Thanks to NIH funding, MCIRCC now offers a multi-year, multidisciplinary training program for advanced training in emergency critical care research. After we interviewed David Machado-Aranda in May, we now turn to Cindy Hsu, MD, PhD, whose K12 research focuses on using valproic acid (VPA) to improve the outcomes of patients who endure out-of-hospital cardiac arrest (OHCA).
More than 350,000 Americans suffer from cardiac arrest each year, and the survival rate for OHCA remains dismally low at only 20%. Although treatment options (e.g. CPR and targeted temperature management) have improved in the past decade, neurologic injury is still the most common cause of death after OHCA. Hsu hopes her research will not only impact the survival rate, but also improve the functional outcome of OHCA patients so they are not dependent on ventilators and long-term care.
Hsu was inspired by prior studies, including those done recently by Dr. Robert Neumar’s laboratory, that showed VPA could improve survival rate and neurologic outcomes in rat cardiac arrest models. Also at U-M, Dr. Hasan Alam’s laboratory has been using high dose VPA in a polytrauma porcine model with encouraging results. Drawing from these studies, Hsu is eager to apply their findings to a porcine cardiac arrest model.
“Valproic acid induces pro-survival proteomic changes in trauma, hemorrhagic shock, and traumatic brain injury porcine models. I want to take this one step further to see if VPA could work in a porcine cardiac arrest model, with hope of translating our findings to clinical trials one day,” Hsu said.
Valproic acid is a seizure medication that also functions as a histone deacetylase inhibitor, which allows the DNA to unwrap around histones and increase certain gene expressions. However, its exact neuroprotective mechanisms at work for cardiac arrest remain unknown. It is Hsu’s hope that she will understand these mechanisms at a granular level after she completes her research.
Hsu will employ an adaptive design model adopted from the clinical studies of U-M’s Dr. William Barsan for her large animal experiments. Compared to randomized double-blinded studies, an adaptive design model allows researchers to adjust the size of treatment groups based on their ongoing performance, thus optimizing the experiment as it progresses instead of waiting until its conclusion.
“Randomized controlled studies are like crossing an intersection with a blindfold on – you are unable to remove it until you make it all the way across, hopefully unscathed. With adaptive design, you have your eyes open the entire time and can adjust your course to make it across the street safely and accurately,” Hsu explained.
Not only is this a more efficient use of resources, it allows researchers to accurately tease out correct drug dosages in a much quicker timeframe using fewer animals. While Dr. Barsan uses this method in human clinical trials, Hsu believes she will be the first at the U-M to apply adaptive design to a large animal study.
After inducing cardiac arrest in the animals, Hsu’s team will perform CPR to restart their hearts. Some animals will then undergo hypothermic targeted temperature management (HTTM) after VPA or placebo infusion, while the others will receive these interventions at normal temperature. HTTM is induced in human patients after OHCA to protect the brain from further damage after restoration of blood flow. Once the HTTM animals are slowly rewarmed to normal temperature, they will recover while on a ventilator over the next several days. Hsu will then test the neurocognitive function of the animals that are able to come off the ventilator.
Hsu’s project is a prime example of MCIRCC’s multidisciplinary approach. Not only will Hsu utilize the research of Drs. Neumar, Alam, and Barsan, she will also incorporate the resources of MCIRCC’s Large Animal Operative & Intensive Care Unit managed by Dr. Hakam Tiba. In addition, Hsu will be working closely with Manjunath Pai, PharmD, to understand how cardiac arrest and hypothermia affects the pharmacokinetics and pharmacodynamics of VPA. By bringing together research from the Departments of Emergency Medicine and Surgery, as well as the College of Pharmacy, Hsu will bring new perspectives to OHCA care.
“It would be incredibly difficult for me to do a study like this on my own. It is a very ambitious project that is all about team science. MCIRCC’s mentorship, core facilities, and infrastructures will help me accomplish the project goals much more efficiently,” said Hsu.