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Use of Levosimendan in Intensive Care Unit Settings: An Opinion Paper.

ABSTRACT: Levosimendan is an inodilator that promotes cardiac contractility primarily through calcium sensitization of cardiac troponin C and vasodilatation via opening of adenosine triphosphate-sensitive potassium (KATP) channels in vascular smooth muscle cells; the drug also exerts organ-protective effects through a similar effect on mitochondrial KATP channels. This pharmacological profile identifies levosimendan as a drug that may have applications in a wide range of critical illness situations encountered in intensive care unit medicine: hemodynamic support in cardiogenic or septic shock; weaning from mechanical ventilation or from extracorporeal membrane oxygenation; and in the context of cardiorenal syndrome. This review, authored by experts from 9 European countries (Austria, Belgium, Czech republic, Finland, France, Germany, Italy, Sweden, and Switzerland), examines the clinical and experimental data for levosimendan in these situations and concludes that, in most instances, the evidence is encouraging, which is not the case with other cardioactive and vasoactive drugs routinely used in the intensive care unit. The size of the available studies is, however, limited and the data are in need of verification in larger controlled trials. Some proposals are offered for the aims and designs of these additional studies.

SUBMITTER: Herpain A

PROVIDER: S-EPMC6319595 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Use of Levosimendan in Intensive Care Unit Settings: An Opinion Paper.

Herpain Antoine A Bouchez Stefaan S Girardis Massimo M Guarracino Fabio F Knotzer Johann J Levy Bruno B Liebregts Tobias T Pollesello Piero P Ricksten Sven-Erik SE Riha Hynek H Rudiger Alain A Sangalli Fabio F

Journal of cardiovascular pharmacology 20190101 1

Levosimendan is an inodilator that promotes cardiac contractility primarily through calcium sensitization of cardiac troponin C and vasodilatation via opening of adenosine triphosphate-sensitive potassium (KATP) channels in vascular smooth muscle cells; the drug also exerts organ-protective effects through a similar effect on mitochondrial KATP channels. This pharmacological profile identifies levosimendan as a drug that may have applications in a wide range of critical illness situations encoun ...[more]

PMID: 30489437

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Project description:BACKGROUND:In most emergency situations or severe illness, patients are unable to consent for clinical trial enrollment. In such circumstances, the decision about whether to participate in a scientific study or not is made by a legally designated representative. OBJECTIVE:To address the willingness of patients admitted to the intensive care unit (ICU) to be enrolled in a scientific study as volunteers, and to assess the agreement between patients' and their legal representatives' opinion concerning enrollment in a scientific study. METHODS:This survey was conducted in two hospitals in São Paulo, Brazil. Patients (≥18 years) with preserved cognitive functions accompanied by a surrogate admitted to the ICU were eligible for this study. A survey containing 28 questions for patients and 8 questions for surrogates was applied within the first 48h from ICU admission. The survey for patients comprised three sections: demographic characteristics, opinion about participation in clinical research and knowledge about the importance of research. The survey for legal representatives contained two sections: demographic characteristics and assessment of legal representatives' opinion in authorizing patients to be enrolled in research. RESULTS:Between January 2017 and May 2018, 208 pairs of ICU patients and their respective legal representatives answered the survey. Out of 208 ICU patients answering the survey, 73.6% (153/208) were willing to be enrolled in the study as volunteers. Of those patients, 65.1% (97/149) would continue participating in a research even if their legal representative did not support their enrollment. Agreement between patients' and surrogates' opinion concerning participation was poor [Kappa = 0.11 (IC95% -0.02 to 0.25)]. If a consent for study participation had been obtained, 69.1% (103/149) of patients would continue participating in the study until its conclusion, and 23.5% (35/149) would allow researchers to use data collected to date, but would withdraw from the study on that occasion. CONCLUSION:The majority of patients admitted to the ICU were willing to be enrolled in a scientific study as volunteers, also after a deferred informed consent procedure has been used. Nevertheless, contradictory opinions between patients and their and their legal representatives' concerning enrollment in a scientific study were often observed.

Project description:Critically ill intensive care unit (ICU) patients commonly develop severe muscle wasting and impaired muscle function, leading to delayed recovery, with subsequent increased morbidity and financial costs, and decrease quality of life of survivors. Acute Quadriplegic Myopathy (AQM) is one of the most common neuromuscular disorders associated with ICU-acquired muscle weakness. Although there are no available treatments for the ICU-acquired muscle weakness, it has been demonstrated that early mobilization can improve its prognosis and functional outcomes. This study aims at improving our understanding of the effects of passive mechanical loading on skeletal muscle structure and function by using a unique experimental rat ICU model allowing analyses of the temporal sequence of changes in mechanically ventilated and pharmacologically paralyzed animals at durations varying from 6 h to 14 days. Results show that passive mechanical loading alleviated the muscle wasting and the loss of force-generation associated with the ICU intervention, resulting in a doubling of the functional capacity of the loaded vs. unloaded muscles after a 2-week ICU intervention. We demonstrated that the improved maintenance of muscle structure and function is likely a consequence of a reduced oxidative stress, and a reduced loss of the molecular motor protein myosin. A complex temporal gene expression pattern, delineated by microarray analysis, was observed with loading-induced changes in transcript levels of sarcomeric proteins, muscle developmental processes, stress response, ECM/cell adhesion proteins and metabolism. Thus, the results from this study show that passive mechanical loading alleviates the severe negative consequences on muscle structure and function associated with mechanical silencing in ICU patients, strongly supporting early and intense physical therapy in immobilized ICU patients. This study aims to unravel the effects of passive mechanical loading on skeletal muscle structure and function in an experimental rat ICU model at duration varying between 6h and 14 days. A total of 23 experimental female Sprague-Dawley rats were included in this study. The experimental rats were anaesthetized, treated with the neuromuscular blocking agent (NMBA) M-NM-1-cobrotoxin, mechanically ventilated and monitored for durations varying from 6h to 4 days (n=13), from 5 to 8 days (n=4), and from 9 to 14 days (n=6). The left leg of the animal was activated for 6 hours at the shortest duration and 12 hours per day at durations 12 hours and longer throughout the experiment, using a mechanical lever arm that produced a continuous passive maximal ankle joint flexions-extensions at a speed of 13.3 cycles per minute. Muscle biopsies were obtained from gastrocnemius muscle (proximal part) immediately after euthanasia, were quickly frozen in liquid propane cooled by liquid nitrogen, and stored at -80M-BM-0C. RNA was extracted.

Project description:Purpose: To determine whether inotrope administration is associated with increased all-cause mortality in cardiogenic shock (CS) patients and to identify inotropes superior for improving mortality. Methods: This retrospective cohort study analyzed data retrieved from the Philips Electronic ICU (eICU) database, a clinical database of 200,859 patients from over 208 hospitals located throughout the United States. The database was searched for patients admitted with CS to the intensive care unit (ICU) between 2014 and 2015. We evaluated 34,381 CS patients. They were classified into the inotrope and non-inotrope groups based on whether inotropes were administered during hospitalization. The primary endpoint was all-cause hospital mortality. Findings: In total, 15,021 (43.69%) patients received inotropes during hospitalization. The in-hospital mortality rate was significantly higher in the inotrope group than in the non-inotrope group (2,999 [24.03%] vs. 1,547 [12.40%], adjusted hazard ratio: 2.24; 95% confidence interval [CI]: 2.09-2.39; p < 0.0001). After propensity score matching according to the cardiac index, 359 patients were included in each group. The risk of ICU (OR 5.65, 95% CI, 3.17-10.08, p < 0.001) and hospital (OR 2.63, 95% CI: 1.75-3.95, p < 0.001) mortality in the inotrope group was significantly higher. In the inotrope group, the administration of norepinephrine ≤0.1 μg/kg/min and dopamine ≤15 μg/kg/min did not increase the risk of hospital mortality, and milrinone administration was associated with a lower mortality risk (odds ratio: 0.559, 95% CI: 0.430-0.727, p < 0.001). Meanwhile, the administration of >0.1 μg/kg/min dobutamine, epinephrine, and norepinephrine and dopamine >15 μg/kg/min was associated with a higher risk of hospital mortality. Conclusions: Inotropes should be used cautiously because they may be associated with a higher risk of mortality in CS patients. Low-dose norepinephrine and milrinone may associated with lower risk of hospital mortality in these patients, and supportive therapies should be considered when high-dose inotropes are administered.

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Use of Levosimendan in Intensive Care Unit Settings: An Opinion Paper.

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Use of Levosimendan in Intensive Care Unit Settings: An Opinion Paper.

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