1. Targeted temperature management at 33⁰c vs 36⁰c after cardiac arrest
Jannien Senekal
February 2014
RBWH

2. Background and rationale
Experimental animal studies and previous RCT suggest improvement in mortality and neurological function with induced hypothermia after cardiac arrest
International guidelines: Target temp of ⁰C for 12 – 24h after resuscitation from out-of-hospital cardiac arrest
Systematic review: Evidence inconclusive
Grade level of evidence low
Previous trials:
Small
High risk of bias
Select populations
Did not treat hyperthermia in the control groups

3. Bernard et al NEJM 2002;346:557 – 63
Comparison of effects of moderate hypothermia and normothermia in patients who remained unconscious after resuscitation from out-of-hospital cardiac arrest
77 patients: Randomly assigned to treatment with hypothermia (core body temp reduced to 33⁰C within 2h after the return of spontaneous circulation and maintained at that temp for 12h) OR normothermia
Primary outcome measure:
Survival to hospital discharge with sufficient good neurological function to be discharged home or to a rehabilitation facility
Conclusions:
Treatment with moderate hypothermia appeared to have improved outcomes

4. M. Holzer et al NEJM 2002;346:549-56
Studied whether mild systemic hypothermia increases the rate of neurological recovery after resuscitation from cardiac arrest due to ventricular fibrillation
Multicenter
Patients randomly assigned to undergo therapeutic hypothermia (target temp ⁰C) over a period of 24h OR standard treatment with normothermia
275 patients enrolled:
137 in hypothermia group and 138 to normothermia group
55% had favourable outcome in hypothermia group as compared to 39% in the normothermia group
Complication rate did not differ significantly between the 2 groups
Conclusions:
In pts who were successfully resuscitated after cardiac arrest secondary to VF therapeutic hypothermia increased the rate of a favourable neurological outcome and reduced mortality

5. TARGETED TEMPERATURE MANAGEMENT AT 33 c VS 36 c AFTER CARDIAC ARREST Nielsen et al

6. DEBATE IN REGARD TO PREVIOUS EVIDENCE:
1. Should therapeutic hypothermia be extended to patients outside the originally described populations?
2. What is the most beneficial target temperature for therapeutic hypothermia?

7. Temperature during the intervention period was actively controlled and
WHAT WAS THE BIG DIFFERENCE TO APPROACH WITH TTM IN COMPARISON TO PREVIOUS TRIALS IN REGARDS TO THE CONTROL GROUP?
Temperature during the intervention period was actively controlled and
Aimed to prevent fever during the first 3 days after cardiac arrest

8. PATIENTS ≥ 18yrs Unconscious (GCS < 8 ) on admission to hospital
After out-of-hospital cardiac arrest of presumed cardiac cause – irrespective of initial rhythm
>20 consecutive minutes of spontaneous circulation after resuscitation: no chest compressions have been required and signs of circulation persist

12. Exclusion criteria Interval from ROSC to screening > 240min (4h)
Unwitnessed arrest with asystole
Suspected or known acute intracranial haemorrhage / stroke
Body temp < 30 degrees
Obvious or suspected pregnancy
Known bleeding diasthesis (medically induced coagulopathy ie warfarin / clopidogrel did not exclude the patient)
Known limitations in therapy
Known disease making 180d survival unlikely
Known pre-arrest cerebral performance category 3 - 4
SBP <80mmHg in spite of fluid loading / vasopressor / inotrope/ IABP

13. Randomization and intervention:
Randomly assigned 1:1 ratio
Randomisation centrally with use of computer generated assignment sequence
Healthcare physician caring for trial patients were aware of intervention; others not
Intervention period: 36h
Commenced at time of randomisation
Measures to achieve assigned temperature as rapidly as possible – at discretion of sites 
After 28h gradual rewarming to 37⁰C in hourly increments of 0.5⁰C commenced in both groups
Intention was to maintain temp for unconscious patients < 37.5⁰C until 72h after the arrest

16. Neurological prognostication
All pts treated until minimum 72h after the intervention
Neurological evaluation done on pts not regaining consciousness
Exceptions
Myoclonic status in first24h and bilateral absence of N20 peak on SSEP
Brain dead due to herniation
Ethical reasons
External blinded physicians evaluated the patient at the end of phase 3 and made a statement on neurological prognosis
Neurological examination based on:
Clinical
SSEP
EEG

17. Findings allowing for discontinuation of active intensive care
Brain death due to herniation
Severe myoclonus & absence N20 peak on SSEP
Minimum 72h after intervention period:
Persistent coma with motor score 1 – 2 and bilateral absence N20-peak
Minimum 72h after the end of the intervention period:
Persisting coma with a motor score 1-2 and treatment refractory status epilepticus

18. Results:
Total of 950 patients were enrolled between November 2010 and January 2013
Of these patients 476 were randomly assigned to 33⁰C group
474 to the 36⁰C group
The 2 groups had similar pre randomization characteristics

19. TEMPERATURE MANAGEMENT
Temp was managed with:
Intravascular cooling catheter in 24% of patients
Surface cooling system in 76% of patients in both groups
16 patients assigned to the 33⁰ C group were rewarmed before reaching the intended time point of 28h after randomization

21. WITHDRAWAL OF LIFE-SUSTAINING THERAPY
During first 7 days of hospitalisation life sustaining therapy was withdrawn in 247 patients
Reasons for withdrawal included:
Brain death
Multiorgan failure
Ethical concerns
Protocol defined approach to neurologic prognostication was used to make recommendations regarding the continuation or withdrawal of life-sustaining therapy

22. PRIMARY OUTCOME: All-cause mortality through the end of the trial SECONDARY OUTCOME: Composite of poor neurological function or death defined as a cerebral performance category of 3 -5

24. Follow-up and outcomes
The mean period of follow up for all patients was 256 days
At end of trial – deaths:
235 of 473 (50%) in 33⁰ C group
225 of 466 (48%) in 36⁰ C group
Groups did not differ with respect to the composite outcome of death or poor neurological function at 180 days

25. Adverse events
One or more serious adverse event occurred in 93% of 33⁰ C group and 90% in the 36⁰ C group
Hypokalaemia more frequent in the 33 ⁰C group
Other:
Seizures
Bleeding
Infection
Arrhythmia
Electrolyte and metabolic disorder
RRT

26. SUMMARY International, multicentre, randomized trial
No significant differences between the 2 groups in overall mortality at the end of the trial or in the composite of poor neurologic function or death at 180 days

27. Limitations:
ICU staff members were aware of the assigned target temperature. Minimized by blinded outcome assessment
In one country ethical approval required written consent from a legal surrogate before randomization resulting in a substantial proportion of eligible pts being excluded
No detailed data on dose and type of sedation or the use of neuromuscular blocking agents

28. How is this study applicable to us?
Clinically relevant to our practice
Patients included corresponds with the patient population that we would be managing in terms of ie age group and pre-existing IHD and hypertension
Response time to cardiac arrest with bystander CPR and advanced life support similar to what we would be expecting in our practice as well as average ROSC reasonable and similar to experiences with patients within our environment
Exclusion criteria reasonable and in keeping with our practice
Temperature measures taken realistic and able to be employed in our unit ie no special expertise required

29. Does this study change management?
TIME FOR CONSULTANT DEBATE…………….

30. TAKE HOME MESSAGE
There may be a clinically relevant benefit of controlling the body temp at 36⁰C instead of allowing fever to develop in patients who have been resuscitated after cardiac arrest

31. References
Target temp management after out-of-hospital cardiac arrest – a randomized, parallel group, assessor-blinded clinical trial – rationale and design Am Heart J April ;4 ( )
Targeted temperature management at 33 C vs 36 C after cardiac arrest Nielsen et al NEJM 369;23 including supplementary appendix
Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia Bernard et al NEJM 346;8
Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest Holzer et al NEJM 346;8