Department of O UTCOMES R ESEARCH

Defeating Thermoregulatory Defenses 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

Defeating Thermoregulatory Defenses Temperature monitoring Hypothermia benefits & risks Normal thermoregulation Anesthetic-induced inhibition Other drugs Drug combinations

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

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

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

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

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

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

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

Normal Thermoregulation

Regulation Impaired in the Elderly

20% Contribution of Skin Temperature

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

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?

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

Dexmedetomidine & Meperidine

Buspirone & Dexmedetomidine

Buspirone & Meperidine Synergy

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

Department of O UTCOMES R ESEARCH

Skin Warming Facilitates Hypothermia

Nefopam: Isolated Anti-shivering Action

Nefopam & Clonidine

Nefopam & Meperidine

Nefopam & Alfentanil

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