Clinical trial NCT04599816: Levosimendan Administration in Pulmonary Hypertension
Official title: Levosimendan Administration in High Risk Cardiac Surgery Patients With Pulmonary Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Hypertension, Pulmonary
Cardiac Failure
Pulmonary Vascular Resistance Abnormality
Keywords: pulmonary vascular resistance
pulmonary hypertension
vasodilators
cardiopulmonary bypass
Lead sponsor: Aretaieion University Hospital
Sponsor class: OTHER
First posted: 2020-10-23
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: change from baseline in mean pulmonary arterial pressure (MPAP)
timeFrame: 20 minutes after levosimendan administration, at the end of surgery and 2 hours after Intensive Care Unit (ICU) admission
Secondary outcomes:
measure: change from baseline in pulmonary vascular resistance (PVR)
timeFrame: 20 minutes after levosimendan administration, at the end of surgery and 2 hours after Intensive Care Unit (ICU) admission
measure: change from baseline in mean arterial pressure (MAP)
timeFrame: 20 minutes after levosimendan administration, at the end of surgery and 2 hours after Intensive Care Unit (ICU) admission
measure: change from baseline in systemic vascular resistance (SVR)
timeFrame: 20 minutes after levosimendan administration, at the end of surgery and 2 hours after Intensive Care Unit (ICU) admission
measure: change from baseline in pulmonary capillary wedge pressure (PCWP)
timeFrame: 20 minutes after levosimendan administration, at the end of surgery and 2 hours after Intensive Care Unit (ICU) admission
measure: change from baseline in cardiac output (CO)
timeFrame: 20 minutes after levosimendan administration, at the end of surgery and 2 hours after Intensive Care Unit (ICU) admission
measure: change from baseline in tricuspid annular plane systolic excursion (TAPSE)
timeFrame: 20 minutes after levosimendan administration, at the end of surgery, 2 hours after Intensive Care Unit (ICU) admission and 80 hours after levosimendan administration
measure: change from baseline in fractional area change
timeFrame: 20 minutes after levosimendan administration, at the end of surgery, 2 hours after Intensive Care Unit (ICU) admission and 80 hours after levosimendan administration
Other outcomes:
measure: change from baseline in blood levels of levosimendan
timeFrame: 20 minutes, 6 hours, 12 hours, 24 hours and 80 hours after administration
measure: change from baseline in blood levels of interleukin-6 (IL-6)
timeFrame: end of surgery, 6 hours, 12 hours and 24 hours after Intensive Care Unit (ICU) admission
Locations:
city: Athens
country: Greece
facility: Onassis Cardiac Surgery Center
Study officials:
affiliation: Aretaieion University Hospital
name: Kassiani Theodoraki, PhD, DESA
role: PRINCIPAL_INVESTIGATOR
References:
citation: Theodoraki K, Rellia P, Thanopoulos A, Tsourelis L, Zarkalis D, Sfyrakis P, Antoniou T. Inhaled iloprost controls pulmonary hypertension after cardiopulmonary bypass. Can J Anaesth. 2002 Nov;49(9):963-7. doi: 10.1007/BF03016884.
citation: Theodoraki K, Thanopoulos A, Rellia P, Leontiadis E, Zarkalis D, Perreas K, Antoniou T. A retrospective comparison of inhaled milrinone and iloprost in post-bypass pulmonary hypertension. Heart Vessels. 2017 Dec;32(12):1488-1497. doi: 10.1007/s00380-017-1023-2. Epub 2017 Jul 17.
citation: Haddad F, Couture P, Tousignant C, Denault AY. The right ventricle in cardiac surgery, a perioperative perspective: II. Pathophysiology, clinical importance, and management. Anesth Analg. 2009 Feb;108(2):422-33. doi: 10.1213/ane.0b013e31818d8b92.
citation: Hansen MS, Andersen A, Nielsen-Kudsk JE. Levosimendan in pulmonary hypertension and right heart failure. Pulm Circ. 2018 Jul-Sep;8(3):2045894018790905. doi: 10.1177/2045894018790905. Epub 2018 Jul 6.
citation: Boost KA, Hoegl S, Dolfen A, Czerwonka H, Scheiermann P, Zwissler B, Hofstetter C. Inhaled levosimendan reduces mortality and release of proinflammatory mediators in a rat model of experimental ventilator-induced lung injury. Crit Care Med. 2008 Jun;36(6):1873-9. doi: 10.1097/CCM.0b013e3181743e63.
citation: Kundra TS, Nagaraja PS, Bharathi KS, Kaur P, Manjunatha N. Inhaled levosimendan versus intravenous levosimendan in patients with pulmonary hypertension undergoing mitral valve replacement. Ann Card Anaesth. 2018 Jul-Sep;21(3):328-332. doi: 10.4103/aca.ACA_19_18.
citation: Elhassan A, Essandoh M. Inhaled Levosimendan for Pulmonary Hypertension Treatment During Cardiac Surgery: A Novel Application to Avoid Systemic Hypotension. J Cardiothorac Vasc Anesth. 2019 Apr;33(4):1169-1170. doi: 10.1053/j.jvca.2018.11.039. Epub 2018 Nov 28. No abstract available.
citation: Zhang J, Gage EM, Ji QC, El-Shourbagy TA. A strategy for high-throughput analysis of levosimendan and its metabolites in human plasma samples using sequential negative and positive ionization liquid chromatography/tandem mass spectrometric detection. Rapid Commun Mass Spectrom. 2007;21(14):2169-76. doi: 10.1002/rcm.3046.