I.V. fluid therapy does not result in the extracellular volume distribution expected from Starling's original model of semi-permeable capillaries subject to hydrostatic and oncotic pressure gradients within the extracellular fluid. Fluid therapy to support the circulation relies on applying a physiological paradigm that better explains clinical and research observations. The revised Starling equation based on recent research considers the contributions of the endothelial glycocalyx layer (EGL), the endothelial basement membrane, and the extracellular matrix. The characteristics of capillaries in various tissues are reviewed and some clinical corollaries considered. The oncotic pressure difference across the EGL opposes, but does not reverse, the filtration rate (the 'no absorption' rule) and is an important feature of the revised paradigm and highlights the limitations of attempting to prevent or treat oedema by transfusing colloids. Filtered fluid returns to the circulation as lymph. The EGL excludes larger molecules and occupies a substantial volume of the intravascular space and therefore requires a new interpretation of dilution studies of blood volume and the speculation that protection or restoration of the EGL might be an important therapeutic goal. An explanation for the phenomenon of context sensitivity of fluid volume kinetics is offered, and the proposal that crystalloid resuscitation from low capillary pressures is rational. Any potential advantage of plasma or plasma substitutes over crystalloids for volume expansion only manifests itself at higher capillary pressures.

Within minutes of a traumatic impact, a robust inflammatory response is elicited in the injured brain. The complexity of this post-traumatic squeal involves a cellular component, comprising the activation of resident glial cells, microglia, and astrocytes, and the infiltration of blood leukocytes. The second component regards the secretion immune mediators, which can be divided into the following sub-groups: the archetypal pro-inflammatory cytokines (Interleukin-1, Tumor Necrosis Factor, Interleukin-6), the anti-inflammatory cytokines (IL-4, Interleukin-10, and TGF-beta), and the chemotactic cytokines or chemokines, which specifically drive the accumulation of parenchymal and peripheral immune cells in the injured brain region. Such mechanisms have been demonstrated in animal models, mostly in rodents, as well as in human brain. Whilst the humoral immune response is particularly pronounced in the acute phase following Traumatic brain injury (TBI), the activation of glial cells seems to be a rather prolonged effect lasting for several months. The complex interaction of cytokines and cell types installs a network of events, which subsequently intersect with adjacent pathological cascades including oxidative stress, excitotoxicity, or reparative events including angiogenesis, scarring, and neurogenesis. It is well accepted that neuroinflammation is responsible of beneficial and detrimental effects, contributing to secondary brain damage but also facilitating neurorepair. Although such mediators are clear markers of immune activation, to what extent cytokines can be defined as diagnostic factors reflecting brain injury or as predictors of long term outcome needs to be further substantiated. In clinical studies some groups reported a proportional cytokine production in either the cerebrospinal fluid or intraparenchymal tissue with initial brain damage, mortality, or poor outcome scores. However, the validity of cytokines as biomarkers is not broadly accepted. This review article will discuss the evidence from both clinical and laboratory studies exploring the validity of immune markers as a correlate to classification and outcome following TBI.

Improvement (defined broadly as purposive efforts to secure positive change) has become an increasingly important activity and field of inquiry within healthcare. This article offers an overview of possible methods for the study of improvement interventions. The choice of available designs is wide, but debates continue about how far improvement efforts can be simultaneously practical (aimed at producing change) and scientific (aimed at producing new knowledge), and whether the distinction between the practical and the scientific is a real and useful one. Quality improvement projects tend to be applied and, in some senses, self-evaluating. They are not necessarily directed at generating new knowledge, but reports of such projects if well conducted and cautious in their inferences may be of considerable value. They can be distinguished heuristically from research studies, which are motivated by and set out explicitly to test a hypothesis, or otherwise generate new knowledge, and from formal evaluations of improvement projects. We discuss variants of trial designs, quasi-experimental designs, systematic reviews, programme evaluations, process evaluations, qualitative studies, and economic evaluations. We note that designs that are better suited to the evaluation of clearly defined and static interventions may be adopted without giving sufficient attention to the challenges associated with the dynamic nature of improvement interventions and their interactions with contextual factors. Reconciling pragmatism and research rigour is highly desirable in the study of improvement. Trade-offs need to be made wisely, taking into account the objectives involved and inferences to be made.

The implementation of evidence-based treatments to deliver high-quality care is essential to meet the healthcare demands of aging populations. However, the sustainable application of recommended practice is difficult to achieve and variable outcomes well recognised. The NHS Institute for Innovation and Improvement Sustainability Model (SM) was designed to help healthcare teams recognise determinants of sustainability and take action to embed new practice in routine care. This article describes a formative evaluation of the application of the SM by the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for Northwest London (CLAHRC NWL).Data from project teams’ responses to the SM and formal reviews was used to assess acceptability of the SM and the extent to which it prompted teams to take action. Projects were classified as ‘engaged,’ ‘partially engaged’ and ‘non-engaged.’ Quarterly survey feedback data was used to explore reasons for variation in engagement. Score patterns were compared against formal review data and a ‘diversity of opinion’ measure was derived to assess response variance over time.Of the 19 teams, six were categorized as ‘engaged,’ six ‘partially engaged,’ and seven as ‘non-engaged.’ Twelve teams found the model acceptable to some extent. Diversity of opinion reduced over time. A minority of teams used the SM consistently to take action to promote sustainability but for the majority SM use was sporadic. Feedback from some team members indicates difficulty in understanding and applying the model and negative views regarding its usefulness.The SM is an important attempt to enable teams to systematically consider determinants of sustainability, provide timely data to assess progress, and prompt action to create conditions for sustained practice. Tools such as these need to be tested in healthcare settings to assess strengths and weaknesses and findings disseminated to aid development. This study indicates the SM provides a potentially useful approach to measuring teams’ views on the likelihood of sustainability and prompting action. Securing engagement of teams with the SM was challenging and redesign of elements may need to be considered. Capacity building and facilitation appears necessary for teams to effectively deploy the SM.

Three hundred twenty-five women with metastatic adenocarcinoma of the breast who had failed one prior chemotherapeutic regimen for advanced disease were randomized to receive 14 mg/m2 of mitoxantrone or 75 mg/m2 of doxorubicin intravenously (IV) every 3 weeks. Enrollment was closed on October 31, 1984, after 165 patients were randomized to mitoxantrone and 160 patients to doxorubicin. Patients randomized to the two treatment groups were compared for response rate, duration of response, time to progression or death, time to treatment failure (TTF), and survival. The response rate to mitoxantrone was 20.6%, to doxorubicin 29.3% (P = .07). The median response duration was 151 days for the mitoxantrone group and 126 days for the doxorubicin group (P = .16). The median TTF was 70 days in the mitoxantrone group and 104 days in the doxorubicin group (P = .36). The median survival of patients initially randomized to receive mitoxantrone was 273 days; for doxorubicin 268 days (P = .40). There were three responses among 77 patients crossed over to mitoxantrone after initial treatment with doxorubicin. The major dose-limiting toxicity for both drugs was leukopenia. There was significantly less severe and less frequent toxicity with mitoxantrone administration. Severe nausea and vomiting occurred in 9.5% of mitoxantrone patients and 25.3% of doxorubicin patients (P less than .001). The incidence of severe stomatitis and mucositis was 0.6% in the mitoxantrone group and 8.4% in the doxorubicin group (P = .001). Severe alopecia occurred in 5.1% of mitoxantrone patients and 61.0% of doxorubicin patients (P less than .001). A life-table comparison of the cumulative dose to the development of a cardiac event showed that mitoxantrone had significantly less cardiotoxicity than doxorubicin (P = .0005). This study demonstrates that mitoxantrone is active as a single agent in the treatment of metastatic breast cancer. Compared with doxorubicin it appears to be marginally less active and significantly less toxic. We conclude that mitoxantrone can be used alone or with other standard drugs to palliate the symptoms of metastatic breast cancer, especially in settings where drug toxicity is an important consideration.

ObjectivesPopulation ageing has been associated with an increase in comorbid chronic disease, functional dependence, disability and associated higher health care costs. Frailty Syndromes have been proposed as a way to define this group within older persons. We explore whether frailty syndromes are a reliable methodology to quantify clinically significant frailty within hospital settings, and measure trends and geospatial variation using English secondary care data set Hospital Episode Statistics (HES).SettingNational English Secondary Care Administrative Data HES.ParticipantsAll 50 540 141 patient spells for patients over 65 years admitted to acute provider hospitals in England (January 2005—March 2013) within HES.Primary and secondary outcome measuresWe explore the prevalence of Frailty Syndromes as coded by International Statistical Classification of Diseases, Injuries and Causes of Death (ICD-10) over time, and their geographic distribution across England. We examine national trends for admission spells, inpatient mortality and 30-day readmission.ResultsA rising trend of admission spells was noted from January 2005 to March 2013(daily average admissions for month rising from over 2000 to over 4000). The overall prevalence of coded frailty is increasing (64 559 spells in January 2005 to 150 085 spells by Jan 2013). The majority of patients had a single frailty syndrome coded (10.2% vs total burden of 13.9%). Cognitive impairment and falls (including significant fracture) are the most common frailty syndromes coded within HES. Geographic variation in frailty burden was in keeping with known distribution of prevalence of the English elderly population and location of National Health Service (NHS) acute provider sites. Overtime, in-hospital mortality has decreased (>65 years) whereas readmission rates have increased (esp.>85 years).ConclusionsThis study provides a novel methodology to reliably quantify clinically significant frailty. Applications include evaluation of health service improvement over time, risk stratification and optimisation of services.

National surveys have revealed significant differences in patient outcomes following admission to hospital with acute exacerbation of COPD which are likely to be due to variations in care. We developed a care bundle, comprising a short list of evidence-based practices to be implemented prior to discharge for all patients admitted with this condition, based on a review of national guidelines and other relevant literature, expert opinion and patient consultation. Implementation was then piloted using action research methodologies with patient input. Actively involving staff was vital to ensure that the changes introduced were understood and the process followed. Implementation of a care bundle has the potential to produce a dramatic improvement in compliance with optimum health care practice.

Background The identification and articulation of programme theory can support effective design, execution and evaluation of quality improvement (QI) initiatives. Programme theory includes an agreed aim, potential interventions to achieve this aim, anticipated cause/effect relationships between the interventions and the aim and measures to monitor improvement. This paper outlines the approach used in a research and improvement programme to support QI initiatives in identifying and articulating programme theory: the action effect method. Background to method development Building on a previously used QI method, the driver diagram, the action effect method was developed using co-design and iteration over four annual rounds of improvement initiatives. This resulted in a specification of the elements required to fully articulate the programme theory of a QI initiative. The action effect method The action effect method is a systematic and structured process to identify and articulate a QI initiative's programme theory. The method connects potential interventions and implementation activities with an overall improvement aim through a diagrammatic representation of hypothesised and evidenced cause/effect relationships. Measure concepts, in terms of service delivery and patient and system outcomes, are identified to support evaluation. Discussion and conclusions The action effect method provides a framework to guide the execution and evaluation of a QI initiative, a focal point for other QI methods and a communication tool to engage stakeholders. A clear definition of what constitutes a wellarticulated programme theory is provided to guide the use of the method and assessment of the fidelity of its application.