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Advanced Physiologic Monitoring Laboratory Texas Heart Institute TAMU ENGR 281 ESP A Brief Look at Engineering in Medical Research April 5, 2006 Alan Brewer, BSBE, MBA Advanced Physiologic Monitoring (APM) Disclosures Major portions of this research were supported by a grant from TATRC, a department of the U.S. Army, under a sub-contact from UT-HSC-H. Other smaller portions of this research were supported by various other grants including the MacDonald Foundation. The APM department expresses its gratitude and appreciation to all supporting parties. Advanced Physiologic Monitoring (APM) Team Members Dr. S. Ward Casscells, III, MD – PI Dr. Amany Ahmed, MD Dr. Muhammad S. Munir, MD Dr. K. J. Shankar, MD Dr. Igor Stupin, MD Alan Brewer, BSBio Engr, MBA Bioengineer (F/T) – to be hired Texas Medical Center – Houston, TX Texas Heart Institute Texas Medical Center – Houston, TX Largest Medical Center in the World Direct Employment - over 65,000 Approximately 45 Institutions including over 12 separate hospitals Two Medical schools, Dental, Pharmacy, four Nursing schools, School of Public Health, Graduate School of Biological sciences Affiliations with UT, Texas A&M U, Rice U and U of H Immense amounts of research continuously underway, $3.5B for 2000-2004 alone Over 5M patient visits per year, 6600+ beds 22,000+ students Texas Medical Center – Houston, TX Academic and Research Institutions Baylor College of Medicine The University of Texas M. D. Anderson Cancer Houston Academy of Medicine-Texas Medical Center Library Houston Community College System, Health Science Programs Prairie View A&M University, College of Nursing Rice University Texas A&M University Health Science Center - Institute of Biosciences and Technology Texas Heart Institute Texas Southern University College of Pharmacy & Health Sciences Texas Woman's University Institute of Health Sciences-Houston University of Houston College of Pharmacy The University of Texas Health Science Center at Houston - Dental Branch, Graduate School of Biomedical Sciences, Harris County Psychiatric Center, Medical School, School of Health Information Sciences, School of Nursing, School of Public Health Michael E. DeBakey High School for Health Professions Potential Roles for Engineers in Medical Research Experiment Design Good hypothesis development Insure endpoints are “testable” Control for extraneous or confounding influences Prototype Device Design and Construction Materials Software Safety Data Collection, Analysis and Interpretation DAQ Implementation Optics Telemetry Complex Imaging Project management Why is a modern pacemaker (or many other medical devices) similar to a space vehicle? or a down hole instrument package? or an undersea probe? etc? Operate in a hostile environment Measure environment continuously and react independently Impractical to service more than infrequently, thus high reliability is paramount Must telemeter real-time and stored data to “mission control” upon command Highly advantageous to be remotely programmable as desired Data up- and down-links must be secure from interference Very energy efficient to maximize battery life Small in size and weight Able to compress and store data efficiently Small program footprint Past APM accomplishments Manuscript regarding CHF and Core Temperature published in Am Heart Journal in May 2005 American Heart Journal, Vol 149, no 5, May 2005 APM Priority Projects Swine Study – Local Myocardial Temperature and Ischemia Detection DAQ was developed for this study Hamster Study – CHF and Hypothermia Prospective Clinical Study – CHF and Hypothermia APM Swine Study Engineering Local Myocardial Temperature and Ischemia Detection Experiment design – Understanding heat transfer Sensor selection and modification, device prototyping DAQ development, LabVIEW Data analysis APM Hamster Study Engineering Body Temperature as a Predictor of Impending Heart Failure/CHF Experiment design Biotelemetry sensor selection Data analysis Swine Study Project Status April 3, 2006 Pilot study - Four experiments performed Six more subjects planned and requested Sensor improvements made and validated – more minor modifications desired Results from pig #1 and pig #4 were promising Results from pig #2 and pig #3 were equivocal Surgery for epicardial temperature sensor placement is non-complicated, but proper location is still a possible issue Issues with trans-venous approach to RADI wire in CS and balloon placements (esp. in RCA) for swine subjects Clinical Need for Better Ischemia Detection Driven by - 12 million in USA with coronary artery disease (CAD) One-half suffer angina pectoris Thus silent myocardial ischemia (SMI) is signifcant problem, estimated that 2 to 4 % of USA population have SMI. Pain is a poor predictor Patients with angina also have intermittent SMI Anesthetized patients cannot register pain symptoms, also some disabled patients Clinical Need Clinical Need driven by – Episodic diagnostic testing is inconvenient and costly Exercise treadmill testing Low sensitivity, high false-positive rate Not tolerated by many patients Must be confirmed by radionuclide imaging techniques (perfusion scintigraphy or exercise ventriculography) or stress echocardiography Holter or 30-day ambulatory monitoring not highly specific e.g. LBBB, etc. can mask SMI in H-ECG Serial testing as method of monitoring for SMI is even more problematic Clinical Need Clinical Need driven by – Currently, real-time diagnosis of SMI by ECG is problematic Electrolyte imbalance, Rx side-effects, and non- cardiac events can manifest with S-T segment shifts in ECG Sensor positioning relative to local ischemia, and near-field versus far-field signal amplitudes complicate using intra-cardiac ECG for SMI detection Ischemia Project - Added Opportunities Clinical opportunities – As feature for implantable cardiac devices (e.g. pacemakers and ICD’s) There is a spectrum of possible utilizations of this technology in such devices (one end of the spectrum) - Stored diagnostic for physician retrieval and use at time of device follow-up (opposite end of the spectrum) - Potential modulator/input to automatically programmed pacing parameters (e.g. upper-rate tracking limit) Project History – Prior Studies Literature states that one-half of myocardial heat production is carried away convectively by the coronary blood flow Other significant heat fluxes are to the lungs, airways, great vessels and the cardiac blood flow Open-chest themography shows distinctly cooler regions of the epicardium result from coronary ligation Closed-chest heat fluxes are more complex and difficult to model Predictions were for small amplitude thermal signatures Why is the thermal signal small? Normally other significant heat fluxes are to the lungs, airways, great vessels and the cardiac intra- cavity blood flow • Once a local region becomes cooler, the direction of heat flux will reverse from the normal direction Project History – Canine Studies Team initially pursued a closed-chest experiment using endovascularly placed sensors in a canine model Right atrium blood flow Coronary sinus blood flow Right ventricular apex myocardium Project History – Canine Studies But… Long procedure times Well-developed canine collateral myocardial circulation Sensor positioning issues – RV not sensitive as hoped RADI device used for CS temperatures Small amplitude signals This clarified need for accuracy, resolution and drift Swine Project - Hypotheses Hypotheses generated that - Ischemic myocardium quickly will become colder than surrounding non-ischemic myocardium Temperature drop with sudden ischemia will be as or more rapid than changes in surface 12-lead ECG morphologies. Temperature drop with sudden ischemia will be as or more widespread than locally measured changes in the intra-cardiac electrogram morphologies. Temperature in the coronary sinus will show distinct changes if significant volumes of myocardium become ischemic. Instrumentation Development “DAQ” and sensor system Hi-res (0.05 ° C), reasonably rapid response (tc ≈ 1.5 sec) and 1000 samples/sec LabVIEW-based 3 temperatures, plus 12-lead ECG and up to 3 channels of intra- cardiac electrograms DAQ Design Issues for Pilot study Other user requirements Minimize custom components Simultaneous display of 15-lead ECG and 3 temperature channels Automatic file saving and labeling Annotation markers and comments record capability Adjustable ECG filters to accommodate electrically noisy OR Swine Study - Sensor Design Issues Which is better – Thermistor or Thermocouple? Adapted sensor Thermocouple sensor No intrinsic heat production Bare sensor Accurate to 0.05 °C goal if properly calibrated Small yet rugged and reusable Rapid time constant, << 1 sec when bare sensor Sensor Design Issues, cont Thermocouple sensor Hard to place bare sensors in 2-0 prolene suture myocardium for pig # 1 inserted into PTFE Clinical requirements for swine tube pre-shrinking study allowed changes for improved #2 sewing surgical placement needle attached Added sewing needle to sensor to PTFE shrink tubing Protects thermocouple and provides for easy method to Adapted sensor secure sensor in position These changes increased time constant of thermal response to approximately 1.0 to 1.5 sec Bare sensor Sensor Placement Placement designed to match each sensor with a “Target Ischemic Zone” Sensor Target Position Zone/Vessel Anterior LV LAD Posterior- Circumflex Lateral LV Lateral RV RCA Advanced Physiologic Monitoring (APM) Warning! The following two slides contain graphic medical images of swine hearts ex-vivo Swine Study Epicardial Sensor Placements Implantation is similar to temporary epicardial pacing wire Approx 4 mm depth Clip Swine Study Epicardial Sensor Placements Sensor placement Hypertrophic complications heart with grossly thickened left ventricle Too shallow Clip Swine Project – Preliminary Results In our closed-chest swine with PCI-induced ischemia model -- Ischemic myocardium becomes colder (by about 0.5 ° C) than other non-ischemic myocardium in approx 2 minutes or less. The temperature drop due to acute ischemia occurs at the same time or slightly before changes are observable in surface 12-lead ECG morphologies. The temperature of non-ischemic myocardium remains stable and consistently tracks with minor body temperature variations The temperature of non-ischemic myocardium neither increases nor decreases when other portions of the myocardium suffer an ischemic insult Detailed data analysis ongoing Pig 2 CFX Occlusion – 2005-12-02 – 12:14 pm Pig 2 CFX Occlusion – 2005-12-02 – 12:15 pm Advanced Physiologic Monitoring (APM) Future research opportunities Extend this study to a 30-day chronic model using telemetry Look in detail at confounding influences Environmental temperature Fever Activity and exercise Project Status – Hamster Study Expanded Study Design Plans BIO-TO-2 Cardiomyopathic Syrian Hamsters ETA-F20 or CTA-F40 transmitter (DSI) implanted intraperitoneal or Sub-Q under anesthesia CONTROL CONSTANT SELECTIVE No therapy INTERVENTION INTERVENTION Room Sustained Sustained TT of Temperature Thermotherapy 25 °C in event of 21°C (TT) of 25 °C hypothermia. All animals followed and monitored via implanted device and manually until symptoms exacerbate, then euthanized @ ≤ 6 months Project Status Prospective CHF Study “Low Body Temperature is a Marker of Poor Prognosis in CHF Patients” Approved by SLEH/THI IRB for non-significant risk study status CHF NYHA III and IV patients already followed by a CHF clinic and optimally medically managed All patients record temp BID Follow for 6 months Compare hospitalization rates, mortality, other endpoints; and track utilization 22 patients now recruited, of 140 patients planned Project Status Prospective CHF Study Hypothesis: In HF patients, low and/or falling body temperature can predict a poorer prognosis, compared to HF patients whose body temperature remains consistently normothermic Prospective Study Proposal Study Design Population: Patients enrolled at THI HF Clinic Recruit 140 patients per inclusion & exclusion criteria 1. Pts. receive ‘optimal medical management’ 2. Pts. record oral temp (BID) within 1 hour after waking up and within 1 hour prior to retiring All Pts.’s that complete data reviewed against endpoints 1. Normothermic vs. hypothermic/falling temp 2. Negative for endpoints vs. positive for endpoints Prospective Study Proposal Primary Endpoints 1. Hospitalization for CHF 2. Mortality 3. Significant CHF decompensation episode not requiring hospitalization, but necessitating unscheduled physician visit(s) and adjustment to CHF therapy 4. Assignment to “Status 1A” on heart transplantation list 5. Implantation of LVAD device Prospective Study Proposal Inclusion Criteria 1. CHF (Tx for at least 30 days prior) 2. LVEF ≤ 40% (measured within last 1 year) 3. NYHA Class III or IV 4. Age ≥ 18 yrs and ≤ 70 yrs 5. Stable Rx’s for ≥ 7 days Prospective Study Proposal Exclusion Criteria 1. Recent implantation of CRT ICD or CRT pacemaker (within 30 days) 2. Recent CVA (within 30 days) 3. Recent participant in another clinical trial (within 30 days) 4. Significant liver disease 5. Thyroid Dysfunction (TSH level outside of normal limits; or current hyper- or hypo-thyroid abnormality) 6. Current alcohol or other drug abuse 7. Active infection or sepsis 8. Living conditions are without reasonable heat and AC 9. Unable or unwilling to provide consent Prospective Study Proposal Routine Follow-up 1. QOL survey – Minn. Living with Heart Failure Survey (administered monthly) 2. In each clinic visit BNP, Bio-impedance hemodynamic state measurement, Na+, BUN, creatinine, uric acid etc. will be checked Alan Brewer Served on Bioengineering Curriculum Advisory Board since inception BSBE ’77 TAMU, MBA ’84 HBS Texas Heart Institute as Bioengineer Instrumentation Laboratory, Inc. - Mass Hewlett-Packard Medical (now part of Philips) - Mass Intermedics, Inc. - Texas Alaris Medical Systems - California Texas Heart Institute – Back to Texas Prior Guest lecturer (’04 and 05) at TAMU for Entrepreneurial Studies course Venture Capital in Perspective Sources of Equity Capital for Start-ups Classical Venture Capital is defined to consist of seed, early, and expansion-stage financing. VC$ Debt Financing SBA loan guarantees only help 2-3% of all 28% startups Other Sources Grants SBIR/STTR grants - from various agencies 72% Equity Financing 72% from informal sources (founders, family, friends, and foolhardy strangers (“4 F’s”), corporate VC and professional VC Source: Kauffman Center for Entrepreneurial Fewer than 2% of all new business Leadership, Babson College, 2002. (per Inc. magazine) are started with venture capital Advanced Physiologic Monitoring (APM) Thank you and Questions?
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