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 Name Diuretics Loop diuretic Heart stimulators Vasodilators Digitalis Catecholamines Phosphodiesterase -inhibitors Nitrates Furosemide Digoxin Methyldigoxin Digitoxin Dopamine Dobutamine Norepinephrine Epinephrine Amrinone Milrinone Nitroglycerin Sodium nitroprusside Isosorbide 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 Urgency Hypertensive Emergency Markedly elevated BP Without severe symptoms or progressive target organ damage BP should be reduced within hours Oral agents Markedly elevated BP With acute or progressing target organ damage BP 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 D

BP

≤100 mmHg 

Hypertensive Urgency

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

HTN Crisis Definitions

 Hypertensive emergency

Severely elevated BP (>180/120mmHg) Evidence of target-organ damage Acute onset

BRAIN

,

HEART, KIDNEYS

,

RETINA

HYPERTENSIVE EMERGENCY Accelerated-malignant hypertension with papilledema Cerebrovascular conditions Hypertensive brain infarction with severe hypertension Intracerebral hemorrhage Subarachnoid hemorrhage Head trauma Cardiac conditions Acute aortic dissection Acute left ventricular failure Acute or impending myocardial infarction After coronary bypass surgery Renal conditions Acute glomerulonephritis Renovascular hypertension Renal crises from collagen-vascular diseases Severe hypertension after kidney transplantation

Hypertensive emergency (cont’d) Excess circulating catecholamines Pheochromocytoma crisis Food or drug interactions with monoamine oxidase inhibitors Sympathomimetic drug use (cocaine) Rebound hypertension after sudden cessation of antihypertensive drugs automatic hyperreflexia after spinal cord injury Eclampsia Surgical conditions Severe hypertension in patients requiring immediate surgey Postoperative hypertension Postoperative bleeding from vascular suture lines Severe body burns Severe epistaxis Thrombotic thrombocytopenic purpura

Pathophysiology

 circulating cathecolamines  Activation of the renin-angiotensin-aldosterone axis  Altered baroreceptor function

vascular resistance

Pathophysiology

 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 Sodium nitroprusside Nitroglycerin 0.25-10 ugr/kg/min 5-500 ug/min Immediate 1-3 minutes Duration of Action 1-2 minutes after infusion stopped 5-10 minutes Labetolol HCl Fenoldopan HCl 20-80 mg every 10-15 min or 0.5-2 mg/min 0.1-0.3 ug/kg/min 5-10 minutes <5 minutes 3-6 minutes 30-60 minutes Nicardipine HCl Esmolol HCl 5-15 mg/h 5-10 minutes 15-90 minutes 250-500 ug/kg/min IV bolus, then 50-100 1-2 minutes 10-30 minutes ug/kg/min by infusion; may repeat bolus after 5 minutes or increase infusion to 300 ug/min

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 Acute Pulmonary edema/ Diastolic dysfunction Acute Ischemia Coroner Hypertensive encephalopaty Acute Aorta Dissection Preeclampsia, eclampsia Acute Renal failure / microangiopathic anemia Sympathetic crises/ cocaine oveerdose Acute postoperative hypertension Acute ischemic stroke/ intracerebral bleeding Nicardipine , fenoldopam, or nitropruside combined with nitrogliceryn and loop diuretic Esmolol, metoprolol, labetalol, verapamil, combined with low dose of nitrogliceryn and loop diuretics Labetalol or esmolol combined with diuretics Nicardipine , labetalol, fenoldopam Labetalol or combined Nicardipine and esmolol or combine nitropruside with esmolol or IV metoprolol Labetalol or nicardipine Nicardipine Verapamil, diltiazem, or benzodiazepin nicardipine combined with Esmolol, Nicardipine , Labetalol Nicardipine, or fenoldopam labetalol, fenoldopam Marik Paul E, Varon Joseph, CHEST 2007;131:1949-62

Nitroglycerin

Nitroglycerin is a potent venodilator and only at high doses affect arterial tone . It reduces BP by reducing cardiac ouput and preload which are undesirable effects in patient with compromised cerebral and renal perfusion

Nifedipine

Nifedipine has been widely used via oral or sublingual administration in the management of hypertensive emergencies . This mode of administration has not been approved by FDA and since JNC VI because it may cause sudden uncontrolled and severe reductions in blood pressure may precipitate cerebral, renal, and myocardial ischemia that have been associated with fatal outcomes

Clonidine

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

USE OF NICARDIPINE

•

Nicardipine : . Dihydropiridine class of CCB

•

Reduce peripheral resistance --- blood pressure

•

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

Calcium Channel Blocker Mechanism

Ca ++

 

Ca ++ plus Calmodulin



Myosin Kinase

     

Actin-Myosin Interaction



Contraction



Ca ++ Blocking effect of CCB Ca ++



Ca ++ plus Calmodulin

 

Myosin Kinase

   

Ca ++

NICARDIPINE

CHARACTERISTIC

1.

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

Pharmacodynamic action ⊿

%) 60 Mean blood pressure 40 20 0 Vertebral artery blood flow Renal blood flow Perdipine: 3



g/kg/min



20 min

Coronary blood flow

(Hypertensive patients, n = 9)

Baseline value Mean blood pressure Vertebral artery blood flow Renal artery blood flow Coronary artery blood flow 103  11 mmHg 183  65 mL/min 563  29mL/min 121  42 mL/min

-10

-

20 (

⊿

%)

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

Tissue selectivity between Calcium Antagonist

Bristow et al. Br J Pharmacol1984; 309:82

Comparison between Calcium Antagonist

Drug Verapamil (phenylalkylamine) Diltiazem (benzothiazepin) Nicardipine (dihydropyridine ) Coronary Vasodilation Suppression of Cardiac Contractility Suppression of SA Node Suppression of AV Node ++++ ++++ +++++ +++++ +++ +++++ ++ 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  PCWP  15 mmHg, and SBP  2.5 L/min/m 100 mmHg (n=81) 2 ,  Design: Multicenter, randomized, placebo-controlled, double-blind comparative study  Treatment: Enrolled patients were randomly allocated to receive either 1) Intravenous infusion of nicardipine 1  g/kg/min for 1 hour or 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

(mmHg) 200 Nicardipine (n=28) 175 150 Placebo (n=28) NS NS NS 125 100 ** ** ** *: p<0.05

**: p<0.01

(vs baseline) NS NS NS 75 ** ** ** 50 Baseline 15 30 60 (min) [Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]

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

(L/min/m 2 ) 5 4 Nicardipine (n=28) Placebo (n=28) 3 ** 2 ** NS ** NS NS *: p<0.05

**: p<0.01

(vs baseline) 1 0 Baseline 15 30 60 (min) [Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]

Changes in Pulmonary Capillary Wedge Pressure (mmHg) (PCWP) Following IV-Infusion of Nicardipine and Placebo 40 Nicardipine (n=20) 30 NS NS Placebo (n=19) NS 20 * * ** *: p<0.05

**: p<0.01

(vs baseline) 10 0 Baseline 15 30 60 (min) [Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]

Changes in Pulmonary Vascular Resistance (PVR) Following IV-Infusion of Nicardipine and Placebo (dyne ･ sec/cm 5 ) 3000 Nicardipine (n=28) NS NS NS Placebo (n=29) 2000 ** 1000 ** ** *: p<0.05

**: p<0.01

(vs baseline) 0 Baseline 15 30 60 (min) [Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]

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

(L/min/m 2 ) 3.4

3.0

2.6

2.2

1.8

0 60 min 30 min 15 min Nicardipine (n=20) Placebo (n=19) (Mean ± SD) Baseline 15 min Baseline 30 min 60 min 14 18 22 26 30 34 Pulmonary Capillary Wedge Pressure (PCWP) 38 （ mmHg ） [Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995]

Comparison Study with Intravenous Diltiazem

Subjects:

Patients requiring a rapid reduction in BP (DBP  115 mmHg) Design: Multicenter, randomized, single-blind comparative study Dosage Nicardipine: Started at 0.5  g/kg/min  Increased up to 10  g/kg/min if necessary Diltiazem: 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 of antihypertensive effect

better than Diltiazem Stability Effect

120 100 80 60 40 20 0 95.8

69 Stable Perdipine Diltiazem 24.1

4.2

Slightly unstable 6.8

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

Nicardipine vs Nitrovasodilators

Drug Rapid Onset of Peak Effect Nicardipine (Perdipine ® IV) ++++ Nitroprusside

++++

Nitroglycerin

+++

Afterload Reduction Preload Reduction Coronary Steal Reported Coronary Dilation: Large Vessel ++++ 0 0 +++

++++ ++ + + + ++++ 0 ++++

Coronary Dilation: Small Vessel Tachycardia +++ +

+/ ++ +/ ++

Potential for Symptomatic Hypotension Ease of Administration + ++++

++ ++ +++ +++

Cyanide Toxicity 0

++++ 0 Pepine CJ. Intravenous nicardipine: cardiovascular effects and clinical relevance. Clin Ther. 1988;10:316-25.

DOSIS PERDIPINE Acute hypertensive crises during surgery Hypertensive emergencies DIV (



g/kg/min) 2 - 10 0.5 – 6 Bolus (



g/kg) 10 – 30 0.5

1 Acute hypertensive crises during surgery Hypertensive emergencies 2 6 (



g/kg/min) 10

Dosage and Administration

Start 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 frequently Before 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 action parenteral titratable

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 supply increase cardiac index



in patients with acute heart failure

THANK YOU FOR YOUR ATTENTION

TAKE CARE OF YOUR HEART