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Hypothermia in Cardiac Arrest: Should we be hot to cool?

Hypothermia in Cardiac Arrest: Should we be hot to cool?. Vanessa R. Cole, MD December 17, 2002 Resident Grand Rounds. Clinical Case. 55 yo WM w/DM, PVD, h/o CVA transferred to NCBH CCU after cardiac arrest

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Hypothermia in Cardiac Arrest: Should we be hot to cool?

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  1. Hypothermia in Cardiac Arrest:Should we be hot to cool? Vanessa R. Cole, MD December 17, 2002 Resident Grand Rounds

  2. Clinical Case • 55 yo WM w/DM, PVD, h/o CVA transferred to NCBH CCU after cardiac arrest • Family reports USOH, states he felt “hypoglycemic”, then clenched his teeth & became unresponsive • Pulseless & apneic at OSH ED • Resuscitated with atropine, epinephrine • Delayed airway obtained 40 mins into code

  3. Clinical Case • Initial PEA, junctional rhythm after resuscitation • Briefly responsive, then became hypotensive • Coded again • To NCBH CCU on epinephrine & dopamine gtts, externally paced • Intubated, obtunded, pupils fixed at 4 mm, no corneal reflexes • ABG: 7.30/37/120/18/98% on 100% FiO2 • Lactate: 8 meq/L

  4. Questions • Would hypothermia have any benefit on neurologic prognosis in this patient? • In which patients, if any, has hypothermia after cardiopulmonary arrest been shown to improve outcome? • What are the harms associated with hypothermia?

  5. History of hypothermia in clinical use • Pathophysiology • Summary of major animal studies • Small clinical trials • 2 randomized controlled trials • Summary/Conclusions • CCU protocol • Future directions

  6. 1950’s 4 published case reports 320C to 340C for 24-72 hrs after cardiac arrest 3/4 patients recovered without neurologic deficit 5/56-11/58 Johns Hopkins Hospital Review of 27 cases 12 w/hypothermia 320C to 340C for 34-84 hrs 15 w/normothermia 8 normothermics excluded 1/7 normothermics, 6/12 hypothermics survived w/o deficit History of hypothermia

  7. Adverse effects of hypothermia • Coagulopathy - platelet dysfunction, prolonged PT/PTT •  CO,  SVR • EKG changes, arrhythmias •  susceptibility to infection •  blood viscosity •  extracellular potassium

  8. Mild = 34 + 20C Moderate = 30 + 20C Deep = 15-250C Profound < 150C Protective = cooling before the insult Preservative = cooling during the insult Resuscitative = cooling to reverse the insult, support recovery Definitions

  9. Reperfusion Injury

  10. Reperfusion injury • Barbiturates - thiopental • Ca2+ channel blockers - lidoflazine • Corticosteroids • Free radical scavengers • Neurotransmitter receptor blockers

  11. Reperfusion injury Cooling: • Retard enzymatic rxns, suppress production of free radicals • Reduction of O2 demand in low-flow regions • Inhibition of excitatory NT synthesis • Protection of membrane fluidity • Reduction of intracellular acidosis • Decrease in cerebral edema and ICP

  12. Animal Studies • 5 consecutive studies of hypothermia in dog model of cardiac arrest 1990-1996 • Hypothermia after v.fib arrest improved outcome w/bypass & CPR for resuscitation • Profound hypothermia was detrimental • Moderate hypothermia was beneficial to brain, detrimental to heart • Benefit of cooling best achieved if begun immediately • 12 hr protocol w/greatest benefit

  13. Clinical Trial of Induced Hypothermia in Comatose Survivors of Out-of-Hospital Cardiac Arrest* • Prospective study of active patients, retrospective review of controls, unblinded assessment of GOCS score • Australia, 11/93-3/96, 22 pts/group • Included: unconscious w/ROSC after out-of-hospital cardiac arrest • Excluded: refractory hypotension, coma for other reasons, age < 16yrs, poss. pregnancy, transfer from other hospital • Cooling: 330C w/ice packs X 12 hrs *Bernard SA et al. Annals of Emergency Medicine, 1997. 30: 146.

  14. Glascow Outcome Coma Score (GOCS)

  15. Clinical Trial of Induced Hypothermia in Comatose Survivors of Out-of-Hospital Cardiac Arrest* • No significant differences in study groups • Depth of coma similar • Core temp < 340C at a mean of 74 mins • More bradycardia, acidosis, K+ (assoc w/ rewarming) in hypothermia group • No complications of hypothermia *Bernard SA et al. Annals of Emergency Medicine, 1997. 30: 146.

  16. Clinical Trial of Induced Hypothermia in Comatose Survivors of Out-of-Hospital Cardiac Arrest* • Good outcome achieved in significantly more hypothermia patients • Mortality significantly reduced in hypothermia group *Bernard SA et al. Annals of Emergency Medicine, 1997. 30: 146.

  17. Clinical Trial of Induced Hypothermia in Comatose Survivors of Out-of-Hospital Cardiac Arrest* Limitations: • Retrospective controls introduce potential differences in patient groups • Unblinded assessment of outcome, ? bias • Not all v. fib arrests • Small numbers, may not have power to detect adverse effects of treatment *Bernard SA et al. Annals of Emergency Medicine, 1997. 30: 146.

  18. Preliminary Clinical Outcome Study of Mild Resuscitative Hypothermia After Out-of-Hospital Cardiopulmonary Arrest* • Prospective study of active patients, retrospective review of controls, assessment of recovery & survival to discharge • Japanese suburban hospital, 1995 • 13 pts in hypothermia group, 15 controls • Included: lack of hypotension, age < 70 yrs • Excluded: trauma, CNS disease, or terminal illness as cause of arrest • Cooling: 33-340C w/cooling blankets & EtOH on trunk/extremities X 48 hrs *Yangawa et al. Resuscitation, 1998. 39: 61.

  19. Preliminary Clinical Outcome Study of Mild Resuscitative Hypothermia After Out-of-Hospital Cardiopulmonary Arrest* • Cooling within 78+28 mins of ROSC • Target temp w/in 336+180 mins of initiation • 11/13 pts completed cooling protocol 3 10 *Yangawa et al. Resuscitation, 1998. 39: 61.

  20. Preliminary Clinical Outcome Study of Mild Resuscitative Hypothermia After Out-of-Hospital Cardiopulmonary Arrest* • No significant differences in survival to discharge • For survivors, period of no cerebral perfusion was longer in hypothermia group • Full recovery more frequent with hypothermia (3/13 vs. 1/15, p = NS) • 11/13 (85%) hypothermics developed pna vs. 5/15 (33%) normothermics (p = 0.02) *Yangawa et al. Resuscitation, 1998. 39: 61.

  21. Preliminary Clinical Outcome Study of Mild Resuscitative Hypothermia After Out-of-Hospital Cardiopulmonary Arrest* Limitations: • Retrospective controls introduce potential differences in patient groups • Fewer witnessed collapses in hypothermia group may have blunted effect • Variable etiologies of arrest *Yangawa et al. Resuscitation, 1998. 39: 61.

  22. Hypothermia After Cardiac Arrest: Feasibility & Safety of an External Cooling Protocol * • Prospective cohort study from 7/98-10/99 • UT Houston, Cleveland Clinic, Baylor • 156 screened, 15 eligible, consent obtained in 9 pts • Included: out-of-hospital arrest, ROSC, hypothermia w/in 90 mins, age 18-85 yrs, GCS < 8, informed consent from family • Excluded: cardiac instability, acute ischemia, sepsis, need for pressors, shock, coagulopathy, QTc > 470 ms, in-hospital arrest, other conditions precluding treatment *Felberg et al. Circulation, 2001. 104: 1799.

  23. Hypothermia After Cardiac Arrest: Feasibility & Safety of an External Cooling Protocol * • Cooling: 330C w/axillary & groin ice packs until cooling blankets placed, iced saline gastric lavage X 24 hrs • Outcome: 10 – feasibility of cooling 20 – discharge disposition, MMSE, Rankin score at 30 days *Felberg et al. Circulation, 2001. 104: 1799.

  24. Hypothermia After Cardiac Arrest: Feasibility & Safety of an External Cooling Protocol * • 78+20 mins from ACLS to start of cooling • 301+178 mins from initiation of cooling to goal temperature • 1 pt did not complete protocol • 4/9 survived: 3/9 Rankin score=0, MMSE=30 1/9 Rankin score=3, MMSE=20 • Pts w/good outcome had shorter anoxic periods *Felberg et al. Circulation, 2001. 104: 1799.

  25. Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia * • Randomized controlled trial, 9/96-6/99 • Multiple Australian hospitals • Included: v. fib upon arrival of EMS, ROSC, persistent coma, transfer to participating ED • Excluded: < 18 yrs ♂, < 50 yrs ♀, shock, causes of coma other than CA, ICU bed unavailable in participating center *Bernard et al. New England Journal of Medicine, 2002. 346: 557.

  26. Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia * *Bernard et al. New England Journal of Medicine, 2002. 346: 557.

  27. Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia * • Cooling: 330C w/ice packs to head, neck, torso, limbs X 12 hrs • Normothermia: 370C, rewarmed if hypothermic on arrival • Temperature monitored via PA catheter or bladder temp probe Outcome: 10 – disposition @ hospital D/C determined by blinded rehab specialist 20 – hemodynamic, biochemical, hematologic effects of cooling *Bernard et al. New England Journal of Medicine, 2002. 346: 557.

  28. Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia * • 4 patients randomized to hypothermia were not cooled • Clinical characteristics similar • More males, more w/bystander CPR in normothermia group (non-significant) • Hypothermia – bradycardia,  SVR, hyperglycemia w/cooling,  K+ w/rewarming • No clinically significant adverse events *Bernard et al. New England Journal of Medicine, 2002. 346: 557.

  29. Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia * • Age & time from collapse to ROSC affected outcome • After adjustment for these factors, OR increased to 5.25 (95% CI 1.47-18.76, p=0.011) for good outcome *Bernard et al. New England Journal of Medicine, 2002. 346: 557.

  30. Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia * Limitations: • Clinicians were not blinded to tx assignment, ? bias in care & outcome • Suboptimal randomization scheme • Lack of long-term follow-up *Bernard et al. New England Journal of Medicine, 2002. 346: 557.

  31. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest * • Randomized controlled trial, 3/96-1/01 • 9 centers in 5 European countries • Included: witnessed CA, v. fib or pulseless v. tach, presumed cardiac origin of arrest, age 18-75 yrs, 5-15 mins from collapse to 1st resuscitation attempts, < 60 mins from collapse to ROSC *The Hypothermia After Cardiac Arrest Study Group. NEJM, 2002. 346: 549.

  32. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest * • Excluded: TM temp < 300C on admission, comatose prior to arrest, pregnancy, response to verbal commands after ROSC, MAP < 60 for > 30 mins after ROSC, O2 sat < 85% for > 15 mins after ROSC, preceding terminal illness, factors that made follow-up unlikely, enrollment in another study, CA after EMS arrival, known coagulopathy *The Hypothermia After Cardiac Arrest Study Group. NEJM, 2002. 346: 549.

  33. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest * *The Hypothermia After Cardiac Arrest Study Group. NEJM, 2002. 346: 549.

  34. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest * • Cooling: 320C-340C w/ external cooling device X 24 hrs • Goal to reach target bladder temp in 4 hrs; if not, ice packs applied • Temperature monitored via TM thermometer initially, then bladder probe *The Hypothermia After Cardiac Arrest Study Group. NEJM, 2002. 346: 549.

  35. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest * *The Hypothermia After Cardiac Arrest Study Group. NEJM, 2002. 346: 549.

  36. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest * Outcome: • 10 – Favorable neurologic outcome at 6 mos, defined as Pittsburgh CPC of 1 or 2 • Neurologic outcome obtained in blinded fashion • 20 – Overall mortality at 6 mos, rate of complications during the 1st 7 days after CA • Clinicians involved in pt care during 1st 48 hrs were unblinded *The Hypothermia After Cardiac Arrest Study Group. NEJM, 2002. 346: 549.

  37. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest * • 14 patients hypothermia discontinued early • 1 pt per group lost to neurologic follow-up • Clinical characteristics similar • Control group - larger # of pts w/DM, CAD, BLS performed by bystander (non-significant) *The Hypothermia After Cardiac Arrest Study Group. NEJM, 2002. 346: 549.

  38. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest * • Median interval between ROSC & initiation of cooling 105 mins • Median interval between ROSC & target temperature 8 hrs • 19 pts never reached target temperature • Ice packs required in 70% of pts *The Hypothermia After Cardiac Arrest Study Group. NEJM, 2002. 346: 549.

  39. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest * Bladder Temperature in the Normothermia and Hypothermia Groups. *The Hypothermia After Cardiac Arrest Study Group. NEJM, 2002. 346: 549.

  40. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest * • Adjusting for DM, CAD, BLS from bystander resulted in increased treatment effect • RR for favorable neurologic outcome 1.47 (95% CI 1.09-1.82) • RR for death 0.62 (95% CI 0.36-0.95) *The Hypothermia After Cardiac Arrest Study Group. NEJM, 2002. 346: 549.

  41. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest * Cumulative Survival in the Normothermia and Hypothermia Groups. *The Hypothermia After Cardiac Arrest Study Group. NEJM, 2002. 346: 549.

  42. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest * • 73% of hypothermic pts & 70% of normothermic pts developed complications (p=0.70) • Sepsis, pna more likely in hypothermia group (non-significant) • Total # of complications similar in the two groups (p=0.09) *The Hypothermia After Cardiac Arrest Study Group. NEJM, 2002. 346: 549.

  43. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest * Limitations: • Clinicians not blinded to treatment assignment • Large # of strict inclusion/exclusion criteria • Included only witnessed CA, which represents small # of out-of-hospital arrests *The Hypothermia After Cardiac Arrest Study Group. NEJM, 2002. 346: 549.

  44. Summary • 2 RCTs demonstrate a favorable neurologic outcome in pts treated w/mild hypothermia, 320C-340C for 12-24 hrs in setting of v. fib or v. tach arrest w/ROSC • Larger RCT demonstrates a significant decrease in mortality at 6 months • Neither study had a greater number of complications in hypothermia group

  45. Conclusions • Permanent brain damage seen in 10-30% of survivors of out-of-hospital CA in U.S. • No therapy w/documented efficacy in preventing brain damage after CA • Hypothermia has a long clinical history & a body of animal studies supporting its use • Pathophysiologic basis

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