Diuretics, Mortality, and Nonrecovery of Renal Function in Acute Renal Failure Ravindra L. Mehta, MD Context Acute renal failure is associated with high mortality and morbidity. Diuretic
agents continue to be used in this setting despite a lack of evidence supporting theirbenefit. Objective To determine whether the use of diuretics is associated with adverse or
favorable outcomes in critically ill patients with acute renal failure. Design Cohort study conducted from October 1989 to September 1995.
care units at 4 academic medical centers affiliated with the University of California.
Patients were categorized by the use of diuretics on the day of nephrology consulta-
tion and, in companion analyses, by diuretic use at any time during the first week fol-lowing consultation.
volume, depending on the cause of theARF, accompanying conditions (eg,
Main Outcome Measures All-cause hospital mortality, nonrecovery of renal func-
tion, and the combined outcome of death or nonrecovery. Results Diuretics were used in 326 patients (59%) at the time of nephrology con-
sultation. Patients treated with diuretics on or before the day of consultation were older
and more likely to have a history of congestive heart failure, nephrotoxic (rather thanischemic or multifactorial) origin of acute renal failure, acute respiratory failure, and
lower serum urea nitrogen concentrations. With adjustment for relevant covariates
and propensity scores, diuretic use was associated with a significant increase in the
risk of death or nonrecovery of renal function (odds ratio, 1.77; 95% confidence in-
during ARF in an effort to “convert” oli-
terval, 1.14-2.76). The risk was magnified (odds ratio, 3.12; 95% confidence interval,
1.73-5.62) when patients who died within the first week following consultation were
excluded. The increased risk was borne largely by patients who were relatively unre-
of requiring dialysis.1-4 Despite the ubiq-
Conclusions The use of diuretics in critically ill patients with acute renal failure was
uity of this practice, there is scant evi-
associated with an increased risk of death and nonrecovery of renal function. Al-
though observational data prohibit causal inference, it is unlikely that diuretics afford
any material benefit in this clinical setting. In the absence of compelling contradictory
Indeed, the “conversion” of oliguric to
data from a randomized, blinded clinical trial, the widespread use of diuretics in criti-cally ill patients with acute renal failure should be discouraged.
nonoliguric ARF may reflect the sever-ity of disease (diuretic-responsive ARF)
rather than a valid (and favorable) re-sponse to therapy.5-7 Moreover, the use
ery of renal function, although all stud-
of diuretics may increase the risk of ARF
renal function in critically ill patients
tings,11-13 raising the possibility that di-
indirect effects of delaying dialytic sup-
Author Affiliations: Division of Nephrology, Univer-
San Francisco; Emil Paganini, MD, Cleveland Clinic
sity of California, San Diego, Medical Center (Dr Mehta
Foundation, Cleveland, Ohio; T. Alp Ikizler, MD,
and Mss Pascual and Soroko); and Divisions of Ne-
Vanderbilt University, Nashville, Tenn; and Jonathan
phrology, Moffitt-Long Hospitals and UCSF–Mt Zion
Himmelfarb, MD, Maine Medical Center, Portland.
Medical Center, University of California, San Fran-
Corresponding Author and Reprints: Glenn M. Cher-
tow, MD, MPH, Department of Medicine Research,
Members of The Project to Improve Care in Acute Re-
University of California San Francisco, UCSF Laurel
nal Disease (PICARD) Study Group include Ravindra
Heights, Suite 430, 3333 California St, San Francisco,
L. Mehta, MD, University of California, San Diego;
CA 94118-1211 (e-mail: [email protected]See also p 2599 and Patient Page.
Glenn M. Chertow, MD, MPH, University of California,
2002 American Medical Association. All rights reserved.
(Reprinted) JAMA, November 27, 2002—Vol 288, No. 20 2547
able exit criteria set at PϽ.05. Vari-
line at the time of hospital discharge.
individually to evaluate for residual con-
Data were collected on all intensive care
1995. Acute renal failure was defined us-
failure based on a modification of the cri-
rion of PϽ.25. With diuretic use as the
lished criteria for each organ system fail-
dicting the likelihood or “propensity”
or not taking diuretics on each of the first
7 days following consultation and “ever”
or “never” using diuretics during this
atinine levels of 1 mg/dL or more (Ն88.4
clusion criteria included previous dialy-
sis, kidney transplantation, urinary tract
study participants or their next-of-kin.
calculated the total daily dose of loop di-
pital discharge. A total of 851 ARF cases
disease-specific severity of illness scores
to death or the provision of dialysis for
pared with the t test or the Wilcoxon
rank test. PՅ.05 (2-tailed) was consid-
ered statistically significant. All analyses
Mantel-Haenszel 2 test. Variables with
2548 JAMA, November 27, 2002—Vol 288, No. 20 (Reprinted) 2002 American Medical Association. All rights reserved. Factors Associated With Diuretic Use
Characteristics for the diuretic and no diuretic groups on the day of nephrol- ogy consultation are shown in T Table 1. Baseline Patient Characteristics on First Day of Nephrology Consultation* No Diuretic Diuretic P Demographics and History
diuretic-treated patients on day 1 of ICU
portion of patients given diuretics over-
ences in severity-of-illness scores, mean
Systolic blood pressure, mean (SD), mm Hg
vs 87.3, P=.08) and day 3 (92.8 vs 82.7,
Diastolic blood pressure, mean (SD), mm Hg
PϽ.001). Sixty-six (29%) of the 226 pa-
Central venous pressure, mean (SD), mm Hg§
Pulmonary artery wedge pressure, mean (SD), mm Hg§
Calculation of the
Systemic vascular resistance, mean (SD), dynes·s·cm−5§
rive the propensity score for diuretic use
X = (Age ϫ0.113) − (Nephrotoxic Eti-
*ARF indicates acute renal failure; CRI, chronic renal insufficiency; CHF, congestive heart failure; BUN, blood urea ni-
trogen; and APACHE, Acute Physiology and Chronic Health Evaluation. To convert milligrams per deciliter to micro-
moles per liter (creatinine), multiply by 88.4. To convert milligrams per deciliter to millimoles per liter (BUN), multiply
Propensity Score = (e or 2.7182818X)/
†Entry included as candidate variable for propensity score; physiologic variables not included in propensity score be-
cause not available on all or nearly all patients.
‡Hyperkalemia was defined as a potassium level of more than 6 mEq/L.
§For selected physiologic indicators, sample sizes range from 90 to 180 for “no diuretic” group and 133 to 260 for
2002 American Medical Association. All rights reserved.
(Reprinted) JAMA, November 27, 2002—Vol 288, No. 20 2549 Table 2. Effect of Diuretics on Mortality and Nonrecovery of Renal Function Compared With OR (95% CI) Covariate and Propensity
time to initiation of dialysis, there were
Variable Unadjusted Covariate Adjusted Score Adjusted
uretics for any of these parameters.
*Covariate adjusted for age; sex; log urine output; serum creatinine level; blood urea nitrogen level; respiratory, he-
Index of Diuretic Responsiveness
patic, and hematologic failure; and heart rate. The referent group was no diuretics; time was first day of intensivecare unit consultation. OR indicates odds ratio; CI, confidence interval.
†Area under receiver operating characteristic (ROC) curve = 0.76; goodness-of-fit 2 P = .89.
‡Area under ROC curve = 0.82; goodness-of-fit 2 P = .39. §Area under ROC curve = 0.85; goodness-of-fit 2 P = .84.
Area under ROC curve = 0.81; goodness-of-fit 2 P = .58.
lated the furosemide dose equivalent permilliliter per day of urine output as an
Mortality and Nonrecovery of Renal Function and Diuretic Use
ence, 1-2 days; PϽ.01 for each of con-
as “ever” vs “never” users of diuretics,
in-hospital mortality, nonrecovery of re-
the first week following consultation.
a priori selected a ratio of 1.0 to stratify
nal function (TABLE 2). In the covariate-
nal function in “ever” users of diuret-
liliter ratio of 1.0 or higher on the day
and the first consultation day values for
CI, 1.61-5.36). In contrast, patients with
a dose equivalent per milliliter ratio of
equivalent per milliliter ratio of 0.5 (OR,
tion. In these models, there were no sig-
Single vs Combination Diuretic Use, Specific Diuretic Use, and Dosage
Ͻ0.5, respectively). In other words, the
increase in risk was borne largely by pa-
sive to diuretics. Moreover, the risk as-
length of stay by use of diuretics on the
vs 22.5 days; P = .95). However, subse-
significantly longer lengths of stay (me-
FIGURE 1 shows the relative differ-
sons were at least PϽ.01 for each of con-
2550 JAMA, November 27, 2002—Vol 288, No. 20 (Reprinted) 2002 American Medical Association. All rights reserved. Figure 1. Time Trends in Mean Serum Creatinine Levels, Mean Blood Urea Nitrogen Levels, and Median Urine Output Among the 416 Patients Who Survived for at Least 7 Days After Nephrology Consultation in the Intensive Care Unit (ICU)
No DiureticsTotal Daily Furosemide Equivalent/Total Urine Output <1.0Total Daily Furosemide Equivalent/Total Urine Output ≥1.0
Groups are stratified by day 1 status: no diuretics vs diuretic therapy with response. To convert milligrams per deciliter to micromoles per liter, multiply by 88.4. Toconvert milligrams per deciliter to millimoles per liter, multiply by 0.357.
for patients stratified by diuretic use and
Figure 2. Time to Death or Dialysis From Day of Consultation in Intensive Care Unit
tion of dialysis. FIGURE 2 shows the as-
Total Daily Furosemide Equivalent/Total Urine Output <1.0
per milliliter ratio and the time to death
dose equivalent per milliliter ratios (log-
despite little evidence of benefit.25,26 In-
deed, several prospective clinical trials
Total Daily Furosemide Equivalent/Total Urine Output<1.0
prevention and/or treatment of ARF.14,17,27
Most studies15-17 were relatively small and
effect of diuretics or indirect effects ei-
Groups are stratified by day 1 status. For those pa-tients who were diuretic resistant (furosemide equiva-
lent per milliliter ratio Ն1.0), the No. at risk for days
1, 2, 3, and 5 were 35, 19, 10, and 3, respectively.
Analysis includes 411 of the 416 patients who sur-vived at least 7 days after nephrology consultation in
any material benefit of diuretics in ARF,
the intensive care unit. Data are excluded for 5 pa-
tential deleterious effects.12,26-28 For ex-
ample, Lassnigg et al12 showed that post-
serum creatinine level of Ն0.5 mg/dL [44
atinine level (associated either with low
tion of ARF or recognition of the severity
creatinine generation or dilution with ex-
2002 American Medical Association. All rights reserved.
(Reprinted) JAMA, November 27, 2002—Vol 288, No. 20 2551
the timing of dialysis. The relative 1- to
to initiation of dialysis in patients tak-
ing diuretics suggests that practice pat-
evaluate the effect of diuretics, as we
could in a prospective randomized trial.
not taking diuretics. If persons die from
have suggested,35-37 delay in initiation of
tion observed may be due to a direct del-
eterious effect of diuretic agents, a delay
effect, forestalling dialysis with volume
termine that diuretics are harmful, it is
highly unlikely that diuretics afford ARF
importance of severity of renal injury in
patients any material benefit. In the ab-
from a randomized, blinded clinical trial,
ity of dialysis services may differ). These
patients were critically ill. Therefore, we
use of high-dose diuretics in critically ill
Author Contributions: Study concept and design:
Mehta, Chertow. Acquisition of data: Mehta, Pascual.
patients included in this study had a sig-
Analysis and interpretation of data: Mehta, Pascual,
Soroko, Chertow. Drafting of the manuscript: Mehta, Pascual, Chertow.
Verho38 in a multicenter French study. Critical revision of the manuscript for important in-tellectual content: Mehta, Soroko, Chertow. Statistical expertise: Soroko, Chertow. Obtained funding: Mehta, Chertow. Administrative, technical, or material support: Mehta. Study supervision: Mehta, Pascual, Chertow. Funding/Support: This study was supported by grant
RO1-DK53412-0 from the National Institutes of
more diuretic-responsive patients. If this
Health, National Institute of Diabetes and Digestiveand Kidney Diseases, Bethesda, Md. Previous Presentation: This study was presented in
equivalent per milliliter per day of urine
abstract form at the ASN/ISN World Congress of Ne-phrology, San Francisco, Calif, October 15, 2001.
cal trials (1995-1999) that tested the ef-
ment urine output (eg, atrial natriuretic
REFERENCES 1. Klahr S, Miller SB. Acute oliguria. N Engl J Med. 1998;338:671-675. 2. Sladen RN. Oliguria in the ICU: systematic ap-
proach to diagnosis and treatment. Anesthesiol Clin
sustained oliguria.28,39 In a recent sur-
North Am. 2000;18:739-752. 3. Bellomo R, Ronco C. Indications and criteria for ini-
tiating renal replacement therapy in the intensive care
diothoracic Intensivists,12 11 of 38 used
unit. Kidney Int Suppl. 1998;66:S106-S109. 4. Wilson WC, Aronson S. Oliguria: a sign of renal
alysis in the short term is extremely high.
success or impending renal failure? Anesthesiol Clin
In this way, the practice of a “diuretic
“renoprotection” and 34 of 38 used fu-
North Am. 2001;19:841-883. 5. Anderson RJ, Linas SL, Berns AS, et al. Nonol-
iguric acute renal failure. N Engl J Med. 1977;296:
1134-1138. 6. Diamond JR, Yoburn DC. Nonoliguric acute renal
ing the optimal timing of initiation of di-
failure. Arch Intern Med. 1982;142:1882-1884.
alysis (or hemodiafiltration) in ARF will
7. Brown RS. Renal dysfunction in the surgical pa-
tient: maintenance of high output state with furose-mide. Crit Care Med. 1979;7:63-68. 8. Gerlach AT, Pickworth KK. Contrast medium- 2552 JAMA, November 27, 2002—Vol 288, No. 20 (Reprinted) 2002 American Medical Association. All rights reserved.
induced nephrotoxicity: pathophysiology and preven-
19. Mehta RL, McDonald B, Gabbai FB, et al. A ran- 30. Liano F, Gallego A, Pascual J, et al. Prognosis of
tion. Pharmacotherapy. 2000;20:540-548.
domized clinical trial of continuous versus intermit-
acute tubular necrosis: an extended prospectively con-
9. Solomon R, Werner C, Mann D, D’Elia J, Silva P. Ef-
tent dialysis for acute renal failure. Kidney Int. 2001;
trasted study. Nephron. 1993;63:21-31.
fects of saline, mannitol, and furosemide to prevent acute
31. McCarthy JT. Prognosis of patients with acute re-
decreases in renal function induced by radiocontrast
20. Hanley JA, McNeil BJ. The meaning and use of
nal failure in the intensive-care unit: a tale of two eras.
agents. N Engl J Med. 1994;331:1416-1420.
the area under a receiver operating characteristic (ROC)
Mayo Clin Proc. 1996;71:117-126. 10. Weinstein JM, Heyman S, Brezis M. Potential del-
curve. Radiology. 1982;143:29-36. 32. Chertow GM, Lazarus JM, Paganini EP, et al, for
eterious effect of furosemide in radiocontrast ne-
21. Lemeshow S, Hosmer DW Jr. A review of good-
the Auriculin Anaritide Acute Renal Failure Study
phropathy. Nephron. 1992;62:413-415.
ness of fit statistics for use in the development of lo-
Group. Predictors of mortality and the provision of di-
11. Davidman M, Olson P, Kohen J, Leither T, Kjell-
gistic regression models. Am J Epidemiol. 1982;115:
alysis in patients with acute tubular necrosis. J Am Soc
strand C. Iatrogenic renal disease. Arch Intern Med.22. Rosenbaum PR, Rubin DB. Reducing bias in ob- 33. Liano F, Pascual J. Outcomes in acute renal fail- 12. Lassnigg A, Donner E, Grubhofer G, Presterl E,
servational studies using subclassification on the pro-
ure. Semin Nephrol. 1998;18:541-550.
Druml W, Hiesmayr M. Lack of renoprotective ef-
pensity score. J Am Stat Assoc. 1984;79:516-524. 34. Mehta RL, McDonald B, Gabbai FB, et al. Ne-
fects of dopamine and furosemide during cardiac sur-
23. Kaplan E, Meier P. Nonparametric estimation from
phrology consultation in acute renal failure: does tim-
gery. J Am Soc Nephrol. 2000;11:97-104.
incomplete observations. J Am Stat Assoc. 1958;53:
ing matter? Am J Med. In press. 13. Visweswaran P, Massin EK, Dubose TD Jr. Man- 35. Levy EM, Viscoli CM, Horwitz RI. The effect of
nitol-induced acute renal failure. J Am Soc Nephrol.24. Mehta RL, Pascual MT, Gruta CG, Zhuang S, Cher-
acute renal failure on mortality: a cohort analysis.
tow GM. Refining predictive models in critically ill pa-
14. Brown CB, Ogg CS, Cameron JS. High dose fu-
tients with acute renal failure. J Am Soc Nephrol. 2002;
36. Chertow GM, Levy EM, Hammermeister KE,
rosemide in acute renal failure: a controlled trial. Clin
Grover F, Daley J. Independent association between
25. Kellum JA. Diuretics in acute renal failure: pro-
acute renal failure and mortality following cardiac sur-
15. Kleinknecht D, Ganeval D, Gonzalez-Duque LA,
tective or deleterious? Blood Purif. 1997;15:319-
gery. Am J Med. 1998;104:343-348.
Fermanian J. Furosemide in acute oliguric renal fail-
37. Bates DW, Su L, Yu DT, et al. Mortality and costs
ure: a controlled trial. Nephron. 1976;17:51-58. 26. Venkataram R, Kellum JA. The role of diuretic
of acute renal failure associated with amphotericin B
16. Gubern JM, Sancho JJ, Simo J, Sitges-Serra A. A
agents in the management of acute renal failure. Con-
therapy. Clin Infect Dis. 2001;32:686-693.
randomized trial on the effect of mannitol on post-
trib Nephrol. 2001;(132):158-170. 38. Cantarovich F, Verho MT. A simple prognostic in-
operative renal function in patients with obstructive
27. Kellum JA. The use of diuretics and dopamine in
dex for patients with acute renal failure requiring di-
jaundice. Surgery. 1988;103:39-44.
acute renal failure: a systematic review of the evi-
alysis: French multicentric prospective study on furo-
17. Shilliday IR, Quinn KJ, Allison ME. Loop diuretics
dence. Crit Care (Lond). 1997;1:53-59.
semide in acute renal failure requiring dialysis. Ren Fail.
in the management of acute renal failure: a prospec-
28. Lewis J, Salem MM, Chertow GM, et al, for the
tive, double-blind, placebo-controlled, randomized
Anaritide Acute Renal Failure Study Group. Atrial na-
39. Bellomo R, Chapman M, Finfer S, Hickling K, My-
study. Nephrol Dial Transplant. 1997;12:2592-
triuretic factor in oliguric acute renal failure. Am J Kid-
burgh J, for the Australian and New Zealand Inten-
sive Care Society (ANZICS) Clinical Trials Group. Low-
18. Chang RW, Jacobs S, Lee B, Pace N. Predicting 29. Bullock ML, Umen AJ, Finkelstein M, Keane WF.
dose dopamine in patients with early renal dysfunction:
deaths among intensive care unit patients. Crit Care
The assessment of risk factors in 462 patients with acute
a placebo-controlled randomised trial. Lancet. 2000;
renal failure. Am J Kidney Dis. 1985;5:97-103.
It is possible to fly without motors, but not withoutknowledge and skill. 2002 American Medical Association. All rights reserved.
(Reprinted) JAMA, November 27, 2002—Vol 288, No. 20 2553
hours after last dose of iodine in eight normal subjects with normal body weight who achieved whole body io- Evidence that the dine sufficiency had a mean ± SD of 1.1±0.18 mg/L.3,7 We have arbitrarily defined as a normally functioning Administration of Vitamin C iodine retention mechanism, baseline serum inorganic iodide levels between 0.65 and 1.3 mg/L 24 hours after Improves a
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