1. Department of O UTCOMES R ESEARCH

2. Therapeutic Hypothermia 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. Therapeutic Hypothermia Hypothermia benefits Potential complication Normal thermoregulation Inducing thermal tolerance www.OR.org

4. 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

5. Initial Cardiac Arrest Studies, 2002 Bernard, et al. N=77 randomized Primary outcome: survival with good function 33°C for 12 hours Odds 5.5 (95% CI: 1.5 – 19, P=0.01 Hypothermia Study Group N=275 randomized Primary outcome: survival with good function 33°C for 24 hours Odds 1.4 (95% CI: 1.1 – 1.8), P=0.01

6. Neilson, et al. NEJM 2013 N=950 Odds 1.06 95% CI: 0.9-1.3 P=0.51 All-cause mortality

7. Neonatal Hypoxemia Number-needed-to-treat ≈8 More and longer cooling no better Shankaran, JAMA 2014 33.5°C for 72 hours, vs. 32°C for 120 hours Azzopardi, NEJM 2014

8. Organ Donation 572 transplanted kidney from 370 randomized donors Niemann, NEJM 2015

9. Major Studies Not Showing Benefit Elective cerebral aneurism surgery IHAST, Todd, et al. Acute Myocardial infarction Dixon, et al. Brain Trauma Clifton, et al. Negative results may reflect design Late and slow cooling Speed of rewarming

10. Major Studies in Progress Stroke Brain trauma Acute myocardial infarction Sepsis

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

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

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

14. Thermoregulatory Model

15. Normal Thermoregulation

16. Regulation Impaired in the Elderly

17. Anesthesia Impairs Regulation

18. Opioids Impairs Regulation

19. Meperidine: Special Anti-Shiver Effect

20. 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

21. No Special Effect of Nalbuphine

22. Atropine Increases Thresholds

23. Dexmedetomodine: Special Effect?

24. Nefopam: Isolated Anti-shivering Action

25. 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

26. Dexmedetomidine & Meperidine

27. Buspirone & Dexmedetomidine

28. Nefopam & Clonidine

29. Nefopam & Meperidine

30. Nefopam & Alfentanil

31. Buspirone & Meperidine Synergy

32. Interactions Dexmedetomidine & Meperidineadditive Clonidineadditive Buspironeadditive Nefopam & Clonidineantagonistic Meperidineantagonistic Alfentaniladditive Meperidine & buspironesynergistic

33. 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

34. 20% Contribution of Skin Temperature

35. Skin Warming Facilitates Hypothermia

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

37. Department of O UTCOMES R ESEARCH

38. Cooled IV 40 ml/kg over 30 min