SummaryBackgroundIntracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography.MethodsIn a systematic review of OVID MEDLINE—with additional hand-searching of relevant studies' bibliographies— from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5–24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known.FindingsOf 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56–76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36–0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46–11·60; p<0·0001), antiplatelet use (1·68, 1·06–2·66; p=0·026), and anticoagulant use (3·48, 1·96–6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75–0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95–6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03–0·07).InterpretationIn this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects i...

Background and Purpose-Lower respiratory tract infections frequently complicate stroke and adversely affect outcome. There is currently no agreed terminology or gold-standard diagnostic criteria for the spectrum of lower respiratory tract infections complicating stroke, which has implications for clinical practice and research. The aim of this consensus was to propose standardized terminology and operational diagnostic criteria for lower respiratory tract infections complicating acute stroke. Methods-Systematic literature searches of multiple electronic databases were undertaken. An evidence review and 2 rounds of consensus consultation were completed before a final consensus meeting in September 2014, held in Manchester, United Kingdom. Consensus was defined a priori as ≥75% agreement between the consensus group members. Results-Consensus was reached for the following: (1) stroke-associated pneumonia (SAP) is the recommended terminology for the spectrum of lower respiratory tract infections within the first 7 days after stroke onset; (2) modified Centers for Disease Control and Prevention (CDC) criteria are proposed for SAP as follows-probable SAP: CDC criteria met, but typical chest x-ray changes absent even after repeat or serial chest x-ray; definite SAP: CDC criteria met, including typical chest x-ray changes; (3) there is limited evidence for a diagnostic role of white blood cell count or C-reactive protein in SAP; and (4) there is insufficient evidence for the use of other biomarkers (eg, procalcitonin). Conclusions-Consensus operational criteria for the terminology and diagnosis of SAP are proposed based on the CDC criteria. These require prospective evaluation in patients with stroke to determine their reliability, validity, impact on clinician behaviors (including antibiotic prescribing), and clinical outcomes.

F o r S t r o k Background and PurposeThe pro-inflammatory cytokine interleukin-1 (IL-1) has a deleterious role in cerebral ischemia, which is attenuated by IL-1 receptor antagonist (IL-1Ra). IL-1 induces peripheral inflammatory mediators, such as interleukin-6 (IL-6), which are associated with worse prognosis after ischemic stroke. We investigated whether subcutaneous (SC) IL-1Ra reduces the peripheral inflammatory response in acute ischemic stroke. MethodsSCIL-STROKE was a single-center, double-blind, randomized, placebo-controlled phase 2 trial of SC IL-1Ra (100mg administered twice daily for three days) in patients presenting within 5h of ischemic stroke onset. Randomization was stratified for baseline NIHSS score and thrombolysis. Measurement of plasma IL-6 and other peripheral inflammatory markers was undertaken at five time points. The primary outcome was difference in concentration of log(IL-6) as area under the curve to Day 3. Secondary outcomes included exploratory effect of IL-1Ra on three month outcome with the modified Rankin Scale (mRS). ResultsWe recruited 80 patients (mean age 72, median NIHSS 12) of whom 73% received intravenous thrombolysis with alteplase. IL-1Ra significantly reduced plasma and plasma C-reactive protein (p<0.001). IL-1Ra was well-tolerated with no safety concerns.Allocation to IL-1Ra was not associated with a favorable outcome on mRS: OR (95% CI) = 0.67 (0.29 to 1.52); p=0.34. Exploratory mediation analysis suggested that IL-1Ra improved clinical outcome by reducing inflammation, but there was a statistically significant, alternative mechanism countering this benefit. ConclusionsIL-1Ra reduced plasma inflammatory markers which are known to be associated with worse clinical outcome in ischemic stroke. SC IL-1Ra is safe and well-tolerated. Further 3

Although a number of studies indicate that the pyrogenic activity of lipopolysaccharide (LPS) and/or interleukin (IL)-1 is mediated via induction of IL-6, this has been questioned by recent evidence demonstrating a dissociation between fever and circulating IL-6. The present study reexamines this relationship by use of human recombinant interleukin-1 receptor antagonist (IL-1ra). Injection of LPS (100 micrograms/kg ip) into rats induced fever (2.0 degrees C) that was significantly inhibited (P < 0.05) when IL-1ra (16 mg/kg ip) was given 1 and 2 h after LPS. The rise in plasma IL-6 preceded the febrile response by 1-1.5 h and, although the concentrations of bioactive IL-6 in plasma and cerebrospinal fluid (CSF) were not reduced at 4 h, at 2 h plasma and CSF IL-6 bioactivity was inhibited by 80 and 70%, respectively, after a single injection of IL-1ra (16 mg/kg ip). Intracerebroventricular injection of IL-1ra (200 micrograms/rat) inhibited LPS fever but did not affect the plasma IL-6 bioactivity measured 2 or 4 h after intraperitoneal LPS. These data show that peripheral IL-1 plays a part in the induction of both fever and the rise in plasma IL-6 that precedes it, and that IL-1 within the brain is also important in the induction of fever by LPS.