Hypothermia in Cardiac Arrest: Should we be hot to cool

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Hypothermia in Cardiac ArrestShould 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

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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

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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?

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• 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

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History of hypothermia

• 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

• 1950s
• 4 published case reports
• 320C to 340C for 24-72 hrs after cardiac arrest
• 3/4 patients recovered without neurologic deficit

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Adverse effects of hypothermia

• Coagulopathy - platelet dysfunction, prolonged
  PT/PTT
• ? CO, ? SVR
• EKG changes, arrhythmias
• ? susceptibility to infection
• ? blood viscosity
• ? extracellular potassium

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Definitions

• Mild 34 20C
• Moderate 30 20C
• Deep 15-250C
• Profound lt 150C

• Protective cooling before the insult
• Preservative cooling during the insult
• Resuscitative cooling to reverse the insult,
  support recovery

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Reperfusion Injury
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Reperfusion injury

• Barbiturates - thiopental
• Ca2 channel blockers - lidoflazine
• Corticosteroids
• Free radical scavengers
• Neurotransmitter receptor blockers

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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

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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

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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 lt 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.
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Glascow Outcome Coma Score (GOCS)
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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 lt 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.
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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.
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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.
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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 lt 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.
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Preliminary Clinical Outcome Study of Mild
Resuscitative Hypothermia After Out-of-Hospital
Cardiopulmonary Arrest

• Cooling within 7828 mins of ROSC
• Target temp w/in 336180 mins of initiation
• 11/13 pts completed cooling protocol

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Yangawa et al. Resuscitation, 1998. 39 61.
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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.
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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.
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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 lt 8,
  informed consent from family
• Excluded cardiac instability, acute ischemia,
  sepsis, need for pressors, shock, coagulopathy,
  QTc gt 470 ms, in-hospital arrest, other
  conditions precluding treatment

Felberg et al. Circulation, 2001. 104 1799.
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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.
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Hypothermia After Cardiac Arrest Feasibility
Safety of an External Cooling Protocol

• 7820 mins from ACLS to start of cooling
• 301178 mins from initiation of cooling to goal
  temperature
• 1 pt did not complete protocol
• 4/9 survived
• 3/9 Rankin score0, MMSE30
• 1/9 Rankin score3, MMSE20
• Pts w/good outcome had shorter anoxic periods

Felberg et al. Circulation, 2001. 104 1799.
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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 lt 18 yrs ?, lt 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.
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Treatment of Comatose Survivors of
Out-of-Hospital Cardiac Arrest with Induced
Hypothermia
Bernard et al. New England Journal of Medicine,
2002. 346 557.
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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 _at_ 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.
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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.
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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, p0.011) for good
  outcome

Bernard et al. New England Journal of Medicine,
2002. 346 557.
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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.
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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, lt 60 mins from collapse
  to ROSC

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

• Excluded TM temp lt 300C on admission, comatose
  prior to arrest, pregnancy, response to verbal
  commands after ROSC, MAP lt 60 for gt 30 mins after
  ROSC, O2 sat lt 85 for gt 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.
37
Mild Therapeutic Hypothermia to Improve the
Neurologic Outcome after Cardiac Arrest
The Hypothermia After Cardiac Arrest Study
Group. NEJM, 2002. 346 549.
38
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.
39
Mild Therapeutic Hypothermia to Improve the
Neurologic Outcome after Cardiac Arrest
The Hypothermia After Cardiac Arrest Study
Group. NEJM, 2002. 346 549.
40
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.
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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.
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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.
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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.
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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.
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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.
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Mild Therapeutic Hypothermia to Improve the
Neurologic Outcome after Cardiac Arrest

• 73 of hypothermic pts 70 of normothermic pts
  developed complications (p0.70)
• Sepsis, pna more likely in hypothermia group
  (non-significant)
• Total of complications similar in the two
  groups (p0.09)

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

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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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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

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CCU protocol
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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

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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

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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

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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

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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 lt1 change of moderate to
  severe neurologic disability
• Discussion with family, life support withdrawn

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THANKS!!

• Christian Sinclair
• Raquel Watkins
• Sandi Manus
• Dr. Little