Presented at the Third Annual Barsan Emergency Medicine Research Forum

1. Cardiac Arrest, Valproic Acid &
My K12 Journey
Cindy H. Hsu, MD, PhD
Assistant Professor
Division of Emergency Critical Care
Division of Acute Care Surgery
Department of Emergency Medicine & Surgery

2. Disclosures
• NIH K12HL133304-01 (K12 Career Development in
Emergency Critical Care Research)
• NIH Loan Repayment Program

3. 430,000 sudden cardiac deaths
annually in the United States

4. Major Cause of Death = Neurologic Injury
33%
67%
75%
25%
Other
Neurologic injury
Out-of-hospital
cardiac arrest
In-hospital
cardiac arrest Lavers et al. Intensive Care
Med. 2004;30:2126–2128

5. NO PHARMACOLOGIC
TREATMENT
IMPROVES POST-ARREST
NEUROLOGIC OUTCOME

6. Valproic AcidValproic Acid: An Old Drug with New Tricks?

7. Adapted from Higgins et al. Pharm Res (2017) 34:1658–1672
AKT/mTOR  Neuroprotection
HDAC inhibitor  cell cycle/anti-apoptosis
Master transcription factors  Neurogenesis
3
2
1

8. Valproic Acid & Cardiac Arrest
Crit Care Med. 2017 Nov;45(11):e1149-e1156

9. Valproic acid improves survival after
asphyxial cardiac arrest in rats
300 mg/kg IV VPA initiated at 5 min after ROSC and infused over 20 min
Oh JS et al. Crit Care Med. 2017 Nov;45(11):e1149-e1156

10. Up to 140 mg/kg VPA is safe in healthy subjects
Clin Pharmacokinet. 2018 Feb;57(2):209-219
FDA approval = up to 60 mg/kg/day for seizures or bipolar disorder

11. Hypothesis
Valproic acid improves the survival and
neurologic outcome of OHCA survivors

12. Steps toward a cardiac arrest RCT
Dose-finding experiments in
swine cardiac arrest model
Early phase 2 clinical trial
(Go/No-Go study)
Multicenter adaptive RCT
Pharmacokinetics & pharmacodynamics
Safety/tolerability
Biomarkers of target engagement
Adaptive dose-finding in humans
Identify responders vs non-responders
Pharmacokinetics & pharmacodynamics
Safety/tolerability
Biomarkers of target engagement

13. Specific Aims
• Aim 1: Determine optimal biomarkers for VPA
neuroprotection after VF cardiac arrest by using high
throughout RNA sequencing
• Aim 2: Determine the neuroprotective effect of VPA after
VF cardiac arrest

14. Aim 1
• Determine optimal biomarkers for VPA neuroprotection
after VF cardiac arrest by using high throughout RNA
sequencing

15. Aim 1 Biomarker Study Design
V-fib
arrest
CPR DefibAcclimation
7 days 8 min 12 min 20 min 90min 60 min 60 min
Group Allocation
• Placebo (n=5): Controlled normothermia + saline
• VPA (n=5): Controlled normothermia + 150mg/kg VPA over 90 min
• VPA (n=5): Controlled normothermia + 75mg/kg VPA over 90 min
• VPA (n=5): Controlled normothermia + 300mg/kg VPA over 90 min
• Sham-operated (n=3): Instrumentation + anesthesia only, no CA
End
infusion
Sustained
ROSC
Start infusion
1 hr
Post-
infusion
2 hr
Post-
infusion
t0 t8 t20 t40 t130 t190 t250
Randomization
Biomarker
Study (Aim 1)

16. 300 mg/kg 150 mg/kg? ?
80% 40% 20% 10%
% Free
VPA
VPA
Dose
What VPA dose is protective in humans?

17. 0
50
100
150
200
250
300
350
400
10' CPR 20'
CPR/Post
VPA
1h ROSC 4h ROSC 6h ROSC 12h
ROSC
24h
ROSC
VPConcentration(mg/L)
Total and Free VPA Concentration-Time Profile
Total
Free
Expected Free
VPA Pharmacokinetics in Swine VF Arrest during TTM
(150 mg/kg VPA)
Equivalent to 60-90 mg/kg in human

18. Using biomarkers of target engagement to
identify VPA responders
Adapted from Perez-Gracia et al.
Cancer Treat Rev, 2017. 53: p. 79-97

19. Are buccal epithelial cells better neuronal
surrogates for biomarker studies?
Neurons
Buccal
PBMCs
PBMCs = Peripheral Blood Mononuclear Cells

20. 150 mg/kg VPA infusion

21. 300 mg/kg VPA infusion

22. Lactate Trend
0
2
4
6
8
10
12
14
16
18
300 mg/kg VPA Lactate
0
2
4
6
8
10
12
14
16
18
BL 6 min 35 min 90 min/End
infusion
1hr post-
infusion
2hr post-
infusion
150 mg/kg VPA Lactate
ROSC ROSC
150 mg/kg VPA 300 mg/kg VPA

23. Baseline 2 hours post-infusion
150 mg/kg
VPA
300 mg/kg
VPA
0.7 mcg/kg/min
Epi gtt
0.25 mcg/kg/min
Epi gtt

24. Aim 2
• Determine the neuroprotective effect of VPA after VF
cardiac arrest

25. Aim 2 Experimental Design
V-fib
arrest
CPR DefibAcclimation
7 days 8 min 12 min 20 min 90min Day 1 – 4
Group Allocation
• Placebo (n=5): Controlled normothermia + saline
• VPA (n=5): Controlled normothermia + 150mg/kg VPA over 90 min
• VPA (n=5): Controlled normothermia + 75mg/kg VPA over 90 min
• Sham-operated (n=3): Instrumentation + anesthesia only, no CA
End
infusion
Sustained
ROSC
Start infusion
t0 t8 t20 t40 t130
Randomization
Days 1-4
Survival &
Neurologic Outcome
Assessment (Aim 2)
Day 1
PK studies PBMCs
Buccal swabs
Brain harvest

26. Future Directions
• Determine the synergistic neuroprotective effect of VPA
with targeted temperature management in porcine VF
model
• Translate our findings to an early phase 2 clinical trial in
order to:
– Determine most efficacious neuroprotective VPA dose in OHCA
patients
– Identify VPA therapeutic responders

27. Acknowledgment
Bob NeumarHasan Alam Bill Barsan Kevin Ward Demetri
Yannopoulos
Bob BartlettRudi Ansbacher
Hakam Tiba B. McCraken B. Cummings Alvaro Rojas-Pena T. Sanderson V. Nikolian A. Williams

28. Acknowledgment
• Dr. Kyle Gunnerson
• Carmen Colmenero
• Chandler Rygalski
• UROP Students
• Denise Poirier
• Tess Bonham
• Stephanie Laurinec
• Jennifer Fowler
• Acute, Critical Care, Surgery, & Transplant CTSU Staff
• EC3 colleagues & nurses
• Department of EM Research Admin Office
• MCIRCC & NHLBI

29. Cindy Hsu, MD, PhD
hcindy@med.umich.edu
@CHsu1012
Thank You!