Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

Hans Kirkegaard; Eldar Søreide; Inge de Haas; Ville Pettilä; Fabio Silvio Taccone; Urmet Arus; Christian Storm; Christian Hassager; Jørgen Feldbæk Nielsen; Christina Ankjær Sørensen; Susanne Ilkjær; Anni Nørgaard Jeppesen; Anders Morten Grejs; Christophe Henri Valdemar Duez; Jakob Hjort; Alf Inge Larsen; Valdo Toome; Marjaana Tiainen; Johanna Hästbacka; Timo Laitio; Markus B Skrifvars

doi:10.1001/jama.2017.8978

Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

Hans Kirkegaard, Eldar Søreide, Inge de Haas, Ville Pettilä, Fabio Silvio Taccone, Urmet Arus, Christian Storm, Christian Hassager, Jørgen Feldbæk Nielsen, Christina Ankjær Sørensen, Susanne Ilkjær, Anni Nørgaard Jeppesen, Anders Morten Grejs, Christophe Henri Valdemar Duez, Jakob Hjort, Alf Inge Larsen, Valdo Toome, Marjaana Tiainen, Johanna Hästbacka, Timo LaitioMarkus B Skrifvars

Department of Clinical Medicine

112 Citations (Scopus)

Abstract

IMPORTANCE: International resuscitation guidelines recommend targeted temperature management (TTM) at 33°C to 36°C in unconscious patients with out-of-hospital cardiac arrest for at least 24 hours, but the optimal duration of TTM is uncertain. OBJECTIVE: To determine whether TTM at 33°C for 48 hours results in better neurologic outcomes compared with currently recommended, standard, 24-hour TTM. DESIGN, SETTING, AND PARTICIPANTS: This was an international, investigator-initiated, blinded-outcome-assessor, parallel, pragmatic, multicenter, randomized clinical superiority trial in 10 intensive care units (ICUs) at 10 university hospitals in 6 European countries. Three hundred fifty-five adult, unconscious patients with out-of-hospital cardiac arrest were enrolled from February 16, 2013, to June 1, 2016, with final follow-up on December 27, 2016. INTERVENTIONS: Patients were randomized to TTM (33 ± 1°C) for 48 hours (n = 176) or 24 hours (n = 179), followed by gradual rewarming of 0.5°C per hour until reaching 37°C. MAIN OUTCOMES AND MEASURES: The primary outcome was 6-month neurologic outcome, with a Cerebral Performance Categories (CPC) score of 1 or 2 used to define favorable outcome. Secondary outcomes included 6-month mortality, including time to death, the occurrence of adverse events, and intensive care unit resource use. RESULTS: In 355 patients who were randomized (mean age, 60 years; 295 [83%] men), 351 (99%) completed the trial. More patients in the 48-hour group had a favorable outcome, but this was not statistically significant. Six-month mortality was not different between the groups. Adverse events were more common in the 48-hour group than in the 24-hour group. There was no significant difference in the time to mortality (hazard ratio, 0.79; 95% CI, 0.54-1.15; P = .22). The median length of ICU stay (151 vs 117 hours; P < .001), but not hospital stay (11 vs 12 days; P = .50), was longer in the 48-hour group than in the 24-hour group. (Table Presented) CONCLUSIONS AND RELEVANCE: In unconscious survivors from out-of-hospital cardiac arrest admitted to the ICU, targeted temperature management at 33°C for 48 hours did not significantly improve 6-month neurologic outcome compared with targeted temperature management at 33°C for 24 hours. However, the study may have had limited power to detect clinically important differences, and further research may be warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01689077.

Original language	English
Journal	J A M A: The Journal of the American Medical Association
Volume	318
Issue number	4
Pages (from-to)	341-350
Number of pages	10
ISSN	0098-7484
DOIs	https://doi.org/10.1001/jama.2017.8978
Publication status	Published - 25 Jul 2017

Keywords

Aged
Body Temperature
Brain Diseases
Cardiopulmonary Resuscitation
Female
Humans
Hypothermia, Induced
Male
Middle Aged
Out-of-Hospital Cardiac Arrest
Time Factors
Unconsciousness
Comparative Study
Journal Article
Multicenter Study
Pragmatic Clinical Trial
Randomized Controlled Trial

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10.1001/jama.2017.8978

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Kirkegaard, H., Søreide, E., de Haas, I., Pettilä, V., Taccone, F. S., Arus, U., Storm, C., Hassager, C., Nielsen, J. F., Sørensen, C. A., Ilkjær, S., Jeppesen, A. N., Grejs, A. M., Duez, C. H. V., Hjort, J., Larsen, A. I., Toome, V., Tiainen, M., Hästbacka, J., ... Skrifvars, M. B. (2017). Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial. J A M A: The Journal of the American Medical Association, 318(4), 341-350. https://doi.org/10.1001/jama.2017.8978

Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest : A Randomized Clinical Trial. / Kirkegaard, Hans; Søreide, Eldar; de Haas, Inge et al.

In: J A M A: The Journal of the American Medical Association, Vol. 318, No. 4, 25.07.2017, p. 341-350.

Research output: Contribution to journal › Journal article › Research › peer-review

Kirkegaard, H, Søreide, E, de Haas, I, Pettilä, V, Taccone, FS, Arus, U, Storm, C, Hassager, C, Nielsen, JF, Sørensen, CA, Ilkjær, S, Jeppesen, AN, Grejs, AM, Duez, CHV, Hjort, J, Larsen, AI, Toome, V, Tiainen, M, Hästbacka, J, Laitio, T & Skrifvars, MB 2017, 'Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial', J A M A: The Journal of the American Medical Association, vol. 318, no. 4, pp. 341-350. https://doi.org/10.1001/jama.2017.8978

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abstract = "IMPORTANCE: International resuscitation guidelines recommend targeted temperature management (TTM) at 33°C to 36°C in unconscious patients with out-of-hospital cardiac arrest for at least 24 hours, but the optimal duration of TTM is uncertain. OBJECTIVE: To determine whether TTM at 33°C for 48 hours results in better neurologic outcomes compared with currently recommended, standard, 24-hour TTM. DESIGN, SETTING, AND PARTICIPANTS: This was an international, investigator-initiated, blinded-outcome-assessor, parallel, pragmatic, multicenter, randomized clinical superiority trial in 10 intensive care units (ICUs) at 10 university hospitals in 6 European countries. Three hundred fifty-five adult, unconscious patients with out-of-hospital cardiac arrest were enrolled from February 16, 2013, to June 1, 2016, with final follow-up on December 27, 2016. INTERVENTIONS: Patients were randomized to TTM (33 ± 1°C) for 48 hours (n = 176) or 24 hours (n = 179), followed by gradual rewarming of 0.5°C per hour until reaching 37°C. MAIN OUTCOMES AND MEASURES: The primary outcome was 6-month neurologic outcome, with a Cerebral Performance Categories (CPC) score of 1 or 2 used to define favorable outcome. Secondary outcomes included 6-month mortality, including time to death, the occurrence of adverse events, and intensive care unit resource use. RESULTS: In 355 patients who were randomized (mean age, 60 years; 295 [83%] men), 351 (99%) completed the trial. More patients in the 48-hour group had a favorable outcome, but this was not statistically significant. Six-month mortality was not different between the groups. Adverse events were more common in the 48-hour group than in the 24-hour group. There was no significant difference in the time to mortality (hazard ratio, 0.79; 95% CI, 0.54-1.15; P = .22). The median length of ICU stay (151 vs 117 hours; P < .001), but not hospital stay (11 vs 12 days; P = .50), was longer in the 48-hour group than in the 24-hour group. (Table Presented) CONCLUSIONS AND RELEVANCE: In unconscious survivors from out-of-hospital cardiac arrest admitted to the ICU, targeted temperature management at 33°C for 48 hours did not significantly improve 6-month neurologic outcome compared with targeted temperature management at 33°C for 24 hours. However, the study may have had limited power to detect clinically important differences, and further research may be warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01689077.",

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author = "Hans Kirkegaard and Eldar S{\o}reide and {de Haas}, Inge and Ville Pettil{\"a} and Taccone, {Fabio Silvio} and Urmet Arus and Christian Storm and Christian Hassager and Nielsen, {J{\o}rgen Feldb{\ae}k} and S{\o}rensen, {Christina Ankj{\ae}r} and Susanne Ilkj{\ae}r and Jeppesen, {Anni N{\o}rgaard} and Grejs, {Anders Morten} and Duez, {Christophe Henri Valdemar} and Jakob Hjort and Larsen, {Alf Inge} and Valdo Toome and Marjaana Tiainen and Johanna H{\"a}stbacka and Timo Laitio and Skrifvars, {Markus B}",

year = "2017",

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day = "25",

doi = "10.1001/jama.2017.8978",

language = "English",

volume = "318",

pages = "341--350",

journal = "J A M A: The Journal of the American Medical Association",

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TY - JOUR

T1 - Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest

T2 - A Randomized Clinical Trial

AU - Kirkegaard, Hans

AU - Søreide, Eldar

AU - de Haas, Inge

AU - Pettilä, Ville

AU - Taccone, Fabio Silvio

AU - Arus, Urmet

AU - Storm, Christian

AU - Hassager, Christian

AU - Nielsen, Jørgen Feldbæk

AU - Sørensen, Christina Ankjær

AU - Ilkjær, Susanne

AU - Jeppesen, Anni Nørgaard

AU - Grejs, Anders Morten

AU - Duez, Christophe Henri Valdemar

AU - Hjort, Jakob

AU - Larsen, Alf Inge

AU - Toome, Valdo

AU - Tiainen, Marjaana

AU - Hästbacka, Johanna

AU - Laitio, Timo

AU - Skrifvars, Markus B

PY - 2017/7/25

Y1 - 2017/7/25

N2 - IMPORTANCE: International resuscitation guidelines recommend targeted temperature management (TTM) at 33°C to 36°C in unconscious patients with out-of-hospital cardiac arrest for at least 24 hours, but the optimal duration of TTM is uncertain. OBJECTIVE: To determine whether TTM at 33°C for 48 hours results in better neurologic outcomes compared with currently recommended, standard, 24-hour TTM. DESIGN, SETTING, AND PARTICIPANTS: This was an international, investigator-initiated, blinded-outcome-assessor, parallel, pragmatic, multicenter, randomized clinical superiority trial in 10 intensive care units (ICUs) at 10 university hospitals in 6 European countries. Three hundred fifty-five adult, unconscious patients with out-of-hospital cardiac arrest were enrolled from February 16, 2013, to June 1, 2016, with final follow-up on December 27, 2016. INTERVENTIONS: Patients were randomized to TTM (33 ± 1°C) for 48 hours (n = 176) or 24 hours (n = 179), followed by gradual rewarming of 0.5°C per hour until reaching 37°C. MAIN OUTCOMES AND MEASURES: The primary outcome was 6-month neurologic outcome, with a Cerebral Performance Categories (CPC) score of 1 or 2 used to define favorable outcome. Secondary outcomes included 6-month mortality, including time to death, the occurrence of adverse events, and intensive care unit resource use. RESULTS: In 355 patients who were randomized (mean age, 60 years; 295 [83%] men), 351 (99%) completed the trial. More patients in the 48-hour group had a favorable outcome, but this was not statistically significant. Six-month mortality was not different between the groups. Adverse events were more common in the 48-hour group than in the 24-hour group. There was no significant difference in the time to mortality (hazard ratio, 0.79; 95% CI, 0.54-1.15; P = .22). The median length of ICU stay (151 vs 117 hours; P < .001), but not hospital stay (11 vs 12 days; P = .50), was longer in the 48-hour group than in the 24-hour group. (Table Presented) CONCLUSIONS AND RELEVANCE: In unconscious survivors from out-of-hospital cardiac arrest admitted to the ICU, targeted temperature management at 33°C for 48 hours did not significantly improve 6-month neurologic outcome compared with targeted temperature management at 33°C for 24 hours. However, the study may have had limited power to detect clinically important differences, and further research may be warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01689077.

AB - IMPORTANCE: International resuscitation guidelines recommend targeted temperature management (TTM) at 33°C to 36°C in unconscious patients with out-of-hospital cardiac arrest for at least 24 hours, but the optimal duration of TTM is uncertain. OBJECTIVE: To determine whether TTM at 33°C for 48 hours results in better neurologic outcomes compared with currently recommended, standard, 24-hour TTM. DESIGN, SETTING, AND PARTICIPANTS: This was an international, investigator-initiated, blinded-outcome-assessor, parallel, pragmatic, multicenter, randomized clinical superiority trial in 10 intensive care units (ICUs) at 10 university hospitals in 6 European countries. Three hundred fifty-five adult, unconscious patients with out-of-hospital cardiac arrest were enrolled from February 16, 2013, to June 1, 2016, with final follow-up on December 27, 2016. INTERVENTIONS: Patients were randomized to TTM (33 ± 1°C) for 48 hours (n = 176) or 24 hours (n = 179), followed by gradual rewarming of 0.5°C per hour until reaching 37°C. MAIN OUTCOMES AND MEASURES: The primary outcome was 6-month neurologic outcome, with a Cerebral Performance Categories (CPC) score of 1 or 2 used to define favorable outcome. Secondary outcomes included 6-month mortality, including time to death, the occurrence of adverse events, and intensive care unit resource use. RESULTS: In 355 patients who were randomized (mean age, 60 years; 295 [83%] men), 351 (99%) completed the trial. More patients in the 48-hour group had a favorable outcome, but this was not statistically significant. Six-month mortality was not different between the groups. Adverse events were more common in the 48-hour group than in the 24-hour group. There was no significant difference in the time to mortality (hazard ratio, 0.79; 95% CI, 0.54-1.15; P = .22). The median length of ICU stay (151 vs 117 hours; P < .001), but not hospital stay (11 vs 12 days; P = .50), was longer in the 48-hour group than in the 24-hour group. (Table Presented) CONCLUSIONS AND RELEVANCE: In unconscious survivors from out-of-hospital cardiac arrest admitted to the ICU, targeted temperature management at 33°C for 48 hours did not significantly improve 6-month neurologic outcome compared with targeted temperature management at 33°C for 24 hours. However, the study may have had limited power to detect clinically important differences, and further research may be warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01689077.

KW - Aged

KW - Body Temperature

KW - Brain Diseases

KW - Cardiopulmonary Resuscitation

KW - Female

KW - Humans

KW - Hypothermia, Induced

KW - Male

KW - Middle Aged

KW - Out-of-Hospital Cardiac Arrest

KW - Time Factors

KW - Unconsciousness

KW - Comparative Study

KW - Journal Article

KW - Multicenter Study

KW - Pragmatic Clinical Trial

KW - Randomized Controlled Trial

U2 - 10.1001/jama.2017.8978

DO - 10.1001/jama.2017.8978

M3 - Journal article

C2 - 28742911

SN - 0098-7484

VL - 318

SP - 341

EP - 350

JO - J A M A: The Journal of the American Medical Association

JF - J A M A: The Journal of the American Medical Association

IS - 4

ER -

Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

Abstract

Keywords

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