Pharmacological targeting of secondary brain damage following ischemic or hemorrhagic stroke, traumatic brain injury, and bacterial meningitis - a systematic review and meta-analysis

Beez et al. BMC Neurology (2017) 17:209 DOI 10.1186/s12883-017-0994-z RESEARCH ARTICLE Open Access Pharmacological targeting of secondary brain damage following ischemic or hemorrhagic stroke, traumatic brain injury, and bacterial meningitis - a systematic review and meta-analysis Thomas Beez1*† , Hans-Jakob Steiger1† and Nima Etminan2 Abstract Background: The effectiveness of pharmacological strategies exclusively targeting secondary brain damage (SBD) following ischemic stroke, aneurysmal subarachnoid hemorrhage, aSAH, intracerebral hemorrhage (ICH), traumatic brain injury (TBI) and bacterial meningitis is unclear. This meta-analysis studied the effect of SBD targeted treatment on clinical outcome across the pathological entities. Methods: Randomized, controlled, double-blinded trials on aforementioned entities with ‘death’ as endpoint were identified. Effect sizes were analyzed and expressed as pooled risk ratio (RR) estimates with 95% confidence intervals (CI). 123 studies fulfilled the criteria, with data on 66,561 patients. Results: In the pooled analysis, there was a minor reduction of mortality for aSAH [RR 0.93 (95% CI:0.85–1.02)], ICH [RR 0.92 (95% CI:0.82–1.03)] and bacterial meningitis [RR 0.86 (95% CI:0.68–1.09)]. No reduction of mortality was found for ischemic stroke [RR 1.05 (95% CI:1.00–1.11)] and TBI [RR 1.03 (95% CI:0.93–1.15)]. Additional analysis of “poor outcome” as endpoint gave similar results. Subgroup analysis with respect to effector mechanisms showed a tendency towards a reduced mortality for the effector mechanism category “oxidative metabolism/ stress” for aSAH with a risk ratio of 0.86 [95% CI: 0.73–1.00]. Regarding specific medications, a statistically significant reduction of mortality and poor outcome was confirmed only for nimodipine for aSAH and dexamethasone for bacterial meningitis. Conclusions: Our results show that only a few selected SBD directed medications are likely to reduce the rate of death and poor outcome following aSAH, and bacterial meningitis, while no convincing evidence could be found for the usefulness of SBD directed medications in ischemic stroke, ICH and TBI. However, a subtle effect on good or excellent outcome might remain undetected. These results should lead to a new perspective of secondary reactions following cerebral injury. These processes should not be seen as suicide mechanisms that need to be fought. They should be rather seen as well orchestrated clean-up mechanisms, which may today be somewhat too active in a few very specific constellations, such as meningitis under antibiotic treatment and aSAH after surgical or endovascular exclusion of the aneurysm. Keywords: Ischemic stroke, Hemorrhagic stroke, Meningitis, Traumatic brain injury, Secondary brain damage, Neuroprotection, Randomized controlled trials * Correspondence: † Equal contributors 1 Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This 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. Beez et al. BMC Neurology (2017) 17:209 Background The term ‘secondary brain damage (SBD)’ refers to delayed detrimental functional and structural sequelae after various types of acute cerebral injury. The underlying mechanisms are triggered by the primary ictus, such as ischemic or hemorrhagic stroke (aneurysmal subarachnoid, aSAH or intracerebral hemorrhage, ICH) or traumatic brain injury (TBI) and intracranial infections [1–4]. Numerous mechanisms contributing to the pathogenesis of SBD following the aforementioned acute cerebral events have been identified over the past decades, which subsequently led to the development and clinical investigation of numerous experimental pharmacological treatments focused on different SBD mechanisms. SBD mechanisms include impairment of cerebral flood flow and cerebral autoregulation, metabolic dysfunction, edema formation, oxidative stress, disruption of the blood brain barrier and inflammation [1–4]. While some SBD pathomechanisms are specific for ischemic and hemorrhagic stroke, TBI and intracranial infections, other mechanisms are a rather unspecific reaction of the injured brain, such as edema and delayed ischemia. At the present time it remains unclear whether a pharmacological strategy targeting one specific pathomechanism could result in a beneficial effect on outcome [5, 6]. Moreover, the relevance of targeted treatment of SBD, in addition to established general measures of critical care, e.g. avoidance of arterial hypotension, increased intracranial pressure, hyperthermia, and hypoxemia, is uncertain [7–11]. We performed a systematic review and meta-analysis to summarize the currently available randomized clinical trials exclusively targeting specific pathomechanisms of SBD with the aim to improve clinical outcome following ischemic stroke, ICH, SAH, TBI, and bacterial meningitis. In order to obtain practically useful information we grouped the available phase III randomized clinical trials according to addressed pathomechanisms. Methods For this systematic review we used the Cochrane Collaboration format [12] and followed the PRISMA checklist [13]. Search strategy for identification of studies The authors conducted a systematic search of the Pubmed database (http://www.ncbi.nlm.nih.gov/ pubmed) in February 2015 for the terms ischemic stroke, brain infarction, subarachnoid hemorrhage, SAH, intracerebral hemorrhage, intracranial hemorrhage, ICH, traumatic brain injury, brain trauma, TBI and bacterial meningitis. The search was limited to ‘randomized controlled trials’, ‘human studies’ and ‘English’. Additionally, previous review articles or meta-analyses were searched for studies matching our inclusion criteria. The retrieved Page 2 of 12 articles were screened for relevance in a step-wise manner: First the titles were reviewed, then the corresponding abstract and in case of further uncertainty the full-text was screened by the two first authors (TB and HJS) until all retrieved articles were either included or omitted. Types of studies Randomized, blinded, controlled clinical trials studying the efficacy of pharmacological treatment to reduce poor outcome or death due to SBD following ischemic stroke, aneurysmal subarachnoid hemorrhage (aSAH), intracerebral hemorrhage (ICH), traumatic brain injury (TBI) and bacterial meningitis were included, (...truncated)