Therapeutic Hypothermia: The pharmacologic inhibition of thermoregulation

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Therapeutic Hypothermia: The pharmacologic inhibition of thermoregulation

  1. 1. Therapeutic hypothermiaThe pharmacologic inhibitionof thermoregulationBy Theodore Graphos
  2. 2. Patient CaseInitials GM Age 47 Sex M Admitted 10/24/11 Ht 175.0 cm Wt 78.5 kgVitals SituationRR 22 breaths/min Cardiac arrest with ROSCO2Sat 100% HPIBP 150/74 (hypertensive) Cardiac arrest w/ v-fib at home. Brought to BTMC by paramedics and started onHR 63 bpm hypothermia protocol. Subsequent PCI w/ Promus® stent x1.Labs Social HxHgb 15.8 g/dL Drinks daily and smokes 1-1.5 ppdHct 46.4% MedicationsWBC 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 rewarmedK+ 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 rewarmedCKMB 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. 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. 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. 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. 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. 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. 8. Therapeutic Hypothermia 2 large RCTs Published 2002 NEJM Basis for therapeutic hypothermia guidelines
  9. 9. Therapeutic Hypothermia
  10. 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. 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. 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. 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. 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. 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. 16. MerperidinePotential 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. 17. BuspironePotential 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 thresholdBottom 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. 18. DexmeditomidinePotential 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 additiveBottom Line• Moderately effective in preventing shivering• May cause arrhythmias and hypotension
  19. 19. ClonidinePotential 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/mcgBottom Line• Significantly effective• More thoroughly studied than many of the other drugs• May cause bradycardia and hypotension
  20. 20. MagnesiumPotential 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. 21. PropofolPotential 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. 22. FentanylPotential 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. 23. OndansetronPotential 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. 24. TramadolPotential 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. 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. 26. One last study…The only study focused on shivering and included the target population…Outline TreatmentChoi et. al. / 2011 Patients were treated for shivering based on this protocol that isObservational stratified based on severity of shiveringTherapeutic hypothermia patientsn=21323% indicated for cardiac arrestObjectiveLook for risk-factors for requiringmore intensive therapy for shivering Results <1% of patients required a neuromuscular blocker to prevent shivering
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