2. Summary
Background
International resuscitation guidelines recommend targeted temperature
management (TTM) at 33°C to 36°C in unconscious patients with out-of-hospital
cardiac arrest for at least 24 hours, but the optimal duration of TTM is uncertain
Objective
To determine whether TTM at 33°C for 48 hours results in better
neurologic outcomes compared with currently recommended, standard,
24-hour TTM
Methods
• international, investigator-initiated, blinded-outcome-assessor, parallel,
pragmatic, multicenter, randomized clinical superiority trial,10 ICUs at
10 university hospitals in 6 European countries (2013.2.16 ~ 2016.6.1,
f/u ~2016.12.27)
• Inclusion criteria : ICU admission OHCA pt (presumed cardiac origin),
17<age<80, ROSC > 20min, GCS<8
• Exclusion criteria : unwitnessed asystole, noncardiac cause,
collapse~ROSC time >60min, DNR, severe coagulopathy,
arrest~initiation of cooling>240min, SBP<80 despite vasoactive
treatment, ICHm acute stroke…
• TTM(33 ± 1°C) for 48 hr (n = 176) vs. 24 hr (n = 179)
• gradual rewarming of 0.5°C/hr until reaching 37°C
Primary outcome> 6-month neurologic outcome (CPC 1, 2)
Secondary outcome> 6-month mortality, time to death, occurrence of
adverse events, ICU resource use
Statistical analysis>
• 80% power (p=.05), absolute difference of 15% Sample size 338 pts was required
• Modified intention-to-treat analysis(including all randomized pt) / per-protocol
analysis(cooling was terminated earlier pts were excluded)
• Unadjusted, adjusted 6-mon survival analysis : cox proportional hazards regression
• Multivariable analysis : adjusting for trial site, age, sex, initial cardiac arrest rhythm, time
to ROSC, bystander CPR)
Results
• 355 patients were randomized, 351(99%) completed the trial
• Favorable neurologic outcome : 48hr group > 24hr group
(not statistically significant)
• Six-month mortality was not different between the groups
• Adverse event : 48hr group > 24hr group
• Time to mortality : no significant difference
• Median length of ICU stay : 48hr group > 24hr group
• Hospital stay : no significant difference
Conclusion
In unconscious survivors from out-of-hospital cardiac arrest admitted to the ICU,
TTM at 33°C for 48 hours did not significantly improve 6-month neurologic
outcome compared with TTM at 33°C for 24 hours.
However, the study may have had limited power to detect clinically important
differences, and further research may be warranted.
3.
4.
5.
6. Q1. 33도 24시간 vs 48시간으로 비교했는데 왜 36도
normothermia로 유지하는 control group 은 비교하지
않았을까?
33도 24시
간
33도 48시
간
36도 유지
차이 없음
? ?
7. Q1. 33도 24시간 vs 48시간으로 비교했는데 왜 36도
normothermia로 유지하는 control group 은 비교하지
않았을까?
• 33도로 24시간 유지와 48시간 유지를 비교했을 때는 유의미한 차이가 없더라도, 36도로 유지한 control group을 추
가했다면 36도 normothermia group과 48시간 TTM group은 차이가 있을 수 있지 않을까 ? (33도 vs 36도 연구에서는
randomization 기준으로 28시간 이후부터 rewarming 시작함)
• 위 동물 모델 논문에서는 아무것도 안 한 그룹에 비해 nomorthermia 및 24시간 TTM group 이 apoptosis와 관련한
물질들이 유의미하게 줄어드는 것을 확인할 수 있으나 nomorthermia와 24시간 TTM 은 차이가 없었고
nomothermia와 48시간 TTM은 유의미하게 48시간 그룹이 좋았음
• 결국 이 논문에서도 만약 36도 유지 그룹이 추가되어 세군 간에 서로 비교했더라면 24시간, 48시간은 서로 유의미한
차이가 없더라도 36도 정온을 유지하는 것을 reference로 한다면 그보다는 48시간이 더 유의미하게 좋지 않았을까
9. Q2. 왜 48시간 그룹의 adverse event 가 높아질까?
• Therapeutic hypothermia : antiapoptotic effect of brain tissue
Reducing brain injury
duration 길어질 수록 brain은 보존되더라도 다른 organ들에 오래, 더 큰 영향을 끼칠
수 있기 때문에 그만큼 adverse effect 가 높아질 수 있다
• Adverse effects of therapeutic hypothermia
Impaired coagulation : bleeding
Risk of infection ↑: impaired leukocyte fx (ex. Pneumonia etc..)
Slow cardiac conduction, provoke arrhythmia (bradycardia, QT prolongation)
Hyperglycemia : insulin resistance
Cold diuresis : hypovolemia, hypokalemia, hypomagnesaemia, hypophostphatemia
