Diastolic Dysfunction, Left Ventricular Hypertrophy
Conditions
Keywords
levosimendan, heart failure, inotropics, diastolic dysfunction, left ventricular hypertrophy, aortic valve stenosis
Brief summary
This is a clinical, randomised, double-blinded study in which patients eligible for aortic valve replacement are enrolled. Patients receive infusion of either levosimendan or placebo 4 hours prior to surgery and until the end of surgery.
Detailed description
Levosimendan or placebo will be infusion for approximately 4 hours prior to aortic valve replacement in patients with severe hypertrophy of the left ventricle and echocardiographic signs of diastolic dysfunction. Outcome measures will be obtained at some of the following: * Approximately 4 hours prior to surgery. Baseline. Start of levosimendan/placebo infusion * Immediately before surgery * After induction of anaesthesia and before knife time = start of surgery. * At the end of surgery: Levosimendan infusion will stop. * Approximately 4 hours after surgery immediately before extubation. * Approximately 21 hours after surgery * Approximately 96 hours after surgery (day 4) * 6 months after surgery Outcome measures are comprised of invasive measurements, blood samples, transthoracic echocardiography and transoesophageal echocardiography focusing on measures of systolic and diastolic function of the heart. Interim analysis will be conducted after 30 included patients.
Interventions
DRUGlevosimendan
Intravenous infusion, 0,1ug/kg/min, duration 4 hours prior to operation and until the end of operation.
DRUGplacebo drug
Intravenous infusion, colour identical to levosimendan
Sponsors
University of Aarhus
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Eligible for aortic valve replacement * EF \> 45% * Left ventricular posterior wall \> 12mm * Sinus rhythm
Exclusion criteria
* Concomitant bypass operation * Severe mitral insufficiency * Active endocarditis * Insufficient ultrasound opportunity * Systolic blood pressure \< 100 mmHg * moderate-severe renal failure * allergy to levosimendan * lack of patient consent Pregnancy or status of lactating * Fertile women who do not use relevant anticonception
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| E/E'(Unitless) | 4 hours before operation until 21 hour after operation | Ration between early transmitral flow (E) and mitral annular tissue velocity(E'). This ratio is an echocardiographic index of diastolic function |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Isovolumetric Relaxation Time (IVRT) (s) | 4 hours before surgery until 1 hour before operation | Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function |
| Ejection Fraction (Per Cent) | At start of operation until end of operation, approximately 3 hours | Transeosophageal echocardiography: Measure of systolic function |
| Cardiac Index (l/Min/m2) | 4 hours before operation until 1 hour before operation | Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula) |
| Central Venous Pressure (mmHg) | 4 hours before operation until 1 hours before operation | Invasive measurement of pressure in the vena cava |
| Pulmonary Artery Pressures (mmHg) | 4 hours before operation until 1 hour before operation | Invasive measurement of mean pressure in the pulmonary artery |
| Systemic Arterial Pressure (mmHg) | 4 hours before operation until 1 hour before operation | Invasive measurements of arterial mean pressure |
| N-terminal Pro Brain Natriuretic Peptide (NT proBNP)(pg/ml) | 4 hours before operation until 4 hours after operation | blood sample reflecting stretch of the atrium/ventricle |
| Troponin T (ug/l) | 4 hours before operation until 4 hours after operation | Blood sample expressing damage to the myocytes |
| Lactate (mmol/l) | 4 hours before operation until 4 hour after operation | Arterial sampling of blood lactate |
| Mixed Venous Oxygenation (Per Cent) | 4 hours before operation until 4 hour after operation | Oxygen content (per cent of hemoglobin saturated) of venous blood in pulmonary artery |
| E/A Ratio (Unitless) | At the start of operation until the end of operationon, approximately 3 hours | TEE ratio between early (E) transmitral flow and late (A) transmitral flow. An index of diastolic function althought not validated properly yet when measured from the oesophagus |
| Regional Longitudinal Strain (Unitless) | At the start of operation until the end of operation, approximately 3 hours | Transoesophageal echocardiographic (TEE) measure of systolic function. At this time not validated properly against acknowledged indices of systolic function. |
| Need for Conventional Inotropical Agents | From start of operation until 5 days after operation | Conventional inotropics are comprised of all inotropics acting primarily through alfa- or beta- stimulation. |
| Intravenous Fluid Requirement (l) | Within 24 hours from start of operation | Total volume of intravenous fluid required including blood products. |
| No. of Patients With Adverse Event | -4 hours until + 96 hours with respect to start of operation | Development of atrial flutter/fibrillation |
| Time on Heart-lung Machine (Minutes) | From time of cardioplegia until selfsufficient cardiac action, approximately 1 hour | — |
| Intubation Time (Minutes) | From intubation until extubation, approximately 6 hours | Total time intubated including time of operation and in the intensive care ward |
| Postoperative Admission Time at Intensive Care Unit (Hours) | From admission to the intensive care unit until discharge from intensive care unit, approximately 24 hours | Total admission time in the intensive care after operation |
| No. of Patients With Adverse Events | -4 hours until + 96 hours with respect to start of operation | Development of Ventricular tachycardia |
| No. of Patients With Adverse Event. | 4 hours before operation until 1 hour before operation | Occurence of nausea |
| Left Ventricular Rotation (Degrees) | 96 hour after operation until 6 months after operation | TTE: Index of both systolic and diastolic function |
| Peak Systolic Velocity (m/s) | 1 hour before operation until 21 hours after operation | Tissue Doppler measure of systolic function |
| Tricuspid Annular Plane Systolic Excursion (TAPSE) (mm) | 1 hour before operation until 21 hours after operation | Transthoracic echocardiographic measure of systolic function |
| E/A-ratio (Unitless) | 1 hour before operation until 21 hours after operation | Transthoracic echocardiographic ratio between early (E) and late (A) transmitral blood velocities. Index of diastolic function. |
| E'/A'-Ratio (Unitless) | 1 hour before operation until 21 hours after roperation | Tissue Doppler transthoracic echocardiography: Ratio between tissue velocities at the mitral plan during early (E) diastole and late (A) diastole. Index of diastolic function. |
| Inflammatory Parameters | 4 hours before operation until 21 hours after operation | Blood sample values of pro- and antiinflammatory mediators |
| E/A-ratio (Transoesophageal) | from start of operation until end of operation, approximately 3 hours | Transoesophageal echocardiographic measure of diastolic heart function |
| Urine Clearance | from start of operation until 24 hours after operation | Urine analysis. Measure of kidney function. |
| Operation Time (Minutes) | From knife start until knife end, approximately 3 hours | — |
Countries
Denmark
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Levosimendan infusion 0,1ug/kg/min for duration of ca. 4 hours prior to operation and until the end of operation
levosimendan: Intravenous infusion, 0,1ug/kg/min, duration 4 hours prior to operation and until the end of operation. | 10 |
| Placebo Identical placebo
placebo drug: Intravenous infusion, colour identical to levosimendan | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Levosimendan | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 76 years | 73 years | 74 years |
| Region of Enrollment Denmark | 10 participants | 10 participants | 10 participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 7 Participants |
| Sex: Female, Male Male | 8 Participants | 5 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 10 | 6 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
E/E'(Unitless)
Ration between early transmitral flow (E) and mitral annular tissue velocity(E'). This ratio is an echocardiographic index of diastolic function
Time frame: 4 hours before operation until 21 hour after operation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levosimendan | E/E'(Unitless) | 12.6 Unitless |
| Placebo | E/E'(Unitless) | 13.7 Unitless |
Secondary
Cardiac Index (l/Min/m2)
Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)
Time frame: Start of operation until end of operation, approximately 3 hours
Secondary
Cardiac Index (l/Min/m2)
Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)
Time frame: 1 hour before operation until start of operation
Secondary
Cardiac Index (l/Min/m2)
Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)
Time frame: 4 hours after operation until 21 hours after operation
Secondary
Cardiac Index (l/Min/m2)
Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)
Time frame: End of operation operation until approx. 4 hours after operation
Secondary
Cardiac Index (l/Min/m2)
Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)
Time frame: 4 hours before operation until 1 hour before operation
Secondary
Central Venous Pressure (mmHg)
Invasive measurement of pressure in the vena cava
Time frame: 4 hours before operation until 1 hours before operation
Secondary
Central Venous Pressure (mmHg)
Invasive measurement of pressure in the vena cava
Time frame: 4 hours after operation until 21 hours after operation
Secondary
Central Venous Pressure (mmHg)
Invasive measurement of pressure in the vena cava
Time frame: Start of operation until end of operation, approximately 3 hours
Secondary
Central Venous Pressure (mmHg)
Invasive measurement of pressure in the vena cava
Time frame: 1 hour before operation until start of operation
Secondary
Central Venous Pressure (mmHg)
Invasive measurement of pressure in the vena cava
Time frame: End of operation until approx 4 hours after operation
Secondary
E/A-ratio (Transoesophageal)
Transoesophageal echocardiographic measure of diastolic heart function
Time frame: from start of operation until end of operation, approximately 3 hours
Secondary
E/A-ratio (Transoesophageal)
Transoesophageal echocardiographic measure of diastolic heart function
Time frame: from end of operation until approximately 4 hours after operation
Secondary
E/A-ratio (Unitless)
Transthoracic echocardiographic ratio between early (E) and late (A) transmitral blood velocities. Index of diastolic function.
Time frame: 1 hour before operation until 21 hours after operation
Secondary
E/A-ratio (Unitless)
Transthoracic echocardiographic ratio between early (E) and late (A) transmitral blood velocities. Index of diastolic function.
Time frame: 96 hours after operation until 6 months after operation
Secondary
E/A-ratio (Unitless)
Transthoracic echocardiographic ratio between early (E) and late (A) transmitral blood velocities. Index of diastolic function.
Time frame: 21 hours after operation until 96 hours after operation
Secondary
E/A Ratio (Unitless)
TEE ratio between early (E) transmitral flow and late (A) transmitral flow. An index of diastolic function althought not validated properly yet when measured from the oesophagus
Time frame: At the end of operationon until approx 4 hours after operation
Secondary
E/A Ratio (Unitless)
TEE ratio between early (E) transmitral flow and late (A) transmitral flow. An index of diastolic function althought not validated properly yet when measured from the oesophagus
Time frame: At the start of operation until the end of operationon, approximately 3 hours
Secondary
E'/A'-Ratio (Unitless)
Tissue Doppler transthoracic echocardiography: Ratio between tissue velocities at the mitral plan during early (E) diastole and late (A) diastole. Index of diastolic function.
Time frame: 1 hour before operation until 21 hours after roperation
Secondary
E'/A'-Ratio (Unitless)
Tissue Doppler transthoracic echocardiography: Ratio between tissue velocities at the mitral plan during early (E) diastole and late (A) diastole. Index of diastolic function.
Time frame: 21 hours after operation until 96 hours after operation
Secondary
E'/A'-Ratio (Unitless)
Tissue Doppler transthoracic echocardiography: Ratio between tissue velocities at the mitral plan during early (E) diastole and late (A) diastole. Index of diastolic function.
Time frame: 96 hours after operation until 6 months after operation
Secondary
Ejection Fraction (Per Cent)
TTE: Index of systolic function
Time frame: 1 hour before until 21 hour after start of operation
Secondary
Ejection Fraction (Per Cent)
Transeosophageal echocardiography: Measure of systolic function
Time frame: End of operation until approx. 4 hours after operation
Secondary
Ejection Fraction (Per Cent)
TTE: Index of systolic function
Time frame: 96 hours after operation until 6 months after operation
Secondary
Ejection Fraction (Per Cent)
TTE: Index of systolic function
Time frame: 21 hours after operation until 96 hours after start of operation
Secondary
Ejection Fraction (Per Cent)
Transeosophageal echocardiography: Measure of systolic function
Time frame: At start of operation until end of operation, approximately 3 hours
Secondary
Inflammatory Parameters
Blood sample values of pro- and antiinflammatory mediators
Time frame: 4 hours before operation until 21 hours after operation
Secondary
Inflammatory Parameters
Blood sample values of pro- and antiinflammatory mediators
Time frame: 21 hours after operation until 96 hours after operation
Secondary
Intravenous Fluid Requirement (l)
Total volume of intravenous fluid required including blood products.
Time frame: Within 24 hours from start of operation
Secondary
Intubation Time (Minutes)
Total time intubated including time of operation and in the intensive care ward
Time frame: From intubation until extubation, approximately 6 hours
Secondary
Isovolumetric Relaxation Time (IVRT) (s)
Transeosophageal echocardiography: Time from closure of aortic valve to opening of mitral valve. Measure of diastolic function.
Time frame: End of operation until approx. 4 hours after operation
Secondary
Isovolumetric Relaxation Time (IVRT) (s)
Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function
Time frame: 96 hours after operation until 6 months after operation
Secondary
Isovolumetric Relaxation Time (IVRT) (s)
Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function
Time frame: 21 hours after operation until 96 hours after operation
Secondary
Isovolumetric Relaxation Time (IVRT) (s)
Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function
Time frame: 1 hour before operation until 21 hours after operation
Secondary
Isovolumetric Relaxation Time (IVRT) (s)
Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function
Time frame: 4 hours before surgery until 1 hour before operation
Secondary
Lactate (mmol/l)
Arterial sampling of blood lactate
Time frame: 4 hours after operation until 21 hours after operation
Secondary
Lactate (mmol/l)
Arterial sampling of blood lactate
Time frame: 4 hours before operation until 4 hour after operation
Secondary
Left Ventricular Rotation (Degrees)
TTE: Index of both systolic and diastolic function
Time frame: 96 hour after operation until 6 months after operation
Secondary
Mixed Venous Oxygenation (Per Cent)
Oxygen content (per cent of hemoglobin saturated) of venous blood in pulmonary artery
Time frame: 4 hours after operation until 21 hours after operation
Secondary
Mixed Venous Oxygenation (Per Cent)
Oxygen content (per cent of hemoglobin saturated) of venous blood in pulmonary artery
Time frame: 4 hours before operation until 4 hour after operation
Secondary
Need for Conventional Inotropical Agents
Conventional inotropics are comprised of all inotropics acting primarily through alfa- or beta- stimulation.
Time frame: From start of operation until 5 days after operation
Secondary
No. of Patients With Adverse Event
Development of atrial flutter/fibrillation
Time frame: -4 hours until + 96 hours with respect to start of operation
Secondary
No. of Patients With Adverse Event
Occurence of headache
Time frame: 4 hours before operation until approximately 1 hour before operation
Secondary
No. of Patients With Adverse Event
Need for norepinephrine as an antagonist to the vasodilatatory effect of levosimendan
Time frame: 4 hours before operaton until 1 hour before operaton
Secondary
No. of Patients With Adverse Event.
Occurence of nausea
Time frame: 4 hours before operation until 1 hour before operation
Secondary
No. of Patients With Adverse Events
Development of Ventricular tachycardia
Time frame: -4 hours until + 96 hours with respect to start of operation
Secondary
N-terminal Pro Brain Natriuretic Peptide (NT proBNP)(pg/ml)
blood sample reflecting stretch of the atrium/ventricle
Time frame: 4 hours after operation until 21 hours after operation
Secondary
N-terminal Pro Brain Natriuretic Peptide (NT proBNP)(pg/ml)
blood sample reflecting stretch of the atrium/ventricle
Time frame: 4 hours before operation until 4 hours after operation
Secondary
N-terminal Pro Brain Natriuretic Peptide (NT proBNP)(pg/ml)
blood sample reflecting stretch of the atrium/ventricle
Time frame: 21 hours after operation until 96 hours after operation
Secondary
Operation Time (Minutes)
Time frame: From knife start until knife end, approximately 3 hours
Secondary
Peak Systolic Velocity (m/s)
Tissue Doppler measure of systolic function
Time frame: 96 hours after operation until 6 months after operation
Secondary
Peak Systolic Velocity (m/s)
Tissue Doppler measure of systolic function
Time frame: 21 hours after operation until 96 hours after operation
Secondary
Peak Systolic Velocity (m/s)
Tissue Doppler measure of systolic function
Time frame: 1 hour before operation until 21 hours after operation
Secondary
Postoperative Admission Time at Intensive Care Unit (Hours)
Total admission time in the intensive care after operation
Time frame: From admission to the intensive care unit until discharge from intensive care unit, approximately 24 hours
Secondary
Pulmonary Artery Pressures (mmHg)
Invasive measurement of mean pressure in the pulmonary artery
Time frame: 4 hours after operation until 21 hours after operation
Secondary
Pulmonary Artery Pressures (mmHg)
Invasive measurement of mean pressure in the pulmonary artery
Time frame: 4 hours before operation until 1 hour before operation
Secondary
Pulmonary Artery Pressures (mmHg)
Invasive measurement of mean pressure in the pulmonary artery
Time frame: 1 hour before operation until start of operation
Secondary
Pulmonary Artery Pressures (mmHg)
Invasive measurement of mean pressure in the pulmonary artery
Time frame: Start of operation until end of operation, approximately 3 hours
Secondary
Pulmonary Artery Pressures (mmHg)
Invasive measurement of mean pressure in the pulmonary artery
Time frame: End of operation until approx 4 hours after operation
Secondary
Regional Longitudinal Strain (Unitless)
Transoesophageal echocardiographic (TEE) measure of systolic function. At this time not validated properly against acknowledged indices of systolic function.
Time frame: Froml the end of operation until approx 4 hours after operation
Secondary
Regional Longitudinal Strain (Unitless)
Index of systolic function derived from single transthoracic echocardiographic (TTE) projection
Time frame: 96 hours after operation until 6 months after operation
Secondary
Regional Longitudinal Strain (Unitless)
Index of systolic function derived from single transthoracic echocardiographic (TTE) projection
Time frame: 21 hours after operation until 96 hours after operation
Secondary
Regional Longitudinal Strain (Unitless)
Index of systolic function derived from single transthoracic echocardiographic (TTE) projection
Time frame: 4 hours before until 1 hour before start of operation
Secondary
Regional Longitudinal Strain (Unitless)
Transoesophageal echocardiographic (TEE) measure of systolic function. At this time not validated properly against acknowledged indices of systolic function.
Time frame: At the start of operation until the end of operation, approximately 3 hours
Secondary
Regional Longitudinal Strain (Unitless)
Index of systolic function derived from single transthoracic echocardiographic (TTE) projection
Time frame: 1 hour before start of operation until 21 hours after operation
Secondary
Systemic Arterial Pressure (mmHg)
Invasive measurements of arterial mean pressure
Time frame: 4 hours after operation until 21 hours after operation
Secondary
Systemic Arterial Pressure (mmHg)
Invasive measurements of arterial mean pressure
Time frame: 1 hour before operation until start of operation
Secondary
Systemic Arterial Pressure (mmHg)
Invasive measurements of arterial mean pressure
Time frame: 4 hours before operation until 1 hour before operation
Secondary
Systemic Arterial Pressure (mmHg)
Invasive measurements of arterial mean pressure
Time frame: End of operation until approx 4 hours after operation
Secondary
Systemic Arterial Pressure (mmHg)
Invasive measurements of arterial mean pressure
Time frame: Start of operation until the end of operation, approximately 3 hours
Secondary
Time on Heart-lung Machine (Minutes)
Time frame: From time of cardioplegia until selfsufficient cardiac action, approximately 1 hour
Secondary
Tricuspid Annular Plane Systolic Excursion (TAPSE) (mm)
Transthoracic echocardiographic measure of systolic function
Time frame: 1 hour before operation until 21 hours after operation
Secondary
Tricuspid Annular Plane Systolic Excursion (TAPSE) (mm)
Transthoracic echocardiographic measure of systolic function
Time frame: 21 hours after operation until 96 hours after operation
Secondary
Tricuspid Annular Plane Systolic Excursion (TAPSE) (mm)
Transthoracic echocardiographic measure of systolic function
Time frame: 96 hours after operation until 6 months after operation
Secondary
Troponin T (ug/l)
Blood sample expressing damage to the myocytes
Time frame: 4 hours after operation until 21 hours after operation
Secondary
Troponin T (ug/l)
Blood sample expressing damage to the myocytes
Time frame: 21 hours after operation until 96 hours after operation
Secondary
Troponin T (ug/l)
Blood sample expressing damage to the myocytes
Time frame: 4 hours before operation until 4 hours after operation
Secondary
Urine Clearance
Urine analysis. Measure of kidney function.
Time frame: from start of operation until 24 hours after operation