1. Therapeutic Hypothermiain Out of Hospital Cardiac Arresttowards ? Cara Jager Aios Spoed Eisende Geneeskunde AMC Regionale Refereeravond Juli 2013

2. Therapeutic Hypothermia in OHCA: Background • Europe: ± 10 - 20% survives OHCA • Mortality and morbidity largely due to anoxic brain injury • 7-30% good neurological outcome • Therapeutic hypothermia (TH)/ Mild Induced Hypothermia (MIH) recommended current guidelines • Bernard et al. N Engl J Med 2002 • HACA study group. N Engl J Med 2002

3. Therapeutic HypothermiaCurrent Practice • Which population? • Post cardiac arrest/ ROSC • No recent trauma • - GCS ≤ 8 When? - Post cardiac arrest • Where? • Inhospital • How? • External cooling techniques • Internal cooling techniques

4. Therapeutic Hypothermia:Current Practice the Netherlands Induction • Sedation • Cold fluids 4°C • Cool Mattress Maintenance • Target temperature 32°- 34° within 4 hours • 24 hrs Rewarming • Slow, 0.25- 0.5 °C/h within 8 hours • Stop sedation at 36°C • Awake/ Postanoxic coma?

5. Therapeutic HypothermiaReally Effective? PRO Nolan J and Soar J. BMJ 2011 CON Walden AP, Nielsen et al. BMJ 2011

6. ProNeurological Outcome NNT = 5 Arrich et al. Cochrane 2010

7. Therapeutic HypothermiaPRO • Evidence good enough to support mild induced hypothermia in OHCA • Patients with VF • In other circumstances evidence weaker (neurological outcome generally worse) • Package of care in resuscitation protocol • By no means perfect trials

8. Therapeutic HypothermiaCON • Bernard 2002: • Quasi randomization with odd and even dates • Unplanned adaptive design: • nonscheduled interim analysis after inclusion of 80% of the patients (no adjustment of P-value)

9. ConNeurological Outcome Nielsen et al. Int J Cardiology 2011

10. Con • Majority of the trials compared therapeutic hypothermia with no temperature control in the control groups • Control groups: majority not treated for fever, median temp: 37°C - 38°C • Intervention effect due to: • Increased temperature in control group? • Beneficial induced hypothermia? • Both? • Observational data poor outcome with higher temperatures: • OR 2.26 (1.24–4.12) for every degree higher than 37 °C • Clear association, how about causality? Nielsen et al. Int J Cardiology 2011

11. Targeted Temperature Management = TTM trial Targeted Temperature Management = TTM trial Nielsen et al. Am Heart J 2012

12. TTM-trial: protocol • International, multicenter RCT • Assessor blinded • Inclusion: ≥ 850 patients • Controlled hypothermia 33° versus controlled 36° • Standardized treatment decisions • Outcome: • All cause mortality • Poor neurological function • Adverse events • Presented at American Heart Association meeting November 2013 Dallas

13. Therapeutic HypothermiaReally effective? • Current practice: ICU • Timing of Therapeutic hypothermia • Animal models: as early as possible • When?

14. Therapeutic HypothermiaWhen? • Emergency Department? Egmond 2013

15. Optimal timing of TH? Regression-analysis • For every 5 minute delay in initiating TH: increased chance of having a poor neurological outcome OR 1.06 (95% CI 1.02-1.10) • Retrospective observational study • Clear association, how about causality? Sendelbach et al. Resuscitation 2012

16. Therapeutic HypothermiaWhen? • Pre-hospital setting?

17. Therapeutic HypothermiaPre-Hospital Medline 1966 – 06-2013 induced hypothermia [MESH] hypothermia [MESH] hypothermia, induced [MESH] induced mild hypothermia [MESH] induced moderate hypothermia [MESH] cooling [T/A] therapeutic [T/A] AND hypothermia [T/A] therapeutic [T/A] AND cooling [T/A] 50952 prehospital [T/A] pre-hospital [T/A] paramedic*[T/A] 12942 intra-arrest [T/A] intra arrest [T/A] intraarrest [T/A] post-arrest [T/A] post arrest [T/A] postarrest [T/A] 13259 arrest [T/A] cardiac arrest [T/A] OHCA [T/A] out of hospital cardiac arrest [T/A] out-of-hospital cardiac arrest T/A] out of hospital cardiac arrest [MESH] 83480 AND AND 187 hits Limits English Total 173 hits 40 relevant: 8 RCT 8 Review Pre hospital/ Emergency Department: Post-arrest/ post-ROSC Intra-arrest

18. Therapeutic HypothermiaPre- Hospital Diao et al. Resuscitation 2013

19. RCT, n= 37 • Ice cold saline infusion versus normal treatment Bottom line: • Prehospital induction of mild hypothermia is feasible • Cooling rate 2°C/h (95% CI 1.5-2.7) • Not to the level of therapeutic hypothermia ActaAnaesthesiol Scand 2009

20. Kim et al. Circulation 2007 • RCT, n= 125 • Ice cold saline infusion versus normal treatment Bottom line: • Significant lower temperature at hospital arrival with ice cold saline • volume dependent • Not associated with adverse events (i.e. pulmonary edema, rearrest) *P0.0001 by ANOVA

21. Therapeutic HypothermiaPre- Hospital: Improving Outcome? Bernard et al. Circulation 2010 Bernard et al. Crit Care Med 2012

22. 6730= Total cardiac arrests during trial period Prospective multicenter RCT Australia Oct 2005- Nov 2007 6436 = Adults ≥ 15y with cardiac arrest during trial period 4763= Cardiac arrest of presumed cardiac cause 2268= Resuscitation attempted by paramedics Bernard et al 2010 Bernard et al 2012 842= Initial rhythm ventricular fibrillation 1426= Initial rhythm asystole/ PEA 398= ROSC and transport to hospital 309= ROSC and transport to hospital 164= Eligible/ Not enrolled 146= Eligible/ Not enrolled 163= Eligible and enrolled 234= Eligible and enrolled 118= Paramedic cooling 100 ml/min cold saline up to 2l 116= Hospital cooling 82= Paramedic cooling 100 ml/min cold saline up to 2l 82= Hospital cooling 118= Assessed for 1° endpoint 116= Assessed for 1° endpoint 82= Assessed for 1° endpoint 81= Assessed for 1° endpoint

23. PostarrestPrehospital Cooling:Improving Outcome? Bottom line: In pre-hospital cooled group • Significant decrease in temperature at hospital arrival • Less time to reach therapeutic hypothermia (<34°C) • No benefit cooling in the field in patients with OHCA • either VF or nonVF WHY? Bernard et al. 2010 and 2012

24. Rewarming? • Cooling in field or ED same temperature 1h after arrival Bernard et al. 2010

25. Therapeutic HypothermiaPrehospital setting • Feasible lowering temperatures • No outcome differences Diao et al. Resuscitation 2013

26. TherapeuticHypothermia:Summary • Currentpractice • To believeornot to believe TowardsThe ColdChain • Prehospitalcooling: • Post-arrest, feasible • Intra-arrest, the future? • Packageof care?

27. Intra-Arrest? Package of Care? BMC Emergency Medicine 2011 J Translational Medicine 2012

29. Baseline Characteristics Bernard 2010 VF/ VT Bernard 2012 non- VF

30. Baseline Characteristics Diao et al. Resuscitation 2013