Personalized Acute Care Medicine: A Biomarker-Guided Approach by Frederick Korley, MD, PhD
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Presented at the Third Annual Barsan Emergency Medicine Research Forum
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Personalized Acute Care Medicine: A Biomarker-Guided Approach by Frederick Korley, MD, PhD
- 1. Personalized Acute Care Medicine A Biomarker-Guided Approach Frederick Korley, M.D., Ph.D. 2018 Barsan Day
- 3. YOU have been driving blind Target Blood Pressure Counseling regarding TBI outcome HsTnT delta = 6 ng/L
- 4. BEST-TRIP CRASH Good outcome regardless Poor outcome regardless Good outcome due to novel treatment NovelTherapy Problem 1: No Prognostic Biomarkers for TBI
- 5. Solution 1: Prognostic Biomarkers Multi-Center Observational Cohort n = 3,000 Neurofilament light chain (NF-L) Ubiquitin Carboxy- terminal Hydrolase L1 (UCH-L1) Neuron-specific enolase (NSE) Glial Fibrillary Acidic Protein (GFAP) S100B Total and phosphorylated Tau TNF-alpha IL-6 IL-10
- 6. Solution 1: Prognostic Biomarkers • 454 CT negative subjects who had an MRI • 134 CT-, MRI+ (29.5%) • GFAP higher in CT-MRI+ than in CT-MRI- • AUC: 0.76
- 7. Problem 2: No Predictive / Monitoring Biomarkers for TBI BEST-TRIP CRASH Diffuse axonal injuryContusion Hematoma SAH Cerebral edema Increased ICP I have a new drug for cancer
- 8. Solution 2: Monitoring Biomarkers GFAPpg/ml NFLpg/ml Saline VPA Saline VPA Time Time Bio-BOOST 3 Hyperbaric Oxygen in Brain Injury Treatment Brain Oxygen Optimization in Severe TBI OPTIMA-TBI Concussion in U of M Athletes
- 9. Solution 2: Monitoring Biomarkers
- 10. Problem 3: Evaluation of Suspected ACS • 99th%: 14 in Europe and 19 in US • Delta of 6 • Gender-specific cut- offs? • Type 1 versus Type 2 MI
- 11. Solution 3: Troponin Registry • Risk of adverse cardiovascular events in patients with recent onset symptoms, no ECG changes and no dynamic troponin changes • Troponin kinetics provide clues regarding the underlying etiology
- 12. Funding • Career Development Award, Robert Wood Johnson Foundation (PI) • 1 R21 HL140274-01: Predicting Incident Stroke Using Blood Biomarkers of Brain Injury (PI) • 3U01NS08609004S1: Supplement to TRACK-TBI (Awardee) • 1U24NS100659-01: SIREN Network (Co-I) • 1U01NS095926-01A1: HOBIT (Co-I) • Massey Foundation (PI) • UM Injury Center (PI) • Gary Zenkel (Co-PI)
- 13. Acknowledgements TBI collaborators • William Barsan, M.D., Robert Silbergleit M.D., William Meurer, M.D., and SIREN and BOOST-3 Teams • Geoff Manley, M.D., Ph.D. and TRACK TBI • Ramon Diaz-Arrastia, M.D., Ph.D. • Gaylan Rockswold M.D., Ph.D., and HOBIT team • Hasan Alam, M.D., and Lab • Robert Neumar, M.D., Ph.D. • Steve Broglio, Ph.D. Proteomics • Jenny Van Eyk Ph.D. • Mitra Mastali Ph.D. Metabolomics • Kathleen Stringer, Ph.D. Chemical Engineering • Mark Burns, Ph.D. • Sarah Mena, Ph.D. • Zach Pritchard Machine Learning • Kayvan Najarian and Lab Study Coordinators / Research Volunteers • Hayley Falk, M.Sc • Jordan Stav, M.D. • Jonathan Welt Statistics • Jason Goldstick Ph.D. MCIRCC
- 14. Why drive blind when you can see?
Editor's Notes
- My name is Fred Korley and if you have ever wondered "what has this guy been up to? Well wonder no more.
- I can see it in your faces. Some of you are saying.......this is really dumb. Guess what you do the same thing. Anytime you treat a patient to some arbitrary blood pressure, you are driving blind. Anytime you counsel a patient regarding their TBI, you are driving blind and Anytime you rule in or rule out MI using the high sensitivity troponin T and you use the magic number 6 for the delta, You are acting like the man in the video. YOU are driving blind.
- There are three important areas where we currently drive blind and my research is focused on removing these blind spots. The first is the lack of prognostic biomarkers in TBI. For any novel TBI therapy, there are bound to be people who will have a good outcome due to the treatment. But there are also people who will have a good outcome regardless of treatment and people who will have a poor outcome regardless of treatment. Unfortunately, because we have no good ways to identify these subtypes, we don't distinguish between these groups. We enroll every one clinical trials and this makes it more difficult to demonstrate efficacy.
- Here is my approach to dealing with the lack of prognostic biomarkers problem. I am one of the co-investigators of TRACK-TBI which is an NINDS funded multi-center observational cohort of TBI patients. Currently TRACK TBI has enrolled 2800 out of 3000 subjects. We are using a multi-marker approach, where we examine biomarker from injury to different brain cell-types. We examine injury to neuronal cell body using UCHL1 and NSE We examine injury to axons using NFL, total tau and phosphorylated tay We examine injury to astrocytes using GFAP and S100B We are examining cytokines including TNF-alpha, IL-6 and IL-10
- Already some of this work has yielded interesting results that you will start seeing in press soon. The one I want to highlight is the identification of brain injury in TBI patients with a normal head CT We studied 454 CT negative subjects who had a brain MRI. 30% of these CT negative subjects had findings of brain injury on MRI GFAP values were significantly higher in the CT negative MRI positive subjects than in those with both negative CT and MRI GFAP was able to distinguish between these two groups of patients with an AUC of 0.76 Which means that GFAP can pick up brain injury that is not detected by CT.
- The second problem is that there are no biomarkers for subclassifying TBI. Although TBI is made up of different sub-types, We pretty much put everyone in the same bucket. We may use a crude classification scheme like GCS and then we enroll then all in clinical trials. It is just like saying I have a drug for cancer and I am going to enroll all cancer patients…….lung, brain, breast, you name it.
- Here is what my group is doing about this. Some of you may be familiar with Dr. Alam’s study that showed that pigs treated with high dose of valproic acid do better than those treated with saline only. We measured GFAP and NF-L in these pigs and found that those treated with VPA had lower GFAP levels over the first 10 days and lower NFL levels than those treated with saline only. Which implies that serial measurement of these biomarkers may be valuable for monitoring response to therapy. We plan to validate this in a number of studies: first the BOOST which will randomize patients to treatment based on ICP and partial brain tissue oxygenation measures or to ICP measurements alone. We are also looking to validate this in a trial randomizing patients to different doses of hyperbaric oxygen. These two studies are being run by the SIREN network. I also want to mention that I am the PI of a study called OPTIMA-TBI that is randomizing patients to high dose fish oil versus placebo and we monitoring the effect on biomarkers. Finally, with funds from a donor to the university I am also the co-PI of a study examining the diagnosis of concussion in U of M athletes using biomarkers.
- With funds from the massey foundation, I am also working on building a device of contiuous and real-time measurement of multiple biomarkers. THe device can be attached to either an a-line or an EVD.
- Finally, we just started using high sensitivity troponin clinically and I know everyone has their own feelings about this assay. However, without a doubt when you look under the hood, it is not pretty. We are using a cut-off for abnormal troponin that is different from the cut-off used in the rest of the world and it is all based on one study. We are using a delta of 6 for ruling in or ruling out MI based on little data. Some advocate for using a different cut-off for men versus women but there isn’t sufficient data to guide that Finally, we are diagnosing more MI and need new approaches to distinguishing type 1 from type 2 Mis.
- What are we doing about this? I believe unstable angina is very rare in the era of hsTnT. I was not the first to say it. Eugene Brawnwald who first defined unstable angina first wrote about this in 2013. We are building a registry and one of the questions we will answer is whether it is safe to stop the rule out MI process in patients with recent onset symptoms, no ECG changes and no dynamic troponin changes We are also looking at the kinetics of troponin to give us insights into the etiology of troponin elevation. For example I can tell you by looking at these troponin values that this patient whose troponin peaked within 8 hours of initial elevation is unlikely to have type I MI.
- I take all kinds of donations so if you want to support the work in any way, let me know.
- I want to thank everyone who has been helping me along this journey
- Because there really is no reason to drive blind when you can see.