Therapeutic Hypothermia After Cardiac Arrest With Non Shockable Rhythm (HYPERION)

Lascarrou. NEJM 2019; published on-line; DOI:10.1056/NEJMoa1906661

Clinical Question

• In patients with coma following cardiac arrest with a non-shockable rhythm, does moderate hypothermia vs. normothermia, improve neurological outcome?

Background

• The HACA trial in 2000 reported that therapeutic hypothermia following a VF arrest improved favourable neurological outcome. However 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 study compared a targeted temperature of 33C vs. 36C in patients with an out-of-hospital cardiac arrest from a presumed cardiac cause. They reported no significant difference
• A sub-study (n=178) of the TTM trial reported no benefit with 33C vs. 36C in patients with cardiac arrest with an initial non-shockable rhythm. This trial excluded patients with presumed non-cardiac causes of cardiac arrest as well as patients with in-hospital cardiac arrest
• ILCOR guidelines recommend targeted temperature management with target temperature of 32-36C, for all patients with coma following cardiac arrest
• With the current evidence it is unclear if therapeutic hypothermia is of benefit to patients following cardiac arrest with non-shockable rhythms, including those with an in-hospital cardiac arrest

Design

• Randomised controlled trial
  • Randomised by web-based system
  • 1:1 ratio with permuted blocks of varying sizes
  • Stratified by centre and cause of cardiac arrest (presumed cardiac vs. non-cardiac)
• Open-label, blinded-outcome-assessor
• Follow up at 90 days post randomisation, with semi-structured telephone interview by a single psychologist
• 584 patients required to give a 80% power to detect an improvement in the primary outcome from 14% to 23%, with a 2 sided significant level of 5%
• Patients with missing data assumed to have died (1 patient in intervention group and 2 patients in control group)

Setting

• 25 ICUs in France (11 university and 14 community hospitals)
• Data collected: 2014 – 2018

Population

• Inclusion criteria:
  • Age >=18 years
  • Resuscitated from out-of-hospital or in-hospital cardiac arrest with a non-shockable rhythm due to any cause
  • GCS <=8 at ICU admission or if sedated GCS score prior to sedation
• Exclusion criteria:
  • No-flow time (time from collapse to initiation of CPR) > 10 minutes
  • Low-flow time (time from initiation of CPR to return of spontaneous circulation) >60 minutes
  • Epinephrine or norepinephrine infusion >1mcg/kg/min
  • Time from cardiac arrest to screening >300 minutes
  • Moribund; Child-Pugh class C cirrhosis of liver; pregnancy or breast feeding
• Comparing baseline characteristics of intervention vs. control group
  • Age (median): 67 vs. 67
  • Male sex: 65% vs. 63%
  • Charlson comorbidity index (median): 4 vs. 4
  • In-hospital cardiac arrest: 26% vs. 29%
  • By-stander witnessed cardiac arrest: 97% vs. 92%
  • Bystander CPR: 70% vs. 70%
  • 1st monitored rhythm
    • Asystole: 78% vs. 81%
    • PEA: 12% vs. 12%
    • Unknown (not shocked): 11% vs. 7%
  • Cause of cardiac arrest
    • Asphyxia: 56% vs. 55%
    • Cardiac cause: 28% vs. 27%
    • GCS at enrolment (median): 3 vs. 3
    • Circulatory shock: 56% vs. 61%
    • Duration from cardiac arrest to randomisation: 233 vs. 219 minutes
• 584 patients randomised out of 2723 assessed for eligibility

Intervention

• Hypothermia
  • 33C (+/-0.5C) induced and maintained for 24 hours
  • Each centre followed its standard protocol of internal or external cooling
    • Intravascular cooling catheter 15.1%
    • Dedicated closed loop surface device 47.9%
    • Basic external cooling device with no closed loop: 37.0%
  • Cooling began a median of 16 minutes post randomisation, stopped prematurely in 12.7%, with nearly half of these being due to suspected brain death
  • Re-warmed at a rate of 0.25-0.5C per hour to 36.5-37.5C, which was maintained for 24 hours
  • Sedation targeted Richmond Agitation-Sedation Score of -5. Sedation tapered when temperature >36C
  • 3 patients withdrew consent in hypothermia group and not included in analysis

Control

• Normothermia
  • Temperature maintained at 36.5-37.5C for 48 hours according to the standard protocol in each ICU
    • Intravascular cooling catheter 14.8%
    • Dedicated closed loop surface device 34.0%
    • Basic external cooling device with no closed loop 50.8%
  • Of note >5% of patients had temp >38C at each 2 hour time interval for first 48 hours – actual number of patients not stated
  • Sedation given routinely only during first 12 hours, targeting a Richmond Agitation-Sedation score of 0

Management common to both groups

• Decisions regarding limitation of treatment followed current guidelines with a multi-modal assessment of neurological prognosis

Outcome

• Primary outcome: Survival with a favourable neurological outcome – significantly improved in hypothermia group
  • Cerebral Performance Category (CPC) score of 1 or 2 at 90 days
    • 10.2% vs. 5.7%, difference 4.5% (95% C.I. 0.1-8.9), p=0.04
    • Fragility index = 1
• Secondary outcome: comparing intervention vs. control group
  • CPC score at 90 days
    • 1: 5.6% vs. 3.7%
    • 2: 4.6% vs. 2.0%
    • 3: 7.7% vs. 10.4%
    • 4: 0.4% vs. 0%
    • 5: 81.3% vs. 83.2%
  • No significant difference in:
    • Death by day 90: 81.3% vs. 83.2%, difference -1.9 (95% C.I.0 -8 to 4.4)
    • Duration of mechanical ventilation (median): 4.5 vs. 4.0 days
    • Length of ICU stay (median): 4 vs. 4 days
    • Survival to ICU discharge
      • 21.8% vs. 20.5%, Hazard ratio 1.07 (0.75-1.52)
    • Survival to hospital discharge: 19.7% vs. 16.8%, (Hazard ratio 0.81-1.74)
    • Cause of death
      • Withdrawal of life support: 61.9% vs. 65.2%
  • Sources of follow-up information
    • Patient only: 67% vs. 77%
    • Next of Kin only: 33% vs. 21%
  • Time from randomisation to life sustaining withdrawal decision, median (IQR): 5 days (3-6) vs. 4 days (2-6)

Authors’ Conclusions

• 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

Strengths

• Randomised controlled trial
• Blinding of outcome assessor
• Multi-centre
• Decisions regarding withdrawal of life sustaining treatment followed guidelines
• Registered on clinicaltrials.gov

Weaknesses

• There were a number of differences between the intervention and the control group:
  • The intervention group had temperature management for 56-64 hours compared with 48 hours in the control group
  • Patients in the intervention group had sedation for at least 30 hours compared with only at least 12 hours in the control group
  • Patients in the intervention group had their sedation targeted at a RASS score of -5, where as those in the control group had their sedation targeted to a RASS of 0
  • Time from randomisation to decisions regarding life sustaining treatment was longer in the intervention group
  • In the intervention group the source of follow up was more likely to be from next of kin only in comparison to the control group
• A number of patients in normothermia group had temperature >38C. This was not the case in the TTM trial
• Single assessor of primary outcome
• Only performed in 1 country limiting generalisability. A number of patients had their sedation stopped early due to suspected brain death. This would not be a common practice at my local institution
• Low fragility index that was less than both the number of patients that withdrew and the number of patients with missing data

The Bottom Line

• This randomised controlled trial reported significantly improved neurological outcomes in patients with coma following a non-shockable cardiac arrest, who were treated with moderate hypothermia compared with normothermia
• Due to a number of differences between the treatment of the intervention and the control groups, as well as the low fragility index and the significant number of patients who developed a fever in the control group, further evidence is required to confirm these findings

External Links

• [article] Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm
• [further reading] PulmCrit: Hypothermia for non-shockable arrest: let’s not get hot-headed about this
• [further reading] TBL: temperature control trials
• [further reading] TBL: Fragility Index

Metadata

Summary author: David Slessor
Summary date: 10th October 2019
Peer-review editor: Steve Mathieu