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 Diuretics Heart stimulators Vasodilators Generic Name Loop diuretic Furosemide Digitalis Digoxin Methyldigoxin Digitoxin Catecholamines Dopamine Dobutamine Norepinephrine Epinephrine Phosphodiesterase -inhibitors Amrinone Milrinone Nitrates 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 Markedly elevated BP Without severe symptoms or progressive target organ damage BP should be reduced within hours Oral agents Hypertensive Emergency Markedly elevated BP With acute or progressing target organ damage BP should be reduced immediate Parenteral agents Kaplan NM ,Hypertensive Crises in : Clinical hypertension 9th 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 emergency Severely elevated BP (>180/120mmHg) Acute onset Evidence of target-organ damage 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 Altered of the renin-angiotensin-aldosterone axis 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 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++ Blocking effect of CCB Ca++ Ca++ plus Calmodulin Myosin Kinase Ca++ plus Calmodulin Myosin Kinase Actin-Myosin Interaction Contraction Ca++ 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 Perdipine: 3 g/kg/min 20 min ⊿%) Blood flow change rate 60 40 Mean blood pressure Vertebral artery blood flow Renal blood flow Coronary blood flow (Hypertensive patients, n = 9) Baseline value Mean blood pressure Mean blood pressure change rate 20 0 -10 103 11 mmHg Vertebral artery blood flow 183 65 mL/min Renal artery blood flow 563 29mL/min Coronary artery blood flow 121 42 mL/min -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 Coronary Vasodilation Suppression of Cardiac Contractility Suppression of SA Node Suppression of 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-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 NS NS NS *: p<0.05 **: p<0.01 (vs baseline) 125 ** ** ** 100 NS NS Placebo (n=28) 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/m2) 5 Nicardipine (n=28) 4 Placebo (n=28) 3 ** 2 ** NS ** NS *: p<0.05 **: p<0.01 (vs baseline) NS 1 0 Baseline 15 30 60 (min) [Kumada T. et al. Jpn. Pharmacol. Ther. 23:375, 1995] Changes in Pulmonary Capillary Wedge Pressure (PCWP) Following IV-Infusion of (mmHg) Nicardipine and Placebo 40 Nicardipine (n=20) 30 NS NS Placebo (n=19) NS *: p<0.05 **: p<0.01 (vs baseline) 20 * * ** 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/cm5) Nicardipine (n=28) 3000 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/m2) Nicardipine (n=20) 3.4 60 min 3.0 Placebo (n=19) 30 min 2.6 15 min (Mean±SD) Baseline Baseline 2.2 15 min 1.8 30 min 0 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 Perdipine Diltiazem 95.8 69 60 40 24.1 20 4.2 0 6.8 0 Stable Slightly unstable Undeterminable Yoshinaga K. et al. Igaku no Ayumi 1993: 165:437 Nicardipine vs Nitrovasodilators 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 + ++ +++ ++++ ++ +++ 0 ++++ 0 Ease of Administration Cyanide Toxicity Pepine CJ. Intravenous nicardipine: cardiovascular effects and clinical relevance. Clin Ther. 1988;10:316-25. DOSIS PERDIPINE DIV (g/kg/min) Bolus (g/kg) Acute hypertensive crises during surgery 2 - 10 10 – 30 Hypertensive emergencies 0.5 – 6 Acute hypertensive crises during surgery Hypertensive emergencies 0.5 1 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