Year: 2019
Type: dissertation
Study design: Clinical Trial
Abstract: Traumatic injuries remain a leading cause of death worldwide despite advances in resuscitation care, causing substantial burden to society. Trauma complicated with hemorrhagic shock/resuscitation (S/R) represents a form of global ischemia/reperfusion injury that promotes oxidative stress, systemic inflammation, and coagulopathy, which together contribute to organ dysfunction and poor outcomes. Therefore, strategies directed at preventing onset of ischemia/reperfusion injury have substantial potential to improve outcomes. Remote ischemic conditioning (RIC) is a simple non-invasive intervention in which a limb is subjected to sequential cycles of brief ischemia/reperfusion by inflation and deflation of a pressure cuff. RIC protects organs against ischemia/reperfusion injury in both experimental and clinical settings, but its effects in S/R has not been well defined. In this thesis, we investigated the efficacy of RIC in both pre-clinical and clinical settings. We first demonstrated in a murine model of S/R that RIC prevented organ injury and inflammation when administered before shock, during shock, and at resuscitation, suggesting its potential utility in trauma. This protective effect was mediated by induction of antioxidant response through the transcription factor Nrf2. Furthermore, humoral factors liberated by RIC prevented neutrophil migration in response to injury and oxidant-induced mortality. A unique finding was that transfusion with RIC donor blood protected the recipient animal from S/R induced organ injury and inflammation, suggesting a novel paradigm to administer RIC. To translate our findings to the clinical setting, we conducted a Phase II randomized controlled trial to investigate the feasibility and effects on the immune-inflammatory and coagulation profiles of RIC administered to trauma patients sustaining hemorrhagic shock. A total of 50 patients were enrolled, in whom in-hospital RIC was successfully and safely administered to most of the patients. Although RIC did not significantly influence clinical outcomes, RIC prevented neutrophil degranulation, modulated release of Th2 chemokines, and exerted a favourable coagulation profile in the early resuscitation period. Taken together, our work establishes RIC as a potential therapeutic intervention that can be safely administered to patients in the acute injury setting. Future studies aimed at characterizing the mechanisms of RIC and optimizing its administration may lead to beneficial outcomes in trauma patients.
Source: TSpace (University of Toronto)
Author: Chung Ho Leung
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3145830746