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

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 32 - 34⁰C 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

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

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 32 - 34⁰C) 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

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

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?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 2012 163;4 (541 -548) 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