Remote Ischemic Conditioning in Traumatic Brain Injury

Study Overview
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Brief Summary
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Traumatic brain injury (TBI) is a leading cause of death among trauma patients accounting for one-third of all trauma mortalities. Patients who survive the initial trauma are liable to secondary insults from the ensuing inflammatory state in the brain. Treatment goals are aimed at reducing secondary injury. Maintaining adequate brain perfusion, limiting cerebral edema, and optimizing oxygen delivery are part of established treatment protocols. Numerous therapeutics have been evaluated as potential treatment for TBI with very limited success and there is no medication that alters survival. Various novel therapeutic options have been investigated to prevent the secondary brain injury. Remote Ischemic Conditioning (RIC) is one of these therapies. RIC involves decreasing blood flow to a normal tissue usually the arm by inflating the blood pressure cuff 30mmHg over the systolic blood pressure. The decreased blood flow or ischemia is maintained for 5 minutes followed by releasing the pressure and re-perfusion of the arm. This cycle is usually repeated 4 times. RIC has been shown to improve outcomes in patients with heart attacks, strokes, elective neurosurgeries. A prospective observational study and a randomized clinical trial has shown the protective effect of RIC in TBI patients. Additionally, multiple studies in animals have shown that RIC is neuroprotective after TBI. RIC is non-invasive and harmless except for a little discomfort in the arm. The aim of the study is to evaluate the impact of RIC on long term outcomes in patients with TBI.

Detailed Description
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Traumatic brain injury (TBI) remains one of the leading causes of death and disability in the United States. Secondary brain injury caused by the complex interplay of inflammatory mediators induced by a primary insult is the major contributing factor for morbidity and mortality after TBI. While the primary injury is irreversible, the inflammatory cascade leading to the development of the secondary injury may be preventable. As a result, all the current research in TBI is focused on preventing initiation of this secondary insult. Remote ischemic conditioning (RIC) is a process where normal tissues are subjected to short cycles of ischemia and reperfusion, which have been shown to reduce the sequelae of an ischemic injury at a remotely injured site. RIC has been shown to improve the outcomes after myocardial infarction, sepsis, transplantation, reimplantation, and elective neurologic surgery.It is thought to work by releasing endogenous systemic anti-inflammatory mediators and humoral factors and by using neural pathways, rendering global protection to the body against subsequent ischemic insults in a remote are. This protection provided by RIC has two phases, an early (short) phase and a late (prolonged) phase, both of which have proven to be effective in reducing ischemic size and improving survival. Multiple animal studies and a small randomized clinical trial have shown the protective effect of RIC in patients with TBI. The effectiveness of RIC in patients with traumatic brain injury is still under investigation not yet established.

Official Title
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The Effect of Remote Ischemic Conditioning (RIC) on Inflammatory Biomarkers and Outcomes in Patients With TBI

Conditions
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Traumatic Brain Injury, Brain Injuries, Brain Trauma, Brain Injuries, Traumatic

Intervention / Treatment
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* Device: Remote Ischemic Conditioning
* Other: No-Remote Ischemic Conditioning


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 17years. Diagnosis of traumatic brain injury. Glasgow Coma Scale (GCS) ≤13 Intra-cranial hemorrhage (ICH) on initial brain CT scan Exclusion Criteria: Patients with traumatic brain injury >24 hours Transferred from other centers Declined to participate in the study

Ages Eligible for Study
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Minimum Age: 17 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remote Ischemic Conditioning<br>Remote ischemic conditioning will be performed using a standard manual blood pressure cuff. The pressure in the blood pressure cuff will be maintained at 30 mm of Hg higher than the patient's systolic blood pressure. 4 cycles of ischemic conditioning will be performed each day for a period of 7 days. Each cycle consists of 5 min of controlled upper limb ischemia (cuff up) followed by 5 min of reperfusion (cuff down). The total duration of the treatment cycle will be 40 min. The study protocol is based on our published literature in traumatic brain injury. Blood samples will be collected at 0 hours (before randomization). Then the first 4 cycles of RIC (done consecutively) will be performed, blood samples will be taken at 6 hours post randomization and then at 24 hours post randomization. RIC cycles will then be performed on a daily basis followed by taking a blood sample once daily during the patients' length of stay up to a maximum of 7 days | Device: Remote Ischemic Conditioning<br>* Standard manual blood pressure cuff<br>|
| Placebo Comparator: No Remote Ischemic Conditioning<br>Blood samples will be collected at 0 hours (before randomization). Blood samples will then be collected at 6 hours post randomization and 24 hours post randomization. These patients will not receive daily RIC therapy but will only have their blood drawn once daily during the patients' length of stay up to a maximum of 7 days. | Other: No-Remote Ischemic Conditioning<br>* No-Remote Ischemic Conditioning<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the level of Inflammatory Biomarkers (pg/ml) | Level of tumor necrosis factor alpha (TNF-alpha), Level of interleukin 1 (IL-1),Level of interleukin 6 (IL-6), Level of interleukin 8 (IL-8), and Level of interleukin 10 (IL-10). | Before randomization, 6 hours post randomization, 24 hours post randomization, once daily during the patients' length of stay up to a maximum of 7 days afterwards | 
| Change in the level of C-reactive protein C-reactive Protein mg/dl | C-reactive protein | Before randomization, 6 hours post randomization, 24 hours post randomization, once daily during the patients' length of stay up to a maximum of 7 days afterwards | 
| Change in the Level of pro-calcitonin (ng/ml) | Level of pro-calcitonin | Before randomization, 6 hours post randomization, 24 hours post randomization, once daily during the patients' length of stay up to a maximum of 7 days afterwards | 
| Change in the Level of cardiac biomarker: Troponin c (ng/ml) | Troponin c | Before randomization, 6 hours post randomization, 24 hours post randomization, once daily during the patients' length of stay up to a maximum of 7 days afterwards | 
| Change in the Level of cardiac biomarker: Creatinine Phosphokinase (ug/ml) | Creatinine Phosphokinase | Before randomization, 6 hours post randomization, 24 hours post randomization, once daily during the patients' length of stay up to a maximum of 7 days afterwards | 
| Change in the Level of cardiac biomarker: Creatine Kinase MB CKMB (ug/ml) | Creatine Kinase MB | Before randomization, 6 hours post randomization, 24 hours post randomization, once daily during the patients' length of stay up to a maximum of 7 days afterwards | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Discharge Disposition/Destination |  | Last hospitalization day | 
| Mortality |  | Last hospitalization day, 30 days post-discharge | 
| Glasgow Outcome Scale-Extended (points) | Functional independence level assessment: The Extended Glasgow Outcome Scale (GOSE) is a global scale for functional outcome that rates patients into eight categories. The categories of severe disability, moderate disability and good recovery are subdivided into a lower and upper category. The scale will be used to evaluate the patient's functional status | Last hospitalization day, 30 days | 
| Glasgow Coma Scale (points) | Neurological status assessment The Glasgow Coma Scale is divided into three components which are scored separately: ocular response (assessment 1-4 points), motor response (assessment 1-6 points) verbal response (evaluation of 1-5 points). Scores for each component are added together to get the total that will range between a minimum of 3 points (which corresponds to a patient who does not open his eyes and no motor response to stimulation or verbal response) and a maximum value of 15 points (corresponding to a patient with open eyes, obeying orders and maintaining a consistent language). It has been considered that the GCS score between 15 and 13 points corresponds to a slight alteration of consciousness, a score of 12-9 points with moderate impairment and 8 points or less with a serious deterioration in level of consciousness. | Last hospitalization day, 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Remote Ischemic Conditioning, Traumatic Brain Injury