Remote Ischemic Conditioning as a Treatment for Traumatic Brain Injury

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:

• Biomarkers of neuronal injury and systemic inflammation (20-28)
• Radiologic evidence of improved acute- and delayed-phase perfusion (29-33)
• Clinical course in hospital from admission to discharge
• 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.

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

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