Diuretics, Mortality, and Nonrecovery of Renal Function in
Acute Renal Failure
Ravindra L. Mehta, MD; Maria T. Pascual, RN, MPH; Sharon Soroko, MS;
Glenn M. Chertow, MD, MPH; for the PICARD Study Group
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 their benefit.
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.
Patients and
Setting A total of 552 patients
with acute renal failure in intensive 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 consultation and, in companion
analyses, by diuretic use at any time during the first week following
consultation.
Main Outcome
Measures All-cause hospital mortality,
nonrecovery of renal function, and the combined outcome of death or
nonrecovery.
Results Diuretics were used in 326 patients (59%) at the time of
nephrology consultation. 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 than ischemic 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 interval,
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 unresponsive to diuretics.
Conclusions The use of diuretics in critically ill patients with acute renal
failure was associated with an increased risk of death and nonrecovery of renal
function. Although observational data prohibit causal inference, it is unlikely
that diuretics afford any material benefit in this clinical setting. In the
absence of compelling contradictory data from a randomized, blinded clinical
trial, the widespread use of diuretics in critically ill patients with acute
renal failure should be discouraged.
JAMA. 2002;288:2547-2553
Acute renal failure (ARF) in hospitalized
patients may be associated with low, normal, or excess extracellular volume,
depending on the cause of the ARF, accompanying conditions (eg, heart failure,
liver disease), and patterns of administration of crystalloids and colloids.
Diuretic agents are frequently given to augment renal salt and water excretion
in the setting of extracellular volume overload.
Diuretics are also frequently given during ARF
in an effort to "convert" oliguric to nonoliguric ARF, since oliguria
has been recognized as a proxy for the severity of ARF and the likelihood of
requiring dialysis.1-4 Despite the ubiquity
of this practice, there is scant evidence that diuretics provide any material
benefit to patients with ARF. Indeed, the "conversion" of oliguric to
nonoliguric ARF may reflect the severity of disease (diuretic-responsive ARF)
rather than a valid (and favorable) response to therapy.5-7 Moreover, the use of
diuretics may increase the risk of ARF when given before radiocontrast exposure8-10 and in other
clinical settings,11-13 raising the
possibility that diuretics may be harmful in patients with established ARF.
Several randomized clinical trials have explored the use of diuretics in
established ARF and have not shown benefit in survival or recovery of renal
function, although all studies were hampered by low statistical power.14-17
We hypothesized that the use of diuretics during
ARF would be associated with an increase in mortality, hospital length of stay,
and nonrecovery of renal function in critically ill patients with ARF due to
either direct effects or indirect effects of delaying dialytic support. To
explore these questions, we examined data from a cohort of critically ill
patients with ARF. Recognizing the limitations of comparing therapies that have
not been randomly assigned, we attempted to adjust for confounding and practice
variation with regression methods complemented by propensity scores.
Study Cohort
Data were collected on all intensive care unit (ICU) patients with ARF who
received nephrology consultation at 4 teaching hospitals (University of
California San Diego Medical Center, San Diego Veterans Affairs Medical Center,
San Diego Naval Hospital, and University of California, Irvine, Medical Center)
from October 1989 to September 1995. Acute renal failure was defined using
standard laboratory parameters. For patients with no history of kidney disease
or known laboratory values, ARF was defined either by a blood urea nitrogen
(BUN) level of 40 mg/dL or higher (14.3
mmol/L) or a serum creatinine level of 2.0 mg/dL or higher (177 µmol/L). For others, ARF was defined by a sustained rise in
serum creatinine levels of 1 mg/dL or more (88.4
µmol/L) compared with baseline. Exclusion criteria included previous dialysis,
kidney transplantation, urinary tract obstruction, and hypovolemia. Informed
consent was obtained from all study participants or their next-of-kin.
Patients were followed up prospectively from the
time of initial nephrology service consultation through hospital discharge. A
total of 851 ARF cases were initially evaluated. No information on vital status
was available in 31 patients (4%). Of the 820 remaining, data sufficient to
calculate generic and disease-specific severity of illness scores for risk
adjustment were available in 605 patients (74%). Information on the use of
diuretics from the initial ICU consultation day onward was available in 552 patients
(91%), who comprised the analytic sample.
The primary outcome measure was all-cause
hospital mortality. We also considered the combined end point of either
mortality or nonrecovery of renal function and lengths of ICU and hospital
stay. Recovery of renal function was defined as being dialysis independent with
a serum creatinine level of 2.0 mg/dL or less (177
µmol/L) or no more than 20% higher than baseline at the time of hospital
discharge. The origin of ARF was classified as follows: ischemic acute tubular
necrosis, nephrotoxic acute tubular necrosis, multisystem disorder, or
uncertain.
Baseline vital signs, hemodynamic data (where
available), and laboratory data were recorded for the first ICU day and each
day from the time of nephrology consultation. Renal function was assessed daily
from records of urine output, BUN level, and serum creatinine level. Generic
and disease-specific severity-of-illness scores were computed on each
successive ICU day. We determined the number of organ systems in failure based
on a modification of the criteria of Chang et al.18 We used published
criteria for each organ system failure.19 We categorized
patients as taking or not taking diuretics on each of the first 7 days
following consultation and "ever" or "never" using
diuretics during this week. Additionally, we categorized patients treated with
1 vs 2 or more diuretic agents and identified specific medications and daily
doses for secondary analyses. Oliguria was defined as urine output of less than
400 mL/d. To estimate the response to diuretics, we calculated the total daily
dose of loop diuretic (in furosemide equivalents) divided by the total urine
output in milliliters. For this calculation, 1 mg of bumetanide was considered
to be equivalent to 40 mg of furosemide.
Statistical Analysis
Continuous variables were expressed as mean (SD) (or 10% and 90% confidence
limits) or median and compared with the t
test or the Wilcoxon rank sum test where appropriate. Categorical variables
were expressed as proportions and compared with the Mantel-Haenszel 2
test. Variables with significant associations on univariate screening were
considered candidates for multivariable analysis, along with age, sex, and
race. Multivariable logistic regression was performed using backward variable
selection, with variable exit criteria set at P<.05.
Variables not selected by the automated procedure were added back into models
individually to evaluate for residual confounding. The area under the receiver
operating characteristic curve was used to assess model discrimination.20 Calibration was
estimated using the Hosmer-Lemeshow goodness-of-fit test.21
In addition to adjusting for significant
covariates in multivariable regression, residual confounding and selection
effects were addressed using propensity scores.22 To develop the
propensity score, we included in a separate multivariable logistic regression
analysis all factors that differed among the diuretic and no diuretic groups, using
a more liberal significance criterion of P<.25.
With diuretic use as the dependent variable, we fit a model predicting the
likelihood or "propensity" of diuretic use. We then incorporated the
propensity score as a covariate in a logistic regression model using mortality
as the dependent variable. Inclusion of the propensity score as a covariate in
a multivariable regression theoretically normalizes the likelihood of treatment
(in this case, diuretics) and may effectively adjust for unobserved confounding
and selection bias, thereby refining regression estimates. We performed these
analyses again using the combined end point of mortality or nonrecovery of
renal function. Although the primary analysis incorporated data from the day of
consultation, we conducted companion analyses for other time points. Finally,
we used the Kaplan-Meier product limit method23 to calculate the time
to death or the provision of dialysis for ARF (censored at day 60) and compared
survival curves with the log-rank test. P.05 (2-tailed) was
considered statistically significant. All analyses were conducted using SAS
statistical software, version 8 (SAS Institute Inc, Cary, NC).
Factors Associated With
Diuretic Use
Characteristics for the diuretic and no diuretic groups on the day of
nephrology consultation are shown in Table 1.
Few data were missing, except for the invasive physiologic variables, which
were individually available in 40% to 76% of patients. The mean age was
significantly higher and BUN and creatinine levels significantly lower among
diuretic-treated patients on day 1 of ICU consultation. There were no
significant differences in APACHE II (Acute Physiology and Chronic Health
Evaluation II) or APACHE III scores. Among patients who underwent invasive
hemodynamic monitoring, those with higher pulmonary capillary wedge pressure
and lower cardiac index were more likely to be given diuretics. The proportion
of patients given diuretics overall declined from 59% to 44% to 40% during the
first 3 days following consultation, although an increasing fraction of those
taking diuretics were nonoliguric (59% to 80% to 86%). Although there were
initially no differences in severity-of-illness scores, mean APACHE III scores
were lower in diuretic-treated patients on day 2 (91.9 vs 87.3, P = .08) and day 3 (92.8 vs 82.7, P<.001). Sixty-six (29%) of the 226
patients not taking diuretics at the time of consultation were given diuretics
during the following week.
Calculation of the Propensity
Scores
The following equations were used to derive the propensity score for diuretic
use on the first day of consultation:
(1) X
= (Age 0.113) - (Nephrotoxic
Etiology of ARF 0.5645) - (BUN 0.00727) + (Acute
Respiratory Failure 0.5837) + (History of
Congestive Heart Failure 0.8803) - 0.4394
(2) Propensity Score = (e or 2.7182818X)/[1 + (e or 2.7182818X)]
The propensity score itself can be interpreted
as the likelihood of being given diuretics based on the observed array of
covariates included in the model. The mean propensity score was 0.59 (ie, the
fraction of patients given diuretics on day 1); the range was 0.225 10-6to 0.910.
Mortality and Nonrecovery of
Renal Function and Diuretic Use
Two hundred ninety-four (53%) of 552 patients died in-hospital. Fifty-six (19%)
of 294 patients who died recovered renal function before death. Among the 258
patients who survived (47%), 17 (7%) were dialysis dependent after discharge.
We therefore fit distinct logistic regression models for in-hospital mortality,
nonrecovery of renal function, and the combined outcome of mortality or
nonrecovery of renal function (Table 2).
In the covariate-adjusted models, we included age, sex, and the first
consultation day values for heart rate, BUN, creatinine, log urine output, and
respiratory, hematologic, and liver failure based on previous analyses.24 Diuretic use was
associated with a 68% (95% confidence interval [CI], 6%-164%) increase in
in-hospital mortality and a 77% (95% CI, 14%-176%) increase in the odds of
death or nonrecovery of renal function. In these models, there were no
significant interactions between diuretic use and urine output. Neither a
history of congestive heart failure nor the presence of cardiac organ system
failure explained the increased risks observed.
There was no difference in hospital length of
stay by use of diuretics on the first day of consultation (median, 21.5 vs 22.5
days; P = .95). However,
subsequent diuretic use was associated with significantly longer lengths of
stay (median difference, 4-10 days; all comparisons were at least P<.01 for each of consultation days
2-7). The median time from consultation to first dialysis was also
significantly prolonged among patients given diuretics (median difference, 1-2
days; P<.01 for each of
consultation days 1-7).
Since many patients crossover as users and
nonusers of diuretics, we also compared results of patients classified as
"ever" vs "never" users of diuretics, excluding individuals
who died within the first week following consultation. In these analyses (n =
416), the odds ratio (OR) of death or nonrecovery of renal function in
"ever" users of diuretics was 2.01 (95% CI, 1.26-3.20). These results
remained statistically significant after covariate (OR, 3.15; 95% CI,
1.74-5.70) and covariate and day 1 propensity score adjustment (OR, 3.12; 95%
CI, 1.73-5.62). As with the primary analyses, these models exhibited good
discrimination and were well calibrated.
Single vs Combination Diuretic
Use, Specific Diuretic Use, and Dosage
Several diuretic agents and diuretic combinations were used. Of the 326
patients given diuretics on ICU consultation day 1, 203 (62%) were given
furosemide, 189 (58%) were given bumetanide, 106 (33%) were given metolazone,
and 13 (4%) were given hydrodiuril. Loop and thiazide diuretics in combination
were given to 105 patients (32%). The median (with 10%-90% range) doses of
furosemide, bumetanide, and metolazone were 80 (20-320), 10 (2-29), and 10
(5-20) mg/d, respectively. Although diuretic use was associated with mortality,
nonrecovery of renal function, and prolonged time to initiation of dialysis,
there were no significant differences among patients taking single vs
combination diuretics for any of these parameters.
Index of Diuretic
Responsiveness
Since higher doses of diuretics are often used in patients who are oliguric or
have declining urine output, we calculated the furosemide dose equivalent per
milliliter per day of urine output as an index of the degree of diuretic
responsiveness and, potentially, the severity of renal injury. The median dose
equivalent per milliliter ratio was 0.34 mg/mL (10%-90% range, 0.02-4.22).
Expressed in clinical terms, the 10% to 90% ratio ranged from very responsive
(1000 mL associated with a single 20-mg dose of furosemide) to very
unresponsive (114 mL associated with 240 mg of furosemide given twice daily).
We a priori selected a ratio of 1.0 to stratify analyses by diuretic
responsiveness. Patients with a dose equivalent per milliliter ratio of 1.0 or
higher on the day of consultation had a higher odds of death or nonrecovery
compared with nonusers of diuretics (OR, 2.94; 95% CI, 1.61-5.36). In contrast,
patients with a dose equivalent per milliliter ratio of less than 1.0
experienced no significant increase in risk (OR, 1.15; 95% CI, 0.79-1.68).
Results were similar when analyses were stratified by a dose equivalent per
milliliter ratio of 0.5 (OR, 2.75; 95% CI, 1.66-4.54; and OR, 0.97; 95% CI,
0.65-1.45; for dose equivalent per milliliter ratios of 0.5 and <0.5, respectively). In other words, the increase in
risk was borne largely by patients who were relatively unresponsive to
diuretics. Moreover, the risk associated with a high dose equivalent per
milliliter ratio was magnified over time (day 2 following consultation: OR,
3.61; 95% CI, 1.58-8.21; day 3 following consultation: OR, 7.12; 95% CI,
1.67-30.27).
Figure 1
shows the relative differences in mean creatinine levels, mean BUN levels, and
median urine output for patients stratified by diuretic use and the dose
equivalent per milliliter ratio, with values censored at the initiation of
dialysis. Figure 2
shows the association between the dose equivalent per milliliter ratio and the
time to death or dialysis for ARF during hospitalization, comparing patients
not taking diuretics and those with high and low dose equivalent per milliliter
ratios (log-rank 2, P<.001).
Diuretics have been widely used in ARF despite
little evidence of benefit.25, 26 Indeed, several
prospective clinical trials have evaluated the effect of loop diuretic agents,
usually at high doses, in prevention and/or treatment of ARF.14, 17, 27 Most studies15-17 were relatively
small and confounded by cointerventions such as low-dose dopamine hydrochloride
or mannitol. Aside from augmenting urine output, few studies have demonstrated
any material benefit of diuretics in ARF, whereas other studies have suggested
potential deleterious effects.12, 26-28 For example,
Lassnigg et al12 showed that
postoperative ARF (defined as an increase in serum creatinine level of 0.5 mg/dL [44 µmol/L])
was more frequent in patients given furosemide (15%) compared with dopamine
(2%) or isotonic sodium chloride (0%).
In this study, 59% of patients were taking
diuretics at the time of nephrology consultation and 12% started taking
diuretics after consultation. Diuretic use at the time of consultation was
significantly associated with older age, presumed nephrotoxic (rather than
ischemic or multifactorial) ARF origin, a lower BUN level, acute respiratory
failure, and a history of congestive heart failure. After adjusting for
covariates associated with the risk of death,24 diuretic use was
significantly associated with in-hospital mortality and nonrecovery of renal
function, even after adjustment for nonrandom treatment assignment using
propensity scores.
Possible explanations for the associations
observed include a direct toxic effect of diuretics or indirect effects either
related or unrelated to renal function. Providers of care in ICUs may
underestimate the severity of renal injury when urine output is sustained.
Although we and others have shown oliguria to be associated with adverse
outcomes in ARF,19, 24, 29-33 it is unclear
whether diuretic use modifies the effect of oliguria on mortality or
nonrecovery of renal function. We have previously shown that oliguria and a low
serum creatinine level (associated either with low creatinine generation or
dilution with extracellular volume overload) are the 2 factors most closely
related to delay in nephrology consultation among patients who have ARF on ICU
admission.34 If nonoliguria
delays recognition of ARF or recognition of the severity of ARF, then the use
of diuretics might influence ICU management, including the timing of dialysis.
The relative 1- to 2-day delay in time from consultation to initiation of
dialysis in patients taking diuretics suggests that practice patterns differ
among patients taking and not taking diuretics. If persons die from rather than
with ARF, as others and we have suggested,35-37 delay in
initiation of dialysis (waiting for a response to diuretics) may have untoward
effects. These effects could include the worsening of respiratory,
cardiovascular, central nervous system, and immune function due to volume
overload and the effects of uremia.
In addition to the major findings linking
diuretic use to mortality and nonrecovery, we highlighted the potential importance
of severity of renal injury in determining ARF outcomes. Biopsies are rarely
performed in patients with ARF, and no reliable, valid index of ARF severity
has yet been developed. In this study, we showed that the increased risk
associated with diuretic use was largely borne by those individuals who were
relatively resistant to the agents, confirming and extending the findings
previously reported by Cantarovich and Verho38 in a multicenter
French study. In addition, we found that the degree of diuretic resistance on
consultation day 1 predicted subsequent changes in BUN and creatinine
concentrations, with the former paradoxically rising faster in more
diuretic-responsive patients. If this index (total daily furosemide dose
equivalent per milliliter per day of urine output) were validated in other
settings, it might serve as a means to risk stratify patients early in ARF. In
other words, if a patient with early ARF has low or declining urine output
despite high doses of loop diuretics, then further delay in instituting
corrective therapy may not be warranted, since the likelihood of death or the
need for dialysis in the short term is extremely high. In this way, the
practice of a "diuretic challenge" need not be abandoned but rather
modified. Ultimately, identifying the optimal timing of initiation of dialysis
(or hemodiafiltration) in ARF will have to be determined in a prospective
randomized trial.
There are several important limitations to this
study. Even with propensity score adjustment, we cannot truly evaluate the effect of diuretics, as we could in a
prospective randomized trial. Although the propensity score can adjust for
confounding by indication and selection bias, we cannot eliminate residual
confounding due to unobserved factors. We had no kidney biopsy data and no
method by which direct toxic injury induced by diuretics could be proved or
refuted. Therefore, we were unable to derive any mechanistic explanation for
the findings described herein. Although this was a multicenter study, the
hospitals were all within a single region, and the results described may not be
generalizable to other regions or practice settings (eg, settings where the
availability of dialysis services may differ). These patients were critically
ill. Therefore, we cannot extrapolate the results to individuals with less
severe forms of ARF or with ARF in the absence of critical nonrenal disease.
Moreover, since all patients included in this study had a significant increase
in serum creatinine levels, we cannot infer that diuretics would be harmful in
patients very early in ARF, although there is no evidence that they would be of
benefit based on studies in ARF prevention.27
Although the data were collected mainly in the
1990s, ARF practice patterns have not changed significantly since that time. In
randomized clinical trials (1995-1999) that tested the efficacy of other agents
known to augment urine output (eg, atrial natriuretic peptide, low-dose
dopamine), 43% to 55% of patients with ARF in the ICU were treated with
diuretics, even with sustained oliguria.28, 39 In a recent survey of
the European Workgroup of Cardiothoracic Intensivists,12 11 of 38 used
continuous infusions of furosemide for "renoprotection" and 34 of 38
used furosemide bolus injections when urine output decreased to less than 0.5
mL/kg per hour. Although some nonrenal ICU therapies (eg, methods of mechanical
ventilation, frequency of pulmonary artery catheter use, choice of antibiotics)
have changed during the past several years, it is unlikely that these changes
have modified the relations among diuretic use and outcomes in critically ill
patients with ARF.
In summary, we determined that diuretic use was
associated with adverse outcomes in ARF. The increase in mortality and
nonrecovery of renal function observed may be due to a direct deleterious
effect of diuretic agents, a delay in the institution of renal support (in
effect, forestalling dialysis with volume overload or with anticipated reversal
of azotemia), or other or unknown factors. Although we cannot securely
determine that diuretics are harmful, it is highly unlikely that diuretics
afford ARF patients any material benefit. In the absence of compelling
contradictory data from a randomized, blinded clinical trial, we should
discourage the widespread use of high-dose diuretics in critically ill patients
with ARF.
Author/Article Information
Author Affiliations: Division of
Nephrology, University of California, San Diego, Medical Center (Dr Mehta and
Mss Pascual and Soroko); and Divisions of Nephrology, Moffitt-Long Hospitals
and UCSF–Mt Zion Medical Center, University of California, San Francisco (Dr
Chertow).
Corresponding Author and Reprints:
Glenn M. Chertow, MD, MPH, Department of Medicine Research, University of
California San Francisco, UCSF Laurel Heights, Suite 430, 3333 California St,
San Francisco, CA 94118-1211 (e-mail: [log in to unmask]).
Author Contributions: Study concept and design:
Mehta, Chertow.
Acquisition of data: Mehta, Pascual.
Analysis and interpretation of
data: Mehta, Pascual, Soroko,
Chertow.
Drafting of the manuscript: Mehta, Pascual, Chertow.
Critical revision of the
manuscript for important intellectual 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 Health, National Institute of Diabetes and Digestive and Kidney
Diseases, Bethesda, Md.
Previous Presentation: This study was presented in abstract form at the ASN/ISN World
Congress of Nephrology, San Francisco, Calif, October 15, 2001.
Members of The Project to
Improve Care in Acute Renal Disease (PICARD) Study Group include Ravindra L. Mehta, MD, University of California, San
Diego; Glenn M. Chertow, MD, MPH, University of California, San Francisco; Emil
Paganini, MD, Cleveland Clinic Foundation, Cleveland, Ohio; T. Alp Ikizler, MD,
Vanderbilt University, Nashville, Tenn; and Jonathan Himmelfarb, MD, Maine
Medical Center, Portland.
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.