- Email: [email protected]
Is the Administration of Dopamine Associated with Adverse or Favorable Outcomes in Acute Renal Failure?
Is the Administration of Dopamine Associated with Adverse or Favorable Outcomes in Acute Renal Failure? Glenn M. Chertow, MD, MPH, Mohamed H. Sayegh, MD, Boston,Massachusetts, Robin L. Allgren, MD, PhD, Mountain View, California, J. Michael Lazarus, MD, Boston, Massachusetts, for the Auriculin Anaritide Acute Renal Failure Study Group
PURPOSE: To explore the relationship between the administration of low-dose dopamine and outcomes in acute renal failure. PATIENTS: Two hundred and f&y-six patients with acute renal failure randomized to the placebo arm of a multicenter intervention trial were examined. Independent correlates of low-dose (arbitrarily defined as <3 pg/kg/min) and high-dose (arbiiarily defined as 23 pg/kg/min) dopamine administration were identified. The relative risks of death, and the combined outcome of death or dialysis, were estimated using proportional hazards regression with and without adjustment for potential confounding and bias. RESULTS: There were 93 (36%) deaths documented; an additional 52 (20%) patients who survived required dialysis during the 60day study period. The relative risk (RR) of death associated with the administration of low-dose dopamine was 1.11 (95% confidence interval [95% Cl] 0.66 to 1.89). The RR of death was modestly but not significantly reduced, after adjustment for the probability of treatment assignment and for relevant covariates (RR 0.82, 95% Cl 0.42 to 1.60). The RR of death or dialysis associated with the administration of low-dose dopamine was 1.10 (95% Cl 0.71 to 1.71). The RR of death or dialysis was attenuated by adjustment, but not significantly (RR 0.95, 95% Cl 0.58 to 1.58). CONCLUSION: There is insufficient evidence that the administration of low-dose dopamine improves survival or obviates the need for dialysis in persons with acute renal failure. The routine use of low-dose dopamine should be discouraged until a prospective, randomized,
From the Renal Division (GMC, MHS, JML), Department of Medicine, Bngham and Women’s Hospital, Harvard MedIcal School, Boston, Massachusetts, and Scios Nova Inc. (RLA), Mountarn View, California. Presented In abstract form at the 28th Annual Meeting of the American Society of Nephrology, November 5-8, 1995, San Diego, California. Requests for reprints should be addressed to Glenn M. Chertow, MD, MPH, Dialysis Unit Administrative Office, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. Manuscript submitted December 18, 1995 and accepted in revised form March 13, 1996.
01996 by Excerpta All rights reserved.
Medica,
Inc.
placebo-controlled trial establishes its salfety and efficacy. Am J Med. 1996;101:49-53.
L
ow-dose dopamine (<3 ,ug/kg/min) is regularly employed by physicians and surgeons worldwide in the treatment of and attempted prevention of acute renal failure (ARF), despite little clinical data supporting its use in humans. Low-dose dopamine enhances renal perfusion, purportedly via selective renal vasodilation, and promotes natriuresis, 1-7 pharmaco logic characteristics that would be desirable in acute tubular necrosis (ATN), the clinicopathologic consequence of severe ischemic and toxic renal injury. However, the majority of clinical studies performed to date have demonstrated neither a reduction in the risk of ARF when low-dose dopamine has been used prophylactically, nor an improvement in renal function or other outcome parameters (eg, mortality rate or the need for dialysis) in patients with established ARF. It is unclear whether this apparent ineffectiveness reflects a true lack of efficacy, or the failure to demonstrate improved outcomes due to (1) limitations in study design, (2) the inability to adequately ataust for differences in disease severity among treated and untreated groups, or (3) insufficient statistical power. Despite several editorials cautioning against its routine use,*-” the administration of low-dose dopamine is considered by many physicians and surgeons to be the standard of care in patients with ARF. We recently completed a multicenter, randomized, double-blinded, placebo-controlled trial comparing the . . adnum&mtion of synthetic atrial nan-iuretic peptide ( Auriculin Anaritide, ANP) with placebo in 504 subjects with ischemic or toxic ATN. The primary results of this trial will be reported elsewhere.” In this study, there were no restrictions on the prescription, dose, or duration of dopamine treatment, which was administered (nonrandomly) at the discretion of the treating physician The use of dopamine in a large proportion of study subjects provided us the opportunity to evaluate the association of dopamine admmistmtion with ARF outcomes.
METHODS Study Goals and Subjects The primary objectives of this randomized, double-blind, placebo-controlled clinical trial were to 0002-9343/96/$ki.W PII SOOO2-9343(96)00075-7
49
DOPAMINE AND ACUTE RENAL FAILURE OUTCOMES
evaluate the effects of synthetic atrial natriuretic peptide, or ANP (Auriculin Anaritide) on the need for dialysis and mortality among patients with ATN of ischemic or toxic origin. Potential study subjects were adults with ARF whose clinical history was consistent with ATN. Microscopic urinary sediment examination, renal ultrasonography, and determination of the fractional excretion of sodium were among the diagnostic methods employed by investigators to target subjects with ATN. Eligibility was dependent on evidence of progressive renal functional decline, defined as a rise in the serum creatinine concentration of at least 1.0 mg/dL over the previous 24 to 48 hours. Subjects whose ARF was caused by hypoperfusion, urinary tract obstruction, glomerulonephritis, interstitial nephritis, atheroembolic disease, malignant hypertension, renovascular thrombosis or dissection, or hepatorenal syndrome were excluded. In addition, subjects with chronic renal failure (usual serum creatinine greater than 3.0 mg/dL) , prior renal transplantation, circulatory shock (systolic blood pressure less than 90 mm Hg with pressor support), and those for whom dialysis was anticipated within 24 hours were also excluded from t,he study. Diuretics, dopamine, and all other drugs were administered at the discretion of the investigator or treating physician. The need, timing, modality, duration, and intensity of dialysis were left to the clinical discretion of the attending nephrologist on a case-by-case basis. Outcomes were assessedfor up to 60 days following randomization. Dopamine administration was arbitrarily categorized by dose (none, 53 pg/kg/min “low-dose”, and >3 pg/kg/ min “high-dose”) based on the maximal infusion rate received during a 60-hour period, extending from 24 hours before the infusion of study drug or placebo to 12 hours after study drug infusion. We elected to restrict the analysis to placebo recipients (n = 256)) because the vasodilatory effects of ANP might alter dopamine prescription patterns, and to enhance generalizability.
Statistical
Analysis
The study sample was categorized by dopamine dosage, (none, 53 pg/kg/min, and >3 pg/kg/min). Continuous variables, expressed as mean t SD, were compared with Student’s t test or analysis of variance (ANOVA) using general linear models. Scheffe’s test was used for pairwise comparisons. Categorical variables were compared with Fisher’s exact test or chi-square analysis. Multiple logistic regression analysis was employed to identify factors independently associated with the administration of low-dose (53 pg/kg/min) or high-dose (>3 pg/kg/ min) dopamine, respectively, compared with no 50
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treatment. In the evaluation of potential predictive variables, objective criteria (eg, total bilirubin) were uniformly preferred to less well-define’d (eg, acute hepatic dysfunction) or more subjective criteria. As dopamine treatment was assigned nonrandomly, a propensity score (ie, the conditional probability of treatment assignment given the vector of observed covariat.es) was calculated for each individual in an attempt to adjust for selection bias (see equations 1 and 2 below) .I’ In other words, dopamine treatment assignment was modeled as the dependent variable in determining the propensity score. The outcomes of interest were time to death and time to death or dialysis, from the time of study enrollment through day 60. Proportional hazards regression “’ was employed to estimate the relative risk or hazard (an instantaneous failure rate) ratio in respective models. Three models per outcome were fit for each dopamine dose range. The first model, an unadjusted proportional hazards analysi.s, estimated the relative risk associated with dopamine administration, without adjustment for covariates or the likelihood of treatment assignment. The second model adjusted for the propensity score; ie, the model estimated the relative risk at a fixed likelihood of treatment. Finally, the third model included the dopamine dose, the propensity score, and covariates (eg, oliguria) shown in companion analyses to be significantly associated with the outcomes of interest. This fmal model may be considered the best estimate of the “effect” of dopamine, accounting for both confounding and bias. Relative risks (RR) and 95% confidence intervals (95% CI) were calculated based on model coefficients and standard errors, respectively. Statistical analyses were conducted using SAS 6.08 (SAS Institute, Cary, North Carolina). All P values are twosided.
RESULTS Baseline
Characteristics
Table I highlights selected baseline characteristics of the study subjects categorized bly dopamine dose. The mean age was similar across dopamine groups (60.1 ? 19.2 versus 63.5 + 15.4 versus 62.3 f 16.0 years, for none, low-dose dopamine, and highdose dopamine, respectively, P = 0.42). The gender distribution varied somewhat across groups (42% versus 27% versus 37% female, for none, low-dose dopamine, and high-dose dopamine, r’espectively) but was not significantly different (P =: 0.11). The distribution of race and ethnicity was roughly balanced across dopamine categories, with the exception of a trend toward an increased proportion of African-American subjects in the untreated group (24%, versus 15%and 12%in the low-dose dopamine,
DOPAMINE AND ACUTE RENAL FAILURE OUTCOMES TABLE
I
Parameter Age (years) Gender (% female) Race (%I Caucasian African-American Hispanic Other Oliguria (%V Mechanical ventilation (%I’ Arrhythmia (%I’ Myocardial infarction (%I Heart failure, acute (%I Gastrointestinal bleeding (%I Infection (%I Sepsis (%)*r Stroke or seizure (%I Urea nitrogen (mg/dL) Creatinine (mg/dL) Bihrubin (mg/dL) Albumin (g/dL) Leukocyte count (1000/mm3) Hematocnt (%I Platelet count (1000/mm3) Bicarbonate (mEq/L) Potassium (mEq/L) Glucose (mEwI) P co.05
Selected Baseline Characteristics by Dopamine Dose Category None 53 &kg/min >3 pg/kg/min (n = 79) (n = 86) (n = 91) 60.1
?
19.2
42
63.5 k 15.4 27
62.3 t 16.0 37
74 15 8 2 15 52 26 20 9 12 37 24 5 64.3 t 26.5 4.2 t- 1.5’ 3.6 k 5.8 2.7 2 0.6
69 12 14 3: 71 42 15 7 13 56 47 5 69.5 t 31.2 4.3 t 1.4’ 3.3 2 5.5 2.6 5 0.6
12.7 t 6.4
14.6 ? 8.2
30.0 2 4.8
29.7 160 21.0 4.6
P Value NS NS NS
70 24 6 0
22 22 16 9
4 8 48 16
64.5 5.3 3.3 2.8
8 t 27.2 i 2.7 + 7.9 k 0.7
13.9 + 11.7 29.1 5 6.0 163 + 81
140 ? 84
20.9 zt 4.2 4.5 t 0.9
22.4 + 4.5 4.4 k 0.7
154 + 89
159 + 59
k t t t
0.02
NS NS NS 0.04 to.001 NS NS
4.1 118 5.2 0.6
187 ? 90*
for ‘3 vs. 1, ‘2 vs. 1, $3 vs. 2, by chi-square or ScheffC test.
and high-dose dopamine groups, respectively, P = 0.10). There were several important characteristics related to acute medical status that were distributed unevenly across dopamine groups. The proportion of patients requiring mechanical ventilation at the time of randomization was 22%, 52%, and 71% in the none, low-dose dopamine, and high-dose dopamine groups, respectively, reflecting one component of overall disease severity (P < 0.001). Similarly, sepsis (16%, 24%, and 47%, respectively, P < 0.001) and arrhythmias ( 16%,26%, and 42%, respectively, P < 0.001) were more common with increasing dopamine dose. Oliguria was least common in the low-dose dopamine group ( 15%versus 22% and 33% in the none, and high-dose dopamine groups, respectively, P = 0.02). There were no significant differences in the other acute conditions recorded, nor were there substantial differences in baseline laboratory tests, except for serum creatinine concentration (higher in the untreated group), and serum glucose concentration (higher in the high-dose dopamine group). Furthermore, the prevalence of chronic conditions (diabetes, hypertension, coronary artery disease, cirrhosis, metastatic malignancy, chronic congestive heart failure, immunosup-
pression, and chronic obstructive pulmonary disease was similar across dopamine categories (Table II).
Variables Associated with Low-Dose and HighDose Dopamine A multiple logistic regression analysis was performed to identify those variables independently associated with low-dose dopamine administration. These included male sex (odds ratio [OR] 2.33,95% CI 1.12 to 4.86)) mechanical ventilation (OR 3.57, 95%CI 1.72 to 7.41), serum bicarbonate concentration (OR 1.11, 95%CI 1.02 to 1.20 per each mEq increase), and serum creatinine concentration (OR 0.78, 95% CI 0.64 to 0.95 per each mg/dL increase). The area under the model receiver operating characteristic (RX) curve was 0.76, indicating good model discrimination. The conditional probability of low-dose dopamine assignment (ie, propensity score) was calculated using the following equation (equation 1) derived from the logistic regression result. Log odds (low-dose dopamine) = (0.8474*MALE) + ( 1.2728*VENT) + (0.1037 “BICARB) - (0.2501 *CREAT) - 2.0303 An identical analysis was performed to identify inJuly
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TABLE
II Selected Chronic Conditions by Dopamine Dose Category None -3 pg/kg/min >3 pg/kg/min (n = 79) (n = 86) (n = 91)
Parameter Diabetes (%) Hypertension (%) Coronary artery disease (%I Cirrhosis (%) Metastatic malignancy (%I Heart failure, chronic (%) lmmunosuppression (%I Chronic obstructive pulmonary disease (%I
31 63 48 8
P Value
32 54 44 5 3 34 8
21 60 51 5 6 31 3
23 5
NS NS NS NS NS NS NS
3
6
3
NS
1
NS = P>O.O5.
dependent predictors of high-dose dopamine administration, again compared with no dopamine treatment. Mechanical ventilation (OR 6.23, 95% CI 2.89 to 13.43)) arrhythmia (OR 3.49,95% CI 1.52 to 8.01)) sepsis (OR 2.70, 95% CI 1.15 to 6.33), and oliguria (OR 2.03, 95% CI 0.90 to 4.59) were independently associated with high-dose dopamine treatment. The area under this model ROC curve was 0.82, indicating very good discrimination. The conditional probability of high-dose dopamine assignment (ie, propensity score) was calculated using the following equation (equation 2) derived from the logistic regression result.
after adjusting for confounding variables (in this case, male sex, oliguria, mechanical ventilation, acute myocardial infarction [MI], stroke or seizure, chronic immunosuppression, total bilirubin, bicarbonate, and serum albumin concentrations), the risk estimate associated with low-dose dopamine assignment was roughly the same (RR 0.82, 95% CI 0.42 to 1.60). We next examined the combined Ioutcome of death or dialysis. The unadjusted RR of death or dialysis associated with low-dose dopamine administration was 1.10 (95% CI 0.71 to 1.71), again suggesting little to no difference in risk if the groups were directly comparable. Adjusting for the propenLog odds (high-dose dopamine) = (1.8294*VENT) sity score, the RR was 0.94 (95% CI 0.58 to 1.52). As in the previous analysis, there was little change in + (1.2483”ARRHYTH) + (0.9927”SEPSIS) the risk estimate (RR 0.95,95% CI 0.58 to 1.58) after + (0.7064”OLIG) - 1.5514 adjustment for confounding variables (in this case, oliguria, mechanical ventilation, acute MI, arrhythmia, and serum albumin concentration). Therefore, Outcomes Associated with Dopamine there were no statistically significant differences in Administration Three patients (1%) were lost to follow-up; one either outcome measure with low-dose dopamine each at 11, 22, and 33 days. There were 93 deaths administration. High-dose dopamine. To investigate the associ(36%) documented, 73 (78%) of which occurred within 30 days. One hundred and twenty (47%) pa- ation of high-dose dopamine treatment with ARF tients required dialysis, of whom 67 (56%) died dur- outcome, we similarly compared the high-dose dopamine group with the group who received no treating the study period. Low-dose dopamine. The relative risk of death ment. The unadjusted analysis showed a RR of death associated with high-dose dopamine administration associated with low-dose dopamine administration was estimated using the three models described in of 1.43 (95% CI 0.87 to 2.37) suggesting a trend tothe Methods section. An unadjusted analysis showed ward an increase in risk if the groups were directly the relative risk of death to be near unity (RR 1.11, comparable. When adjusted for the propensity score 95% CI, 0.66 to 1.89). This implies that there was (RR 0.74, 95% CI 0.40 to 1.37)) or for both the prolittle to no difference in outcome comparing patients pensity score and confounding variables (RR 0.77, assigned to low-dose dopamine compared with no 95% CI 0.38 to 1.57), the point estimate of RR was changed, suggesting that the increased risk associtreatment, assuming that the groups were directly comparable. Adjusting for the probability of treat- ated with high-dose dopamine treatment may not be ment, however, there was a trend toward reduced attributable to the drug itself. Finally, we compared the high-dose dopamine mortality risk in low-dose dopamine-treated patients (RR 0.74, 95%CI 0.41 to 1.34)) although this was not group with no treatment, looking at the composite statistically significant. The final model showed that outcome, death or dialysis. There was a signilicamly 52
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DOPAMINE AND ACUTE RENAL FAILURE OUTCOMES
increased RR of death or dialysis in the unadjusted analysis (RR 1.77, 95% CI 1.18 to 2.67) that was no longer significant after adjustment for the propensity score (RR 1.02, 95% 0.62 to 1.67) or the propensity score and confounding variables (RR 1.02, 0.62 to 1.69).
DISCUSSION Dopamine, especially at low-dose, has virtually become a standard of care in established ARF, on the basis of some favorable experimental evidence, and theoretical effects that might augment renal recovery in vivo. Unfortunately, there are precious few studies that have prospectively tested low-dose dopamine, either in established ARF or in the prevention of ARF in high-risk patients. To our knowledge, a single prospective, randomized clinical trial was conducted by Lumlertgul et alI4 in 8 patients with ARF related to malaria, and demonstrated a significant reduction in the mean serum creatinine and time to recovery of ARF in the dopamine-treated group. While these findings are of substantial import, as dialysis is not routinely available in many countries where malaria is endemic, the small sample size and specific clinical scenario limit its generalizability. Randomized clinical trials with relatively broad inclusion criteria are the gold standards of clinical investigations. Nevertheless, observational studies can be a valuable source of information. Despite the obvious limitations of observational data, our analysis describes by far the largest sample (N = 256) of patients with ARF treated with dopamine, approximately evenly split among low-dose dopamine, highdose dopamine, and no dopamine treatment groups. Although the groups were not directly comparable, we attempted to adjust for certain aspects of treatment bias based on the distribution of other observed covariates, such as clinical characteristics and laboratory values. The analyses described herein suggest that there are slight trends toward reduced mortality and need for dialysis among patients treated with low-dose dopamine compared with an untreated group (point estimates 0.82 and 0.95 for the outcomes death, and death or dialysis, respectively). Our results should not be used to support the routine use of low-dose dopamine in ARF, however. First, the 95% confidence intervals extend well beyond 1.0. It is conceivable, then, that there may be an increased rather than decreased risk of death or the combined outcome of death or dialysis with low-dose dopamine (that is, the observed trends may be due to chance).
Second, our adjustment for selection bias was incomplete, as the propensity score only adjusted for observed covariates. Other, unobserved factors might have strongly influenced the choice to prescribe or not to prescribe dopamine. Third, there are several potential side effects of low-dose dopamine use, including increased oxygen consumption, tachyarrhythmias, central nervous system effects, and the possible promotion of enteric ischemia; l5 all of which should be carefully considered before administering an unproved treatment. Despite extensive efforts aimed at adjusting for differences in case mix and a relatively large sample size, we were unable to demonstrate that the administration of low-dose dopamine improves survival or obviates the need for dialysis in patients with acute renal failure. In our opinion, the routine USf? of lowdose dopamine should be discouraged until a prospective, randomized, placebo-controlled trial establishes its safety and efficacy.
REFERENCES 1. Goldberg LI. Cardtovascular and renal implications of dopamine: potential clinical applications. Pharmacol Rev. 1972;24:1-29. 2. Kapusta DR, Robie NW. Plasma dopamine In regulation of canine renal blood flow. Am J Physiol. 1988;255:R379-R387. 3. Carey RM, Siragy HM, Ragsdale NV, et al. Dopamlne-1 arld dopamine-2 mechanisms in the control 63% 4. Hollenberg NK, Adams dopamine: haemodynamic Sci. 1973;45:733-742. 5. Lee MR. Dopamlne
of renal
dopamine
and the kidney:
on renal function
ten years
8. Thompson
on. Clrn Sci. 1993;84:357-
JB, et al. Effect of intravenous Infusion of lowin normal individuals and In patients with renal
disease. Am J Nephrol. 1986;6:42-46. 7. McDonald R, Goldberg L, McNay J, Tuttle augmentation of sodium excretion, glomerular
flow. J Clin Invest.
1990;3:59S-
Am J Hypertens.
DF, Mendall P, et al. Renal vascular responses to and angiographic observations in normal man. Clin
375. 6. ter Wee P, Smlt AJ, Rosman dose
function.
E. Effects of dopamlne in man: filtration rate and renal plasma
1964;43:1116-1124.
BT, Cocknll
BA. Renal-dose
dopamine:
a siren
song?
Lancet.
1994;344:7-8. 9. Vincent JL. Renal effects Care Med. 1994;22:5-6. 10. Szerlip HM. Renal-dose
of dopamine: dopamlne:
can our dream fact
and
ever come true?
fiction.
Ann
Intern
Cnt Med.
1991;115:153-154. 11. Marbury TC, Rahman placebo-controlled in the treatment
SN, Sweet RM, et al. A randomized, double-blind, multi-center clinical trial of anaritide atrlal natriuretic peptide of ATN. Am Sot Nephrol. 1995;6:470. Abstract.
12. Rosenbaum subclassification
PR, Rubin DB. Reducing bias in observational on the propensity score. J Am Stat Assoc.
studies
using
1984;79:516-
524. 13.
Cox
DR.
Regression
models
and
life
tables.
1972;74:187-220, 14. Lumlertgul D, Keoplung
J Rqyal
M, Sitprija V, et al. Furosemide malarial acute renal failure. Nephron. 1989;52:40-44. 15. Segal J, Phang T, Walley K. Low-dose dopamlne hastens lschemia in a porcine model of hemmorhagic shock.
Stat
and dopamine
Sot. in
tne onset of gut J Appl Physiol.
1992;73:1159-1164.
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of Medicine@
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53
PURPOSE: To explore the relationship between the administration of low-dose dopamine and outcomes in acute renal failure. PATIENTS: Two hundred and f&y-six patients with acute renal failure randomized to the placebo arm of a multicenter intervention trial were examined. Independent correlates of low-dose (arbitrarily defined as <3 pg/kg/min) and high-dose (arbiiarily defined as 23 pg/kg/min) dopamine administration were identified. The relative risks of death, and the combined outcome of death or dialysis, were estimated using proportional hazards regression with and without adjustment for potential confounding and bias. RESULTS: There were 93 (36%) deaths documented; an additional 52 (20%) patients who survived required dialysis during the 60day study period. The relative risk (RR) of death associated with the administration of low-dose dopamine was 1.11 (95% confidence interval [95% Cl] 0.66 to 1.89). The RR of death was modestly but not significantly reduced, after adjustment for the probability of treatment assignment and for relevant covariates (RR 0.82, 95% Cl 0.42 to 1.60). The RR of death or dialysis associated with the administration of low-dose dopamine was 1.10 (95% Cl 0.71 to 1.71). The RR of death or dialysis was attenuated by adjustment, but not significantly (RR 0.95, 95% Cl 0.58 to 1.58). CONCLUSION: There is insufficient evidence that the administration of low-dose dopamine improves survival or obviates the need for dialysis in persons with acute renal failure. The routine use of low-dose dopamine should be discouraged until a prospective, randomized,
From the Renal Division (GMC, MHS, JML), Department of Medicine, Bngham and Women’s Hospital, Harvard MedIcal School, Boston, Massachusetts, and Scios Nova Inc. (RLA), Mountarn View, California. Presented In abstract form at the 28th Annual Meeting of the American Society of Nephrology, November 5-8, 1995, San Diego, California. Requests for reprints should be addressed to Glenn M. Chertow, MD, MPH, Dialysis Unit Administrative Office, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. Manuscript submitted December 18, 1995 and accepted in revised form March 13, 1996.
01996 by Excerpta All rights reserved.
Medica,
Inc.
placebo-controlled trial establishes its salfety and efficacy. Am J Med. 1996;101:49-53.
L
ow-dose dopamine (<3 ,ug/kg/min) is regularly employed by physicians and surgeons worldwide in the treatment of and attempted prevention of acute renal failure (ARF), despite little clinical data supporting its use in humans. Low-dose dopamine enhances renal perfusion, purportedly via selective renal vasodilation, and promotes natriuresis, 1-7 pharmaco logic characteristics that would be desirable in acute tubular necrosis (ATN), the clinicopathologic consequence of severe ischemic and toxic renal injury. However, the majority of clinical studies performed to date have demonstrated neither a reduction in the risk of ARF when low-dose dopamine has been used prophylactically, nor an improvement in renal function or other outcome parameters (eg, mortality rate or the need for dialysis) in patients with established ARF. It is unclear whether this apparent ineffectiveness reflects a true lack of efficacy, or the failure to demonstrate improved outcomes due to (1) limitations in study design, (2) the inability to adequately ataust for differences in disease severity among treated and untreated groups, or (3) insufficient statistical power. Despite several editorials cautioning against its routine use,*-” the administration of low-dose dopamine is considered by many physicians and surgeons to be the standard of care in patients with ARF. We recently completed a multicenter, randomized, double-blinded, placebo-controlled trial comparing the . . adnum&mtion of synthetic atrial nan-iuretic peptide ( Auriculin Anaritide, ANP) with placebo in 504 subjects with ischemic or toxic ATN. The primary results of this trial will be reported elsewhere.” In this study, there were no restrictions on the prescription, dose, or duration of dopamine treatment, which was administered (nonrandomly) at the discretion of the treating physician The use of dopamine in a large proportion of study subjects provided us the opportunity to evaluate the association of dopamine admmistmtion with ARF outcomes.
METHODS Study Goals and Subjects The primary objectives of this randomized, double-blind, placebo-controlled clinical trial were to 0002-9343/96/$ki.W PII SOOO2-9343(96)00075-7
49
DOPAMINE AND ACUTE RENAL FAILURE OUTCOMES
evaluate the effects of synthetic atrial natriuretic peptide, or ANP (Auriculin Anaritide) on the need for dialysis and mortality among patients with ATN of ischemic or toxic origin. Potential study subjects were adults with ARF whose clinical history was consistent with ATN. Microscopic urinary sediment examination, renal ultrasonography, and determination of the fractional excretion of sodium were among the diagnostic methods employed by investigators to target subjects with ATN. Eligibility was dependent on evidence of progressive renal functional decline, defined as a rise in the serum creatinine concentration of at least 1.0 mg/dL over the previous 24 to 48 hours. Subjects whose ARF was caused by hypoperfusion, urinary tract obstruction, glomerulonephritis, interstitial nephritis, atheroembolic disease, malignant hypertension, renovascular thrombosis or dissection, or hepatorenal syndrome were excluded. In addition, subjects with chronic renal failure (usual serum creatinine greater than 3.0 mg/dL) , prior renal transplantation, circulatory shock (systolic blood pressure less than 90 mm Hg with pressor support), and those for whom dialysis was anticipated within 24 hours were also excluded from t,he study. Diuretics, dopamine, and all other drugs were administered at the discretion of the investigator or treating physician. The need, timing, modality, duration, and intensity of dialysis were left to the clinical discretion of the attending nephrologist on a case-by-case basis. Outcomes were assessedfor up to 60 days following randomization. Dopamine administration was arbitrarily categorized by dose (none, 53 pg/kg/min “low-dose”, and >3 pg/kg/ min “high-dose”) based on the maximal infusion rate received during a 60-hour period, extending from 24 hours before the infusion of study drug or placebo to 12 hours after study drug infusion. We elected to restrict the analysis to placebo recipients (n = 256)) because the vasodilatory effects of ANP might alter dopamine prescription patterns, and to enhance generalizability.
Statistical
Analysis
The study sample was categorized by dopamine dosage, (none, 53 pg/kg/min, and >3 pg/kg/min). Continuous variables, expressed as mean t SD, were compared with Student’s t test or analysis of variance (ANOVA) using general linear models. Scheffe’s test was used for pairwise comparisons. Categorical variables were compared with Fisher’s exact test or chi-square analysis. Multiple logistic regression analysis was employed to identify factors independently associated with the administration of low-dose (53 pg/kg/min) or high-dose (>3 pg/kg/ min) dopamine, respectively, compared with no 50
July
1996
The
American
Journal
of Medicinea
Volume
101
treatment. In the evaluation of potential predictive variables, objective criteria (eg, total bilirubin) were uniformly preferred to less well-define’d (eg, acute hepatic dysfunction) or more subjective criteria. As dopamine treatment was assigned nonrandomly, a propensity score (ie, the conditional probability of treatment assignment given the vector of observed covariat.es) was calculated for each individual in an attempt to adjust for selection bias (see equations 1 and 2 below) .I’ In other words, dopamine treatment assignment was modeled as the dependent variable in determining the propensity score. The outcomes of interest were time to death and time to death or dialysis, from the time of study enrollment through day 60. Proportional hazards regression “’ was employed to estimate the relative risk or hazard (an instantaneous failure rate) ratio in respective models. Three models per outcome were fit for each dopamine dose range. The first model, an unadjusted proportional hazards analysi.s, estimated the relative risk associated with dopamine administration, without adjustment for covariates or the likelihood of treatment assignment. The second model adjusted for the propensity score; ie, the model estimated the relative risk at a fixed likelihood of treatment. Finally, the third model included the dopamine dose, the propensity score, and covariates (eg, oliguria) shown in companion analyses to be significantly associated with the outcomes of interest. This fmal model may be considered the best estimate of the “effect” of dopamine, accounting for both confounding and bias. Relative risks (RR) and 95% confidence intervals (95% CI) were calculated based on model coefficients and standard errors, respectively. Statistical analyses were conducted using SAS 6.08 (SAS Institute, Cary, North Carolina). All P values are twosided.
RESULTS Baseline
Characteristics
Table I highlights selected baseline characteristics of the study subjects categorized bly dopamine dose. The mean age was similar across dopamine groups (60.1 ? 19.2 versus 63.5 + 15.4 versus 62.3 f 16.0 years, for none, low-dose dopamine, and highdose dopamine, respectively, P = 0.42). The gender distribution varied somewhat across groups (42% versus 27% versus 37% female, for none, low-dose dopamine, and high-dose dopamine, r’espectively) but was not significantly different (P =: 0.11). The distribution of race and ethnicity was roughly balanced across dopamine categories, with the exception of a trend toward an increased proportion of African-American subjects in the untreated group (24%, versus 15%and 12%in the low-dose dopamine,
DOPAMINE AND ACUTE RENAL FAILURE OUTCOMES TABLE
I
Parameter Age (years) Gender (% female) Race (%I Caucasian African-American Hispanic Other Oliguria (%V Mechanical ventilation (%I’ Arrhythmia (%I’ Myocardial infarction (%I Heart failure, acute (%I Gastrointestinal bleeding (%I Infection (%I Sepsis (%)*r Stroke or seizure (%I Urea nitrogen (mg/dL) Creatinine (mg/dL) Bihrubin (mg/dL) Albumin (g/dL) Leukocyte count (1000/mm3) Hematocnt (%I Platelet count (1000/mm3) Bicarbonate (mEq/L) Potassium (mEq/L) Glucose (mEwI) P co.05
Selected Baseline Characteristics by Dopamine Dose Category None 53 &kg/min >3 pg/kg/min (n = 79) (n = 86) (n = 91) 60.1
?
19.2
42
63.5 k 15.4 27
62.3 t 16.0 37
74 15 8 2 15 52 26 20 9 12 37 24 5 64.3 t 26.5 4.2 t- 1.5’ 3.6 k 5.8 2.7 2 0.6
69 12 14 3: 71 42 15 7 13 56 47 5 69.5 t 31.2 4.3 t 1.4’ 3.3 2 5.5 2.6 5 0.6
12.7 t 6.4
14.6 ? 8.2
30.0 2 4.8
29.7 160 21.0 4.6
P Value NS NS NS
70 24 6 0
22 22 16 9
4 8 48 16
64.5 5.3 3.3 2.8
8 t 27.2 i 2.7 + 7.9 k 0.7
13.9 + 11.7 29.1 5 6.0 163 + 81
140 ? 84
20.9 zt 4.2 4.5 t 0.9
22.4 + 4.5 4.4 k 0.7
154 + 89
159 + 59
k t t t
0.02
NS NS NS 0.04 to.001 NS NS
4.1 118 5.2 0.6
187 ? 90*
for ‘3 vs. 1, ‘2 vs. 1, $3 vs. 2, by chi-square or ScheffC test.
and high-dose dopamine groups, respectively, P = 0.10). There were several important characteristics related to acute medical status that were distributed unevenly across dopamine groups. The proportion of patients requiring mechanical ventilation at the time of randomization was 22%, 52%, and 71% in the none, low-dose dopamine, and high-dose dopamine groups, respectively, reflecting one component of overall disease severity (P < 0.001). Similarly, sepsis (16%, 24%, and 47%, respectively, P < 0.001) and arrhythmias ( 16%,26%, and 42%, respectively, P < 0.001) were more common with increasing dopamine dose. Oliguria was least common in the low-dose dopamine group ( 15%versus 22% and 33% in the none, and high-dose dopamine groups, respectively, P = 0.02). There were no significant differences in the other acute conditions recorded, nor were there substantial differences in baseline laboratory tests, except for serum creatinine concentration (higher in the untreated group), and serum glucose concentration (higher in the high-dose dopamine group). Furthermore, the prevalence of chronic conditions (diabetes, hypertension, coronary artery disease, cirrhosis, metastatic malignancy, chronic congestive heart failure, immunosup-
pression, and chronic obstructive pulmonary disease was similar across dopamine categories (Table II).
Variables Associated with Low-Dose and HighDose Dopamine A multiple logistic regression analysis was performed to identify those variables independently associated with low-dose dopamine administration. These included male sex (odds ratio [OR] 2.33,95% CI 1.12 to 4.86)) mechanical ventilation (OR 3.57, 95%CI 1.72 to 7.41), serum bicarbonate concentration (OR 1.11, 95%CI 1.02 to 1.20 per each mEq increase), and serum creatinine concentration (OR 0.78, 95% CI 0.64 to 0.95 per each mg/dL increase). The area under the model receiver operating characteristic (RX) curve was 0.76, indicating good model discrimination. The conditional probability of low-dose dopamine assignment (ie, propensity score) was calculated using the following equation (equation 1) derived from the logistic regression result. Log odds (low-dose dopamine) = (0.8474*MALE) + ( 1.2728*VENT) + (0.1037 “BICARB) - (0.2501 *CREAT) - 2.0303 An identical analysis was performed to identify inJuly
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TABLE
II Selected Chronic Conditions by Dopamine Dose Category None -3 pg/kg/min >3 pg/kg/min (n = 79) (n = 86) (n = 91)
Parameter Diabetes (%) Hypertension (%) Coronary artery disease (%I Cirrhosis (%) Metastatic malignancy (%I Heart failure, chronic (%) lmmunosuppression (%I Chronic obstructive pulmonary disease (%I
31 63 48 8
P Value
32 54 44 5 3 34 8
21 60 51 5 6 31 3
23 5
NS NS NS NS NS NS NS
3
6
3
NS
1
NS = P>O.O5.
dependent predictors of high-dose dopamine administration, again compared with no dopamine treatment. Mechanical ventilation (OR 6.23, 95% CI 2.89 to 13.43)) arrhythmia (OR 3.49,95% CI 1.52 to 8.01)) sepsis (OR 2.70, 95% CI 1.15 to 6.33), and oliguria (OR 2.03, 95% CI 0.90 to 4.59) were independently associated with high-dose dopamine treatment. The area under this model ROC curve was 0.82, indicating very good discrimination. The conditional probability of high-dose dopamine assignment (ie, propensity score) was calculated using the following equation (equation 2) derived from the logistic regression result.
after adjusting for confounding variables (in this case, male sex, oliguria, mechanical ventilation, acute myocardial infarction [MI], stroke or seizure, chronic immunosuppression, total bilirubin, bicarbonate, and serum albumin concentrations), the risk estimate associated with low-dose dopamine assignment was roughly the same (RR 0.82, 95% CI 0.42 to 1.60). We next examined the combined Ioutcome of death or dialysis. The unadjusted RR of death or dialysis associated with low-dose dopamine administration was 1.10 (95% CI 0.71 to 1.71), again suggesting little to no difference in risk if the groups were directly comparable. Adjusting for the propenLog odds (high-dose dopamine) = (1.8294*VENT) sity score, the RR was 0.94 (95% CI 0.58 to 1.52). As in the previous analysis, there was little change in + (1.2483”ARRHYTH) + (0.9927”SEPSIS) the risk estimate (RR 0.95,95% CI 0.58 to 1.58) after + (0.7064”OLIG) - 1.5514 adjustment for confounding variables (in this case, oliguria, mechanical ventilation, acute MI, arrhythmia, and serum albumin concentration). Therefore, Outcomes Associated with Dopamine there were no statistically significant differences in Administration Three patients (1%) were lost to follow-up; one either outcome measure with low-dose dopamine each at 11, 22, and 33 days. There were 93 deaths administration. High-dose dopamine. To investigate the associ(36%) documented, 73 (78%) of which occurred within 30 days. One hundred and twenty (47%) pa- ation of high-dose dopamine treatment with ARF tients required dialysis, of whom 67 (56%) died dur- outcome, we similarly compared the high-dose dopamine group with the group who received no treating the study period. Low-dose dopamine. The relative risk of death ment. The unadjusted analysis showed a RR of death associated with high-dose dopamine administration associated with low-dose dopamine administration was estimated using the three models described in of 1.43 (95% CI 0.87 to 2.37) suggesting a trend tothe Methods section. An unadjusted analysis showed ward an increase in risk if the groups were directly the relative risk of death to be near unity (RR 1.11, comparable. When adjusted for the propensity score 95% CI, 0.66 to 1.89). This implies that there was (RR 0.74, 95% CI 0.40 to 1.37)) or for both the prolittle to no difference in outcome comparing patients pensity score and confounding variables (RR 0.77, assigned to low-dose dopamine compared with no 95% CI 0.38 to 1.57), the point estimate of RR was changed, suggesting that the increased risk associtreatment, assuming that the groups were directly comparable. Adjusting for the probability of treat- ated with high-dose dopamine treatment may not be ment, however, there was a trend toward reduced attributable to the drug itself. Finally, we compared the high-dose dopamine mortality risk in low-dose dopamine-treated patients (RR 0.74, 95%CI 0.41 to 1.34)) although this was not group with no treatment, looking at the composite statistically significant. The final model showed that outcome, death or dialysis. There was a signilicamly 52
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increased RR of death or dialysis in the unadjusted analysis (RR 1.77, 95% CI 1.18 to 2.67) that was no longer significant after adjustment for the propensity score (RR 1.02, 95% 0.62 to 1.67) or the propensity score and confounding variables (RR 1.02, 0.62 to 1.69).
DISCUSSION Dopamine, especially at low-dose, has virtually become a standard of care in established ARF, on the basis of some favorable experimental evidence, and theoretical effects that might augment renal recovery in vivo. Unfortunately, there are precious few studies that have prospectively tested low-dose dopamine, either in established ARF or in the prevention of ARF in high-risk patients. To our knowledge, a single prospective, randomized clinical trial was conducted by Lumlertgul et alI4 in 8 patients with ARF related to malaria, and demonstrated a significant reduction in the mean serum creatinine and time to recovery of ARF in the dopamine-treated group. While these findings are of substantial import, as dialysis is not routinely available in many countries where malaria is endemic, the small sample size and specific clinical scenario limit its generalizability. Randomized clinical trials with relatively broad inclusion criteria are the gold standards of clinical investigations. Nevertheless, observational studies can be a valuable source of information. Despite the obvious limitations of observational data, our analysis describes by far the largest sample (N = 256) of patients with ARF treated with dopamine, approximately evenly split among low-dose dopamine, highdose dopamine, and no dopamine treatment groups. Although the groups were not directly comparable, we attempted to adjust for certain aspects of treatment bias based on the distribution of other observed covariates, such as clinical characteristics and laboratory values. The analyses described herein suggest that there are slight trends toward reduced mortality and need for dialysis among patients treated with low-dose dopamine compared with an untreated group (point estimates 0.82 and 0.95 for the outcomes death, and death or dialysis, respectively). Our results should not be used to support the routine use of low-dose dopamine in ARF, however. First, the 95% confidence intervals extend well beyond 1.0. It is conceivable, then, that there may be an increased rather than decreased risk of death or the combined outcome of death or dialysis with low-dose dopamine (that is, the observed trends may be due to chance).
Second, our adjustment for selection bias was incomplete, as the propensity score only adjusted for observed covariates. Other, unobserved factors might have strongly influenced the choice to prescribe or not to prescribe dopamine. Third, there are several potential side effects of low-dose dopamine use, including increased oxygen consumption, tachyarrhythmias, central nervous system effects, and the possible promotion of enteric ischemia; l5 all of which should be carefully considered before administering an unproved treatment. Despite extensive efforts aimed at adjusting for differences in case mix and a relatively large sample size, we were unable to demonstrate that the administration of low-dose dopamine improves survival or obviates the need for dialysis in patients with acute renal failure. In our opinion, the routine USf? of lowdose dopamine should be discouraged until a prospective, randomized, placebo-controlled trial establishes its safety and efficacy.
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