Transcript Therapeutic Hypothermia

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Cara Jager
Aios Spoed Eisende Geneeskunde AMC
Regionale Refereeravond
Juli 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
Which population?
- Post cardiac arrest/ ROSC
When?
- Post cardiac arrest
- No recent trauma
- GCS ≤ 8
Where?
- Inhospital
How?
- External cooling techniques
- Internal cooling techniques
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?
PRO
Nolan J and Soar J.
BMJ 2011
CON
Walden AP, Nielsen et al.
BMJ 2011
NNT = 5
Arrich et al. Cochrane 2010

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

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)
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?
Nielsen et al. Int J Cardiology 2011
Targeted Temperature Management = TTM trial
Nielsen et al. Am Heart J 2012

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

Current practice: ICU

Timing of Therapeutic hypothermia
◦ Animal models: as early as possible
◦ When?

Emergency Department?
Egmond 2013
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
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

Pre-hospital setting?
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
AND
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
187 hits
40 relevant:
Pre hospital/ Emergency Department:
Limits English
8 RCT
Post-arrest/ post-ROSC
Total 173 hits
8 Review
Intra-arrest
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
Bernard et al. Circulation 2010
Bernard et al. Crit Care Med 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
Bernard et al 2010
2268=
Resuscitation attempted by paramedics
842=
Initial rhythm ventricular fibrillation
398=
ROSC and transport to hospital
164=
Eligible/
Not enrolled
234=
Eligible and enrolled
Bernard et al 2012
1426=
Initial rhythm asystole/ PEA
309=
ROSC and transport to hospital
146=
Eligible/
Not 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
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

Cooling in field or ED same temperature 1h
after arrival
Bernard et al. 2010


Feasible lowering temperatures
No outcome differences
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?
BMC Emergency Medicine 2011
J Translational Medicine 2012
Bernard 2010 VF/ VT
Bernard 2012 non- VF
Diao et al. Resuscitation 2013