The TTM trials - why, how and what?
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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/
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The TTM trials - why, how and what?
- 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?
- 21. Cooling time P<0.0001 Hours °Celcius +130 150 min Time To Target <34°C ≈ 280 min (4.5 hours)
- 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
- 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
- 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