Rationale and design of the PeriOperative ISchemic Evaluation-3 (POISE-3) : a randomized controlled trial evaluating tranexamic acid and a strategy to minimize hypotension in noncardiac surgery

Background For patients undergoing noncardiac surgery, bleeding and hypotension are frequent and associated with increased mortality and cardiovascular complications. Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to reduce surgical bleeding; however, there is uncertainty about its efficacy and safety in noncardiac surgery. Although usual perioperative care is commonly consistent with a hypertension-avoidance strategy (i.e., most patients continue their antihypertensive medications throughout the perioperative period and intraoperative mean arterial pressures of 60 mmHg are commonly accepted), a hypotension-avoidance strategy may improve perioperative outcomes. Methods The PeriOperative Ischemic Evaluation (POISE)-3 Trial is a large international randomized controlled trial designed to determine if TXA is superior to placebo for the composite outcome of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events, at 30 days after randomization. Using a partial factorial design, POISE-3 will additionally determine the effect of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of major cardiovascular events, at 30 days after randomization. The target sample size is 10,000 participants. Patients ≥45 years of age undergoing noncardiac surgery, with or at risk of cardiovascular and bleeding complications, are randomized to receive a TXA 1 g intravenous bolus or matching placebo at the start and at the end of surgery. Patients, health care providers, data collectors, outcome adjudicators, and investigators are blinded to the treatment allocation. Patients on ≥ 1 chronic antihypertensive medication are also randomized to either of the two blood pressure management strategies, which differ in the management of patient antihypertensive medications on the morning of surgery and on the first 2 days after surgery, and in the target mean arterial pressure during surgery. Outcome adjudicators are blinded to the blood pressure treatment allocation. Patients are followed up at 30 days and 1 year after randomization. Discussion Bleeding and hypotension in noncardiac surgery are common and have a substantial impact on patient prognosis. The POISE-3 trial will evaluate two interventions to determine their impact on bleeding, cardiovascular complications, and mortality

Patient data meta-analysis of Post-Authorization Safety Surveillance (PASS) studies of haemophilia A patients treated with rAHF-PFM.

SummaryA Post‐Authorization Safety Study (PASS) global program was designed to assess safety and effectiveness of rAHF‐PFM (ADVATE) use in haemophilia patients in routine clinical settings. The main aim of this project was to estimate the rate of inhibitors and other adverse events across ADVATE‐PASS studies by meta‐analysing individual patient data (IPD). Eligible Studies: PASS studies conducted in different countries, between 2003 and 2013, for which IPD were provided. Eligible patients: haemophilia A patients with baseline FVIII:C 150 EDs. Secondary outcomes: de novo inhibitors according to prior exposure and disease severity; other adverse events; annualized bleeding rate (ABR). Analysis: random‐effects logistic regression. Five of seven registered ADVATE‐PASS (Australia, Europe, Japan, Italy and USA) and 1188 patients were included (median follow‐up 384 days). Among severe PTPs with > 150 EDs, 1/669 developed de novo inhibitors (1.5 per 1000; 95% confidence interval [CI] 0.2, 10.6 per 1000). Among all patients included in the PASS studies, 21 developed any type of inhibitors (2.0%, 95% CI: 0.8%, 4.7%). Less than 1% of patients presented with other serious adverse events possibly related to ADVATE. The overall median ABR was 3.83 bleeds/year (first, third quartiles: 0.60, 12.90); 1.66 (0, 4.78) in the 557 patients continuously on prophylaxis ≥ twice/week. Meta‐analysing PASS data from different countries confirmed the overall favourable safety and effectiveness profile of ADVATE in routine clinical settings

Facial Oedema Is Not Always Angioedema: A Case of Spontaneous Pneumomediastinum with Subcutaneous Emphysema during COPD Exacerbation

We report a case of acute facial oedema in an elderly hospitalized patient which was initially misdiagnosed as angioedema secondary to antibiotics in a patient with an allergic diathesis. We describe the differential aetiologies and then the true cause of the oedema, which was an uncommon complication of a very common condition in the elderly: a pneumomediastinum with subcutaneous emphysema probably due to rupture of an emphysematous lung bulla during chronic obstructive pulmonary disease (COPD) exacerbation. Lastly, we focus on the therapeutic procedures instituted for the treatment of the pneumomediastinum

Patient preference for needleless factor VIII reconstitution device: the Italian experience

Background: Needlestick injuries, mostly due to unsafe needle devices, are a frequent adverse event among health care workers and patients on chronic treatment, such as hemophiliacs. To improve the safety of these procedures, a needleless reconstitution system, Bio-Set\uae has been implemented for the sucrose-formulated recombinant factor VIII (rFVIII-FS) Kogenate\uae Bayer (Bayer Healthcare, Berlin, Germany). The aim of this study was to collect patients' satisfaction and safety data regarding the administration of rFVIII-FS with this new device. Methods: This was a multicenter, prospective, postmarketing surveillance study collecting data from seven Italian Haemophilia Centers within the framework of an international project involving patients from nine European countries. The patients were asked to fill out two preference questionnaires (one assessing the old method and one assessing the new method) directly after the training and two further preference questionnaries (assessing the new method) after a period of about 3 and 12 months. Results: A total of 44 male hemophilia A patients were included in the analysis. At the end of the 12-month observation period, physicians assessed the patients' satisfaction with Kogenate\uae Bayer with Bio-Set\uae in 40.9% (n = 18) as "very satisfied" and in 45.5% (n = 20) as "satisfied", whereas "not satisfied" ratings were given for 9.1% (n = 4) of patients (data missing from two patients, 4.5%). The compliance of the patients compared with the last method before switch to the Bio-Set\uae device was rated as "better", "equal", and "worse" in 72.7% (n = 32), 20.5% (n = 9), and 2.3% (n = 1) of patients, respectively. Three patients (6.8%) experienced adverse events, but only one event was related to rFVIII infusion (inhibitor development in a patient who had little prior exposure to rFVIII) itself and not to the new device per se. Conclusions: The great majority of Italian patients who switched from an older method of rFVIII reconstitution to rFVIII-FS with the new reconstitution method preferred the new method. The ease of use, perceived safety from needlesticks, and the speed of reconstitution were identified as main advantages by the majority patients

Effectiveness of the interventions in preventing the progression of pre-frailty and frailty in older adults:a systematic review protocol

REVIEW QUESTION / OBJECTIVE : The objective of this review is to identify the effectiveness of the interventions in preventing progression of pre-frailty and frailty in older adults. More specifically, the review questions are: - What is the effectiveness of interventions in preventing or reducing frailty in older adults? - How does effectiveness vary with degree of frailty? - Are there factors that influence the effectiveness of interventions? - What is the economic feasibility of interventions for pre-frailty and frailty? INCLUSION CRITERIA : Types of participants This review will consider studies that include older adults (female and male) aged 65 years and over, explicitly identified as pre-frail or frail by the researchers or associated medical professionals according to a pre-specified scale or index, and who have received health care and support services in any type of setting (primary care, nursing homes, hospitals). This review will exclude studies that: - Include participants who have been selected because they have one specific illness - Consider people with a terminal diagnosis only. - Types of intervention(s)/phenomena of interest: The clinical/medical component of the review will consider studies that evaluate any type of interventions to prevent the progression of pre-frailty and frailty in older adults. These interventions will include, but will not be limited to, physical activity, multifactorial intervention, psychosocial intervention, health and social care provision, and cognitive, nutrition or medication/medical maintenance and adherence focused interventions. The economic component of the review will consider studies that have performed any type of health economic analysis of ..

Predicting risk and outcomes for frail older adults:a protocol for an umbrella review of available frailty screening tools

The aim of this systematic review is to comprehensively search the available literature and to summarize the best available evidence from systematic reviews in relation to published screening tools to identify pre-frailty and frailty in older adults, that is: (i) to determine their psychometric proprieties; (ii) to assess their capacity to detect pre-frail and frail conditions against established methods; and (iii) to evaluate their predictive ability. More specifically, the review will focus on the following questions: Frailty is an age-related state of vulnerability resulting from a balance between the maintenance of health and the deficits threatening it.1,2 This clinical condition compromises the ability to cope with daily or acute stressors and, further, increases the risk of adverse outcomes, predisposing those involved to disability and dependency on others for daily life activities, and leading to hospitalization and institutional placement.3,4 It is also a predictor of higher mortality rates.4-7 In the absence of biological markers, an operational definition of frailty has been proposed.2,8 This definition is based on physical markers, including weakness with low muscle strength (e.g. poor grip strength), overall slowness (particularly of gait), decreased balance and mobility, fatigability or exhaustion, low physical activity and involuntary weight loss. For diagnostic purposes, at least three of these symptoms must be observed.8 The presence of only one or two of them indicates the earlier stage of frailty, namely, pre-frailty. Despite high predictive validity of this operational definition, and despite its common use in clinical settings, many researchers believe it is insufficient, asserting that it should also include cognitive and mental health domains, and possibly also social domains such as living alone.9-12 Other dimensions recognized as important for identifying frailty are the ability to deal with activities of daily living and quality of life, as for individuals with this clinical condition both of these areas tend to be decreased.9,13 This lack of consensus on the definition of frailty (based on physical markers as opposed to a broader multidimensional approach) is also reflected in divergences related to the prevalence data obtained from epidemiological studies. Systematic comparison of these data14 shows that frailty prevalence differs from 4% to 17% in the population aged 65 and over, and in case of pre-frailty, prevalence varies from 19% to 53% of the same age group, with average values of 10.7% and 41.6%, respectively. The divergences between estimates are also conditioned by demographic variables such as age and gender. Namely, for elders aged 80-84 the prevalence of frailty is estimated as 15.7%, and for elders over the age of 84, 26.1%. Additionally, women tend to have higher rates of frailty than men. Although the condition of frailty has been studied for years, there is no consensus on its pathophysiologic mechanism. According to some authors2,8,15, this state of increased vulnerability is due to accumulation of subthreshold decrements in physiologic reserves that affects multiple physiologic systems. Other authors16,17 have described frailty in terms of progressive dysregulation in a number of main physiologic systems and their complex interconnected network, and subsequent depletion of homeostatic reserve and resiliency. Recently, discussion on the psychopathological mechanism of this clinical condition has been enriched by new theoretical proposals associating frailty to reduced capacity to compensate ageing-related molecular and cellular damage.13,18 In all these approaches it is assumed that the development of frailty may be modulated by disease. In other words, it can be precipitated or exacerbated by the occurrence of comorbid pathological conditions.19-21 It is also suggested that increased vulnerability for adverse health outcomes can precede the onset of chronic diseases.19,20 However, according to Bergman et al19, it is probable that in this case, frailty is just a manifestation of subclinical and undiagnosed stages of such diseases. Because of the high prevalence and the severity of adverse outcomes of frailty, its screening should be a priority in appropriate components of primary care networks (including general practice, geriatrics, psychology, etc.), as well as in institutional or community care settings. Early diagnosis of this clinical condition can help improve care for older adults, making possible the minimization of the risk of pre-frail states developing into frail states (primary prevention), and implementation of therapeutic measures in order to attenuate or delay underlying conditions and symptoms, or to ameliorate the impact on independence or healthy and engaged lifestyles (loss of which would in turn have a further impact on frailty development, i.e. secondary prevention).2,4 In more advanced stages, frailty assessment provides valuable data necessary to plan and implement intervention strategies oriented to the preservation of functional status or to control the progression of adverse outcomes, such as recurrent hospitalizations, institutionalization or death (tertiary prevention).2,4 The evidence obtained from the implementation of various types of interventions for frailty indicates that the frailty condition can be managed and reduced.22-25 Screening for frailty can also provide information on populations at high risk of disability and poor prognosis, and help to identify reversible risk factors.2 These data are especially important for determining variables that make specific interventions more beneficial to specific patients. In order to identify individuals at risk of frailty, several assessment tools have been developed. The most widely cited focus on physical markers of frailty2,8 or are based on the accumulation of deficits from physical, cognitive, mental health and functional domains.13,26 However, both types of measures seem to be insufficient. The first one does not cover all dimensions of frailty and consequently does not provide indications useful to treatment choice and care planning, and the last one is time consuming and thus is difficult to integrate into day-to-day health care practice.27 In more recent approaches, the indices created for frailty assessment integrate demographic, medical, social and functional information, and demonstrate their usefulness either for diagnostic purposes or to predict adverse health outcomes.28 According to the literature, there are more than 20 different measures being used for frailty screening. Nonetheless, it is still unknown how their characteristics match different samples within the frail/pre-frail condition and robust populations, and what is the best fit between these measures, purposes (e.g. to predict need for care, mortality or potential response to intervention) and contexts/populations to assess frailty in older age. Also, the reliability and validity of these measures need to be clarified, as well as the comparative sensitivity and specificity in identifying patients at risk of a poor prognosis. A scoping search identified a large number of relevant systematic reviews; however in most cases they are confined to specific assessment measures related to a specific clinical model (phenotype model8, cumulative deficits model13 and predictive model28). For a clear view and objective evaluation of existing tools, this set of evidence needs to be systematized, compared and synthesized. In other words, it is essential to conduct an umbrella review. A preliminary search of the JBI Database of Systematic Reviews and Implementation Reports, the Cochrane Database of Systematic Reviews, Prospero, CINAHL and Medline has revealed that there is currently no overview of reviews or umbrella review (neither published nor in progress) on this topic of sufficient reliability, validity and capacity to detect pre-frail and frail conditions, and with predictive accuracy of available screening tools for frailty in older adults29 The main goal of this umbrella review is to consolidate the available evidence regarding screening for pre-frailty and frailty from the published literature. More specifically, reviews will be summarized in order to determine the quality of screening tools in terms of frailty diagnosis and frailty prognosis

Understanding frailty:meanings and beliefs about screening and prevention across key stakeholder groups in Europe

Innovative methods to manage frailty are critical to managing the needs of an ageing population. Evidence suggests there are opportunities to reverse or prevent frailty through early intervention. However, little is known about older adults’, families’ and practitioners’ beliefs about the malleability of frailty. This study examined European stakeholders’ accounts of the acceptability and feasibility of frailty screening and prevention to inform future intervention development. Semi-structured focus groups and individual interviews were conducted in three European Union countries (Italy, Poland and the United Kingdom) with key stakeholders – frail and non-frail older adults, family care-givers, and health and social care professionals. Thematic analysis identified four themes: synchronicity between the physical and the psychological in frailty, living with frailty in the social world, the need for a new kind of care, and screening for and preventing frailty. Findings emphasised the need for a holistic approach to frailty care and early intervention. Integrated care services and advocacy were important in the organisation of care. Central to all stakeholders was the significance of the psychological and social alongside the physical elements of frailty and frailty prevention. Support and care for older adults and their family care-givers needs to be accessible and co-ordinated. Interventions to prevent frailty must encompass a social dimension to help older adults maintain a sense of self while building physical and psychological resilience

Perceptions and experiences of frailty interventions:quantitative and qualitative results from a survey of partners within the European Innovation Partnership on Active and Healthy Ageing (EIP-AHA)

The European Innovation Partnership on Active and Healthy Ageing (EIP-AHA) was launched by the European Commission in 2011 to promote innovation in ageing research. This paper explores the experiences of partners delivering frailty interventions within Europe, registering their programmes with the EIP-AHA. Data were collected using an online survey from 21 partners in seven countries. A mixed-method approach was used with inductive thematic analysis of free-text responses to improve data richness. Responses indicated that there was a lack of consistency between EIP-AHA partners in methods of defining, screening and measuring for frailty and pre-frailty. Open responses to survey questions about intervention facilitators, moderators and barriers were coded into two themes: working with stakeholders and project management. We concluded that EIP-AHA partners are providing interventions addressing physical, cognitive and wellbeing elements of frailty. However, there needs to be an increase in the proportion of interventions that consistently apply valid methods of screening and/or measuring frailty and pre-frailty. Most, but not all projects are targeting pre-frail older adults, suggesting an appropriate balance of prevention in a useful ‘intervention window’ but also a growing understanding that frailty at later stages is amenable to intervention. Findings suggest design manipulations to improve outcomes and adherence to interventions, specifically inclusion of a perceived benefit/reward for older adults, e.g. a social aspect or health-care promotion

Risk of recurrence after venous thromboembolism in men and women: patient level meta-analysis

Objective To determine the effect of sex on the risk of recurrent venous thromboembolism in all patients and in patients with venous thromboembolism that was unprovoked or provoked (by non-hormonal factors)

A Very Big Hand Is a Very Big Problem: Soft-Tissue Infection, Venous Thrombosis, or Just an Insect Sting?

A 67-year-old woman developed severe edema of her right hand and forearm, for which she was treated with antibiotics, without benefit. The echography excluded a venous thrombosis. Subsequently, she referred a wasp sting before the development of the edema. Specific Hymenoptera venom immunoglobulin E (IgE) was found to be positive for paper wasp and yellow jacket. A large local reaction (LLR) was diagnosed due to the hymenoptera sting. Self-injectable epinephrine was prescribed for possible, though unlikely, systemic reactions following hymenoptera stings