Akut Dekompanze Kalp Yetersizliği: Vazodilatör tedavi; Hangi ajan

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1 Akut Dekompanze Kalp Yetersizliği: Vazodilatör tedavi; Hangi ajan
Akut Dekompanze Kalp Yetersizliği: Vazodilatör tedavi; Hangi ajan? Ne dozda? Hangi kan basıncına kadar? Prof.Dr.M.Birhan YILMAZ Cumhuriyet Üniversitesi Tıp Fakültesi Kardiyoloji AD, Sivas

2 AKY AKY: anormal kardiyak fonksiyona ikincil olarak tedavi gerektirecek düzeyde (de novo veya tekrar) semptom ve bulguları ortaya çıkması durumudur. (azalmış kardiyak debi bozulmuş organ perfüzyonu, konjesyon, artmış PCWP) 2. Kardiyak disfonksiyon: a) sistolik veya diyastolik disfonk b) kardiyak ritm anormalliklerine c) ön yük ardyük uyumsuzluğuna bağlı olabilir 3. Acil tedavi gerektirir. The Task Force on Acute Heart Failure of the European Society of Cardiology

3 Hemodinamik alt gruplar
Mor:10.1% Mor:2.2% Yüksek KB Normal Normal Pulmoner ödem 2.2 Cardiac index L/min/m 2 Mor:22.4% 2.0 Normal KB Mor:55.5% Hipovolemik şok 1.5 Kardiyojenik şok Is arbitrary 1.0 0.5 Düşük KB 5 10 15 18 20 25 30 35 40 Pulmonary Wedge Pressure Forrester Α et al: Am J Cardiol 1977; 39:137

4 ADKY’de tedavi seçenekleri
I. Diüretikler II. Vazodilatörler III. İnotroplar

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6 Periferik vazokonstriksiyon
Miyokard hasarı Sıvı retansiyonu Aritmi v.d. Periferik vazokonstriksiyon Venöz vazokonstriksiyon Arteriyel vazokonstriksiyon Periferik ödem Pulmoner ödem Artmış miyokard iş yükü Artmış miyokard iş yükü Organ hipoperfüzyonu Miyokard iskemisi

7 Graph showing effect of acute congestive heart failure (CHF) and subsequent administration of intravenous nitroglycerin (NTG) on the splanchnic vascular pressure–volume relation. Graph showing effect of acute congestive heart failure (CHF) and subsequent administration of intravenous nitroglycerin (NTG) on the splanchnic vascular pressure–volume relation. Acute CHF produced a significant shift to the left, and subsequent administration of NTG produced a shift of the pressure-volume curve to the right, which actually went beyond the original control curve. Data represent mean±SEM. *P<.001 vs control; †P<.001 vs CHF and control. Wang S Y et al. Circulation 1995;91: Copyright © American Heart Association

8 1 mmHg=1.36 cmH2O

9 ADKY tedavisi çok az ya da çok zayıf kanıtlara dayanır!!!

10 95 Oxygen saturation (%) Cotter et al. Lancet 1998; 351:389-393
Nitrates Furosemide 95 Oxygen saturation (%) Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema Dr Gad Cotter MD a  b, Einat Metzkor MD a, Edo Kaluski MD a, Zwi Faigenberg MD c, Rami Miller EMS c, Avi Simovitz EMS c, Ori Shaham EMS c, Doron Marghitay EMS c, Maya Koren MD a, Alex Blatt MD a, Yaron Moshkovitz MD b, Ronit Zaidenstein MD a, Ahuva Golik MD a Summary Background Nitrates and furosemide, commonly administered in the treatment of pulmonary oedema, have not been compared in a prospective clinical trial. We compared the efficacy and safety of these drugs in a randomised trial of patients with severe pulmonary oedema and oxygen saturation below 90%. Methods Patients presenting to mobile emergency units with signs of congestive heart failure were treated with oxygen 10 L/min, intravenous furosemide 40 mg, and morphine 3 mg bolus. 110 patients were randomly assigned either to group A, who received isosorbide dinitrate (3 mg bolus administered intravenously every 5 min; n=56) or to group B, who received furosemide (80 mg bolus administered intravenously every 15 min, as well as isosorbide dinitrate 1 mg/h, increased every 10 min by 1 mg/h; n=54). Six patients were withdrawn on the basis of chest radiography results. Treatment was continued until oxygen saturation was above 96% or mean arterial blood pressure had decreased by 30% or to below 90 mm Hg. The main endpoints were death, need for mechanical ventilation, and myocardial infarction. The analyses were by intention to treat. Findings Mechanical ventilation was required in seven (13%) of 52 group-A patients and 21 (40%) of 52 group-B patients (p=0·0041). Myocardial infarction occurred in nine (17%) and 19 (37%) patients, respectively (p=0·047). One patient in group A and three in group B died (p=0·61). One or more of these endpoints occurred in 13 (25%) and 24 (46%) patients, respectively (p=0·041). Interpretation High-dose isosorbide dinitrate, given as repeated intravenous boluses after low-dose intravenous furosemide, is safe and effective in controlling severe pulmonary oedema. This treatment regimen is more effective than high-dose furosemide with low-dose isosorbide nitrate in terms of need for mechanical ventilation and frequency of myocardial infarction Cotter et al. Lancet 1998; 351:

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12 ALARM-HF: IV treatment at admission
inotropes Mebazaa et al Intensive Care Medicine 2011

13 Hastane içi ölüm Tüm kohort Günler Epinefrin Norepinefrin Dopamin
0.6 Epinefrin 0.5 Norepinefrin Hastane içi ölüm 0.4 0.3 Dopamin Dobutamin 0.2 Tüm kohort 0.1 Diuretik Levosimendan 0.0 Nitrat 5 10 15 20 25 30 Günler Mebazaa et al Intensive Care Medicine 2011

14 Use of vasodilators in ALARM-HF
SBP hypertension Use of vasodilators in ALARM-HF Before propensity score match After propensity score match IV vasodilatators No N=1805 N=2362 N=1007

15 Sonuçlar IV diüretik ve IV vazodilatör tedavisi hastaneye başvurudan ortalama 30 dk sonra başlanıyor [0.0 – 1.0 ve 0.0 – 2] IV vazodilatör ajan olarak hemen hemen her yerde nitratlar kullanılıyor: nitrogliserin 76 %, isosorbite dinitrate 19 % Hastane içi ölüm: - Eşleştirme öncesi 7.6 vs 14.2 % +/- vazodilatör tedavi - Eşleştirme sonrası 7.8 vs 11 % +/- vazodilatör tedavi

16 Mebazaa et al Intensive Care Medicine 2011
SBP < 100 mmHg (n=318) SBP mmHg (n=334) SBP mmHg (n=618) SBP > 160 mmHg (n=694) Mebazaa et al Intensive Care Medicine 2011

17 6. Ay tüm nedenlere bağlı ölüm
ASCEND-HF çalışması: Nesiritid Acute HF < 24 hrs from IV RX 24–168 hrs Rx Plasebo 6. Ay tüm nedenlere bağlı ölüm Dispne iyileşmesi 30 günlük ölüm ve rehosp. Plasebo=Konvansiyonel tedavi (nitratlar)

18 Birinci son nokta % P=0.31 Hazard Ratio 0.93 (95% CI: 0.8,1.08) 10.1
9.4 3.6 6.0 12 10.1 4.0 6.1 Plasebo 10 Nesiritid 8 % 6 4 2 30 gün ölüm ve rehosp. 30 gün ölüm KY rehosp. Risk Diff (95 % CI) (-2.1; 0.7) (-1.3; 0.5) (-1.2; 1.0)

19 30 gün ölüm/yeniden yatış alt gruplar
Tüm hastalar N=6836 Gelişte SKB < 123 ≥ 123 N=3346 N=3490 Bazal EF (%) <40 ≥ 40 N=4362 N=1187 MDRD GFR (mL/min/m2) <60 ≥ 60 N=3395 N=3093 KAH öyküsü No Yes N=3092 N=3742 DM öyküsü N=3923 N=2913 Risk Difference <0: Favors Nesiritide; Risk Difference >0: Favors Placebo Difference (%) and 95% Confidence Interval Hernandez AHA 2010

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21 Copyright © The American College of Cardiology.
From: Effects of Vasodilation in Heart Failure With Preserved or Reduced Ejection Fraction: Title and subTitle BreakImplications of Distinct Pathophysiologies on Response to Therapy J Am Coll Cardiol. 2012;59(5): doi: /j.jacc Figure Legend: Nitroprusside caused greater blood pressure (BP) reduction in heart failure with preserved ejection fraction (HFpEF) (black) compared with heart failure with reduced ejection fraction (HFrEF) (red), whereas augmentation in stroke volume (SV) and cardiac output were greater in HFrEF compared with HFpEF. PCWP = pulmonary capillary wedge pressure; SBP = systolic blood pressure. Date of download: 10/8/2012 Copyright © The American College of Cardiology. All rights reserved.

22 Vazodilatörler Nitrogliserin Nitroprussid Nesiritid Relaksin
Ularitid (Urodilatin)

23 Organik Nitratlar (Nitrovazodilatörler)
23 Organik Nitratlar (Nitrovazodilatörler) Nitrates — Nitrates are a first-line therapy for the treatment of acute anginal symptoms. While they act as venodilators, coronary vasodilators, and modest arteriolar dilators [5,6], the primary antiischemic effect of nitrates is to decrease myocardial oxygen demand by producing systemic vasodilation more than coronary vasodilation. This systemic vasodilation reduces LV systolic wall stress. (See "Nitrates in the management of stable angina pectoris"). In patients with exertional stable angina, nitrates improve exercise tolerance, time to onset of angina, and ST-segment depression during exercise testing. In combination with beta blockers or calcium channel blockers, nitrates produce greater antianginal and antiischemic effects. There are various preparations of nitrates available; there is no difference in efficacy among these preparations (show table 1).   Sublingual nitroglycerin — Sublingual nitroglycerin remains the therapy of choice for acute anginal episodes and prophylactically for activities known to elicit angina. The onset of action is within several minutes and the duration of action is 30 to 40 minutes. The initial dose is 0.3 mg (1/200 grains); one-half the dose (0.15 mg or 1/400 grains) can be used if the patient becomes hypotensive. The traditional recommendation is for patients to take one nitroglycerin dose sublingually every five minutes for up to three doses before calling for emergency medical services (EMS) evaluation. However, studies suggest that this approach may result in significant delays in obtaining EMS assistance [7,8]. As a result, the 2004 ACC/AHA guidelines recommend contacting EMS if chest pain or discomfort is unimproved or worsening five minutes after one nitroglycerin dose has been taken [9]. For patients known to their providers to have frequent angina, physicians may consider a selected, more tailored message that takes into account the frequency and character of the patient's angina and their typical time course of response to nitroglycerin.   Chronic nitrate therapy — Chronic nitrate therapy, in the form of an oral or transdermal preparation (isosorbide dinitrate, isosorbide mononitrate, or transdermal nitroglycerin) can prevent or reduce the frequency of recurrent anginal episodes and improve exercise tolerance [10,11]. However, tolerance to long-acting nitrates can develop and has limited their use as first-line therapy. A 12 to 14 hour nitrate-free interval must be observed in order to avoid tolerance [12,13], and some patients have a reduced anginal threshold during this period. As a result, many physicians prefer chronic nitrate therapy for second-line antianginal therapy. (See "Nitrates in the management of stable angina pectoris", section on Nitrate tolerance). When using isosorbide dinitrate, a recommended dosing schedule is beginning with a dose of 10 mg at 8 AM, 1 PM, and 6 PM, which results in a 14 hour nitrate dose-free interval. The dose is increased to 40 mg three times daily as needed. Alternatively, isosorbide dinitrate can be taken twice daily at 8 AM and 4 PM. The extended release preparation of isosorbide mononitrate, which is administered once per day, may be preferable to improve compliance. The starting dose is 30 mg once daily and can be titrated to 120 mg once daily as needed. This preparation is particularly useful in patients who have effort-induced angina. However, since the effect lasts only about 12 hours, some patients may develop nocturnal or rebound angina. Such patients require twice daily dosing or additional antianginal therapy.   Transdermal nitroglycerin — Use of a transdermal patch is a convenient way to administer nitroglycerin. The patient must remember to remove the patch for 12 to 14 hours. Since most patients have angina with activity, we suggest that the patch be applied at 8 AM and removed at 8 PM. The occasional patient with significant nocturnal angina can be treated with a patch-on period from 8 PM to 8 AM. We begin with a dose of 0.2 mg per hour; the dose can be increased to 0.8 mg per hour as needed.

24 Organik Nitratlar (Nitrovazodilatörler)
Gliserol ve benzeri polialkollerin nitrat esterleridirler. 100 yıldan fazla süredir kullanılmaktadırlar. Ön ilaç, denitrate edilerek aktif NO oluşturur. O yüzden bu ilaçlar nitrovazodilatör olarak adlandırılıyorlar… Isosorbide mononitrate & Isosorbide dinitrate Pentaerythritol Tetranitrate (PETN) Sodium nitroprusside PDE5 inhibitörleri: Sildenafil, Tadalafil, Vardenafil (yıkım yolundan etki) nitrogliserin izosorbid dinitrat

25 Etki mekanizması Vücutta nitrik oksid (NO) açığa çıkararak etkilerini oluştururlar. NO, solubl guanilat siklaz’ı aktive eder; hücre içinde sGMP düzeyini yükseltir. sGMP damar düz kaslarında gevşemeye neden olur. Tüm düz kaslı yapıları gevşetirler. Venödilatasyon dana dominant etkidir.. Koroner dilatasyon yaparlar. Kan basıncını düşürürler ve refleks taşikardi yaparlar. The nitrates and nitrites are probably denitrated in smooth muscle and the resulting nitric oxide (NO) activates guanylate cyclase and increase the synthesis of cyclic GMP.  A cyclic GMP-dependent protein is stimulated and this leads to dephosphorylation of the light chain of myosin and resulting in smooth muscle relaxation (Note: (i) The cyclic GMP system is similar to that of the opposing cyclic-AMP system and consists of guanylate cyclase, cyclic GMP-dependent protein kinase and phosphodiesterase  (ii) phosphorylation of the light chain of myosin would result in smooth muscle contraction e.g. as mediated through the action of calcium-calmodulin.)   

26 Farmakokinetik özellikler
Hepsi lipofilik Ciltten, mukozalardan hızlı emilirler. Sublingual Transdermal Oral yoldan kullanılabilirler. GİS emilimleri tama yakındır; ancak ilk-geçiş etkisine uğrarlar. Biyoyararlanımları düşüktür. Karaciğerde denitrasyona uğrayarak metabolize edilirler.

27 Bolus 2 mikrogram/kg/dk+ 0.01 mikrogram/kg/dk -
başlangıç maksimum Nitrogliserin 10-20 mikrogram/dk (0.2 mikrogram/kg/dk) 200 mikrogram/dk İsosorbid dinitrat 1 mg/saat 10 mg/saat Nitroprussid 0.3 mikrogram/kg/dk 5 mikrogram/kg/dk Nesiritid Bolus 2 mikrogram/kg/dk mikrogram/kg/dk - Nitrogliserin NİTROGLYCERİN 25 mg, 1 flakon PERLİNGANİT 10 mg/10 ml, 10 ampul İsosorbid dinitrat CARDİOKET %0.1, 10 ml’lik 10 ampul

28 Nitrovazodilatörlerin KY’de Olumsuz Etkileri
Nitrogliserin&İsosorbiddinitrat Taşikardi2 Taşifilaksi3 Refleks sempatik aktivasyona bağlı nörohormonal aktivasyon 4 Nitroprussid Titrasyon zor Aşırı hipotansiyon riski nedeniyle arteriyel monitorizasyon gereksinimi3 Taşikard3 Koroner çalma3 Pulmoner şant artışı3 Thiocyanate toksisitesi3 Refleks sempatik aktivasyona bağlı nörohormonal aktivasyon 4,5 Currently available vasodilators sometimes used for management of acute CHF have well-known limitations. Importantly, typical vasodilators cause reflex activation of the sympathetic nervous system (SNS). Vasoconstriction, sodium and water retention, and renin secretion caused by sympathetic activation antagonize the effectiveness of the vasodilators themselves and also of diuretics, B-blockers, ACE inhibitors, and angiotensin II antagonists. The efficacy of nitroglycerin is further limited by rapid development of tachyphylaxis. Sodium nitroprusside can cause “coronary steal” in patients with coronary artery disease whereby blood is diverted from the ischemic penumbra to normal myocardium. Nitroprusside also causes pulmonary shunting, which can worsen oxygenation. 1 Publication Committee for the VMAC Investigators. JAMA 2002; 287 (12): 2 Robertson R, et al. ''Chapter 32: Drugs Used for the Treatment of Myocardial Ischemia'' in Pharmacologic Basis of Therapeutics,Goodman and Gilman, Eds. 9th. Edition 1996, McGraw-Hill. 3 Kelly and T Smith, ‘‘Chapter 34: Pharmacologic Treatment of Heart Failure’‘, in The Pharmacologic Basis of Therapeutics, 9th. Ed. Goodman and Gilman, eds McGraw-Hill. 4 Abraham W. Natriuretic peptides in heart failure. Heart Failure 1996; 12: 5 J Oates, J. Chapter 33: Antihypertensive Agents and Drug Treatment of Hypertension’‘, in The Pharmacologic Basis of Therapeutics, 9th. Ed. Goodman and Gilman, eds McGraw-Hill.

29 Kullanımda dikkat Nitrogliserin’in iv infüzyonu için cam şişe, infüzyon borusu olarak polietilen boru kullanılır. Polivinilklorürden (PVC) yapılmış olağan borular kullanılırsa, ilaç molekülleri infüzyon setinin çeperine yapışır ve damara ulaşan ilaç miktarı azalır. Geleneksel olarak venodilatör etki dominant, yüksek dozda arteriyel vazodilatör

30 Kullanımda dikkat! Nitroprussid, sürekli arter KB monitorizasyon ve LH PA kateter gerektirir Işığa hassas Arteriyel vazodilatör etki dominant

31 Diğer vazodilatörler

32 Novartis Faz III çalışması: RLX030 (RELAX-AHF çalışması, relaksin) 6 aylık mortaliteyi azalttı!!!
Dahil edilme kriteri SKB>125 mmHg AHA’da sunulacak….

33 Ularitid (urodilatin), 32 a
Ularitid (urodilatin), 32 a.a, böbreklerde sentezlenen natriüretik peptit Yapısındaki küçük bir farktan dolayı (N-terminal kısımdaki 4 a.a. Sayesinde) ANP’nin tersine yıkıma (nötral endopeptidaz) dirençli… TRUE-AHF çalışmasında test ediliyor… Dahil edilme kriteri SKB>110 mHg

34 Kılavuz ne diyor? Vazodilatörler her ne kadar ön yük ve ard yükü azaltıp, atım volümünü iyileştirseler de, dispneyi iyileştirdikleri veya diğer klinik son noktaları iyileştirdiklerine dair güçlü kanıtlar yoktur. Vazodilatör ajanlar muhtemelen en fazla hipertansif hastalarda faydalıdır ve tercihen SKB>110 mmHg’de kullanılmalıdır (ESC 2012, Uzman görüşü!!!) Vazodilatör ajanlar SKB<90 mmHg’de kullanılmamalıdır (ESC 2008, Uzman görüşü!!!) SKB Ne kadar düşürelim?: %15-30 (yüksekse) Ne kadar hızlı??

35 46,599 ED ADKY (ADHERE) * * * * * 4,096 Acilde 1.1 hr
Vasoaktif tedavi Başlama yerine göre 4,096 Acilde hr 3,499 yatınca hr * * *P = * * * Mortality % ICU Hospital ICU LOS % Invasive Rate (%) Transfer LOS (days) (days) Procedures 253% 500% 150% 155% 142% Peacock WF. Congest Heart Fail ;15(6):

36 ‘Time to Vasoactives vs. Mortality’
288 hospitals 163,457 ADHF hospitalizations 46,811 (29%) received vasoactives Sadece vazodilatör tedavi Herhangi bir vazoaktif tedavi Inotropes Only Mortalite 0.02 0.04 0.06 0.08 0.10 0.14 0.12 Time to therapy: Tedavi başlangıcına kadar geçen zaman Peacock WF. Ann Emerg Med. 2003;42(4):S26.

37 Sabrınız için Teşekkürler