A multicentre randomized pilot trial on the effectiveness of different levels of cooling in comatose survivors of out-of-hospital cardiac arrest: the FROST-I trial
To obtain initial data on the effect of different levels of targeted temperature management (TTM) in out-of-hospital cardiac arrest (OHCA).
We designed a multicentre pilot trial with 1:1:1 randomization to either 32 °C (n = 52), 33 °C (n = 49) or 34 °C (n = 49), via endovascular cooling devices during a 24-h period in comatose survivors of witnessed OHCA and initial shockable rhythm. The primary endpoint was the percentage of subjects surviving with good neurologic outcome defined by a modified Rankin Scale (mRS) score of ≤ 3, blindly assessed at 90 days.
At baseline, different proportions of patients who had received defibrillation administered by a bystander were assigned to groups of 32 °C (13.5%), 33 °C (34.7%) and 34 °C (28.6%; p = 0.03). The percentage of patients with an mRS ≤ 3 at 90 days (primary endpoint) was 65.3, 65.9 and 65.9% in patients assigned to 32, 33 and 34 °C, respectively, non-significant (NS). The multivariate Cox proportional hazards model identified two variables significantly related to the primary outcome: male gender and defibrillation by a bystander. Among the 43 patients who died before 90 days, 28 died following withdrawal of life-sustaining therapy, as follows: 7/16 (43.8%), 10/13 (76.9%) and 11/14 (78.6%) of patients assigned to 32, 33 and 34 °C, respectively (trend test p = 0.04). All levels of cooling were well tolerated.
There were no statistically significant differences in neurological outcomes among the different levels of TTM. However, future research should explore the efficacy of TTM at 32 °C.
Clinical trial registration
ClinicalTrials.gov unique identifier: NCT02035839 (http://clinicaltrials.gov).
KeywordsBrain injury Cardiac arrest Post-cardiac arrest syndrome Resuscitation Sudden death Targeted temperature management
This work was supported by ZOLL Medical Corporation, Inc. (USA).
Compliance with ethical standards
Conflict of interest
E. Lopez-de-Sa: Research Grant; Modest; ZOLL Medical Corporation, Inc. (USA), Boehringer Ingelheim, Servier. Speakers Bureau; Modest; Daiichi Sankyo, Rovi, Servier, BARD. Consultant/Advisory Board; Modest; AstraZeneca. M. Juarez: Research Grant; Modest; ZOLL Medical Corporation, Inc. (USA). E. Armada: Research Grant; Modest; ZOLL Medical Corporation, Inc. (USA). J.C. Sanchez-Salado: None. P.L. Sanchez: None. P. Loma-Osorio: Research Grant; Modest; ZOLL Medical Corporation, Inc. (USA), Sanofi. Honoraria; Modest; Sanofi, Daiichi Sankyo, AstraZeneca, Pfizer. A. Sionis: None. M.C. Monedero: Research Grant; Modest; ZOLL Medical Corporation, Inc. (USA), Lilly. M. Martinez-Selles: Research Grant; Modest; ZOLL Medical Corporation, Inc. (USA). M. Sanchez-Gracia: None. A. Ariza: Research Grant; Modest; ZOLL Medical Corporation, Inc. (USA). A. Uribarri: Research Grant; Modest; ZOLL Medical Corporation, Inc. (USA). J.M. Garcia-Acuña: None. P. Villa: None. P.J. Perez: Research Grant; Modest; ZOLL Medical Corporation, Inc. (USA). C. Storm: Research Grant; Significant; Fresenius Deutschland. Speakers Bureau; Modest; Philips, C.R. BARD, ZOLL Medical Corporation, Inc., Medivance, Covidien, Nonin Medical, German Heart Foundation. A. Dee: Employment; Significant; ZOLL Medical Corporation, Inc. J.L. Lopez-Sendon: Research Grant: Modest; Sanofi, Servier, AstraZeneca, GlaxoSmithKline, Menarini, Novartis. Consultant/Advisory Board; Modest; Boehringer Ingelheim, Daiichi Sankyo. Other; Modest; Servier.
- 1.Nolan JP, Morley PT, Vanden Hoek TL, Hickey RW, Kloeck WG, Billi J, Bottiger BW, Morley PT, Nolan JP, Okada K, Reyes C, Shuster M, Steen PA, Weil MH, Wenzel V, Hickey RW, Carli P, Vanden Hoek TL, Atkins D, International Liaison Committee on Resuscitation (2003) Therapeutic hypothermia after cardiac arrest: an advisory statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation. Circulation 108:118–121CrossRefGoogle Scholar
- 2.Castrejon S, Cortes M, Salto ML, Benittez LC, Rubio R, Juarez M, Lopez de Sa E, Bueno H, Sanchez PL, Fernandez Aviles F (2009) Improved prognosis after using mild hypothermia to treat cardiorespiratory arrest due to a cardiac cause: comparison with a control group. Rev Esp Cardiol 62:733–741CrossRefGoogle Scholar
- 3.Stub D, Schmicker RH, Anderson ML, Callaway CW, Daya MR, Sayre MR, Elmer J, Grunau BE, Aufderheide TP, Lin S, Buick JE, Zive D, Peterson ED, Nichol G, ROC Investigators (2015) Association between hospital post-resuscitative performance and clinical outcomes after out-of-hospital cardiac arrest. Resuscitation 92:45–52CrossRefGoogle Scholar
- 4.Lopez-de-Sa E, Rey JR, Armada E, Salinas P, Viana-Tejedor A, Espinosa-Garcia S, Martinez-Moreno M, Corral E, Lopez-Sendon J (2012) Hypothermia in comatose survivors from out-of-hospital cardiac arrest: pilot trial comparing two levels of target temperature. Circulation 126:2826–2833CrossRefGoogle Scholar
- 5.Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, Pellis T, Stammet P, Wanscher M, Wise MP, Aneman A, Al-Subaie N, Boesgaard S, Bro-Jeppesen J, Brunetti I, Bugge JF, Hingston CD, Juffermans NP, Koopmans M, Kober L, Langorgen J, Lilja G, Moller JE, Rundgren M, Rylander C, Smid O, Werer C, Winkel P, Friberg H, TTM Trial Investigators (2013) Targeted temperature management at 33 °C versus 36 °C after cardiac arrest. N Engl J Med 369:2197–2206CrossRefGoogle Scholar
- 6.Moler FW, Silverstein FS, Holubkov R, Slomine BS, Christensen JR, Nadkarni VM, Meert KL, Clark AE, Browning B, Pemberton VL, Page K, Shankaran S, Hutchison JS, Newth CJ, Bennett KS, Berger JT, Topjian A, Pineda JA, Koch JD, Schleien CL, Dalton HJ, Ofori-Amanfo G, Goodman DM, Fink EL, McQuillen P, Zimmerman JJ, Thomas NJ, van der Jagt EW, Porter MB, Meyer MT, Harrison R, Pham N, Schwarz AJ, Nowak JE, Alten J, Wheeler DS, Bhalala US, Lidsky K, Lloyd E, Mathur M, Shah S, Wu T, Theodorou AA, Sanders RC Jr, Dean JM, TTM Trial Investigators (2015) Therapeutic hypothermia after out-of-hospital cardiac arrest in children. N Engl J Med 372:1898–1908CrossRefGoogle Scholar
- 11.Kirkegaard H, Soreide E, de Haas I, Pettila V, Taccone FS, Arus U, Storm C, Hassager C, Nielsen JF, Sorensen CA, Ilkjaer S, Jeppesen AN, Grejs AM, Duez CHV, Hjort J, Larsen AI, Toome V, Tiainen M, Hastbacka J, Laitio T, Skrifvars MB (2017) Targeted temperature management for 48 vs 24 h and neurologic outcome after out-of-hospital cardiac arrest: a randomized clinical trial. JAMA 318:341–350CrossRefGoogle Scholar
- 15.Nolan JP, Soar J, Cariou A, Cronberg T, Moulaert VR, Deakin CD, Bottiger BW, Friberg H, Sunde K, Sandroni C (2015) European Resuscitation Council and European Society of Intensive Care Medicine Guidelines for Post-resuscitation Care 2015: Section 5 of the European Resuscitation Council Guidelines for Resuscitation 2015. Resuscitation 95:202–222CrossRefGoogle Scholar
- 16.Dragancea I, Wise MP, Al-Subaie N, Cranshaw J, Friberg H, Glover G, Pellis T, Rylance R, Walden A, Nielsen N, Cronberg T, TTM Trial Investigators (2017) Protocol-driven neurological prognostication and withdrawal of life-sustaining therapy after cardiac arrest and targeted temperature management. Resuscitation 117:50–57CrossRefGoogle Scholar
- 18.Lybeck A, Cronberg T, Aneman A, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, Wanscher M, Stammet P, Wise MP, Nielsen N, Ullen S, Friberg H, TTM Trial Investigators (2018) Time to awakening after cardiac arrest and the association with target temperature management. Resuscitation 126:166–171CrossRefGoogle Scholar
- 20.Dankiewicz J, Nielsen N, Linder A, Kuiper M, Wise MP, Cronberg T, Erlinge D, Gasche Y, Harmon MB, Hassager C, Horn J, Kjaergaard J, Pellis T, Stammet P, Unden J, Wanscher M, Wetterslev J, Aneman A, Ullen S, Juffermans NP, Friberg H, TTM Trial Investigators (2017) Infectious complications after out-of-hospital cardiac arrest—a comparison between two target temperatures. Resuscitation 113:70–76CrossRefGoogle Scholar