Rheo-Erythrocrine Dysfunction as a Biomarker for RIC Treatment in Acute Ischemic Stroke (ENOS)

Grethe Andersen

Status: Completed

Conditions: Ischemic Stroke; Central Nervous System Diseases; Stroke, Acute; Cerebrovascular Disorders

Treatments: Device: Remote Ischemic Conditioning; Device: Sham Remote Ischemic Conditioning

Study type: Interventional

Funder types: Other

Identifiers

NCT04266639

ENOS

Details and patient eligibility

About

This study aims to investigate whether Remote Ischemic Conditioning (RIC) improves rheo-erythrocrine dysfunction in acute ischemic stroke

Full description

Stroke is a leading cause of death and disability worldwide. Of all strokes, 85% are ischemic strokes caused by a thrombus or an embolus. The additional 15% are caused by hemorrhage. Currently the only approved treatments for ischemic strokes are thrombolysis given within 4.5 hours and thrombectomy performed within 6 hours of symptom onset - in some cases up to 24 hours. The majority of stroke patients are not however eligible for acute reperfusion therapy, mainly due to time constrains and late presentation. Novel neuroprotective strategies available for all stroke patients are thus urgently needed.

Remote Ischemic Conditioning (RIC) is a simple intervention in which transient ischemia is induced in an extremity by repetitive inflation-deflation of a blood pressure cuff. It remains uncertain exactly how the protective effect of RIC is transmitted and communicated between the extremity and the brain. Both humoral, immunological and neuronal pathways seem to be involved. Treatment with RIC and has proven to be a safe, feasible and low-cost treatment in clinical settings.

Biomarkers of the RIC treatment is a new area of stroke research and are important to establish in order to assess and predict responders of the conditioning treatment. Rheo-erythrocrine dysfunction of the Red Blood Cell (RBC) is a novel biomarker in both ischemic strokes in general and on the effect of RIC. Red Blood Cells with a diameter of 6-8 μm must be highly deformable in order to deliver oxygen to brain tissue by travelling through micro vessels with a diameter of just 2-3 μm. RBC's can carry nitric oxide as NO2-/s-nitrosylated proteins. These proteins improve RBC deformability and induce hypoxic vasodilation thereby improving passage through the microvasculature. RBC's also express Erythrocyte Nitric Oxide Synthase 3, which regulate the rheo-erythrocrine function. Erythrocyte Nitric Oxide Synthase 3 is activated by shear stress and provide an extra source of NO for hypoxic vasodilation. Preliminary data have shown that experimental stroke on mice seems to cause a rheo-erythrocrine dysfunction of the RBC's leading to a loss of deformability. The RBC's become rigid, which can lead to occlusion of micro vessels in the brain and further ischemic damage. Loss of deformability can be measured as a reduced Elongation Index (EI) by ektacytometry and may be attenuated by RIC.

Enrollment: 45 patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

STROKE PATIENTS

Inclusion Criteria:

• Onset to randomization < 48 hours
• Independent in daily living (mRS 0-2)
• Legal competent
• Ambulatory
• Documented ischemic stroke on baseline MRI

Exclusion Criteria:

• Prior stroke, dementia or other known neurological condition Pregnancy
• Contraindications to MRI
• Investigators discretion
• Known upper extremity peripheral arterial stenosis Diabetes

CONTROLS

Inclusion Criteria:

• Independent in daily living (mRS 0-2) Ambulatory
• Legal competent
• Non vascular diagnosis (e.g. epilepsy, migraine etc.)

Exclusion Criteria

• Prior stroke, dementia or other known neurological condition
• Pregnancy
• Contraindications to MRI
• Investigators discretion
• Known upper extremity peripheral arterial stenosis Diabetes

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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45 participants in 3 patient groups

Remote Ischemic Conditioning

Active Comparator group

Description:

Remote Ischemic Conditioning (RIC) is applied during the in-hospital phase using an automated RIC device. Treatment characteristics: Five cycles (50 minutes), each consisting of five minutes of cuff inflation followed by five minutes of cuff deflation. The cuff pressure will be 200 mmHg; if initial systolic blood pressure is above 175 mmHg, the cuff is automatically inflated to 35 mmHg above the systolic blood pressure. * Initial Remote Ischemic Conditioning: \< 2 hours from inclusion * Remote Ischemic Postconditioning: twice daily for 7 days Usual care with or without acute reperfusion therapy

Treatment:

Device: Remote Ischemic Conditioning

Sham - Remote Ischemic Conditioning

Sham Comparator group

Description:

Sham Remote Ischemic Conditioning (Sham-RIC) is applied during the in-hospital phase using an automated Sham-RIC device. Treatment characteristics: Five cycles (50 minutes), each consisting of five minutes of cuff inflation followed by five minutes of cuff deflation. The cuff pressure will be always be 20 mmHg. * Initial Sham Remote Ischemic Conditioning: \< 2 hours from inclusion * Sham Remote ischemic Postconditioning: twice daily for 7 days Usual care with or without acute reperfusion therapy.

Treatment:

Device: Sham Remote Ischemic Conditioning

Controls

No Intervention group

Description:

The control group will not receive treatment with Remote Ischemic Conditioning.