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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT03176823
Other study ID # RIC in TBI
Secondary ID
Status Completed
Phase N/A
First received
Last updated
Start date May 3, 2019
Est. completion date March 3, 2024

Study information

Verified date March 2024
Source Unity Health Toronto
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Completed
Enrollment 44
Est. completion date March 3, 2024
Est. primary completion date November 1, 2023
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility 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

Study Design


Intervention

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

Locations

Country Name City State
Canada St Michaels Hospital Toronto Ontario

Sponsors (2)

Lead Sponsor Collaborator
Unity Health Toronto Defence Research and Development Canada

Country where clinical trial is conducted

Canada, 

References & Publications (44)

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

Blevins CA, Weathers FW, Davis MT, Witte TK, Domino JL. The Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5): Development and Initial Psychometric Evaluation. J Trauma Stress. 2015 Dec;28(6):489-98. doi: 10.1002/jts.22059. Epub 2015 Nov 25. — View Citation

Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HT, Redington AN, Nielsen TT. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet. 2010 Feb 27;375(9716):727-34. doi: 10.1016/S0140-6736(09)62001-8. — View Citation

Bouma GJ, Muizelaar JP, Choi SC, Newlon PG, Young HF. Cerebral circulation and metabolism after severe traumatic brain injury: the elusive role of ischemia. J Neurosurg. 1991 Nov;75(5):685-93. doi: 10.3171/jns.1991.75.5.0685. — View Citation

Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma. 2003 Jun;54(6):1127-30. doi: 10.1097/01.TA.0000069184.82147.06. — View Citation

Chen J, Graham SH, Zhu RL, Simon RP. Stress proteins and tolerance to focal cerebral ischemia. J Cereb Blood Flow Metab. 1996 Jul;16(4):566-77. doi: 10.1097/00004647-199607000-00006. — View Citation

DAHL NA, BALFOUR WM. PROLONGED ANOXIC SURVIVAL DUE TO ANOXIA PRE-EXPOSURE: BRAIN ATP, LACTATE, AND PYRUVATE. Am J Physiol. 1964 Aug;207:452-6. doi: 10.1152/ajplegacy.1964.207.2.452. No abstract available. — View Citation

Davies WR, Brown AJ, Watson W, McCormick LM, West NE, Dutka DP, Hoole SP. Remote ischemic preconditioning improves outcome at 6 years after elective percutaneous coronary intervention: the CRISP stent trial long-term follow-up. Circ Cardiovasc Interv. 2013 Jun;6(3):246-51. doi: 10.1161/CIRCINTERVENTIONS.112.000184. Epub 2013 May 21. — View Citation

Di Battista AP, Buonora JE, Rhind SG, Hutchison MG, Baker AJ, Rizoli SB, Diaz-Arrastia R, Mueller GP. Blood Biomarkers in Moderate-To-Severe Traumatic Brain Injury: Potential Utility of a Multi-Marker Approach in Characterizing Outcome. Front Neurol. 2015 May 26;6:110. doi: 10.3389/fneur.2015.00110. eCollection 2015. — View Citation

Er F, Nia AM, Dopp H, Hellmich M, Dahlem KM, Caglayan E, Kubacki T, Benzing T, Erdmann E, Burst V, Gassanov N. Ischemic preconditioning for prevention of contrast medium-induced nephropathy: randomized pilot RenPro Trial (Renal Protection Trial). Circulation. 2012 Jul 17;126(3):296-303. doi: 10.1161/CIRCULATIONAHA.112.096370. Epub 2012 Jun 26. — View Citation

Gouvier WD, Blanton PD, LaPorte KK, Nepomuceno C. Reliability and validity of the Disability Rating Scale and the Levels of Cognitive Functioning Scale in monitoring recovery from severe head injury. Arch Phys Med Rehabil. 1987 Feb;68(2):94-7. — View Citation

Hall K, Cope DN, Rappaport M. Glasgow Outcome Scale and Disability Rating Scale: comparative usefulness in following recovery in traumatic head injury. Arch Phys Med Rehabil. 1985 Jan;66(1):35-7. — View Citation

Hunter JV, Wilde EA, Tong KA, Holshouser BA. Emerging imaging tools for use with traumatic brain injury research. J Neurotrauma. 2012 Mar 1;29(4):654-71. doi: 10.1089/neu.2011.1906. Epub 2011 Oct 17. — View Citation

Joseph B, Pandit V, Zangbar B, Kulvatunyou N, Khalil M, Tang A, O'Keeffe T, Gries L, Vercruysse G, Friese RS, Rhee P. Secondary brain injury in trauma patients: the effects of remote ischemic conditioning. J Trauma Acute Care Surg. 2015 Apr;78(4):698-703; discussion 703-5. doi: 10.1097/TA.0000000000000584. — View Citation

Kim J, Whyte J, Patel S, Avants B, Europa E, Wang J, Slattery J, Gee JC, Coslett HB, Detre JA. Resting cerebral blood flow alterations in chronic traumatic brain injury: an arterial spin labeling perfusion FMRI study. J Neurotrauma. 2010 Aug;27(8):1399-411. doi: 10.1089/neu.2009.1215. — View Citation

Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, Handa N, Fukunaga R, Kimura K, Mikoshiba K, et al. 'Ischemic tolerance' phenomenon found in the brain. Brain Res. 1990 Sep 24;528(1):21-4. doi: 10.1016/0006-8993(90)90189-i. — View Citation

Kreutzer JS, Seel RT, Gourley E. The prevalence and symptom rates of depression after traumatic brain injury: a comprehensive examination. Brain Inj. 2001 Jul;15(7):563-76. doi: 10.1080/02699050010009108. — View Citation

Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001 Sep;16(9):606-13. doi: 10.1046/j.1525-1497.2001.016009606.x. — View Citation

Leung CH, Caldarone CA, Wang F, Venkateswaran S, Ailenberg M, Vadasz B, Wen XY, Rotstein OD. Remote Ischemic Conditioning Prevents Lung and Liver Injury After Hemorrhagic Shock/Resuscitation: Potential Role of a Humoral Plasma Factor. Ann Surg. 2015 Jun;261(6):1215-25. doi: 10.1097/SLA.0000000000000877. — View Citation

Levin HS, Boake C, Song J, Mccauley S, Contant C, Diaz-Marchan P, Brundage S, Goodman H, Kotrla KJ. Validity and sensitivity to change of the extended Glasgow Outcome Scale in mild to moderate traumatic brain injury. J Neurotrauma. 2001 Jun;18(6):575-84. doi: 10.1089/089771501750291819. — View Citation

Lewis LM, Schloemann DT, Papa L, Fucetola RP, Bazarian J, Lindburg M, Welch RD. Utility of Serum Biomarkers in the Diagnosis and Stratification of Mild Traumatic Brain Injury. Acad Emerg Med. 2017 Jun;24(6):710-720. doi: 10.1111/acem.13174. Epub 2017 May 18. — View Citation

Liu X, Sha O, Cho EY. Remote ischemic postconditioning promotes the survival of retinal ganglion cells after optic nerve injury. J Mol Neurosci. 2013 Nov;51(3):639-46. doi: 10.1007/s12031-013-0036-2. Epub 2013 Jun 5. — View Citation

Liu X, Zhao S, Liu F, Kang J, Xiao A, Li F, Zhang C, Yan F, Zhao H, Luo M, Luo Y, Ji X. Remote ischemic postconditioning alleviates cerebral ischemic injury by attenuating endoplasmic reticulum stress-mediated apoptosis. Transl Stroke Res. 2014 Dec;5(6):692-700. doi: 10.1007/s12975-014-0359-5. Epub 2014 Jul 22. — View Citation

Lopez-Aguilera F, Plateo-Pignatari MG, Biaggio V, Ayala C, Seltzer AM. Hypoxic preconditioning induces an AT2-R/VEGFR-2(Flk-1) interaction in the neonatal brain microvasculature for neuroprotection. Neuroscience. 2012 Aug 2;216:1-9. doi: 10.1016/j.neuroscience.2012.04.070. Epub 2012 May 6. — View Citation

McMillan T, Wilson L, Ponsford J, Levin H, Teasdale G, Bond M. The Glasgow Outcome Scale - 40 years of application and refinement. Nat Rev Neurol. 2016 Aug;12(8):477-85. doi: 10.1038/nrneurol.2016.89. Epub 2016 Jul 15. — View Citation

Pei H, Wu Y, Wei Y, Yang Y, Teng S, Zhang H. Remote ischemic preconditioning reduces perioperative cardiac and renal events in patients undergoing elective coronary intervention: a meta-analysis of 11 randomized trials. PLoS One. 2014 Dec 31;9(12):e115500. doi: 10.1371/journal.pone.0115500. eCollection 2014. — View Citation

Ren C, Gao M, Dornbos D 3rd, Ding Y, Zeng X, Luo Y, Ji X. Remote ischemic post-conditioning reduced brain damage in experimental ischemia/reperfusion injury. Neurol Res. 2011 Jun;33(5):514-9. doi: 10.1179/016164111X13007856084241. — View Citation

Schneiderman AI, Braver ER, Kang HK. Understanding sequelae of injury mechanisms and mild traumatic brain injury incurred during the conflicts in Iraq and Afghanistan: persistent postconcussive symptoms and posttraumatic stress disorder. Am J Epidemiol. 2008 Jun 15;167(12):1446-52. doi: 10.1093/aje/kwn068. Epub 2008 Apr 17. — View Citation

Schochl H, Solomon C, Traintinger S, Nienaber U, Tacacs-Tolnai A, Windhofer C, Bahrami S, Voelckel W. Thromboelastometric (ROTEM) findings in patients suffering from isolated severe traumatic brain injury. J Neurotrauma. 2011 Oct;28(10):2033-41. doi: 10.1089/neu.2010.1744. Epub 2011 Sep 23. — View Citation

Schoen M, Rotter R, Gierer P, Gradl G, Strauss U, Jonas L, Mittlmeier T, Vollmar B. Ischemic preconditioning prevents skeletal muscle tissue injury, but not nerve lesion upon tourniquet-induced ischemia. J Trauma. 2007 Oct;63(4):788-97. doi: 10.1097/01.ta.0000240440.85673.fc. — View Citation

Seel RT, Kreutzer JS, Rosenthal M, Hammond FM, Corrigan JD, Black K. Depression after traumatic brain injury: a National Institute on Disability and Rehabilitation Research Model Systems multicenter investigation. Arch Phys Med Rehabil. 2003 Feb;84(2):177-84. doi: 10.1053/apmr.2003.50106. — View Citation

Semple BD, Bye N, Rancan M, Ziebell JM, Morganti-Kossmann MC. Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2-/- mice. J Cereb Blood Flow Metab. 2010 Apr;30(4):769-82. doi: 10.1038/jcbfm.2009.262. Epub 2009 Dec 23. — View Citation

Shen Y, Kou Z, Kreipke CW, Petrov T, Hu J, Haacke EM. In vivo measurement of tissue damage, oxygen saturation changes and blood flow changes after experimental traumatic brain injury in rats using susceptibility weighted imaging. Magn Reson Imaging. 2007 Feb;25(2):219-27. doi: 10.1016/j.mri.2006.09.018. Epub 2006 Nov 28. — View Citation

Sloth AD, Schmidt MR, Munk K, Kharbanda RK, Redington AN, Schmidt M, Pedersen L, Sorensen HT, Botker HE; CONDI Investigators. Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. Eur Heart J. 2014 Jan;35(3):168-75. doi: 10.1093/eurheartj/eht369. Epub 2013 Sep 12. — View Citation

Stein SC, Smith DH. Coagulopathy in traumatic brain injury. Neurocrit Care. 2004;1(4):479-88. doi: 10.1385/NCC:1:4:479. — View Citation

Struchen MA, Hannay HJ, Contant CF, Robertson CS. The relation between acute physiological variables and outcome on the Glasgow Outcome Scale and Disability Rating Scale following severe traumatic brain injury. J Neurotrauma. 2001 Feb;18(2):115-25. doi: 10.1089/08977150150502569. — View Citation

Thelin EP, Nelson DW, Bellander BM. A review of the clinical utility of serum S100B protein levels in the assessment of traumatic brain injury. Acta Neurochir (Wien). 2017 Feb;159(2):209-225. doi: 10.1007/s00701-016-3046-3. Epub 2016 Dec 12. — View Citation

Thompson WH, Thelin EP, Lilja A, Bellander BM, Fransson P. Functional resting-state fMRI connectivity correlates with serum levels of the S100B protein in the acute phase of traumatic brain injury. Neuroimage Clin. 2016 May 9;12:1004-1012. doi: 10.1016/j.nicl.2016.05.005. eCollection 2016. — View Citation

Vos PE, Jacobs B, Andriessen TM, Lamers KJ, Borm GF, Beems T, Edwards M, Rosmalen CF, Vissers JL. GFAP and S100B are biomarkers of traumatic brain injury: an observational cohort study. Neurology. 2010 Nov 16;75(20):1786-93. doi: 10.1212/WNL.0b013e3181fd62d2. — View Citation

Vos PE, Lamers KJ, Hendriks JC, van Haaren M, Beems T, Zimmerman C, van Geel W, de Reus H, Biert J, Verbeek MM. Glial and neuronal proteins in serum predict outcome after severe traumatic brain injury. Neurology. 2004 Apr 27;62(8):1303-10. doi: 10.1212/01.wnl.0000120550.00643.dc. — View Citation

Wang Y, Ge P, Yang L, Wu C, Zha H, Luo T, Zhu Y. Protection of ischemic post conditioning against transient focal ischemia-induced brain damage is associated with inhibition of neuroinflammation via modulation of TLR2 and TLR4 pathways. J Neuroinflammation. 2014 Jan 24;11:15. doi: 10.1186/1742-2094-11-15. — View Citation

Warren AM, Boals A, Elliott TR, Reynolds M, Weddle RJ, Holtz P, Trost Z, Foreman ML. Mild traumatic brain injury increases risk for the development of posttraumatic stress disorder. J Trauma Acute Care Surg. 2015 Dec;79(6):1062-6. doi: 10.1097/TA.0000000000000875. — View Citation

Wei D, Ren C, Chen X, Zhao H. The chronic protective effects of limb remote preconditioning and the underlying mechanisms involved in inflammatory factors in rat stroke. PLoS One. 2012;7(2):e30892. doi: 10.1371/journal.pone.0030892. Epub 2012 Feb 8. — View Citation

Zarbock A, Schmidt C, Van Aken H, Wempe C, Martens S, Zahn PK, Wolf B, Goebel U, Schwer CI, Rosenberger P, Haeberle H, Gorlich D, Kellum JA, Meersch M; RenalRIPC Investigators. Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial. JAMA. 2015 Jun 2;313(21):2133-41. doi: 10.1001/jama.2015.4189. — View Citation

* Note: There are 44 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary 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
Primary 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
Primary 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
Primary 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
Primary 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
Primary 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
Primary 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
Primary 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
Primary 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
Primary 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
Primary 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
Primary 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
Primary 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 Cerebral vascular perfusion, acute 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. 24 hours
Secondary Intracranial Pressure (ICP) measurement, first 24 hours The number of episodes of ICP >20 mmHg, measured in 15 minute increments, over the first 24 hours. 24 hours
Secondary Intracranial Pressure (ICP) measurement, 24-96 hours The number of episodes of ICP >20 mmHg, measured in 15 minute increments, over 24-96 hours. 24 hours, 96 hours
Secondary Escalation along an established care algorithm 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. 12 months
Secondary Mortality beyond 12 hours post-admission 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. 12 months
Secondary Incidence of surgical decompression beyond 12 hours post-admission 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. 12 months
Secondary Hospital length of stay, number of days Number of continuous calendar days or partial calendar days admitted to an acute-care hospital. 12 months
Secondary Intensive Care Unit length of stay, number of days Number of continuous calendar days or partial calendar days admitted to an intensive-care unit. 2 months
Secondary Total duration of mechanical ventilation, number of days Number of calendar days or partial calendar days including treatment with invasive ventilation. 2 months
Secondary Destination of discharge Home (functionally independent), rehabilitation facility, or chronic care facility 12 months
Secondary Glasgow Outcomes Scale, Extended (GOSE) - neurocognitive test 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. discharge, 3 months, 6 months, and 12 months
Secondary Disability Rating Scale (DRS) - neurocognitive function rating 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. discharge, 3 months, 6 months, and 12 months
Secondary Patient Health Questionnaire 9th edition (PHQ-9) - neurological - self assessment 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. discharge, 3, 6, and 12 months
Secondary Posttraumatic Stress Disorder Checklist for the Diagnostic and Statistical Manual of Mental Disorders 5th edition (PCL-5) - neurological - self assessment 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. discharge, 3 months, 6 months, and 12 months
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