Background and Purpose- The purpose of these guidelines is to provide an up-to-date comprehensive set of recommendations in a single document for clinicians caring for adult patients with acute arterial ischemic stroke. The intended audiences are prehospital care providers, physicians, allied health professionals, and hospital administrators. These guidelines supersede the 2013 Acute Ischemic Stroke (AIS) Guidelines and are an update of the 2018 AIS Guidelines. Methods- Members of the writing group were appointed by the American Heart Association (AHA) Stroke Council's Scientific Statements Oversight Committee, representing various areas of medical expertise. Members were not allowed to participate in discussions or to vote on topics relevant to their relations with industry. An update of the 2013 AIS Guidelines was originally published in January 2018. This guideline was approved by the AHA Science Advisory and Coordinating Committee and the AHA Executive Committee. In April 2018, a revision to these guidelines, deleting some recommendations, was published online by the AHA. The writing group was asked review the original document and revise if appropriate. In June 2018, the writing group submitted a document with minor changes and with inclusion of important newly published randomized controlled trials with >100 participants and clinical outcomes at least 90 days after AIS. The document was sent to 14 peer reviewers. The writing group evaluated the peer reviewers' comments and revised when appropriate. The current final document was approved by all members of the writing group except when relationships with industry precluded members from voting and by the governing bodies of the AHA. These guidelines use the American College of Cardiology/AHA 2015 Class of Recommendations and Level of Evidence and the new AHA guidelines format. Results- These guidelines detail prehospital care, urgent and emergency evaluation and treatment with intravenous and intra-arterial therapies, and in-hospital management, including secondary prevention measures that are appropriately instituted within the first 2 weeks. The guidelines support the overarching concept of stroke systems of care in both the prehospital and hospital settings. Conclusions- These guidelines provide general recommendations based on the currently available evidence to guide clinicians caring for adult patients with acute arterial ischemic stroke. In many instances, however, only limited data exist demonstrating the urgent need for continued research on treatment of acute ischemic stroke.

Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.

American Heart Association Council on cardiovascular nursing.

Background and Purpose—Stroke mortality has been declining since the early 20th century. The reasons for this are not completely understood, although the decline is welcome. As a result of recent striking and more accelerated decreases in stroke mortality, stroke has fallen from the third to the fourth leading cause of death in the United States. This has prompted a detailed assessment of the factors associated with the change in stroke risk and mortality. This statement considers the evidence for factors that have contributed to the decline and how they can be used in the design of future interventions for this major public health burden. Methods—Writing group members were nominated by the committee chair and co-chair on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council’s Scientific Statements Oversight Committee and the American Heart Association Manuscript Oversight Committee. The writers used systematic literature reviews, references to published clinical and epidemiological studies, morbidity and mortality reports, clinical and public health guidelines, authoritative statements, personal files, and expert opinion to summarize evidence and to indicate gaps in current knowledge. All members of the writing group had the opportunity to comment on this document and approved the final version. The document underwent extensive American Heart Association internal peer review, Stroke Council leadership review, and Scientific Statements Oversight Committee review before consideration and approval by the American Heart Association Science Advisory and Coordinating Committee. Results—The decline in stroke mortality over the past decades represents a major improvement in population health and is observed for both sexes and for all racial/ethnic and age groups. In addition to the overall impact on fewer lives lost to stroke, the major decline in stroke mortality seen among people <65 years of age represents a reduction in years of potential life lost. The decline in mortality results from reduced incidence of stroke and lower case-fatality rates. These significant improvements in stroke outcomes are concurrent with cardiovascular risk factor control interventions. Although

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Factors Influencing the Decline in Stroke Mortality A Statement From the American Heart Association/American Stroke Association

Stroke is ranked as the second leading cause of death worldwide with an annual mortality rate of about 5.5 million. Not only does the burden of stroke lie in the high mortality but the high morbidity also results in up to 50% of survivors being chronically disabled. Thus stroke is a disease of immense public health importance with serious economic and social consequences. The public health burden of stroke is set to rise over future decades because of demographic transitions of populations, particularly in developing countries. This paper provides an overview of stroke in the 21st century from a public health perspective.

https://downloads.hindawi.com/journals/srt/2018/3238165.pdf

Stroke in the 21st Century: A Snapshot of the Burden, Epidemiology, and Quality of Life.

Recent clinical and experimental studies have highlighted a complex role for the immune system in the pathophysiological changes that occur after acute stroke. Sensors of the innate immune system such as Toll-like receptors, or effectors such as the lectin pathway of complement activation and innate immune cells, are activated by brain ischaemia and tissue damage, leading to amplification of the inflammatory cascade. Activation of the adaptive arm of the immune system, mediated by lymphocyte populations including T and B cells, regulatory T cells, and γδT cells, in response to stroke can lead to deleterious antigen-specific autoreactive responses but can also have cytoprotective effects. Increased incidence of infections is observed after acute stroke, and might result from activation of long-distance feedback loops between the CNS and peripheral immune organs, which are thought to play a part in stroke-induced immunodepression. Ongoing clinical trials are investigating whether the preventive use of antibiotics improves functional outcome after stroke. This Review discusses the multifaceted role of the immune system in the pathophysiology of acute stroke.

The immunology of acute stroke.

stroke is the main cause of disability in high-income countries, and ranks second as a cause of death worldwide. Patients with acute stroke are at risk for infections, but reported post-stroke infection rates vary considerably. We performed a systematic review and meta-analysis to estimate the pooled post-stroke infection rate and its effect on outcome. MEDLINE and EMBASE were searched for studies on post-stroke infection. Cohort studies and randomized clinical trials were included when post-stroke infection rate was reported. Rates of infection were pooled after assessment of heterogeneity. Associations between population- and study characteristics and infection rates were quantified. Finally, we reviewed the association between infection and outcome. 87 studies were included involving 137817 patients. 8 studies were restricted to patients admitted on the intensive care unit (ICU). There was significant heterogeneity between studies (P < 0.001, I2 = 97%). The overall pooled infection rate was 30% (24-36%); rates of pneumonia and urinary tract infection were 10% (95% confidence interval [CI] 9-10%) and 10% (95%CI 9-12%). For ICU studies, these rates were substantially higher with 45% (95% CI 38-52%), 28% (95%CI 18-38%) and 20% (95%CI 0-40%). Rates of pneumonia were higher in studies that specifically evaluated infections and in consecutive studies. Studies including older patients or more females reported higher rates of urinary tract infection. Pneumonia was significantly associated with death (odds ratio 3.62 (95%CI 2.80-4.68). Infection complicated acute stroke in 30% of patients. Rates of pneumonia and urinary tract infection after stroke were 10%. Pneumonia was associated with death. Our study stresses the need to prevent infections in patients with stroke.

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Post-stroke infection: a systematic review and meta-analysis

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.

Antibiotic therapy for preventing infections in patients with acute stroke.

This paper is based on a Cochrane Review published in The Cochrane Library 2018, Issue 1 (see www.thecochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and The Cochrane Library should be consulted for the most recent version of the review.

Antibiotic Therapy for Preventing Infections in People With Acute Stroke

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 Conclusions: Patients treated with BBs prior to stroke have a higher rate of infection and pneumonia.

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

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.

https://journals.sagepub.com/doi/pdf/10.1177/1747493018798557

Jan-Dirk Vermeij

Papers

Post-stroke infection: a systematic review and meta-analysis

Antibiotic therapy for preventing infections in patients with acute stroke.

Antibiotic Therapy for Preventing Infections in People With Acute Stroke

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

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