Intensive Care Medicine

, Volume 40, Issue 12, pp 1832–1842 | Cite as

Impact of intra-arrest therapeutic hypothermia in outcomes of prehospital cardiac arrest: a randomized controlled trial

  • Guillaume Debaty
  • Maxime Maignan
  • Dominique Savary
  • François-xavier Koch
  • Stéphane Ruckly
  • Michel Durand
  • Julien Picard
  • Christophe Escallier
  • Renaud Chouquer
  • Charles Santre
  • Clemence Minet
  • Dorra Guergour
  • Laure Hammer
  • Hélène Bouvaist
  • Loic Belle
  • Christophe Adrie
  • Jean-François Payen
  • Françoise Carpentier
  • Pierre-Yves Gueugniaud
  • Vincent Danel
  • Jean-François Timsit
Seven-Day Profile Publication

Abstract

Purpose

Mild therapeutic hypothermia (TH) is recommended as soon as possible after the return of spontaneous circulation to improve outcomes after out-of-hospital cardiac arrest (OHCA). Preclinical data suggest that the benefit of TH could be increased if treatment is started during cardiac arrest. We aimed to study the impact of intra-arrest therapeutic hypothermia (IATH) on neurological injury and inflammation following OHCA.

Methods

We conducted a 1:1 randomized, multicenter study in three prehospital emergency medical services and four critical care units in France. OHCA patients, irrespective of the initial rhythm, received either an infusion of cold saline and external cooling during cardiac arrest (IATH group) or TH started after hospital admission (hospital-cooling group). The primary endpoint was neuron-specific enolase (NSE) serum concentrations at 24 h. Secondary endpoints included IL-6, IL-8, and IL-10 concentrations, and clinical outcome.

Results

Of the 245 patients included, 123 were analyzed in the IATH group and 122 in the hospital-cooling group. IATH decreased time to reach temperature ≤34 °C by 75 min (95 % CI: 4; 269). The rate of patients admitted alive to hospital was not different between groups [IATH n = 41 (33 %) vs. hospital cooling n = 36 (30 %); p = 0.51]. Levels of NSE and inflammatory biomarkers were not different between groups [median NSE at 24 h: IATH 96.7 μg/l (IQR: 49.9–142.8) vs. hospital cooling 97.6 μg/l (IQR: 74.3–142.4), p = 0.64]. No difference in survival and cerebral performance were found at 1 month.

Conclusions

IATH did not affect biological markers of inflammation or brain damage or clinical outcome.

Keywords

Therapeutic hypothermia Cardiopulmonary resuscitation Resuscitation Cardiac arrest Post-cardiac arrest syndrome 

Supplementary material

134_2014_3519_MOESM1_ESM.pptx (46 kb)
Figure S1 (electronic supplement): 1-month survival according to initial rhythm. IATH: Intra-arrest therapeutic Hypothermia; VF/VT: Ventricular Fibrillation/Ventricular Tachycardia, PEA: Pulseless electrical activity (PPTX 45 kb)
134_2014_3519_MOESM2_ESM.pdf (5 kb)
Figure S2 (electronic supplement): Probability of Survival. Shown are Kaplan–Meier estimates of the probability of survival for patients assigned to Intra arrest therapeutic hypothermia or hospital cooling group within the first 30 days after randomization. The p value was calculated with logrank analysis. (PDF 5 kb)

References

  1. 1.
    Deakin CD, Nolan JP, Soar J, Sunde K, Koster RW, Smith GB, Perkins GD (2010) European Resuscitation Council Guidelines for Resuscitation 2010 Section 4. Adult advanced life support. Resuscitation 81:1305–1352PubMedCrossRefGoogle Scholar
  2. 2.
    Hypothermia after Cardiac Arrest Study G (2002) Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 346:549–556CrossRefGoogle Scholar
  3. 3.
    Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, Gabrielli A, Silvers SM, Zaritsky AL, Merchant R, Vanden Hoek TL, Kronick SL, American Heart A (2010) Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 122:S768–S786PubMedCrossRefGoogle Scholar
  4. 4.
    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, Investigators TTMT (2013) Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med 369:2197–2206PubMedCrossRefGoogle Scholar
  5. 5.
    Dumas F, Grimaldi D, Zuber B, Fichet J, Charpentier J, Pene F, Vivien B, Varenne O, Carli P, Jouven X, Empana JP, Cariou A (2011) Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients?: insights from a large registry. Circulation 123:877–886PubMedCrossRefGoogle Scholar
  6. 6.
    Bruel C, Parienti JJ, Marie W, Arrot X, Daubin C, Du Cheyron D, Massetti M, Charbonneau P (2008) Mild hypothermia during advanced life support: a preliminary study in out-of-hospital cardiac arrest. Crit Care 12:R31PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Bernard SA, Smith K, Cameron P, Masci K, Taylor DM, Cooper DJ, Kelly AM, Silvester W, Rapid Infusion of Cold Hartmanns I (2010) Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial. Circulation 122:737–742PubMedCrossRefGoogle Scholar
  8. 8.
    Bernard SA, Smith K, Cameron P, Masci K, Taylor DM, Cooper DJ, Kelly AM, Silvester W, Rapid Infusion of Cold Hartmanns I (2012) Induction of prehospital therapeutic hypothermia after resuscitation from nonventricular fibrillation cardiac arrest. Crit Care Med 40:747–753PubMedCrossRefGoogle Scholar
  9. 9.
    Kim F, Nichol G, Maynard C, Hallstrom A, Kudenchuk PJ, Rea T, Copass MK, Carlbom D, Deem S, Longstreth WT Jr, Olsufka M, Cobb LA (2014) Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial. J Am Med Assoc 311:45–52CrossRefGoogle Scholar
  10. 10.
    Abella BS, Zhao D, Alvarado J, Hamann K, Vanden Hoek TL, Becker LB (2004) Intra-arrest cooling improves outcomes in a murine cardiac arrest model. Circulation 109:2786–2791PubMedCrossRefGoogle Scholar
  11. 11.
    Nozari A, Safar P, Stezoski SW, Wu X, Kostelnik S, Radovsky A, Tisherman S, Kochanek PM (2006) Critical time window for intra-arrest cooling with cold saline flush in a dog model of cardiopulmonary resuscitation. Circulation 113:2690–2696PubMedCrossRefGoogle Scholar
  12. 12.
    Zhao D, Abella BS, Beiser DG, Alvarado JP, Wang H, Hamann KJ, Hoek TL, Becker LB (2008) Intra-arrest cooling with delayed reperfusion yields higher survival than earlier normothermic resuscitation in a mouse model of cardiac arrest. Resuscitation 77:242–249PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Wang H, Barbut D, Tsai MS, Sun S, Weil MH, Tang W (2010) Intra-arrest selective brain cooling improves success of resuscitation in a porcine model of prolonged cardiac arrest. Resuscitation 81:617–621PubMedCrossRefGoogle Scholar
  14. 14.
    Darbera L, Chenoune M, Lidouren F, Kohlhauer M, Adam C, Bruneval P, Ghaleh B, Dubois-Randé J-L, Carli P, Vivien B (2013) Hypothermic liquid ventilation prevents early hemodynamic dysfunction and cardiovascular mortality after coronary artery occlusion complicated by cardiac arrest in rabbits. Crit Care Med 41:e457–e465PubMedCrossRefGoogle Scholar
  15. 15.
    Menegazzi JJ, Rittenberger JC, Suffoletto BP, Logue ES, Salcido DD, Reynolds JC, Sherman LD (2009) Effects of pre-arrest and intra-arrest hypothermia on ventricular fibrillation and resuscitation. Resuscitation 80:126–132PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Yannopoulos D, Zviman M, Castro V, Kolandaivelu A, Ranjan R, Wilson RF, Halperin HR (2009) Intra-cardiopulmonary resuscitation hypothermia with and without volume loading in an ischemic model of cardiac arrest. Circulation 120:1426–1435PubMedCrossRefGoogle Scholar
  17. 17.
    Wijdicks EF, Hijdra A, Young GB, Bassetti CL, Wiebe S, Quality Standards Subcommittee of the American Academy of N (2006) Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 67:203–210PubMedCrossRefGoogle Scholar
  18. 18.
    Neumar RW, Nolan JP, Adrie C, Aibiki M, Berg RA, Bottiger BW, Callaway C, Clark RS, Geocadin RG, Jauch EC, Kern KB, Laurent I, Longstreth WT Jr, Merchant RM, Morley P, Morrison LJ, Nadkarni V, Peberdy MA, Rivers EP, Rodriguez-Nunez A, Sellke FW, Spaulding C, Sunde K, Vanden Hoek T (2008) Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation 118:2452–2483PubMedCrossRefGoogle Scholar
  19. 19.
    Adrie C, Adib-Conquy M, Laurent I, Monchi M, Vinsonneau C, Fitting C, Fraisse F, Dinh-Xuan AT, Carli P, Spaulding C, Dhainaut JF, Cavaillon JM (2002) Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome. Circulation 106:562–568PubMedCrossRefGoogle Scholar
  20. 20.
    Calderon LM, Guyette FX, Doshi AA, Callaway CW, Rittenberger JC, Post Cardiac Arrest S (2014) Combining NSE and S100B with clinical examination findings to predict survival after resuscitation from cardiac arrest. Resuscitation 85(8):1025–1029PubMedCrossRefGoogle Scholar
  21. 21.
    Oksanen T, Tiainen M, Skrifvars MB, Varpula T, Kuitunen A, Castren M, Pettila V (2009) Predictive power of serum NSE and OHCA score regarding 6-month neurologic outcome after out-of-hospital ventricular fibrillation and therapeutic hypothermia. Resuscitation 80:165–170PubMedCrossRefGoogle Scholar
  22. 22.
    Tiainen M, Roine RO, Pettila V, Takkunen O (2003) Serum neuron-specific enolase and S-100B protein in cardiac arrest patients treated with hypothermia. Stroke 34:2881–2886PubMedCrossRefGoogle Scholar
  23. 23.
    1991 Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest: the ‘Utstein style’. Prepared by a Task Force of Representatives from the European Resuscitation Council, American Heart Association, Heart and Stroke Foundation of Canada, Australian Resuscitation Council. Resuscitation 22:1–26Google Scholar
  24. 24.
    Gueugniaud PY, David JS, Chanzy E, Hubert H, Dubien PY, Mauriaucourt P, Braganca C, Billeres X, Clotteau-Lambert MP, Fuster P, Thiercelin D, Debaty G, Ricard-Hibon A, Roux P, Espesson C, Querellou E, Ducros L, Ecollan P, Halbout L, Savary D, Guillaumee F, Maupoint R, Capelle P, Bracq C, Dreyfus P, Nouguier P, Gache A, Meurisse C, Boulanger B, Lae C, Metzger J, Raphael V, Beruben A, Wenzel V, Guinhouya C, Vilhelm C, Marret E (2008) Vasopressin and epinephrine vs. epinephrine alone in cardiopulmonary resuscitation. N Engl J Med 359:21–30PubMedCrossRefGoogle Scholar
  25. 25.
    Vesin A, Azoulay E, Ruckly S, Vignoud L, Rusinovà K, Benoit D, Soares M, Azeivedo-Maia P, Abroug F, Benbenishty J, Timsit JF (2013) Reporting and handling missing values in clinical studies in intensive care units. Intensive Care Med 39:1396–1404PubMedCrossRefGoogle Scholar
  26. 26.
    Raghunathan TE, Lepkowski JM, Van Hoewyk J, Solenberger P (2001) A multivariate technique for multiply imputing missing values using a sequence of regression models. Survey Methodol 27:85–96Google Scholar
  27. 27.
    Neumar RW, Otto CW, Link MS, Kronick SL, Shuster M, Callaway CW, Kudenchuk PJ, Ornato JP, McNally B, Silvers SM, Passman RS, White RD, Hess EP, Tang W, Davis D, Sinz E, Morrison LJ (2010) Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 122:S729–S767PubMedCrossRefGoogle Scholar
  28. 28.
    Castren M, Nordberg P, Svensson L, Taccone F, Vincent JL, Desruelles D, Eichwede F, Mols P, Schwab T, Vergnion M, Storm C, Pesenti A, Pachl J, Guerisse F, Elste T, Roessler M, Fritz H, Durnez P, Busch HJ, Inderbitzen B, Barbut D (2010) Intra-arrest transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness). Circulation 122:729–736PubMedCrossRefGoogle Scholar
  29. 29.
    Rundgren M, Karlsson T, Nielsen N, Cronberg T, Johnsson P, Friberg H (2009) Neuron specific enolase and S-100B as predictors of outcome after cardiac arrest and induced hypothermia. Resuscitation 80:784–789PubMedCrossRefGoogle Scholar
  30. 30.
    Cunningham RT, Young IS, Winder J, O’Kane MJ, McKinstry S, Johnston CF, Dolan OM, Hawkins SA, Buchanan KD (1991) Serum neurone specific enolase (NSE) levels as an indicator of neuronal damage in patients with cerebral infarction. Eur J Clin Invest 21:497–500PubMedCrossRefGoogle Scholar
  31. 31.
    Skogseid IM, Nordby HK, Urdal P, Paus E, Lilleaas F (1992) Increased serum creatine kinase BB and neuron specific enolase following head injury indicates brain damage. Acta Neurochir (Wien) 115:106–111CrossRefGoogle Scholar
  32. 32.
    Martens P, Raabe A, Johnsson P (1998) Serum S-100 and neuron-specific enolase for prediction of regaining consciousness after global cerebral ischemia. Stroke 29:2363–2366PubMedCrossRefGoogle Scholar
  33. 33.
    Meynaar IA, Oudemans-van Straaten HM, van der Wetering J, Verlooy P, Slaats EH, Bosman RJ, van der Spoel JI, Zandstra DF (2003) Serum neuron-specific enolase predicts outcome in post-anoxic coma: a prospective cohort study. Intensive Care Med 29:189–195PubMedGoogle Scholar
  34. 34.
    Rosen H, Sunnerhagen KS, Herlitz J, Blomstrand C, Rosengren L (2001) Serum levels of the brain-derived proteins S-100 and NSE predict long-term outcome after cardiac arrest. Resuscitation 49:183–191PubMedCrossRefGoogle Scholar
  35. 35.
    Schoerkhuber W, Kittler H, Sterz F, Behringer W, Holzer M, Frossard M, Spitzauer S, Laggner AN (1999) Time course of serum neuron-specific enolase. A predictor of neurological outcome in patients resuscitated from cardiac arrest. Stroke 30:1598–1603PubMedCrossRefGoogle Scholar
  36. 36.
    Huntgeburth M, Adler C, Rosenkranz S, Zobel C, Haupt WF, Dohmen C, Reuter H (2014) Changes in neuron-specific enolase are more suitable than its absolute serum levels for the prediction of neurologic outcome in hypothermia-treated patients with out-of-hospital cardiac arrest. Neurocrit Care 20:358–366PubMedCrossRefGoogle Scholar
  37. 37.
    Deasy C, Bernard S, Cameron P (2011) Design of the RINSE trial: the rapid infusion of cold normal saline by paramedics during CPR. BMC Emerg Med 11:17Google Scholar
  38. 38.
    Polderman KH, Herold I (2009) Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods. Crit Care Med 37:1101–1120PubMedCrossRefGoogle Scholar
  39. 39.
    Annborn M, Bro-Jeppesen J, Nielsen N, Ullén S, Kjaergaard J, Hassager C, Wanscher M, Hovdenes J, Pellis T, Pelosi P, Wise MP, Cronberg T, Erlinge D, Friberg H (2014) The association of targeted temperature management at 33 and 36 °C with outcome in patients with moderate shock on admission after out-of-hospital cardiac arrest: a post hoc analysis of the target temperature management trial. Intensive Care Med 40:1210–1219Google Scholar
  40. 40.
    Merchant RM, Abella BS, Peberdy MA, Soar J, Ong ME, Schmidt GA, Becker LB, Vanden Hoek TL (2006) Therapeutic hypothermia after cardiac arrest: unintentional overcooling is common using ice packs and conventional cooling blankets. Crit Care Med 34:S490–S494PubMedCrossRefGoogle Scholar
  41. 41.
    Srinivasan V, Nadkarni VM, Yannopoulos D, Marino BS, Sigurdsson G, McKnite SH, Zook M, Benditt DG, Lurie KG (2006) Rapid induction of cerebral hypothermia is enhanced with active compression-decompression plus inspiratory impedance threshold device cardiopulmonary resusitation in a porcine model of cardiac arrest. J Am Coll Cardiol 47:835–841PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2014

Authors and Affiliations

  • Guillaume Debaty
    • 1
    • 2
  • Maxime Maignan
    • 1
    • 2
  • Dominique Savary
    • 3
  • François-xavier Koch
    • 2
  • Stéphane Ruckly
    • 4
    • 12
  • Michel Durand
    • 5
  • Julien Picard
    • 5
  • Christophe Escallier
    • 2
  • Renaud Chouquer
    • 6
  • Charles Santre
    • 6
  • Clemence Minet
    • 7
  • Dorra Guergour
    • 8
  • Laure Hammer
    • 7
  • Hélène Bouvaist
    • 9
  • Loic Belle
    • 10
  • Christophe Adrie
    • 11
  • Jean-François Payen
    • 5
  • Françoise Carpentier
    • 2
  • Pierre-Yves Gueugniaud
    • 12
  • Vincent Danel
    • 2
  • Jean-François Timsit
    • 4
    • 13
  1. 1.UJF-Grenoble 1/CNRS/TIMC-IMAG UMR 5525/Team PRETAGrenobleFrance
  2. 2.SAMU 38, Pôle Urgences-Médecine AiguëCHU GrenobleGrenoble Cedex 09France
  3. 3.Department of Emergency Medicine, SAMU 74Annecy HospitalAnnecyFrance
  4. 4.University Joseph Fourrier, Albert Bonniot InstituteLa Tronche CedexFrance
  5. 5.Department of Anesthesiology and Critical CareGrenoble University HospitalGrenobleFrance
  6. 6.Department of Anesthesiology and Critical CareAnnecy HospitalAnnecyFrance
  7. 7.Department of Intensive Care MedicineGrenoble University HospitalGrenobleFrance
  8. 8.Department of Biochemistry Toxicology PharmacologyGrenoble University HospitalGrenobleFrance
  9. 9.Department of CardiologyGrenoble University HospitalGrenobleFrance
  10. 10.Department of CardiologyAnnecy HospitalAnnecyFrance
  11. 11.Physiology DepartmentCochin Hospital, ICUParisFrance
  12. 12.SAMU 69, Hospices Civils de LyonUniversity of Lyon 1LyonFrance
  13. 13.UMR 1137-IAME Team 5-(DeSCID) Decision Sciences in Infectious Diseases, Control and Care, Inserm/Univ Paris DiderotParisFrance

Personalised recommendations