Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest

Dankiewicz J for the TTM2 Trial Investigators. NEJM June 17, 2021 DOI:10.1056/NEJMoa2100591

Clinical Question

• In patients who are unconscious following out-of-hospital cardiac arrest, does targeted hypothermia compared with targeted normothermia, impact all-cause mortality?

Background

• There have been several randomised trials investigating temperature management following cardiac arrest
• The HACA trial (n=137) and Bernard trials (n=77) published in NEJM in 2002 reported that therapeutic hypothermia following a VF arrest improved favourable neurological outcome. However, small sample sizes and other methodological flaws meant the evidence was of low certainty. A number of patients in the control group developed fever and it was therefore unclear if the reported benefits were from hypothermia or the avoidance of fever
• The TTM (2013) study (n=950) compared a targeted temperature of 33°C vs. 36°C in patients with an out-of-hospital cardiac arrest from a presumed cardiac cause. They reported no significant difference in all-cause mortality
• The HYPERION trial (n=584) showed that in patients with coma following a non-shockable cardiac arrest, the use of moderate hypothermia improved favourable neurological outcome at 90 days compared with targeted normothermia
• The European Resuscitation Council released new guidelines in March 2021. These suggest:
  • maintaining a target temperature at a constant value between 32 and 36°C for at least 24 h
  • avoidance of fever (> 37.7°C) for at least 72 h after ROSC in patients who remain in coma
• Fever is associated with worse outcomes

Design

• International, multicentre, parallel group trial
• Randomised, superiority trial
• Co-enrolment with the TAME trial (Targeted Therapeutic Mild Hypercapnia)
• Randomisation occurred in the emergency department
• Web-based allocation using permuted blocks of varying sizes (stratified by site + TAME randomisation) in 1:1 ratio
• Pre-specified secondary outcomes (neurological outcome and health related quality of life) and subgroup analyses (sex, age, time to ROSC, initial rhythm and whether shock present on admission)
• Outcomes assessed at 30 days, 6 months, 24 months (ongoing)
• Blinding:
  • Non blinded clinicians, however assessors of prognosis, participants, outcome assessors, statisticians, data managers blinded.
  • Duplicate manuscripts were written for each scenario before randomisation was revealed
• Outcome assessment was by face-to-face interview (72%) or telephone interview (particularly used when the COVID-19 pandemic began). Where possible the patient and a proxy were used to obtain information
• MRS was performed via a structured interview with interviewers receiving formal training
• Power Calculation: A total of 1862 participants gave a power of 90% (alpha 0.05, NNT 13.3) to detect an absolute risk reduction of 7.5% in mortality (assuming 55% mortality). This was increased to 1900 to account for loss to follow-up

Setting

• Number of countries: 14 countries, 61 institutions
  • Highest recruiting countries: Sweden, UK, Switzerland, France, Czech Republic
• Dates of randomisation: pilot phase began late 2017. Active recruiting through 2018 to early 2020
• Last data collection: 6-month follow-up completed mid 2020 with 24 month follow-up ongoing

Population

• Inclusion:
  • Out-of-hospital cardiac arrest of presumed cardiac or unknown cause
  • Sustained ROSC: >20 minutes of circulation without need for chest compressions
  • Unconscious: as defined by the FOUR score motor response <4 and not able to obey verbal command
  • No limitations to management in place
  • Inclusion must be no later than 180 minutes after ROSC
• Exclusion:
  • Unwitnessed cardiac arrest with initial rhythm asystole
  • Temperature on admission < 30°C
  • On ECMO prior to ROSC
  • Suspected pregnancy
  • Intracranial bleed
  • Severe COPD with long-term home O2
• 4355 patients screened.
  • 55% not randomised due to exclusion criteria:
    • most commonly >180 minutes since ROSC, non-cardiac cause for arrest, not unconscious, limitations to care in place
  • 1900 randomised
  • 1861 analysed as intention to treat (39 withdrew consent)
    • 930 in Hypothermia arm, 931 in Normothermia arm
  • 1850 analysed for survival (11 lost to follow-up)
• Baseline characteristics between groups (Hypothermia vs Normothermia). No significant difference in:
  • Age (mean 64 vs. 64)
  • Sex (80% male vs. 79%)
  • Shockable Rhythm (72% vs. 75%)
  • Bystander CPR (82% vs. 78%)
  • Shocked on admission (28% vs. 30%)
    • Defined as SBP < 90mmHg for > 30 minutes or evidence of end-organ hypoperfusion
  • Median time to ROSC (25 minutes vs. 25 minutes)
  • Temperature on admission (35.3°C vs. 35.4°C)
  • Lactate (5.9 vs 5.8)
  • STEMI (41% vs 40%)

Intervention

• Hypothermia group: target temperature 33C
  • Rapid cooling achieved by cold fluids and physical cooling devices (surface or intravascular devices).
  • A feedback-controlled system used to maintain target temperature (bladder temperature probe)
  • Rewarming began after 28 hours (increase temperature by no more than 0.3°C per hour until 40 hours)
  • 95% of patients received cooling
  • 70% cooled with external devices and 30% with intravascular devices

Control

• Normothermia group: In participants who developed a temperature of 37.8°C (trigger), a device was used and set at 37.5°C
  • Pharmacological and conservative therapies initiated first
  • Physical cooling devices (surface or intravascular) used if temperature ≥ 37.8°C
    • Physical cooling devices could be placed prophylactically, but no active cooling was provided for patients who had a spontaneous temperature of <37.8C
  • A feedback-controlled system used to maintain target temperature
  • 46% of patients needed a device to achieve target temperature (of these 69% used surface cooling, and 31% used intravascular cooling)
  • In 1st 24 hours ~5% of temperatures recorded at >38C

Management common to both groups

• Normothermia from 40 – 72 hours (36.5°C – 37.7°C) – temperature management could be initiated after 40 hours
• Sedation mandated in both groups until the end of the intervention period (40 hours)
• Protocolised step-wise protocol for treatment of shivering
• At 96 hours a neurological assessment was performed by a blinded clinician – only following this was withdrawal of life sustaining treatments allowed for presumed poor neurological outcome.
  • Standardised criteria for what was considered a likely poor neurological outcome were used
• Other than above patients were managed as per clinician preferences. There were no differences (hypothermia vs normothermia) in:
  • Cardiac catheter rates: 78% vs. 78%
    • 90% vs 87% within 2 hours
  • PCI: 38% vs. 38%
  • CAGs: 1% vs 2%
  • AICD: 16% vs 16%

Outcome

• Primary outcome: No difference in all-cause mortality at 6 months
  • Comparing HYPOTHERMIA vs NORMOTHERMIA
    • 50% (465/925) vs 48% (446/925)
      • RR 1.04 (95% CI 0.94-1.14, p = 0.37)
      • HR for death in hypothermia group 1.08 (95% CI 0.95-1.23)
• Secondary outcomes: No difference in secondary outcomes
• Comparing HYPOTHERMIA vs. NORMOTHERMIA
  • Proportion of people with a poor functional outcome (modified Rankin scale, mRS 4-6) at 6 months: 55% vs 55% (RR 1.00, 95% CI 0.92 – 1.09)
  • Health-related quality of life: EQ-VAS (patient perception of outcome) (Scale 0-100, with 0 being the worst health, 100 being perfect health)
    • Mean score 74 vs 75
• Adverse events:
  • Higher rates of arrhythmias with haemodynamic instability in hypothermia group:
    •  24% vs 16% (RR 1.45, 95% CI 1.21 – 1.75, p<0.001)
  • Comparing hypothermia vs normothermia, no difference in:
    • • Pneumonia: 36% vs 35%
      • Sepsis: 11% vs 9%
      • Bleeding: 5% vs 5%
      • Skin complications due to the device: 1% vs <1%

Authors’ Conclusions

• In patients suffering out-of-hospital cardiac arrest, induced hypothermia did not lead to lower mortality
• Functional outcome and health related quality of life did not improve from hypothermia

Strengths

• This was an excellently conducted randomised trial with large numbers and a superb effort from all involved
• Design based on data achieved from multiple previous trials meaning a robust sample size calculation and estimate of absolute risk reduction
  • Mortality in trial (50%) similar to that used in power calculations
• Excellent internal validity:
  • Although 56% of those screened seems like a large proportion not to be enrolled, only 1.6% were for unknown reasons
  • Allocation concealment and blinding of everyone involved except (understandably) treating clinicians
  • Intention to treat analysis
  • Clear separation between groups
  • Near complete follow-up
    • < 1% missing data on mortality
    • 94% had functional outcome assessed by mRS
  • Protocolised care minimised variability in practice
    • Only 3 protocol deviations related to temperature management
• External validity high due to the multicentre and multinational nature of the study

Weaknesses

• Median temperature of 34°C in the hypothermia arm achieved at 3 hours after randomisation. Cooling was not implemented pre-hospital. It is logistically very difficult to achieve any earlier rapid cooling for many reasons (e.g. patients needing to go to cardiac catheter lab)
  • The trial does not answer the question as to whether ultra-early cooling may be beneficial
• An ARR of 7.5% was an ambitious difference to achieve, particularly given the TTM results which showed no difference between 33°C and 36°C. However, the authors based this on the original 2002 trials
• It would be helpful to know exact numbers of patients in the normothermia group who were febrile. A graph is given in the supplementary index but it is difficult to give accurate numbers looking at this graph
• The trial does not guide our management of In-Hospital-Cardiac-Arrest, so generalisability to this cardiac arrest group is limited
• 20% of patients were co-enrolled in the TAME trial, 10% in each group. This could potentially be a confounder but this will not be known until the results of this trial are published

The Bottom Line

• I will aim for normothermia in my patients following out of hospital cardiac arrest. I will implement targeted temperature management if temperature exceeds 37.7°C
• Future exploration may include a trial of normothermia vs no targeted temperature management

External Links

• Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest
• Translating Targeted Temperature Management Trials into Postarrest Care

Metadata

Summary author: Celia Bradford @celiabradford
Summary date: June 17 2021
Peer-review editor: George Walker

Picture by: iStock