INTRODUCTION: Mild therapeutic hypothermia (MTH) is being used after cardiac arrest for its expected improvement in neurological outcome. Safety of MTH concerning inducibility of malignant arrhythmias has not been satisfactorily demonstrated. This study compares inducibility of ventricular fibrillation (VF) before and after induction of MTH in a whole body swine model and evaluates possible interaction with changing potassium plasma levels. METHODS: The extracorporeal cooling was introduced in fully anesthetized swine (n = 6) to provide MTH. Inducibility of VF was studied by programmed ventricular stimulation three times in each animal under the following: during normothermia (NT), after reaching the core temperature of 32°C (HT) and after another 60 minutes of stable hypothermia (HT60). Inducibility of VF, effective refractory period of the ventricles (ERP), QTc interval and potassium plasma levels were measured. RESULTS: Starting at normothermia of 38.7 (IQR 38.2; 39.8)°C, HT was achieved within 54 (39; 59) minutes and the core temperature was further maintained constant. Overall, the inducibility of VF was 100% (18/18 attempts) at NT, 83% (15/18) after reaching HT (P = 0.23) and 39% (7/18) at HT60 (P = 0.0001) using the same protocol. Similarly, ERP prolonged from 140 (130; 150) ms at NT to 206 (190; 220) ms when reaching HT (P < 0.001) and remained 206 (193; 220) ms at HT60. QTc interval was inversely proportional to the core temperature and extended from 376 (362; 395) at NT to 570 (545; 599) ms at HT. Potassium plasma level changed spontaneously: decreased during cooling from 4.1 (3.9; 4.8) to 3.7 (3.4; 4.1) mmol/L at HT (P < 0.01), then began to increase and returned to baseline level at HT60 (4.6 (4.4; 5.0) mmol/L, P = NS). CONCLUSIONS: According to our swine model, MTH does not increase the risk of VF induction by ventricular pacing in healthy hearts. Moreover, when combined with normokalemia, MTH exerts an antiarrhythmic effect despite prolonged QTc interval.

2nd Department of Medicine 1st Faculty of Medicine Charles University Prague and General University Hospital U Nemocnice 2 Prague 2 128 00 Czech Republic

2nd Department of Surgery Cardiovascular Surgery 1st Faculty of Medicine Charles University Prague and General University Hospital U Nemocnice 2 Prague 2 128 00 Czech Republic

3rd Department of Medicine 1st Faculty of Medicine Charles University Prague and General University Hospital U Nemocnice 2 Prague 2 128 00 Czech Republic

Department of Cardiology Na Homolce Hospital Roentgenova 2 37 Prague 5 150 30 Czech Republic

Department of Physiology 1st Faculty of Medicine Charles University Prague Albertov 5 Prague 2 128 00 Czech Republic

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Hypothermia after Cardiac Arrest Study G Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549–56. doi: 10.1056/NEJMoa012689. PubMed DOI

Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557–63. doi: 10.1056/NEJMoa003289. PubMed DOI

Belliard G, Catez E, Charron C, Caille V, Aegerter P, Dubourg O, et al. Efficacy of therapeutic hypothermia after out-of-hospital cardiac arrest due to ventricular fibrillation. Resuscitation. 2007;75:252–9. doi: 10.1016/j.resuscitation.2007.04.014. PubMed DOI

Castrejon S, Cortes M, Salto ML, Benittez LC, Rubio R, Juarez M, et al. Improved prognosis after using mild hypothermia to treat cardiorespiratory arrest due to a cardiac cause: comparison with a control group. Rev Esp Cardiol. 2009;62:733–41. doi: 10.1016/S0300-8932(09)71686-0. PubMed DOI

Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, et al. Part 9: post-cardiac arrest care, American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;2010(122):S768–86. doi: 10.1161/CIRCULATIONAHA.110.971002. PubMed DOI

Holzer M, Mullner M, Sterz F, Robak O, Kliegel A, Losert H, et al. Efficacy and safety of endovascular cooling after cardiac arrest: cohort study and Bayesian approach. Stroke. 2006;37:1792–7. doi: 10.1161/01.STR.0000227265.52763.16. PubMed DOI

Arrich J, European Resuscitation Council Hypothermia After Cardiac Arrest Registry Study G Clinical application of mild therapeutic hypothermia after cardiac arrest. Crit Care Med. 2007;35:1041–7. doi: 10.1097/01.CCM.0000259383.48324.35. PubMed DOI

Deakin CD, Nolan JP, Soar J, Sunde K, Koster RW, Smith GB, et al. European Resuscitation Council Guidelines for Resuscitation 2010 Section 4. Adult advanced life support. Resuscitation. 2010;81:1305–52. doi: 10.1016/j.resuscitation.2010.08.017. PubMed DOI

Lampe JW, Becker LB. State of the art in therapeutic hypothermia. Annu Rev Med. 2011;62:79–93. doi: 10.1146/annurev-med-052009-150512. PubMed DOI PMC

Abella BS, Zhao D, Alvarado J, Hamann K, Vanden Hoek TL, Becker LB. Intra-arrest cooling improves outcomes in a murine cardiac arrest model. Circulation. 2004;109:2786–91. doi: 10.1161/01.CIR.0000131940.19833.85. PubMed DOI

Kuboyama K, Safar P, Radovsky A, Tisherman SA, Stezoski SW, Alexander H. Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study. Crit Care Med. 1993;21:1348–58. doi: 10.1097/00003246-199309000-00019. PubMed DOI

Takata K, Takeda Y, Sato T, Nakatsuka H, Yokoyama M, Morita K. Effects of hypothermia for a short period on histologic outcome and extracellular glutamate concentration during and after cardiac arrest in rats. Crit Care Med. 2005;33:1340–5. doi: 10.1097/01.CCM.0000166351.19369.D3. PubMed DOI

Ostadal P, Mlcek M, Kruger A, Horakova S, Skabradova M, Holy F, et al. Mild therapeutic hypothermia is superior to controlled normothermia for the maintenance of blood pressure and cerebral oxygenation, prevention of organ damage and suppression of oxidative stress after cardiac arrest in a porcine model. J Transl Med. 2013;11:124. doi: 10.1186/1479-5876-11-124. PubMed DOI PMC

Wolff B, Machill K, Schumacher D, Schulzki I, Werner D. Early achievement of mild therapeutic hypothermia and the neurologic outcome after cardiac arrest. Int J Cardiol. 2009;133:223–8. doi: 10.1016/j.ijcard.2007.12.039. PubMed DOI

Nielsen N, Hovdenes J, Nilsson F, Rubertsson S, Stammet P, Sunde K, et al. Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand. 2009;53:926–34. doi: 10.1111/j.1399-6576.2009.02021.x. PubMed DOI

Kim F, Nichol G, Maynard C, Hallstrom A, Kudenchuk PJ, Rea T, et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial. JAMA. 2014;311:45–52. doi: 10.1001/jama.2013.282173. PubMed DOI

Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, et al. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med. 2013;369:2197–206. doi: 10.1056/NEJMoa1310519. PubMed DOI

Belohlavek J, Kucera K, Jarkovsky J, Franek O, Pokorna M, Danda J, et al. Hyperinvasive approach to out-of hospital cardiac arrest using mechanical chest compression device, prehospital intraarrest cooling, extracorporeal life support and early invasive assessment compared to standard of care. A randomized parallel groups comparative study proposal. "Prague OHCA study". J Transl Med. 2012;10:163. doi: 10.1186/1479-5876-10-163. PubMed DOI PMC

Busch HJ, Eichwede F, Fodisch M, Taccone FS, Wobker G, Schwab T, et al. Safety and feasibility of nasopharyngeal evaporative cooling in the emergency department setting in survivors of cardiac arrest. Resuscitation. 2010;81:943–9. doi: 10.1016/j.resuscitation.2010.04.027. PubMed DOI

Castren M, Nordberg P, Svensson L, Taccone F, Vincent JL, Desruelles D, et al. Intra-arrest transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness) Circulation. 2010;122:729–36. doi: 10.1161/CIRCULATIONAHA.109.931691. PubMed DOI

Testori C, Holzer M, Sterz F, Stratil P, Hartner Z, Moscato F, et al. Rapid induction of mild therapeutic hypothermia by extracorporeal veno-venous blood cooling in humans. Resuscitation. 2013;84:1051–5. doi: 10.1016/j.resuscitation.2013.03.013. PubMed DOI

Sharma A, Weerwind P, Ganushchak Y, Donker D, Maessen J: Towards a proactive therapy utilizing the modern spectrum of extracorporeal life support: a single-centre experience. Perfusion 2014. 0267659114530455 (Epud ahead of print) PubMed

Koht A, Cane R, Cerullo LJ. Serum potassium levels during prolonged hypothermia. Intensive Care Med. 1983;9:275–7. doi: 10.1007/BF01691254. PubMed DOI

Soeholm H, Kirkegaard H. Serum Potassium Changes During Therapeutic Hypothermia After Out-of-Hospital Cardiac Arrest-Should It Be Treated? Ther Hypothermia Temperature Manage. 2012;2:30–6. doi: 10.1089/ther.2012.0004. PubMed DOI

Mirzoyev SA, McLeod CJ, Bunch TJ, Bell MR, White RD. Hypokalemia during the cooling phase of therapeutic hypothermia and its impact on arrhythmogenesis. Resuscitation. 2010;81:1632–6. doi: 10.1016/j.resuscitation.2010.08.007. PubMed DOI

Lebiedz P, Meiners J, Samol A, Wasmer K, Reinecke H, Waltenberger J, et al. Electrocardiographic changes during therapeutic hypothermia. Resuscitation. 2012;83:602–6. doi: 10.1016/j.resuscitation.2011.11.016. PubMed DOI

Khan JN, Prasad N, Glancy JM. QTc prolongation during therapeutic hypothermia: are we giving it the attention it deserves? Europace. 2010;12:266–70. doi: 10.1093/europace/eup376. PubMed DOI

Kelly P, Ruskin JN, Vlahakes GJ, Buckley MJ, Jr, Freeman CS, Garan H. Surgical coronary revascularization in survivors of prehospital cardiac arrest: its effect on inducible ventricular arrhythmias and long-term survival. J Am Coll Cardiol. 1990;15:267–73. doi: 10.1016/S0735-1097(10)80046-4. PubMed DOI

Reinelt P, Karth GD, Geppert A, Heinz G. Incidence and type of cardiac arrhythmias in critically ill patients: a single center experience in a medical-cardiological ICU. Intensive Care Med. 2001;27:1466–73. doi: 10.1007/s001340101043. PubMed DOI

McGlone JJ, Swanson J. Update on the Guide for the Care and Use of Agricultural Animals in Research and Teaching. J Dairy Sci. 2010;93:12. doi: 10.3168/jds.2009-2244. PubMed DOI

Sprung J, Cheng EY, Gamulin S, Kampine JP, Bosnjak ZJ. Effects of acute hypothermia and beta-adrenergic receptor blockade on serum potassium concentration in rats. Crit Care Med. 1991;19:1545–51. doi: 10.1097/00003246-199112000-00018. PubMed DOI

Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med. 2009;37:S186–202. doi: 10.1097/CCM.0b013e3181aa5241. PubMed DOI

Polderman KH, Peerdeman SM, Girbes AR. Hypophosphatemia and hypomagnesemia induced by cooling in patients with severe head injury. J Neurosurg. 2001;94:697–705. doi: 10.3171/jns.2001.94.5.0697. PubMed DOI

van der Linde HJ, Van Deuren B, Teisman A, Towart R, Gallacher DJ. The effect of changes in core body temperature on the QT interval in beagle dogs: a previously ignored phenomenon, with a method for correction. Br J Pharmacol. 2008;154:1474–81. doi: 10.1038/bjp.2008.265. PubMed DOI PMC

Lasky RE, Parikh NA, Williams AL, Padhye NS, Shankaran S. Changes in the PQRST intervals and heart rate variability associated with rewarming in two newborns undergoing hypothermia therapy. Neonatology. 2009;96:93–5. doi: 10.1159/000205385. PubMed DOI PMC

Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med. 2002;112:58–66. doi: 10.1016/S0002-9343(01)01011-7. PubMed DOI

Tiainen M, Parikka HJ, Makijarvi MA, Takkunen OS, Sarna SJ, Roine RO. Arrhythmias and heart rate variability during and after therapeutic hypothermia for cardiac arrest. Crit Care Med. 2009;37:403–9. doi: 10.1097/CCM.0b013e31819572c4. PubMed DOI

Storm C, Hasper D, Nee J, Joerres A, Schefold JC, Kaufmann J, et al. Severe QTc prolongation under mild hypothermia treatment and incidence of arrhythmias after cardiac arrest–a prospective study in 34 survivors with continuous Holter ECG. Resuscitation. 2011;82:859–62. doi: 10.1016/j.resuscitation.2011.02.043. PubMed DOI

Sykora R, Janda R. [Therapeutic hypothermia after non-traumatic cardiac arrest for 12 hours: Hospital Karlovy vary from 2006 to 2009] Vnitr Lek. 2011;57:72–7. PubMed

Riaz A, Hieb H, Foley B, Mulvihill N, Crean P, Murphy RT, et al. Safety of therapeutic hypothermia in post VF/VT cardiac arrest patients. Ir Med J. 2013;106:55–6. PubMed

Nishiyama N, Sato T, Aizawa Y, Nakagawa S, Kanki H. Extreme QT prolongation during therapeutic hypothermia after cardiac arrest due to long QT syndrome. Am J Emerg Med. 2012;30:638. PubMed

Schwarzl M, Steendijk P, Huber S, Truschnig-Wilders M, Obermayer-Pietsch B, Maechler H, et al. The induction of mild hypothermia improves systolic function of the resuscitated porcine heart at no further sympathetic activation. Acta physiologica. 2011;203:409–18. doi: 10.1111/j.1748-1716.2011.02332.x. PubMed DOI

Lubanda JC, Kudlicka J, Mlcek M, Chochola M, Neuzil P, Linhart A, et al. Renal denervation decreases effective refractory period but not inducibility of ventricular fibrillation in a healthy porcine biomodel: a case control study. J Transl Med. 2015;13:4. doi: 10.1186/s12967-014-0367-y. PubMed DOI PMC

Chorro FJ, Guerrero J, Ferrero A, Tormos A, Mainar L, Millet J, et al. Effects of acute reduction of temperature on ventricular fibrillation activation patterns. Am J Physiol Heart Circ Physiol. 2002;283:H2331–40. PubMed

Harada M, Honjo H, Yamazaki M, Nakagawa H, Ishiguro YS, Okuno Y, et al. Moderate hypothermia increases the chance of spiral wave collision in favor of self-termination of ventricular tachycardia/fibrillation. Am J Physiol Heart Circ Physiol. 2008;294:H1896–905. doi: 10.1152/ajpheart.00986.2007. PubMed DOI

Belohlavek J, Mlcek M, Huptych M, Svoboda T, Havranek S, Ost’adal P, et al. Coronary versus carotid blood flow and coronary perfusion pressure in a pig model of prolonged cardiac arrest treated by different modes of venoarterial ECMO and intraaortic balloon counterpulsation. Crit Care. 2012;16:R50. doi: 10.1186/cc11254. PubMed DOI PMC

Havranek S, Belohlavek J, Mlcek M, Huptych M, Boucek T, Svoboda T, et al. Median frequencies of prolonged ventricular fibrillation treated by V-A ECMO correspond to a return of spontaneous circulation rate. Int J Artif Organs. 2014;1:48–57. doi: 10.5301/ijao.5000291. PubMed DOI

Menegazzi JJ, Salcido DD, Housler GJ, Logue ES. Feasibility of initiating extracorporeal life support during mechanical chest compression CPR: a porcine pilot study. Resuscitation. 2012;83:130–3. doi: 10.1016/j.resuscitation.2011.07.030. PubMed DOI PMC

Ten years of our translational research in the field of veno-arterial extracorporeal membrane oxygenation

Microcirculatory blood flow during cardiac arrest and cardiopulmonary resuscitation does not correlate with global hemodynamics: an experimental study