View source for EBQ:TTM Trial

{{JC info
| title=Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest
| abbreviation=TTM
| expansion=Targeted Temperature Management 
| published=2013-17-11
| author=Nielsen, Niklas et al
| journal=The New England Journal of Medicine
| year=2013
| volume= 369
| issue= 23
| pages=2197-2206
| pmid= 24237006
| fulltexturl=http://www.nejm.org/doi/full/10.1056/NEJMoa1310519
| pdfurl=http://www.nejm.org/doi/pdf/10.1056/NEJMoa1310519
| status = Complete
}}

==Clinical Question==
'''Is there a survival benefit to targeted temperature management at 33°C or 36°C in out-of-hospital cardiac arrest patients who remain unconscious after return of spontaneous circulation?'''

==Conclusion==
'''In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit compared with a targeted temperature of 36°C.'''

==Major Points==
{{Therapeutic hypothermia overview}}

==Design==
Multicenter, International, randomized trial with 1:1 concealed allocation of 950 out-of-hospital cardiac arrest patients to temperature control for 24 hours at 33°C versus 36°C with blinded outcome assessment

==Population Studied== 
===Inclusion Criteria===
*Age >= 18 years
*Out-of-hospital cardiac arrest of presumed cardiac cause
*Unconsciousness (Glasgow Coma Score <8) after sustained return of spontaneous circulation (ROSC) (20 minutes of circulation)

===Exclusion Criteria===
* Conscious patients
* Pregnancy
* Out-of-hospital cardiac arrest of presumed non-cardiac cause
* Cardiac arrest after arrival in hospital
* Known bleeding diathesis
* Suspected or confirmed acute intracranial bleeding
* Suspected or confirmed acute stroke
* Temperature on admission <30°C
* Unwitnessed asystole
* Persistent cardiogenic shock
* Known limitations in therapy
* Known disease making 180 day survival unlikely
* Known pre-arrest cerebral performance category 3 or 4, >240 minutes from ROSC to randomisation

===Baseline Characteristics===
* Average Age: 81
* Sex: 83% Male
* Cardiac Arrest Location: 53% at Home, 41% Public location
* Bystander Witness: 89.5%
* Shockable Rhythm: 80%
* Asystole: 56%
*Time from Cardiac Arrest: 1 min

==Interventions== 
Patients were randomized to either 33°C or 36°C
The core body temperature was set as quickly as possible at the predefined target temperature, according to intervention allocation, with 4°C intravenous solutions, 43 ice – packs 8, 44 and commercially available cooling devices 45 at the discretion of the treating physician . The target core temperature was then maintained for 24 h. After the maintenance period core temperature was gradually raised to normothermia of 37°C during 8 hours with a rewarming rate of 0.5°C/hour in both groups. 

Body temperature was then maintained at normothermia 37 ±0.5°C until 72 hours from sustained ROSC in both treatment groups, as long as the patient was in the ICU, using pharmacological treatment and temperature management systems when applicable

==Outcomes==
===Primary Outcomes=== 
*Survival to end of trial (at least 180 days)
**33°C: 50%
**36°C 48% 
::95% CI 0.89-1.28; P=0.51

===Secondary Outcomes===
*Composite outcomes of all-cause mortality and poor neurological function (Cerebral Performance Category (CPC) 3 and 4 and modified Rankin Scale (mRS) 4 and 5) at 180 days. 
*All – cause mortality and CPC and mRS at 180 – days
*'''Any Adverse Events'''
**33°C group: 93%
**36°C group: 90% (p=0.086)

====Adverse events====
*Bleeding
*Pneumonia
*Sepsis
*Electrolyte disorders
*Hyperglycaemia
*Hypoglycaemia
*Cardiac arrhythmia
*Renal replacement therapy

==Tertiary Outcomes==
Complete neurological recovery
*Best neurological outcome during trial period
*Quality of life 
*Biomarkers at 24, 48 and 72 hours

==Discussion==
*This trial successfully adopted a protocol for handling the problem of withdrawal of life support confounding long term prognosis measurements
*Pre-arrest rhythms included Ventricular tachycardia,fibrillation and out of hospital cardiac arrest unlike Bernard 2002 and [[HACA]] 2002
*The study was powered to detect a RRR of 20% or an ARR of ~11%, so the study was not powered to detect a smaller treatment effect 
* TTM differs from the Bernard 2002 and HACA 2002 trials since it was a larger multi center randomized controlled trial with rhythms not limited to VT/VF
*Hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year.<ref>Moler FW. et al. Therapeutic hypothermia after out-of-hospital cardiac arrest in children. N Engl J Med. 2015 May 14;372(20):1898-908</ref>

===Criticism===
*The population in this trial was less selective and included both shockable and nonshockable rhythm which makes delineating a ideal population for temperature ranges impossible to determine. <ref name="nejm">[http://www.nejm.org/doi/pdf/10.1056/NEJMe1312700 Rittenberg, Jon. "Temperature Management and Modern Post-Cardiac Arrest Care" NEJM Editorial. 2013. </ref>
*Subgroup analysis may be confounded by a trial enrollment of all comers especially if degrees of hypothermia should be adjusted for brain injury severity. <ref name="nejm"></ref>
*Temperature control to prevent fever may be more important than the specific target temperatures
*Staff caring for the patients could not be blinded but the physicians performing the data interpretation were blinded.

==Funding==
Independent research grants from the Swedish Heart–Lung Foundation, Arbetsmarknadens Försäkringsaktie- bolag Insurance Foundation, Swedish Research Council, Re- gion Skåne (Sweden), National Health Service (Sweden), Thel- ma Zoega Foundation, Krapperup Foundation, Thure Carlsson Foundation, Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research, Skåne University Hospital, TrygFonden (Denmark), and European Clinical Research In- frastructures Network
==See Also==
{{Hypothermia_Cardiac_Arrest_Links}}


==Sources==
<references/>

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