Time to get hyped about the Hyperion Trial?

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Cooling post-cardiac arrest patients with non-shockable rhythms.

Background Information


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Cardiac arrest from non-shockable rhythms now accounts for the majority of out of hospital cases and are associated with a poor prognosis.[1] Less than 15% of these patients have good neurologic outcomes when compared to the 65% that suffer a cardiac arrest with a shockable rhythm.[2] Therapeutic hypothermia, the use of targeted temperature management to reduce neurologic sequelae that occurs as a result of the severe hypoxia in cardiac arrest is a mainstay treatment in the Advanced Cardiac Life Support (ACLS) Guidelines for shockable rhythms.[3]

This cool intervention use has been widely debated as beneficial in improving neurologic outcomes in post-cardiac arrest patients with non-shockable rhythms. Recent studies have also called into question the exact temperature patients should be cooled (i.e. 33oC vs 36oC).[4,5]

The authors of the Therapeutic Hypothermia After Cardiac Arrest in Non-Shockable Rhythms (HYPERION) Trial sought to answer whether moderate therapeutic hypothermia at 33OC or normothermia at 37oC would improve the neurologic outcome in patients who achieved a return of spontaneous circulation (ROSC) following a cardiac arrest with a non-shockable rhythm.


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Study Design

The HYPERION Trial was a multi-center, open-label, blinded-outcome assessor, randomized control trial across 11 university hospital ICUs and 14 community hospital ICUs in France. The protocol involved standardization of several variables including sedation, neuromuscular blockade and management of the expected adverse effects of each.           

Patients were randomly assigned using a 1:1 ratio into one of two groups using a web-based system that was available 24-hours a day. The moderate therapeutic hypothermia group, with a targeted temperature of 33oC during the first 24 hours followed by slow rewarming over the next 24 hours. The normothermia group maintained a targeted temperature of 37oC +/- 0.5oC for 48 hours.

Eligible patients included those above the age of 18 years old who suffered an out-of-hospital or in-hospital cardiac arrest due to any cause and had a Glasgow Coma Scale (CGS) 8 or less at ICU admission. If sedated before ICU admission, the last GCS previously determined by the ED physician was used.


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Patients who had greater than 60 minutes of CPR (despite obtaining ROSC), no initiation of CPR or downtime of more than 10 minutes, were hemodynamically unstable or had more than 300 minutes of time pass between their cardiac arrest and screen were ineligible for the study. Additionally, pregnant, breastfeeding, those with severe hepatic dysfunction and those without health insurance were excluded from enrollment.

The authors of the HYPERION trial utilized the Cerebral Performance Category (CPC) score to determine the neurologic outcome (Figure 1). The primary outcome of this study was survival with a favorable 90-day neurologic outcome defined as a score of 2 or less. This was assessed during a phone interview done by one psychologist blinded to the group assignments. Secondary outcomes included mortality, mechanical ventilation duration, infections, hematologic adverse events, ICU and hospital lengths of stay.

hyperion trial chart

Study Results

In the study, 2,723 patients were assessed for eligibility, 2,139 did not meet inclusion criteria leaving 584 to under randomization and further analysis. 284 patients were randomized to the hypothermia group and 297 were randomized to the normothermia group. The median time from arrest to randomization was 232.5 minutes in the hypothermia group and 219 minutes in the normothermia group. The cause of the cardiac arrest was non-cardiac in two-thirds of patients.

In the hypothermia group, 29 patients had CPC scores of 1 or 2 on day 90 compared to the 17 in the normothermia group and were statistically significant. Additionally, 16 fewer patients had died by 90 days in the hypothermia group compared to the normothermia group. Survival to ICU discharge in the hypothermia and normothermia group was 62 and 61 patients, respectively. Interestingly, the incidence of prespecified adverse events, duration of mechanical ventilation and ICU length of stay were not statistically different between the two groups.

This was a well-organized and thought out a study that aimed to answer important questions about hypothermia in post-cardiac arrest patients. Compared to other post-cardiac arrest trials, this patient population was very sick. This is evident by the fact that 82.3% of the total of 581 patients died during follow-up. Moderate therapeutic hypothermia improved neurologic prognosis but not survival at 90 days. In fact, the statistically significant benefit is very marginal and may have been due to the phone interview having been conducted by only one psychologist. Furthermore, how reliable is a phone interview in determining the neurologic status of a post-cardiac arrest patient at 90 days? Lastly, while definitive temperature control using adaptive control devices were used, this study provides no information about whether 33oC vs 36oC is preferable.

Bottom Line

The authors conclude that moderate therapeutic hypothermia at 33oC for 24 hours may improve neurologic outcomes at 90 days in post-cardiac arrest patients with non-shockable rhythms, however, their statistically significant findings are marginal and worth repeating.

While therapeutic hypothermia may be neurologically beneficial for post-cardiac arrest patients with non-shockable rhythms, further studies are needed to investigate the body’s effect at a temperature of 33oC. It is unclear whether the body’s response to this specific temperature or the avoidance of fever in these patients ultimately leads to better neurologic outcomes.

REFERENCES

 

  1. Myat A, et al. Out-of-hospital cardiac arrest: current concepts. Lancet 2018; PMID: 29536861
  2. Kirkegaard H, et al. Targeted temperature management for 48 vs 24 hours and neurologic outcome after out-of-hospital cardiac arrest: a randomized clinical trial. JAMA 2017; PMID: 28742911
  3. Lascarrou J-B, et al. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. N Engl J Med. October 2019. PMID: 31577396
  4. Nielsen N, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med 2013; PMID: 24237006
  5. Frydland M, et al. Target temperature management of 33°C and 36°C in patients with out-of-hospital cardiac arrest with initial non-shockable rhythm — a TTM sub-study. Resuscitation 2015; PMID: 25629544
  6. Ramzy M, “HYPERION: Targeted Temperature Management in Cardiac Arrest Patients with Non-Shockable Rhythms”, REBEL EM blog, November 18, 2019. Available here

 

ABOUT THE AUTHOR

Mark Ramzy, DO, has been involved in EMS for over 15 years and currently serves as the EMRA Critical Care Chair and is completing a critical care fellowship at the University of Pittsburgh. He presented his research on Double Defibrillation as a Rising Star at ACEP’s Critical Care Committee meeting this past fall. Dr. Ramzy continues to be a regular contributor to the #FOAMed community as an author and contributor to the free critical appraisal blog REBEL EM. Follow him on Twitter at @MRamzyDO

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