HYPERION

In Review

Lascarrou J-B. "Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm". N Engl J Med. 2019. Epub ahead of print:.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In adults who are comatose following return of spontaneous circulation from a non-shockable rhythm, targeted temperature management of 33°C for 24 hours led to improved survival with favourable neurologic outcomes at 90 days.

Bottom Line

In patients comatose patients after a non-shockable rhythm (non-VF/pVT) therapeutic hypothermia for 24 hours should be utilized.

Major Points

Hypothermia has been studied as a potential therapy for avoiding poor neurologic outcomes post-arrest since the early 2000’s. Initially, trials like HACA demonstrated survival and neurologic benefit with TTM of 32-34°C in patients experiencing out-of-hospital VF or pulseless VT arrest (shockable rhythms). The TTM trial in 2013 acted more as a “dose finding” trial, comparing 33°C and 36°C and lacked a control arm, in patients with shockable and non-shockable rhythms. Both groups had similar neurologic and mortality outcomes. Some argue that the true benefit of the therapy may be in the prevention of hyperthermia rather than in therapeutic cooling..

The HYPERION trial in 2019 included patients from 25 French ICUs, comparing therapeutic hypothermia (TTM) for patients with non-shockable rhythms. In patients that were comatose following ROSC, they were randomized to either 33°C (n=284) or 37°C (n=297). The primary outcome of survival with favourable neurologic outcome of a Cerebral Performance Category (CPC) of 1 or 2 at 90 days, 10.2% from the hypothermia group as compared to 5.7% from the normothermia group (ARR 4.5%; 95% CI 0.1 to 8.9) which led to a NNT = 22. This may be compared to a NNT = 15 for bystander CPR and NNT = 112 for epinephrine.. Other secondary outcomes did not find significance.

A 2012 Cochrane review reported that mild hypothermia likely improves survival and neurologic outcome after cardiac arrest. Hypothermia therapy isn’t without risk or complications. Lower temperatures have been associated with decreased cardiac output, infection, electrolyte and glucose abnormalities, and exposure to sedation and potentially paralysis to help maintain temperature and patient comfort. The ideal target temperature for treatment following ROSC after cardiac arrest have not been established.

Guidelines

American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care (2015, adapted)

• All adult comatose patients following ROSC receive Targeted Temperature Management (TTM) [Class 1 for VF/pVT from out-of-hospital cardiac arrest (OHCA) and Class 1 for non-VF/pVT]
• and maintain TTM between 32-36°C [Class I]

Design

• Multicenter, open-label, outcome assessor-blinded, randomized, controlled trial
• N=581
  • Hypothermia (33°C) (n=284)
  • Normothermia (37°C) (n=297)
• Setting: 25 academic and community ICU in France
• Enrollment: January 2014 to January 2018
• Follow-up: 90 days
• Analysis: intention-to-treat
• Primary Outcome: survival with good neurological function (Cerebral Performance Category of 1 or 2) at 90 days

Population

Inclusion Criteria

• ≥ 18 years old
• in or out of hospital cardiac arrest from any cause
• non-shockable rhythm (pulseless electrical activity or asystole)
• Glasgow Coma Scale (GCS) ≤ 8 At ICU admission

Exclusion Criteria

• no flow/perfusion time > 10 minutes (collapse to CPR)
• low-flow/perfusion > 60 minutes (CPR to ROSC)
• continuous epinephrine or norepinephrine infusion >1 mcg/kg/min
• time from cardiac arrest to screening > 300 minutes
• moribund condition
• Child–Pugh-Turcotte class C
• pregnancy or breast-feeding
• status of being under guardianship
• inmate at a correctional facility
• previous inclusion in another randomized, controlled trial involving patients with cardiac arrest in which the neurologic outcome at 90 days was assessed as the primary end point
• lack of health insurance
• refusal by next of kin for inclusion

Baseline Characteristics

Hypothermia Group displayed

• Demographics: Median age 67 years, 66% male
• Comobidities: median Charlson comorbidity index 4, 34% chronic pulmonary disease, 57% chronic heart disease
• location of arrest: 48.6% residence, 25.7% public place, 25.7% in-patient
• arrest details:
  • Rhythm: 77.8% asystole, 11.6% plus less electrical activity, 10.6% unknown
  • Bystander: 96.5% witnessed, 70.4% CPR initiated
  • Cause: Asphyxia 55.6%, Cardiac cause 27.8%, Anaphylaxis 1.4%, Neurologic cause 2.5%, Pulmonary embolism 3.5%, Other medical cause 7.0%, Trauma 0.4%, Drug poisoning 0.4%, Drowning 1.4%

Interventions

• Hypothermia of 33 ± 0.5°C maintained for 24 hours, then slow rewarming of 0.25-0.50°C/h to 36.5-37.5°C, then maintained for 24 hours
• Normothermia of 36.5-37.5°C maintained for 48 hours

Outcomes

Comparisons are Hypothermia vs. Normothermia.

Primary Outcomes

Survival with a Cerebral Performance Category (CPC) of 1 or 2 at 90 days

10.2% vs. 5.7% (ARR 4.5%; 95% CI 0.1 to 8.9) NNT = 22

Secondary Outcomes

90 Day mortality

81.3% vs. 83.2% (ARI −1.9%; 95% CI −8.0 to 4.4)

ICU Mortality

78.2% vs. 79.5% (ARR 0.93%; 95% CI 0.78 to 1.10)

Survival to ICU discharge

21.8% vs. 20.5% (ARR 1.07%; 95% CI 0.75 to 1.52)

Survival to Hospital discharge

19.7% vs. 16.8% (ARR 1.19%; 95% CI 0.81 to 1.74)

Subgroup Analysis

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%

Adverse Events

Reported as similar between groups

Criticisms

• 10% of population had an unknown rhythm which may have affected findings
• telephone interviewers used to assess neurologic outcomes, not in person assessments
• TTM was utilized for longer than 24 hours to avoid rebound hyperthermia but may have led to bias
• Patients with missing data were coded as died

Funding

• French Ministry of Health
• nonprofit health care institution Centre Hospitalier Départemental Vendée
• Laerdal Foundation