Lilja: Cognitive Function in Survivors of Out-of-Hospital Cardiac Arrest After Target Temperature Management at 33ºC Versus 36ºC

Lilja et al. Circulation.2015, Published online February 13

Clinical Question

  • In patients with out-of-hospital (OOH) cardiac arrest does a target temperature management (TTM) of 33°C vs. 36°C improve cognitive function at 6 months?


  • Randomised controlled trial
  • Treating clinicians non-blinded
  • Face-to-face follow up at ~180 days
    • examiners blinded for TTM allocation but not whether or not patient was a control
  • With study sample size, >80% power to detect a 10% difference between the groups based on the Rivermead Behavioural Memory Test profile score


  • 5 European countries
  • Out of 36 sites who participated in the TTM Trial, twenty sites completed this follow-up study
  • Follow-up occurred between June 2011 – September 2013


  • Follow-up study of TTM Trial:
    • Inclusion: adult patients who were unconscious (GCS < 8) on admission to hospital after OOH cardiac arrest of presumed cardiac cause.
    • Exclusion: > 6 hours from return of spontaneous circulation to enrolment screening, unwitnessed arrest with systole, hypothermia < 30°C, suspected or known intracranial haemorrhage.
  • In addition a control group was included:
    • cohort of patients who had a ST elevation myocardial infarction treated with percutaneous coronary intervention
    • patients matched for age, gender, country and time-point of hospitalisation
    • 119 control patients
  • 652 patients treated with therapeutic hypothermia included
    • comparing 33°C vs. 36°C group no significant difference in co-morbidities, bystander CPR, shockable rhythm
  • 342 patients treated with TTM alive at 180 days of whom 287 completed follow up
    • comparing 33°C vs. 36°C  vs. control group
      • age: 63 vs. 60 vs. 64, p=0.04
      • previous ischaemic heart disease: 28% vs. 19% vs. 13%, p=0.01
      • bystander CPR: 74% vs. 84% vs. N/A, p=0.03
      • 1st monitored rhythm shockable: 93% vs. 96% vs. N/A, p=.032


  • 28 hours of temperature management with a target of
    • a) 33°C
    • b) 36°C
  • followed by gradual warming to 37°C at 0.5°C per hour and avoidance of pyrexia for 72 hours from randomisation


  • Recruited from cohort of ST-elevation myocardial infarction patients treated with percutaneous coronary intervention
    • matched for age, gender, country and time-point of hospitalisation


  • Primary outcome: Rivermead Behavioural Memory Test (RBMT)
    • no significant difference between 33°C vs. 36°C, p=0.56
  • Secondary outcomes:
    • Comparing 33°C vs. 36°C,
      • no significant difference in
        • Executive dysfunction as tested by Frontal Assessment Battery (FAB), p=0.43
        • Symbol Digit Modalities Test (SDMT) assessing mental speed and agitation, p=0.31
    • Including only patients who completed follow-up and the matched STEMI controls
      • STEMI controls had significantly better SDMT scores than 33°C and 36°C treatment groups (unadjusted p=0.0001, covariate-adjusted p=0.002)
      • No significant difference in:
        • RBMT (unadjusted p=0.46, covariate-adjusted p=0.06)
        • FAB, (unadjusted p=0.22, covariate-adjusted p=0.008)
        • Hospital Anxiety and Depression rating Scale (HADS),
          • depression, p=0.99
          • anxiety, p=0.89

Authors’ Conclusions

  • Survivors of patients with OOH cardiac arrest who were treated with targeted temperature management of 33°C vs. 36°C had no difference in cognitive outcome


  • Randomised controlled trial
  • Blinding of assessor of primary outcome to TTM allocation
  • Low number of patients lost to follow up
  • Investigated multiple assessment measures of cognitive outcome
  • Use of CONSORT diagram


  • Due to the nature of the study baseline differences in cognitive function cannot be assessed. With relatively small numbers of patients included there is a greater probability of random differences in baseline cognitive function between the treatment groups
  • RBMT test may be insensitive for very mild impairment. The authors stated that the updated RBMT-3 version was not available when this study commenced
  • FAB has not been validated in an OOH cardiac arrest population
  • Proportionately fewer TTM patients with poor neurological recovery (cerebral performance category 3 or 4) were followed-up than those with good recovery. This will bias toward less cognitive impairment in the OHCA group compared to the STEMI-control group, but should still allow accurate comparison between 33ºC and 36ºC. It will under-estimate cognitive impairment from cardiac arrest. (see table for data)
Of note patients in the original TTM Trial had a median time of 1 minute (inter-quartile range 0-2 minutes) from cardiac arrest to initiation of basic life support. Therefore these results may not apply to patients who have a delay in initiation of basic life support.

The Bottom Line

  • In patients that have basic life support quickly initiated following an OOH cardiac arrest the use of targeted temperature management of 33°C vs. 36°C does not affect cognitive function at six months

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