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1 Department of Radiology, Cardiovascular and Interventional Radiology,
University of Tennessee, 865 Jefferson Ave., Ste. 121C, Memphis, TN
38163.
2 Department of Radiology, Cardiovascular and Interventional Radiology,
University of Minnesota, MMC 292, 420 Delaware St. S.E., Minneapolis, MN
55455.
3 Department of Radiology, Cardiovascular and Interventional Radiology, Mayo
Clinic, St. Mary's Hospital, Rm. 6-460, 1216 2nd St. S.W., Rochester, MN
55902.
Received November 13, 2001;
accepted after revision February 19, 2002.
Address correspondence to D. W. Hunter.
Abstract
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MATERIALS AND METHODS. We retrospectively reviewed the records of all patients who received fenoldopam mesylate to determine the acute and, when possible, the longer term effects on kidney function.
RESULTS. Twenty-nine cases were reviewed. The average serum creatinine value before contrast administration was 2.55 µg/dL (range, 1.3-5.8 µg/dL). Twenty-four hours after contrast administration, serum creatinine was measured in 28 of the 29 patients. The serum creatinine values had decreased in 16 of the 28 patients by an average of 0.55 µg/dL. In nine patients, the serum creatinine value had not changed. Two of the three increases in the serum creatinine value appear to have been caused primarily by problems that did not involve the contrast material.
CONCLUSION. The use of fenoldopam mesylate at appropriate doses offers patients at high risk for contrast-associated nephropathy a chance to avoid this complication. To learn the extent and true nature of the effect of fenoldopam mesylate in this patient population requires a rigorous scientific trial, which is currently underway.
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Approximately 2 hr before the contrast injection, fenoldopam mesylate was administered by IV drip to each patient at a rate of 0.1 µg/kg per minute. Each patient's blood pressure was checked every 20 min. The infusion rate of fenoldopam mesylate was increased every 20 min in increments of 0.1 µg/kg per minute until a rate of 0.5 µg/kg per minute was reached. However, the infusion rate was not increased if the diastolic pressure had decreased 20 mm Hg, systolic pressure decreased 30 mm Hg, or systolic pressure dropped to less than 110 mm Hg. If the systolic blood pressure decreased by 40 mm Hg or dropped below 100 mm Hg, the infusion rate was either decreased to the next lower dose, or the infusion was stopped for 10 min and restarted at the next lower dose. In patients with hypertension, a drop in systolic pressure of as much as 44% of the original value was expected. In some patients, this effect was desired because antihypertensive medications had been stopped before the procedure.
Infusion of fenoldopam mesylate was maintained at the highest achieved dose throughout the procedure and for a minimum of 4 hr after the termination of the contrast injection. Serum creatinine was measured before the procedure and, if possible, daily for 2 or 3 days after the procedure. After we observed that most patients appeared to benefit from the treatment, we obtained permission from the institutional review board of the hospital to retrospectively review all the patient records and initiated plans for a prospective trial.
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The average serum creatinine value for all patients before the procedure was 2.55 µg/dL. This value represents the average of the values obtained on the day of the procedure in all patients. The average serum creatinine value 24 hr after the procedure was 2.28 µg/dL, which represents an average decrease of 12%. The patients were placed in one of four groups on the basis of the severity of kidney dysfunction at the time of the procedure. The serum creatinine value before the procedure, the historical maximum serum creatinine value, and the average amount of contrast material used for the procedure for the four patient groups are summarized in Table 1. The number and percentage of patients in each group who had a decrease of 0.2 µg/dL or greater, an increase of 0.2 µg/dL or greater, or no change in the serum creatinine value at 24 hr are summarized in Table 2. The average values and range of values for any decrease or increase in serum creatinine are also provided in Table 2. No change in the serum creatinine value was defined as a value at 24 hr after the procedure that differed from the value before the procedure by 0.1 µg/dL or less.
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In 28 of the 29 patients a serum creatinine value was obtained 24 hr after the procedure. The patient without a serum creatinine measurement at 24 hr had a starting serum creatinine value of 2.7 µg/dL, underwent outpatient angiography, and returned for coronary angiography 12 days later. At that time, the creatinine value was found to have dropped to 2.4 µg/dL. Of the 28 creatinine values recorded at 24 hr, 16 had decreased, nine had not changed, and three had increased.
The serum creatinine value had increased in three patients. In one patient, the serum creatinine value had increased 0.3 µg/dL after the contrast material was administered, and this level was the same 5 days later. We believe that the increase in the serum creatinine level in this patient resulted from exposure to contrast material. The other two patients had more marked increases in serum creatinine values. One was a patient with a transplanted kidney who experienced severe bleeding with prolonged hematuria and an obstruction of the collecting system by a clot after undergoing a biopsy. A percutaneous nephrostomy drainage catheter was placed, and arteriography and embolization of a pseudoaneurysm were performed. After 24 hr, the serum creatinine value had increased 0.2 µg/dL. The maximal increase was 1.5 µg/dL (2.7-4.2 µg/dL). Most of this increase occurred on days 4 and 5 after the procedure. The serum creatinine value eventually stabilized at 3.3 µg/dL on day 32. The patient's course was complicated by rejection and eventual loss of the kidney.
The third patient with an increased serum creatinine value was scheduled to undergo bilateral stenting of the renal artery for azotemia. One kidney showed markedly better function and was stented first. The procedure, however, was complicated by what appeared angiographically to be diffuse embolization or the spasm of peripheral branches followed by stent thrombosis. The thrombosis was immediately opened with thrombolytics. The patient had a serum creatinine value of 3.5 µg/dL before the procedure. Twenty-four hours after the procedure, the value had risen to 4.4 µg/dL and peaked at 5.8 µg/dL 2 days after the procedure. However, the patient did not require dialysis, and the serum creatinine level eventually stabilized at 3.7 µg/dL 21 days after the procedure and then slowly decreased to 2.6 µg/dL at 2 months after the procedure. Therefore, during the first week after contrast medium administration, the serum creatinine value in only two patients (2/29 or 7%) rose to more than 0.5 µg/dL, the threshold most commonly used to define kidney failure in recent studies [1, 2]; however, kidney failure in these two patients could not be definitively attributed to the contrast material.
Two patients in group 1 had a serum creatinine value just before the procedure of 1.3 and 1.4 µg/dL. They were chosen to receive fenoldopam mesylate and included in this analysis because they had both hypertension and diabetes and because the most recent serum creatinine value before the day of the procedure was 1.5 and 1.6 µg/dL, respectively.
Two patients were of particular interest to us because they underwent angiographic procedures both with and without fenoldopam mesylate during the period of analysis. One patient had a history of severe neurofibromatosis with multiple pseudo- and true aneurysms of the intercostal arteries that bled spontaneously causing life-threatening hemothoraces. On one occasion, with a serum creatinine value of 5.8 µg/dL, this patient underwent a complex 2-day attempt to embolize all the intercostal arteries. He received a continuous infusion of fenoldopam mesylate during those 2 days. His serum creatinine value was 3.9 µg/dL 24 hr after the 2-day angiographic procedure and then 4.2 µg/dL at 48 and 72 hr. After he began to bleed again on day 3, he underwent repeated angiography and embolization without fenoldopam mesylate at the request of the referring service. One day later, no other obvious clinical problems that negatively affect kidney function were detected, but the patient's serum creatinine value had risen to 6.6 µg/dL, which was treated with three episodes of acute dialysis over 1 week. His course continued to deteriorate, and he died 2 months later having never recovered kidney function.
The second patient underwent angiography to evaluate possible atherosclerotic stenoses in his pelvic and renal arteries. He received fenoldopam mesylate, and the serum creatinine value decreased from 2.7 µg/dL before the procedure to 2.4 µg/dL 12 days later. He required a coronary angiogram at that time for which he did not receive fenoldopam mesylate. Twenty-four hours later, his serum creatinine value had risen to 2.6 µg/dL.
Six of the 29 patients were not able to reach the maximal fenoldopam mesylate dose of 0.5 µg/kg per minute. The average fenoldopam mesylate dose achieved was 0.46 µg/kg per minute, which indicates that most patients were able to tolerate a dose close to or at the maximal dose of 0.5 µg/kg per minute. The average decrease in systolic pressure for all patients was 27.9 mm Hg. The average decrease in systolic pressure for those patients who reached the maximum dose of 0.5 µg/kg per minute was 22.9 mm Hg. The average drop in systolic blood pressure for patients who did not achieve the maximal dose of 0.5 µg/kg per minute was 44 mm Hg. Most patients could be treated with one or two vials of fenoldopam mesylate with a resulting cost to the hospital of from $200 to $400 per patient.
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The exact mechanism of contrast-associated nephropathy remains poorly understood. Contrast agents have been shown to have various deleterious effects on the kidney. Today, the most widely accepted theory is that the negative effect of contrast material is related primarily to its hemodynamic effects [18], which consist of a brief initial rise in renal blood flow followed by a prolonged fall and gradual return to baseline [19]. The vasoconstrictive phase lasts at least 2 hr, and one study (Tumlin JA et al., presented at the Society of Cardiovascular and Interventional Radiology meeting, March 1999) indicated that this phase may extend to 3-4 hr after contrast administration. Most important, animal models indicate that blood flow is particularly impaired to the outer portion of the medulla where most of the metabolic effort involving ion exchange occurs [20]. This reduction in medullary blood flow appears to decrease flow to the tubular cells, particularly those in the thick ascending limb, below an ischemic threshold at which cellular damage ensues. This damage is likely mediated by free radicals, which is one explanation for the profound effect noted in the recent study using N-acetylcysteine, a free radical scavenger [1]. Histologically, damage is often associated with a pattern of vacuolization in the affected tubular cells that has been described as osmotic nephrosis. The exact roles of osmolarity and chemotoxicity in this process and the contributions of osmolarity, chemotoxicity, and hemodynamic alterations to the ischemic changes that occur at the tubular level are still unresolved. The explanation for contrast-associated nephropathy will likely involve an interaction of factors such as reduced blood flow, medullary hypoxia, the concentration of the contrast material, and the amount of time that the contrast material remains in contact with critical tissues.
The definition of what constitutes kidney failure in patients with contrast-associated nephropathy has been the subject of extensive debate. Some authors advocate using absolute increases in serum creatinine levels, whereas others advocate using percentages of change from baseline. Definitions range from an extreme increase of at least 1 µg/dL (88 µmol/L) or a 50% increase above baseline to a less severe and more widely accepted limit of an increase of 0.5 µg/dL (44 µmol/L) or a 25% increase above baseline [10]. For a physiologically meaningful definition to be achieved, a combination of absolute and percentage increases may be necessary. Interestingly, the most recent studies appear to have settled on a simple definition of kidney failure as being an increase of serum creatinine of 0.5 µg/dL over baseline at 48 hr [1, 2]. Because a pure and objective definition of acute kidney failure remains to be established, we elected to simply report the absolute values of the change in serum creatinine levels in our patients.
Previous Attempts to Prevent Contrast-Associated Nephropathy
Before N-acetylcysteine was recently studied by Tepel et al.
[1], many agents had been
investigated as potential therapeutic drugs for the prevention or treatment or
both of contrast-associated nephropathy. Diuretics (mannitol, furosemide),
vasoactive agents (calcium channel blockers, atrial natriuretic peptide), and
dopamine have shown promise in animal models
[21,22,23];
however, none of these therapies has been consistently found to prevent or
improve contrast-associated nephropathy in humans. Some agents, such as
mannitol, are clearly detrimental to some high-risk groups. Nonspecific
stimulation of dopamine receptors by so-called renal doses of dopamine is
known to increase renal blood flow and the glomerular filtration rate
[24]. Unfortunately, these
results have not been consistent and reproducible in all patient groups. This
lack of consistency may result from the contradictory effect of stimulation of
dopamine type 1 receptors that increase renal blood flow and dopamine type 2
receptors that decrease renal blood flow. In addition, some studies have used
dopamine at doses of 3-4 µg/kg per minute, which results in
-receptor stimulation and, therefore, potential renal vasoconstriction
[21,
24]. No studies have shown an
unequivocally positive effect of dopamine on contrast-associated
nephropathy.
Fenoldopam Mesylate and Contrast-Associated Nephropathy
Although it is closely related to dopamine, fenoldopam mesylate is a pure
dopamine type 1 receptor agonist that appears to have physiologic effects that
are distinctly different from and more specific than dopamine. Therefore,
fenoldopam mesylate may have a positive role in the treatment and prevention
of contrast-associated nephropathy. Fenoldopam mesylate produces
vasodilatation in vessels rich in dopamine type 1 receptors, such as the
renal, mesenteric, and peripheral arteries. Even at high doses, fenoldopam
mesylate does not stimulate dopamine type 2 or adrenergic receptors
[25,
26]. The United States Federal
Drug Administration has approved fenoldopam mesylate for hypertension control
because of its effect on peripheral dopamine type 1 receptors. Fenoldopam
mesylate potently relaxes both renal afferent and efferent glomerular
arterioles in vitro [27];
however, in vivo it appears to preferentially vasodilate efferent glomerular
arterioles [28]. This
observation gives rise to an interesting finding that although renal blood
flow increases markedly, glomerular filtration rate is frequently unaffected.
Testing of fenoldopam mesylate on animals has indicated that fenoldopam
mesylate is six times more potent than dopamine in increasing renal blood flow
and decreasing renal vascular resistance and that, unlike other vasodilators
that have been studied, fenoldopam mesylate appears to induce a preferential
increase in flow to the critical medullary regions
[29]. Although no definite
proof that this effect will ameliorate or prevent contrast-associated
nephropathy is available yet, anecdotal evidence such as our case series and
work by Bakris et al. [30],
showing that selective dopamine type 1 receptor stimulation with fenoldopam
mesylate prevents contrast-associated decreases in renal blood flow in
volume-depleted dogs, is promising. This effect was achieved at an extremely
low dose of 0.01 µg/kg per minute, which increases renal blood flow
minimally and does not affect blood pressure.
In healthy volunteers, fenoldopam mesylate produces a dose-related increase in renal blood flow of up to 75% at a dose of 0.5 µg/kg per minute [31]. No increase in renal blood flow occurs above this level. Most of the effect, approximately 80%, is achieved at a dose of 0.3 µg/kg per minute [32], which suggests that all or most patients may obtain adequate hemodynamic effect from fenoldopam mesylate at a dose of less than 0.5 µg/kg per minute. Although the glomerular filtration rate at doses of 0.3-0.5 µg/kg per minute is unchanged, urine volume and water and sodium excretion are increased. These changes may have a protective effect by preventing sludging and obstruction of the tubules. Although fenoldopam mesylate was initially introduced in the 1960s as an antihypertensive agent, the doses that we have used to increase renal blood flow (up to a maximum of 0.5 µg/kg per minute) are in the lower portion of the dose range used to treat patients in hypertensive crisis; this range extends from 0.3 µg/kg per minute to a maximum of approximately 1.6 µg/kg per minute. Doses of 0.3-0.5 µg/kg per minute, which significantly reduce blood pressure in individuals with hypertension, are associated with no change in systolic blood pressure and with minimal reduction in diastolic blood pressure in normotensive individuals [32].
Studies of fenoldopam mesylate in individuals with hypertension have indicated that at doses of 0.3-0.5 µg/kg per minute, systolic blood pressure decreases by an average of 15-20 mm Hg and diastolic pressure, by an average of 10-15 mm Hg. For this reason, using fenoldopam mesylate to increase renal blood flow in patients with hypertension requires patient monitoring because the dose is increased to a level at which an antihypertensive effect can occur. Although the level of hypotension that is induced is not dangerous in most patients, a systolic blood pressure of less than 100-110 mm Hg could decrease the renal perfusion pressure to a point at which the protective effect of fenoldopam mesylate on the kidney may be lost. In addition, slight tachycardia is induced by the drop in blood pressure. This tachycardia may be related to norepinephrine and could result in worsening heart failure in patients who have severe baseline heart failure. For this reason, fenoldopam mesylate needs to be used with caution and at potentially lower doses in patients with severe congestive heart failure.
The clinical activity of fenoldopam mesylate, which is administered IV, begins almost immediately and is clearly noticeable 5 min after administration. The antihypertensive effect becomes stable in 15-20 min after initiation of the drug, which means that monitoring blood pressure every 15-20 min is reasonable. At a dose of 0.1 µg/kg per minute or less, the effects on blood pressure are minimal. If the drug is started at a lower dose, such as 0.1 µg/kg per minute, and increased slowly to the 0.3-0.5 µg/kg per minute range, the effects on blood pressure are less pronounced than if a higher dose were used as the starting dose. With this method, the effects can also be easily controlled, even in those patients who have high blood pressure as a baseline. The drug has no rebound effect and can be stopped at any time. The elimination half-life is approximately 5-10 min; therefore, the antihypertensive effect will disappear rapidly once the drug is stopped. The drug is metabolized quickly and does not depend on the cytochrome P-450 enzyme system in the liver. Therefore, the dose does not need to be adjusted for patients who have liver or kidney failure. To date, no interactions with other drugs have been reported.
Our data represent only anecdotal evidence because ours is a retrospective analysis of a completely uncontrolled group of patients at high risk for contrast-associated nephropathy who were undergoing a diverse set of procedures. No concurrent control group was chosen for comparison because all patients at highest risk for this sequela during this time interval were treated. No historical controls were analyzed because the inherent biases of selecting a historical control group make the scientific rigor of such an exercise dubious. However, some degree of historical comparison may be valid because many interventionalists have experience with this type of patient, particularly in modern times.
Published reports indicate that 10-45% of patients who are at high risk for contrast-associated nephropathy reach a threshold at which they are defined as having acute kidney failure [1, 2, 10, 14,15,16, 33, 34]. However, in addition, a larger number of patients with whom we are all familiar, up to 75% in one series [35], have a small early increase in the serum creatinine level that may not lead to a diagnosis of acute kidney failure. This early rise during the first 24-48 hr after contrast administration was not seen in 25 of the 28 patients for whom serum creatinine was measured soon after the procedure and, as a result, led to a noticeable change in the attitude of the interventionalists performing these procedures. The normal anxiety about these cases was replaced with an eagerness to see whether the results could be replicated.
Interventional radiologists have many other means of reducing the incidence of contrast-associated nephropathy. They can eliminate the nothing-by-mouth-after-midnight order in favor of an order that allows clear liquids up to 2 hr before the procedure and that increases IV hydration. They can eliminate potentially nephrotoxic drugs during the 24 hr before contrast administration and can use small doses of contrast material with careful digitally subtracted imaging technique. Finally, interventional radiologists have the option, which we frequently used during this study period, of using carbon dioxide and gadolinium as alternative contrast agents, whereas this option is not available to cardiologists, neurointerventionalists, and those supervising contrast-enhanced CT studies. The need for chemical adjuncts to ameliorate the negative effects of contrast administration may be less in interventional radiology than in other areas in which iodinated contrast material is used.
An increase in the serum creatinine level that was definitively caused by contrast material was seen in only 4% (1/28) of our patients. In patients like ours who are at high risk for contrast-associated nephropathy, this rate is exceptionally low and this effect was seen not only at 24 hr. Sixteen patients had serum creatinine values obtained between 3 and 7 days after the procedure when the maximal elevation of serum creatinine value should occur. Only one patient who had either no change or a decrease in serum creatinine at 24 hr had a later increase, and this increase occurred in a patient who had an increase of 0.1 µg/dL at 24 hr after the procedure. The maximal rise in this patient was 0.3 µg/dL. In addition, we previously published our results that showed 100% mortality at 6 months in patients with combined liver and kidney dysfunction who were undergoing placement of a transjugular intrahepatic portosystemic shunt [36]. Of the six patients with this same type of hepatorenal dysfunction who received a transjugular intrahepatic portosystemic shunt with fenoldopam mesylate assistance, one died of causes unrelated to liver or renal dysfunction, and three have outlived the 6-month limit, which we regard as extremely promising.
In conclusion, our experience suggests that fenoldopam mesylate may benefit patients who need intravascular contrast material but who are at high risk for contrast-associated nephropathy. Fenoldopam mesylate may be especially beneficial to patients who must receive a large dose of contrast material such as those undergoing complex peripheral or coronary interventions, computerized tomography, or both. Although determining whether fenoldopam mesylate was the primary reason for the marked protective effect seen in our patients is impossible on the basis of anecdotal case reports, the results are promising enough to indicate that a prospective randomized trial of fenoldopam mesylate versus hydration is warranted.
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