Department of OUTCOMES RESEARCH
Defeating Thermoregulatory Defenses
Daniel I. Sessler, M.D.
Michael Cudahy Professor and Chair
Department of OUTCOMES RESEARCH
The Cleveland Clinic
No conflicts related to this presentation
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Defeating Thermoregulatory Defenses
Temperature monitoring
Hypothermia benefits & risks
Normal thermoregulation
Anesthetic-induced inhibition
Other drugs
Drug combinations
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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
Myocardial Outcomes: n=300
Core Temp
(°C)
Myocardial
Events (%)
Normothermic
Hypothermic
P
36.7 ± 0.1
35.3 ± 0.1
<0.001
2
7
0.04
Frank, et al., JAMA,
1997
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
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
Normal Thermoregulation
Sweating
Active vasodilation
37
Vasoconstriction
36
Shivering
Regulation Impaired in the Elderly
37
36
Shivering
Threshold
(°C)
35
34
40
60
80
Age (yr)
100
20% Contribution of Skin Temperature
38
Core
Temperature
(°C)
Vasoconstriction
36
Shivering
34
30
34
38
Skin Temperature (°C)
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
39
Sweating
37
Vasoconstriction
Threshold 35
(°C)
33
Shivering
31
0
0.5
0.8
Desflurane (MAC Fraction)
Opioids Impairs Regulation
38
37
Threshold
(°C) 36
35
34
0
100
200
300
[Total Alfentanil] (ng/ml)
Meperidine: Special Anti-Shiver Effect
38
Sweating
36
Threshold
(°C)
Vasoconstriction
34
Shivering
32
0.1
0.3
0.5
[Meperidine] (µg/mL)
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
38
Sweating
Temp.
(°C)
Vasoconstriction
36
Shivering
34
0.0
0.2
0.4
Nalbuphine (µg/ml)
0.6
Atropine Increases Thresholds
39
Sweating (°C)
*
39
*
38
38
37
37
36
36
37
Shivering (°C)
140
*
36
Vasoconstriction (°C)
HR (bpm)
*
120
100
80
35
60
40
34
Control
Atropine
Control
Atropine
Dexmedetomodine: Special Effect?
Sweating
37
Constriction
Threshold
(°C)
36
35
Shivering
34
0.0
0.2
0.4
0.6
0.8
[Dexmedetomidine] (ng/ml)
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
0.0
-0.5
D Shivering
Threshold
(°C)
-1.0
-1.5
-2.0
-2.5
-3.0
Dex
Mep
Combo
Dex+Mep
Buspirone & Dexmedetomidine
0.0
-0.5
-1.0
D Shivering
Threshold
(°C)
-1.5
-2.0
-2.5
-3.0
-3.5
Bus
Dex
Combo
Bus + Dex
Buspirone & Meperidine Synergy
36
35
Shivering
Threshold
(°C)
34
33
32
Control Buspirone Combination
Meperidine
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 OUTCOMES RESEARCH
Skin Warming Facilitates Hypothermia
Nefopam: Isolated Anti-shivering Action
38
37
Threshold
(°C)
36
35
34
0
25
50
75
[Nefopam] (ng/ml)
100
Nefopam & Clonidine
P=0.034
0.5
0
D Shivering
Threshold
(°C)
-0.5
-1
-1.5
-2
-2.5
-3
Nefopam
Clonidine
Combi1
Nef & Clo
Nefopam & Meperidine
0.5
P<0.001
0
D Shivering -0.5
Threshold
-1
(°C)
-1.5
-2
-2.5
-3
Nefopam Meperidine Combi2 Nef & Mep
Nefopam & Alfentanil
0
P=0.55
-0.5
D Shivering
Threshold (°C)
-1
-1.5
-2
-2.5
-3
Nefopam
Alfentanil
Combi3
Nef & Alf
Drug Combination Summary
Nefopam &
• Clonidine
• Meperidine
• Alfentanil
antagonistic
antagonistic
additive
Dexmedetomidine &
• Meperidine
• Clonidine
• Buspirone
Meperidine & buspirone
additive
additive
additive
synergistic