1. Introduction to Temperature Therapy and Cooling

2. Temperature Therapy Perspectives on Cooling Vital sign Maslov’s hierarchy of needs - shelter Nature’s design-metabolic protection –Hibernation- Self protection mechanism –Animals seek cool environment when ischemic Intuitive-”Cooling prevents spoilage” Learned-”Ice on injuries reduces swelling and tissue damage” Physiological and biochemical rationale –Tissue metabolic rates decrease as body temperature decreases

3.  Levels of Hypothermia-°C 36.6-37.5=Normothermia 34-36.5=Mild hypothermia 28-33.5=Moderate hypothermia 17-27.5=Deep hypothermia 4-16.5=Profound hypothermia 35.5 = Shivering >37.5=Hyperthermia 36.5 = Vasoconstriction 37.5 = Vasodilatation

4. Temperature Therapy Historically, limited to temperature preservation, i.e. warming in surgery, shock, etc. Investigation of cooling as a therapy limited by body’s complex thermoregulatory mechanisms –Core vs. peripheral dynamics –Tolerance to change varies significantly individual to individual –Inability to cool with any precision and predictability –Requirement to paralyze/anesthetize patient to overcome thermoregulatory responses –Significant complications that occur below 28°C

5. The Thermoregulatory System 35  C 36  C 37  C Anterior Hypothalamus Vasodilation Vasoconstriction Nonshivering Shivering Brain (non- hypothalamic) Spinal Cord Deep Tissues Skin Sweating Cooling Heat loss protection Thermogenesis

6. Techniques to Induce Hypothermia Surface cooling techniques –Slow and imprecise –Cumbersome –Limited in depth with non-paralyzed patient Lavage –Moderately invasive and uncomfortable –Slow and imprecise IV infusions –Limited volumetric capacity Cardiopulmonary bypass –Invasive and resource intensive

7. Cooling as a Therapy Despite challenges, long history of clinical and research investigation 1940 - Neurosurgeon Temple Fay reported on first whole body cooling* 1950 – Bigelow and Shumway published on hypothermia as a cardioprotective agent that is the foundation for today’s modern CPB technique** Transplant surgeons and cell physiologists routinely use cooling to preserve cells and tissues Cooling is gold standard in many cardiac surgery and neurosurgery procedures * NY State J. Med 1940; 40: 1351-54 ** Ann Surg 1950; 132: 849

8. Cooling as Therapy Background Extensive research and evidence of the beneficial effects and mechanisms of cooling –Pre-clinical evidence of mechanisms, basic science –Clinical trials evidencing the clinical benefits of cooling Despite current technical challenges of cooling, several recently published clinical studies demonstrate the benefits of cooling in: –Cardiac Arrest* –Stroke** * NEJM 2002; 345: 549-56, NEJM 2002; 346: 557-63 ** Stroke 2002; 32: 1847-54

9. Cooling as Therapy In Cardiac Arrest Trial Results Two independent studies utilized surface cooling on intubated, paralyzed patients vs. standard of care Multi-center, prospective, randomized trial in Australia* –77 pts: 43 hypothermia, 34 control –33°C x 12 hours following resuscitation from cardiac arrest –Good neurologic outcome : 49% of cooled, 26% of controls (p=.046) Multi-center, prospective, randomized trial in Europe ** –275 pts: 137 hypothermia, 138 control –32°C to 34°C x 24 hours –Good neurologic outcome in: 55% of cooled, 39% of controls (p=.009) –Mortality 41% in cooled vs 55% control, P=.02 * NEJM 2002; 346: 557-63 ** NEJM 2002; 345: 549-56

10. Hypothermia in Malignant Stroke* Study Design –Single center trial of mild cooling –25 patients with severe MCA strokes and increased ICP –Cooling via surface cooling, cool infusions and cold washing –Cooling to 33°C within 14 hours after stroke, for 48 - 72 hours Results –Decreased ICP with mortality of 44%, as compared to 80% in historical controls –Concluded that moderate hypothermia in the treatment of severe cerebral ischemia is not associated with severe side effects and may help control critically elevated ICP values and improve clinical outcome in these patients * Stroke 1998;29: 2461-2466

11. Hypothermia in Head Trauma Single center, prospective, randomized trial* –82 patients (40 - hypothermia to 33°C x 24 hrs) –Improved outcome at 3 and 6 months in pts with initial Glasgow Coma Scale score 5 - 7 Multicenter, prospective, randomized trial ** –392 pts (199 - hypothermia to 33°C x 48 hrs) –Overall results negative –Positive results in patients < 45 years who were normovolemic * NEJM 1997; 336: 540-6 ** NEJM 2001; 344: 556-63

12. Surface Cooling Limitations Surface cooling used in COOL AID * feasibility trial demonstrated limitations of surface cooling Target temperature of 32°C Actual temperatures reached as low as 28°C Wide range in actual temperatures and slow cooling times Intensive cooling regime including blankets, alcohol wipes with paralyzed and intubated patients Target Temperature Target Temperature * Stroke 2001; 32: 1847-54

13. Endovascular Temperature Therapy-Goals Safe Rapid cooling to target therapeutic levels in ischemic tissues Precise cooling, maintenance, and re-warming capabilities Minimally invasive, venous catheter-based method Comfortably cool awake patients Ease of use in a variety of locations, ICU, CCU, ER, etc. Minimize resource intensity Minimal hemodynamic effects

14. Endovascular Temperature Therapy System Advanced heat exchange technology System Components: o oController o oHeat exchange cassette o oHeat exchange catheter o oTemperature sensor FDA 510(k) clearance in June of 2002 for use in cardiac surgery patients to achieve and/or maintain normothermia TM

15. Easy to use graphical interface facilitates system set-up and entry of cooling/warming parameters Rapid cooling/warming capability with precise control (+/-0.3°C) Integrated temperature feedback loop automatically adjusts rate of patient cooling/warming to targets specified by operator Redundant safety systems with both audible and visible alarms Self diagnosing, provides user-friendly trouble shooting directions Controller TM

16. Delivered through standard 10Fr sheath Expands to 27Fr when inflated Surface treatment to minimize thrombogenicity 25 cm long heat exchanger Central lumen for OTW placement Helical multi-lumen construction maximizes surface area for heat exchange Catheter TM

17. Cools or warms circulating saline via surface contact with cold/warm plates in the controller Catheter pre-attached to cassette, no assembly required Insulated foam lines reduce heat loss All in one design facilitates rapid set- up and therapy initiation Cassette is easily removed from controller to facilitate patient transfer Cassette TM

18. Shivering Management Skin Sensor Management Drug-Brain Threshold Endovascular Temperature Optimal Endovascular Therapy is dependent on successfully managing three interdependent factors Buspirone and Meperidine to reduce shivering threshold Use of warm air blanket to “fool” skin receptors Rate of core cooling and maintenance

19. Cooling the Awake Patient Treatment Procedure Administer Buspirone and Meperidine Prepare System Place catheter and temperature sensor Initiate cooling to target of 33°C Place warming blanket Maintain at 33°C for prescribed duration Re-warm to normothermia at controlled rate Remove catheter and warming blanket

20. Clinical Trials of Cooling Ongoing or completed trials –AMI (Radiant Medical - Endovascular) –Ischemic Stroke (Radiant Medical -Endovascular) –Hemorrhagic Stroke (Endovascular) –Cardiac Arrest (Surface) –Aneurysm Surgery (Endovascular & Surface) –Brain Injury (Surface)