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      Therapeutic hypothermia in traumatic brain injury

      abstract
      1 ,
      Critical Care
      BioMed Central
      2nd Innsbruck Hypothermia Symposium
      7-9 June 2012

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          Abstract

          Hypothermia has profound effects on the brain function but importantly is potentially protective against both focal and global injuries. Aspects of the biochemical response to acute ischaemia and trauma, which are associated with poor outcome, can be inhibited by cooling. Unlike many pharmacological treatments that tend to antagonise a single neurochemical process, hypothermia offers a simple method of inhibiting multiple pathological processes simultaneously. It therefore has the potential, if applied correctly, to improve outcomes after acute brain injuries, where drug trials have so far failed. The systemic cooling of patients after acute brain injury is an established treatment modality in many neuro-ICUs. It is a strategy for protecting the injured brain that makes intuitive sense and can reduce both intracranial pressure and the potential for ischaemic secondary insults. Basic science evidence also suggests that cooling can attenuate many secondary biochemical cascades that are activated after acute injury. However, despite these multiple lines of supportive evidence there is as yet no confirmation from a high-quality randomised controlled trial that prophylactic hypothermia improves outcome or reduces mortality. This talk will look at the potentially beneficial effects of hypothermia on the biochemistry of acute brain injury, consider the reasons for the failure to demonstrate clinical efficacy and review the supportive data from meta-analysis, suggesting how hypothermia might be best delivered. Finally I will discuss EuroTherm3235, a European Society of Intensive Care Medicine funded multicentre randomised controlled trial investigating prophylactic hypothermia in traumatic brain injury, which draws on the lessons from the available literature.

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          Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial.

          The inconsistent effect of hypothermia treatment on severe brain injury in previous trials might be because hypothermia was induced too late after injury. We aimed to assess whether very early induction of hypothermia improves outcome in patients with severe brain injury. The National Acute Brain Injury Study: Hypothermia II (NABIS: H II) was a randomised, multicentre clinical trial of patients with severe brain injury who were enrolled within 2·5 h of injury at six sites in the USA and Canada. Patients with non-penetrating brain injury who were 16-45 years old and were not responsive to instructions were randomly assigned (1:1) by a random number generator to hypothermia or normothermia. Patients randomly assigned to hypothermia were cooled to 35°C until their trauma assessment was completed. Patients who had none of a second set of exclusion criteria were either cooled to 33°C for 48 h and then gradually rewarmed or treated at normothermia, depending upon their initial treatment assignment. Investigators who assessed the outcome measures were masked to treatment allocation. The primary outcome was the Glasgow outcome scale score at 6 months. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, NCT00178711. Enrolment occurred from December, 2005, to June, 2009, when the trial was terminated for futility. Follow-up was from June, 2006, to December, 2009. 232 patients were initially randomised a mean of 1·6 h (SD 0·5) after injury: 119 to hypothermia and 113 to normothermia. 97 patients (52 in the hypothermia group and 45 in the normothermia group) did not meet any of the second set of exclusion criteria. The mean time to 35°C for the 52 patients in the hypothermia group was 2·6 h (SD 1·2) and to 33°C was 4·4 h (1·5). Outcome was poor (severe disability, vegetative state, or death) in 31 of 52 patients in the hypothermia group and 25 of 56 in the normothermia group (relative risk [RR] 1·08, 95% CI 0·76-1·53; p=0·67). 12 patients in the hypothermia group died compared with eight in the normothermia group (RR 1·30, 95% CI 0·58-2·52; p=0·52). This trial did not confirm the utility of hypothermia as a primary neuroprotective strategy in patients with severe traumatic brain injury. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            European society of intensive care medicine study of therapeutic hypothermia (32-35°C) for intracranial pressure reduction after traumatic brain injury (the Eurotherm3235Trial)

            Background Traumatic brain injury is a major cause of death and severe disability worldwide with 1,000,000 hospital admissions per annum throughout the European Union. Therapeutic hypothermia to reduce intracranial hypertension may improve patient outcome but key issues are length of hypothermia treatment and speed of re-warming. A recent meta-analysis showed improved outcome when hypothermia was continued for between 48 hours and 5 days and patients were re-warmed slowly (1°C/4 hours). Previous experience with cooling also appears to be important if complications, which may outweigh the benefits of hypothermia, are to be avoided. Methods/design This is a pragmatic, multi-centre randomised controlled trial examining the effects of hypothermia 32-35°C, titrated to reduce intracranial pressure 20 mmHg in accordance with the Brain Trauma Foundation Guidelines, 2007. Discussion The Eurotherm3235Trial is the most important clinical trial in critical care ever conceived by European intensive care medicine, because it was launched and funded by the European Society of Intensive Care Medicine and will be the largest non-commercial randomised controlled trial due to the substantial number of centres required to deliver the target number of patients. It represents a new and fundamental step for intensive care medicine in Europe. Recruitment will continue until January 2013 and interested clinicians from intensive care units worldwide can still join this important collaboration by contacting the Trial Coordinating Team via the trial website http://www.eurotherm3235trial.eu. Trial registration Current Controlled Trials ISRCTN34555414
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              Software tools for implementing simulation studies in adaptive seamless designs: introducing R package ASD

              Adaptive designs for clinical trials have the potential to improve the efficiency of clinical research by, for instance, seamlessly combining different stages of a clinical development programme. Adaptive seamless designs (ASD) combining phases II and III with adaptations such as treatment or subgroup selection are becoming increasingly widely used. The work required to develop application specific software for each new trial is a potential barrier to the more extensive use of ASD, particularly as simulation studies are often required at the planning stage to explore a range of options prior to deciding on an appropriate design. A number of common analysis methods (e.g. weighted inverse normal combination functions) and simulation tools for assessing the performance of a number of design options, are available in some widely used commercial packages, but currently no free software exists for planning and simulation of ASD. Parsons et al. [1] developed R package asd specifically for undertaking simulations to investigate designs for treatment selection based on early outcomes [2]. The freely available software simulates normal test statistics, rather than individual patient data, in the setting of treatment selection, providing flexibility to deal with combinations of scales (e.g. normal, binary) for both early and final outcomes, for two stage designs. Two examples for normally distributed and binomially distributed final outcomes are described with code demonstrating implementation in the software and output to show how this methodology can be used explore a range of options prior to deciding on an appropriate trial design. The software is flexible and fast, allowing many design options to be explored, and is currently in the process of being extended in a new version that will also include simulations for subpopulation selection. The software is available from the Comprehensive R Archive Network [http://cran.r-project.org/] and more details can be found at the Package Website [http://cran.r-project.org/web/packages/asd/].
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                Author and article information

                Conference
                Crit Care
                Crit Care
                Critical Care
                BioMed Central
                1364-8535
                1466-609X
                2012
                7 June 2012
                : 16
                : Suppl 2
                : A11
                Affiliations
                [1 ]University of Edinburgh, Department of Anaesthesia, Critical Care and Pain Medicine, Intensive Care Unit, Western General Hospital, Edinburgh, UK
                Article
                cc11269
                10.1186/cc11269
                3389471
                444f7de1-1da9-4172-8895-230c2316620a
                Copyright ©2012 Rhodes; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                2nd Innsbruck Hypothermia Symposium
                Portoroz, Slovenia
                7-9 June 2012
                History
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                Meeting Abstract

                Emergency medicine & Trauma
                Emergency medicine & Trauma

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