HHYPERTENSIONYPERTENSION I INN T THEHE

IINPATIENTNPATIENT S SETTINGETTING

Mechanisms and Pharmacologic ManagementMechanisms and Pharmacologic Management

Dedicated to the memory of

LEON I. GOLDBERG, MD, PHD

A pioneer in the research of dopaminereceptor 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 InpatientAntihypertensive 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

Epidemiology and Relevance

• EM

• MICU

• SICU

• OR

• PACU

• Obstetrics Suite

Parenteral Treatment of HypertensionMay be Required in ...

• Uncontrolled or Malignant Hypertension

• Drug-Induced Hypertension

– cocaine, amphetamines

– drug withdrawal

– drug-drug interactions

• Endocrine Disorders

Parenteral Treatment of HypertensionMay be Required for Medical Emergencies

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

Factors in the Development ofAcute Hypertension

PACUPACU

Pain

Anxiety

Distended Bladder

Hypervolemia

Vasoconstriction

ER/CCER/CC

Myocardial Ischemia

Hypercarbia/

Hypoxemia

Reduced organ perfusion

-Renal

-Cerebral

OROR

Vascular clamping (afterload)

Hyperdynamic Myocardium

Malignant

Hyperthermia

Diastolic Dysfunction

Adverse Consequences ofUncontrolled Hypertension

• Postsurgical– Hemorrhage– Suture line disruption– Aortic dissection

• End Organ Injury– Myocardial ischemia– Stroke– Renal failure

• Pulmonary Edema

Adrenergic ToneBaroreceptor

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

Afterload

Renin-Angiotensin-Aldosterone Regulation of Blood Pressure

Blood Pressure

KidneyVasoconstriction

Angiotensin IRenin

SubstrateAngiotensin II

Renin

Sodium & Water Reabsorption

Aldosterone

Adrenal Cortex

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.”

Goldman L, Caldera DL. Anesthesiology 1979;50:285-292

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

JNC VI. Arch Intern Med 1997;157:2413-2448

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.

JNC VI. Arch Intern Med 1997;157:2413-2448

Uncomplicated Stage 3 HTN Hypertensive Crises urgencies emergencies

Classification of Severe Hypertension

JNC VI. Arch Intern Med 1997;157:2413-2448

Hypertension with

Progressive target organ damage

Hypertensive Urgencies:Defined by Effects or Setting

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*

*JNC VI. Arch Intern Med 1997;157:2413-2448

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)

Achieve target BP within 2-4 hours

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• Other Vasodilators

Common Vasodilators

Intravenous Agents for Hypertensive Emergencies

AgentAgent Onset Duration DisadvantagesCyanide,

Thiocyanate1-2 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

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

Adrenergic Antagonists

Intravenous Agents for Hypertensive Emergencies

AgentAgent Onset Duration Disadvantages

Beta BlockerEffects

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 BlockerEffects

Heart Block,Acute CHF

Combines Beta Blockade With Vasodilation

CatecholamineExcess

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 SituationsIdeal 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

• Thiocyanate

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

2Na+

NO+

CN-

CN-

Fe++

CN-

CN-

CN-

44% of fractional weight is cyanide

4 of the 5 CN ions are promptly released

Sodium Nitroprusside

Signs Of Cyanide Toxicity

• Increased mixed venous saturation

• Increased metabolic acidosis

• Loss of consciousness and abnormal breathing patterns

• Death may be very rapid

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

• Methemoglobinemia

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

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

Provides non-oral route for NPO patients

Requires breaking capsule, sublingual administration

Absorption variable

- Abrupt hypotension may occur

- May exacerbate myocardial ischemia

Nifedipine Capsules: Characteristics

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

Dopamine and Fenoldopam

HO

HO

DOPAMINE

NH · CH3SO3H

OH

HO

HO

Cl

FENOLDOPAMMESYLATE

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• Inotropy

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

Frishman WH, Hotchkiss H. Am Heart J, 1996;132:861-867

Peripheral Dopamine Receptor SubtypesDADA11 DADA22

LocationLocation• Postsynaptic smooth Postsynaptic smooth

muscle muscle • Proximal tubuleProximal tubule• Cortical collecting ductCortical collecting duct

• Presynaptic Presynaptic • GlomerulusGlomerulus• Renal nervesRenal nerves• Adrenal cortexAdrenal cortex

Secondary Secondary MessengerMessenger

G-protein linked increased G-protein linked increased adenylate cyclaseadenylate cyclase

Inhibition of adenylate cyclase Inhibition of adenylate cyclase decreased NE releasedecreased NE release

SystemicSystemicEffectsEffects

Peripheral vasodilationPeripheral vasodilation Peripheral vasodilationPeripheral vasodilation

Renal Effects*Renal Effects*

• Increased RBFIncreased RBF• Increased GFR or no Increased GFR or no

changechange• 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)

• DiuresisDiuresis

• Decreased RBFDecreased RBF• Decreased GFRDecreased GFR• Decreased Na and HDecreased Na and H220 0

excretionexcretion• Decreased aldosteroneDecreased aldosterone

* 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

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

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

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 flowto vital organs

Decrease in systemicvascular resistance

Decrease in blood pressure

Direct increase insodium excretion

Fenoldopam Metabolism:Conjugation Without Cytochrome P450 Interaction

NH

OH

ClHO

CH O3

NH

OH

Cl

HO

3CH O

NH

OH

Cl

HO

HO

NH

OH

ClHO

O SO32 NH

OH

Cl

HO

O SO3

2

NH

OH

Cl

HO

O

OH

OHHO

COOHO

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

Pla

sma

Fen

old

op

am (

ng

/ml)

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)

Neurex: data on file

Time (Minutes)Time (Minutes)

Mea

n D

iast

oli

c B

loo

d P

ress

ure

- (

mm

Hg

)+

/- S

tan

dar

d E

rro

rM

ean

Dia

sto

lic

Blo

od

Pre

ssu

re -

(m

mH

g)

+/-

Sta

nd

ard

Err

or

6565

7070

7575

8080

8585

9090

9595

1010 2020 3030 4040 5050 6060

Fenoldopam Time of Onset Of Antihypertensive EffectFenoldopam Time of Onset Of Antihypertensive Effect

Neurex: data on file

Time (hr)Time (hr)

Pla

sma

Fen

old

opam

(n

g/m

l)P

lasm

a F

enol

dop

am (

ng/

ml)

00

1010

2020

3030

4040

00 66 1212 1818 2424 3030 3636 4242 4848 5454 6060 6666 7272

Dose 0.00 g/kg/minDose 0.00 g/kg/min

Dose 0.04 g/kg/minDose 0.04 g/kg/min

Dose 0.1 g/kg/minDose 0.1 g/kg/min

Dose 0.4 g/kg/minDose 0.4 g/kg/min

Dose 0.8 g/kg/minDose 0.8 g/kg/min

Dose-Dependent PharmacokineticsDose-Dependent Pharmacokinetics

t1/2 = 5 mint1/2 = 5 min

Vd = 42 LVd = 42 L

Neurex: data on file

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

Fenoldopam: Pharmacokinetics

Predictable hemodynamic effect

Rapid onset of effect

Predictable dose response for lowering BP

No rebound hypertension

Fenoldopam: Pharmacodynamics

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

Fenoldopam: Potential Benefits

Overallefficacy

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 dosageg/kg/min

BP (mmHg) Pre Post

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

FNDSNP

FNDSNP

FNDSNP

FNDSNP

FNDSNP

FND=fenoldopam SNP=sodium nitroprusside

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 TrialFenoldopam vs. Sodium Nitroprusside in Treatment of Acute Severe Hypertension

Panacek EA, et al. Acad Emerg Med 1995;2:959-965

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 Nitroprussideon BP and HR During 6 Hour Infusion

Blo

od

Pre

ssu

re (

mm

Hg)

Maintenance Time (Hours)

He

art

Ra

te (

bp

m)

= p < 0.05; FNP vs SNPNitroprusside Fenoldopam ** *

Panacek EA, et al. Acad Emerg Med 1995;2:959

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

PP

P PP

P

P

P

P

P P PP

P PP

P

E

E

E

E E

EE

E

E

E

EE

EE

E

E

E

G

G

G G

G G

G

G G

GG

G GG

G G G

H

H H

H HH

H H

H

H

HH

H

HH

H

H

0 1 2 3 4100

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 AEEx Ex

Ellis D, et al. (abstract)

4 Hour Systolic Blood Pressure

P

PP

PP

PP P

P PP

P PP

P

P

P

E

E

E

E

E

E

E E

E

EE E E

EE E

E

G

G

GG

G GG G

G

GG

G

G G

G

G G

H

HH

H

H H HH

H

H H HH

H H

H H

0 1 2 3 4170

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

Ellis D, et al. (abstract)

4 Hour Heart Rate

P P P P P P P P PP

PP P P P P PE

EE E

EE E E

E E

E EE E

EE

E

G

GG G G G

G

G GG

G

G

G

G G GG

H

HH

HH

HH H H

HH

HH H H

H

H

0 1 2 3 470

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

Ellis D, et al. (abstract)

Objective End Organ DamageMalignant 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)

Ellis D, et al. (abstract)

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

Transition to Oral Medications

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 yrsPlc 47.4 yrs Nif 60 ± 9 yrs SNP 61.6 yrs

Design Randomized Randomized RandomizedDouble-blind Single-blind Single-blindPlacebo-controlled Positive-control (Nifedipine i.v.) Positive-control

(Nitroprusside)

Entry Criteria Surgery with 24 hours CABG within 24 hours Surgery with 24 hoursSBP 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

Mathur V, et al. Crit Care Med 1998;26(Suppl) (abstract)

Nifedipine (n=63)

Fenoldopam (n=59)

118

112

106

100

94

88

820 10 20 30 40 50 60 120 240 360 post

60post 180

post360

end infusion

*

****

*

* p < 0.0001, fenoldopam vs. nifedipine

Mean Arterial Blood Pressure

Time (min)

Mea

n A

rter

ial B

lood

Pre

ssur

e (m

mH

g)

Mathur, et al.

.

time (min)

0

20

40

60

80

100%

of

pati

en

ts w

ith

no r

esp

on

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)

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.

120

130

140

150

160

170

180

190

0 m

in

15

min

30

min

60

min

12

0 m

in

PV

R (

dyn

es

.se

c.c

m-5

)

fenoldopam

nifedipine

*

*

* p < 0.05

*

Mathur, et al.

.

POST360

POST180

240120603015

14

12

10

8

6

4

CO

RAP

PCWPfen

nif

fen

nif

nif

fen

time (minutes)

Pu

lmon

ary

cap

illa

ry w

ed

ge p

ress

ure

, P

CW

P (

mm

Hg

)R

igh

t atr

ial

pre

ssu

re,

RA

P (

mm

Hg

)C

ard

iac O

utp

ut,

CO

(L

/min

)

0

end infusion

nif = nifedipine

fen = fenoldopam

*

* p<0.02

Filling Pressures and Cardiac Output

Mathur, et al.

Heart Rate

nifedipine

fenoldopam

6050403020100

110

100

90

80

70

60

Time (min)

p = NS, fenoldopam vs. nifedipine

He

art

Ra

te (

bp

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

han

ge

from

bas

elin

e

FND

SNP

(Results of Dog Studies)

-25

-20

-15

-10

-5

0

5

10

15

Halothane Anestheia (1 MAC)%

ch

ang

e fr

om b

asel

ine

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.

Ren

al B

lood

Flo

wR

enal

Blo

od F

low

Ren

al B

lood

Flo

wR

enal

Blo

od F

low

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)

PlaceboFenoldopam

80

60

40

0

Scr

osal

PO

2 (

torr

)

40

30

20

0M

ucos

al P

O2 (

torr

)

80

60

40

0

Muc

osal

Hbo

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)

00

2020

4040

6060

8080

100100

120120

140140

-10-10Urinary Flow RateUrinary Flow Rate Sodium ExcretionSodium Excretion Creatinine ClearanceCreatinine Clearance

FenoldopamFenoldopam NitroprussideNitroprusside

Cha

nge

from

Bas

elin

e (%

)C

hang

e fr

om B

asel

ine

(%)

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 HypertensionComparison of Renal Effects in Severe Hypertension

Elliott WJ, et al. Circulation 1990;81:970-977

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 (

mL/

min

)

030 90 150 210 270

UN

aV (E

q/m

in)

125

250

375

500

625

750

PlaceboFenoldopam

Urine volume (UV) and urinary sodium (UNaV)before, during and afterinfusion

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

FNDPlacebo

PAH

0

20

40

60

80

100

120

140

160

B E R

INCC

ml/m

in

ml/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

Clearance of PAH and inulin (IN) in 10 hypertensive patients

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

Jorkasky DK, et al. Am J Kidney Dis 1992;19:567-572

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 nitroprussideC

hang

e (%

) 160

200

Creatinine clearance

Urine flow Sodium excretion

Potassium excretion

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)

Fen

old

op

am C

on

cen

trat

ion

(n

g/m

L)

Ren

al P

lasm

a F

low

(m

L/m

in/1

.73m

2)

Fenoldopam

Placebo

*p<0.05 compared with placebo with both diets combined

Trials Using IV Fenoldopam

Disease StateDisease StateNumber of

StudiesNumber of

Studies

Hypertensive emergency 1 94Severe hypertension 10 348Mild-to-moderate hypertension 7 127Postoperative hypertension 3 89CHF 6 167Renal failure 4 75Hepatic disease 4 48Transplant 2 21Other 3 40

Total patients 1,009Healthy subjects 258

Total Experience 1,267

Hypertensive emergency 1 94Severe hypertension 10 348Mild-to-moderate hypertension 7 127Postoperative hypertension 3 89CHF 6 167Renal failure 4 75Hepatic disease 4 48Transplant 2 21Other 3 40

Total patients 1,009Healthy 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

None Known

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.

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 fenoldopam.

Adverse Events*Adverse Events*

EventEventNitroprusside

(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

*Neurex: data on file

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 StudiesSummary of All IV Studies

*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) 1000 mL 40 g/mL

2 mL (20 mg) 500 mL 40 g/mL

1 mL (10 mg) 250 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

Adapted from Sladen R, et al. Problems in Anesthesia 1997;9(3):314-331

Table 2. High-Risk Procedures and Events

• Cardiac surgery

• Vascular surgery

• Biliary tract and hepatic surgery

• Urogenital surgery

• Complicated obstetrics

• Major trauma

Adapted from Sladen R, et al. Problems in Anesthesia 1997;9(3):314-331

Incidence of Acute Renal Failure:Perioperative Risk Factors Requiring Dialysis

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

CR CL <60

Prior HeartSurgery IABP

Valve NYHA IV

NYHA IV PVD NYHA IV

Valve

Cardiomegaly

6.1%2.1%

2.1%0.9%

YesNo

YesNoYesNoYesNo

YesNo YesNo YesNo

YesNo YesNo

YesNo

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

• Patients with increased afterload

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)

The Cost of Renal Failure

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

VariableVariable 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 patientsAll patients1. No renal dysfunction1. No renal dysfunction 2.02.0 3.13.1 5.95.9 7.57.52. Renal dysfunction2. Renal dysfunction 4.84.8 6.56.5 10.010.0 11.711.73. Renal failure3. Renal failure 11.611.6 14.914.9 12.412.4 13.913.9

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