Made possible by an educational grant from Neurex Corporation

HYPERTENSION IN THE INPATIENT SETTING Mechanisms and Pharmacologic Management
Made possible by an educational grant from Neurex Corporation ©American Medical Communications, Inc.

Dedicated to the memory of
LEON I. GOLDBERG, MD, PHD A pioneer in the research of dopamine receptor pharmacology and physiology Dedicated to the memory of LEON I. GOLDBERG, MD, PHD A pioneer in the research of dopamine receptor pharmacology and physiology Dear Colleague: When I arrived at the University of Chicago more than a decade ago, I was confronted with a challenging clinical situation involving the management of hypertension in a patient with preexisting renal insufficiency and multiple risk factors for perioperative acute renal failure. Fortunately, I had the opportunity to discuss this difficult case with Dr. Leon Goldberg, Professor of Pharmacology and Medicine and Chairman of the Committee on Clinical Pharmacology at the University of Chicago. At the time, Dr. Goldberg was already legendary for his research and publications on the effects of dopamine on cardiac and renal function. My meeting with Dr. Goldberg led to an invitation to work in his laboratory investigating a new dopaminergic analog called SKF/82526, a compound with highly selective DA1 receptor agonist affinity and specificity. Work was already being conducted to develop an oral form of the agent for chronic therapy of hypertension, as well as an intravenous form for hypertensive emergencies. Dr. Goldberg believed that because of the rapid onset and short half-life of SKF/82526, the agent might be particularly useful in the perioperative setting. He suggested that I investigate the hypotensive and renal protective effects of the agent during anesthesia. These investigations represented an exciting time in my life, which I can only now appreciate fully. Unfortunately, our studies were abruptly interrupted when this unique and special mentor was diagnosed with lymphoma. The loss of Leon Goldberg coincided with the discontinuation of SmithKline Beecham’s investigations of SKF/82526. Today, SKF/82526 is commercially available as Corlopam (fenoldopam). When I look back at the dedication and contributions of Leon Goldberg and other pioneers in the field of dopamine research, it is gratifying to see this important agent made available by Neurex Corporation. The availability of Corlopam represents the culmination of an enormous amount of research, resulting in an innovative approach to the many challenges of antihypertensive therapy that we still face. Solomon Aronson, MD, FACC Department of Anesthesia and Critical Care The University of Chicago Medical Center

Learning Objectives Outline the prevalence, pathology, and pathophysiology of hypertension in the inpatient setting. Identify treatment goals and treatment options for the severely hypertensive patient. Discuss the pharmacologic profile and potential benefits of fenoldopam in the treatment of hypertension. SLIDE 2 This slide library is designed to be flexible, so that specialists may tailor a presentation to audiences with different informational needs. Slides are numbered for identification purposes only. The material presented is drawn from anesthesiology, critical care, internal medicine, and surgical sources. All these specialties encounter this clinical entity on a daily basis. We hope this material will be helpful in reviewing the basic mechanisms and pharmacologic management of this common clinical problem. A. Anesthesia/ Critical Care Background Slides A 1-11 B. Emergency Medicine Background Slides B 1-12 C. Treatment Options Slides C 1-15 D. Fenoldopam and Dopamine Slides D 1-6 E. Fenoldopam Pharmacology Slides E 1-11 F. Fenoldopam Efficacy / Blood Pressure Slides F 1-17 G. Fenoldopam Efficacy / Renal Slides G 1-9 H. Package Insert/Safety Slides H 1-8 I. Dosing and Administration Slides I 1-3 J. Supplemental Information Slides J 1-6

Situations Requiring Inpatient Antihypertensive Treatment
Preexisting Hypertension Primary / Essential Secondary No Preexisting Hypertension Acute Crisis Perioperative SLIDE A1 Preexisting hypertension can be primary or secondary. Primary hypertension is essential hypertension. Secondary hypertension is commonly caused by renal diseases. Inpatient hypertension may occur both in patients with preexisting hypertension, as well as in those who were previously normotensive. A common occurrence in the perioperative setting is the development of hypertension acutely, de novo, in the previously normotensive patient.

Epidemiology and Relevance
At least 45% of hospitalized patients have preexisting hypertension About 25% of surgical patients have preexisting hypertension Hypertensive patients frequently have coexisting cardiac and vascular disease SLIDE A2 Hypertensive crisis refers to both urgent and emergency situations. These situations most often evolve from untreated or uncontrolled primary or secondary hypertension. Of the 50 millions Americans who are hypertensive, 1% to 2% will experience a hypertensive crisis. The etiology of hypertensive crisis is unknown. Whatever the triggering event, the common denominator appears to be intense peripheral vasoconstriction. References Burris JF, Freis ED. Hypertensive emergencies. In Messerli FH (ed): Cardiovascular Drug Therapy. Philadelphia, WB Saunders Co., 1996: Mathur VS, Ellis D, Fellmann J, Luther RR. Therapeutics for hypertensive urgencies and emergencies: fenoldopam, a novel systemic and renal vasodilator. Cardiovasc Rev Rep 1998, in press. Goldman L, Caldera DL, Nussbaum SR, et al. Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med 1977;297: O’Hare JP, Hoyt L. Surgery in the nephritic and hypertensive patients. N Engl J Med 1929;200: Prys-Roberts C, Meloche R, Foex P. Studies of anesthesia in relation to hypertension. I. Cardiovascular responses of treated and untreated patients. Br J Anaesth 1971;43: Goldman L, et al. N Engl J Med 1977;297:

Parenteral Treatment of Hypertension May be Required in ...
EM MICU SICU OR PACU Obstetrics Suite SLIDE A3 Hypertensive crises requiring parenteral treatment may occur in a variety of in-hospital settings, as depicted in this slide.

Parenteral Treatment of Hypertension May be Required for Medical Emergencies
Uncontrolled or Malignant Hypertension Drug-Induced Hypertension cocaine, amphetamines drug withdrawal drug-drug interactions Endocrine Disorders SLIDE A4 Emergency hypertension is dangerous primarily because vital end organs may be damaged. Extreme and/or abrupt increases in blood pressure can cause arteriolar fibrinoid necrosis, which can precipitate endothelial damage, platelet and fibrin deposition, and the loss autoregulatory function. Arteriolar damage can also impair blood blow, especially to the kidneys. If blood pressure is not controlled, arteriolar necrosis rapidly leads to end-organ ischemia and, ultimately to death. Untreated malignant hypertension has an 80% to 90% 1-year mortality rate; and at 4 years, the mortality rate reaches 98%. Treated properly, however, the complications of this type of hypertensive crisis are largely reversible, and the 5-year survival rate is as high as 75%. References Ram CVS. Hypertensive crises. In Hurst JW (ed): Medicine for the Practicing Physician (4th ed). Stamford, Connecticut, Appleton & Lange, 1996: Calhoun DA, Oparl SO. Treatment of hypertensive crisis. N Engl J Med 1990;323:

Parenteral Treatment of Hypertension May Be Required During/After Perioperative Period
Cardiac Surgery Major Vascular Surgery carotid endarterectomy aortic surgery Neurosurgery Head and Neck Surgery Renal Transplantation Major Trauma - Burns or Head Injury SLIDE A5 Certain surgical procedures are associated with an increased risk for hypertension. Control of hypertension may be more important during or immediately after these procedures. References Towne JB, Bernhard VM. The relationship of postoperative hypertension to complications following carotid endarterectomy. Surgery 1980;88: Pouttu J. Hemodynamic responses during general anesthesia for renal transplantation in patients with and without hypertensive disease. Acta Anaesthesiol Scand 1989;33: Owall A ,Gordon E, et al. Clinical experience with adenosine for controlled hypotension during cerebral aneurysm surgery. Anesth Analg 1987;66:

Factors in the Development of Acute Hypertension
ER/CC Myocardial Ischemia Hypercarbia/ Hypoxemia Reduced organ perfusion -Renal -Cerebral OR Vascular clamping (afterload) Hyperdynamic Myocardium Malignant Hyperthermia Diastolic Dysfunction PACU Pain Anxiety Distended Bladder Hypervolemia Vasoconstriction SLIDE A6 A variety of factors may contribute to the development of acute hypertension. Some of the more common causes of acute hypertension within specific in-hospital settings are depicted in this slide.

Adverse Consequences of Uncontrolled Hypertension
Postsurgical Hemorrhage Suture line disruption Aortic dissection End Organ Injury Myocardial ischemia Stroke Renal failure Pulmonary Edema SLIDE A7 Intraoperative and postoperative hypertension may cause additional problems specific to the surgical patient. Tighter control of blood pressure may be indicated during these periods, depending on patient factors and the surgical aspects of the case. Diastolic blood pressure values greater than 120 mmHg are associated with a 20% risk of pulmonary edema. References Charlson ME, MacKenzie CR, Golf JP, et al. Risk for postoperative congestive heart failure. Surg Gynecol Obstet 1991;172: Gal TJ, Cooperman LH. Hypertension in the immediate postoperative period. Br J Anaesth 1975;47:70-74. Towne JB, Bernhard VM. The relationship of postoperative hypertension to complications following carotid endarterectomy. Surgery 1980;88:

Sympathetic Nervous System Regulation of Blood Pressure
CNS Adrenal Gland Adrenergic Tone Catecholamines Baroreceptor Reflexes SLIDE A8 The understanding of the role of catecholamines in blood pressure regulation has yielded a number of therapies for the acute management of hypertension. Beta blockers have been used for decades to control heart rate and cardiac output in order to control adrenergically mediated hypertensive episodes. Ganglionic blockers and alpha blockers are highly efficacious in the management of increased adrenergic tone. Veins Arteries Capacitance Resistance Afterload Preload Volume/Pressure Cardiac Output Renin/Angiotensin Heart Kidney Blood Pressure

Renin-Angiotensin-Aldosterone Regulation of Blood Pressure
Renin Substrate Angiotensin I Angiotensin II Renin SLIDE A9 This diagram of the renin-angiotensin-aldosterone system highlights the control of blood pressure. Aldosterone increases intravascular volume by increasing sodium and water reabsorption. Angiotensin II increases blood pressure by causing peripheral vasocontriction. A number of drug therapies have been developed that work at several different sites in this system. Aldosterone Vasoconstriction Kidney Adrenal Cortex Sodium & Water Reabsorption Blood Pressure

Preoperative Hypertension
“Effective intraoperative management may be more important than preoperative hypertensive control in terms of decreasing clinically significant blood pressure lability and cardiovascular complications in patients who have mild to moderate hypertension.” SLIDE A10 Very severe hypertension, even for very brief periods of time, can be detrimental to the cardiovascular system. Severe hypertension is more likely to occur in those patients with preexisting hypertension undergoing an acute stress such as surgery. Attention to both systolic and diastolic hypertension is important to decrease the risk to the patient in the perioperative period. Cardiogenic pulmonary edema is a very serious postoperative event associated with poor outcome It is important to prevent any severe hypertension from occurring. However, there is little evidence that a short period of hypertension that is self-limited is as important as a prolonged episode of moderate hypertension. The relationship of the timing of the hypertension to the patient’s clinical course is of importance. Post-CABG hypertension can be associated with significant bleeding, which places the patient at risk. References Goldman L, Caldera DL. Risks of general anesthesia and elective operation in the hypertensive patient. Anesthesiology 1979;50: Charlson M, MacKenzie CR, Gold JP, et al. Intraoperative blood pressure. What patterns identify patients at risk for postoperative complications? Ann Surg 1990;212: Wolfsthal SD. Is blood pressure control necessary before surgery? Med Clin North Am 1993;77: Goldman L, Caldera DL. Anesthesiology 1979;50:

Inpatient Hypertension: Therapeutic Considerations
Therapy Treat the underlying cause Provide adequate anesthesia/analgesia Administer antihypertensive medications SLIDE A11 Only after the obvious causes of hypertension are addressed and the patient has received adequate analgesia should vasoactive agents be administered. Anesthesiologists must remember to provide adequate and appropriate analgesia, amnesia, hypnosis, muscle relaxation and sympatholysis in the control of intraoperative hypertension.

Hypertension in the United States
50 million adults have high blood pressure 25% are unaware of this condition 72.6% are not well controlled at goal of <140/90 Majority have additional CV risk factors SLIDE B1 Hypertension is extremely common in the United States, affecting over a quarter of all adults. A large number of affected individuals are unaware of their hypertension. Additionally, approximately three quarters of those affected do not currently have their hypertension well controlled. Most of these individuals have additional cardiovascular risk factors. (This information is adapted from the Joint National Commission on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, which was published by the National Institutes of Health in 1997.) Reference The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997;157: JNC VI. Arch Intern Med 1997;157:

Classification of Blood Pressure*
Hypertensive+ Stage 1 Or 90-99 SLIDE B2 Severe hypertension is defined as systolic blood pressure >180 or a diastolic blood pressure >110 mmHg. (JNC, 6th Report, Stage 3) Severe hypertension is present in about 10% of all patients with high blood pressure. Severe hypertension is common in the acute care setting. Despite increased screening procedures and a wide array of available medications, severe hypertension continues to be a relatively common problem in the acute care setting. Reference The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997;157: Stage 2 Or Stage3** 180 Or 110 *When SBP and DBP fall into different categories, use higher classification. +Based on average of at least two readings or at least two visits. **Assess for presence of risk factors and target organ disease. JNC VI. Arch Intern Med 1997;157:

Classification of Severe Hypertension
Uncomplicated Stage 3 HTN Hypertensive Crises urgencies emergencies SLIDE B3 Severe hypertension is generally categorized as a hypertensive urgency, hypertensive emergency, or uncomplicated severe hypertension. This classification is based upon the acute effects of the severe hypertension or underlying conditions that may place the patients at some risk. Reference The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997;157: JNC VI. Arch Intern Med 1997;157:

Hypertensive Urgencies: Defined by Effects or Setting
Hypertension with  Progressive target organ damage SLIDE B4 Hypertensive urgencies are also not defined solely by the level of high blood pressure. The degree of hypertension seen with urgencies overlaps substantially with the “emergency” class. The feature that distinguishes hypertensive urgencies is the absence of acute severe end-organ impairment, but the presence of “high-risk” conditions or settings that would otherwise place the patient at greater risk for an acute complication. These include patients in the perioperative period or those with serious underlying medical conditions. Patients with optic disc edema, even without other neurologic symptoms, also would fall into this category. Patients with underlying target organ impairment (such as mild renal failure) who are showing progressive worsening—but not necessarily acute severe worsening—would also fall into this category. Reference The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997;157:

Hypertensive Emergencies:
Defined by Effects Severe HTN with acute end organ damage:  Central nervous system  Myocardial ischemia or heart failure  Renal damage  Active hemorrhage  Eclampsia  Microangiopathic hemolytic anemia  Aortic dissection SLIDE B5 True hypertensive emergencies are defined not just by the level of blood pressure, but more importantly, by the end-organ effect of the hypertension. There are a number of organ systems that are particularly sensitive to acute, severe elevations in blood pressure; these are listed on this slide. In addition, there are some conditions that constitute a true hypertensive emergency, even when there are only modest elevations in the blood pressure. These include acute intracranial hemorrhage and aortic dissection.

Hypertensive Emergencies Are More Than Blood Pressure Measurement
Hypertensive emergencies generally occur with DBP 140 mm Hg, but can be much lower Baseline level of hypertension and rate of rise are also important There is much overlap between groups and categories, i.e., cannot be defined by BP alone SLIDE B6 Most commonly, true hypertensive emergencies occur in the setting of severe elevations in blood pressure, such as a diastolic blood pressure greater than or equal to 140 mmHg. However, hypertensive emergencies can also occur at much lower blood pressures. It is also important to emphasize that blood pressure level alone does not distinguish well between categories of acute severe hypertension. Kincaid-Smith P. Aust N Z J Med 1981;11(Suppl 1):64-68

Common Etiologies Medication noncompliance / withdrawal Accelerated hypertension in a patient with preexisting hypertension Renovascular hypertension Acute glomerulonephritis SLIDE B7 Hypertensive emergencies most commonly occur in certain settings. Perhaps the most common is medication noncompliance or withdrawal. (Withdrawal from clonidine is particularly important here.) The second most common setting is probably acute accelerated hypertension in a patient with existing hypertension. The diagnoses of renovascular hypertension or acute glomerulonephritis should also be considered in these patients.

Other Etiologies  Sympathomimetic drug poisonings  Eclampsia  Pheochromocytoma  MAO inhibitor interactions SLIDE B8 There are other, less common causes of hypertensive emergencies. Some of these conditions may be more likely in certain patient populations or settings than in others. These include sympathetic drug poisoning; for example, amphetamines or cocaine. Eclampsia is usually evident for other reasons, and pheochromocytomas and MAO inhibitor toxicity are substantially less common.

Treatment Guidelines*
 Hypertensive Emergencies Initiate treatment immediately  Hypertensive Urgencies Reduce BP within a few hours  Non-urgent Stage 3 Hypertension Reduce BP within one week SLIDE B9 The Sixth Joint National Commission Report recommends these treatment initiation guidelines, based upon the category of acute severe hypertension. Hypertensive emergencies should have treatment initiated immediately, whereas hypertensive urgencies can have treatment initiation within a period of multiple hours. Nonurgent severe hypertension does not require acute treatment. Treatment can be initiated, but the most important aspect is close follow-up. Reference The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997;157: *JNC VI. Arch Intern Med 1997;157:

Initial Approach  Multiple confirmations of BP, including all four extremities  Assess target organ involvement  Frequent monitoring of vital signs  Initiate treatment immediately  Use titratable therapy (parenteral) SLIDE B10 The initial approach to a patient with a hypertensive emergency involves evaluation to confirm the diagnosis followed by early initiation of parenteral therapy. The therapeutic goal is to obtain blood pressure control within several hours.

Endpoints of Antihypertensive Therapy
Reduce MAP by 20-25% or Reduce MAP to mmHg (whichever is higher) Achieve target BP within 2-4 hours SLIDE B11 For most patients the target blood pressure is a mean arterial pressure of 110 to 120 mmHg. This target prevents problems with altering cerebral blood flow rates in patients who may have had underlying chronic hypertension.

Hypertensive Emergencies: Control the BP for Patients with . . .
Aortic dissection Active arterial hemorrhage Acute myocardial infarction SLIDE B12 In the setting of hypertensive emergencies, some conditions warrant complete normalization of the blood pressure in order to best treat the emergency condition. Examples of such situations are listed on this slide in order from least to most controversial. Intracranial hemorrhage

IV Therapeutics Alpha Blockers ACE Inhibitors Beta Blockers
Calcium Channel Blockers Diuretics Dopamine-1 Agonists Ganglionic Blockers Nitrovasodilators Other Vasodilators SLIDE C1 This is a list of the most common classes of IV agents available for the treatment of hypertension in the inpatient setting.

Intravenous Agents for Hypertensive Emergencies
Common Vasodilators Agent Onset Duration Advantages Disadvantages Nitroprusside Nitroglycerin Fenoldopam Hydralazine Nicardipine Enalaprilat Immediate 2-5 min <5 min 10-20 min 5-15 min 15-30 min 1-2 min 3-5 min 5-10 min 3-8 hrs 1-4 hrs 6 hr Cyanide, Thiocyanate Potent, Titratable Tolerance, Variable Efficacy Coronary Perfusion SLIDE C2 In the category of vasodilators, there are a number of different agents that are used for the treatment of hypertensive emergencies. However, as shown by the information on the slide, only nitroprusside, nitroglycerin and fenoldopam approach the kinetics of the ideal agent—with rapid onset, titratability and rapid offset. Renal Perfusion Increased IOP Tachycardia, Headache Eclampsia Avoid in CHF or Cardiac Ischemia CNS Protection CHF, Acute LV Failure Avoid in MI Modified from the 6th Joint National Commission Reports, NIH, 1997

Intravenous Agents for Hypertensive Emergencies Adrenergic Antagonists
Onset Duration Advantages Disadvantages Labetalol Phentolamine Esmolol 5-10 min 1-2 min 2 min 3-6 hrs 3-10 min 10-20 min Combines Beta Blockade With Vasodilation Beta Blocker Effects Heart Block, Acute CHF SLIDE C3 The most common intravenous adrenergic blocking agents and their therapeutic characteristics are listed here. Catecholamine Excess Tachycardia Aortic Dissection, Perioperative Beta Blocker Effects Heart Block, Acute CHF Modified from the 6th Joint National Commission Reports, NIH, 1997

Acute Hypertensive Situations Ideal Therapeutic Agent
 Parenteral administration  Rapid onset and offset (minutes)  Easy titratability  Reliable efficacy  Safe across patient populations  Ease of use  Cost effectiveness SLIDE C4 Very few agents possess all the characteristics of an ideal therapy for hypertensive emergencies. Although the kinetics of nitroglycerin are fairly ideal, its antihypertensive efficacy in patients with severe elevations in blood pressure is variable. Sodium nitroprusside has both ideal kinetics and efficacy, but has several disadvantages. This leaves fenoldopam as the only other agent that approaches nitroprusside as an “ideal” therapeutic option. Like sodium nitroprusside, fenoldopam kinetics and efficacy are ideal. Unlike sodium nitroprusside, however, there are fewer logistical and safety concerns with fenoldopam.

Sodium Nitroprusside Profile
Advantages Immediate onset Short duration of action Potent Limitations Light sensitive Arterial catheter usually recommended ICU-level care usually required SLIDE C5 Sodium nitroprusside has been used extensively for over 45 years. Although sodium nitroprusside has ideal kinetics for the management of hypertensive crisis, it has other characteristics that make it less than an ideal choice. Many of the disadvantages listed here are related directly to its potential for cyanide toxicity. Additional problems may be encountered due to administration or storage issues. In terms of hypertension, sodium nitroprusside can cause an unwanted redistribution of blood to nonvital end organs.

Sodium Nitroprusside Adverse Effects
Excessive Hypotension Tachyphylaxis (hyperdynamic response) Redistribution of Flow Intrapulmonary Shunt Coronary Steal Reduced Renal Blood Flow Platelet Dysfunction Toxicity Cyanide Thiocyanate SLIDE C6 The use of sodium nitroprusside is contraindicated in these conditions and situations. This is a direct result of the drug’s toxicity and toxic metabolites.

Metabolism of Sodium Nitroprusside
Oxyhemoglobin Non-enzymatic Nitroprusside Radical Methemoglobin Cyanmethemoglobin CN- SLIDE C7 Sodium nitroprusside combines with hemoglobin to produce one molecule of cyanmethemoglobin and four cyanide ions. Methemoglobin will combine with cyanide ion to form more cyanmethemoglobin. The amount of methemoglobin is limited. Thiosulfate reacts irreversibly with cyanide ion by the hepatic rhodanese system to form thiocyanate. Thiocyanate is eliminated in the urine. Remaining cyanide binds to cytochromes, causing toxicity. Thiocyanate is also toxic. Renal failure results in increases in plasma thiocyanate levels. References Tinker JH, Michenfelder JD. Sodium nitroprusside: pharmacology, toxicology and therapeutics. Anesthesiology 1976;45: Michenfelder JD, Tinker JH. Cyanide toxicity and thiosulfate protection during chronic administration of sodium nitroprusside in the dog. Anesthesiology 1977;47: Thiosulfate Cytochrome Oxidases Hepatic Rhodanase Inactive Cytochromes Thiocyanate (SCN-) TOXICITY Renal Excretion Tinker JH, Michenfelder JD. Anesthesiology 1976;45:

Sodium Nitroprusside 2 NO+ CN- Na+ Fe++
SLIDE C8 It is estimated that exposure to sodium nitroprusside is as high as 480,000 patient days per year. It is conceivable that mortality from this exposure could be as high as 1%. If so, mortality from cyanide toxicity could be as high as 1,000 deaths per year. Signs and symptoms of cyanide toxicity are difficult to detect since they are often attributed to critically ill conditions. References Johanning RJ, Zaske DE, Tschida SJ, et al. A retrospective study of sodium nitroprusside use and assessment of the potential risk of cyanide poisoning. Pharmacotherapy 1995;15: Robin ED, McCauley, R. Nitroprusside-related cyanide poisoning. Time (long past due) for urgent, effective interventions. Chest 1992;102: Tung A, Lynch J, McDade WA, Moss J. A new biological assay for measuring cyanide in blood. Anesth Analg 1997;85: 4 of the 5 CN ions are promptly released 44% of fractional weight is cyanide

Signs Of Cyanide Toxicity
Increased mixed venous saturation Increased metabolic acidosis Loss of consciousness and abnormal breathing patterns Death may be very rapid SLIDE C9 Cyanide toxicity goes unrecognized due to the lack of reliable assays. This table of cyanide levels highlights the extremely narrow toxic-therapeutic ratio for sodium nitroprusside use. Reference Tung A, Lynch J, McDade WA, Moss J. A new biological assay for measuring cyanide in blood. Anesth Analg 1997;85:

Additional Costs Often Associated With Nitroprusside Infusions
Arterial blood gas measurements Lactate concentrations Cyanide / thiocyanate monitoring Invasive blood pressure monitoring SLIDE C10 Although the acquisition cost of sodium nitroprusside is typically inexpensive, additional costs are associated with its use.

Nitroglycerin Coronary vasodilator
Direct venodilator (variable arterial effects) Requires special tubing for administration Side effects: headaches and tachycardia Variable efficacy and tachyphylaxis Methemoglobinemia SLIDE C11 Although in some ways, nitroglycerin has characteristics of an ideal antihypertensive agent for hypertensive emergencies, the problem is that the drug affects the venous circulation more than the arterial circulation. As such, nitroglycerin frequently is not adequate as a single agent to treat patients with severe elevations in blood pressure. Additionally, there are problems with the rapid development of tachyphylaxis.

Esmolol: Characteristics
Easy to titrate Short t½ (8 min.) 1 selective antagonist Quick onset of action Metabolized by red blood cell esterases Myocardial depression Caution in patients with reactive airway disease SLIDE C12 This slide presents some of the characteristics of esmolol, a short-acting beta blocker that is sometimes used for quick blood pressure control, but more often used for control of heart rate. Reference Abdelwahab W, Frishman W, Landau A. Management of hypertensive urgencies and emergencies. J Clin Pharmacol 1995;35:

Labetalol: Characteristics
Combined alpha-beta blocker Half-life 4-6 hours Dose response is variable Blunts reflex tachycardia Myocardial depression Caution in patients with reactive airway disease SLIDE C13 Labetalol is another beta blocker sometimes used for blood pressure control. Reference Abdelwahab W, Frishman W, Landau A. Management of hypertensive urgencies and emergencies. J Clin Pharmacol 1995;35:

Nifedipine Capsules: Characteristics
Provides non-oral route for NPO patients Requires breaking capsule, sublingual administration Absorption variable - Abrupt hypotension may occur - May exacerbate myocardial ischemia SLIDE C14 It is not uncommon for “sublingual” nifedipine to be used for the treatment of acute severe hypertension, and even for hypertensive emergencies. However, this is clearly not ideal for multiple reasons. In addition, its use has been associated with serious complications in at least a subset of patients. The FDA specifically cautions against the use of this agent for hypertensive emergencies.

Nicardipine: Characteristics
Dihydropyridine Water soluble and light stable (allows for IV infusion) Slow onset and offset Arterial catheter not mandatory May accumulate Variable duration of hypertensive effect SLIDE C15 Nicardipine is the first dihydropyridine calcium channel blocker to be available commercially in intravenous form. The half-life of the agent is relatively long (approximately 40 minutes). A potential disadvantage is the persistence of the arterial vasodilatory effect after discontinuation of the drug. Reference Abdelwahab W, Frishman W, Landau A. Management of hypertensive urgencies and emergencies. J Clin Pharmacol 1995;35: Kikura M, Levy JH. New cardiac drugs. Int Anesthesiol Clin 1995;33:21-37.

Dopamine and Fenoldopam
Cl HO HO NH2 NH · CH3SO3H SLIDE D1 Fenoldopam has relatively unique actions and represents a new category of antihypertensive medications. While the structure of fenoldopam is based upon dopamine, this slide highlights clear differences between the two. Although fenoldopam was derived from dopamine, the structural changes highlighted here resulted in an agent that is highly specific for only DA1 receptors, and is ten times more potent than dopamine as a renal vasodilator. HO HO DOPAMINE FENOLDOPAM MESYLATE OH

Receptor Profiles of Dopamine and Fenoldopam
Similarities Both drugs agonize peripheral DA1 receptors Blood pressure reduction (vasodilation) Increased renal blood flow and Na excretion Maintenance of or increase in GFR Differences Dopamine also agonizes DA2 receptors Blood pressure reduction (if high, norepinephrine) Decreased renal blood flow and Na excretion Decreased GFR Dopamine also agonizes B1 and alpha1 receptors Blood pressure elevation (vasoconstriction) Chronotropy Inotropy SLIDE D2 This slide provides a further explanation of how fenoldopam differs from dopamine. Traditional in vivo and in vitro pharmacology studies indicate that the pharmacological activity of fenoldopam is due to stimulation of postsynaptic dopamine-1 receptors, with little activity at the presynaptic dopamine-2 receptors. Fenoldopam exhibits full agonist activity, and is approximately 10 times more potent than dopamine. References Tiberi M, Caron MG. High agonist-independent activity is a distinguishing feature of the dopamine D1B receptor subtype. J Biol Chem 1994;269:

Dopamine Receptor Agonists
Actions of Dopaminergic Agonists Dopamine Fenoldopam DA1 (vasodilation) DA2 (vasodilation, emesis inhibits prolactin)  (vasoconstriction) 1 (inotropic, chronotropic )  2 (vasodilation) SLIDE D3 Dopamine interacts with a variety of adrenergic receptors and both major subtypes of peripheral dopaminergic receptors. Its interaction with these different receptor types is somewhat dose dependent, although clearly there is overlap of receptor activation at many doses. In contrast, fenoldopam interacts only with DA1 receptors, and therefore is not associated with the adverse effects related to alpha1 and beta1 activation. Reference Frishman WH, Hotchkiss H. Selective and nonselective dopamine receptor agonists: an innovative approach to cardiovascular disease treatment. Am Heart J 1996;132: +++ = Major action ++ = Moderate action + = Minimal action = No action Frishman WH, Hotchkiss H. Am Heart J, 1996;132:

Peripheral Dopamine Receptor Subtypes
DA1 DA2 Postsynaptic smooth muscle Proximal tubule Cortical collecting duct Presynaptic Glomerulus Renal nerves Adrenal cortex Location Secondary Messenger G-protein linked increased adenylate cyclase Inhibition of adenylate cyclase decreased NE release SLIDE D4 Peripheral dopamine receptors can be subtyped into two major receptor classes. Fenoldopam interacts only with DA1 receptors; “low-dose” dopamine interacts with both. This chart depicts similarities and differences between DA1 and DA2 receptors. Although the systemic effects are similar, there may be different effects of the receptors on renal function. Peripheral DA1 receptors are located postsynaptically on the smooth muscle of arteries and arterioles and on the tubules of the kidney. The highest concentrations of peripheral DA1 receptors are in the kidney, located on both the afferent and efferent arterioles of the glomerulus and on the tubules. Other vascular beds with appreciable concentrations of DA1 receptors include the mesentery, coronary, and cerebral vasculature. Fenoldopam does not cross the blood-brain barrier and has no central nervous system effects. Reference Carey RM, Siragy HM, Ragsdale NV, et al. Dopamine-1 and dopamine-2 mechanisms in the control of renal function. Am J Hypertens 1990;3 (6 Pt 2):59S-63S. Systemic Effects Peripheral vasodilation Peripheral vasodilation Increased RBF Increased GFR or no change Natriuresis (inhibition of NA/K ATPase via protein kinase C and NA/H exchanger via adenyl cyclase) Diuresis Decreased RBF Decreased GFR Decreased Na and H20 excretion Decreased aldosterone Renal Effects* * Carey RM, et al. Am J Hypertens, 1990;3(6Pt2):59S-63S

Dopamine: Lack of Pharmacological Specificity
BP effects variable, dose-dependent 1: increased heart rate, tachyarrhythmias 1: vasoconstriction Minute ventilation decreases Possible respiratory depression SLIDE D5 In addition to activating DA1 and DA2 receptors, dopamine activates alpha and beta adrenergic receptors. Dopamine causes norepinephrine release from sympathetic nerve terminals, and is a substrate for norepinephrine biosynthesis. These properties make the pharmacology of dopamine complex. At low doses (0.5 to 2.5 µg/kg/min)—the so-called “renal dose”—dopamine acts primarily on DA1 and DA2 receptors, resulting in systemic vasodilation. In the kidney, DA1 and DA2 receptors may have opposing effects. DA1 receptors mediate an increase in renal blood natriuresis. DA2 receptors mediate a decrease in renal blood flow and natriuresis. At somewhat higher doses (2 to 5 µg/kg/min), dopamine interacts with -adrenergic receptors, increasing heart rate and contractility. At doses >5 µg/kg/min, dopamine also stimulates -adrenergic receptors, causing vasoconstriction and elevated blood pressure. Reference Carey RM, Siragy HM, Ragsdale NV, et al. Dopamine-1 and dopamine-2 mechanisms in the control of renal function. Am J Hypertens 1990;3(6 Pt 2):59S-63S.

Physiologic Effects Fenoldopam
Does not cross BBB Systemic Vasodilation Coronary Vasodilation without “steal” (in animals) Reflex tachycardia Metabolized by conjugation No P450 interaction SLIDE D6 Fenoldopam’s activation of dopaminergic receptors on the proximal and distal renal tubules inhibits sodium reabsorption and results in diuresis and natriuresis, whereas activation of the renal vascular receptors in both afferent and efferent glomerular arterioles results in an increase in renal blood flow. In general, glomerular filtration rate increases in hypertensive patients and is maintained in normotensive patients. Animal studies indicate that fenoldopam also causes vasodilation in the splanchnic and coronary vascular beds. A study in dogs with experimental occlusion of the left anterior descending coronary artery demonstrated that fenoldopam improved the perfusion of normal and ischemic borderline myocardium. A study in pigs demonstrated a dose-dependent increase in gut mucosal oxygenation with fenoldopam. References Shi Y, Zalewski A, Bravette B, et al. Selective dopamine-1 receptor agonist augments regional myocardial blood flow: comparison of fenoldopam and dopamine. Am Heart J 1992;124: 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: Germann R, Hasibeder W, Haisjackl M, et al. Dopamine-1-receptor stimulation and mucosal tissue oxygenation in the porcine jejunum. Crit Care Med 1995;23:  RBF  Na excretion  H2O excretion Maintains GFR during BP lowering Mesenteric vasodilation  Mucosal PO2 (in animals)

Dopamine Receptor Affinities
SLIDE E1 Peripheral D1 receptors are located postsynaptically on the smooth muscle of arteries and arterioles and on the tubules of the kidney. The highest concentrations of peripheral D1 receptors are in the kidney, and they are found both on the afferent and efferent arterioles of the glomerulus and on the tubules. Other vascular beds with appreciable concentrations of D1 receptors include the mesentery, coronary and cerebral vasculature. There are no D1 receptors on the veins, and fenoldopam does not have venodilator activity, unlike vasodilators that act via nitric oxide release (i.e., nitroprusside and nitroglycerin). There is no evidence that fenoldopam causes venodilation or changes in cardiac preload. References Carey RM, Siragy HM, Ragsdale NV, et al. Dopamine-1 and dopamine-2 mechanisms in the control of renal function. Am J Hypertens 1990;3(6 Pt 2):59S-63S. Frishman WH, Hotchkiss H. Selective and nonselective dopamine receptor agonists: an innovative approach to cardiovascular disease treatment. Am Heart J 1996;132: GOLDBERG and RAJFER

Fenoldopam Receptor Activity
Selective peripheral dopamine-1 (DA1) receptor agonism Systemic vasodilation Regional vasodilation (especially renal) Renal proximal and distal tubular effects No binding to DA2 or beta-adrenergic receptors No alpha-adrenergic agonism, but is an alpha1 antagonist Does not cross blood brain barrier SLIDE E2 Fenoldopam is the product of an extensive search for a specific, peripherally acting dopamine-1 agonist. Dopamine is the parent compound, and by appropriate molecular modification, many of the undesirable properties—such as lack of receptor specificity of dopamine—were eliminated. Over 500 compounds were synthesized and phamacologically screened for activity as systemic and renal vasodilators. Fenoldopam was identified as having the optimal mix of potency, receptor specificity, and lack of effects on the central nervous system. The primary phamacological actions of fenoldopam are cardiovascular and renal. The drug does not inhibit or induce platelet aggregation and has no effect on the coagulation system. There are no data on the effects of fenoldopam on cerebral blood flow, but in the clinical trial experience, there is no evidence for a steal phenomenon in the cerebral or coronary circulation. Reference Weinstock J, Wilson JW, Ladd DL, Brenner M. Dopaminergic benzazepines with divergent cardiovascular profiles. Am Chem Soc Symp Ser 1996;224:L157-L167.

Mechanism of Action of Fenoldopam
Fenoldopam infusion Selective stimulation of D1-dopamine receptors Direct increase in sodium excretion Adenylyl cyclase activation Increase in intracellular concentration of cAMP SLIDE E3 When D1 receptors are stimulated, adenyl cyclase is activated, which in turn raises the intracellular concentration of cyclic adenosine monophosphate (cAMP). This biochemical signal leads to vascular smooth muscle relaxation, resulting in vasodilation. Vasodilation of systemic arteries lowers systemic vascular resistance, thus decreasing blood pressure. Localized vasodilation, most prominent in the cardiovascular and renal systems, may preserve blood flow in the face of reduced systemic blood pressure. References Brogden RN, Markham A. Fenoldopam: a review of its pharmacodymic and pharmacokinetic properties and intravenous clinical potential in the management of hypertensive urgencies and emergencies. Drugs 1997;54: Hoffman BB, Lefkowitz RJ. Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In Hardman JG, Limbird LE (eds): The Pharmacological Basis of Therapeutics (9th ed). New York, McGraw-Hill, 1996: Mathur VS, Ellis D, Fellman J, Luther RR. Therapeutics for hypertensive urgencies and emergencies: fenoldopam, a novel systemic and renal vasodilator. Cardiovasc Rev Rep 1998, in press. Vascular smooth muscle relaxation Vasodilation of renal arteries Vasodilation of coronary arteries Vasodilation of mesenteric arteries Vasodilation of systemic arteries Maintenance of blood flow to vital organs Decrease in systemic vascular resistance Decrease in blood pressure

Fenoldopam Metabolism: Conjugation Without Cytochrome P450 Interaction
Fenoldopam-8-O-Methyl Fenoldopam-7-O-Methyl Cl Cl HO CH O 3 NH Cl NH CH O HO HO 3 NH HO SLIDE E4 Fenoldopam is rapidly and extensively metabolized by conjugation in the liver. Only 4% is excreted unchanged. The metabolites are inactive. Fenoldopam is not metabolized by the cytochrome P450 system; nor does it induce or inhibit the cytochrome P450 system in the liver. This reduces the chance of drug-drug interactions. There is no change in clearance in patients with end-stage liver or end-stage renal disease. OH OH Cl Cl HO OH O SO 3 NH NH 2 2 COOH O SO HO 3 O Cl O OH HO NH OH OH OH HO Fenoldopam-8-Sulfate Fenoldopam-7-Sulfate (1R),(1S)Fenoldopam-7-O-B-Glucuronide OH

Fenoldopam Metabolism
Metabolism via conjugation Metabolites pharmacologically inactive No cytochrome P450 interactions No known metabolic drug interactions 88% albumin bound Elimination: 90% urine, 10% feces No dose adjustment for renal or hepatic impairment SLIDE E5 Fenoldopam has excellent metabolic and safety profiles. Because metabolism is via hepatic conjugation, no dosage adjustment is necessary in hepatic failure. Fenoldopam is unusual because it has been demonstrated to maintain or improve renal blood flow and function while lowering blood pressure.

Plasma Fenoldopam (ng/ml)
Pharmacokinetics 40 Onset 40 Offset Dose 0.00 g/kg/min Dose 0.04  g/kg/min 30 30 Dose 0.1  g/kg/min Dose 0.4  g/kg/min SLIDE E6 Fenoldopam has a short half-life of 4 to 5 minutes. Steady state is reached at 20 minutes. Plasma drug levels are dose proportional at steady state. Plasma levels remain constant with prolonged (up to 48 hours) continuous constant-rate infusion. The plasma level decay at infusion termination is rapid and predictable even after prolonged infusion. There is no accumulation at higher doses or with prolonged infusion times up to 48 hours. Pharmacokinetics are linear and are best described by the one-compartment model. Dose 0.8  g/kg/min Plasma Fenoldopam (ng/ml) 20 20 10 10 1 2 3 4 5 6 48 49 50 51 52 53 54 Time (hr) Time (hr) Neurex: data on file

Fenoldopam Time of Onset Of Antihypertensive Effect
95 90 85 Mean Diastolic Blood Pressure - (mmHg) +/- Standard Error SLIDE E7 Time of onset is rapid and predictable. In general, higher initial starting doses produce more pronounced and more rapid reductions in blood pressure. 80 75 70 65 10 20 30 40 50 60 Time (Minutes) Neurex: data on file

Dose-Dependent Pharmacokinetics
Dose 0.00 mg/kg/min 40 Dose 0.04 mg/kg/min Dose 0.1 mg/kg/min Dose 0.4 mg/kg/min 30 Dose 0.8 mg/kg/min SLIDE E8 Blood pressure pharmacodynamics are well correlated with plasma fenoldopam levels. This will be shown in slides that follow. Plasma Fenoldopam (ng/ml) 20 t1/2 = 5 min Vd = 42 L 10 6 12 18 24 30 36 42 48 54 60 66 72 Time (hr) Neurex: data on file

Fenoldopam: Pharmacokinetics
 t½ (~ 5 min)  Small volume of distribution  Rapid attainment of steady state (~ 30 min)  Plasma concentrations proportional to dose  No alteration in pharmacokinetics over 48 hr infusion  Rapid elimination upon discontinuation SLIDE E9 A number of studies have examined the pharmacokinetics of fenoldopam. It can be concluded that this agent has a very short half-life and a fairly rapid attainment of steady-state plasma levels (about 20 minutes or four half-lives). The steady state plasma concentrations attained when fenoldopam was infused at 0.1 µg/kg/min were similar in diverse patient populations. Plasma levels are predictable relative to dose, and there is no alteration in these kinetics over 48 hours of infusion. These kinetics are fairly similar to those seen with nitroprusside. Pharmacokinetics were not influenced by age, gender, or race in hypertensive emergency patients. Clearance of parent (active) drug is not altered in patients with end-stage renal disease on continuous ambulatory peritoneal dialysis, and is not affected, on average, in severe hepatic failure. The effects of hemodialysis on drug clearance have not been evaluated.

Fenoldopam: Pharmacodynamics
 Predictable hemodynamic effect  Rapid onset of effect  Predictable dose response for lowering BP  No rebound hypertension SLIDE E10 Multiple studies have also examined the pharmcodynamics of fenoldopam. It has been demonstrated that the medication has a highly predictable hemodynamic effect based upon dose. The onset of that effect is quite rapid. With time, there is partial tolerance to its antihypertensive effects, similar to what is observed with nitroprusside. When fenoldopam is discontinued, no blood pressure rebound effect is observed.

Fenoldopam: Potential Benefits
 Rapid, predictable, dose-dependent blood pressure decrease (without overshoot)  Short t½, rapid attainment of steady state titration  Linear pharmacokinetics  No cytochrome P450 interactions  Dose-response curves well defined  No dosing adjustment for pre-existing renal or hepatic impairment  Increases renal blood flow and maintains GFR  Ease of use SLIDE E11 In summary, fenoldopam has a number of benefits such that it approaches an “ideal” agent for the treatment of hypertensive emergencies. Fenoldopam also has some advantages over nitroprusside, particularly in selected subsets of patients. Its use in patients with congestive heart failure or preexisting renal disease is particularly attractive.

Comparison of Fenoldopam and Nitroprusside:
Summary of Randomized Clinical Trials in Patients with Acute Severe Hypertension Reference n Mean dosage g/kg/min BP (mmHg) Pre Post Overall efficacy FNDSNP FNDSNP FNDSNP FNDSNP FNDSNP 17 16 75 78 15 18 9 6 5 FND 0.6 SNP 2.0 FND 0.41 SNP 1.67 FND 0.5 SNP 1.2 FND SNP FND 0.32 SNP 0.93 197/135 196/129 212/135 210/133 217/145 210/136 200/137 194/132 194/128 209/129 159/105 160/101 179/106 171/104 187/112 172/103 160/105 150/102 150/101 169/103 Bednarczyk et al. Am J Cardiol 1989 Panacek et al. Acad Emerg Med 1995 SLIDE F1 There have been a number of clinical trials evaluating the effects of fenoldopam. Many of these were randomized and used nitroprusside as the control comparison. Most enrolled patients had acute severe hypertension; only a subset had what is traditionally considered a true hypertensive emergency. Recently, the results of a dose-ranging study of fenoldopam in patients with true hypertensive emergencies has been reported. Pilmer et al. J Clin Pharmacol 1993 Reisin et al. Hypertension 1990 White et al. Nieren Hoch 1991 FND=fenoldopam SNP=sodium nitroprusside

Randomized Prospective Trial
Fenoldopam vs. Sodium Nitroprusside in Treatment of Acute Severe Hypertension  Prospective, randomized, open-label, multicenter clinical trial  183 patients enrolled with balanced demographics (153 completed)  FND efficacy equal to SNP  Similar adverse event profile SLIDE F2 The single largest prospective randomized clinical trial comparing fenoldopam with nitroprusside is a study of 183 patients published by Panacek and colleagues in Academic Emergency Medicine in 1995. While most of the patients were young to middle-aged adults, the study included patients up to the age of 80 years. Demographics were well balanced between study groups. The study investigators concluded that fenoldopam and nitroprusside have equivalent efficacy and similar overall adverse-event profiles. The study did not look specifically at issues of cyanide toxicity. Reference Panacek EA, Bednarczyk EM, Dunbar LM, et al. Randomized, prospective trial of fenoldopam vs sodium nitroprusside in the treatment of acute severe hypertension. Acad Emerg Med 1995;2: Panacek EA, et al. Acad Emerg Med 1995;2:

* * * Comparative Effects of Fenoldopam and Nitroprusside
on BP and HR During 6 Hour Infusion Nitroprusside Fenoldopam = p < 0.05; FNP vs SNP * 250 * * 200 Blood Pressure (mmHg) 150 SLIDE F3 This figure compares the effects of nitroprusside with fenoldopam on blood pressure and heart rate. Nitroprusside and fenoldopam had virtually equivalent effects on blood pressure and heart rate during the initial 6-hour infusion. Any differences observed between the agents were rather modest and thought to be largely due to the structured dosing algorithm used in the trial. Differences in efficacy that were statistically significant were not thought to be clinically significant by the investigators. Reference Panacek EA, Bednarczyk EM, Dunbar LM, et al. Randomized, prospective trial of fenoldopam vs sodium nitroprusside in the treatment of acute severe hypertension. Acad Emerg Med 1995;2: 100 110 Heart Rate (bpm) 90 70 Baseline Start 0.5 1.0 2.0 4.0 6.0 End Maintenance Time (Hours) Panacek EA, et al. Acad Emerg Med 1995;2:959

Comparative Effects of Fenoldopam and Nitroprusside on BP and HR after 12 Hours of Infusion
Regimen Fenoldopam Nitroprusside n SBP DBP HR 9 229 ± 8 148 ± 6 94 ± 5 8 225 ± 10 134 ± 2 86 ± 4 Baseline (± SEM) SLIDE F4 A subset of patients from this clinical trial received continuous IV antihypertensive titration for periods longer than 12 hours. These patients were specifically examined to determine if there was loss of efficacy over long-term infusion. Although the numbers of patients are relatively small, one can see that there is no evidence of development of tolerance to the effects of fenoldopam. In addition, the reflex tachycardia that occurs when either of these agents is initiated, appears to become much less marked during the prolonged infusions Reference Panacek EA, Bednarczyk EM, Dunbar LM, et al. Randomized, prospective trial of fenoldopam vs sodium nitroprusside in the treatment of acute severe hypertension. Acad Emerg Med 1995;2: SBP DBP HR -54 ± 10 -45 ± 5 -7 ± 5 -45 ± 10 -32 ± 6 -6 ± 4 Change (± SEM) Panacek EA, et al. Acad Emerg Med 1995;2:

Hypertensive Emergency Trial
Study Design Determine pharmacokinetic/pharmacodynamic parameters Patients with end organ damage and DBP ³120 mmHg Double-blind, constant infusion, 4 rates 0.01, 0.03, 0.1, 0.3 mg/kg/min 24-hour infusion, transition to PO after 18 hours No target BP specified Reduction in DBP at 4 hours primary endpoint Statistical comparison vs dose group SLIDE F5 Patients diagnosed with hypertensive emergency were studied in this multicenter, double-blind, randomized, parallel trial. Hypertensive emergency was defined as a diastolic blood pressure greater than 120 mmHg in the presence of acute ongoing end-organ damage. After baseline examinations and measurements, eligible patients were randomized to continuous infusion of fenoldopam at one of four constant infusion rates. Treatment was continued for 24 hours, with dose adjustment allowed after the first 4 hours of infusion if required. Supine blood pressure and heart rate were measured every 15 minutes with an automated, noninvasive device, such as a DINAMAP, throughout treatment. The patient population was balanced for demographic parameters: Age: 45  10.4; Gender: 55% male; Race: 78% African American; Mean  SD baseline BP was 208  22/134  15 mmHg. Reference Ellis DJ, Luther RR, Fellmann J, et al. Treatment of hypertensive emergencies with fenoldopam, a peripherally acting dopamine (DA1) receptor agonist (abstract). Crit Care Med 1998;26(Suppl):A23. Ellis D, et al. Crit Care Med 1998;26(Suppl):A23 (abstract)

Efficacy Endpoint Ellis D, et al. (abstract) SLIDE F6
A total of 94 patients were treated with fenoldopam. 89 patients completed 4 hours of infusion and 74 patients completed 24 hours. Both diastolic and systolic blood pressure were reduced rapidly and concordantly. In no case was it necessary to reduce the infusion rate during the first 4 hours. At four hours, diastolic blood pressure was reduced from baseline in a dose-dependent manner. -11.5 mmHg for 0.01 µg/kg/min dose -18.4 mmHg for 0.03 µg/kg/min dose -20.7 mmHg for 0.1 µg/kg/min dose -29.1 mmHg for 0.3 µg/kg/min dose (p = ) There was a reflex increase in heart rate of 4.4 BPM at 0.1 µg/kg/min dose and 11 BPM at 0.3 µg/kg/min dose. The hypotensive effect was maintained throughout the 24-hour treatment, whereas the heart rate returned to baseline within 12 hours. Reference Ellis DJ, Luther RR, Fellmann J, et al. Treatment of hypertensive emergencies with fenoldopam, a peripherally acting dopamine (DA1) receptor agonist (abstract). Crit Care Med 1998;26(Suppl):A23. Ellis D, et al. (abstract)

4 Hour Systolic Blood Pressure
SLIDE F7 Conclusions: Fenoldopam infusion safely and effectively controlled blood pressure in patients with hypertensive emergency. The rate and extent of blood pressure reduction was dose dependent. The hypotensive effect was maintained throughout the 24-hour infusion. Reference Ellis DJ, Luther RR, Fellmann J, et al. Treatment of hypertensive emergencies with fenoldopam, a peripherally acting dopamine (DA1) receptor agonist (abstract). Crit Care Med 1998;26(Suppl):A23. Ellis D, et al. (abstract)

4 Hour Heart Rate Ellis D, et al. (abstract) SLIDE F8
Heart rate did not increase at the three lower doses, but increased at the 0.3 µg/kg/min dose. Interestingly, there was no increase in heart rate when patients assigned to the lower three dose groups were titrated up later. Starting at lower doses and titrating up minimizes reflex increase in heart rate. Reference Ellis DJ, Luther RR, Fellmann J, et al. Treatment of hypertensive emergencies with fenoldopam, a peripherally acting dopamine (DA1) receptor agonist (abstract). Crit Care Med 1998;26(Suppl):A23. Ellis D, et al. (abstract)

Objective End Organ Damage Malignant Hypertension Trial
Encephalopathy (Confusion, TIA) Retinal (III-IV, hemorrhage) Renal Insufficiency (Cr >2.4) SLIDE F9 The patients in the study were clearly very ill. Most patients had more than one manifestation of hypertensive emergency. Reference Ellis DJ, Luther RR, Fellmann J, et al. Treatment of hypertensive emergencies with fenoldopam, a peripherally acting dopamine (DA1) receptor agonist (abstract). Crit Care Med 1998;26(Suppl):A23. Myocardial Ischemia (ECG, chest pain) Papilledema CHF (Pulmonary) Hematuria (edema, CXR, rales) 5 10 15 20 25 30 35 Number of Patients Ellis D, et al. (abstract)

Transition to Oral Medications
 No evidence of rebound effects  Rapid disappearance of drug  Administration before or after discontinuation of infusion  Wide variety of drugs used  Generally successful transfer to oral drugs SLIDE F10 When patients are weaned off of fenoldopam and make the transition to oral medications, no serious rebound effect is observed. The transition to oral medications can be initiated prior to discontinuation of the drug, or immediately after discontinuation of infusion. The selection of other oral antihypertiensive agents is not affected by the use of fenoldopam, so options are not limited.

Safety in Postoperative Hypertension Studies Summary of SKF Studies: Overview
Goldberg, et al. (General Surgery) Mathur, et al. (CABG) Hill, et al. (Cardiovascular) Number Patients 17 (23.5%) 126 (18.2%) 28 (10.7%) (% female) (pilot 8, large study 20) Mean Age (yrs) F 51.0 yrs F 62.8 ± 8 years F 58.6 yrs Plc 47.4 yrs Nif 60 ± 9 yrs SNP 61.6 yrs Design Randomized Randomized Randomized Double-blind Single-blind Single-blind Placebo-controlled Positive-control (Nifedipine i.v.) Positive-control (Nitroprusside) Entry Criteria Surgery with 24 hours CABG within 24 hours Surgery with 24 hours SBP 20% preop baseline MAP 105 mmHg for 5 minutes SBP >130 mmHg requiring IV therapy Baseline BP 121 (SBP) F ± 9.1 (MAP) F 143 ± 3/81 ± 2.8 F (mmHg) 125 (SBP) P ± 8.5 (MAP) Nifed 148 ± 2.9/82 ± 2.6 SNP SLIDE F11 This slide summarizes the postoperative studies in hypertension with fenoldopam as treatment. Goldberg compared safety and efficacy of IV fenoldopam to placebo. Fenoldopam reduced blood pressure to the therapeutic goal in 8 of 8 patients, while placebo achieved the goal in only 4 of 8 patients (p = 0.05). At the end of the titration period, therapeutic goal blood pressure was similar to baseline in the fenoldopam group. Fenoldopam lowered systolic and diastolic pressures to goal in a mean time of 28 minutes, compared with placebo at 42.5 minutes. Hill compared fenoldopam with sodium nitroprusside for control of blood pressure following coronary artery bypass graft surgery in 20 patients. Both fenoldopam and sodium nitroprusside caused a rapid and significant fall in systolic arterial pressure (p 0.001) and a fall in systemic vascular resistance (p 0.001). Fenoldopam caused a significant increase in cardiac index (p 0.001) and in stroke volume (p = 0.001) compared with sodium nitroprusside. Fenolodopam appears to control systolic arterial pressure as effectively as sodium nitroprusside, but may have more beneficial effects on cardiac output and on some aspects of renal function. References Goldberg ME, Cantillo J. Fenoldopam infusion for the treatment of postoperative hypertension. J Clin Anesth 1993;5: Hill AJ, Feneck RO, Walesby RK. A comparison of fenoldopam and nitroprusside in the control of hypertension following coronary artery surgery. J Cardiothorac Vasc Anesth 1993;7: Mathur V, Luther R, Ellis D, et al. Fenoldopam: a novel treatment for hypertension following coronary artery bypass graft surgery (abstract). Crit Care Med 1998;26(Suppl):A23.

A Comparative Trial of Fenoldopam and Nifedipine in Postoperative Hypertension
Prospective, randomized, single-blinded, multicenter controlled trial Patient Population 126 postsurgical CABG patients MAP >105 mmHg for >5 minutes Adequate sedation / analgesia Design Single-blind, drug randomization, dose titration Dosing (up to 24 hours) IV fenoldopam: mg/kg/min IV nifedipine: mg/hr SLIDE F12 Postoperative hypertension is a frequent and serious problem following coronary artery bypass graft surgery (CABG). Because of its contribution to myocardial ischemia, bleeding, premature graft closure, and neurologic complications, it is imperative that post-CABG hypertension be rapidly and effectively controlled. This study evaluated fenoldopam versus nifedipine in terms of efficacy in controlling hypertension in 126 CABG patients over a 22-month period. Blood pressure control was defined as reduction of mean arterial pressure to mmHg or by a >15 mmHg reduction, compared with baseline, within 30 minutes. Those who achieved and sustained this control for another 30 minutes were considered successes. Those who achieved this control but sustained it for less than 30 minutes were considered partial successes. Those who failed to achieve this control were considered treatment failures. Success was achieved in 76% of the fenoldopam group compared with 30% in the nifedipine group (p = ). Treatment failure occurred in 10% and 60% of the fenoldopam and nifedipine groups, respectively. Median time to achieve control was 10 minutes and 40 minutes, respectively. Study drug-related adverse events leading to discontinuation occurred with a frequency of 13% in the fenoldopam group and 14% in the nifedipine group. Reference Mathur V, Luther R, Ellis D, et al. Fenoldopam: a novel treatment for hypertension following coronary artery bypass graft surgery (abstract). Crit Care Med 1998;26(Suppl):A23. Mathur V, et al. Crit Care Med 1998;26(Suppl) (abstract)

Mean Arterial Blood Pressure
118 112 end infusion 106 Nifedipine (n=63) SLIDE F13 In absolute terms, the mean arterial pressure shown here is plotted over time in both groups. The mean arterial pressure was significantly lower in the fenoldopam arm during the first 60 minutes of therapy. Following discontination of study drug, patients were treated with a variety of oral or parenteral antihypertensive agents. Reference Mathur V, Luther R, Ellis D, et al. Fenoldopam: a novel treatment for hypertension following coronary artery bypass graft surgery (abstract). Crit Care Med 1998;26(Suppl):A23. Mean Arterial Blood Pressure (mmHg) 100 * 94 Fenoldopam (n=59) * 88 * * * * 82 10 20 30 40 50 60 120 240 360 post post post 60 180 360 Time (min) * p < , fenoldopam vs. nifedipine Mathur, et al.

Time to Blood Pressure Response
(MAP < 90 mmHg or first MAP decrease by > 15 mmHg) SLIDE F14 This is a Kaplan-Meier survival curve depicting the time at which mean arterial pressure first declined to 90 mmHg or declined by 15 mmHg. The percentage of patients remaining without the achievement of these blood pressure parameters is plotted against time. The median time to blood pressure response in the fenoldopam group was 10 minutes, compared with 40 minutes in the nifedipine group. Reference Mathur V, Luther R, Ellis D, et al. Fenoldopam: a novel treatment for hypertension following coronary artery bypass graft surgery (abstract). Crit Care Med 1998;26(Suppl):A23. Mathur, et al.

Pulmonary Vascular Hemodynamics
Pulmonary vascular resistance (PVR) decreased significantly during fenoldopam but not during nifedipine treatment. Pulmonary artery pressures (PAP) did not change significantly during therapy with either drug. SLIDE F15 As depicted in this slide, there was a statistically significant fall in pulmonary vascular resistance during treatment with fenoldopam, while there was no significant reduction with nifedipine. Reference Mathur V, Luther R, Ellis D, et al. Fenoldopam: a novel treatment for hypertension following coronary artery bypass graft surgery (abstract). Crit Care Med 1998;26(Suppl):A23. Mathur, et al.

Filling Pressures and Cardiac Output
SLIDE F16 This is a somewhat complicated slide depicting the effects of both drugs on cardiac output, right atrial pressure, and pulmonary capillary wedge pressure over time. As you can see, both drugs tended to increase cardiac output and lower right atrial pressure and pulmonary artery wedge pressure over time, but these differences, relative to baseline, did not achieve statistical significance. Likewise, the differences between drugs on these measurements did not achieve statistical significance. Reference Mathur V, Luther R, Ellis D, et al. Fenoldopam: a novel treatment for hypertension following coronary artery bypass graft surgery (abstract). Crit Care Med 1998;26(Suppl):A23. Mathur, et al.

p = NS, fenoldopam vs. nifedipine
Heart Rate 110 fenoldopam 100 nifedipine 90 SLIDE F17 Both drugs tended to cause a reflexive increase in heart rate, but the effects were not statistically significant relative to baseline or when drugs were compared with each other. In conclusion, intravenous fenoldopam is an effective and relatively safe treatment for post-CABG hypertension. Fenoldopam lowers blood pressure more consistently and rapidly than does nifedipine in this setting. Reference Mathur V, Luther R, Ellis D, et al. Fenoldopam: a novel treatment for hypertension following coronary artery bypass graft surgery (abstract). Crit Care Med 1998;26(Suppl):A23. Heart Rate (bpm) 80 70 p = NS, fenoldopam vs. nifedipine 60 10 20 30 40 50 60 Time (min) Mathur, et al.

RBF During General Anesthesia With Induced Hypotension
(Results of Dog Studies) RBF During General Anesthesia RBF During Induced Hypotension MAP 50-60 MAP 50-60 SLIDE G1 The next several slides present data on the renal effects of fenoldopam from a variety of studies. Distinct consistencies can be observed. In the first study shown, the authors compared the systemic hemodynamic and renal vascular effects of hypotension induced by fenoldopam with those produced by the most commonly used hypotensive agent, sodum nitroprusside, in 10 dogs. Both agents reduced mean arterial pressure; however, renal blood flow was preseved during fenoldopam-induced hypotension (214  16 mL/min at baseline and 197  16 mL/min after fenoldopam-induced hypotension). In contrast, RBF decreased from 223  17 to 167  12 mL/min during sodium nitroprusside-induced hypotension (p 0.02). The authors concluded that fenoldopam, preserves blood flow to the kidney during induced hypotension. On the other hand, sodium nitroprusside is a nonselective arteriolar and venous vasodilator that redistributes blood flow away from the kidneys during induced hypotension. Similar results were found in the second study. Renal blood flow increased during fenoldopam-induced hypotension (11  7%) and decreased (21  8%) during sodium nitroprusside-induced hypotension (p 0.01). References Aronson S, Goldberg LI, Roizen, MF, et al. Effects of fenoldopam on renal blood flow and systemic hemodynamics during isoflurane anesthesia. J Cardiothorac Vasc Anesth 1991;5:29-32. Aronson S, Goldberg LI, Roizen, MF, et al. Preservation of renal blood flow during hypotension induced with fenoldopam in dogs. Can J Anesth 1990;7: Renal Blood Flow Renal Blood Flow 1. 2. Aronson S, et al. J Cardiothorac Vasc Anesth 1991;5:29-32 Aronson S, et al. Can J Anesth 1990;37(3):

Gut Mucosal Oxygenation (in vivo pig study)
80 80 40 60 30 60 Scrosal PO2 (torr) Mucosal PO2 (torr) Mucosal Hbo2 (%) 40 20 40 SLIDE G2 Breakdown of the gut mucosa is theorized to cause translocation of gut flora, sepsis, ARDS and multiple organ failure syndrome. The objective of this study was to evaluate the effects of dopamine-1 receptor stimulation on intestinal mucosal tissue oxygenation in pigs. Methods: Prospective, experimental, placebo-controlled trial (n = 8, fenoldopam; n = 6, saline) Measurements: Via thermodilution PA catheter, arterial line, jejunal venous catheter, and jejunal mucosal surface oxygen electrodes Results: Fenoldopam increased systemic oxygen delivery by 56% (p 0.001) above baseline values. Mean arterial pressure remained unchanged. Fenoldopam produced a 51% increase in mucosal Po2, and a 31% increase in mucosal hemoglobin oxygen saturation, but no change in serosal Po2. Conclusions: Fenoldopam improves tissue oxygenation of the porcine jejunum in a dose-related manner. Dopamine-1 receptor agonists should be evaluated in patients at risk for intestinal mucosal ischemia. Reference Germann R, Hasibeder W, Haisjackl M, et al. Dopamine-1-receptor stimulation and mucosal tissue oxygenation in the porcine jejunum. Crit Care Med 1995;23: 0.0 0.6 1.2 2.4 4.8 9.6 0.0 0.6 1.2 2.4 4.8 9.6 0.0 0.6 1.2 2.4 4.8 9.6 Dose (g/min/kg) Dose (g/min/kg) Dose (g/min/kg) Placebo Fenoldopam Figure 1: Values expressed as mean + SEM. Fenoldopam (solid squares), Placebo (open squares). P values for differences compared with placebo for mucosal pO2, <0.001; for mucosal HgB saturation, < #p<0.05, compared with baseline value. Germann R, et al. Crit Care Med 1995;23:

Comparison of Renal Effects in Severe Hypertension
140 Bar graphs of relative effects of infusion of either fenoldopam or nitroprusside on renal parameters, measured for each patients percent change from baseline (before infusion), and then averaged. 120 100 80 Change from Baseline (%) SLIDE G3 The renal and hemodynamic effects of intravenous fenoldopam were compared with those of sodium nitroprusside in 28 patients with an average blood pressure of 219/137 mm/Hg, most of whom presented with acute target organ damage. Both drugs lowered blood pressure. In the fenoldopam group, there were significant increases in urinary flow (92  21 to 168  37 mL/h, p 0.003), sodium excretion (227  73 to 335  90 mEq/min, p 0.001), and creatinine clearance (70  11 to 93  13 mL/h, p 0.003). In the nitroprusside group, all of these parameters decreased, although not significantly. In a direct comparison of the agents, the increments in urinary flow rate, sodium excretion, and creatinine clearance were significantly greater (p 0.001) in the fenoldopam group. Significant differences were also obtained when these parameters were calculated as percentage increase over baseline. Fenoldopam and nitroprusside are both effective in severe, accelerated or malignant hypertension, but fenoldopam has additional salutary renal effects in these patients, which may be particularly relevant when preservation of renal function is important. Reference Elliott, WJ, Weber RR, Nelson KS, et al. Renal and hemodynamic effects of intravenous fenoldopam versus nitroprusside in severe hypertension. Circulation 1990;81: 60 40 20 -10 Urinary Flow Rate Sodium Excretion Creatinine Clearance Fenoldopam Nitroprusside Elliott WJ, et al. Circulation 1990;81:

Fenoldopam: Renal Function in Hypertensives
Results Baseline Experimental Recovery Placebo Fenoldopam 25 20 15 V (mL/min) 10 5 SLIDE G4 Fenoldopam was infused intravenously in 17 patients with essential hypertension (mean blood pressure: 152/101 mmHg). Fenoldopam reduced blood pressure in a dose-dependent fashion at doses between and 0.5 µg/kg/min, and the antihypertensive effect was sustained during 2-hour infusions. In 10 patients studied during free-water diuresis, fenoldopam increased renal plasma flow by 42%, glomerular filtration rate by 6%, and sodium excretion by 202%, while lowering mean arterial pressure by 12% (all p 0.05). Similar promotion of sodium excretion was observed during blood pressure reduction in six additional patients studied without water loading. Pronounced enhancement of renal function in spite of blood pressure reduction suggests that fenoldopam might have a special role in the treatment of patients with hypertension and renal impairment. Reference Murphy MB, McCoy CE, Weber RR, et al. Augmentation of renal blood flow and sodium excretion in hypertensive patients during blood pressure reduction by intravenous administration of the dopamine1 agonist fenoldopam. Circulation 1987;76: Urine volume (UV) and urinary sodium (UNaV) before, during and after infusion 30 90 150 210 270 750 625 500 375 UNaV (Eq/min) 250 125 30 90 150 210 270 Murphy MB, et al. Circulation 1987;76:

Fenoldopam: Renal Function in Hypertensives
Results C C PAH IN 800 160 700 140 600 120 500 100 ml/min ml/min 400 FND 80 Placebo 300 60 SLIDE G5 This slide shows the effects of fenoldopam on the clearance rates of PAH (para-aminohippurate) and inulin in 10 hypertensive subjects. Renal plasma flow increased by 42%, from 509 mL/min to 732 mL/min, after mean arterial pressure was reduced via fenoldopam infusion. In contrast, there was no significant increase in renal plasma flow in the control group. Reference Murphy MB, McCoy CE, Weber RR, et al. Augmentation of renal blood flow and sodium excretion in hypertensive patients during blood pressure reduction by intravenous administration of the dopamine1 agonist fenoldopam. Circulation 1987;76: 200 40 100 20 B E R B E R Clearance of PAH and inulin (IN) in 10 hypertensive patients B=baseline E=experimental data R=values after termination of fenoldopam or dextrose Murphy MB, et al. Circulation 1987;76:

Reversal of Hemodynamic Effects of Cyclosporine
In CsA-treated renal transplant patients Renal plasma increased significantly FeNa in urine volume tended to increase GFR and free water clearance were unchanged BP fell (mean of 18/6 mmHg) No change in CsA levels while on fenoldopam SLIDE G6 Cyclosporine causes renal vasoconstriction and reduces renal blood flow, which may contribute to chronic nephrotoxicity. The efficacy of fenoldopam with its renal vasodilator properties was evaluated in six male patients whose condition was stable 3 to 6 months after renal transplantation. Glomerular filtration rate and effective renal plasma flow were measured by inulin and PAH clearances at baseline after acute oral administration of 100 mg of fenoldopam, and after three weeks of oral therapy (100 mg TID). Fenoldopam significantly reverses the renal vasoconstriction caused by cyclosporine in renal transplant recipients. Further investigation of fenoldopam in preventing cyclosporine-induced nephrotoxicity appears warranted. Reference Jorkasky DK, Audet P, Shusterman N, et al. Fenoldopam reverses cyclosporine-induced renal vasoconstriction in kidney transplant recipients. Am J Kidney Dis 1992;19: Jorkasky DK, et al. Am J Kidney Dis 1992;19:

The Multicenter PEEP Study
In respiratory failure patients on PEEP and pressors treated with fenoldopam CrCl increased significantly Urine flow tended to increase Na and potassium excretion tended to increase No significant change in blood pressure SLIDE G7 Patient Selection: 33 intubated patients with respiratory failure in MICU and SICU Mean age — 57.8  15.1 years All patients were on vasopressors for blood pressure support. PEEP decreased urine output by at least 25%. No CRF or dialysis needed. No pretreatment with vasodilators, dopamine, or diuretics. Study Design: Open, prospective, uncontrolled trial PEEP increased every 2 hours until urinary flow volume decreased by at least 25% compared with baseline Intravenous fenoldopam titrated up (0.1 to 1.3 µg/kg/min) over 4-hour period as long as mean arterial pressure remained stable Outcome Variables: urinary flow rate, creatinine clearance, systemic hemodynamics, and electrolyte excretion Reference Schuster HP, Suter PM, Hemmer M, et al. Fenoldopam improves renal dysfunction secondary to ventilation with PEEP. Intensivmedizin 1991;28: Schuster HP, et al. Intensivmedizin 1991;28:

Efficacy: Chronic Renal Insufficiency
Fenoldopam Sodium nitroprusside 200 160 Change (%) 120 SLIDE G8 This study was conducted to examine the effects of fenoldopam on blood pressure and renal function, compared with the effects of sodium nitroprusside, in severely hypertensive patients with impaired renal function. Renal function and systemic hemodynamics were studied in 19 patients with diastolic blood pressure 120 mmHg and impaired renal function (creatinine clearance 70 mL/min.) An additional 22 patients with nonimpaired renal function were studied under the same conditions. Study design was open-label, positive control (SNP). Blood pressure fell equally in both treatment groups. Conclusions: Fenoldopam, but not nitroprusside, improved renal function in severely hypertensive patients at all levels of baseline renal function, while lowering blood pressure. Because of these effects, fenoldopam may be particularly useful in treating severely hypertensive patients with impaired renal function. Reference Schusterman 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: 80 40 -20 Creatinine clearance Urine flow Sodium excretion Potassium excretion Shusterman NH, et al. Am J Med 1993;95:

Fenoldopam: Renal Plasma Flow
Dose Response of RBF in normotensives 20 * * 18 16 Fenoldopam * 14 SLIDE G9 The objective of this study was to determine the relationship of renal plasma flow to fenoldopam dose and to determine at what dose fenoldopam could improve renal hemodynamics without causing blood pressure reduction. Design: Randomized, placebo-controlled, double-blinded trial. Crossover from high to low salt diet to determine effect of volume status on the relationship. Subjects: 14 normal males— 10 randomized to fenoldopam, 4 to placebo Doses: 0.03, 0.1, and 0.3 µg/kg/min fixed infusions Renal hemodynamics were assessed by renal plasma flow (PAH), glomerular filtration rate (inulin), electrolyte excretion, hormone levels (epinephrine, norepinephrine, supine plasma renin, and aldosterone). Conclusions: Fenoldopam increases renal blood flow in a dose-dependent manner. A dose of 0.03 µg/kg/min is associated with significant increases in renal blood flow and urine volume without alterations in blood pressure or heart rate in normotensives. At doses of 0.1 to 0.3 µg/kg/min, renal blood flow increased further. Systolic blood pressure did not change, but diastolic blood pressure decreased minimally (about 2 mmHg at these doses.) Reference Swan SK, Lambrecht L, Anjum S, et al. Renal effects of fenoldopam, a novel parenteral antihypertensive, in normotensive subjects (abstract). J Am Soc Nephrol 1997(September);8:323A. 12 Renal Plasma Flow (mL/min/1.73m2) Fenoldopam Concentration (ng/mL) 10 Placebo 8 6 4 2 Infusion Dose (mcg/kg/min) *p<0.05 compared with placebo with both diets combined Neurex: data on file

Trials Using IV Fenoldopam
Number of Studies Number of Patients/Subjects Disease State Hypertensive emergency 1 94 Severe hypertension Mild-to-moderate hypertension 7 127 Postoperative hypertension 3 89 CHF 6 167 Renal failure 4 75 Hepatic disease 4 48 Transplant 2 21 Other 3 40 Total patients 1,009 Healthy subjects 258 Total Experience 1,267 SLIDE H1 The clinical efficacy of fenoldopam is well established for mild to severe hypertension, including hypertensive emergencies. Fenoldopam has been under clinical investigation since 1981 and has been administered intravenously to more than 1,000 patients with a variety of conditions. Individuals with hypertension, congestive heart failure, renal failure, hepatic cirrhosis, and cardiogenic shock (NYHA class III and IV) have received fenoldopam in clinical trials. Most of the studies were conducted in patients with hypertension. The efficacy of fenoldopam has proved to be equivalent to that of the commonly used antihypertensive, sodium nitroprusside. Analysis of subgroups—defined by age, gender, race, severity of hypertension or other disease states—showed no difference in response. Clinical trials involving the intravenous administration of fenoldopam to 1,009 patients and 258 normal subjects demonstrate that fenoldopam is safe and well tolerated. Overall, there was a very low incidence of adverse events, and little indication of any organ-specific or unexpected reactions. It is noteworthy that there have been no reports of transient ischemic attack, stroke, angina, or myocardial infarction.

Fenoldopam: Indication
In-hospital, short-term (up to 48 hours) management of severe hypertension when rapid, but quickly reversible, emergency reduction of blood pressure is clinically indicated, including malignant hypertension with deteriorating end organ function. Transition to oral therapy with another agent can begin at any time after blood pressure is stable during fenoldopam infusion. SLIDE H2 The next several slides present essential information from the Corlopam package insert.

Fenoldopam: Contraindications
None Known SLIDE H3 There are no known contraindications to fenoldopam.

Fenoldopam: Warnings Contains sodium metabisulfate, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes, in certain susceptible people. Overall prevalence of sulfite sensitivity in general population is unknown but probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. SLIDE H4 The only warning refers to the potential for anaphylactic reaction to one of the ingredients.

Fenolodopam: Precautions
Intraocular pressure that changes within diurnal variation Tachycardia Hypotension Hypokalemia Pregnancy category B Nursing mothers Data suggests no carcinogenesis, mutagenesis, or impairment of fertility Safety and effectiveness in children has not been established SLIDE H5 This slide summarizes the precautions. In a clinical study of 12 patients with open-angle glaucoma or ocular hypertension (mean baseline IOP was 29.2 mmHg with a range of 22.0 to 33.0 mmHg), infusion of fenoldopam at escalating doses ranging from 0.05 to 0.5 µg/kg/min over a 3.5-hour period caused a dose-dependent increase in IOP. At peak effect, the IOP was raised by a mean of 6.5 mmHg (range -2.0 to +8.5 mmHg, corrected for placeo effect). Upon discontinuation of the infusion, the IOP returned to baseline values within 2 hours. Corlopam administration to patients with glaucoma or intraocular hypertension should be undertaken with caution. Corlopam causes a dose-related tachycardia, particularly with infusion rates above 0.1 µg/kg/min. Tachycardia diminishes over time, but remains substantial at higher doses. Corlopam may occasionally produce symptomatic hypotension, and close monitoring of blood pressure during administration is essential. It is particularly important to avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or hemorrhage. Decreases in serum potassium occasionally to values below 3.0 meq/L were observed after less than 6 hours of infusion. It is not clear if the hypokalemia reflects a pressure natriuresis with enhanced potassium-sodium exchange or a direct drug effect. Patient management should include appropriate attention to serum electrolytes. Fenoldopam is excreted in milk in rats. It is not known whether fenoldopam is excreted in human milk. Caution should be used when fenoldopam is administered to a nursing woman.

Fenoldopam: Precautions
No formal interaction studies; intravenous fenoldopam has been administered safely with drugs such as digitalis and sublingual nitroglycerin. Limited experience with concomitant antihypertensive agents: beta blockers, alpha blockers, calcium channel blockers, ACE inhibitors, and diuretics (both thiazide-like and loop). Use of beta-blockers in conjunction with fenoldopam not studied in hypertensive patients: concomitant use should be avoided. Caution should be exercised: unexpected hypotension could result from beta-blocker inhibition of reflex response to fenoldopam. SLIDE H6 There have been no reported drug interactions. Exercise caution when using concomitantly with other agents.

Adverse Events* Fenoldopam (n=117) Nitroprusside (n=119) Event
Hypotension/Decreased BP Flushing 10 9 ECG abnormal 2 0 Nausea/vomiting Headache Dizziness 4 5 Hypokalemia (<3.0) 8 5 *Neurex: data on file SLIDE H7 The safety of fenoldopam, when compared with sodium nitroprusside, can be determined by analyzing nitroprusside-controlled titration-to-effect studies. These studies treated severely hypertensive patients with fenoldopam (n = 117) or nitroprusside (n = 119) for up to 24 hours. Fenoldopam and nitroprusside doses ranged from 0.1 to 1.5 µg/kg/min and from 1.0 to 8.0 µg/kg/min, respectively. The most common and/or serious adverse events are shown here. Adverse events were relatively minor, and incidence was similar between the two groups.

Summary of All IV Studies
Adverse Events* Summary of All IV Studies Clinical Events (N = 1,009) Patients No. (%) Headache 116 (11) Flushing 53 (5) Nausea 52 (5) Hypotension 48 (5) Decreased serum potassium 36 (4) ECG abnormalities 29 (3) Tachycardia 29 (3) Vomiting 29 (3) Dizziness 27 (3) Extrasystoles 23 (2) Dyspnea 16 (2) SLIDE H8 Clinical trials involving the intravenous administration of fenoldopam to 1,009 patients and 258 normal subject demonstrate that fenoldopam is safe and well tolerated. Study doses ranged from 0.01 to 2.5 µg/kg/min, with most patients receiving 0.1 to 0.7 µg/kg/min. Cumulative doses of 0.12 to 523 mg have been studied. Most infusions lasted for 2 to 12 hours. Headache, flushing (cutaneous dilation), nausea (not necessarily due to vasodilation), and hypotension occurred in 5% of the patient population, all attributable to the primary pharmacological effect of fenoldopam. Less common adverse events, including tachycardia, palpitations, and ECG abnormalities could be linked to fenoldopam’s mechanism of action. ECG abnormalities were nonspecific and similar to what is seen with nitroprusside and other vasodilators. Overall, there was a very low incidence of adverse events, and little indication of any organ-specific or unexpected reactions. Adverse events listed here occurred in 2% of the patients. *Occurrence >2% in Combined SKF and Neurex Fenoldopam IV Therapeutic Studies

Fenoldopam: Preparation
Ampules MUST BE DILUTED before infusion Diluted in: 0.9% Sodium Chloride Injection USP 5% Dextrose Injection USP mL of Concentrate (mg of drug) Added to Final Concentration 4 mL (40 mg) mL mg/mL 2 mL (20 mg) mL mg/mL 1 mL (10 mg) mL mg/mL SLIDE I-1 Warning: Contents of ampules must be diluted before infusion. Each ampule is for single use only. Corlopam should be administered by continuous intravenous infusion. A bolus dose should not be used. A calibrated mechanical infusion pump is recommended for proper control of infusion rate.

Fenoldopam: Dosage and Administration
Dosing Recommendations Usual starting dose = 0.1 mg/kg/min Rapid titratable blood pressure control Minimal increase in heart rate Higher starting dose recommended For more rapid onset of blood pressure control For greater magnitude of effect SLIDE I-2 The dose rate of Corlopam must be individualized according to body weight and according to the desired rapidity and extent of pharmacodynamic effect. An initial dose of Corlopam that produces the desired magnitude and rate of blood pressure reduction may be selected. In general, the higher the initial dose of Corlopam, the greater and more rapid the blood pressure reduction.

Fenoldopam: Dosage and Administration
Fenoldopam should be administered by continuous intravenous infusion A bolus dose should not be used Initial dose should be titrated upward or downward, no more frequently than every 15 minutes Recommended increments for titration are 0.05 to 0.1 mg/kg/min Use of infusion pump or syringe pump recommended Intraarterial hemodynamic monitoring at discretion of treating physician SLIDE I-3 Initial dose can be titrated upward or downward no more frequently than every 15 minutes (and less frequently as goal pressure is approached.) In clinical trials, Corlopam treatment was safely performed without the need for intra-arterial blood pressure monitoring. Blood pressure and heart rate were monitored at frequent intervals, typically every 15 minutes. Frequent blood pressure monitoring is recommended. Corlopam infusion can be abruptly discontinued or gradually tapered prior to discontinuation. Once blood pressure is stable, oral antihypertensive agents can be added during or following infusion. In controlled trials, patients have received IV Corlopam for up to 48 hours.

Table 1. Causes of Acute Renal Failure
Acute tubular necrosis Ischemic Nephrotoxic Renal vascular injury Preexisting renal insufficiency Systemic disease with renal involvement Acute interstitial nephritis Acute glomerulonephritis SLIDE J1 Perioperative acute renal failure (ARF) remains one of the most feared entities in the ICU. Mortality from ARF ( 60% to 90%) has changed little over the last two decades. Table 1 lists the causes of acute renal failure. The most common cause of perioperative ARF is acute tubular necrosis, which accounts for 80% to 90% of perioperative renal failure. Causes of Acute Renal Failure* Acute tubular necrosis Ischemic shock, trauma, sepsis Nephrotoxic endogenous nephrotoxins (hemoglobin, bilirubin, myoglobin, uric acid) exogenous nephrotoxins (volatile anesthetics, radiocontrast dyes, aminoglycoside antibiotics amphotericin B, cyclosporin A, cisplatinum Renal vascular injury Direct renal injury Increased intraabdominal pressure Arterial or venous obstruction or compression Atheromatous embolism, thrombosis Preexisting renal insufficiency Diabetes, hypertension, atherosclerosis Systemic disease with renal involvement Vasculitides, lupus, scleroderma, myeloma, amyloid disease Sickle cell crisis Acute interstitial nephritis Nephrotoxic, hypersensitivity reactions Acute glomerulonephritis Streptococcal immune complex disease ———————— *Adapted from Sladen RN, Prough DS. Perioperative renal protection. Problems in Anesthesia 1997;9: Adapted from Sladen R, et al. Problems in Anesthesia 1997;9(3):

Table 2. High-Risk Procedures and Events
Cardiac surgery Vascular surgery Biliary tract and hepatic surgery Urogenital surgery Complicated obstetrics Major trauma SLIDE J2 The primary goal of preoperative assessment is to identify the patient who is at high risk for perioperative acute renal failure. Although the risk for permanent renal injury is extremely low in most patients, even temporary acute renal failure is associated with high morbidity, mortality and cost. Relatively mild insults may precipitate acute renal failure in high-risk situations. Table 2 lists high-risk clinical situations that may precipitate acute tubular necrosis. High-Risk Procedures and Events* Cardiac surgery Biliary tract and hepatic surgery Preexisting renal insufficiency Urogenital surgery Emergency procedures Complicated obstetrics Sepsis (bacterial endocarditis) Major trauma Prolonged cardiopulmonary bypass Direct renal trauma Postoperative cardiac dysfunction Hemorrhagic shock Vascular surgery Massive blood transfusion Preexisting renal insufficiency Elevated intraabdominal pressure Preoperative dye studies Rhabdomyolysis Sepsis (infected grafts) Sepsis: multiorgan dysfunction syndrome Aortic cross-clamp direct renal ischemia (suprarenal cross-clamp) myocardial ischemia, low cardiac output declamping hypotension Renal artery atheromatous embolism Ruptured aortic aneurysm ———————— *Adapted from Sladen RN, Prough DS. Perioperative renal protection. Problems in Anesthesia 1997;9: Adapted from Sladen R, et al. Problems in Anesthesia 1997;9(3):

Chertow GM, et al. Circulation 1997;95:878-884
Incidence of Acute Renal Failure: Perioperative Risk Factors Requiring Dialysis CR CL <60 No Yes Prior Heart Surgery IABP No Yes No Yes 9.5% SLIDE J3 Acute renal failure is one of the most serious complications of cardiac surgery. When acute renal failure is severe enough to require dialysis, morbidity and mortality are markedly increased despite dialysis and supportive intensive care. Over the past several years, investigators have attempted to identify risk factors for the development of acute renal failure. This algorithm is based on a prospective cohort study of 43,642 patients who underwent coronary artery bypass or valvular heart surgery in 43 Department of Veterans Affairs Medical Centers between April 1987 and March 1994. The analysis is an attempt to identify independent predictors of acute renal failure requiring dialysis. References Chertow GM, Lazarus JM. Preoperative renal risk stratification. Circulation 1997;95: Valve NYHA IV Cardiomegaly No Yes No Yes No Yes 0.4% 1.3% 2.8% NYHA IV PVD NYHA IV No Yes No Yes No Yes 2.3% 5.0% 0.9% 2.1% 1.1% Valve No Yes 2.1% 6.1% Chertow GM, et al. Circulation 1997;95:

Considerations in Patient Selection for Fenoldopam
When maintenance of renal function (GFR) and increase in RBF is desired Patients at high risk for renal ischemia Patients with pre-existing hepatic or renal impairment When increased urine flow and natriuresis/diuresis is desired Patients on cyclosporine Patients with increased afterload SLIDE J4 Based on numerous scientific and clinical data, fenoldopam may be useful in the following clinical situations.

Considerations when Choosing IV Therapies
Cost of drug Cost of intensive care setting (ICU vs. floor) Cost of monitoring (A-line vs. cuff) Cost of medical personnel Cost of monitoring for side effects (lactate levels) Cost of treating side effects (colloid/crystalloid for hypotension) SLIDE J5 It is now well recognized that there are more costs to be considered when selecting therapeutic agents than acquisition costs alone. This slide lists a number of considerations relevant to selecting an IV antihypertensive agent.

The Cost of Renal Failure
Variable Length of Stay in Critical Length of Stay in Hospital Care Unit Ward Unadjusted Adjusted for Unadjusted Adjusted for Preoperative Preoperative Factors Factors SLIDE J6 The objective of this study was to determine the incidence and characteristics of postoperative renal dysfunction and failure, perioperative predictors of dysfunction, and the effect of renal dysfunction and failure on in-hospital resource utilization and patient disposition after discharge. The setting of the study was 24 university hospitals. Subjects included 2,222 patients undergoing myocardial revascularization with or without concurrent valvular surgery. Postoperative renal dysfunction or renal failure are associated with prolonged intensive care unit and hospital stays, significant increases in mortality, and greater need for specialized long-term care. Resources should be redirected to mitigate renal injury in high-risk patients. References Mangano CM, Diamonstone LS, Ramsay JG, et al. Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization. Ann Intern Med 1998;128: All patients 1. No renal dysfunction 2. Renal dysfunction 3. Renal failure days Mangano CM, et al, Ann Intern Med 1998;(3):

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