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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

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

Vanessa R. Cole, MD

December 17, 2002

Resident Grand Rounds

clinical case
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
clinical case3
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
questions
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?
slide5
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
history of hypothermia
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
adverse effects of hypothermia
Adverse effects of hypothermia
  • Coagulopathy - platelet dysfunction, prolonged PT/PTT
  •  CO,  SVR
  • EKG changes, arrhythmias
  •  susceptibility to infection
  •  blood viscosity
  •  extracellular potassium
definitions
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
reperfusion injury10
Reperfusion injury
  • Barbiturates - thiopental
  • Ca2+ channel blockers - lidoflazine
  • Corticosteroids
  • Free radical scavengers
  • Neurotransmitter receptor blockers
reperfusion injury11
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
animal studies
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
slide14

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.

slide16

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.

slide17

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.

slide18

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.

slide20

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.

slide21

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.

slide22

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.

slide23

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.

slide24

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.

slide25

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.

slide26

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.

slide28

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.

slide29

Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia *

*Bernard et al. New England Journal of Medicine, 2002. 346: 557.

slide30

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.

slide31

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.

slide32

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.

slide33

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.

slide35

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.

slide36

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.

slide37

Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest *

*The Hypothermia After Cardiac Arrest Study Group. NEJM, 2002. 346: 549.

slide38

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.

slide39

Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest *

*The Hypothermia After Cardiac Arrest Study Group. NEJM, 2002. 346: 549.

slide40

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.

slide41

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.

slide42

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.

slide43

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.

slide44

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.

slide45

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.

slide46

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.

slide47

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.

summary
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
conclusions
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
conclusions51
Conclusions
  • Out-of-hospital CA claims 225,000 lives annually in U.S.
  • 13-19% witnessed arrests due to v. fib w/ROSC
  • 4,000-6,000 potential lives saved w/mild therapeutic hypothermia
  • HACA – nationwide implementation would prevent 3% of unfavorable neurologic outcomes in pts w/CA
future studies
Future Studies
  • Double-blinded
  • Investigate cardiopulmonary arrest due to causes other than v. fib & v. tach
  • Optimal duration & timing of cooling
  • Best cooling method
  • Cost-benefit analysis
questions54
Questions
  • Would hypothermia have any benefit on neurologic prognosis in this patient?
  • NO!
  • Pt did not have documentation of initial rhythm
  • Required high-dose pressors & external pacing
  • Prolonged period between arrest, ROSC, & arrival to NCBH CCU
questions55
Questions
  • In which patients, if any, has hypothermia after cardiopulmonary arrest been shown to improve outcome?
  • Hypothermia should be applied ASAP after ROSC in pts w/v.fib or v. tach arrest, severe residual neurologic deficit, & no contraindications
questions56
Questions
  • What are the harms associated with hypothermia?
  • Many potential harms with prolonged & profound hypothermia
  • In pts cooled to 320C-340C for 12-24 hrs, no more complications than control pts
  • Non-significant trend toward higher # of infectious complications
conclusion of case
Conclusion of Case
  • Hypothermia was not initiated
  • Head CT: diffuse cerebellar/cerebral edema consistent w/anoxic injury, L→R shift of 3mm, inferior transtentorial herniation
  • Neurology consult: <1% change of moderate to severe neurologic disability
  • Discussion with family, life support withdrawn
thanks
THANKS!!
  • Christian Sinclair
  • Raquel Watkins
  • Sandi Manus
  • Dr. Little