Niklas Nielsen talks about the TTM trial as seen through a 2019 lens. The video and references from the talk and all the rest of the goodness from The Big Sick 2019 in Zermatt is up at https://scanfoam.org/

1. The TTM-trials-why, how and what
NIKLAS NIELSEN, MD, PHD, A/PROF ZERMATT FEB 7TH 2019

3. Improving survival rates….
Swedish Cardiac Arrest Registry
Survivors after 1 month
www.HLR.nu

4. In 2010….
• Hypothermia established
• Guidelines were firm
• Everyone happy….

5. TTM-trial – 2010-2013
• 950 randomised to 33°or 36°C
• Out-of-hospital cardiac arrest
• Cardiac cause
• Europe and Australia

7. HACA-trial compared to TTM-trial
HACA-trial 2002
TTM-trial 2013

8. Temperature profile
Mean ± 2SD
P<0.0001
Hours
°Celcius

9. P=0.51
No difference in survival
HR=1.06 95% CI 0.89 to 1.28; P=0.51

10. Neurological and QoL assessment in the
TTM-trial - a novel approach
Performance outcome
Clinician reported outcome
Patient reported outcome
Observer reported outcome
Cronberg et al. JAMA Neurology 2015
Detailed assessment in subgroup

11. No difference in neurological function
Cronberg et al, JAMA Neurology 2015
P=0.77
P=0.57
P=0.71
P=0.32
P=0.78
P=0.87

12. ….or quality of life!
P=0.45
P=0.79
Cronberg et al, JAMA Neurology 2015

13. Trial conclusion:
A target temperature of 33°C did not
confer any benefit compared to 36°C

15. No difference detected in any of
the sub or post hoc studies of
TTM!

16. 48
49
43
23
21
35
29
36
14
19
16
12
13
6
7
10
8
7
7
49
46
0 20 40 60 80 100
STEMI-controls*
Cardiac arrest 36°C*
Cardiac arrest 33°C*
Cardiac arrest 36°C ALL
Cardiac arrest 33° ALL
Normal
Mild
Moderate
Severe
Dead
%
Figure 2. Categorical outcome for the Rivermead Behavioural Memory Test (RBMT)
Memory
Lilja et al. Circulation. 2015

17. 87
80
77
39
38
13
20
23
15
13
46
49
0 20 40 60 80 100
STEMI-
controls*
Cardiac arrest
36°C*
Cardiac arrest
33°C*
Cardiac arrest
36°C ALL
Cardiac arrest
33° ALL
Normal
Impaired
Dead
%
Figure 3. Categorical outcome for the Frontal Assessment Battery (FAB)
Executive function
Lilja et al. Circulation. 2015

18. 66
43
48
21
24
11
9
17
5
8
22
48
34
25
22
49
46
0 20 40 60 80 100
STEMI-controls*
Cardiac arrest 36°C*
Cardiac arrest 33°C*
Cardiac arrest 36°C ALL
Cardiac arrest 33°C ALL
Normal
Bordeline
Impaired
Dead
%
Figure 4. Categorical outcome for the Symbol Digit Modalities test (SDMT)
Attention/Processing speed
Lilja et al. Circulation. 2015

19. Was the trial representative?

20. Cooling time
P<0.0001
Hours
°Celcius

21. Cooling time
P<0.0001
Hours
°Celcius
+130
150 min
Time To Target <34°C ≈ 280 min (4.5 hours)

22. Cooling time
P<0.0001
Hours
°Celcius
Nielsen, AAS, 2009

23. P<0.0001
Hours
°Celcius
Cooling time
Kirkegaard, JAMA, 2017

24. P<0.0001
Hours
°Celcius
Cooling time
Tömte, CCM, 2011

25. Temperature control
+/-2 SD
IQR

26. Temperature control
Median ± IQR

27. Severity of illness
• 25 minutes to ROSC
• Lactate 6.7 mmol/L
• All patients unconscious (median GCS 3)
• Overall mortality 50%

28. Conclusion TTM-trial
• Represents clinical practice
• Did not show that hypothermia does not work
• Did not demonstrate efficacy of fever
treatment
• It did show similar outcome with two separate
temperature targets both strictly controlled
• Possible to perform large cardiac arrest trials
in international collaboration

29. Nolan J et al. Resuscitation 2015
Nolan J et al. Intensive Care Med 2015
2015 ERC/ESICM guidelines

30. Nolan J et al. Resuscitation 2015
Nolan J et al. Intensive Care Med 2015
Evidence and recommendation GRADE

31. Nolan J et al. Resuscitation 2015
Nolan J et al. Intensive Care Med 2015
Evidence and recommendation GRADE

32. Nolan J et al. Resuscitation 2015
Nolan J et al. Intensive Care Med 2015
Evidence and recommendation GRADE

35. Nothing
36°C
35°
34°33°C or lower

36. Timing of TTM
• PRINCE trial
• PRINCESS trial
• Kim-trial
• Bernard-trials

37. Timing of TTM
33,5
34,0
34,5
35,0
35,5
36,0
36,5
0 30 60 90 120 150 180 210 240 270 300
Temperature(°C)
Time from collapse (minutes)
ROSC
Hospital
Arrival
Systemic Cooling
Started
291102
189 minutes
p=0.03
Treatment
Control
Castrén et al 2010

38. Timing of TTM
Castrén et al 2010

39. Witnessed cardiac arrest
Randomization
No pre hosp coolingPrehosp cooling
Continued TTM ICU Start TTM ICU
PRINCESS-trial

40. Duration of TTM
• TTH48 trial comparing 24 versus 48 hours of cooling

41. From: Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital
Cardiac ArrestA Randomized Clinical Trial
JAMA. 2017;318(4):341-350. doi:10.1001/jama.2017.8978
Copyright 2017 American Medical
Association. All Rights Reserved.

42. Copyright 2017 American Medical
Association. All Rights Reserved.
From: Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital
Cardiac ArrestA Randomized Clinical Trial
JAMA. 2017;318(4):341-350. doi:10.1001/jama.2017.8978

44. Hypothermia or early treatment of fever
Targeted hypothermia versus targeted
normothermia after out-of-hospital cardiac
arrest
-the TTM2-trial

45. Hypothesis
Rapid cooling to 33°C improves
outcome when compared to
normothermia and early treatment of
fever (37.8°C) in unconscious adults
admitted after OHCA

46. Mackowiak 1992 – 148 individuals

47. Mackowiak 1992
”The upper limit of normal
body temperature is 37.7°C”

48. Obermeyer 2017 – 35000 individuals

49. Obermeyer 2017
”The upper limit of normal
body temperature is 37.7°C”

50. OHCA
33°C <37.8°C
Full organ support minimum 96 h
Neurological prognostication
Continued care discretion of caregivers
40hours

51. Inclusion criteria
1. Adult
2. Comatose out of hospital cardiac arrest, presumed
cardiac cause
3. Sustained ROSC
4. Eligible for intensive care admission without
restriction or limitations
5. Within 3 hours from ROSC

52. Exclusion criteria
1. Unwitnessed cardiac arrest with initial rhythm
asystole
2. Temperature at admission <30°C
3. On ECMO prior to ROSC
4. Obvious or suspected pregnancy
5. Intracranial bleeding
6. On home oxygen

53. Trial flow
• 1. Targeted temperature management to
33°C
• 2. Observe and keep temperature below
fever 37.8°C

54. Intervention period
HACA-trial 2002

55. Intervention period
HACA-trial 2002
TTM2-trial 2017

56. Intervention period
HACA-trial 2002
TTM2-trial 2017

57. Intervention period
HACA-trial 2002
TTM2-trial 2017

58. Intervention period
HACA-trial 2002
TTM2-trial 2017

59. Young et al ICM 2012
Patients with infections Patients without infections

60. Primary outcome
Landmark 180-day
all cause mortality

61. Secdondary outcomes
Performance outcome
Clinician reported outcome
Patient reported outcome
Observer reported outcome
Detailed assessment in subgroup

62. Power and sample size
• Previous trials had power to detect or
reject ≥20%RRR
• RRR 14% (ARR 7.5%)
• 90% power
• 1900 patients

63. Differences from TTM1?
• Shorter window of inclusion
• More emphasis on reaching low fast
• Increased separation
• Longer follow up
• Larger sample size

64. Status

65. Status

70. Baseline characteristics
33°C 36°C
No. 473 466
Age
Male sex
64+/-12
83 %
64+/-13
79 %
Arrest in place of
residence
Arrest in public place
Bystander witnessed
Bystander CPR
Shockable rhythm
52 %
42 %
89 %
73 %
79 %
55 %
40 %
90 %
73 %
81 %
Arrest to ROSC (min) 25 [18-40] 25 [16-40]
Circulatory shock on
adm.
Lactate mmol/L
15 %
6.7±4.5
14 %
6.7±4.5
ST-elevation infarction 40 % 42 %
GCS 3 [3-4] 3 [3-4]

71. Time to CPR- no flow
Basic life support = Bystander CPR

72. Time to BLS in HACA-trial?
HACA 2002
Zeiner 2001

73. Hypothermia more effective when
longer no flow
- observational study
Testori Resuscitation, 2011

74. Hypothermia more effective when
longer no flow
- observational study
Testori Resuscitation, 2011

75. No flow time in TTM-trial
Dankiewicz 2015, Resuscitation

76. No flow time in TTM-trial
Dankiewicz 2015, Resuscitation

77. Temperature and mortality
Saxena et al ICM 2015

78. We actually have little knowledge on
this….
• Almost all human data are observational
• Associations rather than causality
• Fever may be a epiphenomenon?
• Does fever cause damage or is it a symptom of illness?

79. The theoretical benefit and cost of fever
Young, Nielsen, Saxena ICM 20

80. The theoretical benefit and cost of fever
Young, Nielsen, Saxena ICM 20

81. Wild type temperature trajectory CA-ROSC to 48 h
Zeiner, Archives of Int Med 2001
HACA-trial, NEJM 2002

82. Subgroups…….
AGE
GENDER
RHYTHM
SHOCK
DOWNTIME