Department of OUTCOMES RESEARCH Therapeutic Hypothermia Daniel I
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Department of OUTCOMES RESEARCH
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
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: 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. 9 -1. 3 P=0. 51
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
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
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)
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
Normal Thermoregulation
Regulation Impaired in the Elderly
Anesthesia Impairs Regulation
Opioids Impairs Regulation
Meperidine: Special Anti-Shiver Effect
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
Atropine Increases Thresholds
Dexmedetomodine: Special Effect?
Nefopam: Isolated Anti-shivering Action
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
Buspirone & Dexmedetomidine
Nefopam & Clonidine
Nefopam & Meperidine
Nefopam & Alfentanil
Buspirone & Meperidine Synergy
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 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
Skin Warming Facilitates Hypothermia
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
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