1. Targeted Temperature Management Post Cardiac Arrest
Graham Wong MD MPH FRCPC FACC
Director, Coronary Care Unit and Associate Head of Cardiology, Vancouver General Hospital
Regional Medical Lead, Acute Cardiac Care VCHA/PHC
Associate Professor of Medicine, University of British Columbia

2. Disclosures Travel honoraria: Bard Canada
Co-Chair: 2016 CCS Guidelines “Optimal In hospital Care of the Post Cardiac Arrest Patient”

3. Challenge for the CCS Guidelines
Provide guidance for the practical application of TTM:
Appropriate population and method of application
Timing and duration of implementation
Target temperature and duration, including fever management
Development of a “Post arrest Cardiac Arrest Bundle” encompassing all aspects of in hospital CA care, including TTM

4. TTM: State of the Art 2015
Justification for TTM and physiology of induced hypothermia
Induction
Optimal method of inducing TTM
Initiation relative to ROSC
Rate of cooling
Maintenance
Target temperature
Precision
Duration
Rewarming
Rate of rewarming and duration

5. TTM: State of the Art 2015
Justification for TTM and physiology of induced hypothermia
Induction
Optimal method of inducing TTM
Initiation relative to ROSC
Rate of cooling
Maintenance
Target temperature
Precision
Duration
Rewarming
Rate of rewarming and duration

6. Pathophysiology of ischemia/reperfusion cerebral injury
ISCHEMIA/HYPOXIA
ENERGY FAILURE
LOSS OF TRANSMEMBRANE
POTENTIAL
SYNAPTIC FAILURE
GLUTAMINE RELEASE &ACCUMULATION
OF INTRACELLULAR Ca2+
ACTIVATION OF CATABOLIC ENZYMES
AND NO SYNTHASE
REPERFUSION
DISRUPTION OF
BLOOD BRAIN
BARRIER
CELL MEDIATED
INFLAMMATION
CEREBRAL EDEMA
CELLULAR OXIDATIVE
AND INFLAMMATORY
DAMAGE
CEREBRAL MICROVASCULAR HYPOPERFUSION
CEREBRAL INFLAMMATION AND INCREASED APOPTOSIS

7. Potential benefits of TTM
K. Polderman. Crit Care Med 2009; 37 (7) (Suppl): S186-S202

8. Annals of Surgery 1958:148:
Anesthesia and Analgesia 1959; 38:

9. Analyzed 19/27 CA pts who had neurological dysfunction following ROSC:
1/7 who did NOT receive TTM survived with no residual deficits (14%)
6/12 who received TTM survived with no residual deficits (50%)

10. NEJM 2002; 346 (8)

11. 2010 ILCOR Recommendations
“Adult patients who are comatose (not responding in a meaningful way to verbal commands) with spontaneous circulation after out-of-hospital VF cardiac arrest should be cooled to 32°C to 34°C for 12 to 24 hours. Induced hypothermia might also benefit comatose adult patients with spontaneous circulation after OHCA from a nonshockable rhythm or in-hospital cardiac arrest.”
Hazinski et al. Circulation 2010; S122: S

12. TTM: State of the Art 2015 Induction Maintenance Rewarming
Optimal method of inducing TTM
Initiation relative to ROSC
Rate of cooling
Maintenance
Target temperature
Precision
Duration
Rewarming
Rate of warming and duration

13. Methods of inducing TTM
ADVANTAGES
DISADVANTAGES
IV COLD FLUID/
ICE PACKS
Low cost
Easily available
Rapid initiation
Imprecision
May overshoot target temperature
SURFACE COOLING
cooling blankets
Arctic Sun
CritiCool
Blanketrol III
EMCOOLS
As with IV fluid *PLUS*
Increased precision with feedback control
Older pads: radio-opaque
Rare risk of skin reaction/dermal injury
INTRAVASCULAR
ThermoGard XP
InnerCool RTx
Less shivering
Rapid achievement of target temperature
Invasive
Potential delay in initiation (needs MD)
Risk of thromboembolism/infection
CORE
ECMO
RRT
Rapid induction of cooling
Precise temperature management
Resource and personnel intensive
Adapted from Oh et al. Crit Care 2015; DOI /s

14. Surface vs Intravascular
Gillies et al Resuscitation 2010
81:
Hoedemaekers et al. Crit Care 2007; 11
doi: /cc6104
BR water circulating
CC air circulating
AS gell coated cooling system
CG intravascular cooling

15. Complications: Surface vs endovascular
Propensity matched: no difference in mortality or neruological outcomes with surface
Surface cooling: higher incidence of adverse events (hyperthermia, rewarming hypoglycemia and hypotension; not seen with hydrogel pads with feedback control)
53.3% of surface cooling: cooling blankets
N=803 (559 surface cooling, 244 endovascular cooling)
Oh et al. Crit Care 2015; DOI /s

16. Conclusions
Surface and endovascular cooling had faster rates of temperature change compared to conventional means
Surface cooling had higher rates of adverse events than endovascular cooling, but this was not seen with hydrogel pad based cooling
Feedback control appeared to mitigate some of the issues of surface control methods compared to endovascular cooling techniques

17. TTM: State of the Art 2015 Induction Maintenance Rewarming
Optimal method of inducing TTM
Initiation relative to ROSC
Rate of cooling
Maintenance
Target temperature
Precision
Duration
Rewarming
Rate of rewarming and duration

18. Initiation, duration and time to target temp after ROSC
TRIAL
TTM METHOD
STARTING TEMPERATURE
(0C)
GOAL TEMPERATURE
TIME TO ACHIEVE GOAL TEMP AFTER ROSC
(MIN)
DURATION OF ACTIVE THERAPY
(HRS)
HACHIMI
COLD HELMET
35.5 (median) 34
180
N/A
HACA
SURFACE
32-34
480 (8hrs) 24
BERNARD
34.9 (mean) 33
(0.90C drop in temp/hr;
temp at 6 hrs was 32.70C) 12
LAURENT
CVVHD/TTM
36 (mean) 32
240 16
TTM – 330C
MIXED
35.2 (mean)
28(Fever control 72hrs)
TTM – 360C
35.3 (mean) 36
Hachami et al. Rescusitation 2001; HACA NEJM 2002; Bernard et al NEJM 2002; Laurent et al JACC 2005; Nielsen et al NEJM 2003

19. Paradox between time to achieve goal temp and outcomes?
Time interval (min)
“Poor”
outcome
(N=222)
“Good”
(N=99)
P value
Down time
21 (10-36)
11 (6-27)
0.002
Preinduction time
114 (34-260)
97.5 (36-230) NS
Induction time
180 (
236.5 ( )
0.004
MV regression: best outcomes when time to goal temp >300min
Worst outcomes when <120 minutes
Perman et al Rescuscitation 2015; 88: 84-89

20. TTM: State of the Art 2015 Induction Maintenance Rewarming
Optimal method of inducing TTM
Initiation relative to ROSC
Rate of cooling
Maintenance
Target temperature
Precision
Duration
Rewarming
Rate of rewarming and duration

21. Limitations of underpinning 2010 ILCOR/ESR/AHA TTM Recommendations
Quality of evidence prior to 2011 considered poor1
Relative small # of pts in 2 largest RCT
(Total 213 in both HACA and Barnard trials)
No comparison of normothermia vs pyrexia control
Patients in HACA control arm had temperatures >370C
1. Nielsen et al. Int J Cardiol 2011; 151:

22. Nielsen et al. N Engl J Med 2013; 369:2197-2206

23. Nielsen et al. N Engl J Med 2013; 369:2197-2206

24. TTM vs HACA
HACA
N=275
TTM Trial
N=939
None related to arctic sun specifically, add ones for ttm in general
TTM: surface and intravascular
HACA: cooling blankets: took 8 hours to get to desired temperature
HACA Study Group. N Engl J Med 2002; 346:
Nielsen et al. N Engl J Med 2013; 369:

25. Safety of 33 vs 360C in TTM Trial
Selected SAE
330C (%)
360C (%)
P value
Tonic clonic seizures
7.7
7.3
0.85
Intracranial bleeding
0.4
1.4
0.09
GI bleeding
5.4
5.1
0.84
Pneumonia 52 46
0.089
Severe sepsis 10
0.92
Bradycardia requiring pacing
5.2
6.4
0.43
Recurrent cardiac arrest
9.1
0.6
Hypokalemia 19 13
0.018
Hypoglycemia
5.5
4.9
0.68
ANY SAE 93 86
0.086
N Engl J Med 2013;369: DOI: /NEJMoa

26. ?Clinical and Methodological Issues: 330C vs 360C
No signal of harm of 330C compared to 360C
TTM trial designed as a superiority trial
Not felt appropriate to use a superiority trial to declare equivalence or noninferiority1
Piaggio et al. JAMA 2006;

27. TTM: State of the Art 2015 Induction Maintenance Rewarming
Optimal method of inducing TTM
Initiation relative to ROSC
Rate of cooling
Maintenance
Target temperature
Precision
Duration
Rewarming
Rate of rewarming and duration

28. Rate of rewarming: does it matter?
Bouwes et al. Resucitation 2012; 83:

29. Rewarming and fever Prevalence up to 42% post CA1
Rebound pyrexia seen in pts treated with TTM and those who were not1
Post CA pyrexia associated with worse neurological outcomes2
1.Gebhardt et al Resuscitation 2013; 84:
2.Leary et al Resuscitation 2013; 84:

30. Conclusions
No randomized data demonstrating a superior method of providing TTM
No randomized data demonstrating optimal time to initiate TTM
No randomized data guiding the optimal duration of TTM management
No randomized data guiding the importance of precision of TTM
No randomized data guiding the optimal rate of cooling nor rewarming with TTM
Suggestion that overly rapid achievement of goal temperature may be harmful
No difference between 33 and 360C for clinical outcomes and mortality; methodological issues require further discussion before choosing a preferred temperature
Suggestion that fever management up to 72hrs may be of additional benefit to early TTM

31. TTM: State of the Art 2015 Induction Maintenance Rewarming
Optimal method of inducing TTM NO PREFERRED METHOD
Initiation relative to ROSC “AS SOON AS POSSIBLE”
Rate of cooling 0.5 – 1.00C/HR
Maintenance
Target temperature C OR 360C MAY BE APPROPRIATE
Precision LIKELY OF GREATEST IMPORTANCE AT 360C
Duration 24HRs
Rewarming
Rate of rewarming and duration FEVER CONTROL UP TO 72HRS

32. “The history of premature adoption of TH in light of the well-done trial by Nielsen et al raises a critical question to not only the neurological, but also the medical community as a whole: what level of evidence is necessary for widespread adoption or guideline development of a purported therapeutic procedure? In the case of TH, substantial health care resources were used without challenging the underlying assumption of the value of TH.”
Neal Little. JAMA Neurology 2014; 71: