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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.
ACUTERENALFAILURE(ARF)IN PatientsandSettingAtotalof552patientswithacuterenalfailureinintensive
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- Study Cohort
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 Statistical Analysis
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§ Propensity Scores
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.
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(Reprinted) JAMA, November 27, 2002—Vol 288, No. 20 2553

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