Prolonged or deeper cooling after cardiac arrest

Research Center
for Emergency
Medicine
Prolonged or deeper cooling after cardiac
arrest
Hans Kirkegaard
Professor in Prehospital and Emergency Medicine
Director of Research Center for Emergency Medicine
Aarhus University

Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
No economical conflict of interest
Principal Investigator of TTH48
E-mail: hanskirkegaard@dadlnet.dk

Targeted Temperature Management
• Need to know
– How fast
– How deep
– How long
• Depending on age?
– How to rewarm
• Nice to know
– Post Hypot. fever
– Surface/i.v.
– Bleeding
– Circulation
– Prognostication
• Who to cool
• When to stop

• We recommend selecting and maintaining a constant
target temperature between 32°C and 36°C for
those patients in whom targeted temperature
management is used
• Evidence: One RCT of 939 patients
– Targeted temperature management at 33°C versus
36°C after cardiac arrest. N Engl J Med.
2013;369:2197-2206

Targeted Temperature Management
• Need to know
– How fast
– How deep
– How long
• Depending on age?
– How to rewarm
• Nice to know
– Post Hypot. fever
– Surface/i.v.
– Bleeding
– Cirkulation
– Prognostication
• Who to cool
• When to stop

We suggest that if targeted temperature management
is used, duration should be at least 24 hours as done
in the 2 largest previous RCTs: No data

Time Differentiated Therapeutic Hypothermia:
The TTH48 Trial
• Comatose victims from out of hospital cardiac
arrest are randomized to:
24 versus 48 hours of targeted
temperature management at 33 ºC

Why 48 hours
• To balance a clear augmentation of “cooling dose” against
an expected prolonged ICU stay and the risk for more
adverse events

TTH48, Hypothesis and Outcome
• Hypothesis
– Cooling for 48 hours at 33 ºC results in a better neurologic
outcome, compared to cooling for 24 hours
• Primary Outcome
– Blinded CPC score at 6 months following cardiac arrest
• Secondary Outcome
– Mortality and adverse events
• Power
– The trial was designed to detect an absolute difference
between groups of 15% or more, requiring 355 pt. in total

Inclusion Criteria
• Out of hospital cardiac arrest with a presumed cardiac
cause
• Re-established circulation after resuscitation (when CPR
isn’t necessary for 20 minutes and there are clinical signs of
circulation)
• Glasgow Coma Score (GCS) < 8
• Age ≥ 18 years and < 80 years

Aarhus, Aalborg, Odense
Copenhagen
Helsinki
Tallinn
Stavanger
Brussels
Turku
Berlin

JAMA 2017; 318(4):341-51

Temperature

Main results

Adverse events

Probability of death

Length of stay

Bystander CPR and interventional
cardiology

Subgroup analyses: age

The TTH48 Team at AUH www.tth48.com
COAGULATION
CARDIAC FUNCTION
PROGNISTICATION

The American Journal of Medicine 2016

Resuscitation 2017(115): 23-31

Coagulation
• Platelet aggregation was below the normal range post
cardiac arrest, but prolonged TTM had no further decisive
effect on aggregation compared with standard TTM.
• Impaired clot formation measured by thrombin generation
was observed when TTM was prolonged compared with
when it was of standard duration.
• The prolonged group seemed to have no increased risk of
bleeding.
• Thus, it is safe to prolong the TTM beyond 24 hours.
A. Jeppesen et al. Critical Care 2016; 30; 20:118;
Platelets, in press;
Resuscitation 2017; 118: 126

Perspectives
• Our findings will probably not change current guidelines
• To perform a Trial with a power to detect a differences of
5% or more between the 48 and 24 hour group would
require approximately 3.000 patients.
• It would be more relevant to repeat the study in a larger
group of younger patients (< 60 years). The number of
patients needed to detect a difference of 5% or 10% in this
group would be much lover.

Conclusion
• In targeted temperature management there is no evidence
to support a lower temperature limit than the
recommended at 32 ˚C
• Prolonged targeted temperature management at 33˚C did
not result in better neurologic outcome
• Prolonged cooling seemed not to affect cardiac function
• Prolonged cooling seemed not to increase the risk of
bleeding
• Prolonged cooling would be relevant to investigate further
in the <60 years of age population.

Thank You Malmø

JAMA 2014;
312: 2629-39

How long should we cool Neonates?
• longer cooling, deeper cooling, or both compared
to hypothermia at 33.5°C for 72 hours did not
reduce NICU death
• Will shorter or more shallow cooling, or both
compared to hypothermia at 33.5°C for 72
hours reduce NICU death?

Studies in Children
Therapeutic hypothermia after out-of-hospital cardiac arrest in Children.
THAPCA Trial. N Engl J Med 2015; 372: 1898-908.

THAPCA-OH Clinical Trial
• 295 children > 2 days < 18 years: 48 hours of TH
Normothermia 36.0 – 37.5 degrees
Hypothermia 32 – 34 degrees for 48 h
Rewarming 16 h
36.0 – 37.56 h
• Results:Survival with a VABS-II score > 70 at 1 year
Normothermia 12% Survival: 29%
Hypothermia 20% Survival: 38%
CONCLUSION: Therapeutic hypothermia, as compared with
therapeutic normothermia, did not confer a significant benefit
with respect to survival with good functional outcome at 1 year.

Coagulation
• Influence of temperature on thromboealstometry and
platelet aggregation in cardiac arrest patients undergoing
targeted temperature management
– A. Jeppesen et al. Critical Care 2016 Apr 30; 20(1):118
• Platelet aggregation during targeted temperature
management after out-of-hospital cardiac arrest: a
randomised clinical trial
– A. Jeppesen et al. Platelets, in press
• Prolonged targeted temperature management compromises
thrombin generation: a randomised clinical trial
– A. Jeppesen et al. Resuscitation 2017; 118: 126-32

Prolonged or deeper cooling after cardiac arrest

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