Perihaematomal oedema evolution over two weeks after spontaneous intracerebral haemorrhage and association with outcome: prospective cohort study.

Introduction We know little about the evolution of perihaematomal oedema (PHO) >24 hours after ICH onset. We aimed to determine the trajectory of PHO after ICH onset and its association with outcome. Methods We did a prospective cohort study using a pre-specified scanning protocol in adults with first-ever spontaneous ICH and measured absolute PHO volumes on CT head scans at ICH diagnosis and 3±2, 7±2 and 14±2 days after ICH onset. We used the largest ICH if ICHs were multiple. The primary outcomes were (a) the trajectory of PHO after ICH onset and (b) the association between PHO (absolute volume at the time when most repeat CT head scans were obtained, and change in PHO volume at this time compared with the first CT head scan) and poor functional outcome (modified Rankin scale 3-6 at 90 days). We pre-specified multivariable logistic regression models of this association adjusting analyses for potential confounders: age, GCS, infratentorial ICH location and intraventricular extension. Results In 106 participants of whom forty nine (46%) were female, with a median ICH volume 7ml (interquartile range [IQR] 2-22ml), the trajectory of median PHO volume was an increase from 14ml (IQR 7-26ml) at diagnosis to 18ml (IQR 8-40ml) at 3±2 days (n=87), 20ml (IQR 8-48ml) at 7±2 days (n=93) and 21ml (IQR 10-54ml) at 14±2 days (n=78) (p=<0.001). PHO volume at each time point was collinear with ICH volume at diagnosis (│r│>0.7) but the change in PHO volume between diagnosis and each time point was not. Given collinearity, we used total lesion (i.e. ICH+PHO) volume instead of PHO volume in a logistic regression model of its association at each time point with outcome. Increasing total lesion (ICH+PHO) volume at day 7±2 was associated with poor functional outcome (adjusted OR per ml 1.02, 95% CI 1.00-1.03; p=0.036) but the increase in PHO volume between diagnosis and day 7±2 was not associated with poor functional outcome (adjusted OR per ml 1.03, 95% CI 0.99-1.07; p=0.132). Conclusion PHO volume increases throughout the first two weeks after onset of mild to moderate ICH. Total lesion (ICH+PHO) volume at day 7±2 was associated with poor functional outcome but the change in PHO volume between diagnosis and day 7±2 was not. Prospective cohort studies with larger sample sizes are needed to investigate these associations and their modifiers.

Baseline perihematomal edema, C-reactive protein, and 30-day mortality are not associated in intracerebral hemorrhage.

Background: The relationship between baseline perihematomal edema (PHE) and inflammation, and their impact on survival after intracerebral hemorrhage (ICH) are not well understood. Objective: Assess the association between baseline PHE, baseline C-reactive protein (CRP), and early death after ICH. Methods: Analysis of pooled data from multicenter ICH registries. We included patients presenting within 24 h of symptom onset, using multifactorial linear regression model to assess the association between CRP and edema extension distance (EED), and a multifactorial Cox regression model to assess the association between CRP, PHE volume and 30-day mortality. Results: We included 1,034 patients. Median age was 69 (interquartile range [IQR] 59-79), median baseline ICH volume 11.5 (IQR 4.3-28.9) mL, and median baseline CRP 2.5 (IQR 1.5-7.0) mg/L. In the multifactorial analysis [adjusting for cohort, age, sex, log-ICH volume, ICH location, intraventricular hemorrhage (IVH), statin use, glucose, and systolic blood pressure], baseline log-CRP was not associated with baseline EED: for a 50% increase in CRP the difference in expected mean EED was 0.004 cm (95%CI 0.000-0.008, p = 0.055). In a further multifactorial analysis, after adjusting for key predictors of mortality, neither a 50% increase in PHE volume nor CRP were associated with higher 30-day mortality (HR 0.97; 95%CI 0.90-1.05, p = 0.51 and HR 0.98; 95%CI 0.93-1.03, p = 0.41, respectively). Conclusion: Higher baseline CRP is not associated with higher baseline edema, which is also not associated with mortality. Edema at baseline might be driven by different pathophysiological processes with different effects on outcome.

Prehospital identification of intracerebral haemorrhage: a scoping review of early clinical features and portable devices.

INTRODUCTION: Prehospital identification of intracerebral haemorrhage (ICH) in suspected stroke cases may enable the initiation of appropriate treatments and facilitate better-informed transport decisions. This scoping review aims to examine the literature to identify early clinical features and portable devices for the detection of ICH in the prehospital setting. METHODS: Three databases were searched via Ovid (MEDLINE, EMBASE and CENTRAL) from inception to August 2022 using prespecified search strategies. One reviewer screened all titles, abstracts and full-text articles for eligibility, while a second reviewer independently screened 20% of the literature during each screening stage. Data extracted were tabulated to summarise the key findings. RESULTS: A total of 6803 articles were screened for eligibility, of which 22 studies were included for analysis. Among them, 15 studies reported on early clinical features, while 7 considered portable devices. Associations between age, sex and comorbidities with the presence of ICH varied across studies. However, most studies reported that patients with ICH exhibited more severe neurological deficits (n=6) and higher blood pressure levels (n=11) at onset compared with other stroke and non-stroke diagnoses. Four technologies were identified for ICH detection: microwave imaging technology, volumetric impedance phase shift spectroscopy, transcranial ultrasound and electroencephalography. Microwave and ultrasound imaging techniques showed promise in distinguishing ICH from other diagnoses. CONCLUSION: This scoping review has identified potential clinical features for the identification of ICH in suspected stroke patients. However, the considerable heterogeneity among the included studies precludes meta-analysis of available data. Moreover, we have explored portable devices to enhance ICH identification. While these devices have shown promise in detecting ICH, further technological development is required to distinguish between stroke subtypes (ICH vs ischaemic stroke) and non-stroke diagnoses.

Acute care bundles should be used for patients with intracerebral haemorrhage: An expert consensus statement.

PURPOSE: Intracerebral haemorrhage (ICH) is the most devastating form of stroke and a major cause of disability. Clinical trials of individual therapies have failed to definitively establish a specific beneficial treatment. However, clinical trials of introducing care bundles, with multiple therapies provided in parallel, appear to clearly reduce morbidity and mortality. Currently, not enough patients receive these interventions in the acute phase. METHODS: We convened an expert group to discuss best practices in ICH and to develop recommendations for bundled care that can be delivered in all settings that treat acute ICH, with a focus on European healthcare systems. FINDINGS: In this consensus paper, we argue for widespread implementation of formalised care bundles in ICH, including specific metrics for time to treatment and criteria for the consideration of neurosurgical therapy. DISCUSSION: There is an extraordinary opportunity to improve clinical care and clinical outcomes in this devastating disease. Substantial evidence already exists for a range of therapies that can and should be implemented now.

Code ICH: A Call to Action.

Intracerebral hemorrhage is the most serious type of stroke, leading to high rates of severe disability and mortality. Hematoma expansion is an independent predictor of poor functional outcome and is a compelling target for intervention. For decades, randomized trials aimed at decreasing hematoma expansion through single interventions have failed to meet their primary outcomes of statistically significant improvement in neurological outcomes. A wide range of evidence suggests that ultra-early bundled care, with multiple simultaneous interventions in the acute phase, offers the best hope of limiting hematoma expansion and improving functional recovery. Patients with intracerebral hemorrhage who fail to receive early aggressive care have worse outcomes, suggesting that an important treatment opportunity exists. This consensus statement puts forth a call to action to establish a protocol for Code ICH, similar to current strategies used for the management of acute ischemic stroke, through which early intervention, bundled care, and time-based metrics have substantially improved neurological outcomes. Based on current evidence, we advocate for the widespread adoption of an early bundle of care for patients with intracerebral hemorrhage focused on time-based metrics for blood pressure control and emergency reversal of anticoagulation, with the goal of optimizing the benefit of these already widely used interventions. We hope Code ICH will endure as a structural platform for continued innovation, standardization of best practices, and ongoing quality improvement for years to come.

Effects of oral anticoagulation in people with atrial fibrillation after spontaneous intracranial haemorrhage (COCROACH): prospective, individual participant data meta-analysis of randomised trials.

BACKGROUND: The safety and efficacy of oral anticoagulation for prevention of major adverse cardiovascular events in people with atrial fibrillation and spontaneous intracranial haemorrhage are uncertain. We planned to estimate the effects of starting versus avoiding oral anticoagulation in people with spontaneous intracranial haemorrhage and atrial fibrillation. METHODS: In this prospective meta-analysis, we searched bibliographic databases and trial registries using the strategies of a Cochrane systematic review (CD012144) on June 23, 2023. We included clinical trials if they were registered, randomised, and included participants with spontaneous intracranial haemorrhage and atrial fibrillation who were assigned to either start long-term use of any oral anticoagulant agent or avoid oral anticoagulation (ie, placebo, open control, another antithrombotic agent, or another intervention for the prevention of major adverse cardiovascular events). We assessed eligible trials using the Cochrane Risk of Bias tool. We sought data for individual participants who had not opted out of data sharing from chief investigators of completed trials, pending completion of ongoing trials in 2028. The primary outcome was any stroke or cardiovascular death. We used individual participant data to construct a Cox regression model of the time to the first occurrence of outcome events during follow-up in the intention-to-treat dataset supplied by each trial, followed by meta-analysis using a fixed-effect inverse-variance model to generate a pooled estimate of the hazard ratio (HR) with 95% CI. This study is registered with PROSPERO, CRD42021246133. FINDINGS: We identified four eligible trials; three were restricted to participants with atrial fibrillation and intracranial haemorrhage (SoSTART [NCT03153150], with 203 participants) or intracerebral haemorrhage (APACHE-AF [NCT02565693], with 101 participants, and NASPAF-ICH [NCT02998905], with 30 participants), and one included a subgroup of participants with previous intracranial haemorrhage (ELDERCARE-AF [NCT02801669], with 80 participants). After excluding two participants who opted out of data sharing, we included 412 participants (310 [75%] aged 75 years or older, 249 [60%] with CHA2DS2-VASc score ≤4, and 163 [40%] with CHA2DS2-VASc score >4). The intervention was a direct oral anticoagulant in 209 (99%) of 212 participants who were assigned to start oral anticoagulation, and the comparator was antiplatelet monotherapy in 67 (33%) of 200 participants assigned to avoid oral anticoagulation. The primary outcome of any stroke or cardiovascular death occurred in 29 (14%) of 212 participants who started oral anticoagulation versus 43 (22%) of 200 who avoided oral anticoagulation (pooled HR 0·68 [95% CI 0·42-1·10]; I2=0%). Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events (nine [4%] of 212 vs 38 [19%] of 200; pooled HR 0·27 [95% CI 0·13-0·56]; I2=0%). There was no significant increase in haemorrhagic major adverse cardiovascular events (15 [7%] of 212 vs nine [5%] of 200; pooled HR 1·80 [95% CI 0·77-4·21]; I2=0%), death from any cause (38 [18%] of 212 vs 29 [15%] of 200; 1·29 [0·78-2·11]; I2=50%), or death or dependence after 1 year (78 [53%] of 147 vs 74 [51%] of 145; pooled odds ratio 1·12 [95% CI 0·70-1·79]; I2=0%). INTERPRETATION: For people with atrial fibrillation and intracranial haemorrhage, oral anticoagulation had uncertain effects on the risk of any stroke or cardiovascular death (both overall and in subgroups), haemorrhagic major adverse cardiovascular events, and functional outcome. Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events, which can inform clinical practice. These findings should encourage recruitment to, and completion of, ongoing trials. FUNDING: British Heart Foundation.

Management of major bleeding for anticoagulated patients in the Emergency Department: an European experts consensus statement.

An increasing number of patients presenting to the emergency department (ED) with life-threatening bleeding are using oral anticoagulants, such as warfarin, Factor IIa and Factor Xa inhibitors. Achieving rapid and controlled haemostasis is critically important to save the patient's life. This multidisciplinary consensus paper provides a systematic and pragmatic approach to the management of anticoagulated patients with severe bleeding at the ED. Repletion and reversal management of the specific anticoagulants is described in detail. For patients on vitamin K antagonists, the administration of vitamin K and repletion of clotting factors with four-factor prothrombin complex concentrate provides real-time ability to stop the bleeding. For patients using a direct oral anticoagulant, specific antidotes are necessary to reverse the anticoagulative effect. For patients receiving the thrombin inhibitor dabigatran, treatment with idarucizamab has been demonstrated to reverse the hypocoagulable state. For patients receiving a factor Xa inhibitor (apixaban or rivaroxaban), andexanet alfa is the indicated antidote in patients with major bleeding. Lastly, specific treatment strategies are discussed in patients using anticoagulants with major traumatic bleeding, intracranial haemorrhage or gastrointestinal bleeding.

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.

Clinical features and novel technologies for prehospital detection of intracerebral haemorrhage: a scoping review protocol.

INTRODUCTION: The detection of intracerebral haemorrhage (ICH) in the prehospital setting without conventional imaging technology might allow early treatment to reduce haematoma expansion and improve patient outcomes. Although ICH and ischaemic stroke share many clinical features, some may help in distinguishing ICH from other suspected stroke patients. In combination with clinical features, novel technologies may improve diagnosis further. This scoping review aims to first identify the early, distinguishing clinical features of ICH and then identify novel portable technologies that may enhance differentiation of ICH from other suspected strokes. Where appropriate and feasible, meta-analyses will be performed. METHODS: The scoping review will follow the recommendations of the Joanna Briggs Institute Methodology for Scoping Reviews as well as the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist. A systematic search will be conducted using MEDLINE (Ovid), EMBASE (Ovid) and CENTRAL (Ovid). EndNote reference management software will be used to remove duplicate entries. Two independent reviewers will screen titles, abstracts and full-text reports according to prespecified eligibility criteria using the Rayyan Qatar Computing Research Institute software. One reviewer will screen all titles, abstracts and full-text reports of potentially eligible studies, while the other reviewer will independently screen at least 20% of all titles, abstracts and full-text reports. Conflicts will be resolved through discussion or by consulting a third reviewer. Results will be tabulated in accordance with the scoping review's objectives along with a narrative discussion. ETHICS AND DISSEMINATION: Ethical approval is not required for this review, as it will only include published literature. The results will be published in an open-access, peer-reviewed journal, presented at scientific conferences and form part of a PhD thesis. We expect the findings to contribute to future research into the early detection of ICH in suspected stroke patients.

Early mobilisation is associated with lower subacute blood pressure and variability in ICH: A retrospective cohort study✰.

BACKGROUND: Very early rehabilitation after stroke appears to worsen outcome, particularly in intracerebral haemorrhage (ICH). Plausible mechanisms include increased mean blood pressure (BP) and BP variability. AIMS: To test associations between early mobilisation, subacute BP and survival, in observational data of ICH patients during routine clinical care. METHODS: We collected demographic, clinical and imaging data from 1372 consecutive spontaneous ICH patients admitted between 2 June 2013 and 28 September 2018. Time to first mobilisation (defined as walking, standing, or sitting out-of-bed) was extracted from electronic records. We evaluated associations between early mobilisation (within 24 h of onset) and both subacute BP and death by 30 days using multifactorial linear and logistic regression analyses respectively. RESULTS: Mobilisation at 24 h was not associated with increased odds of death by 30 days when adjusting for key prognostic factors (OR 0.4, 95% CI 0.2 to 1.1, p = 0.07). Mobilisation at 24 h was independently associated with both lower mean systolic BP (-4.5 mmHg, 95% CI -7.5 to -1.5 mmHg, p = 0.003) and lower diastolic BP variability (-1.3 mmHg, 95% CI -2.4 to -0.2 mg, p = 0.02) during the first 72 h after admission. CONCLUSIONS: Adjusted analysis in this observational dataset did not find an association between early mobilisation and death by 30 days. We found early mobilisation at 24 h to be independently associated with lower mean systolic BP and lower diastolic BP variability over 72 h. Further work is needed to establish mechanisms for the possible detrimental effect of early mobilisation in ICH.

The Future of LAAC-In 5, 10, and 20 Years.

Early experience with percutaneous LAA closure documented complication rates of ∼10%, with failure to implant devices in ∼10% of patients. These numbers are unrecognizable in contemporary practice due to the iterative changes made largely in the last 10 years. Here we look forward to ask what might change, and when, to bring percutaneous LAA closure out of the niche early adopter centers into routine use. We consider the opportunity to incorporate different technologies into LAAc devices in the context of managing patient with atrial fibrillation. Finally, we consider how to make the procedure safer and more effective.

Intracerebral haemorrhage.

Intracerebral haemorrhage (ICH) is a dramatic condition caused by the rupture of a cerebral vessel and the entry of blood into the brain parenchyma. ICH is a major contributor to stroke-related mortality and dependency: only half of patients survive for 1 year after ICH, and patients who survive have sequelae that affect their quality of life. The incidence of ICH has increased in the past few decades with shifts in the underlying vessel disease over time as vascular prevention has improved and use of antithrombotic agents has increased. The pathophysiology of ICH is complex and encompasses mechanical mass effect, haematoma expansion and secondary injury. Identifying the causes of ICH and predicting the vital and functional outcome of patients and their long-term vascular risk have improved in the past decade; however, no specific treatment is available for ICH. ICH remains a medical emergency, with prevention of haematoma expansion as the key therapeutic target. After discharge, secondary prevention and management of vascular risk factors in patients remains challenging and is based on an individual benefit-risk balance evaluation.

Prevention of venous thromboembolism in acute spontaneous intracerebral haemorrhage: A survey of opinion.

INTRODUCTION: People immobilized following acute spontaneous intracerebral haemorrhage (ICH) are at risk of venous thromboembolism (VTE) but the role of short-term prophylactic anticoagulation remains uncertain. We surveyed UK clinical practice and opinion regarding preventing VTE after ICH. PATIENTS AND METHODS: An online survey was sent to stroke healthcare professionals within the United Kingdom and Ireland via a professional society (British and Irish Association of Stroke Physicians (BIASP)). RESULTS: One hundred and twenty-three staff members responded to the survey, of whom 80% were consultant stroke physicians. All responders except one considered the issue to be important or extremely important, but only 5 (4%) were "extremely certain" and 51 (41%) "fairly certain" regarding the optimal treatment approach. Intermittent pneumatic compression (IPC) devices alone were the most used method (in 60%) followed by IPC devices and switching to low molecular weight heparin (LMWH) (in 30%). We identified high levels of uncertainty regarding the role of anticoagulation, and its optimal timing; uncertainty was greater in lobar compared to deep ICH. Most respondents (93%) consider a randomised controlled trial investigating the role of pharmacological VTE prophylaxis after acute ICH as important and would consider participation. DISCUSSION AND CONCLUSION: The optimal method for the prevention of VTE in non-traumatic ICH patients remains an area of clinical uncertainty. Clinical trials assessing short-term anticoagulation in patients after acute ICH would be beneficial in providing evidence to resolve this clinical dilemma.

Selective brain entry of lipid nanoparticles in haemorrhagic stroke is linked to biphasic blood-brain barrier disruption.

Haemorrhagic stroke represents a significant public health burden, yet our knowledge and ability to treat this type of stroke are lacking. Previously we showed that we can target ischaemic-stroke lesions by selective translocation of lipid nanoparticles through the site of blood-brain barrier (BBB) disruption. The data we presented in this study provide compelling evidence that haemorrhagic stroke in mice induces BBB injury that mimics key features of the human pathology and, more importantly, provides a gate for entry of lipid nanoparticles-based therapeutics selectively to the bleeding site. Methods: Haemorrhagic stroke was induced in mice by intra-striatal collagenase injection. lipid nanoparticles were injected intravenously at 3 h, 24 h & 48 h post-haemorrhagic stroke and accumulation in the brain studied using in-vivo optical imaging and histology. BBB integrity, brain water content and iron accumulation were characterised using dynamic contrast-enhanced MRI, quantitative T1 mapping, and gradient echo MRI. Results: Using in-vivo SPECT/CT imaging and optical imaging revealed biphasic lipid nanoparticles entry into the bleeding site, with an early phase of increased uptake at 3-24 h post-haemorrhagic stroke, followed by a second phase at 48-72 h. Lipid nanoparticles entry into the brain post-haemorrhage showed an identical entry pattern to the trans-BBB leakage rate (Ktrans [min-1]) of Gd-DOTA, a biomarker for BBB disruption, measured using dynamic contrast-enhanced MRI. Discussion: Our findings suggest that selective accumulation of liposomes into the lesion site is linked to a biphasic pattern of BBB hyper-permeability. This approach provides a unique opportunity to selectively and efficiently deliver therapeutic molecules across the BBB, an approach that has not been utilised for haemorrhagic stroke therapy and is not achievable using free small drug molecules.

Iatrogenic cerebral amyloid angiopathy: an emerging clinical phenomenon.

In the last 6 years, following the first pathological description of presumed amyloid-beta (Aß) transmission in humans (in 2015) and subsequent experimental confirmation (in 2018), clinical cases of iatrogenic cerebral amyloid angiopathy (CAA)-attributed to the transmission of Aß seeds-have been increasingly recognised and reported. This newly described form of CAA is associated with early disease onset (typically in the third to fifth decade), and often presents with intracerebral haemorrhage, but also seizures and cognitive impairment. Although assumed to be rare, it is important that clinicians remain vigilant for potential cases, particularly as the optimal management, prognosis, true incidence and public health implications remain unknown. This review summarises our current understanding of the clinical spectrum of iatrogenic CAA and provides a diagnostic framework for clinicians. We provide clinical details for three patients with pathological evidence of iatrogenic CAA and present a summary of the published cases to date (n=20), identified following a systematic review. Our aims are: (1) To describe the clinical features of iatrogenic CAA, highlighting important similarities and differences between iatrogenic and sporadic CAA; and (2) To discuss potential approaches for investigation and diagnosis, including suggested diagnostic criteria for iatrogenic CAA.

Scale-up of ABC care bundle for intracerebral haemorrhage across two hyperacute stroke units in one region in England: a mixed methods evaluation of a quality improvement project.

BACKGROUND: Intracerebral haemorrhage (ICH) accounts for 10%-15% of strokes in the UK, but is responsible for half of all annual global stroke deaths. The ABC bundle for ICH was developed and implemented at Salford Royal Hospital, and was associated with a 44% reduction in 30-day case fatality. Implementation of the bundle was scaled out to the other hyperacute stroke units (HASUs) in the region from April 2017. A mixed methods evaluation was conducted alongside to investigate factors influencing implementation of the bundle across new settings, in order to provide lessons for future spread. METHODS: A harmonised quality improvement registry at each HASU captured consecutive patients with spontaneous ICH from October 2016 to March 2018 to capture process and outcome measures for preimplementation (October 2016 to March 2017) and implementation (April 2017 to March 2018) time periods. Statistical analyses were performed to determine differences in process measures and outcomes before and during implementation. Multiple qualitative methods (interviews, non-participant observation and project document analysis) captured how the bundle was implemented across the HASUs. RESULTS: HASU1 significantly reduced median anticoagulant reversal door-to-needle time from 132 min (IQR: 117-342) preimplementation to 76 min (64-113.5) after implementation and intensive blood pressure lowering door to target time from 345 min (204-866) preimplementation to 84 min (60-117) after implementation. No statistically significant improvements in process targets were observed at HASU2. No significant change was seen in 30-day mortality at either HASU. Qualitative evaluation identified the importance of facilitation during implementation and identified how contextual changes over time impacted on implementation. This identified the need for continued implementation support. CONCLUSION: The findings show how the ABC bundle can be successfully implemented into new settings and how challenges can impede implementation. Findings have been used to develop an implementation strategy to support future roll out of the bundle outside the region.

The Future of LAAC-In 5, 10, and 20 Years.

Early experience with percutaneous LAA closure documented complication rates of ∼10%, with failure to implant devices in ∼10% of patients. These numbers are unrecognizable in contemporary practice due to the iterative changes made largely in the last 10 years. Here we look forward to ask what might change, and when, to bring percutaneous LAA closure out of the niche early adopter centers into routine use. We consider the opportunity to incorporate different technologies into LAAc devices in the context of managing patient with atrial fibrillation. Finally, we consider how to make the procedure safer and more effective.

Hyperacute prediction of functional outcome in spontaneous intracerebral haemorrhage: systematic review and meta-analysis.

Purpose: To describe the association between factors routinely available in hyperacute care of spontaneous intracerebral haemorrhage (ICH) patients and functional outcome. Methods: We searched Medline, Embase and CINAHL in February 2020 for original studies reporting associations between markers available within six hours of arrival in hospital and modified Rankin Scale (mRS) at least 6 weeks post-ICH. A random-effects meta-analysis was performed where three or more studies were included. Findings: Thirty studies were included describing 40 markers. Ten markers underwent meta-analysis and age (OR = 1.06; 95%CI = 1.05 to 1.06; p < 0.001), pre-morbid dependence (mRS, OR = 1.73; 95%CI = 1.52 to 1.96; p < 0.001), level of consciousness (Glasgow Coma Scale, OR = 0.82; 95%CI = 0.76 to 0.88; p < 0.001), stroke severity (National Institutes of Health Stroke Scale, OR=1.19; 95%CI = 1.13 to 1.25; p < 0.001), haematoma volume (OR = 1.12; 95%CI=1.07 to 1.16; p < 0.001), intraventricular haemorrhage (OR = 2.05; 95%CI = 1.68 to 2.51; p < 0.001) and deep (vs. lobar) location (OR = 2.64; 95%CI = 1.65 to 4.24; p < 0.001) were predictive of outcome but systolic blood pressure, CT hypodensities and infratentorial location were not. Of the remaining markers, sex, medical history (diabetes, hypertension, prior stroke), prior statin, prior antiplatelet, admission blood results (glucose, cholesterol, estimated glomerular filtration rate) and other imaging features (midline shift, spot sign, sedimentation level, irregular haematoma shape, ultraearly haematoma growth, Graeb score and onset to CT time) were associated with outcome. Conclusion: Multiple demographic, pre-morbid, clinical, imaging and laboratory factors should all be considered when prognosticating in hyperacute ICH. Incorporating these in to accurate and precise models will help to ensure appropriate levels of care for individual patients.

Zebrafish drug screening identifies candidate therapies for neuroprotection after spontaneous intracerebral haemorrhage.

Despite the global health burden, treatment of spontaneous intracerebral haemorrhage (ICH) is largely supportive, and translation of specific medical therapies has not been successful. Zebrafish larvae offer a unique platform for drug screening to rapidly identify neuroprotective compounds following ICH. We applied the Spectrum Collection library compounds to zebrafish larvae acutely after ICH to screen for decreased brain cell death and identified 150 successful drugs. Candidates were then evaluated for possible indications with other cardiovascular diseases. Six compounds were identified, including two angiotensin-converting enzyme inhibitors (ACE-Is). Ramipril and quinapril were further assessed to confirm a significant 55% reduction in brain cell death. Proteomic analysis revealed potential mechanisms of neuroprotection. Using the INTERACT2 clinical trial dataset, we demonstrated a significant reduction in the adjusted odds of an unfavourable shift in the modified Rankin scale at 90 days for patients receiving an ACE-I after ICH (versus no ACE-I; odds ratio, 0.80; 95% confidence interval, 0.68-0.95; P=0.009). The zebrafish larval model of spontaneous ICH can be used as a reliable drug screening platform and has identified therapeutics that may offer neuroprotection. This article has an associated First Person interview with the first author of the paper.