Preventive ceftriaxone in patients at high risk of stroke-associated pneumonia. A post-hoc analysis of the PASS trial.

BACKGROUND: Infections complicate the acute phase of stroke in one third of patients and especially pneumonia is associated with increased risk of death or dependency. In randomized trials of stroke patients, preventive antibiotics reduced overall infections, but did not reduce pneumonia or improve outcome. This may be explained by broad selection criteria, including many patients with a low risk of pneumonia. To assess the potential of selection of patients at high risk of pneumonia, we performed a post-hoc analysis in the Preventive Antibiotics in Stroke Study (PASS). METHODS: PASS was a multicentre phase 3 trial in acute stroke patients who were randomized to preventive ceftriaxone for four days within 24 hours or standard care. For this analysis patients were divided based on the ISAN risk score for pneumonia as follows: low (0-6), medium (7-14) and high (15-21). Primary outcomes were pneumonia rate during admission as judged by the treating physician, and by an independent committee; secondary outcomes were overall infections and unfavorable outcome (modified Rankin Scale ≥3). We adjusted with multivariable regression for possible confounders: age, stroke subtype and severity, pre-stroke dependency and diabetes. RESULTS: Pneumonia occurred more frequently in higher risk groups (25.7% (high), 9.0% (medium) 1.5%, (low)). The absolute difference in pneumonia rate between patients treated with ceftriaxone or standard care increased with the ISAN score (low: 0.5%, medium: 1.2%, high: 10.1%). After adjustment ceftriaxone reduced overall infections in the low and medium groups, not in the high-risk group. There was a trend towards reduction of pneumonia as judged by the committee (3.7% vs 13.6%, aOR = 0.164, p = 0.063) in the high-risk group. CONCLUSIONS: This post-hoc analysis of PASS confirmed higher rates of pneumonia with higher ISAN scores, and suggests that in acute stroke patients with an ISAN score of ≥15, preventive ceftriaxone for four days may reduce pneumonia rate.

Leukocyte Count Predicts Carotid Artery Stenosis in Men with Ischemic Stroke: Sub Study of the Preventive Antibiotics in Stroke Study (PASS).

Background: Inflammation is important in the development of atherosclerosis. Research suggested sex-dependent differences for the value of inflammatory markers for risk stratification of stroke patients with internal carotid artery stenosis (ICAS). We investigated whether leukocytes and thrombocytes were associated with ≥50% ICAS in acute stroke and whether this was sex-dependent. Patients included in the Preventive Antibiotics in Stroke Study (PASS) were used. PASS is a randomized controlled trial that randomized between four days of preventive ceftriaxone intravenously or standard stroke care alone. It investigated whether ceftriaxone could improve functional outcome at three months after stroke. Methods: Patients included in PASS were evaluated for the predictive value of leukocytes and thrombocytes for ICAS. Ischemic stroke and TIA patients were selected out of PASS patients. Logistic regression analysis was performed adjusting for NIHSS and other covariates. Results: 2550 patients were included in PASS. 1413 of 2550 patients (55%) were evaluated in this sub study. Female patients showed a mean of 8.55 × 109/L for leukocytes and 259 × 109/L for thrombocytes. Men showed a mean of 8.29 × 109/L for leukocytes and 224 × 109/L for thrombocytes. Multivariate logistic regression analysis showed that leukocytes were independently associated with ICAS ≥ 50% in male patients (OR 1.094, p = 0.008), but not in female patients (OR 1.041, p = 0.360). Thrombocytes were not associated with ICAS. Conclusions: We conclude that blood leukocyte count independently predicts ICAS in men after acute stroke, but not in women. Clinical Trial unique identifier: ISRCTN66140176.

Immunodepression, Infections, and Functional Outcome in Ischemic Stroke.

Stroke remains one of the main causes of mortality and morbidity worldwide. Immediately after stroke, a neuroinflammatory process starts in the brain, triggering a systemic immunodepression mainly through excessive activation of the autonomous nervous system. Manifestations of immunodepression include lymphopenia but also dysfunctional innate and adaptive immune cells. The resulting impaired antibacterial defenses render patients with stroke susceptible to infections. In addition, other risk factors like stroke severity, dysphagia, impaired consciousness, mechanical ventilation, catheterization, and older age predispose stroke patients for infections. Most common infections are pneumonia and urinary tract infection, both occur in ≈10% of the patients. Especially pneumonia increases unfavorable outcome and mortality in patients with stroke; systemic effects like hypotension, fever, delay in rehabilitation are thought to play a crucial role. Experimental and clinical data suggest that systemic infections enhance autoreactive immune responses against brain antigens and thus negatively affect outcome but convincing evidence is lacking. Prevention of poststroke infections by preventive antibiotic therapy did not improve functional outcome after stroke. Immunomodulatory approaches counteracting immunodepression to prevent stroke-associated pneumonia need to account for neuroinflammation in the ischemic brain and avoid further tissue damage. Experimental studies discovered interesting targets, but these have not yet been investigated in patients with stroke. A better understanding of the pathobiology may help to develop optimized approaches of preventive antibiotic therapy or immunomodulation to effectively prevent stroke-associated pneumonia while improving long-term outcome after stroke. In this review, we aim to characterize epidemiology, risk factors, cause, diagnosis, clinical presentation, and potential treatment of poststroke immunosuppression and associated infections.

Prevalence, predictors and outcome of carotid stenosis: a sub study in the Preventive Antibiotics in Stroke Study (PASS).

BACKGROUND: The prevalence of carotid artery stenosis (CAS) in acute ischaemic stroke (AIS) patients is historically reported at 15-20%, but an up-to-date estimate is lacking. We hypothesise it is lower than historically reported, due to better risk management to date. The study aims to study prevalence, predictors and survival of CAS in AIS patients. METHODS: We included patients with AIS from the Preventive Antibiotics in Stroke Study (PASS), a large Dutch randomized, multicentre, open-label phase III trial that included 2538 patients with acute stroke and randomised between standard care or preventive ceftriaxone. Patients with stroke in the anterior circulation that underwent diagnostic testing of the internal carotid artery (ICA) were eligible for this sub study and used in these secondary analyses. Logistic regression analyses were performed to identify predictors for CAS ≥ 50%. Additionally, an ordinal regression was performed to assess the association between presence of CAS at baseline and functional outcome at three months on the modified Rankin scale (mRS). RESULTS: 1480 patients with AIS were included; 277 had CAS (18.7%; 95%CI:17.7-19.7). Age, hypertension, smoking and male gender were found as best-fit predictors for presence of CAS. Significant shift in mRS score after 90 days for CAS ≥50% towards a higher mRS score with an OR of 1.66 (95% CI 1.30-2.10) was found. CONCLUSIONS: Current prevalence of CAS is 18.7%, which is higher than we expected. Gender, smoking and hypertension are important factors associated with CAS. Patients with CAS had a significantly higher mRs score after 90 days. TRIAL REGISTRATION: Unique identifier: ISRCTN66140176.

Preventive antibiotic therapy in acute stroke patients: A systematic review and meta-analysis of individual patient data of randomized controlled trials.

Introduction: Infection after stroke is associated with unfavorable outcome. Randomized controlled studies did not show benefit of preventive antibiotics in stroke but lacked power for subgroup analyses. Aim of this study is to assess whether preventive antibiotic therapy after stroke improves functional outcome for specific patient groups in an individual patient data meta-analysis. Patients and methods: We searched MEDLINE (1946-7 May 2021), Embase (1947-7 May 2021), CENTRAL (17th September 2021), trial registries, cross-checked references and contacted researchers for randomized controlled trials of preventive antibiotic therapy versus placebo or standard care in ischemic or hemorrhagic stroke patients. Meta-analysis was performed by a one-step and two-step approach. Primary outcome was functional outcome adjusted for age and stroke severity. Secondary outcomes were infections and mortality. Results: 4197 patients from nine trials were included. Preventive antibiotic therapy was not associated with a shift in functional outcome (mRS) at 3 months (OR1.13, 95%CI 0.98-1.31) or unfavorable functional outcome (mRS 3-6) (OR0.85, 95%CI 0.60-1.19). Preventive antibiotics did not improve functional outcome in pre-defined subgroups (age, stroke severity, timing and type of antibiotic therapy, pneumonia prediction scores, dysphagia, type of stroke, and type of trial). Preventive antibiotics reduced infections (276/2066 (13.4%) in the preventive antibiotic group vs. 417/2059 (20.3%) in the control group, OR 0.60, 95% CI 0.51-0.71, p < 0.001), but not pneumonia (191/2066 (9.2%) in the preventive antibiotic group vs. 205/2061 (9.9%) in the control group (OR 0.92 (0.75-1.14), p = 0.450). Discussion and conclusion: Preventive antibiotic therapy did not benefit any subgroup of patients with acute stroke and currently cannot be recommended.

Disruptions of Anaerobic Gut Bacteria Are Associated with Stroke and Post-stroke Infection: a Prospective Case-Control Study.

In recent years, preclinical studies have illustrated the potential role of intestinal bacterial composition in the risk of stroke and post-stroke infections. The results of these studies suggest that bacteria capable of producing volatile metabolites, including trimethylamine-N-oxide (TMAO) and butyrate, play opposing, yet important roles in the cascade of events leading to stroke. However, no large-scale studies have been undertaken to determine the abundance of these bacterial communities in stroke patients and to assess the impact of disrupted compositions of the intestinal microbiota on patient outcomes. In this prospective case-control study, rectal swabs from 349 ischemic and hemorrhagic stroke patients (median age, 71 years; IQR: 67-75) were collected within 24 h of hospital admission. Samples were subjected to 16S rRNA amplicon sequencing and subsequently compared with samples obtained from 51 outpatient age- and sex-matched controls (median age, 72 years; IQR, 62-80) with similar cardiovascular risk profiles but without active signs of stroke. Plasma protein biomarkers were analyzed using a combination of nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS). Alpha and beta diversity analyses revealed higher disruption of intestinal communities during ischemic and hemorrhagic stroke compared with non-stroke matched control subjects. Additionally, we observed an enrichment of bacteria implicated in TMAO production and a loss of butyrate-producing bacteria. Stroke patients displayed two-fold lower plasma levels of TMAO than controls (median 1.97 vs 4.03 µM, Wilcoxon p < 0.0001). Finally, lower abundance of butyrate-producing bacteria within 24 h of hospital admission was an independent predictor of enhanced risk of post-stroke infection (odds ratio 0.77, p = 0.005), but not of mortality or functional patient outcome. In conclusion, aberrations in trimethylamine- and butyrate-producing gut bacteria are associated with stroke and stroke-associated infections.

Association Between Low Blood Pressure and Clinical Outcomes in Patients With Acute Ischemic Stroke.

Background and Purpose- Low blood pressure is uncommon in patients with acute ischemic stroke (AIS). We assessed the association between baseline low blood pressure and outcomes in patients with AIS. Methods- Post hoc analysis of the PASS (Preventive Antibiotics in Stroke Study). We compared patients with AIS and low (<10th percentile) baseline systolic blood pressure (SBP) to patients with normal SBP (≥10th percentile <185 mm Hg). The first SBP measured at the Emergency Department was used. Outcomes included in-hospital mortality, major complications <7 days of stroke onset, and functional outcome at 90 days (modified Rankin scale score). We used regression analysis to calculate (common) odds ratios and adjusted for predefined prognostic factors. Results- Two thousand one hundred twenty-four out of 2538 patients had AIS. The cutoff for low SBP was 130 mm Hg (n=212; range, 70-129 mm Hg). One thousand four hundred forty patients had a normal SBP (range, 130-184 mm Hg). Low SBP was associated with an increased risk of in-hospital mortality (8.0% versus 4.2%; adjusted odds ratio [aOR], 1.58; 95% CI, 1.13-2.21) and complications (16.0% versus 6.5%; aOR, 2.56; 95% CI, 1.60-4.10). Specifically, heart failure (2.4% versus 0.1%; aOR, 17.85; 95% CI, 3.36-94.86), gastrointestinal bleeding (1.9% versus 0.1%; aOR, 26.04; 95% CI, 2.83-239.30), and sepsis (3.3% versus 0.5%; aOR, 5.53; 95% CI, 1.84-16.67) were more common in patients with low SBP. Functional outcome at 90 days did not differ (shift towards worse outcome: adjusted common odds ratio, 1.24; 95% CI, 0.95-1.61). Conclusions- Whether it is cause or consequence, low SBP at presentation in patients with AIS was associated with an increased risk of in-hospital mortality and complications, specifically heart failure, gastrointestinal bleeding, and sepsis. Clinicians should be vigilant for potentially treatable complications. Clinical Trial Registration- URL: https://www.controlled-trials.com. Unique identifier: ISRCTN66140176.

Antibiotic Class and Outcome in Post-stroke Infections: An Individual Participant Data Pooled Analysis of VISTA-Acute.

Introduction: Antibiotics used to treat post-stroke infections have differing antimicrobial and anti-inflammatory effects. Our aim was to investigate whether antibiotic class was associated with outcome after post-stroke infection. Methods: We analyzed pooled individual participant data from the Virtual International Stroke Trials Archive (VISTA)-Acute. Patients with ischemic stroke and with an infection treated with systemic antibiotic therapy during the first 2 weeks after stroke onset were eligible. Antibiotics were grouped into eight classes, according to antimicrobial mechanism and prevalence. The primary analysis investigated whether antibiotic class for any infection, or for pneumonia, was independently associated with a shift in 90 day modified Rankin Scale (mRS) using ordinal logistic regression. Results: 2,708 patients were eligible (median age [IQR] = 74 [65 to 80] y; 51% female; median [IQR] NIHSS score = 15 [11 to 19]). Pneumonia occurred in 35%. Treatment with macrolides (5% of any infections; 9% of pneumonias) was independently associated with more favorable mRS distribution for any infection [OR (95% CI) = 0.59 (0.42 to 0.83), p = 0.004] and for pneumonia [OR (95% CI) = 0.46 (0.29 to 0.73), p = 0.001]. Unfavorable mRS distribution was independently associated with treatment of any infection either with carbapenems, cephalosporins or monobactams [OR (95% CI) = 1.62 (1.33 to 1.97), p < 0.001], penicillin plus ß-lactamase inhibitors [OR (95% CI) = 1.26 (1.03 to 1.54), p = 0.025] or with aminoglycosides [OR (95% CI) = 1.73 (1.22 to 2.46), p = 0.002]. Conclusion: This retrospective study has several limitations including effect modification and confounding by indication. Macrolides may have favorable immune-modulatory effects in stroke-associated infections. Prospective evaluation of the impact of antibiotic class on treatment of post-stroke infections is warranted.

Antibiotic treatment for pneumonia complicating stroke: Recommendations from the pneumonia in stroke consensus (PISCES) group.

PURPOSE: The microbiological aetiology of pneumonia complicating stroke is poorly characterised. In this second Pneumonia in Stroke ConsEnsuS statement, we propose a standardised approach to empirical antibiotic therapy in pneumonia complicating stroke, based on likely microbiological aetiology, to improve antibiotic stewardship. METHODS: Systematic literature searches of multiple databases were undertaken. An evidence review and a round of consensus consultation were completed prior to a final multi-disciplinary consensus meeting in September 2017, held in Barcelona, Spain. Consensus was approached using a modified Delphi technique and defined a priori as 75% agreement between the consensus group members.Findings: No randomised trials to guide antibiotic treatment of pneumonia complicating stroke were identified. Consensus was reached for the following: (1) Stroke-associated pneumonia may be caused by organisms associated with either community-acquired or hospital-acquired pneumonia; (2) Treatment for early stroke-associated pneumonia (<72 h of stroke onset) should cover community-acquired pneumonia organisms; (3) Treatment for late stroke-associated pneumonia (≥72 h and within seven days of stroke onset) should cover community-acquired pneumonia organisms plus coliforms +/- Pseudomonas spp. if risk factors; (4) No additional antimicrobial cover is required for patients with dysphagia or aspiration; (5) Pneumonia occurring after seven days from stroke onset should be treated as for hospital-acquired pneumonia; (6) Treatment should continue for at least seven days for each of these scenarios. DISCUSSION: Consensus recommendations for antibiotic treatment of the spectrum of pneumonia complicating stroke are proposed. However, there was limited evidence available to formulate consensus on choice of specific antibiotic class for pneumonia complicating stroke. CONCLUSION: Further studies are required to inform evidence-based treatment of stroke-associated pneumonia including randomised trials of antibiotics and validation of candidate biomarkers.

Post-stroke infections and preventive antibiotics in stroke: Update of clinical evidence.

This review provides an update of evidence on post-stroke infections and the use of preventive antibiotics in stroke. Infection is a common complication after stroke, affecting between 15% and 30% of the patients. The predictors for post-stroke infection can be divided into three categories: clinical factors, anatomical (stroke related) factors and immunological factors. The relation between the occurrence of a post-stroke infection and functional outcome remained subject of debate, but it seems likely that the occurrence of these infections has a causal relation with poor functional outcome and mortality. In the first meta-analysis on preventive antibiotic therapy, almost a decade ago, its beneficial effect on post-stroke infection rate was clear; however, the effect on functional outcome remained uncertain because included studies were small and heterogeneous. Afterwards, three large phase-3 RCTs were published and a Cochrane meta-analysis was performed. It has now become clear that, despite the finding that overall infections are reduced, preventive antibiotic therapy in the acute phase of stroke does neither improve functional outcome, nor decrease mortality rates. This does not yet mean that further research on preventive antibiotics in stroke is useless: the pathophysiology and etiology of post-stroke infections are unclear and the use of preventive antibiotics in specific subgroups of stroke patients could still be very effective. This is currently being studied. Besides, preventive antibiotic therapy might be cost-effective by increasing quality-adjusted life years. Thirdly, research for the upcoming years might put more emphasis on the effect of stroke on immunological alterations.

Microbiological Etiologies of Pneumonia Complicating Stroke: A Systematic Review.

BACKGROUND AND PURPOSE: Identifying the causal pathogens of pneumonia complicating stroke is challenging, and antibiotics used are often broad spectrum, without recourse to the microbiological cause. We aimed to review existing literature to identify organisms responsible for pneumonia complicating stroke, before developing a consensus-based approach to antibiotic treatment. METHODS: A systematic literature review of multiple electronic databases using predefined search criteria was undertaken, in accordance with Cochrane and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidance. Published studies of hospitalized adults with ischemic stroke, intracerebral hemorrhage, or both, which identified microbiological etiologies for pneumonia complicating stroke up to January 1, 2017, were considered. Analysis included summary statistics and random-effects meta-analysis where appropriate. RESULTS: Fifteen studies (40% ischemic stroke, 60% ischemic stroke and intracerebral hemorrhage) involving 7968 patients were included. Reported occurrence of pneumonia varied considerably between studies (2%-63%) with a pooled frequency of 23% (95% confidence interval, 14%-34%; I2=99%). Where reported (60%), the majority of pneumonia occurred within 1 week of stroke (78%). Reported frequency of positive culture data (15%-88%) varied widely. When isolated, aerobic Gram-negative bacilli (38%) and Gram-positive cocci (16%) were most frequently cultured; commonly isolated organisms included Enterobacteriaceae (21.8%: Klebsiella pneumoniae, 12.8% and Escherichia coli, 9%), Staphylococcus aureus (10.1%), Pseudomonas aeruginosa (6%), Acinetobacter baumanii (4.6%), and Streptococcus pneumoniae (3.5%). Sputum was most commonly used to identify pathogens, in isolation (40%) or in conjunction with tracheal aspirate (15%) or blood culture (20%). CONCLUSIONS: Although the analysis was limited by small and heterogeneous study populations, limiting determination of microbiological causality, this review suggests aerobic Gram-negative bacilli and Gram-positive cocci are frequently associated with pneumonia complicating stroke. This supports the need for appropriately designed studies to determine microbial cause and a consensus-based approach in antibiotic usage and further targeted antibiotic treatment trials for enhanced antibiotic stewardship.

Development and internal validation of a prediction rule for post-stroke infection and post-stroke pneumonia in acute stroke patients.

INTRODUCTION: Patients with acute stroke are at high risk for infection. These infections are associated with unfavourable outcome after stroke. A prediction rule can identify the patients at the highest risk for strategies to prevent infection. We aim to develop a prediction rule for post-stroke pneumonia and other infections in patients with acute stroke. PATIENTS AND METHODS: We used data from the Preventive Antibiotics in Stroke Study, a multicentre randomised trial comparing preventive ceftriaxone vs. standard stroke care in patients with acute stroke. Possible predictors for post-stroke pneumonia or infection were selected from the literature. Backward elimination logistic regression analysis was used to construct prediction rules for pneumonia or infection. Internal validation was performed and a risk chart was constructed. We adjusted for preventive antibiotic use. RESULTS: Pneumonia was diagnosed in 159 of the 2538 included patients, and infection in 348. Pneumonia was predicted by higher age, male sex, pre-stroke disability, medical history of chronic obstructive pulmonary disease, more severe stroke, dysphagia and intracerebral haemorrhage (rather than ischaemic stroke). Infections were predicted by higher age, male sex, history of diabetes, chronic obstructive pulmonary disease, more severe stroke, dysphagia, use of bladder catheter, preventive antibiotic use and intracerebral haemorrhage. With the prediction rule developed, risks for pneumonia ranged from 0.4% to 56.2% and from 1.8% to 88.0% for infection. Discrimination of the score was good (C-statistic, 0.84; 95% CI: 0.81-0.87 and 0.82; 95% CI: 0.79-0.84 for pneumonia and infection). CONCLUSIONS: The Preventive Antibiotics in Stroke Study pneumonia and infection rule identify patients at the highest risk for post-stroke pneumonia or infection and may be used for future studies and novel therapies, after confirmation in an external population.

Development and validation of the Dutch Stroke Score for predicting disability and functional outcome after ischemic stroke: A tool to support efficient discharge planning.

INTRODUCTION: We aimed to develop and validate a prognostic score for disability at discharge and functional outcome at three months in patients with acute ischemic stroke based on clinical information available on admission. PATIENTS AND METHODS: The Dutch Stroke Score (DSS) was developed in 1227 patients with ischemic stroke included in the Paracetamol (Acetaminophen) In Stroke study. Predictors for Barthel Index (BI) at discharge ('DSS-discharge') and modified Rankin Scale (mRS) at three months ('DSS-3 months') were identified in multivariable ordinal regression. The models were internally validated with bootstrapping techniques. The DSS-3 months was externally validated in the PRomoting ACute Thrombolysis in Ischemic StrokE study (1589 patients) and the Preventive Antibiotics in Stroke Study (2107 patients). Model performance was assessed in terms of discrimination, expressed by the area under the receiver operating characteristic curve (AUC), and calibration. RESULTS: At model development, the strongest predictors of Barthel Index at discharge were age per decade over 60 (odds ratio = 1.55, 95% confidence interval (CI) 1.41-1.68), National Institutes of Health Stroke Scale (odds ratio = 1.24 per point, 95% CI 1.22-1.26) and diabetes (odds ratio = 1.62, 95% CI 1.32-1.91). The internally validated AUC was 0.76 (95% CI 0.75-0.79). The DSS-3 months, additionally consisting of previous stroke and atrial fibrillation, performed similarly at internal (AUC 0.75, 95% CI 0.74-0.77) and external validation (AUC 0.74 in PRomoting ACute Thrombolysis in Ischemic StrokE (95% CI 0.72-0.76) and 0.69 in Preventive Antibiotics in Stroke Study (95% CI 0.69-0.72)). Observed outcome was slightly better than predicted.Discussion: The DSS had satisfactory performance in predicting BI at discharge and mRS at three months in ischemic stroke patients. CONCLUSION: If further validated, the DSS may contribute to efficient stroke unit discharge planning alongside patients' contextual factors and therapeutic needs.

Continuation or Discontinuation of Anticoagulation in the Early Phase After Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: There is no consensus on whether anticoagulation should be continued or temporarily stopped in patients suffering acute ischemic stroke while using anticoagulation. We assessed treatment variations and outcomes in these patients. METHODS: Post hoc analysis of PASS (Preventive Antibiotics in Stroke Study). We included patients with acute ischemic stroke who used anticoagulation at admission. We compared clinical outcomes, thrombotic, and major bleeding events at 3 months. RESULTS: Nine percent (192/2101) of the patients with acute ischemic stroke used anticoagulation at admission (186 vitamin K antagonists). Anticoagulation was discontinued in 35/192 (18%) patients. These patients had higher National Institutes of Health Stroke Scale scores than patients in whom anticoagulation was continued (median, 13 versus 4; P<0.001). Thrombotic events occurred more frequently in patients in whom anticoagulation was discontinued (11% versus 3%; P=0.038). There were no major bleeding events in either group. Mortality and clinical outcomes at 90 days were worse in patients in whom anticoagulation was discontinued (mortality, 31% versus 15%; P=0.019 and modified Rankin Scale score of 0-2, 20% versus 55%; P<0.001). After adjustment for potential confounders, there were no statistically significant differences between groups. CONCLUSIONS: In our study, clinicians tended to continue anticoagulation in patients with acute ischemic stroke. Discontinuation was associated with an increased risk of thrombotic events and worse clinical outcome. Risk of major bleeding was not increased in patients in whom anticoagulation was continued. CLINICAL TRIAL REGISTRATION: URL: https://www.controlled-trials.com. Unique identifier: ISRCTN66140176.

Preventive Antibiotics in Stroke Study (PASS): A cost-effectiveness study.

OBJECTIVE: To evaluate the cost-effectiveness of preventive ceftriaxone vs standard stroke unit care without preventive antimicrobial therapy in acute stroke patients. METHODS: In this multicenter, randomized, open-label trial with masked endpoint assessment, 2,550 patients with acute stroke were included between 2010 and 2014. Economic evaluation was performed from a societal perspective with a time horizon of 3 months. Volumes and costs of direct, indirect, medical, and nonmedical care were assessed. Primary outcome was cost per unit of the modified Rankin Scale (mRS) and per quality-adjusted life year (QALY) for cost-effectiveness and cost-utility analysis. Incremental cost-effectiveness analyses were performed. RESULTS: A total of 2,538 patients were available for the intention-to-treat analysis. For the cost-effectiveness analysis, 2,538 patients were available for in-hospital resource use and 1,453 for other resource use. Use of institutional care resources, out-of-pocket expenses, and productivity losses was comparable between treatment groups. The mean score on mRS was 2.38 (95% confidence interval [CI] 2.31-2.44) vs 2.44 (95% CI 2.37-2.51) in the ceftriaxone vs control group, the decrease by 0.06 (95% CI -0.04 to 0.16) in favor of ceftriaxone treatment being nonsignificant. However, the number of QALYs was 0.163 (95% CI 0.159-0.166) vs 0.155 (95% CI 0.152-0.158) in the ceftriaxone vs control group, with the difference of 0.008 (95% CI 0.003-0.012) in favor of ceftriaxone (p = 0.006) at 3 months. The probability of ceftriaxone being cost-effective ranged between 0.67 and 0.89. Probability of 0.75 was attained at a willing-to-pay level of €2,290 per unit decrease in the mRS score and of €12,200 per QALY. CONCLUSIONS: Preventive ceftriaxone has a probability of 0.7 of being less costly than standard treatment per unit decrease in mRS and per QALY gained.

Antibiotic therapy for preventing infections in people with acute stroke.

BACKGROUND: Stroke is the main cause of disability in high-income countries and ranks second as a cause of death worldwide. Infections occur frequently after stroke and may adversely affect outcome. Preventive antibiotic therapy in the acute phase of stroke may reduce the incidence of infections and improve outcome. In the previous version of this Cochrane Review, published in 2012, we found that antibiotics did reduce the risk of infection but did not reduce the number of dependent or deceased patients. However, included studies were small and heterogeneous. In 2015, two large clinical trials were published, warranting an update of this Review. OBJECTIVES: To assess the effectiveness and safety of preventive antibiotic therapy in people with ischaemic or haemorrhagic stroke. We wished to determine whether preventive antibiotic therapy in people with acute stroke:• reduces the risk of a poor functional outcome (dependency and/or death) at follow-up;• reduces the occurrence of infections in the acute phase of stroke;• reduces the occurrence of elevated body temperature (temperature ≥ 38° C) in the acute phase of stroke;• reduces length of hospital stay; or• leads to an increased rate of serious adverse events, such as anaphylactic shock, skin rash, or colonisation with antibiotic-resistant micro-organisms. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (25 June 2017); the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 5; 25 June 2017) in the Cochrane Library; MEDLINE Ovid (1950 to 11 May 2017), and Embase Ovid (1980 to 11 May 2017). In an effort to identify further published, unpublished, and ongoing trials, we searched trials and research registers, scanned reference lists, and contacted trial authors, colleagues, and researchers in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) of preventive antibiotic therapy versus control (placebo or open control) in people with acute ischaemic or haemorrhagic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently selected articles and extracted data; we discussed and resolved discrepancies at a consensus meeting with a third review author. We contacted study authors to obtain missing data when required. An independent review author assessed risk of bias using the Cochrane 'Risk of bias' tool. We calculated risk ratios (RRs) for dichotomous outcomes, assessed heterogeneity amongst included studies, and performed subgroup analyses on study quality. MAIN RESULTS: We included eight studies involving 4488 participants. Regarding quality of evidence, trials showed differences in study population, study design, type of antibiotic, and definition of infection; however, primary outcomes among the included studies were consistent. Mortality rate in the preventive antibiotic group was not significantly different from that in the control group (373/2208 (17%) vs 360/2214 (16%); RR 1.03, 95% confidence interval (CI) 0.87 to 1.21; high-quality evidence). The number of participants with a poor functional outcome (death or dependency) in the preventive antibiotic therapy group was also not significantly different from that in the control group (1158/2168 (53%) vs 1182/2164 (55%); RR 0.99, 95% CI 0.89 to 1.10; moderate-quality evidence). However, preventive antibiotic therapy did significantly reduce the incidence of 'overall' infections in participants with acute stroke from 26% to 19% (408/2161 (19%) vs 558/2156 (26%); RR 0.71, 95% CI 0.58 to 0.88; high-quality evidence). This finding was highly significant for urinary tract infections (81/2131 (4%) vs 204/2126 (10%); RR 0.40, 95% CI 0.32 to 0.51; high-quality evidence), whereas no preventive effect for pneumonia was found (222/2131 (10%) vs 235/2126 (11%); RR 0.95, 95% CI 0.80 to 1.13; high-quality evidence). No major side effects of preventive antibiotic therapy were reported. Only two studies qualitatively assessed the occurrence of elevated body temperature; therefore, these results could not be pooled. Only one study reported length of hospital stay. AUTHORS' CONCLUSIONS: Preventive antibiotics had no effect on functional outcome or mortality, but significantly reduced the risk of 'overall' infections. This reduction was driven mainly by prevention of urinary tract infection; no effect for pneumonia was found.

Hyperglycemia predicts poststroke infections in acute ischemic stroke.

OBJECTIVE: To investigate whether admission hyperglycemia predicts poststroke infections and, if so, whether poststroke infections modify the effect of admission hyperglycemia on functional outcome in ischemic stroke. METHODS: We used data from acute ischemic stroke patients in the Preventive Antibiotics in Stroke Study (PASS), a multicenter randomized controlled trial (n = 2,550) investigating the effect of preventive antibiotics on functional outcome. Admission hyperglycemia was defined as blood glucose ≥7.8 mmol/L and poststroke infection as any infection during admission judged by an expert adjudication committee. Functional outcome at 3 months was assessed with the modified Rankin Scale. RESULTS: Of 1,676 nondiabetic ischemic stroke patients, 338 (20%) had admission hyperglycemia. After adjustment for potential confounding variables, admission hyperglycemia was associated with poststroke infection (adjusted odds ratio [aOR] 2.31, 95% CI 1.31-4.07), worse 3-month functional outcome (common aOR 1.40, 95% CI 1.12-1.73), and 3-month mortality (aOR 2.11, 95% CI 1.40-3.19). Additional adjustment for poststroke infection in the functional outcome analysis, done to assess poststroke infection as an intermediate in the pathway from admission hyperglycemia to functional outcome, did not substantially change the model. In patients with recorded diabetes mellitus (n = 418), admission hyperglycemia was not associated with poststroke infection (aOR 0.49, 95% CI 0.15-1.58). CONCLUSIONS: In nondiabetic acute ischemic stroke patients, admission hyperglycemia is associated with poststroke infection and worse functional outcome. Poststroke infections did not modify the effect of admission hyperglycemia on functional outcome in ischemic stroke.

Pre-Stroke Use of Beta-Blockers Does Not Lower Post-Stroke Infection Rate: An Exploratory Analysis of the Preventive Antibiotics in Stroke Study.

BACKGROUND: Stroke-associated infections occur frequently and are associated with unfavorable outcome. Previous cohort studies suggest a protective effect of beta-blockers (BBs) against infections. A sympathetic drive may increase immune suppression and infections. AIM: This study is aimed at investigating the association between BB treatment at baseline and post-stroke infection in the Preventive Antibiotics in Stroke Study (PASS), a prospective clinical trial. METHODS: We performed an exploratory analysis in PASS, 2,538 patients with acute phase of stroke (24 h after onset) were randomized to ceftriaxone (intravenous, 2 g per day for 4 days) in addition to stroke unit care, or standard stroke unit care without preventive antibiotic treatment. All clinical data, including use of BBs, was prospectively collected. Infection was diagnosed by the treating physician, and independently by an expert panel blinded for all other data. Multivariable analysis was performed to investigate the relation between BB treatment and infection rate. RESULTS: Infection, as defined by the physician, occurred in 348 of 2,538 patients (14%). Multivariable analysis showed that the use of BBs at baseline was associated with the development of infection during clinical course (adjusted OR (aOR) 1.61, 95% CI 1.19-2.18; p < 0.01). BB use at baseline was also associated with the development of pneumonia (aOR 1.56, 95% CI 1.05-2.30; p = 0.03). Baseline BB use was not associated with mortality (aOR 1.14, 95% CI 0.84-1.53; p = 0.41) or unfavorable outcome at 3 months (aOR 1.10, 95% CI 0.89-1.35; p = 0.39). CONCLUSIONS: Patients treated with BBs prior to stroke have a higher rate of infection and pneumonia.

Preventive Ceftriaxone in Patients with Stroke Treated with Intravenous Thrombolysis: Post Hoc Analysis of the Preventive Antibiotics in Stroke Study.

BACKGROUND: The Preventive Antibiotics in Stroke Study (PASS), a randomized open-label masked endpoint trial, showed that preventive ceftriaxone did not improve functional outcome at 3 months in patients with acute stroke (adjusted common OR 0.95; 95% CI 0.82-1.09). Post-hoc analyses showed that among patients who received intravenous thrombolysis (IVT), patients who received ceftriaxone had a significantly better outcome as compared with the control group. This study aimed to gain more insight into the characteristics of these patients. METHODS: In PASS, 2,550 patients were randomly assigned to preventive antibiotic treatment with ceftriaxone or standard care. In current post-hoc analysis, 836 patients who received IVT were included. Primary outcome included functional status on the modified Rankin Scale, analyzed with adjusted ordinal regression. Secondary outcomes included infection rate and symptomatic intracerebral hemorrhage (sICH) rate. RESULTS: For all patients in PASS, the p value for the interaction between IVT and preventive ceftriaxone regarding functional outcome was 0.03. Of the 836 IVT-treated patients, 437 were administered ceftriaxone and 399 were allocated to the control group. Baseline characteristics were similar. In the IVT subgroup, preventive ceftriaxone was associated with a significant reduction in unfavorable outcome (adjusted common OR 0.77; 95% CI 0.61-0.99; p = 0.04). Mortality at 3 months was similar (OR 0.75; 95% CI 0.48-1.18). Preventive ceftriaxone was associated with a reduction in infections (OR 0.43; 95% CI 0.28-0.66), and a trend towards an increased risk for sICH (OR 3.09; 95% CI 0.85-11.31). Timing of ceftriaxone administration did not influence the outcome (aOR 1.00; 95% CI 0.98-1.03; p = 0.85). CONCLUSIONS: According to the post-hoc analysis of PASS, preventive ceftriaxone may improve the functional outcome in IVT-treated patients with acute stroke, despite a trend towards an increased rate of post-IVT-sICH.

Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations.

OBJECTIVE: To determine the genotype-phenotype association in patients with adenosine deaminase-2 (ADA2) deficiency due to identical homozygous R169Q mutations inCECR1 METHODS: We present a case series of nine ADA2-deficient patients with an identical homozygous R169Q mutation. Clinical and diagnostic data were collected and available MRI studies were reviewed. We performed genealogy and haplotype analyses and measured serum ADA2 activity. ADA2 activity values were correlated to clinical symptoms. RESULTS: Age of presentation differed widely between the nine presented patients (range: 0 months to 8 years). The main clinical manifestations were (hepato)splenomegaly (8/9), skin involvement (8/9) and neurological involvement (8/9, of whom 6 encountered stroke). Considerable variation was seen in type, frequency and intensity of other symptoms, which included aplastic anaemia, acute myeloid leukaemia and cutaneous ulcers. Common laboratory abnormalities included cytopenias and hypogammaglobulinaemia. ADA2 enzyme activity in patients was significantly decreased compared with healthy controls. ADA2 activity levels tended to be lower in patients with stroke compared with patients without stroke. Genealogical studies did not identify a common ancestor; however, based on allele frequency, a North-West European founder effect can be noted. Three patients underwent haematopoietic cell transplantation, after which ADA2 activity was restored and clinical symptoms resolved. CONCLUSION: This case series revealed large phenotypic variability in patients with ADA2 deficiency though they were homozygous for the same R169Q mutation inCECR1 Disease modifiers, including epigenetic and environmental factors, thus seem important in determining the phenotype. Furthermore, haematopoietic cell transplantation appears promising for those patients with a severe clinical phenotype.