Department of OUTCOMES RESEARCH Therapeutic Hypothermia Daniel I

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Department of OUTCOMES RESEARCH

Department of OUTCOMES RESEARCH

Therapeutic Hypothermia Daniel I. Sessler, M. D. Michael Cudahy Professor and Chair Department of

Therapeutic Hypothermia Daniel I. Sessler, M. D. Michael Cudahy Professor and Chair Department of OUTCOMES RESEARCH The Cleveland Clinic No conflicts related to this presentation www. OR. org

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

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

Potential Benefits of Mild Hypothermia 33 -35°C ameliorates ischemia in animals Decreased tissue metabolism

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

Initial Cardiac Arrest Studies, 2002 Bernard, et al. • N=77 randomized • Primary outcome:

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

All-cause mortality Neilson, et al. NEJM 2013 N=950 Odds 1. 06 95% CI: 0.

All-cause mortality Neilson, et al. NEJM 2013 N=950 Odds 1. 06 95% CI: 0. 9 -1. 3 P=0. 51

Neonatal Hypoxemia Azzopardi, NEJM 2014 Number-needed-to-treat ≈8 More and longer cooling no better •

Neonatal Hypoxemia Azzopardi, NEJM 2014 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

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

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

Major Studies Not Showing Benefit Elective cerebral aneurism surgery • IHAST, Todd, et al.

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

Major Studies in Progress Stroke Brain trauma Acute myocardial infarction Sepsis

Major Studies in Progress Stroke Brain trauma Acute myocardial infarction Sepsis

Blood Loss Normothermia reduced blood loss 22% (95% CI 337%, P = 0. 027)

Blood Loss Normothermia reduced blood loss 22% (95% CI 337%, P = 0. 027)

Transfusion Requirement 22% less blood loss (95% CI 3 -37%, P = 0. 03)

Transfusion Requirement 22% less blood loss (95% CI 3 -37%, P = 0. 03)

Surgical Site Infections: n=200 N ormothermic H ypothermic P Temperature 36. 6 ± 0.

Surgical Site Infections: n=200 N ormothermic H ypothermic P Temperature 36. 6 ± 0. 5 34. 7 ± 0. 6 <0. 001 I nfections (%) 6 19 <0. 01 12. 1 ± 4. 4 14. 7 ± 6. 5 =0. 001 H ospitalization (days) Three-fold reduction in infection risk from local or systemic warming confirmed by Melling, et al. , Lancet, 2001

Thermoregulatory Model

Thermoregulatory Model

Normal Thermoregulation

Normal Thermoregulation

Regulation Impaired in the Elderly

Regulation Impaired in the Elderly

Anesthesia Impairs Regulation

Anesthesia Impairs Regulation

Opioids Impairs Regulation

Opioids Impairs Regulation

Meperidine: Special Anti-Shiver Effect

Meperidine: Special Anti-Shiver Effect

What’s Special About Meperidine? A “dirty” drug Kappa activity? • Most other commonly used

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

No Special Effect of Nalbuphine

No Special Effect of Nalbuphine

Atropine Increases Thresholds

Atropine Increases Thresholds

Dexmedetomodine: Special Effect?

Dexmedetomodine: Special Effect?

Nefopam: Isolated Anti-shivering Action

Nefopam: Isolated Anti-shivering Action

Drug Combinations Single non-anesthetic drugs insufficient Drug combinations • Possibly increase efficacy – Especially

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 1 A partial agonist • Dexmedetomidine: central alpha-2 agonist

Dexmedetomidine & Meperidine

Dexmedetomidine & Meperidine

Buspirone & Dexmedetomidine

Buspirone & Dexmedetomidine

Nefopam & Clonidine

Nefopam & Clonidine

Nefopam & Meperidine

Nefopam & Meperidine

Nefopam & Alfentanil

Nefopam & Alfentanil

Buspirone & Meperidine Synergy

Buspirone & Meperidine Synergy

Interactions Dexmedetomidine & • Meperidine • Clonidine • Buspirone Nefopam & • Clonidine •

Interactions Dexmedetomidine & • Meperidine • Clonidine • Buspirone Nefopam & • Clonidine • Meperidine • Alfentanil Meperidine & buspirone additive antagonistic additive synergistic

Non-pharmacologic Approaches Core temp tightly controlled • Less controlled age >80 years Skin temp

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

20% Contribution of Skin Temperature

20% Contribution of Skin Temperature

Skin Warming Facilitates Hypothermia

Skin Warming Facilitates Hypothermia

Recommendations Powerful drugs needed to induce thermal tolerance • Surface cooling provokes thermoregulatory defenses

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

Department of OUTCOMES RESEARCH

Department of OUTCOMES RESEARCH

Cooled IV 40 ml/kg over 30 min

Cooled IV 40 ml/kg over 30 min