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

2. Therapeutic Hypothermia in OHCA: Background
Europe: ± % 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 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

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, °C/h within 8 hours
Stop sedation at 36°C
Awake/ Postanoxic coma?

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

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

7. 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

8. 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)

9. Con Neurological 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
Nielsen et al. Am Heart J 2012

12. 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

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

14. Therapeutic Hypothermia When?
Emergency Department?
Egmond 2013

15. 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 )
Retrospective observational study
Clear association, how about causality?
Sendelbach et al. Resuscitation 2012

16. Therapeutic Hypothermia When?
Pre-hospital setting?

17. 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 –
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

18. Therapeutic Hypothermia Pre- Hospital
Diao et al. Resuscitation 2013

19. 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 )
Not to the level of therapeutic hypothermia
Acta Anaesthesiol Scand 2009

20. 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)
*P by ANOVA

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

22. Bernard et al 2010 Bernard et al 2012 Prospective multicenter RCT
Australia
Oct 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

23. 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 and 2012

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

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

26. 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?

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