Chung Ho Leung, Institute of Medical Science
Supervisor: Dr. Ori Rotstein (Vice-President of Research and Innovation, Unity Health Toronto)
Co-supervisor: Dr. Christopher Caldarone (Chief, Congenital Heart Surgery, Texas Children’s Hospital)
PhD thesis: Effect of Remote Ischemic Conditioning in Hemorrhagic Shock/Resuscitation
Traumatic injuries remain a leading cause of death worldwide causing substantial burden to society. In particular, resuscitation following hemorrhagic shock induces global ischemia/reperfusion injury that promotes oxidative stress, immune dysfunction, and coagulopathy, which together contribute to organ dysfunction and poor outcomes. Therefore, strategies directed at preventing the onset of ischemia/reperfusion injury have substantial potential to improve outcomes.
There were three overarching objectives in my thesis, which was supported by a Mitacs-Accelerate award: 1) develop an intervention against ischemia/reperfusion injury in an animal model of hemorrhagic shock 2) in a clinical trial examine the feasibility of administering this intervention to trauma patients 3) evaluate the effects of this intervention in trauma patients.
In a proof of principle study, we demonstrated in a murine model of hemorrhagic shock that an anti-inflammatory therapeutic known as remote ischemic conditioning (RIC) - 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 - prevented organ injury and inflammation when administered before shock, during shock, and at resuscitation, thus suggesting its potential utility in trauma patients. This work was awarded first place in the Institute of Medical Science’s Laidlaw Manuscript Competition and published in the journal Annals of Surgery.
We hypothesized the protective effects of RIC was mediated by up regulation of antioxidant response. Indeed, our results showed that RIC was ineffective in animals deficient in Nrf2, the master regulator of anti-oxidant gene response. Furthermore, we discovered that 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 hemorrhagic shock/resuscitation induced organ injury and inflammation, suggesting a novel paradigm to administer RIC.
To potentially translate our findings to the clinical setting, we conducted a Phase II randomized controlled trial at St. Michael’s Hospital 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. We found that RIC decreased levels of neutrophil degranulation, modulated the release of Th2 chemokines, and exerted a favourable coagulation profile in the early resuscitation period.
Taken together, my thesis establishes RIC as a potential therapeutic intervention that can be safely administered to trauma 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. I would like to acknowledge my supervisors Dr. Rotstein and Dr. Caldarone for giving me the unique opportunity to conduct research in both basic and clinical settings, which resulted in a number of major publications.
After graduation, I joined SickKids as a Grant Development Office Coordinator. In this role, I manage research funding opportunities, grant proposals, and award nominations for SickKids Research Institute faculties. I have continued to pursue my interest in cooking by taking courses in the George Brown Culinary Arts program. Moving forward, I am interested in achieving an MBA degree and pursuing leadership roles in research administration and business development with a view to advance innovative therapeutics from bench to bedside.