Advertisement

Intensive Care Medicine

, Volume 44, Issue 11, pp 1807–1815 | Cite as

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

  • Esteban Lopez-de-SaEmail author
  • Miriam Juarez
  • Eduardo Armada
  • José C. Sanchez-Salado
  • Pedro L. Sanchez
  • Pablo Loma-Osorio
  • Alessandro Sionis
  • Maria C. Monedero
  • Manuel Martinez-Sellés
  • Juán C. Martín-Benitez
  • Albert Ariza
  • Aitor Uribarri
  • José M. Garcia-Acuña
  • Patricia Villa
  • Pablo J. Perez
  • Christian Storm
  • Anne Dee
  • Jose L. Lopez-Sendon
Original

Abstract

Purpose

To obtain initial data on the effect of different levels of targeted temperature management (TTM) in out-of-hospital cardiac arrest (OHCA).

Methods

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.

Results

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.

Conclusions

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).

Keywords

Brain injury Cardiac arrest Post-cardiac arrest syndrome Resuscitation Sudden death Targeted temperature management 

Notes

Funding source

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.

Supplementary material

134_2018_5256_MOESM1_ESM.doc (746 kb)
Supplementary material 1 (DOC 745 kb)

References

  1. 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. 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. 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. 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. 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. 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
  7. 7.
    Langhelle A, Nolan J, Herlitz J, Castren M, Wenzel V, Soreide E, Engdahl J, Steen PA, 2003 Utstein Consensus Symposium (2005) Recommended guidelines for reviewing, reporting, and conducting research on post-resuscitation care: the Utstein style. Resuscitation 66:271–283CrossRefGoogle Scholar
  8. 8.
    Quinn TJ, Dawson J, Walters MR, Lees KR (2009) Functional outcome measures in contemporary stroke trials. Int J Stroke 4:200–205CrossRefGoogle Scholar
  9. 9.
    Jennett B, Bond M (1975) Assessment of outcome after severe brain damage. Lancet 1:480–484CrossRefGoogle Scholar
  10. 10.
    Nolan JP, Berg RA, Bernard S, Bobrow BJ, Callaway CW, Cronberg T, Koster RW, Kudenchuk PJ, Nichol G, Perkins GD, Rea TD, Sandroni C, Soar J, Sunde K, Cariou A (2017) Intensive care medicine research agenda on cardiac arrest. Intensive Care Med 43:1282–1293CrossRefGoogle Scholar
  11. 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
  12. 12.
    Laver S, Farrow C, Turner D, Nolan J (2004) Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med 30:2126–2128CrossRefGoogle Scholar
  13. 13.
    Weinrauch V, Safar P, Tisherman S, Kuboyama K, Radovsky A (1992) Beneficial effect of mild hypothermia and detrimental effect of deep hypothermia after cardiac arrest in dogs. Stroke 23:1454–1462CrossRefGoogle Scholar
  14. 14.
    Leonov Y, Sterz F, Safar P, Radovsky A (1990) Moderate hypothermia after cardiac arrest of 17 min in dogs. Effect on cerebral and cardiac outcome. Stroke 21:1600–1606CrossRefGoogle Scholar
  15. 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. 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
  17. 17.
    Ponz I, Lopez-de-Sa E, Armada E, Caro J, Blazquez Z, Rosillo S, Gonzalez O, Rey JR, Monedero Mdel C, Lopez-Sendon JL (2016) Influence of the temperature on the moment of awakening in patients treated with therapeutic hypothermia after cardiac arrest. Resuscitation 103:32–36CrossRefGoogle Scholar
  18. 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
  19. 19.
    Paul M, Bougouin W, Geri G, Dumas F, Champigneulle B, Legriel S, Charpentier J, Mira JP, Sandroni C, Cariou A (2016) Delayed awakening after cardiac arrest: prevalence and risk factors in the Parisian registry. Intensive Care Med 42:1128–1136CrossRefGoogle Scholar
  20. 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
  21. 21.
    Salinas P, Lopez-de-Sa E, Pena-Conde L, Viana-Tejedor A, Rey-Blas JR, Armada E, Lopez-Sendon JL (2015) Electrocardiographic changes during induced therapeutic hypothermia in comatose survivors after cardiac arrest. World J Cardiol 7:423–430CrossRefGoogle Scholar
  22. 22.
    Staer-Jensen H, Sunde K, Olasveengen TM, Jacobsen D, Draegni T, Nakstad ER, Eritsland J, Andersen GO (2014) Bradycardia during therapeutic hypothermia is associated with good neurologic outcome in comatose survivors of out-of-hospital cardiac arrest. Crit Care Med 42:2401–2408CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature and ESICM 2018

Authors and Affiliations

  • Esteban Lopez-de-Sa
    • 1
    Email author
  • Miriam Juarez
    • 2
  • Eduardo Armada
    • 1
  • José C. Sanchez-Salado
    • 3
  • Pedro L. Sanchez
    • 4
  • Pablo Loma-Osorio
    • 5
  • Alessandro Sionis
    • 6
  • Maria C. Monedero
    • 1
  • Manuel Martinez-Sellés
    • 2
    • 7
  • Juán C. Martín-Benitez
    • 8
  • Albert Ariza
    • 3
  • Aitor Uribarri
    • 4
  • José M. Garcia-Acuña
    • 9
  • Patricia Villa
    • 10
  • Pablo J. Perez
    • 11
  • Christian Storm
    • 12
  • Anne Dee
    • 13
  • Jose L. Lopez-Sendon
    • 1
  1. 1.Acute Cardiac Care Unit, Cardiology DepartmentHospital Universitario La Paz, IdiPaz. CIBERCVMadridSpain
  2. 2.Cardiology DepartmentHospital Universitario Gregorio Marañón. CIBERCVMadridSpain
  3. 3.Cardiology DepartmentHospital Universitario de BellvitgeBarcelonaSpain
  4. 4.Cardiology DepartmentHospital Universitario de SalamancaSalamancaSpain
  5. 5.Cardiology DepartmentHospital Universitario Josep TruetaGironaSpain
  6. 6.Intensive Cardiac Care Unit, Cardiology DepartmentHospital de Sant Pau. IIB-Sant Pau. CIBERCV, Universitat Autònoma de BarcelonaBarcelonaSpain
  7. 7.Universidad Complutense, Avenida Séneca 2, Universidad EuropeaMadridSpain
  8. 8.Intensive Care DepartmentHospital Clínico San CarlosMadridSpain
  9. 9.Cardiology DepartmentComplejo Hospitalario Universitario de Santiago. CIBERCVLa CoruñaSpain
  10. 10.Intensive Care DepartmentHospital Universitario Principe de AsturiasMadridSpain
  11. 11.Cardiology DepartmentHospital Universitario de CanariasSanta Cruz de TenerifeSpain
  12. 12.Department of Internal Medicine, Nephrology and Intensive CareCharité-UniversitätsmedizinBerlinGermany
  13. 13.Biostatistics DepartmentZOLL Medical CorporationSan JoseUSA

Personalised recommendations