Therapeutic Hypothermiain Out of Hospital Cardiac Arresttowards

Cara JagerAios Spoed Eisende Geneeskunde AMCRegionale RefereeravondJuli 2013

?

◦ 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 in OHCA: Background

Where?- Inhospital

Therapeutic HypothermiaCurrent Practice

When?- Post cardiac arrest

How?- External cooling techniques- Internal cooling techniques

Which population?- Post cardiac arrest/ ROSC- No recent trauma- GCS ≤ 8

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:Current Practice the Netherlands

Therapeutic HypothermiaReally Effective?

PRONolan J and Soar J.BMJ 2011

CONWalden AP, Nielsen et al.BMJ 2011

ProNeurological Outcome

Arrich et al. Cochrane 2010

NNT = 5

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 HypothermiaPRO

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)

Therapeutic HypothermiaCON

ConNeurological Outcome

Nielsen et al. Int J Cardiology 2011

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?

Con

Nielsen et al. Int J Cardiology 2011

Targeted Temperature Management = TTM trial

Nielsen et al. Am Heart J 2012

Targeted Temperature Management = TTM trial

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 meetingNovember 2013 Dallas

TTM-trial: protocol

Current practice: ICU

Timing of Therapeutic hypothermia◦ Animal models: as early as possible

◦ When?

Therapeutic HypothermiaReally effective?

Emergency Department?

Therapeutic HypothermiaWhen?

Egmond 2013

Regression-analysis For every 5 minute delay in initiating TH:

increased chance of having a poor neurological outcomeOR 1.06 (95% CI 1.02-1.10)

Retrospective observational study◦ Clear association, how about causality?

Optimal timing of TH?

Time Intervals N mean SD

Arrest to ROSC (min) 172 24 14.6

Arrest to initiation TH (min) 172 94.4 81.6

Arrest to target temperature (min) 172 309 151

Target temperature maintained (h) 172 23.1 5.4

Sendelbach et al. Resuscitation 2012

Pre-hospital setting?

Therapeutic HypothermiaWhen?

40 relevant:

8 RCT

8 Review

Therapeutic HypothermiaPre-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

AND

187 hits

Limits English

Total 173 hits

Pre hospital/ Emergency Department:

Post-arrest/ post-ROSC

Intra-arrest

Therapeutic HypothermiaPre- Hospital

Diao et al. Resuscitation 2013

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

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)

Kim et al. Circulation 2007

*P0.0001 by ANOVA

Therapeutic HypothermiaPre- Hospital: Improving Outcome?

Bernard et al. Circulation 2010

Bernard et al. Crit Care Med 2012

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

842=Initial rhythm ventricular fibrillation

1426= Initial rhythm asystole/ PEA

398=ROSC and transport to hospital

234=Eligible and enrolled

164=Eligible/

Not enrolled

118=Paramedic cooling

100 ml/min cold salineup to 2l

116=Hospital cooling

118=Assessed for 1° endpoint

116=Assessed for 1° endpoint

309=ROSC and transport to hospital

146=Eligible/

Not enrolled

163=Eligible and enrolled

82=Paramedic cooling

100 ml/min cold salineup to 2l

82=Hospital cooling

82=Assessed for 1° endpoint

81=Assessed for 1° endpoint

Bernard et al 2010 Bernard et al 2012

Prospectivemulticenter RCT

AustraliaOct 2005- Nov 2007

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

Postarrest Prehospital Cooling:Improving Outcome?

WHY?

Bernard et al. 2010 and 2012

Rewarming?

Bernard et al. 2010

Cooling in field or ED same temperature 1h after arrival

Feasible lowering temperatures No outcome differences

Therapeutic HypothermiaPrehospital setting

Diao et al. Resuscitation 2013

Current practice◦ To believe or not to believe

Towards The Cold Chain Prehospital cooling:

◦ Post-arrest, feasible◦ Intra-arrest, the future?

Package of care?

Therapeutic Hypothermia:Summary

Intra-Arrest? Package of Care?

BMC Emergency Medicine 2011

J Translational Medicine 2012

Baseline Characteristics

Bernard 2010 VF/ VT Bernard 2012 non- VF

Diao et al. Resuscitation 2013

Baseline Characteristics