Clinical Review
Targeted temperature management after out-of-hospital cardiac arrest Who, when, why, and how? Brian E. Grunau
MD
Jim Christenson
MD
Steven C. Brooks
MD MHSc
Abstract Objective To provide a succinct review of the evidence, framed for the emergency department clinician, for the application of targeted temperature management (TTM) for patients after out-of-hospital cardiac arrest (OHCA). Sources of information MEDLINE, EMBASE, and the Cochrane database were searched for prospective and retrospective studies relevant to the indications of TTM, optimal timing of TTM initiation, method of cooling, and target temperature.
Editor’s key points • Although targeted temperature management (TTM) is a widely recommended therapy for patients after out-of-hospital cardiac arrest (OHCA), many questions remain regarding the patient populations who would benefit from this therapy, as well as the optimal time to initiate therapy, method of cooling, and goal temperature. • Current evidence indicates that TTM within a comprehensive protocol for resuscitated patients after OHCA, compared with usual care, is a beneficial intervention for patients who are not responsive to verbal commands after OHCA. • An organized protocol for resuscitated patients after OHCA including the use of TTM with a goal temperature of 32°C to 36°C should be implemented in all OHCA patients upon arrival to the ED, followed by timely transfer to a critical care environment.
POINTS DE REPÈRE DU RÉDACTEUR
• Bien que la gestion ciblée de la température (GCT) soit un traitement communément recommandé pour les patients ayant subi un arrêt cardiaque hors de l’hôpital (ACHH), de nombreuses questions demeurent quant aux populations de patients qui en bénéficieraient, au moment optimal pour amorcer le traitement, aux méthodes de refroidissement et aux valeurs de température ciblées. • Les données probantes actuelles indiquent que, comparativement aux soins habituels, la GCT suivant un protocole complet pour les patients réanimés ayant subi un arrêt cardiaque hors de l’hôpital est une intervention bénéfique lorsque ces derniers ne réagissent pas aux commandes verbales après un ACHH. • Un protocole structuré pour les patients réanimés après un ACHH, incluant l’utilisation de la GCT visant des valeurs de de 32 °C à 36 °C, devrait être mis en œuvre pour tous les patients dès leur arrivée à l’urgence, suivi d’un transfert aux soins intensifs en temps opportun. This article has been peer reviewed. Cet article a fait l’objet d’une révision par des pairs. Can Fam Physician 2015;61:129-34
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Main message Two prospective interventional trials reported improved neurologically intact survival with the use of TTM (goal temperatures of 32°C to 34°C) compared with no temperature management in comatose OHCA patients with shockable initial cardiac arrest rhythms. A more recent, high-quality randomized controlled trial including OHCA patients with shockable and nonshockable initial rhythms compared TTM at 33°C versus TTM at 36°C. Despite the study being well powered, superiority of one target temperature over the other was not demonstrated. The benefit of TTM in patients with initial nonshockable rhythms is not clear; h o w e v e r, s o m e o b s e r v a t i o n a l studies have suggested benefit. There is no evidence that any particular method of temperature regulation is superior. The relationship between time and TTM initiation has not been well established. Conclusion Targeted temperature management, with a target temperature between 32°C and 36°C, as a component of comprehensive critical care is a beneficial intervention for comatose patients with return of spontaneous circulation after OHCA.
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Clinical Review | Targeted temperature management after out-of-hospital cardiac arrest
Gestion ciblée de la température après un arrêt cardiaque hors de l’hôpital Qui, quand, pourquoi et comment? Résumé O b j e c t i f Présenter une synthèse des données probantes, élaborée à l’intention des cliniciens des services d’urgence, en ce qui concerne les mesures de gestion ciblée de la température (GCT) chez les patients ayant subi un arrêt cardiaque hors de l’hôpital (ACHH). Sources des données On a effectué une recherche dans MEDLINE, EMBASE et la base de données Cochrane pour trouver des études prospectives et rétrospectives concernant les indications de la GCT, le moment optimal pour amorcer la GCT, les méthodes de refroidissement et les valeurs de température ciblées. Message principal Dans deux études interventionnelles prospectives, on a signalé une amélioration du taux de survie sans lésion neurologique avec l’utilisation de la GCT (températures ciblées de 32 °C à 34 °C) comparativement à celui des patients comateux victimes d’un ACHH et présentant des rythmes initiaux à l’arrêt cardiaque justifiant une défibrillation dont la température n’avait pas été prise en charge. Plus récemment, une étude randomisée contrôlée de grande qualité portant sur des patients victimes d’un ACHH et présentant des rythmes initiaux justifiant ou non une défibrillation comparait la GCT à 33 °C à la GCT à 36 °C. Bien que l’étude ait été bien menée, elle n’a pas démontré la supériorité de l’une ou l’autre des températures ciblées. Les avantages de la GCT chez les patients présentant des rythmes initiaux ne justifiant pas une défibrillation ne sont pas clairs même si, dans certaines études observationnelles, on a fait valoir certains bienfaits. Il n’y a pas de données probantes établissant qu’une méthode particulière de régulation de la température soit supérieure à une autre. Le moment opportun d’amorcer la GCT n’a pas été bien établi. Conclusion La gestion ciblée de la température, visant des valeurs entre 32 °C et 36 °C, en tant que composante des soins intensifs complets est une intervention bénéfique pour les patients comateux qui ont eu un rétablissement de la circulation spontanée après un ACHH.
C
ardiac arrest affects approximately 40 000 victims per year in Canada1 and is associated with low rates of survival to hospital discharge.2,3 Targeted temperature management (TTM) has been used for patients after out-of-hospital cardiac arrest (OHCA)
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with the objective of improving neurologic outcomes and lowering rates of mortality. In spite of numerous studies examining the use of TTM, questions remain in terms of the patient populations who would benefit from this therapy, as well as the optimal time to initiate therapy, method of cooling, and goal temperature. In light of this, we sought to provide a succinct review of the evidence related to TTM, framed for the emergency department (ED) clinician, for resuscitated patients after OHCA.
Case description A 55-year-old patient arrived at a 10-bed rural ED with emergency medical services (EMS). His wife heard him fall to the ground at home and when she found him unresponsive she immediately performed cardiopulmonary resuscitation (CPR). Emergency medical services arrived at the scene, confirmed pulselessness, continued CPR, and applied an automated external defibrillator (AED). The AED advised, “No shock.” After one cycle of CPR was performed, the AED delivered a defibrillatory shock, which resulted in a sustained return of spontaneous circulation (ROSC). On arrival in the ED, the patient’s vital signs were as follows: blood pressure of 135/70 mm Hg, heart rate of 50 beats per minute, temperature of 36.9°C, oxygen saturation of 92%, and a Glasgow Coma Scale score of 3 (eye opening = 1, verbal response = 1, motor response = 1). The patient was not intubated. Pupillary response was absent and there was no corneal reflex.
Sources of information We performed a MEDLINE search from January 1, 1900, to December 31, 2013, to identify all studies examining neurologic outcomes or mortality in patients with OHCA of presumed cardiac causes relevant to the following questions. • Does TTM improve outcomes and, if so, in which populations have studies shown benefits? (Trials comparing TTM to usual care and those comparing TTM of different temperature targets were included.) • Does earlier initiation of TTM improve outcomes compared with later initiation? • Are certain techniques of patient cooling, for the purpose of TTM, associated with improved outcomes? Studies were included regardless of language of publication. The search strategy used and combined the following MeSH terms: heart arrest, induced hypothermia, humans, and adult. A similar search was performed in EMBASE. The Cochrane database of systematic reviews was searched using the term hypothermia. We included all prospective and retrospective human adult studies of randomized, pseudo-randomized, and observational
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Targeted temperature management after out-of-hospital cardiac arrest | Clinical Review designs. References of studies examined were also reviewed to widen the search.
Main message Our search yielded 445 citations. After review for relevance by title and abstract, we reviewed 145 articles in full. We included 57 of these in the final review. Indications for TTM Initial shockable rhythms (ventricular fibrillation [VF] and pulseless ventricular tachycardia): Two prospective interventional trials, both published in 2002, examined the use of TTM after OHCA with a presumed cardiac cause, with goal temperatures of 32°C to 34°C. Bernard et al enrolled 77 patients (men older than 17 and women older than 49 years of age) with an initial rhythm of VF in “persistent coma” after OHCA and compared TTM with those receiving usual care.4 Targeted temperature management was initiated by EMS in the intervention group and continued for 12 hours. Forty-nine percent of patients in the TTM group had a “good outcome” (discharged to a rehabilitation facility or home) compared with 26% in the control group (P = .046). The Hypothermia after Cardiac Arrest Study Group randomized 273 patients aged 18 to 75 years after witnessed OHCA with an initial rhythm of VF or nonperfusing ventricular tachycardia who had no “response to verbal commands” and an interval time of collapse to EMS arrival of 5 to 15 minutes. 5 The intervention group received TTM for 24 hours, commencing in hospital; 55% of patients had favourable outcomes (cerebral performance category score of 1 or 2) compared with 39% among those who received usual care (P = .009). Further, there was a reduction in mortality. In addition, several observational studies have reported benefits in mortality and neurologic outcomes when comparing the use of TTM with historical controls in patients with initial shockable rhythms.6-10 The protocols of the initial 2 studies examining TTM4,5 used target temperatures of 32°C to 34°C. Subsequent widespread implementation of TTM and guidelines endorsed this strategy11,12; however, evidence supporting these specific temperature goals was lacking. It was theorized by some that the true benefit of TTM was in its ability to prevent hyperthermia after cardiac arrest, as opposed to a benefit of subnormal temperatures.13 Nielsen et al performed a multicentre randomized controlled trial, enrolling 950 unconscious patients after OHCA, comparing targeted temperature groups of 33°C and 36°C.14 Patients of all initial rhythms, with the exception of unwitnessed asystole, were considered for inclusion; however, 79% of participants had shockable initial cardiac rhythms. The study was powered to detect an absolute reduction in mortality of 11%. Targeted
temperature management was initiated within 240 minutes of ROSC and was continued, with mandatory sedation, for 28 hours followed by slow rewarming. Measures to avoid hyperthermia continued for a total of 72 hours. An assessor-blinded standardized evaluation for neuroprognostication took place 72 hours after the rewarming phase to make recommendations for further life-sustaining treatment. Despite being well powered, superiority of one target temperature over the other was not demonstrated in terms of neurologic outcomes or mortality. There have been no studies comparing patients with a TTM goal of 36°C with usual care. Initial nonshockable rhythms (pulseless electrical activity and asystole): No large prospective randomized studies have examined the use of TTM in patients with nonshockable initial rhythms in comparison with usual care; however, several retrospective studies, all with target temperatures of 32°C to 34°C, have indicated benefit.15,16 Testori et al reviewed 374 cases with nonshockable initial rhythms and reported better neurologic outcomes and a lower mortality rate in those treated with TTM. 16 Conversely, in other similarly designed studies, including one study examining 1145 consecutive cardiac arrests,17 benefit was limited to only those with initial shockable rhythms.18-22 Nielsen and colleagues compared temperature targets of 33°C and 36°C in patients with initial nonshockable rhythms in a subgroup analysis and reported no benefit seen with the more aggressive TTM goal.14 Given the low survival rate of OHCA patients with nonshockable initial rhythms, extremely large sample sizes would be required to detect benefit.23 Several observational studies have examined the implementation of TTM in all resuscitated patients after OHCA, regardless of initial rhythm, and have reported benefit in neurologic outcomes or mortality.24-32 To isolate the effect of TTM on nonshockable rhythms, Kim et al performed a meta-analysis incorporating data pertaining only to these rhythms from 10 non-randomized studies involving 1292 patients. They concluded that TTM was associated with reduced in-hospital mortality (relative risk 0.84; 95% CI 0.78 to 0.92); however, there was no statistical benefit seen in neurologic outcomes at hospital discharge.23 The authors concluded that the quality of evidence was low and that high-quality randomized trials were required. It is unclear why patients with initial nonshockable rhythms have a worse prognosis considering that the pathophysiology of anoxic brain injury is likely similar in all instances of cerebral hypoperfusion.33 Resuscitated patients after OHCA with initial non-shockable rhythms are much more likely to have had longer collapse-to-ROSC durations,34 which might play a role in the worse outcomes observed. 4
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Clinical Review | Targeted temperature management after out-of-hospital cardiac arrest Oddo et al performed a multivariable analysis on prospective data from 74 resuscitated patients after OHCA treated with TTM to assess for predictors of outcomes.34 They reported that initial arrest rhythm, in contrast to time from collapse to ROSC, was not independently associated with neurologic outcomes or mortality. Soga et al reported similar outcomes for patients with shockable and nonshockable rhythms whose collapse-toROSC interval was 16 minutes or less.35 The sole data point of shockable versus nonshockable initial rhythms for the decision on whether to initiate TTM in a patient is likely overly simplistic and negates other variables that might play a large role in the success of this treatment and patient outcomes.
Issues of timing Time to initiation of cooling and time to target temperature in studies investigating TTM, with goal temperatures of 32°C to 34°C, vary widely. Multiple animal models have shown benefits of earlier and faster cooling strategies 36-40 ; however, the importance of this variable on outcomes in humans remains unknown. Four retrospective studies have reported benefits of earlier cooling, including improved neurologic outcomes and mortality rates.41-44 Conversely, some studies have indicated a lack of benefit for shorter time to target temperature,45,46 and 4 studies reported worse outcomes.47-50 Five RCTs examined the effects of prehospital TTM induction using cold saline. 51-55 No study found significant differences in patient neurologic outcomes or mortality; however, differences in mean patient temperatures between intervention and control groups at hospital arrival were modest (0.8°C to 1.3°C).
Methods of TTM Multiple methods of cooling for TTM have been described, including use of ice bags, cold saline infusions, cooling blankets, and intravascular or intranasal cooling devices. There is no evidence to suggest that any one method is superior.11 Cold saline has been proposed as a favoured option for induction of TTM owing to its relatively low cost, convenience, universal availability, and ease of use in patient transport. The American Heart Association currently recommends a cold intravenous fluid bolus to induce TTM. 11 Several studies, including 4 randomized controlled trials, have reported cold saline infusions to be safe and effective while not inducing pulmonary edema. 51-53,56-65 However, a recent large study that randomized patients to prehospital administration of a rapid 2-L bolus of 4°C normal saline, compared with usual care, reported increased prehospital recurrence of cardiac arrest and pulmonary edema within the first 12 hours of hospitalization; there was no
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difference in overall mortality.55 Cold saline infusions are effective induction agents but appear less effective in the maintenance of a particular body temperature.56
Case resolution The patient was moved to a resuscitation bay in the ED with a cardiac monitor, 2 large-bore intravenous catheters were placed, and oxygen was administered to achieve an oxygen saturation of 94%. An endotracheal tube was inserted and sedation was commenced. A 500-mL bolus of 4°C normal saline was initiated, with a goal temperature of 36°C, and a bladder temperature catheter was inserted for monitoring. A total of 1 g of acetaminophen was given rectally. The regional cardiac referral centre was contacted and arrangements were made for urgent transport. Standard of care within the region included delay of neuroprognostication until at least 72 hours for all patients after OHCA, regardless of initial neurologic status. An additional 500-mL bolus of cooled saline was given and a surface-cooling blanket was applied until advanced care transport paramedics arrived.
Conclusion Unanswered questions remain with regard to the optimal TTM strategy and the magnitude of its effectiveness. However, there is compelling evidence that TTM protocols,* compared with the usual care before the TTM era, lead to improved outcomes for patients with initial shockable rhythms and nonshockable rhythms. Recent data presented by Nielsen and colleagues support the conclusion that when employing the protocol of 108 or more hours described in the study—including strict temperature control, mandatory sedation, and delayed standardized prognostication—TTM with a goal temperature of 33°C is not superior to a goal of 36°C.14 Current evidence indicates that TTM within a comprehensive protocol for resuscitated patients after OHCA, compared with usual care, is a beneficial intervention for patients after OHCA who are not responsive to verbal commands. Normal saline at 4°C is effective for initial temperature regulation; however, until there is further evidence supporting the safety of this technique, it might be advisable to avoid large rapid boluses. An organized protocol for resuscitated patients after OHCA including the use of TTM with a goal temperature of 32°C to 36°C should be implemented in all OHCA patients upon arrival to the ED, followed by timely transfer to a critical care environment. Dr Grunau is an emergency physician at St Paul’s Hospital in Vancouver, BC, and Clinical Assistant Professor in the Department of Emergency Medicine
*Further information on targeted temperature management protocols can be found at www.emergencymedicine. utoronto.ca/research/ptmr/CS/SPARC.htm.
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Targeted temperature management after out-of-hospital cardiac arrest | Clinical Review at the University of British Columbia in Vancouver. Dr Christenson is an emergency physician at St Paul’s Hospital and Professor in and Head of the Department of Emergency Medicine at the University of British Columbia. Dr Brooks is an emergency physician at Kingston General Hospital in Ontario and Assistant Professor in the Department of Emergency Medicine at Queen’s University in Kingston. Contributors All authors contributed to the literature review and interpretation, and to preparing the manuscript for submission. Competing interests None declared Correspondence Dr Brian Grunau, Emergency Department, St Paul’s Hospital, 1081 Burrard St, Vancouver, BC V6Z 1Y6; e-mail [email protected] References 1. Heart and Stroke Foundation [website]. Statistics. Ottawa, ON: Heart and Stroke Foundation; 2015. Available from: www.heartandstroke.com/site/ c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics.htm. Accessed 2011 Oct 31. 2. Vaillancourt C, Stiell IG. Cardiac arrest care and emergency medical services in Canada. Can J Cardiol 2004;20(11):1081-90. 3. Nichol G, Thomas E, Callaway CW, Hedges J, Powell JL, Aufderheide TP, et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA 2008;300(12):1423-31. 4. 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(8):557-63. 5. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346(8):549-56. Erratum in: N Engl J Med 2002;346(22):1756. 6. Reinikainen M, Oksanen T, Leppänen P, Torppa T, Niskanen M, Kurola J. Mortality in out-of-hospital cardiac arrest patients has decreased in the era of therapeutic hypothermia. Acta Anaesthesiol Scand 2012;56(1):110-5. 7. Storm C, Nee J, Krueger A, Schefold JC, Hasper D. 2-year survival of patients undergoing mild hypothermia treatment after ventricular fibrillation cardiac arrest is significantly improved compared to historical controls. Scand J Trauma Resusc Emerg Med 2010;18:2. 8. Takeuchi I, Takehana H, Satoh D, Fukaya H, Tamura Y, Nishi M, et al. Effect of hypothermia therapy after outpatient cardiac arrest due to ventricular fibrillation. Circ J 2009;73(10):1877-80. 9. 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(2):252-9. 10. Bro-Jeppesen J, Kjaergaard J, Horsted TI, Wanscher MC, Nielsen SL, Rasmussen LS, et al. The impact of therapeutic hypothermia on neurological function and quality of life after cardiac arrest. Resuscitation 2009;80(2):171-6. Epub 2008 Dec 25. 11. Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, et al. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122(18 Suppl 3):S768-86. 12. Deakin CD, Morrison LJ, Morley PT, Callaway CW, Kerber RE, Kronick SL, et al. Part 8: advanced life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation 2010;81(Suppl 1):e93-174. 13. Nielsen N, Friberg H, Gluud C, Herlitz J, Wetterslev J. Hypothermia after cardiac arrest should be further evaluated—a systematic review of randomised trials with meta-analysis and trial sequential analysis. Int J Cardiol 2011;151(3):333-41. 14. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med 2013;369(23):2197-206. Epub 2013 Nov 17. 15. Lundbye JB, Rai M, Ramu B, Hosseini-Khalili A, Li D, Slim HB, et al. Therapeutic hypothermia is associated with improved neurologic outcome and survival in cardiac arrest survivors of non-shockable rhythms. Resuscitation 2012;83(2):202-7. 16. Testori C, Sterz F, Behringer W, Haugk M, Uray T, Zeiner A, et al. Mild therapeutic hypothermia is associated with favourable outcome in patients after cardiac arrest with non-shockable rhythms. Resuscitation 2011;82(9):1162-7. 17. Dumas F, Grimaldi D, Zuber B, Fichet J, Charpentier J, Pene F, et al. Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients?: insights from a large registry. Circulation 2011;123(8):877-86.
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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(9):1348-58. 38. Colbourne F, Sutherland GR, Auer RN. Electron microscopic evidence against apoptosis as the mechanism of neuronal death in global ischemia. J Neurosci 1999;19(11):4200-10. 39. 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(22):2786-91. 40. Jia X, Koenig MA, Shin HC, Zhen G, Pardo CA, Hankey DF, et al. Improving neurological outcomes post-cardiac arrest in a rat model: immediate hypothermia and quantitative EEG monitoring. Resuscitation 2008;76(3):431-42.
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Clinical Review | Targeted temperature management after out-of-hospital cardiac arrest 41. 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(2):223-8. 42. Sendelbach S, Hearst MO, Johnson PJ, Unger BT, Mooney MR. Effects of variation in temperature management on cerebral performance category scores in patients who received therapeutic hypothermia post cardiac arrest. Resuscitation 2012;83(7):829-34. 43. Chiota NA, Freeman WD, Barrett K. Earlier hypothermia attainment is associated with improved outcomes after cardiac arrest. J Vasc Interv Neurol 2011;4(1):14-7. 44. Mooney MR, Unger BT, Boland LL, Burke MN, Kebed KY, Graham KJ, et al. Therapeutic hypothermia after out-of-hospital cardiac arrest: evaluation of a regional system to increase access to cooling. Circulation 2011;124(2):206-14. 45. Nielsen N, Hovdenes J, Nilsson F, Rubertsson S, Stammet P, Sunde K, et al. Outcome, timing and adverse events in therapeutic hypothermia after out-ofhospital cardiac arrest. Acta Anaesthesiol Scand 2009;53(7):926-34. 46. Larsen LP, Kristensen KV, Kirkegaard H. Therapeutic hypothermia after cardiac arrest [article in Danish]. Ugeskr Laeger 2009;171(17):1392-6. 47. Italian Cooling Experience (ICE) Study Group. Early- versus late-initiation of therapeutic hypothermia after cardiac arrest: preliminary observations from the experience of 17 Italian intensive care units. Resuscitation 2012;83(7):823-8. 48. Haugk M, Testori C, Sterz F, Uranitsch M, Holzer M, Behringer W, et al. Relationship between time to target temperature and outcome in patients treated with therapeutic hypothermia after cardiac arrest. Crit Care 2011;15(2):R101. 49. Benz-Woerner J, Delodder F, Benz R, Cueni-Villoz N, Feihl F, Rossetti AO, et al. Body temperature regulation and outcome after cardiac arrest and therapeutic hypothermia. Resuscitation 2012;83(3):338-42. 50. Vanston VJ, Lawhon-Triano M, Getts R, Prior J, Smego RA Jr. Predictors of poor neurologic outcome in patients undergoing therapeutic hypothermia after cardiac arrest. South Med J 2010;103(4):301-6. 51. Bernard SA, Smith K, Cameron P, Masci K, Taylor DM, Cooper DJ, et al. Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial. Circulation 2010;122(7):737-42. 52. Kim F, Olsufka M, Longstreth WT, Maynard C, Carlbom D, Deem S, et al. Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline. Circulation 2007;115(24):3064-70. Epub 2007 Jun 4. 53. Kämäräinen A, Virkkunen I, Tenhunen J, Yli-Hankala A, Silfvast T. Prehospital therapeutic hypothermia for comatose survivors of cardiac arrest: a randomized controlled trial. Acta Anaesthesiol Scand 2009;53(7):900-7. Epub 2009 Jun 3.
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54. Bernard SA, Smith K, Cameron P, Masci K, Taylor DM, Cooper DJ, et al. Induction of prehospital therapeutic hypothermia after resuscitation from nonventricular fibrillation cardiac arrest. Crit Care Med 2012;40(3):747-53. 55. 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(1):45-52. 56. Kliegel A, Janata A, Wandaller C, Uray T, Spiel A, Losert H, et al. Cold infusions alone are effective for induction of therapeutic hypothermia but do not keep patients cool after cardiac arrest. Resuscitation 2007;73(1):46-53. Epub 2007 Jan 22. 57. Kim F, Olsufka M, Carlbom D, Deem S, Longstreth WT Jr, Hanrahan M, et al. Pilot study of rapid infusion of 2 L of 4 degrees C normal saline for induction of mild hypothermia in hospitalized, comatose survivors of out-of-hospital cardiac arrest. Circulation 2005;112(5):715-9. Epub 2005 Jul 25. 58. Kliegel A, Losert H, Sterz F, Kliegel M, Holzer M, Uray T, et al. Cold simple intravenous infusions preceding special endovascular cooling for faster induction of mild hypothermia after cardiac arrest—a feasibility study. Resuscitation 2005;64(3):347-51. 59. Bernard S, Buist M, Monteiro O, Smith K. Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: a preliminary report. Resuscitation 2003;56(1):9-13. 60. Virkkunen I, Yli-Hankala A, Silfvast T. Induction of therapeutic hypothermia after cardiac arrest in prehospital patients using ice-cold Ringer’s solution: a pilot study. Resuscitation 2004;62(3):299-302. 61. Jacobshagen C, Pax A, Unsöld BW, Seidler T, Schmidt-Schweda S, Hasenfuss G, et al. Effects of large volume, ice-cold intravenous fluid infusion on respiratory function in cardiac arrest survivors. Resuscitation 2009;80(11):1223-8. 62. Kilgannon JH, Roberts BW, Stauss M, Cimino MJ, Ferchau L, Chansky ME, et al. Use of a standardized order set for achieving target temperature in the implementation of therapeutic hypothermia after cardiac arrest: a feasibility study. Acad Emerg Med 2008;15(6):499-505. 63. Spiel AO, Kliegel A, Janata A, Uray T, Mayr FB, Laggner AN, et al. Hemostasis in cardiac arrest patients treated with mild hypothermia initiated by cold fluids. Resuscitation 2009;80(7):762-5. 64. Larsson IM, Wallin E, Rubertsson S. Cold saline infusion and ice packs alone are effective in inducing and maintaining therapeutic hypothermia after cardiac arrest. Resuscitation 2010;81(1):15-9. Epub 2009 Oct 22. 65. Bruel C, Parienti JJ, Marie W, Arrot X, Daubin C, Du Cheyron D, et al. Mild hypothermia during advanced life support: a preliminary study in out-ofhospital cardiac arrest. Crit Care 2008;12(1):R31.
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Targeted temperature management after out-of-hospital cardiac arrest Who, when, why, and how? Brian E. Grunau
MD
Jim Christenson
MD
Steven C. Brooks
MD MHSc
Abstract Objective To provide a succinct review of the evidence, framed for the emergency department clinician, for the application of targeted temperature management (TTM) for patients after out-of-hospital cardiac arrest (OHCA). Sources of information MEDLINE, EMBASE, and the Cochrane database were searched for prospective and retrospective studies relevant to the indications of TTM, optimal timing of TTM initiation, method of cooling, and target temperature.
Editor’s key points • Although targeted temperature management (TTM) is a widely recommended therapy for patients after out-of-hospital cardiac arrest (OHCA), many questions remain regarding the patient populations who would benefit from this therapy, as well as the optimal time to initiate therapy, method of cooling, and goal temperature. • Current evidence indicates that TTM within a comprehensive protocol for resuscitated patients after OHCA, compared with usual care, is a beneficial intervention for patients who are not responsive to verbal commands after OHCA. • An organized protocol for resuscitated patients after OHCA including the use of TTM with a goal temperature of 32°C to 36°C should be implemented in all OHCA patients upon arrival to the ED, followed by timely transfer to a critical care environment.
POINTS DE REPÈRE DU RÉDACTEUR
• Bien que la gestion ciblée de la température (GCT) soit un traitement communément recommandé pour les patients ayant subi un arrêt cardiaque hors de l’hôpital (ACHH), de nombreuses questions demeurent quant aux populations de patients qui en bénéficieraient, au moment optimal pour amorcer le traitement, aux méthodes de refroidissement et aux valeurs de température ciblées. • Les données probantes actuelles indiquent que, comparativement aux soins habituels, la GCT suivant un protocole complet pour les patients réanimés ayant subi un arrêt cardiaque hors de l’hôpital est une intervention bénéfique lorsque ces derniers ne réagissent pas aux commandes verbales après un ACHH. • Un protocole structuré pour les patients réanimés après un ACHH, incluant l’utilisation de la GCT visant des valeurs de de 32 °C à 36 °C, devrait être mis en œuvre pour tous les patients dès leur arrivée à l’urgence, suivi d’un transfert aux soins intensifs en temps opportun. This article has been peer reviewed. Cet article a fait l’objet d’une révision par des pairs. Can Fam Physician 2015;61:129-34
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Main message Two prospective interventional trials reported improved neurologically intact survival with the use of TTM (goal temperatures of 32°C to 34°C) compared with no temperature management in comatose OHCA patients with shockable initial cardiac arrest rhythms. A more recent, high-quality randomized controlled trial including OHCA patients with shockable and nonshockable initial rhythms compared TTM at 33°C versus TTM at 36°C. Despite the study being well powered, superiority of one target temperature over the other was not demonstrated. The benefit of TTM in patients with initial nonshockable rhythms is not clear; h o w e v e r, s o m e o b s e r v a t i o n a l studies have suggested benefit. There is no evidence that any particular method of temperature regulation is superior. The relationship between time and TTM initiation has not been well established. Conclusion Targeted temperature management, with a target temperature between 32°C and 36°C, as a component of comprehensive critical care is a beneficial intervention for comatose patients with return of spontaneous circulation after OHCA.
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Clinical Review | Targeted temperature management after out-of-hospital cardiac arrest
Gestion ciblée de la température après un arrêt cardiaque hors de l’hôpital Qui, quand, pourquoi et comment? Résumé O b j e c t i f Présenter une synthèse des données probantes, élaborée à l’intention des cliniciens des services d’urgence, en ce qui concerne les mesures de gestion ciblée de la température (GCT) chez les patients ayant subi un arrêt cardiaque hors de l’hôpital (ACHH). Sources des données On a effectué une recherche dans MEDLINE, EMBASE et la base de données Cochrane pour trouver des études prospectives et rétrospectives concernant les indications de la GCT, le moment optimal pour amorcer la GCT, les méthodes de refroidissement et les valeurs de température ciblées. Message principal Dans deux études interventionnelles prospectives, on a signalé une amélioration du taux de survie sans lésion neurologique avec l’utilisation de la GCT (températures ciblées de 32 °C à 34 °C) comparativement à celui des patients comateux victimes d’un ACHH et présentant des rythmes initiaux à l’arrêt cardiaque justifiant une défibrillation dont la température n’avait pas été prise en charge. Plus récemment, une étude randomisée contrôlée de grande qualité portant sur des patients victimes d’un ACHH et présentant des rythmes initiaux justifiant ou non une défibrillation comparait la GCT à 33 °C à la GCT à 36 °C. Bien que l’étude ait été bien menée, elle n’a pas démontré la supériorité de l’une ou l’autre des températures ciblées. Les avantages de la GCT chez les patients présentant des rythmes initiaux ne justifiant pas une défibrillation ne sont pas clairs même si, dans certaines études observationnelles, on a fait valoir certains bienfaits. Il n’y a pas de données probantes établissant qu’une méthode particulière de régulation de la température soit supérieure à une autre. Le moment opportun d’amorcer la GCT n’a pas été bien établi. Conclusion La gestion ciblée de la température, visant des valeurs entre 32 °C et 36 °C, en tant que composante des soins intensifs complets est une intervention bénéfique pour les patients comateux qui ont eu un rétablissement de la circulation spontanée après un ACHH.
C
ardiac arrest affects approximately 40 000 victims per year in Canada1 and is associated with low rates of survival to hospital discharge.2,3 Targeted temperature management (TTM) has been used for patients after out-of-hospital cardiac arrest (OHCA)
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with the objective of improving neurologic outcomes and lowering rates of mortality. In spite of numerous studies examining the use of TTM, questions remain in terms of the patient populations who would benefit from this therapy, as well as the optimal time to initiate therapy, method of cooling, and goal temperature. In light of this, we sought to provide a succinct review of the evidence related to TTM, framed for the emergency department (ED) clinician, for resuscitated patients after OHCA.
Case description A 55-year-old patient arrived at a 10-bed rural ED with emergency medical services (EMS). His wife heard him fall to the ground at home and when she found him unresponsive she immediately performed cardiopulmonary resuscitation (CPR). Emergency medical services arrived at the scene, confirmed pulselessness, continued CPR, and applied an automated external defibrillator (AED). The AED advised, “No shock.” After one cycle of CPR was performed, the AED delivered a defibrillatory shock, which resulted in a sustained return of spontaneous circulation (ROSC). On arrival in the ED, the patient’s vital signs were as follows: blood pressure of 135/70 mm Hg, heart rate of 50 beats per minute, temperature of 36.9°C, oxygen saturation of 92%, and a Glasgow Coma Scale score of 3 (eye opening = 1, verbal response = 1, motor response = 1). The patient was not intubated. Pupillary response was absent and there was no corneal reflex.
Sources of information We performed a MEDLINE search from January 1, 1900, to December 31, 2013, to identify all studies examining neurologic outcomes or mortality in patients with OHCA of presumed cardiac causes relevant to the following questions. • Does TTM improve outcomes and, if so, in which populations have studies shown benefits? (Trials comparing TTM to usual care and those comparing TTM of different temperature targets were included.) • Does earlier initiation of TTM improve outcomes compared with later initiation? • Are certain techniques of patient cooling, for the purpose of TTM, associated with improved outcomes? Studies were included regardless of language of publication. The search strategy used and combined the following MeSH terms: heart arrest, induced hypothermia, humans, and adult. A similar search was performed in EMBASE. The Cochrane database of systematic reviews was searched using the term hypothermia. We included all prospective and retrospective human adult studies of randomized, pseudo-randomized, and observational
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Targeted temperature management after out-of-hospital cardiac arrest | Clinical Review designs. References of studies examined were also reviewed to widen the search.
Main message Our search yielded 445 citations. After review for relevance by title and abstract, we reviewed 145 articles in full. We included 57 of these in the final review. Indications for TTM Initial shockable rhythms (ventricular fibrillation [VF] and pulseless ventricular tachycardia): Two prospective interventional trials, both published in 2002, examined the use of TTM after OHCA with a presumed cardiac cause, with goal temperatures of 32°C to 34°C. Bernard et al enrolled 77 patients (men older than 17 and women older than 49 years of age) with an initial rhythm of VF in “persistent coma” after OHCA and compared TTM with those receiving usual care.4 Targeted temperature management was initiated by EMS in the intervention group and continued for 12 hours. Forty-nine percent of patients in the TTM group had a “good outcome” (discharged to a rehabilitation facility or home) compared with 26% in the control group (P = .046). The Hypothermia after Cardiac Arrest Study Group randomized 273 patients aged 18 to 75 years after witnessed OHCA with an initial rhythm of VF or nonperfusing ventricular tachycardia who had no “response to verbal commands” and an interval time of collapse to EMS arrival of 5 to 15 minutes. 5 The intervention group received TTM for 24 hours, commencing in hospital; 55% of patients had favourable outcomes (cerebral performance category score of 1 or 2) compared with 39% among those who received usual care (P = .009). Further, there was a reduction in mortality. In addition, several observational studies have reported benefits in mortality and neurologic outcomes when comparing the use of TTM with historical controls in patients with initial shockable rhythms.6-10 The protocols of the initial 2 studies examining TTM4,5 used target temperatures of 32°C to 34°C. Subsequent widespread implementation of TTM and guidelines endorsed this strategy11,12; however, evidence supporting these specific temperature goals was lacking. It was theorized by some that the true benefit of TTM was in its ability to prevent hyperthermia after cardiac arrest, as opposed to a benefit of subnormal temperatures.13 Nielsen et al performed a multicentre randomized controlled trial, enrolling 950 unconscious patients after OHCA, comparing targeted temperature groups of 33°C and 36°C.14 Patients of all initial rhythms, with the exception of unwitnessed asystole, were considered for inclusion; however, 79% of participants had shockable initial cardiac rhythms. The study was powered to detect an absolute reduction in mortality of 11%. Targeted
temperature management was initiated within 240 minutes of ROSC and was continued, with mandatory sedation, for 28 hours followed by slow rewarming. Measures to avoid hyperthermia continued for a total of 72 hours. An assessor-blinded standardized evaluation for neuroprognostication took place 72 hours after the rewarming phase to make recommendations for further life-sustaining treatment. Despite being well powered, superiority of one target temperature over the other was not demonstrated in terms of neurologic outcomes or mortality. There have been no studies comparing patients with a TTM goal of 36°C with usual care. Initial nonshockable rhythms (pulseless electrical activity and asystole): No large prospective randomized studies have examined the use of TTM in patients with nonshockable initial rhythms in comparison with usual care; however, several retrospective studies, all with target temperatures of 32°C to 34°C, have indicated benefit.15,16 Testori et al reviewed 374 cases with nonshockable initial rhythms and reported better neurologic outcomes and a lower mortality rate in those treated with TTM. 16 Conversely, in other similarly designed studies, including one study examining 1145 consecutive cardiac arrests,17 benefit was limited to only those with initial shockable rhythms.18-22 Nielsen and colleagues compared temperature targets of 33°C and 36°C in patients with initial nonshockable rhythms in a subgroup analysis and reported no benefit seen with the more aggressive TTM goal.14 Given the low survival rate of OHCA patients with nonshockable initial rhythms, extremely large sample sizes would be required to detect benefit.23 Several observational studies have examined the implementation of TTM in all resuscitated patients after OHCA, regardless of initial rhythm, and have reported benefit in neurologic outcomes or mortality.24-32 To isolate the effect of TTM on nonshockable rhythms, Kim et al performed a meta-analysis incorporating data pertaining only to these rhythms from 10 non-randomized studies involving 1292 patients. They concluded that TTM was associated with reduced in-hospital mortality (relative risk 0.84; 95% CI 0.78 to 0.92); however, there was no statistical benefit seen in neurologic outcomes at hospital discharge.23 The authors concluded that the quality of evidence was low and that high-quality randomized trials were required. It is unclear why patients with initial nonshockable rhythms have a worse prognosis considering that the pathophysiology of anoxic brain injury is likely similar in all instances of cerebral hypoperfusion.33 Resuscitated patients after OHCA with initial non-shockable rhythms are much more likely to have had longer collapse-to-ROSC durations,34 which might play a role in the worse outcomes observed. 4
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Clinical Review | Targeted temperature management after out-of-hospital cardiac arrest Oddo et al performed a multivariable analysis on prospective data from 74 resuscitated patients after OHCA treated with TTM to assess for predictors of outcomes.34 They reported that initial arrest rhythm, in contrast to time from collapse to ROSC, was not independently associated with neurologic outcomes or mortality. Soga et al reported similar outcomes for patients with shockable and nonshockable rhythms whose collapse-toROSC interval was 16 minutes or less.35 The sole data point of shockable versus nonshockable initial rhythms for the decision on whether to initiate TTM in a patient is likely overly simplistic and negates other variables that might play a large role in the success of this treatment and patient outcomes.
Issues of timing Time to initiation of cooling and time to target temperature in studies investigating TTM, with goal temperatures of 32°C to 34°C, vary widely. Multiple animal models have shown benefits of earlier and faster cooling strategies 36-40 ; however, the importance of this variable on outcomes in humans remains unknown. Four retrospective studies have reported benefits of earlier cooling, including improved neurologic outcomes and mortality rates.41-44 Conversely, some studies have indicated a lack of benefit for shorter time to target temperature,45,46 and 4 studies reported worse outcomes.47-50 Five RCTs examined the effects of prehospital TTM induction using cold saline. 51-55 No study found significant differences in patient neurologic outcomes or mortality; however, differences in mean patient temperatures between intervention and control groups at hospital arrival were modest (0.8°C to 1.3°C).
Methods of TTM Multiple methods of cooling for TTM have been described, including use of ice bags, cold saline infusions, cooling blankets, and intravascular or intranasal cooling devices. There is no evidence to suggest that any one method is superior.11 Cold saline has been proposed as a favoured option for induction of TTM owing to its relatively low cost, convenience, universal availability, and ease of use in patient transport. The American Heart Association currently recommends a cold intravenous fluid bolus to induce TTM. 11 Several studies, including 4 randomized controlled trials, have reported cold saline infusions to be safe and effective while not inducing pulmonary edema. 51-53,56-65 However, a recent large study that randomized patients to prehospital administration of a rapid 2-L bolus of 4°C normal saline, compared with usual care, reported increased prehospital recurrence of cardiac arrest and pulmonary edema within the first 12 hours of hospitalization; there was no
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difference in overall mortality.55 Cold saline infusions are effective induction agents but appear less effective in the maintenance of a particular body temperature.56
Case resolution The patient was moved to a resuscitation bay in the ED with a cardiac monitor, 2 large-bore intravenous catheters were placed, and oxygen was administered to achieve an oxygen saturation of 94%. An endotracheal tube was inserted and sedation was commenced. A 500-mL bolus of 4°C normal saline was initiated, with a goal temperature of 36°C, and a bladder temperature catheter was inserted for monitoring. A total of 1 g of acetaminophen was given rectally. The regional cardiac referral centre was contacted and arrangements were made for urgent transport. Standard of care within the region included delay of neuroprognostication until at least 72 hours for all patients after OHCA, regardless of initial neurologic status. An additional 500-mL bolus of cooled saline was given and a surface-cooling blanket was applied until advanced care transport paramedics arrived.
Conclusion Unanswered questions remain with regard to the optimal TTM strategy and the magnitude of its effectiveness. However, there is compelling evidence that TTM protocols,* compared with the usual care before the TTM era, lead to improved outcomes for patients with initial shockable rhythms and nonshockable rhythms. Recent data presented by Nielsen and colleagues support the conclusion that when employing the protocol of 108 or more hours described in the study—including strict temperature control, mandatory sedation, and delayed standardized prognostication—TTM with a goal temperature of 33°C is not superior to a goal of 36°C.14 Current evidence indicates that TTM within a comprehensive protocol for resuscitated patients after OHCA, compared with usual care, is a beneficial intervention for patients after OHCA who are not responsive to verbal commands. Normal saline at 4°C is effective for initial temperature regulation; however, until there is further evidence supporting the safety of this technique, it might be advisable to avoid large rapid boluses. An organized protocol for resuscitated patients after OHCA including the use of TTM with a goal temperature of 32°C to 36°C should be implemented in all OHCA patients upon arrival to the ED, followed by timely transfer to a critical care environment. Dr Grunau is an emergency physician at St Paul’s Hospital in Vancouver, BC, and Clinical Assistant Professor in the Department of Emergency Medicine
*Further information on targeted temperature management protocols can be found at www.emergencymedicine. utoronto.ca/research/ptmr/CS/SPARC.htm.
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Targeted temperature management after out-of-hospital cardiac arrest | Clinical Review at the University of British Columbia in Vancouver. Dr Christenson is an emergency physician at St Paul’s Hospital and Professor in and Head of the Department of Emergency Medicine at the University of British Columbia. Dr Brooks is an emergency physician at Kingston General Hospital in Ontario and Assistant Professor in the Department of Emergency Medicine at Queen’s University in Kingston. Contributors All authors contributed to the literature review and interpretation, and to preparing the manuscript for submission. Competing interests None declared Correspondence Dr Brian Grunau, Emergency Department, St Paul’s Hospital, 1081 Burrard St, Vancouver, BC V6Z 1Y6; e-mail [email protected] References 1. Heart and Stroke Foundation [website]. Statistics. Ottawa, ON: Heart and Stroke Foundation; 2015. Available from: www.heartandstroke.com/site/ c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics.htm. Accessed 2011 Oct 31. 2. Vaillancourt C, Stiell IG. Cardiac arrest care and emergency medical services in Canada. Can J Cardiol 2004;20(11):1081-90. 3. Nichol G, Thomas E, Callaway CW, Hedges J, Powell JL, Aufderheide TP, et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA 2008;300(12):1423-31. 4. 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(8):557-63. 5. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346(8):549-56. Erratum in: N Engl J Med 2002;346(22):1756. 6. Reinikainen M, Oksanen T, Leppänen P, Torppa T, Niskanen M, Kurola J. Mortality in out-of-hospital cardiac arrest patients has decreased in the era of therapeutic hypothermia. Acta Anaesthesiol Scand 2012;56(1):110-5. 7. Storm C, Nee J, Krueger A, Schefold JC, Hasper D. 2-year survival of patients undergoing mild hypothermia treatment after ventricular fibrillation cardiac arrest is significantly improved compared to historical controls. Scand J Trauma Resusc Emerg Med 2010;18:2. 8. Takeuchi I, Takehana H, Satoh D, Fukaya H, Tamura Y, Nishi M, et al. Effect of hypothermia therapy after outpatient cardiac arrest due to ventricular fibrillation. Circ J 2009;73(10):1877-80. 9. 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(2):252-9. 10. Bro-Jeppesen J, Kjaergaard J, Horsted TI, Wanscher MC, Nielsen SL, Rasmussen LS, et al. The impact of therapeutic hypothermia on neurological function and quality of life after cardiac arrest. Resuscitation 2009;80(2):171-6. Epub 2008 Dec 25. 11. Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, et al. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122(18 Suppl 3):S768-86. 12. Deakin CD, Morrison LJ, Morley PT, Callaway CW, Kerber RE, Kronick SL, et al. Part 8: advanced life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation 2010;81(Suppl 1):e93-174. 13. Nielsen N, Friberg H, Gluud C, Herlitz J, Wetterslev J. Hypothermia after cardiac arrest should be further evaluated—a systematic review of randomised trials with meta-analysis and trial sequential analysis. Int J Cardiol 2011;151(3):333-41. 14. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med 2013;369(23):2197-206. Epub 2013 Nov 17. 15. Lundbye JB, Rai M, Ramu B, Hosseini-Khalili A, Li D, Slim HB, et al. Therapeutic hypothermia is associated with improved neurologic outcome and survival in cardiac arrest survivors of non-shockable rhythms. Resuscitation 2012;83(2):202-7. 16. Testori C, Sterz F, Behringer W, Haugk M, Uray T, Zeiner A, et al. Mild therapeutic hypothermia is associated with favourable outcome in patients after cardiac arrest with non-shockable rhythms. Resuscitation 2011;82(9):1162-7. 17. Dumas F, Grimaldi D, Zuber B, Fichet J, Charpentier J, Pene F, et al. Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients?: insights from a large registry. Circulation 2011;123(8):877-86.
18. Don CW, Longstreth WT, Maynard C, Olsufka M, Nichol G, Ray T, et al. Active surface cooling protocol to induce mild therapeutic hypothermia after out-of-hospital cardiac arrest: a retrospective before-and-after comparison in a single hospital. Crit Care Med 2009;37(12):3062-9. 19. Vaahersalo J, Hiltunen P, Tiainen M, Oksanen T, Kaukonen KM, Kurola J, et al. Therapeutic hypothermia after out-of-hospital cardiac arrest in Finnish intensive care units: the FINNRESUSCI study. Intensive Care Med 2013;39(5):826-37. Epub 2013 Feb 16. 20. Storm C, Nee J, Roser M, Jörres A, Hasper D. Mild hypothermia treatment in patients resuscitated from non-shockable cardiac arrest. Emerg Med J 2012;29(2):100-3. 21. Oddo M, Schaller MD, Feihl F, Ribordy V, Liaudet L. From evidence to clinical practice: effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest. Crit Care Med 2006;34(7):1865-73. 22. Martinell L, Larsson M, Bång A, Karlsson T, Lindqvist J, Thoren AB, et al. Survival in out-of-hospital cardiac arrest before and after use of advanced postresuscitation care: a survey focusing on incidence, patient characteristics, survival, and estimated cerebral function after postresuscitation care. Am J Emerg Med 2010;28(5):543-51. 23. Kim YM, Yim HW, Jeong SH, Klem ML, Callaway CW. Does therapeutic hypothermia benefit adult cardiac arrest patients presenting with non-shockable initial rhythms?: a systematic review and meta-analysis of randomized and non-randomized studies. Resuscitation 2012;83(2):188-96. Epub 2011 Aug 9. 24. Sunde K, Pytte M, Jacobsen D, Mangschau A, Jensen LP, Smedsrud C, et al. Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest. Resuscitation 2007;73(1):29-39. Epub 2007 Jan 25. 25. Bernard SA, Jones BM, Horne MK. Clinical trial of induced hypothermia in comatose survivors of out-of-hospital cardiac arrest. Ann Emerg Med 1997;30(2):146-53. 26. Busch M, Soreide E, Lossius HM, Lexow K, Dickstein K. Rapid implementation of therapeutic hypothermia in comatose out-of-hospital cardiac arrest survivors. Acta Anaesthesiol Scand 2006;50(10):1277-83. 27. Storm C, Steffen I, Schefold JC, Schefold JC, Krueger A, Oppert M, et al. Mild therapeutic hypothermia shortens intensive care unit stay of survivors after out-of-hospital cardiac arrest compared to historical controls. Crit Care 2008;12(3):R78. 28. Knafelj R, Radsel P, Ploj T, Noc M. Primary percutaneous coronary intervention and mild induced hypothermia in comatose survivors of ventricular fibrillation with ST-elevation acute myocardial infarction. Resuscitation 2007;74(2):227-34. 29. Hinchey PR, Myers JB, Lewis R, De Maio VJ, Reyer E, Licatese D, et al. Improved out-of-hospital cardiac arrest survival after the sequential implementation of 2005 AHA guidelines for compressions, ventilations, and induced hypothermia: the Wake County experience. Ann Emerg Med 2010;56(4):348-57. 30. Rittenberger JC, Guyette FX, Tisherman SA, DeVita MA, Alvarez RJ, Callaway CW. Outcomes of a hospital-wide plan to improve care of comatose survivors of cardiac arrest. Resuscitation 2008;79(2):198-204. 31. Holzer M, Müllner 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(7):1792-7. 32. Granja C, Ferreira P, Ribeiro O, Pina J. Improved survival with therapeutic hypothermia after cardiac arrest with cold saline and surfacing cooling: keep it simple. Emerg Med Int 2011;2011:395813. 33. Arrich J, Holzer M, Havel C, Müllner M, Herkner H. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev 2012;9(9):CD004128. 34. Oddo M, Ribordy V, Feihl F, Rossetti AO, Schaller MD, Chiolero R, et al. Early predictors of outcome in comatose survivors of ventricular fibrillation and non-ventricular fibrillation cardiac arrest treated with hypothermia: a prospective study. Crit Care Med 2008;36(8):2296-301. 35. Soga T, Nagao K, Sawano H, Yokoyama H, Tahara Y, Hase M, et al. Neurological benefit of therapeutic hypothermia following return of spontaneous circulation for out-of-hospital non-shockable cardiac arrest. Circ J 2012;76(11):2579-85. Epub 2012 Jul 20. 36. Sterz F, Safar P, Tisherman S, Radovsky A, Kuboyama K, Oku K. Mild hypothermic cardiopulmonary resuscitation improves outcome after prolonged cardiac arrest in dogs. Crit Care Med 1991;19(3):379-89. 37. 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(9):1348-58. 38. Colbourne F, Sutherland GR, Auer RN. Electron microscopic evidence against apoptosis as the mechanism of neuronal death in global ischemia. J Neurosci 1999;19(11):4200-10. 39. 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(22):2786-91. 40. Jia X, Koenig MA, Shin HC, Zhen G, Pardo CA, Hankey DF, et al. Improving neurological outcomes post-cardiac arrest in a rat model: immediate hypothermia and quantitative EEG monitoring. Resuscitation 2008;76(3):431-42.
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| Vol 61: february • février 2015
