Hypertension in the Inpatient setting

H

H

YPERTENSION

YPERTENSION

I

I

N

N

T

T

HE

HE

I

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NPATIENT

NPATIENT

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S

ETTING

ETTING

Mechanisms and Pharmacologic Management

Dedicated to the memory of

L

EON

I

.

G

OLDBERG,

MD

,

P

H

D

A pioneer in the research of dopamine

receptor pharmacology and physiology

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.

Situations Requiring Inpatient

Antihypertensive Treatment

Preexisting Hypertension • Primary / Essential • Secondary No Preexisting Hypertension • Acute Crisis • Perioperative

• 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

Goldman L, et al. N Engl J Med 1977;297:845-850

• EM • MICU • SICU • OR • PACU • Obstetrics Suite

Parenteral Treatment of Hypertension

May be Required in ...

• Uncontrolled or Malignant Hypertension • Drug-Induced Hypertension – cocaine, amphetamines – drug withdrawal – drug-drug interactions • Endocrine Disorders

Parenteral Treatment of Hypertension

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

Factors in the Development of

Acute Hypertension

PACU PACU Pain Anxiety Distended Bladder Hypervolemia Vasoconstriction ER/CC ER/CC Myocardial Ischemia Hypercarbia/ Hypoxemia Reduced organ perfusion -Renal -Cerebral OR OR Vascular clamping (afterload) Hyperdynamic Myocardium Malignant Hyperthermia Diastolic Dysfunction

Adverse Consequences of

Uncontrolled Hypertension

• Postsurgical – Hemorrhage

– Suture line disruption – Aortic dissection

• End Organ Injury – Myocardial ischemia – Stroke

– Renal failure

Adrenergic Tone Baroreceptor Reflexes Volume/Pressure Renin/Angiotensin Preload Cardiac Output

Blood Pressure

Catecholamines Adrenal Gland CNS Veins Arteries Capacitance Resistance

Sympathetic Nervous System Regulation of Blood Pressure

Heart Kidney

Renin-Angiotensin-Aldosterone Regulation of Blood Pressure

Blood Pressure

Kidney Vasoconstriction Angiotensin I Renin Substrate Angiotensin II Renin

Sodium & Water Reabsorption

Aldosterone

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.”

Therapy

– Treat the underlying cause

– Provide adequate anesthesia/analgesia – Administer antihypertensive medications

Inpatient Hypertension:

Therapeutic Considerations

 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

Hypertension in the United States

Classification of Blood Pressure*

Hypertensive+

Stage 1 140-159 Or 90-99

Stage 2 160-179 Or 100-109

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.

Uncomplicated Stage 3 HTN Hypertensive Crises

 urgencies

 emergencies

Classification of Severe Hypertension

Hypertension with

 Progressive target organ damage

Hypertensive Urgencies:

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

Hypertensive Emergencies:

Defined by Effects

Hypertensive Emergencies Are More Than

Blood Pressure Measurement

Kincaid-Smith P. Aust N Z J Med 1981;11(Suppl 1):64-68

• 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

Hypertensive Emergencies:

Common Etiologies

• Medication noncompliance / withdrawal

• Accelerated hypertension in a patient with preexisting hypertension

• Renovascular hypertension • Acute glomerulonephritis

 Sympathomimetic drug poisonings  Eclampsia

 Pheochromocytoma

 MAO inhibitor interactions

Hypertensive Emergencies:

Other Etiologies

 Hypertensive Emergencies

Initiate treatment immediately  Hypertensive Urgencies

Reduce BP within a few hours

 Non-urgent Stage 3 Hypertension Reduce BP within one week

Treatment Guidelines*

 Multiple confirmations of BP, including all four extremities

 Assess target organ involvement  Frequent monitoring of vital signs  Initiate treatment immediately

 Use titratable therapy (parenteral)

Hypertensive Emergencies:

Initial Approach

Endpoints of Antihypertensive

Therapy

Reduce MAP by 20-25% or Reduce MAP to 110-120 mmHg (whichever is higher)

Achieve target BP within 2-4 hours

Reduce MAP by 20-25%

or

Reduce MAP to 110-120 mmHg

(whichever is higher)

Hypertensive Emergencies:

Control the BP for Patients with . . .

• Aortic dissection

• Active arterial hemorrhage

• Acute myocardial infarction • Intracranial hemorrhage

IV Therapeutics

• Alpha Blockers • ACE Inhibitors • Beta Blockers

• Calcium Channel Blockers • Diuretics

• Dopamine-1 Agonists • Ganglionic Blockers • Nitrovasodilators

Common Vasodilators

Intravenous Agents for Hypertensive Emergencies

Agent

Agent Onset Duration Disadvantages

Cyanide, Thiocyanate 1-2 min 3-5 min 5-10 min 3-8 hrs 1-4 hrs 6 hr Immediate 2-5 min <5 min 10-20 min 5-15 min 15-30 min Nitroprusside Nitroglycerin Fenoldopam Hydralazine Nicardipine Enalaprilat Advantages Tolerance, Variable Efficacy Increased IOP Tachycardia, Headache Avoid in CHF or Cardiac Ischemia Avoid in MI Potent, Titratable Coronary Perfusion Renal Perfusion Eclampsia CNS Protection CHF, Acute LV Failure

Adrenergic Antagonists

Intravenous Agents for Hypertensive Emergencies

Agent

Agent Onset Duration Disadvantages

Beta Blocker Effects Heart Block, Acute CHF 3-6 hrs 3-10 min 10-20 min 5-10 min 1-2 min 2 min Labetalol Phentolamine Esmolol

Modified from the 6th Joint National Commission Reports, NIH, 1997

Advantages Tachycardia Beta Blocker Effects Heart Block, Acute CHF Combines Beta Blockade With Vasodilation Catecholamine Excess Aortic Dissection, Perioperative

 Parenteral administration

 Rapid onset and offset (minutes)  Easy titratability

 Reliable efficacy

 Safe across patient populations  Ease of use

 Cost effectiveness

Acute Hypertensive Situations

Ideal Therapeutic Agent

Sodium Nitroprusside Profile

Advantages

• Immediate onset

• Short duration of action • Potent

Limitations

• Light sensitive

• Arterial catheter usually recommended • ICU-level care usually required

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

•Excessive Hypotension

•Tachyphylaxis (hyperdynamic response) •Redistribution of Flow

• Intrapulmonary Shunt • Coronary Steal

• Reduced Renal Blood Flow

•Platelet Dysfunction •Toxicity

• Cyanide

Metabolism of Sodium Nitroprusside

Tinker JH, Michenfelder JD. Anesthesiology 1976;45:340-354

Thiocyanate (SCN-) Thiosulfate Renal Excretion Cytochrome Oxidases Inactive Cytochromes

CN

-TOXICITY Hepatic Rhodanase Nitroprusside Nitroprusside Radical Oxyhemoglobin Methemoglobin Non-enzymatic Cyanmethemoglobin

2

Na+ NO+ CN -CN -Fe++ CN -CN -CN

-44% of fractional weight is cyanide

4 of the 5 CN ions are promptly released

Signs Of Cyanide Toxicity

• Increased mixed venous saturation • Increased metabolic acidosis

• Loss of consciousness and abnormal breathing patterns

Additional Costs Often Associated With

Nitroprusside Infusions

• Arterial blood gas measurements • Lactate concentrations

• Cyanide / thiocyanate monitoring • Invasive blood pressure monitoring

Nitroglycerin

• Coronary vasodilator

• Direct venodilator (variable arterial effects) • Requires special tubing for administration • Side effects: headaches and tachycardia • Variable efficacy and tachyphylaxis

Esmolol: Characteristics

• Easy to titrate

• Short t_½ (8 min.)

 1 selective antagonist

• Quick onset of action

• Metabolized by red blood cell esterases • Myocardial depression

Labetalol: Characteristics

• Combined alpha-beta blocker • Half-life 4-6 hours

• Dose response is variable • Blunts reflex tachycardia • Myocardial depression

 Provides non-oral route for NPO patients

 Requires breaking capsule, sublingual administration  Absorption variable

- Abrupt hypotension may occur

- May exacerbate myocardial ischemia

Nicardipine: Characteristics

• Dihydropyridine

• Water soluble and light stable (allows for IV infusion) • Slow onset and offset

• Arterial catheter not mandatory • May accumulate

Dopamine and Fenoldopam

HO HO DOPAMINE NH · CH₃SO₃H OH HO HO Cl FENOLDOPAM MESYLATE NH2

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

Dopamine Receptor Agonists

Dopamine Fenoldopam DA₁ (vasodilation) +++ +++ DA₂ (vasodilation, emesis +++ - inhibits prolactin)  (vasoconstriction) ++ -₁ (inotropic, chronotropic) +++ - ₂ (vasodilation) +

-Actions of Dopaminergic Agonists

+++ = Major action ++ = Moderate action + = Minimal action - = No action

Peripheral Dopamine Receptor Subtypes

DA

DA₁₁ DADA₂₂

Location

Location

• Postsynaptic smooth _{Postsynaptic smooth}

muscle

muscle

• Proximal tubule_{Proximal tubule}

• Cortical collecting duct_{Cortical collecting duct}

• Presynaptic _Presynaptic

• Glomerulus_Glomerulus

• Renal nerves_{Renal nerves}

• Adrenal cortex_{Adrenal cortex}

Secondary

Secondary

Messenger

Messenger G-protein linked increased _{adenylate cyclase}G-protein linked increased _{adenylate cyclase} Inhibition of adenylate cyclase _{decreased NE release}Inhibition of adenylate cyclase _{decreased NE release}

Systemic

Systemic

Effects

Effects Peripheral vasodilationPeripheral vasodilation Peripheral vasodilationPeripheral vasodilation

Renal Effects* Renal Effects* • Increased RBF_{Increased RBF} • Increased GFR or no _{Increased GFR or no} change change

• Natriuresis _Natriuresis (inhibition of NA/K (inhibition of NA/K ATPase via protein kinase C and

ATPase via protein kinase C and

NA/H exchanger via adenyl

NA/H exchanger via adenyl

cyclase)

cyclase)

• Diuresis_Diuresis

• Decreased RBF_{Decreased RBF}

• Decreased GFR_{Decreased GFR}

• Decreased Na and HDecreased Na and H₂₂0 0 excretion

excretion

• Decreased aldosterone_{Decreased aldosterone}

Dopamine: Lack of Pharmacological

Specificity

• BP effects variable, dose-dependent

 1: increased heart rate, tachyarrhythmias

 1: vasoconstriction

• Minute ventilation decreases

Physiologic Effects Fenoldopam

Systemic Vasodilation Does not cross BBB • Coronary Vasodilation without “steal” (in animals) • Reflex tachycardia • Metabolized by conjugation • No P450 interaction •  RBF •  Na excretion •  H₂O excretion • Maintains GFR during BP lowering • Mesenteric vasodilation •  Mucosal PO₂ (in animals)

Dopamine Receptor Affinities

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

Mechanism of Action of Fenoldopam

Fenoldopam infusion

Selective stimulation of D₁-dopamine receptors Adenylyl cyclase activation

Increase in intracellular concentration of cAMP 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 Direct increase in sodium excretion

Fenoldopam Metabolism:

Conjugation Without Cytochrome P450 Interaction

NH OH Cl HO CH O₃ NH OH Cl HO 3 CH O NH OH Cl HO HO NH OH Cl HO O SO₃ 2 NH OH Cl HO O SO₃ 2 NH OH Cl HO O OH OH HO COOH O Fenoldopam-8-O-Methyl Fenoldopam-7-O-Methyl Fenoldopam-8-Sulfate _{Fenoldopam-7-Sulfate} (1R),(1S)Fenoldopam-7-O-B-Glucuronide

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

Pharmacokinetics

Time (hr) 0 1 2 3 4 5 6 0 10 20 30 40 _Onset P la sm a F en o ld o p am ( n g /m l) 48 49 50 51 52 53 54 Dose 0.00 g/kg/min Dose 0.04  g/kg/min Dose 0.1  g/kg/min Dose 0.4  g/kg/min Dose 0.8  g/kg/min Offset 0 10 20 30 40 Time (hr)

Time (Minutes) Time (Minutes) M ea n D ia st o li c B lo o d P re ss u re ( m m H g ) + S ta n d ar d E rr o r M ea n D ia st o lic B lo o d P re ss u re ( m m H g ) + S ta n d ar d E rr o r 65 65 70 70 75 75 80 80 85 85 90 90 95 95 10 10 2020 3030 4040 5050 6060

Fenoldopam Time of Onset Of Antihypertensive Effect

Fenoldopam Time of Onset Of Antihypertensive Effect

Time (hr) Time (hr) P la sm a F en ol d op am ( n g/ m l) P la sm a F en ol d op am ( n g/ m l) 0 0 10 10 20 20 30 30 40 40 0 0 66 1212 1818 2424 3030 3636 4242 4848 5454 6060 6666 7272 Dose 0.00 g/kg/min Dose 0.00 g/kg/min Dose 0.04 g/kg/min Dose 0.04 g/kg/min Dose 0.1 g/kg/min Dose 0.1 g/kg/min Dose 0.4 g/kg/min Dose 0.4 g/kg/min Dose 0.8 g/kg/min Dose 0.8 g/kg/min

Dose-Dependent Pharmacokinetics

Dose-Dependent Pharmacokinetics

t_1/2 = 5 min t_1/2 = 5 min V_d = 42 L V_d = 42 L

 t_½ (~ 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

 Predictable hemodynamic effect  Rapid onset of effect

 Predictable dose response for lowering BP  No rebound hypertension

 Rapid, predictable, dose-dependent blood pressure decrease (without overshoot)

 Short t_½, 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

Overall efficacy

Comparison of Fenoldopam and Nitroprusside:

Summary of Randomized Clinical Trials in Patients with Acute Severe Hypertension

Bednarczyk et al. Am J Cardiol 1989

Reisin et al.

Hypertension 1990 Panacek et al.

Acad Emerg Med 1995 Pilmer et al.

J Clin Pharmacol 1993

White et al.

Nieren Hoch 1991

Reference n Mean dosage

g/kg/min _{Pre Post} BP (mmHg) 17 16 75 78 15 18 9 9 6 5 FND 0.6 SNP 2.0 FND 0.41 SNP 1.67 FND 0.5 SNP 1.2 FND 0.1-1.5 SNP 0.5-3.5 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 FNDSNP FNDSNP FNDSNP FNDSNP FNDSNP

 Prospective, randomized, open-label, multicenter clinical trial

 183 patients enrolled with balanced demographics (153 completed)

 FND efficacy equal to SNP  Similar adverse event profile

Randomized Prospective Trial

Fenoldopam vs. Sodium Nitroprusside in

Treatment of Acute Severe Hypertension

70 90 110 100 150 200 250

Baseline Start 0.5 1.0 2.0 4.0 6.0 End

Comparative Effects of Fenoldopam and Nitroprusside on BP and HR During 6 Hour Infusion

B lo o d P re ss u re ( m m H g)

Maintenance Time (Hours)

H e a rt R a te ( b p m ) = p < 0.05; FNP vs SNP Nitroprusside Fenoldopam * * *

Nitroprusside

Comparative Effects of Fenoldopam and Nitroprusside on BP and HR after 12 Hours of Infusion

Panacek EA, et al. Acad Emerg Med 1995;2:959-965 9 229 ± 8 148 ± 6 94 ± 5 -54 ± 10 -45 ± 5 -7 ± 5 Fenoldopam 8 225 ± 10 134 ± 2 86 ± 4 -45 ± 10 -32 ± 6 -6 ± 4 Baseline (± SEM) Change (± SEM) n SBP DBP HR SBP DBP HR Regimen

Hypertensive Emergency Trial

Ellis D, et al. Crit Care Med 1998;26(Suppl):A23 (abstract)

Study Design

• Determine pharmacokinetic/pharmacodynamic parameters

• Patients with end organ damage and DBP 120 mmHg • Double-blind, constant infusion, 4 rates

– 0.01, 0.03, 0.1, 0.3 g/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. 0.01 dose group

Efficacy Endpoint

P P P _P P P P P P P P P P P P P P E E E E E E E E E E E E E E E E E G G G G G _G G G G G G _G G G G _{G G} H H H H H H H _H H H H H H H H H H 0 1 2 3 4 100 110 120 130 140 Infusion Time (Hr) P _{0.01 µg/kg/min; comparator} E 0.03 µg/kg/min; p = 0.06* G 0.1 µg/kg/min; p = 0.018* H _{0.3 µg/kg/min; p = 0.0001*}

Mean Diastolic Blood Pressure

* Paired t-test v ersus lowest dose group

N=94 N=89

Rx Fail AE Ex Ex AE

4 Hour Systolic Blood Pressure

P P P P P P P P P _P P P _P P P P P E E E E E E E E E E E _E E E E E E G G G G _G G G G G G _G G G G G G G H H H H H H _H H H H H H _H H H H _H 0 1 2 3 4 170 180 190 200 210 220 Infusion Time (Hr) P 0.01 µg/kg/min; comparator E 0.03 µg/kg/min; p = NS* G 0.1 µg/kg/min; p = NS* H 0.3 µg/kg/min; p = 0.0004* Mean Systolic Blood Pressure

* Paired t-test v ersus lowest dose group

N=94 N=89

4 Hour Heart Rate

P _{P P} P P _P P P _P P P P _{P P} P P P E E E E E _E E E E E E E _{E E} E E _E G G G G G G G G G G G G G G _G G G H H H _H H H H _{H H} H H H H H H H H 0 1 2 3 4 70 80 90 100 110 120 Infusion Time (Hr) P 0.01 µg/kg/min; comparator E 0.03 µg/kg/min; p = NS* G 0.1 µg/kg/min; p = NS* H 0.3 µg/kg/min; p = 0.005*

Mean Heart Rate

* Paired t-test v ersus lowest dose group

Objective End Organ Damage

Malignant Hypertension Trial

Hematuria CHF Papilledema Myocardial Ischemia Renal Insufficiency Retinal Encephalopathy 0 5 10 15 20 25 30 35 Number of Patients (Confusion, TIA) (III-IV, hemorrhage) (Cr >2.4) (ECG, chest pain)

(Pulmonary) (edema, CXR, rales)

 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

Safety in Postoperative Hypertension Studies

Summary of SKF Studies: Overview

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 114.1 ± 9.1 (MAP) F 143 ± 3/81 ± 2.8 F (mmHg) 125 (SBP) P 114.2 ± 8.5 (MAP) Nifed 148 ± 2.9/82 ± 2.6 SNP Goldberg, et al. (General Surgery) Mathur, et al. (CABG) Hill, et al. (Cardiovascular)

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: 0.1 - 1.6 g/kg/min – IV nifedipine: 0.6 - 1.25 mg/hr

Nifedipine (n=63) Fenoldopam (n=59) 118 112 106 100 94 88 82 0 10 20 30 40 50 60 120 240 360 post 60 post 180 post 360 end infusion * * * * * * * p < 0.0001, fenoldopam vs. nifedipine

Mean Arterial Blood Pressure

Time (min) M ea n A rt er ia l B lo od P re ss ur e (m m H g) Mathur, et al.

. time (min) 0 20 40 60 80 100 % o f p at ie n ts w it h n o r es p o n se 10 20 30 40 50 60 fenoldopam , n=59 nifedipine, n=63 p=0.0001, fenoldopam vs. nifedipine

Time to Blood Pressure Response

(MAP

(MAP << 90 mmHg or first MAP decrease by 90 mmHg or first MAP decrease by >> 15 mmHg) 15 mmHg)

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.

120 130 140 150 160 170 180 190 0 m in 1 5 m in 3 0 m in 6 0 m in 1 2 0 m in P V R ( d yn e s .s e c .c m -5 ) fenoldopam nifedipine * * * p < 0.05 * Mathur, et al.

. POST 360 POST 180 240 120 60 30 15 14 12 10 8 6 4 CO RAP PCWP fen nif fen nif nif fen time (minutes) P u lm o n ar y c ap ill ar y w ed g e p re ss u re , P C W P ( m m H g ) R ig h t at ri al p re ss u re , R A P ( m m H g ) C ar d ia c O u tp u t, C O ( L /m in ) 0 end infusion nif = nifedipine fen = fenoldopam * *_p<0.02

Filling Pressures and Cardiac Output

Heart Rate

nifedipine fenoldopam 60 50 40 30 20 10 0 110 100 90 80 70 60 Time (min) p = NS, fenoldopam vs. nifedipine H e a rt R a te ( b p m ) Mathur, et al.

RBF During General Anesthesia With

Induced Hypotension

Aronson S, et al. J Cardiothorac Vasc Anesth 1991;5:29-32

-25 -20 -15 -10 -5 0 5 10 15

Isoflurane Anesthesia (1 MAC)

% c h an g e fr om b as el in e FND SNP

(Results of Dog Studies)

-25 -20 -15 -10 -5 0 5 10 15

Halothane Anestheia (1 MAC)

% c h an g e fr om b as el in e FND SNP MAP 50-60 MAP 50-60

Aronson S, et al. Can J Anesth 1990;37(3):380-384

RBF During General Anesthesia RBF During Induced Hypotension

1. 1. 2.2. R en al B lo od F lo w R en al B lo od F lo w R en al B lo od F lo w R en al B lo od F lo w

Germann R, et al. Crit Care Med 1995;23:1560-1566

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, <0.001. #p<0.05, compared with baseline value.

Gut Mucosal Oxygenation

(in vivo pig study)

Placebo Fenoldopam 80 60 40 0 S cr os al P O2 ( to rr ) 40 30 20 0 M uc os al P O2 ( to rr ) 80 60 40 0 M uc os al H bo 2 ( % ) 0.0 0.6 1.2 2.4 4.8 9.6 Dose (g/min/kg) 0.0 0.6 1.2 2.4 4.8 9.6 Dose (g/min/kg) 0.0 0.6 1.2 2.4 4.8 9.6 Dose (g/min/kg)

0 0 20 20 40 40 60 60 80 80 100 100 120 120 140 140 -10 -10

Urinary Flow Rate

Urinary Flow Rate Sodium ExcretionSodium Excretion Creatinine ClearanceCreatinine Clearance

Fenoldopam

Fenoldopam Nitroprusside_{Nitroprusside}

C ha ng e fr om B as el in e (% ) C ha ng e fr om B as el in e (% )

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.

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.

Comparison of Renal Effects in Severe Hypertension

Comparison of Renal Effects in Severe Hypertension

Fenoldopam: Renal Function in Hypertensives

Murphy MB, et al. Circulation 1987;76:1312-1318

Results 25 20 15 10 5 0

Baseline Experimental Recovery

30 90 150 210 270 V ( m L/ m in ) 0 30 90 150 210 270 U N a V ( E q/ m in ) 125 250 375 500 625 750 Placebo Fenoldopam

Urine volume (UV) and

urinary sodium (U_NaV)

before, during and after infusion

Fenoldopam: Renal Function in Hypertensives

Murphy MB, et al. Circulation 1987;76:1312-1318

Results 0 100 200 300 400 500 600 700 800 B E R FND Placebo PAH 0 20 40 60 80 100 120 140 160 B E R IN C C m l/m in m l/m in B=baseline E=experimental data

R=values after termination of fenoldopam or dextrose

B=baseline

E=experimental data

R=values after termination of fenoldopam or dextrose

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

The Multicenter PEEP Study

In respiratory failure patients on PEEP and pressors treated with fenoldopam

Schuster HP, et al. Intensivmedizin 1991;28:348-355

• CrCl increased significantly • Urine flow tended to increase

• Na and potassium excretion tended to increase • No significant change in blood pressure

• CrCl increased significantly • Urine flow tended to increase

• Na and potassium excretion tended to increase • No significant change in blood pressure

Efficacy: Chronic Renal Insufficiency

Shusterman NH, et al. Am J Med 1993;95:161-168

0 40 80 120

-20

Fenoldopam Sodium nitroprusside

C h an ge ( % ) ₁₆₀ 200 Creatinine

Fenoldopam: Renal Plasma Flow

Neurex: data on file

Dose Response of RBF in normotensives

200 300 400 500 600 700 800 Baseline 0.03 0.1 0.3 20 18 16 14 12 10 8 6 4 2 0 * * *

Infusion Dose (mcg/kg/min)

F en o ld o p am C o n ce n tr at io n ( n g /m L ) R en al P la sm a F lo w ( m L /m in /1 .7 3m 2) Fenoldopam Placebo

Trials Using IV Fenoldopam

Disease State Disease State Number of Studies Number of Studies Hypertensive emergency 1 94 Severe hypertension 10 348 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 Hypertensive emergency 1 94 Severe hypertension 10 348 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 Number of Patients/Subjects Number of Patients/Subjects

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.

Fenoldopam: Contraindications

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

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

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

Adverse Events*

Adverse Events*

Event Event Nitroprusside (n=119) Nitroprusside (n=119) Fenoldopam (n=117) Fenoldopam (n=117) Hypotension/Decreased BP 10 15 Flushing 10 9 ECG abnormal 2 0 Nausea/vomiting 20 18 Headache 18 19 Dizziness 4 5 Hypokalemia (<3.0) 8 5

*Neurex: data on file

Hypotension/Decreased BP 10 15 Flushing 10 9 ECG abnormal 2 0 Nausea/vomiting 20 18 Headache 18 19 Dizziness 4 5 Hypokalemia (<3.0) 8 5

Adverse Events*

Adverse Events*

Clinical Events (N = 1,009) Clinical Events (N = 1,009) Patients No. (%) 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) 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)

Summary of All IV Studies

Summary of All IV 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) 1000 mL 40 g/mL

2 mL (20 mg) 500 mL 40 g/mL

Fenoldopam: Dosage and Administration

Dosing Recommendations

• Usual starting dose = 0.1 g/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

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 g/kg/min

• Use of infusion pump or syringe pump recommended

• Intraarterial hemodynamic monitoring at discretion of treating physician

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

Table 2. High-Risk Procedures and Events

• Cardiac surgery • Vascular surgery

• Biliary tract and hepatic surgery • Urogenital surgery

• Complicated obstetrics • Major trauma

Incidence of Acute Renal Failure:

Perioperative Risk Factors Requiring Dialysis

Chertow GM, et al. Circulation 1997;95:878-884

CR CL <60 Prior Heart Surgery IABP Valve NYHA IV NYHA IV PVD NYHA IV Valve Cardiomegaly 6.1% 2.1% 2.1% 0.9% Yes No Yes No Yes No Yes No Yes No No Yes No _Yes Yes No No Yes Yes No 0.4% 1.3% 2.8% 9.5% 5.0% 2.3% 1.1%

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

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

The Cost of Renal Failure

Mangano CM, et al, Ann Intern Med 1998;(3):194-203

Variable

Variable Length of Stay in Critical Length of Stay in Critical Length of Stay in Hospital Length of Stay in Hospital Care Unit

Care Unit Ward Ward

Unadjusted Adjusted for Unadjusted Unadjusted Adjusted for Unadjusted Adjusted for Adjusted for

PreoperativePreoperative Preoperative Preoperative

FactorsFactors Factors Factors All patients All patients 1. No renal dysfunction 1. No renal dysfunction 2.02.0 3.13.1 5.95.9 7.57.5 2. Renal dysfunction 2. Renal dysfunction 4.84.8 6.56.5 10.010.0 11.711.7 3. Renal failure 3. Renal failure 11.611.6 14.914.9 12.412.4 13.913.9 days days