Effect of Remote Ischemic Conditioning on Trauma Patients With Hemorrhagic Shock

Study Overview
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Brief Summary
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The purpose of the study is to evaluate whether remote ischemic conditioning is a safe and effective intervention to prevent the development of inflammation and coagulopathy in trauma patients with hemorrhagic shock.

Detailed Description
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Dysfunction of vital organs is one of the major reasons why trauma victims die after sustaining a major injury, even though the organs themselves may not have been directly injured. The inability to clot blood as a result of inflammation further contributes to complications in a majority of these patients. One intervention proposed to protect against impaired organ function is called Remote Ischemic Conditioning, wherein application of intermittent occlusion and release of blood flow to the arm by sequentially inflating and deflating a blood pressure cuff can protect against the development of distant organ injury and inflammation following a severe traumatic event. In a pilot study, we will investigate the effects of remote ischemic conditioning in trauma patients with hemorrhagic shock, with a view to evaluate its effects on the immune system and coagulation profiles, both of which are known to be deranged in these patients. These studies will potentially benefit patients and will serve as a proof of principle for the use of remote ischemic conditioning in the trauma setting.

Official Title
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Effect of Remote Ischemic Conditioning on Neutrophil Function and the Immune-Inflammatory and Coagulation Profiles in Trauma Patients With Hemorrhagic Shock

Conditions
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Hemorrhagic Shock

Intervention / Treatment
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* Device: Pneumatic tourniquet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥16 years of age or estimated weight ≥50kgs if age is unknown; Victim of blunt or penetrating trauma Hemorrhagic shock defined as: One or more episodes of systolic blood pressure ≤90mmHg at any time prior to enrollment into the study; An identified source of blood loss (abdomen, chest, pelvis/retroperitoneum, extremities, external) or Blood products (RBC, Platelets, Plasma, etc.) has been ordered to the trauma room. Admitted to St. Michael's Hospital directly from the scene of injury within 3 hours of the injury Application and completion of Remote Ischemic Conditioning (RIC) within 4 hours of the injury Exclusion Criteria: Pregnancy Non-hemorrhagic shock (i.e. tension pneumothorax, cardiac tamponade, spinal shock, etc.) Major burns > 20% total body surface area Fracture of both lower extremities (i.e. traumatic amputation, fractures) Absence of vital signs prior to admission, ongoing CPR, possibly dead on admission or not expected to survive beyond a few hours. Injury in both legs (traumatic amputation, fractures, etc.) Patients with a systolic blood pressure above 200mmHg Patients treated with anticoagulants, antiplatelet therapy (Warfarin, Aspirin), steroids or with a known bleeding disorder or known abnormality of blood flow to the limb (if known) Patients with osteoporosis or other bone disorders, peripheral nerve injury, abnormal nerve supply, peripheral neuropathy (if known) or preexisting traumatic injury to the limb. Morbid obesity (largest cuff size won't fit) If RIC is done clinically before research protocol begins.

Ages Eligible for Study
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Minimum Age: 16 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Sham Remote Ischemic Conditioning<br>Sham inflation of pneumatic tourniquet pressure cuff at 0 mmHg on the thigh for 5 minutes and release for 5 minutes (repeated for 4 cycles) applied to trauma patients on arrival to hospital | Device: Pneumatic tourniquet<br>* Four cycles of brief occlusion of bloodflow to the thigh (5 minutes) followed by reperfusion (5 minutes) using a pneumatic tourniquet Remote Ischemic Conditioning<br>|
| Experimental: Remote Ischemic Conditioning<br>Inflation of pneumatic tourniquet pressure cuff at 250mmHg on the thigh for 5 minutes and release for 5 minutes (repeated for 4 cycles) applied to trauma patients on arrival to hospital | Device: Pneumatic tourniquet<br>* Four cycles of brief occlusion of bloodflow to the thigh (5 minutes) followed by reperfusion (5 minutes) using a pneumatic tourniquet Remote Ischemic Conditioning<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neutrophil Oxidative Burst Activity | Change in neutrophil oxidative burst activity (dihydrorhodamine, DHR) over 24 hours from admission. Measured by flow cytometry using whole blood samples. | 0 (Admission), 1, 3, and 24 hours after intervention | 
| Neutrophil Oxidative Burst Activity (PMA Stimulated) | Change in PMA stimulated neutrophil oxidative burst activity (dihydrorhodamine, DHR) over 24 hours. Measured by flow cytometry using whole blood samples. | 0 (Admission), 1, 3, and 24 hours after intervention | 
| Neutrophil Adhesion Molecule Expression (CD11b) | Change in neutrophil adhesion molecule (CD11b) expression over 24 hours from admission. Measured by flow cytometry using whole blood samples. | 0 (Admission), 1, 3, 24 hours after intervention | 
| Neutrophil Adhesion Molecule Expression (CD62L) | Change in neutrophil adhesion molecule (CD62L) expression over 24 hours from admission. Measured by flow cytometry using whole blood samples. | 0 (Admission), 1, 3, and 24 hours after intervention | 
| Endothelial Injury (Heparan Sulfate) | Change in plasma levels of endothelial injury marker Heparan Sulfate over 24 hours from Admission | 0 (Admission), 1, 3, and 24 hours after intervention | 
| Endothelial Injury (Hyaluronan) | Change in plasma levels of endothelial injury marker Hyaluronan over 24 hours from Admission | 0 (Admission), 1, 3, 24 hours | 
| Endothelial Injury (Syndecan-1) | Change in plasma levels of endothelial injury marker Syndecan-1 over 24 hours from Admission | 0 (Admission), 1, 3, and 24 hours after intervention | 
| Plasma TNF-α | Change in plasma levels of inflammatory mediator TNF-α over 24 hours from Admission | 0 (Admission), 1, 3, and 24 hours after intervention | 
| Plasma IL-6 | Change in plasma levels of inflammatory mediator IL-6 over 24 hours from Admission | 0 (Admission), 1, 3, 24 hours | 
| Plasma IL-8 | Change in plasma levels of inflammatory mediator IL-8 over 24 hours from Admission | 0 (Admission), 1, 3, 24 hours | 
| Plasma IL-10 | Change in plasma levels of anti-inflammatory mediator IL-10 over 24 hours from Admission | 0 (Admission), 1, 3, 24 hours | 
| ROTEM EXTEM CT | Change in ROTEM parameter Clotting Time (CT) over 24 hours from Admission | 0 (Admission), 1, 3, 24 hours | 
| ROTEM EXTEM CFT | Change in ROTEM parameter Clot Formation Time (CFT) over 24 hours from Admission | 0 (Admission), 1, 3, 24 hours | 
| ROTEM EXTEM A10 | Change in ROTEM parameter A10 over 24 hours from Admission | 0 (Admission), 1, 3, 24 hours | 
| ROTEM EXTEM Alpha Angle | Change in ROTEM parameter Alpha Angle over 24 hours from Admission | 0 (Admission), 1, 3, 24 hours | 
| ROTEM EXTEM ML | Change in ROTEM parameter maximum lysis (ML) over 24 hours from Admission | 0 (Admission), 1, 3, 24 hours | 
| Plasma D-Dimer | Change in plasma D-Dimer levels over 24 hours from Admission | 0 (Admission), 1, 3, 24 hours | 
| Plasma Protein C | Change in plasma Protein C levels over 24 hours from Admission | 0 (Admission), 1, 3, 24 hours | 
| Plasma Fibrinogen | Change in plasma fibrinogen levels over 24 hours from Admission | 0 (Admission), 1, 3, 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilator Free Days | Secondary clinical outcomes | up to 28 days or discharge | 
| ICU Free Days | Secondary clinical outcomes | up to 28 days or discharge | 
| Hospital Free Days | Secondary clinical outcomes | up to 28 days or discharge | 
| Nosocomial Infections | Secondary clinical outcomes | up to 28 days or discharge | 
| 24 Hour Mortality | Secondary clinical outcomes | up to 28 days or discharge | 
| 28 Day Mortality | Secondary clinical outcomes | up to 28 days or discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemorrhagic Shock, Remote Ischemic Conditioning