Advancing Perioperative Medicine

1. Advancing PerioperativeMedicine Mark F. Newman, MD Merel H. Harmel Professor and Chairman

2. Environment for Success • CT Surgery • Orthopedics • Cardiology • Neurosurgery • General Surgery • Psychiatry • Behavioral Medicine • Pulmonary • DCRI • Pediatrics • Neurology • Radiology • Obstetrics • Urology • Neurosciences • ADRC • BIAC • FIND Lab

3. Perioperative Medicine Podgoreanu (2005) JACC;46(11):1965-77

4. Systemic Host Response Gene B Gene C Gene N Gene A Pharmacologic Interventions Exposure to CPB Anesthesia Surgical Injury OR Environment Adverse event -inflammation -thrombosis -oxidative stress -neuroendocrine response Normal outcome GENOTYPE PHENOTYPE Perioperative Stress: the Ultimate Gene-Environment Interaction “controlled trauma” COMORBID CONDITIONS ALLOSTATIC LOAD Podgoreanu MV et al, J Am Coll Cardiol 2005;46(11):1965-77

5. Perioperative Medicine OR Perioperative Medicine

6. OR0.5 [0.3-0.8] OR0.1 [0.02-0.9] Podgoreanu et al. Circulation 2006;114:I.275-I.281

7. Lobato et al. Circulation 2011;124:S143-S148

8. First genomewide association studies (GWAS) in perioperative medicine: acute kidney injury and postoperative atrial fibrillation AKI Stafford-Smith et al. Anesth Analg 2011;SCA

10. Cognitive Change Over Five Years 2 1.5 Not Impaired at Discharge Impaired at Discharge 1 0.5 Change from Baseline 0 -0.5 -1 -1.5 -2 5 Year Discharge 6 Week 6 Month Time of Evaluation Newman. NEJM, 2001.

13. A Genetic Basis for Cognitive Decline After Cardiac Surgery • 2 minor alleles protective against POCD: CRP 1059G/C and SELP 1087G/A • Model C-statistic = 0.7, p<0.0001 • Absolute risk reduction in POCD: • 20.6% for CRP 1059C carriers • 15.2% for SELP 1087A carriers • Multiple comparison adjustment by permutation testing • Population substructure – analysis restricted to Caucasians; genomic control Mathew et al. J Am Coll Cardiol 49 (19):1934-1942, 2007

14. Nerve injury pain syndromes • Persistent pain after severe nerve injury • Thoracotomy • Amputation • Neuropathic allodynia • Affects up to 50% of patients • Very difficult to treat

15. Military Medicine

16. Veterans Injury Pain Evaluation Research(VIPER) • DOD award # DM102142, $1.5M • Molecular signatures of chronic pain subtypes • 175 OIF/OEF/OND amputees • 12 enrolled since starting in Jan 2012 • Metabolomic, genomic, genetic and epigenetic determinants of persistent nerve injury pain

17. Molecular Signatures of Chronic Pain Subtypes Human (1) PI: Andrew Shaw MD Org: Duke University Medical Center Problem, Hypothesis and Military Relevance • Problem: (1) There are no good tests to differentiate between different types of chronic amputation pain. (2) There are no good ways to measure susceptibility to chronic pain subtypes (phantom limb pain, neuralgia, CRPS). • Hypothesis: (1) Plasma protein signatures can identify each type of amputation pain. (2) Sequencing the genes of these proteins can identify patients at risk for each type of pain. • Military Relevance: New, objective tools facilitating the differential diagnosis and risk assessment of chronic pain states would allow more focused deployment of rehabilitation resources, and thus permit earlier return to functional status for injured warriors. Timeline and Direct Cost Proposed Solution • Aim 1a: Describe the molecular (proteomic) signatures of phantom pain, neuralgia pain and Complex Regional Pain Syndrome (CRPS) in 450 war injured amputees. • Aim 1b: Describe the biology of chronic amputation pain subtypes in terms of the peptides and proteins expressed in early and late blood samples from amputees • Aim 2a: Generate list of candidate risk genes for each subtype of amputation pain. • Aim 2b: Sequence genes of proteins from Aim 2a to find new polymorphisms associated with functional differences and risk of each pain subtype.

18. Comparative Pain Genomics • Fly.....Mouse.....Human

20. 0 0 0 1 1 1 Smart Screening • Demographics • History Existing Models: McSPI Baseline Risk Assessment Refined Risk Assessment Comprehensive Risk Assessment Hi Lo Specificity • History & Demographics: McSPI • Standard labs • Intraoperative procedural variables • Stable Molecular: SNPs • CRP (3`UTR 1846C/T) • IL6 (-174G/C) • Existing Models: Grocott SNPs • Integrate Existing Data • Dynamic • Gene Expression • Protein Expression • Cytokines • EndoCAB • Metabolomics: CRP • Vascular Imaging • New Tissue/Blood Bank Analyses? • Integrate Data

21. ACES-5 integrates both residency and fellowship training into a continuum. This continuum provides a total of 12 - 13 months research experience and subspecialization within the 5 years. ACES-6 is designed to integrate intensive research training into the residency and early faculty sequence. Both programs provide additional stipend support and are designed to attract top recruits and provide opportunity for academic progression. Academic Career Enrichment Scholars (ACES)

22. The work described is that of the Duke PEGASUS group and in particular the key efforts of Drs. Mihai Podgoreanu, Joseph Mathew, Andy Shaw,, Miklos Kertai, Ian Welsby, Mark Stafford-Smith and many other outstanding Duke investigators.