Vascular Dysfunction:

Sequelae of Acute
Hypertension
Overview

Introduction: Scope of the problem

Effects of acute BP elevation on the vessel wall
Traditional parenteral antihypertensive treatment
Pharmacokinetic profiles and key clinical studies
Guidelines for use

Clinical trial update: New paradigm in management

of acute hypertension
Acute and chronic hypertension: Clinical context

Chronic
hypertension

Acute
vascular
reactivity

Hypertensive
emergencies
Courtesy of S Aronson, MD.
Sympathetic overactivation drives acute
hypertension

Chronic hypertension Arteriosclerosis

Sympathetic overactivation

Acute hypertension

Important triggers include clonidine withdrawal, cocaine abuse,

certain surgical settings

Calhoun DA, Oparil S. N Engl J Med. 1990;323:1177-83.

Cheung AT. J Card Surg. 2006;21(suppl):S8-14.
Weitz HH. Med Clin North Am. 2001;85:1151-69.
Components of blood pressure: New focus on
pulse pressure

PRESSURE

HR x SV = CO
BP*/ CO = SVR
CO x MAP = work
MAP = 1/3 PP + DBP

All in the absence of pulsations

FLOW

Courtesy of S Aronson, MD.

Perioperative ISH associated with postoperative
adverse events
N = 2069 scheduled for CABG

Event rate (%) Odds ratio

No ISH ISH
(n = 1457) (n = 612)

Renal failure/insufficiency 6.7 8.8 1.3 (0.9-1.9)

Stroke 6.3 10.1 1.7 (1.2-2.3)

LV dysfunction 29.1 34.3 1.3 (1.0-1.6)

Renal failure/insufficiency, 33.2 40.9 1.4 (1.1-1.7)

stroke, LV dysfunction, death

ISH = isolated systolic hypertension Aronson S et al. Anesth Analg. 2002;94:1079-84.

Proposed risk index for renal dysfunction/failure
post-CABG: Importance of pulse pressure
N = 4801 scheduled for bypass

Preoperative risk factors Score Intraoperative risk factors Score

Age >75 years 7 >2 Inotropes 10

Pulse pressure (mm Hg) Intra-aortic balloon pump 15

40 0
Cardiopulmonary bypass 6
41-60 4
122 min
61-80 8
81-100 12
>100 16

History
CHF 9
MI 6
Renal disease 13

Multicenter Study of Perioperative Ischemia (McSPI) Aronson S et al. Circulation. 2007;115:733-42.

Acute hypertension:
Subgroups and settings

Acute hypertension

Hypertensive Hypertensive Perioperative

urgency emergency hypertension

Emergency Intensive care Operating room

department unit Postanesthesia care
JNC 7 definitions

Hypertensive emergency BP >180/120 mm Hg complicated by

evidence of impending or
progressive end-organ damage

Hypertensive urgency Severe elevation in BP without

progressive end-organ damage

Chobanian AV et al. Hypertension. 2003;42:1206-52.

Hypertensive urgencies/emergencies:
Patients and organ systems at risk
1% of hypertensives (1990 data). Contemporary prevalence may be lower

Cardiopulmonary Ocular
ADHF Papilloedema
ACS
Acute pulmonary edema Renal
Acute aortic syndromes Acute renal dysfunction

Neurovascular
Hypertensive encephalopathy
Stroke

ACS = acute coronary syndrome Calhoun DA, Oparil S. N Engl J Med. 1990;323:1177-83.
ADHF = acute decompensated heart failure Marik PE, Varon J. Chest. 2007;131:1949-62.
Hypertensive urgencies/emergencies:
Prevalence of organ system complications
N = 449 presenting to Emergency Department with hypertensive
urgency/emergency
Incidence (%)
CNS
Cerebral infarction 24.5
Hypertensive encephalopathy 16.3
Intracerebral/subarachnoid hemorrhage 4.5
CV
Pulmonary edema 22.5
Acute congestive heart failure 14.3
ACS 12.0
Eclampsia 4.5
Aortic dissection 2.0

Zampaglione B et al. Hypertension. 1996;27:144-7.

Hypertensive urgencies/emergencies:
Most common presenting symptoms

Urgencies Emergencies
Headache (22%) Chest pain (27%)
Epistaxis (17%) Dyspnea (22%)
Faintness and psychomotor Neurological deficit (21%)
agitation (10%)

Zampaglione B et al. Hypertension. 1996;27:144-7.

Perioperative hypertension:
Scope of the problem

Generally acknowledged to be common but little data

available on exact prevalence in contemporary surgical
practice
Markers of increased risk for perioperative BP include:
History of hypertension
Type of surgery
Cardiac
Carotid
Peripheral vascular
Abdominal aortic
Intraperitoneal/intrathoracic
Pheochromocytoma tumor
Skarvan K. Curr Opin Anaesthesiol. 1998;11:29-35.
Weitz HH. Med Clin North Am. 2001;85:1151-69.
Erstad BL, Barletta JF. Ann Pharmacother. 2000;34:66-79.
Perioperative antihypertensive therapy is
common in cardiac surgery
N = 1660 patients, (N = 191 anesthesiologists)
100 Prior hypertension (n = 845)
90 No prior hypertension (n = 815)
80
70
60
Patients 50
(%)
40
30
20
10
0
Preoperative Intraoperative Postoperative ICU

Mean MAP 106.0 86.3 97.1 109.0

threshold for
treatment (mm Hg)
Vuylsteke A et al. J Cardiothorac Vasc Anesth. 2000;14:269-73.
Effects of Acute
BP Elevation on
the Vessel Wall
Pathophysiology overview

Sustained neurohormonal activation and vasoconstriction leads to

Endothelial decompensation
Altered vascular structure

Vicious cycle of homeostatic failure begins, leading to

Loss of cerebral and local autoregulation
Organ system ischemia and dysfunction
Myocardial infarction
 Pathophysiology of hypertension

INAPPROPRIATELY HIGH
SYMPATHETIC OUTFLOW

Increased large
arterial stiffness

Abnormal venoconstriction
and high venous return Inappropriately high Increased
cardiac output systemic
resistance

INAPPROPRIATELY HIGH ABNORMAL RENAL

RENIN RELEASE SALT/WATER HANDLING
Courtesy of JL Izzo Jr, MD.
The endothelium modulates vascular tone

Catecholamines
NO AT-II
Endogenous Endogenous TxA2
vasodilators vasoconstrictors
ET1
PGI2 Aldosterone
ADH (vasopressin)

Courtesy of JJ Ferguson III, MD.

Proposed vascular pathophysiology
of hypertensive urgency

CAMs Catecholamines
NO AT-II
Endogenous TxA2
Endogenous
vasodilators
(-) (+) vasoconstrictors ET1
PGI2 Aldosterone
ADH (vasopressin)

Acute BP triggers cellular adhesion molecular expression

Vaughan CJ, Delanty N. Lancet. 2000;356:411-7.

Courtesy of JJ Ferguson III, MD.
Proposed vascular pathophysiology
of hypertensive emergency

TxA2

Overwhelmed control of vascular tone leads to coagulation cascade activation

Loss of endothelial activity coupled with coagulation and platelets promotes DIC

Vaughan CJ, Delanty N. Lancet. 2000;356:411-7.

Courtesy of JJ Ferguson III, MD.
Endothelial shear stress
Proportional to the product of blood
viscosity () and spatial gradient of
blood velocity at the wall (dv/dy).

ESS = endothelial shear stress Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.

Endothelial mechanoreceptors sense changes
in shear stress

ESS = endothelial shear stress Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.

Shear stress rapidly activates endothelial signal
transduction and gene expression

Signal Transduction Gene Expression

Maximum activation Maximum
activation

Activation
Activation

Basal activity
Basal activity
Ras
ERK MCP-1 mRNA
JNK C-fos mRNA

min min
0 30 60 0 60 120 180 240

Chien S et al. Hypertension. 1998;31[part 2]:162-9.

Definition and example of pulsatile, low, and
oscillatory ESS

Low and oscillatory ESS

(<10-12 dyne/cm2)
- Direction: Bidirectional (oscillatory)
- Magnitude: Low time-average

Pulsatile ESS
(15-70 dyne/cm2)
- Direction: Unidirectional
- Magnitude: Physiologic time-average

Cross-section

Blood
flow

ESS = endothelial shear stress Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.

Implications of low and high shear stress

Effects of low Effects of high

shear stress shear stress

Atherosclerosis Endothelial dysfunction

Plaque rupture Vascular injury
Thrombosis
Neurohumoral activation
Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.
Perioperative triggers
of adverse physiologic states

Surgical trauma Physiologic state

Anesthesia/analgesia Inflammatory

Intubation/extubation
Hypercoagulable
Pain
Hypothermia Stress
Bleeding/anemia
Fasting Hypoxia

Transfusion

Devereaux PJ et al. CMAJ. 2005;173:627-34.

Proposed mechanisms of perioperative MI
Hypercoagulable
Inflammation Stress Hypoxia
state

TNF- PAI-1 Catecholamine and Oxygen delivery

IL-1 Factor VIII cortisol levels
IL-6 Platelet reactivity
CRP Antithrombin III

Coronary artery BP
shear stress HR
Plaque fissuring FFAs
Relative insulin
Plaque fissuring deficiency

Oxygen demand

Acute coronary Myocardial

thrombosis ischemia

Perioperative myocardial infarction

Devereaux PJ et al. CMAJ. 2005;173:627-34.

Summary: The pathophysiology of acute
hypertensive syndromes

Mechanical
Release of humoral
BP stress on the
vasoconstrictors
vessel wall

Further release of BP
humoral Pressure
vasoconstrictors natriuresis

Volume
Fibrinoid necrosis depletion
of small blood Endothelial
vessels damage
RAAS Vasopressin
activation endothelin
Activation of the catecholamines
Major physiologic
clotting cascade derangements
Courtesy of JJ Ferguson III, MD.
Pathophysiology of acute hypertensive
syndromes: A vicious cycle

Vasoconstrictor release

Tissue Vascular
ischemia injury

Courtesy of JJ Ferguson III, MD.

Traditional Parenteral
Antihypertensive
Treatment

Pharmacology and selected clinical trials

Profile of an ideal parenteral antihypertensive

Treats underlying pathophysiology

Rapid onset of action
Predictable dose response
Minimal dosage adjustments
Highly selective
No increase in intracranial pressure
Rapidly reversible
Low risk of overshoot hypotension or adverse reaction
Easy conversion to oral agents
Acceptable cost-benefit ratio
Levy JH. Anesthesiol Clin North Am. 1999;17:567-79.
Oparil S et al. Am J Hypertens. 1999;12:653-64.
Sodium nitroprusside: Profile

Arterial and venodilator

Preload and afterload

Onset: Immediate
Duration of action: 1-2 min
Adverse effects
Nausea, vomiting, muscle twitching, sweating, thiocyanate and
cyanide intoxication, coronary steal, maldistribution of blood
flow

Light sensitive: requires special delivery system

Chobanian AV et al. Hypertension. 2003;42:1206-52.
Aggarwal M, Khan IA. Cardiol Clin. 2006;24:135-146.
Esmolol: Profile

Blocks 1 receptors of heart and vasculature

Heart rate, cardiac output, and stroke volume

Onset: 1-2 min

Duration of action: 10-30 minutes
Adverse effects:
Hypotension, nausea, asthma, 1st degree heart block, HF

Chobanian AV et al. Hypertension. 2003;42:1206-52.

Aggarwal M, Khan IA. Cardiol Clin. 2006;24:135-146.
Fenoldopam: Profile

Selective dopamine-1 receptor agonist

Peripheral vascular resistance
Renal blood flow, natriuresis, and diuresis

Onset: <5 min

Duration of action: 30 min
Adverse effects:
Tachycardia, headache, nausea, flushing

Chobanian AV et al. Hypertension. 2003;42:1206-52.

Oparil S et al. Am J Hypertens. 1999;12:653-664.
Labetalol: Profile

1- and 1-receptor blocker

Peripheral vascular resistance (1 blockade)
No reflex tachycardia (1 blockade)
Maintains coronary, cerebral, and renal blood flow

Onset: 5-15 min

Duration of action: 4-6 hours
Adverse effects:
Vomiting, scalp tingling, bronchoconstriction, dizziness, nausea,
heart block, orthostatic hypotension

Chobanian AV et al. Hypertension. 2003;42:1206-52.

Marik P, Varon J. Chest. 2007;131:1949-62.
Nicardipine: Profile

2nd generation dihydropyridine calcium channel blocker

Coronary and cerebral arterial vasodilation
No negative inotropic or dromotropic effects
Systemic vascular resistance

Onset: 5-15 min

Duration of action: 15-30 mins
Adverse effects:
Tachycardia, headache, flushing, local phlebitis

Chobanian AV et al. Hypertension. 2003;42:1206-52.

Levy JH. Tex Heart Inst J. 2005;32:467-71.
BP reduction with IV nicardipine
15 10 8
200
180
160
140
mm Hg

120
100
80
60
40
20
0
3:00 4:00 5:00 6:00 7:00 8:00 9:00
Time
Target
SBP Target SBP MAP DBP
MAP Range
Courtesy of WF Peacock, MD
Nicardipine vs SNP for perioperative
hypertension
N = 139 following cardiac or noncardiac surgery

# Dose changes
Time to
response Cardiac Noncardiac Adverse
(min) patients patients events

14.1 1* 1.5 0.2 1.6 0.1 7%

Nicardipine
(n = 51) (n = 18) (n = 33) (5/71)

30.4 3.5 5.1 1.4 4.6 0.6 18%

SNP
(n = 51) (n = 15) (n = 36) (12/68)

*P = 0.0029 vs SNP, P 0.05 vs SNP

Significant treatment differences

in 2/5 centers (P < 0.05) Halpern NA et al. Crit Care Med. 1992;20:1637-43.
Fenoldopam vs SNP in acute hypertension:
Similar hemodynamic effects
N = 153 evaluable patients; acute end-organ damage not a study requirement

250

* *
200

150
Blood
Heart rate
pressure
100 (bpm)
(mm Hg)
110

90

70
Baseline Start 0.5 1.0 2.0 4.0 6.0 End

Maintenance time (hours)

Fenoldopam (FNP) SNP

*P < 0.05 FNP vs SNP Panacek EA et al. Acad Emerg Med. 1995;2:959-65.
Fenoldopam vs dopamine: Similar effects
on perioperative renal function
N = 80 cardiac surgery patients at high risk for perioperative renal
dysfunction*
45
40
35
30
Patients 25 Fenoldopam
(%) 20 Dopamine
15
10
5
0
Cr elevation Cr elevation Renal replacement
25% 50% therapy
Bove T et al.
*Continuous Improvement in Cardiac Surgery Program score >10 Circulation. 2005;111:3230-5.
Currently available parenteral antihypertensive
treatments: Summary

Many options are available, offering vasodilation

via a number of different mechanisms
All are associated with limitations
Short-acting formulations with improved safety profile
vs sodium nitroprusside and minimal effects on heart
rate, CNS, contractility, and intracranial pressure are
now available

Oparil S et al. Am J Hypertens. 1999;12:653-64.

Newer Parenteral
Antihypertensive
Treatment

Pharmacology
Parenteral antihypertensive treatment
Approved Class Investigational Class
SNP Vasodilator Nesiritide B-type natriuretic peptide

Esmolol -blocker Diazoxide* K+ channel agonist

Phentolamine -blocker Torsemide* Loop diuretic

Nitroglycerin Vasodilator

Fenoldopam D1 agonist
Nicardipine CCB
Labetalol /-blocker
Hydralazine Vasodilator
Enalaprilat ACEI
Clevidipine CCB

Chobanian AV et al. Hypertension. 2003;42:1206-52.

Nordlander M et al. Cardiovasc Drug Rev. 2004;22:227-50.
Peacock WF et al. Am J Emerg Med. 2005;23:327-31.
*Limited data only Hennessy A et al. ANZJOG. 2007;47:279-85.
Calcium channel blockers in acute hypertension

1st generation: Nifedipine

2nd generation: Nicardipine

3rd generation: Clevidipine

Marik PE, Varon J. Chest. 2007;131:1949-62.

Clevidipine: Pharmacokinetic overview

Dihydropyridine calcium channel blocker (CCB)

T 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
Nordlander M et al. Cardiovasc Drug Rev. 2004;22:227-50.
Clevidipine: Principles of use

Clevidipine is indicated for the reduction of blood

pressure when oral therapy is not feasible or not
desirable
Linear relationship between dosage and arterial blood
concentrations
Relationship maintained for dose rates up to 7 nmol/kg per min

Rapid clearance following infusion discontinuation

BP returns to baseline within 10 min

Ericsson H et al. Anesthesiology.

Anesthesiology. 2000;92:993-
2000;92:993-1001.
Clevidipine prescribing information. http://www.cleviprex.com/media/ClevidipinePI.pdf
http://www.cleviprex.com/media/ClevidipinePI.pdf..
Nesiritide: Pharmacokinetic overview

Recombinant B-type natriuretic peptide (BNP)

Venous and arteriolar dilation
Preload
Afterload
Cardiac output

No direct inotropic effects

Approved only for treatment of acute decompensated
heart failure

Marcus LS et al. Circulation. 1996;94:3184-9.

Zellner C et al. Am J Physiol. 1999;276:H1049-57.
Hypertensive
Urgencies/Emergencies:
Guidelines
Hypertensive emergencies: JNC 7 consensus
recommendations*

Admit to ICU
Administer short-acting parenteral antihypertensive
with close monitoring
BP by 25% within 1 hour
BP to 160/100-110 mm Hg over next 2-6 hours
BP to 130/85 mm Hg over next 24-48 hours

*Expert opinion Chobanian AV et al. Hypertension. 2003;42:1206-52.

Hypertensive urgencies: JNC 7 consensus
recommendations*

Some patients may benefit from short-acting oral

antihypertensive treatments
However, in one recent study, resting for 60 min was associated
with BP of >20% in 1/3 of patients
In addition, no evidence that failure to BP in emergency
department is associated with short-term risk

Adjust or reinstitute antihypertensive regimen

to gradually BP over next few days

Chobanian AV et al. Hypertension. 2003;42:1206-52.

*Expert opinion Duarte M et al. Presented at ASH. 2006.
JNC 7: Treatment of acute hypertension in
preeclampsia
Consider if childbirth is imminent

Dosing Precautions

Hydralazine 5 mg IV bolus, then 10 mg

q20-30 min to max 25 mg;
Repeat in several hr
Labetalol 20 mg IV bolus, then
(second-line) 40 mg 10 min later, 80 mg
q10 min for 2 additional
doses to max 220 mg
Nifedipine 10 mg po, repeat q20 min Precipitous BP when
(controversial) to max 30 mg using with MgSO4

SNP 0.25 g/kg per min to max Cyanide poisoning may

(rarely-when others fail) 5 g/kg per min occur if used >4 hr

Chobanian AV et al. Hypertension. 2003;42:1206-52.

BP management in acute aortic syndrome

Goal: Decrease aortic wall stress by rapidly BP and HR

IV -blockers and SNP or oral ACEI

IV CCBs if -blockers contraindicated

All patients should also be evaluated to determine if surgical management

is necessary

Nienaber CA, Eagle KA. Circulation. 2003;108:772-8.

Marik PE, Varon J. Chest. 2007;131:1949-1962.
AHA/ASA guideline: BP management
in acute hemorrhagic stroke

SBP >200 mm Hg or MAP >150 mm Hg

Consider aggressive BP with continuous IV infusion
Monitor BP q5 min

SBP >180 mm Hg or MAP >130 mm Hg; ICP evident or suspected

Monitor ICP
Administer intermittent or continuous IV antihypertensive treatment
to keep cerebral perfusion pressure 60-80 mm Hg

SBP >180 mm Hg or MAP >130 mm Hg and no ICP

Administer intermittent or continuous IV antihypertensive treatment
to achieve modest BP (eg, target BP 160/90 mm Hg or MAP 110 mm Hg)
Reexamine patient q15 min

ICP = intracranial pressure Broderick J et al. Stroke. 2007;38:2001-23.

AHA/ASA guideline: BP management
in acute ischemic stroke
Candidates for rtPA or other acute reperfusion intervention

Labetalol 10-20 mg IV
over 1-2 min
May repeat once

or
SBP >185 mm Hg If BP not
or Nitropaste 1-2 in controlled,
DBP >110 mm Hg consider
or SNP
Nicardipine infusion 5 mg/hr
and uptitrate by 2.5 mg/hr
q5-10 min
When desired BP attained,
reduce to 3 mg/hr

rtPA = recombinant tissue plasminogen activator Adams HP Jr et al. Stroke. 2007;38:1655-711.

Hypertensive urgencies/emergencies: Issues

Lack of consensus on defining emergencies and

urgencies
Clinical trial data lacking:
BP target
BP measure (SBP, DBP, MAP?)
Prevalence in disease states other than chronic hypertension

Consensus that overly rapid BP may result in

cerebral/coronary/renal hypoperfusion
Patients have rightward shift of end-organ autoregulatory curve

Adapted from Cherney D, Straus S. J Gen Intern Med. 2002;17:937-45.

Chobanian AV et al. Hypertension. 2003;42:1206-52.
Perioperative Hypertension:
Guidelines
Perioperative hypertension:
No consensus on degree of BP control

No formal guidelines on definitions, treatment

strategies, and BP goals
General strategy is to maintain MAP 20% of baseline
Treatment threshold in clinical studies varies:
MAP: 90-110 mm Hg
SBP: 110-175 mm Hg
DBP: 95-110 mm Hg

Cheung AT. J Card Surg. 2006;21(suppl):S8-14.

Vuylsteke A et al. J Cardiothorac Vasc Anesth. 2000;14:269-73.
Management of
Hypertensive
Emergencies
New paradigm in treatment of acute hypertension

Acute vascular injury has chronic sequelae

SBP too high SBP too low

Cardiac overload Thrombosis?
Vascular damage Organ dysfunction

Prevention of exaggerated BP variation (too high/too low) is desirable

Courtesy of JL Izzo Jr, MD.

Hypertensive urgencies/emergencies: Issues

Lack of consensus on defining emergencies and

urgencies
Consensus that overly rapid BP may result in
cerebral/coronary/renal hypoperfusion
Patients have rightward shift of end-organ autoregulatory curve
Clinical trial data lacking on how rapidly to BP in various
disease states

Cherney D, Straus S. J Gen Intern Med. 2002;17:937-45.

Chobanian AV et al. Hypertension. 2003;42:1206-52.
VELOCITY: Study design
Evaluation of the Effect of Ultrashort-Acting Clevidipine in the Treatment of
Patients with Severe Hypertension

Multicenter, open-label, uncontrolled

SBP target range prespecified by investigators

N = 126 with acute severe hypertension (BP >180/115 mm Hg)

Clevidipine infusion started at 2 mg/hr

Doubling every 3 min until SBP target range achieved

Primary efficacy measure: % patients at SBP target range within 30 min

Primary safety measure: % patients below SBP target range within 3 min
NIH. www.clinicaltrials.gov.
Varon J et al. Chest. 2007;132(suppl):477S.
Peacock WF et al. Ann Emerg Med. 2007;50(suppl 1):S8-S9.
VELOCITY: Clevidipine in acute hypertension

89% of patients reached SBP target range within 30 min

10.9 min (median)

1.6% had SBP fall below target range within 3 min

Infusion continued in these patients without any adverse effects

91.3% successfully transitioned to oral therapy

Patients became eligible after 18 hours of IV therapy

Peacock WF et al. Ann Emerg Med. 2007;50(suppl 1):S8-S9.

PROACTION: Effects of Nesiritide on BP
Prospective Randomized Outcomes Study of Acutely Decompensated
Congestive Heart Failure Treated Initially as Outpatients with Nesiritide, N = 237
Standard care + placebo
20 16.7
Standard care + nesiritide

10
P < 0.017 P < 0.001

0
-1.2
SBP -5
-10 P < 0.03
(mm Hg) -8.4
-12.3
-20

-30
-28.7
<101 101-140 >140
-40
Baseline SBP (mm Hg)

Peacock WF et al. Am J Emerg Med. 2005;23:327-331.

Limited data on other parenteral
antihypertensives for hypertensive emergencies

Diazoxide
Oral formulation used to treat hyperinsulinemia-related
hypoglycemia
Mini-bolus formulation shown to be similar in efficacy to IV
hydralazine; N = 124 pregnant women with acute hypertension
Torsemide
Loop diuretic
Similar efficacy as enalaprilat; N = 52 patients with severe
hypertension + acute pulmonary edema

Hennessy A et al. ANZJOG. 2007;47:279-85.

Dyadyk AI et al. Eur Heart J Suppl. 2007;28(suppl):866. Abstract P4836.
Follow-up care in hypertensive emergencies

Goal: Transition to oral therapy as soon as patient can

tolerate therapy
Monitor carefully: Abrupt switch may result in BP
Most patients may be discharged on oral medication
within 24-72 hours
Clinical setting offers an opportunity to improve BP
control and medication adherence

Vidt DG. In: Hypertension Primer. In press.

STAT Registry: Addressing knowledge gaps
in contemporary acute hypertension
Studying the Treatment of Acute Hypertension

Patient
Frequency characteristics

Management Clinical
with IV agents outcomes
STAT: Design

Multicenter, US, hospital-based observational study

N ~ 2500 consecutive patients, BP >180/110 mm Hg* treated with

IV antihypertensive agents in a critical care setting Jan-Dec 2007

Main clinical outcomes measures:

In-hospital mortality, end-organ damage (stroke, encephalopathy,
CHF, renal failure), 6-month survival

*or >140/90 mm Hg + subarachnoid hemorrhage

STAT: Exclusion criteria

Severe, uncontrolled hypertension related to surgery

Pregnant or post-partum (<1 month)
IV antihypertensive treatment begun >24 hours
following admission
Comfort measures only orders
Transfer from other hospital for reason other than acute
hypertension
IV antihypertensive treatment initiated off-site
STAT: Sources of antihypertensive
management data

Survey completed by pharmacy, emergency medicine,

and intensive care medicine team members
Objectives:
Characterize how IV antihypertensives are used
Describe variability in IV antihypertensive usage
1st/2nd line agents
Dosage
Duration
Endpoints of therapy
Document incidence of adverse drug events
Case report form will provide additional patient information on BP
at specified intervals during IV administration and transition to oral
therapy
Management of
Perioperative
Hypertension
ESCAPE: Design overview
Efficacy Study of Clevidipine Assessing its Pre/postoperative
Antihypertensive Effect in Cardiac Surgery

Clevidipine* Primary endpoint:

ESCAPE-1
Incidence of bailout
N = 105 with preoperative
within 30 min
SBP 160 mm Hg
Placebo

Secondary endpoints:
Time to SBP 15%
ESCAPE-2 Clevidipine* MAP from baseline
N = 110 with postoperative HR from baseline
SBP >140 mm Hg Incidence of bailout
Placebo by causality

Levy JH et al. Anesth Analg. 2007;105:918-25.

NIH. www.clinicaltrials.gov.
*0.4-8.0 g/kg per min infusion Singla N et al. Anesthesiology. 2005;103:A292.
ESCAPE-1: Rapid control of preoperative SBP
30

20
HR
10

0
Mean %
change -10
SBP
-20

-30

-40
0 10 20 30 40 50 60

Time (min)

Levy JH et al. Anesth Analg. 2007;105:918-25.

ESCAPE: Clevidipine superior to placebo

ESCAPE-1 ESCAPE-2

Clevidipine Placebo Clevidipine Placebo

Bailout (%) 7.5* 82.7 8.2* 79.6

Median time to 6 NE 5.3 NE

SBP 15%
(min)
MAP (%) -31.2 -11.2 -28.9 -8.7

*P = 0.0001 vs placebo Levy JH et al. Anesth Analg. 2007;105:918-25.

NE = not estimable Singla N et al. Anesthesiolgy. 2005;103:A292.
ECLIPSE program: Overview
Evaluation of Clevidipine in the Perioperative Treatment of Hypertension
Assessing Safety Events
Clevidipine*
ECLIPSE-NTG
Nitroglycerin Primary efficacy
endpoint:
Randomized BP control within
Open-label Clevidipine* defined SBP
N = 1964 ranges
ECLIPSE-SNP
scheduled Primary safety
for cardiac SNP
endpoints:
surgery All-cause death,
MI, stroke, renal
Clevidipine*
dysfunction
ECLIPSE-NIC

Nicardipine
NIH. www.clinicaltrials.gov.
*2-16 mg/hr infusion Aronson S. Presented at ACC. 2007.
ECLIPSE: Comparison of primary safety
endpoints by treatment

ECLIPSE-NTG ECLIPSE-SNP ECLIPSE-NIC

Event rate Clevidipine NTG Clevidipine SNP Clevidipine NIC
(%)

Death 2.8 3.4 1.7 4.7 4.4 3.2

MI 3.3 3.5 1.4 2.3 2.3 1.1

Stroke 1.6 2.3 1.1 1.5 0.6 1.1

Renal 6.9 8.1 8.5 9.1 8.3 5.9

dysfunction

Aronson S et al. Presented at ACC. 2007.

ECLIPSE: Combined effects on primary safety
endpoints

10

8
Clevidipine Comparators
6
Event rate
(%)
4

0
Death MI Stroke Renal
dysfunction

Aronson S et al. Presented at ACC. 2007.

BP control assessed via AUC analysis

Upper

SBP
(mm Hg)

Lower

Cumulative AUC calculated for excursions outside

prespecified range.
Lower AUC = tighter BP control.

0 6 12 18 24
AUC = area under the curve Time (hours) Aronson S et al. Presented at ACC. 2007.
ECLIPSE: Clevidipine vs comparators for
perioperative BP control

20 P < 0.05
P < 0.05

15

AUC*
(mm Hg 10
x min/hr)

Clevidipine 0
Comparator NTG SNP NIC
ECLIPSE
*Excursions outside SBP 85-145 mm Hg
pre/postoperatively or 75-135 mm Hg intraoperatively Aronson S et al. Presented at ACC. 2007.
ECLIPSE: Relation of perioperative BP control
to 30-day mortality
Odds ratios calculated for BP excursions of 1-5 mm Hg sustained for 60 min
post hoc analysis
SBP above/below range*
(x 60 min)
I mm Hg

2 mm Hg

3 mm Hg

4 mm Hg

5 mm Hg
0 1 2 3 4
Unadjusted odds ratio (95% CI)
*SBP 85-145 mm Hg pre/postoperatively
or 75-135 mm Hg intraoperatively Aronson S et al. Presented at ACC. 2007.
ECLIPSE: Predictors of postoperative renal
dysfunction
N = 1512 undergoing cardiac surgery
Odds ratio (95% CI) P

Preop serum Cr 1.2 mg/dL 4.71 (3.067-7.235) <0.0001

Race (African American) 2.166 (1.19-3.943) 0.0114

Primary CABG + valve 1.957 (1.158-3.307) 0.0122

BP (4th quartile AUC*) 1.725 (1.111-2.68) 0.0152

Surgery duration (hours) 1.263 (1.054-1.515) 0.0116

Age (years) 1.037 (1.013-1.062) 0.0023

BMI 1.05 (1.016-1.086) 0.0042

Unadjusted
*Excursions outside SBP 85-145 mm Hg
pre/postoperatively or 75-135 mm Hg
intraoperatively Aronson S et al. Presented at ASA. 2007.
ECLIPSE: Overview of perioperative BP control

Excursions outside a targeted BP range are

correlated with 30-day mortality
Relationship is direct and proportionate to the
magnitude of excursions
Data suggest that great attention should be given
to precise perioperative BP control
Future analysis of this finding is warranted

Aronson S et al. Presented at ASA. 2007.

Summary: Acute hypertension

Nonsurgical patients
Little studied in past decade
Multiple knowledge gaps
Patient characteristics
Treatment patterns
Outcomes
Perioperative patients
Frequent finding
Emerging data demonstrate importance of tighter BP control than
currently recommended