A presentation by Hans Kirkegaard at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine.
All available content from SSAI2017: https://scanfoam.org/ssai2017/
Delivered in collaboration between scanFOAM, SSAI & SFAI.
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Prolonged or deeper cooling after cardiac arrest
1. 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
2. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
No economical conflict of interest
Principal Investigator of TTH48
E-mail: hanskirkegaard@dadlnet.dk
3. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
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
4. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
• 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
5. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
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
6. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
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
7. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
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
8. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
Why 48 hours
• To balance a clear augmentation of “cooling dose” against
an expected prolonged ICU stay and the risk for more
adverse events
9. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
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
10. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
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
11. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
Aarhus, Aalborg, Odense
Copenhagen
Helsinki
Tallinn
Stavanger
Brussels
Turku
Berlin
12. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
13. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
JAMA 2017; 318(4):341-51
14. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
15. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
Temperature
16. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
Main results
17. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
Adverse events
18. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
Probability of death
19. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
Length of stay
20. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
Bystander CPR and interventional
cardiology
21. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
22. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
Subgroup analyses: age
23. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
24. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
The TTH48 Team at AUH www.tth48.com
COAGULATION
CARDIAC FUNCTION
PROGNISTICATION
25. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
The American Journal of Medicine 2016
26. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
Resuscitation 2017(115): 23-31
27. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
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
28. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
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.
29. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
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.
30. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
Thank You Malmø
31. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
32. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
JAMA 2014;
312: 2629-39
33. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
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?
34. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
Studies in Children
Therapeutic hypothermia after out-of-hospital cardiac arrest in Children.
THAPCA Trial. N Engl J Med 2015; 372: 1898-908.
35. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
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.
36. Research Center for Emergency Medicine • Aarhus University Hospital • Aarhus University
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