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      Time-differentiated target temperature management after out-of-hospital cardiac arrest: a multicentre, randomised, parallel-group, assessor-blinded clinical trial (the TTH48 trial): study protocol for a randomised controlled trial

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          Abstract

          Background

          The application of therapeutic hypothermia (TH) for 12 to 24 hours following out-of-hospital cardiac arrest (OHCA) has been associated with decreased mortality and improved neurological function. However, the optimal duration of cooling is not known. We aimed to investigate whether targeted temperature management (TTM) at 33 ± 1 °C for 48 hours compared to 24 hours results in a better long-term neurological outcome.

          Methods

          The TTH48 trial is an investigator-initiated pragmatic international trial in which patients resuscitated from OHCA are randomised to TTM at 33 ± 1 °C for either 24 or 48 hours. Inclusion criteria are: age older than 17 and below 80 years; presumed cardiac origin of arrest; and Glasgow Coma Score (GCS) <8, on admission. The primary outcome is neurological outcome at 6 months using the Cerebral Performance Category score (CPC) by an assessor blinded to treatment allocation and dichotomised to good (CPC 1–2) or poor (CPC 3–5) outcome. Secondary outcomes are: 6-month mortality, incidence of infection, bleeding and organ failure and CPC at hospital discharge, at day 28 and at day 90 following OHCA. Assuming that 50 % of the patients treated for 24 hours will have a poor outcome at 6 months, a study including 350 patients (175/arm) will have 80 % power (with a significance level of 5 %) to detect an absolute 15 % difference in primary outcome between treatment groups. A safety interim analysis was performed after the inclusion of 175 patients.

          Discussion

          This is the first randomised trial to investigate the effect of the duration of TTM at 33 ± 1 °C in adult OHCA patients. We anticipate that the results of this trial will add significant knowledge regarding the management of cooling procedures in OHCA patients.

          Trial registration

          NCT01689077

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          Most cited references28

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          Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest: the Utstein Style. A statement for health professionals from a task force of the American Heart Association, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, and the Australian Resuscitation Council.

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            Modulation of neuro-inflammation and vascular response by oxidative stress following cerebral ischemia-reperfusion injury.

            The mechanisms leading to cellular damage from ischemia-reperfusion (I/R) injury are complex and multi-factorial. Accumulating evidence suggests an important role for oxidative stress in the regulation of neuro-inflammation following stroke. Gene expression studies have revealed that the increase in oxygen radicals post-ischemia triggers the expression of a number of pro-inflammatory genes. These genes are regulated by the transcription factor, nuclear factor-kappa-B (NF-kappaB) which is redox-sensitive. It is hypothesised that changes in the oxidative state may modulate alterations in the neuro-inflammatory response following an I/R injury. Furthermore, NF-kappaB is involved in the transcriptional regulation of adhesion molecules, which play an important role in leukocyte-endothelium interactions. Recent studies have demonstrated that adhesion molecule-mediated leukocyte recruitment is associated with increased tissue damage in stroke, while mice lacking key adhesion molecules conferred neuro-protection. Nevertheless, the involvement of oxidative stress in leukocyte recruitment and the subsequent regulated cell injury is yet to be elucidated. While leukocyte infiltration into the ischemic brain is detrimental, leukocyte accumulation in the microvasculature was shown to be one of the many factors implicated in reduced reperfusion. Although this "no-reflow" phenomenon was confirmed in a variety of animal models of cerebral ischemia, the exact mechanism is still uncertain. This review aims to highlight the impact that oxidative stress has in the regulation of post-ischemic neuro-inflammation and the implication for the cerebral microvasculature after injury.
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              Impact of therapeutic hypothermia onset and duration on survival, neurologic function, and neurodegeneration after cardiac arrest.

              Post-cardiac-arrest therapeutic hypothermia improves outcomes in comatose cardiac arrest survivors. This study tests the hypothesis that the efficacy of post-cardiac-arrest therapeutic hypothermia is dependent on the onset and duration of therapy. Prospective randomized laboratory investigation. University research laboratory. A total of 268 male Long Evans rats. Post-cardiac-arrest therapeutic hypothermia. Adult male Long Evans rats that achieved return of spontaneous circulation after a 10-min asphyxial cardiac arrest were block randomized to normothermia (37°C ± 1°C) or therapeutic hypothermia (33°C ± 1°C) initiated 0, 1, 4, or 8 hrs after return of spontaneous circulation and maintained for 24 or 48 hrs. Therapeutic hypothermia initiated 0, 1, 4, and 8 hrs after return of spontaneous circulation resulted in 7-day survival rates of 45%*, 36%*, 36%*, and 14%, respectively, compared to 17% for normothermic controls and survival with good neurologic function rates of 24%*, 24%*, 19%*, and 0%, respectively, compared to 2% for normothermic controls (*p < .05 vs. normothermia). These outcomes were not different when therapeutic hypothermia was maintained for 24 vs. 48 hrs. In contrast, hippocampal CA1 pyramidal neuron counts were 53% ± 27%*, 53% ± 19%*, 51% ± 24%*, and 65% ± 16%* of normal, respectively, when therapeutic hypothermia was initiated 0, 1, 4, or 8 hrs after return of spontaneous circulation compared to 9% in normothermic controls (*p < .01 vs. normothermia). Furthermore, surviving neuron counts were greater when therapeutic hypothermia was maintained for 48 hrs compared to 24 hrs (68% ± 15%* vs. 42% ± 22%, *p < .0001). In this study, post-cardiac-arrest therapeutic hypothermia resulted in comparable improvement of survival and survival with good neurologic function when initiated within 4 hrs after return of spontaneous circulation. However, histologic assessment of neuronal survival revealed a potentially broader therapeutic window and greater neuroprotection when therapeutic hypothermia was maintained for 48 vs. 24 hrs.

                Author and article information

                Contributors
                hanskirkegaard@dadlnet.dk
                bodil.steen.rasmussen@rn.dk
                dehaas@dadlnet.dk
                joerniel@rm.dk
                susailkj@rm.dk
                AnneKaltoft@dadlnet.dk
                anni.jeppesen@gmail.com
                andersgrejs@gmail.com
                christophe.duez@gmail.com
                alfil@broadpark.no
                Ville.Pettila@hus.fi
                Valdo.toome@regionaalhaigla.ee
                Urmet.Arus@regionaalhaigla.ee
                Fabio.Taccone@erasme.ulb.ac.be
                christian.storm@charite.de
                Markus.Skrifvars@hus.fi
                eldar.soreide@sus.no
                Journal
                Trials
                Trials
                Trials
                BioMed Central (London )
                1745-6215
                4 May 2016
                4 May 2016
                2016
                : 17
                : 228
                Affiliations
                [ ]Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital and Aarhus University, Aarhus, Denmark
                [ ]Department of Anaesthesiology and Intensive Care Medicine, Aalborg University Hospital, Aalborg, Denmark
                [ ]Hammel Neurorehabilitation Centre and University Research Clinic, Aarhus University, Hammel, Denmark
                [ ]Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark
                [ ]Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
                [ ]Department of Cardiology, Stavanger University Hospital, Stavanger, Norway
                [ ]Department of Clinical Science, University of Bergen, Bergen, Norway
                [ ]Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Helsinki University Hospital and Helsinki University, Helsinki, Finland
                [ ]Intensive Care, Inselspital, Bern University Hospital, Bern, Switzerland
                [ ]Department of Anesthesiology, Intensive Care and Emergency Medicine, North Estonia Medical Centre, Tallinn, Estonia
                [ ]Department of Intensive Cardiac Care, North Estonia Medical Centre, Tallinn, Estonia
                [ ]Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium
                [ ]Department of Internal Medicine, Nephrology and Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany
                [ ]Department of Anaesthesiology and Intensive Care, Stavanger University Hospital, Stavanger, Norway
                [ ]Department of Clinical Medicine, University of Bergen, Bergen, Norway
                Article
                1338
                10.1186/s13063-016-1338-9
                4855491
                27142588
                23af6078-2232-48a7-add0-c317b897e04b
                © Kirkegaard et al. 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 19 November 2015
                : 6 April 2016
                Funding
                Funded by: The Danish Heart Foundation (99,180 €)
                Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/501100004102, Laerdal Foundation for Acute Medicine (31,100 €);
                Funded by: The Danish Society of Anaesthesiology and Intensive Care Medicine (6,700 €)
                Funded by: The Augustinus Foundation (67,000 €)
                Funded by: The Scandinavian Society of Anaesthesiology and Intensive Care Medicine (16,750 €)
                Categories
                Study Protocol
                Custom metadata
                © The Author(s) 2016

                Medicine
                out-of-hospital cardiac arrest,target temperature management,mild therapeutic hypothermia,prolonged target temperature management

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