A Cold-Case

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Nick Reis
Nick Reis

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A little deeper….or colder

Hypothermia is believed to be neuroprotective after a period of global brain hypoxia by decreasing the cerebral inflammatory response and minimizing the cerebral metabolic rate. The 2015 guidelines of the International Liaison Committee on Resuscitation (ILCOR), recommends targeted temperature management (TTM) with a target of 32°C to 36°C and is currently advocated for all patients with coma after successful resuscitation from cardiac arrest. The American Heart Association recommends TTM as a Class 1C for patients presenting with an initial non-shockable rhythm (NSR). The data is conflicted as to whether TTM should be applied to this group of patients who, among all cardiac arrest patients, have poorer prognoses. The objective of the Therapeutic Hypothermia after Cardiac Arrest in Nonshockable Rhythm (HYPERION) trial was to assess whether moderate therapeutic hypothermia at 33°C, as compared with targeted normothermia (37°C), would improve neurologic outcome in patients with coma who had been successfully resuscitated after both inpatient and out of hospital cardiac arrests with NSR.

What did they do?

HYPERION was an open-label, randomized, controlled, blinded-outcome-assessor, pragmatic, multicenter trial in 25 ICUs in France (11 university hospitals and 14 community hospitals) comparing moderate therapeutic hypothermia (TH) at 33°C during the first 24 hours vs. targeted normothermia (TN) at 37°C in the first 24 hours. Only in patients with coma (GCS<8) after the return of spontaneous circulation (ROSC) related to cardiac arrest with an initial NSR were included.  A total of 584 patients underwent randomization with 581 included in the analysis. At each center, patients were randomized 1:1 and underwent TTM with the center’s standard protocol. The trial protocol involved the standardization of sedation, neuromuscular blockade, and the management of expected adverse events.

All surviving patients were followed until day 90 after randomization. The primary outcome was survival with a favorable day-90 neurologic outcome (CPC 1-2). The CPC score at 90 days was assessed during a semi-structured telephone interview adapted from the validated French version of the 5-item Glasgow Outcome Scale by a single psychologist who was unaware of the group assignments and who had been specifically trained for the trial. The secondary outcomes were mortality, mechanical ventilation duration, length of stay in the ICU and hospital, infections, and hematologic adverse events.

What did they find?

The primary outcome of CPC score 1-2 and there was a statistically significant difference in favor of TH. 29 of 284 patients assigned to the TH group and 17 of the 297 patients assigned to the TN group (10.2% vs. 5.7%; difference, 4.5 percentage points; 95% confidence interval [CI], 0.1 to 8.9; P=0.04) had CPC scores of 1-2 at day 90. Mortality, the duration of mechanical ventilation, and the length of stay between the 2 groups were similar. No significant differences were identified between the groups regarding prespecified serious adverse events.

What should we take away from this?

Survivors of cardiac arrest due to NSR undergoing TH at 33°C for 24 hours had a higher percentage of patients with favorable neurologic outcomes at day 90 than was observed with targeted normothermia. Some important limitations were identified in this study that should be recognized in regard to the final outcome. First, both in-hospital and of-hospital cardiac arrests were grouped together in the population studied. The difference of accessible resources and the similarity in interventions available and administered pre-hospital and within the hospital in achieving ROSC were not discussed. As a heterogeneous group can we more confidently say this data is more applicable as it applies to all arrests with non-shockable rhythms or does the mixed population make the data less meaningful?  The primary outcome (CPC score) was assessed via telephone interview by a single psychologist. No face-to-face patient-provider assessment took place and the final CPC score was determined by this single provider. TTM in the hypothermia group was longer in duration (56-64hrs) compared to the normothermia group (48hrs). Additionally, a substantial proportion of patients had body temperatures above 38°C, notably after the period of TTM. Fevers were reported more in the TN group, this may be attributed to the less sophisticated cooling interventions used in this group and the overall short duration of cooling compared to the TH group. These differences may have impacted the primary outcome. Lastly, patients with missing data were assumed to have died. The fragility index was calculated to be 1 indicating that an outcome change in a single patient would make the difference in the primary outcome nonsignificant. Only a total of 3 patients’ data were missing (1 in TH and 2 in TN), small but important with a fragility index of 1. 

Both RCT and observational studies have assessed the benefits of TTM in this patient population with conflicting results. Recently Barbarawi et al. conducted a meta analysis including 30 studies (5 RCTs and 25 observational) totalling 10,703 patients, 4,023 of whom received TTM and 6,680 received standard care. Fifteen studies were performed primarily on patients with an initial NSR. Investigators found that TTM in patients with initial NSR was associated with significantly higher survival rates and better neurologic outcomes compared with standard care without TTM. However, analyses from the included RCTs did not support this conclusion. Once again conflicting yet supportive of TTM in this patient population. 


  1. Lascarrou JB, Merdji H, Le Gouge A, Colin G, Grillet G, Girardie P, Coupez E, Dequin PF, Cariou A, Boulain T, Brule N, Frat JP, Asfar P, Pichon N, Landais M, Plantefeve G, Quenot JP, Chakarian JC, Sirodot M, Legriel S, Letheulle J, Thevenin D, Desachy A, Delahaye A, Botoc V, Vimeux S, Martino F, Giraudeau B, Reignier J; CRICS-TRIGGERSEP Group. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. N Engl J Med. 2019 Dec 12;381(24):2327-2337. doi: 10.1056/NEJMoa1906661. Epub 2019 Oct 2. PMID: 31577396.

  2. Barbarawi M, Alabdouh A, Barbarawi O, Lakshman H, Alkasasbeh M, Rizk F, Bachuwa G, Alkotob ML. Targeted Temperature Management in Cardiac Arrest Patients With an Initial Non-Shockable Rhythm: A Systematic Review and Meta-Analysis. Shock. 2020 Nov;54(5):623-630. doi: 10.1097/SHK.0000000000001550. PMID: 32433212.


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