Physical activity service provision in hospice care: A national mixed-methods study.

BACKGROUND: Physical activity (PA) interventions help people with advanced incurable diseases to manage symptoms and improve their quality of life. However, little is known about the extent to which PA is currently delivered in hospice care in England. OBJECTIVES: To determine the extent of and intervention features of PA service provision in hospice care in England alongside barriers and facilitators to their delivery. METHODS: An embedded mixed-methods design using (1) a nationwide online survey of 70 adult hospices in England and (2) focus groups and individual interviews with health professionals from 18 hospices. Analysis of the data involved applying descriptive statistics to the numeric items and thematic analysis to the open-ended questions. Quantitative and qualitative data were collected and analyzed separately. RESULTS: The majority of responding hospices (n = 47/70, 67%) promoted PA in routine care. Sessions were most often delivered by a physiotherapist (n = 40/47, 85%) using a personalized approach (n = 41/47, 87%) and included resistance/thera bands, Tai Chi/Chi Qong, circuit exercises, and yoga. The following qualitative findings were revealed: (1) variation among hospices in their capacity to deliver PA, (2) a desire to embed a hospice culture of PA, and (3) a need for an organizational commitment to PA service provision. SIGNIFICANCE OF RESULTS: While many hospices in England deliver PA, there is considerable variation in its delivery across sites. Funding and policy action may be needed to support hospices to initiate or scale up services and address inequity in access to high-quality interventions.

Hypercapnic acidosis reduces oxidative reactions in endotoxin-induced lung injury.

BACKGROUND: Hypercapnic acidosis frequently occurs when patients with acute lung injury are initially ventilated with low tidal volume "protective" strategies. Hypercapnic acidosis per se, in the absence of any change in tidal volume or airway pressure, is protective when instituted before the onset of injury. However, the mechanisms by which hypercapnic acidosis confers this protection are incompletely understood, in particular, the effects on pulmonary oxidative reactions, which are potent mediators of tissue damage, have not been previously examined in vivo. METHODS: After anesthesia, tracheostomy, and the intratracheal instillation of endotoxin to establish lung injury, rats were mechanically ventilated for 6 h in normocapnia (21% O2, 0% CO2). Rats were then randomized to either normocapnic (21% O2, 0% CO2) or hypercapnic (21% O2, 5% CO2) ventilation and a nonspecific nitric oxide synthase inhibitor (N-monomethyl-L-arginine) or vehicle. Dihydrorhodamine was administered intravenously, and the lungs were removed for determination of the oxidative formation of rhodamine by spectrofluorimetry after 20 min. Thus, rats were randomly assigned to either: normocapnia-endotoxin (n = 12), normocapnia-endotoxin-N-monomethyl-L-arginine (n = 9), hypercapnia-endotoxin (n = 11), or hypercapnia-endotoxin-N-monomethyl-L-arginine (n = 10). RESULTS: Hypercapnic acidosis significantly reduced the pulmonary oxidative reactions in the inflamed lung compared with normocapnia. Nitric oxide synthase blockade did not alter endotoxin-induced oxidative reactions. CONCLUSIONS: Hypercapnic acidosis reduced oxidative reactions in the acutely injured lung in vivo, within minutes of onset and was not reliant on nitric oxide-dependent peroxynitrite production. This rapid onset antioxidant action is a previously undescribed mechanism by which hypercapnic acidosis could act, even when acute lung injury is well established.

Sustained hypercapnic acidosis during pulmonary infection increases bacterial load and worsens lung injury.

OBJECTIVE: Hypercapnic acidosis is commonly permitted in patients with acute respiratory distress syndrome during the use of protective ventilation strategies. Hypercapnic acidosis is also a common complication of multiple lung diseases and is associated with a poor prognosis, although the mechanisms by which it leads to increased mortality is not known. Previous studies using noninfective models of lung injury show that acute (<6 hrs) hypercapnic acidosis reduced lung damage by an anti-inflammatory effect. We hypothesized that this anti-inflammatory effect would be detrimental in vivo in the presence of untreated bacterial infection and sustained hypercapnia (>48 hrs) and, furthermore, that if bacterial reproduction were controlled by antibiotic therapy, then the anti-inflammatory effects of hypercapnic acidosis would no longer prove detrimental. DESIGN: This study was a prospective, randomized animal study. SETTING: This study was conducted at a university research laboratory. SUBJECTS: Study subjects were adult male Wistar-Kyoto rats. INTERVENTIONS: After intratracheal instillation of Escherichia coli under general anesthesia, rats were housed in normocapnic (21% O2, 0% CO2) or hypercapnic (21% O2, 5% CO2) environments for 2 days. Rats were then reanesthetized for assessment of physiological and quantitative stereologic indices of lung damage, quantitative bacterial counts, and neutrophil phagocytosis. MEASUREMENTS AND MAIN RESULTS: Hypercapnic acidosis was associated with higher lung bacterial colony counts, more structural damage, and lower static lung compliance than normocapnia. Neutrophils isolated from hypercapnic rats demonstrated impaired phagocytosis. In a further separate series of experiments, in which rats were given antibiotic therapy, lung damage was not different between normocapnic and hypercapnic acidosis groups. CONCLUSIONS: Prolonged hypercapnic acidosis worsened bacterial infection-induced lung injury. Our findings suggest an immunosuppressive effect of hypercapnic acidosis and have important implications for protective ventilation strategies that permit hypercapnic acidosis in patients with adult respiratory distress syndrome and in the management of hypercapnic acidosis during infective exacerbations of chronic obstructive pulmonary disease and other lung diseases.

Airway nitric oxide output is reduced in bronchiectasis.

BACKGROUND: Increased concentrations of exhaled nitric oxide (NO) have been detected in inflammatory lung diseases including asthma and have been attributed to increased expression and activity of inducible nitric oxide synthase (iNOS) within the airways. However, previous studies of exhaled NO in patients with bronchiectasis have yielded conflicting results, with reports of both increased and normal NO values. Recent evidence from animal models suggests that chronic airway infection reduces NO production within the lung, despite causing increased iNOS expression. We tested the hypothesis that, in human subjects with bronchiectasis, chronic airway infection reduces NO output from the conducting airways. METHODS: Using a recently described two-compartment model, we measured separately the contributions of the conducting airways and the alveoli to exhaled NO in nine patients with stable bronchiectasis and eight control subjects before and after inhaled glucocorticoid therapy. RESULTS: We found that airway NO output was significantly lower in bronchiectasis than in normal airways whereas NO output from the alveoli was similar to that of control subjects. High-dose inhaled glucocorticoid therapy did not alter airway or alveolar NO production. CONCLUSIONS: These findings demonstrate that, in patients with bronchiectasis, airway NO output is reduced and that iNOS does not contribute significantly to airway NO production.

Atelectasis causes alveolar injury in nonatelectatic lung regions.

RATIONALE: Many authors have suggested that the mechanism by which atelectasis contributes to injury is through the repetitive opening and closing of distal airways in lung regions that are atelectatic. However, neither the topographic nor mechanistic relationships between atelectasis and distribution of lung injury are known. OBJECTIVES: To investigate how atelectasis contributes to ventilator-induced lung injury. METHODS: Surfactant depletion was performed in anesthetized rats that were then allocated to noninjurious or injurious ventilation for 90 min. MEASUREMENTS: Lung injury was quantified by gas exchange, compliance, histology, wet-to-dry weight, and cytokine expression, and its distribution by histology, stereology, cytokine mRNA expression, in situ hybridization, and immunohistochemistry. Functional residual capacity, percent atelectasis, and injury-induced lung water accumulation were measured using gravimetric and volumetric techniques. MAIN RESULTS: Atelectasis occurred in the dependent lung regions. Injurious ventilation was associated with alveolar and distal airway injury, while noninjurious ventilation was not. With injurious ventilation, alveolar injury (i.e., histology, myeloperoxidase protein expression, quantification, and localization of cytokine mRNA expression) was maximal in nondependent regions, whereas distal airway injury was equivalent in atelectatic and nonatelectatic regions. CONCLUSIONS: These data support the notion that lung injury associated with atelectasis involves trauma to the distal airways. We provide topographic and biochemical evidence that such distal airway injury is not localized solely to atelectatic areas, but is instead generalized in both atelectatic and nonatelectatic lung regions. In contrast, alveolar injury associated with atelectasis does not occur in those areas that are atelectatic but occurs instead in remote nonatelectatic alveoli.

Hypercapnic acidosis does not modulate the severity of bacterial pneumonia-induced lung injury.

OBJECTIVE: Deliberate induction of hypercapnic acidosis protects against lung injury after ischemia-reperfusion, endotoxin-induced, and ventilation-induced lung injury. The efficacy of hypercapnic acidosis in bacterial lung infection, a common cause of acute respiratory distress syndrome, is not known. Furthermore, its effect may differ depending on the presence or absence of antibiotic therapy. We investigated whether hypercapnic acidosis-induced by adding CO2 to inspired gas-would protect against acute lung injury induced by pulmonary Escherichia coli instillation in an in vivo model in the presence and absence of effective antibiotic therapy. DESIGN: Prospective randomized animal study. SETTING: University research laboratory. SUBJECTS: Adult male Wistar-Kyoto rats. INTERVENTIONS: The animals were anesthetized and ventilated. In series 1, rats were administered intravenous ceftriaxone (100 mg x kg) and randomized to normocapnia (Normocapnia-ABx; Fico2 0.00, n = 10) or hypercapnia (Hypercapnia-ABx; Fico2 0.05, n = 10) groups. E. coli (8.4 x 10 colony forming units) was instilled intratracheally. Series 2 animals did not receive antibiotics. They were randomized to normocapnia (Normocapnia, n = 10) or hypercapnia (Hypercapnia, n = 10) groups, and intratracheal E. coli was administered. All animals were ventilated for 6 hrs. MEASUREMENTS AND MAIN RESULTS: In series 1, there were no differences between Hypercapnia-ABx and Normocapnia-ABx groups with regard to: (a-a)o2 gradient (mean +/- sem; 215 +/- 13 vs. 252 +/- 22 mm Hg), Pao2, bronchoalveolar lavage neutrophil count, static lung compliance, or histologic injury. Lung bacterial yield was not different between the groups. In series 2, in the absence of antibiotic therapy, there were no differences between Hypercapnia and Normocapnia groups in: (a-a)o2 gradient (mean +/- sem, 345 +/- 25 vs. 332 +/- 23 mm Hg), systemic Pao2, bronchoalveolar lavage neutrophil count, or static lung compliance. Lung bacterial yield was not altered by hypercapnia in either series 1 or 2. CONCLUSIONS: We conclude that hypercapnic acidosis did not alter the magnitude of the lung injury induced by intratracheal E. coli instillation in the presence or absence of antibiotics.

The structural basis of pulmonary hypertension in chronic lung disease: remodelling, rarefaction or angiogenesis?

Chronic lung disease in humans is frequently complicated by the development of secondary pulmonary hypertension, which is associated with increased morbidity and mortality. Hypoxia, inflammation and increased shear stress are the primary stimuli although the exact pathways through which these initiating events lead to pulmonary hypertension remain to be completely elucidated. The increase in pulmonary vascular resistance is attributed, in part, to remodelling of the walls of resistance vessels. This consists of intimal, medial and adventitial hypertrophy, which can lead to encroachment into and reduction of the vascular lumen. In addition, it has been reported that there is a reduction in the number of blood vessels in the hypertensive lung, which could also contribute to increased vascular resistance. The pulmonary endothelium plays a key role in mediating and modulating these changes. These structural alterations in the pulmonary vasculature contrast sharply with the responses of the systemic vasculature to the same stimuli. In systemic organs, both hypoxia and inflammation cause angiogenesis. Furthermore, remodelling of the walls of resistance vessels is not observed in these conditions. Thus it has been generally stated that, in the adult pulmonary circulation, angiogenesis does not occur. Prompted by previous observations that chronic airway inflammation can lead to pulmonary vascular remodelling without hypertension, we have recently shown, using quantitative stereological techniques, that angiogenesis can occur in the adult pulmonary circulation. Pulmonary angiogenesis has also been reported in some other conditions including post-pneumonectomy lung growth, metastatic disease of the lung and in biliary cirrhosis. Such angiogenesis may serve to prevent or attenuate increased vascular resistance in lung disease. In view of these more recent data, the role of structural alterations in the pulmonary vasculature in the development of pulmonary hypertension should be carefully reconsidered.

Combined confocal microscopy and stereology: a highly efficient and unbiased approach to quantitative structural measurement in tissues.

Understanding the relationship of the structure of organs to their function is a key component of integrative physiological research. The structure of the organs of the body is not constant but changes, both during growth and development and under conditions of sustained stress (e g. high altitude exposure and disease). Recently, powerful new techniques have become available in molecular biology, which promise to provide novel insights into the mechanisms and consequences of these altered structure-function relationships. Conventionally structure-function relationships are studied by microscopic examination of tissue sections. However, drawing conclusions about the three-dimensional structure of an organ based on this two-dimensional information frequently leads to serious errors. The techniques of stereology allow precise and accurate quantification of structural features within three-dimensional organs that relate in a meaningful way to integrated function. For example, knowledge of changes in the total surface area of the capillary endothelium in a n organ can be related directly to changes in fluid filtration and permeability, or knowledge of total vessel length and mean radius allows deductions about vascular resistance. Confocal microscopy add s enormously to the power of stereological approaches. It reduces the difficulties and labour involved in obtaining suitable images. Moreover, when used in conjunction with new analytical software, it allows convenient application of stereology to small samples and those in which it is essential to maintain a specific orientation for interpretation. The information obtained will allow us to examine in a quantitative manner the altered structure-function relationships produced by manipulation of single genes and regulatory pathways in whole organisms.

Type 2 nitric oxide synthase and protein nitration in chronic lung infection.

Inflammation in the lung can lead to increased expression of inducible nitric oxide synthase (iNOS) and enhanced NO production. It has been postulated that the resultant highly reactive NO metabolites may have an important role in host defence, although they might also contribute to tissue damage. However, in a number of inflammatory lung diseases, including bronchiectasis, iNOS expression is increased but no elevation of airway NO can be detected. A potential explanation for this finding is that NO is rapidly scavenged by reaction with superoxide radicals, forming peroxynitrite, which is preferentially metabolized via nitration and nitrosation reactions. To test this hypothesis, anaesthetized, specific pathogen-free rats were inoculated with Pseudomonas aeruginosa incorporated into agar beads (chronically infected group) or sterile agar beads (control group). Ten to 15 days later, the lungs were isolated and fixed. Pseudomonas organisms were isolated from the lungs of the chronically infected group. These lungs showed extensive inflammatory cell infiltration and tissue damage, which were not observed in control lungs. Expression of iNOS was increased in the chronically infected group when compared with the control group. However, the mean number of cells staining for nitrotyrosine in the chronically infected group was not significantly different from that in the controls, nor was there an excess of nitrotyrosine, nitrate, nitrite or nitrosothiol concentrations in the infected lungs. Thus, no evidence was found of increased NO metabolites in chronically infected lungs, including products of the peroxynitrite pathway. These findings suggest that chronic infection does not cause increased iNOS activity in the lung, despite increased expression of iNOS.

Hypercapnic acidosis attenuates endotoxin-induced acute lung injury.

Deliberate induction of prophylactic hypercapnic acidosis protects against lung injury after in vivo ischemia-reperfusion and ventilation-induced lung injury. However, the efficacy of hypercapnic acidosis in sepsis, the commonest cause of clinical acute respiratory distress syndrome, is not known. We investigated whether hypercapnic acidosis--induced by adding CO2 to inspired gas--would be protective against endotoxin-induced lung injury in an in vivo rat model. Prophylactic institution of hypercapnic acidosis (i.e., induction before endotoxin instillation) attenuated the decrement in arterial oxygenation, improved lung compliance, and attenuated alveolar neutrophil infiltration compared with control conditions. Therapeutic institution of hypercapnic acidosis, that is, induction after endotoxin instillation, attenuated the decrement in oxygenation, improved lung compliance, and reduced alveolar neutrophil infiltration and histologic indices of lung injury. Therapeutic hypercapnic acidosis attenuated the endotoxin-induced increase in the higher oxides of nitrogen and nitrosothiols in the lung tissue and epithelial lining fluid. Lung epithelial lining fluid nitrotyrosine concentrations were increased with hypercapnic acidosis. We conclude that hypercapnic acidosis attenuates acute endotoxin-induced lung injury, and is efficacious both prophylactically and therapeutically. The beneficial actions of hypercapnic acidosis were not mediated by inhibition of peroxynitrite-induced nitration within proteins.