Reference

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

Web Link

https://www.nejm.org/doi/full/10.1056/NEJMoa2100591

Date

01/07/2021

Clinical Question

Is targeted hypothermia (TH) of 33^oC for 28 hrs. [followed by controlled rewarming] superior to targeted normothermia (TN) of 37.5^oC in reducing 6-month overall mortality in patients with coma following out of hospital cardiac arrest?

Methodology

Design

Randomized controlled trial – Open label (blinded outcome assessment), Superiority design

Setting

Multicenter (14 countries, 61 institutions)

Population

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 <30^oC on admission

                   On ECMO prior to ROSC

                   Treatment limitations

Factors

Intervention: for 40 hrs. immediately after screening

TH group: For 28 hrs. TH of 33^oC with surface/ intravascular device

                   Then gradual rewarming up to 37^oC for next 12 hrs.

TN group: Target 37.5^oC 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 protocol driven neurological prognosis assessed and then life supportive therapies were withdrawn if poor prognosis

Analysis

Intension to treat analysis

Outcomes

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

Follow up

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

Authors’ conclusion:

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

Validity

• The internal validity of the study seems to be excellent as the methodology is apparently sound and flawless.
• Perfect randomization has minimized confounding factors.  
• Though it is an open label trial due the inherent nature of the factor assessed, blinding of the assessor has minimized the effect.
• Low attrition with minimum drop-out rate also contributes to high internal validity.

• However, there are factors which may limit the external validity of the study and hence the generalizability.
• In both groups, approximately 80% of patients have been offered bystander CPR prior to the admission which may not be replicated all the communities.
• Shockable rhythm predominated with 72-75% and asystolic arrests contributed only 13% due to the exclusion of unwitnessed asystolic arrests, leading to the confinement of study results in highly selected patient population.

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.

Strengths

·        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

Weaknesses

·        Median temperature of 34^oC 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.

Comments

·        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

Reviewer

Dilshan Priyankara MBBS, MD, MRCP(UK), EDIC

Consultant Intensivist, National Hospital of Sri Lanka, Colombo, Sri Lanka

Disclaimer

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