Levosimendan Infusion in Critically Ill Patients With Cardiogenic Shock

To determine whether Levosimendan infusion in patients with cardiogenic shock and cardiorenal syndrome refractory to standard inotropic therapy, improves hemodynamics and renal function, whilst being safe.

Study Overview

• Status: Completed
• Conditions: Cardiogenic Shock; Acute Kidney Failure; Cardiorenal Syndrome
• Intervention / Treatment: Drug: Levosimendan

Detailed Description

Cardiogenic Shock or the state of systemic hypoxia albeit initially preserved intra-vascular volume and intact vascular function, is solely the result of insufficient cardiac output [1-2]. The ensuing centralization and redistribution of blood-volume, is induced by a stimulation of the renin-angiotensin system, as well as vasopressin and endogenous catecholamine liberation [2-3]. Precipitating Cardiogenic Shock has a direct effect on the kidney, also called the cardiorenal syndrome [4].

The overall consensus for the therapy of cardiogenic shock is the use of inotropes to increase cardiac output and reverse organ hypoxia [2], nevertheless their increase of myocardial and glomerular oxygen consumption make them a double edged sword to use in cardiogenic shock and more prominently in cardiogenic shock coupled with pronounced cardiorenal syndrome.

Levosimendan is an inotropic agent that was developed for the treatment of severely decompensated heart failure. It exerts its inotropic effects primarily through sensitizing Troponin C to calcium and thereby increasing contraction of cardiac myofilaments during systole [5]. Unlike other inotropic agents, Levosimendan acts independently of the beta adrenergic receptor [5]. Additionally, the effect of Levosimendan could be beneficial for the kidneys function by decreasing pre-glomerular arteriolar vasotonus whilst keeping post-glomerular arteriolar vasotonus constant [6].

In light of the scarce but promising literature the question arises if Levosimendan can safely ameliorate cardiac and renal function concomitantly in patients presenting the combination of cardiogenic shock and cardiorenal syndrome.

• Study Type: Observational
• Enrollment (Actual): 43

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

All patients consecutively admitted to the medical ICU of the University Hospital Zurich aged over 18 years, with an underlying cardiogenic shock, receiving Levosimendan

Description

Inclusion Criteria:

• Levosimendan
• Cardiogenic Shock
• Continuous monitoring of cardiac output at the start of and during treatment with Levosimendan

Exclusion Criteria:

• Extracorporal hemodynamic support or an implanted ventricular assist device
• Previous therapy with Levosimendan during the index hospitalization
• Refusal of participation in the study

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Levosimendan Treated Group; All patients consecutively admitted to the medical ICU of the University Hospital Zurich aged over 18 years, with an underlying cardiogenic shock, receiving Levosimendan.

Drug: Levosimendan; Levosimendan was administered according to a standardized treatment protocol. A total dose of 12.5mg or 25mg (corresponding to one or two ampoules) was given at an infusion rate of 0.05 μg/kg/min to 0.2μg/kg/min with or without a loading dose (6 μg/kg or 3 μg/kg over 10 minutes). The decision about total dose, infusion rate and loading dose was at the discretion of the treating physician.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Cardiac Index	Temporal development of Cardiac Index post Levosimendan Infusion up until 120 hours	Mixed Model Assessment at 0, 1, 2, 4, 6, 12, 24, 48, 72, 96 and 120 hours post Levosimendan Infusion
Change in Cardiac Preload Pressures	Temporal development of Wedge Pressure/ Central Venous Pressure post Levosimendan Infusion up until 120 hours	Mixed Model Assessment at 0, 1, 2, 4, 6, 12, 24, 48, 72, 96 and 120 hours post Levosimendan Infusion
Change in Mean Arterial Pressure	Temporal development of Mean Arterial Pressure post Levosimendan Infusion up until 120 hours	Mixed Model Assessment at 0, 1, 2, 4, 6, 12, 24, 48, 72, 96 and 120 hours post Levosimendan Infusion
Change in Vasoactive/ Inotropic Dosage	Temporal development of Norepinephrine/ Dobuatmine Dosage post Levosimendan Infusion up until 120 hours	Mixed Model Assessment at 0, 1, 2, 4, 6, 12, 24, 48, 72, 96 and 120 hours post Levosimendan Infusion
Change in Renal Function	Temporal development of eGFR (Creatinin estimated) post Levosimendan Infusion up until 120 hours	Mixed Model Assessment at 0, 1, 2, 4, 6, 12, 24, 48, 72, 96 and 120 hours post Levosimendan Infusion
Change in Fluid Balance	Temporal development of Fluid Balance post Levosimendan Infusion up until 120 hours	Mixed Model Assessment at 0, 1, 2, 4, 6, 12, 24, 48, 72, 96 and 120 hours post Levosimendan Infusion

Collaborators and Investigators

• Sponsor: University of Zurich
• Investigators: Principal Investigator: Marco Maggiorini, Medizinische Intensivstation D-HOER 27, UniversitatsSpital Zürich

Publications and helpful links

General Publications

• Bragadottir G, Redfors B, Ricksten SE. Effects of levosimendan on glomerular filtration rate, renal blood flow, and renal oxygenation after cardiac surgery with cardiopulmonary bypass: a randomized placebo-controlled study. Crit Care Med. 2013 Oct;41(10):2328-35. doi: 10.1097/CCM.0b013e31828e946a.
• Califf RM, Bengtson JR. Cardiogenic shock. N Engl J Med. 1994 Jun 16;330(24):1724-30. doi: 10.1056/NEJM199406163302406. No abstract available.
• van Diepen S, Katz JN, Albert NM, Henry TD, Jacobs AK, Kapur NK, Kilic A, Menon V, Ohman EM, Sweitzer NK, Thiele H, Washam JB, Cohen MG; American Heart Association Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Quality of Care and Outcomes Research; and Mission: Lifeline. Contemporary Management of Cardiogenic Shock: A Scientific Statement From the American Heart Association. Circulation. 2017 Oct 17;136(16):e232-e268. doi: 10.1161/CIR.0000000000000525. Epub 2017 Sep 18.
• Hochman JS. Cardiogenic shock complicating acute myocardial infarction: expanding the paradigm. Circulation. 2003 Jun 24;107(24):2998-3002. doi: 10.1161/01.CIR.0000075927.67673.F2. No abstract available.
• Ronco C, House AA, Haapio M. Cardiorenal syndrome: refining the definition of a complex symbiosis gone wrong. Intensive Care Med. 2008 May;34(5):957-62. doi: 10.1007/s00134-008-1017-8. Epub 2008 Feb 5.
• Papp Z, Edes I, Fruhwald S, De Hert SG, Salmenpera M, Leppikangas H, Mebazaa A, Landoni G, Grossini E, Caimmi P, Morelli A, Guarracino F, Schwinger RH, Meyer S, Algotsson L, Wikstrom BG, Jorgensen K, Filippatos G, Parissis JT, Gonzalez MJ, Parkhomenko A, Yilmaz MB, Kivikko M, Pollesello P, Follath F. Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol. 2012 Aug 23;159(2):82-7. doi: 10.1016/j.ijcard.2011.07.022. Epub 2011 Jul 23.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 30, 2011
• Primary Completion (ACTUAL): April 30, 2014
• Study Completion (ACTUAL): April 30, 2014

Study Registration Dates

• First Submitted: May 31, 2021
• First Submitted That Met QC Criteria: June 7, 2021
• First Posted (ACTUAL): June 8, 2021

Study Record Updates

• Last Update Posted (ACTUAL): June 8, 2021
• Last Update Submitted That Met QC Criteria: June 7, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Levosimendan; Inotropic Agent
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Kidney Diseases; Urologic Diseases; Myocardial Infarction; Infarction; Heart Failure; Shock; Renal Insufficiency; Acute Kidney Injury; Shock, Cardiogenic; Cardio-Renal Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Protective Agents; Cardiotonic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Simendan
• Other Study ID Numbers: Levosimendan

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No