Remote Ischemic Conditioning as a Treatment for Traumatic Brain Injury

NCT03176823 | Completed

• 1 other identifier: RIC in TBI
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

The prevention of secondary brain injury is a primary goal in treating patients with severe traumatic brain injury (TBI). Secondary brain injury results from tissue ischemia induced by increased vascular resistance in the at-risk brain tissue due to compression by traumatic hematomas, and development of cytotoxic and vasogenic tissue edema. While traumatic hematomas may be managed surgically, cytotoxic and vasogenic edema with resulting perfusion impairment perpetuates brain ischemia and injury. Animal models suggest that remote ischemic conditioning (RIC) can reverse these effects and improve perfusion. Based on these findings it is hypothesized that RIC will exert beneficial effects on TBI in man, thereby representing a new therapeutic strategy for severe TBI. Patients presenting to our institution suffering from severe TBI will be considered for enrollment. Eligible patients will have sustained a blunt, severe TBI (defined by Glasgow Coma Scale \<8) with associated intra-cranial hematoma(s) not requiring immediate surgical decompression, with admission to an intensive care unit and insertion of an intra-cranial pressure monitor. Patients will be randomized to RIC versus sham-RIC intervention cohorts. RIC interventions will be performed using an automated device on the upper extremity delivering 20 cumulative minutes of limb ischemia in a single treatment session. The planned enrollment is a cohort of 40 patients. Outcomes of this study will include multiple domains. Our primary outcome will include serial assessments of validated serum biomarkers of neuronal injury and systemic inflammation. Secondary outcomes will include descriptions of the clinical course of each patient, radiologic assessment of brain perfusion, and neurocognitive and psychological assessment post-discharge. If clinical outcomes are improved using RIC, this study would support RIC as a novel treatment for TBI. Its advantages include safety and simplicity and, requiring no specialized equipment, its ability to be used in any environment including pre-hospital settings or in austere theatres. The investigators anticipate that TBI patients treated with RIC will have improved clinical, biochemical, and neuropsychological outcomes compared to standard treatment protocols.

Conditions

Traumatic Brain Injury; Trauma, Nervous System; Reperfusion Injury; Ischemia, Brain

Keywords

Brain injury; Remote ischemic conditioning (RIC); Trauma; Biomarkers

Outcome Measures

Primary Outcomes (13)

• Neuron Specific Enolase (NSE) - biomarker

  Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.

  Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours

• S100A12 - biomarker

  Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.

  Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours

• Calcium Binding Protein Beta (S100B) - biomarker

  Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.

  Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours

• Glial Fibrillary Acidic Protein (GFAP) - biomarker

  Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.

  Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours

• Monocyte Chemoattractant Protein (MCP1) - biomarker

  Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.

  Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours

• Epinephrine - biomarker

  Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.

  Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours

• Norepinephrine - biomarker

  Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.

  Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours

• Interleukin 10 (IL10) - biomarker

  Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.

  Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours

• Interleukin 1 Beta (IL1B) - biomarker

  Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.

  Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours

• Tumor Necrosis Factor Alpha (TNF Alpha) - biomarker

  Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.

  Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours

• International Normalized Ratio (INR) - standard lab test.

  Standard coagulation parameter, to be measured at all time points specified below.

  Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours

• Prothrombin Time (PTT) - standard lab test.

  Standard coagulation parameter, to be measured at all time points specified below

  Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours

• Rotational Thromboelastometry (ROTEM), standard lab test.

  ROTEM coagulation assessment using the commercial ROTEM device traditionally used for the assessment of trauma-induced coagulopathy, to be measured at all time points specified below

  Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours

Secondary Outcomes (14)

• Cerebral vascular perfusion, acute

  24 hours

• Intracranial Pressure (ICP) measurement, first 24 hours

  24 hours

• Intracranial Pressure (ICP) measurement, 24-96 hours

  24 hours, 96 hours

• Escalation along an established care algorithm

  12 months

• Mortality beyond 12 hours post-admission

  12 months

Study Arms (2)

Control Arm

SHAM COMPARATOR

Control-arm patients will be treated with standard "Best Practice" management of traumatic brain injury, with the addition of sham-RIC. The sham intervention will use a purpose-built device which will visually and audibly mimic a functional RIC device, with the key distinction being non-inflation of the arm cuff with resultant non-occlusion and no induced ischemia. To mask patient enrollment, all patients in both study arms will have the arm and RIC device draped in an opaque sheet so that the extremity distal to the RIC device are not visible to medical staff during the period of intervention.

Other: Best Practice Management of Traumatic Brain Injury

RIC Arm

EXPERIMENTAL

The RIC treatment will be applied with a purpose-built commercial RIC device which will aid in standardizing dose and delivery. Therapeutic RIC will be provided by the CellAegis Technologies autoRIC device on an upper extremity. As with the control cohort, this cohort will undergo complete extremity draping.

Device: CellAegis Technologies autoRIC device; Other: Best Practice Management of Traumatic Brain Injury

Interventions

CellAegis Technologies autoRIC device DEVICE

The autoRIC device from CellAegis technologies will be applied as per the manufacturer's instructions on an upper extremity. The device will automatically inflate and deflate a blood pressure cuff to supra-systolic blood pressures, maintaining an occlusive pressure for a period of five minutes, followed by five minutes of re-perfusion with cuff deflation, completing a ten minute cycle. This cycle will repeat four times for a cumulative total of twenty minutes of occlusive conditioning over forty minutes of intervention time.

Also known as: Remote Ischemic Conditioning

RIC Arm

Best Practice Management of Traumatic Brain Injury OTHER

Standard treatment of TBI in a dedicated trauma-neuro intensive care unit will include a tiered management strategy corresponding to many published treatment algorithms, including the American College of Surgeons Trauma Quality Improvement Program (ACS TQIP) guidelines for the management of intra-cranial hypertension. Standard practice without limitations will be applied to both cohorts of patients in this study.

Control Arm; RIC Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Severe blunt traumatic brain injury presenting to St Michael's Hospital within 48 hours of trauma
• Glasgow Coma Scale (GCS) less than or equal to 12
• Presence on CT Scan of intra-cranial hematoma which adequately explains level of consciousness (epidural, subdural, subarachnoid hematomae)
• Able to undergo intervention within 48 hours of trauma

You may not qualify if:

• Age \<18 years
• Lack of informed consent or withdrawal of consent, provided by legal substitute decision maker
• Unknown timing of trauma
• Unable to safely undergo ischemic conditioning of the upper extremity due to major trauma, previous surgery, known vascular disease or previous radiation treatment
• Acute significant injury (those injuries which in isolation would require admission to hospital) outside the head and neck region
• Pre-hospital therapeutic anticoagulation or anti-platelet agent use
• Surgical intervention within 12 hours of presentation to hospital, excluding pressure monitor insertion
• Patient death within 24 hours of admission
• Pre-intervention insertion of intra-cranial pressure monitor, as surgical trauma may influence biomarker measurements

Sponsors & Collaborators

• Unity Health Toronto: lead
• Defence Research and Development Canada: collaborator

Study Sites (1)

St Michaels Hospital

Toronto, Ontario, M5B 1W8, Canada

Location

Related Publications (44)

• ACS TQIP Best Practices in the Management of Traumatic Brain Injury. 2015.

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MeSH Terms

Conditions

Brain Injuries, Traumatic; Trauma, Nervous System; Reperfusion Injury; Brain Ischemia; Brain Injuries; Wounds and Injuries

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Vascular Diseases; Cardiovascular Diseases; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cerebrovascular Disorders

Study Officials

• Ori D Rotstein, MD

  Unity Health Toronto - St. Michael's hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: While it is not technically possible to mask participants to the application of RIC versus sham therapies, all participants in this trial by design will be intubated in an intensive care unit with severe traumatic brain injury; it is improbable that our inability to mask the patients will compromise outcomes or induce bias as patients are unlikely to have consciousness or memory of the therapy.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This trial is a prospective double-blind parallel cohort study of patients undergoing either standard of care plus placebo (sham-RIC) or standard treatment plus a single session of upper extremity remote ischemic conditioning.

Study Record Dates

• First Submitted: May 15, 2017
• First Posted: June 6, 2017
• Study Start: May 3, 2019
• Primary Completion: November 1, 2023
• Study Completion: March 3, 2024
• Last Updated: March 15, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)