EBQ:TTM Trial

Complete Journal Club Article
Nielsen, Niklas et al. "Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest". The New England Journal of Medicine. 2013. 369(23):2197-2206.
PubMed Full text PDF

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.

Marjor Points

  • Therapeutic Hypothermia, define as deliberate cooling of a patient to 32-33.9°C (90-93F) who has no return of spontaneous neurologic activity after cardiac arrest. The goal is to reduce the repercussion injury to the brain which may be related to free radical formation, micro and macro circulation disruption and protease activation. At therapeutic temperatures the disruption of inflammatory and damaging cascades within the brain are thought to be decreased. [1] In patients who have been successfully resuscitated after cardiac arrest due to ventricular fibrillation, therapeutic mild hypothermia increased the rate of a favorable neurologic outcome and reduced mortality.[2]
  • The HACA Trial (Hypothermia after Cardiac Arrest) randomized patients after witness Ventricular Fibrillation (VF) and pulseless Ventricular Tachycardia (VT) to 32-34°C Hypothermia. There was a significant patient centered outcome and 6 month mortality decrease in the hypothermia group. A later trial by Bernard et. al. demonstrated similar benefit as did the Cochrane review. The TTM Trial (33°C vs 36°C) found similar mortality and morbidity benefits however 33°C may not confer benefit over 36°C.[1][3][4]
  • Standard care established by the ACCF/AHA 2013 guidelines, recommend therapeutic hypothermia for any comatose patient with a STEMI and out of hospital cardiac arrest from VF or puleless VT[5]
  • Although use of prehospital cooling reduced core temperature by hospital arrival and reduced the time to reach a temperature of 34°C, it did not improve survival or neurological status among patients resuscitated from prehospital VF or those without VF.[6]
  • In comatose children who survived out-of-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year. [7]


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.[8]

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. [9]
  • Subgroup analysis may be confounded by a trial enrollment of all comers especially if degrees of hypothermia should be adjusted for brain injury severity. [9]
  • 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


Sources

  1. 1.0 1.1 Arrich J, Holzer M, Herkner H, Müllner M. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database of Systematic Reviews 2009. PMID
  2. The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549-56
  3. Bernard SA et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557-63
  4. Nielsen N et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med Nov 17 2013 doi: 10.1056/NEJMoa1310519
  5. http://www.ncbi.nlm.nih.gov/pubmed/23256913
  6. Kim F et al. Effect of Prehospital Induction of Mild Hypothermia on Survival and Neurological Status Among Adults With Cardiac Arrest A Randomized Clinical Trial. *JAMA Nov 17 2013
  7. Moler FWTherapeutic hypothermia after out-of-hospital cardiac arrest in children.
  8. 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
  9. 9.0 9.1 [http://www.nejm.org/doi/pdf/10.1056/NEJMe1312700 Rittenberg, Jon. "Temperature Management and Modern Post-Cardiac Arrest Care" NEJM Editorial. 2013.