1. Therapeutic hypothermia
The pharmacologic inhibition
of thermoregulation
By Theodore Graphos

2. Patient Case
Initials GM Age 47 Sex M Admitted 10/24/11 Ht 175.0 cm Wt 78.5 kg
Vitals Situation
RR 22 breaths/min Cardiac arrest with ROSC
O2Sat 100% HPI
BP 150/74 (hypertensive) Cardiac arrest w/ v-fib at home. Brought to BTMC by paramedics and started on
HR 63 bpm hypothermia protocol. Subsequent PCI w/ Promus® stent x1.
Labs Social Hx
Hgb 15.8 g/dL Drinks daily and smokes 1-1.5 ppd
Hct 46.4% Medications
WBC 15.7 x 103/μL For hypothermia protocol:
SCr 0.64 mg/dL  Propofol 25-50 mcg/kg/min IV cont. infusion
 Acetaminophen 650 mg PO every 6 hours until rewarmed
K+ 3.7 mEq/L
 Merperidine 25 mg IV push every 3 hours as needed for shivering (3 doses)
Mg2+ 2.2 mEq/L
 Buspirone 30 mg NG every 8 hours until rewarmed
CKMB 20.8 ng/mL
 Vecuronium 5 mg IV push (2 doses)
Troponin-I 1.67 ng/mL
 Cisatracurium 1-3 mcg/kg/min IV cont. infusion
 Magnesium sulfate 2 g IV (0 doses)

3. Therapeutic Hypothermia
INDICATION
Unconscious adults with out-of-hospital cardiac
arrest from V-fib and with ROSC
PROCEDURE
Core body temp reduced to 32-34 C for 24 hours
BENEFITS
Decreased damage from cerebral ischemia and
improved neurologic outcomes

4. Therapeutic Hypothermia
How does it work?
Many proposed mechanisms
• Reduced cerebral O2 demand and metabolism
• Preservation of the blood-brain barrier
• Decreased glutamate release, preventing excitiotoxicity
• Suppressed inflammatory cells and cytokines
• Increased expression of brain-derived neurotrophic growth factor

5. Thermoregulation
“Interthreshold range”
▫ Core body temperature is typically
maintained between 36.5 and 37.5 ˚C Vasodilation
Sweating
Mechanisms Interthreshold Range 37 C
The body has two ways to respond to hypothermia:
Vasoconstriction
1) Autonomic
• Vasoconstriction Shivering
• Shivering
2) Behavioral (e.g. grabbing your coat)
* not exact

6. Thermoregulation
1) Vasoconstriction
▫ Retains heat
▫ Very effective
▫ Typically occurs just
below 37 C
2) Shivering
▫ Generates heat
▫ Not very effective
▫ Typically occurs 1 C below the vasoconstriction threshold

7. The Problem…
Both of these defensive mechanisms are
HARMFUL in therapeutic hypothermia
Vasoconstriction… Shivering…
• Slows surface cooling modalities • Counterproductive to cooling
• Increases systemic vascular • Metabolically stressful  Poor
resistance  Hypertension  neurologic outcomes
Fatal cardiac events • Increases fatal cardiac events

8. Therapeutic Hypothermia
2 large RCTs
Published 2002
NEJM
Basis for
therapeutic
hypothermia
guidelines

9. Therapeutic Hypothermia

10. NMBAs
Current guidelines recommend using NMBAs with
sedation to prevent shivering
However, NMBAs have many disadvantages…
▫ No train-of-four monitoring in hypothermia
▫ Has no effect on vasoconstriction
▫ Can mask inadequate sedation
▫ Must monitor EEG closely (seizures)
▫ Altered metabolism of NMBAs in hypothermia may prolong
recovery
▫ Prolonged paralysis can lead to neuropathy

11. NMBAs
Using NMBAs
 Use only when other treatment has failed to adequately
control shivering
 Patient must FIRST be adequately sedated
 Titrate to control shivering
 Monitor EEG or BIS closely for seizure activity
 Reevaluate the potential to discontinue the NMBA after
each phase of cooling
— The shivering response is worst during cooling and rewarming. Once cooled
below about 33.5 C, shivering is markedly reduced or absent.

12. NMBAs
Using NMBAs
 Use only when other treatment has failed to adequately
control shivering
 Patient must FIRST be adequately sedated
 Titrate to control shivering
 Monitor EEG or BIS closely for seizure activity
 Reevaluate the potential to discontinue the NMBA after
each phase of cooling
— The shivering response is worst during cooling and rewarming. Once cooled
below about 33.5 C, shivering is markedly reduced or absent.

13. NMBAs
Using NMBAs
 Use only when other treatment has failed to adequately
control shivering
 Patient must FIRST be adequately sedated
 Titrate to control shivering
 Monitor EEG or BIS closely for seizure activity
 Reevaluate the potential to discontinue the NMBA after
each phase of cooling
— The shivering response is worst during cooling and rewarming. Once cooled
below about 33.5 C, shivering is markedly reduced or absent.

14. Other Options
Studies, mostly about post-anesthesia
shivering, suggest alternative targets
Vasodilation
• 5-HT receptors Sweating
• NMDA receptors
• α2 receptors Interthreshold Range 37 C
• Opioid receptors
Vasoconstriction
• Others
Shivering
* not exact

15. Other Options
Studies, mostly about post-anesthesia
shivering, suggest alternative targets
Vasodilation
Sweating
• 5-HT receptors
• NMDA receptors
• α2 receptors Interthreshold Range
37 C
• Opioid receptors
• Others
Vasoconstriction
These targets prevent shivering by
increasing the interthreshold range Shivering
* not exact

16. Merperidine
Potential mechanism(s) Studies
• κ-receptor agonist Outline Treatment
• Reuptake inhibitor Kurz et. al. / 1997
Experimental
Merperidine [0.6 mcg/mL]
Merperidine [1.8 mcg/mL]
Healthy volunteers (n=9)
• NMDA antagonist Control
Results
• α2 agonist  Merperidine decreased vasoconstriction threshold by 3.3 1.5 C·mcg-1·mL (r2=0.92 0.08) and
shivering threshold by 6.1 3.0 C·mcg-1·mL (r2=0.97 0.05)
Outline Treatment
Kranke et. al. / 2004 Merperidine 12.5-25 mg
Systematic review Control
Postoperative patients (n=250)
Results
 Decreased incidence of post-anesthesia shivering in patients receiving merperidine (RB 1.67,
95% CI 1.37-2.03)
Bottom Line
• Very effective at reducing the shivering threshold, but not enough by itself
• Used in almost every hypothermia protocol
• Risk of seizure with prolonged administration

17. Buspirone
Potential mechanism(s) Studies
• 5-HT1A partial agonist Outline Treatment
Merperidine IV [0.8 mcg/mL]
• Affects balance between NE Mokhtarani et. al. / 2001
Experimental Merperidine IV [0.4 mcg/mL] + Buspirone 30 mg PO
and 5-HT that controls Healthy volunteers (n=8) Buspirone 60 mg PO
Control
thermoregulation
Results
 Both merperidine and buspirone significantly lowered the shivering threshold (p<0.05)
 Merperidine and buspirone acted synergistically to lower shivering threshold (p=0.006)
Outline Treatment
Lenhardt et. al. / 2001 Buspirone 60 mg PO
Experimental Dexmeditomidine IV [0.6 ng/mL]
Healthy volunteers (n=8) (Combination of the above)
Control
Results
 Both dexmeditomidine and buspirone significantly lowered the shivering threshold (p<0.05)
 Dexmeditomidine and buspirone were additively in lowering the shivering threshold
Bottom Line
• Effective by itself, but not enough for monotherapy
• Acts synergistically with merperidine, but only additively with dexmeditomidine
• No significant effect on BP or HR by itself

18. Dexmeditomidine
Potential mechanism(s) Studies
• α2 agonist Outline Treatment
Dexmeditomidine [0.4 ng/mL]
• Hyperpolarizes neurons Talke et. al. / 1997
Experimental Dexmeditomidine [0.8 ng/mL]
which suppresses neuronal Healthy volunteers (n=9) Control
firing linked to Results
thermosensitivity  Dexmeditomidine decreased vasoconstriction threshold by 1.61 ± 0.80 °C·ng-1·mL (r2=0.88 ±
0.19) and shivering threshold by 2.40 ± 0.90 °C·mcg/mL (r2=0.93 ± 0.10)
Outline Treatment
Doufas et. al. / 2003 Merperidine IV [0.3 mcg/mL]
Experimental Dexmeditomidine IV [0.4 ng/mL]
Healthy volunteers (n=10) (Combination of the above)
Control
Results
 Both merperidine and dexmeditomidine significantly lowered the shivering threshold (p<0.001)
 Merperidine and dexmeditomidine were not synergistic (p=0.19) but additive
Bottom Line
• Moderately effective in preventing shivering
• May cause arrhythmias and hypotension

19. Clonidine
Potential mechanism(s) Studies
• α2 agonist Outline Treatment
• Hyperpolarizes neurons Nicolaou et. al. / 1997
Experimental
Clonidine 3 mcg/kg PO
Clonidine 6 mcg/kg PO
which suppresses neuronal Healthy volunteers (n=6) Clonidine 9 mcg/kg PO
Control
firing linked to
Results
thermosensitivity
 Significantly reduced the shivering threshold and vasoconstriction threshold (p<0.01)
 Dose-dependent decrease in shivering threshold of 0.13 0.05 C/mcg and vasoconstriction
threshold of 0.19 0.09 C/mcg
Bottom Line
• Significantly effective
• More thoroughly studied than many of the other drugs
• May cause bradycardia and hypotension

20. Magnesium
Potential mechanism(s) Studies
• NMDA receptor antagonist Outline Treatment
Merperidine
• Affects thermoregulatory Zweifler et. al. / 2004
Experimental Merperidine + buspirone
noradrenergic and Healthy volunteers (n=22) Merperidine + ondansetron
Merperidone + ondansetron + MgSO4
serotonergic neurons
Results
 Significantly more vasodilation during hypothermia in patients receiving MgSO4 (p=0.024)
 Significantly higher patient comfort scores in patients receiving MgSO4 (p<0.001)
 No significant differences in SBP, DBP, or MAP
 Some significant decreases in HR in MgSO4 group
Outline Treatment
Wadhwa et. al. / 2005 MgSO4 80 mg/kg + 2 g/hr
Experimental Control
Healthy volunteers (n=9)
Results
Significantly reduced the shivering threshold (p=0.04)
Bottom Line
• Minor but significant reduction in shivering threshold
• May improve patient comfort
• No hypotension, unlike some other anti-shivering medications

21. Propofol
Potential mechanism(s) Studies
• Unknown Outline Treatment
Matsukawa et. al. / 1995 Propofol [2 mcg/mL]
Experimental Propofol [4 mcg/mL]
Healthy volunteers (n=5) Propofol [8 mcg/mL]
Control
Results
 Significantly reduced the shivering threshold and vasoconstriction threshold at all
concentrations (p<0.05)
 Dose-dependent decrease in vasoconstriction threshold of 0.6 ± 0.1 °C·mcg-1·mL (r2=0.98 ±
0.02) and shivering threshold of 0.7 ± 0.1 °C·mcg-1·mL (r2=0.95 ± 0.05)
Bottom Line
• Significantly effective and provides simultaneous sedation
• Part of most protocols
• May cause hypotension
• Neuroprotective

22. Fentanyl
Potential mechanism(s) Studies
• μ-receptor agonist Outline Treatment
Alfonsi et. al. / 1995 Merperidine IV 0.85 mg/kg
Experimental Fentanyl IV 1.7 mcg/kg
General surgery patients (n=52) Lignocaine IV 1 mg/kg
Control
Results
Decreased incidence of post-anesthesia shivering in patients receiving fentanyl (p<0.01)
Bottom Line
• Moderately effective in preventing shivering, but requires high doses
• Not to be used as an anti-shivering medication

23. Ondansetron
Potential mechanism(s) Studies
• 5-HT3 antagonist Outline Treatment
Ondansetron ~50mg IV
• Affects balance between NE Komatsu et. al. / 2006
Experimental Control
and 5-HT that controls Healthy volunteers (n=10)
thermoregulation Results
 Nonsignificant decrease in shivering threshold (p=0.76)
 Nonsignificant decrease in vasoconstriction threshold (p=0.70)
Outline Treatment
Powell et. al. / 2000 Ondansetron 4 mg IV
Experimental Ondansetron 8 mg IV
Surgical patients (n=82) Control
Results
 Ondansetron 8 mg decreased incidence of post-anesthesia shivering in (p=0.003)
Bottom Line
• Unsure of effect
• More research is needed

24. Tramadol
Potential mechanism(s) Studies
• 5-HT reuptake inhibitor Outline Treatment
Tramadol 125 mg PO
• NE and dopamine reuptake De Witte et. al. / 1998
Experimental Tramadol 250 mg PO
inhibitor Healthy volunteers (n=8) Tramadol 250 mg PO + Naloxone 1.1 mg IV
Control
• α2 agonist Results
• Weak opioid agonist  Tramadol 250 mg significantly increased the interthreshold range (p=0.04)
Outline Treatment
Kranke et. al. / 2004 Tramadol 0.5-3 mg/kg
Systematic review Control
Postoperative patients (n=250)
Results
 Decreased incidence of post-anesthesia shivering in patients receiving tramadol (RB 1.93, 95%
CI 1.56-2.39)
Bottom Line
• Appears to be effective at lowering the shivering threshold
• Not commonly used in current protocols
• More research is needed

25. Evidence
Evidence in this area is poor…
▫ NO studies in the target population
▫ Cannot reliably compare results between studies
But most recent reviews of this topic agree that…
▫ Shivering is potentially associated with negative outcomes and
should always be treated
▫ Further research is needed to find the “gold standard” for
prevention of shivering in therapeutic hypothermia
▫ NMBAs should be avoided unless other agents have failed

26. One last study…
The only study focused on shivering and included the target population…
Outline Treatment
Choi et. al. / 2011 Patients were treated for shivering based on this protocol that is
Observational stratified based on severity of shivering
Therapeutic hypothermia patients
n=213
23% indicated for cardiac arrest
Objective
Look for risk-factors for requiring
more intensive therapy for shivering
Results
<1% of patients required a neuromuscular blocker to prevent shivering

27. References
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