Home » Targeted Temperature Management
Dankiewicz J, Cronberg T, et al. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. N Engl J Med. 2021 Jun 17;384(24):2283-2294. doi: 10.1056/NEJMoa2100591
Is targeted hypothermia (TH) of 33oC for 28 hrs. [followed by controlled rewarming] superior to targeted normothermia (TN) of 37.5oC in reducing 6-month overall mortality in patients with coma following out of hospital cardiac arrest?
Randomized controlled trial – Open label (blinded outcome assessment), Superiority design
Multicenter (14 countries, 61 institutions)
4355 patients screened, 1900 enrolled (90% power), 1861 randomized
Baseline characteristics similar in both groups
Inclusion: Adults with out of hospital cardiac arrest irrespective of rhythm
presumably cardiac/ unknown origin
All were unconscious, not obeying to verbal commands and
no verbal response to pain
Exclusion: Interval from ROSC to screening more than 3 hrs.
Unwitnessed arrest with asystole on assessment
Temperature <30oC on admission
On ECMO prior to ROSC
Intervention: for 40 hrs. immediately after screening
TH group: For 28 hrs. TH of 33oC with surface/ intravascular device
Then gradual rewarming up to 37oC for next 12 hrs.
TN group: Target 37.5oC maintained, if conservative measures failed then
surface/intravascular devices used. If below targets no active
cooling or warming
Following intervention, if patient in coma, normothermia until 72 hrs.
Both groups, sedation maintained for the intervention period
At 96 hrs. protocol driven neurological prognosis assessed and then life supportive therapies were withdrawn if poor prognosis
Intension to treat analysis
Primary: Death from any cause at 6 months
Secondary: Poor functional state at 6 months (4-6 of modified Rankin)
Number of days alive and out of hospital until day 180
Survival in time to death analysis
Health related quality of life (EQ-5D-5L questionnaire)
Adverse events: pneumonia, sepsis, bleeding, skin complications
hemodynamically unstable arrhythmia
6 months (missing data <1%)
Results and Conclusion by Authors
No significant difference in primary or secondary outcomes
Outcomes are similar across all prespecified subgroups
Hemodynamically unstable arrhythmia is significantly frequent in TH group
In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia
Analysis of Results
· Intension to treat analysis and minimum missing data increase the preciseness of the study results
· Impact of study results is significant since it emphasizes the non-superiority of TH over TN with higher level of evidence.
· This study aims to answer a valid clinical question which has got insufficient evidence in previous literature
· It is a perfectly conducted study with sound scientific approach enhancing internal validity
· It has demonstrated non-superiority of trial interventions for selected study population with sound statistical analysis, strengthening the scientific evidence for the clinical question raised
· Median temperature of 34oC was achieved 3 hrs. after randomization in TH group, though logistically it would be difficult to achieve it faster
· There are factors which are described above limiting the external validity which may compromise the application of the trail evidence in all the clinical situations.
· It needs to be stressed that targeted normothermia was maintained by interventions as per protocol and the study does not assess the clinical questions related to normothermia with conservative measures which is beyond its area concerned.
· This perfectly conducted study emphasizes the non-superiority of targeted hypothermia over targeted normothermia in selected patients in out of hospital cardiac arrest.
· Therefore, it supports clinicians to continue their practice of either acquiring targeted hypothermia or maintaining targeted normothermia without outcome difference.
· However, it should be stressed out that, if targeted normothermia is selected, interventional approach would be required in addition to conservative measures.
· The personal opinion of the author of this review is to maintain targeted normothermia for patients who are compatible with study population.
· Additionally, it needs to be highlighted that special consideration should be paid for the selection of patients for the clinical intervention to make them comparable to study population.
Author of the critical appraisal
Nuwan Ranawaka MBBS, MD, MRCP(UK), MRCP(Lon)
Consultant Intensivist, National Hospital of Sri Lanka, Colombo, Sri Lanka
Dilshan Priyankara MBBS, MD, MRCP(UK), EDIC
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of Ceylon College of Critical Care Specialists
Ceylon College of Critical Care Specialists