An update in the management of

Hypertensive Emergency In Patients with Acute

Heart Failure

Yerizal Karani

Acute Heart failure

Acute Heart Failure

ESC Guideline. For diagnosis and treatment of Acute and chronic HF. 2008

Major Drugs for the Treatment of Acute Heart Failure

Classification Generic NameDiuretics Loop diuretic Furosemide

Heart stimulators

DigitalisDigoxin

MethyldigoxinDigitoxin

CatecholaminesDopamine

DobutamineNorepinephrine

Epinephrine

Phosphodiesterase-inhibitors

AmrinoneMilrinone

Vasodilators NitratesNitroglycerin

Sodium nitroprussideIsosorbide dinitrate

Hypertensive Emergency

Definitions A hypertensive emergency is a situation that requires immediate

reduction in blood pressure (BP) with parenteral agents because of acute or progressing target organ damage.

A hypertensive urgency is a situation with markedly elevated BP but without severe symptoms or progressive target organ damage, wherein the BP should be reduced within hours, often with oral agents.

Kaplan, 2002

Hypertensive Crises

Hypertensive EmergencyHypertensive Urgency

Markedly elevated BP Without severe symptoms or

progressive target organ damageBP should be reduced within hours

Oral agents

Markedly elevated BP With acute or progressing

target organ damageBP should be reduced immediate

Parenteral agents

Kaplan NM ,Hypertensive Crises in : Clinical hypertension 9 th Ed, Lippincott Williams & Wilkins 2006:609-630

HTN Crisis Definitions

Severe (stage 2) acute elevation of BP SBP ≤ 160 mmHg DBP ≤ 100 mmHg

Hypertensive Urgency No evidence of organ failure BP reduction over several hours to days Oral treatment adequate

HTN Crisis Definitions

Hypertensive emergencySeverely elevated BP (>180/120mmHg) Acute onset

Evidence of target-organ damage

BRAIN, HEART, KIDNEYS, RETINA

HYPERTENSIVE EMERGENCYAccelerated-malignant hypertension with papilledemaCerebrovascular conditions

Hypertensive brain infarction with severe hypertensionIntracerebral hemorrhageSubarachnoid hemorrhageHead trauma

Cardiac conditionsAcute aortic dissectionAcute left ventricular failureAcute or impending myocardial infarctionAfter coronary bypass surgery

Renal conditionsAcute glomerulonephritis Renovascular hypertensionRenal crises from collagen-vascular diseasesSevere hypertension after kidney transplantation

Hypertensive emergency (cont’d)Excess circulating catecholamines

Pheochromocytoma crisisFood or drug interactions with monoamine oxidase inhibitorsSympathomimetic drug use (cocaine)Rebound hypertension after sudden cessation of antihypertensive drugsautomatic hyperreflexia after spinal cord injury

EclampsiaSurgical conditions

Severe hypertension in patients requiring immediate surgeyPostoperative hypertensionPostoperative bleeding from vascular suture lines

Severe body burnsSevere epistaxisThrombotic thrombocytopenic purpura

Pathophysiology

circulating cathecolamines

Activation of the renin-angiotensin-aldosterone axis

Altered baroreceptor function

Pathophysiology vascular resistance

Endothelial damage

Arteriolar fibrinoid necrosis

Loss of autoregulatory function

Target organ ischemia

Management of Hypertensive emergency General principle :• the goal is, inhibit the progression of organ damage• parenteral drugs must be used• balance the benefit and the organ perfusion,

particularly brain, myocardium and kidney

Therapeutic guidelines

• do not lower BP more than 25% over the first 1 hour unless necessary to protect other organs

• reduce the SBP of 160 mmHg, DBP of 100 mmHg, or MAP of 120 mmHg, in the first 24 hours

• begin the concomitant long-term therapy soon after the initial emergency treatment

• attempt the established normotension within e few days

Parenteral Drugs for Treatment of Hypertensive Emergencies based on JNC 7

Drugs Dose Onset Duration of Action

Sodium nitroprusside

0.25-10 ugr/kg/min Immediate 1-2 minutes after infusion stopped

Nitroglycerin 5-500 ug/min 1-3 minutes 5-10 minutes

Labetolol HCl 20-80 mg every 10-15 min or 0.5-2 mg/min

5-10 minutes 3-6 minutes

Fenoldopan HCl 0.1-0.3 ug/kg/min <5 minutes 30-60 minutes

Nicardipine HCl 5-15 mg/h 5-10 minutes 15-90 minutes

Esmolol HCl 250-500 ug/kg/min IV bolus, then 50-100 ug/kg/min by infusion; may repeat bolus after 5 minutes or increase infusion to 300 ug/min

1-2 minutes 10-30 minutes

Chobanian AV et al, The JNC 7 report, JAMA 2003;389-2560-70

Parenteral Drugs for Treatment of Hypertensive Emergencies based on CHEST 2007

Acute Pulmonary edema / Systolic dysfunction

Nicardipine, fenoldopam, or nitropruside combined with nitrogliceryn and loop diuretic

Acute Pulmonary edema/ Diastolic dysfunction

Esmolol, metoprolol, labetalol, verapamil, combined with low dose of nitrogliceryn and loop diuretics

Acute Ischemia Coroner Labetalol or esmolol combined with diuretics

Hypertensive encephalopaty Nicardipine, labetalol, fenoldopam

Acute Aorta Dissection Labetalol or combined Nicardipine and esmolol or combine nitropruside with esmolol or IV metoprolol

Preeclampsia, eclampsia Labetalol or nicardipine

Acute Renal failure / microangiopathic anemia

Nicardipine or fenoldopam

Sympathetic crises/ cocaine oveerdose

Verapamil, diltiazem, or nicardipine combined with benzodiazepin

Acute postoperative hypertension

Esmolol, Nicardipine, Labetalol

Acute ischemic stroke/ intracerebral bleeding

Nicardipine, labetalol, fenoldopam

Marik Paul E, Varon Joseph, CHEST 2007;131:1949-62

Nitroglycerin

Nitroglycerin is a potent venodilator and only at high doses affectarterial tone. It reduces BP by reducing cardiacouput and preload which are undesirable effects in patient withcompromised cerebral and renal perfusion

NifedipineNifedipine has been widely used via oral or sublingualadministration in the management of hypertensiveemergencies. This mode of administration has not beenapproved by FDA and since JNC VI because it may causesudden uncontrolled and severe reductions in blood pressuremay precipitate cerebral, renal, and myocardial ischemia thathave been associated with fatal outcomes

Clonidine

Central alfa blocker, sedative effect CI : in patient with Cerebrovascular accident Rebound effect

• Nicardipine :. Dihydropiridine class of CCB

• Reduce peripheral resistance --- blood pressure

• water soluble, light insensitive, -- can be parenteraly used (deference with nifedipine / sodium nitroprusid)

USE OF NICARDIPINE

Ca++ plus Calmodulin

Myosin Kinase

Ca++ plus Calmodulin

Actin-Myosin Interaction Contraction

Myosin Kinase

Ca++ Ca++

Blocking effect of CCB

Ca++ Ca++

Calcium Channel Blocker Mechanism

NICARDIPINE

CHARACTERISTIC1.VASOSELECTIVITY

Nicardipine selectivity 30.000 x in smooth muscle cells blood vessels compared with myocardium

2. Myocardial depression (-)3. Negative inotropic (-)4. Rapid and stable antihypertensive effects, reduce blood

pressure gradually < 25% in 2 hours, minimal effects to heart rate

5. Increase blood flow in major organ : Renal, coroner, cerebral

Actions to increase organ blood flow

Perdipine: 3 g/kg/min 20 min

(Shoji Suzuki, et al., The 20th Annual Scientific Meeting of the Japanese Society of Hypertension: 1997)

60

40

20

0

-10

-20

Vertebral artery

blood flow

Renal blood flow

Coronary blood flow

Baseline value

121 42 mL/min

563 29mL/min

183 65 mL/min

103 11 mmHg

Coronary artery blood flow

Renal artery blood flow

Vertebral arteryblood flow

Mean blood pressure

⊿%)

( %)⊿

(Hypertensive patients, n = 9)

Pharmacodynamic action

Blo

od fl

ow c

hang

e ra

teM

ean

bloo

d pr

essu

re c

hang

e ra

te

Mean bloodpressure

Tissue selectivity betweenCalcium Antagonist

Bristow et al. Br J Pharmacol1984; 309:82

Comparison between Calcium Antagonist

Drug Coronary Vasodilation

Suppressionof Cardiac

ContractilitySuppressionof SA Node

Suppressionof AV Node

Verapamil(phenylalkylamine) ++++ ++++ +++++ +++++

Diltiazem(benzothiazepin) +++ ++ +++++ ++++

Nicardipine(dihydropyridine ) +++++ 0 + 0

Kerins DM. Goodman Gilman’s.10th ed.2001:843-70

Perdipine Injection

- Clinical data for Acute Heart Failure -

Comparison Study with Placebo in Patients with AHF

Subjects:Patients with acute heart failure with CI 2.5 L/min/m2,PCWP 15 mmHg, and SBP 100 mmHg (n=81) Design:

Multicenter, randomized, placebo-controlled, double-blindcomparative study Treatment:Enrolled patients were randomly allocated to receive either 1) Intravenous infusion of nicardipine 1 g/kg/min for 1 houror

2) Intravenous infusion of placebo for 1 hour

[Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]

Changes in Arterial Pressure Following IV-Infusion of Nicardipine and Placebo

[Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]

(mmHg)200

150

100

50

175

125

75

NS NS

**

** ** **

** **

NS

NSNSNS

Baseline 15 30 60 (min)

Placebo(n=28)

Nicardipine(n=28)

*: p<0.05**: p<0.01(vs baseline)

Changes in Cardiac Index (CI) Following IV-Infusion of Nicardipine and Placebo

[Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]

5

4

3

2

1

0

Baseline 15 30 60 (min)

**

NS NS NS

(L/min/m2)

** **

Placebo(n=28)

Nicardipine(n=28)

*: p<0.05**: p<0.01(vs baseline)

Changes in Pulmonary Capillary Wedge Pressure (PCWP) Following IV-Infusion of

Nicardipine and Placebo

[Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]

Baseline 15 30 60 (min)

40

30

20

10

0

*

NSNSNS

**

(mmHg)

*

Placebo(n=19)

Nicardipine(n=20)

*: p<0.05**: p<0.01(vs baseline)

Changes in Pulmonary Vascular Resistance (PVR) Following IV-Infusion of Nicardipine and Placebo

[Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]

Placebo(n=29)

Nicardipine(n=28)

*: p<0.05**: p<0.01(vs baseline)

30

3000

2000

1000

0

**

** **

NS NS NS

(dyne ･ sec/cm5)

Baseline 15 60 (min)

Changes in Pulmonary Capillary Wedge Pressure (PCWP) and Cardiac Index (CI)

[Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]

(Mean±SD)

（ mmHg ）Pulmonary Capillary Wedge Pressure (PCWP)

Car

diac

Inde

x (C

I)(L/min/m2)

60 min

30 min

15 min

15 min

30 min60 min

Baseline Baseline

0 14 18 22 26 30 34 38

3.4

3.0

2.6

2.2

1.8

Placebo(n=19)

Nicardipine(n=20)

Comparison Study with Intravenous Diltiazem

Subjects:Patients requiring a rapid reduction in BP (DBP 115 mmHg)

Design:Multicenter, randomized, single-blind comparative study

DosageNicardipine: Started at 0.5 g/kg/min

Increased up to 10 g/kg/min if necessaryDiltiazem: Started at 5 g/kg/min

Increased up to 15 g/kg/min if necessary

Duration of drug administration Dose titration: 1 hour Maintenance infusion: 24 hours

Yoshinaga K. et al. Igaku no Ayumi 1993: 165:437

Stability Effect

0

69

24.1

6.8

95.8

4.20

20

40

60

80

100

120

Stable Slightly unstable Undeterminable

%

PerdipineDiltiazem

Stability of antihypertensive effect better than Diltiazem

Yoshinaga K. et al. Igaku no Ayumi 1993: 165:437

Nicardipine vs Nitrovasodilators

Pepine CJ. Intravenous nicardipine: cardiovascular effects and clinical relevance. Clin Ther. 1988;10:316-25.

Drug Nicardipine(Perdipine® IV)

Nitroprusside Nitroglycerin

Rapid Onset of Peak Effect ++++ ++++ +++

Afterload Reduction ++++ ++++ +

Preload Reduction 0 ++ ++++

Coronary Steal Reported 0 + 0

Coronary Dilation: Large Vessel +++ + ++++

Coronary Dilation: Small Vessel +++ +/- +/-

Tachycardia + ++ ++

Potential for Symptomatic Hypotension

+ ++ +++

Ease of Administration ++++ ++ +++

Cyanide Toxicity 0 ++++ 0

DOSIS PERDIPINE

0.5 – 6Hypertensive emergencies

10 – 302 - 10Acute hypertensive crises during surgery

Bolus(g/kg)

DIV(g/kg/min)

(g/kg/min)0.5 1 2 6 10

Hypertensive emergencies

Acute hypertensive crises during surgery

Dosage and AdministrationStart with the lowest dose. Eg 0.5 mcg/BW/min 15 drops monitoring, if in 5-15 minutes there’s no significant blood pressure reducing Increasing drip until 20 drop , and then can be increased until desirable blood pressure achieved ( about 3-5 drops each after monitoring)Monitoring blood pressure and heart rate frequentlyBefore choose to switch to oral, 1 hour before Perdipine is stopped, give oral drugs and Perdipine is tappered of

TAKE HOME MESSAGES Hypertensive Crises:

urgent situation need rapid management to prevent organ damage

Antihypertensive agent:should be fast actionparenteraltitratable

TAKE HOME MESSAGES Nicardipine (Perdipine ®):

Calcium Antagonist recommended by JNC 7, AHA, 2007, CHEST 2007 to manage hypertensive emergency

Nicardipine (Perdipine ®): has favorable antiischemic increase myocardial oxygen supplyincrease cardiac index in patients with acute heart failure

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