Effect of Fenoldopam Mesylate in Critically Ill Patients at Risk for Acute Renal Failure is Dose Dependent

Abstract

Background: Acute renal failure (ARF) is common and difficult to prevent, especially in intensive care unit (ICU) patients with cancer. Therapeutic trials with various agents have generally been ineffective in preventing ARF. We describe the effects of two different doses of the dopamine DA-1 receptor agonist fenoldopam mesylate on renal function in a series of critically ill cancer patients at risk of developing ARF. Methods: We performed a retrospective chart review of 100 consecutive patients who received fenoldopam mesylate for at least 72 h in the medical and surgical ICUs of The University of Texas M. D. Anderson Cancer Center who were at risk of developing ARF. Eighteen patients received low-dose fenoldopam mesylate (≤ 0.05 µg/kg/min). The remaining 82 patients received high-dose fenoldopam mesylate (0.07–0.1 µg/kg/min). Data were collected relating to drug dosage, patient demographics, severity of illness, and indices of renal function. Results: Patients were moderately ill, with a mean APACHE II score of 18 ± 6 at initiation of fenoldopam infusion. Eighty-five percent of patients had at least two risk factors for the development of ARF, and 20% had four. For the group overall, the incidence of ARF was 13%, and the hospital mortality rate was 37%. When compared with the low-dose group, patients who received high-dose fenoldopam had a significantly shorter ICU length of stay despite a significantly higher APACHE II score (p = 0.01). The high-dose group also had a highly significant decrease in serum creatinine levels at 72 h (p = 0.005). Conclusions: These data support the hypothesis that fenoldopam mesylate may provide a degree of dose-dependent renal protection in cancer patients with early acute renal failure.

• acute renal failure
• dopamine
• dose effect
• fenoldopam mesylate
• prevention

Introduction

Acute renal failure (ARF) occurs commonly in hospitalized patients, particularly in the critical care setting.[1] Despite the ready availability of renal replacement therapies, morbidity and mortality rates remain high. Although death is not usually attributed directly to the presence of ARF, renal failure is an independent risk factor for mortality and complicates the care of critically ill patients.[2] Furthermore, mortality rates are significantly higher in patients with ARF who require dialysis than they are in those who do not.[3] Therefore, any treatment that decreases the incidence or severity of renal failure or lessens the need for dialysis might be expected to decrease the morbidity and mortality associated with the development of ARF.

Low-dose dopamine has routinely been used to prevent the development of ARF despite scant evidence of efficacy. Its use was prompted by the observation thatdopamine increases renal blood flow and induces a natriuresis and diuresis in normal human subjects.[4] These effects are attributed to stimulation of dopamine type 1 (DA-1) receptors and might be expected to provide renal protection to patients at risk for ARF. Recent studies, however, have not found that low-dose dopamine is beneficial in patients with early renal dysfunction.[5&6] In addition, there is some evidence that use of dopamine for this indication may be harmful.[7&8] This lack of benefit may be related to dopamine's effects on the pituitary gland and other organs, such as the immune system and gastrointestinal tract, or to a spillover effect on α and β adrenergic receptors.[9]

The pure DA-1 receptor agonist fenoldopam mesylate has been approved as an intravenous infusion to treat hypertensive emergencies. Like low-dose dopamine, it increases renal blood flow and glomerular filtration rate in both animals and healthy human volunteers.[10&11] Studies on the effectiveness of fenoldopam in preventing ARF in high-risk patients are conflicting.[12-15] Furthermore, any salutary effects of fenoldopam on renal function may be dose dependent.[16]

The critical care unit at The University of Texas M. D. Anderson Cancer Center has administered fenoldopam to high-risk cancer patients to prevent ARF since 1999. In this paper, we report our experience with the first 100 patients who received fenoldopam for this indication.

Subjects and Methods

A consecutive group of 100 patients who received fenoldopam for 72 h or longer between February 1999 and August 2000 was identified by screening a pharmacy database at The University of Texas M. D. Anderson Cancer Center. We reviewed each patient's medical record for demographic information and data relating to severity of illness, renal function, type of cancer, hemodynamic indices, and fenoldopam dosage. Each patient received fenoldopam because of the presence of one to four risk factors for the development of ARF. These included the following:

1. The presence of hypotension (defined as systolic BP less than 90 mmHg for 1 h or more, or the administration of any vasopressor other than dobutamine).

2. Hypoxemia (O₂ saturation less than 90% for at least 1 h).

3. The presence of at least two of four signs of the systemic inflammatory response syndrome.[17]

4. Administration of known nephrotoxic agents.

For the purposes of this retrospective analysis, patients were divided into two groups based on the dose of fenoldopam infused. The low-dose group of patients received fenoldopam at a dose of ≤ 0.05 µg/kg/min, while the high-dose patients received fenoldopam at 0.07–0.1 µg/kg/min. The clinical variables assessed included peak serum creatinine levels, percentage change in creatinine from baseline levels (Δ creatinine), urine output, need for renal replacement therapy, length of stay in the ICU and hospital, and ICU and hospital mortality rates. Acute renal failure (ARF) was defined as a doubling of the baseline serum creatinine level within 7 days.

One-way ANOVA with Bonferroni posttesting was used to compare changes from baseline serum creatinine through time. To compare the effects of fenoldopam dose, we compared change in baseline creatinine values in the low- and high-dose groups using the student's unpaired t-test. Chi-square tests were used to compare the incidence of risk factors in different patient groups (medical or surgical) and the incidence of dialysis and mortality. All analyses were carried out using GraphPad Prism v4 (GraphPad Software, San Diego, CA, USA).

Results

The baseline characteristics of the patients are summarized in Table 1. All patients received fenoldopam for maintenance of renal perfusion because of the presence of at least one risk factor for the development of ARF. Overall, 85% of patients had at least two defined risk factors (see Subjects and Methods) for the development of ARF, and 20% had all four. Most patients were Caucasian men. Surgical patients outnumbered medicalpatients, and respiratory disease was the most common reason for ICU admission. Patients were moderately ill, with a mean APACHE II score of 18 ± 6 at the time fenoldopam infusion was started.

Table 1. Baseline Characteristics of Patients Treated with Fenoldopam [Mean (SD)].

Characteristic	Low-dose group	High-dose group	p Value
n	18	82
Age	60 (13)	58 (14)	0.66
Male gender (%)	67	56	0.44
Oliguric (%)	6	15	0.30
Two or more risk factors (%)	83	85	0.83
Baseline BUN (mg/dL)	27 (24)	33 (23)	0.30
Baseline creatinine (mg/dL)	1.32 (0.9)	1.49 (0.9)	0.47
Fluid/day (1 mL)	6053 (4801)	4831 (2866)	0.1
Baseline APACHE II	15.6 (5.2)	19.2 (6.0)	0.03

Eighteen patients received low-dose fenoldopam, whereas 82 patients received high-dose fenoldopam. There was no difference between groups with regard to type of cancer, age, gender, number of ARF risk factors, presence of oliguria, baseline renal function, or volume of intravenous fluids given during infusion. However, patients in the high-dose fenoldopam group had a significantly higher predicted mortality rate based on APACHE II scoring.

Patient outcome is reported in Table 2. The overall incidence of ARF was 13% and did not differ between the two groups. Likewise, there was no difference between the groups in ICU or hospital mortality rates, averaging 32% and 37%, respectively, for the overall cohort. However, despite their significantly higher APACHE II scores, the high-dose fenoldopam group had a significantly shorter length of stay in the ICU.

Table 2. Patient Outcomes [Mean (SD)].

Variable	Low-dose group	High-dose group	p Value
Delta creatinine (mg/dL)	0.40 (0.9)	− 0.14 (0.7)	0.01
Acute renal failure (%)	22	11	0.20
Dialysis (%)	22	15	0.43
ICU stay (days)	21 (21)	12 (11)	0.01
Hospital stay (days)	32 (23)	27 (21)	0.42
ICU survival (%)	72	67	0.62
Hospital survival (%)	72	61	0.37

The effects of different doses of fenoldopam on renal function are shown in Fig. 1. Patients who received low-dose fenoldopam experienced an increase in baseline serum creatinine levels at 72 h, while the serum creatinine in the high-dose group decreased from baseline at 72 h. As shown in Fig. 2, the change in serum creatinine between the two groups is statistically significant.

Figure 1. Serum creatinine values in patients receiving low- and high-dose fenoldopam infusions at baseline and after 72 h. Differences from baseline are not significant.

Figure 2. Change in patients' serum creatinine after a 72 h infusion of low- or high-dose fenoldopam.

Discussion

Acute kidney failure is a common and serious complication in critically ill patients. Hemodialysis and other renal replacement therapies remain the only established treatments for ARF, yet morbidity and mortality rates remain high. In addition, the care of such patients is very costly.[18] Therefore, therapies that can prevent or reverse early renal dysfunction may decrease mortality rates and reduce costs. The pathogenesis of ARF in patients with cancer is multifactorial and includes hypoxia, intrarenal vasoconstriction, inflammation, apoptosis, and reperfusion injury.[19] Previous clinical trials with agents known to affect one or more of these factors, such as atrial natriuretic peptide and insulin-like growth factor 1 have failed to demonstrate any benefit.[20-23]

Patients with cancer represent a good study population for this problem, because they are at particularly high risk for acute renal failure due to the multitude of potentially nephrotoxic therapies utilized during their treatment. The routine use of intravenous (IV) contrast, aminoglycoside antibiotics, immunosuppressive drugs, and chemotherapeutic agents is part of this risk. Inaddition, volume depletion from anorexia, nausea and vomiting, and hypotension from sepsis are potent and common risk factors in this patient population.

Low-dose dopamine is commonly administered to critically ill patients at risk for development of ARF in an attempt to increase renal blood flow and preserve the glomerular filtration rate. To date, no human trial has clearly documented any benefit from the use of lowdose dopamine. The randomized, placebo-controlled trial of low dose dopamine in patients with early renal dysfunction reported by the ANZICS Clinical Trials Group in 2000 showed that the administration of dopamine provided no benefits.[5]

Fenoldopam mesylate is a pure DA-1 receptor agonist approved for the treatment of malignant hypertension. In low doses, it improves renal blood flow and glomerular filtration rate in both animals and healthy human volunteers.[10&11] Because of the receptor selectivity of fenoldopam, there is interest in its use as a renoprotective agent, although data regarding its effectiveness are contradictory. Small trials suggest fenoldopam can preserve renal function after ischemic injury during coronary artery bypass grafting or aortic aneurysm repair.[13], [24&25] Other trials using fenoldopam to prevent ARF from radio contrast in high-risk individuals are also supportive.[12], [15] However, a recent randomized controlled trial failed to document any efficacy of fenoldopam to prevent radio-contrast nephropathy.[14] In addition, there may exist a dose-response effect to the renoprotection of fenoldopam.[16]

This study reviews the outcome of 100 consecutive ICU patients at risk of developing ARF who were treated with fenoldopam for renal protection. In comparison to patients who received low-dose fenoldopam, patients in the high-dose group experienced a significant decline in serum creatinine from baseline levels at 72 h. This decline occurred despite the fact that these patients had a higher (albeit not significantly) starting creatinine value than the low-dose group, suggesting that, on average, they had a smaller functioning nephron mass at the time the infusion was started. This observation is consistent with a dose-response effect to the renoprotection afforded by fenoldopam. Furthermore, patients in the high-dose group had significantly shorter lengths of ICU stays, despite a higher initial mean APACHE II score.

Although 85% of patients had at least two risk factors for the development of ARF, and 20% had four, ARF developed in only 13% of the patients. The overall incidence of ARF in similar patients is reported in other studies to be 25%.[26&27] Despite the critically ill status of the patients studied, particularly the universal presence of malignancy, ICU and overall survival rates were 68% and 63%, respectively.

In conclusion, our results support the hypothesis that fenoldopam mesylate preserves renal function in critically ill patients at risk for ARF. In addition, the possibility of a dose-response effect to the renoprotection afforded by administration of fenoldopam should be considered when designing or interpreting future clinical trials of this agent.

Acknowledgments

This work was supported by departmental funds and institutional research grant #1-8779701 to Dr. Shaw and was presented at the Eight World Congress on Intensive and Critical Care Medicine in Sydney, Australia, October 2001.