1) Detailed neurological examinations and blinded prognostication were conducted in the TTM trials to minimize bias in outcomes. 2) Follow-up assessments at 6 months in TTM1 found cognitive impairment, depression, and reduced quality of life in about one third of patients despite similar mortality between groups. 3) Extended cognitive testing in TTM1 at 6 months revealed memory, executive function, and processing speed impairments in about half of patients, more than in risk-factor matched controls, showing long-term cognitive consequences after cardiac arrest.

1. Lessons from the TTM-trial and
planning for the next
NIKLAS NIELSEN

2. Disclosures
Steering group member of the TTM and TTM2 trials
Funding from Swedish governmental sources and several non-profit organizations.
Lecture fees from BARD Medical
Advisory board Braincool AB
Niklas Nielsen
Associate professor
Department of Anesthesiology and Intensive Care
Helsingborg Hospital
Department of Clinical Sciences
Lund University, Sweden

3. TTM-trial – 2010-2013
• 950 were randomised
• Out-of-hospital cardiac arrest
• Cardiac cause
• Europa och Australien
• 33°C vs 36°C
Funded by:
Swedish Heart Lung Foundation
AFA-insurance Foundation, Sweden
Swedish Research Council
Governmental and Regional funding within the Swedish National Health System
TrygFoundation, Denmark
Zoega, Krapperup, Thure Carlsson, Trolle-Wachtmeister foundations, Sweden

4. Temperature profile
Mean ± 2SD
30
31
32
33
34
35
36
37
38
39
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
TTM36 TTM33
P<0.0001
Hours
°Celcius

5. P=0.51
TTM-trial 2013
HR=1.06 95% CI 0.89 to 1.28; P=0.51

6. 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

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

8. NO DIFFERENCE!

10. Nolan J et al. Resuscitation 2015
Nolan J et al. Intensive Care Med 2015
2015 ERC guidelines (similar with AHA)!

11. Nolan J et al. Resuscitation 2015
Nolan J et al. Intensive Care Med 2015

12. Nolan J et al. Resuscitation 2015
Nolan J et al. Intensive Care Med 2015

13. Nolan J et al. Resuscitation 2015
Nolan J et al. Intensive Care Med 2015

14. ILCOR 2015
This is a dilemma…

15. …which reflects clinical practice of today….
• Different approaches to Targeted Temperature Managemet….
1. Those relying on the early trials from 2002: 33°C
2. Those relying on the TTM-trial: 36°C
3. Those who can’t decide: 34 or 35 or 37°C
4. Those who are agnostic or dogmatic or confused: No TTM

17. • Worse temp control!
• More fever!
• Tendecy to worse survival!

18. • Good compliance with 36-protocol!
• Less complications? Easier?
• Clinical advantage?

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

21. 40 hour intervention period
HACA-trial 2002
TTM2-trial 2017

22. 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

23. Primary outcome
180-day
mortality

24. Secondary outcomes
Functional status
Quality of life

25. Tertiary outcomes (6 months)
1. Montreal Cognitive Assessment
2. Symbol Digit Modalities Test
3. Two Simple Questions
4. Informant Questionnaire on Cognitive Decline in the Elderly
5. 30 second chair stand test

26. Power and sample size
• Previous trials had power to detect or reject ≥20%RRR
• RRR 15%
• 90 % power
• Based on the mortality rate in TTM1 we will include:
•1900 patients

28. Ethical approvals
• Italy
• USA
• New Zealand
• Germany
• Holland
• UK
• Switzerland
• Sweden
• Luxembourg

29. Common biobank
• Integrated biobank of Luxembourg
• Admission, 24 hours, 48 hours, 72 hours
• Validation and discovery of biomarkers of brain damage

30. Funding
• Swedish Research Council
• Swedish Heart and Lung Foundation
• Stig and Ragna Gorthon Foundation
• Knutsson Foundation
• ALF/Regional grants

32. Neurological prognostication in the
TTM-trials
TOBIAS CRONBERG

33. Disclosures
Steering group member of the TTM and TTM2 trials
Funding from Swedish governmental sources and several non-profit organizations.
No industry sponsoring
Tobias Cronberg
Associate professor
Department of Neurology
Skåne University Hospital
Department of Clinical Sciences
Lund University, Sweden

34. Most patients die from brain injury
Dragancea, Resuscitation, 2017

35. TTM may delay recovery for patients with
good outcome
CA 72h 1 W 6M
SEDATION
TTM
Neurological
function
PRE-TTM

36. Premature withdrawal of life-sustaining
treatment (WLST)
• Premature WLST (<72 hours) is common
– 1/3 of all deaths in hospital after OHCA was due to WLST-N < 72 hours.
• Premature WLST is an important potential source of bias in trials
on temperature modulation after cardiac arrest
– The intervention is difficult to conceal for the treating team
– Self-fulfilling prophecy
Elmer et al, Resuscitation, 2016

37. Prognostication was blinded and delayed to a median
117 hours in the TTM-trial
48% 15% 33%
Dragancea, Resuscitation, 2017

38. Prognostication was blinded and delayed to a median
117 hours in the TTM-trial
48% 15% 33%
Dragancea, Resuscitation, 2017

39. Prognostication was blinded and delayed to a median
117 hours in the TTM-trial
48% 15% 33%
Dragancea, Resuscitation, 2017

40. The prognosticator recommended to “continue care”(CC), “do-
not-escalate”(DNE) or “withhold active intensive care”(WAIC)
37
18
45
continue care do-not-escalate withhold intensive
care
0
10
20
30
40
50
All prognosticated patients (N=313)
Dragancea, Resuscitation, 2017

41. Mortality was high at 6-months regardless of
recommendation
Dragancea, Resuscitation, 2017

42. The recommendation was reflected in the time
to death
Dragancea, Resuscitation, 2017

43. More precise prognostication may reduce
suffering and costs
Dragancea, Resuscitation, 2017

44. Sandroni. ICM 2014 AND Nolan, ERC/ESICM guidelines, Resuscitation and ICM 2015
European Recommendations for prognostication
>72 hours

45. Neurological prognostication in the TTM2-trial
• Clinical examination according to the FOUR-score
• Daily clinical examination and routine EEG at 48-96 hours are
mandatory
• CT, MRI, SSEP and serum NSE are optional investigations
• Formal prognostication of all patients who are still in the ICU 96
hours after randomisation

46. An external physician blinded for allocation will
evaluate the prognosis
• Neurologist, intensivist or other specialist experienced in
neuroprognostication after cardiac arrest
• Not involved in the patients care.
• Blinded for treatment allocation
• Will make a statement on the prognosis for neurological recovery
• Will not be involved in decisions on WLST

47. In the TTM2 trial the prognosis is considered likely poor if
A, B and C criteria are fulfilled;
A. Confounding factors such as severe metabolic derangement
and lingering sedation has been ruled out
B. The patient has no response or a stereotypic extensor
response to bilateral central and peripheral painful stimulation
at ≥ 96 hours after randomisation.
C. At least two of the below mentioned signs of a poor prognosis
are present:

48. At least two of the below mentioned signs of a poor
prognosis are present:
1. Bilateral absence of pupillary and corneal reflexes at 96h after CA or later
2. A prospectively documented early status myoclonus (within 48 hours)
3. A highly malignant EEG-pattern according to the TTM2 definition without reactivity
to sound and painful stimulation.
4. CT brain with signs of global ischaemic injury, such as: generalised oedema with
reduced grey/white matter differentiation and sulcal effacement.
5. MRI-brain with signs of global, diffuse, or bilateral multifocal ischaemic lesions.
6. Serial serum-NSE samples consistently higher than locally established levels
associated with a poor outcome
7. Bilaterally Absent SSEP N20-responses more than 48 hours after randomisation.

49. EEG – highly malignant patterns
Westhall et al, Neurology, 2016
Suppressed
background
(amplitude ,10 mV,
100% of the
recording)
Suppressed
background with
superimposed
continuous periodic
discharges.
Burst-suppression
Burst-suppression
with superimposed
discharges

50. In concordance with Swedish updated
recommendations
Rylander et al, Läkartidningen, 2017

51. Detailed Neurological Follow-up in
the TTM-trials
GISELA LILJA

52. …given the neurological status is a major determinant of
overall functional outcome, either the primary or
secondary measures of a good study should include some
measure of neurological recovery
Primary outcome for resuscitation sciences studies:
a consensus statement from AHA
Becker, Aufderheide et al. Circulation. 2011

53. Cerebral Performance Categories (CPC) scale
CPC 1. Good cerebral performance: conscious, alert, able to
work, might have mild neurologic or psychological deficit.
CPC 2. Moderate cerebral disability: conscious, sufficient cerebral
function for Independent activities of daily life. Able to work in sheltered environment.
CPC 3. Severe cerebral disability: conscious, Dependent on others for daily support because of
impaired brain function. Ranges from ambulatory state to severe dementia or paralysis.
CPC 4. Coma or vegetative state
CPC 5. Death
Jennett, Lancet, 1975(1)480-4
P
O
O
R
G
O
O
D
91% of survivors
9% of survivors

54. For very large randomized controlled trials that may have a major
impact on public health policy, longer-term end points such as 90 days
coupled with neuro-cognitive and quality-of-life assessments should
be considered.
…for assessment of cognitive meaures, it was the consensus of the experts
that at least 1 measure of memory, attention/processing speed, and
executive function be incorporated into a brief cognitive battery
Primary outcome for resuscitation science studies:
a consensus statement from AHA
Becker et al. Circulation. 2011

55. Long-term outcome follow-up TTM1
A brief screening face-to-face at 6 month
Clinician-reported outcome
• Cerebral Performance Category scale (CPC)
• modified Rankin Scale (mRS)
Patient-reported outcome
• Two Simple Questions (TSQ)
• Short-Form Questionnaire 36 version 2 (SF-36v2)
Performance outcome
• MiniMental Status Examination (MMSE)
Observer-reported outcome
• Informant Questionnaire on Cognitive Decline for Cardiac Arrest (IQCODE-CA)
Nielsen, Wetterslev et al. NEJM. 2013
Cronberg, Lilja et al. JAMA Neurol. 2015

56. Problems at 6 months
Patient-reported outcome (TSQ, SF-36v2)
82% no need for help in everyday activities 18%
64% reported a complete mental recovery 36%
HRQoL comparable to normative data
Performance outcome (MMSE)
The majority had scores within the normal range 31%
Observer-reported outcome (IQCODE-CA)
38% reported unchanged cognitive performance in everday activities 62%
Cronberg, Lilja et al. JAMA Neurol. 2015

57. 6 months follow-up in the TTM-trial
The two intervention groups very similar outcome irrespective if reported by the examiner,
the patient, a relative/informant or objective screening
Many patients (36%) and relatives (62%) reported problems that indicated that life was not
the same as before the arrest
These problems were not identified with crude outcome measures as the CPC (>90%
good outcome)

58. For very large randomized controlled trials that may have a major
impact on public health policy, long,er-term end points such as 90 days
coupled with neuro-cognitive and quality-of-life assessments should
be considered.
…for assessment of cognitive meaures, it was the consensus of the experts
that at least 1 measure of memory, attention/processing speed and
executive function be incorporated into a brief cognitive battery
Primary outcome for resuscitation science studies:
a consensus statement from AHA
Becker et al. Circulation. 2011

59. Extended 6-months follow-up in the TTM-trial

60. Extended follow-up TTM
Assessments performed at same time as the main-study follow-up, 20 of original 36 sites, 5 countries
Original randomization kept
N=287 (90% of eligible included)
Control group of ST elevation myocardial infarction patients (N=119)
– Expected to have similar risk-factors for cognitive decline
– No CA
– Matched for
» Country
» Gender
» Age
» Time-point for hospitalization
Lilja, Nielsen et al. BMC Cardiovascular Disorders, 2013

61. Memory
0 10 20 30 40 50 60 70 80 90 100
STEMI
OHCA
48
46
35
32
17
22
Normal
Mild
Moderate-severe
Rivermead Behavioural Memory Test (RBMT)
Lilja, Nielsen et al. Circulation, 2015

62. Executive function
0 10 20 30 40 50 60 70 80 90 100
STEMI
OHCA
87
78
13
22
Frontal Assessment Battery
(FAB)
Lilja, Nielsen et al. Circulation, 2015

63. Attention/Processing speed
0 10 20 30 40 50 60 70 80 90 100
STEMI
OHCA
66
46
11
13
22
41
Normal
Mild
Moderate-severe
Symbol Digit Modalities Test (SDMT)
Lilja, Nielsen et al. Circulation, 2015

64. Cognitive impariment in cardiac arrest survivors
Increased risk for brain injury related to the cardiac arrest
BUT cognitive impairment should be seen in the context of
– Age
– Cardiovascular risk factors
e.g. hypertension, diabetes
Gottesman. JAMA Neurol. 2014
Selnes. NEJM. 2012
– Critical illness related cognitive impairment
e.g. baseline decline, neuroinflammatory processes, sleep disturbances, pain, use of sedatives and
analgesics, systematic factors as hypotension, hypo/hyper glyceamia, delirium
Wilcox. Critical Care Med. 2013
Pandharipande. NEJM.2013
Wolters. Intensive care Med. 2013
– Psychological distress

65. Cognitive problems in the TTM cohort
Did they represent psychological distress or a neurological outcome due
to e.g. anoxic etihology?

66. Extended 6-months follow-up in the TTM-trial

67. Cognitive impairment more common
0
10
20
30
40
50
60
70
80
90
100
anxiety
depression
cognitive impairment
76
87
24.713
6
28.6
11
7
46.7
Normal
Mild
Mod/sev
Anxiety and/or depression: 27%
Cognitive impairment: 47%
Incl. low (mild) scores: 75%
Lilja, Nilsson et al. Resuscitation. 2015

68. Long-term outcome after cardiac arrest TTM1
Objectie cognitive impairment was found in more than half by assessments
Cognitive impairment was common also in a risk-factor matched control group, indicating that cognitive problems
after OHCA may be due several factors
Emotional problems and cognitive impairments related but cognitive impairment much more common
Cognitive impairment (processing speed, memory), fatigue, depression and mobility restrictions identified to
be the most important varaibles for the patients levels of societal particpation

69. Some questions that remains
• Did we use the best assessment/s?
• Did we use the right time-point/s?
• Did we ask the right questions?

70. Planning for the next…TTM2
Temperature Management
After successful resuscitation, patients who survive a cardiac arrest often remain
severely ill and require intensive care. Controlling body temperature is a potential
treatment that may prevent brain damage. The TTM2-trial aims to study how to
best apply this intervention.
(http:// ttm2trial.org/ clinics)
Contact (/ contact) Login (http:// www.ecrf.ttm2trial.org)
TTM2 (/ ) M ENUM ENU

71. TTM2 Outcome Assessments

72. TTM1 vs. TTM2
A brief screening face-to-face
Clinician-reported outcome
• Cerebral Performance Category scale (CPC) Glasgow Outcome Scale-Extended GOS-E
• modified Rankin Scale (mRS)
Patient-reported outcome
• Two Simple Questions (TSQ)
• Short-Form Questionnaire 36 version 2 (SF-36v2) EQ-5D-5L
Performance outcome
• MiniMental Status Examination (MMSE) Montreal Cognitive Assessment (MoCA)
• Symbol Digit Modalities Test (SDMT)
Observer-reported outcome
• Informant Questionnaire on Cognitive Decline (IQCODE-CA)

73. Time-points

74. TTM1 vs. TTM 2
At hospital discharge 5 hours to 414 days
At 30 days (telephone)
At 3 months
At 6 months (face-to-face) Long enough?
At the end of the trial
At 24 months (face-to-face)

75. Cardiovascular risk factors in TTM 2
Framingham risk scores
Total cholesterol
HDL cholesterol
Smoker?
Diabetes?
Systolic blood pressure
Treatment for high blood pressure?
HBA1C
Length/weight (BMI)
Physical activity
Two questions (based on AHA recommendations for phyiscal activity, 2007)
30 seconds chair stand test

76. Summary and some final reflections
Follow-up of long-term outcome in clincial trials far from easy
Too not loose clincially relevant effects beyond dead or alive it has to be done
Extensive efforts are however needed to collect good quality data, and this have to be inlcuded already in the
study design e.g. to prevent missing data and increase inter-rater reliability
Large clincial trials as TTM1 and TTM2 fantastic oppertunities to learn more about outcome after OHCA
Important that we continue to evaluate the best methods

77. www.ttm2trial.org
@ttm2trial
ttm2@ttm2trial.org

78. 7th International Hypothermia and Temperature Management Symposium
• 27th to 29th August 2018 (Sydney, Australia)
• ANZICS-Clinical Trials Group Winter Meeting: 26th-27th