Remote Ischemic Conditioning as a Treatment for Traumatic Brain Injury

Not Applicable

Completed

• Conditions: Traumatic Brain Injury; Reperfusion Injury; Trauma, Nervous System; Ischemia, Brain
• Interventions: Device: CellAegis Technologies autoRIC device; Other: Best Practice Management of Traumatic Brain Injury

• Registration Number: NCT03176823
• Lead Sponsor: Unity Health Toronto

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.

Detailed Description

Traumatic brain injury is a leading cause of morbidity and mortality in victims of blunt trauma, leading to a tremendous economic cost, chronic neuropsychological sequelae and productive years of life lost. Treatment of inoperable primary brain injury consists largely of supportive care to support natural healing and prevention or reduction of secondary insults (1).

Many of the phenomena of secondary injury are related to ischemic sequelae of injury progression. Brain parenchymal edema increases both regional and global intra-cranial pressures, decreasing perfusion pressure, resulting in impaired perfusion, an oxygen debt, and ischemic injury (2). Local compression from traumatic hematomas may act in concert with edema to further impair perfusion. One strategy that has been successfully employed in the treatment of other ischemic insults is an intervention known as "remote ischemic conditioning" (RIC). RIC is felt to induce systemic responses which promote physiologic adaptations to moderate ischemia and minimize the impact of subsequent ischemic insults. Because these effects are systemic, extremity ischemic conditioning may impact brain injury. In the setting of TBI, where all patients carry a risk of ischemic secondary injury, early intervention with RIC may minimize the harm of secondary ischemic insults and improve outcomes.

The systemic effects of RIC have been demonstrated in a variety of organ systems and mechanisms of ischemia. Application of RIC has demonstrable benefits in preventing ischemia-induced organ dysfunction in insults to the heart (3-6), kidneys (7,8), and ocular organ systems (9). Our recent work has demonstrated its benefit in preventing organ injury following hemorrhagic shock (10). The technique has also demonstrated promise in reducing brain injury secondary to stroke or neurosurgical trauma (11-13).

Ischemic conditioning of brain injuries has proven benefits in animal models. Limb preconditioning reduces toxic oxygen free radicals, reduces neuronal apoptosis, reduces intra-cranial inflammation, improves integrity of the blood-brain barrier, and reduces brain parenchymal edema (14,15). RIC also improves microvascular perfusion to ischemic tissues which, in the brain, may reduce secondary injury by promoting perfusion to the at-risk injured brain (16). Even when performed after the intra-cranial trauma in a "post-conditioning" model, limb ischemic conditioning is associated with decreased apoptosis, decreased edema, and decreased brain infarction volumes (17,18). A single recent trial of RIC in human TBI patients showed a decrease in serum biomarkers of central nervous system (CNS) injury in the conditioned cohort (19).

Given the promising findings of the remote ischemic conditioning technique in reducing biomarkers of intra-cranial inflammation, an assessment of the clinical effectiveness of post-traumatic remote ischemic conditioning in modifying the outcomes of patients with isolated severe traumatic brain injuries is warranted.

Outcomes of this proposed prospective, randomized controlled trial will fall into the following validated categories:

1. Biomarkers of neuronal injury and systemic inflammation (20-28)

2. Radiologic evidence of improved acute- and delayed-phase perfusion (29-33)

3. Clinical course in hospital from admission to discharge

4. Neurocognitive and neuropsychological outcomes, 6 month follow-up (34-46)

The known physiologic effects of RIC are theoretically beneficial to patients suffering severe TBI who are at risk of clinical deterioration due to secondary injury. By mitigating the effects of inflammation and edema and improving microvascular perfusion, at-risk brain tissue may be salvaged and thus patient outcomes improved. This theory is supported by the existing evidence and a well-planned selection of outcome measures including biochemical, clinical, and radiographic outcomes may demonstrate the benefits of RIC in this patient population.

Study Timeline

• Study First Submitted: 2017-05-15
• Study First Submitted QC: 2017-06-01
• Study First Posted: 2017-06-06
• Study Start: 2019-05-03
• Primary Completion: 2023-11-01
• Status Verified: 2024-03
• Study Completion: 2024-03-03
• Last Update Submitted: 2024-03-13
• Last Update Posted: 2024-03-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 44

Inclusion Criteria

• 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

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Exclusion Criteria

• 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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
RIC Arm	Best Practice Management of Traumatic Brain Injury	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.
RIC Arm	CellAegis Technologies autoRIC device	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.
Control Arm	Best Practice Management of Traumatic Brain Injury	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.

Primary Outcome Measures

Name	Time	Method
Monocyte Chemoattractant Protein (MCP1) - biomarker	Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours	Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Neuron Specific Enolase (NSE) - biomarker	Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours	Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Calcium Binding Protein Beta (S100B) - biomarker	Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours	Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Norepinephrine - biomarker	Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours	Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Interleukin 10 (IL10) - biomarker	Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours	Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Rotational Thromboelastometry (ROTEM), standard lab test.	Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours	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
S100A12 - biomarker	Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours	Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Glial Fibrillary Acidic Protein (GFAP) - biomarker	Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours	Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Epinephrine - biomarker	Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours	Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Interleukin 1 Beta (IL1B) - biomarker	Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours	Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Tumor Necrosis Factor Alpha (TNF Alpha) - biomarker	Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours	Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
International Normalized Ratio (INR) - standard lab test.	Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours	Standard coagulation parameter, to be measured at all time points specified below.
Prothrombin Time (PTT) - standard lab test.	Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours	Standard coagulation parameter, to be measured at all time points specified below

Secondary Outcome Measures

Name	Time	Method
Intracranial Pressure (ICP) measurement, 24-96 hours	24 hours, 96 hours	The number of episodes of ICP \>20 mmHg, measured in 15 minute increments, over 24-96 hours.
Mortality beyond 12 hours post-admission	12 months	Patient deaths occurring in the first 12 hours will result in patient-exclusion as it is unlikely that these patients would have had different outcomes regardless of treatment strategies.
Hospital length of stay, number of days	12 months	Number of continuous calendar days or partial calendar days admitted to an acute-care hospital.
Glasgow Outcomes Scale, Extended (GOSE) - neurocognitive test	discharge, 3 months, 6 months, and 12 months	The GOSE scale assessing neurocognitive function will be assessed on hospital, discharge, at three months post-discharge, and at 6 and 12 months post-discharge.
Patient Health Questionnaire 9th edition (PHQ-9) - neurological - self assessment	discharge, 3, 6, and 12 months	The PHQ-9 screen for mental health disorders will be assessed on hospital discharge, at three months post-discharge, and at 6 and 12 months post-discharge.
Cerebral vascular perfusion, acute	24 hours	Patients will undergo Arterial Spin Loading Functional Magnetic Resonance Imaging (fMRI) at 72 hours post-RIC to quantify blood flow to the acutely ischemic brain parenchyma.
Intracranial Pressure (ICP) measurement, first 24 hours	24 hours	The number of episodes of ICP \>20 mmHg, measured in 15 minute increments, over the first 24 hours.
Escalation along an established care algorithm	12 months	Patient care interventions will be plotted against the Tier 1, Tier 2, and Tier 3 categories of interventions described by the American College of Surgeons Trauma Quality Improvement Program (ACS TQIP) guidelines for the management of traumatic intracranial hypertension.
Total duration of mechanical ventilation, number of days	2 months	Number of calendar days or partial calendar days including treatment with invasive ventilation.
Destination of discharge	12 months	Home (functionally independent), rehabilitation facility, or chronic care facility
Posttraumatic Stress Disorder Checklist for the Diagnostic and Statistical Manual of Mental Disorders 5th edition (PCL-5) - neurological - self assessment	discharge, 3 months, 6 months, and 12 months	The PCL-5 screen for Post-Traumatic Stress Disorder will be assessed on hospital discharge, at three months post-discharge, and at 6 and 12 months post-discharge.
Incidence of surgical decompression beyond 12 hours post-admission	12 months	Patient progression to need for definitive surgery occurring in the first 12 hours will result in patient-exclusion as it is unlikely that these patients would have had different outcomes regardless of treatment strategies.
Intensive Care Unit length of stay, number of days	2 months	Number of continuous calendar days or partial calendar days admitted to an intensive-care unit.
Disability Rating Scale (DRS) - neurocognitive function rating	discharge, 3 months, 6 months, and 12 months	The DRS scale assessing neurocognitive function will be assessed on hospital discharge, at three months post-discharge, and at 6 and 12 months post-discharge.

Trial Locations

Locations (1)

St Michaels Hospital; 🇨🇦 Toronto, Ontario, Canada