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Slide 1 - CEProfs - Texas A_M University


									Advanced Physiologic Monitoring Laboratory
        Texas Heart Institute

               ENGR 281

         A Brief Look at
 Engineering in Medical Research

                   April 5, 2006
             Alan Brewer, BSBE, MBA
Advanced Physiologic Monitoring (APM)

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
    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
 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
    APM Swine Study Engineering
   Local Myocardial Temperature and Ischemia Detection

 Experiment design – Understanding heat
 Sensor selection and modification, device
 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
 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
  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
    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
 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
    (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
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
         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
  Project History – Canine Studies
 Long procedure times
 Well-developed canine collateral myocardial circulation
 Sensor positioning issues – RV not
  sensitive as hoped
 RADI device used for CS
 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
 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
 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
    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
    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)

   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

                                4 mm

               Swine Study
         Epicardial Sensor Placements

Sensor placement
complications                heart with
                             thickened left

 Too shallow

 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
    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
   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
          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
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
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
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
                     Alan Brewer
 Served on Bioengineering Curriculum Advisory Board since
 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
                     Sources                     Grants
                                                 SBIR/STTR grants - from various agencies
                                                 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

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