1. Department of O UTCOMES R ESEARCH

2. Defeating Thermoregulatory Defenses www.OR.org Daniel I. Sessler, M.D. Michael Cudahy Professor and Chair Department of O UTCOMES R ESEARCH The Cleveland Clinic No conflicts related to this presentation

3. Defeating Thermoregulatory Defenses Temperature monitoring Hypothermia benefits & risks Normal thermoregulation Anesthetic-induced inhibition Other drugs Drug combinations www.OR.org

4. Temperature Monitoring Core Sites Pulmonary artery Distal esophagus Nasopharynx Tympanic membrane thermocouple Other generally-reliable sites Mouth Axilla Bladder Sub-optimal Forehead skin Infrared “tympanic” Infrared “temporal artery” Rectal Anesth Analg 2008

5. Potential Benefits of Mild Hypothermia 33-35°C ameliorates ischemia in animals Decreased tissue metabolism contributes But is not a major factor Other potential mechanisms Reduced calcium influx and release of glutamate –Reduced activation of the neuroexcitatory cascade –Decreased apoptosis Reduced free-radical production Maintenance of vascular permeability and BBB Reduced clotting in response to micro-thrombi Suppression of pro-inflammatory cytokines

6. Evidence in Humans Improves neurologic outcome after cardiac arrest Bernard, et al. and Hypothermia Study Group Now recommended by European and American Heart Associations Number needed to treat: ≈6 Improves neurologic outcome in asphyxiated neonates Shankaren, et al.; Gluckman, et al.; Eicher, et al. Number needed to treat: ≈6 No benefit in major human trials Brain trauma: Clifton, et al. Anurysm surgery: Todd, et al. Acute myocardial infarction: Dixon, et al Stroke Essentially untested

7. Frank, et al., JAMA, 1997 Myocardial Outcomes: n=300 NormothermicHypothermicP Core Temp (°C) 36.7 ± 0.135.3 ± 0.1<0.001 Myocardial Events (%) 270.04 That hypothermia causes myocardial ischemia was confirmed by Nesher, et al, Ann Thorac Surg, 2001

8. Blood Loss Normothermia reduced blood loss 22% (95% CI 3-37%, P = 0.027)

9. Transfusion Requirement 22% less blood loss (95% CI 3-37%, P = 0.03)

10. Surgical Wound Infections: n=200 Three-fold reduction in infection risk from local or systemic warming confirmed by Melling, et al., Lancet, 2001

11. Normal Thermoregulation

12. Regulation Impaired in the Elderly

13. 20% Contribution of Skin Temperature

14. Non-pharmacologic Approaches Core temp tightly controlled Less controlled age >80 years Skin temp contributes 20% 4°C skin warming permits 1°C of core cooling 4°C skin cooling raises defended core temp 1°C Endovascular cooling Provokes less response than surface cooling Combine with surface warming for best results

15. Anesthesia Impairs Regulation

16. Opioids Impairs Regulation

17. Meperidine: Special Anti-Shiver Effect

18. What’s Special About Meperidine? A “dirty” drug Kappa activity? Most other commonly used opioid are pure µ agonists Meperidine has both µ and kappa activity Anti-cholinergic effect? Central alpha-2 agonist? Effective treatment for postoperative shivering

19. No Special Effect of Nalbuphine

20. Atropine Increases Thresholds

21. Dexmedetomodine: Special Effect?

22. Drug Combinations Single non-anesthetic drugs insufficient Drug combinations Possibly increase efficacy –Especially with additive or synergistic interactions Potential reduction in side-effects Drugs of particular interest Meperidine Buspirone: serotonin 1A partial agonist Dexmedetomidine: central alpha-2 agonist

23. Dexmedetomidine & Meperidine

24. Buspirone & Dexmedetomidine

25. Buspirone & Meperidine Synergy

26. Recommendations Powerful drugs needed to induce thermal tolerence Surface cooling provokes thermoregulatory defenses Combine endovascular cooling and skin warming Use additive or synergistic drug combinations of effective drugs Additive: meperidine & dexmedetomodine Additive: buspirone & dexmedetomodine Synergistic: buspirone & meperidine Best combinations Reduce shivering threshold ≈2°C Clinical effect totals ≈3°C when combined with skin warming Beware of complications: MI, coagulapathy, infection

27. Department of O UTCOMES R ESEARCH

28. Skin Warming Facilitates Hypothermia

29. Nefopam: Isolated Anti-shivering Action

30. Nefopam & Clonidine

31. Nefopam & Meperidine

32. Nefopam & Alfentanil

33. Drug Combination Summary Nefopam & Clonidineantagonistic Meperidineantagonistic Alfentaniladditive Dexmedetomidine & Meperidineadditive Clonidineadditive Buspironeadditive Meperidine & buspironesynergistic