No description available.

Despite receiving oxygen therapy, many COPD patients experience extended periods of hypoxemia during routine daily activities. In others, inappropriately high oxygen flow rates can depress hypoxic drive leading to worsening CO2 retention. As flow-rates during LTOT are fixed, oxygen delivery will not respond to patients' fluctuations in oxygen demand. The research project has aimed to develop and evaluate a closed-loop control method capable of actively varying flow-rates in response to the measured oxygen demand. We demonstrate how SpO2 from ambulatory or overnight pulse oximetry can be used as feedback into an automated O2 flow-rate controller. A model to mimic the patient oxygen saturation response has been developed in a computer simulation to help characterize the closed-loop system. With the collaboration of the Academic Unit for Sleep and Breathing at the Royal Brompton Hospital, the controller response has also been validated against patient saturation measurements recorded during overnight pulse oximetry monitoring. Preclinical computer simulations indicated an improved matching between oxygen supply and demand, maintaining SpO2 above threshold to maximize therapeutic efficacy. An investigational system capable of regulating the Saturation Driven Oxygen Therapy (SDOT) was constructed. In a randomised cross-over clinical pilot study, we further evaluated the SDOT system against constant-flow LTOT during exercise. The clinical results indicate that compared to standard oxygen therapy, SDOT produced a significant reduction in time spent with hypoxemia, decreased the extent of hypoxemia and lowered mean heart rates during exercise. Moreover, for patients with acceptable resting oxygen levels, SDOT provided conservation benefits by reducing the rate of oxygen consumption. The study established the potential to significantly improve the efficacy and economic delivery of this gold standard therapy.

Introduction: Patients with COPD are characterised by symptoms of dyspnoea, limited exercise tolerance and low levels of physical activity which can lead to reduced quality of life. Pulmonary rehabilitation (PR) is recommended, however, not all are able to participate and there is a large dropout rate from this service. Home-based programmes aiming to enhance self-management skills can potentially provide an alternative model of delivery, allowing increased options for treatment. As one of the key components of PR is to enhance exercise endurance and physical activity, valid and reliable measures are needed to determine programme effectiveness. Therefore, the first aim of this thesis is to determine the validity, reproducibility and sensitivity of the SenseWear Pro 2 Armband, activity monitor (SWM) to be used in the main trial. The primary aim of this thesis is to describe the noninferiority randomised control trial of the effectiveness of the home based Self-management Programme of Activity Coping and Education (SPACE for COPD) in comparison to PR in patients with COPD. Methods: Validation of methods; One subject (EH) completed a battery of repeated walking tests using the speeds from the endurance shuttle walk test. Minute by minute energy expenditure (EE) and step counts were recorded from 9 SWM and indirect calorimetry was used as the criterion measure to determine the validity of EE output from the monitor.

No description available.

(a) The Ventilation in Pulmonary Hypoxemia: The role played by chemical constituents of the blood in controlling pulmonary ventilation has been the subject of numerous investigations for over one hundred years since Kussmaul and Tenner in 1857 showed that a chemical stimulus was involved by experiments in which a large increase in ventilation was produced by breathing low oxygen mixtures and by rebreathing from a bag. The earliest theory which attempted to account for these observations was put forward by Rosenthal in 1862, and again in 1882. He suggested that the oxygen content of the blood determined the ventilatory response. He discounted any place for CO2 in the regulation of ventilation on the basis of experiments showing that inhalation of high concentrations of CO2 (20 to 30%) did not affect the breathing. Pflüger had shown in 1868, however, that both excess of C02 provided it was not too great, and oxygen lack stimulated the ventilation. In a series of brilliant cross circulation experiments on dogs, Frédéricq (1901) appeared to confirm the then prevalent assumption that the influence of these factors was a direct one upon the brain, but the Heymans (1927), father and son, were later to show that there were chemosensitive areas of the aortic arch and carotid sinus capable of responding to alterations in the concentrations of C02 and oxygen in the perfusate, and that these receptors transmitted impulses to the respiratory centres by the vagus nerves. Further studies by Heymans and Riglant (1933) and v. Euler, Liljestrand and Zotterman (1939) showed in anaesthetised cats that the carotid sinus nerves were in a state of continuous tonic excitation. When the oxygen saturation of the blood fell even slightly below the normal of 96% this chemoreceptor discharge of nervous impulses increased. Gesell, Lapides and Levin showed in 1940 that blocking these sinus nerve impulses in animals by the application of cold to the nerves depressed the ventilation when the animals were breathing room air at rest. These observations were confirmed by Marshall and Rosenfeld (1936). All of these workers agreed that hypoxaemia was more effective than CO2 excess in increasing the peripheral chemoreceptor activity, whereas CO2 excess in the arterial blood was the major factor in stimulating the central respiratory control mechanism. The relative importance of the central and peripheral mechanisms in maintaining the pulmonary ventilation under varying conditions was estimated in a quantitative way by Gesell et al. (v.s.) using the cold block technique. The part played by the peripheral chemoreceptors in controlling the ventilation in response to a fixed degree of hypoxaemia varied between 0 and 100% according to the concentration of CO2 which the animals breathed. The greater the amount of CO2 in the inspirate the less was the effect on the ventilation of blocking the nerves. When 5 or 6% CO2 was inspired nerve blocking had no effect, showing that in these circumstances respiration was 100% controlled by a central mechanism which was presumably insensitive to liypoxaenia. Bjurstedt (1946) and Gernandt (1946) confirmed these observations and found that the greater the acidity of the blood, the less was the effect upon respiration of blocking the sinus nerves. Bjurstedt also showed that in the early stages of acute hypoxia, the peripheral chemoreceptors played a large part in controlling the respiration; but this part gradually decreased with time until, over a period of six to ten hours, it became slight as the pH of the blood fell towards normal. The maximum hypoxaemic stimulus to respiration coincided with the time at which the pH was most raised due to CO2 washout. The mechanism of the compensatory decrease in plasma bicarbonate which resulted in the return of the blood pH towards normal was assumed to be a renal one due to diminished tubular reabsorption of bicarbonate. This renal compensatory phenomenon had been studied by Haldane (J.S.), Kellas and Kennaway in 1919 and also by Haldane (J.B.S.) in 1921. They observed that the initial alkalinity of the blood upon acute exposure to hypoxia gradually decreased with time, the pH of the blood becoming less upon continued exposure. Y. Henderson in studying the same process in 1919 showed that the "hypocapnia was followed by a hypocarbia". Winterstein (1956) noted that hypoxaemic human subjects given 100% oxygen to breath in the early stages of the period of oxygen lack reacted by becoming apnoeic. If the anoxaemia was continued over a longer time the duration of apnoea due to breathing oxygen decreased. All of these observations point to a direct relationship between the magnitude of the hypoxaemic stimulus to respiration and the pH of the blood. It would appear to be reasonable to test the implication that hypoxaemic emphysematous subjects with marked CO2 retention and lowered blood pH should show little or no immediate decrease in pulmonary ventilation on breathing high concentrations of oxygen.

No description available.

Debilitating lung disorders such as chronic pulmonary disease (COPD) and bronchopulmonary dysplasia (BPD) are presently incurable. The World Health Organization (WHO) predicts that by 2030, COPD will rise to become the third leading cause of death. Much of the increase in COPD is associated with the increase in tobacco use and the exposure to smoke combustion from fuel. COPD includes chronic bronchitis and emphysema. It is caused not only by inhalation of polluted air, but also by infections as well as genetic predispositions. To protect the respiratory airways, goblet cells in the bronchiole epithelium produce and secrete a viscous substance known as mucus along with enzymes to breakdown and remove inhaled toxins. Repeated and prolonged exposure to these toxins cause an overproduction of both mucus and enzyme secretion to become uncontrollable. As a result, the airway epithelium becomes scarred and fibrotic. These enzymes breakdown the delicate alveolar cell walls creating enlarged alveoli space. Elastic fibers in these cell walls are also destroyed resulting in a loss of elastic recoil narrowing the airways thus obstructing airflow. It becomes difficult to obtain enough oxygen into the blood and to remove excess carbon dioxide. These changes lead to a shortness of breath and other symptoms. Unfortunately, the symptoms of COPD cannot be eliminated with current treatment available and the condition inevitably worsens over time. Treatment available might not eliminate symptoms, but they can sometimes slow the progression of the disease. Transplantation and oxygen therapy are two of the common forms of treatment. The problem with these therapies is that it requires the patient to be relatively healthy, so therefore assessable to few patients. One possible way to treat COPD would be to somehow induce regeneration in these lungs or to impart, self-heal. Unfortunately, adult lung tissue seems incapable of spontaneous repair therefore understanding how to activate repair mechanism would greatly improve the prospects of effective treatments and the prognosis for COPD patients. Previous studies including the use of experimental adult rat model of emphysema has suggested one way to induce lung regeneration is via the endogenous metabolite of vitamin A, retinoic acid (RA). In the current study, we have described a mouse model of disrupted alveolar development using a dose-dependent glucocorticoid steroid, dexamethasone administered postnatally to create serve loss of alveolar surface area. When RA is induced to these animals as adults the lung architecture is restored to normal. This remarkable effect may be because RA is involved in alveolar development. We also provide evidence that RA and its agonists are required for the ongoing maintenance of alveolar structure and function because rats deprived of dietary retinol lose alveoli and show pathological features of emphysema. Alveolar regeneration with RA and its agonists may therefore be an important part of a novel therapeutic approach for the treatment of respiratory diseases characterized by reduced gas-exchanging surface areas such as BPD and emphysema.

No description available.

Neutral proteinases, released by inflammatory leukocytes, have been implicated in the pathogenesis of pneumoconiosis but there has been no systematic study of the proteolytic acitivty of leukocytes from dust-exposed lung. The aim of the present study was, therefore, to assess the bronchoalveolar leukocyte profile and proteolytic activity of the leukocytes in a rat model of pneumoconiosis. An assay, based on the breakdown of [<SUP>125</SUP>I] fibronectin, that would measure the overall proteolytic activity of the bronchoalveolar leukocytes and indicate their potential to damage the connective tissue of the alveolar septum was developed and validated. Increased proteolytic activity was found in the inflammatory bronchoalveolar leukocyte populations and so the relative role of macrophages and neutrophils was assessed by separation into distinct populations; both inflammatory macrophages and neutrophils had increased proteolytic activity. The important features governing the inflammogenicity of particles were addressed by measuring the inflammation-generating properties of a variety of fibrogenic and non-fibrogenic particles in rats exposed by intratracheal instillation or inhalation. The number of leukocytes recruited to the alveolar region was measured by bronchoalveolar lavage. Only fibrogenic mineral dusts had the ability to produce a sustained alveolitis in which the proteolytic activity of the bronchoalveolar leukocytes remained elevated. The pathogenicity of fibrogenic particles is likely, therefore, to be related to their ability to evoke and sustain an increased lung proteinase burden. The sustained alveolitis with fibrogenic particles was not related to lack of clearance of dust from the lung. Both quartz and coalmine dust elicited persistent alveolitis, but titanium dioxide, which is no more readily cleared than silica or coalmine dust, failed to sustain the inflammation. Properties of the particle surface, at least in the case of quartz, appear to play a part in their inflammogenicity. Altering the surface of quartz particles by coating them with aluminium lactate reduced their ability to recruit inflammatory leukocytes but did not alter the proteolytic activity of the leukocytes. The tissue response to the aluminium-coated quartz particles was also less than that elicited by native quartz with fewer and less-severe lesions. The foregoing serve to substantiate the role of inflammatory leukocytes in the pathogenesis of pneumoconiosis. Only when there is a sustained alveolitis with an overall increased proteinase burden, does pathological change occur in the lung. Reducing the magnitude and/or the duration of the alveolitis markedly suppresses the development of the tissue lesions.

No description available.