Levosimendan Administration in Pulmonary Hypertension

Study Overview
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Brief Summary
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The aim of the study is to examine the pharmacokinetics and pharmacodynamic properties of Levosimendan in cardiac surgery patients with pulmonary hypertension and impaired right ventricular function.

Detailed Description
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Pulmonary hypertension (PH) is a pathophysiological disorder hemodynamically characterized by increased pulmonary vascular resistance and pressure. This can lead to right ventricle pressure overload and failure which is worsened by cardiopulmonary bypass (CPB) and extracorporeal circulation and is accompanied by high rates of morbidity and mortality in cardiac surgery patients. Pharmacological agents used to decrease pulmonary vascular resistance and right ventricle afterload are prostaglandins, iloprost, milrinone, nitric oxide (NO) and recently Levosimendan. These agents can be administered intravenously or via inhalation. In this study, Levosimendan will be administered in patients with pulmonary hypertension undergoing cardiac surgery. The aim of the study is to examine the pharmacokinetics and pharmacodynamic properties of Levosimendan in cardiac surgery patients with pulmonary hypertension and impaired right ventricular function. The drug will be administered in different doses to define the dose at which Levosimendan administration reduces pulmonary vascular resistance and pressure without causing significant reduction of systemic vascular resistance and pressure. The anti-inflammatory effect of the perioperative use of Levosimendan in cardiac surgery will also be studied. In this setting, 45 patients with PH caused by left sided heart disease, will be assigned into three groups: GROUP A: Administration of Levosimendan at a dosage of 3mcg/kg after anesthesia induction. GROUP B: Administration of Levosimendan at a dosage of 6mcg/kg after anesthesia induction. GROUP C: Administration of Levosimendan at a dosage of 12mcg/kg after anesthesia induction. Before and after the administration of the drug, heart function will be evaluated by hemodynamic measurements obtained by the Swan-Ganz catheter. These parameters will be heart rate (HR), blood pressure (BP), mean pulmonary arterial pressure (MPAP), central venous pressure (CVP), cardiac output (CO), pulmonary capillary wedge pressure (PCWP), cardiac index (CI), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR). Transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE) will also be used. The anti-inflammatory action of Levosimendan will also be evaluated by interleukin-6 (IL-6) measurements. This study will lead to conclusions regarding the effectiveness of Levosimendan administration in the treatment of right heart failure and PH in cardiac surgery patients.

Official Title
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Levosimendan Administration in High Risk Cardiac Surgery Patients With Pulmonary Hypertension

Conditions
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Hypertension, Pulmonary, Cardiac Failure, Pulmonary Vascular Resistance Abnormality

Intervention / Treatment
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* Drug: levosimendan at a dose of 3 mcg/kg
* Drug: levosimendan at a dose of 6 mcg/kg
* Drug: levosimendan at a dose of 12 mcg/kg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients with pulmonary hypertension due to left ventricular dysfunction based on echocardiographic diagnosis preoperatively elective cardiac surgery Exclusion Criteria: primary pulmonary hypertension thromboembolic disease chronic obstructive pulmonary disease emergency surgery redo surgery inability to consent to the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: levosimendan administration at a dose of 3 mcg/kg after anesthesia induction<br>levosimendan will be administered at a dose of 3 mcg/kg after anesthesia induction | Drug: levosimendan at a dose of 3 mcg/kg<br>* levosimendan will be administered intravenously at a dose of 3 mcg/kg after anesthesia induction<br>|
| Active Comparator: levosimendan administration at a dose of 6 mcg/kg after anesthesia induction<br>levosimendan will be administered at a dose of 6 mcg/kg after anesthesia induction | Drug: levosimendan at a dose of 6 mcg/kg<br>* levosimendan will be administered intravenously at a dose of 6 mcg/kg after anesthesia induction<br>|
| Active Comparator: levosimendan administration at a dose of 12 mcg/kg after anesthesia induction<br>levosimendan will be administered at a dose of 12 mcg/kg after anesthesia induction | Drug: levosimendan at a dose of 12 mcg/kg<br>* levosimendan will be administered intravenously at a dose of 12 mcg/kg after anesthesia induction<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change from baseline in mean pulmonary arterial pressure (MPAP) | a Swan-Ganz catheter will be used for hemodynamic measurements | 20 minutes after levosimendan administration, at the end of surgery and 2 hours after Intensive Care Unit (ICU) admission | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change from baseline in pulmonary vascular resistance (PVR) | a Swan-Ganz catheter will be used for hemodynamic measurements | 20 minutes after levosimendan administration, at the end of surgery and 2 hours after Intensive Care Unit (ICU) admission | 
| change from baseline in mean arterial pressure (MAP) | a Swan-Ganz catheter will be used for hemodynamic measurements | 20 minutes after levosimendan administration, at the end of surgery and 2 hours after Intensive Care Unit (ICU) admission | 
| change from baseline in systemic vascular resistance (SVR) | a Swan-Ganz catheter will be used for hemodynamic measurements | 20 minutes after levosimendan administration, at the end of surgery and 2 hours after Intensive Care Unit (ICU) admission | 
| change from baseline in pulmonary capillary wedge pressure (PCWP) | a Swan-Ganz catheter will be used for hemodynamic measurements | 20 minutes after levosimendan administration, at the end of surgery and 2 hours after Intensive Care Unit (ICU) admission | 
| change from baseline in cardiac output (CO) | a Swan-Ganz catheter will be used for hemodynamic measurements | 20 minutes after levosimendan administration, at the end of surgery and 2 hours after Intensive Care Unit (ICU) admission | 
| change from baseline in tricuspid annular plane systolic excursion (TAPSE) | transthoracic and transesophageal echocardiography will be used for echocardiographic measurements | 20 minutes after levosimendan administration, at the end of surgery, 2 hours after Intensive Care Unit (ICU) admission and 80 hours after levosimendan administration | 
| change from baseline in fractional area change | transthoracic and transesophageal echocardiography will be used for echocardiographic measurements | 20 minutes after levosimendan administration, at the end of surgery, 2 hours after Intensive Care Unit (ICU) admission and 80 hours after levosimendan administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pulmonary vascular resistance, pulmonary hypertension, vasodilators, cardiopulmonary bypass