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![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]](https://image.slidesharecdn.com/2-190615202648/75/The-TTM-trials-why-how-and-what-70-2048.jpg)
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The TTM trials - why, how and what?
The TTM trial from 2010-2013 investigated the effects of targeted temperature management (cooling) in out-of-hospital cardiac arrest patients, comparing 33°C and 36°C temperature targets. The trial concluded that there was no significant difference in survival or neurological outcomes between the two temperature targets, suggesting that hypothermia may not be beneficial. Subsequent studies, including the TTM2 trial, aimed to further explore temperature management strategies in this context.
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The TTM trials - why, how and what?
- 1. The TTM-trials-why, howand what NIKLAS NIELSEN, MD, PHD, A/PROF ZERMATT FEB 7TH 2019
- 3. Improving survival rates…. SwedishCardiac Arrest Registry Survivors after 1 month www.HLR.nu
- 4. In 2010…. • Hypothermiaestablished • 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 toTTM-trial HACA-trial 2002 TTM-trial 2013
- 8. Temperature profile Mean ±2SD P<0.0001 Hours °Celcius
- 9. P=0.51 No difference insurvival HR=1.06 95% CI 0.89 to 1.28; P=0.51
- 10. Neurological and QoLassessment 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 inneurological 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 oflife! P=0.45 P=0.79 Cronberg et al, JAMA Neurology 2015
- 13. Trial conclusion: A targettemperature of 33°C did not confer any benefit compared to 36°C
- 15. No difference detectedin 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 4060 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 4060 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 4060 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 trialrepresentative?
- 20.
- 21. Cooling time P<0.0001 Hours °Celcius +130 150 min TimeTo Target <34°C ≈ 280 min (4.5 hours)
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- 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 • Representsclinical 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 etal. Resuscitation 2015 Nolan J et al. Intensive Care Med 2015 2015 ERC/ESICM guidelines
- 30. Nolan J etal. Resuscitation 2015 Nolan J et al. Intensive Care Med 2015 Evidence and recommendation GRADE
- 31. Nolan J etal. Resuscitation 2015 Nolan J et al. Intensive Care Med 2015 Evidence and recommendation GRADE
- 32. Nolan J etal. Resuscitation 2015 Nolan J et al. Intensive Care Med 2015 Evidence and recommendation GRADE
- 35.
- 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 36,5 030 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 Castrénet al 2010
- 39. Witnessed cardiac arrest Randomization Nopre 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 TemperatureManagement 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 AmericanMedical 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 earlytreatment of fever Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest -the TTM2-trial
- 45. Hypothesis Rapid cooling to33°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 upperlimit of normal body temperature is 37.7°C”
- 48. Obermeyer 2017 –35000 individuals
- 49. Obermeyer 2017 ”The upperlimit of normal body temperature is 37.7°C”
- 50. OHCA 33°C <37.8°C Full organsupport 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. Unwitnessedcardiac 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
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- 59. Young et alICM 2012 Patients with infections Patients without infections
- 60. Primary outcome Landmark 180-day allcause mortality
- 61. Secdondary outcomes Performance outcome Clinicianreported outcome Patient reported outcome Observer reported outcome Detailed assessment in subgroup
- 62. Power and samplesize • 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.
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- 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 BLSin HACA-trial? HACA 2002 Zeiner 2001
- 73. Hypothermia more effectivewhen longer no flow - observational study Testori Resuscitation, 2011
- 74. Hypothermia more effectivewhen longer no flow - observational study Testori Resuscitation, 2011
- 75. No flow timein TTM-trial Dankiewicz 2015, Resuscitation
- 76. No flow timein TTM-trial Dankiewicz 2015, Resuscitation
- 77. Temperature and mortality Saxenaet al ICM 2015
- 78. We actually havelittle 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 benefitand cost of fever Young, Nielsen, Saxena ICM 20
- 80. The theoretical benefitand cost of fever Young, Nielsen, Saxena ICM 20
- 81. Wild type temperaturetrajectory CA-ROSC to 48 h Zeiner, Archives of Int Med 2001 HACA-trial, NEJM 2002
- 82.