Use of levosimendan in cardiogenic shock

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Due to the failure of classic inotrope agents, a sensitizer agent, levosimendan, has been used as a rescue therapy in such situations. In order to assess the effectiveness of levosimendan to treat CS, we studied its hemodynamic effects on patients with CS. A retrospective study was conducted at the ICU of the Military Hospital of Tunis between January 2004 and December 2009, and between January 2011 and December 2013. Twenty-six patients with CS refractory to catecholamines were included in our study. When catecholamines failed to improve the hemodynamic condition, levosimendan was introduced. This treatment was administered in two steps: a loading dose of 12 µg/kg/min was infused for 30 min; and then continuous infusion was given for 24 h at a dose of 0.1 µg/kg/min. Levosimendan significantly increased mean arterial pressure to 76 ± 7 mmHg at 48 h and cardiac index to 3.19 ± 0.68 L/min/m2 and decreased pulmonary wedge pressure to 17 ± 3 mmHg at 48 h. Pulmonary arterial systolic pressure, pulmonary arterial diastolic pressure, and mean pulmonary arterial pressure were significantly reduced at 24 h. A significant decrease in lactate from 3.77 ± 2.93 to 1.60 ± 1.32 mmol/L, by 72 h, was also noted. Levosimendan significantly reduced systemic vascular resistance and pulmonary vascular resistances. Administration of levosimendan also reduced the need for catecholamines. Our study confirms the efficacy of levosimendan to stabilize hemodynamic parameters in patients with CS." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/3-296/v1", "name": "Use of levosimendan in cardiogenic shock" } } ] } Home Browse Use of levosimendan in cardiogenic shock ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Janen F, El Arayedh K, Labbene I et al. Use of levosimendan in cardiogenic shock [version 1; peer review: peer review discontinued] . F1000Research 2014, 3 :296 ( https://doi.org/10.12688/f1000research.5820.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Use of levosimendan in cardiogenic shock [version 1; peer review: peer review discontinued] Fayçal Janen 1 , Khaoula El Arayedh 2 , Iheb Labbene 3 , Chihebeddine Romdhani 3 , Mustapha Ferjani 3 Fayçal Janen 1 , Khaoula El Arayedh 2 , [...] Iheb Labbene 3 , Chihebeddine Romdhani 3 , Mustapha Ferjani 3 PUBLISHED 05 Dec 2014 Author details Author details 1 Pharmacy Department, Military Hospital of Tunis, Monfleury,Tunis, 1008, Tunisia 2 Pharmacy Department, Basic Health Group of South Tunis, 90 Sayada Street Bellevue, Tunis, 1009, Tunisia 3 Université Tunis El Manar, Faculté de Médecine de Tunis, LR12DN01, Intensive Care Unit, Military Hospital of Tunis, Monfleury Tunis, 1008, Tunisia OPEN PEER REVIEW PEER REVIEW DISCONTINUED Abstract Cardiogenic shock (CS) is acute inadequate tissue perfusion caused by the heart's inability to pump an adequate amount of blood. Due to the failure of classic inotrope agents, a sensitizer agent, levosimendan, has been used as a rescue therapy in such situations. In order to assess the effectiveness of levosimendan to treat CS, we studied its hemodynamic effects on patients with CS. A retrospective study was conducted at the ICU of the Military Hospital of Tunis between January 2004 and December 2009, and between January 2011 and December 2013. Twenty-six patients with CS refractory to catecholamines were included in our study. When catecholamines failed to improve the hemodynamic condition, levosimendan was introduced. This treatment was administered in two steps: a loading dose of 12 µg/kg/min was infused for 30 min; and then continuous infusion was given for 24 h at a dose of 0.1 µg/kg/min. Levosimendan significantly increased mean arterial pressure to 76 ± 7 mmHg at 48 h and cardiac index to 3.19 ± 0.68 L/min/m 2 and decreased pulmonary wedge pressure to 17 ± 3 mmHg at 48 h. Pulmonary arterial systolic pressure, pulmonary arterial diastolic pressure, and mean pulmonary arterial pressure were significantly reduced at 24 h. A significant decrease in lactate from 3.77 ± 2.93 to 1.60 ± 1.32 mmol/L, by 72 h, was also noted. Levosimendan significantly reduced systemic vascular resistance and pulmonary vascular resistances. Administration of levosimendan also reduced the need for catecholamines. Our study confirms the efficacy of levosimendan to stabilize hemodynamic parameters in patients with CS. READ ALL READ LESS Keywords levosimendan, cardiogenic shock, hemodynamic variables, mortality Corresponding Author(s) Fayçal Janen ( [email protected] ) Close Corresponding author: Fayçal Janen Competing interests: No competing interests were disclosed. Grant information: Supported by a grant from the Research Laboratory LR12DN01 and The Military Hospital of Tunis. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2014 Janen F et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication). How to cite: Janen F, El Arayedh K, Labbene I et al. Use of levosimendan in cardiogenic shock [version 1; peer review: peer review discontinued] . F1000Research 2014, 3 :296 ( https://doi.org/10.12688/f1000research.5820.1 ) First published: 05 Dec 2014, 3 :296 ( https://doi.org/10.12688/f1000research.5820.1 ) Latest published: 05 Dec 2014, 3 :296 ( https://doi.org/10.12688/f1000research.5820.1 ) Introduction Cardiogenic shock (CS) is a clinical condition of acute inadequate tissue perfusion caused by the heart’s inability to pump an adequate amount of blood 1 , 2 . Pharmacological treatment of CS is based on positive inotropic agents 3 , 4 . Due to the failure of classic inotrope agents, a sensitizer agent, levosimendan, has been used as rescue therapy in such situations. This drug has both positive inotropic and myocardial relaxing properties, which increase the affinity of myofilaments within the myocardial cell to calcium without raising intracellular concentrations of calcium or AMPc 5 – 8 . Levosimendan can improve the hemodynamic status of patients with CS without increasing the consumption of myocardial oxygen and without increasing the risk of arrhythmia 9 , 10 ; however, few studies have been conducted on the use of levosimendan to treat CS. The purpose of our study was to assess the effectiveness of levosimendan to treat CS by studying its hemodynamic effects on 26 patients with CS and who were refractory to catecholamines. Materials and methods A retrospective study was conducted at the ICU in the Military Hospital of Tunis for two periods: between January 2004 and December 2009, and from January 2011 until December 2013. All patients had CS and were aged >18 years. Patients who died within 48 h were excluded from the study. The diagnosis of CS was made if hypotension was <90 mmHg for more than 30 min and there were signs of low perfusion in the absence of a hypovolemia or cardiac arrhythmia. These signs were associated with a cardiac index of 18 mmHg, and high doses of catecholamines had been ineffective to restore mean arterial pressure to 65 mmHg (i.e., dobutamine at >15 µg/kg/min and noradrenaline at >0.6 µg/kg/min). When catecholamines failed to improve the hemodynamic condition and there were persistent signs of low peripheral perfusion, levosimendan was introduced (Orion Pharma, Espoo, Finlande). This treatment was administered in two steps: a loading dose of 12 µg/kg/min was infused for 30 min; and then continuous infusion was given for 24 h at a dose of 0.1 µg/kg/min. The pulmonary artery was catheterized using a 7.5-Fr Swan Ganz catheter with continuous cardiac output and mixed venous saturation measurements (Edwards Life sciences, North Carolina, USA). This catheter allowed us to collect hemodynamic parameters from each patient at just before administration of levosimendan (i.e., T0), at 30 and 90 min, and at 2, 4, 8, 12, 24, and 48 h. Doses of catecholamine and plasma-lactate concentrations were recorded on days 0, 1, 2, and 3. Values of the left-ventricular ejection fraction were collected on days 0, 1, 2, 7, and 15. The primary endpoints were the evolution of hemodynamic parameters (the cardiac index, pulmonary pressure, and SvO 2 ). Data were recorded and analyzed using Microsoft Excel (2007) software and Epi Info 6.0.4 ( http://www.cdc.gov ). Continuous variables were expressed as their means ± standard deviations and were compared between groups using Student’s two-tailed t-test. Non-parametric tests were also used where necessary (Mann–Whitney U test). Fisher’s exact (or the chi-squared) test was used to compare categorical variables, as appropriate. A p -value of <0.05 was considered statistically significant. The local ethics committee approved the use of the patients’ data for this study. Results patient Number age years gender weight Kg etiology Coronarography angioplasty APACHE II MOF Evolution Dead : D. Survivor : S length of stay PAM 0 mmHg PAM 30 PAM 90 PAM H2 PAM H4 PAM H8 PAM H12 PAM H24 PAM H48 HR 0 beat/min HR 30 HR 90 HR H 2 HR H4 HR H8 HR H12 HR H24 HR H48 POD 0 mm Hg POD 30 POD 90 POD H2 POD H4 POD H8 POD H12 POD H24 POD H48 IC 0 L/min/m2 IC 30 IC 90 IC H2 IC H4 IC H8 IC H12 IC H24 IC H48 PAPO 0 mm Hg PAPO 30 PAPO 90 PAPO H2 PAPO H4 PAPO H8 PAPO H12 PAPO H24 PAPO H48 RVS 0 dyne/s/cm2 RVS 30 RVS 90 RVS H2 RVS H4 RVS H8 RVS H12 RVS H24 RVS H48 SVO2 0 (%) SVO2 30 SVO2 90 SVO2 H2 SVO2 H4 SVO2 H8 SVO2 H12 SVO2 H24 SVO2 H48 PAP S 0 mmHg PAP S 30 PAP S 90 PAP S H2 PAP S H4 PAP S H8 PAP S H12 PAP S H24 PAP S H48 PAP M 0 mmHg PAP M 30 PAP M 90 PAP M H2 PAP M H4 PAP M H8 PAP M H12 PAP M H24 PAP M H48 PAP D 0 mmHg PAP D 30 PAP D 90 PAP D H2 PAP D H4 PAP D H8 PAP D H12 PAP D H24 PAP D H48 RVP 0 dyne/s/cm2 RVP 30 RVP 90 RVP H2 RVP H4 RVP H8 RVP H12 RVP H24 RVP H48 type of catecholamines used Noradre 0 ug/kg/min Noradre H24 Noradre H48 Noradre H72 DOBU 0 ug/kg/min DOBU H24 DOBU H48 DOBU H72 Adre 0 ug/kg/min Adre H24 Adre H48 Adre H72 Lact 0 mmol/L Lact H48 Lact H72 FE 0 (%) FE H24 FE H48 FE J7 FE J 15 1 33 F 70 peripartum cardiomyopathy 13 4 D 2 56 56 58 59 64 65 63 66 77 132 133 123 128 127 119 118 111 86 14 11 8 14 17 22 15 15 12 1.7 1.8 1.9 1.9 2 2.1 2.3 2.3 2.4 32 21 23 22 24 19 18 19 17 1985 2017 2121 1890 1897 1654 1678 1432 55 56 55 61 63 66 69 67 46 40 38 36 35 36 34 35 37 29 30 28 29 25 25 26 29 24 26 20 24 21 19 21 235 356 295 253 200 229 243 243 ADRE 1.6 2 5.6 3.6 21 27 2 63 M 80 myocardial infarction yes 23 4 D 43 61 72 72 86 73 75 75 73 75 100 118 123 110 103 92 98 100 95 18 14 11 27 22 14 14 25 24 2.2 2.6 2.8 3.3 3.1 3.2 3.3 3.2 3.4 30 18 18 14 14 19 16 16 16 2092 1771 1740 1440 1324 1523 1478 1212 1210 66 73 72 73 76 78 78 75 72 48 39 36 32 32 33 32 34 32 36 26 25 20 22 25 23 22 23 26 20 18 17 17 17 21 18 18 218 246 200 145 206 150 170 150 165 ADRE 1.7 0.7 0.3 0.02 3 3.3 2 25 33 37 46 58 3 35 F 72 peripartum cardiomyopathy 14 5 S 10 60 59 62 65 67 71 68 75 74 130 131 128 124 121 120 114 89 87 23 25 20 23 30 30 25 29 25 1.9 1.9 2.2 2.6 2.5 3 3.2 3.1 3.4 25 19 18 21 20 18 17 16 14 1546 1428 1511 1302 1179 1102 1065 1189 1155 57 61 59 67 72 75 76 74 73 42 39 38 39 37 38 33 32 32 32 26 25 28 27 27 23 24 22 23 17 18 19 22 20 17 18 16 295 295 255 215 224 240 150 206 188 NOR 0.58 0.23 0.1 0.01 2.2 1.6 1.1 29 35 47 60 60 4 19 M 55 dilated cardiomyopathy 11 4 D 8 54 57 61 61 65 65 64 67 69 126 128 126 119 121 117 99 104 99 22 21 15 14 12 12 11 10 12 2.0 2.3 2.7 2.6 2.8 3.0 3.0 3.0 3.2 28 23 22 22 21 20 19 19 19 NOR:DOBU 0.4 0.1 0.05 0.02 10 5 4 4 17 11 6.5 16 22 28 27 5 67 M 75 myocardial infarction yes 16 4 D 3 62 63 8 64 68 73 71 72 74 124 122 123 119 115 110 99 94 89 28 26 24 24 22 16 17 16 18 1.8 1.9 1.9 2.2 2.4 2.6 2.5 3 3.4 26 20 19 17 19 19 18 15 14 1810 1564 1224 1216 1300 1212 980 879 876 54 54 56 59 60 64 63 68 69 44 38 38 35 36 36 34 33 31 33 28 27 24 27 26 26 24 24 29 20 22 21 22 23 20 16 17 311 337 337 255 267 215 256 240 235 NOR:DOBU 0.51 0.21 0.1 0.05 9 6 6 4 4 4 2.2 22 30 28 6 77 M 79 dilated cardiomyopathy yes 23 2 D 10 55 56 57 60 62 65 65 69 68 108 130 102 100 99 91 97 89 91 19 20 22 18 15 17 15 17 17 1.7 1.8 1.9 2.2 2.3 2.2 2.5 2.5 2.7 28 20 19 18 20 16 18 17 17 1723 1204 1199 1203 1100 1012 917 921 861 56 55 59 62 64 64 71 75 72 62 69 70 50 59 55 40 47 43 28 35 40 35 42 28 17 21 18 384 133 436 348 237 412 NOR/DOBU 0.69 0.33 0.12 0.07 15 8 5 0 4.1 3.5 2.2 21 32 33 36 7 55 F 78 myocardial infarction yes 14 2 S 16 61 67 81 84 70 95 90 82 89 136 140 109 99 98 110 99 89 90 24 26 16 22 19 15 17 16 16 2.3 3.8 6.6 4.2 3.9 4.4 4.7 4.7 4.6 24 15 17 21 19 18 17 20 17 1274 630 800 702 767 1042 890 719 930 54 65 68 71 75 69 71 73 75 45 42 43 40 38 37 37 35 34 34 26 29 31 29 25 26 28 25 28 17 19 22 20 21 18 19 19 348 232 145 190 205 127 153 136 139 NOR/DOBU 0.5 0.3 0.2 0.02 10 4 0 0 2.9 1.9 1.2 30 36 46 47 50 8 69 M 80 myocardial infarction yes 37 4 D 10 65 64 66 70 71 72 73 73 74 98 103 108 92 87 92 97 88 87 24 23 19 20 18 21 16 16 17 2.2 2.8 3.5 3.3 3.6 3.4 3.3 3.4 3.5 31 24 20 26 25 24 25 23 22 1466 1355 1046 1046 998 969 901 850 734 58 57 59 64 65 71 69 72 71 55 47 46 47 48 44 43 43 39 42 38 36 37 37 33 34 34 30 33 27 20 24 25 27 26 25 22 367 400 366 267 257 212 218 259 183 NOR 0.47 0.44 0.21 0.13 2.9 1.8 1.3 28 35 47 47 9 62 F 90 mitral valvulopathy 28 3 S 18 70 74 73 73 72 78 74 75 72 46 44 45 50 47 69 68 60 63 22 28 16 12 13 8 15 16 15 1.6 1.7 1.9 2.2 2.5 2.9 2.9 3.1 3.4 27 22 22 18 16 15 15 15 9 2250 2153 2418 2223 1890 1927 1631 1532 1335 57 64 64 65 71 73 74 78 73 39 37 34 35 32 28 26 26 33 32 27 27 25 25 19 18 19 16 25 19 17 19 19 13 13 14 11 235 235 211 255 288 110 83 103 165 NOR/DOBU 0.45 0.15 0.01 0.02 8 5 3 0 2.5 1.6 1.4 38 45 50 50 56 10 28 F 77 peripartum cardiomyopathy 18 3 S 9 62 62 76 77 78 78 80 76 80 110 112 122 108 112 109 98 96 96 22 21 15 14 12 12 11 10 12 2.0 2.3 2.7 2.6 2.8 3.0 3.0 3.0 3.4 28 23 22 22 21 20 19 19 19 NOR 0.15 0.15 0.15 0.07 1.9 1.2 0.5 21 23 28 49 52 11 35 M 68 myocardial infarction no 24 4 S 11 64 64 68 67 75 77 76 84 84 100 108 110 100 98 100 88 100 85 20 27 22 25 11 8 16 11 11 1.7 1.6 2.1 2 3.8 4.5 3.9 3.6 3.4 22 24 21 22 18 17 19 19 16 2092 1854 1740 1671 1340 1220 1235 1626 1422 57 61 60 68 65 68 70 72 70 42 39 34 35 34 35 30 29 25 26 25 25 24 23 20 22 19 19 376 280 147 160 133 176 NOR/DOBU 0.36 0.36 0.3 0.24 9 6 6 6 2.3 1.6 0.9 28 35 38 40 51 12 44 F 74 viral cardiomyopathy 35 4 S 28 58 55 59 70 74 71 70 71 72 140 140 140 135 135 135 135 122 110 19 13 21 14 16 14 15 20 21 1.6 2.6 2.5 2.3 2.2 2.4 2.3 2.4 2.5 34 34 27 29 30 30 28 30 27 1970 1293 1210 1940 2091 1907 1910 1708 1636 48 58 60 59 61 57 49 62 64 55 51 51 42 48 44 43 43 40 39 38 36 33 35 35 33 34 32 30 28 24 22 28 27 25 27 25 250 123 288 139 182 167 174 133 160 ADRE 1.5 20 8 6 6 2 5.2 3 1.5 25 33 42 40 52 13 69 M 69 myocardial infarction no 29 4 D 2 65 60 66 69 70 68 71 70 102 110 88 89 95 105 100 89 87 17 13 23 16 26 18 8 26 1.8 1.7 1.7 1.7 1.6 1.6 1.7 1.6 1.7 23 24 22 24 22 22 19 14 14 2116 2224 2028 2500 2223 2500 2985 2200 61 63 59 60 54 55 54 58 42 40 38 42 36 33 30 26 30 29 28 30 27 25 23 17 25 23 23 22 21 19 18 12 311 235 282 282 250 150 188 150 ADRE 1.4 15 6.5 8 4.5 8.7 21 23 28 49 52 14 50 M 78 myocardial infarction yes 17 3 S 56 81 72 73 77 77 81 70 78 83 87 96 98 96 86 87 77 89 93 18 14 14 10 11 12 14 14 11 3.1 3.4 3.3 3.4 2.8 3.1 2.8 3.5 4.1 25 20 19 18 18 19 19 22 21 1626 1367 1435 1584 1872 1781 1600 1463 1405 64 72 75 74 71 73 70 74 72 46 41 40 38 36 38 36 40 39 34 28 28 26 25 25 24 30 29 25 23 21 20 20 19 20 23 23 232 188 218 188 200 155 143 183 156 NOR/DOBU 0.3 0.2 17 6 2 0.9 32 40 42 55 52 15 52 M 75 myocardial infarction yes 25 4 D 6 83 87 90 85 85 87 83 75 88 85 88 90 99 102 100 96 80 75 25 28 28 22 23 22 16 15 23 2.0 2.3 3 2.9 3.3 3.3 3 3.2 3.3 40 36 34 32 34 32 24 19 21 2191 2042 1655 1744 1495 1564 1793 1500 1580 61 63 66 70 75 66 68 72 70 58 56 53 52 39 36 45 42 38 41 29 24 36 32 29 33 24 16 190 209 166 170 133 125 ADRE 3.6 3.4 2.5 0.5 3.8 0.3 0.4 21 25 33 16 74 F 120 myocardial infarction yes 22 4 D 16 67 55 57 56 58 56 65 61 67 60 60 60 60 60 60 60 60 60 25 28 23 23 23 20 18 17 23 2.2 2.3 2.4 2.3 2.5 2.8 2.9 2.8 2.4 23 22 23 24 18 18 16 17 16 1533 953 1148 1162 1021 1020 1288 1257 1456 61 60 63 64 58 67 65 59 64 39 38 37 39 35 35 32 33 33 31 29 29 31 26 26 25 25 24 23 24 23 25 20 19 18 19 19 291 243 200 243 256 229 248 229 267 NOR/DOBU 1.2 1.1 1.2 0.8 18 15 15 8 2.2 1.1 1.6 28 27 35 42 41 17 73 F 88 myocardial infarction yes 21 3 D 10 58 56 58 59 64 65 63 66 89 100 108 110 100 98 100 88 100 85 14 11 8 14 17 22 15 15 12 2.4 2.8 3.5 3.3 3.6 3.4 3.3 3.4 3.6 27 22 22 18 16 15 15 15 15 55 56 55 61 63 66 69 72 74 52 49 44 44 40 38 37 37 37 31 26 26 22 20 19 19 19 19 DOBU 14 8 5 4 2.5 1.6 25 33 37 18 66 M 76 myocardial infarction yes 19 4 D 12 66 64 66 70 71 72 73 73 74 140 140 140 135 135 135 135 122 110 18 14 11 27 22 14 14 14 16 1.7 1.8 1.9 1.9 2 2.1 2.3 2.3 2.3 24 15 17 21 19 18 17 18 17 66 73 72 73 76 78 78 75 72 48 47 45 40 44 42 41 40 41 28 26 21 25 23 22 21 22 21 NOR 0.65 0.66 0.18 0.02 1.9 2.2 29 35 37 19 33 F 101 peripartum cardiomyopathy 20 3 S 6 62 67 81 84 70 95 90 82 89 60 62 65 68 62 61 74 63 66 23 25 20 23 30 30 25 23 25 2.1 2.6 2.8 3.3 3.1 3.2 3.3 3.2 3.3 28 20 19 18 20 16 18 16 18 57 61 59 67 72 75 76 74 73 53 50 44 41 40 42 38 40 38 32 26 23 22 24 20 22 20 22 DOBU 12 7 3 0 2.3 1.6 0.9 30 36 46 47 50 20 32 F 65 peripartum cardiomyopathy 22 3 S 5 57 56 57 60 62 65 65 69 68 102 110 88 89 95 105 100 89 87 22 21 15 14 12 12 11 10 12 2.3 3.8 6.6 4.2 3.9 4.4 4.7 4.7 4.6 26 20 19 17 19 19 18 19 18 61 63 66 70 75 66 68 72 70 48 46 40 39 37 39 39 38 39 30 24 23 21 23 23 22 23 22 DOBU 20 15 10 10 5.2 3 1.5 28 35 46 49 49 21 52 F 49 viral cardiomyopathy 18 4 S 12 63 63 8 64 68 73 71 72 74 87 96 98 96 86 87 77 89 93 28 26 24 24 22 16 17 16 18 1.7 1.8 1.9 2.2 2.3 2.2 2.5 2.5 2.8 28 23 22 22 21 20 19 20 19 54 54 56 59 60 64 63 68 69 49 47 42 41 40 40 39 37 39 32 27 26 25 25 24 22 24 22 NOR 0.77 0.55 0.33 0.16 4.5 8.7 2.3 38 45 50 50 56 22 65 M 76 myocardial infarction yes 21 3 S 6 63 72 72 86 73 75 75 73 75 85 88 90 99 102 100 96 80 75 19 20 22 18 15 17 15 17 17 1.8 1.9 1.9 2.2 2.4 2.6 2.5 3 3 32 21 23 22 24 19 18 17 17 56 55 59 62 64 64 71 75 72 56 55 44 46 45 43 42 41 40 36 25 27 26 24 23 22 21 21 DOBU 15 10 5 2 2 0.9 0.9 28 35 38 40 51 23 29 F 66 peripartum cardiomyopathy 13 2 S 4 62 59 62 65 67 71 68 75 74 110 112 122 108 112 109 98 96 96 24 26 16 22 19 15 17 16 16 1.8 2.3 2.7 2.6 2.8 3.0 3.0 3.0 3.0 30 18 18 14 14 19 16 17 16 54 65 68 71 75 69 71 73 75 55 51 39 39 35 35 40 37 38 34 22 22 18 18 23 20 21 20 DOBU 12 12 5 7 3.8 1.3 1.4 25 33 42 40 52 24 68 M 62 mitral valvulopathy 22 4 D 3 52 57 61 61 65 65 64 67 69 46 44 45 50 47 69 68 60 63 24 23 19 20 18 21 16 16 17 1.9 1.9 2.2 2.6 2.5 3 3.2 3.1 3.2 25 19 18 21 20 18 17 16 17 58 57 59 64 65 71 69 72 71 48 47 41 40 40 39 40 39 38 29 23 22 22 21 22 21 20 21 NOR 0.90 0.75 0.66 0.33 2.2 2.1 32 38 39 25 39 F 78 mitral valvulopathy 15 2 S 15 54 57 61 60 64 66 68 68 69 130 132 118 115 117 105 100 100 90 25 25 24 23 23 24 22 19 20 2.2 2.3 2.4 2.3 2.5 2.8 2.9 2.8 2.4 26 20 19 17 19 19 18 19 18 55 58 60 59 61 57 49 62 64 42 40 38 42 40 37 37 39 42 25 23 26 23 21 21 19 19 18 NOR/DOBU 0.55 0.40 0.12 0.05 14 10 7 5 2.2 1.1 1.6 24 30 35 40 45 This is a portion of the data; to view all the data, please download the file. Dataset 1. Data used for retrospective analysis of the effects of levosimendan for cardiogenic shock. Data was collected at the ICU in the Military Hospital of Tunis between Jan 2004 and Dec 2009, and between Jan 2011 and Dec 2013. PAM: Mean Arterial Pressure (mmHg); HR: Heart Rate (beat/min); POD: Right Atrial Pressure (mmHg); IC: Cardiac Index (L/min/m 2 ); PAPO: Pulmonary Wedge Pressure (mmHg); RVS: Systemic Vascular Resistance (dyne/s/cm 2 ); SVO2: Mixed Venous Oxygen Saturation (%); PAP: Pulmonary arterial systolic pressure (mmHg); Mean Pulmonary Arterial Pressure (mmHg); PAP D: Pulmonary arterial diastolic pressure (mmHg); RVP: Pulmonary Vascular Resistance (mmHg); Noradre: Norepinephrine (ug/kg/min); DOBU: Dobutamine (ug/kg/min); Adre: Epinephrine (ug/Kg/min); Lact: Arterial Lactate (mmol/L); FE: Left Ventricular Ejection fraction (%). Twenty-six patients who were hospitalized for CS met our criterion for inclusion in this study. The status of CS was mainly secondary to myocardial infarction (in 42% of cases) and to cardiomyopathy of the peripartum (in 31% of cases). The demographic data are shown in Table 1 . Table 1. Distribution of demographic parameters. Parameters Value Number of patients 26 Age (years) 51 ± 18 Gender ratio (male/female) 0.85 APACHE II medium 20 ± 7 Multiple organ-failure score 3.4 ± 1 Average length of stay in ICU (days) 13 ± 12 Etiology of CS - Myocardial infarction 12 - Peripartum cardiomyopathy 6 - Dilated myocardiopathy 3 - Other pathology 5 History of patients - Coronary-artery disease 5 - Diabetes 5 - Arteritis ischemic lower limbs 3 - Smoking 4 Evolution - Survival 14 - Death 12 The hemodynamic data at inclusion showed a mean arterial pressure of 63 ± 7 mmHg, a cardiac index of 1.96 ± 0.29 l/min/m 2 , and a pulmonary capillary wedge pressure of 28 ± 4 mmHg. Levosimendan resulted in significantly improved mean arterial pressure to 76 ± 7 mmHg at 48 h (p=0.001 compared to T0) and cardiac index to 3.19 ± 0.68 L/min/m 2 (p<0.0001 compared to T0) ( Figure 1 ) without any significant modification to either heart rate (101 ± 28 to 86 ± 13, p=0.26) or the emergence of rhythm disturbance. Figure 1. Data are expressed as mean values of cardiac index of all our patients. Levosimendan decreased pulmonary wedge pressure to 17 ± 3 mmHg at 48h (p=0.001 compared to T0). Pulmonary arterial systolic pressure was significantly reduced to 38 ± 5 mmHg after 48 h, compared to 49 ± 6 mmHg at inclusion (p=0.016 compared to T0). Pulmonary arterial diastolic pressure was significantly reduced to 20 ± 4 mmHg at 24 h, compared to 29 ± 4 mmHg at inclusion (p<0.001 compared to T0). Mean pulmonary arterial pressure was significantly reduced to 26 ± 5 mmHg after 24 h compared to 35 ± 5 mmHg at inclusion (p=0.001 compared to T0). There was a significant decrease in lactate from 3.77 ± 2.93 to 1.60 ± 1.32 mmol/L after 72 h. Levosimendan significantly reduced systemic vascular resistance (1834 ± 308 to 1321 ± 304 dyne/s/cm 2 , p<0.0001) and pulmonary vascular resistances (289 ± 64 to 204 ± 78 dyne/s/cm 2 , p=0.001). Administration of levosimendan also reduced the need for catecholamines ( Figure 2 ), thus leading to a gradual reduction in the need for catecholamines in six patients. Figure 2. Data are expressed as mean values from 15 patients who received norepinephrine, 15 patients who received Dobutamine and 5 patients who received epinephrine. Administration of levosimendan improved SvO2 to 70 ± 5% after 24 h of infusion. The evolution of the left-ventricle ejection fraction showed bottom-up kinetics as a function of time, which ranged from 26 ± 5% at inclusion to 54 ± 5% by day 15. Discussion Levosimendan is a calcium sensitizer. Its main mechanism of action is to increase the binding affinity of troponin C to Ca 2+ and to stabilize its conformation. It also directly increases cardiac contractility without raising intracellular concentrations of calcium or AMPc. This makes levosimendan one of the best inotropic agents and causes least arrhythmia. In addition to its positive inotropic affects, levosimendan can caused vasodilatation of many vascular areas by opening ATP-dependent potassium channels. This increased coronary blood flow without increasing consumption of myocardial oxygen, thus explains the good tolerance of levosimendan in cases of coronary syndrome and also its effects as an anti-ischemic and a cardio-protector. Many clinical studies have been conducted to assess the effects of levosimendan on hemodynamic parameters. The first studies focused on patients with decompensated heart failure. The main aim of these authors was to compare levosimendan with dobutamine (i.e., the main type of catecholamine used during low cardiac output). Three main studies have been published: the LIDO, SURVIVE, and CASINO studies. In the LIDO study, 203 patients were hospitalized for severe cardiac failure and received either levosimendan (a loading dose of 24 µg/kg/min infused for 10 min; and then continuous infusion for 24 h at a dose of 0.1 µg/kg/min, n =103) or dobutamine (a dose of 5 µg/kg/min was given without a loading dose, n =100). Levosimendan increased the cardiac index by ≥30% and decreased pulmonary capillary wedge pressure by ≥25% in 29 patients compared to only 15 patients receiving dobutamine (hazard ratio=1.9, CI= of 95%, p =0.022) 11 , 12 . A decline in the need for catecholamines and the resumption of beta blockers occurred more frequently in patients that received levosimendan 14 . Mortality rate was also lower in patients that received levosimendan compared to dobutamine after 1 month (7.8% vs. 17%, p =0.045) and at 6 months (26% vs. 38%, p =0.029) 9 , 11 – 13 . The SURVIVE study was a multicenter study that included 1327 randomized patients with severe cardiac failure and who had a left-ventricle ejection fraction of <30%. This study chose mortality as the main criterion for judgment and assessed the effectiveness of levosimendan compared to dobutamine 11 . When the analyses focused on early mortality rates during the first 5 days, levosimendan was more effective than dobutamine (4.4% vs. 6%), indicating that levosimendan could be an alternative to dobutamine for patients with acute cardiac insufficiency. However, this favorable trend was not found in the longer term 11 . During the 180 days of follow-up, there were 173 deaths (26%) in the group receiving levosimendan ( n =664) compared to 185 (28%) in the group receiving dobutamine ( n =663) 15 . However, the main criterion of mortality at 6 months may not be appropriate to judge the effectiveness of this treatment when its main benefits were observed at an early stage 16 . The CASINO study was a randomized, controlled, double-blind study that included 299 patients with decompensated congestive heart failure. The study compared levosimendan therapy with dobutamine, and with a placebo. The study showed positive results for its first assessment criterion: i.e., mortality rate at 6 months. The authors reported that improved survival was associated with the use of levosimendan 16 . In the light of these results, levosimendan represents a significant advance in the treatment of cardiac insufficiency. These studies have helped to expand levosimendan’s indications and have also assessed its contribution to treat CS. Many authors have evaluated the hemodynamic effects of levosimendan in the course of CS. Delle et al. concluded that administration of levosimendan to 10 patients with CS led to a significant increase in the cardiac index and significantly decreased vascular resistance 17 . Russ et al. obtained similar results when they prescribed levosimendan to 56 patients with CS. They reported a significant increase in the cardiac index (from 2.1 ± 0.56 to 3.0 ± 1.11 l/min/m 2 at 24 h, p <0.01) associated with a significant decrease in systemic vascular resistance (from 1208 ± 333 to 858 ± 299 dynes/s/mm -4 at 24 h, p <0.01), whereas mean arterial pressure and pulmonary wedge pressure were slightly but non-significantly decreased. An improved SOFA score was found after 72 h of levosimendan treatment, suggesting improved organic function 18 . Labriola et al. also reported the same variations in hemodynamic parameters as described by Delle et al. and Russ et al. , which were distinguished by the development of a significant increase in the left-ventricle ejection fraction 19 . According to the study of Berry et al. , a continuous decrease in noradrenalin, dobutamine, and milrinone was associated with improved hemodynamic parameters in 93 patients with CS who received a continuous infusion of levosimendan for 26 h at a dose of 0.096 µg/kg/min 20 . Labbene et al. analyzed the hemodynamic effects of levosimendan in 16 patients hospitalized with CS and who were refractory to catecholamine 21 . The evolution of hemodynamic parameters after infusion of levosimendan was marked by a significant increase in the cardiac index (from 2.01 ± 0.4l to 3.4 ± 0.65 l/min/m 2 at 48 h) of SvO 2 (from 57% ± 5% to 70% ± 3%) and the left-ventricular ejection fraction (from 26 ± 6% to 52 ± 5%). There was also a significant decrease in pulmonary wedge pressure from 28 ± 5 to 17 ± 5 mmHg, and of pulmonary arterial systolic pressure, of diastolic arterial systolic pressure, of average arterial systolic pressure of systemic vascular resistance (from 1833 ± 308 to 1216 ± 304 dyne/s/cm 2 at 48 h), and of pulmonary vascular resistances (from 289 ± 64 at T0 to 179 ± 44 dyne/s/cm 2 at 4 h) 21 . Our results agree with those from the literature and show the effectiveness of levosimendan to treat CS when it is refractory to catecholamines. At the recommended dose, levosimendan improves hemodynamic parameters by increasing the cardiac index and SvO 2 . It is responsible for the drop in systemic vascular resistance and pulmonary vascular resistances, and reduces the need for catecholamines. Other studies have also confirmed the efficacy of levosimendan to stabilize hemodynamic parameters in patients with CS 22 – 25 . Conclusion Our results show that levosimendan was efficacious at treating CS, and that it has several advantages compared to other isotropic agents. However, it is expensive (compared to dobutamine) and the absence of a net profit on long-term survival represents a limit to its wide-spread use in pathologies with a poor prognosis, such as CS. Further randomized studies that include a placebo and a larger patient population with CS are needed to precisely determine the indications for levosimendan and to assess its cost in relation to patient survival. Data availability F1000Research : Dataset 1. Data used for retrospective analysis of the effects of levosimendan for cardiogenic shock, 10.5256/f1000research.5820.d40172 26 Author contributions IL and MF conceived the study. IL and FJ designed the experiments. KEA, CR and IL carried out the research. KEA and FJ prepared the first draft of the manuscript. IL, FJ and KEA contributed to the experimental design and preparation of the manuscript. All authors were involved in the revision of the draft manuscript and have agreed to the final content. Competing interests No competing interests were disclosed. Grant information Supported by a grant from the Research Laboratory LR12DN01 and The Military Hospital of Tunis. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments The authors thank Newmed Publishing Services for language editing and submission support, provided on a pro bono basis. Faculty Opinions recommended References 1. Leurent G: [Ischaemic cardiogenic shock. Where do we stand in 2012?]. Ann Cardiol Angeiol (Paris). 2012; 61 : 417–422. PubMed Abstract | Publisher Full Text 2. Lambert Y, Boutout F: Etat de choc cardiogénique dans les premières heures. Encycl Méd Chir. Elsevier, Masson, Paris. Médecine d’urgence, 25-020-A-20, 2007; 14. 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Lehmann A, Lang J, Boldt J, et al. : Levosimendan in patients with cardiogenic shock undergoing surgical revascularization: a case series. Med Sci Monit. 2004; 10 (8): MT89–93. PubMed Abstract 23. Katsytadze I, Amosova E, Purdkyi I, et al. : Long term effects of levosimendan therapy in patients with cardiogenic shock. Resuscitation. 2013; 84 (Supplement 1): S8–S98. Publisher Full Text 24. Zobel C, Reuter H, Schwinger RH: [Treatment of cardiogenic shock with the Ca2+ sensitizer levosimendan]. Med Klin (Munich). 2004; 99 (12): 742–746. PubMed Abstract | Publisher Full Text 25. Greif M, Zwermann L, Reithumann C, et al. : Levosimendan as rescue therapy in severe cardiogenic shock after ST-elevation myocardial infarction. Acute Card Care. 2008; 10 (3): 185–190. PubMed Abstract | Publisher Full Text 26. Janen F, El Arayedh K, Labbene I, et al. : Dataset 1 in: Use of levosimendan in cardiogenic shock. F1000Research. 2014. Data Source Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 05 Dec 2014 ADD YOUR COMMENT Comment Author details Author details 1 Pharmacy Department, Military Hospital of Tunis, Monfleury,Tunis, 1008, Tunisia 2 Pharmacy Department, Basic Health Group of South Tunis, 90 Sayada Street Bellevue, Tunis, 1009, Tunisia 3 Université Tunis El Manar, Faculté de Médecine de Tunis, LR12DN01, Intensive Care Unit, Military Hospital of Tunis, Monfleury Tunis, 1008, Tunisia Competing interests No competing interests were disclosed. Grant information Supported by a grant from the Research Laboratory LR12DN01 and The Military Hospital of Tunis. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (1) version 1 Published: 05 Dec 2014, 3:296 https://doi.org/10.12688/f1000research.5820.1 Copyright © 2014 Janen F et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication). Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Janen F, El Arayedh K, Labbene I et al. Use of levosimendan in cardiogenic shock [version 1; peer review: peer review discontinued] . F1000Research 2014, 3 :296 ( https://doi.org/10.12688/f1000research.5820.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Peer review discontinued Peer review at F1000Research is author-driven. Currently no reviewers are being invited. What does this mean? Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 05 Dec 2014 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Peer review discontinued Peer review at F1000Research is author-driven. Currently no reviewers are being invited. What does this mean? Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Click here to access the data. The problem Spreadsheet data files may not format correctly if your computer is using different default delimiters (symbols used to separate values into separate cells) - a spreadsheet created in one region is sometimes misinterpreted by computers in other regions. You can change the regional settings on your computer so that the spreadsheet can be interpreted correctly. How to fix it Save downloaded CSV file Open spreadsheet program (e.g. Excel) Click the ‘Data’ tab at the top Click the ‘From text’ icon (top left) Browse for downloaded CSV file, click ‘Import’ Ensure ‘Delimited’ radio button is selected, click ‘Next’ Check one of the appropriate delimiter checkboxes (you can visualize the formatting by looking at the data preview below these options) Click ‘Finish’ Downloaded data do not display as expected? Download the data (11.33KB) Dataset citation: Janen F, El Arayedh K, Labbene I et al. . Dataset 1 in: Use of levosimendan in cardiogenic shock. 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