Although all patients undergoing cardiac surgery are at risk for renal dysfunction, there are
certain preoperative clinical parameters which have been shown to place patients at
particularly high risk for postoperative renal demise. These factors include age greater than
70 (with those patients greater than 80 years being at particular high risk), history of New
York Heart Association Class 3 or 4 congestive heart failure, previous coronary artery bypass
grafting, pre-operative creatinine level 1.24-1.77 mmol/dL, type I diabetes, preoperative
glucose >166 mmol/dL, cardiopulmonary bypass time >3 hours, and low cardiac output states
(those states requiring intra-aortic balloon pump (IABP) or with cardiac index of less than
1.5 or requiring more than 3 inotropic drugs).1 Recently, there has been interest in the
pharmacologic manipulation of peripheral dopamine receptors (DA1 and DA2) in an attempt to
augment and preserve renal function. Goldberg and colleagues localized DA1 receptors to
vascular smooth muscle postsynaptic membranes in renal, coronary, cerebral, mesenteric, and
peripheral artery vasculature, in the proximal convoluted tubule, and in the cortical
collecting ducts of the nephron.6,7 Stimulation of the DA1 receptor activates adenylate
cyclase causing vascular smooth muscle vasodilation and naturesis with increased urinary
sodium excretion by inhibiting sodium-potassium ATPase-dependent processes at the proximal
convoluted tubule and the thick portion of the ascending loop of Henle.6,8,9 The greatest
effect of DA1 receptor activation occurs in the renal vasculature (mostly at afferent
arteriole)9, causing an increase of renal blood flow up to 35% in normal patients and up to
77% in those patients with renal vascular disease.10,11 DA2 receptors are found in the renal
parenchyma, presynaptic nerve terminals of adrenergic nerves and sympathetic ganglia, and in
the adrenal cortex.10 DA2 receptor activation leads to inhibition of norepinephrine release
(as part of a negative feedback loop) and inhibition of angiotensin II mediated release of
aldosterone.10,12 With activation of DA2 receptors in the kidney, a resultant decrease in
renal blood flow, decrease in glomerular filtration rate, and decrease in diuresis and
naturesis is observed, effects that are opposite to and may offset DA-1 receptor agonism.
Mayes and colleagues showed no improvement in renal function in patient undergoing CABG with
"renal-dose" dopamine.6, 13 It is theorized that dopamine's inability to provide renal
protection may be due to its lack of specificity for DA-1 receptors and resultant
dose-dependent agonism for DA-2 receptors and alpha1-adrenergic receptors.6, 14, 15 As
mentioned, dopamine's activation of these receptors results in decreased renal blood flow,
glomerular filtration rate, and sodium excretion6, 16, thereby offsetting the effects of DA-1
receptor agonism.
Fenoldopam is the first commercially available selective DA1 receptor agonist. Fenoldopam is
a selective agonist for DA1 receptors with no activity at DA2 receptors, alpha adrenergic
receptors, or beta adrenergic receptors. Currently, Fenoldopam is used as an intravenous
infusion for hypertensive emergencies. When given to hypertensive patients in doses of
0.025-0.5 mcg/kg/min, a reduction in blood pressure is seen in a linear and dose dependent
manner.9, 17, 18, 19, 20 Despite reductions in perfusion pressure, glomerular filtration rate
and renal blood flow are equivalent or even increased.9, 20, 21 When given to normotensive
patients at doses of 0.03-0.3 mcg/kg/min, Vandana and colleagues have shown that Fenoldopam
significantly increased renal blood flow in a dose-dependent manner when compared with
placebo with no change in systolic blood pressure and minimal changes in diastolic blood
pressure (1 mmHg @ 0.3 mcg/kg/min dose) and heart rate (14 bpm @ 0.3 mcg/kg/min dose). In
addition, there were no serious or severe side effects even at the highest doses.9 These
observations are consistent with prior studies of Fenoldopam in both normotensive22 and
hypotensive23 patients. Fenoldopam's lack of effects on venous capacitance as well as the
lesser role that resistance plays in determining blood pressure in normotensive patients may
further explain the negligible effect that Fenoldopam has on blood pressure in normotensive
subjects. This leads to a theoretic "renal protection" provided by Fenoldopam at doses which
elicit negligible deleterious effects.
As mentioned, Fenoldopam is a selective DA1 receptor agonist created through modification of
the dopamine molecule with the addition of chloride, sulfur, and a benzene ring.10 These
changes result in agonistic effects exclusively on the DA-1 receptor with no DA2 receptor
activation and no direct or indirect actions on both alpha and beta adrenergic receptors.10
Fenoldopam has a short half-life of 5-10 minutes, a linear relationship between plasma
concentration and infusion rate, and a small volume of distribution allowing rapid
intravenous titration.24 These characteristics make Fenoldopam ideal for intravenous infusion
with a steady-state plasma concentration being achieved within 30-60 minutes, steady-state
concentrations remaining constant during infusion, and with a negligible concentration (<0.2
mcg/L) 2 hours after discontinuation as demonstrated by Allison and colleagues.24 Hepatic
clearance of Fenoldopam occurs through conjugation via sulfation or glucuronidation.10
Klecker and colleagues demonstrated that drug-drug interactions are negligible due to
parallel pathways of metabolism.25 Recent studies by Garwood and colleagues and Caimmi and
colleagues have shown preservation of renal function by perioperative infusion of Fenoldopam
as indicated by lower creatinine level at discharge in those patients at high risk for
perioperative renal demise.26, 27 However, a prospective randomized control trial has yet to
be performed. There is also uncertainty that these reductions in serum creatinine levels at
discharge are of any practical benefit in terms of reduced morbidity, reduced length of stay,
reduced cost, or improved clinical performance. In addition, an optimal dose for Fenoldopam
for this clinical indication has yet to be determined. For this pilot study, Fenoldopam will
be infused at 0.03 mcg/kg/min or 0.1 mcg/kg/min. These doses were chosen due to their proven
effectiveness to significantly increase renal blood flow with minimal effects on blood
pressure and heart rate.9 The goal of this study is to evaluate the effectiveness of
Fenoldopam, a new selective dopamine-1 receptor agonist, in the reduction of postoperative
renal dysfunction in a high-risk subset of patients undergoing cardiac surgery in a
prospective randomized control pilot study. This will be accomplished through infusion of
Fenoldopam at 0.03 mcg/kg/min, 0.1 mcg/kg/min, or placebo in a double blinded, randomized,
prospective trial where postoperative creatinine, urine output, and progression to renal
dysfunction will be observed. Renal dysfunction will be defined as an increase in serum
creatinine by greater than 50% of the preoperative value or a serum creatinine that exceeds
2.0 mg/dL at any time postoperatively prior to discharge.. In addition, length of ICU stay,
length of hospital stay, ventilator requirements, need for diuretics, need for perioperative
inotropes/vasopressors, and need for discharge to extended care facilities will be examined
for each group. The null hypothesis is that Fenoldopam will not reduce the incidence of
postoperative renal dysfunction.
