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Does Increased Non-Linear Behavior Caused By Dynamic Variables Increase Ventilatory-Induced Lung Injury (VILI)?
Funder
National Health and Medical Research Council
Funding Amount
$109,625.00
Summary
Acute lung injury (ALI) is precipitated by a variety of different insults, either directly to the lung or elsewhere to the body. Approximately 50% of the patients die. ALI is characterized by an increase in the leakiness of the barrier that normally separates the blood from the airspaces. The fluid which consequently floods the airspaces not only makes it difficult for patients to adequately obtain oxygen, but also dramatically increases the work of breathing by changing the surface forces withi ....Acute lung injury (ALI) is precipitated by a variety of different insults, either directly to the lung or elsewhere to the body. Approximately 50% of the patients die. ALI is characterized by an increase in the leakiness of the barrier that normally separates the blood from the airspaces. The fluid which consequently floods the airspaces not only makes it difficult for patients to adequately obtain oxygen, but also dramatically increases the work of breathing by changing the surface forces within the lungs. As a result, the patients must be mechanically ventilated. However, the very act of using a positive pressure to inflate the lungs often creates further damage, either through repeated opening and closing of collapse tissue or through its over distension. Ventilatory-induced lung injury (VILI), in itself is estimated to contribute to ~30% of the mortality. The best way shown to minimize VILI is through the use of small programmed breaths so as not to overinflate the lungs while still allowing adequate gas exchanges, superimposed upon a background pressure, in order to pre-inflate the lungs and prevent them from repeatedly collapsing. A remaining problem is that just as a rubber band changes its elasticity as it is stretched, so too the lung changes its mechanical properties during distension. Moreover, the lung is considerably more complex since different regions have different elasticities, which change differentially as air flows in and out of them. Airflow in turn depends on regional differences in the location, size, and number of conducting airways. Indeed, we have recently shown for the first time that dynamic changes in lung mechanics may contribute to VILI in patients, despite the use of safe ventilation modalities. This application proposes to examine the extent to which dynamic changes in lung mechanic contribute to VILI in an animal model, as a prelude to more costly, large scale clinical trials aimed at improving mortality.Read moreRead less
A Randomised Controlled Trial Of Non-invasive Ventilation In Stable, Hypercapnic Chronic Airflow Limitation
Funder
National Health and Medical Research Council
Funding Amount
$331,622.00
Summary
Chronic airflow limitation is a major cause of illness and death in Australia. Long term oxygen therapy is well established as one means of assisting people with chronic lung disease. Survival is still poor particularly when an individual is hypercapnic. Non-invasive ventilation used at night with a mask has been used in chronic hypercapnic respiratory failure from other causes with very good results. This study looks at whether non-invasive mask ventilation improves survival, improves clinical ....Chronic airflow limitation is a major cause of illness and death in Australia. Long term oxygen therapy is well established as one means of assisting people with chronic lung disease. Survival is still poor particularly when an individual is hypercapnic. Non-invasive ventilation used at night with a mask has been used in chronic hypercapnic respiratory failure from other causes with very good results. This study looks at whether non-invasive mask ventilation improves survival, improves clinical outcome measures and reduces health costs in people with chronic airflow limitation. The ventilatory support will be used at night during sleep and will be a bilevel positive airway pressure device. Apart from measuring the cost-benefit of home ventilatory support, this study will examine the relationship between the time of commencement of home ventilatory support and outcomes. In addition the relationships between daytime awake PaCO2, lung function, and body mass in CAL patients and the likely response to home ventilatory support will be examined.Read moreRead less
Assessment Of Physical Therapies To Improve Secretion Clearance In Patients With Cystic Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$302,310.00
Summary
People with cystic fibrosis (CF) produce thick mucus that is not cleared normally from the lungs. This retained mucus often becomes infected, which progressively damages the lungs. Various physical therapies which may help clear secretions are being used in CF. These include several types of devices which provide positive pressure to the airways. However, it is not known to what extent these devices, or other interventions such as manual chest physiotherapy and exercise, enhance mucus clearance. ....People with cystic fibrosis (CF) produce thick mucus that is not cleared normally from the lungs. This retained mucus often becomes infected, which progressively damages the lungs. Various physical therapies which may help clear secretions are being used in CF. These include several types of devices which provide positive pressure to the airways. However, it is not known to what extent these devices, or other interventions such as manual chest physiotherapy and exercise, enhance mucus clearance. As a result, it is not currently possible to scientifically prescribe intervention(s) to enhance mucus clearance in CF. This is partly because much of the research that has been performed in this area has been poorly-designed or has used inaccurate measures. Also, recent research has shown that these therapies may have significant effects beside their effect on mucus clearance. For instance, bacterial infection and the exchange of oxygen and carbon dioxide between the blood supply and air in the lung may all be affected by these interventions. Notably, the extent of benefit or detriment seen in these parameters does not always correlate with the effect on mucus clearance. We therefore believe a series of experiments is necessary to provide evidence upon which the scientific selection of mucus clearance therapies may be based. We have developed a new technique which allows clearance of mucus from the airways to be objectively measured in three-dimensions (3D). We intend to use the 3D technique to examine the effects of three different positive pressure devices, exercise, and manual chest physiotherapy on mucus clearance. Based on the outcomes of this research, we intend to compare the most appropriate therapy to performing no mucus clearance therapy in a short term trial. This trial will assess changes in the following: bacterial infection, mucus plugging in the airways, how well the lungs move air and exchange oxygen and carbon dioxide, and the patient's quality of life.Read moreRead less
RCT Of Headbox Oxygen Vs CPAP For Neonatal Respiratory Distress In Non-tertiary Hospitals
Funder
National Health and Medical Research Council
Funding Amount
$225,500.00
Summary
Each year in NSW hundreds of babies are transferred from local general hospital nurseries to a hospital with Neonatal Intensive Care Unit (NICU) because of breathing difficulties. Frequently, mothers are unable to accompany their babies at the time of transfer, leading to stress. When a mother is eventually transferred she is often separated from her partner and local supports causing further anxiety. In addition, if a baby has to be transferred, invasive procedures may be needed to ensure safet ....Each year in NSW hundreds of babies are transferred from local general hospital nurseries to a hospital with Neonatal Intensive Care Unit (NICU) because of breathing difficulties. Frequently, mothers are unable to accompany their babies at the time of transfer, leading to stress. When a mother is eventually transferred she is often separated from her partner and local supports causing further anxiety. In addition, if a baby has to be transferred, invasive procedures may be needed to ensure safety. Currently, babies who need oxygen in a local hospital are placed in a crib with a clear plastic box around their head and oxygen is run into the box (headbox oxygen). There is an alternative method of providing oxygen called CPAP (Continuous Positive Airway Pressure). This involves giving the oxygen directly into the baby's nose via soft rubber prongs. CPAP has been used since the 1970's. It is the main form of respiratory support for infants in many NICUs in Australia and the world. There is some evidence that death and lung disease may be reduced. However, the babies in these studies are sicker and smaller than babies in local hospital nurseries. CPAP is used in some local nurseries in New Zealand, however no studies have been done to see if CPAP reduces the need for inter-hospital transfer. The study will involve hospitals that have been selected because of their level of on site medical and nursing staff. These hospitals will have support and advice from two NICUs that use CPAP as their main form of respiratory support. Babies who need oxygen will be randomly allocated to either have headbox oxygen or CPAP. If the baby becomes so unwell such that certain preset criteria are met, the baby will be transferred to a NICU in the usual way. If CPAP safely reduces the need for inter-hospital transfer, many parents will be saved the anxiety associated with transfer, and the separation it often causes.Read moreRead less
Expanding The Role For Non-Invasive Ventilation In Cystic Fibrosis (CF)
Funder
National Health and Medical Research Council
Funding Amount
$315,375.00
Summary
Many patients with Cystic Fibrosis (CF) have disturbed breathing during sleep and poor sleep quality. Our preliminary data shows the problems may be worse during flare ups of the disease, with patients having less dreaming (REM) sleep causing reduced daytime attention and concentration. This could have adverse consequences for exam performance, work ability and driving skills. Also, even with maximum treatment, flare ups can result in permanent loss of lung capacity and quality of life. We propo ....Many patients with Cystic Fibrosis (CF) have disturbed breathing during sleep and poor sleep quality. Our preliminary data shows the problems may be worse during flare ups of the disease, with patients having less dreaming (REM) sleep causing reduced daytime attention and concentration. This could have adverse consequences for exam performance, work ability and driving skills. Also, even with maximum treatment, flare ups can result in permanent loss of lung capacity and quality of life. We propose a novel approach to treat the flare ups with short-term portable assisted ventilation (nBVS) as well as standard treatment as we strongly believe that the portable ventilator will improve gas exchange with better matching of ventilation and blood flow and will hasten recovery. We believe that long term nBVS will be superior to oxygen therapy alone in delaying the onset of respiratory failure and improving survival. We have convincing evidence to suggest that nBVS improves ventilation perfusion distributions rapidly and that this benefit increases over 6 months of regular use. The likely explanation is that it keeps the airways open and reduces mucus plugging. In short, nBVS is a treatment in its own right for abnormal gas exchange in CF. The ideal time for nBVS is during sleep when it can be used for a long time period when patients are most at risk of falls in oxygen saturation. In summary, we believe that nBVS is likely to have a major impact in delaying the progession of disease and improving patient outcomes. Almost all patients with CF have evidence of sinus disease and many have nasal polyps. We have convincing questionnaire data showing an association between sinusitis, nasal obstruction and poor sleep quality. Our preliminary sleep study data in patients with active sinusitis confirm multiple arousals and sleep fragmentation. We plan to examine the impact of sinus surgery in improving sleep disordered breathing and quality of life in patients with CF.Read moreRead less
Cell Stretch As A Physicochemical Secondary Stimulus In Initiating Lipopolysaccharide (LPS)-Mediated Acute Lung Injury
Funder
National Health and Medical Research Council
Funding Amount
$368,750.00
Summary
Acute lung injury (ALI) is an often fatal condition caused by direct or indirect injuries. When the injury occurs directly, eg pneumonia, lung cells release mediators that attract blood cells involved in defending the body. Once in the lungs, these cells are activated and engulf or release reactive molecules that destroy the invading organism a process known as inflammation. When the injury occurs indirectly, eg sepsis, ALI can arise from the spill-over of mediators created elsewhere in the body ....Acute lung injury (ALI) is an often fatal condition caused by direct or indirect injuries. When the injury occurs directly, eg pneumonia, lung cells release mediators that attract blood cells involved in defending the body. Once in the lungs, these cells are activated and engulf or release reactive molecules that destroy the invading organism a process known as inflammation. When the injury occurs indirectly, eg sepsis, ALI can arise from the spill-over of mediators created elsewhere in the body. Reactive molecules produced can damage the lung barrier separating the blood from the air. Consequently, fluid leaks into the airspaces making breathing difficult and hindering gas exchange. Gram (-) bacteria are the major cause of sepsis, pneumonia, and ALI. The inflammation is initiated by lipopolysaccharide (LPS), the major component of the bacterial cell wall. We have shown that LPS also changes breathing and the distribution of air and blood flow in lungs. This creates localised changes in cell stretch and the amounts of carbon dioxide (CO2) in the airspaces. Previously we showed that cell stretch releases surfactant , a substance that makes breathing easier. We now hypothesise that cell stretch is an important secondary stimulus in initiating ALI. We will use: 1. isolated lung cells to determine which cell types release mediators in response to LPS, and whether: * stretch stimulates their release * release is coordinated between the cell types * release is affected by the amount of CO2 2. isolated lungs to determine whether the pattern of ventilation, blood flow, and amounts of CO2 alter the release of the mediators, and whether these changes affect surfactant secretion and the ability to inflate the lungs. 3. animal models to also determine whether the pattern of respiration changes the course of the respiratory failure. Understanding the mechanisms that cause the disease will lead to better treatments.Read moreRead less
Respiratory-control Deficits In A Model Of Sleep Apnoea During Early Development: Mechanisms And Associations
Funder
National Health and Medical Research Council
Funding Amount
$206,717.00
Summary
A recent study showed that it is possible to induce changes in the respiratory control system of piglets after birth. This new study will examine the mechanism of that change, and develop diagnostic tools that can detect whether similar changes have occurred in babies. The results will help to diagnose the complications of respiratory problems in young babies, and will guide research regarding the potential site of the abnormalities that predispose to SIDS. Piglets have very similar development ....A recent study showed that it is possible to induce changes in the respiratory control system of piglets after birth. This new study will examine the mechanism of that change, and develop diagnostic tools that can detect whether similar changes have occurred in babies. The results will help to diagnose the complications of respiratory problems in young babies, and will guide research regarding the potential site of the abnormalities that predispose to SIDS. Piglets have very similar development of the brain and respiratory system to human infants during early development after birth. This study uses piglets to model exposure to factors that occur during infancy, and thus model some of the common respiratory diseases, including risk factors for the sudden infant death syndrome (SIDS). For example, infants may have upper-airway obstruction during sleep, or may get their face trapped in bed clothes so that they breath a mixture of lower oxygen and higher carbon-dioxide than that found in fresh air. We recently found that, during early development of piglets, repeated exposure to these types of gas mixes depressed respiratory responses tested later. Thus, respiratory responses become less vigorous over time, and this finding could explain how the exposures complicate infants' respiratory problems, or increase their risk for SIDS: Less vigorous responses mean the infant does not wake or move, the exposure becomes more severe, and may finally cause death. This study will examine piglets after such repeated exposure to: 1. find out whether heart-rate variability is reduced, in the same way as babies who later died from SIDS 2. develop a new diagnostic tool, to show the site where the abnormality is located 3. determine whether brain chemical alterations could explain the change in breathing 3. find out if exposure to cigarette smoke, known to increase respiratory problems in babies, causes even more severe disturbance of respiratory control in piglets.Read moreRead less
Changing Decision-making Behaviour In General Practice By Providing Access To Online Evidence.
Funder
National Health and Medical Research Council
Funding Amount
$206,375.00
Summary
The case for a shift to evidence-based practice, and the substantial economic and health outcome benefits of that shift, have been repeatedly made. Despite the vision, significant barriers to evidence-based practice remain, and the demonstration of a positive role for on-line systems would result in a significant change in strategies for clinician behaviour change. This study will make a specific and significant contribution to our understanding of the efficacy and effectiveness of online eviden ....The case for a shift to evidence-based practice, and the substantial economic and health outcome benefits of that shift, have been repeatedly made. Despite the vision, significant barriers to evidence-based practice remain, and the demonstration of a positive role for on-line systems would result in a significant change in strategies for clinician behaviour change. This study will make a specific and significant contribution to our understanding of the efficacy and effectiveness of online evidence retrieval systems as a component in any evidence-based strategy, through a rigorous and controlled approach to the study of clinical behaviour change. It will also provide a powerful test of the value of search filters as a specific technology in support of evidence retrieval. The focus on prescribing patterns in NHMRC priority areas as an outcome measure will also provide a significant data set reflecting current practice in primary care.Read moreRead less