Landmark Practice Advances in Acute Blood Pressure Management New Therapeutic Paradigms for the Emer

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Landmark Practice Advances in Acute Blood
Pressure ManagementNew Therapeutic Paradigms
for the Emergency Medicine Specialist
Year 2008 Milestone Summit

• Program Chairman
• Charles V. Pollack Jr. M.A. M.D. FACEP
  FAAEM FAHA
• Professor and Chairman
• Emergency Medicine Pennsylvania
  HospitalUniversity of Pennsylvania Health System
• Philadelphia

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CME-accredited symposium jointly sponsored by
the University of Massachusetts Medical School
and CMEducation Resources LLCCommercial
Support Sponsored by an independent educational
grant from The Medicines CompanyMission
statement Improve patient care through
evidence-based education expert analysis and
case study-based managementProcesses Strives
for fair balance clinical relevance on-label
indications for agents discussed and emerging
evidence and information from recent
studiesCOI Full faculty disclosures provided
in syllabus and at the beginning of the program
Welcome and Program Overview
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Program Educational Objectives

• As a result of this educational activity
  physicians will learn
• To identify underlying chronic and acute
  precipitants of acute elevations in systemic
  blood pressure and how these syndromes presents
  across multiple disease states and patient
  populations.
• To assess and implement optimal pharmacologic
  interventions for patients presenting with
  manifestations of acute pressure syndromes
  including elevated systolic or diastolic blood
  pressure end organ dysfunction and other
  cardiovascular renovascular and/or
  neurovascular derangements.
• Learn to characterize identify and evaluate
  myriad acute disease states producing serious
  and/or life-threatening elevations in systemic
  blood pressure among them hypertensive urgency
  hypertensive crisis ischemic stroke
  drug-induced acute pressure syndromes
  subarachnoid hemorrhage intracerebral
  hemorrhage pulmonary edema and related
  conditions.

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Program Faculty
Program Chairman  Charles V. Pollack Jr MA MD
FACEP FAAEM Chairman Department of Emergency
Medicine Pennsylvania Hospital Professor of
Emergency Medicine University of Pennsylvania
School of Medicine Philadelphia
Pennsylvania   Kurt C. Kleinschmidt MD
FACEP Associate Professor Department of Emergency
Medicine University of Texas Southwestern Medical
Center Dallas Texas   Richard L. Summers
MD Professor of Emergency Medicine Department of
Emergency Medicine Department of Physiology and
Biophysics University of Mississippi Medical
School Jackson Mississippi
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Faculty COI Disclosures
Charles V. Pollack Jr MA MD FACEP
FAAEM Grant/Research Support GSK
sanofi-aventis Consultant sanofi-aventis
Schering-Plough The Medicines Company Speakers
Bureau sanofi-aventis Schering-Plough Richard
L. Summers MD Speakers Bureaus Schering
Plough Medicines Co. BMS sanofi-aventis
Scios Kurt C. Kleinschmidt MD FACEP Speakers
Bureau sanofi-aventis BMS Consultant The
Medicines Company Research Support The Medicines
Company
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Acute Pressure SyndromesHypertensive Urgencies
and Emergencies Giving Hypertension
theHyperattention It Deserves
Introduction and Chairmans Overview

• Charles V. Pollack Jr. M.A. M.D. FACEP
  FAAEM FAHAProgram Chairman
• Chairman Emergency Medicine Pennsylvania
  HospitalProfessor of Emergency Medicine
  University of Pennsylvania
• Philadelphia PA

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Hypertension An Epidemic

• Affects at least 65 million Americans
• Affects at least 1 BILLION individuals worldwide
• Most current (2003) evidence basis for chronic
  managementThe Seventh Report of the Joint
  National Committee on the Prevention Detection
  Evaluation and Treatment of High Blood Pressure
  Hypertension (JNC 7)lacks guidance for acute
  management of patients presenting to an ED with
  hypertension especially severe acute elevations
  of BP

JNC 7 JAMA 2003 2892560-2572.
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Hypertensive Urgenciesand Emergencies

• Epidemiologic data are largely lacking
• It is thought that 1 of patients with
  hypertension will eventually present to the ED in
  hypertensive crisis
• In a single-center Italian study HU or HE
  accounted for 3 of all medicine admissions and
  27.5 of all medical emergencies
• HUHE ratio of 31 in that study
• Patients with HU much more likely to be unaware
  of their hypertension diagnosis than those with HE

Zampaglione et al Hypertension 199627144.
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Studying the Treatment of Acute HyperTension The
STAT Registry

• Goals of the STAT registry
• Better understand the clinical condition of acute
  HTN managed in a critical care setting and
  treated with IV antihypertensive drugs
• Improve immediate and long-term outcomes of
  patients with acute severe HTN
• Design
• Multicenter US-based observational
  cross-sectional survey
• Adult patients with acute severe HTN (BP gt180/110
  mmHg) treated with IV antihypertensive agents in
  a critical care setting

Kleinschmidt K et al. Society for Academic
Emergency Medicine 2008 Annual Meeting. Poster
140.
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STAT Registry Analysis
Patient outcomes ()


N1588 (all patients) n1405 (patients alive
at discharge and with 90-day follow-up).
Kleinschmidt K et al. Society for Academic
Emergency Medicine 2008 Annual Meeting. Poster
140.
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Presenting Symptoms

• Hypertensive Urgencies
• Arrhythmia
• Epistaxis
• Headache
• Psychomotor agitation
• Usual Primary ED Diagnosis
• Hypertension

• Hypertensive Emergencies
• Chest pain
• Dyspnea
• Neurologic deficits
• Usual Primary ED Diagnosis
• CVA
• Acute pulmonary edema
• Hypertensive encephalopathy
• Acute heart failure

Zampaglione et al Hypertension 199627144.
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Causes of Hypertensive Crises

• Essential hypertension
• Medication noncompliance
• Secondary hypertension
• Aortic coarctation
• Cushings syndrome
• Elevated ICP
• Renal dysfunction
• Pregnancy
• Hyperparathyroidism
• Hyperthyroidism
• Pheochromocytoma
• Primary aldosteronism

JNC 7 JAMA 2003 2892560-2572.
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Goals of ED Therapy of Hypertensive Crises

• Hypertensive urgency can generally be managed
  with oral medications and the goal is gradual BP
  lowering over 24-48 hours
• Important to prevent too-rapid lowering due to
  autoregulation of flow by pressure in brain
  heart and kidneys
• Goal in hypertensive emergency is to reduce MAP
  by 10-15 and/or to a DBP of 110 . . . within one
  hour
• Aortic dissection requires even more rapid
  lowering
• Once initial reduction achieved transition to
  oral agents
• Dug of choice for initial therapy often depends
  on which end-organ system is affected and on
  comorbidities

JNC 7 JAMA 2003 2892560-2572.
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Why Are We Here Tonight

• Severe hypertension is increasingly prevalent as
  population ages and obesity and diabetes become
  more common
• Currently available agents for the management of
  acute severe BP elevation leave much to be
  desired advancements are possible
• There is a new agentthe first parenteral
  antihypertensive agent approved by the FDA in 10
  years--that has been tested specifically in the ED

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Welcome to This Program!

• We will review the scope pathophysiology and
  epidemiology of hypertension as well as
  hypertensive urgencies and emergencies as they
  present in the ED
• We will review and assess current therapy and
  goals of BP management in the ED
• We will look to the near future of management of
  acute severe hypertension

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Year 2008 Milestone Summit
Pathophysiology and Unrecognized Complications of
Acute Pressure Elevations Implications for
Clinical Management in the Emergency Department
Richard L. Summers MD Professor of Emergency
Medicine Department of Emergency
Medicine Department of Physiology and
Biophysics University of Mississippi Medical
School Jackson Mississippi
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Physiology of Arterial Pressure Control and
Pathophysiology of Acute Pressure Syndromes
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MAP (CO x SVR) CVP
Where MAP is mean arterial pressure CO is
cardiac output SVR is systemic vascular
resistance CVP is central venous pressure
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Physiology and Pathophysiology of Arterial
Pressure Control

• Guyton AC Coleman TG. Quantitative analysis of
  the pathophysiology of hypertension. Circ Res
  1969 May24(5 Suppl)1-19.

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Hierarchy of Control
AC Guyton
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Summers RL Rapid Clinical Assessment of
Hemodynamic Profiles and Targeted Treatment of
Patients with Acutely Decompensated Heart
Failure Wet and Cold Profile. Clin Cardiol
2004 27 (Suppl. V) V10-11.
Mean Arterial Pressure

• Primary Goal of the Circulation System is the
  Delivery of Oxygen and Nutrients to the Tissues

• MAP (CO x SVR) CVP
• Where
• CO is cardiac output
• SVR is systemic vascular resistance
• CVP is central venous pressure

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Control of Arterial Pressure
Hypertension
Normal
Intake

• Genetic
• Diet
• Neurohormonal
• Intrarenal

Urine Na Excretion (x normal)
Na Intake
1
S
100 150 200
Arterial Pressure

Total Peripheral Resistance
Extracellular Fluid Volume
Arterial Pressure
Cardiac Output
X
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Chronic Control of Arterial Pressure
Hypertension
Normal
Intake

• Genetic
• Diet
• Neurohormonal
• Intrarenal

Urine Na Excretion (x normal)
Na Intake
1
S
100 150 200
Arterial Pressure

Total Peripheral Resistance
Extracellular Fluid Volume
Arterial Pressure
Cardiac Output
X
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Renal Function and MAP Control
7 6 5 4 3 2 1 0
Renal function curve
Fluid Intake and Output (times normal)
Equilibrium pressure
Net intake
0 50 100 150 200
Arterial Pressure
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Acute Control of Arterial Pressure
Hypertension
Normal
Intake

• Genetic
• Diet
• Neurohormonal
• Intrarenal

Urine Na Excretion (x normal)
Na Intake
1
S
100 150 200
Arterial Pressure

Total Peripheral Resistance
Extracellular Fluid Volume
Arterial Pressure
Cardiac Output
X
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Acute on Chronic Pathology
Guyton AC. Long-term arterial pressure control
an analysis from animal experiments and computer
and graphic models. Am J Physiol. 1990 Nov259(5
Pt 2)R865-77.
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Hall JE The kidney hypertension and
obesity.Hypertension. 200341(3 Pt 2)625-33.
Acute Elevation of MAP
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Acute Pressure Syndrome
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Sympathetic Nervous System Regulation of Blood
Pressure
Adrenal Gland
CNS
Adrenergic Tone
Catecholamines
Baroreceptor Reflexes
Veins
Arteries
Capacitance
Resistance
Afterload
Preload
Volume/Pressure
Renin/Angiotensin
Cardiac Output
Heart
Kidney
Blood Pressure
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Renin-Angiotensin-Aldosterone Regulation of
Blood Pressure
Renin Substrate
Angiotensin I
Angiotensin II
Renin
Aldosterone
Vasoconstriction
Kidney
Adrenal Cortex
Blood Pressure
Sodium Water Reabsorption
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Acute Blood Pressure Elevations
Complications Associated with Acute Pressure
Syndromes
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JNC 7 Nomenclature

• Normal BP Systolic lt 120 Diastolic lt 80
• Prehypertension S 120-139 D 80-89
• Stage 1 hypertension S 140-159 D 90-99
• Stage 2 hypertension S gt 160 D gt 100
• Stage 3 hypertension (JNC 6)
• Systolic gt 180 Diastolic gt 110
• Functionally this is hypertensive urgency
• What about crisis emergency and urgency

JNC 7 JAMA 2003 2892560-2572.
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JNC 7 Nomenclature

• Using JNC 7 nomenclature hypertensive crisis
  is an acute severe stage 2 or 3 elevation in
  blood pressure
• Crisis is then differentiated into hypertensive
  emergencies (involving some end-organ damage)
  and urgencies (no end-organ damage)

JNC 7 JAMA 2003 2892560-2572.
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End-Organ Damage

• Cardiopulmonary
• Acute heart failure
• Acute coronary syndrome
• Acute pulmonary edema with respiratory failure
• Dissecting aorta
• CNS
• Hypertensive encephalopathy
• CVA
• Ocular
• Exudates
• Papilledema
• Retinal hemorrhages
• Renal
• Acute renal failure

JNC 7 JAMA 2003 2892560-2572.
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Hypertensive Emergencies
Encephalopathy Stroke
Aortic Dissection
Decompensated Heart Failure
Acute Coronary Syndrome
Acute Renal Failure
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CT Scan
Right middle cerebral artery CVA
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MRI Confirmation
Posterior leukoencephalopathy
Posterior fossa
Occipital lobes
Edema predominately of the white matter of the
parieto-occipal regions and post. fossa
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CT Angiogram
Distal (type B) aortic dissection
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Vasculopathy of Hypertensive Emergencies
Vaugh and Delanty Lancet 2000
41
Eye Grounds
Grade 3 K-W Retinopathy
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Clinical Management of APS
Implications for Clinical Management of Acute
Pressure Syndromes
43
Physiologic Targets of Therapy
MAP CO X TPR
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Goals of ED Tx of Hypertensive Cases

• HU can generally be managed with oral medications
  and requires BP lowering over 24-48 hours
• Important to prevent too-rapid lowering due to
  autoregulation of flow by pressure in brain
  heart and kidneys
• Goal in HE is to reduce MAP by 10-15 and/or to a
  DBP of 110 within one hour
• Aortic dissection requires even more rapid
  lowering
• Once initial reduction is achieved transition to
  oral agents
• Drug of choice for initial therapy often depends
  on which end-organ system is affected and on
  comorbidities

JNC 7 JAMA 2003 2892560-2572
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Long-term Relationship Between CO and MAP
200 150 100 50 0
Cardiac
Pulmonary disease
Pagets disease
Hyperthyroidism
Removal of 4 limbs
Beriberi
A-V Shunts
Hypothyroidism
Anemia
Normal
Arterial Pressure of Cardiac Output (percent of
normal)
Output
Arterial Pressure
40 60 80 100 120 140 160
Total Peripheral Resistance (percent of normal)
Guyton AC. The relationship of cardiac output and
arterial pressure control. Circulation. 1981
Dec64(6)1079-88.
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Reaching Treatment Targets
The biggest mistake in treating hypertensive
emergencies is the over-correction of blood
pressure!
47
Autoregulation and Blood Flow
Without Autoregulation
With Autoregulation
100 50 0 -50
CO
AP
Percent Change
AP
TPR
CO
TPR
5.0 5.82 5.0 5.19
Blood Volume (liters)
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Cerebral Autoregulation
100
Brain Blood Flow maximal
Normotensive
50
0
50
100
150
200
250
Systolic BP mm Hg
49
Adapted Cerebral Autoregulation
100
Brain Blood Flow maximal
Normotensive
encephalopathy ischemia
50
Hypertensive
0
50
100
150
200
250
Systolic BP mm Hg
50
Approach to BP in Acute Ischemic Stroke
Eligible for Thrombolytic Therapy
No
Yes
Initial BP
Labetalol or Nicardipine or Clevidipine for BP gt
185/110
gt 220/120 Labetalol or Nicardipine or Clevidipine
lt 220/120 No RX
Adams et al. Stroke 2005
51
Special Populations with APS
Special Cases of Acute Pressure Syndromes
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Causes of Hypertensive Crises

• Essential hypertension
• Medication noncompliance
• Secondary hypertension
• Aortic coarctation
• Cushings syndrome
• Elevated ICP
• Renal dysfunction
• Pregnancy
• Hyperparathyroidism
• Hyperthyroidism
• Pheochromocytoma
• Primary aldosteronism

JNC 7 JAMA 2003 2892560-2572
53
Cocaine
NE
Coronary Vasoconstriction
Hypertensive Crisis Tachycardia
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Atherosclerotic Renal Artery Stenosis
Suspect with hypertensive emergency and flash
pulmonary edema
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Obesity and Hypertension
Systolic Blood Pressure (mmHg)
Relationship between body mass index and mean
systolic and diastolic blood pressure in 22354
Korean subjects.
Jones et al.
56
Obesity
Renal Medullary Compression
SNS Activity
RAS Activity
Glucos Intolerance
Tubular NaCl Reabsorption
Renal Vasodilation
Volume Expansion
Lipids
Arterial Hypertension
Glucose
Glomerular Hypertension
Glomerulosclerosis
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The Pressure is OnTaking it OffThe Current ED
Armamentarium forAcute Blood Pressure
ManagementThe Good News and Bad News About
Established Treatment OptionsDo We Need a New
Paradigm for ED Care
Year 2008 Milestone Summit

• Kurt Kleinschmidt MD FACEP FACMT
• Professor of Surgery Division of Emergency
  Medicine
• Chief Section of Toxicology
• Director Toxicology Fellowship Program
• UT Southwestern Medical Center
• Director of the Chest Pain Protocol
• Parkland Memorial Hospital
• Dallas Texas

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Objectives

• Summarize findings of the STAT Registry -
  Illuminating the need for
• Heightened vigilance
• New more definitive approaches to management
• Compare current options to decrease acute severe
  hypertension and its associated conditions
• Toxicity
• Overshoot
• Rapidity of BP control
• PK
• PD

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Acute Severe Hypertension has High Morbidity
Mortality and Readmission Rates Results from
the STAT Registry

• CB Granger J Gore J Katz K Kleinschmidt A
  Wyman F Peacock F Anderson on behalf of the
  STAT Investigators. Presented at the European
  Society of Cardiology Annual Meeting September
  2 2008.

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Inclusion Criteria

• gt18 years of age
• Presenting with acute severe HTN
• Treated
• In a critical care setting
• Treated with an IV agent
• Severe hypertension
• At least one SBP gt180 mmHg and/or
• At least one DBP gt110 mmHg
• SAH patients with SBP gt140 and/or DBP gt90

1588 Patients 25 US Hospitals
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First IV Antihypertensive
62
Number of Different IV BP Meds During
Hospitalization by First Received
First IV Antihypertensive
Percent of Patients
63
Median SBP Over 24 h by First IV BP Med
64
STAT Results

• Median time to SBP of lt160 mmHg - 4 hrs
• Return to gt180 after initial control 60
• Iatrogenic hypotension 4
• Recurrent severe HTN re-start parenteral
  therapy 29
• No documentation of follow-up appointment being
  either scheduled or attended 65

65
Patient Outcomes
n1588 (all patients) n1415 (all patients
alive at discharge and with 90-day follow-up)
66
Short-Term (2 to 6 month) Outcomes

• OASIS-5 NEJM 2006
• GUSTO IIb NEJM 1996
• GRACE JAMA 2007
• IMPACT-HF J Cardiac Failure 2004
• STAT Registry results

67
STAT Summary

• Acute severe hypertension
• Recurrent condition
• Associated with poor medical adherence
• Heterogeneous management ICU admission drugs
  used BP targets
• Alarmingly poor follow-up
• High mortality and morbidity especially with new
  or worsening end-organ damage
• Major need - Improve prevention and treatment of
  this understudied condition

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Agents Currently Used
Nitroglycerin

• Diuretics

Clonidine

• ACE Inhibitors

Fenoldopam
Nifedipine
Diazoxide
Nicardipine
Nitroprusside
Esmolol
Labetalol
Hydralazine
Rynn et al J Pharm Pract 200518363-76.
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Guidelines

• JNC VII refers to the JNC VI
• JNC VII does not add any new information.
• JNC VII has no discussion of parenteral agents

7th Report of the Joint National Committee on
Prevention Detection Evaluation and Treatment
of High Blood Pressure. Hypertension.
2003421206-1252. 6th Report of the Joint
National Committee on Prevention Detection
Evaluation and Treatment of High Blood Pressure.
Arch Intern Med. 19971572413-2416.
71
Pharmacological Interventions for Hypertensive
Emergencies (2008)

• Does anti-hypertensive drug therapy
• as compared to placebo or no treatment
• affect mortality and morbidity
• in patients presenting with a hypertensive
  emergency
• Does one first-line antihypertensive drug class
• as compared to another antihypertensive drug
  class
• affect mortality and morbidity in these patients

72
Selected Studies

• Unconfounded
• Truly randomized
• Compared an antihypertensive drug versus
• Placebo
• No treatment
• Another antihypertensive drug from a different
  class
• Patients presenting with a hypertensive emergency.

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What Was Found

• Fifteen randomized controlled trials
• 869 patients
• Two trials included a placebo arm
• All studies (except one) were open-label
• Seven drug classes were evaluated in those
  trials
• Nitrates (9 trials)
• ACE-inhibitors (7)
• Diuretics (3)
• CCBs (6) alpha-1 adrenergic antagonists (4)
  direct vasodilators (2) and dopamine agonists (1)

74
Treatment of HTN Emergencies

• There is no RCT evidence demonstrating that
• Anti-hypertensive drugs reduce mortality or
  morbidity
• There is a drug or drug class that is most
  effective in reducing mortality and morbidity.

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Mechanisms

• NO - Nitric oxide
• GC - Guanylyl cyclase
• GMP activates myosin light chain phosphatase
  (MLCP)
• MLCP dephosphorylates myosin light chains

76
Nitroglycerin

• Arterial coronary venodilator
• Onset - 2-5 minutes t ½ 4 mins
• Duration 5-10 minutes
• Dose
• Start at 5 g/min (vs 20 )
• Titrate by 5 g/min (vs 10)q 3-5 mins
• Problems
• Headache (gt 25)
• HR
• Vomiting
• Use during relative hypovolemia
• Met-hemoglobinemia
• Tachyphylaxis w/i hours (need drug free
  intervals)

The 7th Report of the JNC. JAMA
20032892560-2571.
77
Nitroglycerin PCWP vs Time
0 1 2 3 4 5 6 7 8
180
160
NTG dose
140
120
100
Change in PCWP (mm Hg)

Nitroglycerin Dose (mcg/min)
80
Change in PCWP

60



40

Plt0.05 vs baseline
20
0
0
3
6
9
12
15
18
21
24
Time (hr)
n9 (3 hr) n12 (gt3 hr) Added to standard
therapy
Elkayam U et al. Am J Cardiol 200493237.
78
Organic Nitrates Tolerance Theories

• Decreased bioconversion to nitric oxide1
• Cellular depletion of sulfhydryl groups23
• Neurohumoral adaptations4
• Superoxide anion production5
• Upregulation of endothelin6

• Münzel T. Am J Cardiol. 19967724C-30C.
• Parker JD Parker JO. N Engl J Med.
  1998338520-531.
• Needleman P Johnson EMJ. J Pharmacol Exp Ther.
  1973184709-715.
• Münzel T et al. J Am Coll Cardiol.
  199627297-303.
• Münzel T et al. J Clin Invest. 199595187-194.
• Münzel T et al. Proc Natl Acad Sci.
  1995925244-5248.

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Nitroprusside

• Arterial venodilator
• s preload afterload
• No chronotropic effect but HR (baroreceptors)
• Onset 1-2 minutes t ½ 3-4 mins
• Start _at_ 0.5 g/kg/min titrate
• Average effective dose is 3 g/kg/min (0.5-10
  g/kg/min)

The 7th Report of the JNC. JAMA
20032892560-2571.
80
Nitroprusside

• Problems
• Pregnancy
• Coronary steal
• Dose dependent in CBF
• (Avoid if ICP possibly )
• Hypoxia ( V/Q mismatch)
• Requires special delivery system
• Usually requires direct artery pressure
  monitoring
• N/V twitching sweating
• Metabolized to CN then thiocyanate
• Careful in pts w/ hepatic or renal dysfunction

81
Nitrovasodilators
Pepine CJ. Clin Ther. 198810316-325.
82
Cyanide Toxicity

• Tachyphylaxis - important sign of impending
  toxicity
• Neurological manifestations
• Hyperpnea
• Headache Vertigo
• Altered mental status
• Coma Seizures
• Laboratory manifestations
• Lactic acidosis
• Increased base deficit

Sipe EK et al. Am Surg. 200167685-686.
83
Labetalol

• Competitive selective 1 non-selective
  -blocker
• gt blockade (4-8 Xs more)
• blockade is 1/10 of Clonidines
• blockade is ¼ Propranolols
• Treatment Considerations
• Elimination t½ 8 hoursclinical effect 4-6
  hrs
• 5 orthostatic hypotension
• Paradoxical HTN with low doses
• ( block only unopposed )

84
Labetalol

• No in CBF good if h/o cerebrovasc ds.
• No in HR MV02 un ed
• Indications
• Catechol excess pheo MAOI emergencies
  clonidine withdrawal
• Preg induced HTN
• Dose
• 20-40 mg IV q 30 mins max 300 mg
• BP drops w/in 5 mins
• max response in 10 mins
• IV drip _at_ 2 mg/min (may start w/ 20 mg bolus)
• PO 200 mg

85
Labetalol

• Issues
• No in cerebral renal or coronary blood flow
• Intermediate time to onset (5-15 minutes)
• Moderate effect
• Negative chronotropic effects1
• Negative inotropic effects2
• May exacerbate reactive airway disease
• Caution in elderly or decreased hepatic function

• Hoffman BB. In Hardman JG Limbird LE eds.
  Goodman and Gilmans Pharmacological Basis of
  Therapeutics. 10th ed. New York NY
  McGraw-Hill1997215-268.
• Le Bret F et al. J Cardiothorac Vasc Anesth.
  19926433.

86
Hydralazine

• Indications pregnancy
• Direct arteriolar vasodilator
• Concerns
• Reflex tachycardia
• Increases MVO2 MI
• Chronic Use - SLE syndrome
• IV Onset 10 mins
• Duration 3-8 hrs
• Metab hepatic acetylation renal elimination
• 50 of pop is slow acetylators
• Decrease dose in renal failure
• Eclamptic dose 10-20 mg iv repeat in 30 min.
  prn

87
Hydralazine

• Not listed as a consideration in a 2008 EMCREG
  Consensus recommendation published in Ann Emerg
  Medicine except for pregnancy

But Was 4 in the STAT Registry!!!
88
Esmolol

• Load 500 mcg/kg over one minute
• Then four-minute maintenanceinfusion of 50
  mcg/kg/min
• If inadequate
• Repeat loading dose overone minute
• Increase maintenance infusion by 50 mcg/kg/min
• Max maintenance dose200 mcg/kg/min
• As BP target is approached omit subsequent
  loading doses and titrate the maintenance dosage
  up or down to endpoint

89
Esmolol

• Advantages
• Treats tachycardia and hypertension
• Cardioprotective
• Short duration of effect
• Disadvantages
• Bradycardia
• Reactive airway disease
• Pulmonary edema
• Hypotension common
• Caution in renal dysfunction
• Extravasation is dangerous to tissues

Oparil S et al. Am J Hypertension.
199912653-664.
90
-Blocker vs Combined - and -Blocker

• G Gs Pharmacological Basis of
  Therapeutics.10th ed. 1997215-268.
• 2. Varon J Malik PE. Chest. 2000118214-227.

91
Calcium Channel Blockers

• Frishman WH et al. Med Clin North Am.
  198872523-547.
• Adapted from Goodman and Gilmans The
  Pharmacologic Basis of Therapeutics. 9th ed. 2001.

92
Dihydropyridine CCB Nicardipine

• Arterial selective vasodilator1
• Significant SVR2-6
• Cerebral and coronary vasodilator
• Vascular smooth muscle selective1
• Minimal myocardial depression
• No AV nodal depression
• No significant in ICP7

1.Clarke B et al. Br J Pharmacol. 198379333P.
2.Lambert CR et al. Am J Cardiol.
198760471-476. 3.Silke B et al. Br J Clin
Pharmacol. 198520169S-176S. 4.Lambert CR et
al Am J Cardiol. 198555652-656. 5. Visser CA
et al. Postgrad Med J. 19846017-20. 6. Silke
B et al. Br J Clin Pharmacol. 198520169S-176S.
7. Nishiyama MT et al. Can J Anaesth.
2000471196-1201.
93
Nicardipine

• Start at 5 mg/h titrate by 2.5 mg/h q5 15
  min15 mg/h max
• Half life
• Redistribution t½ 2.7 mins
• Intermediate t½ 44 mins
• Terminal after long infusion 14.4 hours
• After d/c concentration rapidly 50 in 1st
  2 hrs
• Onset 5-10 min
• Duration 15-30 mins may gt 4 hours

The 7th Report of the JNC. JAMA
20032892560-2571.
94
Nicardipine

• HR
• H/A
• Flushing
• Local phlebitis
• Caution with ACS
• Vomiting
• Caution with decreased renal or hepatic function

95
Safety Profiles of Nicardipine Nitroprusside

• NiCardene IV package insert.
• Nitropress package insert.

96
Nicardipine vs Adrenergic Blockers
97
Fenoldopam

• Selective dopamine-1 receptor agonist decreasing
  PVR while increasing RBF natriuresis and
  diuresis
• Six times more potent than dopamine in producing
  renal vasodilation
• Given IV and titrated onset of action 10 minutes
  and effects persist for an hour after
  discontinuation
• May cause T-wave flattening angina atrial
  fib/flutter and reflex tachycardia

Rynn et al J Pharm Pract 200518363-76.
98
Clevidipine

• Approved by the FDA for use in hypertension when
  intravenous therapy is required
• A dihydropyridine calcium channel blocker
• t ½ 1 minute
• Steady state achieved very quickly
• Tested in emergency medicine and critical care
  patients
• Dr. Pollack will present key clinical trials and
  analyze implications for ED use

99
Acute Severe HypertensionNew Options and
Landmark Advances for ED Management of Serious
Elevations in Blood Pressure
From Threat to Therapy A Year 2008 EM Update

• Charles V. Pollack Jr MA MD FACEP FAAEM FAHA
• Program Chairman
• Chairman Department of Emergency Medicine
• Pennsylvania Hospital
• Professor of Emergency Medicine
• University of Pennsylvania
• School of Medicine
• Philadelphia Pennsylvania

100
Common Therapeutic Agents

• ACE Inhibitors
• Diazoxide
• Esmolol
• Hydralazine
• Nicardipine
• Nitroglycerin

• Clonidine
• Diuretics
• Fenoldopam
• Labetalol
• Nifedipine
• Nitroprusside

Rynn et al J Pharm Pract 200518363-76.
101
Common Therapeutic AgentsDr. Klineschmidt has
just reviewed their limitations

• ACE Inhibitors
• Diazoxide
• Esmolol
• Hydralazine
• Nicardipine
• Nitroglycerin

• Clonidine
• Diuretics
• Fenoldopam
• Labetalol
• Nifedipine
• Nitroprusside

Rynn et al J Pharm Pract 200518363-76.
102
Emerging Therapy for Acute Pressure Syndromes

• So Whats New

103
Clevidipine The First Third-Generation Calcium
Channel Blocker
Whiting RL et al. Angiology. 199041987-991.
104
The Clevidipine Molecule

• A rationally designed dihydropyridine calcium
  channel blocker
• t ½ 1 minute
• Steady state achieved in 2 minutes
• Protein binding gt99.5
• High clearance rate (independent of dosing rate
  metabolized by extrahepatic tissues)
• Small Vol/dist 0.17 L/kg

105
Metabolism by Plasmaand Tissue Esterases

• Clevidipine is rapidly metabolized by esterases
  in blood and extravascular tissue to an inactive
  carboxylic acid metabolite independent of renal
  or hepatic function!

106
Linear Pharmacokinetics

• At steady state there is a linear relationship
  between dosage and arterial blood concentrations
• Linear relationship maintained for dosages as
  high as 104 mg/hr (21.9 mcg/kg/min)

120
100
80
Clevidipine Concentration at Css (nmol/L)
60
40
20
0
0
5
10
15
20
35
25
30
Dose Rate (nmol/kg/min)
Reproduced from Ericsson H et al.
Anesthesiology. 200092993-1001. Ericsson H et
al. Anesthesiology. 200092993-1001. Ericsson H
et al. Br J Clin Pharmacol. 199947531-538.
107
Linear Dose Response

• Linear dose response in postoperative cardiac
  surgery patients
• Effective in 95 of patients at 16 mg/hr

Responders treatment success gt10 decrease in
MAP or gt20 decrease in MAP at each measured
concentration. Bailey JM et al. Anesthesiology.
2002961086-1094.
108
Rapid Onset of Effect

• BP-lowering effects seen within 23 minutes of
  clevidipine infusion

SBP Changes
SBP changes for patients receiving clevidipine
during a 30-minute treatment period. Levy JH et
al. Anesthesiology. 2005103A354.
109
Rapid Cessation of Effect
Recovery of Mean Arterial Pressure
(MAP) Following Cessation of Clevidipine
Infusion
0 -5 -10 -15 -20 -25

• 50 return BP to baseline SBP in 3 -10 minutes

MAP of baseline (Mean SE)
0 3 6 9 12 15 18
21 24 27 30
Time after stop of infusion (minutes)
Data on file The Medicines Company
110
Selectivity of Calcium Channel Antagonists
Nicardipine
Myocardial SA Node AV Node IV
Agent Vasodilation Depression Suppression Suppress
ion Clevidipine 5 0 0 0 Nicardipine 5 0 0 0
Diltiazem 3 2 5 4 Verapamil 4 4 5 5
The chiral center of clevidipine SA
sinoatrial AV atrioventricular
Kerins DM et al. In Goodman and Gilmans
Pharmacological Basis of Therapeutics.
2001843-870. Massie BM. Am J CardioI.
19978023I-32I.
111
Potential ED Issues with Nicardipine

• Prolonged duration of activity
• Drug requires reconstitution and new USP
  mandates mean that this typically must be done in
  the Pharmacy thereby delaying use in the ED
• Never specifically studied in the ED

112
There Are ED Data for Clevidipine

• EValuation of the Effect of ULtraShOrt Acting
  Clevidipine In the Treatment of Severe
  HYpertension

113
Overview and EnrollmentCriteria

• Multicenter phase 3 open-label single-arm
  study to confirm the safety and efficacy of
  clevidipine using a predefined nonweight-based
  dosing algorithm in patients presenting in the ED
  or ICU with severe HTN
• Inclusion criteria
• Age 18 years
• SBP gt180 mmHg and/or DBP gt115 mmHg assessed on 2
  successive occasions 15 minutes apart
• Exclusion criteria
• SBP 180 mmHg and DBP 115 mmHg
• Expectation that the patient will not tolerate IV
  antihypertensive therapy for a minimum of 18
  hours
• Known or suspected aortic dissection

Pollack CV et al. Ann Emerg Med. 2008 Jun 6.
Epub ahead of print.
114
Objectives

• Primary end points
• Patients in whom SBP fell to within the
  patient-specific SBP initial target range (ITR)
  within 30 minutes of initiating infusion
• Patients in whom SBP fell below the lower limit
  of the SBP ITR within 3 minutes of initiating
  infusion
• Secondary end points
• Time to achieve SBP ITR within the initial 30
  minutes
• Proportion of patients successfully transitioned
  to oral antihypertensive therapy
• Safety of prolonged (18 hours) clevidipine

Pollack CV et al. Ann Emerg Med. 2008 Jun 6.
Epub ahead of print.
115
VELOCITY Sites
116
Titration Algorithm
Initiate clevidipine infusion at initial rate of
2 mg/h (4 mL/h)
BP and HR measured with cuff every 3 min pre-ITR
ITR
BP and HR measured with cuff every 15 min
post-ITR for 2 h then hourly until oral therapy
2 h
45
30
0
3
6
9
12
15
18
21
24
27
60
90
75
18-96 h
Time post-infusion (min)
Maintain or further titrate after first 30 min to
achieve desired long-term reduction in SBP
continue treatment for 18-96 h
Determine ITR for each patient prior to infusion
Titrate every 3 min in doubling increments (2-4
4-8 up to 32 mg/h maximum) to achieve
prespecified ITR
Downward titration was also permitted.
ITRinitial target range (specific for each
patient 20-40 mmHg between upper and lower
limits)
Pollack CV et al. Ann Emerg Med. 2008 Jun 6.
Epub ahead of print.
117
Patient Demographics
Safety population N126.
Pollack CV et al. Ann Emerg Med. 2008 Jun 6.
Epub ahead of print.
118
Baseline Characteristics
Safety population N126.
Pollack CV et al. Ann Emerg Med. 2008 Jun 6.
Epub ahead of print.
119
VELOCITY Patient Disposition
ITT (patients enrolled) N131
No clevidipine n5
SBP UL of target range n14
mITT (patients with SBP gtUL of target
range) N117
Safety (patients who received at least 1
dose) N126
lt18 hr treatment n9
DNC n12
18 hr continuous infusion n117
DNC n7
Completed Patients n105
Completed Patients n114
Completed Patients n110
Pollack CV et al. Ann Emerg Med. 2008 Jun 6.
Epub ahead of print.
120
Clevidipine Rapidly LoweredBP to Target in 91
of Patients
Primary end point results Kaplan-Meier curve
demonstrating probability of attaining SBP ITR
within 30 minutes (mITT population n117)
100
91
90
80
70
60
Probability of SBP ITR attainment in 30 minutes
()
50
40
30
20
10
0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
Minutes
Patients whose SBP was above their prespecified
ITR at the time of clevidipine initiation.
Pollack CV et al. Ann Emerg Med. 2008 Jun 6.
Epub ahead of print.
121
Clevidipine MinimizedOvershoot in BP Management

• 2 patients (1.6) fell below the lower ITR limit
  within the first 3 minutes
• In 1 patient the ITR was narrower than specified
  by protocol (205-195 mmHg) with SBP 15 mmHg
  below the lower limit
• In 1 patient the lower limit was 160 mmHg and
  the SBP fell 4 mmHg below this
• Both patients continued clevidipine infusion
  beyond 18 hours without AEs

Pollack CV et al. Ann Emerg Med. 2008 Jun 6.
Epub ahead of print.
122
Rapid Sustained BP Control

• Per protocol patients were infused for a minimum
  of 18 h
• Dose adjustments2
• On average 2 dose adjustments were needed to
  attain ITR
• Mean number of adjustments needed after
  attainment of ITR through 18 h 0.33/h

0
5
30-min titration to ITR
10
Mean SBP reduction from baseline () 1
15
20
Additional titration BP adjustment and
maintenance
25
30
0
3
6
9
12
15
18
Time After Start of Infusion (h)
1. Pollack CV et al. Ann Emerg Med. 2008 Jun 6.
Epub ahead of print. 2. Data on file. The
Medicines Company.
123
Safety Profile in Severe Hypertension

• Most common AEs reported in the safety population
  (n126) included
• Headache 6.3 (8/126)
• Nausea 4.8 (6/126)
• Vomiting 3.2 (4/126)
• Serious AEsreported from initiation of
  clevidipine to 7 days laterwere experienced by
  8.7 (11/126) of patients
• Incidence of AEs leading to study drug
  discontinuation 4.8

Pollack CV et al. Ann Emerg Med. 2008 Jun 6.
Epub ahead of print.
124
Clevidipine Did Not Raise Serum Triglyceride
Levels

• Clevidipine is formulated and administered in a
  lipid emulsion
• Changes in serum triglyceride (TG) concentrations
  were assessed in VELOCITY
• Median percentage change in serum TG
  concentrations was zero
• Additional post hoc analyses were conducted to
  evaluate the relationship of TG to total lipid
  dose exposure
• No relationship was observed when TG
  concentrations at baseline and 6 hours
  post-infusion were examined on the basis of the
  total clevidipine dose received

Pollack CV et al. Ann Emerg Med. 2008 Jun 6.
Epub ahead of print.
125
Transition to Oral Antihypertensives

• 97.5 (115/118 eligible patients) transitioned
  successfully to oral antihypertensive therapy
  within 6 hours

97.5
Successful transition to oral therapy was defined
as transition with systolic blood pressure
remaining within the applicable (last identified)
target range at 6 hours after stopping
clevidipine.
Pollack CV et al. Ann Emerg Med. 2008 Jun 6.
Epub ahead of print.
126
Renal Impairment Cohort

• Clevidipine reduced SBP in a post hoc analysis of
  patients with renal dysfunction (dialysis
  dependent and nondialysis dependent)

5
With renal dysfunction (n22)
0
Without renal dysfunction (n95)
5
10
Mean SBP change from baseline ()
15
20
25
30
35
3
6
9
12
15
18
21
24
27
30
Time (min)
Peacock WF et al. Society of Critical Care
Medicine 37th Critical Care Congress 2008.
Poster 310.
127
Acute Heart Failure Cohort

• Clevidipine decreased SBP in a post hoc analysis
  of patients with AHF and severe hypertension
  without causing hypotension

5
With acute heart failure (n17)
0
Without acute heart failure (n100)
5
10
Mean SBP change from baseline ()
15
20
25
30
35
3
6
9
12
15
18
21
24
27
30
Time (min)
Peacock WF et al. Society of Critical Care
Medicine 37th Critical Care Congress 2008.
Poster 302.
128
NonWeight-Based Dosing Regimen(as Used in
VELOCITY)
Initiate clevidipine IV infusion at 1-2 mg/h
Double the dose every 90 sec initially then as
BP approaches goal increase dose by less than
double and lengthen time between dose
adjustments to every 5-10 min 1- to 2-mg/h
increase will generally produce an additional 2-
to 4-mmHg decrease in SBP
Monitor BP and heart rate continuously
during infusion and then until vital signs are
stable
129
NonWeight-Based Dosing RegimenClevidipine as
labeled

• The desired therapeutic response for most
  patients occurs at doses of 4-6 mg/h
• Most patients were treated with maximum doses of
  16 mg/h or less
• There is limited short-term experience with doses
  up to 32 mg/h
• Because of lipid load restrictions no more than
  1000 mL or an average of 21 mg/h of clevidipine
  infusion is recommended per 24-hour period
• In clinical trials 55 hypertensive patients were
  treated with gt500 mL of clevidipine infusion per
  24-hour period
• There is little experience with infusion
  durations beyond 72 hours at any dose

130
What We Learned From VELOCITY

• Clevidipine reliably lowered BP to pre-specified
  target range in 90 of patients within 30 minutes
• Predictably reached target BP without overshoot
  in a median 10.9 min
• Clevidipine was easy to administer andwell
  tolerated
• Peripheral venous administration and BP
  monitoring via a cuff was safe and feasible in
  the ED

131
Summary

• Hypertension is extremely prevalent in US
  society and as population ages hypertensive
  crises will become increasingly common in the ED
• Debate over terminology and numerical definitions
  is all too prevalent in the literature
• Choices among available agents are often
  difficult and none is ideal across the spectrum
• Must balance effective reduction with avoidance
  of over-reduction and its complications

132
Summary

• As ED LOS increases care of BP derangements will
  fall ever more in the purview of the emergency
  physician
• Even with prompt transfer of HU/HE patients to
  the inpatient setting this is one of the few
  areas where emergency physicians and intensivists
  actually approach definitive care in much the
  same way
• Clevidipine offers a novel safe multi-setting
  multi-disciplinary approach to management of
  acute severe hypertension that has been studied
  specifically in the ED