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.

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.

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.

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.

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.

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.

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.

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.

Co-design of a Smartphone App for People Living With Dementia by Applying Agile, Iterative Co-design Principles: Development and Usability Study.

BACKGROUND: The benefits of involving those with lived experience in the design and development of health technology are well recognized, and the reporting of co-design best practices has increased over the past decade. However, it is important to recognize that the methods and protocols behind patient and public involvement and co-design vary depending on the patient population accessed. This is especially important when considering individuals living with cognitive impairments, such as dementia, who are likely to have needs and experiences unique to their cognitive capabilities. We worked alongside individuals living with dementia and their care partners to co-design a mobile health app. This app aimed to address a gap in our knowledge of how cognition fluctuates over short, microlongitudinal timescales. The app requires users to interact with built-in memory tests multiple times per day, meaning that co-designing a platform that is easy to use, accessible, and appealing is particularly important. Here, we discuss our use of Agile methodology to enable those living with dementia and their care partners to be actively involved in the co-design of a mobile health app. OBJECTIVE: The aim of this study is to explore the benefits of co-design in the development of smartphone apps. Here, we share our co-design methodology and reflections on how this benefited the completed product. METHODS: Our app was developed using Agile methodology, which allowed for patient and care partner input to be incorporated iteratively throughout the design and development process. Our co-design approach comprised 3 core elements, aligned with the values of patient co-design and adapted to meaningfully involve those living with cognitive impairments: end-user representation at research and software development meetings via a patient proxy; equal decision-making power for all stakeholders based on their expertise; and continuous user consultation, user-testing, and feedback. RESULTS: This co-design approach resulted in multiple patient and care partner-led software alterations, which, without consultation, would not have been anticipated by the research team. This included 13 software design alterations, renaming of the product, and removal of a cognitive test deemed to be too challenging for the target demographic. CONCLUSIONS: We found patient and care partner input to be critical throughout the development process for early identification of design and usability issues and for identifying solutions not previously considered by our research team. As issues addressed in early co-design workshops did not reoccur subsequently, we believe this process made our product more user-friendly and acceptable, and we will formally test this assumption through future pilot-testing.

Radiologically defined acute hydrocephalus in aneurysmal subarachnoid haemorrhage.

BACKGROUND: Ventriculomegaly is common in aneurysmal subarachnoid haemorrhage (aSAH). An imaging measure to predict the need for cerebrospinal fluid (CSF) diversion may be useful. The bicaudate index (BCI) has been previously applied to aSAH. Our aim was to derive and test a threshold BCI above which CSF diversion may be required. METHODS: Review of prospective registry. The derivation group (2009-2015) included WFNS grade 1-2 aSAH patients who deteriorated clinically, had a repeat CT brain and underwent CSF diversion. BCI was measured on post-deterioration CTs and the lower limit of the 95% confidence interval (95%CI) was the hydrocephalus threshold. In a separate test group (2016), in WFNS ≥ 2 patients, we compared BCI on diagnostic CTs with CSF diversion within 24 hours. RESULTS: The derivation group (n = 62) received an external ventricular (n = 57, 92%) or lumbar drain (n = 5, 8%). Mean post-deterioration BCI was 0.19 (95%CI 0.17-0.22) for age ≤49 years, 0.22 (95%CI 0.20-0.23) for age 50-64 years and 0.24 (95%CI 0.22-0.27) for age ≥65 years. Hydrocephalus thresholds were therefore 0.17, 0.20 and 0.22, respectively. In the test group (n = 105), there was no significant difference in BCI on the diagnostic CT between good and poor grade patients aged ≤49 years (p = 0.31) and ≥65 years (p = 0.96). 30/66 WFNS ≥ 2 patients underwent CSF diversion, although only 15/30 (50%) exceeded BCI thresholds for hydrocephalus. CONCLUSION: A significant proportion of aSAH patients may undergo CSF diversion without objective evidence of hydrocephalus. Our threshold values require further testing but may provide an objective measure to aid clinical decision making in aSAH.

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-1ß, 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-1ß, 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-1ß, 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-1ß, 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.

Longitudinal transcriptomics define the stages of myeloid activation in the living human brain after intracerebral hemorrhage.

Opportunities to interrogate the immune responses in the injured tissue of living patients suffering from acute sterile injuries such as stroke and heart attack are limited. We leveraged a clinical trial of minimally invasive neurosurgery for patients with intracerebral hemorrhage (ICH), a severely disabling subtype of stroke, to investigate the dynamics of inflammation at the site of brain injury over time. Longitudinal transcriptional profiling of CD14+ monocytes/macrophages and neutrophils from hematomas of patients with ICH revealed that the myeloid response to ICH within the hematoma is distinct from that in the blood and occurs in stages conserved across the patient cohort. Initially, hematoma myeloid cells expressed a robust anabolic proinflammatory profile characterized by activation of hypoxia-inducible factors (HIFs) and expression of genes encoding immune factors and glycolysis. Subsequently, inflammatory gene expression decreased over time, whereas anti-inflammatory circuits were maintained and phagocytic and antioxidative pathways up-regulated. During this transition to immune resolution, glycolysis gene expression and levels of the potent proresolution lipid mediator prostaglandin E2 remained elevated in the hematoma, and unexpectedly, these elevations correlated with positive patient outcomes. Ex vivo activation of human macrophages by ICH-associated stimuli highlighted an important role for HIFs in production of both inflammatory and anti-inflammatory factors, including PGE2, which, in turn, augmented VEGF production. Our findings define the time course of myeloid activation in the human brain after ICH, revealing a conserved progression of immune responses from proinflammatory to proresolution states in humans after brain injury and identifying transcriptional programs associated with neurological recovery.

Therapeutic Variation in Lowering Blood Pressure: Effects on Intracranial Pressure in Acute Intracerebral Haemorrhage.

INTRODUCTION: Intracerebral haemorrhage (ICH) is associated with high morbidity and mortality. Blood pressure (BP) control is one of the main management strategies in acute ICH. Limited data currently exist regarding intracranial pressure (ICP) in acute ICH. The relationship between BP lowering and ICP is yet to be fully elucidated. METHODS: We conducted a systematic review to investigate the effects of BP lowering on ICP in acute ICH. The study protocol was registered on PROSPERO (CRD42019134470). RESULTS: Following PRISMA guidelines, MEDLINE, EMBASE and CENTRAL were searched for studies on ICH with BP and ICP or surrogate measures. 1096 articles were identified after duplicates were removed; 18 studies meeting the inclusion criteria. Dihydropyridine calcium channel blockers (CCBs) were the most common agent used to lower BP, but had a varying effect on ICP. Other BP-lowering agents used also had a varying effect on ICP. DISCUSSION AND CONCLUSION: Further work, including large observational or randomized interventional studies, is needed to develop a better understanding of the effect of BP lowering on ICP in acute ICH, which will assist the development of more effective management strategies. TRIAL REGISTRATION: The study protocol was registered on PROSPERO (CRD42019134470) on 29/05/2019.

Are do-not-resuscitate orders associated with limitations of care beyond their intended purpose in patients with acute intracerebral haemorrhage? Analysis of the ABC-ICH study.

Implementation of an acute bundle of care for intracerebral haemorrhage (ICH) was associated with a marked improvement in survival at our centre, mediated by a reduction in early (<24 hours) do-not-resuscitate (DNR) orders. The aim of this study was to identify possible mechanisms for this mediation. We retrospectively extracted additional data on resuscitation attempts and supportive care. This observational study utilised existing data collected for the Acute Bundle of Care for ICH (ABC-ICH) quality improvement project between from 2013 to 2017. The primary outcome was whether a patient received an early (<24 hours) DNR order. We used multivariable logistic regression to estimate the adjusted association between clinically meaningful factors, including an indicator for a change in treatment on the introduction of the ABC care bundle. Early DNR orders were associated with a reduced odds of escalation to critical care (OR: 0.07, 95% CI: 0.03 to 0.17, p<0.001). Commencement of palliative care within 72 hours was far more likely (OR: 8.76, 95% CI: 4.74 to 16.61, p<0.001) if an early DNR was in place. The cardiac arrest team were not called for an ICH patient before implementation but were called on five occasions overall during and after implementation. Further qualitative evaluation revealed that on only one occasion was there a cardiac or respiratory arrest with cardiopulmonary resuscitation performed. We found no significant increase in resuscitation attempts after bundle implementation but early DNR orders were associated with less admission to critical care and more early palliation. Early DNR orders are associated with less aggressive supportive care and should be judiciously used in acute ICH.

Revisiting promising preclinical intracerebral hemorrhage studies to highlight repurposable drugs for translation.

Intracerebral hemorrhage is a devastating global health burden with limited treatment options and is responsible for 49% of 6.5 million annual stroke-related deaths comparable to ischemic stroke. Despite the impact of intracerebral hemorrhage, there are currently no effective treatments and so weaknesses in the translational pipeline must be addressed. There have been many preclinical studies in intracerebral hemorrhage models with positive outcomes for potential therapies in vivo, but beyond advancing the understanding of intracerebral hemorrhage pathology, there has been no translation toward successful clinical application. Multidisciplinary preclinical research, use of multiple models, and validation in human tissue are essential for effective translation. Repurposing of therapeutics for intracerebral hemorrhage may be the most promising strategy to help relieve the global health burden of intracerebral hemorrhage. Here, we have reviewed the existing literature to highlight repurposable drugs with successful outcomes in preclinical models of intracerebral hemorrhage that have realistic potential for development into the clinic for intracerebral hemorrhage.

Acute intracerebral haemorrhage: diagnosis and management.

Intracerebral haemorrhage (ICH) accounts for half of the disability-adjusted life years lost due to stroke worldwide. Care pathways for acute stroke result in the rapid identification of ICH, but its acute management can prove challenging because no individual treatment has been shown definitively to improve its outcome. Nonetheless, acute stroke unit care improves outcome after ICH, patients benefit from interventions to prevent complications, acute blood pressure lowering appears safe and might have a modest benefit, and implementing a bundle of high-quality acute care is associated with a greater chance of survival. In this article, we address the important questions that neurologists face in the diagnosis and acute management of ICH, and focus on the supporting evidence and practical delivery for the main acute interventions.

Treatment of intracerebral hemorrhage: From specific interventions to bundles of care.

Intracerebral hemorrhage (ICH) represents a major, global, unmet health need with few treatments. A significant minority of ICH patients present taking an anticoagulant; both vitamin-K antagonists and increasingly direct oral anticoagulants. Anticoagulants are associated with an increased risk of hematoma expansion, and rapid reversal reduces this risk and may improve outcome. Vitamin-K antagonists are reversed with prothrombin complex concentrate, dabigatran with idarucizumab, and anti-Xa agents with PCC or andexanet alfa, where available. Blood pressure lowering may reduce hematoma growth and improve clinical outcomes and careful (avoiding reductions ≥60 mm Hg within 1 h), targeted (as low as 120-130 mm Hg), and sustained (minimizing variability) treatment during the first 24 h may be optimal for achieving better functional outcomes in mild-to-moderate severity acute ICH. Surgery for ICH may include hematoma evacuation and external ventricular drainage to treat hydrocephalus. No large, well-conducted phase III trial of surgery in ICH has so far shown overall benefit, but meta-analyses report an increased likelihood of good functional outcome and lower risk of death with surgery, compared to medical treatment only. Expert supportive care on a stroke unit or critical care unit improves outcomes. Early prognostication is difficult, and early do-not-resuscitate orders or withdrawal of active care should be used judiciously in the first 24-48 h of care. Implementation of acute ICH care can be challenging, and using a care bundle approach, with regular monitoring of data and improvement of care processes can ensure consistent and optimal care for all patients.

A Multi-Model Pipeline for Translational Intracerebral Haemorrhage Research.

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.