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Severe Hypertension:
Disease State Awareness
Hypertensive Crisis: JNC-7 definitions
Hypertensive
emergency
Severe elevation in BP
(>180/120 mmHg)
complicated by evidence of
impending or progressive
target organ dysfunction
Hypertensive
urgency
Severe elevation in BP
without progressive
target organ dysfunction
Hypertensive Crisis
Hypertensive
urgency
Emergency
department
Chobanian AV et al. Hypertension. 2003;42:1206-1252.
Hypertensive
emergency
Intensive care
unit
Perioperative
hypertension
Operating room
post-anesthesia
care
Severe Hypertension: Epidemiology
● Hypertensive emergency1
– Hypertension affects approximately 50 million people in the USA and
approximately 1 billion people worldwide.
– Estimates are that approximately 1% of these patients will develop
hypertensive crisis at some point in their lives
– Hospital admissions for hypertensive emergency tripled from 1983 to 1990
(from 23,000/yr to 73,000/yr) in the USA.
● Perioperative hypertension
– Frequently occurs with cardiovascular surgery (30%–80%)2,3
80% incidence following carotid endarterectomy
– Preoperative incidence: 2,4
50% of cardiac surgery patients
25% of non-cardiac surgery patients
– Intraoperative incidence:2
50% of patients undergoing cardiac surgery
1. Varon J, Marik PE. Crit icalCare. 2003 7:374-384
3. Oparil S et al. Am J Hypertens. 1999;12:653-664.
2. Cheung AT. J Card Surg. 2006;21:S8-S14
4. Goldman L et al. N Engl J Med. 1977;297:845-850
Severe Hypertension: Clinical Outcomes
CHF and
Pulmonary
Edema
Aortic
Dissection
Stroke,
Encephalopathy
Severe
HTN
Renal
Dysfunction
Myocardial
Infarction
Severe Hypertension: End-Organ Damage
108 Hypertensive Emergencies*
End-Organ Damage Type
No. of Cases
(%)
Cerebral infarction
ICH or SAH
Encephalopathy
26
5
18
(24.5)
(4.5)
(16.3)
Acute Pulmonary Edema
Acute CHF
Acute MI
24
15
13
(22.5)
(14.3)
(12)
Aortic Dissection
2
(2)
Eclampsia
5
(4.5)
*All Caucasians
Zampaglione, B. Hypertension 1996;27:144-147.
Severe Hypertension:
Short-Term (Up to 6 months) Outcomes
Acute Condition
ACS1,2,3
CHF4
Severe Hypertension5
1.
2.
3.
4.
5.
OASIS-5 NEJM 2006.
GUSTO IIb NEJM 1996.
GRACE JAMA 2007.
IMPACT-HF J Cardiac Failure 2004.
Kleinschmidt, SAEM, STAT registry, 2008
Death
5-7%
8.5%
7-9%
Rehospitalization
30%
26%
37%
Severe Hypertension:
May Occur Throughout the Hospital
● ED
● MICU
● SICU
● OR
● PACU
Varon J, Fromm RE. Postgrad Med. 1996;99:189-203.
Severe Hypertension: Etiologies
● Medical
– Uncontrolled HTN
- Noncompliance
– Drug-induced HTN
- Cocaine, amphetamines
- Drug withdrawal
- Drug-drug interactions
– Endocrine disorders
● Surgical
– Cardiac surgery
– Major vascular surgery
- Carotid endarterectomy
- Aortic surgery
– Neurosurgery
– Head and neck surgery
– Renal transplantation
– Major trauma – burns or
head injury
Varon J, Fromm RE. Postgrad Med. 1996;99:189-203.
Treatment Goals for Hypertensive Emergency
● Reduce MAP by ≤ 25% during the first minute to 1 hour
● If stable, reduce BP to 160/100-110 mmHg in next 2-6
hours
● Gradual reductions toward normal BP over next 24-48
hours
● Excessive falls in BP may cause renal, cerebral, or
coronary ischemia
● Conditions requiring special management
– Ischemic stroke
– Stroke eligible for thrombolytic agents
– Aortic dissection
Chobanian AV et al. Hypertension. 2003;42:1206-1252.
Use of Intravenous (IV) Antihypertensive Therapy
● Hypertensive emergency
● Hypertensive urgency when oral therapy is not feasible
● Perioperative hypertension
● Special patient populations
–
–
–
–
Hemorrhagic stroke
Ischemic stroke prior to thrombolytics
Aortic dissection
NPO patient
Chobanian AV, et al. Hypertension. 2003;42:1206-1252.
Varon J, Marik PE. CHEST. 2000;118:214-227.
Varon J, Marik PE. Crit Care. 2003;7:374-384.
Severe Hypertension:
Treatment Options
Goals of an Ideal Agent for Treatment of Severe
Hypertension
–
–
–
–
–
–
–
–
–
–
Rapid onset of action
Short acting
Easily titratable
Require minimal dosage adjustments
Minimal risk of hypotension (“overshoot”)
Lack significant side effects
Mild reduction in myocardial contractility
Vascular effects confined to arteriolar bed
Easy conversion to oral agents
Low cost, including drug and monitoring costs
Feneck R. Drugs. 2007;67:2023-2044.
Oparil S et al. Am J Hypertens. 1999;12:653-664.
Rynn KO et al. J Pharm Pract. 2005;18:363-376.
IV Antihypertensive Utilization Trends
All Patients Treated with Drug
1,400,000
1,200,444
1,200,000
2004
1,133,717
2005
2006
1,000,000
800,000
735,647
600,000
502,518
400,000
312,432
240,785
200,000
139,104
8,288
0
Nitroglycerin
Labetalol
Thomson Patient Level Data. 2006
Hydralazine
Enalaprilat
Esmolol
SNP
Nicardipine
Fenoldopam
IV Antihypertensive Agents
Agent
Onset/
Duration
Elimination
Half-Life
Adverse Events
Cautions/Concerns
Enalaprilat
<15 min/
12–24 h
11 h
Precipitous fall in BP in high-renin
states, headache, cough, renal
failure, hyperkalemia, angioedema
Avoid in acute MI, long duration of
action
Esmolol
1–2 min/
10–30 min
2–9 min
Heart block, hypotension, nausea,
bronchospasm, overt heart failure,
cardiogenic shock
Reduces cardiac output, which may
impair organ perfusion
Fenoldopam
mesylate
5–15 min/
30 min–4 h
5 min
Tachycardia, headache, nausea,
dizziness, flushing, hypotension,
increased intraocular pressure
Caution with glaucoma
Hydralazine
10–20 min/
1–4 h
1h
Marked hypotension, tachycardia,
flushing
Avoid in aortic dissection, MI, severe
renal disease; prolonged and
unpredictable effects; difficult to titrate
Labetalol
<5 min/
3–6 h
5.5 h
Bradycardia (heart block), overt
heart failure, cardiogenic shock,
edema, nausea, vomiting
Avoid in acute heart failure; severe
bradycardia; heart block, asthma
Nicardipine
5–15 min/
15 min–6 h
44.8 min
Tachycardia, headache, nausea,
flushing, thrombophlebitis,
hypotension, vomiting
Avoid in acute heart failure; caution
with coronary ischemia; long duration of
action
Nitroglycerin
2–5 min/
5–10 min
1–4 min
Flushing, headache, vomiting,
hypotension, methemoglobinemia,
decreased arterial resistance, reflex
tachycardia
Reduction in preload and cardiac
output undesirable in patients with
compromised renal and cerebral
perfusion
Sodium
nitroprusside
Immediate/
2–3 min
2–3 min
Nausea, muscle twitching,
sweating, thiocyanate and cyanide
intoxication, hypotension
Increases intracranial pressure; may
reduce coronary perfusion pressure
(coronary “steal”); cyanide toxicity
Adapted from: Chobanian AV, et al. Hypertension. 2003;42:1206-1252.
Rynn KO et al. J Pharm Pract. 2005;18:363-376.
Enalaprilat
● ACE Inhibitor
– Reduces vasoconstriction and circulating catecholamine levels
– Balanced reduction in afterload and pre-load
– Reduces CVP, PCWP, SVR, with minimal effect on CO, HR
● Pharmacokinetics
– Moderate to slow onset of action
– Longer duration of action
– Full effect may not be seen for 24 hours
● May cause hypotension, acute renal failure,
hyperkalemia, cough, angioedema, and rash
Rynn KO et al. J Pharm Pract. 2005;18:363-376.
Esmolol
● B1 selective adrenergic blocker
– Reduction in heart rate (HR) and cardiac output (CO)
– May see increase in PCWP, CVP, and SVR
● Rapid onset and short duration of action
● Elimination via plasma esterases
● May cause bradycardia, bronchospasm, seizures, and
pulmonary edema
Rynn KO et al. J Pharm Pract. 2005;18:363-376.
Labetalol
● Non-selective adrenergic blocker
–
–
–
–
Alpha-1, Beta-1, Beta-2
1:7 ratio of alpha:beta effects
Reduces SVR with little effects on HR, CO
Little to no effect on cerebral blood flow
● Moderate onset, long duration of action
● Commonly used in HTN emergency and in ICH
● Generally given by IV bolus in ED, OR; IV infusion used in
ICU
● May cause bronchospasm, bradycardia, heart block,
delayed hypotension
Rynn KO et al. J Pharm Pract. 2005;18:363-376.
-Blocker vs Combined - and -Blocker
Parameters
Administration
Onset
Offset (Duration of action)
HR
SVR
Cardiac output
Myocardial O2 balance
Contraindications
Esmolol
-Blocker
Labetalol
- and -Blocker
Bolus
Continuous infusion
Bolus
Continuous infusion
Rapid (60 s)2
Intermediate (peak 5-15 min)2
Rapid (10-20 min)2
Slower (2-4 h)2
Decreased
+/-
0
Decreased
Decreased
+/-
Positive
Positive
Sinus bradycardia
Heart block >1°
Overt heart failure
Cardiogenic shock
Severe bradycardia
Heart block >1°
Overt heart failure
Cardiogenic shock
1. Hoffman BB. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of
Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:215-268.
2. Varon J, Malik PE. Chest. 2000;118:214-227.
Nitroglycerin
● At lower doses, works primarily by ↓ preload
– Reduces CVP, PCWP
● At higher doses, works primarily by ↓ afterload
– Some reduction in SVR, further reduction PCWP
– Increase HR
● Administered as continuous infusion; onset of action
2-5 min; duration of action 5-10 min
● Useful in managing BP
– Angina patients: improved coronary blood flow
– Pulmonary edema/heart failure: decreasing preload
● Limitations: tachyphylaxis, headache, significant
hypotensive effects in patients who are hypovolemic,
caution in RCA IHD
Rynn KO et al. J Pharm Pract. 2005;18:363-376.
Hydralazine
● Directly relaxes arteriolar smooth muscle – reduction in
afterload
– Reduces SVR
– Increases HR
● Used primarily in management of preeclampsia and
eclampsia although some use in the OR, in combination
with pure beta-blockers in patients who are difficult to
control
● Moderate onset; long duration of action
● Limitations:
– reflex tachycardia often dose limiting
– use associated with lupus-like syndrome
Rynn KO et al. J Pharm Pract. 2005;18:363-376.
Sodium Nitroprusside
● Arterial and venous vasodilator
– ↓Preload and afterload
– Reduces SVR, CVP
– Increases HR
● Onset: Immediate
● Duration of action: 1-2 min
● Adverse effects
– Tachycardia, nausea, vomiting, muscle twitching, sweating,
thiocyanate and cyanide intoxication, coronary steal,
maldistribution of blood flow
● Light sensitive: requires special delivery system
Rynn KO et al. J Pharm Pract. 2005;18:363-376.
Nicardipine
● Dihydropyridine calcium channel blocker
– Coronary and cerebral arterial vasodilation
– No negative inotropic or dromotropic effects
– Reduces SVR, little to no effect on HR/CO
● Onset: 5-15 min
● Duration of action: 15 min-6 hours
● Adverse effects:
– Tachycardia (+/-), headache, flushing, local phlebitis
– Fluid load may be an issue for some patients
Adapted from: Chobanian AV, et al. Hypertension. 2003;42:1206-1252.
Rynn KO et al. J Pharm Pract. 2005;18:363-376.
Cleviprex
(clevidipine butyrate)
Cleviprex is a diydropyridine calcium channel blocker indicated for the reduction of blood pressure
when oral therapy is not feasible or not desirable. Please see full prescribing information.
Clevidipine: Overview
● Dihydropyridine calcium channel blocker (CCB)
● T½ ≈ 1 min
● Selective arteriolar dilation
↓ Systemic vascular resistance
↓ Afterload
↑ Stroke volume
↑ Cardiac output
● No venous dilation
– No effect on cardiac filling pressure
● No effect on HR
● Clevidipine is selective for vascular as opposed to myocardial
smooth muscle
Nordlander M et al. Cardiovasc Drug Rev. 2004;22:227-50.
Clevidipine:
Metabolized by Plasma and Tissue Esterases
Clevidipine is rapidly metabolized by esterases in
blood and extravascular tissue to an inactive
carboxylic acid metabolite and formaldehyde
Cl
Cl
Cl
O
O
O
O
Esterases
O
O
O
Cl
HO
OH
O
O
N
H
Clevidipine
O
N
H
Primary metabolite
Reproduced from: Ericsson H, et al. Eur J Clin Pharmacol. 1999;55:61-67.
Ericsson H, et al. Eur J Pharm Sci. 1999;8:29-37.
+
H
H
+
O
Clevidipine: Pharmacokinetics
● Clevidipine butyrate is >99.5% bound to proteins in
plasma at 37°C
● Carboxylic acid metabolite is inactive as an
antihypertensive
● In vitro studies show that clevidipine butyrate and its
metabolite at the concentrations achieved in clinical
practice will not inhibit or induce any CYP enzyme
● 83% of the drug is excreted in the urine or feces, with the
major fraction (63-74%) excreted in urine
Clevidipine Product Information August 2008; The Medicines Company
Vascular and Myocardial Inhibitory Potency of
Various Calcium Antagonists*
In vitro studies comparing effects of calcium antagonists on isolated rat
portal vein (vascular) vs. left ventricular rat papillary muscle (myocardial)
pIC50
Compounds
IC50
Vascular
Myocardial
Selectivity
Ratio
Verapamil
6.6
6.46
1.4
Diltiazem
6.36
5.5
7
Nifedipine
7.62
6.47
14
Felodipine
7.47
5.40
118
Clevidipine
6.37
4.69
48
*Clinical significance of selectivity is unknown
Nordlander M et al. Cardiovasc Drug Rev. 2004;22:227-50.
Clevidipine Clinical Development
Phase I
Phase II
Phase III
N=89
N=300
N=1821
Healthy Volunteers
Patients: Mild to
Moderate Hypertension
N=86
Patients:
Perioperative
N=214
Perioperative
Hypertension
N=1721
Severe
Hypertension
N=100
Tolerability,
Safety, PK
Dose Response
Dose Response:
Clevidipine
vs Placebo
ESCAPE: Efficacy
Clevidipine
vs Placebo
VELOCITY:
Severe Hypertension
PK, Metabolism,
Rates and Routes
of Excretion
PK/BP
Hemodynamics:
Clevidipine vs SNP
ESCAPE: Efficacy
Clevidipine
vs Placebo
PK
PK/PD:
Clevidipine
vs Placebo
BP, HR:
Clevidipine vs SNP
ECLIPSE:
Safety vs NTG
BP, Dose/PK
ECLIPSE:
Safety vs SNP
BP: Clevidipine
vs Placebo
ECLIPSE:
Safety vs NIC
QTc Study
Data on file. The Medicines Company.
Clevidipine: Linear Pharmacokinetics
At steady state, there is a linear relationship between dosage and
arterial blood concentrations
N=12 normal volunteers
Clevidipine Concentration
at Css (nmol/L)*
120
100
80
60
40
20
0
0
5
10
15
20
Dose Rate (nmol/kg/min)
25
30
35
*Css = concentration at steady state; median blood concentration of clevidipine obtained during the last 10 minutes of infusion.
Reproduced from Ericsson H, et al. Anesthesiology. 2000;92:993-1001.
Clevidipine: Linear Dose Response
Phase II dose-ranging study in cardiac surgery patients with hypertension
n=19
100
90
n=9
Responders* (%)
80
70
n=6
60
50
40
n=4
30
20
10
n=1
n=0
0
0
0.05
0.18
0.32
1.37
3.19
Infusion Rate (mcg/kg/min)
*Responders = treatment success: >10% decrease in MAP or >20% decrease in MAP at each measured concentration.
Bailey JM et al. Anesthesiology. 2002;96:1086-1094.
Clevidipine: Ultrashort Half-Life
● Approximate initial phase half-life: 1 min*
Triphasic Elimination
arterial measurements
venous measurements
Representative subject – normal volunteer
Graph developed from mean concentrations
following 7 nmol/kg/min dose given over a 20
minute period;.
Reproduced from Ericsson H et al. Anesthesiology. 2000;92:993-1001.
*Accounts for 85-90% of clevidipine butyrate elimination. Clevidipine Product Information
August 2008; The Medicines Company
Clevidipine: Rapid Onset
BP-lowering effects seen within 1-2 min of clevidipine infusion
Systolic Blood Pressure
Mean % Change From Baseline
10
5
0
–5
–10
–15
–20
–25
–30
0
5
Levy JH et al. Anesth Analg. 2007;1-5:918-925
10
15
20
Time (min)
25
30
N=105
Clevidipine: Rapid Offset
100
Clevidipine Infusion
MAP
MAP (mm Hg)
90
80
70
60
50
40
–5
0
5
10
15
20
25
30
35
Time (min)
N=12 normal volunteers
Reproduced from Ericsson H, et al. Anesthesiology. 2000;92:993-1001.
Clevidipine: Hemodynamics
Effects of Clevidipine on systemic hemodynamics after elective coronary bypass surgery in 9 patients
Systemic Vascular
Resistance
Mean Arterial
Pressure
†
†
†
70
Units
mm Hg
*
1000
0
C1 0.375 0.75 1.5 3 C2
mcg/kg/min
‡
1200
†
†
†
C1 0.375 0.75 1.5 3 C2
mcg/kg/min
C1 is baseline/control before CLV administered
mm Hg
1400
90
80
Central Venous
Pressure
12
10
8
6
4
2
0
C1 0.375 0.75 1.5 3
C2
mcg/kg/min
C2 is post-CLV control after CLV discontinued
*P<0.05, †P<0.001, ‡P<0.01, control vs 0.375, 0.75, 1.5, and 3.0 mcg/kg/min–1 and post-drug control.
Values are mean ± SEM.
Adapted from: Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:186-193.
Clevidipine: Hemodynamics
Effects of Clevidipine on systemic hemodynamics after elective coronary bypass surgery in 9 patients
Cardiac Output
Stroke Volume
†
C1
0.375 0.75
1.5
3
*
75
mL/beat
L • min–1
*
6
5
4
3
2
1
0
C2
70
65
0
C1
Infusion Rate
(µg • kg–1 • min–1)
C1 is baseline/control before CLV administered
0.375 0.75
1.5
3
C2
Infusion Rate
(µg • kg–1 • min–1)
C2 is post-CLV control after CLV discontinued
*P<0.05. †P<0.001.
SVR = systemic vascular resistance; RVEDV = right ventricular end-diastolic volume
Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:186-193.
Clevidipine: Effect on Heart Rate
10
5
HR
0
–5
0
5
10 15 20
Time (min)
Postoperative HR Changes
in Anesthetized Patients
N=61
% Change From Baseline
% Change From Baseline
Preoperative HR Changes
in Non-Anesthetized Patients
N=53
25
30
HR change for patients during the
30-minute treatment period
Levy JH et al. Anesth Analg. 2007;105:918-925.
Singla N et al. Anesthesiology. 2005;103:A292.
5
0
HR
–5
0
5
10 15 20
Time (min)
25
30
HR change for patients during the
30-minute treatment period
Clevidipine: Pharmacodynamics
● Clevidipine is titrated to the desired reduction in blood pressure.
The infusion rate for which half the maximal effect is observed is
approximately 10 mg/hr.
● Onset: In the perioperative patient population, clevidipine
produces a 4-5% reduction in SBP within 2-4 min of starting a 0.4
mcg/kg/min infusion (approximately 1-2 mg/hr).
● Offset: In most patients, full recovery of blood pressure is
achieved within 5-15 minutes after the infusion is stopped.
● Duration of effect: In studies up to 72 hours, there was no
evidence of tolerance; in these studies, if patients were not
transitioned to other antihypertensive therapies, there was some
evidence of rebound hypertension following discontinuation of
clevidipine therapy.
Clevidipine Product Information August 2008; The Medicines Company
Clevidipine: Pharmacodynamics
● Hemodynamics: Clevidipine causes a dose-dependant
decrease in systemic vascular resistance
● Heart rate: An increase in heart rate is a normal
response to vasodilation and decrease in blood
pressure; in some patients these increases in heart
rate can be pronounced. If this occurs, decrease the
dose of clevidipine.
● Electrophysiologic effects: In healthy volunteers,
clevidipine butyrate or its major carboxylic acid
metabolite, at therapeutic and supratherapeutic
concentrations (approximately 2.8 times steady state),
did not prolong cardiac repolarization.
Clevidipine Product Information August 2008; The Medicines Company
IMPORTANT SAFETY INFORMATION
● Cleviprex is intended for intravenous use. Titrate drug depending on the
response of the individual patient to achieve the desired blood pressure
reduction. Monitor blood pressure and heart rate continually during
infusion, and then until vital signs are stable. Patients who receive
prolonged Cleviprex infusions and are not transitioned to other
antihypertensive therapies should be monitored for the possibility of
rebound hypertension for at least 8 hours after the infusion is stopped.
● Cleviprex is contraindicated in patients with allergies to soybeans, soy
products, eggs, or egg products; defective lipid metabolism such as
pathologic hyperlipemia, lipoid nephrosis, or acute pancreatitis if it is
accompanied by hyperlipidemia; and in patients with severe aortic
stenosis.
● Hypotension and reflex tachycardia are potential consequences of rapid
upward titration of Cleviprex. Dihydropyridine calcium channel blockers
can produce negative inotropic effects and exacerbate heart failure.
Monitor heart failure patients carefully. Cleviprex gives no protection
against the effects of abrupt beta-blocker withdrawal.
Cleviprex is a diydropyridine calcium channel blocker indicated for the reduction of blood pressure
when oral therapy is not feasible or not desirable. Please see full prescribing information.
Clevidipine Product Information August 2008; The Medicines Company
IMPORTANT SAFETY INFORMATION:
continued
● Most common adverse reactions (> 2%) are headache, nausea, and
vomiting.
● Cleviprex should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
● Maintain aseptic technique while handling Cleviprex. Cleviprex contains
phospholipids and can support microbial growth. Do not use if
contamination is suspected. Once the stopper is punctured, use and
discard within 4 hours.
Cleviprex is a diydropyridine calcium channel blocker indicated for the reduction of blood pressure
when oral therapy is not feasible or not desirable. Please see full prescribing information.
Clevidipine Product Information August 2008; The Medicines Company