1. science
2. medicine

How Low Should I Go:
Controversies in Therapeutic
Hypothermia
Brian J. O’Neil, MD, FACEP, FAHA
Munuswamy Dayanandan Endowed Chair
Edward S. Thomas Endowed Professor
Wayne State University, School of Medicine
Department of Emergency Medicine
Specialist In Chief, Detroit Medical Center
How Long, How Deep:
Controversies in Therapeutic
Hypothermia
Brian J. O’Neil, MD, FACEP, FAHA
Munuswamy Dayanandan Endowed Chair
Edward S. Thomas Endowed Professor
Wayne State University, School of Medicine
Department of Emergency Medicine
Specialist In Chief, Detroit Medical Center
DISCLOSURES
PI Zoll Cool – ARREST Trial
Previous ECC/ACLS Chair
Current ILCOR and AHA ALS
Writer
Previous research funding from
Medivance
The Current Landscape:
CARES Registry
The Current Landscape:
CARES Registry
The Current Landscape: CARES Registry
Adult Immediate Post-Cardiac Arrest Care
Peberdy et al, Circulation 2010;122:S768-786.
Hypothermia: Potential Mechanisms
Think Hibernation:
•  6% ↓ in metabolic rate per 1 °C reduction
in brain temperature
•  CMR declined to 50% after brain cooling to
32 °C
(CBF & CMR coupled)
•  Blocks release of excitatory amino acid
•  Reduces early calcium rise
Hypothermia is NOT
Monotherapy
•  Hypothermia has been shown to:
•  Improve cell survival signaling processes
(Akt, PKC, etc)
•  Inhibits cytochrome c release from
mitochondria
•  Decrease free radical production and
propagation
•  Decrease lipolysis
•  Effect salutary changes in glutamate receptor
composition and signaling
Prolonged Hypothermia
Cell Death - Proteases
Protein Synthesis Inhibition
Collapse
New Gene Expression
Intracellular signaling
Cerebral Hypoperfusion
48 Hours
24 Hours
2 Hours
Oxidative Stress
Excitatory Amino Acid Release
Energy Failure / Acidosis
NEJM Volume 346:549-556 February 21, 2002 Number 8
NEJM Volume 346:557-563 February 21, 2002 Number 8
•  The HACA group, 136 pts,
•  VF arrest, comatose, stable hemodynamics,
external cooling device,
•  8 hours = median time to target Temp (32-34 C)
•  Cooling continued for a mean of 24 hours
•  Bernard et al (77 pts), VF arrest
•  external cooling, ice bags, initiated by EMS at
ROSC
•  Median 2 hours to target temperature of 33.5
•  cooled for 12 hours
• 
Bernard, S.A., Clinical trial of Induced Hypothermia in Comatose Survivors of Out-of-Hospital Cardiac Arrest.
Journal of Emergency Medicine, 1997
Discharge With Good Neurologic Outcome
HACA: CPC 1or 2
•  75 /136 pts (55%) hypothermia
•  54/137 (39%) in the normothermia group
•  Risk ratio 1.40 (95% CI 1.08 - 1.81)
•  NNT to improve neuro outcome= 6 pts
•  NNT to prevent 1 death = 7 patients
•  NNT to Harm = 141
Bernard et al. (77 pts)
•  Good outcome = 49% v 26%2
1Hypothermia
After Cardiac Arrest Study Group. N Engl J Med. 2002 Feb 21;346(8):549-56.
2Bernard SA et al. N Engl J Med. 2002 Feb 21;346(8):557-63.
• 
• 
• 
• 
950 patient with OOHCA
Consecutive screening
Cooled for 28 hours
Blinded Neurologic assessment at 72 hours
•  Pre-specified criteria for withdrawal
TTM
HACA Trial
TTM Trial Mortality rates
Neurologic Outcomes
Are These Your Patients
TTM
•  90% witnessed, 73% bystander CPR
•  80% with shockable rhythm
•  Average time down till BLS was 1 minute
•  10 min for ACLS
•  No difference in adverse events
•  No difference in adverse events
•  No difference in adverse events
Do you prescribe the lowest
possible dose of antibiotics
to treat an infection, if the
side effect profile is the
same as a higher dose ??
Neumar et al. Rat Asphyxial Arrest
Neumar et al. Rat Asphyxial Arrest
Sawyer et al:
Maybe One Size Does Not Fit Y’all
•  Ideally:
•  Titrate temperature depth to the reduction in
consumption
•  JbSO2, NIRS, Lycos, PET
•  Need to find good marker of neuronal injury
•  Titrate duration to neuronal function
•  Longer ischemia = longer duration
•  Lack of meaningful recovery = longer duration
– EEG,
Neuroprognostication
•  Given the pathophysiological and
pharmacokinetic effects of TH, the time
points for standard assessments should
be shifted, and we suggest that an
appropriate ‘time zero’ in TH‑treated
patients might be the time when the
patient returns to normothermia and all
sedation is discontinued.
Neuroprediction
•  None are good before 72 hours in TH:
•  No pupillary and or corneal reflexes
•  bilateral absence of N20 SSEP
•  EEG:
•  persistent absence of EEG reactivity to external
stimuli
•  presence of persistent burst-suppression after
rewarming
•  intractable and persistent status epilepticus
Conclusions
•  Cool them all unless they push you away
•  Some is better than none
•  Faster to target is better
•  Time to target probably effects duration
•  Duration of ischemia may = TH duration
•  Someday we will Titrate to effect