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Beneficial Impact of Fenoldopam in Critically Ill Patients Withor at Risk for Acute Renal Failure: A Meta-Analysis of

Randomized Clinical Trials

Giovanni Landoni, MD, Giuseppe G.L. Biondi-Zoccai, MD, James A. Tumlin, MD,Tiziana Bove, MD, Monica De Luca, MD, Maria Grazia Calabrò, MD, Marco Ranucci, MD,

and Alberto Zangrillo, MD

Background: Acute kidney injury is common in critically ill patients. Fenoldopam mesylate is a potentdopamine A-1 receptor agonist that increases blood flow to the renal cortex and outer medulla. Becausethere is uncertainty about the benefits of fenoldopam in such a setting, we performed a systematicreview of randomized controlled trials of intensive care unit patients or those undergoing major surgery.

Methods: BioMedCentral, CENTRAL, PubMed, and conference proceedings were searched (up-dated October 2005). Investigators and external experts were contacted. Two unblinded reviewersselected randomized controlled trials that used fenoldopam in the prevention or treatment of acutekidney injury in postoperative or intensive care patients. Studies involving the prevention of contrastnephropathy or containing duplicate data were excluded from analysis. Two reviewers independentlyabstracted patient data, treatment characteristics, and outcomes.

Results: A total of 1,290 patients from 16 randomized studies were included in the analysis. Pooledestimates showed that fenoldopam consistently and significantly reduced the risk for acute kidney injury(odds ratio [OR], 0.43; 95% confidence interval [CI], 0.32 to 0.59; P � 0.001), need for renalreplacement therapy (OR, 0.54; 95% CI, 0.34 to 0.84; P � 0.007), and in-hospital death (OR, 0.64; 95%CI, 0.45 to 0.91; P � 0.01). These benefits were associated with shorter intensive care unit stay(weighted mean difference, �0.61 days; 95% CI, �0.99 to �0.23; P � 0.002). Sensitivity analyses,tests for small-study bias, and heterogeneity assessment further confirmed the main analysis.

Conclusion: This analysis suggests that fenoldopam reduces the need for renal replacement andmortality in patients with acute kidney injury. A large, multicenter, appropriately powered trial will need tobe performed to confirm these results.Am J Kidney Dis 49:56-68. © 2006 by the National Kidney Foundation, Inc.

INDEX WORDS: Kidney; meta-analysis; diuretics; mortality; renal replacement therapy; fenoldopam.

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cute kidney injury is a serious complicationin critically ill patients and is associated

ith markedly increased morbidity and mortal-ty.1-4 Numerous studies using parenteral vasodi-ators to prevent or treat acute kidney injury inostoperative patients or those with multiorganysfunction have given conflicting results.5-7

Fenoldopam mesylate is a benzazepine deriva-ive that is a potent short-acting dopamine A-1eceptor agonist that decreases systemic vascular

From the Department of Cardiothoracic Anesthesia andntensive Care, Università Vita-Salute San Raffaele, Milano,talia e Istituto Scientifico San Raffaele, Milano, Italia;emodynamics and Cardiovascular Interventions Service,bano Terme Hospital, Abano Terme; Department of Cardio-

horacic Anesthesia and Intensive Care, Policlinico Sanonato, San Donato Milanese, Italy; and Emory Universitychool Medicine Renal Division, Atlanta, GA.Received July 14, 2006; accepted in revised form October

1, 2006.Originally published online as doi:10.1053/j.ajkd.2006.10.013

n November 28, 2006.

American Journal o6

esistance while simultaneously increasing renallood flow.8-10 In addition to its use in patientsith hypertensive emergencies,11 fenoldopam ap-ears to improve renal function in patients withevere hypertension12-14 and critically ill pa-ients receiving positive end-expiratory pres-ure.15 Animal model studies and clinical trialsocumented the ability of fenoldopam to aug-ent blood flow to the kidneys and other or-

ans.16 In a recent clinical trial of patients with

This study is part of a senior training project of the Centeror Overview, Meta-analysis, and Evidence-based medicineraining (COMET), based in Milan, Italy (http://it.geocities.om/comet_milano/Home.htm).

Support: None. Potential conflicts of interest: None.Address reprint requests to Giovanni Landoni, MD, De-

artment of Cardiothoracic Anesthesia and Intensive Care,stituto Scientifico San Raffaele, Via Olgettina 60 Milano,0132 Italy. E-mail: landoni.giovanni@hsr.it© 2006 by the National Kidney Foundation, Inc.0272-6386/06/4901-0008$32.00/0

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f Kidney Diseases, Vol 49, No 1 (January), 2007: pp 56-68

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Fenoldopam in Acute Renal Failure 57

epsis, fenoldopam improved perfusion of theastric mucosa in patients with septic shock.17

These clinically useful pharmacological prop-rties have led to the widespread use of fenoldo-am in the prevention or treatment of acuteidney injury. However, clinical studies showinghe clinical efficacy of fenoldopam in patientsith renal disease are sparse and limited by small

ample sizes. Numerous apparently positive re-orts targeted to surrogate end points, yet se-erely underpowered, have appeared in the litera-ure.17-36 A recent trial using fenoldopam toeduce the incidence of death or dialysis at 21ays failed to reach its primary end point, but aost hoc analysis showed promising effects inatients without diabetes.36 Conversely, 2 previ-us studies using fenoldopam as a prophylacticgent failed to prevent the development of acuteidney injury.19,31 To address this problem, weonducted a systematic review and meta-analy-is of data pooled from existing trials to deter-ine the impact of fenoldopam on acute kidney

njury, patient mortality, and length of hospitaltay in critically ill patients.

METHODS

earch Strategy

Pertinent studies were independently searched inioMedCentral, CENTRAL, and PubMed (updated Octo-er 30, 2005) by 2 trained investigators (G.L., G.G.L.B.-.). The full PubMed search strategy, including as key words

enoldopam, kidney disease, and renal failure, was devel-

Table 1. Description of Studie

Author (year of publication)

iancofiore (2004) Liver Trove (2005) Circulatrienza (2006) and Brienza (2003) Crit Caraimmi (2003) J Cardioella Rocca (2004) and Della Rocca (2002) Anesthastaldo (2004) Minervaalpenny I (2001) and Halpenny (2001) J Cardioalpenny II (2002) Eur J Analcangi (2004) MinervacCune (2005) Int Immorelli I (2004) Anestheorelli II (2005) Crit Carittarello (2003) Minervaenzini (2004) Minervaheinbaum (2003) and Sheinbaum (2000) Rev Caumlin (2005) Am J Ki

ped according to Biondi-Zoccai et al37 and is available in e

he Appendix. Additional hand or computerized searchesnvolved recent (2002 to 2005) conference proceedings fromhe International Anesthesia Research Society, Americaneart Association, American College of Cardiology, Ameri-

an Society of Anesthesiology, and European Society ofardiology congresses. In addition, we used backward snow-alling (ie, scanning references of retrieved articles andertinent reviews) and contacted international experts fordditional studies. No language restriction was enforced,nd non–English-language articles were translated beforedditional analysis.

tudy Selection

References obtained from database and literature searchesere independently examined first at the title/abstract levely 2 investigators (G.L., G.G.L.B.-Z.), with divergencesesolved by consensus, and then, if potentially pertinent,etrieved as complete articles. The following inclusion crite-ia were used for potentially relevant studies: (1) randomllocation to treatment, (2) comparison of fenoldopam ver-us control treatment, and (3) performed in surgical orntensive care patients (thus not including patients adminis-ered radiocontrast dye). Exclusion criteria were: (1) studieselecting only patients undergoing procedures with angio-raphic contrast media, (2) nonparallel design (ie, crossover)andomized trials, (3) duplicate publications (in this case,nly the article reporting the longest follow-up was ab-tracted), (4) nonhuman experimental studies, and (5) noutcome data. Two investigators (G.L., G.G.L.B.-Z.) se-ected studies for the final analysis by independently assess-ng compliance to selection criteria. Divergences from selec-ion criteria were resolved by consensus (Table 1).

ata Abstraction and Study Characteristics

Baseline, procedural, and outcome data were abstractedndependently by 2 investigators (G.L., T.B.), with diver-ences resolved by consensus (Table 2). Specifically, we

ded in the Systematic Review

Journal Setting

Liver transplantationCardiac surgery

� abstract ICUVasc Anesth Cardiac surgeryabstract Liver transplantation

esiol Vascular surgeryVasc Anesth � Anaesthesia Cardiac surgerysiol Vascular surgery

esiol ICUrmacol Renal transplantation

ICU (sepsis)ICU (sepsis)

esiol Cardiac surgeryesiol Cardiac surgeryc Med � abstract Vascular surgeryis ICU

s Inclu

ansplione Medthorac

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unophasiologye MedAnestAnest

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xtracted study design (including patient selection and ran-

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Landoni et al58

omization), population, clinical setting, fenoldopam dos-ge, and treatment duration (Table 3), additional treatments,efinition of new or worsening acute kidney injury (Table 4),equirements for renal replacement therapy (RRT), andength of follow-up. At least 2 separate attempts at contact-ng original investigators were made in case of missing data.

The primary end point of our analysis is to determine theffect of fenoldopam on the number of patients progressingo acute kidney injury that requires at least 1 episode of RRT.he coprimary end point is the incidence of in-hospitalortality. Secondary end points include the incidence of

cute kidney injury and hypotension, peak serum creatinineevels, long-term survival, and the duration of intensive carenit (ICU) and hospital stays.

Table 2. Major Excluded Studies

PrincipalInvestigator Journal

No. ofPatients

Reason forExclusion

anucci(2004)

Ann Thorac Surg 216 Nonrandomized(propensitymatchedcohorts)

arwood(2003)

J CardiothoracVasc Anesth

70 Nonrandomized(case series)

ombotz(1998)

Acta AnaesthesiolScand

64 Nonrandomized(case series)

ill (1993) J CardiothoracVasc Anesth

20 No outcome data

acDonald(1990)

Eur J ClinPharmacol

20 No outcome data

Table 3. Number of Patients an

Author (year of publication)

No. ofOverallPatients

No. ofPatients

(fenoldopam)

iancofiore (2004) 140 46

ove (2005) 80 40rienza (2006) and Brienza (2003) 100 50aimmi (2003) 160 80

ella Rocca (2004) and DellaRocca (2002)

43 22

astaldo (2004) 40 20alpenny I (2001) and Halpenny(2001)

31 16

alpenny II (2002) 27 14alcangi (2004) 37 18cCune (2005) 20 10orelli I (2004) 40 20orelli II (2005) 300 150ittarello (2003) 24 12enzini (2004) 30 15heinbaum (2003) andSheinbaum (2000)

58 28

umlin (2005) 160 80 8

nternal Validity Assessment

The internal validity of included trials was appraisedccording to The Cochrane Collaboration methods, ie, judg-ng risk for selection, performance, attrition, and adjudica-ion biases, and expressed as low risk of bias (A), moderateisk of bias (B), high risk of bias (C), or incomplete reportingeading to inability to ascertain the underlying risk of biasD).38 In addition, allocation concealment was explicitlyistinguished as adequate (A), unclear (B), inadequate (C),r not used (D; Table 5). Two independent reviewers (G.L.,.G.L.B.-Z.) appraised study quality, with divergences re-

olved by consensus.

ata Analysis and Synthesis

Agreement for study selection and quality appraisal (Table 5)as assessed with the Cohen � statistic.39 Binary outcomes

rom individual studies were analyzed according to theantel-Haenszel model to compute individual odds ratios

ORs) with pertinent 95% confidence intervals (CI), and aooled summary effect estimate was calculated by means offixed-effects model.40 Weighted means differences (WMDs)nd 95% CI were computed for continuous variables.38 Wessessed the robustness of findings from the primary analy-is to the effects of study population and baseline risk of anyf the primary outcomes through a series of sensitivitynalyses, including a random-effects model, and by with-rawing 1 study at a time.Statistical heterogeneity and inconsistency were mea-

ured by using Cochran Q tests and I2, respectively.41 Theisk of small-study bias (including publication bias) wasssessed by using visual inspection of funnel plots andomputing the Egger test.42 Statistical significance is set at

rventions of Included Studies

. ofentsrols)

Placebo or BestAvailableTreatment

FenoldopamDose

(�g/kg/min)

Duration ofTreatment

(h)

4 Dopamine (1 group) andplacebo (other group)

0.10 96

0 Dopamine 0.05 240 Dopamine 0.10 960 Dopamine or dobutamine

after loop diuretics0.1-0.3 24

1 Dopamine 0.10 48

0 Not reported 0.03 245 Placebo 0.10 14

3 Placebo 0.10 29 Placebo 0.10 960 Placebo 0.025-0.1 480 Placebo 0.10 20 Placebo 0.09 1682 Placebo 0.05 485 Placebo 0.03-0.1 480 Placebo 0.05 24

d Inte

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2

21

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15113

0 Placebo 0.05-0.2 72

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Fenoldopam in Acute Renal Failure 59

he 2-tailed 0.05 level for hypothesis testing and 0.10 foreterogeneity testing. According to Higgins and Green,38 I2

alues around 25%, 50%, and 75% were considered repre-enting low, moderate, and severe statistical inconsistency,espectively. Unadjusted P values are reported throughout.omputations were performed using SPSS 11.0 (SPSS Inc,hicago, IL), and RevMan 4.2 (freeware available from Theochrane Collaboration).38

This study was performed in compliance with The Co-hrane Collaboration and the Quality of Reporting of Meta-nalyses (QUOROM) guidelines.

tatement of Responsibility

The authors had full access to the data and take responsi-ility for its integrity. All authors have read and agree to theanuscript as written.

RESULTS

Database searches, snowballing, and contactsith experts yielded a total of 154 citations (Fig). Excluding 111 nonpertinent titles or abstractsTable 2), we retrieved 43 studies in completeorm and assessed them according to the selec-ion criteria. A total of 27 studies were furtherxcluded because of their nonexperimental de-

Table 4. Definition of Acute Kidney Injury Accord

Author (year of publication)Author Defin

(most in

iancofiore (2004) Serum creatinine �doubling or oligu

ove (2005) 25% Serum creatinrienza (2006) and Brienza (2003) 10% Serum creatinaimmi (2003) 50% Serum creatinella Rocca (2004) and DellaRocca (2002)astaldo (2004)alpenny I (2001) and Halpenny(2001)alpenny II (2002) RRTalcangi (2004)cCune (2005) RRTorelli I (2004)orelli II (2005) Serum creatinine �ittarello (2003) RRTenzini (2004) 25% Serum creatinheinbaum (2003) andSheinbaum (2000)

RRT

umlin (2005) Serum creatinine �refractory pulmo� 25 cm H2O orrefractory metab

Note: To convert serum creatinine in mg/dL to �mol/L, m

ign, including the use of historic controls, or s

ecause of duplicate publication. Specifically,e excluded 4 studies because of duplicate pub-

ication either explicitly acknowledged or al-owed21,24,35 or not.27 We excluded 11 stud-es43-54 because there were no outcome data anddditional details could not be obtained from thenvestigators, 6 crossover trials,9,15,55-57 4 stud-es with matched controls,58-61 and a large pro-pective study with propensity score analysis.62

e finally identified 16 eligible randomized clini-al trials, which were included in the final analy-is (Table 1). Agreement for study selectionppeared high (Cohen �, 0.93; 95% CI, 0.87 to.0).

tudy Characteristics

The 16 included randomized controlled trialsRCTs) randomly assigned 1,290 patients (622atients to fenoldopam and 668 patients to pla-ebo or best available treatment, mostly low-ose dopamine; Table 3). Five trials were per-ormed in cardiac surgery; 3 trials, in vascular

Each Study and Baseline Serum Creatinine Level

Acute Kidney Injuryuthor definition)

Baseline Serum Creatinine(mg/dL; fenoldopam v

controls)

g/dL or serum creatinine 0.8 � 0.2 (fenoldopam) v0.85 � 0.3 (dopamine) v0.88 � 0.2 (placebo)

rease 1.56 � 0.78 v 1.54 � 0.59rease 1.99 � 0.1 v 1.91 � 0.1rease 1.82 � 0.2 v 1.78 � 0.3

1.0 � 0.3 v 0.98 � 0.2

1.1 � 0.3 v 1.0 � 0.41.05 � 0.18 v 1.09 � 0.17

1.12 � 0.19 v 0.98 � 0.141.9 � 0.4 v 2 � 0.74.1 � 3.3 v 4.0 � 2.3

g/dL 1.02 � 0.30 v 1.16 � 0.992.53 � 1.79 v 1.56 � 0.15

rease 1.50 � 0.2 v 1.51 � 0.3

g/dL or clinical uremia orema or wedge pressurehyperkalemia or

idosis

1.17 � 0.12 v 1.25 � 0.2

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Landoni et al60

rial, in renal transplantation, while 5 studiesere performed in the ICU in either selectedatients with sepsis (2 studies) or the overall ICUopulation. All except 1 study17 focused on theenal protective properties of fenoldopam.

Fenoldopam dosage varied across studies, al-ays greater than 0.025 �g/kg/min and mostften 0.1 �g/kg/min, reaching 0.3 �g/kg/min in aingle study. All except 2 studies17,28 had aenoldopam infusion for longer than 12 hours,ith 8 studies reporting a 2-day or longer infu-

ion (median duration, 48 hours). There was notandardization of indications for RRT excepthat patients had to meet standard “clinical crite-ia.” Biochemical definitions for acute kidneynjury (ie, serum creatinine concentrations) alsoere not standardized between trials, and we

valuated the broadest definition of acute kidneynjury indicated by each investigator (Table 4).

Study quality appraisal appeared highly repro-

Table 5. Design Features and Apprais

PrincipalInvestigator

PublicationType

MulticenterEnrollment

Means foRandomiz

Allocatio

iancofiore (2004) Full report Yes Computer-gerandom num

ove (2005) Full report No Computer-gerandom num

rienza 2006 Full report Yes Not reportedrienza 2003 Abstractaimmi (2003) Full report No Not reportedella Rocca (2004) Full report Yes Not reportedella Rocca (2002) Abstractastaldo (2004) Abstract No Not reportedalpenny I† (2001) Full report No Not reportedalpenny† (2001) Full reportalpenny II (2002) Full report No Not reportedalcangi (2004) Abstract No Not reportedcCune (2005) Full report No Not reportedorelli I (2004) Full report No Computer-ge

random numorelli II (2005) Full report Yes Computer-ge

random numittarello (2003) Abstract No Not reportedenzini M (2004) Abstract No Not reportedheinbaum 2003 Full report No Not reportedheinbaum 2000 Abstractumlin (2005) Full report Yes Not reported

Note: Risk of bias expressed as A (low risk), B (moderateo ascertain the underlying risk of bias).

*Allocation concealment expressed as adequate (A), unc†Duplicate reports.

ucible (Cohen �, 0.89; 95% CI, 0.79 to 0.99). 9

ost studies appeared of suboptimal quality,estified by the common lack of details for theethod used for randomized sequence genera-

ion and allocation (Table 5). Adequate alloca-ion concealment was enforced by only 5 studies.n addition, low risks of selection, performance,ttrition, and detection bias could be attributed tonly a minority of trials. Finally, only 5 RCTssed a multicenter design, a feature that does nottrictly impact on internal validity, but usuallyncreases external validity of a trial.

uantitative Data Synthesis

Overall analysis showed that in comparison toest medical therapy, fenoldopam was associatedith significant reductions in the rates of allajor end points. Specifically, fenoldopam use

ecreased the risk of RRT (34 of 525 patients6.5%] in the fenoldopam group versus 59 of 569atients [10.4%] in the control arm; OR, 0.54;

e Internal Validity of Included Studies

AllocationConcealment*

Risk ofSelection

Bias

Risk ofPerformance

Bias

Risk ofAttrition

Bias

Risk ofDetection

Bias

A B A B B

A B A A B

B C C C C

B B D C CD B C B C

B D D D DB B B B B

A B B C CD D D D DB B B B BB B B B B

A A A A B

D D D D DC C C C CD D D D D

A B A B B

(high risk), and D (incomplete reporting leading to inability

), inadequate (C), or not used (D).

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Fenoldopam in Acute Renal Failure 61

eterogeneity � 0.92; I2 � 0%; Fig 2) and ofll-cause mortality (81 of 537 patients [15.1%]ersus 110 of 581 patients [18.9%]; OR, 0.64;5% CI, 0.45 to 0.91; P for effect � 0.01; P foreterogeneity � 0.92; I2 � 0%; Fig 3), as well ascute kidney injury (84 of 525 patients [16.0%]ersus 161 of 569 patients [28.3%]; OR, 0.43;5% CI, 0.32 to 0.59; P for effect � 0.001; P foreterogeneity � 0.09; I2 � 41%; Fig 4).

In addition to an association with greater in-ospital survival, fenoldopam use was associatedith a significant reduction in ICU stay (WMD�0.61 days; 95% CI, �0.99 to �0.23; P for

Figure 1. Flow diagram of the systematic review pro-ess.

Figure 2. Pooled estimates o

ffect � 0.002; P for heterogeneity � 0.82; I2 �%; Fig 5) and shorter time to hospital dischargeWMD � �1.07 days; 95% CI, �2.16 to 0.01; Por effect � 0.05; P for heterogeneity � 0.90; I2

0%; Fig 6). Conversely, use of fenoldopamas associated with a trend toward a greater ratef hypotensive episodes or use of vasopressors118 of 498 patients [23.7%] versus 103 of 544atients [18.9%]; OR, 1.31; 95% CI, 0.93 to.83; P for effect � 0.12; P for heterogeneity �.73; I2 � 0%; Fig 7).Although nonrenal pleiotropic effects of

enoldopam cannot be ruled out, it is likelyhat most benefits of fenoldopam were driveny its renoprotective effect, testified by theignificant, albeit statistically heterogeneous,ower peak serum creatinine levels (WMD �

0.20; 95% CI, �0.24 to �0.16; P for effect0.001; P for heterogeneity � 0.0008; I2 �

3.2%; Fig 8).

dditional Analyses

We assessed the robustness and applicabilityf our findings through a series of sensitivitynalyses, ie, excluding 1 study at a time, switch-ng from fixed-effect to random-effect models,nd computing relative risks, as well as riskifferences. All subanalyses performed exclud-ng 1 RCT at a time remained in the sameirection and magnitude of benefit in support ofenoldopam as the overall analysis for acuteidney injury, RRT, and death. Similarly, random-ffect meta-analyses and relative risk computa-

f risk of need for RRT.

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Landoni et al62

ions confirmed the robustness of the comprehen-ive and primary analyses. We also appraised theobustness and validity of our findings by explor-ng the likelihood of small-study bias by meansf a funnel plot inspection and an Egger test. Weound no major evidence of such bias at eitherraphical or statistical testing for acute kidneynjury, RRT, and death (P at Egger test � 0.391,.9, and 0.974, respectively).

DISCUSSION

We performed a meta-analysis of pooled datarom several small underpowered studies andhowed that fenoldopam is associated with aignificantly lower incidence of acute kidneynjury and overall mortality in critically ill pa-

Figure 3. Pooled estimates of risk o

Figure 4. Pooled estimates of ris

ients. Although significantly underpowered, mosttudies included in this analysis showed positiveurvival trends, consistent with the overall posi-ive results of our meta-analysis.

Despite improvements in intensive care medi-ine and the delivery of RRT, the mortalityssociated with acute kidney injury remains un-cceptably high. The observation that renal bloodow decreases after the onset of acute kidney

njury led to numerous clinical trials investigat-ng the efficacy of parenteral vasodilators ineducing the progression to dialysis-dependentcute kidney injury and improving patient sur-ival.63,64 Numerous animal model studieshowed that parenteral vasodilators can restoreorticomedullary blood flow during periods of

kidney injury in critically ill patients.

k of death from any cause.

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Fenoldopam in Acute Renal Failure 63

schemia and that early administration of thesegents can reduce the burden of necrotic tu-ules.63-66 Use of vasodilators in patients withcute kidney injury is based upon the assumptionhat increasing renal blood flow will reduce pro-ression to dialysis therapy and improve sur-ival. However, previous studies using paren-eral vasodilators, including dopamine, atrialatriuretic peptide, and insulin growth factor 1,ailed to reduce the incidence of dialysis-depen-ent acute kidney injury or overall mortal-ty.5,6,67

To date, 3 meta-analyses of controlled clinicalrials involving the prophylactic or therapeuticse of “renal-dose” dopamine in patients withcute kidney injury failed to show a protectiveffect on the development of acute kidney injuryr need for RRT.68-70 The failure of dopamine tounction as a prophylactic agent may be causedy the divergent effects of specific dopamineeceptors in the mammalian kidney. For ex-mple, activation of dopamine A-1 receptorsncreases renal blood flow in normal and dis-

Figure 5. Pooled es

Figure 6. Pooled estimates of total

ased kidneys, whereas dopamine A-2 receptorctivation leads to prolonged vasoconstric-ion.71,72 Although previous studies failed tohow a renal protective effect, intravenous admin-stration of dopamine to patients at risk of acuteidney injury does not lead to additional renalnjury.68 This observation allowed us to includeCTs comparing renal-dose dopamine with

enoldopam mesylate.The failure of previous vasodilators to im-

rove the outcome of patients with acute kidneynjury may involve deficiencies in trial designnd study end points. For example, previousrials of patients with acute tubular necrosisailed to standardize the initiation of dialysisherapy, thus allowing for the primary end pointf many studies to be determined by individualractice patterns. This lack of uniformity hasllowed for variability in the primary end pointnd reduced the ability to show a significant drugffect. Only a single study used in our analysisad predefined criteria indicating when a patienteached a dialytic end point.73 Moreover, previ-

s of ICU stay (days).

length of hospital stay (days).

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Landoni et al64

us trials varied about the timing of drug admin-stration. A delay in drug administration couldllow for progression to the later phases of acuteidney injury that are no longer responsive toasodilator therapy.74,75 In addition, variable-ffects vasodilator effects on preload, cardiacutput, and onset of hypotension also affectesults of specific trials.

Fenoldopam mesylate is a selective dopamine-1 receptor agonist, was shown to decrease

ystemic vascular resistance in a dose-dependentanner, and is able to augment renal blood flow

n patients with normal renal function and chronicenal failure.8-10,73,76 Recent animal model stud-es further show that the stimulatory effects ofenoldopam on renal blood flow are proportion-

Figure 7. Pooled esti

Figure 8. Pooled estimates of peak serum creatinine (mg/dL)y 88.4.

tely greater in the outer medulla.77 In contrast toopamine, intravenous fenoldopam does not in-rease cardiac output because of its greater speci-city for dopaminergic receptors and lack ofrossover activation of �-adrenergic receptors.10

ost clinicians use fenoldopam in the belief thatmproving renal blood flow and oxygen deliveryill disrupt the progression toward dialysis-ependent acute kidney injury. Between doses of.03 and 0.1 �g/kg/min, fenoldopam can signifi-antly increase renal blood flow without decreas-ng systemic vascular resistance.9,78 Moreover,nfusions as low as 0.03 �g/kg/min showed ben-ficial effects on renal function.9 Despite thebsence of appropriately powered prospectiverials, use of fenoldopam in patients with renal

of risk of hypotension.

. To convert serum creatinine in mg/dL to �mol/L, multiply

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Fenoldopam in Acute Renal Failure 65

ysfunction has become standard practice. More-ver, it has not been established whether improv-ng blood flow in patients with acute kidneynjury can reduce the burden of ischemic tu-ules.79

A recent meta-analysis80 reviewed differentethods to protect renal function during the

erioperative period and concluded that there iso convincing evidence to suggest that pharma-ological or other interventions are effective inhe treatment of patients with acute kidney in-ury. However, Zacharias et al80 included only27,28 of the 16 trials used in our meta-analysis.oreover, several nonrandomized studies showed

hat fenoldopam decreased the incidence of con-rast nephropathy in patients undergoing coro-ary stent placement.81,82 The only large random-zed study examining the efficacy of fenoldopamn preventing contrast nephropathy did not sup-ort these findings.83 These contrasting resultsllustrate the difficulty of using existing trials toeach a consensus on the role of fenoldopam inatients with acute kidney injury. Because noingle prospective study supports a protectiveffect of fenoldopam on decreasing the incidencef acute kidney injury or need for RRT, weonducted a meta-analysis of 16 studies compar-ng fenoldopam with placebo or usual care. Inhe 16 RCTs included in our analysis, fenoldo-am infusion rates ranged between 0.025 and 0.3g/kg/min. In our analysis of 1,290 patientsnrolled in 16 randomized trials, use of fenoldo-am significantly decreased the risk of acuteidney injury, need for RRT, and hospital mortal-ty Moreover, fenoldopam decreased the dura-ion of ICU and total hospital stays. Remarkably,he incidence of hypotension and/or use of vaso-onstrictors did not increase significantly in pa-ients administered fenoldopam. The lack of hy-otension associated with fenoldopam in partay explain the beneficial findings of fenoldo-

am compared with other vasodilators.The limitations of systematic reviews andeta-analyses are well known and include the

evel of uniformity among study populations, asell as the primary end points in each study.84

articular attention should be drawn to the over-ll suboptimal quality of the RCTs includedecause lower quality studies may provide bi-sed effect estimates. However, even after exclud-

ng studies with inadequate allocation conceal- i

ent (Table 5), fenoldopam was associatedignificantly with a decrease in risk of acute renalailure (OR, 0.60; 95% CI, 0.42 to 0.86; P forffect � 0.005; P for heterogeneity � 0.42; I2 �%). A particular limitation of our analysis is theack of uniform clinical indications for the initia-ion of dialysis therapy. In the majority of random-zed trials, initiation of RRT was left to thearticipating physician. An additional limitationf our study is that several studies had to beliminated from the analysis because of missingata and failure to contact the primary investiga-ors. Last, there was no independent measure oflomerular filtration rate from which we couldorrelate infusion with fenoldopam and improve-ents in renal function. Nonetheless, we strived

o comply with the most stringent guidelines ofhe Cochrane Collaboration and the QUOROMtatement. Thus, our results provide the mostomprehensive and thorough comparison ofenoldopam versus control treatment in criticallyll patients at risk of acute kidney injury thaturrently exists. In addition, the validity of ouresults is supported by the lack of evidence ofmall-study bias or statistical heterogeneity. Onlyn individual patient-data meta-analysis or a largend adequately powered RCT could provide aounder and more rigorous appraisal of the clini-al role of fenoldopam in this clinical setting.

In conclusion, intravenous infusion of fenoldo-am mesylate to patients at risk of acute kidneynjury appears to decrease the development ofcute tubular necrosis, requirement for RRT, andverall patient mortality. Given the limitations ofeta-analysis, our analysis supports the renal

rotective effects of fenoldopam mesylate. Aarger multicenter RCT is needed to confirmhese results.

ACKNOWLEDGMENTThe authors sincerely thank the investigators of the trials

ncluded in this review who answered our questions: A.orelli, MD, N. Brienza, MD, P.P. Caimmi, MD, T.R.cCune, MD, D. Pittarello, MD, M. Renzini, MD, and G.iancofiore, MD, for their assistance; and Giardina Gi-seppe, RN, Poli Arianna, RN, Antonioni Giliola, RN, Mellarancesca, RN, and Castelnuovo Lara, RN, for their support

n data entry.

APPENDIX

Search strategy for PubMed, developed accord-

ng to Biondi-Zoccai et al33: (“fenoldopam”

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MeSH Terms] OR fenoldopam[Text Word])ND ((kidney OR renal) AND (failure OR insuf-ciency)) AND ((randomized controlled trial [pt]R controlled clinical trial[pt] OR randomized

ontrolled trials [mh] OR random allocation[mh]R double-blind method [mh] OR single-blindethod[mh] OR clinical trial [pt] OR clinical

rials [mh] OR (“clinical trial” [tw] OR ((singl*tw] OR doubl* [tw] OR trebl* [tw] ORripl*[tw]) AND (mask* [tw] OR blind [tw]))R (“latin square”[tw]) OR placebos [mh] ORlacebo* [tw] OR random* [tw] OR researchesign [mh:noexp] OR comparative study [mh]R evaluation studies [mh] OR follow-up stud-

es [mh] OR prospective studies [mh] OR cross-ver studies [mh] OR control*[tw] OR prospec-iv* [tw] OR volunteer* [tw]) NOT (animal[mh]OT human [mh]) NOT (comment[pt] OR edito-

ial[pt] OR (meta-analysis[pt] NOT clinical trialpt]) OR practice-guideline[pt] OR review[pt]))).

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