Remote Ischemic Conditioning as a Treatment for Traumatic Brain Injury: a Prospective Randomized Controlled Trial.

Unity Health Toronto2 个研究点分布在 1 个国家目标入组 44 人开始时间: 2019年5月3日最近更新: 2024年3月15日

适应症

试验速览

阶段: 不适用
状态: 已完成
发起方: Unity Health Toronto
入组人数: 44
试验地点: 2
主要终点: Monocyte Chemoattractant Protein (MCP1) - biomarker

研究概览研究设计入排标准结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

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.

详细描述

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.

研究设计

研究类型: Interventional
分配方式: Randomized
干预模型: Parallel
主要目的: Treatment
盲法: Triple (Care Provider, Investigator, Outcomes Assessor)

盲法说明

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.

入排标准

年龄范围: 18 Years 至 —（Adult, Older Adult）
性别: All
接受健康志愿者: 否

入选标准

•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

排除标准

•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