Differences in Characteristics and Ambulance Pathway Adherence Between Strokes and Mimics Presenting to a Large UK Centralized Hyper Acute Stroke Unit (HASU)

From Frontiers via Jisc Publications RouterHistory: received 2020-12-24, collection 2021, accepted 2021-03-08, epub 2021-05-10Publication status: PublishedBackground: In Greater Manchester (GM), prehospital clinicians use the Face Arm Speech Test (FAST) to identify suspected stroke patients alongside pathway exclusions. Within the centralized stroke service, patients with a suspected stroke are taken directly to a Hyper Acute Stroke Unit (HASU), often bypassing their local emergency department (ED). However, many of these patients are experiencing an illness that looks like a stroke but is not a stroke. The data collected in the prehospital setting is rarely used in research yet could give valuable insights into the performance of the pathway. Aim: To evaluate the presenting symptoms and final diagnoses of prehospital suspected strokes and to evaluate the adherence of prehospital stroke pathway exclusions. Methods: We analyzed data from all patients brought in by ambulance and admitted on the stroke pathway between 01/09/15 and 28/02/17. Patient demographics and all data recorded in the prehospital setting were evaluated to identify differences in stroke, TIA, and mimic patients. Pathway adherence was assessed according to whether the patient was local or out-of-area (OOA) and bypassed their local ED. Results: A total of 4,216 suspected strokes were identified: 2,213 (52.5%) had a final diagnosis of stroke, 492 (11.7%) experienced a transient ischemic attack (TIA), and 1,511 (35.8%) were stroke mimics. There were 714 (16.9%) patients that were identified as having at least one pathway exclusion or were FAST negative, of which 270 (37.8%) experienced a stroke. The proportion of strokes was significantly lower in those with a pathway exclusion (41.8 vs. 53.5%; p < 0.001) and the proportion of breaches tended to be comparable or higher in the local population. Discussion: There are high volumes of stroke mimics but identified differences indicate there is an opportunity to better utilize prehospital data. Ambulance clinicians were able to correctly overrule FAST negative results and the volume of these suggest that FAST alone may be too restrictive

Phase II randomised, placebo-controlled, clinical trial of interleukin-1 receptor antagonist in intracerebral haemorrhage: BLOcking the Cytokine IL-1 in ICH (BLOC-ICH)

PURPOSE: Recombinant human interleukin-1 receptor antagonist (anakinra) is an anti-inflammatory with efficacy in animal models of stroke. We tested the effect of anakinra on perihaematomal oedema in acute intracerebral haemorrhage (ICH) and explored effects on inflammatory markers. METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled trial in patients with acute, spontaneous, supratentorial ICH between May 2019 and February 2021. Patients were randomised to 100 mg subcutaneous anakinra within 8 h of onset, followed by five, 12-hourly, 100 mg subcutaneous injections, or matched placebo. Primary outcome was oedema extension distance (OED) on a 72 h CT scan. Secondary outcomes included plasma C-reactive protein (CRP) and interleukin-6 (IL-6). FINDINGS: 25 patients (target = 80) were recruited, 14 randomised to anakinra, 11 to placebo. Mean age was 67 and 52% were male. The anakinra group had higher median baseline ICH volume (12.6 ml, interquartile range[IQR]:4.8-17.9) versus placebo (5.5 ml, IQR:2.1-10.9). Adjusting for baseline, 72 h OED was not significantly different between groups (mean difference OED anakinra vs placebo -0.05 cm, 95% confidence interval [CI]: -0.17-0.06, p = 0.336). There was no significant difference in area-under-the-curve to Day 4 for IL-6 and CRP, but a post-hoc analysis demonstrated IL-6 was 56% (95% CI: 2%-80%) lower at Day 2 with anakinra. There were 10 and 2 serious adverse events in anakinra and placebo groups, respectively, none attributed to anakinra. CONCLUSION: We describe feasibility for delivering anakinra in acute ICH and provide preliminary safety data. We lacked power to test for effects on oedema thus further trials will be required

A Multi-Model Pipeline for Translational Intracerebral Haemorrhage Research

From Springer Nature via Jisc Publications RouterHistory: received 2020-05-15, rev-recd 2020-06-18, accepted 2020-06-23, registration 2020-06-24, pub-electronic 2020-07-07, online 2020-07-07, pub-print 2020-12Publication status: PublishedFunder: Stroke Association; doi: http://dx.doi.org/10.13039/501100000364; Grant(s): TSA LECT 2017/02, SA L-RC 19\100000Funder: Medical Research Council; doi: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/N013751/1Abstract: Apart from acute and chronic blood pressure lowering, we have no specific medications to prevent intracerebral haemorrhage (ICH) or improve outcomes once bleeding has occurred. One reason for this may be related to particular limitations associated with the current pre-clinical models of ICH, leading to a failure to translate into the clinic. It would seem that a breakdown in the ‘drug development pipeline’ currently exists for translational ICH research which needs to be urgently addressed. Here, we review the most commonly used pre-clinical models of ICH and discuss their advantages and disadvantages in the context of translational studies. We propose that to increase our chances of successfully identifying new therapeutics for ICH, a bi-directional, 2- or 3-pronged approach using more than one model species/system could be useful for confirming key pre-clinical observations. Furthermore, we highlight that post-mortem/ex-vivo ICH patient material is a precious and underused resource which could play an essential role in the verification of experimental results prior to consideration for further clinical investigation. Embracing multidisciplinary collaboration between pre-clinical and clinical ICH research groups will be essential to ensure the success of this type of approach in the future

Oedema extension distance in intracerebral haemorrhage: Association with baseline characteristics and long-term outcome

Introduction: Oedema extension distance is a derived parameter that may reduce sample size requirements to demonstrate reduction in perihaematomal oedema in early phase acute intracerebral haemorrhage trials. We aimed to identify baseline predictors of oedema extension distance and its association with clinical outcomes. Patients and methods: Using Virtual International Stroke Trials Archive-Intracerebral Haemorrhage, first Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial, and Minimally Invasive Surgery and rtPA for Intracerebral Hemorrhage Evacuation II datasets, we calculated oedema extension distance at baseline and at 72 h measured using computed tomography. Using linear regression, we tested for associations between baseline characteristics and oedema extension distance at 72 h. Ordinal regression (underlying assumptions validated) was used to test for associations between oedema extension distance at baseline and 72 h and oedema extension distance change between baseline and 72 h, and modified Rankin scale scores at 90 days, adjusted for baseline and 72 h prognostic factors. Results: There were 1028 intracerebral haemorrhage cases with outcome data for analyses. Mean (standard deviation, SD) oedema extension distance at 72 h was 0.54 (0.26) cm, and mean oedema extension distance difference from baseline (EED72–0) was 0.24 (0.18) cm. Oedema extension distance at 72 h was greater with increasing baseline haematoma volume and baseline oedema extension distance. Increasing age, lobar haemorrhage, and intraventricular haemorrhage were independently associated with EED72–0. In multifactorial ordinal regression analysis, EED72–0 was associated with worse modified Rankin scale scores at 90 days (odds ratio 1.96, 95% confidence interval 1.00–3.82). Discussion: Increase in oedema extension distance over 72 h is independently associated with decreasing functional outcome at 90 days. Oedema extension distance may be a useful surrogate outcome measure in early phase trials of anti-oedema or anti-inflammatory treatments in intracerebral haemorrhage

Early inflammatory cytokine expression in cerebrospinal fluid of patients with spontaneous intraventricular hemorrhage

We investigated cerebrospinal fluid (CSF) expression of inflammatory cytokines and their relationship with spontaneous intracerebral and intraventricular hemorrhage (ICH, IVH) and perihematomal edema (PHE) volumes in patients with acute IVH. Twenty-eight adults with IVH requiring external ventricular drainage for obstructive hydrocephalus had cerebrospinal fluid (CSF) collected for up to 10 days and had levels of interleukin-1α (IL-1α), IL-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNFα), and C-C motif chemokine ligand CCL2 measured using enzyme-linked immunosorbent assay. Median [IQR] ICH and IVH volumes at baseline (T0) were 19.8 [5.8–48.8] and 14.3 [5.3–38] mL respectively. Mean levels of IL-1β, IL-6, IL-10, TNF-α, and CCL2 peaked early compared to day 9–10 (p < 0.05) and decreased across subsequent time periods. Levels of IL-1β, IL-6, IL-8, IL-10, and CCL2 had positive correlations with IVH volume at days 3–8 whereas positive correlations with ICH volume occurred earlier at day 1–2. Significant correlations were found with PHE volume for IL-6, IL-10 and CCL2 at day 1–2 and with relative PHE at days 7–8 or 9–10 for IL-1β, IL-6, IL-8, and IL-10. Time trends of CSF cytokines support experimental data suggesting association of cerebral inflammatory responses with ICH/IVH severity. Pro-inflammatory markers are potential targets for injury reduction