Clinical trial NCT01591018: SONOlysis in Risk REduction of Symptomatic and Silent Brain infarCtions dUring Cardiac surgEry
Official title: Risk Reduction of Symptomatic and Silent Brain Infarctions During Cardiac Surgery Due to Ultrasound Activation of Endogenous Fibrinolytic System Using Transcranial Doppler Monitoring
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Coronary Artery Bypass Graft Redo
Heart Valve Diseases
Keywords: sonolysis, brain infarction, prevention, cardiac surgery
Lead sponsor: University Hospital Ostrava
Sponsor class: OTHER
Collaborators: name: Palacky University
name: Ministry of Health, Czech Republic
First posted: 2012-05-03
Enrollment: 120
Sex: ALL
Minimum age (years): 40
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The aim of the project is to demonstrate a fibrinolytic effect of sonothrombolysis (continual transcranial Doppler monitoring) using 2 MHz diagnostic probe on the reduction of risk of brain infarctions due to the activation of endogenous fibrinolytic system during cardiac surgery (CS). 120 patients indicated for CS (CABG or valve replacement) will be enrolled into the study in order to demonstrate a twenty-percent risk reduction of number and volume of brain infarctions detected using MRI examination 24 hours after CEA or CS in 5% level of significance. Patients will be randomized - subgroup 1 will undergo a 40-240minute non-diagnostic TCD monitoring during CS, subgroup 2 will undergo interventions without TCD monitoring.

The aim of the project is a concordance with the aim No 1 of the Resort Program of a Research and Development: "Improvement of quality of life of patients using the modern therapeutic methods but with relative small positive effect of quality of life". The aim of the project is in concordance with a priority of announced public grant competition: "Development of the new therapeutic methods of cardiovascular disorders, especially coronary heart disease and stroke". Confirmation of our hypothesis that sonothrombolysis is able to activate endogenous fibrinolytic system during CS with consecutive reduction of the number and volume of brain infarcts, can lead to the increase of the safety of CS in patients. We can presume that up to 50% of patients indicated for CS can be treated using these methods in the future.

Detailed description: AIM OF THE PROJECT The aim of the project is to demonstrate an effect of continual TCD monitoring using 2 MHz diagnostic probe with maximal diagnostic energy on the reduction of risk of brain microinfarctions due to the activation of endogenous fibrinolytic system and mechanical effect on emboli during CS.

The aim of the project is a concordance with the aim No 1 of the Resort program of a research and development in the years 2010-2015: "Improvement of quality of life of patients using the modern therapeutic methods but with relative small positive effect of quality of life". The aim of the project is in concordance with a priority of announced public grant competition: "Development of the new therapeutic methods of cardiovascular disorders, especially coronary heart disease and stroke".

HYPOTHESIS Sonothrombolysis lead to activation of fibrinolytic system in both healthy volunteers and acute stroke patients. In acute stroke patients, mechanical effect of sonothrombolysis is the second effect leading to acceleration of occluded artery recanalization. We hypothesize that combination of mechanical effect and activation of fibrinolytic system durin sonothrombolysis (TCD monitoring) during CS will lead to recanalization of small arterial occlusions caused by microembolization during intervention. The result will be reduction of volume and the number of brain infarctions in the territory of the monitored MCA.

120 patients indicated for CS will be enrolled into the study in order to demonstrate a twenty-percent risk reduction of number and volume of brain infarctions in the territory of athe monitored MCA detected using MRI examination 24 hours after CS in 5% level of statistical significance. Patients will be randomized into 2 subgroups. Subgroup 1 will undergo non-diagnostic TCD monitoring during CS. Subgroup 2 will undergo CS without TCD monitoring.

PATIENTS AND METHODS Patients: 120 patients indicated for CS (isolated coronary artery bypass surgery or isolated heart valve surgery) will be enrolled into the study during a 3-year period. All 120 patients will be randomized for standard CS and TCD monitored CS.

Clinical examinations: Physical and neurological examinations including evaluating of neurological impairment of neurological deficit in NIHSS scale, modified Rankin scale and cognitive testing (Mini Mental State Examination, Clock drawing test) will be performed before and 24 - 72 hours after CS.

Randomization: Randomization using computer generated random allocation will be used, separately for coronary artery bypass surgery and valve surgery patients.

Sonothrombolysis: In patients randomized into sonothrombolysis subgroup, MCA segment in depth 55 mm will be monitored for 40 - 240 minutes using a diagnostic 2 MHz probe with maximal diagnostic energy. Non-diagnostic TCD monitoring will be performed without detection of microembolic signals or detection of changes in blood flow. The second (control) subgroup will undergo a standard CS without sonothrombolysis.

MRI protocol will consists of 4 sequences: 1. Localizer; 2. T2TSE; 3. FLAIR; 4. DWI. Sequences 1-3 will be applied in the same level, they will have the same slice thickness and the same cut number. The slice thickness comprises its own cut thickness (5 mm) + distant factor (30%). Standard number of slices is 19. Standard slice level is considered to be a modified level of skull base due to the minimalization of distant artifacts EPI sequence. T2TSE: TR=4000/TE=99/ETL=9, FOV 230, FOV ph. 75%, matrix 256x256. FLAIR: 8050/112/ETL=21/2 conc., FOV 230, FOV ph. 76,6%, matrix 256x151. EPI-DWI: 4200/139/EPI f.=96/6 av., FOV 230, FOV ph. 100%, phase enc. direction A-P, matrix 128x96 with interpolation, phase partial Fourier 6/8, Bw 1346 Hz/Px, echo spacing 0.83 ms, TA. Sequence called "trace" with three types of MR pictures in every slice: (a) T2\*EPI b=0; (b) DWI b=500; (c) DWI b=1000. The fourth type of images automatically created an ADC map (in-line postprocessing). DWI show a middle (average) diffusivity of every point of examined brain tissue when b value is 500 and 1000. This sequence is applied in order to assess hemorrhage (T2\*EPI) and monitor sites of reduced diffusion (DWI, b=500 and 1000). New infarctions will be evaluated only in the territory of treated ICA.

Adverse effects: All adverse effects during 1 month after UM will be registered, especially all causes for new admissions to the hospital, worsening of neurological symptoms (\>4 points in NIH stroke scale), brain edema, symptomatic and asymptomatic intracranial bleeding detected in control brain MRI.

Study protocol has been approved by the Ethics Committees in accordance with the principles and guidelines of the Declaration of Helsinki, 1975.

Eligibility criteria: Inclusion Criteria:

* age 40-90 years,
* sufficient temporal bone window for TCD with detectable blood flow in MCA,
* independent patient (modified Rankin score 0-2),
* informed consent signed by the patient,
* CS will be performed as an elective surgery with an extracorporeal circulation

Exclusion Criteria:

* contra-indication for MRI examination (pace-maker, implanted metal material, claustrophobia),
* emergent surgery,
* acute myocardial infarction,
* combined cardiac surgery,
* combined cardiac and carotid surgery

Primary outcomes:
measure: Number od Participants With New Brain Infarction in the Monitored MCA Territory Detected Using MRI
timeFrame: 24 hours after intervention
Secondary outcomes:
measure: Cognitive Decline
timeFrame: 30 days after intervention
measure: Number of Participants With Clinical Manifested Brain Infarction
timeFrame: 30 days after intervention
Other outcomes:
Locations:
city: Ostrava
country: Czechia
facility: University Hospital Ostrava
state: Czech Republic
Study officials:
affiliation: University Hospital Ostrava
name: David Skoloudik, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Skoloudik D, Hurtikova E, Brat R, Herzig R; SONORESCUE Trial Group. Sonolysis in Prevention of Brain Infarction During Cardiac Surgery (SONORESCUE): Randomized, Controlled Trial. Medicine (Baltimore). 2016 May;95(20):e3615. doi: 10.1097/MD.0000000000003615.