Fenoldopam, a Dopamine Agonist, for Hypertensive Emergency: A Multicenter Randomized Trial

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Fenoldopam, a Dopamine Agonist, for Hypertensive Emergency: A Multicenter Randomized Trial JAMES A. TUMLIN, MD, LALA M. DUNBAR, MD, PHD, SUZANNE OPARIL, MD, VARDAMAN BUCKALEW, MD, C. VENKATA RAM, MD, VANDANA MATHUR, MD, DAVID ELLIS, MD, DAWN MCGUIRE, MD, JERE FELLMANN, PHD, ROBERT R. LUTHER, MD, FOR THE FENOLDOPAM STUDY GROUP*

Abstract. Despite successful therapies for chronic hypertension, hospital admissions for hypertensive emergency more than tripled between 1983 and 1992. Objective: To examine the safety and efficacy of fenoldopam, the first antihypertensive with selective and specific action on vascular dopamine (DA1) receptors, in a clinical trial involving emergency department patients with true hypertensive emergencies. Methods: Patients with a sustained diastolic blood pressure (DBP) of ⱖ120 mm Hg and evidence of target organ compromise were randomized in a double-blinded manner to one of four fixed doses of intravenous fenoldopam (0.01, 0.03, 0.1, or 0.3 ␮g/kg/min) for 24 hours. The primary endpoint was the magnitude of DBP reduction in each of the three higher-dose groups after four hours of fenoldopam treatment compared with the lowest-dose group. Results: One hundred seven participants from 21 centers were enrolled, and 94 patients received fenoldopam. Evidence of acute target-organ damage included new renal dys-

From Emory University Hospital, Atlanta, GA (JAT); Louisiana State University Medical Center, New Orleans, LA (LMD); University of Alabama–Birmingham, Birmingham, AL (SO); Wake Forest School of Medicine, Winston-Salem, NC (VB); University of Texas Southwestern Medical Center, Dallas, TX (CVR); Neurex Pharmaceuticals, South San Francisco, CA (VM, DE, DM, JF, RRL). Received September 2, 1999; revision received November 24, 1999; accepted December 6, 1999. Presented in abstract form at the Society for Critical Care Medicine annual meeting, San Antonio, TX, 1997, and at the Royal College of Pharmacology annual meeting, Toronto, Ontario, Canada, 1998. Supported by grants from Neurex Pharmaceuticals, a Division of Elan Pharmaceuticals, South San Francisco, CA. The following authors provided support or assistance in study and in manuscript preparation: James Tumlin, Lala Dunbar, Suzanne Oparil, Vardaman Buckalew, C. Venkata Ram, Vandana Mathur, David Ellis, Dawn McGuire, Jere Fellmann, and Robert Luther. No monies were provided to the investigators (outside of study grants to conduct the trial). The last five listed authors were employees of Neurex Pharmaceuticals at the time of the writing of the manuscript. Address for correspondence and reprints: James A. Tumlin, MD, Renal Division Emory University, 1639 Pierce Drive, Woodruff Memorial Building, Room 338, Atlanta, GA 30322. Fax: 404-727-3425; e-mail: [email protected] *Fenoldopam Study Group Investigators: Vardaman Buckalew, MD, Section of Nephrology, The Bowman Gray School of Medicine, Winston-Salem, NC; Joseph J. Calabro, DO, Department of Emergency Medicine, Newark Beth Israel Medical Center, Newark, NJ; Vito Campese, MD, Division of Nephrology, Los

function or hematuria (50%), acute congestive heart failure or myocardial ischemia (48%), and papilledema or grade III–IV hypertensive retinopathy (34%). The DBP decreased in a dose-dependent fashion, with significant differences between the 0.1- and 0.3-␮g/kg/min groups compared with the lowest-dose group. Treatment was well tolerated, and there were no deaths or serious adverse events during follow-up, up to 48 hours. All patients were successfully transitioned to oral or transdermal antihypertensives with maintenance of blood pressure control. Conclusions: Fenoldopam safely and effectively lowers blood pressure in a dose-dependent manner in patients with hypertensive emergencies. Observations supporting potential risk factors for hypertensive emergency are discussed. Key words: fenoldopam; hypertensive emergency; hypertension; hypertensive urgency; dopamine agonist; malignant hypertension; vasodilator agents. ACADEMIC EMERGENCY MEDICINE 2000; 7:653–662

Angeles County and University of Southern California Medical Center, Los Angeles, CA; Michael Culpepper, MD, Renal Nephrology, University of Southern Alabama, Mobile, AL; Lala M. Dunbar, MD, PhD, Department of Emergency Medicine, Louisiana State University Medical Center, New Orleans, LA; Elamin Elamin, MD, Southern Illinois School of Medicine, Springfield, IL; Edward D. Frederickson, MD, Piedmont Hospital, Fuqua Heart Center of Atlanta, Atlanta, GA; Francisco M. Gonzales, MD, Renal Dynamics, Inc., New Orleans, LA; Bruce Hamilton, MD, Endocrinology Department, Baltimore Veterans Administration Medical Center, Baltimore, MD; Daniel Kett, MD, Medical Intensive Care Unit, Jackson Memorial Hospital, Miami, FL; Suzanne Oparil, MD, Hypertension Program, University of Alabama-Birmingham, Birmingham, AL; Edward A. Panacek, MD, Department of Emergency Medicine, Davis Medical Center, Sacramento, CA; Roberto MangooKarim, MD, PhD, Section on Hypertension, Baylor College of Medicine, Houston, TX; C. Venkata Ram, MD, University of Texas, Southwestern Medical Center, Dallas, TX, and Hypertension Center, St. Paul Medical Center, Dallas, TX; Alexander M. Shepard, MD, PhD, Clinical Pharmacology Department, University of Texas Health Science Center, San Antonio, TX; Samuel Spitalewitz, MD, Department of Nephrology and Hypertension, Brookdale Hospital Medical Center, Brooklyn, NY; Carol A. Terregino, MD, Department of Emergency Medicine, Cooper Hospital/University Medical Center, Camden, NJ; James A. Tumlin, MD, Department of Nephrology, Emory University Hospital, Atlanta, GA; John D. Wallin, MD, Section of Nephrology, Louisiana State Medical Center, New Orleans, LA; Karl L. Yang, MD, Division of Respiratory and Environmental Medicine, University of Louisville, Louisville, KY.

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YPERTENSIVE emergency is defined as a condition in which elevated diastolic blood pressure (DBP) (typically above 120 mm Hg) leads to progressive vasculopathy and damage to target organs.1 In contrast to accelerated hypertension, patients with hypertensive emergencies experience disruption of vascular endothelium in the kidney, heart, retina, and central nervous system, leading to thrombosis and fibrinoid necrosis of these target organs.1–6 Despite the development of increasingly effective antihypertensive treatments over the past four decades, hypertensive emergency remains an important and understudied disease. Hospital admissions for hypertensive emergency more than tripled between 1983 and 1992, from 23,000 to 73,000 per year in the United States.7 The first large study of the natural history of malignant hypertension was published in 1939 before the widespread use of antihypertensive agents.8 In this seminal article by Keith and colleagues, untreated malignant hypertension had a one-year mortality of 79% and a median survival of 10.5 months.8 Hypertensive emergency necessitates rapid and controlled reduction of blood pressure in order to prevent death or irreparable target-organ damage. Intravenous sodium nitroprusside (SNP) is a widely used and effective treatment for hypertensive emergency. However, recommendations for intra-arterial pressure monitoring and special handling required to prevent its degradation by light can complicate the use of SNP in the emergency department (ED). Moreover, prolonged infusions of SNP in patients with chronic renal insufficiency can lead to thiocyanate toxicity and decrements in renal function.1,9 Fenoldopam mesylate is a short-acting, parenteral arteriolar vasodilator that lowers systemic vascular resistance by activating dopamine (DA1) receptors. Dopamine receptors are present in mesenteric, coronary, cerebral, and renal arterioles. Stimulation of DA1 receptors initiates a G-proteincoupled activation of adenylate cyclase, resulting in the release of cyclic adenosine monophosphate and arteriolar vasodilation and natriuresis.10–12 In clinical trials, fenoldopam has been used successfully to treat patients with mild to moderate and severe hypertension as well as patients with hypertensive emergencies.13–15 In previous trials comparing fenoldopam with SNP in the treatment of hypertensive emergency, fenoldopam and SNP were found to be equally efficacious.14–16 Moreover, in contrast to treatment with SNP, treatment with fenoldopam improved creatinine clearances in patients with malignant hypertension and concurrent renal insufficiency.16 We conducted a randomized, double-blind study to measure the effectiveness of fenoldopam in

emergency blood pressure reduction at four hours in patients with hypertensive emergencies and acute target-organ damage. We also studied the dose-responsiveness, tolerability, and safety of a 24-hour infusion of fenoldopam in these patients. In this study, although patients could be enrolled with acute or chronic target-organ involvement, 93 of the 94 patients who received study drug had clinical, laboratory, or electrocardiographic (ECG) evidence of acute target-organ compromise. While numerous therapeutic trials have purported to be studies of hypertensive emergencies, evidence of acute target-organ damage in these studies has been lacking or poorly characterized.17,18 To the best of our knowledge, this is the largest prospective trial of patients with confirmed hypertensive emergencies.

METHODS Study Design. This was a prospective, randomized, double-blind, parallel-dose clinical trial of fenoldopam in patients with true hypertensive emergencies. The institutional review board at each study site approved the protocol, and all randomized patients gave informed consent prior to enrollment. Study Setting and Population. The trial was conducted at 21 EDs in the United States from December 1995 to December 1996. Patients eligible for randomization were at least 18 years of age, with three supine DBP measurements (separated by 5 minutes and taken within 1 hour) above 120 mm Hg, and evidence of target-organ damage. Patients could also be randomized if the DBP exceeded 140 mm Hg in the absence of target-organ damage. For the purposes of analysis, data not necessarily available at the time of enrollment (e.g., laboratory or roentgenographic data) were included to document acute target-organ compromise. Criteria of ‘‘definite’’ acute target-organ damage were 1) cardiovascular: acute congestive heart failure (i.e., rales on physical examination; pulmonary vascular congestion or pulmonary edema on chest roentgenogram), or ECG evidence of acute myocardial ischemia, confirmed by a central ECG expert reader, in patients without previous history of such changes; 2) renal: increased blood urea nitrogen (BUN) or serum creatinine (Cr) in patients without history of prior renal disease or, in the absence of previous records, without anemia suggestive of chronic renal insufficiency; hematuria in patients without a history of hematuria; and 3) ophthalmologic: papilledema or grade III–IV hypertensive retinopathy. Additional criteria acceptable as ‘‘probable’’ target-organ damage included two or

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more symptoms consistent with ischemia (i.e., confusion or encephalopathy, acute visual changes, chest pain, dyspnea, transient ischemic attack) or one symptom plus laboratory data supportive of acute deterioration in a previously affected organ system. Examples of such supportive laboratory data included increased BUN/Cr over baseline in patients with a history of mild renal insufficiency, or new hematuria in patients with a history of proteinuria. Signs of chronic target-organ damage such as left ventricular hypertrophy on electrocardiography, cardiomegaly on chest roentgenography, or proteinuria on urinalysis were noted, but were not considered supportive of acute target-organ compromise. Headache, while a common presenting complaint, was not considered evidence in itself of target-organ compromise. Some patients were seen initially in outpatient clinical settings. Patients identified as having accelerated hypertension were then transferred to the main ED and randomized and treated there. Patients treated with oral antihypertensive medications in a clinic or the ED within one hour were not randomized unless their DBP remained unchanged or increased within 30 minutes of oral drug administration. Additional exclusion criteria included glaucoma, uncontrolled ventricular arrhythmia, severe hepatic disease, pheochromocytoma, or serum Cr concentration above 5 mg/dL. Patients known to be intoxicated (under the influence of illegal drugs or alcohol) or who had used dopamine antagonists within the previous 12 hours were not eligible for randomization. Pregnant or lactating women were also excluded. Patients receiving chronic hemodialysis, and patients with serum Cr greater than 5.0 mg/dL were also excluded. Study Protocol. Patients were screened in the ED by the study investigator. Screening procedures included a complete medical history and physical examination, as well as a funduscopic examination, chest roentgenography, 12-lead electrocardiography, complete blood cell count, blood chemistries (SMA-18), urinalysis, and a urine pregnancy test for women of childbearing age. Every patient seen in the ED who met the initial screening criteria was approached for randomization. If, however, the principal investigator at the site thought that a patient may be too unstable for randomization, he or she was given the discretion to withhold enrollment. This was allowed because of the possibility that some patients could be randomized to the 0.01-␮g/kg/min dose. This dose was considered to have a high proportion of nonresponders and therefore patients with critical presentations (e.g., patients with imminent intubation) were not enrolled.

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Using a centralized, phone-in procedure, eligible patients were randomly assigned to receive 0.01, 0.03, 0.1, or 0.3 ␮g/kg/min of fenoldopam (Corlopam, Neurex Pharmaceuticals, South San Francisco, CA). The patients and study investigators were blinded with regard to the dose of fenoldopam administered during the first four hours of the study. The highest dose (0.3 ␮g/kg/min) was selected because previous trials showed that it reduces mean arterial pressure in a majority of patients,9–11 and the lowest dose (0.01 ␮g/kg/min) studied was considered the lowest effective dose. Placebo therapy in patients with hypertensive emergencies was considered unethical. Therefore, the 0.01-␮g/kg/min group was chosen to better define dose–response relationships and, as the minimal effective dose, to serve as the comparator group for the higher doses. At the time of initiation and design of this trial, fenoldopam was still in phase III trails and awaiting Food and Drug Administration (FDA) approval. The dosages in this study were chosen to establish needed dose–response ranges that had never been determined in previous clinical trials. This study was intended to help establish initial dosing guidelines for clinicians treating hypertensive emergencies and provide safety data for all four doses studied. The rate of fenoldopam infusion was constant during the first four hours of the study. A targeted DBP was not set for this time. If the DBP did not decrease sufficiently or the patient’s clinical condition deteriorated, the study investigator was permitted to double the infusion rate, remaining blinded to the dose assignment. Data from patients in whom the study drug infusion rate was blindly increased were included in the analysis of the lower dose. A single dose of intravenous furosemide (40 mg) was permitted. Patients not responding to these maneuvers were considered treatment failures and were withdrawn from the study. After four hours, the study blind could be broken and fenoldopam could be openly titrated in patients with insufficient blood pressure control or in those with deteriorating clinical conditions. Downward titrations were permitted at any time if the principal investigator thought that blood pressure reduction was excessive. Those patients completing the first four hours of the study continued to receive fenoldopam for a total of 24 hours. The dose could be titrated to the desired level of blood pressure reduction at the investigators’ discretion. To facilitate the transition to outpatient care, oral antihypertensive medications were permitted starting 18 hours after initiation of the fenoldopam infusion. Cardiovascular and funduscopic examinations, serum electrolyte determinations, urinalyses, and

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TABLE 1. Mean (⫾SD) Supine Blood Pressure (BP) and Heart Rate at Baseline Initial Dose Level (␮g/kg/min)

Systolic BP (mm Hg) Diastolic BP (mm Hg) Heart rate (beats/min)

0.01 (n = 25)

0.03 (n = 24)

0.1 (n = 22)

0.3 (n = 23)

p-value*

209 ⫾ 21 136 ⫾ 16 87 ⫾ 20

208 ⫾ 26 135 ⫾ 11 84 ⫾ 14

205 ⫾ 24 133 ⫾ 14 81 ⫾ 18

211 ⫾ 17 136 ⫾ 14 80 ⫾ 14

0.83 0.95 0.50

*p-value from one-way analysis of variance.

TABLE 2. Demographics of the Treated Patients Initial Dose Level (␮g/kg/min) 0.01 (n = 25)

0.03 (n = 24)

0.1 (n = 22)

0.3 (n = 23)

p-value

44 ⫾ 11 yr

44 ⫾ 8 yr

44 ⫾ 9 yr

47 ⫾ 14 yr

0.37*

Gender—male

48%

67%

59%

61%

0.60†

Race White African American Hispanic

24% 76% 0%

25% 67% 8%

14% 86% 0%

13% 83% 4%

0.41‡

Age—mean ⫾ SD

*p-value from one-way analysis of variance. †p-value from likelihood ratio chi-square test. ‡p-value from Fisher’s exact test of dichotomous race variable (African American vs other).

12-lead electrocardiography were repeated every six hours. A central expert reader interpreted all electrocardiograms. Cumulative urine volumes were recorded every 12 hours for a total of 48 hours. After assignment to treatment, the blood pressure and heart rate were recorded automatically every 15 minutes using a Critikon Dinamap (Critikon Inc., Tampa, FL) or a similar automated device. The same instrument was used throughout the trial for each patient. No intra-arterial lines were used. Data Analysis. Data from all patients who received fenoldopam were included in the statistical analyses, which were conducted using SAS for Windows, Version 6.11 (Cary, NC). The primary endpoint was change in DBP from baseline after four hours of fenoldopam infusion. Secondary endpoints were change in SBP from baseline and change in heart rate from baseline. The reductions in DBP in the lowest-dose vs the higher-dose groups were compared using a pairwise Student’s t-test. The dose–response relationship was assessed using analysis of variance, as were differences in urine volumes. The time to onset of effect was calculated using a Kaplan-Meier analysis. Data are expressed as mean ⫾ SEM, unless otherwise stated.

RESULTS Study Conduct and Baseline Conditions. Eighty-seven percent of all eligible patients were enrolled in the study. Some centers were unable to enroll any patients into the study. Predictably, medical centers in the south enrolled a proportionately higher number of patients because of the prevalence of severe hypertension among African American patients. Of 107 patients enrolled, data from all 94 patients who received fenoldopam were included in the study analyses. Thirteen patients randomly assigned to treatment did not receive fenoldopam because of disqualifying laboratory values or spontaneous reductions in baseline DBP below treatment criteria prior to treatment. Twenty-five patients were randomly assigned to fenoldopam 0.01 ␮g/kg/min, 22 to 0.03 ␮g/kg/min, 23 to 0.1 ␮g/ kg/min, and 24 to 0.3 ␮g/kg/min. The DBPs, systolic blood pressures (SBPs), and demographic variables at study entry did not differ among the treatment groups (Table 1). African Americans outnumbered whites in each treatment group by a three- to sixfold margin (Table 2). The patients had a number of comorbid conditions including cardiac, cerebrovascular, and renal conditions on admission (Table 3). Diabetes mellitus was present in 15% of patients.

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Target-organ damage by clinical, laboratory, ECG, or radiographic criteria was definite in 66%, and either definite or probable in 84%. Many patients met two or more criteria of target-organ damage as defined in the methods: 50% met the renal criteria, 48% met the cardiovascular criteria, and 34% met the ophthalmologic criteria. The most commonly involved target organs were the kidney and heart (Fig. 1). Headache, a complaint in twothirds of the treated patients, was not considered in and of itself evidence of target-organ compromise; however, 89% of the patients with headache also met other criteria for definite or probable target-organ compromise. Of the patients enrolled for DBPs > 140 mm Hg, all had concomitant evidence of end-organ damage. Fifty-one patients had taken at least one antihypertensive medication within the previous week. Of the 43 patients who had taken no antihypertensives within the previous week, 25 (59%) had a history of either hypertension or left ventricular hypertrophy (LVH). Among patients who gave a history of any antihypertensive use within the previous week, the most commonly used drugs were dihydropyridine calcium channel blockers, clonidine, and angiotensin-converting enzyme (ACE) inhibitors (Table 4). Twenty percent of the patients admitted that they had used cocaine or other illicit drugs within the 72 hours prior to enrollment. Routine drug screening at one urban center revealed that 27% of patients enrolled in the study were positive for urinary cocaine metabolites. Of the 94 patients treated, 88 (94%) completed four hours and 74 (79%) completed 24 hours of fen-

TABLE 3. Incidence of Comorbid Conditions in All Randomized Patients (n = 107) Comorbid Condition* Heart failure LVH/cardiomegaly—by history LVH by electrocardiographic criteria Angina Stroke Diabetes Chronic renal insufficiency or failure Substance abuse within preceding 72 hours

Number (%) of Patients 18 20 83/101† 11 10 16 17 21

(17%) (19%) (82%) (10%) (9%) (15%) (16%) (20%)

*LVH = left ventricular hypertrophy. †Not all 107 patients received electrocardiography.

TABLE 4. Antihypertensive Drug Use during the Week Prior to Enrollment Number of Patients (%) Total patients treated

94 (100%)

Patients taking no antihypertensives

43 (46%)

Patients receiving antihypertensives

51 (54%)

Antihypertensive drug class used* Calcium channel blockers Central ␣2 agonists Diuretics Ace inhibitors Beta blockers Direct vasodilators Nitrates Other antihypertensives

30 28 22 20 14 11 2 2

(59%) (55%) (43%) (39%) (27%) (22%) (4%) (4%)

*Percentages of patients receiving therapy with various drug classes are calculated from the number of patients who received one or more antihypertensive (n = 51).

Figure 1. Objective target-organ damage. TIA = transient ischemic attack; Cr = creatinine; ECG = electrocardiography; CHF = congestive heart failure; CXR = chest x-ray.

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Figure 2. Mean diastolic blood pressure (DBP). *Paired t-test vs lowest-dose group (0.01 ␮g/kg/min).

Figure 3. Mean systolic blood pressure (SBP). *Paired t-test vs lowest-dose group (0.01 ␮g/kg/min).

oldopam infusion. Seventy-one patients (75%) completed four hours without titration of their initially assigned doses. Notably, no patient required downtitration of fenoldopam during the first four hours of therapy. Twenty patients discontinued prematurely before 24 hours of treatment: four with adverse events, two by request, nine who were discharged early with blood pressure control considered satisfactory by the investigator, and five for study protocol violations or other reasons. Efficacy. Mean DBP during the first four hours of fenoldopam infusion decreased from baseline by 11.5 ⫾ 2.5, 18.4 ⫾ 2.5, 20.7 ⫾ 2.8, and 29.1 ⫾ 2.5 mm Hg in the 0.01-, 0.03-, 0.1-, and 0.3-␮g/kg/min

groups, respectively (Fig. 2). Reductions in mean DBP with 0.1 and 0.3 ␮g/kg/min were significantly greater (p < 0.02 and p < 0.001, respectively) than with the lowest dose. When the mean reductions in DBP in the three higher-dose groups were compared with that in the lowest-dose group, there was a statistically nonsignificant trend (p = 0.06) toward a greater reduction in DBP with 0.03 ␮g/ kg/min. Mean SBP after four hours (Fig. 3) decreased by 14.4, 20.1, 22.6, and 37.3 mm Hg in the 0.01-, 0.03-, 0.1-, and 0.3-␮g/kg/min groups, respectively. The reduction in the 0.3-␮g/kg/min group was significantly greater (p < 0.004) than that in the 0.01-␮g/kg/min group. There was no significant difference in SBP reduction between the intermediate-dose groups and the low-dose group. Mean DBP and SBP at 18 and 24 hours were significantly lower than baseline in all groups (all p < 0.001). At 18 hours, there was preservation of dose-responsiveness. The protocol permitted the initiation of oral antihypertensive medications at 18 hours if desired. At 24 hours, after oral antihypertensives had been added, there was no difference in either DBP or SBP among the four treatment groups. The time to onset of effect, defined as 20-mm Hg reduction in the DBP compared with baseline, was inversely dose-dependent. The mean time to achieve a 20-mm Hg reduction in DBP from baseline was 132.8 (⫾15.1), 125 (⫾17), 89.3 (⫾12.6), and 55.2 (⫾12.8) minutes in the 0.01-, 0.03-, 0.1-, and 0.3-␮g/kg/min dose groups, respectively. Five patients were treated with SNP and subsequently were terminated from the study. Patients were withdrawn from the study at 1.5, 2.8, 9.8, 19, and 24 hours into therapy, at which times their DBPs (and fenoldopam doses) were: 159 mm Hg (0.04 ␮g/kg/min), 152 mm Hg (0.1 ␮g/kg/min), 103 mm Hg (1.2 ␮g/kg/min), 108 mm Hg (0.6 ␮g/ kg/min), and 128 mm Hg (0.03 ␮g/kg/min), respectively. Safety. After 48 hours, there was no death, stroke, or myocardial infarction. No patient required hemodialysis during the study. Notably, no patient required dose down-titration because of hypotension or other cause during the initial four hours of therapy. Worsened renal function, defined as an increase in serum creatinine by ⱖ1.0 mg/dL, occurred in seven patients (7.4%). Mean heart rate in the intermediate-dose groups did not differ significantly from that in the lowest-dose group. Heart rates in patients receiving fenoldopam 0.3 ␮g/kg/min for four hours (Fig. 4) increased from baseline by a mean of 11 beats/ min (p < 0.005 vs the lowest dose; 95% CI = 4.2 to 22.1). The mean double-product (heart rate ⫻ SBP), a measure of cardiac work, decreased in all

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treatment groups at four hours. Furthermore, the heart rate increase was not associated with clinical events in any patient, and by 18 hours, heart rate returned to baseline levels. Patients assigned to the lower three dose groups did not have significant increases in mean heart rate, even when their dose was later titrated up. Adverse effects reported during the trial, regardless of their relatedness to the study drug, are listed in Table 5.

DISCUSSION Hypertensive emergencies necessitate precise control of blood pressure in order to maintain targetorgan perfusion and reduce long-term morbidity. Fenoldopam is a new parenteral antihypertensive agent that lowers SBP and DBP through activation of DA1 receptors in peripheral vessels. Its rapid onset, lack of excessive blood pressure reduction, and

TABLE 5. Side Effects Reported Side Effect* Headache Nausea Vomiting Hypokalemia Injection site reaction T-wave inverted Dizziness Urinary tract infection Abdominal pain Back pain Creatinine increased Dyspnea Epistaxis Hypotension Insomnia Postural hypotension Sweating

Number of Patients (%) 15 10 5 5 5 4 3 3 2 2 2 2 2 2 2 2 2

(16%) (11%) (5%) (5%) (5%) (4%) (3%) (3%) (2%) (2%) (2%) (2%) (2%) (2%) (2%) (2%) (2%)

*All side effects, regardless of relationship to fenoldopam, are listed.

Figure 4. Blood pressure (SBP and DBP) and heart rate (HR) through 24 hours. Patients received fixed dose of fenoldopam during the first four hours of the study. Following this, investigators were allowed to (blindly) titrate fenoldopam to clinically desired blood pressure. At 18 hours, investigators were allowed to begin adding oral antihypertensive medications in preparation for discontinuation of fenoldopam at 24 hours. † = 0.01 ␮g/kg/min; O = 0.03 ␮g/kg/min; X = 0.1 ␮g/kg/min; # = 0.3 ␮g/kg/min.

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short (approximately 5 minutes) half-life makes precise titration of blood pressure possible. A consistent dose-related decrease in DBP with fenoldopam was demonstrated in this study among a heterogeneous population of high-risk, seriously ill hypertensive patients, including those with cocaine intoxication and other comorbid conditions. All patients in this trial had a DBP > 120 mm Hg, and 93 of 94 patients had evidence (definite, probable, or possible) of acute target-organ damage. Fenoldopam safely reduced DBP in these patients without the need for invasive intra-arterial monitoring. Dose-responsiveness of antihypertensive effect persisted for the first 18 hours of therapy, at which time oral antihypertensive agents were added to ease the transition to ambulatory care. Sustained antihypertensive effects, over 48 hours of continuous infusion, were demonstrated in a recent trial in which 32 hypertensive patients (DBP 95–119 mm Hg) were randomized to one of four fixed doses of fenoldopam or placebo. Despite abrupt discontinuation of fenoldopam after a 24hour infusion, no rebound hypertension was observed.19 In the present study, there was no serious adverse event associated with fenoldopam treatment and there was a low (4.2%) rate of drug failure. Previous studies have shown that treatment of hypertensive emergencies in patients with chronic renal failure can lead to a decline in renal function. For example, Lawton et al.9 studied 42 patients with malignant hypertension and demonstrated that serum Cr increased by 1.0 mg/dL in 11 of 12 patients (92%) with chronic renal failure. In contrast, only 7 of 94 patients in this study experienced a similar rise in serum Cr. This apparent protective effect of fenoldopam on renal function has been reported in at least two previous studies.11,15 Shusterman et al. compared the effects of fenoldopam vs nitroprusside on renal function in 19 patients with hypertensive crisis and moderate renal insufficiency (mean Crcl 39 mL/min) and found that Cr clearance was significantly increased by fenoldopam, but was reduced by nitroprusside.16 In a similar study, Elliott et al. found that in contrast to nitroprusside, fenoldopam increased Cr clearance, urine volume, and sodium excretion.15 The mechanism by which fenoldopam stabilizes renal function in patients with hypertensive crisis is unknown, but previous studies have shown that fenoldopam is able to preserve glomerular filtration rates during acute lowering of blood pressure.13,15,20–22 Murphy et al. studied 16 patients with moderate hypertension and found that, despite a reduction in diastolic pressure, fenoldopam increased renal plasma flow by 42%.13 Moreover, O’Connell et al. found that the effects of fenoldopam on renal plasma flow are comparatively

greater in hypertensive patients than in normotensive control patients.22 Fenoldopam also has been shown to be a direct inhibitor of proximal and distal tubular sodium transport.22 In the present study, mean urine volumes after 12 hours of infusion were significantly higher in all dosage groups consistent with a previously reported diuretic effect of fenoldopam.23–25 Patients in our study were drawn predominately from hospitals serving inner-city populations. Because hypertensive emergencies are more common among inner-city minority populations, the number of African Americans in our study outnumbered whites by a three- to sixfold margin in each treatment group. In addition to increased prevalence, hypertensive emergencies among minority populations are associated with increased mortality. In a large retrospective analysis of hypertension emergencies, the median survival among whites was 121.0 months, while survival among blacks was only 30.4 months.26 There was no patient death during the 48 hours of follow-up in this study, but no long-term analysis of mortality was made. The lack of a primary care physician and failure of patients to adhere to prescribed antihypertensive regiments have been shown in previous studies to be a risk factor for hypertensive emergency.27 In the current study, only 51 of the 94 (54%) patients enrolled in the study had taken antihypertensive medications during the week preceding randomization. Of these, 25 (59%) had a known history of hypertension. Failure to comply with certain classes of antihypertensive agents can exacerbate hypertension. Tachycardia and rebound hypertension are well-described complications of clonidine withdrawal.28,29 In a study of 30 patients with moderate hypertension, Hamilton et al. found that 40 percent had a 10 mm Hg increase in DBP within 72 hours of clonidine withdrawal.28 However, no patient in their series developed hypertensive emergency. In contrast, 5 of 12 patients in our study who missed oral or patch preparations of clonidine developed a hypertensive crisis within 24 hours. This observation suggests that ‘‘rebound hypertension’’ from central adrenergic agents is a significant source of hypertensive emergencies in the ED. Another potential risk factor for severe hypertension or hypertensive emergency is abuse of vasoactive drugs such as cocaine or methamphetamine.30,31 Using multivariate analysis, Shea et al. demonstrated that illicit drug use among innercity populations is a significant risk factor for the development of hypertensive emergency.27 In our study, 20% of patients reported the use of cocaine or other illicit drugs during the 72 hours prior to study enrollment. While this is a significant pro-

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portion of patients, the true prevalence is likely to be higher. For example, a participating center in the study that routinely screens hypertensive patients for drug use found that 27% of randomized patients had cocaine metabolites in the urine. Moreover, the reliability of patient self-reporting on cocaine use has recently been questioned. In a study of 415 patients presenting for triage to an inner-city hospital, 160 (36%) tested positive for cocaine metabolites, while only 28% admitted to the drug use during the previous 72 hours.32 In the present study, fenoldopam was as effective in treating hypertensive emergencies secondary to cocaine or other sympathomimetics as idiopathic hypertensive crises.

LIMITATIONS AND FUTURE QUESTIONS This study was designed to investigate the ability of fenoldopam at four fixed infusion rates to treat hypertensive emergencies over a four-hour period. As a consequence, the optimal dose fenoldopam needed to achieve a desired DBP was not established in this study. Moreover, the use of fixed infusions does not reflect the typical ED practice of upward titration of a parenteral antihypertensive agent to achieve blood pressure control. The original intent of the study was to establish the efficacy of fenoldopam at one of four fixed dosages over a four-hour time interval. In patients with minimal blood pressure reduction during the first four hours of the study, protocol allowed for a blinded up-titration of the fenoldopam infusion. Moreover, patients with insufficient blood pressure control (as judged by the principal investigator) after the first four hours of the study were allowed to enter into the open label phase of the study and fenoldopam infusion could be titrated to the desired level of control. This approach was chosen so that the safety and efficacy of specific infusion rates of fenoldopam could be tested in the setting of malignant hypertension. We believe this would provide improved dosing recommendations to ED clinicians. Future questions to be determined include whether fenoldopam improves patient survival over other parenteral antihypertensives and whether the stimulation of renal plasma flow by fenoldopam maintains renal function in patients with hypertensive emergency and chronic renal failure.

CONCLUSIONS Fenoldopam was safe and efficacious in treating patients with DBPs > 120 mm Hg and confirmed end-organ damage. The lowering of blood pressure by fenoldopam was dose-dependent and associated with a less than 5% failure rate. In our study, there

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was no death, myocardial infarction, or cerebral ischemic event, despite the inclusion of patients with cardiovascular, neurologic, and renal end-organ damage. Prolonged (24 hours) infusion of fenoldopam in patients with other comorbid conditions was safe and well tolerated. Because of its ability to maintain renal plasma flow and glomerular filtration rate while simultaneously reducing systemic pressures, fenoldopam may offer a selective advantage for patients with hypertensive emergency and chronic renal failure. References 1. Calhoun DA, Oparil S. Treatment of hypertensive crisis. N Engl J Med. 1990; 323:1177–83. 2. Almeida JB, Saragoa MA, Tavares A, Cezareti ML, Draibe SA, Ramos OL. Severe hypertension induces disturbances of renal autoregulation. Hypertension. 1992; 19(suppl II):II-279– II-283. 3. Ledingham JG, Rajagopalan B. Cerebral complications in the treatment of accelerated hypertension. Q J Med. 1979; 48: 25–41. 4. Lip GY, Beevers M, Beevers DG. Complications and survival of 315 patients with malignant-phase hypertension. J Hypertens. 1995; 13:915–24. 5. James SH, Meyers AM, Milne FJ, Reinach SG. Partial recovery of renal function in black patients with apparent endstage renal failure due to primary malignant hypertension. Nephron. 1995; 71:29–34. 6. Davis BA, Crook JE, Vestal RE, Oates JA. Prevalence of renovascular hypertension in patients with grade III or IV hypertensive retinopathy. N Engl J Med. 1979; 301:1273–6. 7. National Center for Health Statistics. Vital and Health Statistics: Detailed Diagnoses and Procedures for Patients Discharged from Short-stay Hospitals: United States, 1983–1990. Hyattsville, MD, 1997. 8. Keith NM, Wagener HP, Barker NW. Some different types of essential hypertension: their course and prognosis. Am J Med Sci. 1939; 197:332–43. 9. Lawton WJ. The short-term course of renal function in malignant hypertensives with renal insufficiency. Clin Nephrol. 1982; 17:277–83. 10. Horn PT, Murphy MB. Therapeutic applications of drugs acting on peripheral dopamine receptors. J Clin Pharmacol. 1990; 30:674–9. 11. Edwards RM. Comparison of the effects of fenoldopam, SK&F R-87516 and dopamine on renal arterioles in vitro. Eur J Pharmacol. 1986; 126:167–70. 12. Hughes AD, Sever PS. Action of fenoldopam, a selective dopamine (DA1) receptor agonist, on isolated human arteries. Blood Vessels. 1989; 26:119–27. 13. Murphy MB, McCoy CE, Weber RR, Fredrickson ED, Douglas FL, Goldberg LI. Augmentation of renal blood flow and sodium excretion in hypertensive patients during blood pressure reduction by intravenous administration of the dopamine I agonist fenoldopam. Circulation. 1987; 76:1312–8. 14. Panacek EA, Bednarczyk EM, Dunbar LM, Foulke GE, Holcslaw TL. Randomized, prospective trial of fenoldopam versus sodium nitroprusside in the treatment of acute severe hypertension. Acad Emerg Med. 1995; 2:959–65. 15. Elliott WJ, Weber RR, Nelson KS, et al. Renal and hemodynamic effects of intravenous fenoldopam versus nitroprusside in severe hypertension. Circulation. 1990; 81:970–7. 16. Shusterman NH, Elliott WJ, White WB. Fenoldopam, but not nitroprusside, improves renal function in severely hypertensive patients with impaired renal function. Am J Med. 1993; 95:161–8. 17. Wilson DJ, Wallin JD, Vlachakis ND, et al. Intravenous labetalol in the treatment of severe hypertension and hypertensive emergencies. Am J Med. 1983; 75(Suppl 4):95–102. 18. Hirschl MM, Binder M, Bur A, et al. Clinical evaluation of different doses of intravenous enalaprilat in patients with hypertensive crises. Arch Intern Med. 1995; 155:2217–23.

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Clin Invest. 1984; 74:2198–207. 26. Lip G, Beevers M, Beevers DG. Complications and survival of 315 patients with malignant-phase hypertension. J Hypertens. 1995; 13:915–24. 27. Shea S, Misra D, Ehrlich MH, Field L, Francis CK. Predisposing factors for severe, uncontrolled hypertension in an inner-city minority population. N Engl J Med. 1992; 327:776– 81. 28. Hamilton BP, Mersey JH, Hamilton J, Kuzbida G, Pavlis R, Levinson P. Withdrawal phenomena in subjects with essential hypertension on clonidine or tiamenidine. Clin Pharmacol Ther. 1984; 36:628–33. 29. Hart GR, Anderson RJ. Withdrawal syndromes and the cessation of antihypertensive therapy. Arch Intern Med. 1981; 141:1125–7. 30. Thakur V, Godley C, Weed S, Cook ME, Hoffman E. Case reports: cocaine-associated accelerated hypertension and renal failure. Am J Med Sci. 1996; 312:295–8. 31. Boghdadi MS, Henning RJ. Cocaine: pathophysiology and clinical toxicology. Heart Lung. 1997; 26:466–83; quiz 484–5. 32. McNagny SE, Parker RM. High prevalence of recent cocaine use and the unreliability of patient self-report in an inner-city walk-in clinic. JAMA. 1992; 267:1106–8.

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REFLECTIONS What do you think is the most important clinical advance our specialty has made? ‘‘The specialty’s contribution to the literature in the field of cardiac and cerebral resuscitation.’’ JOHN WIEGENSTEIN, MD President of ABEM, 1982–1983 ABEM Director, 1976–1986