Technology Pulse
Florida`s First Experience with a Targeted Renal Therapy Infusion System
February 2006
Components of the Benephit Infusion System
The Benephit system is a catheter that enables the administration of physician-specified renal vasodilator therapies directly to the renal arteries, such as fenoldopam (Corlopam, Neurex, Menlo Park, CA) a selective dopamine-1 receptor agonist, and nesiritide (Natrecor®, Scios, Inc., Fremont, CA), a B-type natriuretic peptide (BNP). The system is designed to provide selective infusion to both renal arteries simultaneously, using a single catheter.1-5 Its ability to protect high-risk patients requiring cardiac catheterization and/or coronary intervention from renal failure may help ailing patients who could benefit from TRT to avoid developing contrast-induced nephropathy (CIN) or radiocontrast nephropathy (RCN).
The system (Figure 2) consists of two components: the bifurcated infusion catheter (Figure 3) and an 8 Fr introducer sheath (Figure 4) with two ports. These ports allow simultaneous coronary diagnostic and interventional procedures as well as bilateral renal drug infusion using the system’s bifurcated infusion catheter. The bifurcated infusion catheter features two identical branches designed to allow the infusion of therapeutic drugs into both renal arteries at once. We found that these branches can be placed into the arteries rapidly, with minimal use of contrast media and without the use of guide wires. The introducer sheath enables the introduction of two different catheters through a single vessel access site in the femoral artery. This approach allows concurrent coronary and interventional procedures while infusing the renal arteries.1 Fenoldopam and the CONTRAST Trial The Benephit infusion system is designed to provide TRT as an alternative to systemic intravenous (IV) infusion of medications to treat renal insufficiency related to a number of conditions, including cardiovascular procedures and concomitant conditions such as congestive heart failure (CHF) and diabetes mellitus.
Systemic infusion is limited in many instances because it can cause serious side effects, such as the lowering of blood pressure. Intravenous use of drugs such as fenoldopam and nesiritide is often not administered in higher doses that lead to optimal renal effects because of undesirable systemic effects such as hypotension, increased afterload, or tachycardia in heart failure patients.6-10
Fenoldopam is a selective agonist to peripheral DA1-receptors. These receptors produce vasodilatation, increase renal perfusion and enhance natriuresis. The majority of adverse effects of fenoldopam reported are events from the vasodilatory properties of fenoldopam. Minor side effects include headache, dizziness, and cutaneous flushing. Major concerns are dose-related tachycardia and hypotension, particularly with infusion rates above 0.1 mcg/kg/min, observed after several hours of IV infusion.7-8, 11
The CONTRAST trial,4,6,11 which tested the efficacy of fenoldopam (0.05-0.1 mcg/kg/min IV) in preventing patients at risk for contrast-induced nephropathy, showed no benefit for fenoldopam in preventing further renal function deterioration. Results from the CONTRAST trial were first presented at the American College of Cardiology 2003 Annual Scientific Sessions in Chicago, Illinois, and published in the Journal of the American Medical Association. The doses of fenoldopam in the CONTRAST trial11 did not affect the glomerular filtration rate (GFR) to improve renal function in patients with renal insufficiency; therefore, the trial may have failed due to inadequate dosage rates. An escalation dose is possible, but is limited by development of severe systemic hypotension, tachycardia and requires extended infusion time.4,11 It is well-known that the effects of nesiritide on urinary output and renal hemodynamics are dose-related at infusion rates of 0.015 and 0.030 mcg/kg/min. Thus, it is possible that fenoldopam was not adequately dosed in the CONTRAST trial to maximize renal effects due to fear of dose-related systemic hypotension.2,5 The Initial Two Cases at Osceola Medical Center The first two patients receiving treatment with the Benephit system at Osceola Regional Medical Center were:
A 58-year-old white female with a past medical history of coronary artery disease, hypertension, insulin-dependent diabetes mellitus, dyslipidemia, peripheral vascular disease, and chronic renal insufficiency with a baseline serum creatinine: 2.1 mg/dL and BUN: 54 mg/dL;
A 72-year-old male with a past medical history of hypertension, hypercholesterolemia, non-insulin dependent diabetes mellitus, and chronic renal insufficiency with a baseline serum creatinine: 2.0 mg/dL and BUN: 48 mg/dL.
Both patients were admitted to our institution for further evaluation and management; both achieved inducible ischemia on their nuclear stress test.
The combination of these patients’ conditions, all risk factors for CIN, greatly increases the risk of further renal function deterioration and the development of permanent renal failure from contrast dye following diagnostic and interventional coronary procedures.
By delivering agents to the site where their pharmacologic effect is needed, current drug dosages may have maximum effect. Therefore, TRT with the Benephit infusion system could potentially enable us to treat a considerable group of patients. Virtually 5 million Americans suffer from CHF alone, not including those patients with multiple co-morbidities such as diabetes and impaired kidney function, whose treatment options may have been previously limited due to their existing low cardiac output, hypotension and advanced age. All are at higher risk for developing contrast-induced nephropathy (CIN) following angiographic studies.
Both patients underwent left heart catheterization. Right femoral arterial access was achieved using the modified Seldinger technique with placement of a standard 6 Fr sheath. Subsequently, an abdominal aorta angiographic road-map was obtained through a 6 Fr pigtail catheter to assess the renal arteries (Figure 5). Based on the image, the standard sheath was replaced by an appropriate length Benephit 8 Fr sheath system. The sheath was advanced without difficulty to the region of the renal ostia. The system’s bifurcated renal catheter was advanced through the sheath and was able to perform bilateral renal cannulation for drug infusion (Figure 6).
The Benephit system was used to deliver fenoldopam directly into the renal arteries, increasing blood flow inside the kidneys. Fenoldopam was infused at 0.2mcg/kg/min via IV pump into the renal arteries via the system catheter (refer to the Be-RITe Registry Fenoldopam Dosing Chart, Table 1. FlowMedica’s retrospective, observational Be-RITe International Registry12 is ongoing at several centers.). During the infusion, all 6 Fr catheters required for cardiac catheterization and coronary angioplasty were passed through the second port on the system’s sheath.
The Benephit infusion system was only left in place during the procedure, which reflects on procedural timeframe for fenoldopam infusion. All patients received acceptable amounts of contrast in accordance with established dosing guidelines to prevent contrast nephropathy: 5 ml of contrast per kg body weight divided by serum creatinine level (mg/dl).11 Efforts were made to minimize the volume of contrast material given, particularly in these high-risk patients.
The 8 Fr femoral arterial sheaths were removed in the staging area at Osceola Regional Medical Center, where experienced clinical staff pulls sheaths, applying manual compression or using the C-clamp. The main guidelines are: patient hemodynamically stable and asymptomatic, ACT The pre and 24-hour post serum creatinine levels of our patients is recorded in Table 2. We had positive outcomes and patients were able to avoid further renal dysfunction. Renal vasoconstriction is the final common pathway for many factors, such as medications, contrast media and poor pump function, which contribute to acute renal insufficiency in hospitalized heart failure patients.7 Conclusion A number of strategies have been investigated to prevent CIN in at-risk patients, including administering therapeutic agents through systemic IV infusion, such as IV fenoldopam. However, systemic infusion of vasodilators often is associated with serious side effects such as hypotension, tachycardia, and increased afterload. Researchers believe that the amount of systemic medication that reaches the kidneys often does not attain sufficient levels to be therapeutic and, therefore, that this type of treatment may not be effective. TRT avoids this problem because the drug is delivered in a therapeutic dose directly to the kidneys. Furthermore, since therapeutic agents used for TRT are excreted by the kidneys, side effects are thought to be minimized because the kidneys eliminate most of the drug immediately and, therefore, limit the amount of drug reaching the rest of the body.6-10 In conclusion, the Benephit system appears promising, but additional study is needed. FlowMedica is conducting the Be-RITe Registry, and we look forward to the ongoing data from that registry. Ultimately, a large cohort of patients in a randomized, double-blind clinical trial will be necessary in order to fully determine the safety and utility of this new technology. Reynaldo Grullon can be reached at grumar@earthlink.net
The system (Figure 2) consists of two components: the bifurcated infusion catheter (Figure 3) and an 8 Fr introducer sheath (Figure 4) with two ports. These ports allow simultaneous coronary diagnostic and interventional procedures as well as bilateral renal drug infusion using the system’s bifurcated infusion catheter. The bifurcated infusion catheter features two identical branches designed to allow the infusion of therapeutic drugs into both renal arteries at once. We found that these branches can be placed into the arteries rapidly, with minimal use of contrast media and without the use of guide wires. The introducer sheath enables the introduction of two different catheters through a single vessel access site in the femoral artery. This approach allows concurrent coronary and interventional procedures while infusing the renal arteries.1 Fenoldopam and the CONTRAST Trial The Benephit infusion system is designed to provide TRT as an alternative to systemic intravenous (IV) infusion of medications to treat renal insufficiency related to a number of conditions, including cardiovascular procedures and concomitant conditions such as congestive heart failure (CHF) and diabetes mellitus.
Systemic infusion is limited in many instances because it can cause serious side effects, such as the lowering of blood pressure. Intravenous use of drugs such as fenoldopam and nesiritide is often not administered in higher doses that lead to optimal renal effects because of undesirable systemic effects such as hypotension, increased afterload, or tachycardia in heart failure patients.6-10
Fenoldopam is a selective agonist to peripheral DA1-receptors. These receptors produce vasodilatation, increase renal perfusion and enhance natriuresis. The majority of adverse effects of fenoldopam reported are events from the vasodilatory properties of fenoldopam. Minor side effects include headache, dizziness, and cutaneous flushing. Major concerns are dose-related tachycardia and hypotension, particularly with infusion rates above 0.1 mcg/kg/min, observed after several hours of IV infusion.7-8, 11
The CONTRAST trial,4,6,11 which tested the efficacy of fenoldopam (0.05-0.1 mcg/kg/min IV) in preventing patients at risk for contrast-induced nephropathy, showed no benefit for fenoldopam in preventing further renal function deterioration. Results from the CONTRAST trial were first presented at the American College of Cardiology 2003 Annual Scientific Sessions in Chicago, Illinois, and published in the Journal of the American Medical Association. The doses of fenoldopam in the CONTRAST trial11 did not affect the glomerular filtration rate (GFR) to improve renal function in patients with renal insufficiency; therefore, the trial may have failed due to inadequate dosage rates. An escalation dose is possible, but is limited by development of severe systemic hypotension, tachycardia and requires extended infusion time.4,11 It is well-known that the effects of nesiritide on urinary output and renal hemodynamics are dose-related at infusion rates of 0.015 and 0.030 mcg/kg/min. Thus, it is possible that fenoldopam was not adequately dosed in the CONTRAST trial to maximize renal effects due to fear of dose-related systemic hypotension.2,5 The Initial Two Cases at Osceola Medical Center The first two patients receiving treatment with the Benephit system at Osceola Regional Medical Center were:
A 58-year-old white female with a past medical history of coronary artery disease, hypertension, insulin-dependent diabetes mellitus, dyslipidemia, peripheral vascular disease, and chronic renal insufficiency with a baseline serum creatinine: 2.1 mg/dL and BUN: 54 mg/dL;
A 72-year-old male with a past medical history of hypertension, hypercholesterolemia, non-insulin dependent diabetes mellitus, and chronic renal insufficiency with a baseline serum creatinine: 2.0 mg/dL and BUN: 48 mg/dL.
Both patients were admitted to our institution for further evaluation and management; both achieved inducible ischemia on their nuclear stress test.
The combination of these patients’ conditions, all risk factors for CIN, greatly increases the risk of further renal function deterioration and the development of permanent renal failure from contrast dye following diagnostic and interventional coronary procedures.
By delivering agents to the site where their pharmacologic effect is needed, current drug dosages may have maximum effect. Therefore, TRT with the Benephit infusion system could potentially enable us to treat a considerable group of patients. Virtually 5 million Americans suffer from CHF alone, not including those patients with multiple co-morbidities such as diabetes and impaired kidney function, whose treatment options may have been previously limited due to their existing low cardiac output, hypotension and advanced age. All are at higher risk for developing contrast-induced nephropathy (CIN) following angiographic studies.
Both patients underwent left heart catheterization. Right femoral arterial access was achieved using the modified Seldinger technique with placement of a standard 6 Fr sheath. Subsequently, an abdominal aorta angiographic road-map was obtained through a 6 Fr pigtail catheter to assess the renal arteries (Figure 5). Based on the image, the standard sheath was replaced by an appropriate length Benephit 8 Fr sheath system. The sheath was advanced without difficulty to the region of the renal ostia. The system’s bifurcated renal catheter was advanced through the sheath and was able to perform bilateral renal cannulation for drug infusion (Figure 6).
The Benephit system was used to deliver fenoldopam directly into the renal arteries, increasing blood flow inside the kidneys. Fenoldopam was infused at 0.2mcg/kg/min via IV pump into the renal arteries via the system catheter (refer to the Be-RITe Registry Fenoldopam Dosing Chart, Table 1. FlowMedica’s retrospective, observational Be-RITe International Registry12 is ongoing at several centers.). During the infusion, all 6 Fr catheters required for cardiac catheterization and coronary angioplasty were passed through the second port on the system’s sheath.
The Benephit infusion system was only left in place during the procedure, which reflects on procedural timeframe for fenoldopam infusion. All patients received acceptable amounts of contrast in accordance with established dosing guidelines to prevent contrast nephropathy: 5 ml of contrast per kg body weight divided by serum creatinine level (mg/dl).11 Efforts were made to minimize the volume of contrast material given, particularly in these high-risk patients.
The 8 Fr femoral arterial sheaths were removed in the staging area at Osceola Regional Medical Center, where experienced clinical staff pulls sheaths, applying manual compression or using the C-clamp. The main guidelines are: patient hemodynamically stable and asymptomatic, ACT The pre and 24-hour post serum creatinine levels of our patients is recorded in Table 2. We had positive outcomes and patients were able to avoid further renal dysfunction. Renal vasoconstriction is the final common pathway for many factors, such as medications, contrast media and poor pump function, which contribute to acute renal insufficiency in hospitalized heart failure patients.7 Conclusion A number of strategies have been investigated to prevent CIN in at-risk patients, including administering therapeutic agents through systemic IV infusion, such as IV fenoldopam. However, systemic infusion of vasodilators often is associated with serious side effects such as hypotension, tachycardia, and increased afterload. Researchers believe that the amount of systemic medication that reaches the kidneys often does not attain sufficient levels to be therapeutic and, therefore, that this type of treatment may not be effective. TRT avoids this problem because the drug is delivered in a therapeutic dose directly to the kidneys. Furthermore, since therapeutic agents used for TRT are excreted by the kidneys, side effects are thought to be minimized because the kidneys eliminate most of the drug immediately and, therefore, limit the amount of drug reaching the rest of the body.6-10 In conclusion, the Benephit system appears promising, but additional study is needed. FlowMedica is conducting the Be-RITe Registry, and we look forward to the ongoing data from that registry. Ultimately, a large cohort of patients in a randomized, double-blind clinical trial will be necessary in order to fully determine the safety and utility of this new technology. Reynaldo Grullon can be reached at grumar@earthlink.net
1. Wang DJ, Dowling TC, Meadows D, et al. Nesiritide does not improve renal function in patients with chronic heart failure and worsening serum creatinine. Circulation 2004;110:1620-1625.
2. Cohen, Mauricio G. MD First Experience with Intra-Renal Fenoldopam in a Patient with Heart Failure. The Journal of Invasive Cardiology May 2005;17(5):1042-3931.
3. Dangas G, Iakovou I, Nikolsky, et al. Contrast-induced nephropathy after percutaneous coronary interventions in relation to chronic kidney disease and hemodynamic variables. Am J Cardiol Jan 200;95(1):13-9.
4. Minarsch, Laura CVT, ARRT, CCRP. Renal Protection in the Cath Lab: A Novel Therapeutic Device for High-risk Patients Undergoing PCI. Cath Lab Digest March 2005;13(3):70-71.
5. Stone GW, McCullough PA, Tumlin JA, et al. Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomized controlled trial. JAMA 2003; 290:2284-2291.
6. Madyoon H, Teirstein P, Baim D, et al. Differential Effects between Intravenous and Local Renal Delivery of Fenoldopam on Renal Function and Blood Pressure: A Randomized, Controlled Trial. Am J Cardiol September 30, 2004;TCT-51(Abstract).
7. Mathur VS, Goodson B, Valencia A, et al. Use of Renal First-Pass as a Strategy for Optimizing Drugs with Desirable Renal Effects: Pharmacokinetic Studies of Nesiritide and Fenoldopam. J Am Soc Nephrol 2004;15:111A.
8. Mathur VS, Teirstein P, Patel S, et al. Evidence for reduced systemic exposure to fenoldopam following local renal delivery compared to intravenous delivery. Blood Purif 2004; 22:245(Abstract).
9. Mathur VS, Goodson B, Patel S, et al. Evidence for substantial renal first pass effects of human B-type natriuretic peptide (nesiritide) following intra-renal infusion. J Card Fail 2004;10:S68(Abstract).
10. Mathur VS, Teirstein T, Anderson E, et al. Targeted renal drug delivery with fenoldopam: A multicenter, randomized, controlled trial. J Am Soc Nephrol 2004; 15:346A.
11. Montrella Waybill, M. and Waybill, PN. Contrast Media-induced Nephrotoxicity: Identification of Patients at Risk and Algorithms for Prevention. Journal of Vascular and Interventional Radiology 2001;12:3-9.
12. Cohen M, Fearon W, Weisz G, et al. Use of a New Bifurcated Renal Infusion Catheter for Clinical Management of High-Risk Angiography Patients: Data from the Be-RITe! National Registry. Cardiovasc Radiation Med 2004:5(4):193, and presented at Cardiovascular Revascularization Therapies, March 28-31, 2005, Washington, D.C.
