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Welcome to the first issue of the Future Hospital Journal of the Royal College of Physicians. It is both an honour and pleasure to introduce an initiative designed not only to promote and develop the contents of the RCP report Future hospital: caring for medical patients , published in September 2013, but also to publish original research, reviews, guidance and opinion concerning innovation in systems of clinical practice, administration and management, and the organisation and delivery of health care. In our three editions per year, we aim to promote balanced and responsible debate regarding these issues among the fellows and members of the RCP, and to communicate innovative ideas to clinicians, technical and administrative staff and managers, patients and carers, and those engaged politically in providing and developing current and future healthcare systems. Above all, the editorial board hopes to carry out its mission in a manner that informs, stimulates, and entertains its readers. The task we face in improving healthcare through this medium is significant. At its birth in July 1948 the NHS assumed control of around 480,000 hospital beds, employed 5,000 consultants and in its first 12 months cost the nation £248 million to provide comprehensive healthcare free at the point of access to around 50 million people. Even from the perspective lent by 66 years, radical changes have occurred since this modest nativity. Indeed, Westminster no longer even presides over a truly national health service, responsibility for which has been devolved to Wales, Scotland and Northern Ireland; and in England to Foundation Trusts, or the Trust Development Agency. Indeed, the powers of the current secretary of state to close even a single accident and emergency department appear to be curtailed by legislation designed to free the modern NHS from central control.1 Second, in England alone a consultant …

Your editor is often struck by the number of individuals whom he encounters in various healthcare-related settings who, through their keenness to improve services to the patients they serve identify a perceived or real deficiency in care and assert ‘they should do something about it’. He often muses as to whom ‘they’ actually are? Sometimes this is self-evident. Individuals encountering the day-to-day frustrations associated with providing a clinical service either should be able to overcome these through their own initiative, or turn to line managers or systems of governance for assistance. Indeed, annual appraisal is supposed to bring together the lessons learnt in clinical practice to develop ourselves and improve our performance. However, sometimes ‘they’ are less easy to identify. Do we mean others within the provider arm of the NHS, who may be employed by the public or (increasingly) the private sectors? Do we mean commissioners, who may be difficult to identify or to interact with directly for those working at the coal face, but who seem to place increasing demands upon those that supply services, thereby applying the principles of Outcomes Based Incentivised Commissioning (sic)? Or do we mean ‘the government’? Since the Health and Social Care Act of 2013 arrived to brighten our professional lives, your editor perceives an increasing distance being created between elected politicians taking responsibility for deficiencies (but rather less so for any successes) in healthcare provision and those tasked with overseeing its provision. In an effort to address this question, I have in this column selected three pieces of evidence that have emerged since last I wrote, each of which cast some light upon this issue. The first is the NHS Five Year Forward View (‘5YFV’) published in October 2014 by NHS England, which sets a positive spin on the future, based around …

An aspect of the report of the Future Hospital Commission (FHC) that was considered controversial when it was published 2 years ago was the perception that medical generalism was favoured over the trend towards increased specialisation. This notion was an oversimplification of a complex problem. A compelling component of the evidence gathered by the FHC came from patients and carers, who were engaged at all levels of the exercise. It became clear that they found the tendency for multiple specialists, often with extremely focused areas of expertise limited to a single organ (or indeed a part of that organ), to come to their bedside, pronounce on that specific aspect of their care and then depart to be frustrating, notwithstanding the undoubted improvements in clinical outcomes such specialisation has achieved. In response, a central recommendation of the FHC was that a trained clinician would assume overall responsibility for managing and coordinating each patient's care. This role could be fulfilled by generalists, or delivered by specialists for part of their job plan. All those involved in producing the FHC report were adamant that maintaining and augmenting the access of patients to specialist care could not be compromised in the future hospital; the issue was merely that the coordination of these efforts and their delivery as part of a comprehensive care plan was often lacking. Robert Francis also emphasised this point in his report into the Mid-Staffordshire case, asserting that the responsibility for the delivery of a basic level of care to all patients needed to be …

Aim: We investigated whether plasma levels of the inflammation marker S100A8/A9, could predict acute kidney injury (AKI) onset in patients undergoing cardiac surgery necessitating cardiopulmonary bypass (CPB). Patients & methods: Plasma levels of S100A8/A9 and other neutrophil cytosolic proteins were measured in 39 patients pre- and immediately post-CPB. Results: All markers increased significantly post-CPB with S100A8/A9, S100A12 and myeloperoxidase levels significantly higher in patients who developed AKI within 7 days. S100A8/A9 had good prognostic utility for AKI, with an area under the receiver operating characteristic curve of 0.81 (95% CI: 0.676–0.949) and a cut-off value of 10.6 μg/ml (85.7% sensitivity and 75% specificity) irrespective of age. Conclusion: Plasma S100A8/A9 levels immediately after cardiac surgery, can predict onset of AKI, irrespective of age.

Background Debate remains regarding whether the systemic inflammatory response syndrome (SIRS) identifies patients with clinically important inflammation. Defining criteria may be disproportionately sensitive and lack specificity. We investigated the incidence and evolution of SIRS in a homogenous population (following cardiac surgery) over 7 days to establish the relationship between SIRS and outcome, modeling alternative permutations of the criteria to increase their discriminatory power for mortality, length of stay, and organ dysfunction. Methods We conducted a retrospective analysis of prospectively collected data from a cardiothoracic ICU. Consecutive patients requiring ICU admission for the first time after cardiac surgery (N = 2, 764) admitted over a 41-month period were studied. Results Concurrently, 96.2% of patients met the standard two criterion definition for SIRS within 24 h of ICU admission. Their mortality was 2.78%. By contrast, three or four criteria were more discriminatory of patients with higher mortality (4.21% and 10.2%, respectively). A test dataset suggested that meeting two criteria for at least 6 consecutive h may be the best model. This had a positive and negative predictive value of 7% and 99.5%, respectively, in a validation dataset. It performed well at predicting organ dysfunction and prolonged ICU admission. Conclusions The concept of SIRS remains valid following cardiac surgery. With suitable modification, its specificity can be improved significantly. We propose that meeting two or more defining criteria for 6 h could be used to define better populations with more difficult clinical courses following cardiac surgery. This group may merit a different clinical approach.

Diffuse alveolar hemorrhage is characterized by the presence of red blood cells and free hemoglobin in the alveoli and complicates a number of serious medical and surgical lung conditions including the pulmonary vasculitides and acute respiratory distress syndrome. In this study we investigated the hypothesis that exposure of human alveolar epithelial cells to hemoglobin and its breakdown products regulates chemokine release via iron- and oxidant-mediated activation of the transcription factor NF-κB. Methemoglobin alone stimulated the release of IL-8 and MCP-1 from A549 cells via activation of the NF-κB pathway; additionally, IL-8 required ERK activation and MCP-1 required JNK activation. Neither antioxidants nor iron chelators and knockdown of ferritin heavy and light chains affected these responses, indicating that iron and reactive oxygen species are not involved in the response of alveolar epithelial cells to methemoglobin. Incubation of primary cultures of human alveolar type 2 cells with methemoglobin resulted in a similar pattern of chemokine release and signaling pathway activation. In summary, we have shown for the first time that methemoglobin induced chemokine release from human lung epithelial cells independent of iron- and redox-mediated signaling involving the activation of the NF-κB and MAPK pathways. Decompartmentalization of hemoglobin may be a significant proinflammatory stimulus in a variety of lung diseases.

Purpose The epidemiology of acute kidney injury (AKI) after cardiac surgery depends on the definition used. Our aims were to evaluate the Risk/Injury/Failure/Loss/End-stage (RIFLE) criteria, the AKI Network (AKIN) classification, and the Kidney Disease: Improving Global Outcomes (KDIGO) classification for AKI post–cardiac surgery and to compare the outcome of patients on renal replacement therapy (RRT) with historical data. Methods Retrospective analysis of 1881 adults who had cardiac surgery between May 2006 and April 2008 and determination of the maximum AKI stage according to the AKIN, RIFLE, and KDIGO classifications. Results The incidence of AKI using the AKIN and RIFLE criteria was 25.9% and 24.9%, respectively, but individual patients were classified differently. The area under the receiver operating characteristic curve for hospital mortality was significantly higher using the AKIN compared with the RIFLE criteria (0.86 vs 0.78, P = .0009). Incidence and outcome of AKI according to the AKIN and KDIGO classification were identical. The percentage of patients who received RRT was 6.2% compared with 2.7% in 1989 to 1990. The associated hospital mortality fell from 82.9% in 1989 to 1990 to 15.6% in 2006 to 2008. Conclusions The AKIN classification correlated better with mortality than did the RIFLE criteria. Mortality of patients needing RRT after cardiac surgery has improved significantly during the last 20 years.

Background and objective Acute severe clinical deterioration of patients with cystic fibrosis (CF) may mandate endotracheal intubation. The benefits of intubation were evaluated by examining which pre-admission parameters were associated with intensive care unit (ICU) outcome and assessing the potential benefits of intubation for survivors in terms of time from ICU discharge to death. Methods A retrospective analysis of data from a single centre was undertaken. Results Thirty patients required intubation on 34 occasions (8 per 1000 admissions). Eleven patients died in ICU and 7 after ICU but not hospital discharge. Fifty-nine per cent of 22 patients intubated for pneumothorax and/or haemoptysis survived to hospital discharge. Of the twelve intubated for infective exacerbations, 33% survived to hospital discharge. Those who died after hospital discharge survived 447 days. There were no significant differences for survivors in reasons for intubation, colonizing organism, frequency of infective exacerbations, severity of illness or pulmonary physiology. Osteoporosis and a greater fall in body mass index over the 24 months prior were more frequent in non-survivors. Conclusions Patients with CF developing haemoptysis and/or pneumothorax should be admitted to ICU and intubated promptly, should this be required. Chronic disease markers may be more relevant prognostically than rates of hospitalization or forced expiratory volume in 1 s decline which should not be bars to invasive ventilation.

Every country has finite resources that are expended to provide citizens with social "goods," including education, protection, infrastructure, and health care. Rationing-of any resource-refers to distribution of an allotted amount and may involve withholding some goods that would benefit some citizens. Health-care rationing is controversial because good health complements so many human endeavors. We explored (perceptions regarding) critical care rationing in seven industrialized countries. Academic physicians from England, Spain, Italy, France, Argentina, Canada, and the United States wrote essays that addressed specific questions including: (1) What historical, cultural, and medical institutional features inform my country's approach to rationing of health care? (2) What is known about formal rationing, especially in critical care, in my country? (3) How does rationing occur in my ICU? Responses suggest that critical care is rationed, by varying mechanisms, in all seven countries. We speculate that while no single "best" method of rationing is likely to be acceptable or optimal for all countries, professional societies could serve international health by developing evidence-based guidelines for just and effective rationing of critical care.

Background and objective: ARDS is characterized by bilateral pulmonary infiltrates and refractory hypoxemia attributed to V/Q mismatch. We used dynamic CT to characterize changes in lung composition, regional perfusion and tissue distribution in patients with ARDS in comparison with healthy subjects. Methods: The Fick principle was applied to serial attenuation measurements constructed from sequential CT images acquired during the passage of a bolus of iodinated contrast medium in healthy subjects (n = 3) and patients with ARDS (n = 11). Perfusion was calculated by the Mullani-Gould method and mapped throughout both lungs. Gradients of perfusion and tissue density against vertical height were constructed. Results: In comparison with normal individuals, the tissue component of lungs from patients with ARDS was significantly increased (P

Background The sepsis syndromes, frequently complicated by pulmonary and cardiac dysfunction, remain a major cause of death amongst the critically ill. Targeted therapies aimed at ameliorating the systemic inflammation that characterises the sepsis syndromes have largely yielded disappointing results in clinical trials. Whilst there are many potential reasons for lack of success of clinical trials, one possibility is that the pathways targeted, to date, are only modifiable very early in the course of the illness. More recent approaches have therefore attempted to identify pathways that could offer a wider therapeutic window, such as the receptor for advanced glycation end-products (RAGE) and its ligands.

Purpose To establish the relationship between plasma levels of thioredoxin (Trx) and macrophage migration inhibitory factor (MIF) in systemic inflammatory stress syndrome (SIRS)/sepsis. Methods Enzyme-linked immunosorbent assay measurements of Trx, MIF, IL-6, -8, and -10 and enzyme-linked fluorescent assay determination of procalcitonin (PCT) in plasma from patients with SIRS/sepsis, neutropenic sepsis, healthy volunteers and pre-oesophagectomy patients. Results Thioredoxin was significantly higher in SIRS/sepsis patients [101.3 ng ml−1, interquartile range (IQR) 68.7–155.6, n = 32] compared with that in healthy controls (49.5 ng ml−1, IQR 31.4–71.1, P

08.04.15 KB. Ok to add published paper to spiral, OA paper originally published by Macmillan (now under Wiley)

Rationale and Objectives Pulmonary vascular control mechanisms are complex and likely to differ between species. We wish to quantify regional perfusion and the effects of gravity using computed tomography. Materials and Methods Sequential density measurements following the administration of a bolus of iodinated contrast medium were acquired from four healthy human subjects and four dogs. Results In humans, perfusion (Q) was linear throughout most of the range of vertical height, with an overall gradient of −2.6% cm−1. However, when perfusion was normalized to “tissue” density (blood plus tissue: sQt), maximum perfusion occurred around the mid-range of vertical height, being 9% (range 1–22%) greater than either the dorsal or ventral extreme. Within discrete transverse axial sections, concentric zones of perfusion centered on blood vessels were demonstrated. The relationship between sQt and vertical height in dogs was distinctly linear, with a gradient of −7.2% cm−1. In dogs, the median gradient of Q was −13.6% cm−1 (range −9.7 to −17.1%). Conclusions Differences in regional pulmonary perfusion, particularly the vertical gradient observed in humans and dogs, may in part reflect anatomic differences between the symmetric dichotomous branching structure of the human pulmonary vasculature and the more asymmetrical structure found in dogs.

Background Abnormal plasma and lung iron mobilization is associated with the onset and progression of ARDS and is detectable in specific at-risk populations. Patients with ARDS also have pronounced oxidative and nitrosative stress that can be catalyzed and thereby aggravated by the bioavailability of redox active iron. ARDS of pulmonary and extrapulmonary origin may differ pathophysiologically and require different ventilatory strategies. Evidence suggests that genetic predisposition is relevant to the pathogenesis of ARDS. We therefore explored the hypothesis that polymorphisms from a panel of genes encoding iron-metabolizing proteins determine susceptibility to ARDS. Methods Retrospective case-control study conducted at the adult ICUs of two university hospitals. Patients with ARDS (n = 122) and healthy control subjects (n = 193) were genotyped. Sequence-specific primer polymerase chain reaction was used to genotype selected biallelic single-nucleotide polymorphisms. An audit of the patient database was conducted, and 104 of the 122 ARDS patients were eligible for the final data analysis. Results Preliminary analysis indicated differences between ARDS and healthy control subjects in the incidence of polymorphism of the gene encoding ferritin light chain. Subgroup analysis indicated the prevalence of ferritin light-chain gene −3381GG homozygotes was increased in patients with ARDS of extrapulmonary origin compared to healthy control subjects. Secondly, a common haplotype in the heme oxygenase 2 gene was reduced in patients with ARDS compared to healthy control subjects and was more evident in those with ARDS of direct or pulmonary etiology. Conclusions These results provide preliminary evidence to suggest a distinction in the genetic background of the subpopulations studied, inferring that the ferritin light-chain gene genotype confers susceptibility to ARDS, while the heme oxygenase 2 haplotype is protective against the onset of the syndrome. Such data support further previous findings that suggest abnormalities in iron handling resulting in redox imbalance are implicated in the pathogenesis of ARDS.

Changes in iron homeostatic responses routinely accompany infectious or proinflammatory insults. The systemic inflammatory response syndrome (SIRS) and the development of acute lung injury (ALI) feature pronounced systemic and lung-specific alterations in iron/heme mobilization and decompartmentalization; such responses may be of pathological significance for both the onset and progression of acute inflammation. The potential for excessive iron-catalyzed oxidative stress, altered proinflammatory redox signaling, and provision of iron as a microbial growth factor represent obvious adverse aspects of altered in vivo iron handling. The release of hemoglobin during hemolytic disease or surgical procedures such as those utilizing cardiopulmonary bypass procedures further impacts on iron mobilization, turnover, and storage with associated implications. Genetic predisposition may ultimately determine the extent to which SIRS and related syndromes develop in response to such changes. The design of specific therapeutic interventions based on endogenous stratagems to limit adverse aspects of altered iron handling may prove of therapeutic benefit for the treatment of SIRS and ALI.

Objective: Sepsis and its sequelae are the leading cause of death in critically ill patients. Discovery in the late 1990s of Toll-like receptors as primary sensors of microbial infection led to significant advances in understanding the pathogenesis of sepsis, including emerging differences between Gram-positive and Gram-negative infection and the potential for the manipulation of Toll-like receptors for the treatment of sepsis. This review describes these advances. Methods: Bibliographic search of the literature since 1999, with particular emphasis on the conceptual and therapeutic implications of Toll-like receptors for patients with systemic sepsis. Results and Conclusions: Toll-like receptors initiate the inflammatory processes that underlie the clinical response to infection and therefore represent an important putative target for therapeutic intervention.

Improved patient survival and increasingly complex surgery have expanded the requirement for specialist care for patients with adult congenital heart disease (ACHD). Despite the recent publications of management guidelines for ACHD, data concerning optimal patterns of care in the peri-operative/critical care period of this challenging population are sparse. The aims of the current study were to therefore to determine the pattern of intensive care unit (ICU) management, resource utilisation and predictors of mortality in critically ill ACHD patients. Data were collected prospectively for patients with ACHD stratified for complexity of disease admitted to the ICU of a tertiary cardiothoracic centre (1997–2002). Multivariate analysis of pre-operative indices as predictors of mortality was performed. Of 342 ACHD admissions (total mortality 4.4%, simple 0%, moderate/complex 10.6%), the requirement for specialist investigations and interventions was high, reflected in ICU admission costs per patient (simple $5391 ± 130, moderate $13218 ± 261, complex $30074 ± 689). Standard severity of illness scoring systems did not accurately predict mortality; however, abnormal pre-operative thyroid function (p = 0.0048), creatinine (p = 0.0032) and bilirubin (p = 0.0021) were highly predictive of mortality. Peri-operative mortality in patients with ACHD is low overall but varies with disease complexity. Such patients have a high requirement for specialist ICU investigation/intervention. Although standard severity of illness scoring is unhelpful, simple pre-operative parameters may predict peri-operative mortality. These findings reflect the requirement for specialist care, and have implications for planning service provision, training and operative consent in ACHD patients.

Pathogens contain specific pathogen-associated molecular patterns, which activate pattern recognition receptors of the innate immune system such as Toll-like receptors (TLRs). Although there is a clear evidence of how macrophages sense pathogens, we know less about such processes in vessels. This is critical to understand because activation of vascular cells and the subsequent induction of inflammatory genes by bacteria are crucial events in the development of septic shock. In the current study we have used genetically modified mice to investigate the role of TLRs, adapter proteins, tumor necrosis factor alpha (TNFalpha), and nitric oxide synthase II (NOSII) in vascular dysfunction induced by Gram-positive (Staphylococcus aureus) or Gram-negative (Escherichia coli) bacteria. Our data show that Gram-positive S. aureus or Gram-negative E. coli causes vascular dysfunction via the induction of NOSII. For S. aureus, this process requires TLR2, TLR6, myeloid differentiation factor 88 (MyD88) adapter-like, MyD88, and TNF, but not TLR4 or TLR1. Vascular dysfunction induced by E. coli requires TLR4 but has no requirement for TLR2, TLR1, TLR6, or TNF, and a partial but incomplete requirement of MyD88 and TIR domain-containing adapter inducing interferon-beta. Staphylococcus aureus induced NOSII protein expression in vascular smooth muscle cells but not in macrophages, whereas E. coli induced NOSII in both cell types. Our data are the first to establish the definitive roles of specific TLRs in the sensing of Gram-positive and Gram-negative bacteria by vessels and demonstrate that macrophages and blood vessels may differ in their response to pathogens.

Leadership: a process of social influence in which a person can enlist the aid and support of others in the accomplishment of a common task – Martin Chemers1 Make a decision. Make a DECISION. Make ANY decision. Make it NOW! – staff sergeant to officer cadet, Royal Military Academy Sandhurst (2012). The above definition and quotation respectively provide your editor with food for thought concerning the concept of leadership, which is the special focus of this issue of Future Hospital Journal . On the one hand this appears to be a collaborative and persuasive skill exercised in measured and controlled circumstances; while on the other it involves taking immediate responsibility for executing a task with potentially profound consequences for all involved, and moreover doing so when tired, hungry and challenged by imperfect knowledge and understanding of the situation in which the leader finds themselves. Parallels between this military approach, in which the challenge of leading more experienced operatives through complex manoeuvres is imposed on the successful trainee immediately after qualification, with that applied to pre-registration house officers in 1979 (the year of your editor's graduation) seem superficially to be numerous, excepting the element of physical danger. Thus, a one-in-two rota leading to progressive exhaustion, insertion into the ‘frontline’ with minimal experience immediately post medical school, and the need to convey authority to nursing and allied health professionals with immensely more experience and ability than oneself when fearful of the consequences of ‘getting it wrong’ are strangely familiar concepts. So if this is how leadership is exerted, how can we know if we are ever going to be up to the task? Maybe the armed forces again show the way. The systems employed by Admiralty Interview or Army Officer Selection Boards have been developed over decades and are designed to …

The therapeutic promise of nitric oxide (NO), a potent vasodilator, remains uncertain for adults, and licensed indications are restricted to pediatric practice. This review considers the biologic actions of inhaled nitric oxide, the clinical indications for its administration in adults, and an assessment of its potential therapeutic development.

Acute lung injury and its extreme manifestation, acute respiratory distress syndrome, complicate a wide variety of serious medical and surgical conditions, only some of which affect the lung directly. Despite recent evidence-based advances in clinical management, acute lung injury and acute respiratory distress syndrome are associated with significant mortality. Detailed epidemiology is essential in guiding the recruitment of patients into trials of new therapeutic interventions, thereby improving outcome and allowing directed allocation of scarce resources.The incidence of acute lung injury in the United States overall (17-64 per 100,000 person-years) seems to be higher than in Europe, Australia, and other developed countries (17-34 per 100, 000 person-years). The mortality rates for patients with acute respiratory distress syndrome range from 34 to 58%. The hypothesis that pulmonary and extrapulmonary acute respiratory distress syndromes are different disease entities continues to gain momentum. A genetic predisposition to acute respiratory distress syndrome may contribute to its pathogenesis and outcome.Recent epidemiologic studies of the incidence of acute lung injury and acute respiratory distress syndrome have indicated a similar incidence in developed societies, and they confirm that mortality is falling in comparison with a decade ago. The awaited publication of new consensus guidelines for the definition of acute lung injury and acute respiratory distress syndrome may render new studies necessary.

Volume resuscitation is clinically beneficial in patients with sepsis, but few data exist concerning the effects of fluid administration on early events in the inflammatory process. Vascular permeability, leukocyte rolling and leukocyte adhesion in the rodent mesenteric microcirculation were assessed in vivo using intravital microscopy, and the effect of fluid administration on lipopolysaccharide (LPS)-induced changes recorded. Prospective, repeated measures study. University hospital laboratory. Male Wistar rats in six groups. All animals underwent intravital microscopic examination of mesenteric post-capillary venules. LPS or vehicle was applied topically. Animals received either no additional fluids, 0.9% saline (16 ml/kg per h) or 5% human albumin (16 ml/kg per h) commencing 30 min prior to LPS/vehicle administration. Leukocyte rolling, firm adhesion and blood velocity were observed directly. Vascular permeability was assessed using the flux of fluorescently labelled albumin into the interstitium. LPS significantly increased the median (IQR) number of leukocytes rolling and firmly adherent relative to baseline (at 60 min rolling increased from 12.0 (10.3–13.8) to 40.3 (36.0–47.5) cells/min; adhesion increased from 1 (1–2) to 17 (12–26) cells/100 μm; n=5, p

We aimed to quantify concentrations of inducible heme oxygenase (HO)-1 in the lungs of patients with acute respiratory distress syndrome (ARDS) and to investigate its role as a source of ferrous iron and as a signaling agent for iron regulation. Control of such processes by heme oxygenase has implications for the onset, progression, and resolution of ARDS.Retrospective analysis of archived samples.Adult intensive care unit of a postgraduate teaching hospital.Patients admitted to the adult intensive care unit who fulfilled the American-European Consensus Conference criteria for ARDS.Biochemical and immunohistochemical studies using bronchoalveolar lavage fluid or lung tissue were performed in patients with established ARDS and in those undergoing lung resection (controls).Concentrations of heme oxygenase protein were significantly elevated in lung tissue (193.7 +/- 13.27 vs. 81.0 +/- 16.0%, p.01) and in bronchoalveolar lavage fluid (2.4 x 10(5) vs. 1.4 x 10(5) densitometric units, p = .047) taken from patients with ARDS compared with controls. Concentrations of heme oxygenase protein in bronchoalveolar lavage fluid from patients with ARDS correlated positively and significantly with changes in the concentrations of ferritin (r = .697, p = .02) and the iron saturation of transferrin (r = .8, p = .014) but correlated negatively and significantly with concentrations of bleomycin-detectable (redox-active) iron (r = -.73, p = .031). Significantly elevated (p.05) concentrations of heme oxygenase staining in cell types expressing this protein were detected in patients with ARDS, compared with concentrations in the same cells taken from controls undergoing lung resection.Heme oxygenase protein is elevated in the lungs of patients with ARDS and may contribute to the changes in iron mobilization, signaling, and regulation seen in this condition.

Aim The treatment of patients with pulmonary arterial hypertension remains a challenge. We set out to investigate the use of sildenafil, a selective inhibitor of phosphodiesterase type 5, in patients with this disease. Methods and results Ten patients (8 females, mean age 34.5±3.3 years) with pulmonary hypertension underwent right heart catheterisation with vasodilator testing using incremental doses of intravenous sildenafil without adverse events. All patients were subsequently commenced on oral sildenafil 50 mg t.d.s. Nine patients had repeat right heart catheterisation 3 months after the commencement of oral therapy. There was a significant reduction in mean pulmonary artery pressure (from 55.8±5.9 to 50.4±6.1 mmHg, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(p=0.038\) \end{document}) and pulmonary vascular resistance (from 10.1±1.7 to 8.6±1.5 Wood units, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(p=0.009\) \end{document}), and an increase in cardiac output (from 4.7±0.3 to 5.0±0.4 l/min, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(p=0.15\) \end{document}). Furthermore, there was a significant increase in the 6-minute walk test, a mean of 112 m. In response to a quality-of-life questionnaire, patients indicated marked clinical improvement on sildenafil. Sildenafil was discontinued in 1 patient due to a transient visual disturbance. The only patient previously awaiting transplantation was removed from the active transplantation list. Conclusions Sildenafil is well tolerated in its intravenous and oral forms and appears to improve both pulmonary haemodynamics and the clinical status of patients with pulmonary hypertension after 3 months of oral therapy.

Despite the key role of nutrition in health and the almost universal use of supplemental feeding in the ICU, there is a lack of high-quality evidence to guide clinical practice. Enteral nutrition is superior to TPN in almost all circumstances and most patients in the ICU can be fed successfully by this route. There is little evidence to support the use of special feeds and the role of immunonutrients remains unproven. Nutritional support cannot completely prevent the adverse effects of catabolic illness and overfeeding should be avoided.

Heme oxygenase is the rate-limiting enzyme in the catabolism of heme to carbon monoxide, bilirubin and free iron. Many cell types express heme oxygenase-2 constitutively while heme oxygenase-1 is induced at sites of inflammation and oxidative stress. In systemic blood vessels, carbon monoxide may have an important homeostatic role where, like its better-studied counterpart nitric oxide, it is emerging as a vasodilator and an inhibitor of proliferation. However, much less is known regarding the role of heme oxygenase and carbon monoxide in the pulmonary circulation where vascular responses are very different. Here, using primary cultures of human pulmonary artery smooth muscle cells, we present novel data showing that this cell type expresses heme oxygenase-2 constitutively and, in the presence of oxidants, can induce heme oxygenase-1. We also show that the carbon monoxide-releasing molecule, tricarbonyldichlororuthenium (II) dimer, potently and profoundly inhibits proliferation of human pulmonary artery smooth muscle cells. Pulmonary hypertension is a disease characterised by abnormal vascular smooth muscle cell growth and remodelling of the pulmonary vasculature. Our observations support the growing evidence that the heme oxygenase/carbon monoxide system may play a role in the pathology of pulmonary hypertension.

Acute exacerbations of idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis (IPF/CFA) are rare and typically terminal events, but their relationship to underlying patterns of idiopathic interstitial pneumonias is unknown. We reviewed autopsy material from patients who died of diffuse alveolar damage in the clinical setting of pulmonary fibrosis, both idiopathic and with background fibrosing alveolitis with connective tissue disorders (FA-CTDs), and compared them with cases of acute interstitial pneumonia. Of 15 patients with acute exacerbations of IPF/CFA (n = 12) or FA-CTD (n = 3), 12 had a background pattern of usual interstitial pneumonia and 3 had fibrotic nonspecific interstitial pneumonia. All cases of fibrotic nonspecific interstitial pneumonia were seen in association with FA-CTD. The cause of acute exacerbations is unknown, but our data suggest that toxic effects of oxygen and triggering infection are unlikely causes. In patients with CTDs, it remains uncertain whether the acute exacerbation is related to the fibrosis, the associated CTD, or a combination of these factors. Acute exacerbations of IPF/CFA may be a more common terminal event than previously thought.

The mechanisms underlying myocardial dysfunction in sepsis remain poorly understood. The theoretical benefits of nitric oxide synthase (NOS) inhibition in reversing the haemodynamic changes that characterise septic shock have not been supported by clinical trials, some of which have demonstrated detrimental myocardial effects. We have therefore assessed the effects of endotoxaemia on NOS enzyme expression as well as a number of functional responses of myocardial tissue from rats. Atrial tissue expressed high levels of mRNA for inducible (i) NOS and released increased levels of nitrite after animals were treated with endotoxin. In parallel, the inotropic response stimulated by isoprenaline was reduced in atria from endotoxin-treated animals, an effect that was reversed when endogenous release of NO was maximised. Our results suggest that myocardial contractility is maintained by NO production and that inhibitors may compromise cardiac output; this may explain the deleterious effects of NOS inhibition on cardiac function in clinical trials.

The acute respiratory distress syndrome may complicate both pulmonary and extrapulmonary conditions. There is a growing belief that the predisposition to, and clinical course of, the syndrome may be influenced by the extent to which the lung is directly involved in the precipitating pathologic changes. Several studies have highlighted differences in morphology and respiratory physiology between the two subgroups in the early stages of acute respiratory distress syndrome. Further, preliminary reports have suggested that the effects of therapeutic interventions such as alterations in positive end-expiratory pressure, prone ventilation, and the use of inhaled vasoactive agents may differ between pulmonary and extrapulmonary acute respiratory distress syndrome. There are, however, inconsistencies between various studies addressing these issues, which may relate in part to differences in etiologic case mix. There are also practical difficulties in assigning certain cases to one of these two groups. Finally, there are as yet no outcome data to support any modification of clinical management on the basis of this distinction.

During his ride to work on the London underground earlier this summer, your correspondent was interested to spot a sentence in the editorial columns of a leading newspaper, which read ‘.… it is shocking that it took the inspectors so long to identify and document the problem …’ This sentiment had particular resonance for him in the context of the Future Hospital Journal ( FHJ ), in that a principal driver for the work of the Future Hospital Commission (FHC) emerged from the review of the Mid Staffordshire NHS Foundation Trust by Sir Robert Francis QC. There, the failure not only of inspectors and regulators, but also of clinicians (in the widest sense) and their leaders, managers and inspectors, to identify problems in that Trust, resulted in shocking patient neglect, and saw the NHS at its lowest ebb for decades. However, the sentence did not refer to Mid Staffordshire, but rather to the recent ‘Trojan horse’ episode in Birmingham: the allegations of infiltration of school governing bodies by those seeking to advance specific political and/or religious agendas. The immediate reaction of politicians was to propose that state schools should face unannounced spot inspections. Whether the threat of an inspection, announced or not, improves any public service in many ways underpins the special focus of this issue: regulation and the regulators. The inspection mantra has been applied to other public services, many of which seem to be increasingly under the cosh. Your editor had time to recall without difficulty …

The acute respiratory distress syndrome occurs commonly in critical care. There is an increasing volume of clinical and experimental evidence that poor ventilatory technique that is injurious to the lungs can propagate the systemic inflammatory response and adversely affect mortality. Many ventilatory techniques have been hypothesized to 'protect' the lungs during mechanical ventilation, including tidal volume limitation, high positive end-expiratory pressure, pressure-controlled inverse ratio ventilation, and prone positioning. Experimental techniques include liquid ventilation, surfactant administration and extracorporeal gas exchange. Despite excellent rationale for their use, few techniques, apart from tidal volume limitation, have been shown to improve survival in randomized controlled trials.

We tested the effects of 11 commercially-available isoprostanes on platelet aggregation directly or when triggered by the thromboxane receptor agonist U46619 or collagen in healthy human citrated blood using a whole blood aggregometer. None of the isoprostanes tested triggered aggregation alone, nor facilitated aggregation by a sub-threshold dose of U46619 or collagen. Five isoprostanes inhibited aggregation (rank order of potency 8-iso PGE1>8-iso PGE2>8-iso PGF2α>8-iso PGF3α>8-iso-13,14-dihydro-15-keto PGF2α). Blood incubated with LPS to induce a gross inflammatory response exhibited a time dependent (2 – 12 h) reduction in aggregation to U46619 but maintained a consistent response to collagen. Under these conditions, as in control blood, none of the isoprostanes tested induced aggregation. In fact, the inhibitory actions of isoprostanes on U46619-induced aggregation were enhanced in blood treated with LPS. L-NAME inhibited aggregation induced by U46619 in fresh blood and in blood treated with LPS. In the presence of L-NAME, (with or without LPS) none of the isoprostanes tested induced aggregation but retained their inhibitory action. Thus, in human whole blood the action of 8-iso PGE1, 8-iso PGE2, 8-iso PGF2α, 8-iso PGF3α, and 8-iso-13,14-dihydro-15-keto PGF2α is antiaggregatory. Moreover, this inhibitory capacity is still apparent and may be enhanced in blood subjected to inflammatory stimulation. Keywords: Isoprostanes, whole blood aggregometry, lipopolysaccharide Introduction Isoprostanes are a family of prostaglandin (PG) isomers generated by free radical-catalysed peroxidation and then rearrangement of arachidonic acid (Morrow et al., 1990; 1992). In addition, isoprostanes can be produced by cyclo-oxygenase (COX) dependent pathways (Pratico et al., 1995; Klein et al., 1997; Jourdan et al., 1997a; 1999). Several cell types have been shown to release increased levels of the F2 isoprostane, 8-iso PGF2α, when stimulated with inflammatory mediators or subjected to oxidative stress in vitro (Patrignani et al., 1996; Vacchiano et al., 1998; Jourdan et al., 1999). Furthermore, 8-iso PGF2α levels are elevated in rats in vivo when prooxidant conditions are induced experimentally (Morrow et al., 1992b; Dabbagh et al., 1994; Awad et al., 1994; Lynch et al., 1996). Similarly, elevated isoprostane production has been demonstrated in clinical conditions characterized by oxidant stress including diabetes (Davi et al., 1999), alcoholism (Alehnik et al., 1998), paraquat poisoning (Delanty et al., 1996), myocardial reperfusion (Reilly et al., 1997), critical illness (Carpenter et al., 1998), pre-eclampsia (Walsh et al., 2000) and smoking (Morrow et al., 1995). Consequently, the measurement of 8-iso PGF2α in plasma and urine has been proposed as a relevant and convenient method to monitor oxidant stress in man (Roberts & Morrow, 2000). However, beyond their role as oxidant markers, isoprostanes have demonstrable biological actions in some tissues. 8-iso PGF2α causes contraction of isolated blood vessels, (Kromer & Tippins, 1996; Jourdan et al., 1997b; Gardan et al., 2000; Oliviera et al., 2000), lymphatics, (Sinzinger et al., 1997) and airway (Kawikova et al., 1996) and myometrial smooth muscle (Crankshaw, 1995). Where studied, smooth muscle contraction appears to be mediated in part via thromboxane TP receptors (Fukunaga et al., 1993; Kromer & Tippins, 1996; Jourdan et al., 1997b; Gardan et al., 2000; Oliviera et al., 2000). However, the effects of 8-iso PGF2α on smooth muscle function may be altered in pathophysiological settings. Thus, its vasoconstrictor effect is increased after ischaemia (Kromer & Tippins, 1996; 1999), endothelial damage and nitric oxide synthase (NOS) inhibition (Jourdan et al., 1997b; Sametz et al., 1999). 8-iso PGF2α also has actions on isolated platelets where, in contrast to smooth muscle preparations, it may not apparently fully activate platelet TP receptors to cause aggregation (Pratico et al., 1996; Habib et al., 1999) and instead inhibits the proaggregatory effects of the TP ligand U46619 (Morrow et al., 1992c; Yin et al., 1994). In addition, although the E2 isoprostane, 8-iso PGE2, causes aggregation of platelets in a sub-population of human volunteers, it also inhibits U46619-induced aggregation (Longmire et al., 1994). Whether or not pathophysiological events alter platelet responses to isoprostanes is not known. In addition to 8-iso PGF2α and 8-iso PGE2, a range of synthetic isoprostanes is now available, the majority of which have not been tested in either smooth muscle or platelet preparations. The aims of this study were therefore firstly, to investigate the effects of a range of isoprostanes on aggregation of human whole blood and secondly, to assess the effects of a gross inflammatory stimulus induced by bacterial lipopolysaccharide (LPS), on the response of whole blood to isoprostanes.

OBJECTIVE To assess the possibility that acute respiratory distress syndrome (ARDS) of pulmonary and nonpulmonary origins represent two distinct syndromes. DESIGN Analysis of data collected prospectively from an inception cohort of 117 patients with ARDS. SETTING Adult intensive care unit (ICU), university/postgraduate hospital. MEASUREMENTS AND MAIN RESULTS Differences were sought in mortality and 6-month functional outcome between patients developing ARDS due to pulmonary (group 1) and nonpulmonary (group 2) pathology. Group 1 patients displayed a trend toward increased ICU and in-hospital mortality (42.1% vs. 23.2%, p = .10, and 47.4% vs. 27.9%, p = .11, respectively). No difference was found in ICU length of stay (46.3 +/- 4.9 vs. 39.0 +/- 4.8 days for groups 1 and 2, respectively) nor in duration of positive-pressure ventilation (26.2 +/- 4.3 vs. 20.6 +/- 3.2 days). However, the need for pressure-controlled inverse ratio ventilation was significantly greater in group 1 (16.9 +/- 3.2 vs. 9.1 +/- 1.3 days; p = .033). In survivors, reductions in total lung capacity at 6 months (68.1 +/- 4.6 vs. 61.8 +/- 4.6% predicted for groups 1 and 2, respectively; p = .4), accessible lung volume (74.4 +/- 4.4 vs. 68.9 +/- 4.9% predicted; p = .56), and forced expiratory volume (77.8 +/- 2.9 vs. 80.3 +/- 2.4% predicted; p = .57) did not differ between groups. Gas transfer coefficient was well preserved (84.5 +/- 4.6 vs. 86.6 +/- 4.7% predicted; p = .80). CONCLUSIONS These data suggest a trend toward higher mortality and ventilatory requirements in ARDS of direct etiology, generating a hypothesis worthy of further exploration.

Reactive oxygen species produced at toxic levels are damaging species. When produced at sub-toxic levels, however, they are involved as second messengers in numerous signal transduction pathways. In addition to these findings, we can add the concept that iron (often viewed as the ‘villain’ in free radical biology) can also be considered as a signalling species. Iron is intimately involved in the regulation of its own storage, compartmentalization and turnover. During adult respiratory distress syndrome (ARDS) and sepsis, such regulation may be aberrant or altered in some predisposed way. Such changes may have profound implications for tissue damage, and for the modulation of the inflammatory response in these patients. The search for a genetic predisposition in patients that leads to the development of ARDS associated with abnormalities in iron turnover and signalling would seem to be an important and logical progression for studies into the disease. These may lead eventually to the design of effective treatment regimens that involve the control of iron.

Sepsis is characterized by increased microvascular permeability and regional variations in capillary perfusion, which may be modulated by nitric oxide (NO) and reversed by fluid resuscitation (FR). The effects of saline FR and NO synthase blockade [by NG-nitro-L-arginine methyl ester (L-NAME)] on microvascular albumin transport and perfused capillary density were assessed in anaesthetized Wistar rats with acute normodynamic endotoxaemia. Separate dual-isotope techniques were employed to measure the permeability index (PIA) and the permeability×surface area product index (PIB), which provide different and complementary information regarding blood–tissue albumin exchange. PIA represents the tissue/blood distribution volume ratio of albumin. PIB is a composite measure of endothelial permeability and the vascular surface area available for albumin exchange, and therefore takes into account the effect of altered blood volume. Capillary density was quantified by fluorescence microscopy following circulation of Evans Blue-labelled albumin. Compared with controls, PIA was reduced significantly in lipopolysaccharide (LPS)-treated animals in skeletal muscle and skin, probably due to blood volume redistribution rather than to changes in permeability. PIB was increased significantly in LPS-treated animals in the kidney, mesentery, skeletal muscle, skin and lung, and in the small bowel following FR. FR also improved the LPS-induced metabolic base deficit, but did not alter capillary density. L-NAME significantly attenuated the LPS-induced rise in PIB in the lung. In conclusion, acute endotoxaemia induces tissue-dependent variations in microvascular albumin exchange. FR improves acid–base disturbance in endotoxaemia, through mechanisms other than microvascular recruitment. NO appears to increase microvascular permeability in endotoxaemia, an effect that may be attenuated by L-NAME, particularly in the lung.

Objectives: Cardiopulmonary bypass (CPB) surgery is often associated with mild lung injury and in some patients leads to acute lung injury and acute respiratory distress syndrome (ARDS). Aberrant plasma iron chemistry (increased iron loading of transferrin and/or the presence of redox-active low molecular mass iron) and increased plasma thiol levels are features of this type of surgery and represent a potential pro-oxidant risk for oxidative damage. Oxidative damage is a feature of ARDS, and we hypothesized that pro-oxidant forces may contribute to the onset and progression of ARDS. Design: Prospective, single center, observational study. Setting: University-affiliated tertiary referral cardiothoracic center. Patients: A total of 19 patients with ARDS secondary to CPB surgery and 64 patients with ARDS secondary to a variety of other predisposing causes. Interventions: Supportive techniques appropriate to the treatment of ARDS. Measurements and Main Results: Blood samples were collected into lithium heparin tubes for all patient groups on the first day of the admission of patients to the intensive care unit immediately after the diagnosis of ARDS. Plasma was immediately assayed for thiol content and total protein and albumin levels. Plasma from patients with ARDS secondary to CPB surgery was also assayed for changes in iron chemistry. Nonsurviving patients with ARDS secondary to CPB surgery displayed significantly greater levels of aberrant iron chemistry (elevated levels of iron saturation of transferrin) with decreased iron-binding antioxidant protection and elevated plasma thiol levels than did survivors. Plasma thiol levels in patients with ARDS secondary to other predisposing causes were (with the exception of lung-surgery patients) significantly elevated in survivors compared with those in nonsurvivors of the syndrome. Conclusions: Increased levels of plasma thiol appear to be associated with mortality in patients with ARDS secondary to CPB surgery.

Postpneumonectomy pulmonary oedema (PPO) develops in approximately 5% of patients undergoing pneumonectomy or lobectomy, and has a high associated mortality (>50%). In its extreme form, PPO follows a clinical and histopathological course indistinguishable from acute respiratory distress syndrome. Perioperative fluid overload, impaired lymphatic drainage following node dissection and trauma caused by surgical manipulation have been implicated in the pathogenesis of PPO. However, PPO more probably represents the pulmonary manifestation of a panendothelial injury consequent upon inflammatory processes induced by the surgical procedure, which involves collapse and re-expansion of the operative lung to permit hilar dissection and pulmonary resection. High inspired oxygen concentrations are required to overcome the effects of shunt. Animal studies have shown that pulmonary ischaemia/reperfusion can result in oedema formation, possibly due to the generation of pro-oxidant forces. Moreover, plasma taken from patients undergoing lobectomy or pneumonectomy (but not lesser resections) shows evidence of oxidative damage. Such evidence suggests either that the high inspired oxygen concentrations associated with one-lung ventilation, or ischaemia/reperfusion injury, may modulate post-pneumonectomy pulmonary oedema. Mechanisms by which redox imbalance may result in tissue damage and postpneumonectomy pulmonary oedema are discussed.

There is increasing evidence supporting a role for endothelin-1 (ET-1) in human pulmonary hypertension. The aim of this study was to determine the relative roles of human pulmonary microvascular endothelial cells (HPMVE) and human pulmonary artery smooth muscle (HPASM) cells to produce ET-1 under inflammatory conditions and to investigate further possible control mechanisms of ET-1 production by HPASM. Although HPMVE cells produced more ET-1 than HPASM when cultured with fetal calf serum (FCS) alone and after treatment with cytokines; HPASM produced significant amounts of ET-1 after stimulation with cytokines. Cytokine-stimulated increase in ET-1 production by HPASM was inhibited by cicaprost, a prostacyclin analogue, and other agents that are known to increase intracellular cyclic AMP. Cicaprost also inhibited proliferation of HPASM in response to FCS lending support to the theory that part of the clinical benefit seen in long-term treatment with prostacyclin in pulmonary hypertension may be a result of inhibition of ET-1 production in these cells.

Haem oxygenase-1 (HO-1) is a highly inducible stress protein that removes haem from cells with the release of biliverdin, carbon monoxide and low-molecular-mass iron (LMrFe). Several antioxidant functions have been ascribed to HO; its induction is considered to be a protective event. However, LMrFe produced during haem catabolism might elicit a pro-oxidant response, with deleterious consequences. We therefore investigated the delicate balance between pro-oxidant and antioxidant events with the use of a microsomal lipid peroxidation (LPO) system. By using microsomal-bound HO in an NADPH-dependent LPO system, we assessed the pro-oxidant nature of the released LMrFe and the antioxidant effect of the released bilirubin. Hb, a biologically relevant substrate for HO, was included with the microsomes to supplement the source of haem iron and to promote LPO. We found significant increases in microsomal LPO, by using the thiobarbituric acid (TBA) test, after incubation with Hb. This Hb-stimulated peroxidation was inhibited by HO inhibitors and by iron chelators, suggesting a HO-driven, iron-dependent mechanism. GLC-MS was employed to measure the specific LPO product 4-hydroxy-2-nonenal and to confirm our TBA test results. A HO inhibitor attenuated an increase in intracellular LMrFe that occurred after treatment of rat pulmonary artery smooth-muscle cells with Hb. Additionally, exogenously added bilirubin at an equimolar concentration to the LMrFe present in both microsomal and liposomal systems was unable to prevent the pro-oxidant effect of the iron. Under certain circumstances HO can act as a pro-oxidant and seems to have a role in stimulating microsomal LPO.