Hypertensive Urgencies Hypertensive Urgencies and Emergenciesand Emergencies

Current Challenges for the Emergency Current Challenges for the Emergency PhysicianPhysician

Presented ByPresented By

Budi Yuli Setianto, MD, PhD, FIHA, FINASIM, Budi Yuli Setianto, MD, PhD, FIHA, FINASIM, FAsCC, FAPSICFAsCC, FAPSIC

Hypertension — An EpidemicHypertension — An Epidemic

► Affects at least 65 million AmericansAffects at least 65 million Americans

► Affects at least 1 BILLION individuals worldwideAffects at least 1 BILLION individuals worldwide

► Most current (2003) evidence basis for chronic Most current (2003) evidence basis for chronic management—management—The Seventh Report of the Joint The Seventh Report of the Joint National Committee on the Prevention, National Committee on the Prevention, Detection, Evaluation, and Treatment of High Detection, Evaluation, and Treatment of High Blood Pressure Hypertension (Blood Pressure Hypertension (JNC 7JNC 7))——lacks lacks guidance for acute management of patients guidance for acute management of patients presenting to an ED with hypertension, presenting to an ED with hypertension, especially severe acute elevations of BPespecially severe acute elevations of BP

► Affects at least 65 million AmericansAffects at least 65 million Americans

► Affects at least 1 BILLION individuals worldwideAffects at least 1 BILLION individuals worldwide

► Most current (2003) evidence basis for chronic Most current (2003) evidence basis for chronic management—management—The Seventh Report of the Joint The Seventh Report of the Joint National Committee on the Prevention, National Committee on the Prevention, Detection, Evaluation, and Treatment of High Detection, Evaluation, and Treatment of High Blood Pressure Hypertension (Blood Pressure Hypertension (JNC 7JNC 7))——lacks lacks guidance for acute management of patients guidance for acute management of patients presenting to an ED with hypertension, presenting to an ED with hypertension, especially severe acute elevations of BPespecially severe acute elevations of BP

JNC 7, JAMA 2003; 289:2560-2572.

Hypertensive UrgenciesHypertensive Urgenciesand Emergenciesand Emergencies

Hypertensive UrgenciesHypertensive Urgenciesand Emergenciesand Emergencies

► Epidemiologic data are largely lackingEpidemiologic data are largely lacking

► It is thought that ~ 1% of patients with It is thought that ~ 1% of patients with hypertension will eventually present to the ED hypertension will eventually present to the ED in hypertensive crisisin hypertensive crisis

► In a single-center Italian study, HU or HE In a single-center Italian study, HU or HE accounted for 3% of all medicine admissions accounted for 3% of all medicine admissions and 27.5% of all medical emergenciesand 27.5% of all medical emergencies HU:HE ratio of 3:1 in that studyHU:HE ratio of 3:1 in that study

Patients with HU much more likely to be unaware of Patients with HU much more likely to be unaware of their hypertension diagnosis than those with HEtheir hypertension diagnosis than those with HE

Zampaglione et al, Hypertension 1996;27:144.

Presenting SymptomsPresenting Symptoms

► Hypertensive Hypertensive UrgenciesUrgencies ArrhythmiaArrhythmia EpistaxisEpistaxis HeadacheHeadache Psychomotor agitationPsychomotor agitation

► Usual Primary ED Usual Primary ED DiagnosisDiagnosis HypertensionHypertension

► Hypertensive Hypertensive UrgenciesUrgencies ArrhythmiaArrhythmia EpistaxisEpistaxis HeadacheHeadache Psychomotor agitationPsychomotor agitation

► Usual Primary ED Usual Primary ED DiagnosisDiagnosis HypertensionHypertension

► Hypertensive Hypertensive EmergenciesEmergencies Chest painChest pain DyspneaDyspnea Neurologic deficitsNeurologic deficits

► Usual Primary ED Usual Primary ED DiagnosisDiagnosis CVACVA Acute pulmonary edemaAcute pulmonary edema Hypertensive Hypertensive

encephalopathyencephalopathy Acute heart failureAcute heart failure

► Hypertensive Hypertensive EmergenciesEmergencies Chest painChest pain DyspneaDyspnea Neurologic deficitsNeurologic deficits

► Usual Primary ED Usual Primary ED DiagnosisDiagnosis CVACVA Acute pulmonary edemaAcute pulmonary edema Hypertensive Hypertensive

encephalopathyencephalopathy Acute heart failureAcute heart failure

Zampaglione et al, Hypertension 1996;27:144.

JNC 7 NomenclatureJNC 7 NomenclatureJNC 7 NomenclatureJNC 7 Nomenclature

► Normal BP: Systolic < 120, Diastolic < 80Normal BP: Systolic < 120, Diastolic < 80

► Prehypertension: S = 120-139, D = 80-89Prehypertension: S = 120-139, D = 80-89

► Stage 1 hypertension: S = 140-159, D = 90-99Stage 1 hypertension: S = 140-159, D = 90-99

► Stage 2 hypertension: S Stage 2 hypertension: S >> 160, D 160, D >> 100 100

► Stage 3 hypertension (JNC 6):Stage 3 hypertension (JNC 6):

Systolic > 180, Diastolic > 110Systolic > 180, Diastolic > 110

Functionally, this is “hypertensive urgency”Functionally, this is “hypertensive urgency”

► What about “crisis,” “emergency,” and What about “crisis,” “emergency,” and “urgency”?“urgency”?

► Normal BP: Systolic < 120, Diastolic < 80Normal BP: Systolic < 120, Diastolic < 80

► Prehypertension: S = 120-139, D = 80-89Prehypertension: S = 120-139, D = 80-89

► Stage 1 hypertension: S = 140-159, D = 90-99Stage 1 hypertension: S = 140-159, D = 90-99

► Stage 2 hypertension: S Stage 2 hypertension: S >> 160, D 160, D >> 100 100

► Stage 3 hypertension (JNC 6):Stage 3 hypertension (JNC 6):

Systolic > 180, Diastolic > 110Systolic > 180, Diastolic > 110

Functionally, this is “hypertensive urgency”Functionally, this is “hypertensive urgency”

► What about “crisis,” “emergency,” and What about “crisis,” “emergency,” and “urgency”?“urgency”?

JNC 7, JAMA 2003; 289:2560-2572.

JNC 7 NomenclatureJNC 7 Nomenclature

► Using JNC 7 nomenclature, “hypertensive Using JNC 7 nomenclature, “hypertensive crisis” is an acute, severe, stage 2 or 3 crisis” is an acute, severe, stage 2 or 3 elevation in blood pressureelevation in blood pressure

► Crisis is then differentiated into Crisis is then differentiated into hypertensive “emergencies” (involving hypertensive “emergencies” (involving some end-organ damage) and “urgencies” some end-organ damage) and “urgencies” (no end-organ damage)(no end-organ damage)

► Using JNC 7 nomenclature, “hypertensive Using JNC 7 nomenclature, “hypertensive crisis” is an acute, severe, stage 2 or 3 crisis” is an acute, severe, stage 2 or 3 elevation in blood pressureelevation in blood pressure

► Crisis is then differentiated into Crisis is then differentiated into hypertensive “emergencies” (involving hypertensive “emergencies” (involving some end-organ damage) and “urgencies” some end-organ damage) and “urgencies” (no end-organ damage)(no end-organ damage)

JNC 7, JAMA 2003; 289:2560-2572.

““End-Organ Damage”End-Organ Damage”

► CardiopulmonaryCardiopulmonary Acute heart failureAcute heart failure Acute coronary syndromeAcute coronary syndrome Acute pulmonary edema with respiratory failureAcute pulmonary edema with respiratory failure Dissecting aortaDissecting aorta

► CNSCNS Hypertensive encephalopathyHypertensive encephalopathy CVACVA

► OcularOcular ExudatesExudates PapilledemaPapilledema Retinal hemorrhagesRetinal hemorrhages

► RenalRenal Acute renal failureAcute renal failure

► CardiopulmonaryCardiopulmonary Acute heart failureAcute heart failure Acute coronary syndromeAcute coronary syndrome Acute pulmonary edema with respiratory failureAcute pulmonary edema with respiratory failure Dissecting aortaDissecting aorta

► CNSCNS Hypertensive encephalopathyHypertensive encephalopathy CVACVA

► OcularOcular ExudatesExudates PapilledemaPapilledema Retinal hemorrhagesRetinal hemorrhages

► RenalRenal Acute renal failureAcute renal failure

JNC 7, JAMA 2003; 289:2560-2572.

Causes of Hypertensive CrisesCauses of Hypertensive CrisesCauses of Hypertensive CrisesCauses of Hypertensive Crises

► Essential hypertensionEssential hypertension Medication noncomplianceMedication noncompliance

► Secondary hypertensionSecondary hypertension Aortic coarctationAortic coarctation Cushing’s syndromeCushing’s syndrome Elevated ICPElevated ICP Renal dysfunctionRenal dysfunction Pregnancy Pregnancy HyperparathyroidismHyperparathyroidism HyperthyroidismHyperthyroidism PheochromocytomaPheochromocytoma Primary aldosteronismPrimary aldosteronism

► Essential hypertensionEssential hypertension Medication noncomplianceMedication noncompliance

► Secondary hypertensionSecondary hypertension Aortic coarctationAortic coarctation Cushing’s syndromeCushing’s syndrome Elevated ICPElevated ICP Renal dysfunctionRenal dysfunction Pregnancy Pregnancy HyperparathyroidismHyperparathyroidism HyperthyroidismHyperthyroidism PheochromocytomaPheochromocytoma Primary aldosteronismPrimary aldosteronism

JNC 7, JAMA 2003; 289:2560-2572.

Goals of ED TherapyGoals of ED Therapy of Hypertensive Crises of Hypertensive CrisesGoals of ED TherapyGoals of ED Therapy

of Hypertensive Crises of Hypertensive Crises

► HU can generally be managed with oral HU can generally be managed with oral medications and requires BP lowering over 24-48 medications and requires BP lowering over 24-48 hourshours Important to prevent too-rapid lowering due to autoregulation Important to prevent too-rapid lowering due to autoregulation

of flow by pressure in brain, heart, and kidneysof flow by pressure in brain, heart, and kidneys

► Goal in hypertensive urgency is to reduce MAP by Goal in hypertensive urgency is to reduce MAP by 10-15% and/or to a DBP of 110 . . . within one hour10-15% and/or to a DBP of 110 . . . within one hour Aortic dissection requires Aortic dissection requires even more rapid loweringeven more rapid lowering Once initial reduction achieved, transition to oral agentsOnce initial reduction achieved, transition to oral agents Dug of choice for initial therapy often depends on which end-Dug of choice for initial therapy often depends on which end-

organ system is affected and on comorbiditiesorgan system is affected and on comorbidities

► HU can generally be managed with oral HU can generally be managed with oral medications and requires BP lowering over 24-48 medications and requires BP lowering over 24-48 hourshours Important to prevent too-rapid lowering due to autoregulation Important to prevent too-rapid lowering due to autoregulation

of flow by pressure in brain, heart, and kidneysof flow by pressure in brain, heart, and kidneys

► Goal in hypertensive urgency is to reduce MAP by Goal in hypertensive urgency is to reduce MAP by 10-15% and/or to a DBP of 110 . . . within one hour10-15% and/or to a DBP of 110 . . . within one hour Aortic dissection requires Aortic dissection requires even more rapid loweringeven more rapid lowering Once initial reduction achieved, transition to oral agentsOnce initial reduction achieved, transition to oral agents Dug of choice for initial therapy often depends on which end-Dug of choice for initial therapy often depends on which end-

organ system is affected and on comorbiditiesorgan system is affected and on comorbidities

JNC 7, JAMA 2003; 289:2560-2572.

Why Are We Here Today?Why Are We Here Today?Why Are We Here Today?Why Are We Here Today?

► Severe hypertension is increasingly prevalent Severe hypertension is increasingly prevalent as population ages and obesity and diabetes as population ages and obesity and diabetes become more commonbecome more common

► Currently available agents for the management Currently available agents for the management of acute severe BP elevation leave much to be of acute severe BP elevation leave much to be desired — advancements are possibledesired — advancements are possible

► There is a new agent on the horizon that has There is a new agent on the horizon that has been tested specifically in the EDbeen tested specifically in the ED

► Severe hypertension is increasingly prevalent Severe hypertension is increasingly prevalent as population ages and obesity and diabetes as population ages and obesity and diabetes become more commonbecome more common

► Currently available agents for the management Currently available agents for the management of acute severe BP elevation leave much to be of acute severe BP elevation leave much to be desired — advancements are possibledesired — advancements are possible

► There is a new agent on the horizon that has There is a new agent on the horizon that has been tested specifically in the EDbeen tested specifically in the ED

ED Hypertensive EmergenciesED Hypertensive EmergenciesED Hypertensive EmergenciesED Hypertensive Emergencies

► Hypertensive emergencies and urgenciesHypertensive emergencies and urgencies Account for 3% of all ED visitsAccount for 3% of all ED visits11

► An “Internal Medicine” EDAn “Internal Medicine” ED N=14,209N=14,209 1634 had a medical urgency or emergency1634 had a medical urgency or emergency22

• 27.4% of these were hypertensive crises27.4% of these were hypertensive crises

► Clinical treatment practices vary widelyClinical treatment practices vary widely33

► Hypertensive emergencies and urgenciesHypertensive emergencies and urgencies Account for 3% of all ED visitsAccount for 3% of all ED visits11

► An “Internal Medicine” EDAn “Internal Medicine” ED N=14,209N=14,209 1634 had a medical urgency or emergency1634 had a medical urgency or emergency22

• 27.4% of these were hypertensive crises27.4% of these were hypertensive crises

► Clinical treatment practices vary widelyClinical treatment practices vary widely33

1. Kitiyakara C, Guzman N. J Am Soc Nephrol. 1998;9:133-142. 2. Zampaglione B, et al. Hypertension. 1996;27:144-147. 3. Cherney D, Strauss S. J Gen Intern Med. 2002;17:937-945.

Hypertension in the EDHypertension in the EDHypertension in the EDHypertension in the ED

Four Categories of PresentationFour Categories of Presentation► EmergenciesEmergencies

► UrgenciesUrgencies

► Mild, uncomplicatedMild, uncomplicated

► TransientTransient

Four Categories of PresentationFour Categories of Presentation► EmergenciesEmergencies

► UrgenciesUrgencies

► Mild, uncomplicatedMild, uncomplicated

► TransientTransient

Hypertension FrequencyHypertension Frequency

CategoryCategory FrequencyFrequency► Emergencies Emergencies 1 cerebral and 1 cardiac/shift)1 cerebral and 1 cardiac/shift)

► Urgencies Urgencies ????????????

► Mild, uncomplicated Mild, uncomplicated 1/shift1/shift

► TransientTransient Who cares?Who cares?

CategoryCategory FrequencyFrequency► Emergencies Emergencies 1 cerebral and 1 cardiac/shift)1 cerebral and 1 cardiac/shift)

► Urgencies Urgencies ????????????

► Mild, uncomplicated Mild, uncomplicated 1/shift1/shift

► TransientTransient Who cares?Who cares?

History and PhysicalHistory and Physical

► US Obesity EpidemicUS Obesity Epidemic < 50% exercise more than < 50% exercise more than

occasionallyoccasionally Colorado — the thinnest Colorado — the thinnest

state, only 13% obesestate, only 13% obese Too small a cuff falsely Too small a cuff falsely

elevates BPelevates BP

► US Obesity EpidemicUS Obesity Epidemic < 50% exercise more than < 50% exercise more than

occasionallyoccasionally Colorado — the thinnest Colorado — the thinnest

state, only 13% obesestate, only 13% obese Too small a cuff falsely Too small a cuff falsely

elevates BPelevates BP

Definitions of HypertensionDefinitions of HypertensionDefinitions of HypertensionDefinitions of Hypertension

► Mild, Uncomplicated HTNMild, Uncomplicated HTN Diastolic BP <115 mmHg without Diastolic BP <115 mmHg without

end organ symptomsend organ symptoms Educate, do not treat, arrange Educate, do not treat, arrange

follow upfollow up

► Transient HTNTransient HTN A reaction to some condition A reaction to some condition

• Pain, fright, epistaxis, Pain, fright, epistaxis, drug ODdrug OD

Treat the conditionTreat the condition

► Mild, Uncomplicated HTNMild, Uncomplicated HTN Diastolic BP <115 mmHg without Diastolic BP <115 mmHg without

end organ symptomsend organ symptoms Educate, do not treat, arrange Educate, do not treat, arrange

follow upfollow up

► Transient HTNTransient HTN A reaction to some condition A reaction to some condition

• Pain, fright, epistaxis, Pain, fright, epistaxis, drug ODdrug OD

Treat the conditionTreat the condition

► Hypertensive UrgencyHypertensive Urgency BP at a level that may be potentially harmful, BP at a level that may be potentially harmful,

but without focal findings but without focal findings Usually sustained diastolic > 115 mmHg Usually sustained diastolic > 115 mmHg

(120mmHg)(120mmHg)• Commonly due to non-complianceCommonly due to non-compliance

Ignore systolic BP: MAP= ( 2 Diastolic + Ignore systolic BP: MAP= ( 2 Diastolic + systolic) / 3systolic) / 3

Lower BP over 24-48 hours (give them a Rx)Lower BP over 24-48 hours (give them a Rx)• Avoid rapid BP reductionsAvoid rapid BP reductions

History, physical, and time may be all thatHistory, physical, and time may be all thatis neededis needed

► Hypertensive UrgencyHypertensive Urgency BP at a level that may be potentially harmful, BP at a level that may be potentially harmful,

but without focal findings but without focal findings Usually sustained diastolic > 115 mmHg Usually sustained diastolic > 115 mmHg

(120mmHg)(120mmHg)• Commonly due to non-complianceCommonly due to non-compliance

Ignore systolic BP: MAP= ( 2 Diastolic + Ignore systolic BP: MAP= ( 2 Diastolic + systolic) / 3systolic) / 3

Lower BP over 24-48 hours (give them a Rx)Lower BP over 24-48 hours (give them a Rx)• Avoid rapid BP reductionsAvoid rapid BP reductions

History, physical, and time may be all thatHistory, physical, and time may be all thatis neededis needed

Definition of HypertensionDefinition of HypertensionDefinition of HypertensionDefinition of Hypertension

Definition of Hypertensive Definition of Hypertensive EmergencyEmergency

► Hypertensive EmergencyHypertensive Emergency Increased BP Increased BP WITHWITH end organ damage end organ damage

• At risk: Brain, heart, kidneysAt risk: Brain, heart, kidneys No specific BP criteriaNo specific BP criteria

► Hypertensive EmergencyHypertensive Emergency Increased BP Increased BP WITHWITH end organ damage end organ damage

• At risk: Brain, heart, kidneysAt risk: Brain, heart, kidneys No specific BP criteriaNo specific BP criteria

Acute BP Management — Acute BP Management — ConsiderationsConsiderations

Acute BP Management — Acute BP Management — ConsiderationsConsiderations

► What is the magnitude of:What is the magnitude of: Disease risk?Disease risk? Treatment benefit?Treatment benefit? Treatment risk?Treatment risk?

► How persistent is the benefit?How persistent is the benefit?

► What improved outcome is What improved outcome is there for the patient?there for the patient?

► What is the magnitude of:What is the magnitude of: Disease risk?Disease risk? Treatment benefit?Treatment benefit? Treatment risk?Treatment risk?

► How persistent is the benefit?How persistent is the benefit?

► What improved outcome is What improved outcome is there for the patient?there for the patient?

Hemodynamics and Hemodynamics and Myocardial IschemiaMyocardial Ischemia

Adapted from Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. W.B.Saunders Co.; 2001.

Afterload or SVR

Work

O2 consumption

↓ Myocardial Blood Flow

O2 delivery

↑ Left Ventricular (LV) Wall Tension

Afterload or SVR

Myocardial Ischemia

Increased Afterload Increases OIncreased Afterload Increases O22 Consumption Consumption

and Decreases Oand Decreases O22 Delivery to the Heart Delivery to the HeartIncreased Afterload Increases OIncreased Afterload Increases O22 Consumption Consumption

and Decreases Oand Decreases O22 Delivery to the Heart Delivery to the Heart

NitroglycerinNitroglycerinNitroglycerinNitroglycerin

► Arterial and coronary venodilatorArterial and coronary venodilator Mechanism: cGMPMechanism: cGMP

► Onset, 2-5 minutes, t ½ 4 minutesOnset, 2-5 minutes, t ½ 4 minutes Duration, 5-10 minutesDuration, 5-10 minutes

► Dose: Start at 20-30 Dose: Start at 20-30 g/ming/min Titrate by 10 Titrate by 10 g/ming/min

q 3-5 minutesq 3-5 minutes► May cause headache, May cause headache, HR, HR,

vomiting, methemoglobinemiavomiting, methemoglobinemia ► Special considerationsSpecial considerations

Tachyphylaxis within hoursTachyphylaxis within hours Coronary ischemiaCoronary ischemia

► IV form requires specialIV form requires specialdelivery systemdelivery system

► Arterial and coronary venodilatorArterial and coronary venodilator Mechanism: cGMPMechanism: cGMP

► Onset, 2-5 minutes, t ½ 4 minutesOnset, 2-5 minutes, t ½ 4 minutes Duration, 5-10 minutesDuration, 5-10 minutes

► Dose: Start at 20-30 Dose: Start at 20-30 g/ming/min Titrate by 10 Titrate by 10 g/ming/min

q 3-5 minutesq 3-5 minutes► May cause headache, May cause headache, HR, HR,

vomiting, methemoglobinemiavomiting, methemoglobinemia ► Special considerationsSpecial considerations

Tachyphylaxis within hoursTachyphylaxis within hours Coronary ischemiaCoronary ischemia

► IV form requires specialIV form requires specialdelivery systemdelivery system

The 7th Report of the JNC. JAMA 2003;289:2560-2571.

Nitroglycerin & PCWP versus TimeNitroglycerin & PCWP versus TimeNitroglycerin & PCWP versus TimeNitroglycerin & PCWP versus Time

n=9 (3 hr); n=12 (>3 hr)

Added to standard therapy

n=9 (3 hr); n=12 (>3 hr)

Added to standard therapy

00

2020

4040

6060

8080

100100

120120

140140

160160

180180

00 33 66 99 1212 1515 1818 2121 2424

Time (hr)Time (hr)

Nitr

ogly

cerin

Dos

e (m

cg/m

in)

Nitr

ogly

cerin

Dos

e (m

cg/m

in) C

hange in PC

WP

(mm

Hg)

Change in P

CW

P (m

m H

g)

NTG doseNTG dose

Change in PCWPChange in PCWP

**

**

****

**

**

* * PP<0.05 vs baseline <0.05 vs baseline

Elkayam U et al. Am J Cardiol 2004;93:237. Elkayam U et al. Am J Cardiol 2004;93:237.

00

11

22

33

44

55

66

77

88

Organic Nitrates: Tolerance TheoriesOrganic Nitrates: Tolerance Theories

► Decreased bioconversion to nitric oxideDecreased bioconversion to nitric oxide11

► Cellular depletion of sulfhydryl groupsCellular depletion of sulfhydryl groups2,32,3

► Neurohumoral adaptationsNeurohumoral adaptations44

► Superoxide anion productionSuperoxide anion production55

► Upregulation of endothelinUpregulation of endothelin66

► Decreased bioconversion to nitric oxideDecreased bioconversion to nitric oxide11

► Cellular depletion of sulfhydryl groupsCellular depletion of sulfhydryl groups2,32,3

► Neurohumoral adaptationsNeurohumoral adaptations44

► Superoxide anion productionSuperoxide anion production55

► Upregulation of endothelinUpregulation of endothelin661. Münzel T. Am J Cardiol. 1996;77:24C-30C. 2. Parker JD, Parker JO. N Engl J Med. 1998;338:520-531. 3. Needleman P, Johnson EMJ. J Pharmacol Exp Ther. 1973;184:709-715.4. Münzel T, et al. J Am Coll Cardiol. 1996;27:297-303. 5. Münzel T, et al. J Clin Invest. 1995;95:187-194. 6. Münzel T, et al. Proc Natl Acad Sci. 1995;92:5244-5248.

Nitroprusside — MechanismNitroprusside — MechanismNitroprusside — MechanismNitroprusside — Mechanism

► Spontaneously releases nitric oxide (NO) Spontaneously releases nitric oxide (NO) ► NO activates guanylyl cyclase, increasing cGMPNO activates guanylyl cyclase, increasing cGMP► cGMP activates myosin light chain phosphatase (MLCP)cGMP activates myosin light chain phosphatase (MLCP)► MLCP dephosphorylates myosin light chainsMLCP dephosphorylates myosin light chains► Leads to relaxationLeads to relaxation

► Spontaneously releases nitric oxide (NO) Spontaneously releases nitric oxide (NO) ► NO activates guanylyl cyclase, increasing cGMPNO activates guanylyl cyclase, increasing cGMP► cGMP activates myosin light chain phosphatase (MLCP)cGMP activates myosin light chain phosphatase (MLCP)► MLCP dephosphorylates myosin light chainsMLCP dephosphorylates myosin light chains► Leads to relaxationLeads to relaxation

NitroprussideNitroprusside

► Arterial and venodilatorArterial and venodilator

Decreases preload and afterloadDecreases preload and afterload No chronotropic effect, but HR No chronotropic effect, but HR (baroreceptors) (baroreceptors)

► Onset 1-2 minutes, t ½ 3-4 minutesOnset 1-2 minutes, t ½ 3-4 minutes

Start @ 0.5 Start @ 0.5 g/kg/min, then titrateg/kg/min, then titrate Average effective dose is 3 Average effective dose is 3 g/kg/min (0.5-10 g/kg/min (0.5-10

g/kg/min)g/kg/min)

► Arterial and venodilatorArterial and venodilator

Decreases preload and afterloadDecreases preload and afterload No chronotropic effect, but HR No chronotropic effect, but HR (baroreceptors) (baroreceptors)

► Onset 1-2 minutes, t ½ 3-4 minutesOnset 1-2 minutes, t ½ 3-4 minutes

Start @ 0.5 Start @ 0.5 g/kg/min, then titrateg/kg/min, then titrate Average effective dose is 3 Average effective dose is 3 g/kg/min (0.5-10 g/kg/min (0.5-10

g/kg/min)g/kg/min)

The 7th Report of the JNC. JAMA 2003;289:2560-2571.

Nitropusside: Issues and ConcernsNitropusside: Issues and ConcernsNitropusside: Issues and ConcernsNitropusside: Issues and Concerns

► BP BP ► May cause N/V, twitching, sweatingMay cause N/V, twitching, sweating► Metabolized to CN, then thiocyanateMetabolized to CN, then thiocyanate

RF issue RF issue

► BADNESSBADNESS• PregnancyPregnancy• Coronary steal?Coronary steal?• Dose dependent Dose dependent in CBF in CBF

– Caution with high ICP Caution with high ICP

• Hypoxia (Hypoxia ( Va/Q mismatch) Va/Q mismatch)• Requires special delivery systemRequires special delivery system• Usually requires direct Usually requires direct

artery pressure monitoringartery pressure monitoring

► BP BP ► May cause N/V, twitching, sweatingMay cause N/V, twitching, sweating► Metabolized to CN, then thiocyanateMetabolized to CN, then thiocyanate

RF issue RF issue

► BADNESSBADNESS• PregnancyPregnancy• Coronary steal?Coronary steal?• Dose dependent Dose dependent in CBF in CBF

– Caution with high ICP Caution with high ICP

• Hypoxia (Hypoxia ( Va/Q mismatch) Va/Q mismatch)• Requires special delivery systemRequires special delivery system• Usually requires direct Usually requires direct

artery pressure monitoringartery pressure monitoring

NitrovasodilatorsNitrovasodilatorsNitroprusside versus NitroglycerinNitroprusside versus Nitroglycerin

NitrovasodilatorsNitrovasodilatorsNitroprusside versus NitroglycerinNitroprusside versus Nitroglycerin

DrugDrug NitroprussideNitroprusside NitroglycerinNitroglycerin

Rapid onset of peak effectRapid onset of peak effect ++++++++ ++++++

Afterload reductionAfterload reduction ++++++++ ++

Preload reductionPreload reduction ++++ ++++++++

Coronary steal reportedCoronary steal reported ++ 00

Coronary dilation – large vesselCoronary dilation – large vessel ++ ++++++++

Coronary dilation – small vesselCoronary dilation – small vessel +/-+/- +/-+/-

TachycardiaTachycardia ++++ ++++

Potential for symptomatic hypotensionPotential for symptomatic hypotension ++++ ++++++

Ease of administrationEase of administration ++++ ++++++

Cyanide toxicityCyanide toxicity ++++++++ 00

Pepine CJ. Clin Ther. 1988;10:316-325.

► Very dyspneic

► BP 160/97

► Rales

► Cool skin

► Very dyspneic

► BP 160/97

► Rales

► Cool skin

61-Year-Old Female61-Year-Old Female

Profiles and Therapies of Profiles and Therapies of Advanced Heart FailureAdvanced Heart Failure

Profiles and Therapies of Profiles and Therapies of Advanced Heart FailureAdvanced Heart Failure

YesYes

R. Bourge, UAB CardiologyStevenson LW. Eur J Heart Failure 1999;1:251-257R. Bourge, UAB CardiologyStevenson LW. Eur J Heart Failure 1999;1:251-257

NoNo

Warm and DryPCW and CI

normal

Warm and DryPCW and CI

normal

Warm and WetPCW elevated

CI normal

Warm and WetPCW elevated

CI normal

Cold and WetPCW elevatedCI decreased

Cold and WetPCW elevatedCI decreased

Cold and DryPCW low/normal

CI decreased

Cold and DryPCW low/normal

CI decreased

VasodilatorsNitroprussideNitroglycerine

Nesiritide

VasodilatorsNitroprussideNitroglycerine

Nesiritide

Inotropic DrugsDobutamine

MilrinoneCalcium Sensitizers

Inotropic DrugsDobutamine

MilrinoneCalcium Sensitizers

Nl SVRNl SVR High SVRHigh SVR

Congestion at RestCongestion at RestCongestion at RestCongestion at Rest

LowLowPerfusionPerfusion

at Restat Rest

LowLowPerfusionPerfusion

at Restat Rest

NoNo

YesYes

49% with 49% with BP>140 mmHgBP>140 mmHg49% with 49% with BP>140 mmHgBP>140 mmHg

Acute Pulmonary Edema: AlgorithmAcute Pulmonary Edema: Algorithm

► Nitroglycerin 1 sublingual q 1 minNitroglycerin 1 sublingual q 1 min Until patient improves, IV is in, orUntil patient improves, IV is in, or

requires intubationrequires intubation

► Start at 30 Start at 30 g/ming/min titrate up to 200 titrate up to 200 g/min withing/min within

5-10 minutes5-10 minutes Until dyspnea improves or BP dropsUntil dyspnea improves or BP drops

► If NTG reaches >200 If NTG reaches >200 g/min, changeg/min, changeto nitroprussideto nitroprusside

► Careful if: HOCM, volume depletedCareful if: HOCM, volume depleted

► Nitroglycerin 1 sublingual q 1 minNitroglycerin 1 sublingual q 1 min Until patient improves, IV is in, orUntil patient improves, IV is in, or

requires intubationrequires intubation

► Start at 30 Start at 30 g/ming/min titrate up to 200 titrate up to 200 g/min withing/min within

5-10 minutes5-10 minutes Until dyspnea improves or BP dropsUntil dyspnea improves or BP drops

► If NTG reaches >200 If NTG reaches >200 g/min, changeg/min, changeto nitroprussideto nitroprusside

► Careful if: HOCM, volume depletedCareful if: HOCM, volume depleted

HD NTGHD NTG ControlsControls P valueP value

Mech ventMech vent 20.7 % 46.7 % 0.023

ICU admitICU admit 37.9 % 80.0 % <0.001

Hosp LOS Hosp LOS (days)(days)

4.1 3.4 6.2 7.3 0.171

NSTEMINSTEMI 17.2 % 28.9 % 0.254

Low BPLow BP 3.4 % 0 % 0.210

Levy PD, et al, Acad EM, 13 (5) S107, 2006.

► Systolic BP Systolic BP 160 mmHg or MAP 160 mmHg or MAP 120 120► Failed: O2, SL NTG x 3, furosemideFailed: O2, SL NTG x 3, furosemide► 2 mg IV NTG bolus, titration and repeat q3 minutes, 2 mg IV NTG bolus, titration and repeat q3 minutes,

May repeat x 10May repeat x 10

N = 29 HD nitroglycerin, 45 controlsN = 29 HD nitroglycerin, 45 controls

Patient: 61-Year-Old FemalePatient: 61-Year-Old Female

DR I

MKRG

S SS

SGLG

FC CS SG

SGQVMK V L R

RH

KPS

CardiacCardiac33

Ventricular relaxation Ventricular relaxation (lusitropy)(lusitropy) Antifibrotic (Antifibrotic ( TGF TGF)) AntiremodelingAntiremodeling

CardiacCardiac33

Ventricular relaxation Ventricular relaxation (lusitropy)(lusitropy) Antifibrotic (Antifibrotic ( TGF TGF)) AntiremodelingAntiremodeling

HemodynamicHemodynamic1,21,2

(balanced vasodilation)(balanced vasodilation) VeinsVeins ArteriesArteries Coronary arteriesCoronary arteries

HemodynamicHemodynamic1,21,2

(balanced vasodilation)(balanced vasodilation) VeinsVeins ArteriesArteries Coronary arteriesCoronary arteries

NeurohumoralNeurohumoral22

aldosteronealdosterone44

endothelinendothelin22

norepinephrinenorepinephrine55

NeurohumoralNeurohumoral22

aldosteronealdosterone44

endothelinendothelin22

norepinephrinenorepinephrine55

RenalRenal1,51,5

• DiuresisDiuresis• NatriuresisNatriuresis

RenalRenal1,51,5

• DiuresisDiuresis• NatriuresisNatriuresis

1Marcus LS et al. Circulation. 1996;94:3184; 2Zellner C et al. Am J Physiol. 1999;276(3 pt 2):H1049;3Tamura N et al. Proc Natl Acad Sci U S A. 2000;97:4239; 4Abraham WT et al. J Card Fail. 1998;4:37;5Clemens LE et al. J Pharmacol Exp Ther. 1998;287:67.

Recombinant hBNPRecombinant hBNPRecombinant hBNPRecombinant hBNP

ProactionProaction BP Based on Baseline Thirds BP Based on Baseline Thirds

SBP is a function of the baseline SBPSBP is a function of the baseline SBP► NESNES

Baseline SBP Baseline SBP 100 mmHg 100 mmHg 1.24% decline1.24% decline SBP SBP 140 mmHg140 mmHg 18% decline18% decline

► Standard careStandard care Baseline SBP Baseline SBP 100 mmHg 100 mmHg 17% increase17% increase SBP SBP 140 mmHg 140 mmHg 5.3% decrease5.3% decrease

Heart rate at 6 hoursHeart rate at 6 hours► Nesiritide Nesiritide 5% decrease 5% decrease ► Standard careStandard care 1% decrease 1% decrease► (p=0.029) (p=0.029)

SBP is a function of the baseline SBPSBP is a function of the baseline SBP► NESNES

Baseline SBP Baseline SBP 100 mmHg 100 mmHg 1.24% decline1.24% decline SBP SBP 140 mmHg140 mmHg 18% decline18% decline

► Standard careStandard care Baseline SBP Baseline SBP 100 mmHg 100 mmHg 17% increase17% increase SBP SBP 140 mmHg 140 mmHg 5.3% decrease5.3% decrease

Heart rate at 6 hoursHeart rate at 6 hours► Nesiritide Nesiritide 5% decrease 5% decrease ► Standard careStandard care 1% decrease 1% decrease► (p=0.029) (p=0.029)

Peacock, et al, Cardiology, 2007.

ECG is normal, BP 180/95

54-Year-Old Male, Collapsed At Work54-Year-Old Male, Collapsed At Work54-Year-Old Male, Collapsed At Work54-Year-Old Male, Collapsed At Work

Aortic Dissection — StrategyAortic Dissection — Strategy

► Must decrease shear forcesMust decrease shear forces Shear force Shear force dP/dT dP/dT Do notDo not use inotropics use inotropics

► EsmololEsmolol

► LabetololLabetolol

► Must decrease shear forcesMust decrease shear forces Shear force Shear force dP/dT dP/dT Do notDo not use inotropics use inotropics

► EsmololEsmolol

► LabetololLabetolol

Tintinalli, 4th ed.

Labetalol — MechanismLabetalol — MechanismLabetalol — MechanismLabetalol — Mechanism

► Competitive, selective Competitive, selective 11 and non-selective and non-selective -blocker-blocker > > blockade (4-8 X’s more) blockade (4-8 X’s more) blockade is 1/10 of clonidineblockade is 1/10 of clonidine blockade is ¼ propranolol blockade is ¼ propranolol

► Treatment ConsiderationsTreatment Considerations Elimination t½ = 8 hours:Elimination t½ = 8 hours:

Clinical effect ~ 4-6 hrsClinical effect ~ 4-6 hrs 5%: orthostatic hypotension5%: orthostatic hypotension Paradoxical HTN with low doses Paradoxical HTN with low doses

(( block only, unopposed block only, unopposed ))

► Competitive, selective Competitive, selective 11 and non-selective and non-selective -blocker-blocker > > blockade (4-8 X’s more) blockade (4-8 X’s more) blockade is 1/10 of clonidineblockade is 1/10 of clonidine blockade is ¼ propranolol blockade is ¼ propranolol

► Treatment ConsiderationsTreatment Considerations Elimination t½ = 8 hours:Elimination t½ = 8 hours:

Clinical effect ~ 4-6 hrsClinical effect ~ 4-6 hrs 5%: orthostatic hypotension5%: orthostatic hypotension Paradoxical HTN with low doses Paradoxical HTN with low doses

(( block only, unopposed block only, unopposed ))

► No No in CBF: in CBF: Good if h/o cerebrovascular disease Good if h/o cerebrovascular disease

► No No in HR: in HR: MV0 MV02 2 unchangedunchanged

► IndicationsIndications Catechol’ excess: Catechol’ excess: Pheo, MAOI emergenciesPheo, MAOI emergencies

clonidine withdrawalclonidine withdrawal Pregnancy-induced HTNPregnancy-induced HTN

► DoseDose 20-40 mg IV, q 30 mins, max 300 mg20-40 mg IV, q 30 mins, max 300 mg

– BP drops w/in 5 mins, max response in 10 minsBP drops w/in 5 mins, max response in 10 mins IV drip @ 2 mg/min (may start w/ 20 mg bolus)IV drip @ 2 mg/min (may start w/ 20 mg bolus) PO 200 mgPO 200 mg

Labetalol — StrategyLabetalol — StrategyLabetalol — StrategyLabetalol — Strategy

Labetalol: Combined Labetalol: Combined - and - and -Blocker -Blocker Labetalol: Combined Labetalol: Combined - and - and -Blocker -Blocker

► Issues to considerIssues to consider

No No in cerebral, renal, or coronary in cerebral, renal, or coronaryblood flowblood flow

Intermediate time to onset Intermediate time to onset

Moderate effect Moderate effect

Negative chronotropic effectsNegative chronotropic effects11

Negative inotropic effectsNegative inotropic effects22

May exacerbate reactive airway diseaseMay exacerbate reactive airway disease

► Issues to considerIssues to consider

No No in cerebral, renal, or coronary in cerebral, renal, or coronaryblood flowblood flow

Intermediate time to onset Intermediate time to onset

Moderate effect Moderate effect

Negative chronotropic effectsNegative chronotropic effects11

Negative inotropic effectsNegative inotropic effects22

May exacerbate reactive airway diseaseMay exacerbate reactive airway disease

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. Le Bret F, et al. J Cardiothorac Vasc Anesth. 1992;6:433.

Esmolol — StrategyEsmolol — StrategyEsmolol — StrategyEsmolol — Strategy

► Load: 500 mcg/kg over one minuteLoad: 500 mcg/kg over one minute

► Then four-minute maintenanceThen four-minute maintenanceinfusion of 50 mcg/kg/mininfusion of 50 mcg/kg/min

► If inadequate:If inadequate: Repeat loading dose overRepeat loading dose over

one minuteone minute Increase maintenance infusion by 50 Increase maintenance infusion by 50

mcg/kg/minmcg/kg/min Max maintenance doseMax maintenance dose

200 mcg/kg/min200 mcg/kg/min

► As BP target is approached, omit As BP target is approached, omit subsequent loading doses and titrate subsequent loading doses and titrate the maintenance dosage up or down to the maintenance dosage up or down to endpoint endpoint

-Blocker Treatment Issues — -Blocker Treatment Issues — EsmololEsmolol

►AdvantagesAdvantages Treats tachycardia and hypertensionTreats tachycardia and hypertension CardioprotectiveCardioprotective Short duration of effectShort duration of effect

►DisadvantagesDisadvantages BradycardiaBradycardia Reactive airway diseaseReactive airway disease

►AdvantagesAdvantages Treats tachycardia and hypertensionTreats tachycardia and hypertension CardioprotectiveCardioprotective Short duration of effectShort duration of effect

►DisadvantagesDisadvantages BradycardiaBradycardia Reactive airway diseaseReactive airway disease

Oparil S, et al. Am J Hypertension. 1999;12:653-664.

-Blocker vs Combined -Blocker vs Combined - and - and -Blocker-Blocker

Esmolol Esmolol -Blocker-Blocker

LabetalolLabetalol

- and - and -Blocker-Blocker

AdministrationAdministration BolusBolusContinuous infusionContinuous infusion

BolusBolusContinuous infusionContinuous infusion

OnsetOnset Rapid (60 s)Rapid (60 s)22 Intermediate (peak 5-15 min)Intermediate (peak 5-15 min)22

Offset (Duration of action)Offset (Duration of action) Rapid (10-20 min)Rapid (10-20 min)22 Slower (2-4 h)Slower (2-4 h)22

HRHR DecreasedDecreased +/-+/-

SVRSVR 00 DecreasedDecreased

Cardiac outputCardiac output DecreasedDecreased +/-+/-

Myocardial OMyocardial O22 balance balance PositivePositive PositivePositive

ContraindicationsContraindications Sinus bradycardiaSinus bradycardiaHeart block >1°Heart block >1°

Overt heart failureOvert heart failureCardiogenic shockCardiogenic shock

Severe bradycardiaSevere bradycardiaHeart block >1°Heart block >1°

Overt heart failureOvert heart failureCardiogenic shockCardiogenic 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.

Pregnancy-Induced HTNPregnancy-Induced HTN

► ULN BP 3ULN BP 3rdrd Trimester: 125/75 mmHg Trimester: 125/75 mmHg EmergencyEmergency:: BP> 140/90 BP> 140/90 WITHWITH Hyper-reflexia, altered MS, H/A, epigastric pain, seizuresHyper-reflexia, altered MS, H/A, epigastric pain, seizures

► EclampsiaEclampsia Most often in primips, or old multips (> 35 yrs)Most often in primips, or old multips (> 35 yrs) Usually 3Usually 3rdrd trimester, unless molar preg, or h/o trimester, unless molar preg, or h/o

hypertension or renal diseasehypertension or renal disease Post-partum: Up to 2 weeks laterPost-partum: Up to 2 weeks later

► Tx: Nitroprusside (short), hydralazine, MgSOTx: Nitroprusside (short), hydralazine, MgSO44

► Don’t Use: Don’t Use: ACEI (inhib fetal AII)ACEI (inhib fetal AII) Diuretics (already hypovol) Diuretics (already hypovol)

► ULN BP 3ULN BP 3rdrd Trimester: 125/75 mmHg Trimester: 125/75 mmHg EmergencyEmergency:: BP> 140/90 BP> 140/90 WITHWITH Hyper-reflexia, altered MS, H/A, epigastric pain, seizuresHyper-reflexia, altered MS, H/A, epigastric pain, seizures

► EclampsiaEclampsia Most often in primips, or old multips (> 35 yrs)Most often in primips, or old multips (> 35 yrs) Usually 3Usually 3rdrd trimester, unless molar preg, or h/o trimester, unless molar preg, or h/o

hypertension or renal diseasehypertension or renal disease Post-partum: Up to 2 weeks laterPost-partum: Up to 2 weeks later

► Tx: Nitroprusside (short), hydralazine, MgSOTx: Nitroprusside (short), hydralazine, MgSO44

► Don’t Use: Don’t Use: ACEI (inhib fetal AII)ACEI (inhib fetal AII) Diuretics (already hypovol) Diuretics (already hypovol)

HydralazineHydralazineMechanism and StrategyMechanism and Strategy

► Indications: PregnancyIndications: Pregnancy► Direct arteriolar vasodilatorDirect arteriolar vasodilator► Concerns Concerns

Reflex tachycardiaReflex tachycardia• Increases MVOIncreases MVO22?, MI??, MI?

Chronically causes SLE syndromeChronically causes SLE syndrome► IV Onset: 10 mins,IV Onset: 10 mins,► Duration: 3-8 hrsDuration: 3-8 hrs► Metabolism: hepatic acetylation and renal eliminationMetabolism: hepatic acetylation and renal elimination

50% of pop is “slow acetylator & get complications50% of pop is “slow acetylator & get complications Decrease dose in renal failureDecrease dose in renal failure

► Eclamptic dose: 10-20 mg iv, repeat in 30 minutes prnEclamptic dose: 10-20 mg iv, repeat in 30 minutes prn

► Indications: PregnancyIndications: Pregnancy► Direct arteriolar vasodilatorDirect arteriolar vasodilator► Concerns Concerns

Reflex tachycardiaReflex tachycardia• Increases MVOIncreases MVO22?, MI??, MI?

Chronically causes SLE syndromeChronically causes SLE syndrome► IV Onset: 10 mins,IV Onset: 10 mins,► Duration: 3-8 hrsDuration: 3-8 hrs► Metabolism: hepatic acetylation and renal eliminationMetabolism: hepatic acetylation and renal elimination

50% of pop is “slow acetylator & get complications50% of pop is “slow acetylator & get complications Decrease dose in renal failureDecrease dose in renal failure

► Eclamptic dose: 10-20 mg iv, repeat in 30 minutes prnEclamptic dose: 10-20 mg iv, repeat in 30 minutes prn

This Is Your Brain…..This Is Your Brain…..This Is Your Brain…..This Is Your Brain…..

Any questions………..??Any questions………..??Any questions………..??Any questions………..??

HTN enc HTN enc ISC CVAISC CVA ICHICH SAHSAH TIATIA

OnsetOnset OverOver

24-4824-481-2 Hr1-2 Hr rapidrapid rapidrapid rapidrapid

CNSCNS

ProgressProgressYesYes Over hrsOver hrs Mins-Mins-

hrshrsMinsMins NoNo

LOCLOC LateLate Only if bilat Only if bilat or or brainstembrainstem

UsuallyUsually Usually, Usually, but +/-but +/-

NoNo

Other sxOther sx H/A, sz, H/A, sz, lethargylethargy

Prior Prior TIA, p TIA, p sleepsleep

H/A & H/A & vomitvomit

H/A & H/A & vomitvomit

NoNo

FocalFocal Transient Transient migratorymigratory

FixedFixed FixedFixed NoNo BriefBrief

CSFCSF ICPICP Normal, Normal, unless unless edemaedema

Blood, Blood, ICPICP

No, or No, or blood & blood & ICPICP

NormalNormal

Neurovascular InsultsNeurovascular InsultsNeurovascular InsultsNeurovascular Insults

Neurologic InsultNeurologic InsultNeurologic InsultNeurologic Insult

► Hypertensive encephalopathyHypertensive encephalopathy Waxing and waning symptomsWaxing and waning symptoms

H/A, nausea, vomitingH/A, nausea, vomiting

Retinal findingsRetinal findings

CBF is constant from MAP 60 to 125 mmHgCBF is constant from MAP 60 to 125 mmHg• Overwhelmed in HTN encephalopathyOverwhelmed in HTN encephalopathy• CBF can be dangerously decreased if BP lowered CBF can be dangerously decreased if BP lowered

too muchtoo much

Isolated H/A Isolated H/A IS NOTIS NOT a focal finding a focal finding

► Hypertensive encephalopathyHypertensive encephalopathy Waxing and waning symptomsWaxing and waning symptoms

H/A, nausea, vomitingH/A, nausea, vomiting

Retinal findingsRetinal findings

CBF is constant from MAP 60 to 125 mmHgCBF is constant from MAP 60 to 125 mmHg• Overwhelmed in HTN encephalopathyOverwhelmed in HTN encephalopathy• CBF can be dangerously decreased if BP lowered CBF can be dangerously decreased if BP lowered

too muchtoo much

Isolated H/A Isolated H/A IS NOTIS NOT a focal finding a focal finding

Autoregulation of Cerebral Blood Flow Autoregulation of Cerebral Blood Flow is Affected by Hypertensionis Affected by Hypertension

100 200

Normotensive

Poorly controlledhypertensive

Mean Arterial Pressure (MAP)

Cerebral Blood FlowCerebral Blood FlowCerebral Blood FlowCerebral Blood Flow

Risk of hypertensive

encephalopathy

Risk of ischemia

50 150 250

Loss of AutoregulationLoss of Autoregulation

Adapted with permission from Varon J, Marik PE. Chest. 2000;118:214-227.

Calcium Channel BlockersCalcium Channel BlockersCalcium Channel BlockersCalcium Channel Blockers

NicardipineNicardipine(dihydropyridine)(dihydropyridine)

DiltiazemDiltiazem(benzothiazepine)(benzothiazepine)

VerapamilVerapamil(phenylalkylamine)(phenylalkylamine)

Peripheral Peripheral VasodilationVasodilation11 ++++++++++ ++++++ ++++++

CoronaryCoronaryVasodilationVasodilation22 ++++++++++ ++++++ ++++++++

SuppressionSuppressionof SA Nodeof SA Node22 ++ ++++++++++ ++++++++++

SuppressionSuppressionof AV Nodeof AV Node22 00 ++++++++ ++++++++++

SuppressionSuppressionof Cardiac of Cardiac

ContractilityContractility2200 ++++ ++++++++

1. Frishman WH, et al. Med Clin North Am. 1988;72:523-547. 2. Adapted from Goodman and Gilman’s: The Pharmacologic Basis of Therapeutics. 9th ed. 2001.

Dihydropyridine CCB: NicardipineDihydropyridine CCB: Nicardipine

► Arterial selective Arterial selective vasodilatorvasodilator11

Significant Significant SVR SVR2-62-6

Cerebral and coronary vasodilatorCerebral and coronary vasodilator

► Vascular smooth muscle Vascular smooth muscle selectiveselective11

Minimal myocardial depressionMinimal myocardial depression No AV nodal depressionNo AV nodal depression

► No significant No significant in ICP in ICP77

Oates JA. Brown NJ. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:645-668.

1.Clarke B, et al. Br J Pharmacol. 1983;79:333P. 2.Lambert CR, et al. Am J Cardiol. 1987;60:471-476. 3.Silke B, et al. Br J Clin Pharmacol. 1985;20:169S-176S. 4.Lambert CR, et al Am J Cardiol. 1985;55:652-656.5. Visser CA, et al. Postgrad Med J. 1984;60:17-20. 6. Silke B, et al. Br J Clin Pharmacol. 1985;20:169S-176S. 7. Nishiyama MT, et al. Can J Anaesth. 2000;47:1196-1201.

Nicardipine —Strategy Nicardipine —Strategy

► Start at 5 mg/h: Titrate by 2.5 mg/h Start at 5 mg/h: Titrate by 2.5 mg/h q5 minutes — 15 mg/h max q5 minutes — 15 mg/h max

► Half life:Half life: Redistribution: t½ = 2.7 minutesRedistribution: t½ = 2.7 minutes Intermediate: t½ = 44 minutesIntermediate: t½ = 44 minutes Terminal after long infusion = 14.4 Terminal after long infusion = 14.4

hourshours

► After d/c, concentration declines After d/c, concentration declines rapidly, at least 50% in 1rapidly, at least 50% in 1stst 2 hrs 2 hrs

► Start at 5 mg/h: Titrate by 2.5 mg/h Start at 5 mg/h: Titrate by 2.5 mg/h q5 minutes — 15 mg/h max q5 minutes — 15 mg/h max

► Half life:Half life: Redistribution: t½ = 2.7 minutesRedistribution: t½ = 2.7 minutes Intermediate: t½ = 44 minutesIntermediate: t½ = 44 minutes Terminal after long infusion = 14.4 Terminal after long infusion = 14.4

hourshours

► After d/c, concentration declines After d/c, concentration declines rapidly, at least 50% in 1rapidly, at least 50% in 1stst 2 hrs 2 hrs

Cardene IV [package insert]

Onset of Onset of ActionAction DurationDuration Adverse EventsAdverse Events Special ConsiderationsSpecial Considerations

5-10 min5-10 min 15-30 minutes: 15-30 minutes: May exceed 4 May exceed 4

hourshours

HR, H/A, flushingHR, H/A, flushing

local phlebitislocal phlebitis

Most hypertensive Most hypertensive emergencies; caution with emergencies; caution with

ACSACS

The 7th Report of the JNC. JAMA 2003;289:2560-2571.

Safety Profiles of Nicardipine Safety Profiles of Nicardipine and Nitroprussideand Nitroprusside

Adverse EventsAdverse Events NicardipineNicardipine11 NitroprussideNitroprusside22

HypotensionHypotension 5.6%5.6% 36.9%36.9%

FlushingFlushing NANA 9.8%9.8%

NauseaNausea 4.9%4.9% 11.0%11.0%

DizzinessDizziness 1.4%1.4% 6.8%6.8%

HeadacheHeadache 14.6%14.6% 27.6%27.6%

ThiocyanateThiocyanate NANA 14.0%14.0%

Injection site painInjection site pain 1.4%1.4% NANA

1. Cardene IV [package insert]. 2. Nitropress [package insert].

Nicardipine vs Adrenergic BlockersNicardipine vs Adrenergic Blockers

DrugDrug NicardipineNicardipine EsmololEsmolol LabetalolLabetalol

AdministrationAdministration Continuous Continuous infusioninfusion

BolusBolus

Continuous infusionContinuous infusion

BolusBolus

Continuous Continuous infusion infusion

OnsetOnset RapidRapid RapidRapid IntermediateIntermediate

OffsetOffset RapidRapid RapidRapid SlowerSlower

HRHR11 Minimal increaseMinimal increase DecreasedDecreased +/–+/–

SVRSVR DecreasedDecreased 00 DecreasedDecreased

Cardiac outputCardiac output11 IncreasedIncreased DecreasedDecreased +/–+/–

Myocardial OMyocardial O22 balancebalance22 PositivePositive PositivePositive PositivePositive

Contra-indicationsContra-indications Advanced aortic Advanced aortic stenosisstenosis

Sinus bradycardiaSinus bradycardia

Heart block >1°Heart block >1°

Overt heart failureOvert heart failure

Cardiogenic shockCardiogenic shock

Severe Severe bradycardiabradycardia

Heart block >1°Heart block >1°

Overt heart failureOvert heart failure

Cardiogenic shockCardiogenic shock

SummarySummary

► Hypertension is extremely prevalent in US Hypertension is extremely prevalent in US society, and as population ages, society, and as population ages, hypertensive crises will become increasingly hypertensive crises will become increasingly common in the EDcommon in the ED Debate over terminology and numerical Debate over terminology and numerical

definitions is all too prevalent in the literaturedefinitions is all too prevalent in the literature

► Choices among available agents are often Choices among available agents are often difficult, and none is ideal across the difficult, and none is ideal across the spectrumspectrum Must balance effective reduction with avoidance Must balance effective reduction with avoidance

of over-reduction and its complicationsof over-reduction and its complications

► Hypertension is extremely prevalent in US Hypertension is extremely prevalent in US society, and as population ages, society, and as population ages, hypertensive crises will become increasingly hypertensive crises will become increasingly common in the EDcommon in the ED Debate over terminology and numerical Debate over terminology and numerical

definitions is all too prevalent in the literaturedefinitions is all too prevalent in the literature

► Choices among available agents are often Choices among available agents are often difficult, and none is ideal across the difficult, and none is ideal across the spectrumspectrum Must balance effective reduction with avoidance Must balance effective reduction with avoidance

of over-reduction and its complicationsof over-reduction and its complications

SummarySummary

► As ED LOS increases, care of BP derangements As ED LOS increases, care of BP derangements will fall ever more in the purview of the emergency will fall ever more in the purview of the emergency physicianphysician

► Even with prompt transfer of HU/HE patients to the Even with prompt transfer of HU/HE patients to the inpatient setting, this is one of the few areas inpatient setting, this is one of the few areas where emergency physicians and intensivists where emergency physicians and intensivists actually approach definitive care in much the actually approach definitive care in much the same waysame way

► As ED LOS increases, care of BP derangements As ED LOS increases, care of BP derangements will fall ever more in the purview of the emergency will fall ever more in the purview of the emergency physicianphysician

► Even with prompt transfer of HU/HE patients to the Even with prompt transfer of HU/HE patients to the inpatient setting, this is one of the few areas inpatient setting, this is one of the few areas where emergency physicians and intensivists where emergency physicians and intensivists actually approach definitive care in much the actually approach definitive care in much the same waysame way

Thank you !Thank you !