Enlighten-Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label phase 3 trial with blinded endpoint

BackgroundManagement algorithms for adult severe traumatic brain injury (sTBI) were omitted in later editions of the Brain Trauma Foundation’s sTBI Management Guidelines, as they were not evidence-based.MethodsWe used a Delphi-method-based consensus approach to address management of sTBI patients undergoing intracranial pressure (ICP) monitoring. Forty-two experienced, clinically active sTBI specialists from six continents comprised the panel. Eight surveys iterated queries and comments. An in-person meeting included whole- and small-group discussions and blinded voting. Consensus required 80% agreement. We developed heatmaps based on a traffic-light model where panelists’ decision tendencies were the focus of recommendations.ResultsWe provide comprehensive algorithms for ICP-monitor-based adult sTBI management. Consensus established 18 interventions as fundamental and ten treatments not to be used. We provide a three-tier algorithm for treating elevated ICP. Treatments within a tier are considered empirically equivalent. Higher tiers involve higher risk therapies. Tiers 1, 2, and 3 include 10, 4, and 3 interventions, respectively. We include inter-tier considerations, and recommendations for critical neuroworsening to assist the recognition and treatment of declining patients. Novel elements include guidance for autoregulation-based ICP treatment based on MAP Challenge results, and two heatmaps to guide (1) ICP-monitor removal and (2) consideration of sedation holidays for neurological examination.ConclusionsOur modern and comprehensive sTBI-management protocol is designed to assist clinicians managing sTBI patients monitored with ICP-monitors alone. Consensus-based (class III evidence), it provides management recommendations based on combined expert opinion. It reflects neither a standard-of-care nor a substitute for thoughtful individualized management.Electronic supplementary materialThe online version of this article (10.1007/s00134-019-05805-9) contains supplementary material, which is available to authorized users.

Background: Current guidelines for the treatment of adult severe traumatic brain injury (sTBI) consist of high-quality evidence reports, but they are no longer accompanied by management protocols, as these require expert opinion to bridge the gap between published evidence and patient care. We aimed to establish a modern sTBI protocol for adult patients with both intracranial pressure (ICP) and brain oxygen monitors in place. Methods:Our consensus working group consisted of 42 experienced and actively practicing sTBI opinion leaders from six continents. Having previously established a protocol for the treatment of patients with ICP monitoring alone, we addressed patients who have a brain oxygen monitor in addition to an ICP monitor. The management protocols were developed through a Delphi-method-based consensus approach and were finalized at an in-person meeting. Results:We established three distinct treatment protocols, each with three tiers whereby higher tiers involve therapies with higher risk. One protocol addresses the management of ICP elevation when brain oxygenation is normal. A second addresses management of brain hypoxia with normal ICP. The third protocol addresses the situation when both intracranial hypertension and brain hypoxia are present. The panel considered issues pertaining to blood transfusion and ventilator management when designing the different algorithms.

The trauma PPPDR was almost double that estimated by the National Academies of Sciences. Data regarding P/PP deaths offers opportunity to target research, prevention, intervention, and treatment corresponding to all phases of the trauma system.

Background Numerous pre-clinical studies using bone marrow derived cells for the treatment of traumatic brain injury and stroke have demonstrated efficacy in terms of blood-brain barrier preservation, neurogenesis, and other functional outcomes. Phase 1 clinical trials using bone marrow mononuclear cells infused intravenously in children with severe TBI demonstrated safety and potentially a CNS structural preservation treatment effect. This study sought to confirm the safety, logistic feasibility, and potential treatment effect size of structural preservation/inflammatory biomarker mitigation in adults to guide Phase 2 clinical trial design. Methods Adults (aged 18-55) with severe traumatic brain injury (GCS 5-8) and without signs of serious other injury or irreversible brain injury (see Table 1) were evaluated for entry into the trial. A dose escalation format was performed in 25 patients: 5 controls, followed 5 patients in each dosing cohort (6,9,12 ×106 cells/kg body weight), then 5 more controls. Bone marrow harvest, cell processing to isolate the mononuclear fraction, and re-infusion occurred within 48 hours after injury. Patients were monitored for harvest/infusion related hemodynamic changes, infusional toxicity, and adverse events. Outcome measures included MRI based measurements of supratentorial and corpus callosal volumes as well as DTI based measurements of fractional anisotropy and mean diffusivity of the corpus callosum and the corticospinal tract at the level of the brainstem at 1 month and 6 months post-injury. Functional and neurocognitive outcomes were measured and correlated with imaging data. Inflammatory cytokine arrays were measured in the plasma pre-treatment, post-treatment, and at 1 and 6 month follow-up. Results There were no serious adverse events related to harvest/infusion. There was a mild pulmonary toxicity of the highest dose that was not clinically significant. Despite the treatment group having greater injury severity, there was structural preservation of critical regions of interest that correlated with functional outcomes. Key inflammatory cytokines were down-regulated after BMMNC infusion. Conclusions Treatment of severe, adult traumatic brain injury using an intravenously delivered autologous bone marrow mononuclear cell infusion is safe and logistically feasible. There appears to be a treatment signal as evidenced by CNS structural preservation, consistent with previous pediatric trial data. Inflammatory biomarkers are down-regulated after cell infusion. A Phase 2, prospective, randomized trial excluding the highest dose is warranted and can be powered based upon structural outcome variables.

BackgroundInflammatory mechanism has been implicated in delayed cerebral ischemia (DCI) and poor functional outcomes after subarachnoid hemorrhage (SAH). Identification of cytokine patterns associated with inflammation in acute SAH will provide insights into underlying biological processes of DCI and poor outcomes that may be amenable to interventions.MethodsSerum samples were collected from a prospective cohort of 60 patients with acute non-traumatic SAH at four time periods (< 24 h, 24–48 h, 3–5 days, and 6–8 days after SAH) and concentration levels of 41 cytokines were measured by multiplex immunoassay. Logistic regression analysis was used to identify cytokines associated with DCI and poor functional outcomes. Correlation networks were constructed to identify cytokine clusters.ResultsOf the 60 patients enrolled in the study, 14 (23.3%) developed DCI and 16 (26.7%) had poor functional outcomes at 3 months. DCI was associated with increased levels of PDGF-ABBB and CCL5 and decreased levels of IP-10 and MIP-1α. Poor functional outcome was associated with increased levels of IL-6 and MCP-1α. Network analysis identified distinct cytokine clusters associated with DCI and functional outcomes.ConclusionsSerum cytokine patterns in early SAH are associated with poor functional outcomes and DCI. The significant cytokines primarily modulate the inflammatory response. This supports earlier SAH studies linking inflammation and poor outcomes. In particular, this study identifies novel cytokine patterns over time that may indicate impending DCI.

IntroductionHead injury and exsanguination are the leading causes of death in trauma patients. Hemorrhagic shock triggers systemic endothelial glycocalyx breakdown, potentially leading to traumatic endotheliopathy (EoT). Levels of syndecan-1, a main glycocalyx component, have been used to assess the integrity of the glycocalyx. In TBI patients, it remains unclear whether syndecan-1 shedding occurs and its correlation with outcomes. We aimed to determine the frequency of EoT+, defined as a syndecan-1 level of 40 ng/ml or higher, after TBI in isolated and polytraumatic injury. We also investigated how the presence of EoT+ affected outcomes in TBI patients.MethodsSeverely injured trauma patients were enrolled. From blood samples collected upon patients’ arrival to the hospital, we measured syndecan-1 (main biomarker of EoT+), soluble thrombomodulin (sTM, endothelial activation) adrenaline and noradrenaline (sympathoadrenal activation), and assessed TBI patients’ coagulation capacity.ResultsOf the enrolled patients (n = 331), those with TBI and polytrauma (n = 68) had the highest rate of EoT+ compared to isolated TBI (n = 58) and Non-TBI patients (n = 205) (Polytrauma-TBI 55.9% vs. Isolated-TBI 20.0% vs. non-TBI polytrauma 40.0%; p = 0.001). TBI patients with EoT+ exhibited marked increases in sTM, adrenaline and noradrenaline levels, and physiological and coagulation derangements. In isolated TBI patients, increasing syndecan-1 levels (β for every 10 ng/ml increase: 0.14; 95% CI: 0.02, 0.26) and hypocoagulability were negatively associated with survival.ConclusionsThis study provides evidence of syndecan-1 shedding after TBI supporting the notion that breakdown of the glycocalyx contributes to the physiological derangements after TBI.

BACKGROUND:Minimally invasive surgery procedures, including stereotactic catheter aspiration and clearance of intracerebral hemorrhage (ICH) with recombinant tissue plasminogen activator hold a promise to improve outcome of supratentorial brain hemorrhage, a morbid and disabling type of stroke. A recently completed Phase III randomized trial showed improved mortality but was neutral on the primary outcome (modified Rankin scale score 0 to 3 at 1 yr). OBJECTIVE: To assess surgical performance and its impact on the extent of ICH evacuation and functional outcomes. METHODS: Univariate and multivariate models were used to assess the extent of hematoma evacuation efficacy in relation to mRS 0 to 3 outcome and postulated factors related to patient, disease, and protocol adherence in the surgical arm (n = 242) of the MISTIE trial. RESULTS: Greater ICH reduction has a higher likelihood of achieving mRS of 0 to 3 with a minimum evacuation threshold of ≤15 mL end of treatment ICH volume or ≥70% volume reduction when controlling for disease severity factors. Mortality benefit was achieved at ≤30 mL end of treatment ICH volume, or >53% volume reduction. Initial hematoma volume, history of hypertension, irregular-shaped hematoma, number of alteplase doses given, surgical protocol deviations, and catheter manipulation problems were significant factors in failing to achieve ≤15 mL goal evacuation. Greater surgeon/site experiences were associated with avoiding poor hematoma evacuation. CONCLUSION: This is the first surgical trial reporting thresholds for reduction of ICH volume correlating with improved mortality and functional outcomes. To realize the benefit of surgery, protocol objectives, surgeon education, technical enhancements, and case selection should be focused on this goal.