Dynamic cerebral autoregulation after intracerebral hemorrhage: A case-control study

Background  

Dynamic cerebral autoregulation after intracerebral hemorrhage (ICH) remains poorly understood. We performed a case-control study to compare dynamic autoregulation between ICH patients and healthy controls.     

Gender and Age Interact to Affect Early Outcome after Intracerebral Hemorrhage

Background

Intracerebral hemorrhage (ICH) is a common and devastating form of cerebrovascular disease. In ICH, gender differences in outcomes remain relatively understudied but have been examined in other neurological emergencies. Further, a potential effect of age and gender on outcomes after ICH has not been explored. This study was designed to test the hypothesis that age and gender interact to modify neurological outcomes after ICH.

Methods

Adult patients admitted with spontaneous primary supratentorial ICH from July 2007 through April 2010 were assessed via retrospective analysis of an existing stroke database at Duke University. Univariate analysis of collected variables was used to compare gender and outcome. Unfavorable outcome was defined as discharge to hospice or death. Using multivariate regression, the combined effect of age and gender on outcome after ICH was analyzed.

Results

In this study population, women were younger (61.1+14.5 versus 65.8+17.3 years, p=0.03) and more likely to have a history of substance abuse (35% versus 8.9%, p<0.0001) compared to men. Multivariable models demonstrated that advancing age had a greater effect on predicting discharge outcome in women compared to men (p=0.02). For younger patients, female sex was protective; however, at ages greater than 60 years, female sex was a risk factor for discharge to hospice or death.

Conclusion

While independently associated with discharge to hospice or death after ICH, the interaction effect between gender and age demonstrated significantly stronger correlation with early outcome after ICH in a single center cohort. Prospective study is required to verify these findings.     

Early intervention to promote oral feeding in patients with intracerebral hemorrhage: a retrospective cohort study

Background  

Stroke is a major cause of dysphagia, but little is known about when and how dysphagic patients should be fed and treated after an acute stroke. The purpose of this study is to establish the feasibility, risks and clinical outcomes of early intensive oral care and a new speech and language therapist/nurse led structured policy for oral feeding in patients with an acute intracerebral hemorrhage (ICH).     

Factors Associated with Early Deterioration after Spontaneous Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis

Background and Purpose

Spontaneous intracerebral hemorrhage (ICH) is a devastating form of stroke with a poor prognosis overall. We conducted a systematic review and meta-analysis to identify and describe factors associated with early neurologic deterioration (END) after ICH.

Methods

We sought to identify any factor which could be prognostic in the absence of an intervention. The Cochrane Library, EMBASE, the Global Health Library, and PubMed were searched for primary studies from the years 1966 to 2012 with no restrictions on language or study design. Studies of patients who received a surgical intervention or specific experimental therapies were excluded. END was defined as death, or worsening on a reliable outcome scale within seven days after onset.

Results

7,172 abstracts were reviewed, 1,579 full-text papers were obtained and screened. 14 studies were identified; including 2088 patients. Indices of ICH severity such as ICH volume (univariate combined OR per ml:1.37, 95%CI: 1.12–1.68), presence of intraventricular hemorrhage (2.95, 95%CI: 1.57–5.55), glucose concentration (per mmol/l: 2.14, 95%CI: 1.03–4.47), fibrinogen concentration (per g/l: 1.83, 95%CI: 1.03–3.25), and d-dimer concentration at hospital admission (per mg/l: 4.19, 95%CI: 1.88–9.34) were significantly associated with END after random-effects analyses. Whereas commonly described risk factors for ICH progression such as blood pressure, history of hypertension, and ICH growth were not.

Conclusions

This study summarizes the evidence to date on early ICH prognosis and highlights that the amount and distribution of the initial bleed at hospital admission may be the most important factors to consider when predicting early clinical outcomes.     

Prophylactic activated recombinant factor VII in liver resection and liver transplantation: systematic review and meta-analysis

Background and Aim

Intraoperative blood loss is a frequent complication of hepatic resection and orthotopic liver transplantation. Recombinant activated coagulation factor VII (rFVIIa) is a coagulation protein that induces hemostasis by directly activating factor X. There is no clear information about the prophylactic value of rFVIIa in hepatobiliary surgery, specifically in liver resection and orthotopic liver transplantation. The aim of this study was to assess the effect of rFVIIa prophylaxis to prevent mortality and bleeding resulting from hepatobiliary surgery.

Methods

Relevant randomized trials were identified by searching The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index. Randomized clinical trials comparing different rFVIIa prophylactic schemas against placebo or no intervention to prevent bleeding in hepatobiliary surgery were included. Adults undergoing liver resection, partial hepatectomy, or orthotopic liver transplantation were included. Dichotomous data were analyzed calculating odds ratios (ORs) and 95% confidence intervals (CIs). Continuous data were analyzed calculating mean differences (MD) and 95% CIs.

Results

Four randomized controlled trials were included. There were no significant differences between rFVIIa and placebo for mortality (OR 0.96; 95% CI 0.35–2.62), red blood cell units (MD 0.32; 95% CI −0.08–0.72) or adverse events (OR 1.55; 95% CI 0.97–2.49).

Conclusions

The available information is limited, precluding the ability to draw conclusions regarding bleeding prophylaxis in hepatobiliary surgery using rFVIIa. Although an apparent lack of effect was observed in all outcomes studied, further research is needed.     

Recombinant Factor VIIa Reduces Bleeding after Blunt Liver Injury in a Pig Model of Dilutional Coagulopathy under Severe Hypothermia

Background

Recombinant factor VIIa (rFVIIa) is registered for use in haemophilia with inhibitors and other rare bleeding disorders, but has also been used in various other clinical conditions to terminate life-threatening bleeding. Underlying conditions (e.g. coagulopathy) and dosing may affect treatment efficacy. The objective of the present study was to evaluate the impact of increasing doses of rFVIIa on blood loss and coagulation assays in haemodiluted and hypothermic pigs undergoing blunt liver injury.

Methods

A grade III blunt liver injury was induced in 28 pigs after 70% haemodilution and cooling to 32.6–33.4°C. Ten minutes after trauma, animals randomly received placebo or 90, 180 or 360 μg/kg rFVIIa. Global coagulation parameters, thromboelastometry (TEM) and plasma thrombin generation (TG) were determined at different time points during the observation period of 120 minutes.

Results

Total blood loss was significantly lower following 90 μg/kg rFVIIa (1206 [1138–1470] mL) relative to placebo (2677 [2337–3068] mL; p<0.05), with no increased effect with higher dose levels of rFVIIa. Following trauma and haemodilution, coagulation was impaired relative to baseline in both TEM and TG analysis. At 60 and 120 minutes after trauma, TEM variables improved in the rFVIIa-treated animals compared with the placebo group. Similarly, rFVIIa improved coagulation kinetics in TG. As was observed with blood loss, no significant effect between different rFVIIa dose levels was found in TEM or TG. Macro- and microscopic post-mortem examination did not reveal any signs of thromboembolic events.

Conclusion

Early administration of 90 μg/kg rFVIIa reduced blood loss in pigs undergoing blunt liver injury even after severe haemodilution and hypothermia, with no further effect of higher dose levels. Coagulation assays showed impaired coagulation in coagulopathic animals, with a dose-independent improvement in animals treated with rFVIIa.     

The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells

Introduction  

The aim was to determine the effect of the Bruton tyrosine kinase (Btk)-selective inhibitor PCI-32765, currently in Phase I/II studies in lymphoma trials, in arthritis and immune-complex (IC) based animal models and describe the underlying cellular mechanisms.     

Copeptin as a Marker for Severity and Prognosis of Aneurysmal Subarachnoid Hemorrhage

Background

Grading of patients with aneurysmal subarachnoid hemorrhage (aSAH) is often confounded by seizure, hydrocephalus or sedation and the prediction of prognosis remains difficult. Recently, copeptin has been identified as a serum marker for outcomes in acute ischemic stroke and intracerebral hemorrhage (ICH). We investigated whether copeptin might serve as a marker for severity and prognosis in aSAH.

Methods

Eighteen consecutive patients with aSAH had plasma copeptin levels measured with a validated chemiluminescence sandwich immunoassay. The primary endpoint was the association of copeptin levels at admission with the World Federation of Neurological Surgeons (WFNS) grade score after resuscitation. Levels of copeptin were compared across clinical and radiological scores as well as between patients with ICH, intraventricular hemorrhage, hydrocephalus, vasospasm and ischemia.

Results

Copeptin levels were significantly associated with the severity of aSAH measured by WFNS grade (P = 0.006), the amount of subarachnoid blood (P = 0.03) and the occurrence of ICH (P = 0.02). There was also a trend between copeptin levels and functional clinical outcome at 6-months (P = 0.054). No other clinical outcomes showed any statistically significant association.

Conclusions

Copeptin may indicate clinical severity of the initial bleeding and may therefore help in guiding treatment decisions in the setting of aSAH. These initial results show that copeptin might also have prognostic value for clinical outcome in aSAH.     

Umbilical cord-derived MSC and hyperbaric oxygen therapy effectively protected the brain in rat after acute intracerebral haemorrhage

This study tested the hypothesis that combined therapy with human umbilical cord-derived mesenchymal stem cells (HUCDMSCs) and hyperbaric oxygen (HBO) was superior to either one on preserving neurological function and reducing brain haemorrhagic volume (BHV) in rat after acute intracerebral haemorrhage (ICH) induced by intracranial injection of collagenase. Adult male SD rats (n = 30) were equally divided into group 1 (sham-operated control), group 2 (ICH), group 3 (ICH +HUCDMSCs/1.2 × 10⁶ cells/intravenous injection at 3h and days 1 and 2 after ICH), group 4 (ICH +HBO/at 3 hours and days 1 and 2 after ICH) and group 5 (ICH +HUCDMSCs-HBO), and killed by day 28 after ICH. By day 1, the neurological function was significantly impaired in groups 2-5 than in group 1 (P < .001), but it did not differ among groups 2 to 5. By days 7, 14 and 28, the integrity of neurological function was highest in group 1, lowest in group 2 and significantly progressively improved from groups 3 to 5 (all P < .001). By day 28, the BHV was lowest in group 1, highest in group 2 and significantly lower in group 5 than in groups 3/4 (all P < .0001). The protein expressions of inflammation (HMGB1/TLR-2/TLR-4/MyD88/TRAF6/p-NF-κB/IFN-γ/IL-1ß/TNF-α), oxidative stress/autophagy (NOX-1/NOX-2/oxidized protein/ratio of LC3B-II/LC3B-I) and apoptosis (cleaved-capspase3/PARP), and cellular expressions of inflammation (CD14+, F4/80+) in brain tissues exhibited an identical pattern, whereas cellular levels of angiogenesis (CD31+/vWF+/small-vessel number) and number of neurons (NeuN+) exhibited an opposite pattern of BHV among the groups (all P < .0001). These results indicate that combined HUCDMSC-HBO therapy offered better outcomes after rat ICH.     

A prospective controlled study: Minimally invasive stereotactic puncture therapy versus conventional craniotomy in the treatment of acute intracerebral hemorrhage

Background  

Spontaneous intracerebral hemorrhage (ICH) is a devastating form of stroke with the high mortality twofold to sixfold higher than that for ischemic stroke. But the treatment of haematomas within the basal ganglia continues to be a matter of debate among neurologists and neurosurgeons. The purpose of this study is to judge the clinical value of minimally invasive stereotactic puncture therapy (MISPT) on acute ICH.     

Fate of Diffusion Restricted Lesions in Acute Intracerebral Hemorrhage

Background

Diffusion-restricted lesions on diffusion-weighted imaging (DWI) are detected in patients with intracerebral hemorrhage (ICH). In this study, we aimed to determine the fate of DWI lesions in ICH patients and whether the presence of DWI lesions is associated with functional outcome in patients with ICH.

Methods

This prospective study enrolled 153 patients with acute ICH. Baseline MRI scans were performed within 2 weeks after ICH to detect DWI lesions and imaging markers for small vessel disease (SVD). Follow-up MRI scans were performed at 3 months after ICH to assess the fate of the DWI lesions. We analyzed the associations between the characteristics of DWI lesions with clinical features and functional outcome.

Results

Seventeen of the 153 patients (11.1%) had a total of 25 DWI lesions. Factors associated with DWI lesions were high initial systolic and mean arterial blood pressure (MAP) at the emergency room, additional lowering of MAP within 24 hours, and the presence of white matter hyperintensity and cerebral microbleeds. Thirteen of the 25 DWI lesions (52%) were not visible on follow-up T2-weighted or fluid-attenuated inversion recovery images and were associated with high apparent diffusion coefficient value and a sharper decease in MAP. The regression of DWI lesions was associated with good functional outcome.

Conclusions

More than half of the DWI lesions in the ICH patients did not transition to visible, long-term infarction. Only if the DWI lesion finally transitioned to final infarction was a poor functional outcome predicted. A DWI lesion may be regarded as an ischemic change of SVD and does not always indicate certain cerebral infarction or permanent tissue injury.     

Copeptin is associated with mortality and outcome in patients with acute intracerebral hemorrhage

Background  

Spontaneous intracerebral hemorrhage (ICH) accounts for a high mortality and morbidity. Early prediction of outcome is crucial for optimized care and treatment decision. Copeptin, the C-terminal part of provasopressin, has emerged as a new prognostic marker in a variety of diseases, but its prognostic value in ICH is unknown.     

Receptor-interacting protein 3-phosphorylated Ca2+/calmodulin-dependent protein kinase II and mixed lineage kinase domain-like protein mediate intracerebral hemorrhage-induced neuronal necroptosis

Necroptosis-mediated cell death is an important mechanism in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI). Our previous study has demonstrated that receptor-interacting protein 1 (RIP1) mediated necroptosis in SBI after ICH. However, further mechanisms, such as the roles of receptor-interacting protein 3 (RIP3), mixed lineage kinase domain-like protein (MLKL), and Ca²⁺/calmodulin-dependent protein kinase II (CaMK II), remain unclear. We hypothesized that RIP3, MLKL, and CaMK II might participate in necroptosis after ICH, including their phosphorylation. The ICH model was induced by autologous blood injection. First, we found the activation of necroptosis after ICH in brain tissues surrounding the hematoma (propidium iodide staining). Meanwhile, the phosphorylation and expression of RIP3, MLKL, and CaMK II were differently up-regulated (western blotting and immunofluorescent staining). The specific inhibitors could suppress RIP3, MLKL, and CaMK II (GSK'872 for RIP3, necrosulfonamide for MLKL, and KN-93 for CaMK II). We found the necroptosis surrounding the hematoma and the concrete interactions in RIP3-MLKL/RIP3-CaMK II also both decreased after the specific intervention (co-immunoprecipitation). Then we conducted the short-/long-term neurobehavioral tests, and the rats with specific inhibition mostly had better performance. We also found less blood–brain barrier (BBB) injury, and less neuron loss (Nissl staining) in intervention groups, which supported the neurobehavioral tests. Besides, oxidative stress and inflammation were also alleviated with intervention, which had significant less reactive oxygen species (ROS), tumor necrosis factor (TNF)-α, lactate dehydrogenase (LDH), Iba1, and GFAP surrounding the hematoma. These results confirmed that RIP3-phosphorylated MLKL and CaMK II participate in ICH-induced necroptosis and could provide potential targets for the treatment of ICH patients.

     

Factors associated with in-hospital mortality following intracerebral hemorrhage: a three-year study in Tehran,Iran

Background  

Primary intracerebral hemorrhage (ICH) is one of the common vascular insults with a relatively high rate of mortality. The aim of the current study was to determine the mortality rate and to evaluate the influence of various factors on the mortality of patients with intracerebral hemorrhage (ICH). Demographic characteristics along with clinical features and neuroimaging information on 122 patients with primary ICH admitted to Sina Hospital between 1999–2002 were assessed by multivariate analysis.     

Transplantation of Induced Pluripotent Stem Cells Alleviates Cerebral Inflammation and Neural Damage in Hemorrhagic Stroke

Background

Little is known about the effects of induced pluripotent stem cell (iPSC) treatment on acute cerebral inflammation and injuries after intracerebral hemorrhage (ICH), though they have shown promising therapeutic potentials in ischemic stoke.

Methods

An ICH model was established by stereotactic injection of collagenase VII into the left striatum of male Sprague-Dawley (SD) rats. Six hours later, ICH rats were randomly divided into two groups and received intracerebrally 10 μl of PBS with or without 1×10⁶ of iPSCs. Subsequently, neural function of all ICH rats was assessed at days 1, 3, 7, 14, 28 and 42 after ICH. Inflammatory cells, cytokines and neural apoptosis in the rats’ perihematomal regions, and brain water content were determined on day 2 or 3 post ICH. iPSC differentiation was determined on day 28 post ICH. Nissl⁺ cells and glial fibrillary acidic protein (GFAP)⁺ cells in the perihematoma and the survival rates of rats in two groups were determined on post-ICH day 42.

Results

Compared with control animals, iPSCs treatment not only improved neurological function and survival rate, but also resulted in fewer intracephalic infiltrations of neutrophils and microglia, along with decreased interleukin (IL)-1β, IL-6 and tumour necrosis factor-alpha (TNF-α), and increased IL-10 in the perihematomal tissues of ICH rats. Furthermore, brain oedema formation, apoptosis, injured neurons and glial scar formation were decreased in iPSCs-transplanted rats.

Conclusions

Our findings indicate that iPSCs transplantation attenuate cerebral inflammatory reactions and neural injuries after ICH, and suggests that multiple mechanisms including inflammation modulation, neuroprotection and functional recovery might be involved simultaneously in the therapeutic benefit of iPSC treatment against hemorrhagic stroke.     

Cost-Effectiveness of Apixaban Compared with Warfarin for Stroke Prevention in Atrial Fibrillation

Background

Apixaban was shown to be superior to adjusted-dose warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation (AF) and at least one additional risk factor for stroke, and associated with reduced rates of hemorrhage. We sought to determine the cost-effectiveness of using apixaban for stroke prevention.

Methods

Based on the results from the Apixaban Versus Warfarin in Patients with Atrial Fibrillation (ARISTOTLE) trial and other published studies, we constructed a Markov model to evaluate the cost-effectiveness of apixaban versus warfarin from the Medicare perspective. The base-case analysis assumed a cohort of 65-year-old patients with a CHADS₂ score of 2.1 and no contraindication to oral anticoagulation. We utilized a 2-week cycle length and a lifetime time horizon. Outcome measures included costs in 2012 US$, quality-adjusted life-years (QALYs), life years saved and incremental cost-effectiveness ratios.

Results

Under base case conditions, quality adjusted life expectancy was 10.69 and 11.16 years for warfarin and apixaban, respectively. Total costs were $94,941 for warfarin and $86,007 for apixaban, demonstrating apixaban to be a dominant economic strategy. Upon one-way sensitivity analysis, these results were sensitive to variability in the drug cost of apixaban and various intracranial hemorrhage related variables. In Monte Carlo simulation, apixaban was a dominant strategy in 57% of 10,000 simulations and cost-effective in 98% at a willingness-to-pay threshold of $50,000 per QALY.

Conclusions

In patients with AF and at least one additional risk factor for stroke and a baseline risk of ICH risk of about 0.8%, treatment with apixaban may be a cost-effective alternative to warfarin.     

Cost-Effectiveness of Buprenorphine and Naltrexone Treatments for Heroin Dependence in Malaysia

Aims

To aid public health policymaking, we studied the cost-effectiveness of buprenorphine, naltrexone, and placebo interventions for heroin dependence in Malaysia.

Design

We estimated the cost-effectiveness ratios of three treatments for heroin dependence. We used a microcosting methodology to determine fixed, variable, and societal costs of each intervention. Cost data were collected from investigators, staff, and project records on the number and type of resources used and unit costs; societal costs for participants’ time were estimated using Malaysia’s minimum wage. Costs were estimated from a provider and societal perspective and reported in 2004 US dollars.

Setting

Muar, Malaysia.

Participants

126 patients enrolled in a randomized, double-blind, placebo-controlled clinical trial in Malaysia (2003–2005) receiving counseling and buprenorphine, naltrexone, or placebo for treatment of heroin dependence.

Measurements

Primary outcome measures included days in treatment, maximum consecutive days of heroin abstinence, days to first heroin use, and days to heroin relapse. Secondary outcome measures included treatment retention, injection drug use, illicit opiate use, AIDS Risk Inventory total score, and drug risk and sex risk subscores.

Findings

Buprenorphine was more effective and more costly than naltrexone for all primary and most secondary outcomes. Incremental cost-effectiveness ratios were below $50 for primary outcomes, mostly below $350 for secondary outcomes. Naltrexone was dominated by placebo for all secondary outcomes at almost all endpoints. Incremental treatment costs were driven mainly by medication costs, especially the price of buprenorphine.

Conclusions

Buprenorphine appears to be a cost-effective alternative to naltrexone that might enhance economic productivity and reduce drug use over a longer term.     

Prognostic Value of ICH Score and ICH-GS Score in Chinese Intracerebral Hemorrhage Patients: Analysis From the China National Stroke Registry (CNSR)

Purpose

No strongevidenceofefficacycurrently exists for different intracerebral hemorrhage (ICH) scoring system in predicting the prognosis of ICH in the Chinese population. This study aimed to test the accuracyof the ICH score and the ICH grading scale (ICH-GS) score in predicting the favorable prognosis in a large cohort of ICH patients in China.

Methods

This study was a multicenter, prospective cohort study. Patients diagnosed with ICH between September 2007 and August 2008 from the nationwide China National Stroke Registry (CNSR) databasewere screened andenrolled in this study. Demographics of the patients, treatments, mortalityas well as the clinic and radiologic findings of ICH were collected.AnICH score and anICH-GS score were evaluated for all the patients atadmission. Follow-ups were conducted by phone at 3, 6 and 12 months after ICH onset. The modified Rankin scale (mRS) score was used to evaluate favorable functional outcome and was obtained at hospital dischargeand duringthe 3-, 6- and 12-month follow-up visits.

Results

There were 410 (12.6%) in-hospitalmortalityout of a total of 3,255 ICH patients. Thevalues of the Area Under Curve (AUC)at discharge, 3-, 6- and 12-month follow-up for ICH score were 0.72, 0.76, 0.76 and 0.75, respectively; whilethe numbers for the ICH-GS score were 0.71, 0.77, 0.78 and 0.78, respectively. At 6-month and 12-month follow-up, the ICH-GS score presented a significant better value in predicting favorable prognosis than did the ICH score (P=0.0003 and <0.0001, respectively).

Conclusion

Both the ICH and ICH-GS scores were effective inaccurately predicting the favorable functional outcome of ICH in the Chinese population. For mid-term and long-term prediction, the ICH-GS score was superiorover the ICH score.     

Intervention study of the association of antibiotic utilization measures with control of extended-spectrum β-lactamase (ESBL)-producing bacteria

We investigated the effects of replacing third-/fourth-generation cephalosporins with piperacillin–tazobactam on the rate of acquisition of extended spectrum β-lactamase-producing Klebsiella pneumoniae and Escherichia coli by patients hospitalized in a Department of Respiratory Medicine.This 9-month, prospective, non-controlled, intervention study comprised two phases: a 3-month pre-intervention phase (Phase I) and a 6-month intervention phase (Phase II), during which the use of third-/forth-generation cephalosporins was restricted and replaced by piperacillin–tazobactam. Rectal swabs were obtained within 24 h after admission (baseline screening), weekly, and 48 h before discharge during Phase I and the last 3 months of Phase II (Phase IIb). Swabs were tested for E. coli and K. pneumoniae, and extended spectrum β-lactamase production was detected with the double disc test.Use of third/fourth-generation cephalosporins decreased by 63.0% and 100%, respectively; while the use of piperacillin–tazobactam increased by 28-fold. The rate of acquisition of extended spectrum β-lactamase-producing E. coli and K. pneumoniae together in rectal swab specimens decreased in Phase IIb as compared with Phase I (19.5% vs 29.5%). Few rectal swab specimens were positive for extended spectrum β-lactamases-producing K. pneumoniae, and no substantial decrease in the rate of its acquisition was observed.