significant effect on mortality in diabetes, and sepsis with shock in the furosemide the overall population.
group. Finally, the slow tapering of furosemide In our study, polyuria was the only significant dose in patients who began to recover renal side effect that increased with high-dose furo- function may have favored prerenal failure and semide compared with placebo. Various furo- delayed complete renal recovery. The high uri- semide doses were tested in previous trials of nary output sometimes was difficult to handle patients with established ARF. The only previous during the recovery phase. This is suggested by randomized placebo-controlled used a the significantly greater BUN levels, but not maximum dose of 1.2 g/d, half our study dose. In serum creatinine levels, in the furosemide group 5 other prospective open studies, furosemide 1 week after dialysis discontinuation. In the case doses ranged from 1.2 to 3.2 g/d, and there was of polyuria, we urge a rapid tapering down of no reported toxicity in any of these furosemide dosing.
Very high doses of furosemide were adminis- The difference in serum creatinine levels be- tered as IV infusions in our study (25 mg/kg/d; tween groups at randomization disappeared at maximum, 2 g/d over 4 to 6 hours). The drug was the time of RRT initiation, suggesting that the administered once a day to guarantee that a serum creatinine level increase was slower with ceiling dose was reached, with effective delivery furosemide than placebo before RRT initiation.
of the drug to its site of action in the tubular Because furosemide protection is believed to be lumen. Even greater doses of furosemide were mediated in part by amelioration of medullary administered orally (35 mg/kg/d; maximum, 2.5 hypoxia during the evolution of ARFits im- g/d once daily) to account for altered oral bio- pact may be more significant at an early phase availability in acutely ill This protocol than after established ARF. However, successful of once-daily slow IV infusion or oral intake of conversion of oliguria to diuresis should not high-dose furosemide was not associated with postpone obtaining a consultation with an experi- CANTAROVICH ET AL enced nephrologist and does not justify delaying Simon, Nephrology, Dialysis and Hypertension Department, dialysis therapy, when La Beauchée Hospital, Saint-Brieuc, France.
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3(1), April, 2012. ISSN: 2141- Printed in Nigeria. All rights reserved. © Global Research Publishing, 2012. Caffeine Content of Cocoa and Coffee Beverages in Lagos, Nigeria (pp. 404-411.) C. O. Ogah and O. T.obebe Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Lagos, Nigeria Correspondence Email