Rationaler Einsatz von Katecholaminen und Inotropika

Zusammenfassung

Akutes Herzversagen stellt mit allein 1 Mio. Fällen/Jahr in den USA ein zentrales medizinisches Problem dar. Während ein Teil der Patienten mit Strategien der Vor- und Nachlastsenkung durch Diuretika und Vasodilatatoren gut rekompensiert werden kann, stellt die Gruppe mit schwerer hämodynamischer Kompromittierung und weiter bestehender Hypoperfusion ein besonderes Problem dar (90 Tage Mortalität: 15 %). Zur Überwindung dieser Akutsituation wird der i. v. Einsatz von positiv inotropen Substanzen notwendig. Derzeit stehen als Inotropika Adrenorezeptor-Agonisten (Dopamin, Dobutamin, Noradrenalin, Adrenalin), Phosphodiesterase III Inhibitoren (Milrinon, Enoximon) und Ca²⁺-Sensitizer (Levosimendan) zur Verfügung. Der kurzfristigen hämodynamischen Verbesserung der ersten beiden Gruppen steht die Steigerung des myokardialen Sauerstoffverbrauchs, proarrhythmische Effekte und möglicherweise mittelfristig eine Exzessmortalität gegenüber. Dieses Review beleuchtet den Stellenwert der einzelnen Substanzen im Therapiekonzept des akuten Herzversagens und gibt einen Ausblick auf Neuentwicklungen wie Myosin-Aktivatoren und Na⁺/K⁺-ATPase-Inhibitoren.

Abstract

Acute heart failure syndromes (AHFS) are a growing health problem in Western Countries. Standard treatment includes vasodilators and diuretics, however, the subgroup of patients with AHFS and low cardiac output state represents a special therapeutic challenge that is complicated by high in-hospital and post-discharge mortality and by requiring additional i. v. inotropic support. The current inotropes in use are adrenoreceptor agonists (dopamine, dobutamine, norepinephrine, epinephrine), phosphodiesterase III inhibitors (milrinone, enoximone), and Ca²⁺ sensitizers (levosimendane). While most inotropes yield short-term haemodynamic improvements, they are associated with increased myocardial oxygen consumption, (supra-) ventricular arrhythmias and possibly increased post-discharge mortality. This review highlights current inotropes used in the treatment of AHFS and introduces new drug developments including myosin activators and Na⁺/K⁺ ATPase inhibitors.

Literatur

• 1 Nieminen M S, Harjola V P. Definition and epidemiology of acute heart failure syndromes.  Am J Cardiol. 2005;  96 5G-10G
• 2 Adams Jr. K F, Fonarow G C, Emerman C L. et al . Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE).  Am Heart J. 2005;  149 209-216
• 3 Shin D D, Brandimarte F, De Luca L. et al . Review of current and investigational pharmacologic agents for acute heart failure syndromes.  Am J Cardiol. 2007;  99 4A-23A
• 4 Gheorghiade M, Mebazaa A. Introduction to acute heart failure syndromes.  Am J Cardiol. 2005;  96 1G-4G
• 5 Yano M, Ikeda Y, Matsuzaki M. Altered intracellular Ca²⁺ handling in heart failure.  J Clin Invest. 2005;  115 556-564
• 6 Guimaraes S, Moura D. Vascular adrenoceptors: an update.  Pharmacol Rev. 2001;  53 319-356
• 7 Brodde O E, Michel M C. Adrenergic and muscarinic receptors in the human heart.  Pharmacol Rev. 1999;  51 651-690
• 8 Gauthier C, Leblais V, Kobzik L. et al . The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle.  J Clin Invest. 1998;  102 1377-1384
• 9 Lehtonen L, Poder P. The utility of levosimendan in the treatment of heart failure.  Ann Med. 2007;  39 2-17
• 10 Lohse M J, Engelhardt S, Eschenhagen T. What is the role of beta-adrenergic signaling in heart failure?.  Circ Res. 2003;  93 896-906
• 11 Parissis J T, Farmakis D, Nieminen M. Classical inotropes and new cardiac enhancers.  Heart Fail Rev. 2007;  12 149-156
• 12 Cohn J N, Levine T B, Olivari M T. et al . Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure.  N Engl J Med. 1984;  311 819-823
• 13 Kiuchi K, Shannon R P, Komamura K. et al . Myocardial beta-adrenergic receptor function during the development of pacing-induced heart failure.  J Clin Invest. 1993;  91 907-914
• 14 Engelhardt S, Bohm M, Erdmann E. et al . Analysis of beta-adrenergic receptor mRNA levels in human ventricular biopsy specimens by quantitative polymerase chain reactions: progressive reduction of beta 1-adrenergic receptor mRNA in heart failure.  J Am Coll Cardiol. 1996;  27 146-154
• 15 Freedman N J, Liggett S B, Drachman D E. et al . Phosphorylation and desensitization of the human beta 1-adrenergic receptor. Involvement of G protein-coupled receptor kinases and cAMP-dependent protein kinase.  J Biol Chem. 1995;  270 17 953-17 961
• 16 Chakraborti S, Chakraborti T, Shaw G. beta-adrenergic mechanisms in cardiac diseases: a perspective.  Cell Signal. 2000;  12 499-513
• 17 Lamba S, Abraham W T. Alterations in adrenergic receptor signaling in heart failure.  Heart Fail Rev. 2000;  5 7-16
• 18 O’Rourke B, Kass D A, Tomaselli G F. et al . Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, I: experimental studies.  Circ Res. 1999;  84 562-570
• 19 Fowler M B, Laser J A, Hopkins G L. et al . Assessment of the beta-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response.  Circulation. 1986;  74 1290-1302
• 20 Gheorghiade M, De Luca L, Fonarow G C. et al . Pathophysiologic targets in the early phase of acute heart failure syndromes.  Am J Cardiol. 2005;  96 11G-17G
• 21 Osadchii O E. Cardiac hypertrophy induced by sustained beta-adrenoreceptor activation: pathophysiological aspects.  Heart Fail Rev. 2007;  12 66-86
• 22 Dorn G W, Force T. Protein kinase cascades in the regulation of cardiac hypertrophy.  J Clin Invest. 2005;  115 527-537
• 23 Nieminen M S, Bohm M, Cowie M R. et al . Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: the Task Force on Acute Heart Failure of the European Society of Cardiology.  Eur Heart J. 2005;  26 384-416
• 24 Bellomo R, Chapman M, Finfer S. et al . Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group.  Lancet. 2000;  356 2139-2143
• 25 Maskin C S, Ocken S, Chadwick B. et al . Comparative systemic and renal effects of dopamine and angiotensin-converting enzyme inhibition with enalaprilat in patients with heart failure.  Circulation. 1985;  72 846-852
• 26 Debaveye Y A, Berghe G H Van den. Is there still a place for dopamine in the modern intensive care unit?.  Anesth Analg. 2004;  98 461-468
• 27 Ruffolo Jr. R R, Spradlin T A, Pollock G D. et al . Alpha and beta adrenergic effects of the stereoisomers of dobutamine.  J Pharmacol Exp Ther. 1981;  219 447-452
• 28 Burger A J, Horton D P, LeJemtel T. et al . Effect of nesiritide (B-type natriuretic peptide) and dobutamine on ventricular arrhythmias in the treatment of patients with acutely decompensated congestive heart failure: the PRECEDENT study.  Am Heart J. 2002;  144 1102-1108
• 29 O’Connor C M, Gattis W A, Uretsky B F. et al . Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: insights from the Flolan International Randomized Survival Trial (FIRST).  Am Heart J. 1999;  138 78-86
• 30 Liang C S, Sherman L G, Doherty J U. et al . Sustained improvement of cardiac function in patients with congestive heart failure after short-term infusion of dobutamine.  Circulation. 1984;  69 113-119
• 31 Krell M J, Kline E M, Bates E R. et al . Intermittent, ambulatory dobutamine infusions in patients with severe congestive heart failure.  Am Heart J. 1986;  112 787-791
• 32 Lowes B D, Tsvetkova T, Eichhorn E J. et al . Milrinone versus dobutamine in heart failure subjects treated chronically with carvedilol.  Int J Cardiol. 2001;  81 141-149
• 33 Leier C V. Positive inotropic therapy: an update and new agents.  Curr Probl Cardiol. 1996;  21 521-581
• 34 Jain P, Massie B M, Gattis W A. et al . Current medical treatment for the exacerbation of chronic heart failure resulting in hospitalization.  Am Heart J. 2003;  145 S3-17
• 35 Baumann G, Felix S B, Filcek S A. Usefulness of dopexamine hydrochloride versus dobutamine in chronic congestive heart failure and effects on hemodynamics and urine output.  Am J Cardiol. 1990;  65 748-754
• 36 Perrin G, Papazian L, Martin C. [Dopexamine: a new dopaminergic agonist].  Ann Fr Anesth Reanim. 1993;  12 308-320
• 37 Leier C V, Binkley P F. Parenteral inotropic support for advanced congestive heart failure.  Prog Cardiovasc Dis. 1998;  41 207-224
• 38 Packer M, Carver J R, Rodeheffer R J. et al . Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.  N Engl J Med. 1991;  325 1468-1475
• 39 Cleland J G, Coletta A P, Lammiman M. et al . Clinical trials update from the European Society of Cardiology meeting 2005: CARE-HF extension study, ESSENTIAL, CIBIS-III, S-ICD, ISSUE-2, STRIDE-2, SOFA, IMAGINE, PREAMI, SIRIUS-II and ACTIVE.  Eur J Heart Fail. 2005;  7 1070-1075
• 40 Cuffe M S, Califf R M, Adams Jr. K F. et al . Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial.  JAMA. 2002;  287 1541-1547
• 41 Lalukota K, Cleland J G, Ingle L. et al . Clinical trials update from the Heart Failure Society of America: EMOTE, HERB-CHF, BEST genetic sub-study and RHYTHM-ICD.  Eur J Heart Fail. 2004;  6 953-955
• 42 Gheorghiade M, Veldhuisen D J van, Colucci W S. Contemporary use of digoxin in the management of cardiovascular disorders.  Circulation. 2006;  113 2556-2564
• 43 Haikala H, Nissinen E, Etemadzadeh E. et al . Troponin C-mediated calcium sensitization induced by levosimendan does not impair relaxation.  J Cardiovasc Pharmacol. 1995;  25 794-801
• 44 Pagel P S, Harkin C P, Hettrick D A. et al . Levosimendan (OR-1259), a myofilament calcium sensitizer, enhances myocardial contractility but does not alter isovolumic relaxation in conscious and anesthetized dogs.  Anesthesiology. 1994;  81 974-987
• 45 Jamali I N, Kersten J R, Pagel P S. et al . Intracoronary levosimendan enhances contractile function of stunned myocardium.  Anesth Analg. 1997;  85 23-29
• 46 Moiseyev V S, Poder P, Andrejevs N. et al . Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A randomized, placebo-controlled, double-blind study (RUSSLAN).  Eur Heart J. 2002;  23 1422-1432
• 47 Follath F, Cleland J G, Just H. et al . Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial.  Lancet. 2002;  360 196-202
• 48 Coletta A P, Cleland J G, Freemantle N. et al . Clinical trials update from the European Society of Cardiology Heart Failure meeting: SHAPE, BRING-UP 2 VAS, COLA II, FOSIDIAL, BETACAR, CASINO and meta-analysis of cardiac resynchronisation therapy.  Eur J Heart Fail. 2004;  6 673-676
• 49 Parissis J T, Farmakis D, Bistola V. et al . Levosimendan for the treatment of acute heart failure syndromes: time to identify subpopulations of responding patients.  Am J Cardiol. 2007;  99 146-147
• 50 Kivikko M, Antila S, Eha J. et al . Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure.  Int J Clin Pharmacol Ther. 2002;  40 465-471
• 51 Lee L, Campbell R, Scheuermann-Freestone M. et al . Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment.  Circulation. 2005;  112 3280-3288
• 52 Roberts R K, Cohn D, Petroff V. et al . Liver disease induced by perhexiline maleate.  Med J Aust. 1981;  2 553-554
• 53 Bouche P, Bousser M G, Peytour M A. et al . Perhexiline maleate and peripheral neuropathy.  Neurology. 1979;  29 739-743
• 54 Adamson P B, Vanoli E, Mattera G G. et al . Hemodynamic effects of a new inotropic compound, PST-2744, in dogs with chronic ischemic heart failure.  J Cardiovasc Pharmacol. 2003;  42 169-173
• 55 Rocchetti M, Besana A, Mostacciuolo G. et al . Modulation of sarcoplasmic reticulum function by Na+/K+ pump inhibitors with different toxicity: digoxin and PST2744 [(E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride].  J Pharmacol Exp Ther. 2005;  313 207-215
• 56 Meissner A, Herrmann G, Gerdesmeyer L. et al . Additive effects of milrinone and dobutamine in severe heart failure.  Z Kardiol. 1992;  81 266-271
• 57 Cavusoglu Y. The use of levosimendan in comparison and in combination with dobutamine in the treatment of decompensated heart failure.  Expert Opin Pharmacother. 2007;  8 665-677
• 58 Gilbert E M, Hershberger R E, Wiechmann R J. et al . Pharmacologic and hemodynamic effects of combined beta-agonist stimulation and phosphodiesterase inhibition in the failing human heart.  Chest. 1995;  108 1524-1532
• 59 Haraldsson A, Kieler-Jensen N, Ricksten S E. The additive pulmonary vasodilatory effects of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension.  Anesth Analg. 2001;  93 1439-1445, table
• 60 Hoeper M M, Olschewski H, Ghofrani H A. et al . A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. German PPH study group.  J Am Coll Cardiol. 2000;  35 176-182
• 61 Beale R J, Hollenberg S M, Vincent J L. et al . Vasopressor and inotropic support in septic shock: an evidence-based review.  Crit Care Med. 2004;  32 S455-S465
• 62 Martin C, Viviand X, Leone M. et al . Effect of norepinephrine on the outcome of septic shock.  Crit Care Med. 2000;  28 2758-2765
• 63 Cleland J G, Freemantle N, Coletta A P. et al . Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE.  Eur J Heart Fail. 2006;  8 105-110