Department of OUTCOMES RESEARCH

Therapeutic Hypothermia

www.OR.org

Daniel I. Sessler, M.D.

Michael Cudahy Professor and ChairDepartment of OUTCOMES RESEARCH

The Cleveland Clinic

No conflicts related to this presentation

Therapeutic Hypothermia

Hypothermia benefitsPotential complicationNormal thermoregulationInducing thermal tolerance

www.OR.org

Potential Benefits of Mild Hypothermia

33-35°C ameliorates ischemia in animalsDecreased 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

Neilson, et al.

NEJM 2013

N=950

Odds 1.0695% CI: 0.9-1.3P=0.51

All-cause mortality

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

Organ Donation

572 transplanted kidney from 370 randomized donorsNiemann, 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

StrokeBrain traumaAcute myocardial infarctionSepsis

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 Site Infections: n=200

Normothermic Hypothermic P

Temperature 36.6 ± 0.5 34.7 ± 0.6 <0.001

Infections (%) 6 19 <0.01

Hospitalization(days) 12.1 ± 4.4 14.7 ± 6.5 =0.001

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

Dexmedetomidine & Meperidine

Buspirone & Dexmedetomidine

Nefopam & Clonidine

Nefopam & Meperidine

Nefopam & Alfentanil

Buspirone & Meperidine Synergy

Interactions

Dexmedetomidine &•Meperidine

additive•Clonidine

additive•Buspirone

additive

Nefopam &•Clonidine

antagonistic•Meperidine

antagonistic•Alfentanil

additive

Meperidine & buspirone synergistic

Non-pharmacologic ApproachesCore 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

Cooled IV

40 ml/kg over 30 min