Therapeutic hypothermia after nonshockable cardiac arrest: the HYPERION multicenter, randomized, controlled, assessor-blinded, superiority trial

Jean Baptiste Lascarrou, Ferhat Meziani, Amélie Le Gouge, Thierry Boulain, Jérôme Bousser, Guillaume Belliard, Pierre Asfar, Jean Pierre Frat, Pierre François Dequin, Jean Paul Gouello, Arnaud Delahaye, Ali Ait Hssain, Jean Charles Chakarian, Nicolas Pichon, Arnaud Desachy, Fréderic Bellec, Didier Thevenin, Jean Pierre Quenot, Michel Sirodot, François Labadie, Gaétan Plantefeve, Dominique Vivier, Patrick Girardie, Bruno Giraudeau, Jean Reignier, Clinical Research in Intensive Care and Sepsis (CRICS) Group and HYPERION Study Group, Jean Baptiste Lascarrou, Ferhat Meziani, Amélie Le Gouge, Thierry Boulain, Jérôme Bousser, Guillaume Belliard, Pierre Asfar, Jean Pierre Frat, Pierre François Dequin, Jean Paul Gouello, Arnaud Delahaye, Ali Ait Hssain, Jean Charles Chakarian, Nicolas Pichon, Arnaud Desachy, Fréderic Bellec, Didier Thevenin, Jean Pierre Quenot, Michel Sirodot, François Labadie, Gaétan Plantefeve, Dominique Vivier, Patrick Girardie, Bruno Giraudeau, Jean Reignier, Clinical Research in Intensive Care and Sepsis (CRICS) Group and HYPERION Study Group

Abstract

Background: Meta-analyses of nonrandomized studies have provided conflicting data on therapeutic hypothermia, or targeted temperature management (TTM), at 33°C in patients successfully resuscitated after nonshockable cardiac arrest. Nevertheless, the latest recommendations issued by the International Liaison Committee on Resuscitation and by the European Resuscitation Council recommend therapeutic hypothermia. New data are available on the adverse effects of therapeutic hypothermia, notably infectious complications. The risk/benefit ratio of therapeutic hypothermia after nonshockable cardiac arrest is unclear.

Methods: HYPERION is a multicenter (22 French ICUs) trial with blinded outcome assessment in which 584 patients with successfully resuscitated nonshockable cardiac arrest are allocated at random to either TTM between 32.5 and 33.5°C (therapeutic hypothermia) or TTM between 36.5 and 37.5°C (therapeutic normothermia) for 24 hours. Both groups are managed with therapeutic normothermia for the next 24 hours. TTM is achieved using locally available equipment. The primary outcome is day-90 neurological status assessed by the Cerebral Performance Categories (CPC) Scale with dichotomization of the results (1 + 2 versus 3 + 4 + 5). The primary outcome is assessed by a blinded psychologist during a semi-structured telephone interview of the patient or next of kin. Secondary outcomes are day-90 mortality, hospital mortality, severe adverse events, infections, and neurocognitive performance. The planned sample size of 584 patients will enable us to detect a 9% absolute difference in day-90 neurological status with 80% power, assuming a 14% event rate in the control group and a two-sided Type 1 error rate of 4.9%. Two interim analyses will be performed, after inclusion of 200 and 400 patients, respectively.

Discussion: The HYPERION trial is a multicenter, randomized, controlled, assessor-blinded, superiority trial that may provide an answer to an issue of everyday relevance, namely, whether TTM is beneficial in comatose patients resuscitated after nonshockable cardiac arrest. Furthermore, it will provide new data on the tolerance and adverse events (especially infectious complications) of TTM at 32.5-33.5°C.

Trial registration: ClinicalTrials.gov: NCT01994772 .

Figures

Figure 1
Figure 1
Study flowchart. ICU, intensive care unit; RRT, renal replacement therapy.
Figure 2
Figure 2
Inclusion criteria related to the cardiac arrest and study procedures. CA, cardiac arrest; CCCM, closed chest cardiac massage; ROSC, return of spontaneous circulation.
Figure 3
Figure 3
Benefits from targeted temperature management in relation to patient’s prognosis.
Figure 4
Figure 4
Benefits from targeted temperature management in relation to patient’s prognosis documented in previous studies and expected in the HYPERION trial.

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