Therapeutic Hypothermia in Out of Hospital Cardiac Arrest towards ? Cara Jager Aios Spoed Eisende Geneeskunde AMC Regionale Refereeravond Juli 2013

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

Therapeutic Hypothermia Current 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

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?

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

Pro Neurological Outcome NNT = 5 Arrich et al. Cochrane 2010

Therapeutic Hypothermia PRO 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

Therapeutic Hypothermia CON 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)

Con Neurological Outcome Nielsen et al. Int J Cardiology 2011

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

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

Presented at American Heart Association meeting 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

Therapeutic Hypothermia Really effective? Current practice: ICU Timing of Therapeutic hypothermia Animal models: as early as possible When?

Therapeutic Hypothermia When? Emergency Department? Egmond 2013

Optimal timing of TH? Regression-analysis Time Intervals N mean SD Arrest to ROSC (min) 172 24 14.6 Arrest to initiation TH (min) 94.4 81.6 Arrest to target temperature (min) 309 151 Target temperature maintained (h) 23.1 5.4 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

Therapeutic Hypothermia When? Pre-hospital setting?

Therapeutic Hypothermia Pre-Hospital 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 Medline 1966 – 06-2013 AND 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 187 hits Limits English Total 173 hits 40 relevant: 8 RCT 8 Review Pre hospital/ Emergency Department: Post-arrest/ post-ROSC Intra-arrest

Therapeutic Hypothermia Pre- Hospital Diao et al. Resuscitation 2013

Ice cold saline infusion versus normal treatment Bottom line: 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 Acta Anaesthesiol Scand 2009

Ice cold saline infusion versus normal treatment Bottom line: 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

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

Bernard et al 2010 Bernard et al 2012 Prospective multicenter RCT Australia Oct 2005- Nov 2007 6730= Total cardiac arrests during trial period 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 234= Eligible and enrolled 163= 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

Postarrest Prehospital 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

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

Therapeutic Hypothermia Prehospital setting Feasible lowering temperatures No outcome differences Diao et al. Resuscitation 2013

Therapeutic Hypothermia: Summary Current practice To believe or not to believe Towards The Cold Chain Prehospital cooling: Post-arrest, feasible Intra-arrest, the future? Package of care?

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

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

Baseline Characteristics Diao et al. Resuscitation 2013