Clinical Investigations Levosimendan is superior to enoximone in refractory cardiogenic shock complicating acute myocardial infarction* Joerg T. Fuhrmann, MD; Alexander Schmeisser, MD; Matthias R. Schulze, MD; Carsten Wunderlich, MD; Steffen P. Schoen, MD; Thomas Rauwolf, PhD; Christof Weinbrenner, MD; Ruth H. Strasser, MD Objective: Cardiogenic shock is the leading cause of death in Measurements and main results: Survival rate at 30 days was patients hospitalized for acute myocardial infarction. The objec- significantly higher in the levosimendan-treated group (69%, 11 of ؍ tives were to investigate the effects of levosimendan, a novel 16) compared with the enoximone group (37%, 6 of 16, p inodilator, compared with the phosphodiesterase-III inhibitor 0.023). Invasive hemodynamic parameters during the first 48 hrs enoximone in refractory cardiogenic shock complicating acute were comparable in both groups. Levosimendan induced a trend myocardial infarction, on top of current therapy. toward higher cardiac index, cardiac power index, left ventricular Design: Prospective, randomized, controlled single-center clin- stroke work index, and mixed venous oxygen saturation. In ad- ical trial. dition, lower cumulative values for catecholamines at 72 hrs and Setting: Medical and coronary intensive care unit in a univer- for clinical signs of inflammation were seen in the levosimendan- sity hospital. treated patients. Multiple organ failure leading to death occurred Patients: Thirty-two patients with refractory cardiogenic shock exclusively in the enoximone group (4 of 16 patients). for at least 2 hrs requiring additional therapy. Conclusions: In severe and refractory cardiogenic shock com- Interventions: Infusion of either levosimendan (12 ␮g/kg over plicating acute myocardial infarction, levosimendan, added to 10 min, followed by 0.1 ␮g/kg/min over 50 min, and of 0.2 current therapy, may contribute to improved survival compared ␮g/kg/min for the next 23 hrs) or enoximone (fractional loading with enoximone. (Crit Care Med 2008; 36:2257–2266) dose of 0.5 mg/kg, followed by 2–10 ␮g/kg/min continuously) after KEY WORDS: cardiogenic shock; acute myocardial infarction; initiation of current therapy, always including revascularization, in- levosimendan; calcium sensitizer; enoximone; phosphodiesterase tra-aortic balloon pump counterpulsation, and inotropes. inhibitor ardiogenic shock (CS) is the meet resting metabolic demands (4). The tropic effects at therapeutic doses with- leading cause of death in pa- diagnosis is indicated by the combination out an increase in cyclic adenosine tients hospitalized for acute of low mean arterial blood pressure, low monophosphate (cAMP) or intracellular C myocardial infarction (AMI) cardiac index (CI), elevated pulmonary calcium and, consequently, no increase with mortality rates of up to 60% (1). capillary occlusion pressure (PCOP), and in myocardial oxygen demand (13, 14). Despite recent therapeutic advances, pre- an increase in systemic vascular resis- An improvement in myocardial perfusion dominantly associated with early reperfu- tance index (5). New evidence suggests as a result of vasodilatation, mediated by sion strategies, CS continues to be asso- that a systemic inflammatory response be- the opening of adenosine triphosphate- ciated with a dismal prognosis (2, 3). The cause of the release of inflammatory cyto- dependent potassium channels is avail- syndrome of CS has been defined as the kines, the expression of inducible nitric ox- able (15, 16). Moreover, persistent bene- inability of the heart, as a result of im- ide synthase, and inappropriate vaso- ficial hemodynamic effects are due to the pairment of its pumping function, to de- dilation may play an important role (6, 7). presence of a pharmacologically active liver sufficient blood flow to the tissues to Intra-aortic balloon pump counterpul- metabolite with a prolonged elimination sation and adjunctive medical therapy, half-life (17). Levosimendan has been using inotropic amines, are recom- shown to improve hemodynamic func- *See also p. 2450. mended in CS complicating AMI (5, tion in patients with decompensated From the Department of Internal Medicine and 8–10). In the case of insufficient re- heart failure (18), even in addition to Cardiology, Heart Center Dresden-University Hospital, sponse, reflecting a refractory situation, other inotropes (19), and seems to be safe University of Technology, Dresden, Germany. phosphodiesterase-III inhibitors (PDEIs) in AMI (20). The purpose of the present Presented, in part, at the American Heart Associ- study was to directly compare levosimen- ation scientific sessions, New Orleans, LA, November may be advantageous (11). A different 7–10, 2004 [abstract form (# 2253)]. inotropic mode of action and additional dan with PDEIs on top of established The authors have not disclosed any potential con- vasodilating effects are mediated by therapy in patients with refractory CS flicts of interest. PDEIs (12). Moreover, PDEIs have been complicating AMI. For information regarding this article, E-mail: shown to improve myocardial relaxation [email protected] METHODS Copyright © 2008 by the Society of Critical Care and coronary perfusion (12). Medicine and Lippincott Williams & Wilkins Levosimendan, a novel calcium-sensi- Patients. From April 2003 to July 2005 all DOI: 10.1097/CCM.0b013e3181809846 tizer and inodilator, affords positive ino- patients admitted with AMI accompanied by Crit Care Med 2008 Vol. 36, No. 8 2257 hypotension and peripheral hypoperfusion jor bleeding, severe hepatic failure, severe sys- were routinely performed before administra- were screened. AMI was defined by the pres- temic illness, or sepsis syndrome at the time of tion of the study drug and at 2, 12, 24, and 48 ence of typical chest pain lasting 30 mins and admission were excluded. All patients who had hrs after starting the infusion. Arterial blood an increase in troponin-T value or creatine duration of CS longer than 24 hrs before ar- pressure measurements were performed con- kinase and CK-MB levels. An ST-segment ele- rival were excluded. tinuously using an indwelling arterial cannula vation myocardial infarction needs typical cri- Treatment. All patients were treated in a (Model Leader-Cath., VYGON, Norristown, PA) teria on 12-lead echocardiography (ST eleva- cardiologic intensive care unit. Inotropes and inserted into the radial artery. A pulmonary tion Ͼ2 mm, Q-wave infarction, or a new left vasopressors were titrated according to goal- artery catheter (Model 774HF75, Edwards bundle-branch block). ST-segment elevation directed therapy (for mean arterial blood pres- Lifesciences, Irvine, CA) was used to measure myocardial infarction and also non ST- sure of at least 60 mm Hg and CI of at least 2.5 mean pulmonary artery pressure (MPAP), segment elevation myocardial infarction were L/min/m2). Dosages at the time of randomiza- PCOP, and mixed venous oxygen saturation considered to be included. In all patients re- tion are given in Table 4. Intermittent intra- (Svo2). Pressure values were read from the ferred for percutaneous coronary intervention, venous fluid challenges were provided, if bedside patient monitoring system (Model So- an intra-aortic ballon pump (IABP) (Model 0684- requested, to achieve appropriate filling pres- lar 8000, Marquette-Hellige Medical Systems, 00-0431-01, CS100, Datascope, Fairfield, NY or sures (PCOP). Patients meeting the inclusion Milwaukee, WI) at end-expiration. Cardiac Model 05-840-LWS, AutoCat2Wave, Arrow In- criteria were randomly allocated to receive output measurements were performed using a ternational, Everett, MA) was inserted before- either levosimendan (Abbott Laboratories, Ab- continuous cardiac output monitoring set hand. Successful revascularization was deter- bott Park, IL) or enoximone (Myogen GmbH, (Model VGS2V Vigilance, Edwards Life- mined as residual stenosis of Ͻ30% present in Bonn, Germany) using permuted block alloca- sciences, Irvine, CA). Heart rate, heart-rhythm the artery responsible for infarction. To eval- tion with a block size of four (Fig. 1). Se- and oxygen saturation were also continuously uate the left ventricular ejection fraction quence generation for randomization was recorded. We applied standard formulas for (LVEF) and any mechanical complications, a achieved using a sequence of random numbers calculation of the CI, left ventricular stroke standard 2D-echocardiography (Sonos 5500 from a computerized random-number gener- work index, systemic vascular resistance in- ultrasound system, Agilent Technologies, An- ator. These blocks having equal numbers are dex, and pulmonary vascular resistance index. dover, MA) was performed. The LVEF was cal- used for the treatment groups, with the order Cardiac power index (CPI) was determined by culated by Simpson’s biplane method, as pre- of treatments within the block being randomly the following equation (26): viously described (21). permuted. A random-number sequence was mean arterial pressure ϫ CO The study protocol for this randomized, used to choose a particular block, which sets CPI ϭ prospective, single-center open-label trial the allocation order for the subjects. Each ͫ 451 ͬ comparing levosimendan with enoximone on possible permuted block is assigned a number. ϫ body surface areaϪ1 top of current therapy followed the principles Using each number in the random number of the Declaration of Helsinki of the World sequence in turn selects the next block, deter- Medical Assembly and was approved by the mining the next participant