Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study

Andrea Morelli 0 3 Abele Donati 2 Christian Ertmer 1 Sebastian Rehberg 1 Matthias Lange 1 Alessandra Orecchioni 0 3 Valeria Cecchini 0 3 Giovanni Landoni 7 Paolo Pelaia 2 Paolo Pietropaoli 0 3 Hugo Van Aken 1 Jean-Louis Teboul 6 Can Ince 4 5 Martin Westphal 1 0 Department of Anesthesiology and Intensive Care, University of Rome, 'La Sapienza' , Viale del Policlinico 155, Rome 00161 , Italy 1 Department of Anesthesiology and Intensive Care, University Hospital of Muenster , Albert- Schweitzer-Str. 33, Muenster 48149 , Germany 2 Department of Neuroscience-Anesthesia and Intensive Care Unit, Universita Politecnica delle Marche , Via Tronto 10, Torrette di Ancona 60020 , Italy 3 Department of Anesthesiology and Intensive Care, University of Rome, 'La Sapienza' , Viale del Policlinico 155, Rome 00161 , Italy 4 Department of Intensive Care, Erasmus MC, University Medical Center Rotterdam , 's-Gravendijkwal 230, Rotterdam 3015 CE , The Netherlands 5 Department of Translational Physiology, Academic Medical Center, University of Amsterdam , Meibergdreef 9, Amsterdam 1105 AZ , The Netherlands 6 Hopital de Bicetre, Service of Medical Intensive Care, Centre Hospitalier de Bicetre , rue du General Leclerc 78, Le Kremlin-Bicetre 94270 , France 7 Department of Anesthesia and Intensive Care, Universita Vita-Salute San Raffaele , Via Olgettina 60, Milan 20132 , Italy Introduction: The purpose of the present study was to investigate microcirculatory blood flow in patients with septic shock treated with levosimendan as compared to an active comparator drug (i.e. dobutamine). The primary end point was a difference of 20% in the microvascular flow index of small vessels (MFIs) among groups. Methods: The study was designed as a prospective, randomized, double-blind clinical trial and performed in a multidisciplinary intensive care unit. After achieving normovolemia and a mean arterial pressure of at least 65 mmHg, 40 septic shock patients were randomized to receive either levosimendan 0.2 gkg-1min-1 (n = 20) or an active comparator (dobutamine 5 gkg-1min-1; control; n = 20) for 24 hours. Sublingual microcirculatory blood flow of small and medium vessels was assessed by sidestream dark-field imaging. Microcirculatory variables and data from right heart catheterization were obtained at baseline and 24 hours after randomization. Baseline and demographic data were compared by means of Mann-Whitney rank sum test or chi-square test, as appropriate. Microvascular and hemodynamic variables were analyzed using the Mann-Whitney rank sum test. Results: Microcirculatory flow indices of small and medium vessels increased over time and were significantly higher in the levosimendan group as compared to the control group (24 hrs: MFIm 3.0 (3.0; 3.0) vs. 2.9 (2.8; 3.0); P = .02; MFIs 2.9 (2.9; 3.0) vs. 2.7 (2.3; 2.8); P < .001). The relative increase of perfused vessel density vs. baseline was significantly higher in the levosimendan group than in the control group (dMFIm 10 (3; 23)% vs. 0 (-1; 9)%; P = .007; dMFIs 47 (26; 83)% vs. 10 (-3; 27); P < .001). In addition, the heterogeneity index decreased only in the levosimendan group (dHI -93 (-100; -84)% vs. 0 (-78; 57)%; P < .001). There was no statistically significant correlation between systemic and microcirculatory flow variables within each group (each P > .05). Conclusions: Compared to a standard dose of 5 gkg-1min-1 of dobutamine, levosimendan at 0.2 gkg-1min-1 improved sublingual microcirculatory blood flow in patients with septic shock, as reflected by changes in microcirculatory flow indices of small and medium vessels. Trial registration: NCT00800306. - Introduction Microvascular dysfunction plays a pivotal role in the pathophysiology of septic shock and may occur even in the presence of normal systemic oxygen supply and mean arterial pressure [1]. In this regard, several vasoactive agents, including inotropes, vasodilators, and inodilators, have been investigated in the attempt to preserve or improve microcirculatory blood flow in patients with severe sepsis or septic shock [1-5]. In recent years, much attention has been paid to the use of the calcium sensitizer levosimendan in the treatment of septic myocardial dysfunction [6-10]. Levosimendan increases myocardial contractility while simultaneously exerting vasodilatory properties via activation of ATP-dependent potassium channels (KATP) [11]. In addition, levosimendan exerts anti-ischemic, anti-inflammatory, and anti-apoptotic properties, thereby affecting important pathways in the pathophysiology of septic shock [12-14]. It has been speculated that, owing to these beneficial effects, levosimendan may positively affect myocardial performance and regional hemodynamics, thereby improving microcirculatory perfusion [6-10,12,15,16]. The objective of the present randomized controlled, double-blinded clinical study was, therefore, to elucidate the effects of levosimendan on systemic and microvascular hemodynamics. On this basis, we aimed at rejecting the null hypothesis that there is no difference in sublingual microvascular blood flow - as measured by sidestream dark-field (SDF) imaging [17] - in patients with fluid-resuscitated septic shock treated with levosimendan as compared with an active comparator drug (that is, dobutamine). Materials and methods Patients After approval by the local institutional ethics committee, the study was performed in an 18-bed multidisciplinary intensive care unit (ICU) at the Department of Anesthesiology and Intensive Care of the University of Rome La Sapienza. Informed consent was obtained from the patients next of kin. Enrolment of patients started in January 2008 and ended in April 2009. We enrolled patients who fulfilled the criteria of septic shock that required norepinephrine (NE) to maintain a mean arterial pressure (MAP) of at least 65 mm Hg despite appropriate volume resuscitation (pulmonary arterial occlusion pressure [PAOP] = 12 to 18 mm Hg and central venous pressure [CVP] = 8 to 12 mm Hg) [18]. Exclusion criteria of the study were age of less than 18 years, pregnancy, significant valvular heart disease, present or suspected acute coronary syndrome, and limitations to the use of inotropes (that is, ventricular outflow tract obstruction and mitral valve systolic anterior motion). All patients were sedated with sufentanil and midazolam and received mechanical ventilation using a volume-controlled mode. Hemodynamics, global oxygen transport, and acid-base balance Systemic hemodynamic monitoring of the patients included a pulmonary artery catheter (7.5-F; Edwards Lifesciences, Irvine, CA, USA) and a radial artery catheter. MAP, right atrial pressure, mean pulmonary arterial pressure, and PAOP were measured at end-expiration. Heart rate was analyzed from a continuous recording of electrocardiogram with ST segments monitored. Cardiac index (CI) was measured using the continuous thermodilution technique (Vigilance II; Edwards Lifesciences). Systemic v (...truncated)