Transcript HYPERTENSION IN THE INPATIENT SETTING Mechanisms and

HYPERTENSION IN THE
INPATIENT SETTING
Mechanisms and Pharmacologic Management
Dedicated to the memory of
LEON I. GOLDBERG, MD, PHD
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
No Preexisting
Hypertension
• Primary /
Essential
• Acute Crisis
• Secondary
• Perioperative
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
Goldman L, et al. N Engl J Med 1977;297:845-850
Parenteral Treatment of Hypertension
May be Required in ...
• EM
• MICU
• SICU
• OR
• PACU
• Obstetrics Suite
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
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 of
Acute Hypertension
ER/CC
OR
PACU
Myocardial Ischemia
Vascular clamping
(afterload)
Pain
Hypercarbia/
Hypoxemia
Reduced organ
perfusion
-Renal
-Cerebral
Anxiety
Hyperdynamic
Myocardium
Malignant
Hyperthermia
Diastolic Dysfunction
Distended Bladder
Hypervolemia
Vasoconstriction
Adverse Consequences of
Uncontrolled Hypertension
• Postsurgical
– Hemorrhage
– Suture line disruption
– Aortic dissection
• End Organ Injury
– Myocardial ischemia
– Stroke
– Renal failure
• Pulmonary Edema
Sympathetic Nervous System Regulation of Blood Pressure
CNS
Adrenal
Gland
Baroreceptor
Reflexes
Adrenergic
Tone
Catecholamines
Veins
Capacitance
Arteries
Resistance
Afterload
Preload
Cardiac Output
Volume/Pressure
Renin/Angiotensin
Heart
Kidney
Blood Pressure
Renin-Angiotensin-Aldosterone Regulation of Blood Pressure
Renin
Substrate
Angiotensin I
Angiotensin II
Renin
Aldosterone
Vasoconstriction
Kidney
Sodium & Water
Reabsorption
Adrenal Cortex
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.”
Goldman L, Caldera DL. Anesthesiology 1979;50:285-292
Inpatient Hypertension:
Therapeutic Considerations
Therapy
– Treat the underlying cause
– Provide adequate anesthesia/analgesia
– Administer antihypertensive medications
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
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
Classification of Severe Hypertension
Uncomplicated Stage 3 HTN
Hypertensive Crises
 urgencies
 emergencies
JNC VI. Arch Intern Med 1997;157:2413-2448
Hypertensive Urgencies:
Defined by Effects or Setting
Hypertension with
 Progressive target organ damage
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
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
Kincaid-Smith P. Aust N Z J Med 1981;11(Suppl 1):64-68
Hypertensive Emergencies:
Common Etiologies
• Medication noncompliance / withdrawal
• Accelerated hypertension in a patient with
preexisting hypertension
• Renovascular hypertension
• Acute glomerulonephritis
Hypertensive Emergencies:
Other Etiologies
 Sympathomimetic drug poisonings
 Eclampsia
 Pheochromocytoma
 MAO inhibitor interactions
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
*JNC VI. Arch Intern Med 1997;157:2413-2448
Hypertensive Emergencies:
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)
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
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
Intravenous Agents for Hypertensive Emergencies
Common Vasodilators
Agent
Onset
Duration
Advantages
Disadvantages
Cyanide,
Thiocyanate
Tolerance, Variable
Efficacy
Nitroprusside
Immediate
1-2 min
Potent, Titratable
Nitroglycerin
2-5 min
3-5 min
Coronary Perfusion
Fenoldopam
<5 min
5-10 min
Renal Perfusion
Increased IOP
Hydralazine
10-20 min
3-8 hrs
Eclampsia
Nicardipine
5-15 min
1-4 hrs
CNS Protection
Tachycardia,
Headache
Avoid in CHF or
Cardiac Ischemia
Enalaprilat
15-30 min
6 hr
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
5-10 min
3-6 hrs
Combines Beta
Blockade With
Vasodilation
Beta Blocker
Effects
Heart Block,
Acute CHF
Phentolamine
1-2 min
3-10 min
Catecholamine
Excess
Tachycardia
2 min
10-20 min
Aortic Dissection,
Perioperative
Beta Blocker
Effects
Heart Block,
Acute CHF
Agent
Esmolol
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
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
Metabolism of Sodium Nitroprusside
Oxyhemoglobin
Nitroprusside
Nonenzymatic
Nitroprusside Radical
-
CN
Thiosulfate
Hepatic
Methemoglobin
Cyanmethemoglobin
Cytochrome Oxidases
Rhodanase
-
Inactive Cytochromes
Thiocyanate (SCN )
Renal Excretion
TOXICITY
Tinker JH, Michenfelder JD. Anesthesiology 1976;45:340-354
Sodium Nitroprusside
NO+
-
CN
-
CN
-
2
CN
Na+
Fe
++
-
CN
-
CN
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
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
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
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
Cl
HO
HO
NH · CH3SO3H
NH2
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
Dopamine Receptor Agonists
Actions of Dopaminergic Agonists
DA1 (vasodilation)
DA2 (vasodilation, emesis
inhibits prolactin)
 (vasoconstriction)
1 (inotropic, chronotropic)
 2 (vasodilation)
Dopamine
+++
+++
++
+++
+
Fenoldopam
+++
-
+++ = Major action
++ = Moderate action
+ = Minimal action
= No action
Frishman WH, Hotchkiss H. Am Heart J, 1996;132:861-867
Peripheral Dopamine Receptor Subtypes
Location
DA1
• Postsynaptic smooth
muscle
• Proximal tubule
• Cortical collecting duct
DA2
• Presynaptic
• Glomerulus
• Renal nerves
• Adrenal cortex
Secondary
Messenger
G-protein linked increased
adenylate cyclase
Inhibition of adenylate cyclase
decreased NE release
Systemic
Effects
Peripheral vasodilation
Peripheral vasodilation
• Increased RBF
• Decreased RBF
• Decreased GFR
Renal Effects* • Increased GFR or no
change
• Decreased Na and H20
• Natriuresis (inhibition of NA/K excretion
ATPase via protein kinase C and • Decreased aldosterone
NA/H exchanger via adenyl
cyclase)
• Diuresis
* 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
Does not
cross BBB
Systemic Vasodilation
• Metabolized by conjugation
• No P450 interaction
• Coronary Vasodilation
without “steal”
(in animals)
• Reflex tachycardia
• Mesenteric vasodilation
•  Mucosal PO2
(in animals)
•  RBF
•  Na excretion
•  H2O excretion
• Maintains GFR during
BP lowering
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
Direct increase in
sodium excretion
Increase in intracellular concentration of cAMP
Vascular smooth muscle relaxation
Vasodilation of
renal arteries
Vasodilation of
Vasodilation of
Vasodilation of
coronary arteries mesenteric arteries 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
Cl
HO
Fenoldopam-7-O-Methyl
Cl
CH3O
NH
Cl
NH
HO
CH3O
HO
NH
HO
OH
OH
Cl
Cl
O3SO
OH
HO
NH2
O3SO
COOH
NH2
HO
O
Cl
HO
OH
O
OH
NH
OH
OH
HO
Fenoldopam-8-Sulfate
(1R),(1S)Fenoldopam-7-O-B-Glucuronide
Fenoldopam-7-Sulfate
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
Pharmacokinetics
Plasma Fenoldopam (ng/ml)
40
40
Onset
30
30
20
20
10
10
0
0
0
1
2
3
4
Time (hr)
5
6
Offset
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
48
49
50
51
52
53
54
Time (hr)
Neurex: data on file
Mean Diastolic Blood Pressure - (mmHg)
+/- Standard Error
Fenoldopam Time of Onset Of Antihypertensive Effect
95
90
85
80
75
70
65
10
20
30
40
Time (Minutes)
50
60
Neurex: data on file
Plasma Fenoldopam (ng/ml)
Dose-Dependent Pharmacokinetics
Dose 0.00 g/kg/min
40
Dose 0.04 g/kg/min
Dose 0.1 g/kg/min
Dose 0.4 g/kg/min
30
Dose 0.8 g/kg/min
20
t1/2 = 5 min
Vd = 42 L
10
0
0
6
12
18
24
30
36
Time (hr)
42
48
54
60
66
72
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
Fenoldopam: Pharmacodynamics
 Predictable hemodynamic effect
 Rapid onset of effect
 Predictable dose response for lowering BP
 No rebound hypertension
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
Comparison of Fenoldopam and Nitroprusside:
Summary of Randomized Clinical Trials in Patients with
Acute Severe Hypertension
Reference
n
Mean dosage
g/kg/min
Bednarczyk et al.
Am J Cardiol 1989
17
FND 0.6
197/135
159/105
16
SNP 2.0
196/129
160/101
Panacek et al.
Acad Emerg Med 1995
75
FND 0.41
212/135
179/106
78
SNP 1.67
210/133
171/104
Pilmer et al.
J Clin Pharmacol 1993
15
FND 0.5
217/145
187/112
18
SNP 1.2
210/136
172/103
Reisin et al.
Hypertension 1990
9
FND 0.1-1.5
200/137
160/105
9
SNP 0.5-3.5
194/132
150/102
White et al.
Nieren Hoch 1991
6
FND 0.32
194/128
150/101
5
SNP 0.93
209/129
169/103
FND=fenoldopam
BP (mmHg)
Pre
Post
SNP=sodium nitroprusside
Overall
efficacy
FNDSNP
FNDSNP
FNDSNP
FNDSNP
FNDSNP
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
Panacek EA, et al. Acad Emerg Med 1995;2:959-965
Comparative Effects of Fenoldopam and Nitroprusside
on BP and HR During 6 Hour Infusion
Fenoldopam
250
*
200
*
= p < 0.05; FNP vs SNP
*
150
100
110
90
70
Baseline
Start
0.5
1.0
2.0
4.0
6.0
Heart Rate (bpm)
Blood Pressure (mmHg)
Nitroprusside
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
Baseline
(± SEM)
Change
(± SEM)
Regimen
Fenoldopam
Nitroprusside
n
9
8
SBP
229 ± 8
225 ± 10
DBP
148 ± 6
134 ± 2
HR
94 ± 5
86 ± 4
SBP
-54 ± 10
-45 ± 10
DBP
-45 ± 5
-32 ± 6
HR
-7 ± 5
-6 ± 4
Panacek EA, et al. Acad Emerg Med 1995;2:959-965
Hypertensive Emergency Trial
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
Ellis D, et al. Crit Care Med 1998;26(Suppl):A23 (abstract)
Efficacy Endpoint
Mean Diastolic Blood Pressure
140
E
130
P
G
H
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*
P
E
P
P
P
P
P
E
G
E
120
E
P
E
E
H
G
H
H
G
H
G
H
G
E
E
E
G
G
P
E
P
P
P
E
P
G
H
G
H
110
E
P
E
G
G
G
H
H
Ex
Ex
P
E
E
E
G
H
H
Rx Fail AE
G
P
P
G
H
G
H
H
AE
H
H
100
0
N=94
1
2
Infusion Time (Hr)
3
4
N=89
* Paired t-test v ersus lowest dose group
Ellis D, et al. (abstract)
4 Hour Systolic Blood Pressure
Mean Systolic Blood Pressure
220
210
P
H
E
G
200
P
P
E
P
P
E
E
H
P
P
E
E
E
0.03 µg/kg/min; p = NS*
G
0.1 µg/kg/min; p = NS*
H
P
E
H
G
G
0.01 µg/kg/min; comparator
P
E
H
190
P
P
H
H
G
E
G
E
H
G
P
P
E
H
G
G
0.3 µg/kg/min; p = 0.0004*
E
P
G
H
G
H
180
E
P
E
P
E
P
G
H
G
E
P
E
G
G
H
H
H
G
G
H
G
H
H
170
0
N=94
1
2
Infusion Time (Hr)
3
4
N=89
* Paired t-test v ersus lowest dose group
Ellis D, et al. (abstract)
4 Hour Heart Rate
Mean Heart Rate
120
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*
110
100
H
H
90
PE
H
80
H
H
E
G
P
H
H
H
PGE
PG
E
H
PGE
G
P
E
P
E
G
H
H
E
PG
E
H
H
G
P
H
E
G
E
PG
P
H
H
G
E
G
H
G
E
P
P
G
E
P
E
G
P
E
PG
PGE
70
0
1
2
3
4
Infusion Time (Hr)
* Paired t-test v ersus lowest dose group
Ellis D, et al. (abstract)
Objective End Organ Damage
Malignant Hypertension Trial
Encephalopathy
(Confusion, TIA)
Retinal
(III-IV, hemorrhage)
Renal Insufficiency
(Cr >2.4)
Myocardial Ischemia
(ECG, chest pain)
Papilledema
CHF
(Pulmonary)
Hematuria
(edema, CXR, rales)
0
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
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
(% female)
17 (23.5%)
126 (18.2%)
28 (10.7%)
(pilot 8, large study 20)
Mean Age (yrs)
F 51.0 yrs
Plc 47.4 yrs
F 62.8 ± 8 years
Nif 60 ± 9 yrs
F 58.6 yrs
SNP 61.6 yrs
Design
Randomized
Double-blind
Placebo-controlled
Randomized
Single-blind
Positive-control (Nifedipine i.v.)
Randomized
Single-blind
Positive-control
(Nitroprusside)
Entry Criteria
Surgery with 24 hours
SBP 20% preop baseline
CABG within 24 hours
MAP 105 mmHg for 5 minutes
Surgery with 24 hours
SBP >130 mmHg requiring
IV therapy
Baseline BP
(mmHg)
121 (SBP) F
125 (SBP) P
114.1 ± 9.1 (MAP) F
114.2 ± 8.5 (MAP) Nifed
143 ± 3/81 ± 2.8 F
148 ± 2.9/82 ± 2.6 SNP
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)
Mean Arterial Blood Pressure (mmHg)
Mean Arterial Blood Pressure
118
112
end infusion
106
Nifedipine (n=63)
100
*
94
Fenoldopam (n=59)
*
88
*
*
*
*
82
0
10
20
30
40
50
60
120
240
360
post
60
post
180
post
360
Time (min)
* p < 0.0001, fenoldopam vs. nifedipine
Mathur, et al.
Time to Blood Pressure Response
(MAP < 90 mmHg or first MAP decrease by > 15 mmHg)
100
fenoldopam , n= 59
% of patients with no response
nifedipine, n=63
80
60
40
20
0
10
20
30
40
50
60
time (min)
p= 0.0001, fenoldopam vs. nifedipine
.
Mathur, et al.
Pulmonary Vascular Hemodynamics
180
170
160
*
150
*
fenoldopam
nifedipine
140
*
130
*
120 min
60 min
30 min
15 min
120
0 min
PVR (dynes.sec.cm-5)
190
• 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.
p < 0.05
Mathur, et al.
Filling Pressures and Cardiac Output
14
end infusion
Pulmonary capillary wedge pressure, PCWP (mmHg)
Right atrial pressure, RAP (mmHg)
Cardiac Output, CO (L/min)
nif
12
RAP
nif
fen
PCWP
10
fen
fen = fenoldopam
nif = nifedipine
8
fen
*
CO
6
nif
* p<0.02
.
4
0
15
30
60
time (minutes)
120
240
POST
180
POST
360
Mathur, et al.
Heart Rate
110
fenoldopam
Heart Rate (bpm)
100
nifedipine
90
80
70
p = NS, fenoldopam vs. nifedipine
60
0
10
20
30
40
50
60
Time (min)
Mathur, et al.
RBF During General Anesthesia With
Induced Hypotension
RBF During General Anesthesia
RBF During Induced Hypotension
MAP 50-60
MAP 50-60
15
15
10
10
5
0
FND
-5
SNP
-10
-15
-20
-25
Renal Blood Flow
% change from baseline
Renal Blood Flow
% change from baseline
(Results of Dog Studies)
5
0
FND
-5
SNP
-10
-15
-20
-25
1. Isoflurane Anesthesia (1 MAC)
2. Halothane Anestheia (1 MAC)
Aronson S, et al. J Cardiothorac Vasc Anesth 1991;5:29-32
Aronson S, et al. Can J Anesth 1990;37(3):380-384
Gut Mucosal Oxygenation
(in vivo pig study)
80
60
40
Mucosal Hbo2 (%)
40
Mucosal PO2 (torr)
Scrosal PO2 (torr)
80
30
20
0
0
0.0
0.6
1.2
2.4
4.8
Dose (g/min/kg)
9.6
60
40
0
0.0
0.6
1.2
2.4
4.8
Dose (g/min/kg)
9.6
0.0
0.6
1.2
2.4
4.8
9.6
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, <0.001. #p<0.05, compared with baseline value.
Germann R, et al. Crit Care Med 1995;23:1560-1566
Comparison of Renal Effects in Severe Hypertension
Change from Baseline (%)
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
60
40
20
0
-10
Urinary Flow Rate
Fenoldopam
Sodium Excretion
Creatinine Clearance
Nitroprusside
Elliott WJ, et al. Circulation 1990;81:970-977
Fenoldopam: Renal Function in Hypertensives
Results
V (mL/min)
25
Baseline
Experimental
Recovery
20
15
10
5
0
30
90
150
210
270
30
90
150
210
270
750
UNaV (Eq/min)
Placebo
Fenoldopam
625
500
Urine volume (UV) and
urinary sodium (UNaV)
before, during and after
infusion
375
250
125
0
Murphy MB, et al. Circulation 1987;76:1312-1318
Fenoldopam: Renal Function in Hypertensives
C IN
Results
800
160
700
140
600
120
500
400
FND
Placebo
300
ml/min
ml/min
C PAH
100
80
60
200
40
100
20
0
0
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;76:1312-1318
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
• CrCl increased significantly
• Urine flow tended to increase
• Na and potassium excretion tended to increase
• No significant change in blood pressure
Schuster HP, et al. Intensivmedizin 1991;28:348-355
Efficacy: Chronic Renal Insufficiency
Sodium nitroprusside
Fenoldopam
Change (%)
200
160
120
80
40
0
-20
Creatinine
clearance
Urine flow
Sodium
excretion
Potassium
excretion
Shusterman NH, et al. Am J Med 1993;95:161-168
Fenoldopam: Renal Plasma Flow
20
*
*
800
*
700
Fenoldopam
18
16
14
12
600
10
Placebo
500
8
6
400
4
300
2
0
200
Baseline
0.03
0.1
Fenoldopam Concentration (ng/mL)
Renal Plasma Flow (mL/min/1.73m2)
Dose Response of RBF in normotensives
0.3
Infusion Dose (mcg/kg/min)
*p<0.05 compared with placebo with both diets combined
Neurex: data on file
Trials Using IV Fenoldopam
Disease State
Hypertensive emergency
Severe hypertension
Mild-to-moderate hypertension
Postoperative hypertension
CHF
Renal failure
Hepatic disease
Transplant
Other
Total patients
Healthy subjects
Total Experience
Number of
Studies
Number of
Patients/Subjects
1
10
7
3
6
4
4
2
3
94
348
127
89
167
75
48
21
40
1,009
258
1,267
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*
Fenoldopam
Nitroprusside
(n=117)
(n=119)
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
Event
*Neurex: data on file
Adverse Events*
Summary of All IV Studies
Clinical Events
(N = 1,009)
Patients
No. (%)
Headache
Flushing
Nausea
Hypotension
Decreased serum potassium
ECG abnormalities
Tachycardia
Vomiting
Dizziness
Extrasystoles
Dyspnea
116
53
52
48
36
29
29
29
27
23
16
(11)
(5)
(5)
(5)
(4)
(3)
(3)
(3)
(3)
(2)
(2)
*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)
4 mL (40 mg)
2 mL (20 mg)
1 mL (10 mg)
Added to
1000 mL
500 mL
250 mL
Final Concentration
40 g/mL
40 g/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
CR CL <60
No
Yes
Prior Heart
Surgery
IABP
No
Yes
Valve
No
NYHA IV
Yes
0.4%
No
0.9%
NYHA IV
Yes
2.1%
Yes
9.5%
Cardiomegaly
Yes
1.3%
No
No
No
Yes
2.8%
No
PVD
Yes No
NYHA IV
2.3%
1.1%
Yes
5.0%
Valve
No
2.1%
Yes
6.1%
Chertow GM, et al. Circulation 1997;95:878-884
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
Variable
Length of Stay in Critical
Care Unit
Unadjusted
All patients
1. No renal dysfunction
2. Renal dysfunction
3. Renal failure
Length of Stay in Hospital
Ward
Adjusted for
Preoperative
Factors
Unadjusted
Adjusted for
Preoperative
Factors
days
2.0
4.8
11.6
3.1
6.5
14.9
5.9
10.0
12.4
7.5
11.7
13.9
Mangano CM, et al, Ann Intern Med 1998;(3):194-203