Critical Care Alert: Targeted Temperature Management for Cardiac Arrest with Non-shockable Rhythm - The HYPERION Trial

Article
Lascarrou JB, Merdji H, Le Gouge A, et al. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. N Engl J Med. 2019;381(24):2327-2337.

OBJECTIVE
To assess whether moderate therapeutic hypothermia at 33°C improves neurologic outcomes in comatose patients for whom ROSC was achieved following cardiac arrest with non-shockable rhythm compared to a strategy of targeted normothermia at 37°C.¹

BACKGROUND
Hypoxemic-ischemic brain injury is the most common cause of death in the setting of cardiac arrest. Targeted Temperature Management (TTM), formerly known as therapeutic hypothermia, refers to the use of internal and external cooling methods to lower a patient's core body temperature following a period of interrupted cerebral blood flow, the most notable scenario being following cardiac arrest. This practice is understood to reduce adverse neurologic outcomes that follow ischemia-reperfusion injury. Targeted temperature management (TTM) is now recommended by AHA guidelines for comatose patients following OHCA with ventricular fibrillation as well as OHCA with non-shockable rhythms (asystole, pulseless electrical activity) and for any in hospital cardiac arrest (IHCA).² The use of therapeutic hypothermia does create risk for adverse events, including low cardiac output, electrolyte abnormalities, coagulopathy, infection, and increased sedation requirements. Several small, randomized controlled trials in the early 2000s report use of therapeutic hypothermia with goal of 32°C-34°C following out of hospital cardiac arrest (OHCA) with shockable rhythms as conferring survival benefit and improved neurologic outcome.^3,4 In 2013, Nielsen examined the use of TTM in the setting of OHCA with shockable and non-shockable rhythms and concluded that targeted hypothermia at 33°C did not achieve a reduction in all-cause mortality or improve neurologic outcomes compared to 36°C.⁵ A criticism of this study has been the inclusion of shockable and non-shockable rhythms. To date, no single target temperature to be achieved by TTM has been identified as an optimum for patient centered outcomes such as mortality and neurologic status following achievement of ROSC. Further, it is not well understood if the benefits of therapeutic hypothermia are achieved by the avoidance of fever or due to a lowering of cerebral metabolic demand from hypothermia itself. Conflicting evidence has been reported regarding improvement in neurologic outcomes with the use of therapeutic hypothermia following achievement of ROSC from cardiac arrest with non-shockable rhythms.¹ The HYPERION trial is the first RCT of TTM in the post-ROSC care of patients with non-shockable rhythms.

DESIGN

• Multicenter, open-label, randomized controlled trial
• Blinded-outcome assessment 

Inclusion Criteria

• Patients age 18 or older with OHCA or IHCA with non-shockable rhythm
• Glasgow Coma Scale score 8 or less

Exclusion Criteria

• Zero blood flow for more than 10 minutes (time from arrest to initiation of CPR)
• Low blood flow for more than 60 minutes (time from initiation of CPR to ROSC)
• Major hemodynamic instability (continuous epinephrine or norepinephrine infusion > 1 mcg/kg/min)
• Elapsed time from cardiac arrest to screening for trial greater than 300 minutes
• Moribund condition
• Child-Pugh class C cirrhosis (severe hepatic dysfunction)
• Pregnancy or breastfeeding
• Legal status of being under guardianship or of being an inmate at correctional facility
• Prior inclusion in another RCT of cardiac arrest patients with primary endpoint of neurologic status at 90 days
• Lack of health insurance or decision by next of kin to not participate in trial

Randomization

• Between January 2014 and January 2018, 584 patients in 25 ICUs in France underwent randomization
  • 3 (0.51%) withdrew consent (all were from the hypothermia-assigned group)
  • 581 patients included in final analysis
• 2723 patients screened for trial eligibility
• Eligible patients randomly assigned in 1:1 ratio to treatment intervention group of moderate therapeutic hypothermia (targeted temperature of 33°C for 24 hours with a window of ±5°C, followed by slow rewarming at a rate of 0.25-0.50°C/hour to 36.5-37.5°C which was then maintained for 24 hours) or to control group of normothermia (maintenance of target temperature of 36.5-37.6°C for 48 hours).
• Patients assigned to the hypothermia group received sedation per standard protocol in participating centers with dose-adjustments to obtain a Richmond Agitation Sedation Score (RASS) of -5, with dose-tapering during rewarming following achievement of body temperature greater than 36° Patients assigned to the normothermia group were given routine sedation during the first 12 hours following randomization.
• Final analysis includes 284 patients randomized to the hypothermia group and 297 patients randomized to the normothermia group

Population Characteristics

• Baseline population characteristics were reviewed and are reported to be evenly balanced by the study authors.

OUTCOMES MEASURED

Primary

• Survival with favorable neurologic outcome at 90 days defined as Cerebral Performance Category scale score of 1 (good cerebral performance or minor disability) or 2 (moderate disability)

Secondary

• Mortality
• Duration of mechanical ventilation
• ICU Length of Stay (LOS)
• Hospital LOS
• Infections
• Hematologic adverse events

KEY RESULTS

Primary

• Cerebral Performance Category scale score of 1 or 2 observed amongst subjects randomized for hypothermia (intervention) v. normothermia (control) were, respectively, 10.2% (n=29) and 5.7% (n=17), (HR 4.5, 95% CI 0.1-8.9; p = 0.04)

Secondary

• Overall 90-day mortality was reported for the hypothermia (intervention) and normothermia (control) as, respectively, 81.3% (n=231) and 83.2% (n=247) (95% CI -8.0 to 4.4)
• No statistically significant between-group differences reported for duration of mechanical ventilation, ICU or Hospital LOS, infection or hematologic adverse events.

Median time between randomization and induction of cooling for hypothermia group was 16 minutes, IQR 0 to 53 minutes.

Median time between randomization and achievement of goal temperature 33°C for hypothermia group was 317 minutes, IQR 214 to 477 minutes.

STUDY STRENGTHS

• Randomized, controlled, multicenter trial
• Primary endpoint of CPC scale score is a patient-centered outcome
• 90-day mortality is a robust endpoint
• Blinded outcome assessor
• Heterogeneity of centers participating in study (i.e. not limited to university setting) confers external validity
• Control for confounding by standardization of protocols for sedation, use of neuromuscular blocking agents, and treatment of adverse events
• Multiple body temperature cooling modalities used

STUDY LIMITATIONS

• Small study population size
• CPC scale score is a subjective clinical scoring system with poor inter-rater reliability in post-cardiac arrest
• Primary endpoint performed via telephone interview
• Patients developed body temperatures greater than 38°C following planned TTM window
• TTM used for hypothermia group 56-64 hours but only 48 hours for normothermia group
• Subjects with missing data assumed by authors to have died
  • Only three patients with missing data; hypothermia group n=1, normothermia group n=2
• Fragility index value of 1 suggests that an outcome change for a single study subject would make the difference in primary outcome non-significant
• Study is insufficiently powered for detection of reported between-group difference of primary endpoint with statistical significance
• Physicians overseeing treatment of study subjects not blinded
• Richmond Agitation Sedation Score targets different between hypothermia (-5) and normothermia (0) groups
• Duration of sedation dissimilar between groups
• Closed-loop thermostatic device used in greater proportion of subjects in hypothermia group than normothermia group

AUTHORS' CONCLUSIONS
Among cardiac arrest patients with non-shockable rhythms for whom ROSC is achieved, the use of moderate therapeutic hypothermia (33°C for 24 hours) significantly improves survival with favorable neurologic outcome at 90 days compared to a strategy of targeted normothermia (37°C). No significant between group difference was observed for overall mortality at 90 days. The use of moderate therapeutic hypothermia was not observed to introduce harm compared with targeted normothermia.

DISCUSSION

• HYPERION trial is first RCT to examine neurologic outcomes with TTM use following achievement of ROSC in patients with non-shockable cardiac arrests
• Authors of study report that use of moderate therapeutic hypothermia target temperature of 33°C confers an improvement in neurologic outcome at 90 days compared to targeted normothermia (37°C)
• Reported between group difference of 4.5% is smaller than predicted between group difference
• Study underpowered to detect larger effect-change than reported
• Confidence interval given for primary outcome (CPC 1 or 2) includes 1, suggesting no between-group difference
• Study intrinsically limited by goals of care preventing blinding of physicians treating subjects
• Psychologist assessing CPC scale score at 90 days was blinded to randomization assignment of subjects
• CPC has poor interrater reliability in the post-cardiac arrest setting⁶
• Hypothermia group received a considerably longer mean duration of sedation
• Subjects included in final analysis extremely moribund; 82.3% of subjects did not survive to day 90; 7.9% of all subjects survived to day 90 with a neurologically favorable outcome (defined as CPC scale score of 1 or 2).
• Investigators report that a substantial number of study subjects exhibited hyperthermia.
• It is unclear if benefit of TTM is from achieving hypothermic state or avoidance of fever
• Nielsen 2013 TTM trial exhibits greater control of temperature targets, minimized between-group temperature overlap, avoided hyperthermia in 36°C group

EM TAKE-AWAY 
The HYPERION trial does not provider further clarification if neurologic benefit of TTM is from fever avoidance or hypothermic state itself. Following the 2013 TTM study by Nielsen, the optimum temperature target in therapeutic hypothermia in the post-cardiac arrest setting has continued to elude the medical community. The HYPERION trial reminds us that patients should be cooled; however, it does not provide further resolution on the answer to the 33°C vs 36°C debate.

REFERENCES

1. Lascarrou JB, Merdji H, Le Gouge A, et al. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. N Engl J Med. 2019;381(24):2327-2337.
2. Pebedy MA, Callaway CW, Neumar RW, et al. Part 9: Post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 Suppl 3):S768-S786.
3. Hypothermia after Cardiac Arrest Study Group. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest. N Engl J Med. 2002;346(8):549-556.
4. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia. N Engl J Med. 2002;346(8):557-563.
5. Nielsen N, Wettersley J, Cronberg T, et al. Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest. N Engl J Med. 2013;369(23):2197-2206.
6. Grossestreuer AV, Abella BS, Sheak KR, et al. Inter-rater Reliability of Post-Arrest Cerebral Performance Category (CPC) Scores. Resuscitation. 2016;109:21-24.